Supplement 1 2023
Relationship of lactate and lactate clearance with 28-day mortality in patients with acute renal injury in the emergency department
Alper Gök 1, Fatih Tanrıverdi 2, Alp Şener 2, Ayhan Özhasenekler 2, Mehmet Ergin 2, Muhammed Saltuk Deniz 1, Şervan Gökhan 2
1 Department of Emergency Medicine, Faculty of Medicine, Hacettepe University, Ankara Research and Training Hospital, 2 Department of Emergency Medicine, Faculty of Medicine, Ankara Yıldırım Beyazıt University, Ankara, Turkey
DOI: 10.4328/ACAM.21459 Received: 2022-10-20 Accepted: 2022-11-22 Published Online: 2022-12-07 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S1-5
Corresponding Author: Fatih Tanrıverdi, Üniversiteler Neighbourhood, No:1, 06800, Çankaya, Ankara, Turkey. E-mail: fatihtanriverdi12@gmail.com P: +90 312 552 60 00 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9959-5769
This study was approved by the Ethics Committee of Ankara City Hospital (Date: 2019-09-05, No: 058)
Aim : Acute kidney injury is frequently diagnosed in emergency departments; AKI should be included in the preliminary diagnosis in a wide range of symptoms, from loss of appetite, nausea, vomiting, which can be considered as a mild illness, to uremic encephalopathy, which can be a reason for loss of consciousness at hospital admission. The aim of our study is to show whether lactate and lactate clearance have an effect on 28-day mortality in these patients.
Material and Methods: In our study, the data of 600 patients who applied to the emergency department between 10.10.2019 and 10.06.2020 and were decided on dialysis treatment were examined prospectively. One hundred fifteen patients who met the inclusion criteria were included in the study. Age, gender, chronic diseases, laboratory findings, 28-day mortality status of the patients were recorded.
Results: In our study, in which 115 patients were evaluated, 51 patients (44.34%) deceased. In our study, when ROC analysis of lactate values was performed in patients who had a mortality in 28 days, it was predicted that 80.4% would have no mortality in 28 days for lactate values below 1,215 lactate levels; there may be a mortality rate of 40.6% at levels ≥1,215.
Discussion: AKI is an important cause of mortality and morbidity for patients admitted to the emergency department. It has been shown in our study that lactate is especially effective in mortality. It was found that the lactate clearance value of the deceased patients (-54,77±156,66) was lower than the lactate clearance of the survivors. The lactate 2 value was measured after dialysis in deceased patients, therefore, tissue perfusion and damage weres higher, but there was no statistically significant difference in lactate clearance values between survivors and deceased patients.
Keywords: Acute Kidney Injury, Emergency Department, Lactate, Lactate Clearance, Mortality
Introduction
Acute kidney injury (AKI) can be defined as the deterioration of the filtration and excretory function of the kidney within days/weeks. This causes the retention of nitrogen and other waste products that are cleared from the blood by the kidneys. AKI is not a stand-alone disease; It is a clinical diagnosis that results in a decrease in urine output and an increase in serum creatinine levels. The presence of renal parenchymal damage may not be present, as it is not due to a structural disorder alone [1.2]. AKI is frequently diagnosed in emergency departments; AKI should be included in the preliminary diagnosis in a wide range of symptoms, from loss of appetite, nausea, vomiting, which can be considered as a mild illness, to uremic encephalopathy, which can be a reason for loss of consciousness at hospital admission [3]. It is an important complication, sometimes exceeding 50% in hospitalized patients (10-15% of all hospitalizations) and patients treated in intensive care units [4,5]. Blood gas analysis is important in the diagnosis and treatment of patients diagnosed with AKI; The blood gas parameters guide the patient’s response to treatment/immediate hemodialysis decision.
Lactate in the human body is produced by the breakdown of pyruvate by the enzyme lactate dehydrogenase. In the normal physiological state, the reaction does not affect the lactate level, as it accounts for only one-tenth of the total pyruvate metabolism. As a result, intracellular lactate begins to multiply and pass into the bloodstream. Lactate has a molecular weight of 90 Da; its molecular weight is similar to urea (60 Da) that allows to be removed by hemodialysis [6]. It is thought that the lactate level, measured at the follow-up of the patient is an indicator of organ dysfunction and mortality. However, a single measurement of lactate may be due to static variability. In order to be more clinically useful, it is necessary to define the relationship between lactate clearance (LC) and clinical outcome, which is a measure of the change in lactate levels during the treatment process [7]. A negative result indicates an increase in lactate value compared to the reference after 6 hours, while a positive result indicates a decrease in lactate [8.9].
The aim of our study is to show whether lactate and lactate clearance have an effect on 28-day mortality in these patients.
Material and Methods
Patients who applied to the Emergency Medicine Clinic between 10.10.2019 and 10.06.2020 were examined prospectively. Patients who were diagnosed with acute kidney injury and consulted by a nephrologist and who were given emergency hemodialysis treatment were included in the study. AKI was diagnosed when the patient’s serum creatinine level increased at least 1.5 times or GFR decreased by at least 25% and/or urine output was less than 0.5 ml/kg/h or the patient was anuric. The presence of severe hyperkalemia, severe acidosis, drug intoxication, pulmonary edema, and uremic symptoms were accepted as an indication for emergency hemodialysis [10]. Patient flow diagram is shown in Figure 1. Demographic characteristics, chronic diseases, laboratory parameters, etiological cause of AKI, and 28-day mortality status of 115 patients who met the inclusion criteria of our study were recorded in accordance with the purpose of the study. Lactate clearance was calculated as a percentage of the value obtained by dividing the difference between the lactate value at the time of initial admission and the lactate value measured 6 hours after by the initial lactate value.
Lactate clearance: [Lactate 1 – Lactate 2 (Value measured after 6 hours) x 100] / Lactate 1
Statistical analysis
The Kolmogorov-Smirnov normality test was used for continuous variables in the study. The non-parametric Mann-Whitney-U test was used for the median comparisons of two independent groups whose normality assumption was not provided (p<0.05) as a result of the test. The Independent Samples-t test was used to compare the means of two groups in normally distributed data. For non-normally distributed data, the Kruskal-Wallis test was used to compare medians in multiple groups. The Chi-square test was applied for ratio comparisons of independent frequency data (on 2×2, 3×2, etc. tables). The analysis of factors affecting mortality in patients diagnosed with AKI undergoing hemodialysis was performed with Multiple Logistic Regression analysis. ROC analysis was performed for parameters that were found to be significant for mortality and the area under the curve was calculated. Specificity-sensitivity ratios were calculated for the levels determined for the parameters with significant results. The value, which was used for statistical significance was p<0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
In our study, there was no significant difference in age, living or deceased, and gender distirubition as shown in Table 1.
According to 28-day mortality, neutrophil 1-2, neutrophil-lymphocyte ratio 1-2, urea 1-2, creatine 1-2, white blood cell, pH 1-2, lactate 1-2, HCO3 2, BE 2, K 2 values were statistically significantly different between pre- and post-hemodialysis examinations between alive and deceased patients, as shown in Table 2. There was no significant difference between lactate clearance values. The mean clearance values for survivors were -25.77±80.32; It was found as -54.77±156.66 p 0.471 for those who deceased. Table 3 shows the multiple logistic regression analysis performed with the data obtained when the values that affect each other are subtracted among those with the most significant p-value on 28-day mortality which were evaluated in Table 2. Accordingly, lactate and creatine 1 levels were found to be significant and effective in predicting 28-day mortality.
In the tests mentioned above, it was concluded that the relationship between lactate and 28-day mortality could be valuable. The area under the ROC curve (Figure 2) plotted on the
effect of lactate in predicting 28-day mortality, and the 95% confidence intervals are shown in Table 3. Here, the area under the curve (0.700) is statistically significant. Table 3 shows sensitivity and specificity rates for 28-day mortality estimation for some lactate levels. As an example, it can be interpreted as “80.4% will not die within 28 days at values below 1,215 lactate level, and 40.6% mortality may occur at levels ≥1,215 “.
Discussion
AKI has a clinical course that, if left untreated, is quite mortal [11]. When the data in 2016 were evaluated, it was determined that 66.4% of the patients were taken to emergency hemodialysis. The high rate can be interpreted in favor of asymptomatic patients not receiving treatment in the presence of underlying AKI. In case of emergency service admission, early diagnosis and rapid onset of etiological treatment are extremely important. In our study, the data of 115 patients who were diagnosed with AKI and received their first hemodialysis treatment at emergency service admission were evaluated. In our country, 57.52% of AKI and CKD patients who received the first hemodialysis treatment were male, 42.48% were female, and their mean age was between 45-64 (39.34%) years [12].
In our study, 45.2% of the patients were male and 54.8% were female, although this was not similar to the country in general, but there was no significant difference. However, the mean age of the patients included in our study was 73±14 years, which is higher than the national average. This may be due to the fact that patients over the age of 65 are diagnosed in the emergency room due to the disruption of their routine check-ups.
When GFR decreases, there is an increase in H+ and a decrease in HCO3-; the increase in unmeasured anions causes metabolic acidosis and the base deficit increases; this makes it a reliable parameter for us in monitoring acid production [13]. In our study, when the pH values were examined in terms of mortality before and after dialysis, a significant difference was found between the deceased and the alive patients, and it was found that the pH value was lower in the deceased group.
In the study conducted by Öztürk S. et al., high BUN and creatine and K+ levels were found to increase mortality [14]. In our study, although the mean values for urea and creatine decreased after dialysis, there was a significant difference in mortality in Urea 1-2, Cre 1-2, K+ -2 parameters before and after dialysis. Although higher urea and K+ -2 values were detected in the mortal group, creatinine values showed a negative correlation. Here, it is thought that the creatinine value is lower in patients with a mortal course due to the high creatinine increase in postrenal aby cases and low postrenal aby mortality as the reason for the high creatinine level (postrenal AKI deceased K+-1 mean value 4,78, alive K+-1 mean value 10,5; deceased K+-2 mean value 3,47, alive K+-2 mean value 6,76).
Serum lactate is formed as a result of the glycolysis reaction due to tissue hypoxia and is considered an important biomarker for the evaluation of hemodynamic status in critically ill patients. It is metabolized in the liver and kidneys. Although lactate is a non-toxic molecule, the increase in concentration indicates significant changes in homeostasis and is therefore associated with increased mortality [15,16].
In studies based on the ‘Surviving Sepsis Campaign’ guideline on sepsis by Casserly et al. , high lactate levels were found to be highly correlated with mortality [17].
Similarly, in our study, a significant difference was found in the lactate 1-2 values before and after dialysis in patients who were alive and deceased; It is seen that the lactate values in the deceased group were high on arrival and after dialysis (alive patients’ lactate-1 mean value: 1,8±1,5; Lactate -2: 1,8±1,1, in deceased patients, Lactate-1 mean value: . 3,7±3,5 ; Lactate-2: 4,7±4,7, p<0,05).
When the ROC analysis of the lactate values of the patients who had mortality in 28 days in our study was performed, it was predicted that there would be no mortality in 28 days at a rate of 80.4% in the values below 1.215 mg/dL. Here, the area under the curve (0.700) is statistically significant. Table 3 shows sensitivity and specificity rates for 28-day mortality estimation for some lactate levels. To give an example, it can be interpreted as “80.4% will not die within 28 days at lactate levels below 1,215, and 40.6% mortality may occur at levels ≥1,215 “.
An increase in lactate clearance may indicate resolution of global tissue hypoxia and is associated with a reduced mortality rate in patients with severe sepsis and septic shock [18]. Therefore, lactate clearance is used as a target in the resuscitation of sepsis [19].
Similarly, in our study, it was found that the lactate clearance value of the deceased patients (-54,77±156,66) was lower than the lactate clearance of the survivors (-25,77±80,32). We think that deterioration of kidney functions and an increase in lactate production due to etiology or septic condition occur as a decrease in lactate clearance. The finding obtained in our studyis that the lactate 2 value was measured after dialysis in deceased patients and therefore tissue perfusion and damage were higher, and there was no statistically significant difference in lactate clearance values between survivors and deceased patients. The lack of a significant difference here can be attributed to the low number of patients in the group, and further studies with a larger number of patients are needed.
In the study conducted by Passos R. et al., arrival lactate, lactate value at 4 and 24 hours after dialysis, and lactate clearance were evaluated; Lactate clearance of more than 10% was found to be associated with survival, and the 24th hour lactate value was found to be more prognostically significant. Lactate clearance, which was calculated using the 24th hour lactate value, was found to be associated with a decrease in mortality independent of other factors [20].
Limitations
The biggest limitation of our study is the small number of patients. Apart from this, the inability to differentiate patients according to etiology is another limitation. Failure to upload laboratory findings to the system due to device failure during the working process, the fact that patients who were transferred to another center after dialysis / hospitalized in the external service and intensive care unit could not be followed up in the post-emergency department period played a major role in limiting the number of patients. The importance of data archiving and proper recording of patient information in the system during patient follow-up is clear.
Conclusion
AKI is an important cause of mortality and morbidity for patients admitted to the emergency department. In the literature we searched during our study, very few studies have been found about the effect of lactate and lactate clearance on mortality in AKI in the emergency department. It has been shown in our study that lactate is especially effective on mortality. However, we think that there is a need to study lactate clearance in a larger number of patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content, including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Funding: None
Conflict of interest
The authors declare no conflict of interest.
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Alper Gök, Fatih Tanrıverdi, Alp Şener, Ayhan Özhasenekler, Mehmet Ergin, Muhammed Saltuk Deniz, Şervan Gökhan. Relationship of lactate and lactate clearance with 28-day mortality in patients with acute renal injury in the emergency department. Ann Clin Anal Med 2023;14(Suppl 1):S1-5
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Relationship between first-trimester vitamin D levels and gestational diabetes mellitus
Esra Keles 1, Kurşad Nuri Baydili 2, Ahmet Keles 3, Meltem Pirimoglu 4
1 Department of Gynecologic Oncology, University of Health Sciences, Zeynep Kamil Training and Research Hospital, Istanbul, 2 Department of Biostatistics, Faculty of Medicine, University of Health Sciences, Istanbul, 3 Department of Urology, Prof. Dr. Süleyman Yalçın City Hospital, Istanbul Medeniyet University, Faculty of Medicine, Istanbul, 4 Department of Gynecologic Oncology, Faculty of Medicine, Adiyaman University, Adiyaman, Turkey
DOI: 10.4328/ACAM.21480 Received: 2022-11-04 Accepted: 2022-12-15 Published Online: 2022-12-24 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S6-9
Corresponding Author: Esra Keles, Department of Gynecologic Oncology, University of Health Sciences, Zeynep Kamil Training and Research Hospital, Istanbul, Turkey. E-mail: dresrakeles@hotmail.com P: +90 531 667 45 92 / +90 216 391 06 80 F: +90 216 391 06 90 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8099-8883
This study was approved by the Ethics Committee of Kartal Dr Lütfi Kırdar Training and Research Hospital (Date: 2015-01-13, No: 25)
Aim: In this study, we aimed to examine the association between first-trimester maternal 25(OH)D levels and GDM status.
Material and Methods: We retrospectively reviewed the records of pregnant women admitted to the antenatal outpatient clinic during the first trimester (6–13 weeks) and subsequent oral glucose tolerance testing (OGTT) between September 2013 to June 2014. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria.
Results: A total of 189 pregnant women, of whom 14.8% (28/189) were GDM. It was found that no subject had sufficient levels of 25(OH)D and the majority of patients (69.8% (132/189)) had severe vitamin D deficiency. Binary logistic regression analysis revealed that 25(OH)D levels at 6-14 weeks of gestation, insulin levels had no significant impact on GDM.
Discussion: In the first trimester of pregnancy, 25(OH)D levels were not associated with GDM. Additionally, there was a high frequency of vitamin D deficiency among pregnant women.
Keywords: GDM, Gestational Diabetes Mellitus, Vitamin D Deficiency
Introduction
Gestational diabetes mellitus (GDM) is defined as any degree of glucose elevation during pregnancy [1], with a prevalence ranging from 5% to 25% of all pregnancies [2]. GDM is the most common metabolic disorder diagnosed during pregnancy [3], which leads to short and long-term adverse health consequences for both mothers and their children [4]. There are expanding numbers of studies focusing on the possible causes of GDM, such as interest in vitamin D deficiency, as a possible cause.
Vitamin D plays an important role in pregnancy due to its impact on bone and muscle health [5], regulation of calcium and phosphorus metabolism, glucose balance, placental functions, embryogenesis [6], and maturation of the respiratory system [7]. Given the increasing prevalence of vitamin D deficiency among pregnant [8] and childbearing-aged women in developing countries [9], it is of great importance to evaluate the effect of maternal 25(OH)D level on GDM.
Research on 25(OH)D and GDM has driven for over a decade yielding different results. Several studies have shown a significant relationship between 25(OH)D levels and the risk of GDM [10], whereas others could not demonstrate any significant results on this association [11]. The data regarding the effect of the 25(OH)D level on GDM development and related mechanisms are inconsistent. Thus, in this study, we aimed to examine the relationship between maternal 25(OH)D levels in the early trimester and GDM status.
Material and Methods
We retrospectively searched the results of serum 25(OH)D tests of pregnant women who attended the outpatient clinic of Obstetrics and Gynecology at Zeynep Kamil Women and Children’s Disease Training and Research Hospital for routine antenatal care during the first trimester (6–13 weeks) and subsequent oral glucose tolerance testing (OGTT) between September 2013 to June 2014. Our hospital is a tertiary referral health facility that provides comprehensive level care for mothers, newborns, and children.
The data were extracted from the hospital’s electronic database after the approval by the Research Ethics Committee (Approval number: 25, 13.01.2015). Database management complies with legislation on privacy and this research is under the ethical principles of the Declaration of Helsinki. Informed consent was waived due to the retrospective study design by the same ethics committee that approved this study.
We performed a sample size calculation based on a previously published study [12], a sample size of 20 per group was needed, with a 95% confidence level and a margin error of 0.05
Abstracted data included maternal age, body mass index (BMI), obstetric history, gestational age at admission, first-trimester plasma fasting glucose, 25(OH)D, and insulin levels, results of 75 g OGTT at 24-28 weeks of pregnancy. Patients aged 18 and above who had a singleton pregnancy, had no history of chronic diseases, and complete data were included in the study. Patients who had a history of GDM, type 1 and 2 diabetes, pre-eclampsia, thyroid and parathyroid disease, renal failure or other diseases that influence glucose metabolism, multiple pregnancies, consumption of drugs that interact with glucose, calcium, and vitamin D metabolism, except for vitamin D supplements prescribed during pregnancy, and those who had incomplete data were excluded from the study.
The electrochemiluminescent method (Roche diagnostics GmBH Mannheim, Germany) was used for measuring 25(OH)D3 levels with a COBAS e411 instrument. The analytical sensitivity of the assay was 3ng/ml; the total coefficient of variation percentage (CV%) at 15ng/ml was 5.1%; the total CV at 28 ng/ml was 3.1%. The insulin level was measured using the one-step immuno-enzymatic sandwich method. Glucose levels were measured using the enzymatic UV hexokinase method in the AU5800 auto-analyzer (Beckman Coulter, Brea, CA, USA). All analyses were performed in the biochemistry laboratory of the same hospital.
According to the Endocrine Society Clinical Practice Guidelines, vitamin D sufficiency was defined as >30 ng/mL, insufficiency as 20–30 ng/mL, deficiency as 10-19 ng/mL, and severe deficiency as <10 ng/mL [13]. GDM was defined according to the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria [14]. Gestational age at delivery was calculated based on the first date of the last menstrual period. The parity of women was defined as the total number of children ever born. Body mass index (BMI) was calculated for mothers in the first trimester as weight in kilograms divided by the square of height in meters (kg/m2) and evaluated based on the World Health Organization classification [15].
Statistical Analysis
Analyzes were carried out using the Statistical Package for the Social Science (IBM SPSS, Version 25.0. Armonk, NY: IBM Corp.) for Windows software. Data were expressed as frequency (n) and percentage (%) for qualitative variables and arithmetic mean and standard deviation values (Mean+SD) for quantitative variables. The χ² or Fisher’s exact tests were used for categorical variables and the independent-sample t-test was used for continuous variables. The one-way analysis of variance (ANOVA) test followed by the Tukey post-hoc test was performed for multiple comparisons. The type I error rate was set at 0.05. A p-value <0.05 was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The subjects included in this analysis were those who had 25(OH)D within the first trimester (n=189) and were screened for OGTT at 24-28 weeks of pregnancy. The baseline characteristics of patients diagnosed with GDM and those with normal plasma glucose are summarized in Table 1. Among the study patients, the number of pregnant women with GDM accounted for 14.8% (28/189). The median age of patients with and without GDM was 30 (range: 23-43) and 28 (range: 18-40) years, respectively. There was no significant difference between the two groups with respect to maternal age (p=0,090).
At 6-14 weeks of pregnancy, the insulin levels were higher in the GDM group compared to the non-GDM group (10.9 (range: 2-59.3) vs 7.4 (range: 2.1-73.4)). The insulin levels were significantly different between the two groups (p=0,005).
The subjects were classified according to the cut-offs of 25(OH)D levels. It was found that no subject had sufficient levels of 25(OH)D. The majority of patients had severe vitamin D deficiency. The severe 25(OH)D deficiency at 6-14 weeks of gestation was 12.9% in women with GDM and 87.1% in non-GDM controls. Additionally, 25(OH)D deficiency was found higher in non-GDM women compared to those in GDM women; there was a statistically significant difference observed between the two groups (p=0,049).
Binary logistic regression analysis revealed that 25(OH)D levels at 6-14 weeks of gestation, insulin levels had no significant impact on GDM. Obesity (BMI values: 30-34.9) was statistically significant with GDM (Table 2).
Discussion
This study revealed that there were no significant differences in first trimester 25(OH)D levels between GDM and non-GDM women screened at 24-28 weeks of pregnancy. Additionally, there was a high frequency of vitamin D deficiency among pregnant women. GDM development was not associated with the first trimester maternal 25(OH)D and insulin levels. Notably, none of the pregnant women had sufficient 25(OH)D levels, and all women diagnosed with GDM had 25(OH)D concentrations <20 ng/mL.
The relationship between 25(OH)D deficiency and GDM remains unclear. Our study findings are in line with the study conducted by Bal et al. who also investigated maternal serum 25(OH)D levels in the first trimester in women with and without GDM, and they failed to find an association with 25(OH)D levels compared to those in women at low risk for GDM [16]. Tkachuk et al. investigated the link between maternal serum 25(OH)D levels in the first and second trimesters of pregnancy and GDM [17]. Similar to our findings, they concluded that there was no association between GDM risk and vitamin D levels measured in the first trimesters of pregnancy. A systematic review and meta-analysis study conducted by Martínez-Domínguez et al. reported that they also failed to find an association between the first-trimester maternal serum 25(OH) D levels and the development of GDM [18]. Likewise, Hauta-Alus et al. reported that maternal 25(OH)D levels were similar in women with and without GDM in a mostly vitamin D sufficient population [19]. A cross-sectional study from Turkey found no association between 25(OH)D deficiency and the risk of GDM, which is compatible with our study findings [20].
On the other hand, some studies report a meaningful association between vitamin D deficiency and risk of GDM. Xue et al. have recently examined the complex issue of the relationship between 25(OH) levels and the development of GDM. They concluded that low 25(OH)D levels in the first trimester were associated with an increased risk of GDM [21]. Similarly, a recent study indicated that low 25(OH)D levels were associated with an increased odds of GDM [22]. Another study found that women with low 25(OH)D levels had a higher risk of developing GDM [23]. However, it remains unclear whether vitamin D deficiency contributes to maternal risk of developing GDM. These conflicting results might be related to methodological issues, the techniques used to measure vitamin D, the definition of vitamin D deficiency, the trimester at sampling, and the diagnostic criteria for GDM. Additionally, some factors, such as maternal age, weight gain, lifestyle, family history of diabetes, exposure to sunlight, consumption of prenatal multivitamin supplements, smoking, alcohol consumption, race/ethnicity might have contributed to contradictory findings between studies. It is plausible that several limitations might have influenced the results obtained. Unfortunately, due to the retrospective nature of the study, we were unable to obtain relevant data on the patients’ socioeconomic, demographic characteristics, clinical features, eating habits and dietary intake, and sunlight exposure. Inevitably, another possible source of error is a single-center design with a small sample size, which makes the results less generalizable, and this should be kept in mind in the interpretation of the results. Notwithstanding the relatively limited sample, our research provides valuable insights into the growing body of literature on the association between maternal 25(OH)D level and the development of GDM. We believe that our findings may still be useful as baseline information for subsequent epidemiological studies.
Conclusion
The present study indicated that in the first trimester, 25(OH)D levels were not associated with GDM. Further well-designed, large and prospective cohort studies are needed to develop a deeper understanding of the complex interaction between 25(OH)D status and the development of GDM.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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2. Li G, Wei T, Ni W, Zhang A, Zhang J, Xing Y, et al. Incidence and Risk Factors of Gestational Diabetes Mellitus: A Prospective Cohort Study in Qingdao, China. Front Endocrinol (Lausanne). 2020;11:636.
3. McIntyre HD, Kapur A, Divakar H, Hod M. Gestational Diabetes Mellitus-Innovative Approach to Prediction, Diagnosis, Management, and Prevention of Future NCD-Mother and Offspring. Front Endocrinol (Lausanne). 2020;11:614533.
4. Bianco ME, Josefson JL. Hyperglycemia During Pregnancy and Long-Term Offspring Outcomes. Curr Diab Rep. 2019;19(12):143.
5. Mansur JL, Oliveri B, Giacoia E, Fusaro D, Costanzo PR. Vitamin D: Before, during and after Pregnancy: Effect on Neonates and Children. Nutrients. 2022;14(9):1900.
6. Arshad R, Sameen A, Murtaza MA, Sharif HR, Iahtisham-Ul-Haq, Dawood S, et al. Impact of vitamin D on maternal and fetal health: A review. Food Sci Nutr. 2022;10(10):3230-40.
7. Pilz S, Zittermann A, Obeid R, Hahn A, Pludowski P, Trummer C, et al. The Role of Vitamin D in Fertility and during Pregnancy and Lactation: A Review of Clinical Data. Int J Environ Res Public Health. 2018;15(10):2241.
8. Suárez-Varela MM, Uçar N, Peraita-Costa I, Huertas MF, Soriano JM, Llopis-Morales A, et al. Vitamin D-Related Risk Factors for Maternal Morbidity during Pregnancy: A Systematic Review. Nutrients. 2022;14(15):3166.
9. Da Silveira EA, Moura LANE, Castro MCR, Kac G, Hadler MCCM, Noll PRES, et al. Prevalence of Vitamin D and Calcium Deficiency and Insufficiency in Women of Childbearing Age and Associated Risk Factors: A Systematic Review and Meta-Analysis. Nutrients. 2022;14(20):4351.
10. Amraei M, Mohamadpour S, Sayehmiri K, Mousavi SF, Shirzadpour E, Moayeri A. Effects of Vitamin D Deficiency on Incidence Risk of Gestational Diabetes Mellitus: A Systematic Review and Meta-analysis. Front Endocrinol (Lausanne). 2018;9:7.
11. Luo C, Li Z, Lu Y, Wei F, Suo D, Lan S, et al. Association of serum vitamin D status with gestational diabetes mellitus and other laboratory parameters in early pregnant women. BMC Pregnancy Childbirth. 2022;22(1):400.
12. Ede G, Keskin U, Cemal YM, Samur G. Lower vitamin D levels during the second trimester are associated with developing gestational diabetes mellitus: an observational cross-sectional study. Gynecological Endocrinology. 2019;35(6):525-8.
13. Amrein K, Scherkl M, Hoffmann M, Neuwersch-Sommeregger S, Köstenberger M, Tmava Berisha A, et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr. 2020;74(11):1498-1513.
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15. Rahman M, Rahman SM, Pervin J, Aktar S, El Arifeen S, Rahman A. Body mass index in early-pregnancy and selected maternal health outcomes: Findings from two cohorts in Bangladesh. J Glob Health. 2020;10(2):020419.
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17. Tkachuk AS, Vasukova EA, Anopova AD, Karonova TL, Pustozerov EA, Teplova YA, et al. Vitamin D Status and Gestational Diabetes in Russian Pregnant Women in the Period between 2012 and 2021: A Nested Case-Control Study. Nutrients. 2022;14(10):2157.
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Effects of hypothyroidism and hyperthyroidism on hematological and biochemical parameters
Ali Fuat Gurbuz 1, Kamile Yucel 2
1 Department of Internal Medicine, Health Sciences University, Van Training and Research Hospital, Van, 2 Department of Medical Biochemistry, Faculty of Medicine, KTO Karatay University, Konya, Turkey
DOI: 10.4328/ACAM.21554 Received: 2022-12-19 Accepted: 2023-02-02 Published Online: 2023-02-22 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S10-14
Corresponding Author: Kamile Yucel, Department of Medical Biochemistry, Faculty of Medicine, KTO Karatay University, Konya, Turkey. E-mail: kamile_yucel@hotmail.com P: +90 505 779 98 83 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4088-8932
This study was approved by the Ethics Committee of KTO Karatay University (Date: 2022-05-23, No: 2022/012-05)
Aim: This study aimed to compare the hematological and biochemical parameters of hypothyroid and hyperthyroid patients when they were first diagnosed.
Material and Methods: This study is a retrospective cross-sectional study. Hyperthyroid patients were diagnosed with elevated serum levels of fT3 and/or fT4 but decreased TSH levels compared to reference ranges (fT4: 12.3-20.2 pmol/L; fT3: 3.71–6.70 pmol/L; and TSH, 0.30–3.94 mIU/L). Hypothyroid patients were diagnosed with decreased serum levels of fT3 and/or fT4 but elevated serum levels of TSH.
Results: A total of 727 patients, 349 (277F/72M) diagnosed with hypothyroidism and 378 (306F/72M) diagnosed with hyperthyroidism, were included in this study. The number of women was statistically significantly higher (p<0.01) than men in both hypothyroid (%79) and hyperthyroid (%80) patient groups. When we compared the hypothyroidism and hyperthyroidism groups, we found a statistically significant difference between groups in terms of TSH, fT3, fT4, MPV, PLT, urea, creatinine, LDL-C, TC, TG, and TG/HDL-C ratio. In this study, a significant increase (p<0.01) in serum levels of TG, TC and LDL-C was observed in hypothyroid patients compared to hyperthyroid patients. We also found a negative significant correlation between fT3 and LDL-C in patients with hyperthyroidism (r: – 0.238, p<0.01). Moreover, vitamin B12 deficiency (B12 levels <175 pg\ml), was present in 8% of hypothyroid patients and 6.3% of hyperthyroid patients.
Discussion: Our findings emphasize that it is important to follow up both hypothyroid and hyperthyroid patients in terms of lipid parameters. Especially in patients with hypothyroidism, lipid metabolism is highly affected.
Keywords: Hyperthyroidism, Hypothyroidism, Lipid Metabolism, TG/HDL-C Ratio
Introduction
Thyroid hormones are hormones that affect all systems in the body, and all cells are also targets of thyroid hormones. It has effects on almost all metabolic pathways, especially carbohydrate, protein and lipid metabolism. Two main hormones are synthesized and released from the thyroid gland. These are thyroxine (fT4) and triiodothyronine (fT3). fT4 is a prohormone and is present in higher concentrations than fT3 [1,2]. Triiodothyronine is a biologically active thyroid hormone. There is an inverse relationship between serum thyroid hormones and Thyroid Stimulating Hormone (TSH). Even very small changes in hormones cause big fluctuations in TSH levels [2,3].
Thyroid gland diseases are among the most common endocrine disorders in the world and are second only to diabetes.
These diseases are characterized by abnormal circulating thyroid hormones and TSH levels [2,4]. Hypothyroidism is a disease that occurs with thyroid hormone deficiency or ineffectiveness at the cellular tissue level and progresses with a slowdown in metabolic events. There are classifications of primary, secondary, tertiary, overt and subclinical hypothyroidism. Hypothyroidism may be overt with high TSH and low fT4 levels, or subclinical with a normal fT4 level despite a high TSH level [5,6]. Its prevalence in the community is between 4-5%. 0.8% of women and 0.3% of men have overt hypothyroidism [7].
Hypothyroidism is closely related to increased serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG), as thyroid hormones play a role in the activity of important enzymes in the pathway of cholesterol production and conversion [5,8]. Patients with thyroid dysfunction are likely to have a high incidence of insulin resistance, type 2 diabetes, and cardiovascular disease [9]. Abnormalities in lipid profiles in patients with overt hypothyroidism are well-defined. A study at the Mayo Clinic noted abnormalities in more than 90% of 295 patients with overt hypothyroidism [10].
Hyperthyroidism is a disease that occurs when the thyroid gland is overactive, that is, it produces too much thyroid hormone. Although there are many causes of hyperthyroidism, its frequency is affected by dietary iodine intake, and some cases are due to autoimmune (graves’ disease) disease [11]. While subclinical (normal fT3, fT4 with suppressed TSH) hyperthyroidism is more common in women over 65 years of age than men, overt (high fT3, fT4 with suppressed TSH) hyperthyroidism rates are 0.4 per 1000 women and 0.1 per 1000 men, and the prevalence varies according to age [11,12].
In contrast to hypothyroidism, signs and symptoms of high thyroid hormone exposure to peripheral tissues in hyperthyroidism reflect a hypermetabolic state. A hyperthyroid patient may classically show symptoms such as palpitations, weight loss, irritability, sweating, increased bowel movements, osteoporosis, menstrual irregularity, etc., due to this increased metabolic activity state [12].
In light of this information, we aimed to compare the hematology and biochemistry parameters of hypothyroid and hyperthyroid patients when they were first diagnosed. In the literature, there are studies evaluating the laboratory parameters separately in hypothyroid and hyperthyroid patients. However, as in our study, there is no study comparing both groups in terms of both hematological and biochemical parameters.
Material and Methods
Study population
This study is a retrospective cross-sectional study. After the approval of the ethics committee, patients diagnosed with hypothyroidism and hyperthyroidism in the Department of Internal Medicine of the Van Training and Research Hospital of Health Sciences University Between June 1, 2012 and June 1, 2022 were retrospectively analyzed. A total of 727 (diagnosed with hypothyroidism: 349, diagnosed with hyperthyroidism: 378) patients were included in the study.
The diagnosis of hypothyroidism and hyperthyroidism were made according to the guidelines (available at: https://temd.org.tr/yayinlar/kilavuzlar). Hyperthyroid patients were diagnosed with elevated serum levels of fT3 and/or fT4 but decreased TSH levels compared to reference ranges. Hypothyroid patients were diagnosed with decreased serum levels of fT3 and/or fT4 but elevated serum levels of TSH (reference ranges: fT4: 12.3-20.2 pmol/L; fT3: 3.71–6.70 pmol/L; and TSH: 0.30–3.94 mIU/L).
The inclusion criteria for the study were: age 18- 65 years (men, non-pregnant women), newly diagnosed and untreated patients with hypothyroidism or hyperthyroidism, without other additional disease diagnosis in the system, and having hematological and biochemical parameters results.
The exclusion criteria for the study were: age <18 years >65, pregnant women, patients with diabetes mellitus, hypertension, chronic inflammatory disease etc., patients with missing data on hematological and biochemical parameters.
Age, gender, hematological and biochemical parameters data of the patients were obtained retrospectively from the hospital automation system and patient files. The triglyceride-high-density lipoprotein (HDL-C) ratio (TG/HDL) values were calculated by dividing the TG result by the HDL-C result in the biochemistry results. The obtained data were saved in Excel, and statistical analysis was performed.
Statistical analysis
Statistical analysis of the data was performed using the SPSS 27.0 package program (IBM SPSS, Chicago, IL, USA). The conformity of the data to the normal distribution was examined using visual (histogram and probability graphs) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). In the evaluation of numerical data, arithmetic mean, standard deviation, median (1st quartile-3rd quarter), minimum and maximum values were used. Frequency distributions and percentages were used to summarize categorical data. The Chi-square (χ2) test was used to compare categorical data. Comparison of non-normally distributed numerical data with categorical data was done with the Man-Whitney U test. Correlations of non-normally distributed numerical variables were analyzed with the Spearman correlation coefficient. Cases were considered statistically significant when p was less than 0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 727 patients, 349 (277F/72M) diagnosed with hypothyroidism and 378 (306F/72M) diagnosed with hyperthyroidism, were included in this study. The median age of all patients was 47±14.48 years. The number of women was statistically significantly higher (p<0.01) than men in both hypothyroid (%79) and hyperthyroid (%80) patient groups. There were no statistically significant differences between the hypothyroid and hyperthyroid groups when compared with the Chi-square test in terms of gender (p: 0.59).
When the laboratory parameters of females and males in the hypothyroid group were compared, we found statistically significantly higher levels of platelets (PLT), TC and HDL-C in females compared to males. In males, HGB, AST, ALT, urea, creatinine, Fe, ferritin were statistically significantly higher than in females. In the hypothyroid group, there was no statistically significant difference between men and women in terms of age, thyroid function tests, vitamin D, vitamin B12, HbA1c, LDL-C (p>0.05).
When laboratory parameters of females and males in the hyperthyroid group were compared, we found statistically significantly higher levels of PLT, TC, HDL-C, LDL-C in females compared to males. In males, HGB, MPV, AST, ALT, urea, creatinine, ferritin, vitamin D, TG and TG/HDL-C ratio were statistically significantly higher than in females. In the hyperthyroid group, we found that the fT3 and fT4 levels were significantly lower in females than in males. In the hyperthyroid group, there was no statistically significant difference between men and women in terms of age, vitamin B12, HbA1c, LDL-C (p>0.05). Comparison of laboratory data of patients with hypothyroidism and hyperthyroidism in terms of gender is presented in Table 1.
When we compared the hypothyroid and hyperthyroid groups, we found a statistically significant difference between the groups in terms of TSH, fT3, fT4, MPV, PLT, urea, creatinine, LDL-C, TC, TG, and TG/HDL-C ratio. Comparison of laboratory data of the patients in terms by groups is given in Table 2.
When the groups are examined in terms of correlations, in both hypothyroid and hyperthyroid groups, while there was a positive and significant correlation between LDL-C – age, LDL-C – TC, TG – TC, HGB – ferritin, HGB – Fe, HbA1c – TG, AST – ALT, and urea – creatinine, there was a negative significant correlation between HDL-C -TG. Significant correlations of thyroid function tests with biochemistry and hematology laboratory parameters are shown in Table 3. Moreover, vitamin B12 deficiency (B12 levels <175 pg\ml) was present in 8% of hypothyroid patients and 6.3% of hyperthyroid patients. There was no significant correlation between TSH and vitamin B12 and vitamin D.
Discussion
Thyroid hormones are essential for the normal development, differentiation, metabolic balance and physiological function of all tissues. Both hypothyroidism and hyperthyroidism are more common in females than in males. Our findings in our study are also in this direction [6,11].
Iron deficiency and therefore low ferritin and hemoglobin in women due to reasons such as menstrual cycle and pregnancy are considerably higher than in men. In the findings of our study, we found that HGB, Fe, and ferritin were significantly lower in women in both hypothyroid and hyperthyroid groups compared to men [13].
Mean platelet volume (MPV) indicates mean platelet size and reflects the platelet production rate and stimulation. Some studies have emphasized that there is an increase in MPV in hyperthyroidism and that there is a positive relationship between MPV and TSH [12,14]. Another study on a much larger scale (8424 males, 5198 females) found no association between MPV or PDW and thyroid function [15]. The results of a study in patients with thyroid papillary carcinoma emphasized that MPV is a valuable parameter to monitor the hemostatic status in thyroid disorders [16]. In our study results, we found that the MPV and PLT values were significantly lower in the hyperthyroid group than in the hypothyroid group.
In hypothyroidism and hyperthyroidism, liver and kidney function tests also vary depending on the metabolic rate. In hypothyroidism, renal blood flow decreases, thus affecting the water and electrolyte balance [12,17]. Primary hypothyroidism is associated with reversible elevation of serum creatinine in adults [18]. In a study conducted with 47 overt hypothyroidism, 77 subclinical hypothyroidism and 77 healthy controls, urea and creatinine values were found to be significantly higher in the patient group compared to the control [19]. In our study, urea and creatinine values were significantly higher in the hypothyroid group compared to the hyperthyroid group.
Thyroid hormones increase the utilization of lipid substrates. Hypothyroidism is a well-known cause of hyperlipidemia. The most common lipid abnormality in hypothyroid patients is hypercholesterolemia, mainly due to the increased concentration of LDL-C [10,17,20]. A number of accompanying symptoms of hypothyroidism include hyperlipidemia characterized by up-regulated circulating LDL-C, very TG [21].
A study conducted in 2010 reported that there was a positive correlation between TSH-TC, TSH-HDL-C and TSH-LDL-C in patients with overt hypothyroidism, and a positive correlation between TSH-TC and TSH-LDL-C in patients with subclinical hypothyroidism. In addition, in the same study, it was stated that the TC and LDL-C levels were significantly higher (p<0.001) in hypothyroid patients compared to healthy controls, and TC and LDL-C increased as TSH increased [22]. In 2016, the results of studies conducted with 197 hypothyroid, 230 hyperthyroid and 355 healthy controls reported that the TC, TG and LDL-C levels were significantly higher (p < 0.05) in hypothyroid patients compared to controls, and the LDL-C and HDL levels were significantly lower in hyperthyroid patients compared to controls (p < 0.05) [23]. Another study conducted in 2022 reported that TC, TG and LDL-C levels were significantly higher in hypothyroid patients compared to healthy controls (p < 0.01) [24]. TSH had a positive linear correlation with TC (ρ = 0.277, n = 42, p = 0.04).
In this study, a significant increase (p<0.01) in serum levels of TG, TC and LDL-C was observed in hypothyroid patients compared to hyperthyroid patients, which is consistent with previous studies. We also found a negative significant correlation between fT3 and LDL-C in patients with hyperthyroidism (r: – 0.238, p<0.01).
Limitations of the study
There were some limitations in this study. This study is a retrospective study. In our study, the presence of chronic disease information was obtained from the hospital automation system. There is not enough information about the nutritional habits of the patients and whether they are taking vitamin or mineral supplements. In addition, the absence of a control group in our study is among the limitations of the study.
Conclusion
In this study, a significant increase (p<0.01) was observed in TG, TC and LDL-C levels in hypothyroid patients compared to hyperthyroid patients. We also found a negative significant correlation between fT3 and LDL-C in patients with hyperthyroidism (r: – 0.238, p<0.01). It is important to understand the effect of thyroid hormones on lipid metabolism. Especially in patients with hypothyroidism, lipid metabolism is highly affected. Our findings emphasize that it is important to follow up both hypothyroid and hyperthyroid patients in terms of lipid parameters.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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2. Notas G, Kampa M, Malliaraki N, Petrodaskalaki M, Papavasileiou S, Castanas E. Implementation of thyroid function tests algorithms by clinical laboratories: A four-year experience of good clinical and diagnostic practice in a tertiary hospital in Greece. Eur J Intern Med. 2018;(54):81-6.
3. Wang D, Cheng X, Yu S, Qiu L, Lian X, Guo X, et al. Data mining: Seasonal and temperature fluctuations in thyroid-stimulating hormone. Clin Biochem. 2018; 60:59-63.
4. Troshina EA, Panfilova EA, Mikhina MS, Kim IV, Senyushkina ES, Glibka AA, et al. Clinical practice guidelines for acute and chronic thyroiditis (excluding autoimmune thyroiditis). Probl Endokrinol. 2021;12;67(2):57-83.
5. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017;23;390(10101):1550-62.
6. Wilson SA, Stem LA, Bruehlman RD. Hypothyroidism: Diagnosis and Treatment. Am Fam Physician. 2021;15;103(10):605-13.
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8. Su X, Peng H, Chen X, Wu X, Wang B. Hyperlipidemia and hypothyroidism. Clin Chim Acta. 2022;527:61-70.
9. Gronich N, Deftereos SN, Lavi I, Persidis AS, Abernethy DR, Rennert G. Hypothyroidism is a Risk Factor for New-Onset Diabetes: A Cohort Study. Diabetes Care. 2015;38(9):1657-64.
10. O’Brien T, Dineen SF, O’Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc. 1993;68(9):860-6.
11. Guerri G, Bressan S, Sartori M, Costantini A, Benedetti S, Agostini F, et al. Hypothyroidism and hyperthyroidism. Acta Biomed. 2019;30;90(10):83-6.
12. De Leo S, Lee SY, Braverman LE. Hyperthyroidism. Lancet. 2016; 388(10047):906-18.
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15. Ren X, Meng Z, Liu M, Zhu M, He Q, Zhang Q, et al. No associations exist between mean platelet volume or platelet distribution width and thyroid function in Chinese. Medicine (Baltimore). 2016;95(40):1-8.
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Investigation of antibacterial activity of silver nanoparticles against staphylococcus aureus strain
Suna Kızılyıldırım 1, Cansu Önlen Güneri 2
1 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Suleyman Demirel University, Isparta, 2 Department of Medical Laboratory Techniques, University of Health Sciences Turkey, Ankara, Turkey
DOI: 10.4328/ACAM.21563 Received: 2022-12-26 Accepted: 2023-02-02 Published Online: 2023-02-22 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S15-17
Corresponding Author: Cansu Önlen Güneri, Department of Medical Laboratory Techniques, University of Health Sciences, 06018, Ankara, Turkey. E-mail: cansuonlen@gmail.com P: +90 312 304 63 90 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6112-0693
Aim: Staphylococcus aureus (S. aureus) is an important pathogen that causes hospital and community infections. Silver nanoparticles (AgNPs) have antimicrobial activity against both gram-positive and gram-negative bacteria. Colloidal silver (Ag) based antiseptics have become more popular once again because of the increase in antibiotic resistance. Silver nanoparticles mostly show their effectiveness against bacteria by disrupting bacterial DNA replication and bacterial cytoplasm membranes. In this study, it was aimed to investigate the antibacterial effect of silver nanoparticles against S. aureus strain.
Material and Methods: The antibacterial effect of AgNPs was investigated against S. aureus ATCC 6538 reference strain. The Broth dilution method was used in the analysis of Minimum Inhibitory Concentration (MIC) values of silver nanoparticles. Brain Heart Infusion (BHI) agar plates were used in the Minimum Bactericidal Concentration (MBC) test.
Results: The investigation showed that silver nanoparticles, at a concentration of 1 mg/ml, were effective against S. aureus.
Discussion: As a result, the antibacterial activity of silver nanoparticles has been determined and further research is required.
Keywords: Staphylococcus Aureus, Silver Nanoparticles, Antibacterial
Introduction
Staphylococcus aureus (S. aureus) is both a human pathogen and a commensal bacterium [1]. It causes many infections such as skin and soft tissue infections, pneumonia, bacteremia, infective endocarditis, septic arthritis, and osteomyelitis [2].
The widespread use of antibiotic or antimicrobial agents has led to global concerns such as the rapid emergence of antimicrobial-resistant strains, long-term treatment of infection and increased risk of mortality [3,4]. Because of bacterial evolution and widespread antibiotic use, drug resistance of S. aureus has significantly increased in recent years [5]. Effective agents against antibiotic-resistant S. aureus infections are needed.
Silver nanoparticles (AgNPs) smaller than 100 nm in at least one dimension have drawn a lot of interest due to their antimicrobial effect [6]. Ag-based antiseptics have become more popular once again because of the increase in antibiotic resistance [7]. Colloidal silver (Ag) has been reported to be effective against gram-positive and gram-negative bacteria [8]. Their strategy for attacking staphylococci involves causing permanent harm to bacterial cells by preventing bacterial DNA replication, degrading bacterial cytoplasm membranes, or affecting intracellular adenosine-5’-triphosphate (ATP) levels [9].
In this study, we aimed to examine the antibacterial effect of Ag-NPs on the S. aureus ATCC 6538 strains.
Material and Methods
The study was carried out at Çukurova University, Medical Microbiology Department between 25.03.2022 and 10.08.2022. AgNPs synthesis was performed according to a previously described method [6]. The S. aureus ATCC 6538 reference strain was used to investigate the antibacterial efficacy of silver nanoparticles. This study was conducted in accordance with ethical rules.
Minimum Inhibitory Concentration (MIC) Determination
A standard broth microdilution in MHB was used for the 96-well microtiter plates used for the AgNPs susceptibility testing in accordance with recommendations from the Clinical and Laboratory Standards Institute (CLSI). The test strain was exposed to 0.25-4 mg/mL AgNPs to determine the MICs of AgNPs. Phosphate-buffered saline was used to prepare AgNPs solutions [10].
Minimum Bactericidal Concentration (MBC) Determination
Aliquots of 50 μl from each tube that exhibited no bacterial growth were inoculated on BHI agar plates after the MIC of the AgNPs was determined. The plates were incubated for 24 hours at 37°C [11].
Results
According to the study, the value of AgNPs is efficient against S. aureus strain at 1,2, and 4 mg/mL concentration. BHI agar plate was inoculated with the suspension from the tubes containing 1, 2, and 4 mg/ml. At any of the concentrations (1, 2, or 4 mg/ml), no bacterial growth occurred. As a result, the MIC and MBC values of AgNPs were found to be effective at 1 mg/ml dilution against S. aureus strain.
Discussion
S. aureus is a clinically significant bacterium and a serious public health concern [12]. S. aureus infections, particularly those brought on by antibiotic-resistant strains, are becoming a worldwide epidemic [13].
Ag-NPs have been reported to represent a new generation of antimicrobials [14]. AgNPs are non-toxic and exhibit broad-spectrum antibacterial effects [15]. The antibacterial activity of silver particles against the S. aureus strain was investigated in the study. At a concentration of 1 mg/ml, silver particles in the study were found to be effective against S. aureus.
AgNPs have been determined to completely inhibit bacterial growth at a concentration of 4μg/ml [6]. Additionally, it has been observed that Ag+ ions and Ag-based compounds are effective against resistant bacteria like Methicillin-resistant S. aureus [16]. It has been reported that AgNPs are efficient against S. aureus and that other investigations have shown similar results. The silver particles’ low MIC values demonstrated their effective anti-staphylococcal activity and offered a hope for the future with more clinical applications [17].
Ag nanoparticles show great potential as antimicrobial agents. It has been reported that Ag nanoparticles can lead to valuable discoveries in various fields such as medical technology and antimicrobial systems [18].
Consequently, AgNPs were found to be effective against S. aureus and more comprehensive studies should be done.
Acknowledgment
We would like to thank Professor Dr. Fatih Köksal for contributing to the experiments and the use of laboratory facilities. We would like to thank Professor Dr. Hikmet Çoğun for assistance in nanoparticle synthesis.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler VG. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015;28(3):603-61.
2. Giulieri SG, Tong SYC, and Williamson DA. Using genomics to understand meticillin- and vancomycin-resistant Staphylococcus aureus infections. Microbial Genomics. 2020; 6(1): e000324.
3. Yah CS, Simate GS. Nanoparticles as potential new generation broad spectrum antimicrobial agents. Daru. 2015;23:43.
4. Gurunathan S. Biologically synthesized silver nanoparticles enhances antibiotic activity against Gram-negative bacteria. Journal of Industrial and Engineering Chemistry. 2015;29:217-26.
5. Guo Y, Song G, Sun M, Wang J, Wa Y. Prevalence and Therapies of Antibiotic-Resistance in Staphylococcus aureus. Front Cell Infect Microbiol. 2020;10:107.
6. Mirzajani F, Ghassempour A, Aliahmadi A, Esmaeili MA. Antibacterial effect of silver nanoparticles on Staphylococcus aureus. Res Microbiol. 2011;162(5):542-9.
7. Jones SA, Bowler PG, Walker M, Parsons D. Controlling wound bioburden with a novel silver-containing Hydrofiber dressing. Wound Repair Regen. 2004;12(3):288-94.
8. Platania V, Kaldeli-Kerou A, Karamanidou T, Kouki M, Tsouknidas A, Chatzinikolaidou M. Antibacterial Effect of Colloidal Suspensions Varying in Silver Nanoparticles and Ions Concentrations. Nanomaterials (Basel). 2021;12:31.
9. Franci G, Falanga A, Galdiero S, Palomba L, Rai M, Morelli G, et al. Silver Nanoparticles as Potential Antibacterial Agents. Molecules. 2015;20(5):8856–74.
10. Yuan YG, Peng QL, Gurunathan S. Effects of Silver Nanoparticles on Multiple Drug-Resistant Strains of Staphylococcus aureus and Pseudomonas aeruginosa from Mastitis-Infected Goats: An Alternative Approach for Antimicrobial Therapy. Int J Mol Sci. 2017;18(3): 569.
11. Parvekar P, Palaskar J, Metgud S, Maria R, Dutta S. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of silver nanoparticles against Staphylococcus aureus. Biomater Investig Dent. 2020;7(1):105-9.
12. Gagliotti C, Högberg LD, Billström H, Eckmanns T, Giske CG, Heuer OE, et al. Staphylococcus aureus bloodstream infections: diverging trends of meticillin-resistant and meticillin-susceptible isolates, EU/EEA, 2005 to 2018. Euro Surveill. 2021;26(46):2002094
13. Stefani S, Goglio A. Methicillin-resistant Staphylococcus aureus: related infections and antibiotic resistance. Int J Infect Dis. 2010;14(4):19-22.
14. Li WR, Xie XB, Shi OS, Duan SS, Ouyang YS, Chen YB. Antibacterial effect of silver nanoparticles on Staphylococcus aureus. Biometals. 2011;24(1):135-41.
15. Baker C, Pradhan A, Pakstis L, Pochan DJ, Shah SI. Synthesis and antibacterial properties of silver nanoparticles. J Nanosci Nanotechnol. 2005;5(2):244-9.
16. Lara HH, Garza-Treviño EN, Ixtepan-Turrent L, and Singh DK. Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds. J Nanobiotechnology. 2011;9:30.
17. Swolana D, Wojtyczka RD. Activity of Silver Nanoparticles against Staphylococcus spp. Int J Mol Sci. 2022;23(8): 4298.
18. Kim JS, Kuk E, Yu KN, Kim JH, Park SJ, Lee HJ, et al. Antimicrobial effects of silver nanoparticles. Nanomedicine. 2007;3(1):95-101.
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Could procalcitonin guide the use of antibiotics in acute exacerbation of chronic obstructive pulmonary disease?
Kamil Ozdemir 1, Muhammet Polat 2, Elif Gokcen Polat 3
1 Department of Chest Diseases, Osmaneli Mustafa Selahattin Cetintas State Hospital, 2 Department of Tuberculosis, Bilecik Provincial Health Directorate, 3 Department of Family Medicine, Bilecik Provincial Health Directorate, Bilecik, Turkey
DOI: 10.4328/ACAM.21570 Received: 2023-01-01 Accepted: 2023-03-02 Published Online: 2023-03-23 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S18-21
Corresponding Author: Kamil Ozdemir, Department of Chest Diseases, Osmaneli Mustafa Selahattin Cetintas State Hospital, Bilecik, Turkey. E-mail: ozdemirkamil930@gmail.com P: +90 535 237 85 68 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6663-5573
Aim: Chronic Obstructive Pulmonary Disease (COPD) is predicted to become the third leading cause of death worldwide by 2030. Despite the fact that viral pathogens are play a major role in causing AECOPD, antibiotics are widely used in hospitals and cause various side effects. The purpose of this study is to understand whether procalcitonin levels can be used as a new guideline for antibiotic treatment in AECOPD.
Material and Methods: The study included 54 patients: 20 infectious AECOPD patients and 20 non-infectious AECOPD patients and 14 stable COPD controls. Standard treatment, antibiotics and systemic steroids have been given to the infectious COPD group for 10 days. Standard treatment and steroids have been given to the noninfectious group. Before and after treatment PCT was compared.
Results: In the infectious group, PCT level was above 0,25 pg/L. In the non-infectious group, procalcitonin level was 0,10- 0,25 pg/L. In the control group, procalcitonin level was below 0,1 pg/L. Accordingly, after 10 days, low procalcitonin levels were found in all groups.
Discussion: In our study, it was observed that procalcitonin levels decreased after antibiotic and steroid treatment in infectious AECOPD and after steroid treatment in non-infectious AECOPD. We conclude that a 0,25 pg/L level can be used as a threshold value, antibiotics should be started above 0,25 pg/L, and patients should be observed more closely as this level increased. We observed that after 7-10 days PCT level reduced to under 0.1 pg/L.
Keywords: Procalcitonin, COPD, Antibiotics, Acute Exacerbation, Biomarkers
Introduction
COPD has been reported as the third leading cause of death worldwide in 2016, with around 3 million deaths annually and the incidence is predicted to increase each year until at least 2030 [1]. Exacerbations in chronic obstructive pulmonary disease (COPD) are defined in several ways, although many clinicians and researchers use the classic Anthonisen criteria [2]. Such criteria can lead to antibiotic and corticosteroid overuse, since they do not necessarily differentiate which patients are in need of such treatments, and in case of doubt, treatment will often be initiated, to avoid undertreating [3]. Research has shown that the overall prevalence of bacterial infection was approximately 50% in AECOPD patients, however, nearly 90% of hospitalized AECOPD patients were given antibiotics [4]. The overuse of antibiotics for respiratory infections is an important cause of multidrug resistance. Therefore, it is imperative to develop effective diagnostic tools to guide both corticosteroid and antibiotic treatment in lung patients and in patients with respiratory infections [5].
Procalcitonin (PCT) is a biomarker specific to bacterial pathogens, and the use of PCT-guided algorithms has demonstrated an ability to reduce antibiotic exposure in patients with pneumonia without negatively impacting clinical outcomes in randomized controlled studies.
In response to bacterial-induced cytokines, PCT is released ubiquitously into the bloodstream. Conversely, production is attenuated by cytokines released in response to viral infections [6].
In the patient care setting, serum PCT is measured and then applied clinically based on algorithms that use different thresholds to guide antibacterial initiation or for early discontinuation. The United States (US) Food and Drug Administration (FDA)-approved thresholds for these assays are as follows: antibiotics strongly discouraged if PCT < 0.1 μg·L−1, discouraged for serum levels between 0.1 and 0.25 μg·L−1, recommended for levels > 0.25 to 0.5 μg·L−1, and strongly recommended for levels > 0.5 μg·L−1 [7].
In our study, we aimed to assess the ability of PCT to distinguish between bacterial and nonbacterial causes of AECOPD and to understand how we can use PCT in the most effective way to guide the treatment.
Material and Methods
A total of 54 patients who were admitted to the Yedikule Chest Diseases Training and Research Hospital for AECOPD between January and June 2009 were enrolled in the study.
COPD patients were defined as patients who were 40 years or older with a history of ≥10 years, with dyspnea, chronic cough, biomass exposure, sputum and irreversible airway obstruction proven by spirometry.
The exclusion criteria were patients with symptoms other than COPD, with a psychiatric disorder, patients with extremely low immune function, asthma, those who admitted to the hospital for various reasons, who were treated with steroids or antibiotics in the last 3 weeks. There were 3 groups in the study: Group 1: AECOPD patients who had high Leukocytosis, CRP, sedimentation, high fever and pathogen, isolated from sputum. Group 2: non-infectious AECOPD patients who did not have high Leukocytosis, CRP, sedimentation and no pathogens isolated from sputum and Group 3: a stable COPD control group recruited in this study. Patients who were enrolled in the study have been evaluated according to Anthonisen Criteria and classified their exacerbations as severe, moderate and mild. On admission, in addition to anamnesis of patients, laboratory data were collected, including routine biochemical tests (urea, creatinine, total protein, alanine aminotransferase [ALT], aspartate aminotransferase [AST], LDH, CRP, erythrocyte sedimentation (ESR), spirometry and arterial blood pressure of oxygen [PaO2]. AECOPD patients were admitted to the hospital, and procalcitonin levels were measured. As for stable COPD patients, only PCT levels were measured and no additional treatment was given except for standard treatment, and they were not hospitalized. In determining Procalcitonin levels, Biomerieux, (France) ELISA technique was used.
The study protocol was approved by the ethics committee of Yedikule Chest Diseases Training and Research Hospital.
Statistical analysis
The ANOVA with Tukey HSD test was used to compare age, SFT, blood gas, leukocytes, CRP, total protein and procalcitonin in different groups. All categorical variables (sex, normal, pathologic, etc.) were compared using the Chi-square test. In addition, a comparison of the initial and control PCT was performed using the Wilcoxon test. P<0.05 indicated that the difference has statistical significance. SPSS Inc. released 2009. PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc. was used for statistical analysis.
Results
In this study, a total of 55 patients were included in three groups: 20 patients in group 1, 24 patients in group 2 and 15 patients in group 3. One patient from group 1 and 4 patients from group 2 have been ruled out from study since a pathogen has been isolated from their sputum.
In group 1: the median age was 57± 10.86 (40-82) years, 17 were male and 3 were female patients. Four patients were followed in the hospital and 16 patients were followed as an outpatient. Two patients were in severe attack, 5 patients were moderate and 4 patients were mild. None of the patients required hospitalization in the intensive care unit. Nineteen patients were smokers, 1 patient was a non-smoker but had biomass exposure.
The pathogens isolated from the sputum of patients were Strep. Pneumonia in 14 patients, Klebsiella in 2 patients, Pseudomonas Aeroginosa in 1 patient, Acinetobacter in 1 patient, E. Coli in 1 patient, Proteus Mirabilis in 1 patient. Thirteen of the patients had radiological findings, and 3 of them had no findings. CRP was high in 19 patients and normal in 1 patient. Sedimentation was high in 18 patients and normal in 2 patients. Fifteen patients had leukocytosis and 5 of them were normal.
In group 2: the median age was 63.95± 13.07 (39-84) years, 16 were male and 4 were female patients. Three patients were followed in the hospital, and 17 patients were followed as an outpatient. Six patients were in severe attack, 7 patients were moderate and 7 patients were mild. None of the patients needed hospitalization in the intensive care unit. Eighteen patients were smokers, 2 female patients were non-smokers, but had biomass exposure history. No pathogen was isolated from the sputum of the group 2 patients. Two patients had radiological findings,18 had no findings. CRP was high in 6 patients and normal in 14 patients. Sedimentation was high in 2 patients, normal in 18 patients. All 20 patients had normal leukocyte counts.
In Group 3: 14 patients were recruited with median age of 63.7± 19.86 (46-76) years, 13 were males and 1 was female. All 14 patients were smokers. There was no growth in the sputum culture and no radiological finding in any of the patients. In all patients CRP and sedimentation levels were normal. Group features are showed in Table 1.
There was no statistically significant difference between the groups in terms of smoking. The indication of radiological findings is statistically meaningful in infectious cases compared to non-infectious and stabile groups. Laboratory findings are illustrated in Table 2.
In infectious cases, CRP levels and leukocytosis frequency were significantly higher compared to non-infectious and stable group patients (p<0,001). In infectious cases, sedimentation level was significantly higher compared to non-infectious and stable group patients (p<0,001).
There was no statistically significant difference between the groups in terms of LDH, total protein values (p>0,05). In infectious cases, leukocyte level was significantly higher compared to non-infectious and stable group patients (p<0,001). Comparison of procalcitonin values is presented in Table 3.
In infectious cases, PCT level was significantly higher compared to non-infectious and stable group patients (p<0,001).
There was no statistically significant difference between the groups in terms of post-treatment PCT levels (p>0,05). In all groups, PCT levels were reduced significantly.
Discussion
Patients with an acute exacerbation of COPD combined with respiratory failure develop a systemic inflammatory response, and an elevated PCT level is an indicator of oxidative stress and an inflammatory immune response in patients, providing an effective guide for stopping or starting antibiotics in patients with acute respiratory infections [8].
In order to test this theory, 3 groups of patients have been examined. 20 AECOPD patients who had pathogen isolated from their sputum and had high leukocytosis, CRP, sedimentation ; 20 non-infectious patients who had normal CRP, leukocytosis, sedimentation level, lastly as a control group, 14 stable COPD patients were examined. In addition to standard therapy, antibiotic and systemic corticosteroid therapies were given to infectious AECOPD patients for 10 days. As for non-infectious AECOPD patients, in addition to standard therapy, systemic corticosteroids were administered. At admission and after treatment, PCT levels were measured. In our study, we decided to administer antibiotics based on CRP, leukocytosis, radiological infiltration, purulent sputum, and bacterial pathogen abundance in sputum that leads us to think of a bacterial infection. Indeed, the PCT level of these cases was above 0.25 pg/L, compatible with the literature. Measuring PCT levels and detecting a level above 0.25 pg/L may be considered as a potential guide for antibiotic administration in AECOPD patients, but should be interpreted in conjunction with other clinical and laboratory findings to make informed treatment decisions. When we controlled the PCT level after 10 days in bacterial-infected acute attack patients, we observed that the PCT level reduced under 0.1 pg/L. Also, we observed that the PCT level dropped significantly after 10 days in non-infectious or nonbacterial infectious acute attack patients and stable COPD patients.
We detected that all infectious AECOPD patients with high PCT levels (>0.25 pg/L) were also in the severe attack group based on Anthonisen Group 1. In this context, the high PCT level can be used as a reference for the severity of the attacks. In our analysis, after administering antibiotics to the patients in Group 1, the PCT level dropped under 0.1 pg/L. The PCT level was in the range of 0.1-0.25 pg/L in the non-bacterial AECOPD group.
Recently published results from prospective observational studies indicate that the evaluation of the dynamic changes in biomarker levels over time may give more reliable help in decision- making than absolute values [9]. It has been also concluded in the most recent review that PCT measurements approximately every 48 hours can lead to a reduction in antibiotics of at least 30%, without any obvious disadvantages; in fact, such a strategy reduces mortality and antibiotic-related side effects in patients with lower respiratory tract infections (level 1A evidence), effects that seem likely also to apply to COPD patients [10]. We also came to the same result.
Conclusion
In our study, we found that the 0.25 pg/L cut-off value is in significant agreement with the literature, and as the value gets higher, the patient needs to be followed up more closely. Concurrently, PCT measurement could help prevent unnecessary and long antibiotic usage. Moreover, we concluded that antibiotic treatment could be discontinued if the PCT level falls below 0.1 pg/L after 7-10 days. Overall, the findings of this study indicate that PCT can play an important role in the management of AECOPD to reduce unnecessary antibiotic prescriptions.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: Yedikule Chest Disease Training and Research Hospital Budget.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Pázmány P, Soós A, Hegyi P, Dohos D, Kiss S, Szakács Z, et al. . Inflammatory Biomarkers Are Inaccurate Indicators of Bacterial Infection on Admission in Patients With Acute Exacerbation of Chronic Obstructive Pulmonary Disease-A Systematic Review and Diagnostic Accuracy Network Meta-Analysis. Front Med (Lausanne). 2021; 8:639794.
2. McLean S, Hoogendoorn M, Hoogenveen RT, Feenstra TL, Wild S, Simpson CR, et al. Projecting the COPD population and costs in England and Scotland: 2011 to 2030. Sci Rep. 2016;6(1):1-10.
3. Sivapalan P, Jensen JU. Biomarkers in Chronic Obstructive Pulmonary Disease: Emerging Roles of Eosinophils and Procalcitonin. J Innate Immun. 2022;14 (2):89-97.
4. Ma YM, Huang K, Liang C, Mao X, Zhang Y, Zhan Z, et al. Real-world antibiotic use in treating acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in China: Evidence from the ACURE study. Front Pharmacol 2021; 12:649884.
5. Mathioudakis AG, Janssens W, Sivapalan P, Singanayagam A, Dransfield MT, Jensen JS, et al. Acute exacerbations of chronic obstructive pulmonary disease: in search of diagnostic biomarkers and treatable traits. Thorax. 2020; 75(6):5207.
6. Bremmer DN, DiSilvio BE, Hammer C, Beg M, Vishwanathan S, Speredelozzi D, et al. Impact of Procalcitonin Guidance on Management of Adults Hospitalized with Chronic Obstructive Pulmonary Disease Exacerbations. J Gen Intern Med. 2018;33(5):692-7.
7. Chen K, Pleasants KA, Pleasants RA, Beiko T, Washburn RG, Yu Z et al. Procalcitonin for Antibiotic Prescription in Chronic Obstructive Pulmonary Disease Exacerbations: Systematic Review, Meta-Analysis, and Clinical Perspective. Pulm Ther. 2020;6(2):201-14.
8. Huang L, Wang J, Gu X, Sheng W, Wang Y, Cao B. Procalcitonin-guided initiation of antibiotics in AECOPD inpatients: study protocol for a multicenter randomised controlled trial. BMJ Open. 2021;11(8):e049515.
9. Trásy D, Tánczos K, Németh M, Hankovszky P, Lovas A, Mikor A, et al. Delta procalcitonin is a better indicator of infection than absolute procalcitonin values in critically ill patients: a prospective observational study. J Immunol Res. 2016; 2016:3530752.
10. Moghoofei M, Jamalkandi SA, Moein M, Salimian J, Ahmadi A. Bacterial infections in acute exacerbation of chronic obstructive pulmonary disease: a systematic review and meta-analysis. Infection. 2020; 48(1):19–35.
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Kamil Ozdemir, Muhammet Polat, Elif Gokcen Polat. Could procalcitonin guide the use of antibiotics in acute exacerbation of chronic obstructive pulmonary disease? Ann Clin Anal Med 2023;14(Suppl 1):S18-21
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Retrospective evaluation of patients with intracranial bleeding due to late vitamin K deficiency
Barış Erdoğan 1, Duygu Ceman 2
1 Department of Neurosurgery, Şanlıurfa Train and Research Hospital, Şanlıurfa, 2 Department of Neurosurgery, Sancaktepe Şehit Prof.Dr.İlhan Varank Train and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21582 Received: 2023-01-10 Accepted: 2023-02-11 Published Online: 2023-02-22 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S22-25
Corresponding Author: Barış Erdoğan, Department of Neurosurgery, Şanlıurfa Train and Research Hospital, Eyyubiye, Şanlıurfa, Turkey. E-mail: dr.baris.erdogan@gmail.com P: +90 5462927177 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4946-0748
This study was approved by the Ethics Committee of Harran University (Date: 2021-12-27, No: HRU/21.23.01).
Aim: In this study, we share our clinical experience and raise awareness about the importance of vitamin K prophylaxis. We evaluated
Material and Methods: We retrospectively evaluated the demographic characteristics, clinical and radiological findings of 9 patients with late vitamin K deficiency bleeding (VKDH) who were we followed in our clinic in 2020.
Results: It was determined that none of the 9 patients received postpartum vitamin K prophylaxis. The mean admission international normalized ratio (INR) of the patients was 4.2+1.1. Vitamin K was administered to all patients, and the mean of INR values decreased to 1.1+0.1. The most common complaint of the patients was convulsion (77.8%). Subarachnoid hemorrhage (SAH) + subdural hemorrhage (SDH) were detected in 4 patients, SAH+SDH+intraparenchymal hemorrhage (IPH) in 3 patients, SAH+IPH in 1 patient, and SAH in 1 patient. Surgery was performed on 3 patients. Two patients who were not operated died during their intensive care follow-up. Seven patients were discharged. Hemiplegia developed in 2 patients, and these patients were included in the physical therapy program.
Discussion: Late VKDB is most commonly seen between 2-12 weeks after birth. It causes serious morbidity and mortality. It is difficult to treat, time consuming and costly. It is possible to prevent late VKDB with intramuscular vitamin K prophylaxis after delivery.
Keywords: Hemorrhage, Prophylaxis Vitamin K
Introduction
Vitamin K is a fat-soluble vitamin required for the synthesis of functional molecules of Factor II, Factor VII, Factor IX and Factor X produced by the liver. In the newborn period, enough vitamin K cannot be produced and stored. Among the reasons for this are low level of transfer of vitamin K through the placenta, low bioavailability due to the short half-life of liver stores, low level of vitamin K in breast milk compared to other milks, and insufficient production of intestinal flora due to immaturity. Bleeding due to coagulation disorder secondary to vitamin K deficiency is divided into two according to the time of occurrence. Bleeding between 24 hours and 14 days after birth (days 2-14) is called early vitamin K deficiency bleeding (VKDB) and bleeding between weeks 2-12 is called late VKDB [1-4].
VKDB can lead to a wide range of clinical presentations from mild nose bleeding, bleeding from the umbilical cord, gastrointestinal system bleeding to severe brain hemorrhages. An important feature of late VKDB is that intracranial hemorrhages are seen as the first sign of presentation. According to the study by Klironomy, et al., the incidence in those who did not receive prophylaxis was 4.4-7.2/100.000 [2, 5].
Late type VKDB can cause 30% to 60% of intracerebral hemorrhage. In developed countries, stroke is among the top 10 causes of death in children. It constitutes 50% of non-traumatic hemorrhages. Trauma is the most common cause of intracerebral hemorrhages, but it should be kept in mind in hemorrhages due to vitamin K deficiency and hemostatic disorders. In infants 2-24 weeks of age, findings may sometimes be subtle. It should be kept in mind that intracranial hemorrhage may develop due to vitamin K deficiency in mothers who use antibiotics for a long time and also in children who are exclusively breastfed. Intracranial hemorrhage has a high morbidity and mortality rate [6-8].
We examined 9 patients who were followed up in our clinic for intracranial hemorrhage due to late vitamin K deficiency in 2020. In this study, we aimed to increase awareness of intracranial hemorrhages due to late vitamin K deficiency, which causes significant morbidity and mortality in the neonatal period.
Material and Methods
Between January 2020 and December 2020, 9 patients who applied to the emergency department with intracranial hemorrhage due to late vitamin K deficiency and were later referred to us were evaluated retrospectively. Vitamin K prophylaxis was not applied to all patients, and other causes of bleeding disorders were excluded. Computer tomography (CT) was taken and types of bleeding on CT, operation status, presence of complications and survival were evaluated. All patients were followed up during their hospitalization. Statistical analysis
Descriptive statistics were used to describe continuous variables (mean, standard deviation, minimum, median, maximum). Frequency and percentage values were calculated for the descriptive statistics of categorical variables. Comparison of dependent and non-normally distributed continuous variables was made using the Wilcoxon Signed Rank test. Statistical significance level was determined as 0.05. Analyzes were performed using MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2013).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Four of the patients were female and 5 were male. The mean age of the patients was 8.2+2.7 weeks. Upon admission to the emergency clinic, convulsions were observed in 7 patients (77.8%), fontanel swelling in 6 patients (66.7%), vomiting in 5 patients (55.6%), restlessness in 4 patients (44.4%), irritability in 3 patients (33.3%) and poor sucking (33.3%). Among the symptoms, convulsions were observed most frequently with 25%, followed by swelling in the fontanel in 21.4%, vomiting in 17.9%, restlessness in 14.3%, irritability in 10.7% and poor sucking in 10.7% (Table 1).
It was determined that all patients included in the study did not receive prophylactic postnatal vitamin K. International normalized ratio (INR) values of the patients at admission were checked, and the mean was found to be 4.2 + 1.1. Control INR values of the patients were checked after vitamin K was administered. The mean of the control INR value was found to be 1.1+0.1 (Table 2). The change in INR value was found to be statistically significant.
Radiological imaging detected subarachnoid hemorrhage (SAH) + subdural hemorrhage (SDH) in 4 patients, SAH + SDH +intraparenchymal hemorrhage (IPH) in 3 patients, SAH + IPH in 1 patient, and SAH in 1 patient (Table 3) (Figure a, b, c, d).
In the follow-up of the cases, surgical intervention was performed in 3 patients (33.3%). Hydrocephalus developed in one patient who underwent surgery during the follow-up period and a ventriculoperitoneal shunt system was applied. Two patients who were not operated on died due to general complications during the intensive care follow-up period. The remaining 7 patients survived. Hemiplegia developed in 2 patients who did not undergo surgery. The patients were included in the physical therapy program for rehabilitation. In the follow-up, the patients’ strengths recovered almost completely (Table 3).
There was a statistically significant difference between INR on arrival and INR after Vitamin K.
Discussion
Late VKDB develops as a result of insufficient plasma concentration of active coagulation factors II, VII, IX and X. Although it usually occurs between the 2nd and 12th weeks, when studying the literature, it is reported that the cases can be seen up to 6 months of age. Although vitamin K crosses the placenta, its serum level is not sufficient. The plasma concentration of vitamin K varies between 30% and 60% compared to the normal adults. The concentration of vitamin K in breast milk is physiologically low (breast milk level 1-4mg/L) [5]. According to the study by Pirinccioglu et al, 93.7% of babies are exclusively breastfed for the first 6 months [9]. Considering this high rate, it can be predicted that the risk of late VKDB due to vitamin K deficiency may rise to high rates [10]. It has been stated that there is a risk of bleeding between 50-80% in late VKDB, and it has been observed that the incidence of intracranial hemorrhages has increased. When we examined the literature in terms of bleeding types, we saw that the distribution of bleeding types was different. In the study by Visser et al. on 16 patients, SDH was detected most frequently in 50% [11]. In the study by Zidan et al on 32 patients, SDH was observed in 56.3% of the patients, IPH was observed in 31.3%, and mixed-type bleeding was observed in 12.5% of the patients [12]. Ozdemir et al. in their study on 120 patients found SDH in 28%, IPH in 23%, SAH in 14%, intraventricular bleeding in 8%, IPH+SDH bleeding in 10%, and SDH+SAH in 5% [2]. In our study, we found the most common mixed-type bleeding at 88.9%. We observed only SAH in 1 patient (11.1%). The most common type of bleeding was SDH and SAH with 8 patients in our study. It was followed by IPH in 4 patients. When we compared our study with the literature, we found that mixed-type bleeding was more common and parallel to the literature in terms of bleeding type.
Late VKDB clinical findings are non-specific. It may present with clinical findings such as seizure, fever, vomiting, unconsciousness, generalized hypotonia, impaired sucking, irritability, pallor, and fontanel swelling [9, 12]. Princcioglu et al. in their study conducted with 31 patients found pallor in 24 patients (77.4%), seizures in 18 patients (58%), confusion in 18 patients (18%), vomiting in 14 patients (44%), malnutrition in 11 patients (35%), fontanel pulsation in 19 patients (61%) and swelling in 8 patients (26%) [9]. Our study shows parallelism with the literature in terms of symptoms. Although the most common complaint is seizure, it is respectively followed by swelling in the fontanel, vomiting, restlessness, poor sucking and irritability.
Although late VKDB causes severe neurological sequelae and death, its incidence varies according to the development level of the countries. In a study conducted in Germany, 21% morbidity and 19% mortality were found. In another study conducted in Egypt, mortality was found to be higher with 23.8%. In another study conducted in our country, mortality was 20.8% and morbidity was 48.1% [13]. In our study, 2 patients (22.2%) died due to general complications during the intensive care follow-up period. Hemiplegia developed in 2 non-operated patients and hydrocephalus in 1 operated patient. The literature reports that the incidence of hydrocephalus after intracerebral hemorrhage ranges from 8.9% to 50% depending on the type of bleeding [13]. Hydrocephalus finding is accepted as a poor prognosis finding [14, 15]. Our rate was 33.3%. Ventriculoperitoneal shunt system was applied to the patient who developed hydrocephalus. When our results were compared with the literature, parallelism was observed again.
Prothrombin time (PT) and active partial thromboplastin time (aPTT) values are prolonged in vitamin K deficiency. It is known that bleeding values return to normal within 2-3 hours with the administration of vitamin K [3]. Considering the reasons for not taking vitamin K prophylaxis in our study, it was observed that some cases were not chosen by their parents, and some cases were born at home and subsequently could not access health services. We found that the INR values of the cases were observed to be high at the time of admission and after vitamin K was administered to all cases, the INR values returned to normal. According to our findings, all newborn infants should be given vitamin K prophylaxis to avoid the catastrophic effects of VKDB. Vitamin K prophylaxis can be administered orally or intramuscularly. It has been observed that the oral form is less effective in reducing the risk of ICH than the intramuscular form. Although there are articles that vitamin K prophylaxis may increase the incidence of some childhood cancers, the discussions about this have not been clarified [2, 3, 16].
Conclusion
Although late VKDB is seen between the 2nd and 12th weeks on average, it can be seen up to the 6th month. The morbidity and mortality of late VKDB are high, and it mostly presents with intracranial hemorrhages. Breast milk is poor in terms of vitamin K content, and considering that the majority of newborn babies are fed only with breast milk for the first 6 months, it is seen how high the risk is. The way to reduce this risk is that it is important to administer vitamin K prophylaxis, especially in its intramuscular form. Prophylaxis should be made mandatory and should be applied to all newborns born in or out of the hospital. In this way, morbidity and mortality that may occur in VKDB can be prevented. We can prevent information pollution by providing pregnant women with accurate information about vitamin K prophylaxis during pregnancy follow-up.
Our study was conducted with a limited number of patients. Prophylaxis has become widespread with the increase in routine follow-ups in children. Its incidence has decreased in parallel with the developments in diagnosis and treatment. However, it should be kept in mind that when prophylaxis is not performed, it can cause all kinds of intracranial hemorrhage and lead to serious sequelae and death, as seen in our study.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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3. Schulte R, Jordan LC, Murad A, Naftel RP, Wellons JC, Sidonio R. Rise in Late Onset Vitamin K Deficiency Bleeding in Young Infants Because of Omission or Refusal of Prophylaxis at Birth. Pediatr Neurol. 2014; 50(6): 564-8.
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5. Klironomi I, Celaj E, Kola E, Lluka R, Sala D, Kito I, et al. Intracranial hemorrhage due to late vitamin K deficiency in infants in Albania. Paediatr Croat. 2014; 58(2): 101-6.
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7. Rajeev A, Chawla N. Unusual presentation of late vitamin K deficiency bleeding in an infant. Med J Armed Forces India. 2016; 72(Suppl. 1): S142-3.
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10. Karaci M, Toroslu E, Karsli T, Kanber Y, Uysal S, Albayrak D. Intracranial Haemorrhage Due to Late-Onset Vitamin K Deficiency. HK J Paediatr (New Series). 2015; 20:80-5
11. Visser DY, Jansen NJ, Ijland MM, Konig TJ, Hasselt PM. Intracranial bleeding due to vitamin K deficiency: advantages of using a pediatric intensive care registry. Intensive Care Med. 2011; 37(6): 1014–20.
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14. Bhattathiri PS, Gregson B, Prasad KS, Mendelow AD, Investigators S. Intraventricular hemorrhage and hydrocephalus after spontaneous intracerebral hemorrhage: results from the STICH trial. Acta Neurochir Suppl. 2006; 96:65-8.
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16. Unal E, Ozsoylu S, Bayram A, Ozdemir MA, Yılmaz E, Canpolat M, et al. Intracranial hemorrhage in infants as a serious, and preventable consequence of late form of vitamin K deficiency: A selfie picture of Turkey, strategies for tomorrow. Childs Nerv Syst. 2014; 30(8):1375-82.
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Barış Erdoğan, Duygu Ceman. Retrospective evaluation of patients with intracranial bleeding due to late vitamin K deficiency. Ann Clin Anal Med 2023;14(Suppl 1):S22-25
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The frequency of ESBL producing bacterial infections and related antimicrobial susceptibility in ICU patients: A five-year longitudinal study
Sevda Onuk 1, Aliye Esmaoğlu Çoruh 2, Ayşegül Ulu Kılıç 3, Esma Eren 4, Kürşat Gündoğan 5
1 Department of Intensive Care Unit, Kayseri City Education and Research Hospital, 2 Department of Anesthesiology and Reanimation, Faculty of Medicine, Erciyes University, 3 Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Erciyes University, 4 Department of Clinical Microbiology and Infectious Diseases, Kayseri City Education and Research Hospital, 5 Department of Internal Medicine, Faculty of Medicine, Erciyes University, Kayseri, Turkey
DOI: 10.4328/ACAM.21589 Received: 2023-01-14 Accepted: 2023-02-14 Published Online: 2023-02-24 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S26-30
Corresponding Author: Sevda Onuk, Department of Intensive Care Unit, Kayseri City Education and Research Hospital, 38080, Kocasinan, Kayseri, Turkey. E-mail: sevdaonuk@gmail.com P: +90 5055619676 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7601-1601
This study was approved by the Clinical Research Ethics Committee of Erciyes University (Date: 2019-09-11, No: 2019/603)
Aim: This study aimed to evaluate the incidence of nosocomial infections caused by extended-spectrum β-lactamase (ESBL) producing bacteria and related antimicrobial susceptibility in critically ill patients over a 5-year period.
Material and Methods: The retrospective study was carried out in critically ill patients infected with ESBL-producing pathogens during intensive care unit (ICU) stay. Participants’ medical data between 2014 and 2018 were included. ESBL-positive isolates from clinical specimens were evaluated by species and antibiotic susceptibility.
Results: Ninety of 2456 critically ill patients had ESBL-positive bacterial infections. The mean age of the study sample was 58.7 ±19.1 years and 53.3% were males. ESBL-producing E. coli was noted in 60 (66.7%) patients, K. pneumoniae in 27 (30.0%) patients and K. oxytoca in 3 (3.3%) patients. Colistin (100%), meropenem (94.9%), imipenem (94.0%), and amikacin (90.0%) were active against ≥90% of ESBL-producing pathogens, while ertapenem (89.4%), fosfomycin (87.5%), tigecycline (80.0%) were active against ≥80% of pathogens in ICU. Susceptibility of ESBL producers was remarkably low against levofloxacin (30.8%) and ciprofloxacin (36.7%). The mortality rate of the sample was 25.5%.
Discussion: Our findings revealed that ESBL-producing E. coli was highly responsible for ESBL-positive bacterial infections in ICU. The continued efficacy of colistin, carbapenems and amikacin against ESBL-producing E. coli and K. pneumoniae was exhibited.
Keywords: Intensive Care Unit, ESBL-Producing Bacteria, Nosocomial Infection, Antibiotic Resistance-Susceptibility
Introduction
The extended-spectrum beta-lactamase (ESBL) producing bacteria, the strains of Enterobacteriaceae in particular, show resistance to several classes of antibiotics, limiting the antibiotic therapy choices in patients with nosocomial urinary tract infections (UTIs) and intraabdominal infections [1-4]. Hence, the critical rise in the worldwide prevalence of ESBL (+) Enterobacteriaceae is considered a great challenge in clinical practice given the associated risk of treatment failure, higher morbidity, longer hospital stay and adverse patient outcomes [5,6].
Intensive care unit (ICU) patients are particularly prone to nosocomial infections due to vulnerability related to underlying critical illness, frequent use of invasive procedures and exposure to antibiotics, in addition to limited treatment options due to multidrug-resistant (MDR) ESBL producers preventing provision of adequate treatment [2,4,7-9].
Given the variability in the prevalence of ESBL-producing strains and antimicrobial resistance rates in different geographic regions and over time, local surveillance studies are required to guide empiric treatment in accordance with the bacterial spectrum of pathogens and the extent of antimicrobial resistance [6,9].
This hospital-based descriptive study aimed to evaluate the frequency of ESBL-producing bacterial infections and related antimicrobial susceptibility in Anesthesiology and Medical ICU patients during a five-year period.
Material and Methods
Study population
Between 2014 and 2018, 2456 patients aged >18 years with nosocomial bacterial infection were screened. Critically ill patients infected with ESBL-producing bacteria during ICU stay were included in this hospital-based descriptive study conducted at ICUs of a tertiary care hospital during the study period.
The current study was approved by the local ethics committee. It was conducted in accordance with the Declaration of Helsinki.
Assessments
Data on participants’ demographics (age, gender), APACHE II score, comorbidities, risk factors of nosocomial infection due to ESBL-producing bacteria and clinical outcomes (need for mechanical ventilation (MV), ICU mortality) were recorded. ESBL-positive isolates from clinical specimens were assessed by species and susceptibility to antibiotics.
Definition of isolates and susceptibility testing
Identification of isolated bacteria was performed via conventional methods using VITEK® 2 Compact (bioMérieux, Marcyl’Etoile, France) system. Susceptibility testing was performed with the disc diffusion method in accordance with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations. ESBL production of isolates was determined by double disc synergy method.
Statistical analysis
Descriptive statistics were used. Continuous data were presented as “mean ± standard deviation or median (minimum-maximum) according to the normal distribution with the Shapiro-Wilk test. Categorical data were presented as numbers (percentage (%)).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Demographic and clinical data of the study sample
A total of 90 critically ill adult patients infected with ESBL-producing bacteria during ICU stay were included (Figure 1).
The mean patient age was 58.7 (SD: 19.1, range, 18 to 96) years, and 53.3% of patients were males. The mean APACHE II score of the participants was 16.2±7.1 (Table 1).
Pulmonary disease (14.4%) and diabetes (13.3%), and hypertension (11.1%) were the most common comorbidities. Enteral nutrition (38.9%), transfusion (33.3%), and antibiotic use (25.5%) were the most commonly noted risk factors for developing nosocomial infection due to ESBL-producing bacteria. 55.6% of the participants needed MV treatment during the study period. ICU mortality was 25.5%, as shown in Table 1.
ESBL-positive isolates from clinical specimens by species
Overall, ESBL producers isolated from clinical specimens included ESBL-producing E.coli in 60 (66.7%) patients, K. pneumoniae in 27 (30.0%) patients and K. oxytoca in 3 (3.3%) patients (Figure 2).
ESBL-positive isolates from clinical specimens by antibiotic susceptibility
Of the drugs studied, colistin (100%), meropenem (94.9%), imipenem (94.0%), and amikacin (90.0%) were active against ≥90% of nosocomial infections due to ESBL-producing bacteria. Only ertapenem (89.4%), fosfomycin (87.5%), tigecycline (80.0%) were active against ≥80% of ESBL-producing bacteria (Table 2).
Susceptibility of ESBL-producing pathogens was remarkably low against levofloxacin (30.8%), ciprofloxacin (36.7%), and Sulfamethoxazole-trimethoprim (37.5%). The ESBL (+) isolates from clinical specimens by antibiotic susceptibility of study sample are shown in Table 2 in detail.
Discussion
This hospital-based descriptive study revealed that the frequency of ESBL-positive bacterial infections in a tertiary care ICUs was 3.7% over a 5-year period. The ESBL-producing E. coli (66.7%) and K. pneumoniae (33.3%) were responsible causative pathogens, and ICU mortality rate was 25.5% with provision of enteral nutrition (38.9%) and blood transfusion (33.3%) being the main risk factors. Antimicrobial sensitivity testing revealed the continued efficacy of colistin, carbapenems, and amikacin against ESBL producing E. coli and K. pneumoniae along with resistance to fluoroquinolones and sulfamethoxazole-trimethoprim.
Data from worldwide SMART studies revealed a sustained increase in ESBL producing Enterobacteriaceae strains over time and indicated ESBL production rates for E. coli to range from 1.2%-64.9% and K. pneumoniae to range from 9.5%-46.8% [6,10,11]. High ESBL rates in Turkey have been consistently reported in multinational European studies such as 2004-2010 Tigecycline Evaluation and Surveillance Trial (30.9%) and the Regional Resistance Surveillance study for 2011 (>40.0%) [12,13]. Also, according to data from the HITIT study on analysis of 1196 gram-negative nosocomial isolates in Turkish hospitals in 2004-2005, among the blood isolates, E. coli (31.7% (33.3% in ICUs)) and K. pneumoniae (33.3%) were reported to produce ESBLs [9].
Our findings indicate ESBL-positive E. coli or K. pneumoniae as key pathogens for ICU-related infections during study period. In a past study conducted with 140 anesthesiology ICU patients in 2013 in Turkey, 41 (29.3%) of the patients were reported to be colonized with ESBL (+) E. coli (n=39) or K. pneumoniae (n=2) similar to our study. The ESBL (+) E. coli or K. pneumoniae colonization was determined as an independent risk factor for nosocomial infection development [2]. Notably, SMART 2011-2012 Turkey data revealed that the rate for ESBL (+) E. coli was lower (29.2 versus 52.5%) but the rate of ESBL-positive K. pneumoniae was higher (53.8 versus 39.6%) in the ICU setting than non-ICU setting for intraabdominal infections [6]. The authors also indicated the rates for both ESBL-positive E. coli (49.0%) and K. pneumoniae (44.0%) strains to be higher in Turkey [6] compared to global (2005-2007 and 2009-2010) and European (2002-2011) SMART rates [14,15] and to be compatible with some regions with especially high ESBL rates (e.g., Asia, Latin America, and the Middle East) [11, 16].
In the current study, of the drugs studied, colistin, meropenem, imipenem, and amikacin were sensitive to ≥90% of ESBL producing pathogens, while ertapenem, fosfomycin, tigecycline were active against ≥80% of pathogens in ICU. The susceptibility of ESBL producers was remarkably low against levofloxacin (30.8%), ciprofloxacin (36.7%), and Sulfamethoxazole-trimethoprim (37.5%). Likewise, SMART studies have shown that carbapenems and amikacin are highly susceptible to ESBL producing E. coli strains and K. pneumoniae strains along with resistance of Enterobacteriaceae against the cephalosporins, fluoroquinolones. The continued efficacy of carbapenems and amikacin against a wide range of Enterobacteriaceae was emphasized. [6,14,16-18].
In addition, previous studies from Turkey also indicated low susceptibility to cephalosporins due to increased ESBL (+) rates among E.coli and K. pneumoniae to limit empirical therapeutic options for the UTI treatment of hospital acquired in Turkey [6,19], while the increase in fosfomycin usage, particularly for hospital acquired UTIs has also been noted due to low resistance rates against fosfomycin (~1.6%), rendering it a suitable alternative for empirical treatment in daily practice [19,20].
In a past study from Turkey in 2011, ESBL production was identified in 37(39 %) of 95 E. coli and K. pneumoniae strains, particularly in strains isolated from ICUs (65%) versus clinics (32%), while imipenem, meropenem and ertapenem were reported to be effective in all strains along with higher rates of resistance to antibiotics in ESBL positive versus negative E. coli strains [21]. In a 2010-2011 study from Turkey assessing 76 nosocomial ESBL-producing E. coli strains, most of ESBL-producing E. coli strains were reported to be isolated from samples of ICU patients (35%) followed by internal medicine ward (16%) and general surgery unit (13%). All 76 strains were reported to be sensitive to carbapenems and amikacin [22].
In a past study with 4,680 isolates from critically ill patients and 16,263 isolates from non-critically ill patients collected from 70 United States hospitals between 2018 and 2020, the authors reported the association of ICU versus non-ICU isolates with lower antimicrobial susceptibility and higher rate of ESBL, CRE, MDR, and XDR phenotypes [7]. The authors also noted that the most active agents against Enterobacteriaceae were ceftazidime-avibactam and meropenem-vaborbactam. Strong activity against ESBL producers, carbapenem-resistant Enterobacteriaceae, MDR, and XDR isolates was maintained [7].
A recent prospective study in India with 887 blood culture specimens of patients admitted to ICU with suspected sepsis reported that out of 202 (22.78%) blood culture specimens that yielded microbial growth, gram-negative bacteria (E. coli most commonly) accounted for 45.2% cases, while isolates of gram-negative were susceptible to colistin and tigecycline. 77.3% of isolates were ESBL producers [23]. Colistin and tigecycline sensitivity was evident in 66.7% and 71.4% of ESBL positive isolates in the current study.
Accordingly, it was found that particularly ESBL-producing E. coli and K. pneumoniae were responsible for nosocomial infections in most blood culture isolates from critically ill patients in ICU. Our findings support the consideration of multi-drug resistance as a significant problem associated with increase in hospital costs, duration of ICU stay and mortality [23]. In addition, antimicrobial sensitivity findings are also in consistent with past studies indicating the continued efficacy of carbapenems, amikacin and fosfomycin against ESBL-producing E. coli and K. pneumoniae along with resistance to fluoroquinolones and sulfamethoxazole-trimethoprim [6,7,14,16-18,24]. Indeed, given the likelihood of emergence of resistance particularly in Enterobacteriaceae to compromise the future utility of carbapenems, carbapenem-sparing alternative antibiotics are considered to be of highly importance for treatment strategies. Thus, the administration of carbapenems is suggested for patients who had severe and high inoculum-high risk infections with the use of various carbapenem-sparing antibiotics for milder infections, particularly for UTIs [25].
The retrospective and single center design seems to be the major limitation of our study. It cannot generalize our data to overall critically ill patients.
Conclusion
Our findings revealed that ESBL-producing E. coli were highly responsible for ESBL-positive bacterial infections in ICUs. Colistin, carbapenems, amikacin and fosfomycin have been shown to be consistently effective against ESBL-producing E. coli and K. pneumoniae. The resistance to fluoroquinolones and sulfamethoxazole-trimethoprim showed the risk of increase in ESBL-producing bacterial infections in terms of limited effective treatment options over time in critically ill patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Determination of whole-genome expression differences in larynx cancers
Emine Göktaş 1, Kayhan Öztürk 2, Ayşe Gül Zamani 1, Mahmut Selman Yıldırım 1
1 Department of Medical Genetic, Faculty of Meram Medical, Konya, 2 Department of Otolaryngology, Ataşehir Medicana Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21602 Received: 2023-01-20 Accepted: 2023-02-25 Published Online: 2023-03-11 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S31-36
Corresponding Author: Emine Göktaş, Department of Medical Geneticist, Faculty of Meram Medical, 42090, Meram, Konya, Turkey. E-mail: emineaktas88@hotmail.com P: +90 505 247 22 65 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3635-8763
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2015-03-13, No: 2015/146)
Aim: More than 200.000 new laryngeal cancer cases have been diagnosed worldwide, annually. The incidence and prevalence have increased during the past decades. It also has a high mortality rate. To have a better knowledge about this particular cancer type, we aimed to conduct a comparative analysis of whole genome expression differences between laryngeal squamous cell carcinoma and adjacent normal tissues
Material and Methods: Tissue samples were collected from specimens of laryngeal carcinoma and normal epithelium tissues adjacent to the carcinoma. RNAs isolated from these specimens were used for genome-wide gene expression analysis using microarrays. Genes that were expressed significantly differently in the tumor sample compared to normal tissues were identified. Pathway analysis of these genes was also performed.
Results: It was observed that 24 genes were significantly differentially expressed in cancer tissue. Expressions of MMP1, MMP12, S100A2, S100A3, CK14, CK16, SLC2A1, ITGA6, CEP55, KLK6, LAMC2, IL1F9, TP63, VSNL1, CXCL1, COL4A5, COL4A6, FSCN1, KRT6B, KRT17, WDR66 and ACOT7 genes were increased, while expressions of ITM2A and CFD genes were decreased.
Discussion: Some of the genes mentioned above are known to be involved in the etiology of laryngeal cancer, but to the best of our knowledge, 10 genes have been associated with laryngeal cancer for the first time in our study. These genes might be useful as biomarkers in the clinic, for early diagnosis, prognosis and personalized targeted therapy.
Keywords: Genes Expression, Laryngeal Cancers, Microarray
Introduction
Laryngeal carcinoma remains a considerable cause of morbidity and mortality with ~180,000 new cases and 99,000 deaths, accounting for 50% of mortality worldwide in 2020 [1]. Several genetic and environmental factors have been identified to be associated with the development and progression of laryngeal squamous cell carcinoma (LSCC). Among them, the major etiological agents are tobacco and alcohol consumption. In recent years, these agents have been shown to cause molecular changes and a sequence of events in cells, including oncogene activation, the inhibition of tumor suppressor genes, and changes in the gene expression profiling. Clinical outcomes in laryngeal cancer patients are thought to be based on clinicopathological features; however, few studies have indicated that gene expression alterations, as well as genomic and epigenetic changes, can also be used to predict prognosis. Due to this reason, the molecular characterization of laryngeal cancers seems to be extremely important. Certain success has been achieved in molecular studies on the etiology of larynx cancer. But previous studies on larynx cancers were uncertain and incomprehensive [2,3].
Lately, gene expression profiling (GEP) using microarrays has been identified as a hopeful method to identify variations occurring in the pathophysiology of complex diseases such as cancers. The identification of gene expression changes associated with laryngeal cancer gives us information about the mechanism of the disease and the pathways associated with this disease. Thus, new biological and prognostic markers can be identified [4].
There are many studies in the literature aimed at clarifying the etiology of the disease. But the pathogenesis of this neoplasm and associated pathways are still not fully understood. The lack of significant improvement in survival rates over the past 25 years is proof of this [5]. That is why we aimed to conduct a comparative analysis of whole genome expression differences between laryngeal squamous cell carcinoma and adjacent normal tissues. These efforts will ensure a better understanding of molecular mechanisms underlying laryngeal carcinoma, as well as enable the identification of novel biomarkers and therapeutic targets.
Material and Methods
Tissue Samples
Fresh tumor and adjacent normal tissue biopsy specimens were taken from twelve patients who were diagnosed with larynx cancer between March 2015 and April 2016. Clinical characteristics of the patients are shown in Table 1. These tissues were placed in RNA Later solution and stocked at -80 C until use. The informed consent form was obtained from patients or their families. This study was approved by the ethics committee of Necmettin Erbakan University (decision number 2015/146) and financial support was provided by the Scientific Research Projects of the Necmettin Erbakan University (Project Number:151518008).
RNA isolation
RNA isolation was performed by Norgen Total RNA Purf. Kit (cat.no. 25700). The RNA concentration was detected by Thermo Scıentıfıc Nonodrop 2000c. Then, RNA quality and quantity were identified by Agilent RNA 6000 Nano Kit (reorder-no 5067-1511). Thus, RNA was purified from other molecules with the same absorbance as itself.
Synthesis of cDNA and In Vitro Transcription of Biotin-cRNA
The Obtained RNA was converted to cDNA using the TargetAmp™-Nano Labeling Kit (Illumina® Expression BeadChip®). .before the hybridization step.‘’TargetAmp™-Nano Labeling Kit (Illumina® Expression BeadChip®). First-strand cDNA synthesis was catalyzed by Super Script III Reverse Transcriptase. The produced cDNA was converted to a double-stranded cDNA for use in the subsequent in-vitro transcription reaction. Then, in vitro transcription was performed for obtaining biotinylated cRNA. The synthesized biotin-labeled RNA was cleaned up again (Norgen RNA Clean-Up and Conc. Micro Kit 23600,43200) and cRNA levels of all samples were equalized before being sent to the microarray platform.
Microarray analysis
The biotin-labeled RNA was passed through some stages, including hybridization, washing, labeling with streptavidin, and drying before installing the device. The labeled RNA strand was hybridized to the bead on the BeadChip (HumanHT-12 v4.0 Exp. BeadChip Kit) containing the complementary gene-specific sequence. This kit presents a comprehensive analysis of genome-wide expression. Each channel on the BeadChip contains approximately 47,000 different bead types distributed throughout the entire genome. Also, the entire contents of the kit were created with reference to the National Center for Biotechnology Information Reference Sequence (NCBI RefSeq) database. Hybridization was performed at 58 C for 20h. BeadChips were washed after the overnight hybridization. Thus, RNAs not bound to the probe were removed. Then, BeadChip was labeled with streptavidin. The BeadChips were immediately centrifuged after removal from the wash to prevent surface evaporation. Once the BeadChips were dry, they were stored in a dark and ozone-free environment until they were ready to be scanned. Finally, the BeadChips were read in a microarray laser reader (The Illumina® Whole-Genome Gene Expression Direct Hybridization Assay system).
Bioinformatics analysis
Preliminary analyzes and quality controls of the obtained data were performed using the ‘Genome Studio’ software of the Illumina iScan Microarray system. Fold change (FC) is a strong marker indicating the statistical significance of the genes, which is observed in the gene expression profile. By FC analysis, larger than two- fold changes were accepted as an increase and decrease for each probe. Heat-map analysis for differentially expressed genes was generated and GO (gene ontology) analysis was performed.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
In this study, we identified that 14,294 genes were differentially expressed between laryngeal squamous cancer tissues and non-neoplastic tissues. When the FC value is considered to be 2 for the significance of the expression differences, increased expression of 22 genes (MMP1, MMP12, S100A2, S100A3, CK14, CK16, SLC2A1, ITGA6, CEP55, KLK6, KRT17, LAMC2, IL1F9, TP63, VSNL1, CXCL1, COL4A5, COL4A6, FSCN1, KRT6B, WDR66 and ACOT7) and decreased expression of two genes (ITM2A and CFD) were observed. Fourteen of 24 genes were known to be involved in the etiology of laryngeal tumors in the literature, but as far as we know, the effect on laryngeal cancer of the remaining 10 genes (VSNL1, CXCL1, COL4A5, COL4A6, FSCN1, KRT6B, WDR66, ACOT7, ITM2A, CFD) was identified for the first time in our study. Differentially expressed genes between LSCC and adjacent normal tissues are shown in Table 2. The hierarchical clustering of the expression of these genes is shown in Figure 1.
Also, to determine the biological functions of differentially expressed genes, WikiPathway functional enrichment analysis was carried out using the Gene Spring gx (Agilent) program. WikiPathways was established to contribute to the information about the pathway and to facilitate the access by the biology community. WikiPathways is a new database including and complementing databases such as KEGG, Reactome and Pathway Commons.
The pathways such as cell cycle, G1 to S cell cycle control, cell cycle checkpoints, regulation of DNA replication, DNA replication, degradation of the extracellular matrix were upregulated; however, the pathways such as electron transport chain, oxidative phosphorylation, integrin mediated cell adhesion, the citric acid cycle and respiratory electron transport, adipogenesis, mitochondrial translation, fatty acid triacylglycerol and ketone body metabolism were downregulated. The WikiPathway analysis of the most affected pathways is shown in Table 3.
Discussion
Cancers occur as a consequence of accumulation of genetic aberrations. Almost every neoplasm has its own unique molecular changes. Characterization of these changes is extremely important in matters of clinical care and the development of personalized treatment strategies.
Laryngeal carcinomas have been identified as aggressive tumors because of their high recurrence and metastasis rate. The first step for regional recurrence and distant metastasis is the deterioration of the extracellular matrix components. Matrix metalloproteinases (MMP) are a family of enzymes that play a key role in this process. Overexpression or dysregulation of these enzymes is known to be related to various types of cancer [6]. Krecicki et al. demonstrated strong immunoreactivity of MMP1 in 36(72%) of 50 laryngeal squamous cell carcinoma cases using immunohistochemical methods [7]. Liu et al. reported a difference in MMP12 expression between tumor and normal tissues, also metastatic and non-metastatic tumors [8]. Kallikrein-related peptidase 6 (KLK6), a member of the serine protease family, is involved in cellular processes such as the degradation of the extracellular matrix in a similar way to MMP. In a study of 162 patients with head and neck tumors, KLK6 overexpression was detected in 42.6% of the cases [9,10]. In addition, it has been shown in many cancers, including LSCC carcinoma, that overexpression of the ITGA6 gene, which is involved in cell-cell and cell-matrix interactions, is also effective in tumor invasion and metastasis [11,12]. Similarly, laminin, which is encoded by the LAMC2 gene, which plays a role in cell differentiation, migration and metastasis, was found to be overexpressed in squamous laryngeal cancer cases by microarray technique [13]. We also detected upregulated expression in the MMP1, MMP12, KLK6, LAMC2 and ITGA6 genes in all of our cases.
S100 proteins are one of the components of the Epidermal Differentiation Complex and are known to be related with skin diseases and human cancers, including squamous cell laryngeal cancer, lung, ovarian, renal, colorectal, skin and gastric carcinomas. In the study by Tyszkiewicz et al., while S100A1 and S100A4 genes were down-regulated, S100A2, S100A3, S100A4 and S100A11 genes were found to be significantly up-regulated in 93 cases of head and neck cancer. In our study, we determined that, S100A2 and S100A3 genes were upregulated in all cases [14].
CK14, CK16, KRT17 and KRT6 genes, encoding members of the keratin family, are responsible for the structural integrity of epithelial cells. Lauriola et al. reported that CK 14 expression difference was detected in 54 of 62 laryngeal carcinoma cases by immunocytochemistry, and this expression was strictly associated with S100A2 [15]. Elazezy has shown that keratin 16 overexpression might be related to more aggressive breast cancer [16]. Khanom R. et al. demonstrated that KRT6 and KRT17 were overexpressed in oral squamous cell carcinoma (OSCC) cell lines [17].
CEP55 (centrosomal protein 55kDa) has been identified as a tumor-associated antigen that functions as a regulator in the PI3K/AKT pathway. Its upregulation has been shown to be associated with poor prognosis in various neoplasms [18]. In a study of laryngeal squamous cell carcinoma cases, expression of CEP55 was found to be increased in early and advanced stages of the tumor [19]. Our results also support the oncogenic role of CEP55 in the development of LSCC. IL1F9 (interleukin 1 family, member 9) activates the NF-kappa B and PI3K pathways. As a result of this pathways’ activation, cell growth, differentiation and cell survival increase, while apoptosis is suppressed [20]. PI3K pathway is upregulated in over 90% of head and neck carcinoma cases [21].
In recent years, the Glut-1 protein, encoded by the SLC2A1 gene, has become more and more popular in cancer research areas. Starska et al. observed that SLC2A1 gene expression was upregulated in 83% of 106 laryngeal carcinoma cases and it was associated with poor prognosis [22]. Another study showed that an increase in SLC2A1 gene expression was observed in 30 of 38 head and neck carcinoma patients [23]. In our study, SLC2A1 gene expression was significantly increased, compatible with the literature. TP63, P53 tumor suppressor gene homolog, is highly expressed in various cancers, including laryngeal squamous cell carcinoma [24].
The effect of the genes mentioned above on the etiology of laryngeal cancer has been previously shown in the literature. Although genes including VSNL1, CXCL1, COL4A5, COL4A6, FSCN1, KRT6B, KRT17, WDR66, ACOT7, ITM2A and CFD were known to be altered in other human cancers, they have not been described before in laryngeal squamous cell carcinoma.
Type IV collagen protein plays an important role in migration and adhesion. Therefore, degradation of type IV collagen is related to cancer progression, invasion and metastasis. In a study with colorectal cancer patients, a loss of expression of COL4A5 and COL4A6 was observed due to promoter hypermethylation of genes [25]. Additionally, in well-differentiated esophageal squamous cell carcinoma specimens, the increased expression of COL4A5 and COL4A6 was found [26]. Similarly, FSCN1 (fascin homolog 1) gene encodes a protein that participates in cell migration, motility, adhesion and cellular interactions. Overexpression of FSCN1 causes metastasis of certain types of cancers, via increasing cell motility [27]. Also, increased expression of FSCN1 was detected in 129 cases of oral and oropharyngeal carcinoma [28].
VSNL1 (Visinin-like protein-1) has been identified as a tumor suppressor in a study of esophageal cancer cases, in contrast to a neuroblastoma study, which described it as an oncogene. In addition, VSNL1 can be used as a marker for Alzheimer’s disease and some other neurodegenerative diseases [29,30]
The encoded protein by CXCL1(C-X-C motif chemokine ligand 1) gene takes part in inflammation and acts as a chemoattractant for neutrophils. It is also known that this gene has a tumorigenic, mitogenic and angiogenic effects. Abnormal expression of the protein is associated with the development and progression of melanomas [31]. Also, ACOT7(acyl-CoA thioesterase 7) gene participates in the development of several types of neoplasms including melanomas. ACOT7 upregulation is also associated with poor prognosis in acute myeloid leukemia cases [32,34].
WDR66(WD repeat-containing protein 66) is a large family of proteins involved in various pathways like signal transduction, apoptosis, cell cycle control, transcription regulation and autophagy [35]. Studies have found that WDR66 is overexpressed in gastric carcinoma, thyroid, lung and esophagus carcinomas, and it has been emphasized that these proteins may be tumor markers for these cancers [36,38].
The role of ITM2A in the cellular compartment and in tumorigenesis is currently unknown. However, Nguyen et al. showed that the expression of ITM2A was decreased in cancerous ovarian tissues, and this was interpreted as that this protein might function as a tumor suppressor [39]. CFD has an anti-inflammatory effect through the complement system pathway. Ye H et al. detected decreased CFD gene expression in tongue squamous cell carcinoma cases [40].
In this study, an analysis of expression-altering genes and their pathway analysis were performed. The cell cycle and extracellular matrix degradation pathways were over-represented, while the electron transport chain pathway was under-represented. All affected pathways are shown in Table 3.
Conclusion
We have identified several differentially expressed genes and described their functions in the cell and the affected pathways in laryngeal squamous cell carcinoma. These genes may be used as new biomarkers for diagnosis, prognosis and therapy of LSCC. It is also believed that these genes will shed light on the studies that we wish to do in the future.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: Financial support was provided by the Scientific Research Projects of the Necmettin Erbakan University (Project Number: 151518008).
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Emine Göktaş, Kayhan Öztürk, Ayşe Gül Zamani, Mahmut Selman Yıldırım. Determination of whole-genome expression differences in larynx cancers. Ann Clin Anal Med 2023;14(Suppl 1):S31-36
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A 6-year analysis of cardiovascular implantable electronic device-related endocarditis
Hasan Erdem 1, Sibel Doğan Kaya 2
1 Department of Cardiovasculer Surgery, 2 Department of Infection Disease, University of Health Sciences Kartal Koşuyolu Research and Training Hospital, İstanbul, Turkey
DOI: 10.4328/ACAM.21612 Received: 2023-01-23 Accepted: 2023-03-15 Published Online: 2023-03-23 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S37-40
Corresponding Author: Hasan Erdem, Department of Cardiovasculer Surgery, University of Health Sciences Kartal Koşuyolu Research and Training Hospital, Kartal, İstanbul, Turkey. E-mail: herdemkvc@hotmail.com P: +90 532 393 77 87 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0825-6505
This study was approved by the Clinical Research Ethics Committee of Health Sciences University, Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital (Date: 2020-04-20, No: 2020-3/03-296)
Aim: Advances in interventional cardiology have increased the frequency of use of devices such as cardiovascular implanted electronic devices (CIED) used in cardiac arrhythmias. Endocarditis due to these devices increases morbidity and mortality.
Material and Methods: Demographic data, laboratory tests, results of blood cultures, transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) data of 48 patients who developed infective endocarditis due to CIED in our hospital between January 1, 2013 and March 1, 2019 were retrospectively analyzed.
Results: A total of 48 patients were included in this study. The ratio of females (n=24) and males (n=24) was equal. The mean age of all patients was 55 years. In the surviving patients, in order of frequency of occurrence, hypertension (HT) was in 13 patients (86%), chronic renal failure (CKD) in 9 patients (47%), and diabetes mellitus (DM) in 8 patients (72%). Of the patients who died, 10 (52%) had CRF, 3 (27%) had DM, 2 (66%) had HT and chronic obstructive pulmonary disease (COPD). The most common symptoms in surviving patients were, respectively, fever in 26 (78%), malaise in 19 (76%), respiratory distress in 11 (61%). The most common symptoms in deceased patients were respiratory distress in 7 (%38), fever in 7 (21%), fatigue in 6 (%24); 14 (29%) of the patients referred to our clinic started antibiotic treatment at an external center. Growth was detected in 26 (54%) of all blood cultures. The most frequently isolated pathogens were, respectively, Staphylococcus aureus (n=11) 42%, Streptococcus spp.(n=6) 23%, Enterococcus faecium (n=4) 15%, Citrobacter spp. (n=2) 7%, Diphtheroid spp.(n=1) 3%, Acinetobacter baumannii (n=1) 3%, Brucella mitis (n=1) 3%. Vegetation was observed on the lead in 13 (27%) performed TTEs and/or TEEs. From the time of diagnosis, the average time of surgery was 6 days in surviving patients and 11 days in patients who died.
Discussion: The number of studies and cases related to endocarditis due to CIEDs is limited in our country. Although CIED-related endocarditis is a rare complication of cardiac device implantation, its morbidity and mortality remain high.
Keywords: Lead Endocarditis, Cardiac Implantable Electronic Device, Pacemaker
Introduction
CIEDs are used in the treatment of symptomatic bradycardia and heart failure in patients at risk of sudden cardiac death due to ventricular arrhythmia.
The total number of CIEDs implanted per 1 000 000 people per year is 247. With the aging of the population, it is predicted that these devices will be implanted more and more in our country, as in the whole world [1]. In our country, a total of 22 732 CIEDs were implanted in 2016, 9993 of which were permanent pacemakers, 3485 cardiac resynchronization therapy devices and 9254 were ICDs (available at: https://www.escardio.org/static_file/Escardio/Subspecialty/ EHRA/Publications/Documents/2017/ehra-white-book-2017.pdf.). The Duke criteria are used in the diagnosis of infective endocarditis (IE) due to CIED, vegetations are seen on device wires, adjacent endocardial surfaces or on the valve, but the presence of vegetation only at the tip of the wire can be considered as IE.
It is difficult to diagnose cardiac device-related IE. If a patient with a cardiac device has an unexplained fever, infective endocarditis should be considered first [2]. CIED-associated infective endocarditis accounts for 10-23% of all CIED-related infections. Among all infective endocarditis cases, the rate of those associated with CIED is 10% both in our country and in the world. Although it is recommended to continue the IV antibiotic treatment for at least 2 weeks after the device removal, if the blood culture positivity continues in the first 24 hours after device removal, this period should be extended to 4 weeks [3-5].
Material and Methods
We retrospectively analyzed 48 patients who were followed up in our hospital with the diagnosis of CIED-related endocarditis between January 1, 2013 and March 1, 2019. Patient demographics, TTE/TEE, laboratory findings, causative pathogens and surgical approaches were examined. Ethical approval numbered 2020-3/03-296 and dated 20.04.2020 was obtained from the Non-Interventional Clinical Research Ethics Committee of the Health Sciences University Kartal Kosuyolu Yuksek Ihtisas Training and Research Hospital.
Statistics
Descriptive statistics (mean, median, standard deviation, etc.) were used while summarizing continuous numerical variables. Two-group comparison of numerical variables was analyzed with the Mann-Whitney U test. The statistical significance limit was taken as p<0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The ratio of female and male patients was equal, and the mean age was 55±14.6 years. Mortality developed in 3 (17%) female patients and 9 (38%) male patients. The mean age of the patients living with CIED was 53±11.4 years, and the mean age of the patients who died was 64±12.2 years. The median length of hospital stay was 31.5 (29.0-33.0) days in patients who survived, and 29.5 (28.0-33.5) days in patients who died. The most common symptoms in surviving patients were, respectively, fever in 26 (78%), fatigue in 19 (76%) patients, respiratory distress in 11 (61%) patients. Among those who died, respiratory distress was present in 7 (38%), fever in 7 (21%), and fatigue in 6 (24%) patients (Table 1).
HT, COPD, and obesity were found to be statistically significant (p=0.208, 0.150, 0.150). When comorbid factors were taken into account, the underlying disease was significantly higher in those who died (p=0.012). In the surviving patients, in order of frequency of occurrence, hypertension (HT) was in 13 patients (86%), chronic renal failure (CKD) in 9 patients (47%), and diabetes mellitus (DM) in 8 patients (72%). Of the patients who died, 10 (52%) had CRF, 3 (27%) had DM, and 2 (66%) had HT and Chronic Obstructive Pulmonary Disease (COPD) (Table 2).
Of the 48 patients followed up with CIED infection, 14 (29.1%) were referred from external centers. In these patients, antibiotics were started before blood cultures were taken. Growth was detected in the blood cultures of 26 (54%) patients.
The isolated pathogens, in order of frequency of occurrence, were Staphylococcus aureus (n=11) 42%, Streptococcus spp.(n=6) 23%, Enterococcus faecium (n=4)1%1, Citrobacter spp. (n=2) 7%, Diphtheroid spp.(n=1) 3%, Acinetobacter baumannii (n=1) 3%, and Brucella mitis (n=1) 3%.
Of the patients who were followed up with CIED, 33 (68%) were patients with natural valves and 15 (31%) were patients with prosthetic valves. Considering the valve involvement of vegetation, 9 (18%) patients had aortic valve involvement, 8 (16%) patients had mitral valves, and 1 (2%) patient had a tricuspid valve. In TEE and/or TTE performed on the patients, vegetation on the lead was detected in 13 (27%) patients. Serum leukocytosis was present in 16 (70%) of the surviving patients and 7 (30%) of the deceased patients (p = 0.311). C-reactive protein (CRP) was found to be higher than 20 mg/dl in 27 (80%) of the survivors and in 7 (20%) of the patients who died (p= 0.019). There were 9 (19%) patients with a laboratory value of procalcitonin greater than 1 (ng/ml), and 5 (55%) of these patients died.
For various reasons, 25 out of 48 people (52%) received antibiotics before the examples of blood cultures were taken. The start of antibiotic therapy in the preliminary diagnosis of CIED infection was 41 hours in living patients and 9.9 hours in deceased patients. In these patients, one of the problems in the treatment was lead removal, which was removed by two different methods. The CIEDs we applied to 19 patients (39%) in our study were removed percutaneously. Instruments and techniques such as transvenous manual traction, locking stylet, rotational mechanical dilator sheath systems and traps have been used. The surgical method was applied in 29 (60%) patients.
Surgery
The mediastinum was reached by median sternotomy under general anesthesia. The patient was heparinized and, after bicaval cannulation of the aorta, cardiopulmonary bypass (CPB) was initiated. The aorta was cross-clamped and cardiac arrest was achieved with warm blood cardioplegia. Then, the inner surface of the right atrium was reached by right atriotomy, the infected and thrombosed lead was examined and removed from the atrium and ventricular wall with sharp and blunt dissections. If there was an additional cardiac problem, an intervention was performed. A temporary intracardiac pacemaker was implanted in all patients when exiting CPB. From the time of diagnosis, the average time of surgery was 6 days in surviving patients and 11 days in patients who died.
Discussion
In a study conducted by Osmonov et al. in our country, in a retrospective study of CIED-related IEs that developed within 31 years in a single center, 23 (0.38%) of 5287 patients with CIED were reported to develop IE [6]. When Aksoy et al. examined the main differences in the characteristics and management of IE between both sexes in their 11-year follow-up study of patients with endocarditis, response to antibiotic therapy, need for surgical treatment, surgical intervention rate, and the overall in-hospital mortality were similar in both genders [7-9]. In our study, the ratio of female and male patients was equal. However, among surviving patients, women were more common (21 (87.5%), and among those who died, men were more common (9 (37.5%)). In the study by Bloom et al., the risk factors most commonly associated with endocarditis were diabetes mellitus and chronic kidney disease [10,11]. In our study, HT was detected in 13 (86%) patients, chronic renal failure in 9 patients (47%), and DM in 8 patients (72%), in order of frequency in surviving patients. Of the patients who died, 10 (52%) had CRF, 3 (27%) had DM, 2 (66%) had HT and COPD.
In the study by Massoure et al., 51-80% of 155 patients had a fever, and 68-92% had bacteremia [12]. In a multicenter study by Sohail et al., in 177 patients, fever and chills were found in 55.3%, vegetation in 67.6%, and positive blood cultures in 34.5% [13]. In our study, the most common symptoms in surviving patients were, respectively, fever in 26 (78%), fatigue in 19 (76%) patients, respiratory distress in 11 (61%) patients. Among those who died, respiratory distress was present in 7 (38%), fever in 7 (21%), and fatigue in 6 (24%) patients.
In the study conducted by Sohail et al., blood cultures were positive in 77%, vegetation in 67.6%, and positive blood cultures consistent with endocarditis in 34.5% of patients who were thought to have cardiac device-related infection [13]. Consistent with other studies, blood culture positivity was found to be 54% in our study. In these patients with the preliminary diagnosis of fever of unknown origin, antibiotics were started before blood cultures were taken.
In the study by Rundstrom et al., CRP elevation was observed in 73% to 100% of patients with pacemaker endocarditis and in 34% to 81.8% of leukocytosis cases [14]. In our study, 16 (70%) of the surviving patients and 7 (30%) of the deceased patients had serum leukocytosis. C-reactive protein (CRP) was found to be higher than 20mg/dl in 27 (80%) of the survivors and 7 (20%) of the patients who died. Staphylococci and especially coagulase-negative Staphylococci account for 60-80% of cases. Polymicrobial infection, Corynebacterium spp., Propionibacterium acnes, Gram-negative bacilli and Candida spp. are rarely identified as pathogens in CIED infection [15]. In our study, the most frequently isolated pathogens were Staphylococcus aureus (n=11) 42% and Streptococcus spp (n=6) 23%, Enterococcus faecium (n=4) 1%, Citrobacter spp (n=2) 7.6%, Diphtheroid spp (n=1) 3.8%, Acinetobacter baumannii (n=1) 3%, Brucella mitis (n=1) 3%.
The role of echocardiography is very important in the diagnosis of cardiac device-related IE. Echocardiography helps detect electrode vegetation and tricuspid valve involvement and quantify tricuspid regurgitation [14]. In the multicenter study by Athan et al., fever, vegetation and positive blood culture were high (>80%). In this study, the sensitivity of TTE was low, vegetations were visualized in 30.4% of the patients [16]. In our study, consistent with other studies, vegetation on the lead was observed on ECHO and/or TTE in 13 (27%) patients.
In the majority of patients with cardiac device-associated IE, device removal is required with prolonged administration of antibiotics [14]. In most patients, the lead can be removed percutaneously without the need for surgical intervention. However, if the cardiac device was placed several years ago, percutaneous electrode removal becomes difficult. In such cases, surgical intervention is recommended in the presence of severe tricuspid valve endocarditis and in patients with large vegetations [17]. In our study, 29 (60%) patients underwent surgical treatment.
The 30-day mortality rate for CIED infection is 5-8%. Female gender is a high-risk factor for endocarditis. Successfully treated patients have the same prognosis as patients who have never been infected [18]. In our study, 21 women survived (87%), 3 died (17%), and 15 (62%) male patients survived, 9 died (38%).
Conclusion
In our country, studies and the number of cases of endocarditis related to CIEDs are limited. Although endocarditis from CIEDs is a rare complication of cardiac device implantation, its morbidity and mortality remain high.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Sohail RM, Wilson W, Baddour LM. Infections of nonvalvular cardiovascular devices. In: Bennett JE, Dolin R, Blaser MJ, editors. Mandell, Douglas, and Bennett’s Principles and Practice of In¬fectious Diseases. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015. p.1041-56.
2. Habib G, Hoen B, Tornos P, Thuny F, Prendergast B, Vilacosta I, et al. Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009): the Task Force on the Prevention, Diagnosis, and Treatment of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Society of Chemotherapy (ISC) for Infection and Cancer. Eur Heart J. 2009;30(19):2369-413.
3. Tarakji KG, Ellis CR, Defaye P, Kennergren C. Cardiac implantable electronic device infection in patients at risk. Arrhythm Elect¬rophysiol Rev. 2016; 5(1):65-71.
4. Durante-Mangoni E, Casillo R, Bernardo M. High-dose dap¬tomycin for cardiac implantable electronic device-related infecti¬ve endocarditis. Clin Infect Dis. 2012; 54(3): 347-54.
5. Tascini C, Bongiorni MG, Di Cori A, Di Paolo A, Polidori M, Tagliaferri E, et al. Cardiovascular imp¬lantable electronic device endocarditis treated with daptomycin with or without transvenous removal. Heart Lung. 2012; 41(6):24-30.
6. Osmonov D, Ozcan KS, Erdinler I, Altay S, Yildirim E, Turkkan C, et al. Cardiac device-related endocarditis: 31-years’ experience. J Cardiol. 2013; 61(2):175-80.
7. Aksoy O, Meyer LT, Cabell CH, Kourany WM, Pappas PA, Sexton DJ. Gender differences in infective endocarditis: pre- and co-morbid conditions lead to different management and outcomes in female patients. Scand J Infect Dis. 2007;39(2):101-7.
8. Aksoy O, Sexton DJ, Wang A, Pappas PA, Kourany W, Chu V, et al. Early surgery in patients with infective endocarditis: a propensity score analysis. Clin Infect Dis. 2007;44(3):364–72.
9. Castillo JC, Anguita MP, Delgado M, Ruiz M, Mesa D, Romo E, et al. Clinical characteristics and prognosis of infective endocarditis in women. Rev Esp Cardiol English Ed. 2008;61(1):36-40.
10. Bloom H, Heeke B. Renal insufficiency and the risk of infection from pacemaker or defibrillator surgery. Pacing Clin. Electrophysiol. 2006;29(2):142-5.
11. Lekkerkerker JC, van Nieuwkoop C. Risk factors and time delay associated with cardiac device infections: Leiden device registry. Heart. 2009;95(9):715-20.
12. Massoure PL, Reuter S, Lafitte S. Pacemaker endocarditis: clinical features and management of 60 consecutive cases. Pacing Clin Electrophysiol. 2007;30(1):12-19.
13. Sohail MR, Uslan DZ, Khan AH. Infective endocarditis complicating permanent pacemaker and implantable cardioverter-defibrillator infection. Mayo Clin Proc. 2008;83(1):46-53.
14. Rundstrom H, Kennergren C, Andersson R, Alestig K, Hogevik H. Pacemaker endocarditis during 18 years in Goteborg. Scand J InfectDis 2004; (36): 674-79.
15. Villamil CI, Rodriguez FM, Van den Eynde CA, Jose V, Canedo RC. Permanent transvenous pacemaker infections: An analysis of 59 cases. Eur J Intern Med. 2007;18(6):484-8.
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17. Ruttmann E, Hangler HB, Kilo J, Höfer D, Müller LC, Hintringer F. Transvenous pacemaker lead removal is safe and effective even in large vegetations: an analysis of 53 cases of pacemaker lead endocarditis. Pacing Clin Electrophysiol. 2006;29(3):231-6.
18. Chung EH. European Consensus Document on Cardiac Implantable Electronic Device. American College Cardilogy. 2020;(43):4946–56.
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Hasan Erdem, Sibel Doğan Kaya. A 6-year analysis of cardiovascular implantable electronic device-related endocarditis. Ann Clin Anal Med 2023;14(Suppl 1):S37-40
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Does the level of serotonin and catecholamine metabolites affect the severity of hyperemesis gravidarum?
Ece Sinaci 1, Sinem Ertas 2, İsik Kaban 3
1 Department of Women’s Health, Acibadem Taksim Hospital, 2 Department of Women’s Health and IVF, VKV American Hospital, 3 Department of Women’s Health and IVF, İstanbul Research and Training Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21613 Received: 2023-01-24 Accepted: 2023-02-25 Published Online: 2023-02-28 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S41-44
Corresponding Author: Sinem Ertas, Department of Women’s Health and IVF, VKV American Hospital, 34365, Sisli, Istanbul, Turkey. E-mail: drsinemertas@gmail.com P: +90 535 921 40 60 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1699-616X
This study was approved by the Ethics Committee of Istanbul Research and Training Hospital (Date: 2019-09-11, No: 2019)
Aim: Hyperemesis gravidarum (HG) affects most pregnant women and its etiology is unclear. This study investigates the effect of serotonin and catecholamine metabolite levels on hyperemesis gravidarum severity.
Material and Methods: The study was designed as a prospective observational cohort study with 90 pregnant women who applied to the Gynecology and Obstetrics Clinic between September 2019-January 2020. Women between 18 and 42 years of age were divided into three groups; the first group (Group 1) included women diagnosed with severe hyperemesis gravidarum requiring hospitalization, and the second group (Group 2) included women with hyperemesis gravidarum not requiring hospitalization. The third group (Group 3) included healthy pregnant women in the first trimester. The criteria for hospitalization were ketone positivity in urinalysis and intolerance to oral nutrition. The primary outcome of our study was to examine any difference between groups in terms serotonin, adrenaline, dopamine, metanephrine, noradrenaline, and normetanephrine levels.
Results: A total of 90 women were included; severe HG (Group 1) (n=30), mild HG (Group 2) (n=30) and control (Group 3) (n=30). There was no statistically significant difference between the three groups regarding demographic features. Dopamine values were lower in Group 1 and Group 2 than in the control group (19.5 ±10.6 pg/mL; 16.3 ± 11.1 and 30.8 ±12.9, respectively, the Kruskal-Wallis test p<0.001).
Discussion: In this study, dopamine levels were significantly lower than in the control group. Our study may be useful to elucidate the etiology of HG; however, future studies are needed with a large sample size.
Keywords: Hyperemesis Gravidarum, Serotonin, Catecholamine, Dopamine
Introduction
Hyperemesis gravidarum (HG) is characterized by severe nausea and vomiting in early pregnancy, mostly resulting in maternal nutritional deficiency [1]. Maternal undernutrition has a close relationship with adverse pregnancy outcomes. It is still unclear how HG affects the baby. Throughout history, pregnant women have suffered from HG, and this disease’s incidence varies from country to country [1]. Currently, nausea with or without vomiting is expected in early pregnancy, and HG is the most common indication for hospitalization during the first trimester [2]. In addition, HG has an uncertain etiology and is a significant cause of dehydration, acid-base imbalance, ketonuria, and electrolyte imbalances in early pregnancy [3].
The pathogenesis of HG has not yet been elucidated in detail. However, psychological factors, hormonal changes, abnormal gastrointestinal motility, Helicobacter pylori, nutrient deficiencies (e.g., zinc), changes in lipid levels, autonomic changes in the nervous system, genetic factors, and immunological dysregulation are the suggested theories of pathogenesis [4].
The vomiting center in the dorsal part of the Medulla oblongata, named the ‘chemoreceptor trigger zone,’ is located at the base of the 4th ventricle. It stays outside the blood-brain barrier [5]. This region is sensitive to emetic stimulation of serotonin, dopamine, and its derivative molecules, such as adrenaline and noradrenaline [6, 7] . It is suggested that the serotonin level increases in pregnant women with HG. In addition, 5HT3 receptors are associated with nausea and vomiting, and 5HT3 receptor blockers are used to treat this disorder [8]. On the other hand, there is no study investigating the blood levels of catecholamines and their metabolites in pregnant women with hyperemesis gravidarum. In this study, we aimed to examine whether serotonin and catecholamine levels affect the severity of hyperemesis gravidarum.
Material and Methods
This study was conducted in a prospective observational cohort design in the Gynecology and Obstetrics Clinic between September 2019 and January 2020. The local Ethics Committee approved the study (date: 2019-09-11 number: 2019). All patients gave written informed consent for participation. Women between 18 and 42 years of age were divided into three groups; the first group (Group 1) included women diagnosed with severe hyperemesis gravidarum requiring hospitalization, and the second group (Group 2) included women with hyperemesis gravidarum not requiring hospitalization. The third group (Group 3) included healthy pregnant women in the first trimester. The criteria for hospitalization were ketone positivity in urinalysis and intolerance to oral nutrition. The primary outcome of our study was to examine any differences between groups in terms of serotonin, adrenaline, dopamine, metanephrine, noradrenaline, and normetanephrine levels.
Women were recruited if they did not have any known chronic disease (liver, kidney, heart, hypertension and diabetes etc.), autoimmune disorders; malignancy; multiple pregnancies; the presence of fetal chromosomal and structural anomalies; evidence of active or chronic infection; placental abnormalities.
Gestational age was estimated from the first day of the last menstruation period and/or by first-trimester ultrasonography.
Venous blood samples of the patients were collected early in the morning from their antecubital veins after 12 hours of fasting and before any treatment, food intake, or intravenous solution administration.
Statistical analysis
SPSS 26.0 program was used for the statistical analysis of the data in this study. In the descriptive statistics of the data, mean, standard deviation, median lowest, highest, frequency and ratio values were used. The distribution of variables was measured with the Kolmogorov- Smirnov test. ANOVA (Tukey test), Kruskal-Wallis, and Mann-Whitney U tests were used to analyze independent quantitative data. The Chi-square test was used in the analysis of independent qualitative data, and the Fischer test was used when chi-square test conditions were not met. Statistically, the p-value was taken as <0.05 for a significant difference.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 90 pregnant women with a mean week of gestation of 8.9 ± 2.5 were included in the study. Three groups, each consisting of 30 women, were studied: severe HG (Group 1), mild HG (Group 2), and healthy control groups (Group 3). The mean age of the patients was 29.2±5.7 years in the severe HG group, 28.4± 5.6 years in the mild HG group and 27.1±5.6 years in the control group. There were no statistically significant differences between the groups in terms of gravida, parity, gestational week, or body mass index (Table 1).
The mean dopamine level was 19.5±10.6 ng/ml in the severe HG group, 16.3±11.1 ng/ml in the mild HG group, and 30.8±12.9 ng/ml in the control group. Significant differences in dopamine levels were found between severe HG/control groups and mild HG/control groups (p values < 0.05 for all) (Table 2). The mean metanephrine level was 23.1±8.3 ng/ml in severe HG group, 27.5±10.2 ng/ml in mild HG group, and 22.3±8.5 ng/ml in the control group. Significant differences in metanephrine levels were found between mild HG/severe HG groups and mild HG/control groups (p-values < 0.05), there is no statistically significant difference between severe HG and control groups. The mean TSH level was 0.94±0.54 IU/mL in the severe HG group, 1.06±0.52 IU/mL in the mild HG group and 1.73±1.08 IU/mL in the control group. This result also shows that gestational hyperthyroidism is associated with HG.
Discussion
In the study, we compared the levels of serotonin and catecholamine metabolites in the blood of pregnant women with hyperemesis gravidarum (HG) with the control group. In addition, we analyzed hyperemesis in pregnant women in two groups: severe and mild.
In the study, dopamine values were significantly lower in the hyperemesis gravidarum groups compared to the control group. Metanephrine, an adrenaline metabolite, was slightly higher in the group with nausea and vomiting compared to the control group; but also higher in mild HG than severe HG group (p=0.048). In this study, although mean serotonin levels were higher in the hyperemesis group compared to the control group, it did not reach statistical significance. Few studies investigated the relationship between serotonin levels and hyperemesis gravidarum, but the results are debatable. Borgeat et al. studied serotonin levels by measuring a urinary metabolite of serotonin (hydroxy indole acetic acid) in pregnant women with HG and the control group [9]. No differences in the urinary excretion of serotonin metabolites were noted between the groups. Therefore, the authors concluded that HG was not associated with increased serotonin secretion. In another study, HG group had significantly higher plasma levels of serotonin compared to the control group, and a positive correlation was observed between serotonin levels and the severity of HG [10].
The most prominent finding in our study was the significantly lower dopamine level of pregnant women with HP. There are few data in the literature comparing the dopamine or other catecholamine levels of pregnant women with HG and healthy control groups. Dopamine is a molecule of the catecholamine family, a precursor of catecholamines (adrenaline and noradrenaline), and is associated with multiple physiological functions [11]. Together with its five receptor subtypes, dopamine is closely linked to neurological disorders such as depression, attention deficit–hyperactivity, restless leg syndrome, schizophrenia, Parkinson’s disease [12]. Dopamine receptors, especially D2 and D3 receptors, play a role in the pathophysiology of nausea and vomiting. Dopamine receptor antagonists (e.g. metoclopramide) such as serotonin receptor antagonists (eg Ondansetron) reduce nausea and vomiting and are used in the symptomatic treatment of women with HG [13]. In our study, an association was found between low dopamine blood levels and HG. Still, it is not known whether this is a cause or effect relationship and which pathophysiological or biochemical processes are associated with HP. Further studies are needed to explain the mechanism of low dopamine levels in pregnant women with hiperemesis gravidarum.
In addition, among other laboratory data in the study, thyroid-stimulating hormone levels were found to be decreased in pregnant women with hyperemesis. We concluded that this is due to transient hyperthyroidism during pregnancy [14, 15].
When evaluating the findings of our study, it is important to note the limitations of our study, such as the relatively small sample size, and the subjective diagnosis of hyperemesis. We think that the findings of our study should be supported by further studies. In conclusion, the pathophysiology of HG has not been clarified, more molecular and biochemical studies are needed in this regard on this topic.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Nijsten K, Jansen LA, Limpens J, Finken MJ, Koot MH, Grooten IJ, et al. Long-term health outcomes of children born to mothers with hyperemesis gravidarum: a systematic review and meta-analysis. Am J Obstet Gynecol. 2022;22(3):414-29.
2. Fejzo MS, Trovik J, Grooten IJ, Sridharan K, Roseboom TJ, Vikanes Å, et al. Nausea and vomiting of pregnancy and hyperemesis gravidarum. Nat Rev Dis Primers 2019;5(1):1-17.
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5. Obermeier B, Verma A, Ransohoff RM. The blood–brain barrier. Handb Clin Neurol 2016;133:39-59.
6. Eklund I, Larsson A-S, Gustafsson S, Forsberg A. Patients’ experiences of pain and postoperative nausea and vomiting in the early postoperative period after an elective knee arthroplasty. J Perianesth Nurs 2020;35(4):382-8.
7. Gan TJ, Belani KG, Bergese S, Chung F, Diemunsch P, Habib AS, et al. Fourth consensus guidelines for the management of postoperative nausea and vomiting. Anesth Analg. 2019;131(2):411-8.
8. Sridharan K, Sivaramakrishnan G. Interventions for treating hyperemesis gravidarum: a network meta-analysis of randomized clinical trials. J Matern Fetal Neonatal Med. 2020;33(8):1405-11.
9. Borgeat A, Fathi M, Valiton A. Hyperemesis gravidarum: is serotonin implicated? Am J Obstet Gynecol. 1997;176(2):476-7.
10. Cengiz H, Dagdeviren H, Caypinar SS, Kanawati A, Yildiz S, Ekin M. Plasma serotonin levels are elevated in pregnant women with hyperemesis gravidarum. Arch Gynecol Obstet. 2015;291(6):1271-76.
11. Speranza L, di Porzio U, Viggiano D, de Donato A, Volpicelli F. Dopamine: The neuromodulator of long-term synaptic plasticity, reward and movement control. Cells. 2021;10(4):735.
12. Belkacemi L, Darmani NA. Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function. Pharmacol Res. 2020;161:105124.
13. Abramowitz A, Miller ES, Wisner KL. Treatment options for hyperemesis gravidarum. Arch Womens Ment Health 2017;20(3):363-72.
14. Malek NZH, Kalok A, Hanafiah ZA, Shah SA, Ismail NAM. Association of transient hyperthyroidism and severity of hyperemesis gravidarum. Horm Mol Biol Clin Investig. 2017;30(3): 1-6.
15. Fernández MG. Hyperthyroidism and pregnancy. Endocrinol Nutr. 2013;60(9):535-43.
Download attachments: 10.4328.ACAM.21613
Ece Sinaci, Sinem Ertas, İsik Kaban. Does the level of serotonin and catecholamine metabolites affect the severity of hyperemesis gravidarum? Ann Clin Anal Med 2023;14(Suppl 1):S41-44
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Evaluation of depression, anxiety, stress, and decision regret in kidney transplant recipients
Serkan Akinci 1, Naile Akinci 2
1 Department of Urology, Memorial Bahcelievler Hospital, 2 Department of Nursing, Faculty of Health Sciences, Fenerbahce University, Istanbul, Turkey
DOI: 10.4328/ACAM.21618 Received: 2023-01-26 Accepted: 2023-03-02 Published Online: 2023-03-14 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S45-50
Corresponding Author: Serkan Akinci, Department of Urology, Memorial Bahcelievler Hospital, 34180, Bahçelievler, Istanbul, Turkey. E-mail: dr.s.akinci@gmail.com P: +90 212 408 45 45 / +90 530 458 94 32 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5213-5324
This study was approved by the Clinical Research Ethics Committee of Fenerbahçe University (Date: 2020-12-15, No: 2020/46)
Aim: This study aimed to evaluate decision regret, depression, anxiety, and stress scores in patients after kidney transplantation as well as the effects of patient characteristics on these variables.
Material and Methods: This descriptive study enrolled 340 individuals who underwent kidney transplantation in a private hospital in Istanbul between January 2017 and February 2021. The study sample comprised 302 individuals who volunteered to participate in the study and met the inclusion criteria. The Patient Information Form, Depression, Anxiety, and Stress Scale (DASS 21), and Decision Regret Scale were used as data collection tools.
Results: Mean depression, anxiety, stress, and decision regret scores were 2.454 ± 3.427, 2.589 ± 2.881, 1.825 ± 2.073, and 18.311 ± 20.123, respectively. Notably, these scores increased with an increase in age, and they were higher in single individuals, unemployed patients, nonbelievers, and those with chronic renal failure for a longer duration. Furthermore, depression, anxiety, and stress scores increased with increasing time after transplantation. In the present study, depression, stress, anxiety, and decision regret scores were significantly higher in patients who received transplants from their children.
Discussion: The results of this study indicate that certain personal and clinical characteristics of kidney transplant recipients may affect depression, anxiety, stress, and decision regret after translation. Increasing the existing knowledge of such patients can minimize the risk of adverse effects of transplantation, including both somatic and psychological effects.
Keywords: Transplant Recipients, Depression, Anxiety, Stress, Kidney Failure
Introduction
Kidney transplantation is recognized as the best renal replacement therapy for end-stage renal disease. Moreover, successful kidney transplantation significantly improves the survival and quality of life of such patients [1]. Although it is considered one of the life-saving treatment options for patients with end-stage renal failure, it may negatively affect the psychological, social, and physical well-being of the patient [2, 3]. A previous study reported that depression, anxiety, and stress are common in patients after transplantation; moreover, psychiatric morbidity is high in such patients [4].
According to the latest data from the Turkish Society of Nephrology, until the end of 2020, the number of kidney transplant recipients who were being followed up for functional grafts was 5021 in Turkey; of these, only 21.55% (1121) received cadaveric transplants. This can lead to serious consequences, including psychological, relational, and social changes, for both the patient and their families. Accordingly, kidney transplant recipients may become susceptible to depression and anxiety [5-7].
In the relevant literature, studies on the psychological health of kidney transplant recipients are limited. Although studies involving kidney donors generally report that the donors do not regret their decision, 1%–10% of the donors report feeling pressured, being dissatisfied, or regret about their decision to donate their kidneys and exhibit subsequent changes after kidney donation surgery [5-7]. To the best of our knowledge, no studies in the relevant literature have evaluated decision regret in kidney transplant recipients and the associated factors. Therefore, in this study, we aimed to evaluate depression, anxiety, stress, and decision regret in kidney transplant recipients.
Material and Methods
Purpose and type of research
This descriptive study was conducted to determine decision regret, depression, anxiety, and stress scores after kidney transplantation, as well as the effects of patient characteristics on these variables.
Population and sample of the study
This study enrolled 340 people who underwent kidney transplantation in a private hospital in Istanbul between January 2017 and February 2021, and the sample comprised 302 people who volunteered to participate in the study and met the inclusion criteria.
Inclusion and exclusion criteria
Patients who underwent kidney transplantation, who exhibited no mental or auditory disability that could affect learning for ≥6 months after kidney transplantation, who had no history of psychiatric disorders, who voluntarily agreed to participate in the study, and who had no problems in speaking and understanding Turkish were included in the study. In contrast, those whose donors were lost to follow-up during the study period or were on dialysis, those whose graft was nonfunctional, those who had ≥2 kidney transplants, and cross-transplant patients were excluded from the study.
Data collection tools
The Patient Information Form, Depression, Anxiety, and Stress Scale (DASS 21), and Decision Regret Scale were used as data collection tools in this study.
Patient Information Form
Patient Information Form was developed by the researcher based on the relevant literature. This form comprises nine questions (those related to age, gender, marital status, educational status, employment status, duration of chronic renal failure (CRF), time of kidney transplantation, the identity of the donor, and religious beliefs).
Depression, Anxiety, and Stress Scale (DASS-21)
DASS-21 was developed by Lovibond and Lovibond (available at: https://psycnet.apa.org/doiLanding?doi=10.1037%2Ft01004-000). The scale comprises 21 questions. To measure the dimensions of depression, stress, and anxiety, there are seven questions in each dimension. The Turkish validity–reliability study of this scale was conducted by Yilmaz et al. [8]. Cronbach’s alpha coefficients for DASS-21 subscales were as follows: DASS-Depression α = 0.82, DASS-Anxiety α = 0.80, and DASS Stress α = 0.75.
Decision Regret Scale (DRS)
DRS was developed by Brehaut et al. [9]. The Turkish validity-reliability study of the scale was conducted by Çetin (available at: https://docplayer.biz.tr/20399058-Canli-vericiden-karaciger-nakli-sonrasi-vericinin-ruhsal-ve-bedensel-sagliginin-arastirilmasi.html), [10]. In this 5-point Likert-type scale, the items are scored as 1, “Strongly agree”; 2, “Agree”; 3, “Neither agree nor disagree”; 4, “Disagree”; and 5, “Strongly disagree.” The scores range between 0 and 100. Higher scores indicate higher levels of decision regret. Notably, Cronbach’s alpha coefficient of the Decision Regret Scale was found to be 0.868.
Ethical Considerations
Ethical Aspects of Research
Institutional permission was obtained from the private hospital where the study was conducted, and ethics committee permission was obtained from Fenerbahçe University Clinical Research Ethics Committee on December 15, 2020 (2020/46). This study was conducted in accordance with the principles of the Declaration of Helsinki. Written and verbal consent was obtained from individuals who volunteered to participate in the study.
Statistical analysis
The data obtained in this study were evaluated using SPSS v 22.0 on a computer. Frequency and percentage analyses were used to determine the descriptive characteristics of the participants, and numerical variables were presented as mean and standard deviation. Moreover, kurtosis and skewness values were analyzed to determine whether the research variables were normally distributed. Since the variables exhibited a normal distribution, parametric methods were used to analyze the data.
Relationships between the dimensions determining the scores of the participants were examined using Pearson correlation analyses. Furthermore, T-test, one-way analysis of variance, and post hoc (Tukey, LSD) analyses were used to examine the differences in scale scores in terms of the descriptive characteristics of the participants.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The study sample comprised 302 individuals who volunteered to participate in the study and met the inclusion criteria. Of all participants, 191 (63.2%) were male and 111 (36.8%) were female. A total of 211 (69.9%) participants were single and 91 (30.1%) participants were married. Table 1 shows the descriptive characteristics of the participants and differences in depression, anxiety, stress, and decision regret scores according to the descriptive characteristics.
Table 2 shows mean depression, anxiety, stress and decision regret scores according to clinical features and religious beliefs.
Table 3 shows mean depression, anxiety, stress and decision regret scores according to the relationship between donors and recipients. Figure 1 shows mean depression, anxiety and stress scores. The mean decision regret score was 18.311±20.123.
In correlation analysis, anxiety was significantly correlated with depression (r=0.742, p<0.001). Stress was significantly correlated with depression (r=0.605, p<0.001) and anxiety (r=0.737, p<0.001). Decision regret was significantly correlated with depression (r=0.539, p<0.001), anxiety (r=0.523, p<0.001) and stress (r=0.497, p<0.001).
Discussion
In the present study, the mean depression, anxiety, and stress scores were 2.454 ± 3.427, 2.589 ± 2.881, and 1.825 ± 2.073, respectively. Since the highest score that can be obtained from a DASS-21 subdimension is 21, it can be inferred that the depression, anxiety, and stress scores of the individuals participating in the present study were low. This finding may be explained by the fact that transplantation improves the quality of life after the recipient’s persistent and exhausting struggle against the disease and that the role of the recipient requires not only tolerance and patience to somatic discomfort, but also overcoming the associated emotional burden from diagnosis to transplantation. Similarly, in the studies by Pawlovski et al. [10]
and Czyżewski et al. [11] it was determined that depression, anxiety, and stress scores of patients were low after transplantation. In contrast to the present study, in a previous study by Uyar [3], in 260 transplant recipients, depression, anxiety, and stress scores were slightly above the average, whereas Perveen et al. [12] reported that depression and anxiety were observed in >50% of the included patients. This difference may be attributed to variations in study designs and sample populations.
In the present study, the post-transplant mean decision regret score in kidney transplant recipients was 18.311 ± 20.123 (Min = 0; Max = 95). This result revealed that the participants did not regret their decision at all. To the best of our knowledge, there are no similar studies on recipients in the relevant literature; however, studies involving kidney donors have reported that donors do not regret their decision after transplantation and that they would make a similar decision if they had to. This result can be explained by the positive recipient-donor relationship, appropriate pre-transplant procedures, no encounter with the risk of rejection after surgery, regular follow-up by the transplantation team, provision of rapid solution to problems occurring during transplantation, and the dialysis period and associated problems coming to an end.
Regarding the analysis of sociodemographic characteristics and depression, anxiety, stress, and decision regret scores, it was observed that the scores increased with an increase in age, whereas there was no change in terms of gender and education level. This finding may be attributed to the increase in the incidence of chronic diseases with age, the difficulty in managing the post-transplant process, and increased burden on caregivers. The depression, anxiety, stress, and decision regret scores of married participants were significantly lower than those of single participants (p<0.05). This may be explained by the fact that married people have more support factors; therefore, they can share more burdens of post-transplant difficulties. Regarding employment status, it was found that anxiety, depression, stress, and decision regret scores of unemployed participants were significantly higher than those of employed participants (p<0.05). This can be explained by the fact that employed people have social security, are economically independent, productive, and can socialize more in the work environment. In the literature related to the present study, different findings have been reported. Similar to the results of our study, Bingöl et al. [13] found that depression increased with an increase in age. Doğan et al. [14] found that women and self-employed individuals had higher depression, anxiety, or stress scores. These results may be attributed to sociocultural differences and different transplant management approaches. In the present study, decision regret, depression, stress, and anxiety scores increased with the increasing duration of CRF. Furthermore, Demiroğlu and Bülbül [15] found that depression, anxiety, and stress scores increased as the duration of CRF increased.
In the present study, the stress scores of non-believers were higher than those of believers, which may be associated with fatalism.
In the present study, depression, stress, anxiety, and decision regret scores were found to be significantly higher in patients receiving the transplant from their children than in all other groups (p<0.05). This can be explained by the concern for the health, future, and safety of one’s children in relation to surgery and the cultural perspective that protecting one’s child is a parental duty. The second highest level of decision regret was observed in patients who received the transplant from their siblings (p<0.05). In contrast, depression, anxiety, stress, and decision regret scores were significantly lower in patients receiving transplants from friends and cadavers than in patients in other groups (p<0.05). This result may be attributed to concerns about the health, future, and safety of one’s own children related in relation to the surgery. Similarly, another study by Chen et al. [16] found that depression scores were higher in patients who received transplants from their children compared with those in other groups. This finding may be explained by an increase in feelings of guilt as donor-receiver relationship improves.
Correlation analyses between depression, anxiety, stress, and decision regret scores revealed a moderate correlation between depression, anxiety, and decision regret and a weak correlation between stress and decision regret. This can be explained by the fact that both variables are related to the psychological nature of human beings; hence, they may be intertwined processes affecting each other.
Limitations
The study sample comprised only patients who underwent kidney transplantation in a private hospital. Therefore, the results of this study cannot be generalized to all patients.
Conclusion
Based on the results of the study, it is recommended to increase clinicians’ awareness of the complex psychosocial issues in kidney transplantation, to psychologically assess both the recipient and donor in the pre-transplant period and to include this as a routine pre-transplant procedure, and to take the necessary measures for the problems encountered. By increasing the current level of knowledge of patients, the risk of adverse effects of transplantation can be minimized, including both somatic and psychological effects.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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4. Grubman-Nowak M, Jeżewska M, Szafran-Dobrowolska J, Ślizień AD, Renke M. Occupational Activity After Renal Transplantation vs Quality of Life, Personality Profile, and Stress Coping Styles. Transplant Proc. 2020;52(8):2423-29.
5. De Pasquale C, Pistorio ML, Veroux M, Indelicato L, Biffa G, Bennardi N, et al. Psychological and Psychopathological Aspects of Kidney Transplantation: A Systematic Review. Front Psychiatry. 2020;11:106.
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7. Han Y, Kong Y, Peng S, Wang X. Current Effect of attribution training on early postoperative depression of kidney transplant recipients. Current Psychology. 2022;41:5383–98.
8. Yılmaz Ö, Boz H, Arslan A. Depresyon Anksiyete Stres Ölçeğinin (DASS-21) Türkçe Kısa Formunun Geçerlilik Güvenilirlik Çalışması (The Validity and Reliability Study of the Turkish Short Form of the Depression Anxiety Stress Scale (DASS-21)). Finans Ekonomi ve Sosyal Araştırmalar Dergisi/Journal of Finance, Economics and Social Studies. 2017;2(2):78-91.
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Serkan Akinci, Naile Akinci. Evaluation of depression, anxiety, stress, and decision regret in kidney transplant recipients. Ann Clin Anal Med 2023;14(Suppl 1):S45-50
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The role of the HEART score in the discharge of patients admitted to the emergency department with chest pain
Burcu Doğan 1, Nezih Kavak 2 , Seval Komut 1, Safiye Terzi 3, Engin Deniz Arslan 4
1 Department of Emergency Medicine, Hitit University, Erol Olçok Training and Research Hospital, Çorum, 2 Department of Emergency Medicine, University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, 3 Department of Emergency Service, Kırıkkale Yüksek İhtisas Hospital, Kırıkkale, 4 Department of Emergency Medicine, Antalya Training and Research Hospital, Antalya, Turkey
DOI: 10.4328/ACAM.21622 Received: 2023-01-27 Accepted: 2023-03-02 Published Online: 2023-03-11 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S51-55
Corresponding Author: Burcu Doğan, Department of Emergency Medicine, Hitit University, Erol Olçok Training and Research Hospital, 19000, Çorum, Turkey. E-mail: burcudogan.dr@gmail.com P: +90 532 162 78 85 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1379-7832
This study was approved by the Ethics Committee of University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital (Date: 2018-12-17, No: 57/02)
Aim: In this study, we aimed to determine the incidence of major adverse cardiac events within 6 weeks after discharge of patients admitted to the emergency department (ED) with chest pain and a HEART score of 0-3, and to determine the role of the HEART score in the discharge decision of low-risk patients for acute coronary syndrome from the ED.
Material and Methods: Out of 625 patients admitted to the ED with chest pain, 200 patients with a HEART score of 0-3 were included in the study.
Results: Of the 200 patients included in the study, 199 (99.5%) were discharged from the ED, and 1 patient (0.5%) prediagnosed with unstable angina pectoris was hospitalized in the coronary intensive care unit of an external center. The patient did not undergo angiography in the coronary intensive care unit and was discharged after 24 hours of observation. Angiography was performed in 3 (1.5%) of 199 patients discharged from the ED and was recommended in 1 patient (0.5%) who refused it. Coronary artery disease was detected in 1 of 3 patients who underwent angiography, but a stent was not placed. The angiography results of 2 patients were evaluated as normal. No major adverse cardiac events were seen in any of the 200 patients (0%) at the end of the 6-week follow-up period.
Discussion: The HEART score can guide the emergency physicians in making decisions about the discharge of patients admit to ED with chest pain and at low risk of developing an acute coronary syndrome.
Keywords: Chest Pain, Acute Coronary Syndrome, Risk Score
Introduction
Chest pain is one of the most common reasons for admission to emergency departments (ED). 13-25% of patients with chest pain have acute coronary syndrome (ACS) [1, 2]. ACS is a clinical spectrum with high morbidity and mortality, so early diagnosis and intervention are important for physicians [1, 2]. The diagnosis of ACS in patients with significant ST segment and T wave changes or typical changes in cardiac markers on electrocardiography (ECG) is easy, but difficult without significant change in ECG and cardiac markers. Difficulty in diagnosis can cause problems such as unnecessary investigation, prolonged hospital stay, increased health workload and costs [3].
ED physicians use guidelines for the management of patients with chest pain. The ACC/AHA (American College of Cardiology/American Heart Association) guideline recommends patients with suspected ACS be classified as low, intermediate or high risk; treatment and discharge decisions are made according to this classification [4].
The HEART score was developed by AJ Six, BE Backus, and JC Kelder to classify patients admitted to ED with chest pain as low, moderate, and high risk for having a short-term major adverse cardiac event (MACE), including acute myocardial infarction (AMI), percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) and death, and to specify low-risk patients who can be discharged early from ED [5]. The HEART score has five variables: history, ECG, age, risk factors, and troponin. For each parameter, patients are scored between 0-2 and the total value is 10. Patients with a HEART score of 0–3 are considered low risk, 4-6 intermediate risk and 7–10 high risk. The HEART score was developed based on clinical experience and literature, so it is easier to use in ED compared to other prediction rules. The score can guide emergency physicians for discharge decision of low-risk patients for ACS from ED [3]. The study aimed to determine the incidence of MACE within 6 weeks after discharge of patients admitted to the ED with chest pain and a HEART score of 0-3, and also to determine the role of the HEART score in discharge decisions of low-risk patients for ACS.
Material and Methods
This study is a prospective observational study and was carried out in the emergency department of the University of Health Sciences Dışkapı Yıldırım Beyazıt Training and Research Hospital between December 18, 2018 and January 19, 2019. The study was approved by the Ethics Committee of University of Health Sciences, Dışkapı Yıldırım Beyazıt Training and Research Hospital (Date: 2018-12-17, No: 57/02).
Patients over 18 years of age who admitted to the ED with chest pain, with suspected ACS, who had a HEART score of 0-3, who agreed to participate in the study, and signed a consent form were included in the study. Patients with a significant ST segment elevation on the ECG and requiring urgent invasive intervention, patients with shortness of breath, dizziness, tachycardia, and arrhythmia, with hemodynamic instability, using digoxin and not agreeing to participate in the study were excluded.
Patients’ age, gender, nature of chest pain (characteristics, location, time of onset, whether chest pain persists, duration, spread area), additional symptoms, ECG findings, risk factors (obesity, hypertension, diabetes mellitus, hyperlipidemia, previous MI, cerebrovascular disease, peripheral arterial disease, PCI and CABG history) and troponin levels were evaluated. The HEART score was calculated.
HEART Score Calculation
In the history, factors, described above as the nature of chest pain for assessing typical or atypical chest pain for ACS, were questioned.
Pain in the left hemithorax or retrosternal area, spreading to the left arm or back, accompanied by autonomic symptoms such as nausea, vomiting and sweating, and lasting between 5 and 20 minutes or longer was classified as typical and scored 2 points. If the history was not compatible with typical pain and ACS was not suspected, pain was classified atypical and given 0 points. One point was given if the patient’s pain had characteristics of both typical and atypical pain and increased suspicion for ACS. The history parameter was collected in 3 groups: highly, moderately, and slightly suspicious (Table 1).
MI, PCI, CABG, and sudden cardiac death were defined as MACEs. Patients included in the study were called 6 weeks after discharge by the investigators to learn whether they had MACE or not and, if so, to identify the event.
Statistical analysis
The SPSS 17.0 (for Windows) package program was used for data analysis. The findings obtained from the data form were demonstrated by frequency analysis. The homogeneity of data distribution was evaluated with the Kolmogorov-Smirnov test. The Mann-Whitney U test was used to compare the two groups. The Kruskal-Wallis H test was used for multi-group comparisons. P<0.05 was considered statistically significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Of the 200 patients included in the study, 109 (54.5%) were male and 91 (45.5%) were female. The mean age of the patients was 38.93+11.72 (min. 18-max. 75); 101 patients had stinging chest pain, which was the most common (50.5%) type of pain. The most common location of pain was the left hemithorax in 106 (53%) patients. No spread of pain was described in 116 (58%) patients. There were no additional symptoms in 158 (79%) patients. At the time of admission, 144 patients (72%) stated that they had pain, and 56 patients (28%) stated that they had no pain (Table 2).
History of 35 (17.5%) patients was evaluated as highly suspicious, 59 (29.5%) as moderately suspicious, and 106 (53%) as slightly suspicious. ECG of 122 patients (61%) was normal, 73 patients (36.5%) had nonspecific repolarization anomalies in ECG and 5 patients (2.5%) had significant ST segment depression or T wave inversion.
Obesity, chronic disease history, family history of coronary artery disease, and smoking were questioned as risk factors. Twelve patients (6%) were obese, 69 (34.5%) patients had a family history of coronary artery disease, 99 (49.5%) patients were current smokers and 53 patients (26.5%) had chronic diseases. One hundred twenty-six (63%) patients had 1 or 2 risk factors and 17 patients (49.5%) had 3 or more risk factors. Two (1%) patients’ troponin levels increased in the range of 1-3
times the normal limit.
When the HEART score points were evaluated, 5 (2.5%) patients received 0 points, 41 (20.5%) patients received1 point, 66 (33%) patients received 2 points, and 88 (44%) patients received 3 points (Table 3).
By gender (p=0.409), smoking (p=0.094), the spread of pain (p=0.637), symptoms accompanying chest pain (p=0.625), ECG findings (p=0.558) and troponin levels (p=0.140) subgroups, there was no statistically significant difference for the HEART score (p>0.05). Age (p<0.01), obesity (p=0.045), chronic disease history (p=0.008), family history of coronary artery disease (p=0.035), character (p<0.01) and location of chest pain (p=0.049) are the parameters, which have a statistically significant difference between subgroups for the HEART score (p<0.05).
The HEART score had a statistically significant difference between the age groups (p<0.01). Positive correlation between age and the HEART score was found. The HEART score increased as age increased. Patients with obesity had a higher HEART score than those without obesity, and this difference was significant statistically (p=0.045). Furthermore, the HEART score was different between chronic disease history subgroups, and the difference was statistically significant (p<0.008). Patients with PCI and CABG surgery history had the highest HEART scores, while patients with hypercholesterolemia patients the lowest. The HEART score of patients with a family history of coronary artery disease was found to be higher which was statistically significant (p=0.035). The HEART score was higher in patients with pressure, squeezing and burning chest pain than with stinging chest pain (p<0.01).
Patients with epigastric pain had the highest HEART scores, followed by retrosternal, left hemithorax, diffuse, and right hemithorax pain, respectively, and the difference was statistically significant (p=0.049).
Only 1 (0.5%) of 200 patients included in the study, prediagnosed with unstable angina pectoris was hospitalized in the coronary intensive care unit of the external center and 199 patients (99.5%) were discharged from the ED. In the patient hospitalized in the coronary intensive care unit, it was confirmed that no angiography was performed and the patient was discharged after 24 hours of observation.
Angiography was performed in 3 patients (1.5%) after discharge. Coronary artery disease was diagnosed in 1 patient (0.5%), but no stent was placed. Angiography results were normal in 2 patients (1%). Angiography was recommended to 1 patient (0.5%), but the patient refused it. No MACE developed during the follow-up of the patients included in the study.
Discussion
This study aims to determine the incidence of MACEs after discharge of patients admitted to the ED with chest pain and at low risk for ACS, and also to evaluate the role of the HEART score in the discharge decision of these patients. The most important result of the study is the low incidence of MACEs in the low-risk patient group. This study is remarkable because, to the best of our knowledge, it is the first study on this subject in our country.
Chest pain is one of the most common causes of admission to EDs worldwide, as in our country [6,7]. The diagnosis of ACS in patients who have chest pain and significant ST-segment elevation, ST-segment depression, or elevated cardiac markers is easy; however, some patients have no changes in their ECG or cardiac markers [5,9]. Dustin et al. reported that 1–4% of patients without ECG or cardiac marker changes were diagnosed with significant coronary artery disease on angiography [8]. A missed diagnosis of ACS will result in patients being discharged inappropriately and having MACEs, an increase in inappropriate health practices and physicians facing legal consequences. Jain et al found that the rate of discharge of patients from the ED, despite the presence of ACS, was 2–4%, and the 30-day mortality was as high as 9.1% in this group [10].
Guidelines recommend risk stratification for the management of patients with suspected ACS. It is thought that missed diagnosis rate of ACS decreases over time with different assessment strategies, such as prediction rules for risk classification, and this rate varies between 2-10% [11, 12]. Mahler et al. found that missed diagnosis rate in patients discharged using a prediction rule was <0.05% [13].
The ideal prediction rule for EDs should reliably and effectively identify all patients at low risk for ACS or MACE and they can be discharged safely [2,14].
The HEART score was developed for risk stratification in patients admitted to ED with chest pain [15,16]. In the first published study on the HEART score, the incidence of MACEs was 2.5% in patients with a HEART score of 0-3, and it was stated these patients could be discharged from ED [16]. Similarly, in another study, patients with a HEART score of 0-3 were found to be at low risk for ACS, the incidence of MACEs was 0.99%, and it was mentioned that patients with a HEART score of 0-3 could be discharged from ED early [3].
Similar to initial results, in different studies, the incidence of MACEs has been found to be 0.6-2.5% in patients at low risk. Based on these results, regardless of the cause of chest pain, the HEART score has been reported to have good to excellent efficacy in distinguishing patients at risk of developing MACEs in EDs [3,5,13]. As a result of this study, patients admitted to the ED with chest pain and having a HEART score between 0-3 developed no MACE after discharge. In a survey of 1029 clinicians who participated, 41% stated that <1% and 56.8% stated that missed diagnosis rate of 0.5% could be accepted [17]. In an article published in our country in 2018, this rate was reported as <1% [16].
The HEART score may have an advantage for clinicians that ECG findings are scored in three categories and non-specific ST segment anomalies are classified in a separate group, which is important to avoid missing non-specific ECG anomalies and to reduce missed diagnosis.
Another important advantage of the HEART score is the reduction of costs and economic burden on the health system. Poldervaart et al. found that the HEART score was more cost-effective than the traditional clinical approach [18]. In terms of reducing costs the HEART score does not need a specific kit for troponin measurement. There may be slight differences between various troponin measurements in hospitals, but this does not cause a significant difference in the HEART score results [16].
On the other hand, as advantages there are controversial aspects of the HEART score, such as evaluation of history and ECG may differ on interpretation. Different interpretations of history and ECG will result in a HEART score lower or higher than it should be [16].
Studies have shown that the HEART score was calculated lower by cardiologists compared to emergency physicians and higher by senior physicians compared to less experienced physicians for patients at the border for low and moderate risk [19,20].
In order to prevent bias in this study while evaluating history and ECG, parameters of history were questioned with options in data collection form, and also history parameters and ECG findings were evaluated by a single investigator.
While using the HEART score, ED physicians should be cautious of patients with unstable angina pectoris (USAP). USAP diagnosis is based on the history, so these patients have a low-risk HEART score, and this may result in missed diagnosis and inappropriate discharges [16].
Another issue observed during this study is that the HEART score may be calculated higher inappropriately because laboratory parameters such as kidney function tests and complete blood count, which can affect troponin levels, are not part of the score. Also, many non-cardiac conditions with troponin elevation should be kept in mind [21].
Despite the evaluation of patients with chest pain using the HEART score, some patients with ACS have only angina-like or unusual symptoms. The HEART score is unable to evaluate these patients.
Conclusion
The HEART score may guide emergency physicians in the decision-making process to discharge patients at low risk for ACS. Clinical prediction rules are not perfect and only useful to guide physicians, like the HEART score, which has its own advantages and disadvantages. Physicians should make a final decision by combining clinical evaluation, risk score, and laboratory results.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Tintinalli J, Ma OJ, Yealy D, Meckler G, Stapcyznski J, Cline D, et al. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide. USA: McGraw Hill Medical Books; 2016. p.332-48.
2. Markel D, Marill KA, Schmidt A. Identifying emergency department patients with chest pain who are at low risk for acute coronary syndromes. Emerg Med Pract. 2017;19(7):1-24.
3. Backus BE, Six AJ, Kelder JC, Mast TP, Akker F, Mast G, et al. Chest pain in the emergency room: a multicenter validation of the HEART score. Crit Pathw Cardiol. 2010;9(3):164-9.
4. Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes. Circulation. 2014;130(25):2354-94.
5. Six AJ, Backus BE, Kelder JC. Chest pain in the emergency room: value of the HEART score. Neth Heart J. 2008;16(6):191-6.
6. Başol N, Çığşar G, Atalay E, Can S, Günal E, Özdemir MT, et al. The role of emergency physicians on the management of chest pain. Journal Of Contemporary Medicine. 2016;6(1): 30-4.
7. Leung YK, Cheng NM, Chan CP, Lee A, Wong JK, Yan BP, et al. Early exclusion of major adverse cardiac events in emergency department chest pain patients: a prospective observational study. J Emerg Med. 2017;53(3):287-94.
8. Mark DG, Huang J, Chettipally U, Kene MV, Anderson ML, Hess EP, et al. Performance of coronary risk scores among patients with chest pain in the emergency department. J Am Coll Cardiol. 2018;71(6):606-16.
9. Reaney PDW, Elliott HI, Noman A, Cooper JG. Risk stratifying chest pain patients in the emergency department using HEART, GRACE and TIMI scores, with a single contemporary troponin result, to predict major adverse cardiac events. Emerg Med J. 2018;35(7):420-27.
10. Jain T, Nowak R, Hudson M, Frisoli T, Jacobsen G, McCord J. Short- and Long-Term Prognostic Utility of the HEART Score in Patients Evaluated in the Emergency Department for Possible Acute Coronary Syndrome. Crit Pathw Cardiol. 2016;15(2):40-5.
11. Chang AM, Fischman DL, Hollander JE. Evaluation of chest pain and acute coronary syndromes. Cardiol Clin. 2018;36(1):1-12
12. Newman-Toker DE, Wang Z, Zhu Y, Nassery N, Tehrani AS, Achaffer AC, et al. Rate of diagnostic errors and serious misdiagnosis-related harms for major vascular events, infections and cancers: toward a national incidence estimate using the ‘Big Three’. Diagnosis (Berl). 2020;8(1):67-84.
13. Mahler SA, Hiestand BC, Goff DC Jr, Hoekstra JW, Miller CD. Can the HEART score safely reduce stress testing and cardiac imaging in patients at low risk for major adverse cardiac events? Crit Pathw Cardiol. 2011;10(3):128-33.
14. Jones ID, Slovis CM. Pitfalls in evaluating the low-risk chest pain patient. Emerg Med Clin North Am. 2010;28(1):183-201.
15. Sakamoto JT, Liu N, Koh ZX, Fung NX, Heldeweg MLA, Ng JC, et al. Comparing HEART, TIMI, and GRACE scores for prediction of 30-day major adverse cardiac events in high acuity chest pain patients in the emergency department. Int J Cardiol. 2016; 221:759-64.
16. Brady W, Souza K. The HEART score: A guide to its application in the emergency department. Turk J Emerg Med. 2018;18(2):47–51.
17. Than M, Herbertb M, Flawsc D, Cullend L, Hess E, Hollander JE, et al. What is an acceptable risk of major adverse cardiac event in chest pain patients soon after discharge from the Emergency Department? Int J Cardiol. 2013;166(3):752-4.
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Download attachments: 10.4328.ACAM.21622
Burcu Doğan, Nezih Kavak, Seval Komut, Safiye Terzi, Engin Deniz Arslan. The role of the HEART score in the discharge of patients admitted to the emergency department with chest pain. Ann Clin Anal Med 2023;14(Suppl 1):S51-55
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Relationship between perianal diseases and toilet habits
Burak Mustafa Durna 1, İsmail Hasırcı 2, Mehmet Eşref Ulutaş 2, Ayşe Can 3, Fatih Cemal Tekin 4, Sabri Özden 2, Kemal Arslan 2
1 Department of Family Physicion, University of Health Sciences, Konya City Hospital, 2 Department of General Surgery, University of Health Sciences, Konya City Hospital, 3 Department of Public Health, Faculty of Meram Medical, 4 Department of Emergency Medicine, University of Health Sciences, Konya City Hospital, Konya, Turkey
DOI: 10.4328/ACAM.21623 Received: 2023-01-28 Accepted: 2023-03-02 Published Online: 2023-03-11 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S56-61
Corresponding Author: İsmail Hasırcı, Department of General Surgery, University of Health Sciences, Konya City Hospital, 42100, Karatay, Konya, Turkey. E-mail: drihasirci@hotmail.com P: +90 332 221 00 00 / +90 505 319 84 69 F: +90 332 324 18 54 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8400-3361
This study was approved by the Ethics Committee of Health Sciences University Hamidiye Scientific Research (Date: 2021-09-17, No: 29/13)
Aim: In this study, we aimed to examine the relationship between perianal diseases and body mass index, smoking status, alcohol consumption, dietary and exercise habits, and toilet habits and to compare individuals with and without perianal diseases.
Material and Methods: This case-control study was conducted by administering a questionnaire to 280 individuals, 140 patients and 140 controls, who presented to the General Surgery Training Outpatient Clinic of Konya City Hospital for any reason between November 1, 2021, and January 1, 2022.
Results: Of the participants, 43.5% were female and 56.5% were male. While 70.7% of the participants were aged 18-55 years, 29.3% were aged 56 years and older. The rate of smokers was statistically significantly higher in the patient group than in the control group. Individuals who consumed fiber-rich foods every day were 0.279 times less likely to have perianal diseases than those who consumed high-fiber foods once a month. In addition, those consuming high-fiber foods several times a week were 0.049 times less likely to have perianal diseases than those consuming high-fiber foods once a month.
Discussion: Hemorrhoidal disease and anal fissure are common diseases that can be easily diagnosed and followed up in primary healthcare services. The most important step in the diagnosis of these diseases is anamnesis and physical examination, and sometimes inspection alone can be sufficient. Primary health care providers evaluating their patients with a biopsychosocial approach and making recommendations will significantly contribute to the quality of life of patients.
Keywords: Bowel Habits, Perianal Diseases, Predisposing Factors, Toilet Habits
Introduction
The most common perianal diseases (PADs) are hemorrhoidal disease, anal fissures, and perianal fistulas. Hemorrhoids occur when the cushions containing venous structures in the anal canal prolapse distally and undergo venous distension. Anal fissures are usually caused by midline ruptures distal to the dentate line. Anal fissures can be acute or chronic, and are often located in the posterior midline, sometimes anteriorly, and rarely laterally [1,2]. Perianal fistulas usually emerge in the acute phase of sepsis or within six months after the first treatment. These fistulas mostly originate from the infected crypt and pathways opening outward, usually from a previous site of drainage. Abscess drainage is effective in the treatment of approximately 50% of those with anorectal abscesses, with the remaining 50% developing persistent anal fistulas [3].
The normal defecation process is considered to have three components: spontaneous phasic rectal contractions that begin during filling (autonomic process), relaxation of the anal canal through an enlarged anorectal angle (mostly somatic process), and straining (somatic process). Disorders in these processes are thought to play a role in the emergence of PADs [4,5]. In addition, anal fissures and hemorrhoidal disease are affected by many environmental factors, such as constipation, dietary habits, obesity, pregnancy, psychosocial status, smoking, and alcohol consumption [6,7].
One of the parameters affecting the defecation process is the body position during defecation. The squatting position is common in Asian, African, and Eastern countries, and the sitting position is common in Western countries. The literature also indicates that the length of time spent in the toilet may be associated with PADs [2,5,8].
The determination of common sociodemographic characteristics in patients with PADs and the causes of these diseases can assist in the identification of risky individuals. This will help prevent PADs by changing the attitudes and behaviors of individuals while they are still healthy. Considering the physiological and psychosocial problems that PADs can cause individuals, it is extremely important to apply protective measures. In the current study, we aimed to compare individuals with and without PADs (hemorrhoidal disease and anal fissures) in relation to sociodemographic characteristics, body mass index (BMI), smoking status, alcohol use, constipation, presence of irritable bowel syndrome (IBS) and functional constipation (FC) diagnoses, and dietary, exercise, and toilet habits. With this study, we aimed to contribute to the literature in terms of the etiological data on PADs and the sociodemographic characteristics of this patient group.
Material and Methods
Ethical approval was obtained from the Health Sciences University Hamidiye Scientific Research Ethics Committee, with the decision numbered 29/13 taken at the meeting dated September 17, 2021, and numbered 2021/29.
This research was designed as a case-control study and was conducted using the questionnaire method with 280 individuals, 140 patients and 140 controls, who presented to the General Surgery Training Outpatient Clinic of Konya City Hospital from November 1, 2021, through January 1, 2022. The questionnaire was administered to the individuals who met the study criteria and agreed to respond to the face-to-face questionnaire.
The questionnaire consisted of a total of 51 questions presented in two sections. The first section included 30 questions concerning the participants’ sociodemographic characteristics, height-weight and BMI, smoking status, alcohol consumption habits, dietary and exercise habits, IBS and FC diagnoses according to the Rome IV criteria, and toilet habits. In the second section, the 21-item Beck Anxiety Inventory (BAI) was used to examine the psychiatric background of the patients. Before the administration of the data collection instrument, informed consent was obtained from all participants. The study was conducted in accordance with the principles of the Declaration of Helsinki.
The patient group consisted of individuals who presented to the outpatient clinic with the diagnosis of hemorrhoids and anal fissures. Perianal fistulas were excluded from the study because they mainly contain cryptoglandular abscesses in their etiology. Therefore, in this paper, the term “PADs” refers to both hemorrhoids and anal fissures.
The control group consisted of patients who presented to the outpatient clinic with other diagnoses (gallstones, multinodular goiter, breast disease, etc.) and were confirmed to have no history of hemorrhoidal disease or anal fissures. Patients with previous PADs were not included in the study. In addition, to reveal the effect of other factors, especially toilet habits in a more objective manner, patients with conditions that could increase intra-abdominal pressure or were caused by increased intra-abdominal pressure were excluded from the sample.
Statistical analysis
The statistical analysis of the data was performed using the SPSS v. 27.0 software package (IBM SPSS, Chicago, IL, USA). Numbers and percentages were used to summarize categorical data. The chi-square (χ2) test was used to demonstrate the relationship between categorical variables. A model was constructed using participants’ age, presence of IBS, presence of FC, frequency of fiber-high food consumption, duration of defecation, and toilet time to examine the effect of these variables on the presence of PADs. In the logistic regression analysis of this model, the Forward-LR method was used, and the Hosmer-Lemeshow test was conducted to examine the model fit. In all statistical tests, p < 0.05 was accepted as the significance level.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The study included a total of 280 individuals, 140 (50%) patients and 140 (50%) controls. Table 1 shows the comparison of the sociodemographic characteristics and general characteristics of the participants according to the presence of PADs. Bad habits, such as smoking and alcohol consumption status, of the participants were similar between the patient and the control groups (p > 0.05). The rate of individuals evaluated to have minimal anxiety using BAI was statistically significantly higher in the control group than in the patient group (p < 0.001).
In this study, there was no statistically significant difference between the patient and control groups in relation to the rate of individuals with occupations considered to be risky in terms of PAD development, namely farmers, drivers, students, and civil servants (p > 0.05).
Concerning dietary preferences, the rate of vegetarians was similar between the patient and control groups (p > 0.05, χ2 = 1.098). However, the rates of individuals with a daily consumption of high-fiber foods and those with a daily water consumption of two liters or more were found to be statistically significantly higher in the control group (χ2 = 52.142 and χ2 = 25.583, respectively; p < 0.001 for both). Lastly, the patient group had a significantly higher rate of individuals who did not walk regularly on a weekly basis (p < 0.001, χ2 = 17.367).
Numerical data and comparisons concerning the toilet habits of the participants are given in Table 2. The type of toilet preferred by the participants, position during defecation, cleaning method after defecation, and preferences related to the use of warm or cold water for cleaning were found to be similar between the patient and control groups (p > 0.05).
A model was created using age, presence of IBS, presence of FC, frequency of high-fiber food consumption, duration of defecation, and toilet time to determine risk factors that could have an effect on the development of PADs. It was determined that the established logistic regression model explained 71.0% of the disease status (Nagelkerke’s R squared = 0.710) and had an accuracy rate of 87.1% in identifying individuals with PADs (Table 3).
Discussion
In this study, there was a statistical difference between the groups with and without PADs according to gender, and this difference resulted from the significantly higher rate of women in the patient group. In addition, the rate of participants aged 18-55 years was statistically significantly higher in the patient group. In the literature, there are studies showing whether women or men are more likely to be diagnosed with PADs. Therefore, further studies with larger groups are needed on this subject. Consistent with our findings, previous researchers found that the rate of PADs was generally higher in individuals aged below 40 years and decreased after 65 years [9-12]. There are also publications reporting that low socioeconomic status and decreased physical activity may be associated with PADs, which supports our results. Despite the presence of publications indicating that some occupational groups constitute risk factors for PAD, we found no significant difference in relation to the occupation of the participants in our study. This can be attributed to the different working conditions of individuals with the same occupation or the effect of other confounding factors [9,11,13].
In contrast to previous research reporting a relationship between high BMI and the presence of PADs, we observed no significant difference between the patient and control groups in terms of BMI. This may be related to the generally high BMI values in our participants [14,15].
In this study, the rate of smokers was found to be significantly higher in the patient group with PADs. Although there is evidence in the literature showing that the rate of alcohol consumption is as high as the rate of smoking in PADs, we did not determine a relationship between alcohol consumption and the presence of PADs [11,16].
Concerning the relationship of PADs with FC and IBS, similar results have been reported in many studies. Our findings also revealed that the individuals with IBS were 3.324 times more likely and those with FC were 21,943 times more likely to have PADs than those without these conditions. We found no significant relationship between the toilet type and position and PADs in our study; however, the literature suggests that constipated individuals may have different defecation positions. It is known that constipation and functional bowel disease, which we also detected in our findings, are the causes of anal fissures and recurrent anal fissures, and that prolonged straining may trigger hemorrhoids [17-21].
In this study, important findings were found concerning the relationship between toilet habits and PADs. It was determined that the patients with PADs spent more than five minutes in the toilet for defecation. The rate of defecation less than three times a week was also significantly higher in the patient group. Although we determined that the most common preoccupations of the participants in the toilet were smoking and phone/tablet use, other toilet habits have also been reported in the literature, including reading books and newspapers, as well as smartphone use, especially among young people. Similar to our study, the literature contains evidence that time spent in the toilet is associated with PADs [11,20,22].
There are many studies examining the relationship of PADs with dietary habits and physical activity. It has been reported that high-fiber food consumption is protective against PADs, and increasing the amount of water consumed daily reduces the related symptoms. In our study, the individuals who consumed two liters or more of water per day were at a lower rate in the patient group. In addition, the individuals who consumed high-fiber foods every day were determined to be 0.279 times less likely to have PADs than those who consumed these foods once a month, and the individuals who consumed high-fiber foods a few times a week were 0.049 times less likely to have PADs than those who consumed these foods once a month. Similarly, we observed that the patient group included a lower number of individuals who walked regularly on a weekly basis, confirming the literature suggesting that physical activity accelerates food passage [19, 23].
Among our participants, the rate of those with minimal anxiety according to the BAI scores was statistically significantly higher in the control group than in the patient group. Many studies have reported a relationship between PADs and personality types, anxiety, and depression. Considering that IBS and constipation are also affected by anxiety and depression, the question is whether anxiety and depression are predisposing factors for PADs or cause PADs through these digestive disorders [6,7]. Regardless, it is clear that positive changes that help reduce anxiety will also produce positive results in PADs.
The small number of patients is an important limitation of our study. However, the strengths of our study include the diversity of the data we obtained and the evaluation of many factors. We consider that this study is an important step in terms of guiding further studies to be conducted with a larger number of patients.
Hemorrhoidal disease and anal fissures are problems experienced by many people of all ages. As primary healthcare providers are expected to diagnose these diseases and begin medical or conservative treatment. Considering that a significant portion of individuals with PADs have never attended a hospital, it is important for primary health care providers to evaluate the population they are responsible for in this respect. This depends on the proven predisposing factors and the follow-up of related symptoms and factors by primary healthcare providers.
Conclusion
We consider that our study will contribute to the literature by presenting factors that are effective in PADs and creating a model showing the importance of predisposing factors in the formation of these diseases. This model will assist primary health care providers in identifying which predisposing factor(s) to prioritize. This way, they can play an important role in reducing the prevalence of PADs by encouraging their patients to modify their dietary, exercise, and toilet habits through information and recommendations.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Download attachments: 10.4328.ACAM.21623
Burak Mustafa Durna, İsmail Hasırcı, Mehmet Eşref Ulutaş, Ayşe Can, Fatih Cemal Tekin, Sabri Özden, Kemal Arslan. Relationship between perianal diseases and toilet habits. Ann Clin Anal Med 2023;14(Suppl 1):S56-61
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Percentage of Human Chorionic Gonadotropin change in the forty-eight hours prior to methotrexate injection in predicting treatment success
Erhan Akturk 1, Murat Ibrahim Toplu 1, Cagdas Nurettin Emeklioglu 1, Tugba Salman 1, Fatma Nur Cetinkaya 1, Simten Genc 1, Arzu Yurci 2, Veli Mihmanli 1
1 Department of Obstetrics and Gynecology, Prof. Dr. Cemil Taşçıoğlu City Hospital, 2 Department of IVF and Reproductive Health Center, Bahcelievler Memorial Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21627 Received: 2023-01-30 Accepted: 2023-03-02 Published Online: 2023-03-06 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S62-66
Corresponding Author: Cagdas Nurettin Emeklioglu, Department of Obstetrics and Gynecology, Prof. Dr. Cemil Taşçıoğlu City Hospital, Sisli, Istanbul, Turkey. E-mail: c.n.emeklioglu@gmail.com P: +90 535 912 99 13 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1859-8680
This study was approved by the Ethics Committee of Prof. Dr. Cemil Taşçıoğlu City Hospital (Date: 2019-03-19, No: 1197)
Aim: Although many reports that examine the concentration of β-hCG are available, there is a limited number of articles in the literature about the dynamics of β-hCG. Our aim in this study was to reveal the role of β-hCG percentage change before methotrexate injection on predicting treatment success.
Material and Methods: This retrospective study was conducted between May 2015 and February 2019 at the gynecology department of a tertiary hospital. Medical data of patients who were diagnosed with tubal ectopic pregnancy were reviewed (n:1073). The percentages of β-hCG change between 48 hours before methotrexate injection and day 1 were compared between the failure and success groups. The ROC curve was designed to determine the optimal β-hCG change percentage to predict treatment success.
Results: Four hundred and thirty-four patients were eligible for methotrexate treatment. The median value of β-hCG percentage change before methotrexate injection was significantly higher in the failure group (+13.7(+9.04/+17.68)) compared to the success group (+8.62(+5.8/+11.5)) (p<0.001). The area under the curve was 0.727 with 95% CI(0,659-0,795) (p<0,01). With the cutoff value of 11.27%, sensitivity, specificity, PPV and NPV were 71,2%, 73,4%, 35% and 93%, respectively.
Discussion: Along with HCG concentrations, HCG dynamics should also be investigated as to whether it has a role in the prediction of methotrexate success. We think that utilizing β-hCG dynamics as an additional tool in the prediction of methotrexate treatment outcome should be considered in every case of tubal ectopic pregnancy.
Keywords: Tubal Ectopic Pregnancy, Methotrexate, Beta Human Chorionic Gonadotropin
Introduction
Ectopic pregnancy is encountered in 1-2% of all pregnancies and is accepted as a life-threatening emergency [1]. It is one of the most dangerous titles regarding maternal mortality in the first trimester of pregnancy [2]. Transvaginal ultrasound, along with serial beta-human chorionic gonadotropin (β-hCG) measurements and a high index of suspicion, is the most used tool to detect ectopic pregnancy to prevent adverse consequences.
The goal is an early treatment to prevent tubal rupture, internal hemorrhage and maternal morbidity. Methotrexate treatment is considered a feasible solution in meticulously selected cases [3]. Stovall’s “single dose protocol” is the most commonly preferred one among the methotrexate treatment protocols [4].
Treatment failure risk should be taken into account and cases must be selected appropriately. Presence of fetal cardiac activity, free peritoneal blood, size (>4 cm) of the ectopic mass, high (>5,000 mIU/mL) initial β-hCG concentration, increasing β-hCG concentrations (>50% in 48 hours) before methotrexate, rapid rise of hCG concentrations after methotrexate are the predictive factors for methotrexate failure [5-7]. The documented success rate of treatment in the “single dose protocol” is between 75,45% and 87% [8,9]. Serial β-hCG measurements before methotrexate treatment are efficient to discriminate actual ongoing ectopic pregnancies from spontaneously resolving ones [10]. Presumably, successive β-hCG measurements may detect spontaneous resolution in more than 60% of the cases [11].
Since β-hCG rise before methotrexate treatment might indicate trophoblastic tissue activity, we tried to delineate whether β-hCG percentage change can predict the methotrexate success or not. The role of β-hCG levels on day 1 and 48 hours prior to the methotrexate injection in predicting success was the secondary outcome. Finally, determining a percentage change cutoff value with optimal sensitivity and specificity to predict treatment success was our tertiary outcome.
Material and Methods
This retrospective study was conducted in accordance with the Principles of the Declaration of Helsinki and approved by our local ethics committee (Date: 2019-03-19, No: 1197). Between May 2015 and February 2019, 434 tubal ectopic pregnancy cases who had attended to our gynecology department were included in this study.
Medical data of women who were diagnosed with tubal ectopic pregnancy were reviewed (n:1073). Age, gravidity, parity, date of the last normal menstrual period, body mass index (BMI), day 1 β-hCG and β-hCG at 48 hours prior to the methotrexate injection of all eligible cases were recorded. Tubal ectopic pregnancy diagnosis had been established on both β-hCG level measurements and a transvaginal ultrasound indicating ectopic pregnancy via conforming an inhomogeneous mass next to the ovary, an extraovarian hyperechoic mass or an extrauterine gestational sac with a thin endometrium [12]. Patients presenting with hemodynamic instability, β-hCG levels above 10,000 IU, fetal pole with cardiac activity, severe abdominal pain, or signs of intra-abdominal haemorrhage had been treated surgically (n:238), so they were excluded. Cases that showed spontaneous resolution (n:370), and thirty- one subjects with insufficient data were also excluded. As a result, 434 cases were eligible for the study. Patients are were dievided into two groups according to methotrexate treatment outcome: success group and failure group. As a result, 361 subjects were in the success group, whereas 73 cases were in the failure group.
Single dose protocol had beenwas used in all cases at a dose of 50 mg/m2 [13]. Methotrexate administration day was defined as day 1, and β-hCG measurements were repeated on days 4 and 7 in an inpatient or outpatient setting. Treatment failure had beenwas defined as having symptoms of tubal rupture or β-hCG not falling more than 15% between days 4 and day 7. Treatment success had beenwas defined as recovery.
In this study, we aimed Our aim was to reveal the role of β-hCG percentage change before methotrexate injection oin predicting treatment success. The percentages of β-hCG change between 48 hours before methotrexate injection and day 1 were compared between the ‘failure group’ and the ‘success group’. The Eequation of β-hCG percentage change was as follows:
βhCG change (%)=(βhCG day 1-HCG 48 hours prior to injection)/(βhCG 48 hours prior to injection) x100
Additionally, success and failure groups were compared regarding to both the β-hCG level on day 1 and the β-hCG level 48 hours before methotrexate injection. A receiver-operating characteristic curve was designed to determine the optimal β-hCG level change for treatment success.
Statistical analysis
All analysis was performed using SPSS software (Statistical Package for the Social Sciences, version 25.0, SPSS Inc., Chicago, IL, USA). The Kolmogorov-Smirnov test was used to evaluate the eligibility of the data for normal distribution. Descriptive statistical methods were used to evaluate frequency, percentage, mean (standard deviation (SD)), median (25th and 75th percentiles) when appropriate. The Chi-square test was used for categorical variables. Student t- test was applied for normally distributed data and mean (standard deviation (SD)) was used as the descriptive statistical method. On the other hand, the Mann-Whitney U test was applied for non-normal data, and the median (25th and 75th percentiles) was used as the descriptive statistical method. Finally, a receiver-operating characteristic curve was utilizsed to establish the optimal cutoff value of β-hCG change with the highest sensitivity and specificity for treatment success. A p-P value of less than 0.05 was considered significant.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
In our study, there were 1073 subjects diagnosed with tubal ectopic pregnancy. Of these, 434 patients (40%) were eligible for methotrexate treatment after excluding subjects that got immediate surgery (n:238), those that resolved spontaneously (n:370) and those that had insufficient data (n:31) (Figure 1). Characteristics of variables in the treatment success and treatment failure groups are depicted in Table 1. Difference between the two groups regarding age, gravidity, parity, BMI and gestational week did not reach statistical significance. There was no significant statistical difference regarding day 1 β-hCG levels and β-hCG levels 48 hours before methotrexate injection between the groups (Table 2).
The percentages of β-hCG change between 48 hours before methotrexate injection and day 1 were compared between the ‘failure group’ and the ‘success group’. The median value of β-hCG percentage change before methotrexate injection was significantly higher in the failure group (+13.7(+9.04/+17.68)) compared to the success group (+8.62(+5.8/+11.5)) (p<0.001).
A receiver-operating characteristic curve was established to determine the optimal β-hCG percentage change for treatment outcome. The area under the curve was 0.727 with 95% CI(0,659-0,795) (p<0,01) (Figure 2). With the cutoff value of 11,27%, the characteristics of the model to predict treatment success were as follows: sensitivity: 71.2%, specificity: 73.4%, diagnostic accuracy: 73%, negative predictive value (NPV): 93%, and positive predictive value (PPV): 35%.
Discussion
If patients diagnosed with tubal ectopic pregnancy are not eligible for the expectant management, medical management is acceptable as a plausible alternative for surgery. Methotrexate therapy is the most used pharmacologic treatment for hemodynamically stable patients due to its safety and efficacy [14]. It is of paramount importance to select appropriate patients prior to medical intervention, since patient compliance for follow-up is crucial and treatment failure risk is always present [15]. Methotrexate success for the single dose protocol is reported as a more than a 15% decline in β-hCG levels between days 4 and 7 following methotrexate injection, with a PPV of 93% [16]. Furthermore, this decline was reported as 88-100% indicating treatment success [17,18].
Although β-hCG patterns for ongoing intrauterine pregnancies and resolving pregnancies are well understood, there is no tool or model that can efficaciously specify a β-hCG curve for ectopic pregnancies [19]. In the literature, there are several studies researching β-hCG as a marker for trophoblastic cell activity. Ferreira et al. demonstrated a direct correlation between increased levels of serum β-hCG during the 48 hours prior to surgery with higher trophoblastic cell proliferation and angiogenesis in tubal pregnancy [20]. Oktay et al assessed salpingectomy specimens of tubal ectopic pregnancies for the presence or absence of myosalpingeal invasion and obtained higher serum β-hCG levels in patients having muscular layer trophoblastic invasion compared to the group having no trophoblastic invasion of the muscular layer (13 665 ± 2986 mIU/ml and 2169 ± 870 mIU/ml, respectively; P = 0.0001) [21]. A serum β-hCG cutoff level of 5400 mIU/ml or higher had an 89% PPV and 94% NPV value for the detection of invasion [21]. Pulatoglu et al. indicated that the cutoff β-hCG value, detecting the failure of methotrexate injection with 71.8% sensitivity and 68.2% specificity, was 1362 mIU/mL. In cases having β-hCG levels more than 1362 mIU/mL, the failure rate was 23.9%, while at lower values, the failure rate was 17.9% [22]. This did not reach statistical significance [22]. In our study, there was no difference regarding day1 β-hCG levels and β-hCG value 48 hours before methotrexate injection between the success and failure groups.
Along with HCG concentrations, HCG dynamics should also be investigated as to whether it has a role in the prediction of methotrexate success. Dudley et al. reported that there was a significant increase in the β-hCG change both before and after methotrexate injection in ectopic pregnancies that resulted in rupture: +0.94 vs. +0.16 and +0.38 vs. -0.21 (p<0.01), respectively [23]. In their 401-patient retrospective study, Cohen et al reported that β-hCG percentage change in the 48 hours preceding MTX injection and β-hCG concentration at day 1 were independent predictors for tubal rupture (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 1.04-1.12, p < 0.001 for every percentage change in β-hCG; OR = 1.001, 95% CI = 1.0003-1.002 for every unit change in β-hCG, respectively) [24]. They concluded that in women with β-hCG percentage increment more than 69% in the 48 hours prior to injection, the probability for tubal rupture was 85% [24]. They also indicated that the absolute risk for tubal rupture in women with β-hCG increment of less than 20% is low [24]. In another study, da Costa Soares et al investigated the role of β-hCG increment before methotrexate injection as a success predictor [25]. In their study, the mean β-hCG increment in the methotrexate failure group was significantly higher than in the success group (36% vs. 13%, respectively). By using ROC curve analysis, the optimal cut-off value for success was 11.1% [25]. Similarly, in our present study, the median value of β-hCG percentage change before methotrexate injection was significantly higher in the failure group (+13.7(+9.04/+17.68)) compared to the success group (+8.62(+5.8/+11.5)). When we used ROC curve analysis, the optimal cut-off value for success was 11.27% with a sensitivity of 71,2, which was comparable to that of da Costa Soares [25]. Besides, we obtained a PPV of 35% which is low. In other words, a woman with a positive result in favor of failure, has a 35% chance of failing treatment. On the other hand we obtained an NPV of 93% which is high. In other words, the proportion of the cases giving negative results (methotrexate success prediction) who are really in the success group is 93%. With this aspect, our model with an 11.27% cutoff is stronger in predicting success than in predicting failure. We think that utilizing β-hCG dynamics as an additional tool in the prediction of methotrexate treatment outcome should be considered in every case of tubal ectopic pregnancy.
Study Limitations
A limitation of this study is its retrospective nature. Prospective studies should be conducted to predict methotrexate treatment outcome. In addition, during the study period decisions regarding intervention were based on clinical judgment by different physicians.
Conclusion
In conclusion, β-hCG increment before methotrexate injection is a valuable predictor for methotrexate treatment success. Patients with β-hCG increment less than 11,27% can be reassured for treatment success with an NPV of 93% irrespective of serum β-hCG concentration.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Erhan Akturk, Murat Ibrahim Toplu, Cagdas Nurettin Emeklioglu, Tugba Salman, Fatma Nur Cetinkaya, Simten Genc, Arzu Yurci, Veli Mihmanli. Percentage of Human Chorionic Gonadotropin change in the forty-eight hours prior to methotrexate injection in predicting treatment success. Ann Clin Anal Med 2023;14(Suppl 1):S62-66
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Relationship between lactate value and mortality in critical patients diagnosed with diabetic ketoacidosis
Julide Sayın Kart 1, Özlem Tataroğlu 2
1 Department of Anesthesiology and Reanimation, 2 Department of Emergency Medicine , University of Health Sciences, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21631 Received: 2023-01-31 Accepted: 2023-03-02 Published Online: 2023-03-11 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S67-71
Corresponding Author: Julide Sayın Kart, Department of Anaesthesiology and Reanimation, University of Health Sciences, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey. E-mail: julidesayin@hotmail.com P: +90 507 669 04 64 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7848-3685
This study was approved by the Ethics Committee of University of Health Sciences, Kartal Dr. Lütfi Kırdar City Hospital (Date: 2022-12-28, No: 2022/514/240/21)
Aim: In this study, we aimed to investigate the lactate value and lactate clearance (LC) at the time of presentation to the emergency department and within the first two hours in predicting mortality in patients diagnosed with diabetic ketoacidosis (DKA).
Material and Methods: This retrospectively and observationally planned cohort study was conducted with patients with DKA who presented to the hospital between January 2021 and December 2022. The patients’ demographic characteristics, biochemistry, hemogram, and blood gas results at the time of presentation, second-hour lactate value, and outcome parameters were recorded. Then, LC was calculated for each patient. The patients were divided into groups according to the mortality status and the length of hospital stay. The groups were compared in terms of age, blood gas pH, osmolarity, glucose level, lactate level at presentation and at the second hour, LC, and bicarbonate, blood urea nitrogen, potassium levels, length of stay in hospital, intensive care unit admission, inotropic agent requirement, invasive mechanical ventilation requirement and mortality.
Results: The overall mortality rate was 15.6% (16/102). Age, pH, osmolarity, bicarbonate and sodium levels, and second-hour lactate level significantly differed between the groups (Mann-Whitney U test, p<0.05). The cut-off and area under the curve values of LC were not significant in predicting mortality (p>0.05).
Discussion: Among the patients with DKA who presented to the emergency department, age, the presence of comorbidities, glucose levels at presentation, admission and second-hour lactate values, pH, bicarbonate, potassium, and intensive care unit admission were useful in predicting mortality.
Keywords: Diabetic Ketoacidosis, Lactate, Mortality
Introduction
The number of patients presenting to emergency departments due to complications related to diabetes mellitus (DM) is currently increasing [1]. According to the data of the World Health Organization, deaths due to diabetes rank 19th globally. In the USA, DM is the eighth cause of mortality [2]. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are hyperglycemic emergencies with the highest mortality due to diabetes [3]. Rapid diagnosis of these conditions in emergency departments, and the detection and treatment of the underlying causes are essential to reduce the associated mortality.
One of the complications of DM, with which patients usually present to emergency departments is DKA, which is characterized by hyperglycemia, increased anion gap, ketonemia/ketonuria, and metabolic acidosis [4]. DKA is observed in 0.8% of patients with DM and a potentially fatal complication if not recognized and treated quickly [5,6]. Deaths due to DKA have been reported to occur most frequently within the first three days of presentation to the hospital and within the first 48 hours of admission to the intensive care unit (ICU) [7].
Although lactate is mainly produced in muscle cells, it is the end product of an increased anaerobic metabolism when oxygen delivery cannot meet oxygen consumption [8]. Increased lactate levels may be associated with increased production of lactate in diseases that either cause a decrease in oxygen delivery or reduce its elimination, or both in a multifactorial manner [9]. A high lactate concentration associated with a low blood pH value is useful for demonstrating the severity of the mismatch between the supply, demand, and consumption of energy [10]. An elevated blood lactate level is an important finding in the prediction of prognosis in critical diseases [4]. It is frequently detected in both adult and pediatric patients diagnosed with DKA in emergency departments [11,12].
Lactate clearance is the difference between the lactate value taken at a selected time and the first measured lactate value, i.e., the expression of the ratio of the initial lactate value as a percentage [13]. Some studies have underlined the importance of LC measurement in conditions that may lead to hypoperfusion, such as trauma and sepsis [14,15].
In contrast to patients with sepsis, there are limited studies investigating the role of changes in lactate values in patients with DKA in evaluating the severity of clinical cases, response to treatment, intensive care requirement, and prognosis [16,17]. Therefore, the primary aim of this study was to retrospectively investigate the relationship of the lactate values at presentation and LC with mortality in patients who presented to the emergency department with hyperglycemia and were diagnosed with DKA in 2021 and 2022. The secondary aim was to evaluate the relationship of these parameters with the length of hospital and ICU stay, mechanical ventilation requirement, and inotropic agent requirement.
Material and Methods
This research was performed as a retrospective observational cohort study. Approval was obtained from the ethics committee of University of health Sciences, Kartal Dr. Lutfi Kirdar City Hospital (Decision number:2022/514/240/21 Date: 2022-12-28). Patients who presented to the emergency department of the hospital with the diagnosis of DKA from January 1, 2021 to December 31, 2022 were included in the study. The data of the patients were retrospectively screened from the hospital’s automation system.
The exclusion criteria were age under 18 years, pregnancy, history of chronic renal failure or a trauma, refusal of treatment or transfer to another healthcare institution due to intensive care requirement, not meeting the American Diabetes Association (ADA) diagnostic criteria for DKA, and having missing or erroneous data. The results of routine blood tests conducted in the emergency department, including hemoglobin, hematocrit, glucose, urea, creatinine, troponin, lactate, bicarbonate (HCO3-), carbon dioxide, pH, and base excess values were recorded in the form created in the digital environment. In our emergency department, DKA is diagnosed using ADA Guideline I [18]. According to these criteria, DKA is diagnosed based on the presence of a plasma glucose level of >250 mg/dL, arterial pH of <7.3, serum HCO3- level of <18 mmol/L, and ketone positivity [19]. The patients’ admission and second-hour lactate values were used to calculate LC (lactateadmission – lactatehour 2) / lactateadmission x 100) as a percentage. In addition, age, gender, and the presence of comorbidities were recorded. The length of hospital and ICU stay, and discharge and mortality status were also recorded in the form.
Statistical analysis
SPSS, version 25 was used for statistical analyses. For the statistical evaluation, the study data were summarized using descriptive statistical methods (mean, standard deviation, frequency, minimum-maximum values). The Shapiro-Wilk test was used to determine the normality of data distribution for continuous variables. The significance of differences between the mean values was investigated with the two-sample t-test in the case of a normal data distribution, and with the Mann-Whitney U test in the presence of non-normally distributed data. Fisher’s exact test was conducted as the independent-samples test of categorical variables.
Receiver operating characteristic (ROC) curve analysis was undertaken to determine the ability of the investigated parameters to predict mortality. The significance level was taken as 0.05 for all tests performed.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The screening of the hospital records revealed a total of 125 patients who were diagnosed with DKA in the emergency department over the study period and underwent blood gas measurements at the time of presentation and at the second hour. However, when the patient records were reviewed, it was determined that 23 patients did not meet the inclusion criteria (nine patients were aged <18 years, 9 were transferred to another hospital with ICU indications, three refused treatment, and two had missing data). After these patients were excluded, the remaining 102 patients were included in the sample. Of these patients, 45 (44.11%) were female and 57 (55.88%) were male. The mean age of the patients was 45.5 ± 21 years. While 48 (47%) of the patients were followed up in the emergency department, 54 (53%) were followed up in the ICU. The mortality rate was 15.6% (16/102 patients). The mortality group had significantly higher values for mean age, glucose and potassium at the time of presentation, and lactate at the first and second hours and a significantly lower pH value at the time of presentation (Mann–Whitney U test, p< 0.05) (Table 1). The total length of hospital and ICU stay of the patients was also found to be significantly higher in the mortality group (Table 1).
The presence of comorbidities, ICU admission, mechanical ventilation (MV) requirement, and inotropic agent requirement were also significantly higher in the mortality group (Fisher’s exact test, p < 0.05) (Table 2).
The patients with a hospital stay longer than five days were determined to have lower HCO3 values and higher blood urea nitrogen (BUN) and base excess values at the time of presentation (Fisher’s exact test, p < 0.05).
No significant correlation was found between the length of hospital stay and the initial glucose level, admission and second-hour lactate values, and LC. Table 3 presents the results of the ROC curve analysis performed to determine the power and cut-off values of the investigated variables in the prediction of mortality.
According to the p-values of the ROC curve area, all variables except for pH and the length of hospital stay were significant in predicting mortality (p < 0.05). The highest Youden index value (the distance from the endpoint of the curve to the left corner on the graph) for the prediction of mortality belonged to MV requirement, followed by inotropic agent requirement. Patients with positive results on mechanical ventilation and inotropic agent requirements in the tests performed based on cut-off values had a higher risk of mortality. The sensitivity rate was observed to be high in the tests performed for the variables of the presence of comorbidities, ICU admission, potassium value, MV requirement, inotropic agent requirement, and second-hour lactate values. In addition to MV and inotropic agent requirements, the length of hospital and ICU stay, and BUN and glucose values also had high specificity values. When all results were evaluated together, it was observed that MV and inotropic agent requirements were the most determinant factors for mortality, followed by the length of ICU stay and BUN and second-hour lactate values.
Discussion
Among the metabolic complications of diabetes, DKA and HHS constitute emergencies with the highest mortality rates [3,18]. In the USA, 220,000 patients were hospitalized due to DKA in 2018, and the mortality rate was approximately 1% [16,17]. Although the mortality rate of DKA is <1% in developed countries, such as the USA and UK, this rate is higher, ranging from 3 to 13% in developing countries [20,21]. Mortality is affected by the adequacy of healthcare services, rapid diagnosis of the condition, and rapid initiation of treatment. The mortality rate of our patients was 15.6%, which is consistent with the literature. Researchers have focused on the use of various biomarkers in the prediction of mortality. In the current study, we aimed to evaluate the relationship of mortality with the first-hour and second-hour lactate values and LC in patients who presented to the emergency department with DKA. Our study has certain limitations, such as retrospective design and data being obtained from the hospital’s automation system. Various drugs and metabolic disorders are known to trigger DKA, and insulin deficiency is the most important cause [22,23]; however, we were not able to access such data through the hospital records.
Blood gas analyses in emergency departments are extremely valuable for presenting rapid results and providing important information about the metabolic status of parameters, including lactate, pH, base excess, and HCO3. Changes in blood lactate values help interpret tissue hypoxia when evaluated together with clinical manifestation and treatment, especially in diseases where perfusion is impaired. According to the Surviving Sepsis Campaign, lactate levels should be monitored to reflect the severity of the disease in sepsis and follow up patients on targeted therapy [15]. DKA is a clinical condition presenting with high lactate levels. In our study, there was a significant correlation between elevated first- and second-hour lactate levels and mortality, which is consistent with the literature [22]. However, lactate values were not significant in determining the length of hospital stay.
Many studies have shown that LC follow-up results in better clinical outcomes [13,23]. According to our findings, LC was lower in the group with a hospital stay of >5 days, although this did not reach a statistically significant level. In some studies, LC has been shown to be significant in predicting 30-day mortality [24]. In our study, no significant correlation was observed between LC and mortality, but LC was lower in the mortality group.
We found that the glucose level at the time of presentation to the emergency department and patient age were significantly associated with mortality. We consider that this may be due to the presence of resistant hyperglycemia and age-related comorbidities. This idea is supported by the literature [3,19].In clinical practice, especially in emergency departments, rapid, practical, and effective biochemical markers are needed to predict patient prognosis and determine the optimal treatment process. This can reduce mortality metabolic emergencies, such as DKA. We consider that the most effective biochemical and clinical markers will be identified through further studies. In this study, a significant correlation was found between mortality and important parameters for ICU indication, pH, HCO3, and potassium at the time of presentation (p < 0.05). Similar to the studies in the literature [7], the mortality rate was significantly higher in the patients admitted to the ICU. In addition, the presence of comorbidities and inotropic agent and MV requirements were among the significant factors that increased mortality. Glucose value at presentation, patient age, blood gas parameters, severity of metabolic acidosis, course of lactate values from presentation to the second hour, and the length of ICU and hospital were determined to be appropriate and clinically useful diagnostic markers for patients with DKA.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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2. Ahmad FB, Cisewski JA, Miniño A, Anderson RN. Provisional Mortality Data – United States, 2020. Morb Mortal Wkly Rep. 2021;70(14):519-22.
3. Corwell B, Knight B, Olivieri L, Willis GC. Current diagnosis and treatment of hyperglycemic emergencies. Emerg Med Clin North Am. 2014;32(2):437-52.
4. Taşkın G, Yilmaz M, Yilmaz S, Şirin H, Sapmaz H, Taşlıgil S, et al. Lactate kinetics in intensive care unit admissions due to diabetic ketoacidosis. Gülhane Tıp Dergisi/ Gülhane Medical Journal. 2021;63(3):212 -7.
5. Wilson JF. Diabetic ketoacidosis. Ann Intern Med. 2010;152(1):ITC1-1.
6. Masharani U, Strycker LA, Lazar AA, Wu K, Brooks GA. Hyperlactatemia in diabetic ketoacidosis. Diabet Med. 2022;39(4):e14723.
7. Efstathiou SP, Tsiakou AG, Tsioulos DI, Zacharos ID, Mitromaras AG, Mastorantonakis SE, et al. A mortality prediction model in diabetic ketoacidosis. Clin Endocrinol. 2002;57(5):595-601.
8. Van Hall G. Lactate kinetics in human tissues at rest and during exercise. Acta Physiol. 2010;199(4):499-508.
9. Krzymien J, Karnafel W. Lactic acidosis in patients with diabetes. Pol Arch Med Wewn. 2013;123(3):91-7.
10. Mizock BA, Falk JL. Lactic acidosis in critical illness. Crit Care Med. 1992;20(1):80-93.
11. Cox K, Cocchi MN, Salciccioli JD, Carney E, Howell M, Donnino MW. Prevalence and significance of lactic acidosis in diabetic ketoacidosis. J Crit Care. 2012;27(2):132-7.
12. Cully M, Thompson AD, DePiero AD. Is lactic acidosis predictive of outcomes in pediatric diabetic ketoacidosis? Am J Emerg Med. 2020;38(2):329-32.
13. Scott S, Antonaglia V, Guiotto G, Paladino F, Schiraldi F. Two-hour lactate clearance predicts negative outcome in patients with cardiorespiratory insufficiency. Crit Care Res Pract. 2010;2010:917053.
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15. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77.
16. Morgan TJ, Scott PH, Anstey CM, Bowling FG. Hyperlactatemia in diabetic ketoacidosis is common and can be prolonged: lactate time-series from 25 intensive care admissions. J Clin Monit Comput. 2021;35(4):757-64.
17. Masyuk M, Wernly B, Lichtenauer M, Franz M, Kabisch B, Muessig JM. Prognostic relevance of serum lactate kinetics in critically ill patients. Intensive Care Med. 2019;45(1):55-61.
18. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009;32(7):1335-43.
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Relationship between thyroid transcription factor 1 and prognosis in locally advanced lung adenocarcinoma
Engin Kut, Serkan Menekse
Department of Medical Oncology, Manisa State Hospital, Manisa, Turkey
DOI: 10.4328/ACAM.21632 Received: 2023-02-01 Accepted: 2023-03-12 Published Online: 2023-03-19 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S72-75
Corresponding Author: Engin Kut, Department of Medical Oncology, Manisa State Hospital, 45040, Şehzadeler, Manisa, Turkey. E-mail: drenginkut@gmail.com P: +90 541 188 70 74 F: +90 236 229 26 50 Corresponding Author ORCID ID: https://orcid.org/0000-0002-5328-5607
This study was approved by the Health Sciences Ethics Committee of Manisa Celal Bayar University (Date: 2020-02-05, No: 20.478.486)
Aim: Stage 3 lung cancers are usually treated with chemoradiotherapy. Thyroid transcription factor 1 (TTF-1) is a transcription protein and TTF-1 is positive in 70% of lung adenocarcinomas. Recent studies have reported that TTF-1 is not only a diagnostic marker but also a prognostic marker. However, to the best of our knowledge, there is no study in the literature showing the relationship between prognosis with TTF-1 in stage 3 patients receiving chemoradiotherapy. For this reason, we retrospectively analyzed the relationship between TTF-1 with prognosis in patients with lung adenocarcinoma who received chemoradiotherapy for the first time in the literature.
Material and Methods: Medical data of 108 patients in Manisa State Hospital between 2009 and 2022 were retrospectively analyzed.
Results: Median overall survival was 32.69 (95% CI, 26.61-38.77) months in the TTF-1 positive group versus 15.28 (95% CI, 11.02-19.54) months in the TTF-1 negative group. Median progression-free survival was 19.68 (95% CI, 16,48-22.88) months in the TTF-1 positive group versus 10.91 (95% CI, 10.08-11.73) months in the TTF-1 negative group. In multivariate analyses, both OS and PFS were associated with ECOG performance score (p= 0.023, p=0.005), TTF-1 (p= 0.001, p= 0.01), stage (p=0.008, p=0.009) and albumin (p=. 0.038, 0.007) level at diagnosis.
Discussion: TTF-1 is both a diagnostic and prognostic marker in lung adenocarcinoma. TTF-1 can be used as an easy and inexpensive biomarker to determine the prognosis in patients receiving chemoradiotherapy diagnosed with stage 3 lung adenocarcinoma.
Keywords: Thyroid Transcription Factor 1, Chemoradiotherapy, Lung Cancer, Prognosis
Introduction
Lung adenocarcinoma (LAC) is the most common cancer of the lung, accounting for approximately 40% of all lung cancer cases [1]. 40% of patients diagnosed with non-small cell lung cancer (NSCLC) are locally advanced stage III patients [2]. As a standard, surgery is recommended for all eligible patients in the early stage, while cytotoxic chemotherapy, repeated targeted therapy, or immunotherapy is recommended for stage 4 patients. In stage 3 disease, surgery is recommended only in operable stage 3a disease, while chemoradiotherapy is recommended as standard for other stage 3 diseases [3]. Although some clinical and laboratory findings such as age, sex, performance score, albumin, hemoglobin, and lactate dehydrogenase (LDH) levels are associated with prognosis in patients with stage 3 disease, the most important standard prognostic indicator is still stage [4]. Because, even if patients have the same stage, and the same clinical and laboratory findings, they may show different characteristics in daily practice and their prognosis may be different. Therefore, some other prognostic markers are also needed. Thyroid transcription factor 1 (TTF-1) is a transcription protein with both oncogenic and anti-oncogenic properties required for lung differentiation and morphogenesis [5]. It is used in daily routine practice in the diagnosis of lung adenocarcinoma and the differentiation of lung adenocarcinoma from other cancers. TTF-1 is positive in 70% of lung adenocarcinomas [6]. Recent studies have reported that TTF-1 is not only a diagnostic marker but also a prognostic marker. In studies conducted, it has been reported that TTF-1 positive, early-stage, undergoing surgery patients have a better prognosis, and stage 4 patients have better responses to chemotherapy, targeted therapy, and immunotherapy [7-12]. However, to the best of our knowledge, there is no study in the literature showing the relationship between prognosis and TTF-1 in stage 3 patients receiving chemoradiotherapy. For this reason, in our center, we retrospectively analyzed the relationship between TTF-1 with prognosis in patients with lung adenocarcinoma who received chemoradiotherapy for the first time in the literature.
Material and Methods
Study Population
Medical data of 108 patients who received chemoradiotherapy with the diagnosis of stage 3 lung adenocarcinoma in Manisa State Hospital between 2009 and 2022 were retrospectively analyzed. Patients who were 18 years of age or older at the time of diagnosis, had stage 3 disease, were not suitable for surgery, had undergone immunohistochemical staining with TTF-1, and had lung adenocarcinoma histology were included in the study. Patients who were under the age of 18 at the time of diagnosis, did not have lung adenocarcinoma histology, did not undergo immunohistochemical staining with TTF-1, had a stage other than stage 3 or had stage 3 but did not receive chemoradiotherapy, had more than one primary tumor were excluded from the study. The stage of the disease is determined using positron emission computed tomography (PET) and magnetic resonance imaging (MRI).
Data collection
The patients’ demographic characteristics such as age and sex, Eastern Cooperative Oncology Group (ECOG) performance scores, smoking history, TTF-1 results, stage and their relationship with survival were examined. The patients were divided into groups according to the Eastern Cooperative Oncology Group (ECOG) performance score (<2 and ≥2), TTF-1 (positive, negative) and stage (3A, 3B). When calculating the survival time, the time from the date of chemotherapy to death or the last follow-up for the patients who survived was calculated. Progression-free survival (PFS) was calculated as the time from the initiation of the first treatment to clinical or radiological progression or to death from any cause for the patients who died. The primary endpoint was PFS and OS, and the secondary endpoint was factors affecting PFS and OS.
Ethical Approval
The study was conducted in accordance with the principles of the Declaration of Helsinki and reviewed and approved by the Health Sciences Ethics Committee of Manisa Celal Bayar University (Decision no: 20.478.486, date: 05/02/2020)
Statistical analysis
Descriptive statistics were presented as mean, standard deviation, median, minimum and maximum values for numerical variables and as numbers and percentages for categorical variables. Survival analyses were performed using the Kaplan-Meier method. Factors affecting survival were examined using the Cox regression. P < 0.05 was considered significant in all statistical analyses
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 108 patients, including 91 (84.3%) males, and 17 (15.7%) females were examined. Their mean age was 63.69 ± 9.61 years. TTF-1 was positive in 76 (% 70.4) patients and TTF-1 was negative in 32 (% 29.6) patients. There were 87 (%80.6) smokers ( Table 1). Median cigarettes smoked was 45 (0-150) pack/year. The median albumin level was 3.2 (2.0-4.6) g/dL, the median LDH level was 268 (105-4046) U/L, the median platelet count was 288 (141-585) 103/μL, the median lymphocyte count was 1.7 (0.5-2.8) 103/μL, the median neutrophil count was 5.7 (2.6-1.6) 103/μL and the mean hemoglobin level was 12.66 ± 1.88 g/dL.
The median overall survival was 27.83 (95% CI, 23.67-31.98) months, and the median PFS was 17,08 (95% CI,13.79-20.24) months in all patients.
Stage, ECOG performance score, TTF-1 and albumin level at diagnosis were related to both OS and PFS in univariate and multivariate analyses (Tables 2 and 3)
The survival rates of the patients were respectively 94% at 12 months, 81% at 24 months, 51% at 36 months, 29% at 48 months, and 13% at 60 months in stage 3A disease. In the group with stage 3B disease, the survival rates of the patients were respectively 57% at 12 months, 36% at 24 months, 13% at 36 months, 7% at 48 months, %3 60 months in stage 3B.
The median overall survival was 32.69 (95% CI, 26.61-38.77) months in the TTF-1 positive group versus 15.28 (95% CI, 11.02-19.54) months in the TTF-1 negative group. Median progression-free survival was 19.68 (95% CI, 16,48-22.88) months in the TTF-1 positive group versus 10.91 (95% CI, 10.08-11.73) months in the TTF-1 negative group (Figure 1).
During follow-up, after chemoradiotherapy, local recurrence 51 (47.2%), lung metastasis 41 (38%), brain metastasis 19 (17.6%), bone metastasis 37 (34.3%), adrenal metastasis 25 (23.1%), liver metastasis 13 (12%) were detected.
Discussion
In this study, we retrospectively examined stage 3 patients who received chemoradiotherapy and we found that prognosis was related to TTF-1, ECOG, stage and albumin level.
According to SEER data, when all lung cancers are considered, the 5-years life expectancy is still around 22.9% [13]. Approximately 15-20% of the patients are in the early stage, 50-60% are metastatic, and the rest are at locally advanced stages [13]. Surgery in the early stages is the standard of systemic treatment in the advanced stages. Chemoradiotherapy is recommended for stage 3A and stage 3 B patients who are not suitable for the operation [3].
Although there was a relationship between stage, albumin, ECOG performance score and the prognosis of patients in previous studies, there is still no standard prognostic marker other than stage in daily practice [4]. In daily practice, patients with similar ECOG scores, albumin levels and stages may have different prognoses. Therefore, there is a need for prognostic markers other than these factors. In our study, unlike the literature, we examined the relationship between TTF-1 with prognosis in patients who received chemoradiotherapy for the first time. As a result of our analysis, we found a significant relationship between TTF-1 with prognosis for the first time in the literature.
TTF-1 is expressed in type II pneumocytes and Clara cells and regulates the surfactant and Clara cell secretory protein gene expression to maintain normal lung functions [14]. TTF-1 is a homeodomain nuclear transcription protein of the NKX2 gene family. By binding to specific gene sequences, TTF-1 modulates the transcriptional activation of target genes [15]. The NKX2–1 locus, which encodes TTF-1, is frequently amplified in the lung cancer genome [15]. TTF-1 could be important for the survival of a subset of patients with lung adenocarcinomas expressing TTF-1 based on the lineage-specific dependency model [16]. Therefore, TTF- 1 may be important in the diagnosis and prognosis of lung adenocarcinoma. In previous meta-analyses, TTF-1 has been reported to be associated with prognosis in both early and advanced stages [8]. In subsequent studies, TTF-1 has been reported that there may be a relationship between chemotherapy response and TTF-1, and then between targeted therapies with TTF-1 [10-12]. In addition, TTF-1 has recently been reported that TTF-1 positive patients in lung cancer patients receiving immunotherapy have a better prognosis with or without chemotherapy [17-18]. However, this may be due to the fact that TTF-1 inhibits cell migration and invasion, Ki-67 proliferation index is lower in TTF-1 positive patients and EGFR mutations are higher in TTF-1 positive patients, whereas KRAS mutations are more common in TTF-1 negative patients [19-21].
The relationship between radiotherapy and chemoradiotherapy with TTF-1 is unknown. To our knowledge, there is no study examining this relationship. For this reason, we conducted in this study, we found a significant relationship between disease stage, TTF-1, ECOG performance score, with OS and PFS in both univariance and multivariance analysis.
Although the limitations of our study are that it was retrospective, included a small number of patients, and the driver mutations were not known in the patients in the study, this study is important as it is the first study to show the relationship between prognosis and TTF-1 in patients with stage 3 lung adenocarcinoma and receiving chemoradiotherapy at the time of diagnosis.
Conclusion
TTF-1 is both a diagnostic and prognostic marker in lung adenocarcinoma. TTF-1 can be used as an easy and inexpensive biomarker to determine the prognosis in patients receiving chemoradiotherapy with the diagnosis of stage 3 lung adenocarcinoma.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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2. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021; 27(8):1345-56.
3. Duma N, Santana-Davila R, Molina JR. Non-Small Cell Lung Cancer: Epidemiology, Screening, Diagnosis, and Treatment. Mayo Clin Proc. 2019; 94(8):1623-40.
4. Berghmans T, Paesmans M, Sculier JP. Prognostic factors in stage III non-small cell lung cancer: a review of conventional, metabolic and new biological variables. Ther Adv Med Oncol. 2011; 3(3):127-38.
5. Mu D. The complexity of thyroid transcription factor 1 with both pro- and anti-oncogenic activities. J Biol Chem. 2013; 288(35):24992-25000.
6. Kim JH, Kim HS, Kim BJ, Han B, Choi DR, Kwon JH. Prognostic Impact of TTF-1 Expression in Non-Squamous Non-Small-Cell Lung Cancer: A Meta-Analysis. J Cancer. 2018 ; 9(22):4279-86.
7. Schilsky JB, Ni A, Ahn L, Datta S, Travis WD, Kris MG, et al. Prognostic impact of TTF-1 expression in patients with stage IV lung adenocarcinomas. Lung Cancer. 2017; 108:205-11.
8. Kim JH, Kim HS, Kim BJ, Han B, Choi DR, Kwon JH. Prognostic Impact of TTF-1 Expression in Non-Squamous Non-Small-Cell Lung Cancer: A Meta-Analysis. J Cancer. 2018; 9(22):4279-86.
9. Zhang Y, Wang R, Li Y, Pan Y, Hu H, Zhang Y, et al. Negative Thyroid Transcription Factor 1 Expression Defines an Unfavorable Subgroup of Lung Adenocarcinomas. J Thorac Oncol. 2015; 10(10):1444-50.
10. Park JY, Jang SH, Kim HI, Kim JH, Park S, Hwang YI, et al. Thyroid transcription factor-1 as a prognostic indicator for stage IV lung adenocarcinoma with and without EGFR-sensitizing mutations. BMC Cancer. 2019 13; 19(1):574.
11. Takeuchi A, Oguri T, Yamashita Y, Sone K, Fukuda S, Takakuwa O, et al. Value of TTF-1 expression in non-squamous non-small-cell lung cancer for assessing docetaxel monotherapy after chemotherapy failure. Mol Clin Oncol. 2020; 13(3):9.
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13. Schabath MB, Cote ML. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiol Biomarkers Prev. 2019; 28(10):1563-1579.
14. Johnson H, Cohen C, Fatima N, Duncan D, Siddiqui MT. Thyroid transcription factor 1 and Napsin A double stain: utilizing different vendor antibodies for diagnosing lung adenocarcinoma. Acta Cytol. 2012; 56(6):596-602.
15. Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol Cell. 2013; 50(2):185-99.
16. Tanaka H, Yanagisawa K, Shinjo K, Taguchi A, Maeno K, Tomida S, et al. Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 2007; 67(13): 6007-11.
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Download attachments: 10.4328.ACAM.21632
Engin Kut, Serkan Menekse. Relationship between thyroid transcription factor 1 and prognosis in locally advanced lung adenocarcinoma. Ann Clin Anal Med 2023;14(Suppl 1):S72-75
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A different yet traditional approach to neoadjuvant treatment of breast cancer: The combination of epirubicin and docetaxel
Elif Yüce 1, Serdar Karakullukçu 2, Celal Alandağ 3, Hatice Bülbül 4, İsmail Saygın 5, Halil Kavgacı 6
1 Department of Medical Oncology, Karaman Training and Research Hospital, Karaman, 2 Department of Provincial Health, Rize, 3 Department of Medical Oncology, Sivas Numune Hospital, Sivas, 4 Department of Internal Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, 5 Department of Pathology, Faculty of Medicine, Karadeniz Technical University, Trabzon, 6 Department of Medical Oncology, Karadeniz Medical Park Hospital, Trabzon, Turkey
DOI: 10.4328/ACAM.21633 Received: 2023-02-02 Accepted: 2023-03-12 Published Online: 2023-03-17 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S76-80
Corresponding Author: Elif Yüce, Department of Medical Oncology, Karaman Training and Research Hospital, 70100, Karaman, Turkey. E-mail: merevelif@gmail.com P: +90 507 873 64 69 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3174-7129
This study was approved by the Scientific Research Ethics Committee of Karadeniz Technical University, Faculty of Medicine (Date: 2020-01-21, No: 2019/374)
Aim: Epirubicin-docetaxel (ET) combination is an unusual and less frequently recommended regimen in the neoadjuvant treatment of breast cancer. In this study, we aimed to evaluate the efficacy of this combination.
Material and Methods: The study involved 46 women diagnosed with breast cancer in 2009-2019 who received neoadjuvant therapy. All received epirubicin 80 mg/m2 and docetaxel 75 mg/m2 (on day-1) over a 21-day period, in varying cycles.
Results: The mean age of the patients was 49.3 ± 12.3 years. Twenty-one (45.7%) were premenopausal and 25 (54.3%) postmenopausal, 27 (64.3%) were ≤T2 at the time of diagnosis and 15 (35.7%) were >T2. Clinical involvement of the lymph nodes was present in 36 (80%). Eleven (28.9%) were luminal-A, 20 (52.6%) luminal-B, 2 (5.3%) HER2-positive, and 5 (13.2) triple–negative. Twenty-six (56.5%) patients had received 3 cycles and 20 (43.5%) had more than 3. In the clinical-response evaluation, complete response was observed in 10 (21.7%) patients, partial response in 24 (52.2%), stable disease in 9 (19.6%), and progressive disease in 3 (6.5%). The objective-response rate (ORR) was 73.9%. Total pathological-complete-response (pCR) was observed in 7 (15.2%) patients. pCR rates were higher in patients without clinical-lymph-node involvement (44.4% vs 8.3%, p:0.022). The median follow-up time was 37.5 months.
Discussion: Although the combination of ET in the neoadjuvant treatment of breast cancer is not among the regimens recommended in the guidelines, according to our study, it has a significant contribution to ORR and pCR, especially in node negatives.
Keywords: Breast Cancer, Docetaxel, Epirubicin, Neoadjuvant Chemotherapy, Response
Introduction
Breast cancer is the second most common type of cancer worldwide and one of the most common causes of cancer-related deaths in women [1]. Commencing treatment with neoadjuvant chemotherapy (NACT) in the locally advanced stage has numerous benefits. NACT obviates the need for extensive surgery to the breast and axilla by causing tumor downstaging. Thus, complications that pose a limitation on movement and lower quality of life after total mastectomy, such as lymphedema, are prevented [2]. It is also easier to evaluate the tumor response to systemic therapy with NACT. However, the failure to achieve a complete pathological response with NACT is an important prognostic factor for the risk of recurrence, particularly in the triple-negative and HER2-positive subgroups. At the same time, although there has been shown to be little difference between NACT and adjuvant chemotherapy in terms of overall survival, early initiation of systemic therapy also contributes to early eradication of micrometastases and a decrease in the risk of recurrence [3,4].
Anthracycline and taxane-based chemotherapies are primarily employed in neoadjuvant therapy. The generally recommended treatment in HER2-negative patients is a dose-dense anthracycline (epirubicin or doxorubicin) and cyclophosphamide combination, followed by taxane-based regimens alone (paclitaxel or docetaxel), requiring a total six-month treatment period [5]. The combination of epirubicin and docetaxel (ET) is applied for six cycles at three-week periods and requires a total length of treatment of four months. The ET regimen is not included among the primary options in neoadjuvant therapy in the National Comprehensive Cancer Network (NCCN) guideline. However, due to its tolerability, the regimen can be used in selected patients.
The purpose of this study was to determine the effectiveness of an ET combination in neoadjuvant therapy, to analyze the factors affecting the clinical and pathological response, and to improve our approach to identifying candidates for NACT.
Material and Methods
One hundred twenty-seven patients were diagnosed with breast cancer and received NACT in our center between December 2009 and December 2019. Only 46 patients receiving the ET regimen out of these 127 patients were included in the study. All patients were diagnosed through biopsy, and their post-NACT pathologies were reported in our center. The patients’ clinical, demographic, and pathological characteristics, treatment choices, responses to treatment, and survival/mortality were analyzed retrospectively from the hospital’s data-processing records. Ethical approval for the study was received from Karadeniz Technical University Faculty of Medicine Scientific Research Ethics Committee on 21.1.2020 (document number: 24237859-171, approval number: 2019/374).
Patients diagnosed with pathological breast cancer and scheduled for NACT initially underwent mammography and/or magnetic resonance imaging. Lymph node involvement at the time of diagnosis was evaluated with lymph node biopsy if no radiological consensus was achieved. Thoracic-abdominal computed tomography, bone scintigraphy, or PET-computed tomography were performed to screen for distant metastasis. NACT was performed with intravenous administration of epirubicin 80 mg/m2 and docetaxel 75 mg/m2 on day 1 at varying cycles over 21-day periods. Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) rules were used in the evaluation of clinical responses, and patients were divided into four groups accordingly, complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Pathological response evaluation was carried out by our center’s pathology department. Patients with no tumor cells observed in the breast and axilla were regarded as exhibiting pathological complete response (pCR). Patients were also examined separately in terms of pathological responses for the breast and axilla.
The immunohistochemical method was employed to determine molecular subtypes (luminal A, luminal B, HER2-positive, and triple-negative). Patients were divided into subtypes through the investigation of estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki-67 percentages. Patients who were ER-positive (ER+), with PR ≥20%, HER2-negative, and with Ki67 <10% were regarded as Luminal A. Luminal B cases were defined as ER+, HER2-negative, and with one of Ki67 ≥20% or PR negative <20%, or ER+, HER2-positive, with any Ki67 level and any PR level. HER2+ (non-luminal) tumors were defined as HER2+ and ER- and PR-negative. Triple-negative tumors were defined as ER-, PR-, and HER2-negative.
Statistical analysis
Statistical analysis was performed on SPSS 23.0 software. Descriptive statistics were expressed as numbers and percentages for categorical variables and as mean, median, standard deviation, minimum, and maximum for numerical variables. The One Sample Kolmogorov-Smirnov test was applied to determine the normality of distribution in the groups. Differences in categorical variable rates between independent groups were evaluated using the chi-square test. Alpha significance was set at p<0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
The patients’ general characteristics are summarized in Table 1. Their mean age was 49.3 ± 12.3 years (min. 31, max. 74). All were women; 21 (45.7%) of the 46 patients were premenopausal and 25 (54.3%) postmenopausal. Twenty-seven (64.3%) of the 42 patients whose T stages were known at the time of diagnosis were ≤T2 and 15 were (35.7%) >T2. Lymph node involvement was present in 36 (80%) of the 45 patients whose lymph node status was known at the time of diagnosis, but not in the remaining nine (20%). Eleven (28.9%) of the 38 patients whose immunohistochemistry (IHC) records were available at the time of diagnosis were luminal A, 20 (52.6%) were luminal B, two (5.3%) were HER2-positive, and five (13.2%) were triple-negative. Twenty-six (56.5%) of the entire patient group had received three cycles of ET and 20 (43.5%) more than three. Subtype alteration after neoadjuvant ET was present in four (12.5%) of the 32 patients with residual tumors whose records were available, while no change was present in 28 (87.5%). The median length of follow-up was 37.5 months (min. 13 max. 142).
Clinical response and pathological response rates are summarized in Table 2. Clinical response evaluation revealed CR in 10 (21.7%) patients, PR in 24 (52.2%), SD in nine (19.6%), and PD in three (6.5%). The objective response rate (ORR) was 73.9%. No significant differences in clinical response rates were observed in terms of menopause status, T stage at the time of diagnosis, presence or absence of clinical lymph node involvement at the time of diagnosis, Ki-67 index, and receipt of three or more cycles of ET.
Pathological response analysis revealed pCR in seven (15.2%) patients (Table 2). Pathological responses were evaluated in the breast and axilla together (Table 3). Total pathological response rates in the breast and axilla together were higher in patients without clinical lymph node involvement than in those with such involvement (44.4% vs 8.3%, respectively p:0.022). No significant difference in total pathological complete response rates was observed in terms of menopausal status, T stage at the time of diagnosis, Ki-67 index, molecular subtype, or number of ET cycles. The pCR rate in the axilla alone was higher among patients without clinical lymph node involvement than in those with such involvement (77.8% vs 22.2%, p:0.003). No Grade 3-4 toxicity was observed.
Discussion
Important recent studies have shown the usefulness of NACT in operable breast cancer [3,4]. The importance of the pCR rates obtained with NACT in predicting survival particularly encourages clinicians to use neoadjuvant therapy in high-risk patients [6]. The principal advantages of neoadjuvant therapy include less extensive surgery and the fact that as a result, patients’ quality of life is significantly protected [2].
The first recommended regimens for neoadjuvant therapy in HER2-negative disease in the NCCN guideline are four cycles of dose-dense anthracycline + cyclophosphamide (AC) followed by a three-month paclitaxel regimen or a four-cycle TC (docetaxel+cyclophoshamide) regimen alone [7]. The addition of trastuzumab and pertuzumab in combination with chemotherapy is recommended for HER2-positive disease [8].
The GEPARDUO study showed the superiority of a neoadjuvant AC combination followed by sequential docetaxel therapy over concurrent docetaxel therapy in achieving pCR in operable breast cancer (pCR rates 14.3% vs 7%, respectively, p<0.001). However, the high frequency of hematological side effects in particular with the AC regimen, and the fact that these make the regimen difficult for patients to tolerate, make adherence to it problematic. The use of granulocyte colony- stimulating factor (GCSF) is required for neutropenia prophylaxis in order to prevent the postponement of treatment and a decrease in dose density due to neutropenia. In addition, due to this regimen’s very high emetogenic property, it requires the use of numerous antiemetics and close follow-up to increase compliance [9]. Additionally, doxorubicin is more likely to cause cardiac toxicity than epirubicin. Due to the possibility of cumulative toxicity, patients require careful life-long cardiac follow-up [10]. The standard duration of NACT with sequential therapy is six months (or longer if dose delay is required), but only four months with the ET regimen [8,11]. Epirubicin-docetaxel combination therapy offers a number of advantages, such as easier toleration and follow-up, and a shorter duration than sequential therapy for neoadjuvant therapy. These explains its preference in fragile patients scheduled for NACT.
Previous studies have investigated the efficacy of neoadjuvant ET [6,12]. A study from Korea published in 2020 involved a retrospective evaluation of clinical and pathological responses and factors affecting them in 40 patients receiving neoadjuvant ET. An ORR of 62.5% (2.5% CR + 60% PR) was determined by clinical response analysis, while pCR was observed in 5% of patients by pathological response evaluation. The authors concluded that ET should be considered in neoadjuvant therapy in selected patients [11]. In light of the above, and based on the hypothesis that the ET regimen may be a tolerable option in neoadjuvant therapy, we decided to perform a retrospective analysis of clinical and pathological response rates among patients receiving ET in our center between December 2009 and October 2019. Forty-six of our patients received the ET regimen. These were patients indicated for NACT but whom we considered too fragile to tolerate six-month NACT. Due to the realization of the importance of NACT in recent years and the fact that standards have not yet been established in many developing centers, including our own institution, more than half of our patients received half the treatment they should have been administered. Although this study reflects real-life data, this nevertheless constitutes one of its principal limitations.
The great majority of patients were in the luminal subtype (28.9% luminal A and 52.6% luminal B) at the time of diagnosis (13.2% triple-negative, 5.3% HER2-positive). Combined regimens, including neoadjuvant trastuzumab and pertuzumab are known to be important in achieving pCR in HER2-positive breast cancer [13]. However, two of the HER2-positive patients diagnosed in 2009 in the present study had received a neoadjuvant ET regimen, and partial response was observed in both. This response, seen in a very few patients is insufficient to allow us to make any recommendation regarding neoadjuvant therapy in HER2-positive breast cancer.
Since the patients included in this study had been diagnosed until January 2019, and the importance of preoperative total neoadjuvant therapy has become better understood in recent years, the rate of completion of preoperative NACT among our patients was low. Although 15.2% of patients completed a neoadjuvant six-cycle ET regimen, analysis of clinical responses revealed an ORR of 73.9% (21.7% CR + 52.2% PR). All three (6.5%) of our patients with progression were in the luminal A group, which is known to exhibit the lowest response to neoadjuvant chemotherapy. When the breast and axilla were evaluated together, pCR was present in seven (15.2%) patients. Considering also that more than half (56.5%) of our patients received only three cycles of ET, our findings support the idea that the neoadjuvant ET regimen is not at all inferior to the AC + sequential docetaxel regimen and can be safely used in selected patients.
No clinicopathological characteristic affecting clinical response rates with ET in a statistically significant manner was identified in this study. Evaluation of the breast and axilla both separately and together in terms of pathological response revealed significantly higher pCR rates in both analyses in patients without clinical lymph node involvement (77.8% vs 22.2%, p:0.003, and 44.4% vs 8.3%, p:0.022, respectively). Considering that hematological and cardiac side effects are more controllable, the lower risk of emesis, and the shorter time elapsing to surgery, we think that the ET regimen can be safely employed in HER2-negative patients without lymph node involvement at the time of diagnosis and who are regarded as potential candidates for NACT.
Although we think that our findings are important, there are nevertheless a number of limitations in this research. Patients receiving NACT between 2009 and 2019 were included in the study. Our patient number was low, since the importance of neoadjuvant therapy has become better understood in recent years and because ET is not one of the regimens to which we attach primary consideration in neoadjuvant therapy, and their follow-up times were not particularly long. Further more extensive, prospective studies are now needed to support our findings.
Conclusion
The findings of this study show that the ET combination in the neoadjuvant treatment of breast cancer makes a significant contribution to ORR and pCR, especially in node-negative cases. Although the ET regimen is not included among the primary options in neoadjuvant therapy in the NCCN guideline, in light of the clinical and pathological response rates in this study, we concur with the idea that ET can be safely used in the treatment of HER2-negative NACT candidate patients, particularly those without clinical lymph node involvement. This research now needs to be supported by prospective studies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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6. de Matteis A, Nuzzo F, D’Aiuto G, Labonia V, Landi G, Rossi E, et al. Docetaxel plus epidoxorubicin as neoadjuvant treatment in patients with large operable or locally advanced carcinoma of the breast. Cancer. 2002;94(4):895-901.
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9. Von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: The GEPARDUO study of the German Breast Group. J Clin Oncol . 2005 ;23(12):2676-85.
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Elif Yüce, Serdar Karakullukçu, Celal Alandağ, Hatice Bülbül, İsmail Saygın, Halil Kavgacı. A different yet traditional approach to neoadjuvant treatment of breast cancer: The combination of epirubicin and docetaxel. Ann Clin Anal Med 2023;14(Suppl 1):S76-80
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The effect of social support on anxiety, depression, stress and quality of life in obesity surgery
Yasemin Özyer 1, Kübra Gümüştekin 1, Kadir Yıldırım 2
1 Department of Nursing, Faculty of Health Sciences, Sinop University, Sinop, 2 Department of General Surgery, Medical Park Hospital, Samsun, Turkey
DOI: 10.4328/ACAM.21636 Received: 2023-02-02 Accepted: 2023-03-12 Published Online: 2023-03-15 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S81-85
Corresponding Author: Yasemin Özyer, Department of Nursing, Faculty of Health Sciences, Sinop University, Sinop, Turkey. E-mail: ozyeryaseminn@gmail.com P: +90 368 271 57 57 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2706-8107
This study was approved by the Human Research Ethics Committee of Sinop University (Date: 2022-11-17, No: 2022/190-218)
Aim: Determining the effect of social support on anxiety, depression, stress and quality of life in patients undergoing bariatric surgery is important for the health of individuals. This study was conducted to determine the effect of social support on anxiety, depression, stress and quality of life after bariatric surgery.
Material and Methods: This retrospective study included 155 patients who underwent bariatric surgery. Data were collected using the Introductory Information Form, Multidimensional Scale of Perceived Social Support (MSPSS), Depression, Anxiety, Stress Scale-21 (DASS-21), SF 12 Short Form of Quality- of- Life Scale.
Results: The mean total score of depression was 6.75±5.76, the mean total score of anxiety was 6.90±5.38, the mean total score of stress was 6.72±5.91, the mean total score of the MSPSS was 58.30±22.54, the mean total score of Physical Component Summary Score (PCSS) was 44.52±8.75, and the mean total score of Mental Component Summary Score (MCSS) was 49.95±8.35.
Discussion: There was a difference between the mean subscale scores of “stress” and “a special person” according to gender, between the total MSPSS scores and PCSS -12 subscale scores of the patients according to marital status, and between the mean scores of the PCSS -12 and MCSS-12 subscale scores of the individuals according to having a chronic disease, reflecting the quality of life. In improving the quality of life of patients undergoing bariatric surgery, it is important to understand the social support, physical and mental experiences of the patients in this process and to determine their quality-of -life levels.
Keywords: Obesity, Obesity Surgery, Social Support, Life Quality
Introduction
Obesity is a rapidly increasing public health problem worldwide. This problem has serious consequences due to comorbidities. Obesity negatively affects all physical and mental aspects of the body. In addition to comorbid diseases, it can cause anxiety and depression and negatively affect self-esteem and quality of life [1-4].
In addition to somatic consequences, obesity is also known to have a negative impact on patient well-being. It is known that people with obesity often suffer from social problems, as well as stigmatization, depression, anxiety, eating disorders and body image [3, 5].
Studies have shown that bariatric surgery is associated with improved mental health, mental well-being and quality of life. At the same time, psychological and social support has been shown to significantly affect weight loss and mental health [4]. For this reason, many studies on obesity treatment have been conducted all over the world. Bariatric surgery has been shown to be the gold standard for the fastest, permanent and long-term treatment of obesity [6]. Obesity surgery not only provides weight loss but also helps to improve mental health [7].
Increasing obesity in a globalizing world brings with it anxiety, stress and depression. For this reason, new studies are needed to reveal the psychosocial impact of obesity. In our study, we aimed to determine the effect of social support on anxiety, depression, stress and quality of life after bariatric surgery.
Material and Methods
Design and Sample of the Study
The study included patients who underwent bariatric surgery in a private hospital in Samsun between 0l.0l.2020-01.12.2022. Data were collected from all patients willing and voluntarily to participate in the study between December 2022 and included in the study. In the retrospective study, patients were contacted by telephone and asked the survey questions. After obtaining the verbal consent of the individuals who underwent bariatric surgery, an introductory information form and scale questions were applied to the individuals. Multidimensional Perceived Social Support Scale (MSPSS), Depression, Anxiety, Stress Scale-21 (DASS-21), SF 12 Short Form of Quality of Life Scale were applied. The study included patients who were ≥ 18 years of age, had undergone bariatric surgery, could read and write, and did not have moderate or severe psychosis and dementia.
Data Collection Tools and Variables
Descriptive Information Form consists of questions such as age, marital status, height, weight, and BMI.
Multidimensional Perceived Social Support Scale (MSPSS): The scale was developed by Zimet et al. in 1988 and its validity and reliability in Turkish were validated by Eker and Arkar in 1995 (Eker & Arkar, 1995; Zimet, Dahlem, Zimet, & Farley, 1988). The scale consists of 12 Likert-type items. The scale has three subscales reflecting sources of support: family, friends and special person support. The lowest score that can be obtained from the subscales is 4 and the highest score is 28. The total scale score is obtained by summing the scores obtained from the subscales and the lowest score is 12 and the highest score is 84. A high score obtained from the scale indicates high perceived social support [8].
Depression, Anxiety, Stress Scale-21 (DASS-21) was validated by Sarıçam et al. The 21-item scale is divided into three sub-dimensions [9]. Depression, Anxiety and Stress are evaluated separately. In clinical samples, Cronbach’s alpha internal consistency reliability coefficient was α=0.87 for the depression subscale, α=0.85 for the anxiety subscale and α=0.81 for the stress subscale. In our study, the scores for depression, anxiety and stress were α=0.93, α=0.94 and α=0.96, respectively.
SF-12 Short Form of Quality- of- Life Scale: SF-12 consists of 8 subscales and 12 items, including physical functioning (2 items), physical role (2 items), body pain (1 item), general health (1 item), energy (1 item), social functioning (1 item), emotional role (2 items) and mental health (2 items). Items related to physical and emotional role are answered as (yes or no), while other items have Likert-type options ranging between 3 and 6. The Physical Component Summary Score -12 is obtained from general health, physical functioning, physical role and body pain sub-dimensions, whereas the Mental Component Summary Score -12 is obtained from social functioning, emotional role, mental health and energy sub-dimensions. Both the Physical Component Summary Score -12 and Mental Component Summary Score-12 scores ranged from 0 to 100, with a higher score representing better health [10].
Statistical analysis
Number, percentage, mean, standard deviation, median, minimum and maximum statistics were used to analyze the quantitative data. In addition, Cronbach’s alpha statistics were performed for the scale scores. For quantitative measurements, independent two-sample comparisons were made with the Welch t-test. Independent two-multiple sample comparisons were performed by one-way analysis of variance (ANOVA), and in cases where homogeneity of variance was not achieved, the Welch ANOVA test was used. Post Hoc tests were performed to determine the differences between means when ANOVA test results were significant. When homogeneity of variance was ensured, pairwise comparisons were made with the Tukey HSD test, and when homogeneity of variance was not ensured, this was done with Games-Howell tests. A significance level of 0.05 was accepted. Statistical analyses were performed using the SPSS (version 26) program.
Ethical Approval
Written permission for the study was obtained from Sinop University’s Human Research Ethics Committee on 17.11.2022 under decision number 2022/190-218. The purpose of the study was explained by the researchers before data collection and verbal consent was obtained for participation. The study was conducted in accordance with the Declaration of Helsinki.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 155 people were included in the study. Among the participants, 55.48% were female, 48.39% were single and approximately 58% had higher education. The mean age of the participants was 40.41±9.71 years and the mean BMI was 23.84±2.58. In addition, 60% of the participants had chronic diseases (Table 1).
Descriptive statistics related to scale scores are given in Table 2. The mean total score of the participants was 58.30±22.54, the mean total score of depression was 6.75±5.76, the mean total score of anxiety was 6.90±5.38, the mean total score of stress was 6.72±5.91, the mean total score of PCSS was 44.52±8.75, and the mean total score of MCSS was 49.95±8.35 (Table 2).
When the scale scores were compared with gender groups, the mean score of men (46.36±5.43) was higher than the mean score of women (43.03±10.49) in terms of PCSS -12; the mean score of men (51.92±5.82) was higher than the mean score of women (48.36±9.67) in terms of MCSS-12; the mean score of men (21.35±5.22) was higher than the mean score of women (18.55±8.36) in terms of friend dimension; the mean score of the private person sub-dimension was statistically significantly higher for men (21.26±5.19) than for women (18.02±8.84) as well as that of MSPSS (62.94±15.09) compared to women (54.58±26.59) (p=0.012; p=0.005; p=0.012; p=0.005 and p=0.015, respectively) (Table 3).
When the married and single groups were compared in terms of scale scores, the mean score of the married group for anxiety (8.1±6.33) was significantly higher than the mean score of the single group (5.63±3.76), and the mean score of the married group for stress (8.14±7.12) was significantly higher than the mean score of the single group (5.2±3.75) (p=0.003 and p=0.002, respectively). The mean score of MCSS-12 (48,68±9,95) was significantly higher than the mean score of singles (51,3±5,98); the mean score of the friends sub-dimension was significantly higher for the married (18,13±8,38) than for the singles (21,57±5,3); the mean score of the private person sub-dimension was statistically lower in the married group (18.26±9.4) than among singles (20.75±4.73) and the total score from MSPSS was statistically lower in the married group (54.33±27.66) than among singles (62.55±14.35) (p=0.047; p=0.003; p=0.038 and p=0.021, respectively) (Table 3). When those with and without chronic disease were compared in terms of scale scores, the mean MCSS-12 score of those with chronic disease (52±7.26) was statistically significantly higher than that of those without chronic disease (46.87±8.97), while the mean PCSS-12 score of those with chronic disease (43.19±10.32) was statistically lower than that of those without chronic disease (46.51±5.09) (p<0.001 and p=0.009, respectively) (Table 3).
Discussion
Social relationships and social support in obesity have positive effects on the health of individuals [11]. In our study, multidimensional perceived social support scale sub-dimension and total scores were above average. Social ties, especially close ties between friends and spouses, are an important factor in reducing obesity [11]. Obesity has an important place in the socialization process [12]. Interventions can positively affect individuals’ daily life activities and social relations [2].
We determined that depression and anxiety scores in the study were moderate, and the stress level was normal. Depression, anxiety and social isolation can be seen in obese patients, and as a result, their quality of life can be affected [1, 3]. A study has shown that anxiety disorders and depressive symptoms are more common in obese individuals compared to healthy individuals [13]. Surgical intervention in obesity patients was found to be effective in perceived depression, anxiety and stress symptoms [4]. At the same time, depression and eating disorders have been found to affect the quality of life [2].
In our study, the mean scores from the total quality of life, physical and mental component subscales were found to be close to the average. Poor quality of life is the primary factor in patients’ decision to undergo bariatric surgery. Improvements in patients’ quality of life and social life in the postoperative period support this [14]. Bariatric surgery has a significant impact on the long-term assessment of the quality of life [5]. Improvements have been observed in the psychological, physical and social relations aspects of individuals’ lives in the postoperative period [15].
In our study, men had higher scores in the physical dimension of quality of life and perceived social support sub-dimension (friends and special person) compared to women. Psychosocial problems may accompany the treatment process in individuals undergoing bariatric surgery [1]. One study showed a relationship between emotional eating and quality of life in women. Women who did not gain weight were reported to have higher physical quality of life scores [16]. It is essential to follow up patients for a longer period of time before and after surgery in order to obtain a more realistic assessment of the quality of life [16]. Obesity surgery can play an effective role in the mental health and socialization of patients. Gender and weight loss are important variables in psychological health and important determinants of depression in patients with obesity [4].
In our study, anxiety and stress scores of married individuals were found to be high. At the same time, the mental quality of life score, total multidimensional perceived social support, friend and special person sub-dimension scores of married individuals were low. This result is in parallel with the literature [4]. A study has shown that the family support and assistance received by individuals is effective in making them feel good about themselves [1].
In our study, it was determined that individuals with chronic diseases had high mental component scores and low physical component scores for quality of life. Both physical and mental quality of life scores are thought to be associated with other diseases in relation to weight loss [16].
Conclusion
This present study determined that social support, depression, anxiety, stress and quality of life scores were affected in individuals who underwent bariatric surgery. Determining the level of social support provided to patients undergoing bariatric surgery and understanding the physical and psychological experiences of individuals are decisive in improving their quality of life. The paucity of studies on this topic provided the starting point for our study.
Consequently, it may be recommended to conduct qualitative studies to better understand patients and increase the number of quantitative studies to contribute to the literature.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Yasemin Özyer, Kübra Gümüştekin, Kadir Yıldırım. The effect of social support on anxiety, depression, stress and quality of life in obesity surgery. Ann Clin Anal Med 2023;14(Suppl 1):S81-85
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Epidermal growth factor receptor expression and adjuvant chemoradiotherapy in rectal cancer
Murtaza Parvizi 1, Derya Demir 2, Engin Kut 3, Erhan Ergin 4, Semin Ayhan 5, Başak Doğanavşargil 2
1 Department of Radiation Oncology, Manisa State Hospital, Manisa, 2 Department of Pathology, Faculty of Medicine, Ege University, Izmir, 3 Department of Medical Oncology, Manisa State Hospital, Manisa, 4 Department of Internal Medicine, Manisa State Hospital, Manisa, 5 Department of Pathology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey
DOI: 10.4328/ACAM.21649 Received: 2023-02-10 Accepted: 2023-03-16 Published Online: 2023-03-19 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S86-89
Corresponding Author: Murtaza Parvizi, Department of Radiation Oncology, Manisa State Hospital, 45040, Şehzadeler, Manisa, Turkey. E-mail: 45onkoloji@gmail.com P: +90 532 604 06 40 F: +90 236 229 26 50 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0280-7321
This study was approved by the Health Sciences Ethics Committee of Ege University (Date: 2017-01-27, No: 16-12.1/1)
Aim: Epidermal Growth Factor Receptor (EGFR) is a trans-membrane protein with tyrosine kinase activity and is expressed in 25-80% of colon cancer cases. EFGR expression is prognostic in patients with metastatic colorectal cancer, and anti-EGR- based therapies are routinely used in the treatment of patients with metastatic colorectal cancer. To the best of our knowledge, the relationship between EGFR expression and prognosis in directly operated patients who did not receive neoadjuvant treatment and subsequently received chemo-radiotherapy is unknown. Therefore, we retrospectively evaluated patients with stage 3 rectal cancer who underwent surgery without any preoperative treatment in our center and aimed to investigate the relationship between EGFR expression and prognosis in patients who received adjuvant chemoradiotherapy.
Material and Methods: The data of patients who underwent surgery for rectal cancer and received chemoradiotherapy between 2010 and 2016 at Manisa State Hospital were retrospectively analyzed.
Results: According to EGFR expression, it was 127.01 (95% CI, 85.43-168.59) months in the group with 10% less staining and 47.44 (95% CI, 26.77-68.12) months in the group with 10% or more staining. Lymphovascular invasion (p=0.032), perineural invasion (p=0.023), histologic grade (p=0.004) and EGFR expression percentage (p=0.005) were significantly associated with survival in multivariate analyses
Discussion: The presence of 10% or more EGFR expression, LVI, PNI, and histological grade are significantly associated with survival in stage 3 rectal cancer patients who have undergone surgery and received postoperative chemotherapy. These markers can be used as prognostic biomarkers in the follow-up and treatment of these patients.
Keywords: Epidermal Growth Factor Receptor, Chemoradiotherapy, Rectal Cancer, Prognosis
Introduction
According to the Global Cancer Observatory (GLOBACAN), colorectal cancer is the 4th most common cancer in the world and ranks 3rd in terms of mortality. It is known that mortality rates are gradually decreasing in parallel with successful developments towards improving screening programs and treatment [1]. Similar to these developments, in the oncological statistics for 2017, a decrease in incidence and mortality rates was defined [2]. Epidermal Growth Factor Receptor (EGFR) is a trans-membrane protein with tyrosine kinase activity and is expressed in 25-80% of colon cancer cases [3]. In addition to being known to be more highly expressed in left colon tumors, EGFR expression has been reported to be associated with cancer cell proliferation, apoptosis, angiogenesis, tumor invasion and distant metastasis [4], and therapies targeting EGFR in metastatic patients are currently used in daily practice in lung, colon and head and neck cancers. Currently, neoadjuvant radiochemotherapy is recommended as the standard treatment for patients with clinical >T3 or lymph node-positive rectal cancer [5]. However, in addition to the prejudice against radiotherapy, fear and anxiety about the progression of the disease during the neoadjuvant treatment period, surgery may sometimes be preferred as the first treatment method in rectal cancer cases due to the preference of the patients, the presence of clinical symptoms or the presence of conditions such as ileus, bleeding, etc., that require urgent surgery, or the difference between the radiological stage and the actual pathological stage.
To the best of our knowledge, the relationship between EGFR expression and prognosis in directly operated patients who did not receive neoadjuvant treatment and subsequently received chemo-radiotherapy is unknown. Therefore, we retrospectively evaluated patients with stage 3 rectal cancer who underwent surgery without any preoperative treatment in our center and aimed to investigate the relationship between EGFR expression and prognosis in patients who received adjuvant radiotherapy/radiochemotherapy.
Material and Methods
Study Population
Between 2010 and 2016, 89 patients diagnosed with “Adenocarcinoma of the Rectum” at Manisa State Hospital were retrospectively reevaluated. Among these patients, 50 patients who received neoadjuvant treatment were excluded and 39 patients with stage 3 who received postoperative adjuvant treatment were included in the study.
Data collection
Morphological and clinical prognostic parameters (age, gender, tumor location, tumor size, histological grade of tumor, postoperative TNM stage, perineural invasion (PNI), lymphovascular invasion (LVI), EGFR staining status and severity) were evaluated. The relationship between defined prognostic findings and survival (disease-free survival, overall survival, recurrence, metastasis development, serum CEA, CA19-9 levels at the time of diagnosis) values, EGFR expressions were retrospectively analyzed.
EGFR expression was investigated by immunohistochemistry in rectal adenocarcinoma patients who received adjuvant treatment and evaluated in comparison with morphologic, clinical prognostic parameters and survival time. Overall survival was defined as the time from the date of diagnosis until death. Disease-free survival was defined as postoperative disease progression or death due to any cause.
The hematoxylin-eosin stained slides of the cases were removed from the archive and re-evaluated and blank sections were prepared for immunohistochemical examination from the blocks of the selected appropriate slides (sufficient tumor in the biopsy and/or surgical material). Immunohistochemistry was performed automatically on 3-5 micron thick sections prepared from formalin-fixed paraffin blocks of the cases using EGFR antibody on a Leica BondMax immunohistochemistry device. EGFR (clone: EGFR.113, Leica-Novocastra, 1:20 dilution) primary antibodies were investigated by immunohistochemistry. The severity and intensity of positive staining were evaluated. Membranous and/or cytoplasmic staining was considered positive. EGFR staining intensity and intensity were interpreted semi-quantitatively (staining intensity +1, +2 and +3 positive; staining intensity “negative”, “less than 10% positive”, “10%-49% positive”, “50% or more positive”). EGFR staining and evaluation were performed on the resection material and evaluated.
Ethical approval
The study was conducted in accordance with the principles of the Declaration of Helsinki and reviewed and approved by the Health Sciences Ethics Committee of Ege University (Approved with reference number 70198063-0500.06.04 and identification number 16-12.1/1, Date: 27/01/2017)
Statistical analysis
Descriptive statistics were presented as mean, standard deviation, median, minimum and maximum values for numerical variables and as numbers and percentages for categorical variables. Survival analyses were performed using the Kaplan-Meier method. Factors affecting survival were examined using the Cox regression. p < 0.05 was considered significant in all statistical analyses.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Thirty-nine patients were included in this study. The pathology blocks of 11 patients were excluded from the study because of deterioration due to poor storage conditions and the remaining 28 patients were analyzed. Of the patients, 13 (46.4%) were female and 15 (53.6%) were male. The mean age of the patients was 60.93 (± 9.86) and is summarized in Table 1. All patients in the study received oral capecitabine chemotherapy concurrently with adjuvant radiotherapy followed by adjuvant 6 months of capecitabine oxaliplatin. At the time of evaluation, the median follow-up period was 60 (18.06-168.59) months, during which 2 (7.14%) patients developed local recurrence, 5 (17.86%) patients developed liver metastasis, 4 (14.29%) patients developed lung metastasis, 2 (7.14%) patients developed lymph node metastasis, and 1 (3.57%) patient developed brain metastasis. The presence of EGFR Expression was under 10% in 11(29.95%) patients and 10% or more in 17 (71.05%) patients.
Overall survival was defined as 59.63 (95% CI, 18.08-108.38) months in the group with 10% or more staining. According to EGFR expression, it was 127.01 (95% CI, 85.43-168.59) months in the group with 10% less staining and 47.44 (95% CI, 26.77-68.12) months in the group with 10% or more staining. In univariate analyses, survival was significantly associated with histologic grade (p=0.006), N1 stage (p= 0.036), N2 stage (p=0.002), LVI (p=0.012), PNI (p=0.011) and EGFR expression percentage (p=0. 009) were identified as significant, while LVI (p=0.032), PNI (p=0.023), histologic grade (p=0.004) and EGFR expression percentage (p=0.005) were significantly associated with survival in multivariate analyses (Table 2) (Figure 1).
Discussion
When we look at the studies conducted on patients receiving radiotherapy in rectal cancer, since preoperative radiochemotherapy or radiotherapy is the standard treatment in locally advanced diseases, most of the studies include patients receiving preoperative treatment, but sometimes in daily practice, patients can be operated directly for some reasons and then receive adjuvant radiotherapy. We conducted this study to examine the relationship between EGFR expression and prognosis in this group. In our study, we found a relationship between eEGFR expression and the prognosis of patients with stage 3 rectal cancer who received adjuvant chemoradiotherapy.
Studies started with the first identification of epidermal growth factor (EGF) as an eye-opening protein in baby mice by Staley Cohen in 1962, followed by the identification of the EGFR receptor in 1975 and the determination of increased phosphorylation and tyrosine kinase activity when squamous cell carcinoma cells bind to EGF in the 1980s, began to take its place in clinical oncology [6]. EGFR is a transmembrane protein with tyrosine kinase activity and has been investigated in many cancers and its overexpression has been reported to be associated with proliferation, apoptosis, angiogenesis, tumor invasion and distant metastasis in many tumors [4]. Anti-EGFR-based therapies targeting EGFR in metastatic disease are widely used in colon, lung and head and neck tumors. Studies have also reported that patients with EGFR overexpression have more advanced-stage disease, worse histologic grade and lymphovascular invasion [7]. Longer survival times are observed with treatments including anti-EGFR therapy compared to those without [8-9]. While EGRF expression was defined between 25-80% in colon cancers in different studies, this rate was reported to be around 50-60% in rectal cancers [10]. Despite the observed EGRF expression, EGRF expression was found to be associated with prognosis in some studies involving patients with colon cancer independent of tumor stage, while no association with prognosis was defined in others [10-12]. It has been reported that the reason for the different results in EGFR-prognosis studies and the 25-80% difference between studies on EGFR-EGFR expression is related with the difficulties in the evaluation of staining, kit difference, center difference and staining difficulties in pathology samples in retrospective studies in which old blocks were evaluated [10]. In our study, staining was not detected in 28% of the patients due to storage conditions of old preparations, tissue loss during sectioning, etc.
Huang et al. studied non-metastatic patients who were only operated and received adjuvant chemotherapy, and found a correlation between EGRF expression and prognosis in stage 3 colorectal cancers. They reported the presence of EGFR expression as a negative predictive factor for disease recurrence [11].
Previous studies have reported that EGR expression activates intracellular communication pathways, causing malignant transformation and tumor progression through increased cell proliferation, long-term survival, angiogenesis, antiapoptosis, invasion and metastasis. In studies on radiotherapy, it was reported that after radiotherapy, radiotherapy was associated with the presence of resistant tumor, and patients with EGFR overexpression had more local recurrence, lower stage and worse prognosis [3, 7-15].
Although the standard treatment for stage III rectal cancer is neoadjuvant radiochemotherapy/radiotherapy, stage III patients are rarely referred for postoperative adjuvant treatment in some cases. In our study, we found that patients with EGFR expression above 10% had shorter survival times, and this group of patients had a poor prognosis similar to patients who received preoperative radiochemotherapy/radiotherapy.
We also confirmed the presence of a poor relationship between LVI and PNI and prognosis in our study in accordance with the literature (16-21), but we concluded that the lack of a relationship with T, N stage and histologic grade, which we know are normally associated with prognosis in colorectal cancers, may be due to the small number of cases and the small number of patients between the groups (for example, the number of patients with grade 1 was only 3).
The retrospective nature of our study and the small number of patients constitute the weaknesses of our study. However, in addition to the small number of patients, we believe that it will be beneficial to the deficiency in the literature on this subject. Our study is important because it is the first study to correlate EGRF expression with prognosis in rectal cancer patients who received postoperative radiotherapy and fills the gap in the literature in this field.
Conclusion
According to our study, the presence of EGFR expression of 10% or more, LVI, PNI and histologic grade are significantly associated with survival in operated stage 3 rectal cancer patients. These markers can be used as prognostic biomarkers in the follow-up and treatment of these patients.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
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Murtaza Parvizi, Derya Demir, Engin Kut, Erhan Ergin, Semin Ayhan, Başak Doğanavşargil. Epidermal growth factor receptor expression and adjuvant chemoradiotherapy in rectal cancer. Ann Clin Anal Med 2023;14(Suppl 1):S86-89
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Is double frozen blastocyst transfer better than sequential single frozen blastocyst transfers in womenover >35 years of age?
Sinem Ertas 1, Kayhan Yakın 1, 2, Basak Balaban 2, Bulent Urman 1, 2
1 Department of Women’ Health and IVF Unit, American Hospital, 2 Department of Obstetrics and Gynecology, Faculty of Medicine, Koc University, Istanbul, Turkey
DOI: 10.4328/ACAM.21666 Received: 2023-02-25 Accepted: 2023-03-23 Published Online: 2023-03-24 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S90-94
Corresponding Author: Sinem Ertas, Department of Women’s Health and IVF, American Hospital, 34365, Sisli, Istanbul, Turkey. E-mail: drsinemertas@gmail.com P: +90 535 921 40 60 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1699-616X
This study was approved by the Institutional Review Board (IRB) Ethics Committee of Koc University (Date: 2021-01-16, No: 2021.002.IRB1.002)
Aim: This study aimed to assess live birth rates after double blastocyst transfer versus sequential single blastocyst transfers after freeze-all cycles in women aged over 35 years.
Material and Methods: Between January 2016 and December 2018, we conducted a retrospective analysis of 296 women over 35 years of age who had all their embryos frozen and subsequently transferred. The inclusion criteria were women over 35 years of age who had their entire cohort of embryos frozen at the blastocyst stage for different indications based on physician preference. All patients had at least two good-quality embryos in their frozen cohort. Preimplantation genetic testing cycles were excluded from the study. Demographic data were extracted from patient files and electronic databases. Women were categorized based on their mode of embryo transfer (D-FBT vs. SS-FBT). The couple decided to adopt one or more strategies after consultation. The study’s primary outcome was the live birth rate (LBR) per woman after one double versus two sequential single embryo transfers.
Results: Overall, 296 women underwent 362 embryo transfer cycles (D-FBT=186; SS-FBT=176). When adjusted for female age, the cumulative LBR per woman was similar in D-FBT (46.2%) and SS-FBT (58.2%) (p=0.054, aHR=1.62, 95% CI:1.00-2.60). While one monozygotic twin delivery was observed in the SS-FBT group, 22 of 86 (25.6%) live births after D-FBT were twins.
Discussion: Following a freeze-all cycle, SS-FBTs yielded similar live birth rates (LBR) as D-FBT in women aged over 35 years.
Keywords: Freeze-all, Embryo Transfer, Blastocyst, Multiple Pregnancies, In Vitro Fertilization
Introduction
In the early years of In Vitro Fertilization (IVF), multiple embryos were transferred into the uterus to compensate for low implantation rates. However, advances mainly in the IVF laboratory, including better culture media, more advanced incubators, and particularly embryo vitrification, together with the realization of complications of multiple pregnancies, have reduced the number of embryos recommended for transfer. This paradigm change occurred concurrently with advances in embryo freezing techniques. Embryo vitrification results in excellent post-thaw survival and implantation rates that are equivalent, if not better, than fresh transfers [1]. Freezing all embryos for later transfer quickly became a widespread practice to prevent ovarian hyperstimulation syndrome, hinder the adverse effects of ovarian stimulation on implantation, and correct incidental endometrial pathologies encountered during ovarian stimulation [2, 3].
Currently, it is customary to transfer a single embryo, especially if the quality is good and the patient does not have adverse prognostic factors such as advanced age and previous implantation failures. Vitrification directly contributes to the worldwide acceptance of elective single embryo transfer, which may be the best choice for preventing maternal/fetal complications associated with multiple pregnancies [4-6]. Defining embryo quality for successful elective single embryo transfer (eSET) is fundamental.
According to Turkish IVF legislation, single embryo transfer is mandatory in women under 35 years of age, after which no more than two embryos are allowed. However, a considerable number of patients and physicians prefer embryos to be transferred individually, regardless of age. Although retrospective and prospective studies have compared fresh sequential single embryo transfer versus double embryo transfer, there is a lack of data regarding the outcome of freeze-all cycles.
This study aimed to assess live birth rates after double blastocyst transfer versus sequential single blastocyst transfers after freeze-all cycles in women aged> 35 years.
Material and Methods
Study population and Participants
This study is a retrospective analysis of 362 frozen embryo transfer (FET) cycles in 296 couples undertaken in a single tertiary care private hospital-assisted reproduction center between January 2016 and December 2018. Patients provided consent for anonymous analysis and publication of the gathered data for scientific purposes.
We screened 860 patient files in which the cohort of embryos was cryopreserved at the blastocyst stage for various indications. Of these, 296 women aged 35-45 years who had at least two good-quality blastocysts vitrified on the fifth day were selected. The current Turkish legislation that has been in effect since 2010 allows the transfer of two embryos only after 35 years of age, that is why an older cohort was chosen for analysis [7]. Couples undergoing pre-implantation genetic testing and patients with > 2 prior implantation failures were excluded from the study. Patients were categorized and analyzed based on the mode of embryo transfer [one double frozen blastocyst transfer (D-FBT) versus two sequential single frozen blastocyst transfers (SS-FBT)] (Figure 1).
Demographic and clinical data were extracted from patient files and electronic records.
Interventions
Ovarian stimulation, oocyte retrieval, fertilization, vitrification, and warming
Ovarian stimulation was performed using recombinant follicle-stimulating hormone (FSH) alone or in combination with human menopausal gonadotropin (HMG). Premature luteinizing hormone (LH) surge was suppressed by using a gonadotropin-releasing hormone (GnRH) antagonist in a fixed protocol. The final maturation of oocytes was induced with 250 μg recombinant human chorionic gonadotropin (hCG) or leuprolide acetate in the event of overstimulation. Oocyte retrieval was performed under general anesthesia 35-36 h after the ovulation trigger, using a double-lumen needle. Intracytoplasmic sperm injection (ICSI) was used to fertilize the oocytes.
All included patients had at least two day 5 embryos with grade 3BB and above that were vitrified [8].
Correction of uterine pathology
Patients with endometrial polyps discovered during ovarian stimulation underwent hysteroscopic removal prior to vitrified/warmed embryo transfer.
Endometrial preparation for vitrified/warmed embryo transfer
All vitrified-warmed embryo transfers were performed in an artificial cycle without downregulation. On menstrual cycle day 2 or 3, a baseline transvaginal ultrasound examination was carried out to rule out the presence of a corpus luteum, follicle-s > 10 mm in size, or uterine pathology. If all conditions were met, estradiol valerate tablets (2 mg three times a day) were started. Endometrial thickness, echogenicity, and ovarian activity were checked after 10-12 days. Embryo transfer was planned if the endometrial thickness was at least 8 mm with a triple-line appearance, and there were no follicles measuring 10 mm in size. Embryo transfer was performed on the 6th day after once-daily progesterone gel administration. The dosage was increased to twice daily. All embryo transfers were performed under ultrasound guidance using a Wallace or Cook catheter.
Before embryo transfer, clinicians counseled couples regarding the success and risks of transferring more than one embryo, and encouraged the transfer of a single embryo. The number of embryos to be transferred was determined based on a shared decision between the patient and attending physician.
Statistical evaluation
The collected data were assessed for distribution characteristics using the Kolmogorov-Smirnov test. Continuous variables were defined as median (25th- 75th percentile), and categorical variables were defined as frequency and rate. The two groups were compared using the Mann-Whitney U test for continuous data and the Chi-Square or Fisher’s exact tests for categorical data. The primary outcome was the live birth rate per initiated cycle, and the secondary outcome was the multiple birth rate. A generalized estimating equation model and logistic regression analysis were performed to adjust for confounding factors. Some confounders with biological plausibility derived from the literature were selected. Statistical significance was set at a two-tailed p-value <0.05.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 362 embryo transfer cycles (176 single and 186 double blastocyst transfers) in 296 women aged over 35 years were analyzed (Figure 2). The mean age of the women was 39 years (range: 36-41). The indications for IVF were male factor in 121, female factor in 97, and unexplained in 78 couples. Freeze-all indications were physician preference (n:219), overstimulation and/or serum progesterone level >1.5 ng/mL on the day of hCG administration (n:61), and endometrial polyps discovered during ovarian stimulation (n:16). Descriptive characteristics were comparable between the D-FBT and sequential SS-FBT groups (Table 1).
Gonadotrophin dose, estradiol level on the day of trigger, number of oocytes collected, number of Metaphase II (MII) oocytes, fertilization rate, and number of vitrified blastocysts on day 5 of embryo culture did not differ between the groups (Table 2).
Of the 186 women who had transferred two vitrified-warmed blastocysts, 119 (64%) had a positive pregnancy test result, 86 pregnancies resulted in live births (46.2%), and 33 had preclinical and clinical pregnancy losses (Table 2). Of the 110 women who had transferred a single blastocyst, 52 (47.3%) had a positive pregnancy test result, and 44 pregnancies resulted in live births (40.0%). Sixty-six women (58 who failed to conceive and eight who had a pregnancy loss) underwent a second single blastocyst transfer and achieved a pregnancy rate of 37.9% (25/66) and a live birth rate of 30.3% (20/66). Implantation rates (ultrasound verified gestational sac) were 37.9% in the D-FBT, 44.5% in the first SS-FBT, and 33.3% in the second SS-FBT cycle. While only one monozygotic twin delivery was observed in the SS-FBT group, 22 of 86 deliveries (25.6%) in the D-FBT group were twins. The cumulative live birth rate per initiated cycle was higher in the SS-FBT group (58.2%) than that in the D-FBT group (46.2%). However, when adjusted for female age (the only variable associated with the live birth rate in multivariate analysis), the likelihood of a live birth per cycle initiated was similar between the two groups (p=0.054, aHR=1.62, 95% CI:1.00-2.60).
Discussion
Our results show that when adjusted for female age, SS-FBT results in a similar cumulative live birth rate as one D-FBT in freeze-all cycles. While only one twin delivery was observed with SS-FBT (1 of 44+20; 1.6%), 22 of 86 (25.6%) live births after D-FBT were twins.
IVF success is measured by the rate of a healthy singleton infant delivered with normal weight [5]. eSET is becoming more common because of the recognition of risks associated with multiple pregnancies [9]. In IVF patients with good prognosis, specifically women younger than 37 years of age in their first or second IVF cycle, and when good-quality embryos are available, elective single embryo transfer is recommended by the Practice Committee of the American Society for Reproductive Medicine [10].
eSET results in a higher chance of delivering a term singleton live birth than double embryo transfer (DET). Although this strategy yields a lower pregnancy rate than double embryo transfer in a fresh IVF cycle, this difference is almost entirely overcome by an additional single embryo transfer cycle. The multiple pregnancy rate after eSET is comparable to that observed in spontaneous pregnancies [11]. However, the goal and definition of success can change for couples with prolonged infertility problems. eSET can increase costs, lengthen the time to become pregnant, and reduce the chance of a second child for older couples [12]. Despite all potential adverse maternal outcomes, women older than 35 years are still more inclined to have twin pregnancies [13]. The above notwithstanding, it has been shown that almost 30% of clinicians decide on how many embryos to transfer without consulting their patients. More than one-third of patients do not know if they prefer singleton or twin gestation [14].
One recent study suggested that in cleavage stage freeze-all cycles, eSET should be offered to women aged 35-40 with favorable and average prognosis because the twinning rate can reach more than 20% in these groups; only in the poor prognosis group, DET should be offered [15]. In our study, despite the age of patients > 35 years, the twinning rate was 25.6% in the D-FBT group. However, it should be noted that this group carried favorable characteristics, such as the presence of at least two good-quality blastocysts on day five of embryo development, which cannot be generalized.
Most of the accumulated data regarding the outcomes of single versus double embryo transfers are gathered from the transfer of embryos during fresh IVF cycles. As the freeze-all policy is gaining momentum, it is crucial to know whether transferring sequential single embryos yields equivalent or higher pregnancy rates and lower multiple birth rates than double embryo transfers.
Eum et al. compared the outcomes of double versus sequential single embryo transfer (Seq SET) in both fresh and vitrified-warmed cycles [16]. Single-embryo transfer cycles included both compulsory and elective transfer. They also analyzed the outcomes in terms of female age. In women aged 35 years, pregnancy rates were similar in the elective SET and DET groups (52.0% vs. 54.3%, p = 0.77). Likewise, there was no difference in live birth rates (38.0% vs. 50.0%, p = 0.12). However, the multiple pregnancy rate was significantly higher in the DET group than in the eSET group, regardless of age (p = 0.005 and p = 0.002, respectively). Unfortunately, the study design is prone to introducing several biases that may confound the results. Furthermore, cumulative pregnancy and live birth rates were not assessed.
Park et al. categorized all vitrified-warmed blastocyst transfer cycles into three groups according to the number and quality of blastocysts transferred in women aged > 35 years [17]. This study concluded that to reduce the high number of multiple pregnancies, single good-quality blastocyst transfers are recommended in the freeze-all for patients over 35 years. This study also presumed that SS-FBT would be better than D-FBT in freeze-all cycles over 35 years of age. Another recent study from the same group evaluated patients from all age groups and reached similar conclusions [18].
Long et al. evaluated the effect of blastocyst or cleavage-stage embryo transfers on pregnancy outcomes in 24422 frozen-thawed cycles [19]. According to the results of this study, single-blastocyst embryo transfer appears to be the best choice for all age groups [19].
Monteleone et al. evaluated sequential SET (n:237) versus DET (n:373) strategies in 610 cycles, in which the patients received a fresh or frozen embryo in their first cycles [20]. The success rates were similar between the groups (Sequential SET: 45.9% vs. DET: 46.6%), and the multiple pregnancy rate was significantly lower in the sequential SET (6.7%) group than in the DET (32.2%) group. However, this study differs from ours, as the investigators included cycles in which the patients received either fresh or frozen embryo transfers at the cleavage or blastocyst stages. Furthermore, the patients were relatively younger (Seq SET vs. DET; 33.6-33.9 years, respectively) than those included in our study.
It may be argued that the treatment costs will be lower in the DET group due to the shorter time and fewer cycles utilized to achieve pregnancy. Crawford et al. showed that Seq SET among women younger than 35 years of age resulted in higher treatment costs than DET; however, it also showed that pregnancy/infant-associated medical expenses were markedly lower, resulting in lower overall costs [21]. However, the twinning rate is lower in advanced-aged patients; thus, a cost-effectiveness analysis is needed for this patient group [15].
Conclusion
Our results show that over 35 years of age, SS-FBT has similar LBR success as D-FBT in a freeze-all environment. Thus SS-FBT rather than D-FBT should be offered to women aged > 35 years in the presence of good-quality blastocysts available for transfer. The strengths of this study include the homogenous patient population and the adjustment for all potential confounders. Limitations are the relatively small number of patients analyzed, the fact that only patients aged > 35 years were included, the unavailability of cost-effectiveness analysis, and the retrospective nature of the study. Future studies should analyze double versus sequential single embryo transfers from the perspective of cost-effectiveness. More conclusive evidence can only be obtained in properly designed large-scale randomized studies.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Nagy ZP, Shapiro D, Chang C-C. Vitrification of the human embryo: a more efficient and safer in vitro fertilization treatment. Fertil Steril. 2020;113(2):241-7.
2. Davenport MJ, Vollenhoven B, Talmor AJ. Gonadotropin-Releasing Hormone–Agonist Triggering and a Freeze-All Approach: The Final Step in Eliminating Ovarian Hyperstimulation Syndrome? Obstet Gynecol Surv. 2017;72(5):296-308.
3. Roque M, Valle M, Sampaio M, Geber S, Haahr T, Humaidan P, et al. Freeze-all strategy in IVF/ICSI cycles: an update on clinical utility. Panminerva Medica 2018;61(1):52-57.
4. Technology PCotSfAR, Medicine PCotASfR. Elective single-embryo transfer. Fertil Steril. 2012;97(4):835-42.
5. Cutting R. Single embryo transfer for all. Best Pract Res Clin Obstet Gynaecol. 2018;53:30-37.
6. Gerris J, De Neubourg D. Single embryo transfer after IVF/ICSI: present possibilities and limits. J Obstet Gynecol India. 2005;55(1):26-47.
7. Urman B, Yakin K. New Turkish legislation on assisted reproductive techniques and centres: a step in the right direction? Reprod Biomed Online 2010;21(6):729-31.
8. Kuwayama M. Highly efficient vitrification for cryopreservation of human oocytes and embryos: the Cryotop method. Theriogenology. 2007;67(1):73-80.
9. Kjellberg AT, Carlsson P, Bergh C. Randomized single versus double embryo transfer: obstetric and paediatric outcome and a cost-effectiveness analysis. Hum Reprod. 2006;21(1):210-16.
10. Medicine PCotASfR, Technology PCotSfAR. Criteria for number of embryos to transfer: a committee opinion. Fertil Steril 2013;99(1):44-46.
11. McLernon DJ, Harrild K, Bergh C, Davies MJ, De Neubourg D, Dumoulin J, et al. Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials. BMJ. 2010; 341. DOI: 10.1136/bmj.c6945.
12. Gleicher N. The irrational attraction of elective single-embryo transfer (eSET). Hum Reprod. 2013;28(2):294-7.
13. van Loendersloot L, van Wely M, Goddijn M, Repping S, Bossuyt P, van der Veen F. Pregnancy and twinning rates using a tailored embryo transfer policy. Reproductive Biomedicine Online 2013;26(5):462-9.
14. Glujovsky D, Sueldo CE, Coscia A, De Carvalho P, Lancuba S, Martinez G, et al. Physicians and patients’ motivations to perform elective single or double-embryo transfers: A nationwide survey. Patient Educ Couns. 2018;101(5):945-50.
15. Xue Y, Li K, Zhang S. The effect on twinning rate of transferring double vitrified-warmed embryos in women of advanced reproductive age: a retrospective study. Peer J 2020;8:e8308.
16. Eum JH, Park JK, Kim SY, Paek SK, Seok HH, Chang EM, et al. Clinical outcomes of single versus double blastocyst transfer in fresh and vitrified-warmed cycles. Clin Exp Reprod Med. 2016;43(3):164-8.
17. Park DS, Kim JW, Chang EM, Lee WS, Yoon TK, Lyu SW. Strategies in the transfer of varying grades of vitrified-warmed blastocysts in women aged over 35 years: A propensity-matched analysis. J Obstet Gynaecol Res 2019;45(4):849-57.
18. Park DS, Kim JW, Eum JH, Lee WS, Yoon TK, Lyu SW. Clinical and pregnancy outcomes of double and single blastocyst transfers related with morphological grades in vitrified-warmed embryo transfer. Taiw J Obstet Gynecol. 2020;59(3):398-402.
19. Long X, Wang Y, Wu F, Li R, Chen L, Qian W, et al. Pregnancy Outcomes of Single/Double Blastocysts and Cleavage Embryo Transfers: a Retrospective Cohort Study of 24,422 Frozen-Thawed Cycles. Reprod Sci. 2020;27(12):2271-8.
20. Monteleone PA, Peregrino PF, Baracat EC, Serafini PC. Transfer of 2 embryos using a double-embryo transfer protocol versus 2 sequential single-embryo transfers: The impact on multiple pregnancy. Reprod Sci. 2018;25(10):1501-8.
21. Crawford S, Boulet SL, Mneimneh AS, Perkins KM, Jamieson DJ, Zhang Y, et al. Costs of achieving live birth from assisted reproductive technology: a comparison of sequential single and double embryo transfer approaches. Fertil Steril. 2016;105(2):444-50.
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Sinem Ertas, Kayhan Yakın, Basak Balaban, Bulent Urman. Is double frozen blastocyst transfer better than sequential single frozen blastocyst transfers in womenover >35 years of age? Ann Clin Anal Med 2023;14(Suppl 1):S90-94
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Validity and reliability of the fear of COVID-19 scale (FCV-19) in Turkish pregnant women
Ebru Yuce
Department of Gynecology and Obstetrics, Faculty of Medicine, Yuksek Ihtisas University, Liv Hospital, Ankara, Turkey
DOI: 10.4328/ACAM.21670 Received: 2023-02-28 Accepted: 2023-03-22 Published Online: 2023-03-23 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S95-98
Corresponding Author: Ebru Yuce, Department of Gynecology and Obstetrics, Faculty of Medicine, Yuksek Ihtisas University, Liv Hospital, 06680, Çankaya, Ankara, Turkey. E-mail: dr.ebruk@gmail.com P: +90 312 666 40 00 Corresponding Author ORCID ID: https://orcid.org/0000-0003-4907-7730
This study was approved by the Ethics Committee of Yuksek Ihtisas University (Date: 2020-11-11, No: 2020/13/02)
Aim: The emergence of coronavirus disease 2019 (COVID-19) has not only create international concern, but also caused panic, fear, and an increase in mental health problems among individuals. Fear of COVID-19 Scale (FCV-19S), developed by Ahorsu, was previously reported as a valid psychometric instrument for the assessment of COVID-19 fear among individuals. Validation of the scale among other high-risk groups like pregnant women may help obstetricians develop better coping skills during the pandemic.
Material and Methods: This cross-sectional methodological study included 277 pregnant women admitted for routine follow-up at the outpatient obstetrics clinic of Liv Ankara Hospital, Turkey. Participants were asked to complete the Turkish version of the Hospital Anxiety and Depression Scale (HADS) and FCV-19S. Statistical analysis was performed using SPSS 25 software.
Results: The mean FCV-19S score was 19.2±5.7 (range: 7-35). Cronbach’s alpha for internal consistency evaluating the reliability of FCV-19S, was 0.857, revealing a satisfactory internal consistency. According to the correlation matrix analysis, all items of FCV-19S showed positive and strong correlations with total FCV-19S scores (p<0.001), and positive and moderate correlations with HADS scores (p<0.001).
Discussion: Turkish version of FCV-19S is a valid and reliable clinical tool to assess the anxiety of pregnant women during the COVID-19 pandemic in Turkey.
Keywords: Fear of COVID-19, Pregnant Women, Turkey, Anxiety
Introduction
The emergence of coronavirus disease 2019 (COVID-19) has led to a global health burden worldwide. The World Health Organization (WHO) announced COVID-19 as one of the most critical public health emergencies of the 21st century, considering the mortality and morbidity of the disease itself. The rapid spread of the disease and the high contagiousness have not only created international concern, but also caused panic, fear, and an increase in mental health problems among individuals. As of the second year of the WHO announcement, more than 460 million cases were diagnosed, and more than 6 million people died due to the COVID-19 disease (available from: https://covid19.who.int/). In recent research on COVID-19 pandemic, it has been well documented that the disease is responsible for precipitating several psychological and mental disorders [1].
Since the beginning of the pandemic, many preventive measures have been implemented. Countries have limited their social life, shifted to home-based work, and applied lockdowns and other strict quarantine measures. However, uncertainties regarding the prognosis, rapid deterioration of the health status in infected individuals, myths, and misinformation caused high anxiety and depression. High-risk groups characterized by high clinical vulnerability for severity and mortality by COVID 19 including patients diagnosed with diabetes mellitus, hypertension, and cardiovascular disease have been another public health concern for governments. [2]. Especially after the emergence of the Delta variant in June of 2021, pregnant women have come to be considered another high-risk group. Based on the data from previous severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) epidemics, it has been alleged that COVID may be associated with high incidences of spontaneous miscarriage, preterm delivery, and intrauterine growth restriction as well [3, 4]. It is well known that stress and anxiety during pregnancy can trigger a cascade of events that can cause serious mortality and morbidity. Despite the lack of reliable information on pregnancy and its complications during coronavirus infection, COVID-19 is obviously an influential factor in the mental health of the pregnant [5]. Hence accurate and precise evaluation of COVID-19 anxiety during pregnancy has become eminent for the prevention of adverse maternal and fetal outcomes. It has been previously reported that the Fear of COVID-19 Scale (FCV-19S), developed by Ahorsu et al., is a valid psychometric instrument for the assessment of COVID-19 fear among individuals [6]. In this study, we aimed to evaluate the reliability of FCV-19S’s validation for use in Turkey among pregnant women.
Material and Methods
This cross-sectional methodological study was conducted at Obstetrics and Gynecology Department of the Liv Ankara Hospital affiliated with Yuksek Ihtisas University in Ankara, Turkey. Pregnant women admitted for routine follow-up visits at outpatient clinics were informed about the study, and written informed consent was obtained from those who accepted. Inclusion criteria were age ≥18 years and the ability to understand written and spoken Turkish.
Initially, participants were asked to complete a sheet consisting of basic socio-demographic information. After that, participants completed the Turkish version of the Hospital Anxiety and Depression Scale (HADS) and FCV-19S, respectively translated by Turkish researchers.
The HADS scale is a questionnaire that contains 14 items and consists of 2 subscales: anxiety and depression. HADS has long been proven to be a reliable clinical tool for the assessment of depression and anxiety [7].
FCV-19S is a seven-item scale assessing the responder’s fear of a pandemic situation [6]. Within the scope of the primary hypothesis of the study, the data to be collected using the two scales (HADS and FCV-19S ) will be subjected to a validity-reliability analysis, and within the scope of the secondary hypothesis, associations between scale scores and demographic and clinical characteristics will be analyzed.
The sample size of the study was determined according to multivariate analyzes described elsewhere by Tabachnik and Fidell [8] by assuming the following parameters: a type I error of 5%; a power of 90%. Consequently, 250 pregnant women were recruited with a 10% non-response and/or data loss rate.
Internal consistency was evaluated using Cronbach’s alpha coefficient. Pearson’s correlation analysis was used for correlations between numerical data. Exploratory factor analysis (EFA) was also performed for examining the underlying structure of the tests. Statistical analysis of the study was performed with SPSS 25 software.
The study protocol was approved by the Ethics Committee of Yuksek Ihtisas University (Date:11/11/2020; Approval No: 2020/13/02).
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
A total of 277 pregnant women were included in the study. The basal demographic characteristics of patients are presented in Table 1.
The mean FCV-19S score was 19.2±5.7 (range: 7-35) (Table 2).
The distribution of the responses to FCV-19S items and the distribution of the total FCV-19S scores are shown in Figure 1.
The reliability of the FCV-19S was evaluated using Cronbach’s alpha for its internal consistency, which was 0.857, revealing a satisfactory internal consistency. Also, the reliability was analyzed using item-total score correlations for FCV-19S and correlations with HADS anxiety and depression scores. The correlation matrix is presented in Table 3.
Accordingly, all items of FCV-19S showed positive and strong correlations with total FCV-19S scores and positive and moderate correlations with HADS anxiety and depression scores.
The psychometric characteristics of the FCV-19S regarding construct validity were evaluated using exploratory factor analysis utilizing principal component analysis. The Kaiser-Meyer-Olkin statistics was 0.83, suggesting the adequacy of sampling for the analysis, and Bartlett’s test was statistically significant (p<0.001), indicating that the data matrix was adequate to analyze. The exploratory factor analysis revealed a two-factor structure. The initial factor included the first item of FCV-19S that questioned if the patient had COVID fear, and the second one included the remaining six items (Table 3). A two-factor structure explained 73.1% of the total variance in the sample population.
Discussion
The results of our study show that the fear of COVID-19 scale is a valid and reliable clinical tool to assess the anxiety of pregnant women during the COVID-19 pandemic in Turkey.
Previous studies have shown that the psychometric properties of this 7-item scale can adequately and consistently evaluate COVID-19 fear among individuals. The validity and reliability studies of the scale for use in Arabia, Israel, Italy and Eastern European countries were completed in a short period after the original study was published, and in a recent large-scale study Italian version of the scale was also reported to be a reliable and valid tool for assessing the severity of fear of COVID-19 [9].
Although the detrimental effects of quarantine measures on the mental health of individuals have been well documented [10], there are no properly defined preventive strategies for stress and anxiety related to COVID-19. FCV-19S may help in terms of foreseeing the excessive fear related to disease and help in terms of stress control. Previous studies have pointed out the necessity of the scale in terms of maintaining prevention or intervention programs [11-14].
The validity of the Turkish version of the test among pregnant women, ascertained using the HADS test, enables the early prediction of mental instability in pregnant women accompanying emotional instability related to physiological changes of pregnancy during the pandemic.
In another recent study, among medical students in Vietnam, fear of COVID-19 scale was once again confirmed as being a valid and reliable tool to screen for fear during the pandemic. A remarkable finding of the study was how easy access to medical support significantly decreased the severity of fear according to the scale [15].
Considering the correlation between high scores of FCV-19S and HADS, it can also be concluded that higher overall scores on the FCV-19S indicate a more severe fear of COVID-19 among pregnant women.
The current study has some limitations. Lack of information among patients about coexisting mood disorders or formal diagnoses is the main limitation. Hence, fear may exacerbate the symptoms of those with pre-existing psychiatric disorders, we cannot exclude the role of underlying pathology. The subjectivity of fear may have also interfered with the consistency of the study.
Conclusion
Awareness of COVID-19 fear is crucial for developing better-coping skills during the pandemic. If stress is properly managed, the joy and happiness of pregnancy may balance emotional instability and hence prevent adverse fetal outcomes related to maternal stress derived from fear of COVID-19. Therefore, enlightenment of pregnant women about the risks, prevention strategies, and developing skills for stress management is essential. To the best of our knowledge, this is the first study assessing the fear of COVID-19 during pregnancy. Large scaled studies are required for the assessment of the psychological burden caused by COVID-19 fear among pregnant women.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Shrivastava, SR, Shrivastava PS. COVID-19 and impairment of mental health: public health perspective. Afr Health Sci. 2021; 21(4): 1527-32.
2. Figliozzi S, Masci PG, Ahmadi N, Tondi L, Koutli E, Aimo A, et al. Predictors of adverse prognosis in COVID-19: A systematic review and meta-analysis. Eur J Clin Invest. 2020; 50(10): 3362.
3. Wong SF, Chong KM, Leung TN, Ng WF, Ng TK, Shek CC, et al. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol. 2004; 191(1): 292-7.
4. Alfaraj SH, Al-Tawfiq JA, Memish ZA. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection during pregnancy: Report of two cases and review of the literature. J Microbiol Immunol Infect. 2019; 52(3): 501-3.
5. Suzumori N, Goto S, Sugiura-Ogasawara M. Management strategy of pregnant women during COVID-19 pandemic. Aust N Z J Obstet Gynaecol. 2020; 60(4): E9-E10.
6. Ahorsu DK, Lin CY, Imani V, Saffari M, Griffhits MD, Pakpour AH. The Fear of COVID-19 Scale: Development and Initial Validation. IntJ Ment Health Addict. 2022; 20(3): 1537-45.
7. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 1983; 67(6): 361–70.
8. Tabachnik BJ, Fidel LS, editors. Using multivariate statistics, 7th ed. Boston: Pearson; 2019.p.476-515.
9. Soraci P, Ferrari A, Abbiati FA, Del Fante E, De Pace R, Urso A, et al. Validation and Psychometric Evaluation of the Italian Version of the Fear of COVID-19 Scale. Int J Ment. Health. 2022; 20(4): 1913-22.
10. Barbisch D, Koenig KL, Shih FY. Is There a Case for Quarantine? Perspectives from SARS to Ebola. Disaster Med Public Health Prep. 2015; 9(5): 547-53.
11. Yang Z, Zhang Y, Xu H, Gan M, Ma J, Liu J, et al. Generalized anxiety disorder among rural primary and middle school students during the outbreak of COVID-19: a multicenter study in three southern Chinese cities. BMC Public Health. 2023; 23(1): 327.
12. Pakpour A, Griffiths MD. The fear of COVID-19 and its role in preventive behaviors. J Con Dis. 2020; 2(1): 58-63.
13. Huizink AC, de Rooij SR. Prenatal stress and models explaining risk for psychopathology revisited: Generic vulnerability and divergent pathways. Dev Psychopathol. 2018; 30(3): 1041-62.
14. Stein A, Pearson RM, Goodman SE, Rapa E, Rahman A, McCallum M, et al. Effects of perinatal mental disorders on the fetus and child. The Lancet. 2014; 384(9956): 1800-19.
15. Nguyen HT, Do BN, Pham KM, Kim GB, Dam HT, Nguyen T, et al. Fear of COVID-19 Scale-Associations of Its Scores with Health Literacy and Health-Related Behaviors among Medical Students. Int J Environ Res Public Health. 2020; 17(11): 4164.
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Ebru Yuce. Validity and reliability of the fear of COVID-19 scale (FCV-19) in Turkish pregnant women. Ann Clin Anal Med 2023;14(Suppl 1):S95-98
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How the use of antibiotic irrigation solution affected the infection rates in penile prosthesis implantation?
Selim Taş
Department of Urology, Health Sciences University, Antalya Education and Research Hospital, Antalya, Turkey
DOI: 10.4328/ACAM.21673 Received: 2023-03-02 Accepted: 2023-03-22 Published Online: 2023-03-24 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S99-102
Corresponding Author: Selim Taş, Department of Urology, Health Sciences University, Antalya Education and Research Hospital, 07100, Antalya, Turkey. E-mail: drslmtas@hotmail.com P: +90 533 258 68 57 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8492-4603
This study was approved by the Ethics Committee of Health Sciences University, Antalya Education and Research Hospital (Date: 2020-10-01, No: 298)
Aim: It is common practice to immerse penile implants in antibiotic solution prior to implantation. Our aim was to investigate the effect of irrigation with antibiotic solution prior to implantation of penile prostheses on surgical outcomes and infection rates.
Material and Methods: We retrospectively evaluated the data of 123 patients who underwent penile prosthesis implantation surgery at our clinic between August 2015 and August 2020. We evaluated the effect of irrigation of the prosthesis with an antibiotic solution on success and complications.
Results: The mean age of the patients was 62 years. The average length of hospital stays was 3.3 days, and the average duration of the operation was 70 minutes. Preoperative antibiotic prophylaxis included the administration of 1 g of vancomycin once a day and twice daily doses of 3rd generation cephalosporins. None of the patients experienced any perioperative complications. Of the prostheses, 83 were single-piece (Promedon), 5 were two-piece (Ambicor), 35 were three-piece (AMS 700 CXP). All prostheses were irrigated with an antibiotic solution. After surgery, 5 patients had penile pain, 1 patient had penoscrotal tenderness and itchy lesions, and 4 patients had an infection of the surgical incision site that responded to medical therapy. In addition, 3 patients required the removal of the penile prosthesis.
Discussion: Prosthesis infection may be characterized by only pain without signs of infection, or may progress to penile necrosis and loss. During the first prosthetic surgeries, urologists used a number of solutions based on their previous clinical experience to provide protection from infection. The surgical area was washed with a solution before the incision and every 15 minutes thereafter. After corporotomy, corpus cavernosum washed 3 times using this solution, and the penile prosthesis was implanted after prewashing.
Keywords: Erectile Dysfunction, Antibiotic Solution, Penile Prosthesis Implantation, Infection
Introduction
Erectile dysfunction is defined as the persistent inability to achieve or maintain an erection adequate for satisfactory sexual activity. Its incidence in the population increases with advancing age. It has been estimated that the prevalence of erectile dysfunction of all degrees is 52% in men 40 to 70 years old with higher rates in those older than 70 years [1].
Erectile dysfunction has a significant negative impact on quality of life. Risk factors for erectile dysfunction include aging, chronic illnesses, various medications and cigarette smoking [2]. Identification of erectile dysfunction can be made through questionnaires or a complete medical and sexual history [3].
Treatment of erectile dysfunction should be carried out in steps. First of all, lifestyle changes and oral treatment should be recommended. Intraurethral treatment and a vacuum device may also be tried. Intracavernosal treatment may also be initiated if the above methods are insufficient. Penile prosthesis implantation is recommended as a third-line treatment if there is no response to the treatment in the first two steps [4]. A lot of progress has been made in penile prostheses, which are the last-line treatment, since their first use. Thus, surgical and mechanical complication rates decreased and patient-partner satisfaction levels increased [5].
Penile prosthesis infections are an extremely challenging clinical situation for surgeons and patients. The skin flora is usually the cause of the infection. Since the human skin flora contains many pathogens, a thorough physical and chemical skin cleansing is required before the surgery. Staphylococcus epidermidis is the most common causative agent of penile prosthesis infection. However, causative pathogens including E. coli, P. aeruginosa, S. marcescens, P. mirabilis and methicillin-resistant Staphylococcus aureus can also be encountered [6,7]. Prosthetic infections, which have a frequency of 1-3% in primary prosthesis applications, can increase up to 7% and 18%, respectively, in revision surgeries and additional reconstructive surgeries. The most important data regarding infection rates after prosthetic surgery is that a significant portion of implanted prostheses do not actually cause clinically typical signs of infection. One study showed a high rate of 40-80% of bacterial colonies in penile prosthesis materials removed for non-infectious reasons [8,9]. Measures to prevent the formation of penile prosthesis infections, rather than their treatment, are of great importance. First of all, it is necessary to minimize the length of hospital stay for patients scheduled for prosthesis implantation, to shave the surgical area in the operating room, and to avoid simultaneous surgeries and the use of additional synthetic materials. Before surgery, it is necessary to clean the surgical area with chlorhexidine or povidone-iodine to prevent unnecessary entry and exit to the operating room, to ensure effective control of bleeding during surgery, and to control co-morbid diseases, if any, in the pre-operative period [10,11].
In this study, we planned to evaluate the efficacy of irrigation of penile prostheses with an antibiotic solution before their implantation against infections.
Material and Methods
The study started with the ethical approval of SBU Antalya Training and Research Hospital, dated 01.10.2020 and numbered 298.We retrospectively evaluated the data of 123 patients who underwent penile prosthesis implantation surgery in our clinic between August 2015 and August 2020. All patients underwent general physical examination before surgery. The patients underwent additional further investigations including hormonal tests, intracavernosal injection and stimulation tests, and penile color Doppler ultrasonography before deciding on surgery. Before the penile prosthesis implantation surgery, a preliminary interview was held with the patients and their partners. The patients were informed about the surgical procedure, the type, advantages and disadvantages of prostheses, and possible complications. The necessary psychosocial and sexual evaluation was performed by a psychiatrist. Preoperative evaluation included essential biochemical investigations. Normal urine analysis and culture were expected. Patients with diabetes mellitus with an HbA1c value of 6.8 and above were operated after the blood glucose level was controlled. All patients received a standard antibiotic regimen. All penile prostheses to be implanted were not checked for antibiotic coating before surgery.
Our case was taken to the operating room as the first case of the day. All patients underwent mechanical cleaning of the surgical site before surgery. Prior to the surgery, entry and exit from the operating room were restricted. The surgical field was washed with povidone iodine for 15 minutes before sterile dressing. The surgical area was then covered with a sterile drape. An antibiotic solution was prepared for surgical prophylaxis on the additional table. On an additional table, an antibiotic solution was prepared for surgical prophylaxis, containing a mixture of 2400 mg of gentamicin and 5000 mg of rifampicin in 1000 cc of isotonic saline, and 500 cc of 10% povidone-iodine. The penile prosthesis and its parts were placed in this solution and kept until implantation. The surgical area was washed with solution before the incision and every 15 minutes thereafter. After corporotomy, corpus cavernosum was washed 3 times using this solution, and the penile prosthesis was implanted after prewashing. All patients underwent spinal anesthesia. The patients were re-informed about the use of prostheses after the surgical procedure. If there was no additional precaution, the patient was allowed to use the penile prosthesis in the 6th postoperative week.
The type of prosthesis and the success and complication rates were recorded. For patients who developed complications, subsequent treatments and outcomes were evaluated.
Ethical Approval
Ethics Committee approval for the study was obtained.
Results
Demographical analysis revealed diabetes mellitus (DM) in 46 patients (37.3%), hypertension (HT) in 73 patients (59.3%), coronary artery disease (CAD) in 32 patients (26.0%), 28 smoking patients (22.7%), Peyronie’s disease in 4 patients (3.2%), radiotherapy history in 6 patients (4.8%), radical prostatectomy history in 22 patients (17.8%).
Preoperative IIEF scoring showed severe ED in all patients. In addition, Doppler USG showed the highest frequency of bilateral arterial insufficiency in 90 (73.1%) patients, followed by mixed type in 10 (8.1%) patients and left arterial insufficiency in 5 (4%) patients (Table 1).
The mean age of 123 patients who underwent penile prosthesis surgery was 62 years. The mean duration of ED was 29 months. The mean duration of hospital stay, operation, and follow-up was 3.3 days, 70 minutes, and 13 months, respectively (Table 2).
All patients underwent spinal anesthesia. All patients underwent mechanical cleaning of the surgical site before surgery. The surgical field was washed with povidone-iodine for 15 minutes before sterile dressing. During the surgery, the surgical area was continued to be washed periodically with a solution containing gentamicin, rifampicin and povidone-iodine. Preoperative antibiotic prophylaxis included the administration of 1 g of vancomycin once a day and twice daily doses of 3rd generation cephalosporins. The patients used 750 mg of ciprofloxacin in tablet form twice a day for 7 days after discharge. None of the patients experienced any perioperative complications. Of the prostheses, 83 were single-piece (Promedon), 5 two-piece (Ambicor), 35 three-piece (AMS 700 CXP). After surgery, 12 patients had complications (9.7%), including penile pain in 5 patients, penoscrotal tenderness and itchy lesions, and infection of the surgical incision site that responded to medical therapy in 4 patients. In addition, 3 patients required the removal of the penile prosthesis, of which 1 was a three-piece (AMS 700 CXP) and 2 was a one-piece (Promedon). In all 3 patients, the reason for removing the prosthesis was uncontrolled infections. Moreover, one of these 3 patients had a history of radical prostatectomy and primary hypertension and the other two had a history of controlled DM. All 3 patients were smokers. These patients underwent both removal of the prosthesis and implantation of a new prosthesis with the same characteristics in the same session. No problem recurred in 3 patients who underwent salvage surgery. The use of the penile prosthesis was allowed 6 weeks after the second surgery. The duration of the post-discharge antibiotic regimen was extended up to 2 weeks. No problem was encountered during the 6-month follow-up (Table 3).
Discussion
It is common practice to immerse penile implants in antibiotic solution prior to implantation. One of the most important complications of penile prosthesis implantation is infection of the prosthesis. The most common infectious agents are Staphylococcus epidermidis, Proteus mirabilis, P. aeruginosa and Escherichia coli, respectively. Both the American Urological Association (AUA) and the European Association of Urology (EAU) have developed surgical prophylaxis guidelines for penile prosthesis operations. Prosthesis infection may be characterized by only pain without signs of infection, or may progress to penile necrosis and loss [12,13]. Its incidence varies between 1 and 10%. However, today the average incidence is between 1 and 3% [14,15,16]. During the first prosthetic surgeries, urologists used a number of solutions based on their previous clinical experience to provide protection from infection. However, no one has described a standard procedure. Antiseptic solutions and their associated concentrations have never been evaluated for their effectiveness. When faced with an implant infection, a salvage procedure has been accepted that involves immediate replacement of the infected implant after antiseptic washing of the implant cavities [8].
According to the protocol described by Mulcah, the infected prosthesis is first removed along with all its parts. The corpus cavernosum and the anatomical spaces containing the other parts of the implant can then be irrigated with kanamycin + bacitracin, hydrogen peroxide, vancomycin + gentamycin and povidone-iodine, and then again with hydrogen peroxide and kanamycin + bacitracin. Finally, the new prosthesis can be implanted in the same session [17].
In a review between 2003 and 2018, Pan et al recommended that body cavities and the scrotal pump area be washed with povidone-iodine for not less than 3 minutes, followed by irrigation with saline and antibiotic solutions. However, they did not recommend the active substance, concentration and method of administration of the antibiotic regimen [18].
In this study, we describe a new procedure that involves the use of a mixture of 2400 mg of gentamicin, 5000 mg of rifampicin and 500 cc of 10% povidone-iodine in a 1000 cc isotonic saline solution. The penile prosthesis and all its parts were placed in this mixture and waited until implantation. The surgical area was washed with solution before the incision and every 15 minutes thereafter. After corporotomy, corpus cavernosum was 3 times using this solution, and the penile prosthesis was implanted after prewashing. Penile prosthesis infection was seen in 3 patients who required revision surgery (3.2%). These patients underwent a salvage surgery in which the same procedures were repeated.
In a multicenter study, Henry et al. reported the detection of positive cultures and visible bacterial biofilms on clinically non-infected inflatable penile prostheses in the majority of patients during revision surgery. They also showed that revision washout at revision surgery of inflatable penile prostheses for non-infectious reasons reduces the bacterial load on the implant capsule tissue [19].
Apart from all these classical methods, prosthesis manufacturers have recently produced prostheses coated with antibiotics (minocyclin+rifampicin) and that are able to absorb the antibiotic agent in the solution in which they are immersed, in order to reduce the rates of implant infection. Although implant infection remains a problem, recent advances in antibiotic-coated devices and abundant use of antiseptic irrigation have reduced its incidence [20,21].
On the other hand, in a recent study, the authors reported that the use of repeated antibiotic irrigations in revision surgeries can achieve infection rates comparable to those in patients undergoing primary prosthesis implantation surgery [22]. In our study, we performed irrigation with an antibiotic solution in patients who underwent primary surgery. In our study, all prostheses were irrigated with an antibiotic solution, regardless of whether they were coated with antibiotics. There were 3 patients who required revision surgery (2.4%).
Conclusion
Measures to prevent the formation of penile prosthesis infections, rather than their treatment, are of great importance. Although manufacturers produce antibiotic-coated prostheses, the development of infections is the most feared complication of penile prosthesis implantation. Our study on infections had a retrospective design. All penile prostheses to be implanted were not checked for antibiotic coating before surgery. No samples were taken for culture study during revision surgery. We believe that this study will shed light on more comprehensive studies on this subject, thanks to the new solution we have described.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Funding: None
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Singh JC, Devasia A, Gnanaraj L, Chacko KN. Erectile dysfunction. National Medical Journal of India. 2005;18(3):139.
2. Collica S, Pederzoli F, Bivalacqua T, editors. The epidemiology and pathophysiology of erectile dysfunction and the role of environment. Bioenvironmental issues affecting men’s reproductive and sexual health. London: Elsevier/Academic Press; 2018. p. 439-55.
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4. Dick B, Tsambarlis P, Reddy A, Hellstrom W. An update on: long-term outcomes of penile prostheses for the treatment of erectile dysfunction. Expert Rev Med Devices. 2019;16 (4):281-6.
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6. Al-Shaiji TF, Yaiesh SM, Al-Terki AE, Alhajeri FM. Infected penile prosthesis: literature review highlighting the status quo of prevention and management. The Aging Male. 2020;23(5): 447-56.
7. Henry GD, Gerard DW, Steven K. Updates in inflatable penile prostheses. Urologic Clinics of North America. 2007;34(4):535-47.
8. Mulcahy JJ. Penile implant infections: Prevention and treatment. Curr Urol Rep. 2008;9(6):487-91.
9. Henry G D, Wilson SK, Delk JR, Carson CC, Silverstein A, Cleves MA, et al. Penile prosthesis cultures during revision surgery: a multicenter study. J Urol. 2004; 172(1):153-6.
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11. Selph, J. Patrick; CARSON, Culley C. Penile prosthesis infection: approaches to prevention and treatment. Urologic Clinics, 2011;38.(2): 227-235.
12. Muhammad MH, Idris AL, Fan X, Guo Y, Yu Y, Jin X, et al. Beyond Risk: Bacterial Biofilms and Their Regulating Approaches. Front Microbiol. 2020; 11:928.
13. Richardson B, Caire A, Hellstrom WJ. Retrospective long-term analysis of titan hydrophilic coating: positive reduction of infection compared to non-coated device. J Sex Med. 2010;7 (1):28-9.
14. Wilson SK, Costerton JW. Biofilm and penile prosthesis infections in the era of coated implants: a review. J Sex Med 2012; 9(1):44-53.
15. Carson CC, Mulcahy JJ, Govier FE. Efficacy, safety and patient satisfaction outcomes of the AMS 700CX inflatable penile prosthesis: results of a long-term multicenter study. AMS 700CX Study Group. J Urol. 2000;168(4):376-80.
16. Falcone M, Garaffa G, Gillo A, Dente D, Christopher AN, Ralph DJ. Outcomes of inflatable penile prosthesis insertion in 247 patients completing female to male gender reassignment surgery. BJU Int. 2018; 121(1):139-44.
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18. Pan S, Rodriguez D, Thirumavalavan N, Gross M S, Eid JF, Mulcahy J, et al. The use of antiseptic solutions in the prevention and management of penile prosthesis infections: a review of the cytotoxic and microbiological effects of common irrigation solutions. J Sex Med. 2019;16(6):781-90.
19. Henry GD, Carson CC, Wilson SK, Wiygul J, Tornehl C, Cleves MA, et al. Revision washout decreases implant capsule tissue culture positivity: a multicenter study. J Urol. 2008;179(1):186-90.
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21. Dhabuwala C. In vitro assessment of antimicrobial properties of rifampin-coated Titan(®) Coloplast penile implants and comparison with Inhibizone(®). J Sex Med. 2010; 7(10):3516-9.
22. Kava BR, Kanagarajah P, Ayyathura R. Contemporary revision penile prosthesis surgery is not associated with a high risk of implant colonization or infection: a single-surgeon series. J Sex Med. 2011;8(5):1540-6.
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Selim Taş. How the use of antibiotic irrigation solution affected the infection rates in penile prosthesis implantation? Ann Clin Anal Med 2023;14(Suppl 1):S99-102
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Intraabdominal gossypiboma and associated incidental neuroendocrine tumor: A rare case report
Veysel Kaplanoğlu 1, Serap Gençer 1, Hatice Kaplanoğlu 2, Doğan Öztürk 3, Gülçin Şimşek 4, Selma Uysal Ramadan 1
1 Department of Radiology, Health Sciences University, Ankara Ataturk Sanatory Educatıon and Research Hospıtal, 2 Department of Radiology, Health Sciences University, Dışkapı Yıldırım Beyazıt Training and Research Hospital, 3 Department of General Surgery, Health Sciences University, Ankara Ataturk Sanatory Educatıon and Research Hospıtal, 4 Department of Pathology, Health Sciences University, Ankara Gülhane Educatıon and Research Hospıtal, Ankara, Turkey
DOI: 10.4328/ACAM.21354 Received: 2022-08-11 Accepted: 2022-09-21 Published Online: 2023-02-22 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S103-105
Corresponding Author: Veysel Kaplanoğlu, Department of Radiology, Health Sciences University, Ankara Ataturk Sanatory Educatıon and Research Hospıtal, Ankara, Turkey. E-mail: dr_veysel76@hotmail.com P: +90 505 892 30 61 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1376-0469
The term gossypiboma is used to describe surgical sponges that are retained after surgery and are a rare but serious complication due to its medicolegal consequences. The possibility of gossypiboma should be kept in mind in the differential diagnosis of patients with a history of surgery and presenting with non-specific symptoms. Our case is a 59-years-old male patient who had a history of gastric perforation surgery in another center 20 years ago. There were complaints of swelling and tenderness in the left upper quadrant and non-specific abdominal pain. Laboratory examination revealed specific tumor marker elevation, radiological examinations revealed gossypiboma and incidental abdominal masses. The masses were removed laparoscopically and pathologically reported as gossypiboma and gastrointestinal neuroendocrine tumors. For this purpose, the materials used during the surgery should be carefully counted, postoperative wound and cavity research should be done before the wound is closed, radiologically detectable materials should be used.
Keywords: Gossypiboma, Foreign Body, Abdominal US, CT, MRI
Introduction
Mass lesions caused by a foreign body such as a surgical sponge, pad, or gauze that are retained in the body cavity after a surgical procedure are called gossypiboma or textiloma [1]. The first case of gossypiboma was reported by Wilson in 1884 [1]. The true incidence of gossypiboma is difficult to determine because of the low reporting rate due to medicolegal problems. Retained surgical items have been reported to occur with ranging from rate of 0.356/1000 patients to 1/5500 patients, with a mortality rate ranging from 11 to 35% [2]. Although gossypiboma is most commonly reported in the abdominal cavity, it can also occur following other surgical procedures such as thoracic, cardiovascular, orthopedic, and even neurosurgery operations [2]. Gossypiboma is difficult to diagnose because it can mimic benign or malignant soft tissue tumors of the abdomen and pelvis [3]. Gossypiboma should be kept in mind in the differential diagnosis of patients who have undergone previous surgery and present with an intra-abdominal mass. We present a case of gossypiboma diagnosed as a gastrointestinal neuroendocrine tumor (NET) incidentally detected during radiological imaging.
Case Report
Case Presentation
A 57-year-old male patient was admitted to our general surgery clinic with complaints of nonspecific abdominal pain and postprandial swelling. He had a history of smoking for 40 years and COPD, further he had undergone laparotomy 20 years ago in another center for gastric perforation. Physical examination revealed tenderness in the left upper quadrant and decreased bilateral breath sounds. There was no abnormality in laboratory tests, except for a high level of CEA (6.61 ng\ml). In the abdominal ultrasonography (US), a lesion measuring 14×7.5 cm was detected in the left hypochondriac area, with intense posterior acoustic shadowing, and hyperechoic areas in the anterior region. No apparent vascularity was shown with Color Doppler US in the lesion identified (Figuüre 1). A few mass lesions located in the gastrohepatic area, with lobulated contours, heterogeneous internal structure, and vascularity with color Doppler in the US were observed; the largest one was 7.5×3 cm in size. Contrast-enhanced abdominal computed tomography (CT) revealed a hyperdense mass in the left upper quadrant of the abdomen with a laminar appearance, slightly contrast enhancing smooth and thick-walled, containing calcifications and areas of fluid density. Lobule contoured solid mass lesions with heterogeneous contrast enhancement and containing necrotic areas were detected in hepatogastric, peripancreatic, and paracaval areas; the largest one was 14.7x8x1.6 cm in size (Figure 2). Due to the patient’s history of previous surgery, the lesion in the left upper quadrant was diagnosed as gossypiboma when the current findings were evaluated. The patient underwent laparotomy, and the foreign body located on the lateral of the stomach and the soft tissue mass located in the transverse colon mesentery were removed. The Ppathological evaluation confirmed the diagnosis of gossypiboma and revealed that the accompanying mass lesions belonged to gastrointestinal NET originating from the transverse colonic mucosa (Figure 3). Intravenous contrast-enhanced thorax CT performed in another center to investigate the primary tumor revealed a mass lesion measuring 20×15 mm with spiculated contours in the superior segment of the left lung lower lobe. In the pathological examination after biopsy, the mass was interpreted as non-small cell lung carcinoma. Cyberknife treatment was applied to the patient.
Discussion
Foreign body retained in the body during surgical operations is not uncommon despite the meticulous work of surgical teams. Emergency operations, unplanned procedural changes during surgery, multiple surgical teams, high body mass index (BMI), amount of blood loss, and female gender are among the factors that increase the risk [4]. Surgical sponges retained in the body can cause two biological responses: an aseptic fibrous response due to a foreign body granuloma or an exudative reaction leading to abscess formation. Symptoms depend on the location and size of the foreign body, and the type of reaction that occurs. Gossypiboma may present early with pain with or without mass formation, cause nonspecific symptoms, or remain asymptomatic for a long time [5]. Patients may present with an abdominal mass or subacute intestinal obstruction, rarely fistula and perforation may develop [5]. Chronic and nonspecific presentation complicates the diagnosis [5]. The radiological appearance of gossypiboma is variable. Surgical sponges can be easily recognized on conventional radiography if they contain radiopaque markers [6]. The presence of echogenic wavy structures in a cystic mass with posterior acoustic shadowing on the US has been reported as a diagnostic feature of gossypiboma [6]. The most characteristic finding for gossypiboma on CT is the appearance of a well-circumscribed mass with a hyperdense border formed by the surgical sponge, and a whirl-like pattern formed by the fabric and air bubbles trapped in the center. In contrast-enhanced CT, mild to moderate contrast enhancement can be seen in the thin or thick capsule structure [7]. When the air bubbles are resorbed, the mass may not be distinguishable from other solid masses [7]. Findings in magnetic resonance imaging (MRI) may be variable depending on the stage and fluid content of the mass. However, in general, the mass with a thick well-circumscribed capsule is heterogeneously hypointense on T1-weighted images. On T2-weighted images, it is observed in heterogeneous signal intensity with hypointense areas due to trapped air and hyperintense areas due to fluid content. The wavy appearances of the surgical sponge can be observed as hypointense structures on T1 and T2 weighted images. Mild to moderate enhancement of the capsule may be seen on contrast-enhanced scans [7]. Although radiological examinations are very sensitive in detecting gossypiboma, this pathology can mimic hematoma, granulomatous processes, abscess formation, cystic masses, and neoplasms [8]. Treatment consists of extensive surgical exploration of the abdomen and removal of the gossypiboma, and the definitive diagnosis is usually made intraoperatively. Gossypiboma is easier to prevent than to treat. To reduce the risk, pre-and post-operative counting of the materials used during the surgery, a short but comprehensive routine postoperative wound and cavity investigation before the wound is closed, the use of radiologically detectable materials, radiological scanning if necessary in risky, long-lasting, or multi-team operations will be appropriate. In addition, newer technologies such as barcode systems and electronic chip identification are also being developed to reduce the incidence [8].
Conclusion
Gossypiboma is a rare and preventable postoperative complication. The possibility of gossypiboma should be kept in mind in cases of localized abdominal pain, palpable mass, and infection in patients with a previous operation history. Incidental neoplasms that may accompany gossypiboma can also be seen. The case is presented to increase awareness of this issue.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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2. Susmallian S, Barnea R, Azaria B, Szyper-Kravitz M. Addressing the important error of missing surgical items in an operated patient. Isr J Health Policy Res. 2022;11(1):19.
3. Kawamura Y, Ogasawara N, Yamamoto S, Sasaki M, Kawamura N, Izawa S, et al. Gossypiboma mimicking gastrointestinal stromal tumor causing intestinal obstruction: a case report. Case Rep Gastroenterol. 2012;6(2):232-7.
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6. Bozkurt H, Öğüt B. A gossypiboma masquerading as a mesenteric cyst. Malawi Med J. 2021;33(1):68-70.
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8. Macario A, Morris D, Morris S. Initial clinical evaluation of a handheld device for detecting retained surgical gauze sponges using radiofrequency identification technology. Arch Surg. 2006;141(7):659-62.
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Veysel Kaplanoğlu, Serap Gençer, Hatice Kaplanoğlu, Doğan Öztürk, Gülçin Şimşek, Selma Uysal Ramadan. Intraabdominal gossypiboma and associated incidental neuroendocrine tumor: A rare case report. Ann Clin Anal Med 2023;14(Suppl 1):S103-105
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Stent migration after carotid artery stenting in long-term period: A rare complication
Serhan Yıldırım
Department of Neurology, Kocaeli Derince Training and Research Hospital, Kocaeli, Turkey
DOI: 10.4328/ACAM.21394 Received: 2022-09-17 Accepted: 2023-03-16 Published Online: 2023-03-24 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S106-108
Corresponding Author: Serhan Yıldırım, Department of Neurology, Kocaeli Derince Training and Research Hospital, Derince, Kocaeli, Turkey. E-mail: serhan_yildirim@yahoo.com P: +90 505 576 24 05 F: +90 262 233 46 41 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1997-4003
Stent migration is a rare complication of carotid artery stenting (CAS) and maypresent with ischemic stroke. A 71-year-old male patient with symptomatic left carotid stenosis was treated with CAS. The patient had a transient ischemic attack with mild weakness in the right upper extremity eight months later. Computed tomography angiography showed severe stenosis in the cervical ICA next to the stent. Downward migration of the stent on left ICA with about 50% stenosis next to the stent was seen in DSA. Another stent was placed from the cervical segment of ICA to CCA, covering the stenotic lesion.
Keywords: Stent Migration, Stenting, Long-term, Carotid Artery
Introduction
Carotid artery stenting (CAS) is a treatment option in patients with symptomatic extracranial carotid stenosis [1]. Stroke, myocardial infarction, and death are well-known complications of CAS [2]. Stent restenosis or stent occlusion may occur over the long-term period. Stent migration is a rare complication of CAS.
Stent migration is the movement of the stent upwards or downwards from where it was first placed. There are only three patients with stent migration after CAS in the literature. The cause of stent migration is not known. Badruddin et al. reported that the watermelon-seeding effect might be the cause of stent migration [3]. In this publication, a patient with stent migration after CAS was reported.
Case Report
A 71-year-old male patient with hypertension, diabetes mellitus, coronary artery disease, and smoking had a dysarthria recovered within one hour. There were two lacunary infarctions in the left frontal lobe on diffusion-weighted magnetic resonance imaging. Computed tomography angiography (CTA) showed 80% stenosis in the origin of the left internal carotid artery (ICA). The patient was treated with acetylsalicylic acid (ASA) 100 mg/day and clopidogrel 75 mg/day for two weeks before CAS. Digital subtraction angiography (DSA) showed 65% stenosis in the origin of the left ICA (Figure 1). The diameters of the common carotid artery (CCA) and ICA were respectively 5.7 mm and 3.6mm. A Spider FX 5 mm (Medtronic, Minneapolis, USA) distal protection device was deployed to distal cervical ICA. Predilataion was applied to stenosis using a 3.5x15mm balloon inflated with 6 atm pressure. Then a Protege 8-6x30mm stent (Medtronic, Minneapolis, USA) was placed from ICA to CCA, covering the stenotic lesion (Figure 1). The patient was discharged with ASA 100mg/day, clopidogrel 75mg/day, and atorvastatin 10 mg/day on the following day.
Eights months later, the patient had a transient ischemic attack with mild weakness in the right upper extremity. Doppler ultrasonography (USG) showed a 70-99% restenosis in the distal segment of the stent on the left ICA. There was severe stenosis in the cervical ICA next to the stent on CTA. DSA showed downward migration of the stent on the left ICA, with about 50% stenosis next to the stent (Figure 2). A Spider FX 6 mm (Medtronic, Minneapolis, USA) distal protection device was deployed to distal cervical ICA. Mer 8-6×40 mm stent (Balton, Poland) was placed from the cervical segment of ICA to CCA, covering the stenotic lesion (Figure 3). Then balloon angioplasty (post-dilatation) was applied with a 4.5×20 mm balloon catheter at 8 atm pressure. The patient was discharged home the following day with ASA 100mg/day, clopidogrel 75mg/day, and atorvastatin 10 mg/day treatments.
Discussion
Stent migration is a rare complication of CAS. This complication usually occurs after the placement of flow-diverter stents in the treatment of cerebral artery aneurysms. There are only three case reports about stent migration after CAS. Stent migration was detected immediately in the first patient, at the 15th month in the second patient, and at the eighth month in the third patient, similar to our patient [3-5]. The causes of stent migration are not well-known. The most popular hypothesis is the watermelon-seeding effect, reported by Badruddin et al [3]. The watermelon seeding effect is the instability of the balloon across the stenosis and slipping out of the stenotic segment to a less constrained segment [3]. A significant difference between the diameters of inflow and outflow vessels may cause a watermelon-seeding effect [6]. However, the watermelon-seeding effect does not occur in carotid stents usually. Undersized stents may be another possible risk factor for stent migration [3]. However, the diameter of the stent was not smaller than CCA. The CCA and ICA diameters were 5.7mm and 3.6mm (Figure 1), and an undersized stent was not placed in the first process (Protege 8-6x30mm). Additionally, an increased stent/vessel diameter ratio in the distal segment may migrate the stent to the proximal by causing more radial force [3]. This patient had an increased stent/vessel diameter ratio in the distal segment (1.66 vs. 1.4). However, there are no actual data about this in the literature. There is no definite information about the association between stent migration and stent cell type. Badruddin et al. reported that closed-cell stents with a greater metal surface might provide more contact between endothelium and metal, which may cause more anchoring and prevent the risk of stent migration [3]. Swarnkar et al. reported that open-cell design stents might reduce migration risk by expanding in varying forms across the vessel surface [4]. However, stent migration was reported in both stent types. Stent migration occurred with an open-cell stent in this case.
Another possible cause of stent migration is the expansion of vessels after revascularization [3]. The diameter of the vessel may reduce due to low flow, and the length of the stent may be seen long when it was placed first. However, the vessel may reexpand after establishing the blood flow, rendering the diameter of the stent small for the newly expanded vessel and shortening the stent with the accordion effect [7]. Insufficient neo-endothelialization is another possible cause of stent migration [7]. Neo-endothelialization of the stent begins a few weeks after CAS. Smoking and uncontrolled HT are factors that can affect neo-endothelialization [8]. Thus, patients should give up smoking, and HT should be controlled well after CAS. HT was under control in this patient. However, he continued smoking after the first CAS.
Doppler USG is the Standard technique used to follow patients treated with CAS. Doppler USG should be performed within three months after CAS, every six months for two years, and then annually [8]. This patient did not come to doppler USG control after the procedure. Doppler USG, performed after TIA, showed restenosis in the distal segment of the stent, and stent migration was observed in DSA. If the patient complied with his follow-up program, stent migration could be diagnosed early and treated before causing symptoms.
Conclusion
Stent migration is a rare complication of CAS. Stent migration may occur after six months of CAS, and it may cause acute ischemic stroke. Doppler USG should be performed in all patients within three months after the procedure, and the patients should follow their controls. HT and smoking should be controlled well after CAS. However, all causes of stent migration are not well-known. Further studies will give us more information about this complication.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
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5. Castriota F, De Campos Martins EC, Dall’Olmo CA, Molnar RG, Manetti R, Liso A, et al. Stent migration as a late complication following carotid angioplasty and stenting. Euro Intervention. 2008:4(3):397-9; discussion 400-4.
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7. Tsai YH, Wong HF, Hsu SW. Endovascular management of spontaneous delayed migration of the flow-diverter stent. J Neuroradiol. 2020;47(1):38-45.
8. Zierler RE, Jordan WD, Lal BK, Mussa F, Leers S, Fulton J, et al. The Society for Vascular Surgery practice guidelines on follow-up after vascular surgery arterial procedures. J Vasc Surg.2018;68(1):256-84.
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Serhan Yıldırım. Stent migration after carotid artery stenting in long-term period: A rare complication. Ann Clin Anal Med 2023;14(Suppl 1):S106-108
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Wedge resection of duodenal gist, located on second portion of duodenum. Is it safe? A case report
Fatih Buyuker 1, Mehmet Sait Ozsoy 1, Hakan Baysal 1, Medeni Sermet 1, Berrin Gucluer 2, Gurhan Bas 1
1 Department of General Surgery, 2 Department of Pathology, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.21425 Received: 2022-10-02 Accepted: 2022-12-15 Published Online: 2023-01-04 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S109-111
Corresponding Author: Mehmet Sait Ozsoy, Department of General Surgery, Faculty of Medicine, Istanbul Medeniyet University, Goztepe Prof. Dr. Suleyman Yalcin City Hospital, Dr Erkin Caddesi, No: 1, Kadıköy, Istanbul, Turkey. E-mail: saitozsoy@gmail.com P: +90 532 598 83 83 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2935-8463
The most common location of gastrointestinal stromal tumors (GISTs) in the digestive system is the stomach with a rate of 50-70% and they are only seen in the duodenum at a rate of 3-5%. Due to the complex anatomical structure and localization of the duodenum, it is a region where complications are more common in surgical treatment compared to other localizations of the gastrointestinal tract. In this study, a 56-year-old male patient who underwent wedge resection in a case of GIST located in the 2nd part of the duodenum is presented.
Keywords: Duodenal GIST, Wedge Resection, Pancreas Sparing
Introduction
GISTs originating from intestinal Cajal cells are the most common mesenchymal tumors of the gastrointestinal tract [1]. 1-2% of all gastrointestinal tumors and 20-25% of soft tissue sarcomas originate from GIST [2]. Approximately 50-70% of GISTs are located in the stomach, 3-5% are seen in the duodenum [1, 3]. Curative treatment is still provided by surgical resection in cases of GISTs [4]. In cases of duodenal GIST, the anterior wall of the 2nd part of the duodenum was evaluated. In the patient who underwent wedge duodenal resection, no recurrence was detected in the 5-year follow-up. Surgical treatment alternatives are available such as pancreaticoduodenectomy (PD), pancreatic-sparing duodenectomy (PSD), segmental duodenectomy (SD) or wedge duodenectomy (WD) according to the localization of the tumor. The main goal of all these methods is to provide R0 resection. Unlike adenocancers, GISTs do not tend to lymphatic metastases [5], and local invasion into surrounding tissues is rare [4]. For the reasons listed, radical lymph dissection or wide resections do not contribute to disease-free survival in nonmetastatic cases [6]. In this case report, a case of nonmetastatic GIST located on the anterior wall of the 2nd part of the duodenum was evaluated. In the patient who underwent wedge duodenal resection, no recurrence was detected in the 5-year follow-up.
Case Report
In 2016, a 56-year-old male patient applied to our clinic with complaints of dizziness, weakness, and melena. The patient who applied to the emergency unit with similar complaints in 2009 and 2013 and upper gastrointestinal endoscopy was unremarkable and capsule endoscopy was recommended. Abdominal CT imaging of the patient revealed asymmetric wall thickening localized in the 2nd part of the duodenum (Figure 1). No metastases were detected in cross-sectional imaging. In the upper gastrointestinal endoscopy examination, a submucosal broad-based mass with an ulcerated surface located postbulbar was detected in the duodenum. The patient was operated with a pre- diagnosis of GIST located on the anterior wall of the 2nd part of the duodenum. In laparotomy, a 3*4 cm mass extending laterally was seen on the anterior wall of the duodenum in the 2nd section (Figure 2). The tumor, which was determined not to have pancreatic invasion, was removed by local wedge resection from the anterior surface by providing full kocherization of the duodenum. No tumor was detected at the resection margins in the peroperative frozen-section evaluation.
Duodenum was closed with interrupted Gambee suture technique in the histopathological evaluation of the tumor; 3,6*3,3 cm size, mitotic index 3-4/50 FPHs, Ki67: 3% positive GIST was detected.
In immunohistochemical staining, vimentin and C117 were strongly positive and S100 was negative (Figure 3). No tumor was detected in the surgical margins on histopathological examination. Oral intake was well tolerated on the second postoperative day, and the patient was discharged on the7th postoperative day uneventfully. There is disease-free survival in the 5-year follow-up of the patient.
Discussion
GISTs are mesenchymal tumors that can develop in almost any part of the gastrointestinal tract (GIS). They originate from Cajal cells, which are interstitial pacemaker cells [7]. Rarely diagnosed until the late 1990s, GISTs are the most common mesenchymal tumors of the gastrointestinal tract [7]. GISTs account for 1-2% of all GIS tumors. GISTs are localized mostly in the stomach and 50-70% are detected in the stomach, 30% in the small intestine, 5% in the colon and approximately 1% in the esophagus, respectively. Duodenal GISTs are seen at a rate of approximately 3-5% [7], and are most commonly located in the 2nd part of the duodenum [3]. GISTs have a malignant potential of 10-30%, and a chance of cure can still be achieved with surgical resection [6]. Like other sarcomas, GISTs are resistant to chemotherapy and radiotherapy, and currently available molecular targeted drugs such as imatinib and sunitinib provide disease control but are not curative. In cases of duodenal GIST, surgical treatment alternatives such as PD, pancreatic-sparing duodenectomy (PSD), segmental duodenectomy (SD), wedge local resections are available and can be applied with conservative or laparoscopic/robotic minimally invasive methods [6,7]. GISTs are mesenchymal tumors and, like other sarcomas, lymphatic metastases are rare, so they do not require lymphatic dissection [4, 5]. The absence of lymphatic invasion in patients who underwent PD confirms this situation [6]. In addition, GISTs are encapsulated and local invasion seems rarely [4,6]. The listed reasons make limited resections possible in cases of duodenal GIST adjacent to complicated anatomical structures. However, as in all GIS tumors, R0 resection should be performed. Care should be taken not to injure or rupture the tumor capsule in GIST cases, which are more fragile than adenocancers. Thus, the risk of local recurrence can be minimized. As in our case, duodenal GISTs are most commonly located in the second part [1]. While wedge resection is generally recommended for tumors <2 cm, in our case, the tumor diameter was 3,6 cm in histopathological examination. However, a wedge resection could be performed as it was located anterolaterally and was more than 2 cm away from the ampulla of Vater. In the report of Cavalli, who presented a similar case, a 4-year disease-free survival was reported [8]. PD may provide a more appropriate treatment in the 2nd section tumors that are adherent to the head of the pancreas that involve the medial wall [1]. In tumors located in the lateral wall, cure can be achieved with limited resections in cases where the ampulla Vater can be preserved [7]. Tumor size and mitotic index criteria are important in the follow-up of GISTs. According to the NCCN guideline, tumors <2 cm can be described as benign regardless of the mitotic index, while small bowel GISTs are considered to be more aggressive[ 2]. As tumor size and mitotic index increase, the progression of the disease increases. If recurrence or metastasis is 8.3% in duodenal GIST cases with a tumor size of 2-5 cm and a mitotic index <5/50 HPFs, as in our case, this rate is 85% in cases with tumor diameter >10 cm and mitotic index >5/50 HPFs rises above [2].
Conclusion
We aimed to present a case of GIST, which was located on the anterolateral wall of the 2nd part of the duodenum, in which we performed wedge resection, and no recurrence was detected in the 5-year follow-up. Duodenum has a complex anatomical structure, especially its 2nd part. Complicated anatomical neighborhood also complicates surgical treatments for duodenal tumors. However, especially in the treatment of GIST, PD with higher complications and mortality can be avoided since it does not require lymphadenectomy and allows limited resection with R0 resection.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Huang Y, Chen G, Lin L, Jin X, Kang M, Zhang Y, et al. Resection of GIST in the duodenum and proximal jejunum: A retrospective analysis of outcomes. Eur J Surg Oncol. 2019;(10):1950-6.
2. Menge F, Jakob J, Kasper B, Smakic A, Gaiser T, Hohenberger P. Clinical Presentation of Gastrointestinal Stromal Tumors. Visc Med. 2018; 34(5):335-40.
3. Miettinen M, Kopczynski J, Makhlouf HR, Sarlomo-Rikala M, Gyorffy H, Burke A, et al. Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the duodenum: a clinicopathologic, immunohistochemical, and molecular genetic study of 167 cases. Am J Surg Pathol. 2003;(5):625-41.
4. Bucher P, Egger JF, Gervaz P, Ris F, Weintraub D, Villiger P, et al. An audit of surgical management of gastrointestinal stromal tumours (GIST). Eur J Surg Oncol. 2006; 32(3):310-4.
5. Woodall CE, Scoggins CR. Retroperitoneal and visceral sarcomas: issues for the general surgeon. Am Surg. 2007;(6):631-5.
6. Buchs NC, Bucher P, Gervaz P, Ostermann S, Pugin F, Morel P. Segmental duodenectomy for gastrointestinal stromal tumor of the duodenum. World J Gastroenterol. 2010;16(22):2788-92.
7. Mennigen R, Wolters HH, Schulte B, Pelster FW. Segmental resection of the duodenum for gastrointestinal stromal tumor (GIST). World J Surg Oncol. 2008; 6:105.
8. Cavallini M, Cecera A, Ciardi A, Caterino S, Ziparo V. Small periampullary duodenal gastrointestinal stromal tumor treated by local excision: report of a case. Tumori. 2005; 91(3):264-6.
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Fatih Buyuker, Mehmet Sait Ozsoy, Hakan Baysal, Medeni Sermet, Berrin Gucluer, Gurhan Bas. Wedge resection of duodenal gist, located on second portion of duodenum. Is it safe? A case report. Ann Clin Anal Med 2023;14(Suppl 1):S109-111
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Sarcomatoid urothelial carcinoma accompanied by elevated serum β-HCG: Two case reports
Sena Ece Davarcı 1, Hacer Demir 1, Arif Demirbaş 2, Gülsüm Şeyma Yalçın 3, Çiğdem Özdemir 4, Esra Özgül 5, Meltem Baykara 1
1 Department of Medical Oncology, Afyonkarahisar University of Health Sciences, Afyonkarahisar, 2 Department of Urology, Doruk Hospital, Bursa, 3 Department of Pathology, Afyonkarahisar State Hospital, Afyonkarahisar, 4 Department of Pathology, Afyonkarahisar University of Health Sciences, Afyonkarahisar, 5 Department of Radiology, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey
DOI: 10.4328/ACAM.21473 Received: 2022-11-02 Accepted: 2022-12-31 Published Online: 2023-01-30 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S112-115
Corresponding Author: Sena Ece Davarcı, Faculty of Health Science, Afyonkarahisar University, Afyonkarahisar, Turkey. E-mail: beyaaz3@hotmail.com P: +90 555 222 33 54 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1142-9411
Sarcomatoid urothelial carcinoma is a rare and aggressive variant. Serum β-hCG levels are used as a tumor marker in gestational trophoblastic diseases and germ cell tumors, but may also be elevated in high-grade bladder cancers. Here, we report two urothelial carcinoma cases with sarcomatoid differentiation that relapsed early after surgery with elevated serum β-hCG levels. The first case was a 65-year-old female and the second case was a 67-year-old man with sarcomatoid urothelial carcinoma located in the ureter and renal pelvicalyceal system, both of them relapsed with elevated β-hCG serum level to 146.8 mIU/mL and 242 mIU/mL, respectively. They died a few months after initial diagnosis; 4.9 and 2.5 months respectively.
Both sarcomatoid variant and β-hCG expression were associated with poor prognosis and advanced stage. However, β-hCG is not used as a tumor marker in urinary tract cancers yet, and its relationship with variant pathologies has not been clarified. We need multi-centered studies to reveal this relationship.
Keywords: β-HCG, Sarcomatoid Variant, Urothelial Carcinoma
Introduction
Sarcomatoid urothelial carcinoma is a rare and aggressive variant, which is thought to constitute approximately 0.3% of all urothelial carcinomas [1]. It is mostly located in the bladder and shows both epithelial and mesenchymal differentiation. Ureter and renal pelvis localizations are seen more rarely [2].
Human chorionic gonadotropin (hCG) is a glycoprotein that is secreted from the trophoblastic cells during pregnancy. Serum β-hCG levels are used as a tumor marker in gestational trophoblastic diseases and germ cell tumors, they can also elevate in high-grade bladder cancers and are associated with a poor prognosis [3]. Due to its rarity, we aimed to share two rare cases of urothelial carcinoma, which are accompanied with elevated β-hCG and show sarcomatoid differentiation.
Case Report
Case 1: A 65-year-old female patient applied to the Urology Department with macroscopic hematuria in June 2020. Abdominal MRI detected a 19x30x22 mm mass lesion in the left lateral wall of the bladder. Transurethral resection was performed and she was diagnosed with high-grade urothelial carcinoma with muscle invasion. The pathology result of radical cystectomy + ilioinguinal lymph node dissection surgery did not include immunohistochemical findings, and the pathological stage was pT2bN0. Post-operative abdominal MRI showed a lesion in the left lateral wall of the pelvis, which might be consistent with a 64×18 mm hematoma/lymphocele and a follow-up of the lesion was planned. Postoperatively, adjuvant cisplatin-gemcitabine chemotherapy was initiated on day 44. After the third cycle, the patient tested positive for COVID-19 PCR test and was given home isolation. At the end of home isolation, the patient re-applied to the Urology Department again 27 days after the last chemotherapy with a complaint of abdominal swelling. Abdominal MRI showed lesions in the intra-abdominal region and pelvis, with the largest size being 93×83 mm, which may be consistent with several metastatic cystic implants. Mass excision was performed for pathological diagnostic purposes. Pathology results showed cytokeratin (+), keratin-7 focal (+), p63 diffuse (+), p40 (+), hCG focal (+), Ki-67: 60-70%, vimentin weak (+), CD10 focal (+), S-100 (-), keratin 5/6 (-), keratin-20 (-), which is similar to the initial urothelial carcinoma, but there were regions showing focal sarcomatoid differentiation (Figure 1a and 1b). The pre-operative serum β-hCG level of the patient was 146.8 mIU/mL and postoperative serum β-hCG level regressed to 46 mIU/mL. In the post-operative period, the patient was hospitalized for maintenance therapy before initiation of the next line of chemotherapy, and we determined that her β-hCG level was elevated to 353 mIU/mL. Control abdominal MRI (Figure 1c, 1d and 1e) showed that the intra-abdominal implants had significantly progressed compared to the MRI taken 21 days ago. The chemotherapy could not be initiated because of the rapid deterioration of the general condition of the patient and she died 4.9 months after the first operation.
Case 2: A 67-year-old male patient applied to the Urology Department in September 2020 with right flank pain. In the abdominal USG, grade 4 dilatation in the right kidney and the right ureter was observed. Abdominal CT showed increased nodular thickness in the right pelvicalyceal system and irregularity in the wall along the course of the distal ureter with dilatation in the right ureter, the patient underwent a right nephroureterectomy operation. Pathology results showed a high-grade urothelial carcinoma with sarcomatoid differentiation located in the ureter and renal pelvicalyceal system, and cytokeratin (+) in epithelial component, keratin-7 (+) in the epithelial component, p53 20-30% (+) in the epithelial area, S-100 (-), ACTIN (-), Desmin (-), Vimentin (-), keratin-20 (-), CD34 (-), CD10 (-), EMA (-), and CD99 (-) (Figure 2a, 2b, 2c and 2d). The pathological stage was pT3N1. The abdominal CT performed on post-operative day 36 for baseline evaluation before the adjuvant chemotherapy showed high-density fluids and soft tissues along the ureter trace on the right, which cannot be clearly delineated from iliopsoas muscle. Since residue and hemorrhage could not be distinguished, an abdominal MRI was planned. Meanwhile, the patient applied to the Emergency Room on post-operative day 61 due to severe abdominal pain and he was hospitalized at the Oncology Service due to acute renal failure. His β-hCG was measured at 242 mIU/mL. Patient’s pre-operative β-hCG value had not been measured. Abdominal MRI showed a lesion with the size of 78x84x147 mm, with hemorrhagic intensities, starting from the sub-hepatic region in the right renal lodge, filling the entire retroperitoneal region, and extending to the iliacus muscle. It was found that the lesion infiltrated the right liver lobe, all segments of the iliacus muscle, and the posterior fibers of the psoas muscle and extended to the paraaortic area by pushing the inferior vena cava anteriorly (Figure 2e and 2f). Patient received hemodialysis after developing metabolic acidosis and hyperkalemia. However, patient’s renal function tests did not improve, his general condition deteriorated rapidly, and he died 2.5 months after the first operation.
Discussion
Approximately 75% of urothelial carcinomas consist of pure urothelial carcinomas, while the remaining 25% are histological variants. The sarcomatoid variant constitutes 0.3% of all urothelial carcinomas [1, 4]. Sarcomatoid urothelial carcinoma located in the renal pelvis and/or the ureter is extremely rare, with less than 30 reported cases [2, 5]. Variant histology is important as it determines the risk, shows the prognosis, and can directly impact the treatment [1].
Gu et al. showed that sarcomatoid urothelial carcinomas are associated with more advanced disease and T stage [4]. Also, it is associated with poorer survival data when compared with classical urothelial carcinoma, and upper urinary system ureteral sarcomatoid urothelial carcinoma has the poorest prognosis that the lifespan of these cases does not exceed 1 year [4, 5].
In the study by Douglas et al. investigating the effect of serum β-hCG levels on prognosis in 235 patients diagnosed with urothelial carcinoma, the median survival was worse in the groups with higher β-hCG levels before and after neoadjuvant chemotherapy (18.6 months vs. 4.2 months, respectively) compared to those with lower β-hCG levels (NR vs. 42.7 months respectively). Moreover, in patients with N₁₋₃ or M₁ disease diagnosed for the first time or patients who received another chemotherapy following relapse after previous peri-operative chemotherapy, high pre-treatment and post-treatment β-hCG levels were associated with reduced survival (median 8.6 months vs. 8.4 months, respectively) [3].
Dexeus et al. recommend measuring β-hCG levels prior to chemotherapy in advanced urothelial carcinomas. If the β-hCG level is above 50% of the normal value, regular measurement should be performed as it is a reliable marker for tumor response and progression [6]. Dobrowolski et al. have measured serum β-hCG levels of 79 bladder cancer patients before and 7 days after TUR. They showed that the mean serum β-hCG levels increased with increasing degrees of anaplasia and stage. They stated that the measurement of serum β-hCG levels is a good marker for differentiating superficial and deep tumors [7].
Venyo et al. reported elevated serum β-hCG levels with increasing histological grade. In addition, immunohistochemically, the frequency of β-hCG expression increases in correlation with grade and T stage. In patients with positive staining with β-hCG, recurrence occurs with higher grade and stage [8]. Compatible with the literature, our two cases were high-grade and showed both elevated serum β-hCG levels and β-hCG expression in IHC.
In the first case, adjuvant chemotherapy was initiated after radical cystectomy, but the patient had an early relapse and died 4.9 months after the first operation. The second case, in a rare way, was diagnosed with sarcomatoid urothelial carcinoma located in the renal pelvis and the ureter and presented with recurrence before adjuvant chemotherapy was initiated and died 2.5 months after the operation. The aggressive course of these two cases supports that the sarcomatoid variant and serum β-hCG elevation and IHC expression are associated with poorer survival.
Unfortunately, the serum β-hCG levels were not measured before the operation in the second case. However, with elevated serum β-hCG, β-hCG staining was demonstrated in the tumor tissue immunohistochemically in both cases. In addition, the decrease in serum β-hCG levels after metastasis excision in the first case and its elevation after disease progression supports the studies suggesting that serum β-hCG levels may be associated with the mass amount and that its follow-up in patients with high levels may show the progression.
Conclusion
Due to the fact that sarcomatoid urothelial carcinoma is extremely rare, data in the literature are mostly single-center and retrospective, and include a small number of cases and case reports. In urothelial carcinomas, β-hCG levels can be measured in serum and urine and stained in IHC. However, β-hCG is not used as a tumor marker in urinary tract cancers yet, and its relationship with variant pathologies has not been clarified. Therefore, multi-center, prospective studies involving more patients and pathological variants are needed to demonstrate the importance of β-hCG expression.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
Funding: None
References
1. Lobo N, Shariat SF, Guo CC, Fernandez MI, Kassouf W, Choudhury A, et al. What is the significance of variant histology in urothelial carcinoma? Eur Urol Focus. 2020;6(4):653-63.
2. Mohan BP, Jayalakshmy PL, Letha V, Bhat S. Sarcomatoid Carcinoma of Renal Pelvis Involving Ureter and Renal Parenchyma with Heterologous Osteosarcomatous Differentiation: A Case Report and Review of Literature. Iran J Pathol. 2018;13(1):89-93.
3. Douglas J, Sharp A, Chau C, Head J, Drake T, Wheather M, et al. Serum total hCGβ level is an independent prognostic factor in transitional cell carcinoma of the urothelial tract. Br J Cancer. 2014;110(7):1759-66.
4. Gu L, Ai Q, Cheng Q, Ma X, Wang B, Huang Q, et al. Sarcomatoid variant urothelial carcinoma of the bladder: a systematic review and meta‑analysis of the clinicopathological features and survival outcomes. Cancer Cell Int. 2020;20(1):550.
5. Wang Y, Liu H, Wang P. Primary sarcomatoid urothelial carcinoma of the ureter: a case report and review of the literature. World J Surg Oncol. 2018;16(1):77.
6. Dexeus F, Logothetis C, Hossan E, Samuels ML. Carcinoembryonic Antigen and Beta-Human Chorionic Gonadotropin as Serum Markers for Advanced Urothelial Malignancies. J Urol 1986;136(2):403-7.
7. Dobrowolski ZF, Bryska B, Dolezal M. Prognostic Value of Beta Human Chorionic Gonadotrophin in Blood Serum of Patients with Urinary Bladder Tumors. Int Urol Nephrol. 1994;26(3):301-6.
8. Venyo AKG, Herring D, Greenwood H, Maloney DJL. The expression of Beta Human Chorionic Gonadotrophin (β-HCG) in human urothelial carcinoma. Pan Afr Med J. 2010; 7:20.
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Sena Ece Davarcı, Hacer Demir, Arif Demirbaş, Gülsüm Şeyma Yalçın, Çiğdem Özdemir, Esra Özgül, Meltem Baykara. Sarcomatoid urothelial carcinoma accompanied by elevated serum β-HCG: Two case reports. Ann Clin Anal Med 2023;14(Suppl 1):S112-115
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A case of diffuse large B-cell lymphoma clinically and pathologically confused with breast cancer
Yaşar Culha 1, Meltem Baykara 1, Beyza Ünlü 1, Hacer Demir 1, Sena Ece Davarcı 1, Feriha Pınar Uyar Göçün 2, Ceren Bilkan Öge 2, Filiz Yavaşoğlu 3
1 Department of Medical Oncology, Afyonkarahisar University of Health Sciences, Afyonkarahisar, 2 Department of Pathology, Faculty of Medicine, Gazi University, Ankara, 3 Department of Hematology, Faculty of Medicine, Eskişehir University, Eskişehir, Turkey
DOI: 10.4328/ACAM.21485 Received: 2022-12-04 Accepted: 2023-01-25 Published Online: 2023-02-02 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S116-118
Corresponding Author: Yaşar Culha, Department of Medical Oncology, Afyonkarahisar University of Health Sciences, Afyonkarahisar, Turkey. E-mail: drjasar@hotmail.com P: +90 530 883 97 08 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0317-7552
Primary breast lymphoma is defined as only the presence of disease in the breast without in any other region of the body. Diffuse large B cell lymphoma (DLBCL) is most common among lymphoma types and accounts for approximately 50% of cases. We presented a case that was evaluated as breast cancer after initial pathological reports but diagnosed with DLBCL in further examinations. A 56-year-old woman with breast and axillary mass complaint who was initially evaluated as breast carcinoma and started treatment accordingly was presented. Due to clinical and pathological suspicion, biopsies repeated. The performed tru-cut breast biopsies were found to be compatible with DLBCL. In cases where adequate immunohistochemical examinations cannot be performed or there are conflicting data in the pathology reports, it is very important for the differential diagnosis to be evaluated together with the clinic and in case of doubt, biopsy repeats and pathology samples are re-examined in advanced centers.
Keywords: Breast Cancer, Lymphoma, Repeated Biopsies
Introduction
Lymphoma in the breast develops as primary or secondary. Primary breast lymphoma is defined as only the presence of disease in the breast without any other region of the body [1]. Metastatic breast lymphoma is two-three times more common than primary breast lymphoma, but response to treatment is better. Diffuse large B-cell lymphoma (DLBCL) is the most common among lymphoma types and accounts for approximately 50% of cases. There are also cases reported as follicular lymphoma, mucosa- associated lymphoid tissue (MALT) lymphoma and Burkitt’s lymphoma [1-2]. In this study, we present a case that was evaluated as breast cancer after initial pathological reports in tru-cut biopsy samples taken from masses in the breast and armpit and was diagnosed with DLBCL in further examinations. We present this case with the aim of emphasizing the importance of clinical approach and pathological examinations in the differential diagnosis.
Case Report
A 56-year-old female patient was admitted to the outer center due to swelling in the right breast and armpit that she noticed in the last 1-2 months. Breast ultrasonography performed at this center showed a mass lesion of 88×54 mm that extends from the upper outer quadrant of the right breast to the axillary tail, and the right breast upper outer quadrant tru-cut biopsy is ‘malignant tumoral formation and it is recommended to be evaluated in an advanced center where immunohistochemical examination can be performed for definitive diagnosis and typing’. As a result of this pathology, the patient applied to the oncology department of our hospital. There was a mass extending from the upper outer quadrant of the right breast to the axilla in physical examination of the patient. The boundary separation between the axilla and breast tissue of the mass could not be made clear, and it was about 10-12 cm in size. No additional features or additional lymphadenomegaly were detected in other system examinations. She had a chronic history of hepatitis B and hypertension and was treated with entecavir and amlodipine.
In the breast magnetic resonance imaging (MRI), a mass lesion of 130×68 mm, which indicates the extension from the right breast tail to the axilla, and a mass lesion of 50×39 mm on the upper outer quadrant of the right breast in the anterior part of this, as well as several metastatic lymph nodes with thick cortex, the largest of which was 42×27 mm, were detected in the right axillary area. Positron emission tomography (PET) imaging showed a mass lesion with increased fluorodeoxyglucose (FDG) involvement of 112×54 mm (suvmax: 31.9) indicating extending to the nipple in the right axillary region and lymph nodes with a large size of 22×10 mm in the right axillary area and slightly increased FDG involvement in the large lymph node (suvmax:3.3). With these evaluations, the outer central pathology blocks were re-examined in our hospital and a second tru-cut biopsy was performed from the breast and axial region. ER (-), PR (-), CERBB2 (-), CK7 (-), CD56 (-), CD10 (-), TTF (-), P40 (-) chromogranin (-), synaptophysin (-), Ki-67 %80 (+) were detected in the examination of external central pathology blocks. The pathology report stated that ‘the tumor consists of atypical epithelial cell plates with large hyperchromatic nucleus, high mitosis and apoptosis, and carcinoma infiltration primarily brings to mind low differential/high grade invasive ductal carcinoma’. With these findings, neoadjuvant chemotherapy cyclophosphamide + doxorubicin treatment was started and the second biopsy result was planned to be followed up in our hospital.
The pathology report of the repeated breast tru-cut biopsy shows tissues of the lymph node, larger size lymphocytes forming nodular structures separated from the environment by a sharp boundary, and small-sized lymphocytes surrounding them are monitored. When the case was evaluated together with immunohistochemical studies, it was thought that the samples may primarily belong to the lymph node of intramammarian reactive properties due to the fact that the nodular structures are separated from the environment by the sharp boundary and contain histiocytes. Immunohistochemical examination of CD19 and CD20 follicular structures: (+), CD45 (LCA): (+) , CD79a (+) , pax5 follicular structures: (+) , c-myc 10-15% (+) ki67 1-2 % (+). Reactive lymphoid tissue fragments containing lymphocytes and histiocytes were observed in the tru-cut biopsy of the axillary region. Cytokeratin was negative and CD3, CD20 and Ki 67 were focal (+) in the immunohistochemical examination. After these pathology reports, a re-biopsy decision was taken by discussing the pathology caused by the continued suspicion of lymphoma in the case. During this time, chemotherapy continued.
Multiple tru-cut biopsies from the right axillary region were repeated. As a result of the pathology, pan-keratin and CD45 were (+), some of the lymphocytes were (+) for CD19 and in the pathological interpretation, tissues belonging to lymph nodes with hyalinized parenchyma were seen in the sections, it was reported that small scattered lymphocytes and histiocytes are present in this parenchyma. Accordingly, although lymphoma cannot be excluded and the diagnosis of carcinoma could not be confirmed. With the final pathology report, it was planned to send all existing pathology blocks of the case to an advanced center and examine them. Meanwhile, 4 cycles of cyclophosphamide+doxorubicin chemotherapy were completed and the control breast MRI showed regression of the mass lesion in the breast to 35×19 mm and axillary LAP to 13×8 mm.
Advanced center pathology reports were concluded while the treatment of the case continued with weekly paclitaxel. In the pathological examinations from the advanced center, breast tru-cut biopsies performed at our center and in the hospital before the patient contacted us were found to be compatible with diffuse large B cell lymphoma (Figure 1A). CD20 and Pax5 (+) were in these reports (Figure 1B); MUM 1 and ALK(-), c-myc 25-40% nuclear staining, ki67 was 95% in the first biopsy sample (Figure 1C) and 70-80% in the next one. Axillary tru-cut biopsies taken in our hospital were reported as lymphoid infiltration in reactive and collagen fibrotic tissue. After these reports, the case was considered diffuse large B cell lymphoma and was referred to the hematology clinic. Control PET imaging showed an increased FDG overall with dimensions of 44×20 mm in the right axillaries area (suvmax 5.4) of the malignant mass lesion, according to the previous examination, regression in size and metabolic activity was observed, as well as regression in size and metabolic activity in lymph nodes with slightly increased FDG involvement (suvmax 2.4), which was approximately 12×7 mm in the right axilla. Lymph nodes with increased FDG involvement in the left hilar region (suvmax 8.2) were reported as new findings, and the treatment of R-CHOP (rituximab-cyclophosphamide, doxorubicin, vinchristine and prednisone) was planned by hematology.
Discussion
As a result of clinical and pathological evaluations of the patient’s complaint of a mass in the breast and axilla, it was diagnosed as lymphoma (DLBCL), not breast carcinoma. DLBCL is the most common subtype of metastatic breast lymphoma, which is more common than primary lymphoma of the breast [1-2]. Diffuse large B-cell lymphoma accounts for approximately 30-40% of all non-Hodgkin’s lymphomas in western countries. Since this group of tumors includes heterogeneous clinical, morphological, immunological and cytogenetic features, these tumors show a very variable clinical course and significant biological heterogeneity [3]. DLBCL usually expresses CD45 and pan-B (CD19, CD20, CD79a) markers. CD20 is a highly specific marker for the B cell line. However, although rare, CD20(+) peripheral T-cell lymphoma cases have been reported. In the case we have presented, in some of the biopsies repeated in our hospital and in the pathological examination performed in an advanced center, the neoplastic cells stained with CD20, CD79a, CD19 and Pax5 and diffusely positive staining and for breast origin, keratin 19, GATA-3 and ER, PR with cerbb2 and e-cadherin negative staining were found. Ki-67 is a protein and its high expression is a proliferation marker detected in the G1, G2, S and M phases of the cell cycle. In many studies, regardless of clinical variables, a high Ki-67 index (≥60-80%) in DLBCL indicates decreased total survival [4]. In our case, the Ki-67 index was reported as 80% in the examination of the first biopsy in our hospital, and 1-2% and focal (+) in two repeated biopsy examinations in our hospital. In two separate biopsy samples re-examined in the advanced center, ki-67 was detected at 95% and 80%.
Primary lymphomas of the breast are extremely rare tumors with a poor prognosis. The scarcity of lymphoid tissue in the breast is a reason for the rarity of primary breast lymphoma in the breast [5-6]. Lymph nodes are located in the breast, especially along the lymph channels, in the upper outer quadrant, close to the axillary region. It is suggested that lymphoid neoplasms are formed from these lymphoid structures [6]. The majority of primary breast lymphomas are B-cell lymphomas; diffuse large B-cell type is most common (40-70%) [2]. Lymphomas developing from MALT in the breast have also been reported [2]. Radiographic images of lymphoreticular system malignancies are not specific. There are no characteristic findings to distinguish them from each other, well-circumscribed benign tumors, carcinomas, or diffuse inflammation [7-8]. For a definitive diagnosis, a tru-cut biopsy or excisional biopsy should be performed and should be supported by immunohistochemical studies. In cases where adequate immunohistochemical examinations cannot be performed in the center in the presence of conflicting data in the pathology reports, it is very important for the differential diagnosis to be evaluated together with the clinic, and biopsy repeats in case of doubt and re-evaluation of the pathology samples in advanced centers.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Jennings WC, Baker RS, Murray SS, Howard CA, Parker DE, Peabody LF, et al. Primary breast lymphoma: the role of mastectomy and the importance of lymph node status. Ann Surg. 2007;245(5):784-9.
2. Alsadi A, Lin D, Alnajar H, Brickman A, Martyn C, Gattuso P. Hematologic Malignancies Discovered on Investigation of Breast Abnormalities. South Med J. 2017;110(10):614-20.
3. Arora SK, Gupta N, Srinivasan R, Das A, Nijhawan R, Rajwanshi A, et al. Non-Hodgkin’s lymphoma presenting as breast masses: a series of 10 cases diagnosed on FNAC. Diagn Cytopathol. 2013;41(1):53-9.
4. Miller TP, Grogan T, Dahlberg S, Spier CM, Braziel RM, Banks PM, et al. Prognostic significance of the Ki-67-associated proliferative antigenin aggressive non-Hodgkin’s lymphomas: a prospective Southwest Oncology Group trial. Blood 1994; 83: 1460-3.
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6. Chen M, Zhou J, Qu X. Primary Breast Diffuse Large B-Cell Lymphoma in a 42-Year-Old Female: A Case Report and Review of Literature. J Med Cases. 2021;12(5):181-5.
7. Dawn B, Perry MC. Bilateral non-Hodgkin’s lymphoma of the breast mimicking mastitis. South Med J. 1997;90(3):328-9.
8. Sosa YJ, Pope D, Monetto FEP, Robinson A, Klimberg VS. Hematologic malignancies of the breast: report of three cases. Radiol Case Rep. 2022;17(5):1384-90.
Download attachments: 10.4328.ACAM.21485
Yaşar Culha, Meltem Baykara, Beyza Ünlü, Hacer Demir, Sena Ece Davarcı, Feriha Pınar Uyar Göçün, Ceren Bilkan Öge, Filiz Yavaşoğlu. A case of diffuse large B-cell lymphoma clinically and pathologically confused with breast cancer. Ann Clin Anal Med 2023;14(Suppl 1):S116-118
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Valvular heart involvement in a patient with rheumatoid arthritis
Eray Beşirli 1, Firdevs Ulutaş 2, Zeki Yüksel Günaydın 3, Abdullah Çelik 4, İlknur Şenel 5
1 Department of Internal Medicine, 2 Department of Rheumatology, 3 Department of Cardiology, 4 Department of Cardiac Surgery, 5 Department of İnfectious Diseases, Giresun University Research and Training Hospital, Giresun, Turkey
DOI: 10.4328/ACAM.21637 Received: 2023-02-02 Accepted: 2023-03-12 Published Online: 2023-03-17 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S119-121
Corresponding Author: Firdevs Ulutaş, Department of Rheumatology, Giresun University Research and Training Hospital, Giresun, Turkey. E-mail: firdevsulutas1014@gmail.com P: +90 530 094 46 32 Corresponding Author ORCID ID: https://orcid.org/0000-0001-8441-5219
Infective endocarditis (IE) is a serious cardiac infectious disease with high mortality rates. Rheumatic diseases may be complicated with different cardiac presentations. Herein, we report a Rheumatoid Arthritis patient presented with subacute cardiac valve alterations due to infective endocarditis. In some cases, it may take time to make a clear diagnosis, but it is necessary to be dynamic in this process, especially in different treatment modalities.
Keywords: Rheumatoid arthritis, Infective Endocarditis, Cardiac Involvement, Inflammation, Valve Surgery
Introduction
Infective endocarditis (IE) is an infectious disease of endocard and heart valves with high mortality and morbidity rates in untreated patients. In some cases, the diagnosis of IE is confused with valvular involvement of rheumatic diseases [1]. Premature accelerated atherosclerosis and pericardial involvement are more commonly seen than valvular system involvement in rheumatoid arthritis (RA) patients [2]. Herein, we report a patient who has undergone aortic valve surgery due to IE, resulting in additional aortic valve involvement of RA. An informed consent form was obtained from the patient.
Case Report
A 58-year-old man was diagnosed with multiple septic emboli after ongoing rituximab therapy for active seropositive rheumatoid arthritis. He had also hypertension and chronic kidney disease without cardiovascular system involvement. A fistulizing wound formed subacutely on the right ankle and a 3*5 cm abscess in the gluteal region. After his hospitalization under ampicillin sulbactam we performed further investigation, which resulted in negative abscess culture and negative blood culture, negative serology/radiographic findings for serum brucella, celiac markers, negative quantiferon tests and absence of inflammatory bowel diseases. Antiphospholipid antibody panel, anti-nuclear antibody and panel of extractable nuclear antigens were also negative. Transesophageal echocardiography (TEE) was performed due to developed subfebril fever, diastolic murmur and high acute phase reactants unresponsive to prolonged antibiotic treatment. TEE resulted in degenerated right aortic cuspis, moderate-advanced aortic insufficiency and secondary healing of the right coronary cuspis due to possible infective endocarditis. A suspected area for vegetation, ruptured chordae or papilla are shown in Figure 1. After a multidisciplinary evaluation, we decided on aortic valve replacement for the following reasons: atipically located multiple and newly developed abscesses, echocardiographic signs of recently developed aortic valve insufficiency and the relatively young age of the patient. Perop right aortic cusp degeneration, 7 mm tissue defect (rupture) in non-coronary cuspid and annular proper nodular structures were detected (Figure 2). Histopathological findings were associated with central necrosis and mixed-type inflammatory cells related to rheumatic heart valve involvement without any microorganism. Parenteral antibiotic therapy of the patient was completed in eight weeks.
Discussion
A diagnostic dilemma is still present in the case. However we think it is likely that this patient developed infective endocarditis due to possible intensive immunosuppressive health conditions. Newly developed multiple septic abscesses and newly developed aortic valve dysfunction mainly support our hypothesis. Although diagnostic TEE findings or positive blood cultures in Duke’s can be instructive in such cases, patients can present with heterogeneous clinical conditions [3]. In this case, there were no positive blood cultures and characteristic TEE findings. Rheumatoid factor (RF) may also be positive in IE due to immune activation related to intravascular/cardiac infection. Positive values of RF were initially present in this patient related to RA.
Some patients may have silent cardiac disease. However, the cardiac valvular involvement (nodules, insufficiency, thickening and alterations) was emphasized in addition to pericardial involvement in RA patients. According to some studies, mitral regurgitation is the most common form of valvular disease in RA patients although the aortic disease is well-defined in patients with ankylosing spondylitis [4]. About 30-40% of patients with RA present with valvular diseases in which mitral regurgitation was found in 80% of them. Few trials also found a correlation between cardiac involvement and duration of the inflammatory process in these patients [5]. There are lots of examples of marantic endocarditis in untreated RA patients. Similarly, Giladi H et al, presented a case with buccogingival mucosal abscess and transient ischemic attacks due to mitral valve involvement of rheumatoid nodule and infective endocarditis. The patient improved also after surgery and the 6-week duration of antibiotic therapy [6].
In addition to blood cultures and ecocardiography findings, the histopathologic examination is important in the differential diagnosis. The characteristic histopathologic findings of rheumatoid nodules include central necrosis, surrounded by palisading histiocytes and fibroblasts in addition to mixt type inflammatory infiltrate composed of lymphocytes, plasma cells and histiocytes [7]. In addition, positive valve and/or blood cultures are hard to achieve due to poorly cultivable pathogens. Therefore, valve sequencing rather than valve culture was initially recommended to identify bacteria [8]. Despite all the diagnostic processes, some patients may remain in the gray zone. Echocardiography may be an important screening tool to prevent cardiovascular mortality in RA patients with pericardial and heart valvular involvements.
Conclusion
In some cases, it may take time to make a clear diagnosis, but it is necessary to be dynamic in this process, especially for early antibiotherapies. Heart involvement in RA patients may be underdiagnosed due to asymptomatic patients. Awareness of clinicians on this topic facilitates diagnostic approach, therapeutic options and patient survival.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
Funding: The authors did not receive any financial and/or other support.
References
1. Kyhl F, Rasmussen RV, Lindhardsen J, Smerup M, Fosbøl EL. Rheumatoid arthritis mimicking infective endocarditis with severe aortic regurgitation and aortic root abscess: a case report. Eur Heart J Case Rep. 2021;5(1):ytaa561.
2. Buleu F, Sirbu E, Caraba A, Dragan S. Heart Involvement in Inflammatory Rheumatic Diseases: A Systematic Literature Review. Medicina (Kaunas). 2019;55(6):249.
3. Holland TL, Baddour LM, Bayer AS, Hoen B, Miro JM, Fowler VG. Infective endocarditis. Nat Rev Dis Primers. 2016;2:16059.
4. Owlia MB, Mostafavi Pour Manshadi SM, Naderi N. Cardiac manifestations of rheumatological conditions: A narrative review. ISRN Rheumatol. 2012;2012:463620.
5. Roldan CA, DeLong C, Qualls CR, Crawford MH. Characterization of valvular heart disease in rheumatoid arthritis by transesophageal echocardiography and clinical correlates. Am J Cardiol. 2007;100(3): 496-502.
6. Giladi H, Sukenik S, Flusser D, Liel-Cohen N, Applebaum A, Sion-Vardy N. A rare case of enterobacter endocarditis superimposed on a mitral valve rheumatoid nodule. J Clin Rheumatol. 2008;14(2):97-100.
7. Tennyson C, Kler A, Chaturvedi A, Paschalis A, Venkateswaran R. Rheumatoid nodule on the anterior mitral valve leaflet. J Card Surg. 2018;33(10):643-5.
8. Shrestha NK, Ledtke CS, Wang H, Fraser TG, Rehm SJ, Hussain ST, et al. Heart valve culture and sequencing to identify the infective endocarditis pathogen in surgically treated patients. Ann Thorac Surg. 2015;99(1):33-7.
Download attachments: 10.4328.ACAM.21637
Eray Beşirli, Firdevs Ulutaş, Zeki Yüksel Günaydın, Abdullah Çelik, İlknur Şenel. Valvular heart involvement in a patient with rheumatoid arthritis. Ann Clin Anal Med 2023;14(Suppl 1):S119-121
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The use of double antibiotic paste for the management of huge periradicular lesion and external root resorption: A case report with 22 months follow-up
Muhammed Ayhan 1, Tuğçenur Yıldız 2, Ömer Bilgin 3
1 Department of Endodontics, Amasya Oral and Dental Health Hospital, Amasya, 2 Department of Endodontics, Faculty of Dentistry, Sakarya University, Sakarya, 3 Department of Endodontics, Sultangazi Oral and Dental Health Hospital, İstanbul, Turkey
DOI: 10.4328/ACAM.21651 Received: 2023-02-12 Accepted: 2023-03-20 Published Online: 2023-03-22 Printed: 2023-03-25 Ann Clin Anal Med 2023;14(Suppl 1):S122-124
Corresponding Author: Muhammed Ayhan, Department of Endodontics, Amasya Oral and Dental Health Hospital, 05000, Amasya, Turkey. E-mail: dt.muhammedayhan@gmail.com P: +90 553 843 60 70 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0264-2149
Large lesions may result in root resorption and tooth loss if not treated effectively. A 41-year-old male patient presented with pain in the left mandibular molar region. On clinical examination, there was no swelling, fistula, or sensitivity to percussion, but restoration was in the mandibular left second molar tooth. Radiographic examination revealed a large periapical lesion and external root resorption around the apices of the mandibular left second molar tooth. During treatment, NaOCl was preferred as an irrigation solution, Endoactivator was preferred for irrigation activation, and DAP was preferred as a medicament. Periapical healing was observed three and six months after the first appointment. Complete recovery of the periapical tissues was seen at 22 months of follow-up. The successful outcome seen in this case shows that even teeth with large periapical lesion and external root resorption can be managed conservatively with non-surgical endodontic treatment when effective disinfection is achieved.
Keywords: Antibiotics, Endoactivator, Endodontic Lesion, External resorption, Long-Term Follow-Up
Introduction
Apical periodontitis is an inflammatory lesion in the periodontal tissues that is caused usually by bacterial elements derived from the infected root canal system of teeth. Apical periodontitis may be viewed as a dynamic battle between invading microbes and host cells and tissues. Etiological factors that cannot be eliminated from the root canal space by the host response may initiate a chronic inflammatory process. This results in the resorption of hard tissues, local inflammation, and destruction of periapical tissues [1].
Apical inflammatory root resorption may occur as a result of periradicular inflammation. Teeth diagnosed with apical periodontitis have degrees of root resorption that may or may not be observed on radiography [2]. Since inflammatory root resorption is usually caused by bacterial infection of the root canal system, the ideal treatment prognosis can be achieved using antimicrobial procedures [3, 4].
CH is an effective material used as an intracanal medicament and is highly preferred. However, it is not always effective in battling bacteria in root canals, and its ability to penetrate directly into the dentinal tubules is insufficient. In addition, its effect on bacterial biofilm is lower than double antibiotic paste (DAB) and triple antibiotic paste (TAP). The mixture of ciprofloxacin, metronidazole, and minocycline, known as a TAP, is the most popular medicament in endodontics. But its disadvantage is coronal discoloration. Minocycline was removed from the DAP (ciprofloxacin, metronidazole) to prevent color changes [3].
This case report describes the successful management of huge lesion and external root resorption using DAP as intracanal medicament.
Case Report
A 41-year-old male patient without any systemic disease was admitted to our clinic with a complaint of pain in the left mandibular molar region. On clinical examination, there was no swelling, fistula, or sensitivity to percussion, but restoration was in the mandibular left second molar tooth. As a result of radiographic examination, external root resorption, and periapical lesion were observed in the mesial and distal root of the tooth (Figure 1).
At the first appointment of the treatment, the access cavity was accomplished using a diamond bur under rubber dam isolation. Working length was determined using periapical radiography and with the help of the apex locator using a #50 H-file in the distal canal and a #20 H-file and K-file in the mesial canals. Root canals were shaped by circumferential preparation techniques with hand instruments. Irrigation was performed with 5 mL of 5.25% sodium hypochlorite using a side-perforated needle syringe between each file and activated with Endoactivator (Dentsply, Tulsa Dental, Tulsa, OK, USA), and 5 mL of 17% EDTA was used for final irrigation. Root canals were dried with sterile paper points. Ciprofloxacin and metronidazole were ground into a powder and mixed with distilled water to a creamy consistency. This antibiotic mixture was applied to the canal using a Lentulo spiral. The access cavity was temporarily restored with glass ionomer (Kavitan Plus, Spofa Dental, Jicin, Czech).
The next appointment was made four weeks later, but he returned three months after the first visit. The tooth was asymptomatic to percussion and palpation. In addition, radiological examination revealed that the lesion was healing. After removing the antibiotic mixture from the root, the root canals were re-instrumented and irrigated again with the Endoactivator. The root canal was dried with sterile paper cones. The root canals were obturated with gutta-percha and AH-Plus (Dentsply Sirona, York, PA, USA) sealer using the lateral condensation technique. The permanent restoration of the tooth was made with composite.
At the follow-up appointment six months later, the patient did not have any symptoms and the periapical lesion continued to heal (Figure 2). The patient was recalled for up to 22 months. It was observed that the tooth was functional and clinically asymptomatic and there was no further progress in external root resorption. In addition, there was no visible discoloration of the tooth. Radiographically, it was observed that the periradicular lesion was completely healed and the lamina dura occurred (Figure 3).
Discussion
There are many disadvantages of the surgical option in cystic lesions. These are the reduction of bone support, damage to anatomical structures such as the mental foramen and lower alveolar nerve, and destruction of blood vessels and nerves feeding the teeth adjacent to the surgical area. However, it has been reported that apical lesions up to 20 mm can be healed with root canal treatment [1]. In addition, the cement layer may be eroded due to surface root resorption caused by apical periodontitis. Thus, bacterial mediators can cross the dentinal tubules, stimulating inflammation in the periodontal ligament and causing root resorption [2].
Adequate biomechanical cleaning of the root canal system is a key factor for healing periradicular lesions. However, due to the complex structure of the root canal anatomy, only biomechanical preparation is not sufficient for the elimination of bacteria in the root canals. In addition to chemomechanical preparation, various irrigation activation techniques and medicaments have been suggested for more effective disinfection of root canals [3].
CH is one of the most preferred intracanal medicaments in root canal treatment. However, it is not successful enough in eliminating bacteria due to its limited penetration into the dentinal tubules [3]. In the case report of Taneja and Kumari [5], describing the non-surgical endodontic treatment of teeth with large periradicular lesions, CH was used in the first stage and no healing was obtained. Then the treatment protocol was changed and triple antibiotic paste (TAP) was used instead of CH. As a result, it was reported that the symptoms disappeared and the periradicular lesion healed. Despite the many advantages of triple antibiotic paste, discoloration was reported [6]. In this context, DAP containing metronidazole and ciprofloxacin was developed by removing minocycline from the TAP to prevent coloration. Moreover, DAP and TAP are comparable in their antibacterial activities against Enterococcus faecalis and porphyromonas gingivalis. DAP is the preferred intracanal antibiotic mixture due to its beneficial effects [3].
In the presented case, the cessation of external root resorption, the onset of healing of the lesion, and in clinical examination and healthy appearance of soft tissues were observed at 6 months. However, the complete reconstruction of the trabecular structure, formation of the lamina dura, and the restoration of the periodontal state occurred within 22 months. These indicators indicate that the treatment has been successful. An effective antimicrobial endodontic treatment by applying DAP, including disinfection of dentinal tubules, can stop the inflammatory resorptive formation and provide periradicular healing. This is also supported by the clinical results of our case.
Conclusion
From the presented case it can be concluded that DAP has the potential to be used in teeth has a huge lesion and external root resorption. In addition, it has been seen that teeth with large lesions and external resorption can be treated without the need for surgery by using adequate irrigation activation and medicaments.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and human rights statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. No animal or human studies were carried out by the authors for this article.
Conflict of interest
None of the authors received any type of financial support that could be considered potential conflict of interest regarding the manuscript or its submission.
References
1. Kanmaz F, Altunbaş D, Zan R, Akpınar KE. Nonsurgical endodontic treatment of a large periradicular lesion. Turk Endod J. 2017;2(1):21-4.
2. Kırıcı D, Çolak M, Kuşuçar AN. Eksternal Kök Rezorpsiyonlu Ve Geniş Periapikal Lezyonlu Bir Dişin Endodontik Tedavisi (Endodontic Treatment of a Tooth with External Root Resorption and Large Periapical Lesion). Uluslararası Diş Hekimliği Bilimleri Derg/ International Journal of Dental Sciences. 2019;5(1):10-3.
3. Zan R, Topcuoglu HS, Hubbezoglu I, Gorler O, Altunbas D, Ayhan M. Effect of different irrigation activation methods on non-infected dentinal tubule penetration of medicaments: A CLSM study. Niger J Clin Pract. 2022;25(6):895-902.
4. Sabrah AH, Yassen GH, Gregory RL. Effectiveness of antibiotic medicaments against biofilm formation of Enterococcus faecalis and Porphyromonas gingivalis. J Endod. 2013;39(11):1385-9.
5. Taneja S, Kumari M. Use of triple antibiotic paste in the treatment of large periradicular lesions. J Investig Clin Dent. 2012;3(1):72-6.
6. Parhizkar A, Nojehdehian H, Asgary S. Triple antibiotic paste: momentous roles and applications in endodontics: a review. Restor Dent Endod. 2018;43(3):e28.
Download attachments: 10.4328.ACAM.21651
Muhammed Ayhan, Tuğçenur Yıldız, Ömer Bilgin. The use of double antibiotic paste for the management of huge periradicular lesion and external root resorption: A case report with 22 months follow-up. Ann Clin Anal Med 2023;14(Suppl 1):S122-124
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