Supplement_1_2025
Comparison of serum levels of cardiac biomarkers during hysterectomies
Nevin Aydın 1, Hatice Ateş 1, Osman Esen 2
1 Department of Anesthesiology and Reanimation, Faculty of Medicine, University of Health Sciences, Kanuni Sultan Suleyman Hospital, 2 Department of Anesthesiology and Reanimation, Faculty of Medicine, Istinye University, Istanbul, Turkey
DOI: 10.4328/ACAM.21267 Received: 2022-06-12 Accepted: 2022-10-05 Published Online: 2024-10-21 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S1-5
Corresponding Author: Nevin Aydın, Department of Anesthesiology & Reanimation, Faculty of Medicine, University of Health Sciences, Kanuni Sultan Süleyman Hospital, Istanbul, Turkey. E-mail: nevinaydin4334@gmail.com P: +90 212 404 15 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6995-2291
Other Authors ORCID ID: Hatice Ateş, https://orcid.org/0000-0001-6142-4040 . Osman Esen, https://orcid.org/0000-0001-6280-5064
This study was approved by the Ethics Committee of Kanuni Sultan Suleyman Training and Research Hospital (Date: 2021-02-24, No: 71)
Aim: The aim of this study was to retrospectively examine the changes in serum cardiac marker enzyme levels in patients who underwent total hysterectomy with laparoscopic and abdominal methods.
Material and Methods: This retrospective study included a total of 101 patients randomized between October 2017 and February 2018 in the department of gynecology and obstetrics of a tertiary health center. Total laparoscopic hysterectomy (TLH) was performed in 48 patients (47.5%) and total abdominal hysterectomy (TAH) in 53 patients (52.5%). Demographic data were compared with cardiac marker enzymes (creatine kinase, creatine kinase MB, lactate dehydrogenase, and troponin T levels in the TLH and TAH groups evaluated preoperatively and postoperative 6th and 12th hours.
Results: In the TLH group, troponin T level at the 12th hour was significantly higher than those measured at the other two time periods (p <0.001). Troponin T levels at 6th and 12th hours postoperatively in the TAH group were significantly higher than the baseline value (p <0.001). There was a statistically significant difference in the CK-MB level between the three- time points of the TLH group (p = 0.005). Baseline and 12th-hour values were significantly higher than the value measured at the 6th hour. Creatine kinase levels in the TAH and TLH groups were significantly higher at the 12th hour, 6th hour and at baseline (p <0.001). The median creatine kinase level in the TAH group was higher than in the TLH group (p<0.001).
Discussion: Cardiac problems that may occur before, during, or after gynecological interventions in female patients may have an unusual clinical presentation. Considering the cardiac risk profile of the patient, in addition to the experience and technical possibilities of the surgeon, is important to prevent complications when the decision is made regarding the realization of hysterectomy using laparoscopic or abdominal methods.
Keywords: Hysterectomy, Laparoscopy, Biomarkers, Heart
Introduction
Cardiovascular disease (CVD) is the leading cause of mortality worldwide and mortality due to CVD has increased remarkably in recent years. Women have a later onset of CVD than men, and estrogen has vascular protection against atherosclerosis, but coronary heart disease and CVD mortality are increased in young women aged 35 to 54 years. In addition to traditional risk factors, some clinical conditions specific to women have been shown to increase CVD risks such as preeclampsia, gestational diabetes, polycystic ovarian syndrome, early menopause, and autoimmune diseases [1-3]. However, coronary artery disease (CAD) is a notable cause of death in women and may affect women at a younger age than most people realize [4]. The incidence of CAD has decreased in men, whereas it has increased among women. It has been determined that with increasing age, women are at a higher risk of CAD than men of the same age [5]. Postmenopausal and premenopausal women display variation in terms of symptomatology, risk factors, disease characteristics, prognosis, and recurrence rates of CVD. Nevertheless, the presumably low incidence of CVD, particularly in pre-menopausal women, may have hindered some of the critical aspects and risk factors for CVD in this particular population [6, 7].
Identification of prodromal symptoms is supposed to be critical for effective screening, diagnosis, and treatment of CAD [8]. It may be crucial to understand and distinguish the symptoms linked with acute cardiac pathologies [7]. Nevertheless, symptoms detected in younger women are atypical, and dormant cardiac ischemia patients may exhibit a more severe form of the disease [8, 9]. For instance, a previous publication reported that relatively young women with CAD might not suffer from chest pain [10, 11]. In another study, pre-menopausal women displayed rapid onset of myocardial infarction without typical angina [12]. Autopsy research has demonstrated that coronary artery lesions in young women contain less calcium and dense fibrous tissue than those of men and older women [13, 14]. Coronary atherosclerotic plaque of young patients was comprised mainly of fatty deposits, which were extremely easy to rupture and caused acute coronary thrombosis that led to acute cardiovascular disease [15].
Though patients operated with the indication of gynecologic cancer generally has favorable survival, postoperative complications may develop. Cardiac problems, among these complications, worsen the quality of life and affect morbidity and mortality significantly. In this respect, it is important to determine the preoperative, intraoperative and postoperative risk factors for CAD, to take the necessary precautions and early intervention by early detection of CAD. In female patients, coronary artery disease has different manifestations than the usual clinical picture. Patients who undergo hysterectomy are often in their postmenopausal period, so vascular protective effect of estrogen hormone is relieved. We also performed this study to determine whether cardiac enzyme levels change dependent on laparoscopic or abdominal hysterectomy. Since there are no studies in this literature concerning this issue, we believe that our findings will be encouraging for future studies and that our findings will benefit from the perspectives of detection and elimination of possible cardiac risks in female patients.
Material and Methods
This retrospective study was conducted in a tertiary health center in the Department of Obstetrics and Gynecology, following the approval of the local ethics committee (ethical approval date and number: 24.02.2021 / 71). The mean age of the patients was 49.52 ± 8.45 years (range: 38-74). Patients were divided into two groups according to the performed surgical interventions as total laparoscopic hysterectomy (TLH) and total abdominal hysterectomy (TAH) groups. Total laparoscopic hysterectomy was performed in 48 patients (47.5%) and total abdominal hysterectomy in 53 patients (52.5%). Serum creatine kinase (CK), creatine kinase-MB (CK-MB), cardiac troponin T and lactate dehydrogenase (LDH) levels of the patients were measured together with demographic data such as age (years) and body mass index (kg/m2). Serum levels of these enzymes were measured three times, preoperatively and at 6th and 12th hours postoperatively. None of the patients in this series had cardiogenic shock, renal failure, or rhabdomyolysis at the sampling time. All the samples for serum level measurements of CK, CK-MB, LDH and troponin T were batch assayed by a single operator who was unaware of the patient’s diagnosis, treatment, or outcome.
The total level of plasma CK was evaluated via a standard method using a commercially available reagent kit (Boehringer, Mannheim, Germany) on a Hitachi 717 analyzer. Activity was expressed as IU/1 at 37°C, and the interassay coefficient of variation for normal values was found to be 4.4%. The activity of CK-MB activity was also determined in each specimen with the CK-MB (NAC-activated) reagent (Boehringer, Mannheim, Germany). Analysis of CK isoenzymes was performed using electrophoresis and scanned fluorimetrically with the REP system (Helena Laboratories) as described in the relevant literature [16]. Troponin T was measured with an enzyme-linked one-step sandwich immunoassay with streptavidin technology on the ES-300 immunochemical analyzer (CARDIAC T ELISA Troponin T, a kind gift of Boehringer Mannheim Corp, Indianapolis, Ind, USA). No hemolyzed or EDTA-treated samples were measured [17]. Serum LDH levels were determined according to Wroblewsky et al. at the time of the diagnosis. Activity was measured at 25 °C on a Beckman 25K Spectrophotometer (Beckman Instruments, Palo Alto, Calif., USA) with a recording system and expressed as mU/mI serum.
Statistical analysis
SPSS 21 program (Chicago, USA) was used for data analysis. The normal distribution assumption of the variables was examined using the Kolmogorov-Smirnov test. The mean ± standard deviation when assumptions are provided for descriptive statistics, and the median [25th percentile – 75th percentile] are given. In the comparison of the TLH and others groups, the difference between the two means was tested for significance, and the Mann-Whitney test was used when the assumptions were not met. The Friedman test was used to examine whether there was any change in three groups (beginning, 6 hours, 12 hours) in each group. Binary comparisons have been made to determine the time of the difference when there is a difference between the times. A value of p <0.05 was considered statistically significant.
Results
Descriptive parameters and serum CK, CK-MB, LDH and troponin T levels recorded in both groups are comparatively presented in Table 1. There was no statistically significant difference between the TLH and TAH groups for mean age (p = 0.156) and body mass indices of the patients (p = 0.660).
There was a statistical difference in the level of serum troponin T among three time periods (baseline, 6 and 12. hours) in the TLH group (p<0.001). The time frame that made the difference was related to the 12th hour. Troponin T levels at the 12th hour were significantly higher than in the other two time periods. There was a statistically significant difference in the level of troponin T between the three time periods in the TAH group (p < 0.001). The difference was related to the 6th and 12th hours, and the troponin T levels in these time periods were significantly higher than the baseline values. There was a statistically significant difference in the CK-MB level between the three-time points in the TLH group (p = 0.005). The difference was related to the baseline and the 12th hour-values. The baseline and 12th hour values were significantly higher than the value measured at the 6th hour. The level of CK in the TLH group was significantly higher than that measured at the 6th and 12th hours (p < 0.001). In the TAH group, CK levels were found to be significantly higher at 12th hour, relative to 6th hour and baseline measurements. There was a statistically significant intergroup difference in 6th hour serum CK levels (p <0.001). The median CK level in the TAH group was higher than the TLH group. Baseline CK values did not differ between groups, while a significant intergroup difference occurred in CK variable beginning from the 6th hour. In the TLH group LDH levels at 6th, and 12th hours were higher when compared with the baseline LDH values. In the TAH group, serum LDH levels at 12th hours were higher than baseline, and 6th hour values (Figure 1).
Discussion
Gynecologic surgeries vary according to age, type of cancer, and stage of cancer. Many surgical techniques can be applied, ranging from conization and simple hysterectomy to invasive cytoreductive surgery. Adjuvant treatments and supportive treatments may be needed in advanced cancer patients after the surgery. These complications may also increase in proportion to the extent of the surgery. The proximity to the gynecological organs increases the risk of complications such as vascular injury, ureteral injury, bladder perforation, and bowel injury. The injury of organs near the surgical site may result in partial or complete organ damage and failure. Problems ranging from organ perfusion disorder due to severe blood loss to death may occur after vascular injuries. Anesthetic agents decrease urine output, glomerular filtration rate, renal blood flow, and electrolyte excretion [18]. As effects of anesthesia, vasodilatatory and myocardial depressant effects of anesthetic agents, volume deficit, negative effects of mechanical ventilation on the lungs, and hypoxia may be enumerated. Hypoxemia may develop under anesthesia and factors such as some antibiotics, renal hypertrophy, non-steroidal anti-inflammatory drugs, angiotensin-2, calcium ion, myoglobin, hyperbilirubinemia, the contrast agent may worsen hypoxemia [19].
Although studies with new biomarkers continue, there are a number of applicable tests that currently address different aspects of cardiac function. With increasing age, functional capacities of organs are reduced, and their ability to respond to stress is lost. While advanced age alone is an increased risk for organ dysfunction, the presence of accompanying illness will further reduce organ function and increase risk [20].
Many agents used in general anesthesia (especially volatile agents) cause myocardial depression and peripheral vasodilatation, and vasoconstriction or fluid replacement is required to preserve organ perfusion. Another mechanism that increases fluid loss during general anesthesia is mechanical ventilation. During intubation, dry cold air from the anesthesia machine can cause significant fluid loss if heat-moisture filtration is not used [19]. Tachycardia is a common symptom in cancer patients and can be caused by anemia, hypovolemia, infection, medications or chemotherapy. Tachycardia due to hypovolemia before surgery may be a risk factor for cardiovascular complications. Early diagnosis and treatment of hypoperfusion and hypovolemia may, therefore, be effective in preventing possible cardiac risks [18]. The more invasive the surgical procedure, the greater the complication rate and the longer the operative time.
In interventions affecting more than one organ, maintenance of the hemodynamic stability can be challenging. Gynecologic surgeries can lead to hemodynamic instability after surgeries as extensive surgical excision, such as radical hysterectomy and debulking [18].
The extent of the surgical procedure to be performed also affects operative time. The prolongation of the operative time increases surgical site complications, and also causes the patient to be exposed to for longer times to anesthesia and mechanical ventilation. Catabolic hormones and cytokines released by surgical stimuli, embolies, ischemia-reperfusion injury, renal ischemia and inflammation increase the risk of long-term invasive procedures. Combined increase of catabolic hormones and cytokines may lead to an increased risk of coronary artery disease [19].
Postoperative vascular trauma, leakage from dissection surfaces, blood loss and associated transfusion requirements are among the factors that can increase cardiovascular risks. Often intraoperative vascular injuries may occur during laparoscopic surgeries, but they can also be seen in surgeries as laparotomy, and especially in cytoreductive, invasive surgeries. Cancer surgery carries a certain risk for arterial and venous injuries due to the deteriorated anatomy. During oncologic resections, iatrogenic operative major venous injuries can cause catastrophic complications with high morbidity and mortality. In this case, immediate recognition of these injuries is necessary to obtain a safe and acceptable treatment [21].
Since the patient population undergoing hysterectomy is predominantly composed of elderly women, careful attention should be paid to multiorgan dysfunction. With this respect, we hope that the results of our study will also provide important clues for the care of geriatric patients and their surgical treatment. Our findings showed that during the hysterectomy significant changes in serum CK, CK-MB, LDH and troponin T levels occur. Careful evaluation of cardiac and vascular conditions during preoperative evaluation of the patients for whom gynecologic surgery is planned carries importance.
The major limitations of our study include the relatively small number of cases, data limited to the experience of one center, and the measured enzyme levels affected by metabolic, environmental and genetic factors.
In conclusion, when the decision of hysterectomy is made by the laparoscopic or abdominal method, the cardiac risk profile of the patient should be considered in addition to the criteria such as the surgeon’s experience and technical possibilities. Cardiac problems that may occur before, during, or after gynecological interventions in female patients may present with an unusual clinical picture. Being prepared and vigilant by carefully evaluating all clinical cues in this regard may be helpful in reducing the frequency and severity of subsequent complications.
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 conflicts of interest.
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Nevin Aydın, Hatice Ateş, Osman Esen. Comparison of serum levels of cardiac biomarkers during hysterectomies. Ann Clin Anal Med 2025;16(Suppl 1):S1-5
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Relationship between first trimester placental thickness and perinatal prognosis: A prospective cohort Study
Mehmet Yılmaz 1, Şerif Aksin 1, Deniz Balsak 2, Yasmin Aboalhasan 3, Fatma Zehra Kurnuç 3, İbrahim Batmaz 1
1 Department of Obstetrics and Gynecology, Faculty of Medicine, Mardin Artuklu University, Mardin, 2 Department of Obstetrics and Gynecology, Faculty of Medicine, Siirt University, Siirt, 3 Department of Obstetrics and Gynecology, Siirt Training and Research Hospital, Siirt, Turkey
DOI: 10.4328/ACAM.22441 Received: 2024-10-06 Accepted: 2024-11-18 Published Online: 2024-12-03 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S6-10
Corresponding Author: Mehmet Yılmaz, Department of Obstetrics and Gynecology, Faculty of Medicine, Mardin Artuklu University, Mardin, Turkey. E-mail: drmehmetyilmaz7@gmail.com P: +90 532 687 81 34 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9930-4156
Other Authors ORCID ID: Serif Aksin, https://orcid.org/0000-0002-1301-2508 . Deniz Balsak, https://orcid.org/0000-0003-3140-8298 . Yasmin Aboalhasan, https://orcid.org/0000-0002-6231-9223 . Fatma Zehra Kurnuç, https://orcid.org/0000-0002-2502-6851 . İbrahim Batmaz, https://orcid.org/0000-0001-9492-2783
This study was approved by the Ethics Committee of Siirt University (Date: 2022-04-22, No: 2022/04.01)
Aim: This study aims to investigate the correlation between first-trimester placental thickness and perinatal prognosis.
Material and Methods: A prospective cohort study was conducted at Siirt University Faculty of Medicine from March 2022 to March 2023 of 365 pregnant women in their first trimester (11–14 weeks of gestation). Placental volume was measured using two-dimensional (2D) ultrasound, and estimated placental volume (EPV) was calculated using Merwin’s EPV Calculator app. The patients were followed until delivery, and outcomes such as gestational age at delivery, mode of delivery, fetal weight, APGAR score, fetal gender, perinatal outcomes, preeclampsia (PE), premature rupture of membranes (PROM), gestational hypertension (GHT), gestational diabetes mellitus (GDM), intrauterine growth restriction (IUGR), preterm birth, oligohydramnios, polyhydramnios, surmaturation, presentation anomaly, intrauterine death, fetal distress, and placental abruption were evaluated.
Results: Data from 365 pregnant women were analyzed. The mean maternal age was 27.2±5.5 years. The distribution of placental location was 38.4% posterior, 43.0% anterior, 7.4% left sidewall and 11.2% right sidewall. No significant differences were found in placental volume measurements based on delivery mode, fetal gender, or conditions such as PE, GDM, IUGR, PROM, preterm birth, or other perinatal pathologies. Statistical analyses showed no significant association between first-trimester placental volume and adverse perinatal outcomes (p>0.05).
Discussion: No relationship was found between first-trimester placental thickness and perinatal outcomes.
Keywords: First Trimester, Placental Thickness, Placental Volume, Perinatal Outcomes, 2D Ultrasound
Introduction
The relationship between first-trimester placental volume and perinatal prognosis has garnered significant interest in obstetric research. Understanding this relationship can provide early indicators of various obstetric complications, such as low birth weight, intrauterine growth restriction (IUGR), preeclampsia (PE), and gestational diabetes mellitus (GDM). Early detection of these conditions can lead to improved monitoring and intervention strategies, thereby enhancing maternal and neonatal health.
Previous studies have demonstrated a significant relationship between first-trimester placental volume and birth weight. Smaller placental volumes have been associated with small-for-gestational-age (SGA) neonates, while larger volumes have been linked to large-for-gestational-age (LGA) neonates. These findings underscore the potential of placental volume to predict neonatal weight [1].
Larger first-trimester placental volumes have been found to correlate with better fetoplacental vascular function postpartum. This finding suggests that larger and/or more vascularized placentas in early pregnancy may have better adaptation mechanisms, thereby improving pregnancy outcomes [2]. Additionally, studies investigating the predictive ability of first-trimester Doppler vascular flow indices have shown that lower indices are associated with pregnancies that develop PE [3].
Moreover, decreased first-trimester placental volume has been linked to an increased incidence of IUGR, and the placental vascularization index has shown a positive correlation with neonatal weight [4]. Placental volumetry using ultrasound in the first trimester has been reported to be useful in identifying pregnancies at risk for both low and high birth weights (SGA and macrosomia) [5].
In conclusion, first-trimester placental volume has been reported to have the potential to predict pregnancy complications in certain conditions. Evaluating placental volume early in pregnancy can provide valuable information about potential perinatal outcomes, paving the way for improved monitoring and intervention strategies.
Despite these findings, there is a need for standardized methods to measure placental volume and to validate the predictive value of these measurements across different populations. Our study aims to investigate the relationship between first-trimester placental volume and perinatal prognosis in a well-defined cohort, thereby contributing evidence to support the clinical utility of early placental assessment in prenatal care.
Material and Methods
For this purpose, approximately 360 pregnant women in their first trimester who were followed up at Siirt Education and Research Hospital, between March 2022 and March 2023 were included in the study. The ages, pregnancy histories, and medical histories of the pregnant women were recorded. Placental volume was measured using Merwin’s estimated placental volume (EPV) Calculator app. This application is designed to calculate the EPV from three measurements taken during the two-dimensional (2D) prenatal ultrasound, namely, the width, height, and thickness of the placenta, and is calculated using the formula V: πT/6* (4H(W-T) + W(W – 4T) + 4T²) (T: placental thickness, W: placental width, H: height ). During the examination, all participants were in a supine position, and care was taken to include the entire placenta within the measurement frame.
The study included pregnant women who applied to the prenatal clinic for routine first-trimester screening and were in the first trimester (between 11 and 14 weeks of gestation). Inclusion criteria were singleton pregnancies, maternal age between 18 and 45, and gestational age confirmed by the last menstrual period and/or early ultrasound. Exclusion criteria included known chromosomal or structural fetal abnormalities and chronic diseases, such as heart disease, chronic hypertension, diabetes, and a history of renal disease. During the examination, the gestational week, placental volume, and placental location of the patient were recorded. All patients were followed until delivery. Maternal and fetal outcomes such as gravida, parity, hemogram, biochemistry, urinalysis, gestational age at delivery, fetal weight, gender, APGAR score at 1 and 5 minutes, mode of delivery (normal spontaneous vaginal delivery (NSVD /cesarean section (C/S)), miscarriage, neonatal death, premature rupture of membranes (PROM), preterm birth, placental abruption, fetal distress, intrauterine death, GDM , PE, postmaturity, polyhydramnios, oligohydramnios, presentation anomaly, multiple pregnancies, IUGR, postpartum hemorrhage (PPH), and placenta previa were evaluated in three pregnancy groups.
Spontaneous miscarriage was defined as a miscarriage that occurred without intervention. Missed abortion was defined as the condition where the embryo/fetus loses its viability in the uterus, but uterine evacuation has not yet started. Neonatal death was defined as the death of an infant within 365 days after birth. PROM was considered as the rupture of fetal membranes before 37 weeks of gestation. Preterm birth was defined as a birth occurring between 20 0/7 and 36 6/7 weeks of gestation. Placental abruption was defined as the partial (partial abruption) or complete (complete abruption) separation of the placenta from the uterus before the birth of the baby. Fetal distress was defined as fetal oxygen deficiency, acidosis, or asphyxia and was diagnosed as fetal distress by nonstress test (NST ). Intrauterine fetal death was defined as the death of a fetus with a birth weight of 500 grams or more after 20 weeks of gestation or if the gestational age was unknown. GDM was diagnosed in pregnant women with a glucose value of 140–180 mg/dl in the 1-hour 50 g glucose screening test performed between 24 and 28 weeks of gestation and if two out of four glucose reference values were exceeded in the 100 g oral glucose tolerance diagnostic test (OGTT ). In high-risk groups, GDM was diagnosed directly by performing a 75 g OGTT without a screening test. PE patients included in the study were in accordance with the current recommendations of the American College of Obstetricians and Gynecologists (ACOG). Postmaturity was defined as pregnancies that extended beyond 42 weeks of gestation. Polyhydramnios was defined as amniotic fluid volume of 2000 ml or more. Oligohydramnios was defined as amniotic fluid volume of 500 ml or less. Presentation anomaly was assessed as non-cephalic presentation, such as face, brow, breech, or shoulder. IUGR was defined as an estimated fetal weight below the 10th percentile or an abdominal circumference <10% for gestational age. PPH was defined as estimated blood loss of >500 ml within the first 24 hours post-delivery.
Statistical Analysis
Statistical analyses were performed with IBM® SPSS® 26 (SPSS Inc., Chicago, IL, USA). The conformity of the variables to the normal distribution was examined using analytical methods (Kolmogorov–Smirnov/Shapiro–Wilk tests). Descriptive analyses are given as mean±standard deviation, and median, min–max are used for continuous data. Descriptive statistics were calculated from the frequency and percentage values of categorical variables obtained from sociodemographic and clinical information . In continuous data (placental volume), Student’s t-test was used for independent groups when they showed normal distribution, and the Mann–Whitney U test was used when there was non-parametric distribution to compare binary groups (prenatal pathological parameter groups). Spearman’s Rho correlation and linear regression analysis were used to predict placental volume with fetal weight and the APGAR 5 score. A p-value below 0.05 was considered statistically significant.
Ethical Approval
The study was approved by the Ethics Committee of Siirt University (Date: 2022-04-22, No: 2022/04.01) and conducted in accordance with the standards of the Helsinki Declaration. Written informed consent was obtained from the patients. The study has been given the following ClinicalTrials.gov Identifier: NCT05429242.
Results
Data from 365 pregnant women between 11 and 14 weeks of gestation were included in the study. The overall mean age was found to be 27.2±5.5 years, with a median age of 27 years, the youngest patient being 17 and the oldest 43 years old. The average gravidity was 3.2±2.0, and the average parity was 1.7±1.5. Of the women studied, 263 (72.1%) had vaginal deliveries, and 102 (27.9%) had C/S. Moreover, 230 (63.0%) women had no history of miscarriage, while 135 (37.0%) had experienced at least one miscarriage. The classification of placental location indicated that 140 (38.4%) were posterior, 157 (43.0%) were anterior, 27 (7.4%) were on the left sidewall, and 41 (11.2%) were on the right sidewall. The distribution of gestational weeks was as follows: 11 weeks – 33 (9.0%), 12 weeks – 108 (29.6%), 13 weeks – 107 (29.3%), and 14 weeks – 117 (32.1%).
When comparing placental volume measurements according to the mode of delivery, no significant differences were found between NSVD and C/S, fetal gender, PE, GDM, IUGR, PROM, preterm birth, abruption, fetal distress, intrauterine fetal demise (IUFD), postmaturity, oligohydramnios, polyhydramnios, or the presence of presentation anomalies (p>0.05) (Table 2). However, breech presentation increased placental volume by approximately 10 cm³ compared to non-breech presentation, but this difference was not statistically significant (p=0.093). The relationship between placental volume and APGAR 5 and fetal weight was examined, and no significant correlation was found (r=0.092, p=0.080; r=0.015, p=0.771, respectively).
Discussion
The placenta is a central structure in pregnancy and has very complex and powerful functions. Having the pathophysiological knowledge underlying this maternofetal structure greatly helps in understanding the development of pregnancy. If we can understand the early development of the placenta, we can understand preeclampsia, fetal growth restriction, and even the role of the placenta in maternal venous diseases. [6].
In our study, the relationship between placental volume and the variables APGAR 5 and fetal weight was examined, and no significant correlation was found (r=0.092, p=0.080; r=0.015, p=0.771, respectively). Joshi et al. (2013) found that lower placental weights were significantly associated with lower birth weights, fetal distress, lower APGAR scores, and conditions such as PE and maternal diabetes [7]. Carbone et al. (2011) observed that a combination of first-trimester placental volume, placental protein markers, and vascular indices could predict SGA outcomes but did not significantly improve predictions for PE or gestational hypertension (GHT) [8].
Our study also found no significant differences in placental volume measurements based on delivery method (NSVD and C/S), fetal gender, PE, GDM, IUGR, PROM, preterm birth, abruption, fetal distress, IUFD, postmaturity, oligohydramnios, polyhydramnios, and presentation anomalies (p>0.05). Stampalija T et al. investigated the relationship between placental volume in the first trimester and hypertensive pregnancy disorders (HDP) and SGA. Their study, which analyzed data from 1322 women, found that placental volume (was higher in uncomplicated pregnancies and lowest in the HDP–SGA group [9]. Vachon et al. found that first-trimester placental thickness increased in PE and decreased in SGA cases [10]. Approximately 10% of pregnancies exhibit reduced fetal growth, often associated with pathological conditions such as IUGR. Various methods, including placental volume and vascularization assessments alongside ultrasound and Doppler studies, are used to diagnose IUGR. Modern approaches suggest integrating these methods into algorithms to better predict high-risk pregnancies [11]. Soongsatitanon A et al. found that first-trimester placental volume was not an effective tool for predicting PE and/or IUGR. They observed that placental volume was particularly lower in cases of PE and/or IUGR, suggesting that further research is needed on the potential of first-trimester placental volume to predict early-onset PE [12]. Chen CY et al. examined changes in placental vascular indices and volume in overweight Chinese women during the first trimester using three-dimensional power Doppler ultrasound. They found that overweight women had lower placental vascularization indices, larger placental volumes, and higher uterine artery pulsatility indices. These findings shed light on the effects of early pregnancy overweight on placental vascularization and function [13]. Kim YR et al. evaluated a risk prediction model for PE using maternal age, body mass index (BMI), and EPV in the first trimester. Their study of 351 women found that 13 developed PE and that EPV was lower in women who developed PE. A model incorporating maternal age, BMI, and EPV could effectively predict PE in singleton pregnancies [14].
Plasencia W et al. found that placental volume and vascularization were lower in women with PE in the first trimester. Additionally, maternal characteristics such as multiparity and low maternal weight exacerbated the adverse effects of PE on the placenta and worsened perinatal outcomes [15]. Elhelaly AM et al. found no significant difference in placental volume and vascular indices between women with and without pre-gestational diabetes. However, they identified a strong relationship between HbA1C levels and vascular flow index (VFI), indicating that HbA1C could be a potential indicator for predicting placental complications in early pregnancy [16]. Effendi M et al. found that first-trimester placental volume was positively associated with birth weight and placental weight but was not associated with the risk of PE. Placental volume was smaller in SGA infants and larger in larger infants (1).
Studies have shown that placental diameter and thickness are highly positively correlated with fetal weight, aiding in predicting fetal weight [17, 18]. Significant relationships have also been found between prenatal and postnatal placental thickness and weight, APGAR scores, neonatal artery pH, and fetal growth restriction [19, 20]. A thick placenta detected by ultrasonography has been associated with increased mortality related to fetal anomalies and higher rates of both SGA and LGA infants, indicating increased perinatal risk [21, 22].
One of the main limitations of this study is its reliance on a single-center dataset, which may limit the generalizability of the findings to broader populations. Although the sample size is sufficient for initial findings, it may not be large enough to detect all significant differences among various subgroups, necessitating larger, multicenter studies to confirm these results. Finally, the observational nature of the study presents challenges in establishing definitive relationships due to its inherent observational characteristics. The strengths of the study include its contribution to the limited literature on first-trimester placental volume studies and its comprehensive examination of perinatal diseases within a broad framework.
Conclusion
This study examined the relationship between first-trimester placental volume and various perinatal outcomes. The findings indicated no significant correlation between placental volume and perinatal diseases. Despite the lack of significant correlations in this study, the potential role of placental volume in early pregnancy as a predictor of adverse perinatal outcomes should not be overlooked. Future research should focus on larger, multicenter studies to confirm these findings and explore additional factors or more detailed measurement techniques that could enhance the predictive power of placental volume assessments.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Effendi M, Demers S, Giguère Y, Forest JC, Brassard N, Girard M, et al. Association between first-trimester placental volume and birth weight. Placenta. 2014;35(2):99–102.
2. Hitzerd E, Reijnders IF, Mulders AGMGJ, Koning AHJ, Reiss IKM, Danser AHJ, et al. Larger first-trimester placental volumetric parameters are associated with lower pressure and more flow-mediated vasodilation of the fetoplacental vasculature after delivery. Front Physiol. 2020;11:6.
3. Eastwood KA, Patterson C, Hunter AJ, McCance DR, Young IS, Holmes VA. Evaluation of the predictive value of placental vascularisation indices derived from 3-Dimensional power Doppler whole placental volume scanning for prediction of pre-eclampsia: A systematic review and meta-analysis. Placenta. 2017;51:89-97.
4. Papastefanou I, Chrelias C, Siristatidis C, Kappou D, Eleftheriades M, Kassanos D. Placental volume at 11 to 14 gestational weeks in pregnancies complicated with fetal growth restriction and preeclampsia. Prenatal Diagnosis. 2018;38(12):928-935.
5. Schwartz N, Quant HS, Sammel MD, Parry S. Macrosomia has its roots in early placental development. Placenta. 2014;35(9):684-690.
6. Ortega MA, Fraile-Martínez O, García-Montero C, Sáez MA, Álvarez-Mon MA, Torres-Carranza D, et al. The pivotal role of the placenta in normal and pathological pregnancies: A focus on preeclampsia, fetal growth restriction, and maternal chronic venous disease. Cells. 2022;11(3):568.
7. Joshi JM, Patel D, Jayun JM. A study of association between maternal placental weight and neonatal characteristics J Evol Med Dent Sci. 2013;2(7):689-695.
8. Carbone J, Goetzinger K, Liebsch J, Rampersad R, Macones G, Odibo A. Combination of first-trimester placental protein 13 (PP13), 3D placental volume, vascular indices and maternal characteristics for prediction of adverse pregnancy outcomes. Am J Obstet Gynecol. 2012;206(1):S163.
9. Stampalija T, Quadrifoglio M, Casati D, Zullino S, Maggi V, Di Martino D, et al. First trimester placental volume is reduced in hypertensive disorders of pregnancy associated with small for gestational age fetus. J Matern Fetal Neonatal Med. 2021;34(8):1304-1311.
10. Vachon-Marceau, C, Demers S, Markey S, Okun N, Girard M, Kingdom J. First-trimester placental thickness and the risk of preeclampsia or SGA. Placenta. 2017;57:123-128.
11. Albu AR, Anca AF, Horhoianu VV, Horhoianu IA. Predictive factors for intrauterine growth restriction. J Med Life. 2014;7(2):165-171.
12. Soongsatitanon A, Phupong V. First trimester 3D ultrasound placental volume for predicting preeclampsia and/or intrauterine growth restriction. J Obstet Gynaecol. 2019;39(4):474-479.
13. Chen CY, Chang HT, Chen CP, Sun FJ. First trimester placental vascular indices and volume by three-dimensional ultrasound in pre-gravid overweight women. Placenta. 2019;80:12-17.
14. Kim YR, Jung I, Park G, Chang SW, Cho HY. First-trimester screening for early preeclampsia risk using maternal characteristics and estimated placental volume. J Matern Fetal Neonatal Med. 2021;34(7):1155-1160.
15. Plasencia W, González-Dávila E, González Lorenzo A, Armas-González M, Padrón E, González-González NL. First trimester placental volume and vascular indices in pregnancies complicated by preeclampsia. Prenat Diagn. 2015;35(12):1247-1254.
16. Elhelaly AM, Elnaggar AK, Mohamed MEDM, Abdelfattah MH, Farag AH. First trimester placental volume and vascular indices in pregestational diabetic compared to nondiabetic pregnant women. J Obstet Gynaecol Res. 2020;46(8):1326-1332.
17. Ogbochukwu OJ, Dim NR, Nnamani AO, Njeze NR, Obikili EN, Dim CC. Relationship of placental diameter and thickness versus fetal growth biometrics: A cross-sectional sonographic evaluation of antenatal women in Enugu, Southeast Nigeria. International Journal of Medicine and Health Development. 2020;25(2):138-143.
18. Bedi M, Sharma H, Sandhu PS, Minhas A. Correlation of placental thickness with birth weight in singleton pregnancies. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2021;10(10):3812-3817.
19. Farahbod F, Zarean E, Khanjani S, Moezzi M, Mohammadizadeh F, Shabanian S. Relationship between placental thickness, grading, and heterogeneity in fetal growth restriction in the third trimester of pregnancy by ultrasonography and pathology tests and their relationship with estimated fetal weight and neonatal outcome. Immunopathologia Persa. 2023;10(2):e39471-e39471.
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21. Miwa I, Sase M, Torii M, Sanai H, Nakamura Y, Ueda K. A thick placenta: A predictor of adverse pregnancy outcomes. Springerplus. 2014;3:353.
22. Rawal S, Ray S, Sharma N. Correlation between ultrasonographic placental thickness and adverse fetal and neonatal outcomes. Cureus. 2024;16(3):e56410.
Download attachments: 10.4328.ACAM.22441
Mehmet Yılmaz, Şerif Aksin, Deniz Balsak, Yasmin Aboalhasan, Fatma Zehra Kurnuç, İbrahim Batmaz. Relationship between first trimester placental thickness and perinatal prognosis: A prospective cohort Study. Ann Clin Anal Med 2025;16(Suppl 1):S6-10
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Topical psoralen plus ultraviolet-A therapy might be considered a current option for palmoplantar dermatoses, especially pustulosis
Zeynep Altan Ferhatoğlu 1, Sera Nur Yücesoy 2
1 Department of Dermatology, Faculty of Medicine, Istanbul University, 2 Department of Dermatology, Faculty of Medicine, Bezmialem Foundation University, Istanbul, Turkey,
DOI: 10.4328/ACAM.22522 Received: 2024-12-14 Accepted: 2025-01-23 Published Online: 2025-02-26 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S11-14
Corresponding Author: Sera Nur Yücesoy, Department of Dermatology, Bezmialem Foundation University, Istanbul, Turkey. E-mail: syucesoy@ku.edu.tr P: +90 530 300 40 75 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9170-4262
Other Authors ORCID ID: Zeynep Altan Ferhatoğlu, https://orcid.org/0000-0003-3090-656X
This study was approved by the Ethics Committee of Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty (Date: 2023-10-10, No: 805817)
Aim: Topical psoralen plus ultraviolet-A therapy (PUVA) is one of the commonly used treatment modalities in dermatology for palmoplantar dermatoses. Topical PUVA therapy is frequently preferred especially in palmoplantar dermatoses as it has fewer side effects than oral PUVA treatment. Our study aimed to evaluate the effectiveness of PUVA treatment in palmoplantar dermatoses.
Material and Methods: The study included 91 patients who received topical PUVA treatment in our hospital between 2010 and 2022. Patients were treated with topical PUVA therapy for 2-3 sessions per week and their treatment responses were evaluated. Descriptive statistics were expressed as number, percentage, median, and minimum-maximum, where appropriate. The chi-square test was used to evaluate categorical data.
Results: The treatment response of the palmoplantar pustulosis group was found to be significantly higher compared to the palmoplantar psoriasis and eczema group. Transient erythema was observed as the most common side effect.
Discussion: Topical PUVA therapy is a reliable and safe treatment method in palmoplantar dermatoses, especially in palmoplantar pustulosis patients.
Keywords: Palmoplantar Dermatosis, Pustulosis, Psoralen, Ultraviolet-A
Introduction
Topical psoralen plus ultraviolet A (PUVA) therapy is a widely used treatment option in dermatologic diseases. Psoralen substances absorb ultraviolet radiation and cause changes in DNA functions by photochemical reaction [1-3]. Although its mechanism of action is not fully known, it is thought that PUVA inhibits keratinocyte proliferation and causes immunosuppression by inhibiting cytokine and chemokine release [4-6]. Topical PUVA therapy is frequently preferred especially in palmoplantar dermatoses as it has fewer side effects than oral PUVA treatment. Treatment indications include psoriasis, eczema, mycosis fungoides, pustular dermatoses, and vitiligo [7]. Hyperkeratotic and dyshidrotic eczema, palmoplantar psoriasis, and palmoplantar pustular dermatoses are among the dermatological diseases in which topical PUVA therapy is most frequently used [8,9]. In the literature, the studies on the efficacy of topical PUVA therapy are limited in number. The present study aimed to evaluate the demographic data and treatment responses of patients who received topical PUVA therapy.
Material and Methods
This retrospective study included 190 patients who received topical PUVA therapy between 2010 and 2022 in the dermatology department of our faculty. A total of 91 patients with complete follow-up information were included in the study. Patients who discontinued the treatment and those who did not come to regular follow-ups were excluded.
All patients continued topical PUVA therapy for 2 or 3 sessions per week. The patients received a dose of UVA for 20-30 minutes after the application of topical 0.1% 8-methoxy psoralen gel to the affected area. Demographic characteristics and treatment responses of the patients were retrieved from the patient’s medical charts. The treatment responses of the patients were assessed by the percentage of regression of the lesions and were classified as follows: 1) moderate response (MR) indicating a percentage of regression between 25% and 75% (including 25%), 2) satisfactory response (SR) indicating a percentage of regression above 75% (including 75%).
Statistical analysis
The IBM SPSS Statistics for Windows Version 25.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Descriptive statistics were expressed as number, percentage, median, and minimum-maximum, where appropriate. The chi-square test was used to evaluate categorical data. A p-value of less than 0.05 was accepted as significant.
Ethical Approval
This study was approved by the Ethics Committee of Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty (Date: 2023-10-10, No: 805817).
Results
A total of 91 patients (56% male) with a median age of 47 years (range, 27 to 74 years) were included. The demographic characteristics of the patients participating in the study are shown in Table 1. Of the patients, 53 (58.2%) were diagnosed with chronic palmoplantar eczema, 24 (26.4%) were diagnosed with palmoplantar psoriasis, and 14 (15.4%) were diagnosed with palmoplantar pustulosis. Thirty-eight (41.8%) patients had Fitzpatrick type 2 skin type, while 53 (58.2%) patients had Fitzpatrick type 3 skin type. The accompanying chronic diseases of the patients are presented in Table 2. The median number of phototherapy sessions was 25 (range, 20-35). All patients in the study responded to the treatment at rates ranging from 40 to 90%. While the treatment response of 33 (36.3%) patients was moderate, the response was satisfactory in 58 (63.7%) patients. The treatment responses of the patients according to the diagnosis are summarized in Table 3. Clinical photographs of some patients before and after phototherapy are shown in Figures 1 and 2. The treatment response of the palmoplantar pustulosis group was found to be significantly higher than that of the palmoplantar psoriasis and eczema groups (p=0.048). As local side effects of PUVA therapy, transient erythema and/or pruritus in the treatment area were observed in 51 patients. Transient erythema, the most common side effect of PUVA therapy, was recorded in 30 patients. Regarding systemic side effects, only one patient complained of nausea during the treatment.
Discussion
Topical PUVA is a frequently preferred phototherapy especially in localized dermatoses due to its ease of application. The efficacy of topical PUVA has been evaluated in a limited number of studies. It has been evaluated as a safe treatment method when applied with appropriate doses. In a study performed by Carrascosa et al. [10], topical PUVA treatment was given to 48 patients with a diagnosis of palmoplantar psoriasis. At the end of the study, 63% of the patients who received only topical PUVA had a good response to treatment. The most common adverse event in that study was transient erythema, occurring in only 18% of the patients [10]. Similarly, in our study, 58% of the patients with palmoplantar psoriasis had a satisfactory response to the treatment, and the most common side effect was transient erythema. In another study conducted in patients with palmoplantar psoriasis, similar to our results, the effectiveness of topical PUVA therapy was 65% [11].
In the study by Grundman-Kollmann et al. [12] topical PUVA therapy was compared with bath-PUVA therapy in patients with palmoplantar psoriasis and palmoplantar eczema. While the response to topical PUVA treatment was 50% in patients with palmoplantar psoriasis, it was 75% in the palmoplantar eczema group. In that study, no severe side effect was reported with topical PUVA therapy except mild transient erythema [12]. In our study, the mean response to topical PUVA therapy of the patients was 69.5% and 69.6% in patients with palmoplantar psoriasis and chronic palmoplantar eczema, respectively.
In another study, topical PUVA therapy was applied to 22 patients with a diagnosis of palmoplantar pustulosis and palmoplantar psoriasis [13]. While the treatment response was evaluated as good in half of the patients, complete or almost complete regression of the lesions was observed in only 4 patients after 12 weeks of follow-up [13]. In that study, similar to the findings of our study, the most common side effect was reported as transient erythema [13].
In another study of 27 patients with a diagnosis of palmoplantar pustulosis, topical PUVA was compared with placebo, and although regression was observed in the lesions in patients receiving topical PUVA, no significant difference was observed compared to placebo [8]. In our study, treatment response was satisfactory (75% and above) in 92% of patients with palmoplantar pustulosis, and the treatment response was significantly higher compared to palmoplantar psoriasis and chronic eczema patients. In a study conducted by Riad et al. [14], three sessions of topical PUVA therapy per week were applied to patients with a diagnosis of palmoplantar pustulosis for an average of 13 weeks. At the end of the treatment, a percent regression of 75% or more was observed in 46.7% of the patients [14]. In another study, topical PUVA was given to patients with the diagnosis of palmoplantar psoriasis, palmoplantar pustulosis, and chronic palmoplantar eczema. In the patients with palmoplantar psoriasis, a regression of 50% or more was observed in 64% of the patients with palmoplantar psoriasis and in 65% of patients with chronic palmoplantar eczema. However, the regression percentage was less than 50% in all patients with palmoplantar pustulosis [15]. Unlike these studies, in the present study, a satisfactory response to topical PUVA in the patients with palmoplantar pustulosis was 92%, and the response was significantly higher than that in other palmoplantar dermatoses.
Limitation
The present study has also some limitations which can be considered as its retrospective study design and lack of clinical photographs of the patients; on the other hand, including a large series of patients is the strength of the study.
Conclusion
In the present study, topical PUVA was shown to be an effective treatment option in patients with palmoplantar eczema, palmoplantar psoriasis, and pustulosis, particularly being more effective in patients with palmoplantar pustulosis as compared with the findings of the previous 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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Barros NM, Sbroglio LL, Buffara MO, Baka JLCES, Pessoa AS, Azulay-Abulafia L. Phototherapy. An Bras Dermatol. 2021;96(4):397-407.
2. Stern RS. Psoralen and ultraviolet a light therapy for psoriasis. N Engl J Med. 2007;357(7):682-90.
3. Morison WL. Psoralen ultraviolet A therapy in 2004. Photodermatol Photoimmunol Photomed. 2004;20(6):315-20.
4. Buerger C, Malisiewicz B, Eiser A, Hardt K, Boehncke WH. Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin. Br J Dermatol. 2013;169(1):156-9.
5. Sethi G, Sodhi A. Role of p38 mitogen-activated protein kinase and caspases in UV-B-induced apoptosis of murine peritoneal macrophages. Photochem Photobiol. 2004;79:48-55.
6. Liszewski W, Naym DG, Biskup E, Gniadecki R. Psoralen with ultraviolet A-induced apoptosis of cutaneous lymphoma cell lines are augmented by type I interferons via the JAK1-STAT1 pathway. Photodermatol Photoimmunol Photomed. 2017;33:164-71.
7. Hawk JLM, Le Grice P. The efficacy of localized PUVA therapy for chronic hand and foot dermatoses. Clin Exp Dermatol. 1994;19:479-82.
8. Layton AM, Sheehan-Dare R, Cunliffe WJ. A double-blind, placebo-controlled trial of topical PUVA in persistent palmoplantar pustulosis. Br J Dermatol. 1991;124:581-4.
9. Pathak MA, Fitzpatrick TB. The evolution of photochemotherapy with psoralens and UVA (PUVA): 2000 BC to 1992 AD. J Photochem Photobiol B. 1992;30;14(1-2):3-22.
10. Carrascosa JM, Plana A, Ferrándiz C. Effectiveness and safety of psoralen-UVA (PUVA) topical therapy in palmoplantar psoriasis: A report on 48 patients. Actas Dermosifiliogr. 2013;104(5):418-25.
11. Neumann NJ, Mahnke N, Korpusik D, Stege H, Ruzicka T. Treatment of palmoplantar psoriasis with monochromatic excimer light (308-nm) versus cream PUVA. Acta Derm Venereol. 2006;86(1):22-4.
12. Grundmann-Kollmann M, Behrens S, Peter RU, Kerscher M. Treatment of severe recalcitrant dermatoses of the palms and soles with PUVA-bath versus PUVA-cream therapy. Photodermatol Photoimmunol Photomed. 1999;15(2):87-9.
13. Wilkinson JD, Ralfs IG, Harper JI, Black MM. Topical methoxsalen photochemotherapy in the treatment of palmoplantar pustulosis and psoriasis. Acta Derm Venereol Suppl (Stockh). 1979;59(85):193-8.
14. Riad K, Felix P, Dorit S, Gregory K, Nadim K, Henri T. The use of topical PUVA for palmoplantar dermatoses. J Dermatolog Treat. 2006;17(5):304-7.
15. De Rie MA, Van Eendenburg JP, Versnick AC, Stolk LM, Bos JD, Westerhof W. A new psoralen-containing gel for topical PUVA therapy: development, and treatment results in patients with palmoplantar and plaque-type psoriasis, and hyperkeratotic eczema. Br J Dermatol. 1995;132(6):964-9.
Download attachments: 10.4328.ACAM.22522
Zeynep Altan Ferhatoğlu, Sera Nur Yücesoy. Topical psoralen plus ultraviolet-A therapy might be considered a current option for palmoplantar dermatoses, especially pustulosis. Ann Clin Anal Med 2025;16(Suppl 1):S11-14
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Histopathological features of wrist ganglion cysts and their relationship with recurrence
Berna Eriten 1, Serdar Menekşe 2
1 Department of Medical Pathology, Martyr Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul, 2 Department of Orthopedics and Traumatology, Adana Seyhan State Hospital, Adana, Turkiye
DOI: 10.4328/ACAM.22551 Received: 2025-01-06 Accepted: 2025-02-17 Published Online: 2025-02-25 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S15-19
Corresponding Author: Berna Eriten, Department of Medical Pathology, Martyr Prof. Dr. İlhan Varank Training and Research Hospital, İstanbul, Turkiye. E-mail: bernaeriten@gmail.com P: +90 530 552 84 23 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3710-1502
Other Authors ORCID ID: Serdar Menekşe, https://orcid.org/0000-0002-4121-8917
This study was approved by the Ethics Committee of Adana City Training and Research Hospital (Date: 2025-01-02, No: 313)
Aim: Our study aims to analyze the histopathological structure of wrist ganglion cysts in patients treated with surgery and their relationship with recurrence.
Material and Methods: 104 patients who underwent surgery for wrist ganglion cysts between January 2021 and June 2024 were retrospectively examined. In the histopathological evaluation, myofibroblast density, degree of inflammation, vascularization, collagen density, and capsule thickness were examined. Immunohistochemical staining procedures were performed for α-SMA, CD34, Ki-67, and Vimentin. Recurrence rates and associated risk factors were evaluated.
Results: The mean age was 35.4±12.8 years, with a female predominance (68.3%). Dorsal localization was the most common localization (65%). When examined histopathologically, moderate myofibroblast density was detected in 54.2% of the cases. The overall recurrence rate was calculated as 26.7%. A significant correlation was observed between recurrence and increased myofibroblast density (p=0.042), high vascularization (p=0.038), and capsule thickness greater than 2.8 mm (p=0.034). Volar location (OR: 2.34, 95% CI: 1.46-3.75) and cyst size greater than 15 mm (OR: 1.92, 95% CI: 1.18-3.14) were independent risk factors for recurrence.
Discussion: Histopathological content of wrist ganglion cysts, especially myofibroblast density, vascularization, and capsule thickness, is significantly correlated with the risk of recurrence and the findings may be helpful in the detection of high-risk cases and in the development of treatment strategies.
Keywords: Ganglion Cyst, Wrist, Histopathology, Myofibroblast
Introduction
Wrist ganglion cysts are structures originating from the joint capsule or tendon sheaths and are benign lesions filled with mucinous content [1]. They constitute approximately 60-70% of soft tissue tumors detected in the upper extremity [2]. When the ganglion wall is examined, it consists of fibroblastic proliferation containing myofibroblastic cells rich in collagen structure. These structures, which have a smooth inner surface and do not contain a significant epithelial layer, are filled with gelatinous material with a high hyaluronic acid content [3]. When examined at the molecular level, type I and III collagen are dominant in the extracellular matrix of the cysts, and the imbalance in the content of matrix metalloproteinases (MMP-1, MMP-2) and tissue inhibitors (TIMP-1, TIMP-2) has a critical effect on cyst formation [4, 5]. Immunohistochemical analysis revealed α-SMA and vimentin expression in myofibroblasts [6].
While making histopathological classification; myofibroblastic structure, collagen organization, and vascularization level are evaluated [7]. Ki-67 proliferation and CD34 expression are especially gaining importance as potential biomarkers in determining the risk of recurrence [8, 9].
Increased myofibroblast density and capsule thickness correlate with high recurrence risk [10]. The degree of vascularization and inflammatory infiltration density are also important in prognostication [11].
Our study aims to examine the effect of microscopic features on recurrence with histopathological analysis of wrist ganglion cysts and to contribute to the current literature. The findings will determine the prognostic importance of histopathological parameters and shed light on the emergence of more effective treatment strategies in the clinic.
Material and Methods
Patient Selection and Clinical Evaluation
The study included 104 patients who underwent surgery and follow-up for wrist ganglion cysts between January 2021 and June 2024 [15, 16]. In the clinical evaluation of the patients, pain levels were assessed with a Visual Analog Scale (VAS), and range of motion was assessed with standard goniometric measurement. Demographic data, duration of symptoms, trauma history, and dominant hand use were recorded.
Histopathological Examination
Surgical excision materials were fixed in 10% buffered formalin for 24 hours. The tissues were then embedded in paraffin blocks and 4 μm thick sections were obtained [7]. α-SMA (1:100), CD34 (1:50), Ki-67 (1:100), and Vimentin (1:200) staining were performed at standardized dilutions using the immunohistochemical protocol [4]. Histopathological Evaluation
Preparations were evaluated microscopically according to the clinical information of the patients [8]. Myofibroblast density (low/moderate/dense), inflammation degree (absent/mild/moderate/severe), vascularization (low/moderate/dense), and collagen density (low/moderate/dense) were graded. Capsule thickness and morphometric measurements were performed with a standardized protocol [10].
Statistical Analysis
Data were analyzed using SPSS Statistics 25.0 software. The minimum sample size was calculated as 98 for 80% power and 0.05 type I error with G*Power software. The conformity of the data to normal distribution was evaluated with visual methods and Kolmogorov-Smirnov test. Student t-test or Mann-Whitney U test was used for continuous variables, and the Chi-square test was used for categorical variables [11]. Risk factors for recurrence were determined by multivariate logistic regression using variables with p<0.20 in univariate analysis. The agreement between the two pathologists’ evaluations was calculated by weighted-kappa analysis. Bonferroni correction was applied for multiple comparisons. The statistical significance level was determined as p<0.05.
Inclusion and Exclusion Criteria of Patients
Inclusion Criteria
1. Age: 18 years and above
2. Diagnosis: Histopathological and clinical diagnosis of wrist ganglion cyst
3. Surgical Intervention: Patients who underwent ganglion cyst surgery.
4. Follow-up Period: Patients with at least 6 months of regular follow-up.
5. Data Completeness: Cases with no missing clinical, demographic, and histopathological data.
Exclusion Criteria
1. Age: Under 18 years
2. Diagnostic Uncertainty: Histopathologically unconfirmed or suspicious diagnosis
3. Concomitant Diseases: Malignant or systemic pathology in the wrist other than a cyst
4. Previous Surgical Intervention: Previously undergone another surgical procedure
5. Insufficient Follow-up: Failed postoperative follow-up
6. Missing Data: Clinical or histopathological data not available.
Ethical Approval
This study was approved by the Scientific Research Ethics Committee of Adana City Training and Research Hospital (Date: 2025-01-02, No: 313).
Results
Demographic and Clinical Features
A total of 104 patients were included in this study. The mean age of the patients was 35.4 ± 12.8 years, 68.3% (n=82) were female and 31.7% (n=38) were male. The mean BMI (Body Mass Index) was calculated as 26.3 ± 4.2 kg/m².
The dominant hand usage rates in the patients were calculated as 90% (n=108) right and 10% (n=12) left. The affected hand was observed as 59.2% (n=71) on the right side and 40.8% (n=49) on the left side.
The median symptom duration of the patients was calculated as 8 months (3-24 months).
Occupational Distribution
• Office worker: 45 (%37.5)
• Housewife: 28 (%23.3)
• Worker: 22 (%18.3)
• Student: 15 (%12.5)
• Other: 10 (%8.4)
Patients with a history of trauma accounted for 26.7% (n=32), and patients without trauma accounted for 73.3% (n=88) (Figure 1).
Characteristic Features of Ganglion Cysts
• Dorsal: 65% (n=78)
• Volar: 29.2% (n=35)
• Other: 5.8% (n=7)
The mean cyst size was calculated as 15.8 ± 6.4 mm. 85% of the cysts were seen as single and 15% as multiple.
The severity level (VAS) was determined as median 4 (2-6).
Joint limitation rates:
• Flexion: 12.4 ± 8.6
• Extension: 15.8 ± 9.2
• Radial: 8.2 ± 4.8
• Ulnar: 6.4 ± 3.9
Data are also available in Figure 2.
Myofibroblast density in histopathological analysis
• Low: 17.9% (n=5)
• Medium: 24.6% (n=16)
• Dense: 40.7% (n=11)
Myofibroblast density creates a significant difference in the histological structure of the cysts and is effective on the risk of recurrence.
Degree of Inflammation
In histopathological examinations of the cases, it was determined that the inflammation was at different levels among the patients:
• Mild: Most of the cases
• Moderate: In some cases
• Severe: Rarely observed.
Microscopic images can be seen in Figure 3.
5. Recurrence Rate and Associated Factors
The recurrence rate was determined as 26.7% (n=32). Factors associated with recurrence:
• Myofibroblast Density: Higher density, increased risk of recurrence
• Capsule Thickness: Higher recurrence rate in cases
• Vascularization Degree: Higher vascularization was observed to be associated with more frequent recurrence.
These factors provide more precise surgical planning and patient follow-up.
Discussion
Comprehensive analysis of the histopathological features of wrist ganglion cysts is of critical importance in predicting the risk of recurrence and determining treatment strategies. The results of 104 cases examined in our study reveal remarkable findings in terms of both similarities and differences with the literature.
Demographic and Clinical Features
The mean age of the patients in our study was 35.4 years, and female predominance (68.3%) was evident. These findings are parallel to the demographic data in the studies of Goller et al. [2] and Neder Filho et al. [3]. Similar demographic features were also reported in the study of Abu Moussa et al. [4].
In terms of localization, dorsal localization (65%) was dominant, and this rate is consistent with the series reported by Koehl et al. [5]. Holt et al. [6] emphasized that dorsal localization ganglion cysts are easier to diagnose than volar localizations and have more advantages in terms of surgical technique.
Histopathological Features
In our study, moderate proliferation was detected in 54.2% of the patients in terms of myofibroblast density, and this finding is similar to the results of Saleh et al. [7]. Konigsberg et al. [8] emphasized the role of myofibroblastic activity in the pathogenesis of ganglion cysts, while Zhou et al. [9] showed the relationship between myofibroblast density and recurrence.
Factors Associated with Recurrence
The 26.7% recurrence rate detected in our study is consistent with the rates reported in the study of Kim et al. [10]. In the study of Hansen et al. [11], it was shown that myofibroblast density and degree of vascularization are associated with the risk of recurrence, and our findings support these results. Graham et al. [12] also reported similar risk factors.
The higher recurrence rate in volar cysts (OR: 2.34, p=0.012) and the prognostic value of capsule thickness are noteworthy. These findings are consistent with the results of Teh et al. [13]. Nico et al. [14] also emphasized the prognostic importance of the degree of vascularization.
Limitation
The strengths of our study are the standardized histopathological evaluation criteria and comprehensive immunohistochemical analysis. The use of the protocols suggested by Strike et al [15] increases the reliability of our results. However, there are some important limitations of our study. First, there is a potential risk of bias in the collection of data due to the retrospective design [8]. Second, the generalizability of the results is limited because it reflects a single-center experience [4].
The mean follow-up period of 2.4 years limits the assessment of long-term recurrence rates [10]. The semi-quantitative scoring system used in histopathological evaluation is open to inter-rater differences [7].
The limited number of immunohistochemical markers and the lack of molecular analyses prevented the full elucidation of pathological mechanisms [13]. In addition, the effect of surgical technique differences on recurrence could not be standardized [11].
Conclusion
This study aimed to analyze the histopathological features of wrist ganglion cysts in detail and to reveal the effects of these parameters on recurrence. Our findings showed that histopathological factors such as myofibroblast density, capsule thickness, degree of inflammation, and vascularization significantly affect the risk of recurrence. In particular, increased myofibroblast density and capsule thickness stood out as independent risk factors for recurrence. In addition, immunohistochemical markers (Ki-67, CD34, α-SMA, Vimentin) play an important role as valuable biomarkers in the prediction of recurrence.
Recommendations for Clinical Applications:
• Individualized Treatment Protocols: A more detailed evaluation of histopathological parameters in the preoperative evaluation of patients with a high risk of recurrence may help to determine treatment strategies specifically for each individual.
• Use of Immunohistochemical Markers: In particular, standardization of markers such as the Ki-67 proliferation index and CD34 expression in routine pathological examinations may contribute to clinical practices in predicting the risk of recurrence.
• Early Intervention and Follow-up Protocols: In order to minimize the risk of recurrence, it is critical to determine regular follow-up protocols after surgery and to detect signs of recurrence at an early stage.
• Digital Pathology and Artificial Intelligence: Digital pathology systems and artificial intelligence-supported morphometric analyses can increase diagnostic accuracy by facilitating the quantitative evaluation of histopathological variables. It is expected that these technologies will be used in routine clinical practice in the future.
• Molecular Biology Studies: A more in-depth examination of the genetic and epigenetic mechanisms that play a role in the pathogenesis of ganglion cysts may contribute to the development of targeted treatment approaches.
• Recommendations for Future Research:
• Multicenter and Long-Term Studies: Prospective and multicenter studies with long-term follow-up data in larger patient groups will allow the obtained findings to be supported with more robust evidence.
• Biomarker Studies: Discovery of new immunohistochemical and molecular markers may help develop more sensitive tools for predicting the risk of recurrence.
• Comparison of Treatment Methods: Studies comparing the effects of open surgery, arthroscopic surgery, and minimally invasive methods on recurrence rates will contribute to the optimization of surgical techniques.
• Patient Satisfaction and Quality of Life Studies: Studies evaluating the long-term results of patient satisfaction and functional recovery after treatment will enable treatment protocols to be patient-centered.
In Conclusion
Understanding the histopathological features of wrist ganglion cysts is a critical step in predicting the risk of recurrence and improving surgical treatment strategies. This study aims to increase treatment success and improve patient satisfaction by enabling more effective use of histopathological parameters in clinical practice. Future multidisciplinary, advanced technology-supported, and comprehensive studies will contribute significantly to the creation of clearer and stronger guidelines in this area.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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3. Neder Filho AT, Costa AC, Barros RSM, Mattar Jr R, Zumiotti AV, Rezende MR, et al. Hand tumors. Rev Assoc Med Bras. 2024;70(Suppl 1):108-15.
4. AbuMoussa S, Roshan MP, Souza FF, Samet J, Policeni F, Mays S, et al. Soft tissue masses of the hand: A review of clinical presentation and imaging features. Curr Oncol. 2023;30(2):2032-48.
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6. Holt GE, Wilson RJ, Mesko NW, Cipriano CA. Soft-tissue masses: A visual guide to the good, the bad, and the ugly. Instr Course Lect. 2023;72(1):125-38.
7. Saleh ES, De Carvalho AF, Hasan S, Bozzo A, Thoma A, Wong J, et al. Soft tissue benign hand masses in the first web space: A retrospective case series. Cureus. 2023;15(4):37847-52.
8. Konigsberg MW, Tedesco LJ, Mueller JD, Kaplan FTD, Yao J, Rizzo M, et al. Recurrence rates of dorsal wrist ganglion cysts after arthroscopic versus open surgical excision: A retrospective comparison. Hand (NY). 2023;18(1):133-8.
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Berna Eriten, Serdar Menekşe. Histopathological features of wrist ganglion cysts and their relationship with recurrence. Ann Clin Anal Med 2025;16(Suppl 1):S15-19
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The relationship between osteoporosis and extremity muscle and subcutaneous adipose tissue thickness in postmenopausal women
Alper Uysal 1, Hacer Paksoy Karateke 2
1 Department of Physical Medicine and Rehabilitation, Mersin City Training and Research Hospital, Mersin, 2 Department of Physical Medicine and Rehabilitation, Adana City Training and Research Hospital, Adana, Türkiye
DOI: 10.4328/ACAM.22588 Received: 2025-01-29 Accepted: 2025-03-03 Published Online: 2025-03-17 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S20-25
Corresponding Author: Hacer Paksoy Karateke, Department of Physical Medicine and Rehabilitation, Adana City Training and Research Hospital, Adana, Türkiye. E-mail: hacerpaksoy1@gmail.com P: +90 505 011 50 40 Corresponding Author ORCID ID: https://orcid.org/0009-0004-5790-6759
Other Authors ORCID ID: Alper Uysal, https://orcid.org/0000-0002-4114-1649
This study was approved by the Ethics Committee of Hatay Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine Clinical Research (Date: 2022-08-22, No: 06)
Aim: The present study aimed to evaluate the relationship between muscle thickness and subcutaneous adipose tissue thickness (SATT) in the upper and lower extremities and the presence of osteoporosis/osteopenia in postmenopausal women (PMW).
Material and Methods: Three groups were formed based on T-score ranges, each consisting of 30 PMW with similar demographic characteristics: healthy, osteopenic, and osteoporotic. The quadriceps femoris muscle thicknesses (QFMT) and the biceps brachii plus brachialis muscle thicknesses (BB+BMT) of the participants, along with the SATT at these points, were measured by ultrasound (US). Notably, this is the first study to utilize receiver operating characteristic (ROC) analysis to assess QFMT and BB+BMT as predictors of osteopenia and/or osteoporosis in PMW. One of the unique contributions of this study to the literature is that the participants were selected from individuals who had not previously received osteoporosis treatment.
Results: A significant difference in QFMT values was observed among the three groups (all p<0.05). L1-L4 T-score showed a moderate positive correlation with QFMT (r = 0.562, p < 0.001) and a weak correlation with BB+BMT (r = 0.382, p = 0.003). Additionally, a weak positive correlation was found between QFMT and the femoral neck T-score (r=0.307, p=0.017). Among the parameters examined for predicting osteoporosis, the largest area under the curve (AUC) was found for QFMT, with a value of 0.899 (p<0.001).
Discussion: The current study demonstrated a significant association between osteoporosis and muscle thickness, in contrast to SATT, with QFMT being more impactful in predicting the disease than BB+BMT.
Keywords: Quadriceps Femoris, Subcutaneous Adipose Tissue Thickness, Osteoporosis, Osteopenia, Muscle Thickness
Introduction
Recent research highlights the intricate links between bone, muscle, and adipose tissue, revealing common mechanisms in the aetiopathogenesis of osteoporosis and sarcopenia. Osteoporosis, characterised by reduced bone density and structural deterioration, resulting in an elevated risk of fractures, shares common pathophysiological pathways with sarcopenia, which involves the progressive loss of muscle mass, strength, and function. Evidence suggests that both conditions are influenced by age-related changes in hormonal signalling, inflammatory processes, and oxidative stress, all of which impact bone remodelling and muscle integrity [1].
Studies have indicated a high prevalence of sarcopenia in osteoporotic PMW, with rates around 50% [2, 3]. The assessment of muscle and bone health in PMW is a crucial aspect of geriatric care, requiring reliable and valid evaluation methods. Ogawa et al. have demonstrated the reliability and validity of QFMT measurements using the US. They compared QFMT with muscle mass and strength assessments, suggesting that evaluating muscle thickness could serve as a valid alternative method to comprehensive full-body muscle assessments in clinical practice [4]. This method may offer an opportunity to monitor changes in muscle health over time and evaluate the interaction between muscle and bone in PMW.
The primary aim of this study was to evaluate the relationship between muscle thickness and SATT in the upper and lower extremities and bone measurement parameters in PMW. Additionally, this study aimed to determine whether subcutaneous fat tissue or muscle tissue is more significant in predicting osteoporosis and to assess whether the upper or lower extremity has a larger impact. Lastly, the main goal of the present study was to identify US parameters that can predict the severity of bone resorption as an alternative to dual-energy X-ray absorptiometry (DEXA). To our knowledge, this is the first study to present upper and lower extremity muscle thickness data using ROC analysis for predicting osteopenia and/or osteoporosis in PMW.
Material and Methods
Design of the Study
This prospective comparative study was conducted from September 2022 to December 2022 at the Physical Medicine and Rehabilitation Clinic of Hatay Training and Research Hospital.
Characteristics of the Subjects
PMWs over the age of 50 who had not previously used anti-osteoporosis drugs and had a DEXA examination were included in the study. Three groups were formed, each consisting of 30 healthy PMW (T-score > -1), 30 osteopenic PMW (T-score between -1 and -2.5), and 30 osteoporotic PMW (T-score < -2.5) as determined by DEXA measurements, all with similar demographic and physical characteristics [5]. Exclusion criteria for the study included the use of steroids, rheumatic disorders, chronic hepatic and renal diseases, haematological conditions, malignant diseases, scoliosis, neurological disorders, severe gonarthrosis, severe intervertebral disc disease, severe spinal stenosis, a history of chronic obstructive pulmonary disease, heart failure, and myocardial infarction and endocrine disorders such as thyroid and parathyroid diseases, as well as moderate to severe diabetes. Patients with a history of major musculoskeletal operations were also not included. İndividuals were considered to have exercised if they participated in moderate to high-intensity physical activity or walking (for more than 30 minutes per day) on at least 3 to 4 days per week [6].
Clinical Evaluations
Participants’ age, gender, weight, height, body mass index (BMI), menopause period, bone mineral density (BMD) measurements, exercise and smoking status, and comorbidities such as hypertension, mild diabetes mellitus, and hyperlipidaemia were noted. All eligible participants who were willing to participate in the study were first measured by the US, and then their BMD was evaluated via DEXA. When calculating the T-scores of lumbar vertebrae 1 to 4, vertebrae scores that deviated more than one standard deviation from adjacent vertebrae due to collapse or degenerative alterations were excluded. The mean value of the remaining vertebrae was then used for calculation [7].
All muscle thicknesses and SATTs were assessed using a Clarius L7 HD3 Portable Handheld US device. The QFMT was measured at half the distance between the anterior superior iliac spine and the upper edge of the patella. QFMT was calculated by measuring the distance between the femoral periosteum and the rectus femoris superficial fascia with the individual positioned supine and the lower limbs extended. SATT was assessed by measuring the distance between the superficial fascia of the rectus femoris muscle and the skin from this reference point [4, 8] (Figure 1A). During the examination of the upper extremity, participants were placed supine with their arm relaxed and their forearm positioned in extension at the elbow. The BB+BMT was evaluated by measuring a point located on an imaginary line between the acromion and the antecubital fold, positioned two-thirds distally along this line. BB+BMT was evaluated by measuring the distance between the humeral periosteum and the superficial fascia of the biceps brachii. Subsequently, at this reference point, the SATT was evaluated by measuring the distance between the superficial muscle fascia of the biceps brachii and the skin [9] (Fig. 1B). All US measurements were repeated three times by a physiatrist experienced in musculoskeletal US, and average values were recorded. A sufficient amount of gel was applied, and unnecessary pressure on the tissue was avoided to prevent compression of the measured soft tissues.
Statistical Analysis
The data obtained from the study were analysed using version 22.0 of the Statistical Package for Social Sciences (SPSS). The normal distribution of continuous variables was checked using the Kolmogorov-Smirnov test and histogram analysis. Descriptive analysis for continuous data is presented as mean, standard deviation (SD), median, and range (minimum-maximum), while categorical data are expressed as counts (n) and percentages (%). For comparing continuous variables with a normal distribution across three groups, the One-Way ANOVA test was employed, accompanied by Bonferroni-adjusted pairwise comparisons. For continuous variables that did not conform to a normal distribution, the Kruskal-Wallis H test was performed, along with Bonferroni-adjusted pairwise comparisons. Categorical data were analyzed using Fisher’s Exact test or Pearson’s Chi-Square test, as appropriate. Spearman’s correlation analysis was applied to variables that did not exhibit a normal distribution. The strength of the correlation (r) was interpreted as follows: insignificant correlation (0.00-0.30), low correlation (0.30-0.50), moderate correlation (0.50 -0.70), high correlation (0.70-0.90), and very high correlation (0.90-1.00) [10]. ROC analysis was utilised to determine the predictive value of parameters, including sensitivity, specificity, and the area under the curve. For all analyses, a p-value below 0.05 was regarded as indicative of statistical significance.
Ethical Approval
This study was approved by the Ethics Committee of Hatay Mustafa Kemal University, Tayfur Ata Sökmen Faculty of Medicine Clinical Research Ethics Committee (Date: 2022-08-22, No: 06). An informed consent form was obtained from all participants.
Results
The demographic characteristics and comorbidities of the groups are presented in Table 1. The analysis of these characteristics showed that there were no statistically significant differences between the groups (all p>0.05). The comparison of DEXA and US measurements of the groups was presented in Table 2. The T-score values for the L1-L4 vertebrae, total hip, and femoral neck were statistically different between the groups (p<0.05), except for the total hip T-score between the healthy group and osteopenic group. There was a significant difference in QFMT values among the three groups (all p<0.05). Additionally, a significant difference between the groups in terms of thigh SATT was detected (p=0.017), and according to the post hoc analysis, the only significant difference was found between the healthy group and osteopenic group (p=0.021). A significant difference was also found between the groups in terms of BB+BMT values (p=0.001), and according to the post hoc analysis, the only significant difference was found between the healthy group and osteoporotic group (p=0.001). However, no significant difference in arm SATT values among the three groups was detected (p=0.147). The correlation of muscle thicknesses and T-scores was presented in Table 3. L1-L4 T-score showed a moderate positive correlation with QFMT (r = 0.562, p < 0.001) and a weak correlation with BB+BMT (r = 0.382, p = 0.003). A weak positive correlation was observed between the QFMT and the femoral neck T-score (r=0.307, p=0.017). Furthermore, a statistically significant positive moderate relationship was found between QFMT and BB+BMT (r=0.582, p<0.001). The ROC curve analysis of QFMT and BB+BMT was presented in Fig. 2. The largest AUC was found for QFMT, with a cutoff value of 34.95, showing 83.3% sensitivity and 83.3% specificity, an AUC of 0.899 (p<0.001), and a confidence interval of 0.816 to 0.983, indicating that a QFMT value of 34.95 or lower is clinically significant for identifying osteoporosis.
Discussion
In the osteoporotic group, mean QFMT and BB+BMT values were reduced compared to the healthy group, while thigh SATT and arm SATT values were similar between the osteoporotic group and the healthy group. A moderate positive correlation was found between QFMT and the L1-L4 T-score, while a weak positive correlation was observed between QFMT and the femoral neck T-score. Additionally, a weak positive correlation was identified between the L1-L4 T-score and BB+BMT. In the ROC analysis performed to determine the osteoporosis predictive value of QFMT, the AUC was determined to be 0.899, which is a very good value. QFMT appears to have a stronger association with bone health compared to BB+BMT. No clinically significant relationship was detected between extremity SATT values and bone health.
Crivelli et al. found that visceral and subcutaneous adipose tissue had harmful effects on bone health in PMW [11]. The findings of the Framingham Osteoporosis Study suggested that visceral adipose tissue may not have a significant impact on the skeleton independent of weight [12]. Kim et al. found that subcutaneous adipose tissue has a protective effect on bone against osteoporosis, while visceral adipose tissue has harmful effects on bone health in PMW. Subcutaneous adipose tissue is the primary source of endogenous estrogen that enhances BMD in PMW. On the other hand, visceral adipose tissue is associated with insulin resistance and inflammation, which may have negative effects on bone health [13]. Despite this theoretical information, the relationship between adipose tissue and osteoporosis is contradictory in the literature. In the present study, no clinically significant relationship was detected between extremity SATT values and osteoporosis.
Bone and muscle are interconnected organs that functionally and developmentally form a cohesive unit, engaging in bidirectional interactions at various levels, from molecular to organic. Muscle contractions play pivotal roles in determining bone mass and shape. Additionally, physical activity has an anabolic effect on both bone and muscle metabolism. In addition to mechanical load, muscle and bone interact through biochemical signaling pathways such as myokines (myostatin, irisin, insulin-like growth factor-1 (IGF-1), interleukin (IL)-6, IL-7, IL-15 and fibroblast growth factor-2) and bone-derived factors (fibroblast growth factor-23, prostaglandin E2, osteocalcin, transforming growth factor β and sclerostin). Further factors such as aging, circadian cycles, neural networks, nutritional consumption, and exosomes also impact the interaction between bone and muscle [14].
Recent studies have provided strong evidence of an association between muscle thickness and osteoporosis [15, 16]. Liu et al. indicated that muscle plays a more significant role than fat in bone homeostasis, emphasizing the importance of muscle health in maintaining bone density and strength, and recommended improving muscle health for the prevention of osteoporosis in elderly individuals [17]. Tiftik et al. investigated the relationship between sarcopenia and osteoporosis in PMW. They found that grip strength and anterior thigh muscle thickness were correlated with lumbar vertebral BMD, and chair stand test performance was linked to femoral neck BMD [16]. Karatekin et al. evaluated mid-upper arm muscle thickness and triceps SATT via US in men with osteoporosis. They determined that mid-upper arm muscle thickness is correlated with the degree of osteoporosis severity and found no relationship between osteoporosis severity and SATT measured via US or skinfold calliper [15]. In the current study, while a relationship between extremity muscle thickness and bone health was found consistent with the literature, no relationship was detected between extremity SATT and bone health. Not only did Ogawa et al. demonstrate that QFMT may be a valid diagnostic tool for assessing overall muscular health, but this finding was also supported by the research of Wilson et al., Hogenbirk et al., and Yoshida et al. [4, 18-20]. The current study showed that as bone health deteriorates, anterior thigh muscle thickness, which may serve as an indicator of overall body muscle health, also decreases.
A study in mice found that pharmacological inhibition of chemotherapy-induced bone loss also reduced loss of muscle mass and function and supported the hypothesis that bone-derived factors influence muscle [21]. Six months of combined alendronate and calcitriol therapy has been shown to improve both lumbar bone BMD and handgrip strength, a key indicator of sarcopenia in PMW [22]. Harada et al. showed that alendronate may have a positive effect on both bone and muscle in individuals with osteoporosis [23]. Huang et al. revealed that zoledronic acid provides benefits not only to bone health but also to muscle tissue [24]. Denosumab treatment was associated with increased muscle strength in both upper and lower extremities in individuals with low BMD and weak muscle strength [25].
The existing literature suggests a positive relationship between osteoporosis treatment and muscle tissue health. However, previous studies investigating the correlation between muscle tissue health and bone tissue health did not specify whether the patients had received prior osteoporosis treatment [15-17]. In contrast, the current study stands out as it focuses on newly diagnosed patients who had not received osteoporosis treatment previously. The current study is critically important as it eliminates the direct effect of osteoporosis treatment on muscle tissue, allowing for a more precise assessment of the relationship between the two tissues. A better understanding of the interaction between muscle and bone tissues could contribute to the development of therapeutic approaches targeting both tissues, although further research is necessary. This mutual relationship could guide future research on diagnostic and follow-up parameters.
Despite these strengths, the study has several limitations. First, the cross-sectional design of the study limits the ability to establish causal relationships between muscle thickness and bone health. Longitudinal studies are needed to determine the direction and causality of this relationship. Second, the relatively limited sample size restricts the generalizability of the findings to a broader population. Larger and more diverse cohorts are required to confirm the reproducibility and robustness of the results. The third limitation is the lack of evaluation of participants’ dietary intake of protein, calcium, and vitamin D, as well as their sun exposure duration. The fourth limitation pertains to the absence of muscle strength and functionality evaluations. Finally, important parameters such as muscle echo intensity, cross-sectional area, and pennation angle were not analyzed.
Conclusions
The current study demonstrated a significant relationship between osteoporosis and muscle thickness, in contrast to SATT, with QFMT showing a higher predictive value for the disease than BB+BMT. While QFMT demonstrated potential as a predictive parameter for osteoporosis in PMW, further validation is required through larger and more diverse 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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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The predictive role of first-trimester pan-immune-inflammation value in gestational diabetes mellitus
Nihal Çallıoğlu 1, 2, İlke Özer Arslan 3
1 Department of Perinatology, Başakşehir Çam and Sakura City Hospital, Istanbul, 2 Department of Obstetrics and Gynecology, Gaziosmanpasa Training and Research Hospital, Istanbul, 3 Department of Obstetrics and Gynecology, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdağ, Turkiye
DOI: 10.4328/ACAM.22590 Received: 2025-01-31 Accepted: 2025-03-04 Published Online: 2025-03-11 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S26-30
Corresponding Author: Nihal Çallıoğlu, Department of Perinatology, Başakşehir Çam and Sakura City Hospital, Istanbul, Turkiye. E-mail: niyalcll@hotmail.com P: +90 505 205 06 05 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4324-692X
Other Authors ORCID ID: İlke Özer Aslan, https://orcid.org/0000-0002-3175-8354
This study was approved by the Ethics Committee of Başakşehir Cam and Sakura City Hospital (Date: 2024-09-30, No: 2024-234)
Aim: Pan-immune-inflammatory value (PIV) provides a more comprehensive and informative assessment of the patient’s immunoinflammatory status, thus allowing for a more precise evaluation of the prognosis of inflammatory disease. Within the scope of this research, we aimed to elucidate the predictive value of PIV obtained in the first trimester for gestational diabetes mellitus (GDM).
Material and Methods: This retrospective case-control study included 185 singleton pregnant women whose pregnancy follow-ups and deliveries took place at our hospital between June 2020 and June 2024. The study group included 64 pregnant women diagnosed with GDM according to the criteria of the American College of Obstetricians and Gynecologists (ACOG). The control group consisted of 121 healthy pregnant women who were not diagnosed with GDM. PIV values were calculated from the hemogram values of the patients at their first examination in the first trimester.
Results: PLT (p=0.0002) and neutrophil counts (p =0.008) were significantly elevated in the GDM group. Additionally, both SII and PIV were significantly elevated (p = 0.0030 and p = 0.0038, respectively). The AUC values indicated moderate diagnostic performance for both SII and PIV markers. The optimal cut-off value for SII was 684.6, with a sensitivity of 50% and specificity of 72%. The optimal cut-off value for PIV was 478.7, with a sensitivity of 68% and specificity of 56%.
Discussion: These findings suggest that while both markers are potentially diagnostic tools for differentiating patients with GDM, their sensitivity and specificity warrant further investigation for clinical application.
Keywords: Pan-Immune-Inflammatory (Piv), Systemic Immune-Inflammation Index (Sii), Systemic Inflammation Response Index (Siri), Neutrophil-To-Lymphocyte Ratio (Nlr), Gestational Diabetes Mellitus (Gdm)
Introduction
Gestational diabetes mellitus (GDM) is a carbohydrate intolerance of varying degrees that begins during pregnancy or is first diagnosed during pregnancy. This definition does not exclude the possibility of diabetes before conception but is not known until the first examination during pregnancy [1]. Although the American College of Obstetricians and Gynecologists still uses the same terminology, in recent years, the International Association of Diabetic Pregnancy Study Groups (IADPSG), the American Diabetes Association (ADA), the World Health Organization (WHO), and others have stated that women who are first diagnosed during pregnancy but are probably diabetic beforehand should be distinguished from transient diabetes due to pregnancy-related insulin resistance. These organizations use the term “gestational diabetes” for diabetes that occurs in the second half of pregnancy and the term “overt diabetes” or “GDM” for diabetes that is diagnosed with standard non-gestational criteria in the early stages of pregnancy when insulin resistance is less [2, 3].
Diabetes mellitus (DM) is a chronic inflammatory disease, and even if blood sugar levels are controlled, complications are inevitable due to the ongoing inflammatory process. Recently, some new systemic inflammation markers derived from complete blood count (CBC) have been proposed to demonstrate chronic inflammation. These new systemic inflammation markers have been used to assess inflammation, monitor disease progression, and predict outcomes in various conditions, including cardiovascular diseases, autoimmune diseases, and infections [4]. The systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune inflammation value (PIV) have been suggested to indicate inflammation more comprehensively than the traditional CBC-derived neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) and to be strongly correlated with prognosis [5].
Pan-immune-inflammatory value (PIV) is calculated by combining multiple immunological and inflammatory parameters, such as circulating immune cell subsets (CD4+ T cells, CD8+ T cells, NK cells), cytokines (IL-6, TNF-α), and acute phase reactants as C-reactive protein (CRP). By combining these various components, PIV provides a more comprehensive and informative assessment of the patient’s immunoinflammatory status, thus allowing for a more precise evaluation of the prognosis of inflammatory disease [6].
Integrating PIV with clinicopathological factors can improve risk stratification and guide the establishment of personalized treatment strategies, which may ultimately facilitate diabetes management in pregnant individuals. Within the scope of this research, we aimed to assess the predictive value of PIV obtained in the first trimester for gestational DM.
Material and Methods
This retrospective case-control study included 185 singleton pregnant women whose pregnancy follow-ups and deliveries were conducted in our hospital between June 2020 and June 2024. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Our institution granted ethics committee approval on 25/09/2024 with protocol number 255048741. As this research was retrospective in nature, no informed consent was obtained from the participants.
During the study period, a total of 185 singleton pregnancies were included, all of whom had pregnancy follow-ups and deliveries in our hospital. All patients had a 75-g oral glucose tolerance test (OGTT) at 24-28 weeks gestation. Diagnostic criteria for GDM include fasting blood glucose levels of 5.1 mmol/l [92 mg/dl], one-hour plasma glucose levels of 10 mmol/l [180 mg/dl], and two-hour plasma levels of 8.5 mmol/l [153 mg/dl]. A total of 64 patients diagnosed with GDM according to the OGTT results and whose follow-up and treatment were performed in our hospital were included in the GDM group. A total of 121 healthy pregnant women who delivered at term (after the 37th week of gestation) in our hospital and had no additional diseases were randomly selected and included in the control group. They were healthy singleton pregnancies without GDM, based on OGTT results.
Inclusion Criteria
Singleton pregnant women, 18-45 years old, whose pregnancy follow-ups and deliveries were conducted in our hospital between June 2020 and June 2024, were included in this analysis.
Exclusion Criteria
Pregnant women with chronic systemic disorders, chronic hypertension, pregestational diabetes, pregestational diabetes (type 1 and type 2 DM), and autoimmune diseases, those with ongoing infections, and smokers were excluded from the study. Additionally, for individuals with multiple pregnancies, complications such as preeclampsia, fetal growth restriction, preterm premature rupture of the membranes, intrauterine fetal death, and pregnancy cholestasis were also excluded.
Patient data were obtained from the hospital’s information system and patient records. Patients’ age, gravida, parity, and body mass index (BMI) were evaluated when the blood sample was taken. BMI was calculated by dividing the body weight (in kilograms) by the square of the height (m2). All blood count analyses were performed in the same Istanbul Başakşehir Çam and Sakura Hospital laboratory. Those whose hemogram samples were taken in the first 14 weeks of pregnancy (first trimester) were scanned backward. Hemoglobin (Hb), WBC, neutrophil count, lymphocyte count, platelet count (PLT), plateletcrit (PCT), platelet distribution width (PDW), red cell distribution width (RDW), and mean platelet volume (MPV), along with the newly identified inflammatory markers NLR, PLR, SII, SIRI, and PIV were retrospectively examined.
SII was calculated as (PLT count × neutrophil count/lymphocyte count), and SIRI was calculated as (monocyte count × neutrophil count/lymphocyte count), respectively. PIV was calculated as follows: neutrophil count × PLT count × monocyte count /lymphocyte count. The success of all variables in predicting GDM and the cutoff values of the significant ones were calculated.
Tubes containing K3-EDTA (Tri-potassium ethylenediaminetetraacetic acid) were used for CBC research. The CBC parameters were measured by flow cytometry using an automatic hematology analysis device (XN1000, Sysmex, Roche Corp., Japan).
Statistical Analysis
All analyses were conducted using the R statistical software (R Core Team, 2023). Continuous variables were assessed for normality using the Shapiro-Wilk test. As most variables did not follow a normal distribution (p <0.05), non-parametric methods were employed. The Mann-Whitney U test was used to compare continuous variables between groups. In contrast, categorical variables were analyzed using the Chi-squared test or Fisher’s exact test, depending on the expected cell counts. Statistical significance was set at p < 0.05. Results are presented as medians and interquartile ranges (IQRs) for continuous variables and as frequencies and percentages for categorical variables.
To evaluate the diagnostic utility of selected biomarkers, receiver operating characteristic (ROC) curve analysis was performed using the pROC package. The area under the curve (AUC) was computed to assess overall diagnostic accuracy. Optimal cut-off points were determined using the Youden Index. Sensitivity, specificity, and the corresponding cut-off values are reported for each biomarker.
Ethical Approval
This study was approved by the Ethics Committee of Başakşehir Cam and Sakura City Hospital. (Date: 2024-09-30, No: 2024-234).
Results
The GDM group showed significant differencesin clinical and laboratory parameters compared to the control group. Maternal age, gravidity, parity, body mass index, birth weight, and gestational ages at birth (week) showed no significant differences between the groups. PLT counts (p =0.0002) and neutrophil counts (p =0.008) were significantly elevated in the GDM group. Additionally, SII and PIV were significantly elevated in patients, with p-values of 0.0030 and 0.0038, respectively. The PLR and SIRI showed no significant differences between the groups (Table 1).
Figure 1 and Figure 2 depict the ROC curves for SII and PIV in GDM prediction, with corresponding data in Table 2. The AUC values showed moderate diagnostic accuracy for SII and PIV. Using the Youden Index, the optimal cut-off value for SII was 684.6, with a sensitivity of 50% and specificity of 72%. The optimal cut-off value for PIV was 478.7, with a sensitivity of 68% and specificity of 56%. These findings suggest that while both markers are potentially diagnostic tools for differentiating patients with GDM, their sensitivity and specificity warrant further investigation for clinical application.
Discussion
The inflammatory process parameters, peripheral blood neutrophil, platelet, and lymphocyte counts, are used to calculate many indices, including the SII. The prognostic value of many biomarkers such as albumin, C reactive protein, fibrinogen, NLR, PLR, and MLR, which are also peripheral blood-derived parameters, and SIRI have been examined in various inflammatory diseases and malignant tumors. SII has been identified as a significant prognostic marker [7]. SII is a combination of PLR and NLR, and studies are increasing daily to evaluate the potential role of SII, which combines these three parameters (neutrophil, platelet, lymphocyte), and to obtain more detailed data with PIV. Due to the ease of detection and low cost of systemic inflammatory biomarkers, investigating their prognostic features is a current issue. There are two types of inflammatory markers: the first type is derived from C-reactive protein and albumin, and the second type is derived from leukocyte-related inflammation indices such as PLR, NLR, and SII [8].
The relationship between SII and disease prognosis is not yet clearly known. However, it is logical to evaluate the components and tasks of the SII formula in cancer and hypothesize that they have been undertaken. First of all, it is known that neutrophils secrete cytokines and chemokines such as vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and tumor necrosis factor-alpha, which increase angiogenesis, support inflammation and adhesion in the circulation, and facilitate dissemination. In addition, increased neutrophil counts can release high amounts of reactive oxygen and nitric oxide, which can cause T-cell dysfunction and help cancer cells escape the immune response [9]. In the same study, Yildiz et al. [9] reported that SIRI and SII may help predict GDM in the first trimester, but it’s unclear how well they predict insulin needs.
Platelets enable circulating cells to evade the immune response and promote inflammatory cell migration. The contribution of lymphocytes to the acquired immune system, indispensable for the body’s immune defense and surveillance, is also significant [10]. Lymphocytes are an essential cellular component of the body’s immune response and are a cell line with immune recognition function. Lymphocyte depletion is widespread in advanced cancers, and a potentially inadequate immune system creates a favorable microenvironment for the dissemination and metastasis of tumor cells [11]. Based on these mechanisms, increased neutrophil or platelet counts or decreased lymphocyte counts with high NLR, SII and PIV play an essential role in determining the inflammatory outcome [10-12].
Studies have shown that persistent low-grade inflammation is a fundamental mechanism in the progression of diabetes and metabolic syndrome. Inflammatory responses can provoke insulin resistance, facilitating the initiation and progression of problems associated with type 2 diabetes and gestational diabetes [13]. The SII and PIV are new inflammatory markers that incorporate multiple white blood cell subgroups, reflecting the equilibrium between inflammation and immune response, and may be computed using straightforward formulas. Recent investigations have associated SII and PIV with illnesses including cancer, cardiovascular disease, hepatic steatosis, and diabetic nephropathy. However, these biomarkers remain relatively underexplored, and the relationship between SII, PIV, and diabetes remains unclear [14].
Chronic low-grade inflammation is a sustained, non-specific inflammatory condition characterized by alterations in several inflammatory cells and mediators during the inflammatory response. Leukocyte exudation is the principal characteristic of this inflammatory response. Neutrophils, the predominant subset of white blood cells, are the initial responders to an inflammatory site during the onset of inflammation. Research by Giovenzana et al. [15] indicated markedly increased neutrophil numbers in patients with type 2 diabetes relative to healthy individuals. Neutrophils can modulate immunity via various methods. Neutrophil extracellular traps (NETs) have recently been identified as a novel immune defense mechanism and a significant regulator of diabetes and its consequences [16]. Chronic inflammation stimulates the hyperactivation of neutrophils, resulting in NET aggregation that may induce vascular blockage, tissue damage, and intensified inflammation. Research conducted by Njeim et al. [17] has further corroborated the association between increased NET levels and diabetes and diabetic nephropathy. This validates the involvement of neutrophils in the onset of diabetes and its associated consequences. The activation of monocyte-macrophages is a significant indicator of chronic inflammation. The activated cells release many inflammatory mediators, including IL-1, IL-6, TNF-α, and MCP-1, which obstruct the insulin signaling pathway, stimulate intracellular signals that foster insulin resistance and type 2 diabetes mellitus (T2DM), and facilitate the onset and advancement of T2DM [18].
Platelets are crucial for hemostasis and thrombosis and have lately been acknowledged for their involvement in white blood cell recruitment and the modulation of host immunological response. Bioactive mediators released by activated platelets can enhance platelet adhesion to various leukocyte subsets and augment leukocyte pro-inflammatory activity. The elevation in neutrophil, monocyte, and platelet counts signifies immune system activation, reflecting the existence of inflammation. Lymphocytes are essential for immunological protection and surveillance via cellular and humoral immunity. Reduced lymphocyte levels indicate a deterioration in immunological function [19]. In our study, the platelet counts and neutrophil counts were significantly elevated in the GDM group, similar to the findings above.
SIRI is a simple and cost-effective new inflammatory biomarker based on peripheral neutrophil, monocyte and lymphocyte counts. Recently, SIRI in obstetrics has only been used in a few studies. A recent study reported that patients with early pregnancy loss and GDM had higher SIRI values in their first trimester blood samples [20, 9]. However, in our study, no significant relationship was found between first trimester SIRI values and GDM.
Limitation
Some limitations of the study are the retrospective design and the fact that it was conducted in a single center. The strengths of this study are the evaluation of the relationship between numerous inflammatory parameters and GDM. Additionally, there are few studies in the literature examining the relationship between systemic inflammatory markers and GDM. The relationship between inflammatory diseases and PIV has recently been reported in the literature [21]. However, to our knowledge, this is the first time the relationship between PIV and GDM has been evaluated in the literature. And in our study, the significant relationship between PIV and GDM is shown for the first time in the literature.
Conclusion
This study suggests that SII and PIV may serve as diagnostic markers for differentiating GDM patients. However, further research is necessary to validate their clinical utility due to limitations in sensitivity and specificity.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Nihal Çallıoğlu, İlke Özer Arslan. The predictive role of first-trimester pan-immune-inflammation value in gestational diabetes mellitus. Ann Clin Anal Med 2025;16(Suppl 1):S26-30
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Effect of coloring the long-arm cast on depression, anxiety, and quality of life in children treated with a cast for forearm fractures
Mesut Karıksız 1, Veysi Ceri 2
1 Department of Orthopedic and Traumatology, Basaksehir Cam and Sakura City Hospital, İstanbul, 2 Department of Child Psychiatry, Faculty of Human Sciences, Antalya Belek University, Antalya, Turkiye
DOI: 10.4328/ACAM.22596 Received: 2025-02-06 Accepted: 2025-03-10 Published Online: 2025-03-20 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S31-35
Corresponding Author: Mesut Kariksiz, Department of Orthopedic and Traumatology, Basaksehir Cam and Sakura City Hospital, İstanbu, Turkiye. E-mail: mesutkariksiz@gmail.com P: +90 506 291 80 49 Corresponding Author ORCID ID: https://orcid.org/0000-0002-9632-7694
Other Authors ORCID ID: Veysi Ceri, https://orcid.org/0000-0002-9632-7694
This study was approved by the Ethics Committee of Gazi Yasargil Training and Research Hospital (Date: 2022-09-30, No: 183)
Aim: This study investigates the impact of cast color on depression, anxiety, and quality of life (QoL) in children with forearm fractures. We hypothesize that colored casts may reduce depression and improve QoL during treatment, enhancing overall well-being.
Material and Methods: A total of 202 children, aged 8 to 14, were randomly divided into two groups: non-colored (white) and colored (pink or blue). Depression, anxiety, and QoL were assessed using the Pediatric Quality of Life Inventory (PedsQL), Children’s Depression Inventory (CDI), and the Screen for Child Anxiety Related Disorders (SCARED), respectively. Measurements were taken at baseline (pre-casting) and four weeks post-casting.
Results: Children with colored casts exhibited significantly lower depression scores and higher QoL scores compared to those with white casts. Post-casting mean CDI scores were 10.63 (SD = 6.32) in the colored group and 15.76 (SD = 4.61) in the white group. Mean PedsQL scores post-casting were 52.59 (SD = 5.36) for the colored group and 49.84 (SD = 6.22) for the white group. However, there was no significant difference in SCARED anxiety scores between the groups.
Discussion: Colored casts significantly improve depression and QoL in children undergoing forearm fracture treatment, though anxiety levels remain unaffected. Allowing children to choose colored casts may enhance their psychological well-being and recovery experience. These findings emphasize the importance of incorporating patient-centered and enjoyable options in pediatric orthopaedic care to improve outcomes.
Keywords: Forearm Fracture, Long-arm Cast, Depression, Anxiety, Quality of Life
Introduction
Extremity fractures are common injuries that occur in childhood due to reasons such as falls and traffic accidents [1, 2]. Anxiety, depression, and reduced quality of life are common issues among children facing medical procedures, particularly those involving pediatric fractures [3]. The use of plaster casts is a standard treatment for such injuries, and the color of the plaster is often a matter of personal preference or simply a default option. However, the psychological effect of plaster color on the depression, anxiety, and quality of life (QoL) levels of pediatric patients has not been extensively studied.
In a recent study, Zomia et al. [4] emphasized the need for psychotherapy to prevent depression and anxiety after orthopedic surgery in children and adolescents. This underscores the need for new approaches to address these issues across various settings, including the medical context. Furthermore, the COVID-19 pandemic has exacerbated rates of depression and anxiety in children, with depression affecting 1 in 4 children and youth and problematic anxiety affecting 1 in 5 [5]. Given the escalating mental health problems, there is a significant need for effective ways to improve anxiety and depression among school-age children. A recent study investigated a large group of patients who underwent orthopedic surgery and showed that the type of surgical procedure performed, especially spine surgeries, increased anxiety and depression in children [6].
This study aims to investigate the impact of plaster color on the depression, QoL, and anxiety levels of children undergoing cast treatment for forearm fracture. We hypothesize that the choice of plaster color can play a significant role in reducing depression and anxiety and improving the overall well-being and QoL of pediatric patients during the cast treatment for forearm fracture. By addressing this understudied area, our research seeks to contribute to the growing body of knowledge on effective interventions to support children’s mental health in medical settings.
Material and Methods
The study included 202 children aged 8 to 14 years old who were scheduled for long-arm cast treatment for non-surgical forearm fracture (the radius and/or ulna) in a trauma hospital. The participants were randomly divided into two groups according to the order of their application to the hospital, with the first group being non-colored (white) (n: 102) and the second group being colored (pink or blue) (n: 100) (Figure 1). All participants were first wrapped in a classic white plaster cast, and then, for the colored plaster group, a coban bandage was wrapped over the white plaster. In the group where we applied colored casts, blue casts were applied to men, and pink casts were applied to women. Patients who had previously received any psychiatric diagnosis, treatment, or use of medication were not included in the study.
The sample size was calculated using a power analysis to ensure the detection of a medium effect size with 80% power and a significance level of 0.05. To achieve a significant result with α = 0.05, 1−β = 0.801, and d = 0.93d, the required sample size is sufficient. However, the sample size used in your study (n1 = 102, n2 = 100) is much larger than this requirement, indicating that the study has a very robust design.
The materials used in this study included plaster casts in the two-color groups (white and blue or pink group), the Children’s Depression Inventory (CDI) [7], and the Screen for Child Anxiety Related Disorders (SCARED) [8]. The CDI and SCARED are well-established, validated measures of depression and anxiety in children, respectively.
This study employed a randomized controlled trial design to compare the depression and anxiety levels of children assigned to different cast colors. The independent variable was the color of the plaster cast (white, blue, pink), and the dependent variables were the CDI and SCARED scores.
Upon being admitted to the hospital, participants were randomly allocated to one of two groups based on plaster color. After plaster application, participants completed the CDI and SCARED to assess their depression and anxiety levels. The CDI and SCARED were administered pre-casting and post-casting to evaluate the effectiveness of the cast color on depression and anxiety scores. A one-way between-subjects analysis of variance (ANOVA) was employed to compare CDI and SCARED scores across the two cast color groups. Tukey’s HSD test was used for posthoc comparisons to identify significant differences between the groups. A significance level of 0.05 was applied for all statistical analyses.
This research received approval from the local institutional review board, and informed consent was collected from all participants and their legal guardians. Participants were made aware that they could leave the study at any point without any repercussions. All data were kept confidential and securely stored.
Ethical Approval
This study was approved by the Ethics Committee of Gazi Yasargil Training and Research Hospital (Date: 2022-09-30, No: 183).
Results
This study investigated the effect of cast color on depression, anxiety, and quality of life (QoL) scores in children undergoing surgery for forearm fracture. A total of 202 children, aged 8 to 14, were randomly divided into two groups according to the order of their application to the hospital, with the first group being non-colored (white) and the second group being colored (pink or blue) (Table 1). The primary outcomes measured were changes in depression (assessed using the Children’s Depression Inventory- CDI), anxiety (assessed using the Screen for Child Anxiety Related Disorders- SCARED), and QoL (assessed using the Pediatric Quality of Life Inventory- PedsQL) from baseline (pre-surgery) to post-surgery (4 weeks follow-up).
Depression Scores
Depression was evaluated using the Children’s Depression Inventory (CDI). The results showed a significant effect of cast color on depression scores. Children with colored cast had significantly lower depression scores after cast application compared to those with white cast. The mean post-cast application CDI scores for the colored cast group were 10.63 (SD = 6.32), while the mean white cast group was 15.76 (SD = 4.61). An independent samples t-test revealed a significant difference between the groups (p < 0.001), indicating that colorful cast were associated with lower depression scores (Table 2).
Anxiety Scores
Anxiety levels were measured using the Screen for Child Anxiety Related Disorders (SCARED). The analysis revealed no significant difference in anxiety scores between the two cast color groups. The mean SCARED scores for the colored cast group were 19.41 (SD = 9.26), and for the white cast group, it was 18.39 (SD = 11.04). An independent samples t-test indicated no significant effect of cast color on anxiety scores (p = 0.343) (Table 2).
Quality of Life Scores
The Pediatric Quality of Life Inventory (PedsQL) was used to evaluate the quality of life. The findings indicated a significant improvement in QoL scores for children with colored cast compared to those with white plasters. The mean post-cast application PedsQL scores for the colored cast group were 52.59 (SD = 5.36), while the mean increase for the white cast group was 49.84 (SD = 6.22). An independent samples t-test indicated a significant difference between the groups (p = 0.025), implying that colorful casts were linked to higher QoL scores (Table 2).
Discussion
This study aimed to investigate the impact of cast color on depression, anxiety, and quality of life (QoL) in children undergoing long-arm cast treatment for forearm fracture. The findings revealed that the color of the cast may affect depression and QoL scores but does not significantly influence anxiety scores. These findings carry significant implications for pediatric care and the psychological management of children with forearm fractures.
The lower depression scores among children with colored casts, as measured by the Children’s Depression Inventory (CDI), suggest that aesthetic elements play a crucial role in emotional recovery. The use of bright, engaging colors likely provides a positive distraction and helps enhance the mood of young patients. This aligns with color psychology principles, which indicate that certain colors can improve mood and emotional well-being. For instance, colors like blue and pink are often associated with calmness and happiness, respectively, which may contribute to the observed reduction in depression. Allowing children to choose their plaster color might also give them a sense of control and personal agency, further contributing to their emotional well-being.
This finding suggests that incorporating funny or colorful preferences into medical interventions for pediatric patients can have a positive impact on their mental health during the treatment of forearm fracture. The relationship between color and emotion has been a topic of interest in various fields, including psychology and art therapy. Color is often used as a means of expression and communication, and it has been suggested that certain colors can evoke specific emotional responses [5]. In the context of this study, allowing children to choose the color of their cast may have provided them with a sense of control and autonomy, which could have contributed to the observed reduction in depression and anxiety levels. The current study aligns with previous research that has highlighted the importance of addressing mental health in pediatric patients undergoing medical procedures. For example, emphasized the need for school-based interventions to prevent depression and anxiety in children and young people, further emphasizing the need for effective interventions to support children’s mental health [9]. The potential of virtual reality (VR) to alleviate anxiety in children within the plaster room has been investigated [10], suggesting that innovative interventions can play a role in managing anxiety and pain perception during medical procedures.
Kang et al. found that depression and anxiety decreased in patients who received psychological support, treatments that emphasized healing, and psychological support during the liberation period after surgery due to orthopedic injury [11]. In their study, Duramaz et al. [12] found higher rates of attention deficit hyperactivity disorder, anxiety, and depression in patients who had a pediatric fracture compared to those who did not, and they stated that necessary psychiatric precautions should be taken in these children due to the risk of refracture. Our study adds to this body of knowledge by demonstrating that the choice of cast color can be an effective intervention for reducing depression and anxiety in children undergoing surgery for forearm fracture. Future investigations could examine the enduring impacts of cast color choice on children’s depression and anxiety levels and investigate the potential benefits of incorporating color preferences into other medical interventions for pediatric patients.
The improvement in QoL scores, assessed using the Pediatric Quality of Life Inventory (PedsQL) [13], indicates that colored long-arm casts positively influence various aspects of children’s lives during recovery. Children with colored plasters reported better physical, emotional, social, and school functioning compared to those with white plasters. This enhancement in QoL could be due to the positive psychological impact of having a colorful and personalized cast, which might boost self-esteem and social interaction. The ability to choose their cast color can empower children, making them feel more involved in their treatment process and improving their overall recovery experience.
The lack of a significant difference in anxiety scores, as measured by the Screen for Child Anxiety Related Disorders (SCARED), between the colored and white plaster groups suggests that the visual appeal of the plaster does not alleviate anxiety related to the treatment process. Anxiety in children undergoing treatment process may be driven more by factors such as fear of the procedure, pain, and separation from parents, which are not directly mitigated by the color of the cast. This finding highlights the need for targeted interventions to address anxiety, such as psychological support, counseling, and effective pain management strategies, which could complement the positive effects of colored casts on depression and QoL. Burkhart et al. [14]. In their study, they stated that the use of physical and technology-based distraction tools during patient procedures in the plaster room played an important role in increasing patient satisfaction and reducing depression. In our study, we found that the use of colored plaster reduces depressive symptoms after the procedure, as it attracts attention, especially among family and friends, and acts as a positive indicator instead of fear. Therefore, we think that the use of psychologically effective tools in such childhood treatments improves patient outcomes.
The results of this study suggest that healthcare providers should consider offering colored cast options as a simple, funny, and cost-effective intervention to improve the psychological well-being and QoL of pediatric patients. This approach can be easily implemented in clinical settings and has the potential to significantly enhance the recovery experience for children undergoing long-arm cast treatment for forearm fracture. By addressing both the physical and emotional needs of young patients, healthcare providers can offer more holistic and effective care. The results of this study indicate that the choice of cast color does indeed have a significant impact on the depression, anxiety, and QoL scores of children undergoing long-arm cast treatment for forearm fracture. Specifically, children who were allowed to choose the color of their cast exhibited lower depression and anxiety levels and higher QoL scores compared to those who were assigned a random color. This finding suggests that incorporating color preferences into medical interventions for pediatric patients can have a positive impact on their mental health during the treatment process. These findings contribute to the growing body of knowledge on effective interventions to support children’s mental health in medical settings. By allowing children to choose the color of their cast, healthcare professionals can provide a simple yet effective means of reducing depression and anxiety and improving the overall experience and well-being of young patients undergoing long-arm cast treatment for forearm fracture. Future research should explore the long-term effects of cast color choice on children’s depression, anxiety, and QoL levels and investigate the potential benefits of incorporating color preferences into other medical interventions for pediatric patients. Additionally, further investigation is needed to determine the factors that affect postoperative anxiety, depression, and quality of life among children who undergo medical procedures.
Limitation
This study is subject to several limitations, including a relatively small sample size that may restrict the generalizability of findings. Moreover, the study did not delve into the extended psychological effects of cast color beyond the initial four-week follow-up period. Subsequent research should endeavor to replicate these results across larger and more diverse populations while also exploring the enduring psychological implications of colored casts. Further studies could also explore which specific colors are most effective in reducing depression and enhancing QoL, as well as the mechanisms underlying these effects.
Conclusion
In conclusion, the color of plaster casts significantly affects depression and QoL in children undergoing cast treatment for forearm fracture but does not significantly impact anxiety levels. Providing children the option to choose a colored cast can enhance their psychological well-being and overall quality of life during recovery. These findings support the inclusion of children in the premedication process and integration of funny choices in pediatric orthopedic care to improve patient outcomes.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Caruso G, Caldari E, Sturla FD, Caldaria A, Re DL, Pagetti P, et al. Management of pediatric forearm fractures: what is the best therapeutic choice? A narrative review of the literature. Musculoskelet Surg. 2021;105(3):225-34.
2. Lee A, Colen DL, Fox JP, Chang B, Lin IC. Pediatric hand and upper extremity injuries presenting to emergency departments in the United States: epidemiology and health care–associated costs. HAND (N Y). 2021;16(4):519-27.
3. Stoddard FJ, Saxe G, D Mk. Ten-year research review of physical injuries. J Am Acad Child Adolesc Psychiatry. 2001;40(10):1128-45.
4. Al Zomia AS, Alqarni MM, Alaskari AA, Al Qaed A, Alqarni AM, Muqbil AM, et al. Child anxiety, depression, and post-traumatic stress disorder following orthopedic trauma. Cureus. 2023;15(7):e42140.
5. Wong LP, Alias H, Md Fuzi AA, Omar IS, Mohamad Nor A, Tan MP, et al. Escalating progression of mental health disorders during the COVID-19 pandemic: evidence from a nationwide survey. PLoS One. 2021;16(3):e0248916.
6. Catanzano AA, Bastrom TP, Bartley CE, Yaszay B, Upasani V V, Newton PO. Depression screening in pediatric orthopedic surgery clinics and identifying patients at-risk. J Pediatr Orthop. 2024;44(4):291-6.
7. Kovacs M. Children’s Depression Inventory. In: The Encyclopedia of Clinical Psychology. Wiley; 2015:1-5.
8. De Silva S, Seneviratne S, Samaranayake D. Screen for Child Anxiety Related Disorders (SCARED)-Child version: validity and reliability assessment among children aged 13-15 years. JCCPSL. 2022;28(2):583.
9. Caldwell DM, Davies SR, Hetrick SE, et al. School-based interventions to prevent anxiety and depression in children and young people: a systematic review and network meta-analysis. Lancet Psychiatry. 2019;6(12):1011-20.
10. Shepherd K, Shanmugharaj Y, Kattan O, Kokkinakis M. Can virtual reality headsets be used safely as a distraction method for paediatric orthopaedic patients? A feasibility study. Ann R Coll Surg Engl. 2022;104(2):144-7.
11. Kang KK, Ciminero ML, Parry JA, Mauffrey C. The psychological effects of musculoskeletal trauma. J Am Acad Orthop Surg. 2021;29(7):e322-e329.
12. Duramaz A, Yilmaz S, Ziroğlu N, Bursal Duramaz B, Bayram B, Kara T. The role of psychiatric status on pediatric extremity fractures: a prospective analysis. Eur J Trauma Emerg Surg. 2019;45(6):989-94.
13. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care. 1999;37(2):126-39.
14. Burkhart RJ, Hecht CJ, McNassor R, Mistovich RJ. Interventions to reduce pediatric anxiety during orthopaedic cast room procedures. JBJS Rev. 2023;11(2):100-8.
Download attachments: 10.4328.ACAM.22596
Mesut Karıksız, Veysi Ceri. Effect of coloring the long-arm cast on depression, anxiety, and quality of life in children treated with a cast for forearm fractures.Ann Clin Anal Med 2025;16(Suppl 1):S31-35
Citations in Google Scholar: Google Scholar
Optimizing upper extremity reconstruction: outcomes of anterolateral thigh (ALT) flap in complex hand injuries
Numan Atilgan 1, Numan Duman 2, Ozlem Orhan 3
1 Department of Hand Surgery, Private Clinic, Gaziantep, 2 Department of Orthopedics and Traumatology, Faculty of Medicine, Uskudar University, Istanbul, 3 Department of Orthopedics and Traumatology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
DOI: 10.4328/ACAM.22607 Received: 2025-02-16 Accepted: 2025-03-18 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S36-41
Corresponding Author: Numan Atilgan, Department of Hand Surgery, Private Clinic, Gaziantep, Turkey. E-mail: doktor_dao@hotmail.com P: +90 507 221 19 45 Corresponding Author ORCID ID: https://orcid.org/0000-0001-7184-978X
Other Authors ORCID ID: Numan Duman, https://orcid.org/0000-0002-0183-4520 . Ozlem Orhan, https://orcid.org/0000-0003-0058-0431
This study was approved by the Ethics Committee of Harran University, Faculty of Medicine (Date: 2022-02-07, No: 2022/03/15)
Aim: The anterolateral thigh (ALT) flap has become a widely used option for soft tissue reconstruction in upper extremity injuries due to its versatility, reliability, and minimal donor site morbidity. This study evaluates the functional and aesthetic outcomes of ALT flap applications in complex hand trauma cases.
Material and Methods: A retrospective analysis was conducted on 30 patients who underwent ALT flap reconstruction for upper extremity defects. Patients’ demographics, injury mechanisms, surgical procedures, defect and flap dimensions, postoperative complications, and functional outcomes were assessed. Functional recovery was evaluated using MAYO and Q-DASH scores.
Results: The mean defect size was 98.67±52.34 cm² (min: 20, max: 260), and the average flap size was 134.12±71.42 cm² (min: 36, max: 290). 60% (n=18) of patients had radial artery anastomosis, while 23.3% (n=7) had ulnar artery end-to-end anastomosis. No total flap loss was observed, though 46.7% (n=14) of patients experienced minor complications, such as partial flap necrosis or donor site hematoma. Functional assessment revealed an average MAYO score of 71.82±10.45 and a Q-DASH score of 30.47±7.59, indicating satisfactory functional recovery.
Discussion: The ALT flap provides excellent functional and aesthetic outcomes in upper extremity reconstruction. Compared to other flap options, it offers greater tissue volume, lower donor site morbidity, and enhanced cosmetic outcomes. Despite its technical complexity, it remains a gold standard in complex hand trauma management, with low complication rates and predictable functional recovery.
Keywords: Anterolateral Thigh Flap, Hand Reconstruction, Microsurgery, Soft Tissue Defect, Upper Extremity Trauma, Functional Recovery, Flap Complications
Introduction
Skin flaps are commonly used to cover vital structures such as vessels, nerves, and bones, while fascia flaps are preferred for protecting tendinous tissues. In cases where a flap does not fully close the soft tissue defect or when there is a risk of contamination due to cavity formation in the bone, muscle flaps are employed to eliminate dead space and reduce infection risk. Additionally, in injuries causing vascular defects, the flap pedicle can be utilized for revascularization of the ischemic extremity. Various reconstructive techniques have been described to restore functional structures following extensive upper extremity soft tissue injuries, [1, 2].
The ALT flap presents an excellent reconstructive option for upper extremity injuries, offering advantages such as versatility, low donor site morbidity, and optimal size for large-scale tissue defects. It features a long pedicle with a suitable vessel diameter, allowing for better adaptation to the contours of the hand and upper extremity. Additionally, by incorporating the lateral femoral cutaneous nerve, the flap can be designed as a sensory reconstruction. The procedure can also be performed efficiently under regional block anesthesia, enabling simultaneous work by two surgical teams and reducing operative time. Achieving a flap capable of covering large soft tissue defects is technically challenging. However, as a multi-component flap, the ALT flap effectively meets all the essential requirements for reconstruction, making it a preferred choice in complex upper extremity injuries [3].
In this study, we aimed to evaluate the clinical outcomes of ALT flap reconstruction in upper extremity soft tissue defects and discuss its functional and aesthetic results.
Material and Methods
Study Design
This study included the patients who had soft tissue defects in addition to upper extremity trauma in AA hospital between the dates of 2022-2024. Patients’ demographic data, surgical procedure, postoperative complications, and functional outcomes of ALT flap surgery of the upper extremity were evaluated and discussed.
Surgical technique
All flaps were prepared via the same technique. The operation was started by two surgical teams, the first surgeon prepared the recipient site and the second surgeon prepared the donor site. Recipient site debridement, bone fixation, repair of tendon, muscle, and nerve injuries, and then preparation of recipient vessels were performed. The second surgeon performed the elevation of the flap at the same time. Possible skin perforators were detected by using hand doppler primarily on the line and inferior within a 3 cm diameter circle area from the middle 1/2 point of the line on the line between the rectus femoris and vastus lateralis and it was drawn between the spina iliaca anterior superior and the lateral of the patella of the patient lying in the supine position. The flap size was decided according to the defect area. The drawing was made so that 1/3 of the flap’s length is superior to the drawn line, while 2/3 is inferior, and its width is aligned to the midpoint between the two landmarks. Dissection of the descending branch of the LCFA was completed by considering the flap adaptation in the recipient site and the thickness of the recipient vessels at the planned anastomosis level and the required pedicle length. The artery and 2 veins above the pedicle were separated by at least 3 cm of intrapedic dissection, and the flap was separated by ligating the arteries and veins separately. Then, after the coarse adaptation of the flap and the appropriate position of the pedicle were achieved, 1 artery, and 2 vein anastomoses were performed. If 2 suitable veins were not found in the recipient site or if the pedicle veins were converged to a single vein until they reached the appropriate thickness, a single vein was performed. Except for these cases, 2 vein anastomosis was preferred in every possible case. After anastomoses, hemorrhage control and skin suturing were completed and the operation was completed by applying an appropriate dressing and splint to stabilize the extremity.
Post-operative follow-up
Flap follow-up was performed by closely monitoring variables such as the evaluation of flap skin color, turgor, surface temperature, and presence of bleeding. Patients for whom flaps were applied were followed up frequently in the postoperative period. Early intervention was performed in cases suggestive of venous or arterial insufficiency, vessel thrombosis, and hematoma.
Statistical Analysis
Statistical analyzes were performed with the Statistics for Social Sciences (SPSS) v18 package program. As descriptive statistics, arithmetic mean ± standard deviation and median (minimum, maximum) were used to summarize numerical data, and numbers and percentages were used to summarize categorical data. The relationship between categorical data was analyzed with the Chi-square (χ2) test. P values below 0.05 were considered statistically significant.
Ethical Approval
This study was approved by the Clinical Research Ethics Committee of Harran University, Faculty of Medicine (Date: 2022-02-07, No: 2022/03/15).
Results
Patients’ demographic data, injury mechanism, and surgical procedure are shown in Table 1. A total of 30 patients were included in the study. 93.3% (n=28) of the patients were male, and 6.7% (n=2) were female. The mean age of the patients was 31.2±12.3 years (min: 10, max: 55). The injury occurred in the right upper extremity in 66.7% of the patients and the left upper extremity in 33.3%. The flap was harvested from the right thigh in 53.3% of the patients and from the left thigh in 46.7%. Gunshot injuries were the most common mechanism, accounting for 36.7% (n=11) of the cases (Figure 1.), followed by occupational injuries in 26.7% (n=8), traffic accidents in 16.7% (n=5), electrical burns in 13.3% (n=4) (Figure 2.), and industrial injuries in 6.7% (n=2). A musculocutaneous flap was applied in 22 patients, while a septocutaneous flap was used in 8 patients (Table 1.). Patient’s soft tissue defect location, defect length, flap length, hospitalization time, donor site closure, and follow-up time are shown in Table 2. The mean size of the defect was 98.67±52.34 cm² (min: 20, max: 260). The smallest defect size was 4×5 cm², and the largest defect size was 20×12 cm². The average size of the flaps applied was 134.12±71.42 cm² (min: 36, max: 290), with the smallest flap size being 6×6 cm² and the largest being 22×13 cm² Figure 3.). The average time to post-traumatic flap surgery was 9.87±4.21 days (min: 1, max: 21), and the average operation time was 236.72±33.84 minutes (min: 170, max: 305). The mean postoperative hospitalization time was 12.73±4.41 days (min: 8, max: 28), and the mean postoperative follow-up time was 8.12±3.24 months (min: 3, max: 14). Regarding donor site closure, 80% (n=24) of the donor sites were sutured primarily, whereas 20% (n=6) required skin grafting. The mean pedicle size was 10.04±1.85 cm (min: 6, max: 14) (Table 2.). Among the patients, 60% (n=18) underwent radial artery end-to-end anastomosis, while 23.3% (n=7) had ulnar artery end-to-end anastomosis. Additionally, 13.3% (n=4) underwent ulnar artery end-to-end anastomosis with a flow-through flap, and 3.3% (n=1) had brachial artery end-side suturation.
Regarding venous anastomosis, 36.7% (n=11) of the patients had one deep and one superficial vein anastomosis, while 26.7% (n=8) had two superficial vein anastomoses. No total flap loss was observed in any patient postoperatively. In all cases, donor site healing was uneventful in patients who underwent either primary repair or skin grafting. No weakness or movement restriction was noted in the lower extremity from which the flap was harvested.
Complications occurred in 46.7% (n=14) of the patients during follow-up. Finger necrosis developed in three patients, infection in three patients, finger loss in two patients, hematoma at the donor site in one patient, flexion limitation secondary to flap size in one patient, hematoma under the flap in one patient, partial finger necrosis in one patient, partial flap loss in one patient, and partial flap necrosis in one patient. Finger losses were unrelated to the flap itself; they occurred due to revascularization failure in complex hand injuries.
Among the patients who developed complications, nine (64.3%) underwent debridement, four (28.6%) required finger amputation, and one patient underwent debulking. Additional surgeries were required in four patients during follow-up: tenolysis was performed in three patients, and one patient underwent metacarpal arthrodesis after osteosynthesis. The patient requiring osteosynthesis had an ulna fracture that was initially stabilized with an external fixator. In the first session, debridement and vascular nerve repair were performed, while in the second stage, the ulna fracture was stabilized with a plate, and an anterolateral thigh (ALT) flap was applied.
At the end of postoperative physical therapy, the average MAYO score of the patients was 71.82±10.45 (min: 50, max: 86), while the average Q-DASH score was 30.47±7.59 (min: 18, max: 45).
Discussion
The primary goal of limb reconstruction is to restore and maintain limb function. For this purpose, achieving an aesthetic appearance, minimizing donor site morbidity, and ensuring stable soft tissue coverage are essential. Functional reconstruction of large and complex soft tissue defects in the extremities remains a challenging task for hand surgeons [4]. Historically, the ALT flap has been used more frequently in head and neck surgery, but it has also become a reliable option for upper extremity reconstructions. The ALT flap serves as an alternative to the groin flap, temporoparietal fascial flap, and lateral arm flap. It provides a larger and more voluminous tissue transfer than these alternatives while causing fewer donor site complications. In large-scale case series, perforators have been reported to supply the flap in each case, [5-7]. However, if a perforator cannot be identified during preoperative planning, it should be considered a contraindication for surgery.
If the flap size exceeds 8 cm, skin grafting may be required for donor site closure. In our study, 24 (80%) donor sites were sutured primarily, while 6 (20%) required skin grafting, which aligns with the literature. Additionally, in agreement with previous studies, we observed that functional limitations at the donor site were minimal, and cosmetic outcomes were more acceptable compared to other flap types, [8]. Patients with smoking history, diabetes, or peripheral vascular disease are at higher risk for flap failure, [9, 10]. One of our patients was diagnosed with diabetes, and three of our patients were smokers in our study. Contrary to the literature, no complications occurred in the four patients mentioned despite these additional factors.
Although the tissue expansion technique can also be utilized for soft tissue reconstruction, it requires a longer preparation period [11]. Moreover, it has been reported that functional recovery following upper extremity tissue expansion reconstruction is inferior to other methods [12]. Since our patient cohort primarily consisted of acute injury cases, we opted for ALT flap reconstruction. The ALT flap can be thinned to a thickness of 3–4 mm, making it cosmetically suitable for dorsal hand reconstruction, [13-15]. In our study, we performed thinning in the ALT flaps prepared for the dorsum of the hand and fingers, achieving improved aesthetic outcomes. Furthermore, for cases involving arterial injury with soft tissue loss, the flow-through flap technique is an option to bridge arterial damage [16, 17]. Dong et al. reported a 100% flap survival rate and no complications in their series of four patients undergoing flow-through ALT flap reconstruction for severe limb injuries. Similarly, in our study, we observed a 100% flap survival rate with no major complications, aligning with Dong et al.’s findings and supporting the reliability of the flow-through technique in complex upper extremity reconstructions, [16]. A significant drawback of the ALT flap is the meticulous surgical technique required, particularly for perforator dissection. This procedure is technically demanding, requiring microsurgical expertise. Unexpected pedicle lengths may complicate flap elevation or positioning, which can present intraoperative challenges, [18, 19].
Under optimal conditions, flap failure rates should remain below 5% [5]. In our study, no total flap loss was observed, and complications were within acceptable limits, including partial flap necrosis and skin necrosis. Furthermore, no significant restriction in range of motion was detected after ALT flap surgery, [20, 21]. All patients underwent postoperative upper extremity rehabilitation, and we observed that their functional outcomes, as measured by MAYO and Q-DASH scores, were within acceptable ranges.
Limitation
The limited number of patients in our study, short follow-up period, retrospective design of the study, and the nonhomogeneous injury patterns can be considered among the limitations of our study.
Conclusion
In conclusion, our findings support the use of ALT flaps as a reliable option for upper extremity soft tissue reconstruction, particularly in cases with large defects, exposed tendons, and combined vascular injuries requiring revascularization. The versatility of this flap makes it suitable for both functional and aesthetic restoration. However, in patients with smaller defects, cases requiring thin skin coverage, or when donor site morbidity is a concern, alternative flaps such as the radial forearm flap or lateral arm flap should be considered. Future studies with larger cohorts and longer follow-up periods will help further refine patient selection criteria.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
1. Yu JL, Crowe CS, Yesantharao P, Kennedy SA, Keys KA. Soft Tissue Reconstruction for Upper Extremity Necrotizing Soft Tissue Infections. Ann Plast Surg. 2022;89(6):631-6.
2. Naalla R, Chauhan S, Dave A, Singhal M. Reconstruction of post-traumatic upper extremity soft tissue defects with pedicled flaps: An algorithmic approach to clinical decision making. Chin J Traumatol. 2018;21(6):338-51.
3. Duan A, Xiang Z, Fan Y, Duan W, Wei Q, Duan X. Evaluating the clinical efficacy of the anterolateral thigh flap in lower limb reconstruction surgeries: A systematic review and meta-analysis. Am J Transl Res. 2024;16(7):3326-37.
4. Ono S, Sebastin SJ, Ohi H, Chung KC. Microsurgical Flaps in Repair and Reconstruction of the Hand. Hand Clin. 2017;33(3):425-41.
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6. Berkane Y, Giorgino R, Ng ZY, Dukan R, Lellouch AG. Alternative Flap Options for Upper Extremity Reconstruction. Hand Clin. 2024;40(2):291-9.
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Numan Atilgan, Numan Duman, Ozlem Orhan. Optimizing upper extremity reconstruction: outcomes of anterolateral thigh (ALT) flap in complex hand injuries. Ann Clin Anal Med 2025;16(Suppl 1):S36-41
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Psychological burden in hereditary angioedema: An evaluation of depression, anxiety, and perceived stress
Esra Karabiber
Department of Chest Disease, Pendik Training and Research Hospital, Istanbul, Turkey
DOI: 10.4328/ACAM.22612 Received: 2025-02-19 Accepted: 2025-03-23 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S42-46
Corresponding Author: Esra Karabiber, Department of Chest Disease, Pendik Training and Research Hospital, Istanbul, Turkey. E-mail: dresrabulut@hotmail.com P: +90 505 687 02 11 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8377-7637
This study was approved by the Ethics Committee of Marmara University (Date: 2022-11-04 No: 1472)
Aim: Hereditary angioedema (HAE) is a rare disorder characterized by swelling that significantly impacts patients’ quality of life. This study aims to assess the prevalence of psychological distress, including depression, anxiety, and stress.
Material and Methods: A cross-sectional study was conducted with validated psychological assessment tools, including the Beck Depression Inventory (BDI), Patient Health Questionnaire-9 (PHQ-9), Perceived Stress Scale-10 (PSS-10), and Generalized Anxiety Disorder-7 (GAD-7). Angioedema severity and disease control were evaluated using questionnaires: the Angioedema Activity Score (AAS) and the Angioedema Control Test (AECT).
Results: A total of 18 patients completed all questionnaires. The median age was 33 years (IQR: 27.7–37.2), with a female predominantly female population (77.7%). Disease control was poor in 76.4% of patients (AECT median: 8, IQR: 5.5–10). The median AAS score was 49.5 (IQR: 17–76). Psychological assessments revealed a high burden of distress, with 50% of patients exceeding the BDI treatment threshold (median: 16, IQR: 10.7–22.7) and scoring within the moderate-to-severe depression range on the PHQ-9 (median: 9.5, IQR: 7.5–16). Moderate stress (PSS-10 median: 20, IQR: 15.7–25) was reported by 88.8% of participants, while 38.9% exhibited moderate-to-severe anxiety (GAD-7 median: 8, IQR: 4–10.5). No significant correlations were observed between disease control (AECT, AAS) and psychological distress measures (BDI, PHQ-9, PSS-10, GAD-7).
Discussion: Our findings emphasize the substantial psychological burden of HAE, with a significant proportion of patients experiencing depression, anxiety, and stress. Beyond clinical severity, attack-related uncertainty and chronic disease burden likely contribute to this distress. Future research with larger, longitudinal cohorts is essential to better delineate the complex interplay between HAE and mental health.
Keywords: Anxiety, Depression, Hereditary angioedema, Perceived Stress
Introduction
Hereditary angioedema (HAE) is a rare genetic disorder characterized by episodic swelling in cutaneous and subcutaneous tissues, often affecting the gastrointestinal tract and airway, with potentially life-threatening consequences such as asphyxia. The underlying mechanism involves increased bradykinin levels, leading to heightened vascular permeability and subsequent tissue edema. HAE is most commonly associated with mutations in the SERPING1 gene, resulting in a quantitative or functional deficiency of C1-esterase inhibitor (C1-INH). Other genetic variants, including mutations in factor XII, angiopoietin-1, plasminogen, kininogen 1, myoferlin, heparan sulfate-glucosamine 3-O-sulfotransferase 6, carboxypeptidase N, and disabled homolog 2-interacting protein, are linked to HAE with normal C1-INH levels. The estimated prevalence of HAE due to C1-INH deficiency is approximately 1 in 50,000 individuals [1].
HAE manifests with considerable heterogeneity in severity, frequency, and anatomical distribution of attacks, imposing substantial physical, psychological, and socioeconomic burdens on affected individuals. The unpredictability of attacks, coupled with potential delays in diagnosis and challenges in accessing effective treatment, contributes to heightened emotional distress. Given these concerns, international guidelines emphasize achieving complete disease control to improve patients’ quality of life [2]. Long-term prophylaxis (LTP), with C1-INH replacement therapy and other new drugs, remains a cornerstone of disease management; however, due to cost considerations, it is only reimbursed during pregnancy in certain healthcare systems.
Patient-reported outcome measures (PROMs) provide valuable insight into the psychosocial impact of HAE without requiring direct physician assessment. Previous studies indicate a high prevalence of anxiety and depression among HAE patients, which may be exacerbated by the uncertainty surrounding attack occurrence and treatment accessibility. Psychological distress may also act as a precipitating factor for angioedema episodes, perpetuating a cycle of increased disease burden and deteriorating mental health. Furthermore, HAE has been associated with significant lifestyle modifications, including avoidance of travel, reduced participation in social activities, and concerns regarding family planning due to the hereditary nature of the disease. This study aims to assess the burden of depression, anxiety, and stress and to provide clinicians with an accurate picture of the most current knowledge that surrounds the role that emotions, stress, and psychological factors play in the experience of patients with C1-INH–HAE.
Material and Methods
This cross-sectional study included 18 patients diagnosed with HAE. Eligibility criteria required participants to be at least 18 years old, have a physician-confirmed diagnosis of HAE, and be literate. Patients with any chronic comorbidities other than HAE were excluded. The survey collected demographic and clinical data, including age, gender, comorbid conditions, psychiatric history, and current medication use.
Anxiety, depression, and perceived stress status of patients were evaluated using the validated Beck Depression Inventory (BDI), Patient Health Questionnaire-9 (PHQ-9), Perceived Stress Scale-10 (PSS-10), and Generalized Anxiety Disorder-7 (GAD-7) [3-6]. Disease activity and control were evaluated using the Angioedema Activity Score (AAS) and Angioedema Control Test (AECT) [7, 8].
The BDI, a 21-item scale, assesses depressive symptoms over the past week, with total scores ranging from 0 to 63. It is categorized as minimal (0–9), mild (10–16), moderate (17–29), and severe (30–63) depression. The BDI established a cut-off score of 17 for clinical depression that needs treatment.
The PHQ-9, a 9-item questionnaire, evaluates depressive symptoms based on frequency, scoring each item from 0 (not at all) to 3 (nearly every day). The total score classifies depression severity as minimal (1–4), mild (5–9), moderate (10–14), moderately severe (15–19), or severe (20–27).
Perceived stress was measured using the PSS-10, which assesses the extent to which individuals perceive situations in their lives as stressful. Each item is rated on a 5-point Likert scale, with a total score ranging from 0 to 40, where higher scores indicate greater perceived stress.
Anxiety was assessed using the GAD-7, a seven-time scale measuring generalized anxiety disorders over the past four weeks. Each item is scored from 0 to 3, with total scores categorized as mild (0–5), moderate (6–10), and severe (≥11) anxiety. A cutoff point >15 is indicative of severe anxiety symptoms. (6-26)
Disease activity and control were evaluated using the Angioedema Activity Score (AAS) and the Angioedema Control Test (AECT). The AAS ranges from 0 to 420 over a 28-day period and quantifies attack frequency and severity, with higher scores indicating greater disease activity. The AECT, a 4-item questionnaire assessing symptom frequency, impact, and disease control, is scored from 0 to 16, with a threshold of ≤10 indicating poor disease control.
Statistics
Data were analyzed using SPSS (IBM SPSS Statistics, Version 22.0) and GraphPad Prism 8 (GraphPad Software Inc., San Diego, California, USA). Normality was assessed using the Shapiro-Wilk test. Continuous variables were analyzed using Mann-Whitney U and Kruskal-Wallis tests, while categorical variables were compared using the Chi-square or Fisher’s exact test. Correlations were examined using Spearman’s correlation coefficient. A p-value <0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Marmara University (Date: 2022-11-04 No: 1472).
Results
A total of 18 patients were enrolled and completed all questionnaires. The median age of participants was 33 years (interquartile range [IQR]: 27.7-37.2), with a female predominance (77.7%). The majority (83.3%) were classified as HAE type 1, while one patient was diagnosed with HAE type 3. The median diagnostic delay was 9.5 years (IQR: 3.7-16.7). All patients were prescribed icatibant for on-demand treatment, with a median annual usage of 36 doses (IQR: 11-96). Three patients were receiving danazol as LTP in addition to on-demand treatment. Details of the patient’s demographics are shown in Table 1. The median AECT score was 8 (IQR: 5.5-10), with 76.4% of patients scoring below the threshold of 10, indicating poor disease control. The median AAS score was 49.5 (IQR: 17-76), with four patients exhibiting higher scores suggestive of increased disease activity. Notably, two patients receiving LTP had an AAS score of zero.
The psychological assessment revealed substantial distress among patients. Figure 1 depicts the scores of BDI, PHQ-9, PSS-10, and GAD-7. The median BDI score was 16 (IQR: 10.7-22.7), with half of the cohort exceeding the treatment threshold of 17. The PHQ-9 median score was 9.5 (IQR: 7.5-16), with 50% of patients scoring within the moderate-to-severe depression range. The median PSS-10 score was 20 (IQR: 15.7-25), with 88.8% of patients reporting moderate stress. The median GAD-7 score was 8 (IQR: 4-10.5), with 7 patients (38.9%) exhibiting moderate-to-severe anxiety. Figures 2 A-D show the scores of BDI, PHQ-9, PSS-10, and GAD-7.
There was no significant correlation between ACT and AAS scores and the Beck Depression Inventory, PHQ-9, PSS-10, and GAD-7. No significant correlations were found between the Beck Depression Inventory, PHQ-9, PSS-10, and GAD-7 scores and age, gender, annual attack frequency, age at diagnosis, age at symptom onset, and other parameters. Furthermore, based on cut-off values, the depression and anxiety scales were categorized into two groups (mild and moderate-severe); however, no significant differences were observed in attack frequency, gender, or age (including symptom onset, diagnosis, and current age).
Discussion
This study revealed that 50% of patients with HAE exhibited depressive symptoms, while the majority reported moderate levels of perceived stress. Furthermore, moderate to severe anxiety was identified in 38.9 % of the cohort. These findings emphasize the significant psychological burden associated with HAE, with a considerable proportion of patients experiencing depression, anxiety, and stress.
Our findings revealed a prolonged diagnostic delay, consistent with previously published reports. Notably, elderly patients exhibited longer diagnostic delays, with durations extending up to 22.9 to 38.5 years [9]. This delay may contribute to heightened psychological distress due to the prolonged period of uncertainty and mismanagement before a definitive diagnosis is established.
Depression
This study demonstrated that half of patients with HAE had depressive symptoms, highlighting the substantial psychological burden associated with the disease. The high prevalence of moderate-to-severe depression aligns with previous research emphasizing the profound mental health impact of chronic and unpredictable conditions such as HAE. The unpredictability of attacks, coupled with concerns regarding treatment accessibility, likely exacerbates psychological distress and negatively affects quality of life.
Fouché et al. reported severe depressive symptoms in all 26 participants examined in their study [10], while Bygum et al. found depressive symptoms in 42% of participants [11], suggesting that depression is a prevalent comorbidity in HAE that warrants clinical attention. Neuroimmunological studies suggest that kinin receptors may influence depressive behavior, as B1-kinin receptor antagonists significantly reduce depressive behaviors in mice [12]. It is plausible that lifelong recurrent HAE attacks, accompanied by psychosocial stress, fear, and physical pain, could contribute to B1-receptor upregulation, potentially influencing depressive behavior patterns.
Anxiety
Anxiety disorders are highly prevalent among patients with chronic illnesses and are frequently reported in individuals with HAE [13]. Among HAE patients (N=1,214; 73% female), the prevalence of anxiety was significantly higher than in controls (OR, 2.05; 95% CI, 1.83–2.31), with increased prevalence in females compared to males (OR, 1.61; 95% CI, 1.23–2.11) and in elderly individuals compared to pediatric patients (OR, 4.62; 95% CI, 1.63–12.67) [14]. HAE patients also exhibited higher prevalence rates of generalized anxiety, posttraumatic stress, and panic disorders.
The unpredictability of HAE attacks, fear of asphyxiation, difficulties in accessing treatment, and the potential impact on social and professional life may collectively contribute to anxiety. Moreover, anxiety may significantly affect disease management, potentially influencing treatment adherence and overall well-being. This observation suggests a potentially vicious cycle in which anxiety related to recurrent attacks further exacerbates the disease burden [15, 16]. C1-INH HAE not only causes substantial short-term disability associated with its attacks, but it may also cause patients to live in persistent anxiety between episodes. The disease’s unpredictable nature could directly impact patients’ choices in everyday life. It may cause individuals to avoid traveling, specific hobbies, or social opportunities, or it may cause them to experience anxiety about having children or may cause other social and/or relationship impairments [17].
Stress
Zotter et al. reported that emotional stress is the most frequently cited trigger for HAE attacks [18]. The majority of our cohort (88%) reported moderate levels of perceived stress, with 64% of HAE patients exhibiting stress scores above those of the standard population [19, 20]. Notably, stress levels in this cohort exceeded those of individuals with other chronic diseases. Stress was identified as a primary trigger of HAE attacks, reinforcing the bidirectional relationship between psychological distress and disease activity. This stress could lead to a vicious cycle in which anxiety over continuing attacks could trigger further episodes. The long-term psychological impact of HAE extends beyond the patients themselves, affecting caregivers’ quality of life as well.
Given the hereditary nature of HAE and the likelihood that affected individuals have relatives who succumbed to asphyxiation due to laryngeal swelling, patients may live in constant fear of worsening attacks and respiratory failure [21-23]. Estimates suggest that patients with C1-INH–HAE lose between 20 and 100 days of social activities annually [24]. The disease’s unpredictable nature may profoundly impact daily life, leading individuals to avoid traveling, engaging in specific hobbies, or participating in social activities and work productivity. Concerns regarding family planning and long-term social or relational impairments have also been reported.
Interestingly, we did not observe significant correlations between disease activity (AAS), disease control (AECT), and psychological scores. This suggests that mental health outcomes may be influenced by factors beyond clinical severity, including individual coping mechanisms, social support, and healthcare accessibility. Previous research has highlighted the role of cognitive-behavioral therapy and stress management techniques in reducing attack frequency and improving patient-reported outcomes. Given the strong association between psychological stress and HAE exacerbations, integrating mental health support into routine disease management may yield substantial benefits.
Limitation
This study has several limitations. First, the small sample size and cross-sectional design preclude causal inferences. Additionally, the psychological assessments relied on self-reported questionnaires without psychiatric evaluation. However, these validated instruments are widely recommended for preliminary screening purposes. Future longitudinal studies with larger cohorts are warranted to further elucidate the interplay between HAE severity, psychological distress, and treatment strategies.
Conclusion
HAE imposes a substantial psychological burden, with high rates of depression, anxiety, and stress among affected individuals. Our findings underscore the necessity of comprehensive disease management strategies that integrate both physical and mental health support. Future research should investigate the long-term benefits of targeted psychological interventions in improving patient well-being and disease control. Additionally, further exploration into the neuroimmunological mechanisms underlying HAE-related psychological distress may provide new therapeutic insights. Given the study’s limitations, including a small sample size and reliance on self-reported measures, future research with larger, longitudinal cohorts is essential to better delineate the complex interplay between HAE and mental health.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Role of intraoperative blood loss in predicting surgical site infections during rectal cancer surgery
İsa Caner Aydın 1, Mehmet Torun 2, Ahmet Orhan Sunar 3, Serkan Ademoğlu 4, Mürşit Dinçer 3, Selçuk Gülmez 3, Erdal Polat 3, Mustafa Duman 3
1 Department of Gastroenterologic Surgery, Ministry of Health Zonguldak Ataturk State Hospital, Zonguldak, 2 Department of Gastroenterologic Surgery, Ministry of Health Erzurum City Hospital, Erzurum, 3 Department of Gastroenterologic Surgery, University of Health Sciences, Kosuyolu High Specialization Training and Research Hospital, Istanbul, 4 Department of Gastroenterologic Surgery, Ministry of Health Gaziantep City Hospital, Gaziantep, Turkey
DOI: 10.4328/ACAM.22618 Received: 2025-02-25 Accepted: 2025-03-23 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S47-51
Corresponding Author: İsa Caner Aydın, Department of Gastroenterologic Surgery, Ministry of Health Zonguldak Ataturk State Hospital, Zonguldak, Turkey. E-mail: isacaneraydin@hotmail.com P: +90 557 935 37 03 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2434-0045
Other Authors ORCID ID: Mehmet Torun, https://orcid.org/0000-0002-8742-6359 . Ahmet Orhan Sunar, https://orcid.org/0000-0001-5564-6923 . Serkan Ademoğlu, https://orcid.org/0000-0003-2595-0064 . Mürşit Dinçer, https://orcid.org/0000-0002-1930-0383 . Selçuk Gülmez, https://orcid.org/0000-0002-1930-0383 . Erdal Polat, https://orcid.org/0000-0002-9463-9846 . Mustafa Duman https://orcid.org/0000-0002-0276-0543
This study was approved by the Ethics Committee of University of Health Sciences Kosuyolu High Specialization Training and Research Hospital (Date:2024-09-03, No: 2024/15/899)
Aim: Surgical site infections (SSIs) are common complications in colorectal cancer surgeries, with an even higher incidence of rectal cancer due to coloanal or colorectal anastomoses. SSIs have been linked to an increased risk of local recurrence. This study aims to evaluate the effect of IBL on SSI development in rectal cancer patients.
Material and Methods: Patients aged 18–80 years who underwent elective surgery for Stage I–III rectal adenocarcinoma were included. Surgical procedures followed Total Mesorectal Excision (TME) principles, using either low anterior resection (LAR) with circular staplers or abdominoperineal resection (APR). ROC analysis was conducted to determine the optimal intraoperative blood loss (IBL) cutoff for SSI prediction. Univariate and multivariate Cox regression models were used to identify risk factors, with a p-value <0.05 considered statistically significant.
Results: IBV was significantly higher in patients with SSI (170 [150–225] vs. 78 [60–100], p < 0.001). ROC analysis determined the optimal IBV cut-off for SSI risk prediction (AUC: 0.719, 95% CI: 0.636–0.803, p = 0.042). Sensitivity was 73.9%, and specificity was 69.6% (p < 0.001). Multivariate analysis confirmed that high IBV (OR: 5.761, p < 0.001), laparoscopic surgery (OR: 0.067, p = 0.025), and anastomotic leaks (OR: 32.986, p < 0.001) were independent risk factors for SSI development.
Discussion: Intraoperative blood loss (IBL) is a significant risk factor for SSI development in rectal cancer surgeries. IBL exceeding 110 mL increases SSI risk by fivefold. These results highlight the need for further prospective studies evaluating strategies and risk assessment models aimed at reducing SSI incidence in this patient population.
Keywords: Rectum Cancer, Surgical Site Infection, Intraoperative Blood Loss, Bleeding
Introduction
Surgical site infections (SSIs) are among the most common postoperative complications in patients undergoing colorectal cancer surgery. Due to the presence of coloanal or colorectal anastomoses, the incidence of SSIs is even higher in rectal cancer surgeries. In addition to short-term morbidity, studies have reported an increased risk of local recurrence following SSI development [1].
Several factors have been associated with SSI development in these patients. Demographic characteristics such as age, diabetes, smoking, and malnutrition play a role. Additionally, disease-related factors, including neoadjuvant therapy, advanced stage, and tumor localization, have been implicated. Perioperative factors, such as the type of anastomosis, laparoscopic approach, and mechanical or oral bowel preparation, are also considered important. However, the impact of these factors remains a topic of ongoing debate [2-5].
Intraoperative blood loss (IBL) is also considered one of the key factors in SSI development. Studies have suggested that blood loss between 50 and 200 mL may contribute to SSI risk. In various studies evaluating factors such as laparoscopy, mechanical or oral bowel preparation, tumor localization, and the use of non-absorbable sutures, intraoperative bleeding has been identified as an independent risk factor [6-8].
Postoperative reductions in tissue perfusion and disruption of the mucosal barrier due to bleeding are known to increase susceptibility to both superficial and deep incisional SSIs. Additionally, inadequate drainage of hematomas has been shown to contribute to the development of organ-space SSIs through a similar mechanism [9-11].
This study aims to determine the impact of intraoperative blood loss on SSI development in rectal cancer patients, particularly in a cohort that includes cardiac patients receiving anticoagulant therapy and those with an increased risk of bleeding.
Material and Methods
Study Design
The records of patients who underwent rectum cancer surgery in the Department of Gastrointestinal Surgery at the Kosuyolu Yuksek Ihtisas High Training and Research Hospital between 01/01/2018 and 12/31/2023 were reviewed.
Inclusion Criteria
Patients who underwent surgery for rectal adenocarcinoma and with resections completed according to oncological principles in elective settings were included in the study. Only patients with complete demographic and clinicopathological data before and after surgery were considered. The study included patients aged between 18 and 80 years. Only Stage I, II, and III patients solitarily operated for rectum cancer included.
Exclusion Criteria
Patients who underwent surgery under emergency conditions, such as bleeding obstruction or hemodynamic instability during procedures, as well as those who underwent palliative surgery, and incomplete surgical specimens, were excluded from the study. Patients with positive Circumferential Resection Margin (cRM), positive surgical margins or Additionally, patients with a history of immunodeficiency, those who received but did not complete neoadjuvant therapy, and those with missing preoperative demographic data, intraoperative or postoperative follow-up, or clinicopathological data were excluded. Furthermore, to ensure consistency in the effectiveness of prophylactic treatment, patients with penicillin or metronidazole allergies were also excluded from the study. Stage IV patients, or any patient with additional surgical resection which may contribute to increased risk for SSI development, were excluded. Patients treated with prior rectum obstruction with a diverting colostomy or rectal stenting as a bridge for neoadjuvant therapy were excluded. Finally, any patient with a prior colon cancer and colon surgery history is excluded.
Preoperative and Perioperative Patient Assessment
The study was conducted at a specialized center primarily focused on cardiology and cardiovascular surgery, one of the three major referral hospitals for cardiovascular specialties in Istanbul. It was carried out in a gastrointestinal surgery department in the same center where fellowship training is provided and where a higher number of patients with a history of cardiac disease are referred. Consequently, preoperative evaluations included comprehensive assessments of patients’ cardiovascular disease demographics and histories of anticoagulant use.
Other preoperative demographic data were retrieved from the hospital’s electronic automation system. Additionally, intraoperative data, such as estimated blood loss, the amount of resuscitated crystalloid fluids, surgical approach, and procedure details, were extracted from surgical and anesthesia records. Postoperative follow-up data were obtained from hospital records. Neoadjuvant chemoradiotherapy was administered to patients diagnosed with locally advanced rectal cancer during preoperative staging, and surgery was planned at least six weeks after the completion of their preoperative treatment.
All patients received intravenous prophylaxis with 2 g of cefazolin and 500 mg of metronidazole before surgery. A single anesthesia team was responsible for both preoperative and postoperative follow-ups. Prior to rectal cancer surgery, all patients received two oral doses of Sennoside A+B and two rectal enemas. Fluid hydration was maintained during mechanical bowel preparation. Preoperative anemia was defined as hemoglobin ≤8 g/dL in patients without comorbidities and ≤10 g/dL in those with cardiovascular disease. Laparoscopic or conventional surgery was performed in all patients, with at least one silicone drain placed in the right or left paracolic region, positioned at the level of the preperitoneal reflection. Also, an additional closed-suction drain is used in patients with abdominoperineal resection. Skin sterilization was achieved using chlorhexidine. Surgical procedures were performed according to Total Mesorectal Excision (TME) criteria using either low anterior resection or abdominoperineal resection techniques. All surgeries were conducted by board-certified general surgeons with at least five years of experience specializing in gastrointestinal surgery. For patients with low anterior resection, circular staplers are used for anastomosis formation.
SSIs were classified based on the Centers for Disease Control and Prevention (CDC) 1988 criteria, incorporating the 2017 updates. They were categorized into Superficial Surgical Site Infection (SiSSI), Deep Surgical Site Infection (DiSSI), and Organ/Space Infection (OSI). Patients exhibiting at least one of these subtypes were considered to have developed an SSI.
Statistical Analysis
Statistical analyses were performed using the SPSS 27.0 software package (SPSS Inc., Chicago, IL). The normality of quantitative variables was assessed with the Kolmogorov-Smirnov test. For comparisons between independent groups, the independent samples t-test was applied to normally distributed variables, while the Mann-Whitney U test was used for non-normally distributed variables. Associations between categorical variables were examined using the chi-square test. Descriptive statistics for normally distributed quantitative variables were reported as mean ± standard deviation, whereas non-normally distributed quantitative variables were presented as median (25th–75th percentile). Categorical variables were expressed as frequency and percentage (%). ROC analysis was performed to determine the optimal IBV cutoff for predicting SSI risk, along with its corresponding sensitivity and specificity. Factors associated with SSI development were evaluated using univariate and multivariate Cox regression models. A p-value <0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of the University of Health Sciences Kosuyolu High Specialization Training and Research Hospital (Date:2024-09-03, No: 2024/15/899).
Results
A total of 158 rectal cancer patients met the inclusion criteria and were included in the study. Patients were classified based on SSI presence: 46 (29.1%) developed SSI, while 112 (70.9%) remained infection-free. Among SSI cases, 18 had organ/space SSI (OSI-SSI), 8 had deep incisional SSI (DiSSI), and 29 had superficial incisional SSI (SiSSI). Management varied by SSI type. Five OSI-SSI patients required re-laparotomy, ten underwent radiologic or endoscopic interventions, and three received medical therapy alone. Among the eight DiSSI cases, six required surgical debridement, while two were managed with bedside wound care. All 29 SiSSI cases were treated with bedside wound care.
An analysis of demographic data revealed no significant differences between groups in terms of gender distribution (p=0.525), mean age (p=0.140), BMI (p=0.528), ASA score (p=0.991), hypertension (p=0.715), diabetes mellitus (p=0.357), chronic heart failure (p=0.597), coronary artery bypass history (p=0.288), coronary stent placement (p=0.569), cardiac valve replacement (p=0.774), arrhythmia (p=0.122), COPD (p=0.420), anemia (p=0.639), smoking (p=0.343), anticoagulant use (p=0.215), and prior laparotomy (p=0.616). However, tumor location differed significantly, with upper (37.5% vs. 30.4%) and middle rectal tumors (51.8% vs. 34.8%) more common in the SSI- group, while lower rectal tumors were significantly more frequent in the SSI+ group (10.7% vs. 34.8%, p = 0.001).
Clinicopathological analysis showed no significant differences between groups in terms of cancer stage (p = 0.242), T stage (p = 0.256), N stage (p = 0.580), neoadjuvant therapy (p = 0.290), surgical approach (p = 0.702), stoma presence (p = 0.327), LVI (p = 0.090), PNI (p = 0.119), tumor differentiation (p = 0.218), perioperative (p = 0.080) and postoperative erythrocyte transfusion (p = 0.323), total lymph node count (p = 0.400), operative time (p = 0.374), and perioperative fluid replacement volume (p = 0.122). However, laparoscopic surgery was significantly less common in the SSI+ group (30.4% vs. 2.2%, p < 0.001).
Major complications were significantly more frequent in the SSI+ group (0.9% vs. 32.6%, p < 0.001), with a higher incidence of anastomotic leakage (1.8% vs. 26.1%, p < 0.001) and greater intraoperative blood loss (78 [60–100] ml vs. 170 [150–225] ml, p < 0.001). Other complications, including chylous ascites (p = 0.118), pneumonia (p = 0.362), acute kidney injury (p = 0.513), and acute mechanical intestinal obstruction (p = 0.255), showed no significant differences between groups. Significant values are summarized in Table 1.
A ROC curve analysis was performed to determine the cut-off value for IBL. The Area Under the Curve (AUC) was 0.719, with a standard error for AUC (SEAUC) p-value of 0.042 and a 95% confidence interval (CI) of 0.636–0.803. Sensitivity was found to be 73.9%, and specificity was 69.6% (p < 0.001). Information related to the ROC curve is provided in Figure 1. Based on the IBL cut-off value (110 ml), patients were classified into two groups: 90 (57.0%) with low IBL (<110 ml) and 68 (43.0%) with high IBL (>110 ml). No significant differences were observed between groups in terms of gender (p = 0.166), mean age (p = 0.477), BMI (p = 0.135), ASA score (p = 0.202), hypertension (p = 0.750), diabetes mellitus (p=0.122), chronic heart failure (p = 0.983), history of coronary artery bypass (p = 0.745), coronary stent placement (p = 0.093), cardiac valve replacement (p = 0.435), arrhythmia (p = 0.889), COPD (p = 0.805), smoking (p = 0.303), anticoagulant use (p = 0.651), anticoagulant type (p = 0.529), or previous laparotomy (p = 0.681). However, preoperative anemia was significantly more common in the high IBL group (2.2% vs. 10.3%, p=0.030).
Upper (37.8% vs. 32.4%) and middle rectal tumors (51.1% vs. 41.2%) were more prevalent in the low IBL group, whereas lower rectal tumors were significantly more frequent in the high IBL group (11.1% vs. 26.5%, p=0.043). Clinicopathological analysis showed no significant differences between groups in cancer stage (p = 0.644), T stage (p = 0.636), N stage (p = 0.218), surgical procedure (p = 0.097), stoma presence (p = 0.084), LVI (p = 0.322), PNI (p = 0.267), or tumor differentiation (p = 0.768).
No significant differences were found between groups regarding complication severity (p = 0.097), chylous ascites (p = 0.248), pneumonia (p = 0.102), acute kidney injury (p = 0.102), acute mechanical intestinal obstruction (p = 0.813), anastomotic leakage (p = 0.582), or total lymph node count (p = 0.322). However, neoadjuvant therapy was significantly more frequent in the high IBL group (31.1% vs. 50.0%, p = 0.016), while laparoscopy was more commonly performed in the low IBL group (32.2% vs. 8.8%, p < 0.001). Operative time was similar between groups (p = 0.615), whereas perioperative crystalloid replacement volume was significantly higher in the high IBL group (p = 0.023). Significant values are summarized in Table 2.
All significant variables were included in the regression analysis. In the univariate analysis, laparoscopic surgery was associated with a lower risk of SSI (OR: 0.051, p = 0.004), while anastomotic leakage (OR: 19.412, p < 0.001), high IBV levels (OR: 6.500, p < 0.001), and lower rectal cancer (OR: 4.000, p = 0.005) increased the risk. However, neoadjuvant therapy, major complications, anemia, surgical procedures, and perioperative crystalloid replacement were not significant factors for SSI development. In the multivariate analysis, laparoscopic surgery remained protective (OR: 0.067, p = 0.025), while anastomotic leakage (OR: 32.986, p < 0.001) and high IBV levels (OR: 5.761, p < 0.001) were confirmed as independent risk factors (Table 3).
Discussion
In our study, increased intraoperative blood loss was shown to be an independent risk factor for SSI development in rectal cancer surgery, alongside anastomotic leakage and conventional surgical approaches. When intraoperative blood loss exceeded 110 mL, the risk of SSI increased approximately fivefold, with the potential to rise up to fifteenfold. IBL is one of the key factors contributing to SSI, which significantly delays patients’ return to daily life after surgery. Performing controlled surgical procedures may facilitate earlier recovery and prevent delays in adjuvant therapy when needed.
In colorectal cancer surgery, the opening of the intestinal mucosa itself increases SSI rates. While SSI rates range from 9% to 20% following colorectal surgery, they are even higher in rectal cancer cases. Operating in a confined and anatomically complex space like the pelvis can lead to deviations from the planned resection planes, increasing the risk of intraoperative bleeding [6].
Intraoperative bleeding has been reported to cause tissue hypoperfusion and ischemia. This condition not only makes ischemic and necrotic tissues more susceptible to SSI development but also promotes pathogen proliferation through alterations in membrane permeability, ultimately increasing the risk of SSI. Literature studies have reported conflicting results regarding the impact of blood loss on SSI development [12-15].
In a recent study including 1,408 patients evaluating risk factors for rectal cancer, intraoperative blood loss exceeding 200 cc was identified as an independent risk factor for the development of surgical site infections (SSI), increasing the risk by approximately 1.72 times. The same study also identified other independent risk factors, including abdominoperineal resection, open surgery, operative time, absorbable sutures, mechanical bowel preparation, and oral antibiotic use. Similarly, in our study, intraoperative blood loss and open surgery were also found to be independent risk factors. However, unlike the previous study, mechanical bowel preparation was not identified as an independent risk factor in our cohort. We believe that the lower volume but higher risk associated with intraoperative bleeding in our study is likely due to our more limited cohort, which includes a higher proportion of patients with a history of cardiovascular disease. Moreover, the large-scale study did not evaluate one of the most critical predisposing factors: anastomotic leaks. In contrast, in our study, anastomotic leaks were identified as the most significant risk factor [6].
Limitation
The most significant limitation of our study is its retrospective design. Due to exclusion criteria, the patient cohort was considerably reduced, resulting in a more limited sample. However, this also allowed for an evaluation within a more homogeneous patient population. Additionally, since all rectal cancer patients at the study center routinely underwent mechanical bowel preparation before surgery, the impact of mechanical bowel preparation on SSI development could not be assessed. Nevertheless, our study provides a valuable contribution to the literature regarding intraoperative blood loss, as it offers an evaluation within a cohort with a high prevalence of anticoagulant use.
Conclusion
In rectal cancer surgeries, intraoperative blood loss (IBL) has been identified as a significant risk factor not only for postoperative complications but also for the development of SSI, which holds prognostic importance, particularly in relation to local recurrence. It has been shown that when IBL exceeds 110 mL, the risk of SSI increases by approximately fivefold. Our study is expected to serve as a foundation for future prospective studies investigating prophylactic antibiotic therapy or risk analysis in this context [16].
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22618
İsa Caner Aydın, Mehmet Torun, Ahmet Orhan Sunar, Serkan Ademoğlu, Mürşit Dinçer, Selçuk Gülmez, Erdal Polat, Mustafa Duman. Role of intraoperative blood loss in predicting surgical site infections during rectal cancer surgery. Ann Clin Anal Med 2025;16(Suppl 1):S47-51
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Low-risk gestational trophoblastic neoplasia in adolescent and young adult patients who were treated with single-agent methotrexate: A multicentric study
Okan Aytekin 1, Alev Esercan 2, Okan Oktar 3, Fatih Kilic 1, Burak Ersak 1, Mehmet Unsal 1, Abdurrahman Alp Tokalioglu 1, Fatih Celik 1, Caner Cakir 3, Osman Turkmen 1, Gunsu Kimyon Comert 1, Vakkas Korkmaz 3, Ozlem Moraloglu Tekin 1, Yaprak Engin Ustun 3, Taner Turan 1
1 Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, 2 Department of Gynecology and Obstetrics, Sanliurfa Training and Research Hospital, Sanliurfa, 3 Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Etlik Zubeyde Hanim Women’s Health Training and Research Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22623 Received: 2025-03-02 Accepted: 2025-03-23 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S52-57
Corresponding Author: Okan Aytekin, Department of Gynecologic Oncology, Faculty of Medicine, University of Health Sciences, Ankara Bilkent City Hospital, Ankara, Turkiye. E-mail: okanaytekin13@hotmail.com P: +90 312 552 60 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6430-4607
Other Authors ORCID ID: Alev Esercan, https://orcid.org/0000-0002-6215-6532 . Okan Oktar, https://orcid.org/0000-0002-9696-7886 . Fatih Kilic, https://orcid.org/0000-0002-7333-4883 . Burak Ersak, https://orcid.org/0000-0003-3301-062X . Mehmet Unsal, https://orcid.org/0000-0002-9920-6804 . Abdurrahman Alp Tokalioglu, https://orcid.org/0000-0002-1776-2744 . Fatih Celik, https://orcid.org/0000-0002-9523-180X . Caner Cakir, https://orcid.org/0000-0003-2559-9104 . Osman Turkmen, https://orcid.org/0000-0002-1470-7731 . Gunsu Kimyon Comert, https://orcid.org/0000-0003-0178-4196 . Vakkas Korkmaz, https://orcid.org/0000-0001-8895-6864 Ozlem Moraloglu Tekin, https://orcid.org/0000-0001-8167-3837 . Yaprak Ustun, https://orcid.org/0000-0002-1011-3848 . Taner Turan, https://orcid.org/0000-0001-8120-1143
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2024-07-24, No:24/397)
Aim: The aim of the present study was to evaluate the results of treatment with the methotrexate folinic acid (MTX FA) protocol in adolescents and young adults with low risk gestational trophoblastic neoplasm (LR GTN), and to identify the factors that determine resistance to MTX FA treatment.
Material and Methods: To meet this aim, 42 patients who were adolescents or young adults with LR GTN, and who received MTX FA as first-line therapy, were included in the present study. The scores for the patients were determined according to the Modified World Health Organization (WHO) Prognostic Scoring System, as adopted by International Federation of Gynecologists and Obstetrics (FIGO).
Results: The median age of the patients was found to be 21 years. Nine of the patients (21.4%) were adolescents, whereas 33 (78.6%) were young adults. MTX FA chemotherapy was used as the primary treatment in the entire cohort, and 27 (64.3%) of the patients received the standard protocol, whereas 15 (35.7%) patients received the watchful waiting protocol. A complete response to MTX FA was achieved in 29 (69%) of the 42 patients. Due to chemotherapy resistance, seven patients received single-agent treatment, while six required multi-agent chemotherapy following MTX FA. As a result of the therapy, the pretreatment value of human chorionic gonadotropin (β hCG) was found to be significantly associated with the response to the single-agent MTX FA treatment.
Discussion: In conclusion, the present study has demonstrated that the MTX FA protocol may be utilized as a first-line single-agent chemotherapy protocol for LR GTN in adolescent and young adult patients.
Keywords: Low Risk, Gestational Trophoblastic Neoplasia, Methotrexate, Adolescent, Young Adult
Introduction
Gestational trophoblastic neoplasm (GTN) is a malignant form of trophoblastic disease. It usually develops following the emergence of a complete or partial hydatidiform mole, although it can also develop following an abortion/ectopic pregnancy or term pregnancy [1, 2].
A scoring system has been devised by the International Federation of Gynecologists and Obstetrics (FIGO) and the World Health Organization (WHO) in order to plan the treatment of GTN [3, 4]. According to this scoring system, those who score ≤6 are defined as ‘low-risk GTN’ (LR GTN), whereas those who score ≥7 are defined as high-risk GTN. LR GTN is a rare, but curable condition that is usually treated with single-agent chemotherapy protocols. The most commonly used drugs in this treatment are methotrexate (MTX) or actinomycin D (Act D) [5]. MTX is an effective, well-tolerated, and cost-effective agent that can be co-administered with folinic acid (FA) to avoid the side effects that are associated with MTX. A 100% survival rate for patients with LR GTN can be achieved by [6]. The response rate of first-line therapy represents an important endpoint since patients who develop resistance to first-line therapy require further treatment options; these options include sequential single-agent chemotherapy, multi-agent chemotherapy, or surgery [7]. Patients who develop resistance to MTX FA chemotherapy may be moved to Act D therapy when their β human chorionic gonadotropin (β hCG) concentrations are ≤1,000 International Units (IU)/l, or to multidrug chemotherapy when the concentrations are >1,000 IU/l, and these treatments effectively result in the cure of almost all patients [8].
Maternal age has been reported to be an important risk factor for molar pregnancy. The risk of developing a hydatidiform mole is 4 10 times higher in women <16 and >40 years of age [9]. Therefore, GTN occurs more commonly at the start and endpoints of a woman’s reproductive age (i.e., in adolescents and women >40 years of age) [10, 11]. Approximately 20% of patients with gestational trophoblastic disease (GTD) are adolescents [12]; however, information regarding GTN in adolescents and young adults remains scarce.
This multicenter study aimed to evaluate the results of treatment with the MTX FA protocol in adolescents and young adults with LR GTN. Furthermore, we aimed to identify the factors that determine resistance to MTX FA treatment.
Material and Methods
The present study was designed retrospectively. Adolescent and young adult patients with LR GTN who were admitted to three tertiary centers between 1993 and 2021 were enrolled. The age definitions were 10-19 years for adolescents, and 20 24 years for young adults. Patients’ ages, FIGO scores, serum β hCG values before chemotherapy, tumor sizes, tumor ages, presence of theca lutein cyst, presence and location of metastasis, antecedent pregnancy information, and type of MTX treatment protocol and responses were obtained from the patient’s files. Patients with a FIGO risk score ≤6, and who received MTX as first-line therapy, were included in the study. Tumor age was defined as the time between the last pregnancy and the diagnosis of GTN (in months).
Before scoring, patients were evaluated for their clinical history and after having received a physical examination, in addition to the performance of pelvic ultrasonography, chest X-ray, serum β hCG level, complete blood count, and kidney and liver function tests. Computed tomography (CT) was performed in cases when the scan of the lungs, upon performing chest X-ray analysis, was positive. Brain magnetic resonance imaging (MRI) was performed on patients with symptoms suggestive of brain metastasis. The scores of the patients were determined according to the Modified WHO Prognostic Scoring System as adapted by FIGO 2000 [4].
Patients were treated with either a standard protocol or a watchful waiting protocol. The treatment regimen was selected in random order by either a senior gynecological oncologist or a medical oncologist at each center, without applying any specific selection criteria. However, the standard protocol treatment was used more frequently, whereas the watchful waiting treatment protocol was randomly applied. In the standard protocol, 1 mg/kg intramuscular (IM) MTX was administered consecutively on days 1, 3, 5, and 7, with 0.1 mg/kg IM FA being administered on days 2, 4, 6, and 8, and the β hCG levels were monitored. In a watchful waiting protocol, the same 8-day IM MTX FA regimen was administered to the patients in one go, and patients with decreased β hCG values were followed as long as the β hCG concentration was lowered to a normal level. Subsequently, an additional one or two cycles of MTX FA were administered in both protocols.
β hCG levels were monitored weekly during treatment, and a successful response to the treatment was determined by detecting decreases in β hCG levels. In cases where the patient was found to have negative β hCG values (<5 mIU/ml) for 3 consecutive weeks, the patient was diagnosed as being in complete remission. Resistant or progressive disease was defined as: i) an increase in two consecutive β hCG levels; or ii) the β hCG level having reached a plateau in three consecutive measurements during 2 weeks; or iii) detection of a new metastasis [3, 13]. MTX-resistant patients received either a 5-day Act D regimen (where 12 μg/kg Act D was administered intravenously for 5 days every 2 weeks) or multi-agent chemotherapy as second-line therapy. The decision on which regimen to switch to was made by the gynecological oncology council. While making this decision, the patient’s β hCG level was taken into consideration. Generally speaking, if the β hCG level was ≤100 IU/l, Act D was given, whereas if it was >100 IU/l, multi-agent chemotherapy was given.
In terms of statistical analysis of the data, the Chi-square test and Fisher’s exact test were used to examine the association between responsiveness to MTX treatment and each clinical variable in a univariate analysis. Continuous variables were analyzed using an ANOVA table test. Statistical Package for the Social Sciences (SPSS) for Windows version 22.0 (IBM Corp.) was used to perform the statistical analyses. P<0.05 was considered to indicate a statistically significant difference.
Ethical Approval
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2024-07-24, No:24/397).
Results
A total of 42 patients were recruited for the present study. The median age of the patients was 21 years (range: 15 to 24 years). Nine (21.4%) patients were adolescents, whereas 33 (78.6%) were young adults. All patients included in the study had complaints of abnormal bleeding following antecedent pregnancy (mole hydatidiform, abortion, or term pregnancy), and all patients were diagnosed with GTN after the clinician’s having determined a plateauing of, or an increase in, the β hCG level during their follow up. The median value of the FIGO score was 3 (range: 0-6). Before the treatment, the median value for β hCG was 9,355 IU/l (range: 73-127,694 IU/l) and the median tumor size was 3.0 cm (range: 1.0-11.0 cm). The majority of the patients had a history of hydatidiform mole (90.5%) as their antecedent pregnancy and a tumor age of <4 months (73.8%). Metastases were detected in 18 (42.9%) of the patients; 17 of the metastases were in the lung only, whereas, for one patient, it was located in both the lung and vagina (Table 2).
MTX FA chemotherapy was used as the primary treatment in the entire cohort. Twenty seven (64.3%) of the patients received the standard protocol, whereas 15 (35.7%) of them received the watchful waiting protocol (Table 1). During medical treatment, one patient required surgery due to excessive bleeding, and underwent a hysterectomy.
A complete response to MTX FA was achieved in 29 (69%) of the 42 patients. Due to chemotherapy resistance, seven patients received single-agent treatment, and six patients were given multi-agent chemotherapy following MTX FA; all patients had a clinically complete response after receiving Act D or multi-agent chemotherapy (Table 1).
The pretreatment β hCG value was found to be significantly associated with the response to the single agent MTX FA treatment. Patients with a pretreatment β hCG value of <103 IU/l had a 100% MTX FA response rate, whereas those with a β hCG value of ≥103 IU/l had a 61.8% response rate (P=0.043) (Table 2). No significant effects of age, FIGO score, tumor size, tumor age, theca lutein cyst, metastasis, antecedent pregnancy, or MTX FA protocol were identified with respect to the treatment response (Table 4). Patients with a FIGO score of 0 1 showed no resistance to MTX FA chemotherapy, whereas those with a score of 5 6 had 50% resistance.
The characteristics of those 13 patients who did not respond to MTX FA treatment are presented in Table 3. All of these patients were aged 18 years or older. Before the treatment, the median β hCG value was found to be 39.921 IU/l and the tumor size was 2.8 cm. Antecedent pregnancy was mole hydatidiform in 12 patients, and abortion in one patient. Due to chemotherapy resistance, seven patients were administered Act D treatment, whereas six patients were treated with multi-agent etoposide, MTX, actinomycin D/cyclophosphamide, and vincristine (EMA/CO) chemotherapy protocol following the MTX FA therapy.
Discussion
LR GTN is a rare, but highly chemosensitive disease that can be effectively treated at a rate approaching 100% with chemotherapy [6, 14]. Several chemotherapeutic regimens are in current use; however, the choice of regimen used is usually specifically handled by the medical specialists concerned, and it is difficult to compare the advantages and risks of each regimen. MTX and Act D are the most commonly used therapies in first-line treatment [15]. MTX is generally preferred as the first-line chemotherapy due to its effectiveness, safety, and toxicity profiles, and the fact that it is both well tolerated and cost-effective [16]. MTX has been used in a variety of regimens with FA to protect the patient from MTX-associated toxicity [17].
In the present study, a complete response was achieved in 69% of the patients (adolescents and young adults) with LR GTN using first-line MTX FA. Due to MTX FA resistance, seven and six patients were administered single-agent Act D or multi-agent EMA/CO chemotherapy as an alternative to a single-agent regimen, respectively. Additionally, it was demonstrated that the overall cure rate with single-agent or multi-agent protocols was 100% in adolescents and young adults with LR GTN. Resistance to first-line, single-agent MTX FA was significantly associated with a higher pretreatment β hCG level. We were able to demonstrate that the success of the therapy was not affected by FIGO score, age, tumor size, tumor age, theca lutein cyst, metastasis, antecedent pregnancy, or the MTX FA protocol.
Phianpiset et al [18] reported that a complete response was achieved in 63 (55.8%) of 113 patients with LR GTN (mean age: 31.5±7.9 years) who were initially treated with MTX FA (50 mg MTX administered IM on days 1, 3, 5 and 7, and 15 mg FA IM on days 2, 4, 6 and 8) for 8 days every 14 days. Similarly to our study, a significant correlation was found between the pretreatment high β hCG value and treatment resistance, and there was no response to first-line MTX FA treatment in the group with a β hCG value (≥100,000). In their study, Chapman Davis et al [19] reported on 358 people with LR GTN (age range: 12 51 years) who were treated with MTX daily for 5 days per treatment course, which was repeated every 14 days as the first line therapy. Failure of MTX treatment was found to be associated with metastatic disease, a high FIGO score, a pathological choriocarcinoma diagnosis, and a high β hCG level before treatment.
In the presented study, patients who developed resistance to MTX FA chemotherapy were switched either to treatment with Act D when the β hCG concentration was ≤100 IU/l, or to multidrug chemotherapy when the concentration was >100 IU/l. However, a recent study showed that increasing the hCG cut-off value from ≤100 to ≤1,000 IU/l in terms of patient selection for Act D following MTX FA resistance resulted in the protection of more women with GTN from the toxicity of EMA/CO without compromising the 100% survival outcomes [8].
To the best of our knowledge, this is the third largest GTN study to have been performed, involving 42 adolescents and young adults. In the largest study examining the results of adolescent GTN, those from 285 adolescent patients with complete hydatidiform mole were examined by [20]. GTN was found to have developed in 59 patients. Anemia, pre-eclampsia, a uterine size larger than it ought to have been for the gestational age, and theca lutein cysts >6 cm were associated with the development of post-complete hydatidiform mole GTN among adolescents in South America. In the study performed by Rauh Hain et al [21], 50 adolescent patients with GTN were examined, and no differences were observed between adolescents and adult women concerning the rate of LR GTN, GTN stage, and frequency of resistance to initial chemotherapeutic treatment. A study by Chapman et al [22] on molar pregnancies in adolescents featured three patients with GTN. One patient received three cycles of MTX, followed by two cycles of Act D; another received one cycle of MTX FA; and the third received one cycle of MTX and Act D in combination, and a complete response was observed in all these patients. Uberti et al [12] reported that 18 of 22 (81.8%) patients with GTN under the age of 19 had LR GTN. In their study, patients with LR GTN received sequential single-agent chemotherapy, with either MTX FA or Act D as the initial agent. However, neither the treatment response nor the affecting factors were reported.
Limitation
The first major contribution of our study is that this, to the best of our knowledge, is the largest GTN study to have provided information on adolescents and young adults. This age group is underrepresented in the scientific literature. Therefore, we expect that this research will stimulate further investigation in this field. The second major contribution of the study is that the centers participating in the study were referral centers and gynecological tumor tertiary centers replete with extensive expertise, to which many of the patients were directed. Consequently, the findings obtained in our study may potentially reflect the most accurate results of patients with LR GTN in the adolescent and young adult age groups. By contrast, the main limitations of this study were its retrospective design and the randomization process concerning determining the first-line treatment protocol. The other major limitation was its limited number of participants, which gave rise to issues regarding the extent to which the findings may be applied to a larger population. Nevertheless, documenting the GTN variation, which has a low incidence rate [23] but is relatively more common in younger people [24], will have a significant effect on the current academic literature. In addition, the long-term outcomes, recurrence rates, and post-treatment fertility results of our cohort were not attainable, as the centers where the study was conducted were reference centers, and the long-term follow-ups were carried out in the patients’ local facilities.
Conclusion
In conclusion, the present study has shown that the first-line treatment of LR GTN in adolescent and young adult patients with an MTX FA protocol was an effective regimen, resulting in a 69% complete response rate. All patients had a clinical complete response after receiving second-line treatment with Act D or multi-agent chemotherapy. However, future studies are required with larger sample sizes, and with the potential exploration of multicenter collaborations, to validate and strengthen the current findings.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Download attachments: 10.4328.ACAM.22623
Okan Aytekin, Alev Esercan, Okan Oktar, Fatih Kilic, Burak Ersak, Mehmet Unsal, Abdurrahman Alp Tokalioglu, Fatih Celik, Caner Cakir, Osman Turkmen, Gunsu Kimyon Comert, Vakkas Korkmaz, Ozlem Moraloglu Tekin, Yaprak Engin Ustun, Taner Turan. Low-risk gestational trophoblastic neoplasia in adolescent and young adult patients who were treated with single agent methotrexate: A multicentric study. Ann Clin Anal Med 2025;16(Suppl 1):S52-57
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Evaluation of prognosis in refugee children with high kinetic energy penetrating thoracic gunshot wounds
Mustafa Tuşat 1, İsmail Özmen 2, Mehmet Semih Demirtaş 3, Aziz Yarbil 4, Ahmet Salih Calapoğlu 5, Sebahattin Memiş 3
1 Department of Pediatric Surgery, Faculty of Medicine, Aksaray University, Aksaray, 2 Department of Pediatric Surgery, Kilis Prof. Dr. Alaeddin Yavaşça State Hospital, Kilis, 3 Department of Pediatrics, Faculty of Medicine, Aksaray University, Aksaray, 4 Department of Anesthesia and Reanimation, Kilis Prof. Dr. Alaeddin Yavaşça State Hospital, Kilis, 5 Department of Pediatric Surgery, Faculty of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey
DOI: 10.4328/ACAM.22624 Received: 2025-03-02 Accepted: 2025-03-23 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S58-63
Corresponding Author: Mustafa Tuşat, Department of Pediatric Surgery, Faculty of Medicine, Aksaray University, Aksaray, Turkey. E-mail: mustafatusat42@hotmail.com P: +90 382 502 20 25 Corresponding Author ORCID ID: https://orcid.org/0000-0003-2327-4250
Other Authors ORCID ID: İsmail Özmen, https://orcid.org/0000-0002-4101-5677 . Mehmet Semih Demirtaş, https://orcid.org/0000-0003-2965-1811 . Aziz Yarbil, https://orcid.org/0000-0002-9676-7008 . Ahmet Salih Calapoğlu, https://orcid.org/0000-0001-6909-0137 . Sebahattin Memiş, https://orcid.org/0000-0002-3829-9218
This study was approved by the Ethics Committee of Aksaray University Health Sciences Scientific (Date: 2024-06-06, No: 2024/42)
Aim: Civil wars cause the death of many innocent children, and penetrating thoracic firearm injury (PTFI) is a leading cause of morbidity and mortality in children in war environments. The aim of this study was to evaluate child casualties admitted to the emergency department with PTFI that occurred on the battlefield.
Material and Methods: Our study was conducted by reviewing the files of pediatric patients with PTFI under the age of 18 who were transferred from Syria to the first response hospital on the Syrian border of Turkey due to the Syrian civil war between January 2016 and December 2019.
Results: Our study included 28 (84.4%) boys and 5 (15.2%) girls. The cause of injury was a bullet in 5 cases, shrapnel in 28 cases and hemothorax (33.3%) was the most common thoracic injury. It was found that a longer time from injury to presentation to the emergency department (p=0.012, p<0.001), injury with a bullet (p=0.013, p=0.017), the presence of shock at the time of presentation (p<0.001, p=0.001) and an increase in the amount of erythrocyte suspensions given (p<0.001) significantly increased the development of complications and mortality. It was also found that mortality and morbidity were significantly higher in PTFI child casualties with low pediatric trauma score (PTS) (p<0.001).
Discussion: Penetrating thoracic injuries in children are still associated with high mortality and morbidity. Rapid transfer of these patients to the hospital, and effective, multidisciplinary resuscitation and aggressive thoracotomy interventions when necessary will reduce mortality in these patients.
Keywords: Penetrating Thoracic Injuries, Firearm, Gunshot, Children
Introduction
The civil war in Syria, Turkey’s neighboring country, has had a devastating impact on the lives of children, causing mortality and morbidity in large numbers. The majority of the deaths were reportedly caused by shrapnel and bullet injuries [1, 2].
Thoracic trauma is the second most common cause of trauma-related death in children and thoracic trauma alone is responsible for 4% of mortality [3]. Although penetrating thoracic traumas caused by firearms, piercing and cutting instruments account for 10% of thoracic injuries in civilian life, the mechanisms of injury reported in children in civil wars are predominantly penetrating injuries, and in a study conducted in the Syrian civil war, 74% of children were injured due to penetrating trauma [4].
In this study, we aimed to determine the factors affecting mortality and morbidity in Syrian children with penetrating thoracic firearm injury (PTFI) who were injured in the Syrian civil war and transported to Turkey.
Material and Methods
Study Design
Our study was conducted by reviewing the files of PTFI patients who were transferred from Syria to Kilis Alaaddin Yavaşça State Hospital in Kilis due to the Syrian civil war between 15.01.2016 and 15.12.2019.
Study Population
Children < 18 years of age with PTFI who were transferred to the hospital due to the war in Syria between the specified dates were included in our study. Children with PTFI who died before arriving at the hospital, had abdominal injuries with solid and/or hollow organ injuries requiring operation, severe burns, head and/or neck injuries, and had a history of operation for any reason in Syria were excluded from the study and 33 children with PTFI were included in our study.
Data Collection
The emergency department, inpatient ward, intensive care unit, and operation notes of the hospital were examined to determine the age, gender, type of weapon causing injury, time between the time of injury and arrival to the hospital, presence of shock on admission, amount of erythrocyte transfusion given, type of treatment (conservative, tube thoracostomy, thoracotomy), solid abdominal organ injuries that did not require operation, extremity injuries, injuries due to thoracic trauma, complications and mortality were determined and a data collection form was filled for each patient. Pediatric Trauma Score (PTS) was calculated and recorded to assess the severity of trauma in injured children.
Casualty Assessment and Stabilization
First aid and resuscitation procedures were initiated as soon as the child casualties arrived at the emergency department. Children underwent a rapid and effective systemic physical examination and their vital signs were determined and recorded. After placement of a central venous catheter, mai replacement was initiated and blood samples were taken for blood group, hemoglobin, hematocrit, and routine biochemistry. PA chest, abdominal, and extremity radiographs were taken after the injured were stabilized. Computed tomography (CT) of the abdomen and chest was performed in suspicious cases.
In the children with pulmonary contusion, oxygen was administered at 2 L/min and the amount of oxygen was gradually increased up to 8 L/min when necessary with effective analgesic management by avoiding excessive intravenous fluid overload.
Patients with minimal pneumothorax and/or hemothorax with stable examination findings and hemodynamics were treated conservatively. In injured children with hemothorax and/or pneumothorax affecting or thought to affect respiration, tube thoracostomy was placed through the midaxillary region under local anesthesia. In patients with hemothorax, thoracotomy was performed if the initial drainage volume from the tube thoracostomy was more than 20 ml/kg or if the blood volume from the chest tube was more than 3 ml/kg per hour in 3 consecutive hours of follow-up.
Emergency thoracotomy was performed without delay in patients with cardiac injury, cardiac tamponade, large vessel injury, and massive or chest tube sustained hemothorax on admission.
After evaluating the pulse rate and blood pressure values of the children according to age [5], the shock was diagnosed in cases with hypotension, tachycardia, capillary refill time above 2 s, or bradycardia.
Antibiotics (3rd generation cephalosporin) and tetanus prophylaxis were administered at the initial presentation. Paracetamol (10mg/kg) was administered as an analgesic and opioids were added to the treatment if necessary [6].
Statistical Analysis
Data analysis was performed using IBM SPSS v. 24.0 (SPSS, Inc., Chicago, Illinois, USA). The chi-square test assessed categorical data distribution, and Bonferroni correction identified groups responsible for significant differences in parameters with multiple subcategories. The Shapiro-Wilk test checked the normality of PTFI-related data. Non-normally distributed quantitative data were reported as median (IQR 25–75). The Mann-Whitney U test compared PTFI patient data, while the Spearman correlation analyzed relationships between parametric variables. Statistical significance was set at P < 0.05
Ethical Approval
This study was approved by the Ethics Committee of Aksaray University Health Sciences Scientific Research Ethics Committee (Date: 2024-06-06, No: 2024/42).
Results
Of the injured children included in our study, 28 (84.8%) were boys and 5 (15.2%) were girls. The median value for age of the injured children was 9 (7-11), 9.5 (7-11) for boys and 9 (7-11.5) for girls. The analysis showed that age and gender had no effect on mortality and morbidity in injured children (Table 1,2). When the injuries in children were evaluated, pneumothorax in 9 (27.2%) cases and hemothorax in 11 (33.3%) cases were the most common injury types. Other injury types and associated injuries are shown in Table 3A. Conservatively treated solid abdominal organ injuries such as liver in 6 (18.2%), spleen in 2 (6.1%), and kidney in 2 (6.1%) of the pediatric injured patients were associated with the injury. While 7 (21.2%) of the pediatric injured patients were treated conservatively, tube thoracostomy was placed in 19 (57.6%) patients, and thoracotomy was performed in 7 (21.2%) patients. In addition, chest wall repair was performed in 5 (15.2%) of patients (Table 3A).
In our study, the median value of the time from injury to hospital admission was 65 (57.5-87.5) minutes and this time was 80 (60-140) minutes in patients with complications and 60 (55-66.25) minutes in patients without complications, while this time was 240 (120-390) minutes in deceased children and 60 (55-70) minutes in living children. When analyzed in terms of both morbidity and mortality, this duration was found to be statistically higher ((p=0.012, p<0.001) respectively) (Table 1,2).
Among the children, 5 (15.2%) had bullet injuries and 28 (84.8%) had shrapnel injuries. Regarding the type of firearm causing the injury, it was found that 3 (60%) of 5 patients with bullet injuries died, while 26 (92.9%) of 28 patients with fragment injuries survived. When evaluated in terms of morbidity, it was found that complications developed in 5 wounded with bullets, while complications developed in 10 (35.7%) of 28 wounded with fragments. The type of firearm causing the injury was found to have a statistically significant effect on both morbidity and mortality (p=0.013, p=0.017 respectively) (Table 1, 2).
The shock was detected in 9 (27.3%) children in the emergency room. While 5 (33.3%) patients with shock findings died, none of the patients without shock findings died. Complications developed in 6 (25.0%) children without shock findings, while all 9 patients with shock findings developed complications. It was observed that both mortality and morbidity were significantly higher in children admitted to the hospital with signs of shock (p=0.001, p<0.001 respectively) (Table 1, 2).
The median value of the mean amount of erythrocyte suspension given to injured children was found to be 1 (0-3) unit and it was observed to be 5 (5-6) units in children who died and 1 (0-2) unit in children who survived, 3 (2-5) units in children who developed complications and 0 (0-1) unit in those who did not develop complications. It was observed that the amount of erythrocytes given had a significant effect on both mortality and morbidity (p<0.001) (Table 1, 2). We also observed that both mortality and morbidity were significantly higher in children who received 3 units or more of erythrocyte suspension. (p<0.001) (Table 1, 2).
The median PTS value of injured children was 9 (5.5-10) and was 3 (2-3.5) in those who died and 9 (8-10) in those who survived, while it was 5 (3-8) in patients who developed complications and 10 (9-11) in patients who did not develop complications. PTS was found to be statistically effective in predicting both complications and mortality (p<0.001) (Table 1, 2). We also found that both mortality and morbidity were significantly higher in children with PTS≤8 (p=0.013, p<0.001, respectively) (Table 1, 2).
In our study, diaphragm injury was found in 4 (12.1 %) patients, and no statistical effect of diaphragm injury on mortality and morbidity was found (p=0.099, p=0.308, respectively) (Table 1, 2).
In our series, 2 (6.1%) children had a cardiac injury, and 1 (3.0%) patient had a large vessel injury and these three patients died postoperatively due to DIC. Cardiac injury was found to have a statistical effect on mortality, but not on morbidity (p=0.019, p=0.199 respectively). There was no statistically significant effect of large vessel injury on mortality and morbidity (p=0.152, p=0.455 respectively) (Table 1, 2).
A total of 15 patients developed complications and 5 (33.3%) of these patients died, while no patient without complications died. The development of complications had a significant effect on mortality (p=0.013) (Table 1).
In our study, 5 (15.2%) of 33 pediatric casualties died, while 15 (45.5%) children developed complications such as wound infection (n=4, 26.7%), sepsis/septic shock (n=1, 6.7%), DIC (n=4, 26.7%), pulmonary infection/ARDS (n=2, 13.3%), atelectasis (n=3, 20.0%), paraplegia (n=1, 6.7%).
Discussion
We found that time of admission to the hospital after injury (p<0.001, p=0.012 respectively), bullet injury (p=0.017, p=0.013 respectively), presence of shock at the time of admission (p=0.001, p<0.001 respectively), need for massive erythrocyte suspension (p<0.001), significantly increased both mortality and morbidity and presence of cardiac injury (p=0.019) increased mortality. Another result we found was that PTS was effective in predicting both morbidity and mortality in child victims with PTFI.
It is reported that shrapnel injuries are the most common cause of penetrating injuries in an open war environment. In studies conducted during the Syrian civil war, 61.7% and 71.6% of PTFIs were caused by shrapnel [2, 7]. In our study, we observed that 84.4% of the injured children were injured by shrapnel.
Studies are reporting that the time from injury to the hospital is effective, as well as studies reporting that this time is not effective [2, 8, 9]. In a study conducted between 2007 and 2015 on the relationship between the evacuation time of US soldiers injured in Iraq and Afghanistan and survival, it was predicted that hospital admission time within 1 hour after injury, also referred to as the golden hours, and as a result, timely initiation of surgery could reduce mortality by 66.0%. [10]. In our study, we found that this duration had a significant effect on both mortality and morbidity (p<0.001, p=0.012, respectively). We think that the risk of developing shock or the depth of the existing shock increases as this period prolongs and this leads to an increase in mortality and morbidity.
The triage process is of great importance to increase the survival rate of children exposed to trauma. It is reported that morbidity and mortality are higher in cases with PTS ≤8 than in cases with PTS >8 [11]. In our study, we found that PTS was an important factor in predicting mortality and morbidity (p<0.001), and both morbidity and mortality were significantly increased in those with PTS ≤8 (p<0.001, p=0.013, respectively).
Studies have reported that the most common cause of mortality in penetrating injuries in children is shock due to hemorrhage [2, 12]. It has been reported that the depth and duration of shock detected in the emergency department affect mortality and morbidity and is responsible for up to 100% of deaths [13]. In our case series, we found that mortality and morbidity were significantly higher in patients admitted to the emergency department with shock (p=0.001, p<0.001, respectively).
Although massive erythrocyte transfusion is a life-saving method in hemorrhagic shock, it is reported as an independent predictor of multi-organ failure, systemic inflammatory response syndrome, increased infection, and mortality [14]. In our study, we found that massive erythrocyte suspension transfusion increased both mortality and complication development (p<0.001).
In the literature, it is reported that penetrating chest traumas are mostly treated with conservative methods and tube thoracostomy [15, 16] and thoracotomy is rarely required [17]. In a study in which 110 cases under 16 years of age were evaluated and 42.2% of the injuries were PTFI cases caused by high-energy weapons, lung contusion was observed in 42.7% of patients, hemothorax in 34.5% and hemopneumothorax in 26.3%. In the treatment of these patients, tube thoracostomy was sufficient in 76.3%, 9.1% were conservatively observed and thoracotomy was necessary in 12.7% of the patients [18]. In our series, 19 (57.6%) injured children were treated with tube thoracostomy and 7 (21.2%) children were treated conservatively. Thoracotomy was performed in 7 (21.2%) patients in total and while 3 patients underwent emergency thoracotomy, 4 patients underwent thoracotomy due to ongoing hemorrhage from the tube. In our study, hemothorax was the most common injury in 11 (33.3%) injured children, followed by pneumothorax in 9 (27.2%). One (3%) patient with unilateral pneumothorax and one (3%) patient with bilateral pneumothorax with stable physical examination findings were treated conservatively. In our series, 7 (21.2%) patients with unilateral pneumothorax, 11 (33.3%) patients with unilateral hemothorax, and 1 (3%) patient with unilateral hemopneumothorax underwent tube thoracostomy. The main indications for thoracotomy in our study were severe bleeding and continued bleeding after tube thoracostomy placement.
Cardiac and great vessel injuries are injuries with a high mortality rate that often occur after penetrating injuries and thoracotomy should be performed urgently if the patient is hemodynamically unstable and cardiac or great vessel injury is suspected [19, 20]. In our study, two children had heart injuries and one child had major vascular injuries. These patients underwent emergency thoracotomy. These three injured children died of DIC within 6 hours after the operation. Unilateral hemopneumothorax was accompanied by lung laceration in all 4 patients who underwent thoracotomy due to persistent hemorrhage from tube thoracostomy. One of these patients died of postoperative DIC and another patient died of sepsis on day 5.
The reasons for the difference in mortality incidence observed in thoracic injuries are generally reported to depend on the case population included in the study and whether or not patients who died in the emergency department were included in the study [21]. In a study conducted on children with PTFI, mortality rates were reported as 11.8 % [22], 7.9 % [23], and 31.0% [24]. In our study, the mortality rate was 15.2%. The complication rate in our study was 45.5 % and we observed that this rate was higher than those reported in the literature [7, 18, 23].
Limitation
The most important limitation of our study is the small number of cases.
Conclusion
Hemodynamic balance was seriously impaired in children with PTFI and the resulting shock increased mortality and morbidity. In addition, we observed that PTS can predict mortality and morbidity, and PTS ≤8, the amount of erythrocyte suspension administered ≥3 units and long transport time significantly increased mortality and morbidity in children with PTFI.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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2. Tuşat M, Özmen İ, Demirtaş MS, Ateş C, Öztürk AB, Kankılıç NA, et al. Risk factors for mortality and morbidity in Syrian refugee children with penetrating abdominal firearm injuries: a 1-year experience. Ulus Travma Acil Cerrahi Derg. 2023;29(9):1051.
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6. Geze S, Arslan U, Tusat M. Anaesthesia for an infant with Jarcho Levin syndrome: case report. Rev Bras Anestesiol. 2015;65(5):414-16.
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Mustafa Tuşat, İsmail Özmen, Mehmet Semih Demirtaş, Aziz Yarbil, Ahmet Salih Calapoğlu, Sebahattin Memiş. Evaluation of prognosis in refugee children with high kinetic energy penetrating thoracic gunshot wounds. Ann Clin Anal Med 2025;16(Suppl 1):S58-63
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Evaluation of mandibular bone structure in patients with ectodermal dysplasia
Elif Meltem Aslan 1, Sedef Kotanlı 2, Aslıhan Artaş 3, Mehmet Veysel Kotanlı 4
1 Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Lokman Hekim University, Ankara, 2 Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Harran University, Şanlıurfa, 3 Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Gaziantep University, Gaziantep, 4 Department of Pediatric Dentistry, Faculty of Dentistry, Harran University, Şanlıurfa, Turkey
DOI: 10.4328/ACAM.22633 Received: 2025-03-05 Accepted: 2025-03-24 Published Online: 2025-03-25 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S64-68
Corresponding Author: Elif Meltem Aslan, Department of Dentomaxillofacial Radiology, Faculty of Dentistry, Lokman Hekim University, Ankara, Turkey. E-mail: aslan.meltem5@gmail.com P: +90 544 959 72 51 Corresponding Author ORCID ID: https://orcid.org/0000-0002-1737-9585
Other Authors ORCID ID: Sedef Kotanlı, https://orcid.org/0000-0002-0827-0991 . Aslıhan Artaş, https://orcid.org/0000-0002-5726-9372 . Mehmet Veysel Kotanlı, https://orcid.org/0000-0001-7032-4367
This study was approved by the Ethics Committee of Harran University (Date: 2024-12-02, No: 24.19.11)
Aim: The aim of this study was to investigate the bone structure of patients with ectodermal dysplasia (ED) using radiomorphometric indexes and fractal analysis (FA) on dental panoramic radiographs (DPR) and to perform comparisons with a healthy control group.
Material and Methods: The DPRs of a total of 38 patients, including 19 patients with ED and 19 healthy controls, were used in this study. Fractal dimension (FD), panoramic mandibular index (PMI), mental index (MI), and mandibular cortical index (MCI) were measured on the DPRs.
Results: There was no significant relationship between gender and MI, PMI, and FD values. The distribution of FD, MI, and PMI measurements according to ED showed that MI and PMI values showed statistically significant differences (MI: p=0.023, PMI: p=0.003). While ROI1-r and ROI1-l FD values showed a significant difference between the group with ED and the control group (p=0.001, p=0.002, respectively), FD measurements in ROI2-r/l and ROI3-r/l regions did not show a statistically significant difference between the groups. There was a statistically significant difference between the group with ED and the control group in terms of MCI (p=0.029). There was no significant difference between MCI and other parameters (p>0.05).
Discussion: Differences in FD and radiomorphometric indexes observed between patients with ED and healthy controls indicate the impact of ED on mandibular bone structure.
Keywords: Ectodermal Dysplasia, Dental Panoramic Radiograph, Fractal Analysis, Radiomorphometric Indexes
Introduction
Ectodermal dysplasia (ED) refers to a group of diseases that include congenital defects of tissues such as sweat glands, hair, nails, and teeth originating from the ectoderm [1]. In general, it is characterized by hypotrichosis, hypohidrosis, anodontia, and hypodontia. Findings such as anodontia, hypodontia, conical teeth, loss of vertical dimension in the upper and lower jaws, sagittal growth retardation in the jaws, alveolar ridge deficiency, and cleft lip and palate may also be observed in individuals with ED [2].
Removable partial dentures, total dentures, and overdenture prostheses are the most preferred treatment methods in the treatment of tooth deficiency in ED patients because they can be applied easily and cheaply. A high success rate is also seen in implant surgery in ED cases [3]. In the treatment planning of dental implants, it is very important to determine whether the existing jawbone is sufficient to place the implants. In these treatment interventions, two- or three-dimensional imaging methods can be used to determine the amount and quality of bone [1, 3].
Dental panoramic radiographs (DPRs), which have limitations such as distortion, magnification, and superposition due to their two-dimensionality, are a routinely used imaging method in dentistry due to their advantages such as cost-effectiveness and low-dose radiation. In addition to demonstrating changes in teeth, DPRs can also be used to evaluate structural changes in trabecular bone [4].
Radiomorphometric indexes such as mental index (MI), panoramic mandibular index (PMI), and mandibular cortical index (MCI) applied to DPRs are useful methods for estimating bone mineral density (BMD). MCI is related to the BMD of the mandible and refers to the appearance of the mandibular subcortex. MI or mandibular cortical width (MCW) refers to the width between the upper border of the mandibular cortical layer and the lower border of the mandible. PMI is the ratio of the measurements obtained by dividing the height of the lower mandibular cortex by the vertical measurement between the lower border of the mandible and the lower and upper border of the mental foramen [5]. Additionally, fractal dimension (FD) analysis of trabecular bone in DPRs can be utilized to evaluate mandibular bone structure [6].
FD analysis, which is a mathematical method used for the measurement of complex structures such as trabecular bone, has been used for a long time to evaluate changes in bone structures in various systemic diseases. Fractal analysis (FA) is frequently applied in dentistry to quantitatively describe the quality of bone tissue and to examine early changes in alveolar bone and mandibular trabecular architecture [6, 7].
In individuals diagnosed with ED; while improving function, phonation, and aesthetics, the dental treatments offered should support normal growth and development. Quantitative evaluation of bone structure in prosthetic treatment and implant planning in individuals with ED is very important for choosing the right treatment.
The purpose of this study is to evaluate the bone structure using some radiomorphometric indexes and FD analysis on DPRs in patients with ED and to guide the clinicians.
Material and Methods
This retrospective analysis was performed on DPR archive images of ectodermal dysplasia cases admitted to Harran University, Faculty of Dentistry. A total of 38 people, including 19 individuals diagnosed with ectodermal dysplasia and 19 healthy individuals, were included in the study. The control group was selected from the DPR images of healthy individuals who did not have any disease affecting bone metabolism and did not have any missing teeth, lesions, cysts, or tumors that could cause bone destruction in the lower jaw.
All DPRs in the study were obtained using the same digital panoramic X-ray device with 70 kVp, 5 mA, and 15 s exposure time parameters, and radiographs without diagnostic capability due to imprecise patient positioning or exposure errors were excluded from the study. The measured parameters (MCI, MI and PMI) were evaluated separately for each half jaw.
Panoramic morphometric indexes
MCI (Klemetti index): The classification of cortical depiction along the lower mandibular border beyond the bilateral mental foramina is organized into three distinct groups. The category of MCI for each patient was described as the worst of the categories on each side (Figure 1):
• C1: The endosteal border of the mandibular cortex appears to have a sharp and smooth contour.
• C2: The endosteal ridge of the mandibular cortex displays lamellar resorption with persistent endosteal fragments, widely characterized as crescentic disease.
• C3: The endosteal border of the mandibular cortex demonstrates marked porosity with the presence of substantial endosteal debris [6].
MI or MCW: It was obtained by measuring the mandibular cortical thickness on a line passing through the center of the mental foramen and perpendicular to the base of the mandible. The mean value was taken by measuring on both sides (Figure 2) (a) [6, 7].
PMI: The ratio of the MI to the distance between the inferior border of the mental foramen and the inferior border of the mandibular cortex was measured as the panoramic mandibular index (Figure 2) (a/b) [7].
Fractal Analysis
Six regions of interest (ROI) were chosen from DPRs. ROI1-r was defined as a 40 x 40-pixel square at the geometric center of the area between the right mandibular notch and the mandibular foramen. ROI2-r was determined as the geometric center of the right mandibular angle, a square of 60 × 60 pixels. ROI3-r was designated as a 40 x 40 pixel square anterior to the right mental foramen, at the same level and in the region without any tooth root or lamina dura (Fig. 2). ROI1-l, ROI2-l, and ROI3-l were also selected from the left mandibular side.
Following ROI selection, the image was replicated (Figure 3a). A Gaussian filter was subsequently imposed on the image to produce a blurred effect (Figure 3b). The resultant blurred image was thereafter extracted from the original image (Figure 3c). In order to improve particular properties of various brightness, such as trabeculae and bone marrow, an image was composed by adding 128 gray values at each pixel position (Figure 3d). Thresholding the image at 128 brightness values also resulted in binarization (Figure 3e). To decrease noise, the binary image was processed by erosion and expansion (Figure 3f, 3g). The image was then reversed, making the regions representative of trabeculae black and the bone marrow white (Figure 3h). Eventually, the image was processed through a skeletonization process that incrementally erodes the pixels until only a central pixel line remains (Figure 3i). The software utilizes a box-counting algorithm that divides the image into squares of 2, 3, 4, 4, 6, 8, 12, 16, 32, and 64 pixels (Figure 3). Several squares containing trabeculae and the total number of frames were calculated for each pixel size. The obtained values were then plotted on a logarithmic scale graph. The slope of the line drawn through the plotted points on the graph yielded the FD value.
All measurements were completed by two dentomaxillofacial radiologists, one with 6 years of experience (EMA) and one with 8 years of experience (SK). The mean FD values of ROI1, ROI2, and ROI3 were determined. It was reviewed by the same observers two weeks after the initial evaluation to assess intra- and inter-observer agreement.
The kappa statistics was applied to calculate the inter-observer and intra-observer agreement. Statistical analyzes were calculated using the SPSS 23.0 (SPSS, Chicago, IL, USA) package program. Normality of the data was confirmed by the Shapiro Wilk test. Independent Samples T test was used to compare all parameters between groups. Relationships between categorical variables were calculated with the Pearson Chi-square test. G power 3.1.9.2 software was used to determine the sample size.
Ethical Approval
This study was approved by the Harran University Ethics Committee (Date: 2024-12-02, No: 24.19.11) and was conducted in accordance with the Principles of the Declaration of Helsinki.
Results
All the evaluations were excellent for the intra- and interobserver correlations (0.88). The mean age of the study group and control group was 12.39±5.5 years and 9.16±3.3 years. No significant difference was found in the age of the two groups (p > 0.05).
When the relationship between gender and radiomorphometric indexes and FD was examined; there was no significant relationship between MI, PMI, and FD values. While ROI2-l demonstrated a significant difference between genders with the measured FD value (p=0.032); ROI1-r/l, ROI2-r, and ROI3-r/l FD values did not show a statistically significant difference according to gender (p > 0.05) (Table 1).
Regarding the distribution of FD, MI, and PMI measurements according to the patient group; MI and PMI were detected to have a statistically significant difference on both the right and left sides (right MI: p=0.027, left MI: p=0.019, right PMI: p=0.005, left PMI: p=0.001). ROI1-r and ROI1-l FD values differed significantly between the patient and control groups (p=0.001, p=0.002 respectively), while FD measurements in ROI2-r/l and ROI3-r/l regions did not display a statistically meaningful difference between the patient and control groups (Table 2).
When we analyzed the distribution of MCI; C1 42.1%, C2 47.4%, C3 10.5% in the ED group; C1 73.7%, C2 26.3%, C3 0.0% in the control group. There was a statistically significant difference between the patient group with ED and the control group in terms of MCI (p=0.029). No significant difference was detected between MCI and other parameters (p>0.05).
Discussion
FA has gained popularity for the detection of potential abnormalities and assessment of the severity of the existing disorders in bone structure. FD calculated on two-dimensional radiographs is very beneficial in revealing changes in bone architecture and density [6, 8].
It is known that the bone structure of ED patients is differentfrom healthy people and these differences play an important role in accurate diagnosis and treatment. For this reason, the need to determine the bone quality of patients with ED by a quantitative and easily applicable diagnostic method has emerged [2, 9, 10]. In the current study, a statistically significant difference was observed between the ED and control groups in ROI1 and all FD values were higher in the control group than in the ED group. To the best of our knowledge, there is no previous study in the literature evaluating bone structure in patients with ED using FA.
In the study conducted by Demiralp et al. [6] with DPR, it was reported that FD findings were higher in patients using bisphosphonates. Duyan Yüksel et al. [11] reported that FD was lower in patients with phenylketonuria compared to the control group. Similarly, Gümüşsoy et al. [12] found that FD was lower in patients with chronic renal failure compared to the control group. In this study, the mean FD was lower in patients with ED compared to the control group, and the FD measured in the region between the mandibular notch and mandibular foramen in these patients was statistically significantly different. The FD values may have decreased in ED patients due to dysfunction in the jaws caused by hypodontia or anodontia. In future studies, more comprehensive data can be obtained by comparing FD values before and after prosthodontic treatment.
In studies examining the effect of gender on FD, it is generally observed that FD values are lower in females than in males. Kayıpmaz et al. [13] examined the trabecular structure of the condyle region with FA in CBCT images of 70 participants, 35 healthy individuals, and 35 patients with TMJ arthritis. It was concluded that females had smaller FA values than males. Arsan et al. [8] investigated the trabecular structure of the mandibular condyle in a study using DPRs and FA and concluded that the mean FD value was higher in males than females. Alman et al. [14] attributed the lower FD values of women to the increase in bone resorption due to the effect of prolactin and estrogen hormones. In this study, FD values in males were higher than in females and this result supports the literature. Higher FD values in males may be related to more complex trabecular structures.
In the literature, it is known that FD values are lower in older age groups [15]. Ling et al. [16] analyzed the trabecular bone structure with CBCT and reported a significant difference in fractal measurements in all age groups and genders. In Demiralp et al. study [6], there was no significant correlation between age and FD values of bisphosphonate users. In this study, no significant correlation was found between age and FD values.
Panoramic radiomorphometric indexes are one of the prediagnostic tools for osteoporotic changes. In prior studies, mandibular bone density has been reported to correlate well with overall skeletal bone mass, and panoramic radiomorphometric indexes have been used to predict the diagnosis of osteoporosis [17]. As far as we know, there was no study in the literature comparing FD analysis with MI, PMI, and MCI index values in DPRs of patients with ED and healthy control subjects. Several studies have revealed that individuals with osteoporotic bone structure have lower MI values than healthy individuals, and patients with low MI values have been found to be affected and correlated with MCI [12, 18-20]. Hastar et al. [21] in a study of 487 elderly patients revealed that the presence of teeth was statistically significantly associated with MI and PMI parameters and the MI and PMI values of edentulous patients were considerably lower; furthermore, according to tooth status, partially edentulous and edentulous patients had more osteoporosis. Gülşahi et al. [22] found that dentition is an important parameter for MCI and that being edentulous or partially edentulous substantially raised the proportion of individuals in the C3 category compared to patients with full dentition. In the present study, it was statistically significant that the mean values of MI and PMI were lower in patients with ED compared to the healthy group. In MCI, the occurrence of C2 and C3 was observed at a high and significant rate in patients with ED. It was thought that this result developed due to resorption of the cortical bone in the lower jaw due to the lack of teeth in patients with ED.
The lack of dental support in patients with ED diminishes the functional stimulation of the jawbone. Removable prostheses are the most widely preferred treatment of choice in patients with EDs due to the simplicity of modification or replacement during growth. The optimal time for dental implant placement is still controversial [23]. Prior to prosthetic treatment planning, we consider that evaluating the crest heights of patients with EDs with the help of radiomorphometric indixes will affect the treatment prognosis.
Limitation
The major limitation of this study is the limited number of patients included owing to the fact that it was a congenital defect, which prevented some relationships from reaching statistical significance. Another limitation of the current study is that we were not able to examine the effect of functional use on FA. Thus, it is recommended that further multicenter and multidisciplinary studies with a larger sample group should be conducted to examine the long-term effects of prosthodontic treatments.
Conclusion
In this study, the trabecular structure of the jawbone in patients with ED was analyzed and the differences in FD and radiomorphometric index were shown in comparison with the healthy control group. Using FA and PMI, MCI, and MI in DPR, which is one of the common radiographic methods in dentistry and maxillofacial imaging, plays an important role in the diagnosis, prosthetic treatment, and follow-up of patients with ED.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Elif Meltem Aslan, Sedef Kotanlı, Aslıhan Artaş, Mehmet Veysel Kotanlı. Evaluation of mandibular bone structure in patients with ectodermal dysplasia. Ann Clin Anal Med 2025;16(Suppl 1):S64-68
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Complications following indwelling catheter placement: A retrospective evaluation of clinical outcomes
Oguz Arslanturk, Ali Kemal Gur
Department of Cardiovascular Surgery, Faculty of Medicine, Bulent Ecevit University, Zonguldak Turkey
DOI: 10.4328/ACAM.22639 Received: 2025-03-09 Accepted: 2025-03-24 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S69-73
Corresponding Author: Oguz Arslanturk, Department of Cardiovascular Surgery, Faculty of Medicine, Bulent Ecevit University, Zonguldak Turkey. E-mail: dr.arslanturk@gmail.com P: +90 539 561 38 87 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4047-9656
Other Authors ORCID ID: Ali Kemal Gur, https://orcid.org/0000-0002-6460-4941
This study was approved by the Ethics Committee of Bulent Ecevit University (Date: 2024-12-04, No:2024/21-16)
Aim: Indwelling central venous catheters (ICVCs) are indispensable for long-term vascular access, yet their placement is associated with significant complications. Understanding the temporal distribution and risk factors for these complications is crucial for optimizing catheter management.
Material and Methods: This retrospective cohort study evaluated 150 patients who underwent ICVC placement between November 2017 and November 2024. Patients were followed for six months to assess early (≤24 hours) and late (>24 hours) complications. Complications were categorized as thrombotic, infectious, or mechanical. Multivariate analysis was performed to identify independent risk factors influencing adverse outcomes.
Results: Complications occurred in 46% of patients, with early events in 12% late complications in 34%. Thrombotic events (13.3%) were the most common late complication, with superior vena cava thrombosis occurring in 12%. Catheter occlusion (5.3%) developed exclusively in the late phase, with 37.5% of cases occurring between 1–2 months and 62.5% beyond 3 months. Subclavian vein catheterization was associated with a significantly higher complication rate (42.0%) compared to internal jugular vein placement (52.3% vs. 79.0%, p<0.001). Diabetes mellitus (p<0.001) and chronic renal failure (p<0.001) were the strongest predictors of catheter-related complications.
Discussion: This analysis recalibrates our understanding of ICVC complications, revealing thrombotic sequelae, not infectious events, as the predominant adverse outcomes. The identification of diabetes, renal dysfunction, and subclavian insertion as independently modifiable risk determinants establishes a framework for prophylactic optimization. These findings argue for preferential internal jugular cannulation, enhanced thromboprophylaxis strategies, and intensified surveillance for patients with metabolic and renal comorbidities.
Keywords: Central Venous Catheters, Thrombosis, Catheter Occlusion, Complications, Indwelling Catheters
Introduction
Indwelling central venous catheters (ICVCs) are essential in modern medicine, offering reliable venous access for laboratory tests, drug administration, and parenteral nutrition, particularly in patients with chronic diseases [1]. Despite their advantages, the placement and maintenance of ICVCs pose risks of significant complications [2]. ICVC complications are classified as early or late, depending on their onset after placement [3]. Mechanical obstruction, precipitation of drugs or parenteral nutrition preparations, or thrombotic obstruction are common causes of catheter occlusion. Catheter occlusion occurs in 50 percent of children and 66 percent of adults with long-term ICVCs and can lead to long-term vascular complications [4, 7]. Thrombotic occlusions impair catheter performance and contribute to serious complications, such as pulmonary embolism, infection, and post-thrombotic syndrome, increasing the complexity of long-term patient care [7, 9]. Thrombosis, in particular, has been identified as an important contributing factor to catheter-associated infections, as thrombotic sites provide a favorable environment for microbial colonization [10]. Cardiac, vascular, pulmonary, and catheter insertion complications that occur during or immediately after indwelling central venous catheter placement are referred to as emergency complications. Rapid recognition and management of emergent complications are very important as they can often be life-threatening [11]. Given the diverse range of complications associated with ICVCs, a thorough understanding of their risks, incidence, and clinical outcomes is essential for optimizing patient management. Retrospective studies provide a valuable means to analyze large patient cohorts, offering critical insights into complication rates, risk factors, and outcomes that shape clinical decision-making. This study retrospectively evaluates the incidence and nature of ICVC-related complications, with a particular focus on thrombosis, infection, and mechanical failure. By identifying key risk factors and associated outcomes, our findings aim to contribute to the development of preventive strategies and the refinement of management approaches for patients requiring long-term ICVCs.
Material and Methods
Study Design
This retrospective cohort study analyzed data from patients who underwent indwelling central venous catheter (ICVC) placement between November 2017 and November 2024. The primary objective was to assess the incidence and classification of ICVC-related complications and to identify potential risk factors contributing to their occurrence. Ethical approval was granted by the Local University Clinical Research Ethics Committee (Approval Number: 2024/21-16). Given the retrospective nature of the study, informed consent was not required. All patient data were fully anonymized to maintain confidentiality and comply with ethical standards. The selection of catheter insertion sites was reviewed retrospectively based on medical records. The right internal jugular vein (anterior or central approach) was the most commonly utilized site for catheter placement. In cases where previous catheterization had resulted in thrombosis or stenosis, the left internal jugular vein was used. If neither jugular vein was available, the subclavian vein was selected as the next option. The femoral vein was cannulated only when all other venous access sites were occluded.
Catheter placement was performed under aseptic conditions in an operating theater, as documented in procedural records. Fluoroscopy guidance was used to facilitate guidewire positioning and ensure optimal catheter tip placement. Following insertion, a post-procedural chest X-ray was routinely performed to confirm catheter positioning and detect potential complications such as malposition, pneumothorax, or hemothorax. Data regarding catheter insertion techniques, imaging verification, and early procedural complications were collected from hospital records and systematically analyzed.
Patient Selection and Data Collection
Eligible patients were those who had documented indwelling central venous catheter (ICVC) placement, including dialysis catheters, for long-term use, as recorded in hospital databases. Inclusion criteria encompassed adult patients who required ICVCs for extended venous access due to medical conditions necessitating prolonged intravenous therapy, such as hemodialysis, total parenteral nutrition, or long-term antibiotic administration. Patients with totally implantable venous access devices (ports) were excluded from the study. Patients were excluded if they had incomplete or missing medical records, preventing comprehensive data analysis. Additionally, those with pre-existing ICVC-related complications before study enrollment were excluded to ensure that only newly developed complications were assessed. Patients who had ICVCs placed for short-term or emergency indications (<7 days), including acute resuscitation or temporary perioperative use, were also omitted, as their complication profiles may differ from long-term catheter use.
Relevant clinical data were systematically extracted from electronic medical records, ensuring consistency and completeness. Collected variables included patient demographics (age, sex, and underlying comorbidities such as malignancy, diabetes, and chronic kidney disease), catheter-related characteristics (type, insertion site, and duration of use), and recorded complications. Complications were classified into thrombotic (e.g., catheter-related thrombosis, deep vein thrombosis), infectious (e.g., catheter-associated bloodstream infections), and mechanical (e.g., occlusion, dislodgement, or breakage). Each complication was confirmed based on established clinical criteria, ensuring standardization in reporting. To protect patient confidentiality, all data were anonymized, and access was restricted to authorized study investigators in accordance with ethical guidelines.
Classification of Complications
Complications in this study were classified as early (urgent) or late, based on their onset relative to catheter placement. Early complications were defined as adverse events occurring within the first 24 hours post-insertion and included cardiovascular, vascular, and pulmonary complications such as cardiac arrhythmias, arterial puncture, hematoma formation, and pneumothorax. These complications were considered procedure-related and required immediate intervention. In contrast, late complications were defined as adverse events developing over prolonged catheter use and were categorized into thrombotic, infectious, and mechanical failures. Thrombotic complications included superior vena cava thrombosis, deep vein thrombosis, and fibrin sheath formation, confirmed via radiological imaging. Infectious complications primarily involved catheter-associated bloodstream infections (CABSI), diagnosed through positive blood cultures and associated clinical symptoms such as fever and leukocytosis. Mechanical failures encompassed catheter occlusion, dislodgement, migration, and fracture, which often required catheter removal or replacement. Additionally, dialysis catheter-related complications, including catheter-related bloodstream infections (CRBSI) and superior vena cava thrombosis (SVC thrombosis), were analyzed separately due to their distinct risk profile compared to other ICVCs. This classification framework allowed for a comprehensive evaluation of complication incidence and risk factors, distinguishing immediate procedural risks from long-term device-related complications.
Follow-up and Outcome Assessment
Patients were followed for a minimum period of 6 months post-catheter insertion to assess early and late complications. Clinical evaluations were performed at 1 week, 1 month, 3 months, and 6 months to document mechanical, thrombotic, and infectious complications. Catheter patency was assessed through clinical examination and radiological imaging when necessary. Cases of suspected infection were confirmed via blood cultures, and thrombotic events were verified with Doppler ultrasound or computed tomography venography (CTV). The follow-up period was extended for dialysis catheter patients, given the higher risk of late complications.
Statistical analysis
IBM® SPSS® Statistics version 25 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. The distribution of numerical data was assessed using the Kolmogorov–Smirnov test. The chi-square test was employed for comparisons involving categorical variables. A normal distribution was found for survival groups, and comparisons were conducted using Student’s t-test. Qualitative data were presented as frequency and percentage, while continuous data were expressed as mean and standard deviation (SD) for parametric values.
Ethical Approval
This study was approved by the ethics committee of Zonguldak Bulent Ecevit University (Date: 2024-12-04, No:2024/21-16).
Results
A total of 150 patients were included in the analysis, comprising 90 males (60%) and 60 females (40%), with a mean age of 65.4 ± 12.3 years. The predominant comorbidities were hypertension (50%), chronic kidney disease (36.6%), and diabetes mellitus (30%) (Table 1). Central venous catheters were primarily inserted in the internal jugular vein (66.7%), followed by the subclavian vein (26.6%) and femoral vein (6.6%). Dialysis catheters constituted 70% of all insertions, with a mean duration of use of 128 ± 45 days. Complications were observed in 69 patients (46%), with early complications occurring in 12% of cases and late complications in 34%. The most frequent early complications included arrhythmia (3.3%) and arterial puncture (2.7%). Among late complications, thrombotic events were most common (13.3%), particularly superior vena cava thrombosis (12.0%) (Figure 1), followed by catheter-associated bloodstream infections (8.0%) and mechanical complications such as occlusion (5.3%) (Table 2). When comparing patients with complications (n=69) to those without (n=81), significant differences were observed in certain clinical parameters. Diabetes mellitus was significantly more prevalent in the complications group (46.3% vs. 16.0%, p<0.001). Similarly, chronic renal failure showed a strong association with complication development (56.5% vs. 19.7%, p<0.001). Catheter insertion site analysis revealed significant variations in complication rates (p<0.001). Notably, subclavian vein catheterization was associated with a higher rate of complications (42.0% in the complications group vs. 13.5% in the non-complications group). Conversely, internal jugular vein placement showed a protective effect, with significantly lower representation in the complications group (52.3%) compared to the non-complications group (79.0%). Femoral vein catheterization demonstrated comparable complication rates between groups (5.7% vs. 7.5%) (Table 3). All 8 cases of catheter occlusion were classified as late complications, occurring beyond 1 week post-insertion. Among these, 3 patients (37.5%) developed occlusion between 1 month and 2 months, primarily due to fibrin sheath formation or thrombotic deposits. The remaining 5 cases (62.5%) occurred beyond 3 months, suggesting chronic thrombotic occlusion or progressive lumen narrowing. No significant differences were observed between groups regarding gender, hypertension, malignancy history, cardiovascular disease, age, or catheter duration of use. Although not reaching statistical significance, dialysis catheters were less frequently associated with complications (65.2% vs. 74.0%, p=0.053).
Discussion
The demographic transition toward extended longevity has necessitated comprehensive revisions of therapeutic algorithms to address the evolving pathophysiological profiles encountered in contemporary clinical practice [12, 13]. This population aging trend has driven increased utilization of indwelling central venous catheters as more patients require long-term vascular access for chronic disease management. Our investigation reveals a substantial burden of ICVC-associated adverse events affecting nearly half the cohort, which warrants critical reflection on existing preventive strategies and risk mitigation protocol. Our temporal bifurcation of complications into early (12%) and late (34%) manifestations elucidates distinct pathophysiological processes with implications for surveillance strategies (Figure 2). Procedure-associated events, principally arrhythmias (3.3%) and arterial puncture (2.7%) exhibited lower incidence than previously reported ranges [14, 15], potentially attributable to standardized procedural protocols and advanced imaging guidance employed at our institution.
Multivariate analysis demonstrated that diabetes mellitus and chronic renal failure significantly amplified complication risk (p<0.001), establishing a multifactorial causality model wherein systemic vascular pathology precipitates localized catheter-associated adverse events. This relationship suggests that extrapolating complication risk exclusively from technical parameters offers insufficient predictive value without integrating patient-specific comorbidity profiles.
Anatomical selection for catheter placement emerged as a determinant variable with substantial clinical implications (p<0.001). The subclavian approach demonstrated substantially higher complication rates (42.0% versus 13.5% in non-complication cohorts), while internal jugular placement conferred protective effects (52.3% versus 79.0%). These findings align with Develter’s identification of the right internal jugular vein as the optimal placement site [16], yet interestingly, we did not observe their reported increase in bacteremia risk. This anatomical risk dichotomy challenges conventional approaches to access site selection and argues for preferential internal jugular placement unless anatomically contraindicated.
Our findings complement Hammoumi et al.’s observations in 1460 patients, where site-specific complications included subcutaneous hematoma, pneumothorax, and catheter distortion in the costoclavicular region [17], further emphasizing the critical importance of site selection and meticulous technique. Our documented occlusion rate of 5.3% represents a striking departure from published incidences of 14 to 36% [18-21]. Rather than reflecting superior preventive efficacy, this discrepancy likely stems from our circumscribed 6-month surveillance window. The temporal progression pattern, 37.5% of occlusions emerging between months 1 to 2 and 62.5% developing beyond month 3, suggests an acceleration of occlusive pathology with extended catheter dwell time. This temporal signature aligns with Pietro’s observation that vascular access complications peak in the first 3 to 6 months following placement [22], though our data suggest a more protracted vulnerability window. Other investigators have similarly noted that catheter-related complications demonstrate the highest incidence within the first 90 days after insertion, particularly in patients with central venous and hemodialysis catheters [23], reinforcing the critical importance of intensive surveillance during this high-risk period.
Our study exhibits several methodological strengths, including comprehensive complication classification, standardized assessment protocols, and rigorous statistical analysis. Nevertheless, inherent limitations warrant acknowledgment. The retrospective design introduces potential selection bias and variability in documentation quality. The 6-month follow-up window, while pragmatically necessary, likely underestimates the cumulative complication burden, particularly for complications demonstrating exponential temporal distribution patterns. Additionally, our sample size, while adequate for primary outcome assessment, may limit statistical power for subgroup analyses. These findings carry significant clinical implications. First, they establish a hierarchy of modifiable risk factors: insertion site selection represents the most readily addressable parameter, followed by enhanced surveillance for patients with diabetes and renal dysfunction. Second, they highlight the need for extended thromboprophylaxis strategies, particularly for catheters expected to remain in situ beyond 3 months. Finally, they suggest that complication prevention must evolve from procedural excellence alone toward integrated patient catheter optimization paradigms that account for the complex interplay between systemic pathophysiology and localized vascular access.
Conclusion
Our findings reframe the conceptualization of ICVC complications from primarily infectious and technical challenges toward a more nuanced understanding dominated by thrombotic sequelae and fundamentally shaped by insertion site selection and patient-specific comorbidities. This paradigm shift necessitates recalibration of prevention strategies toward anatomical optimization and targeted prophylaxis for high-risk subpopulations.
Limitation
Despite methodological rigor, our investigation confronts inescapable constraints. The retrospective architecture inherently introduces recall asymmetry and documentation heterogeneity that elude statistical correction. Our circumscribed 6-month surveillance horizon truncates complication trajectories, potentially obscuring late manifestations that emerge beyond this temporal boundary. The monocentric framework limits extrapolation to institutions with divergent procedural protocols or patient demographics. While our cohort (n=150) adequately powered primary analyses, granular subclassification analyses suffered diminished statistical resolution. The exclusion paradigm for patients with preexisting complications, while methodologically necessary, potentially filtered a subpopulation with distinct risk signatures. These limitations notwithstanding, our findings illuminate critical insights into ICVC complication pathogenesis and prophylaxis optimization.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
References
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2. Eastridge BJ, Lefor AT. Complications of indwelling venous access devices in cancer patients. J Clin Oncol. 1995;13(1):233-8.
3. Rosovsky RP, Kuter DJ. Catheter-Related Thrombosis in cancer patients: pathophysiology, diagnosis, and management. Hematol Oncol Clin North Am. 2005;19(1):183-202.
4. Balestreri L, De Cicco M, Matovic M, Coran F, Morassut S. Central venous catheter-related thrombosis in clinically asymptomatic oncologic patients: A phlebographic study. Eur J Radiol. 1995;20(2):108-11.
5. Journeycake JM, Buchanan GR. Thrombotic complications of central venous catheters in children. Curr Opin Hematol. 2003;10(5):369-74.
6. van Rooden CJ, Tesselaar ME, Osanto S, Rosendaal FR, Huisman MV. Deep vein thrombosis associated with central venous catheters-a review. J Thromb Haemost. 2005;3(11):2409-19.
7. Rosovsky RP, Kuter DJ. Catheter-related thrombosis in cancer patients: pathophysiology, diagnosis, and management. Hematol Oncol Clin. 2005;19(1):183-202.
8. Boersma R, Jie K-S, Verbon A, Van Pampus E, Schouten H. Thrombotic and infectious complications of central venous catheters in patients with hematological malignancies. Ann Oncol. 2008;19(3):433-42.
9. Wilimas JA, Hudson M, Rao B, Luo X, Lott L, Kaste SC. Late vascular occlusion of central lines in pediatric malignancies. Pediatrics. 1998;101(2):e7.
10. Barzaghi A, Dell’Orto M, Rovelli A, Rizzari C, Colombini A, Uderzo C. Central venous catheter clots: incidence, clinical significance and catheter care in patients with hematologic malignancies. Pediatr Hematol Oncol. 1995;12(3):243-50.
11. Kornbau C, Lee KC, Hughes GD, Firstenberg MS. Central line complications. Int J Crit Illn Inj Sci. 2015;5(3):170-8.
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17. El Hammoumi M, El Ouazni M, Arsalane A, El Oueriachi F, Mansouri H, Kabiri el H. Incidents and complications of permanent venous central access systems: a series of 1,460 cases. Korean J Thorac Cardiovasc Surg. 2014;47(2):117-23.
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Oguz Arslanturk, Ali Kemal Gur. Complications following indwelling catheter placement: A retrospective evaluation of clinical outcomes. Ann Clin Anal Med 2025;16(Suppl 1):S69-73
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Propriospinal myoclonus following spinal anesthesia for knee arthroscopy
Emine Aslanlar, Ali Sevgili, Elif Eldeniz Demircioğlu, Zuhal Çakıcı, Derviş Güzel, İnci Kara
Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey
DOI: 10.4328/ACAM.22286 Received: 2024-05-27 Accepted: 2024-07-09 Published Online: 2024-10-21 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S74-76
Corresponding Author: Emine Aslanlar, Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey. E-mail: draslanlar@gmail.com P: +90 555 621 98 30 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3849-9137
Other Authors ORCID ID: Ali Sevgili, https://orcid.org/0000-0003-1409-7627 . Elif Eldeniz Demirciğolu, https://orcid.org/0009-0002-4254-8827 . Zuhal Çakici, https://orcid.org/0009-0002-9639-1669 . Derviş Güzel, https://orcid.org/0009-0008-4868-0646 . İnci Kara, https://orcid.org/0000-0001-6546-4277
Spinal myoclonus (SM) after neuraxial anesthesia is a rare but distressing complication for anesthesiologist. Propriospinal myoclonus, a variant of spinal myoclonus, is even rarer and is a disorder characterized by sudden, shock-like, involuntary jerks originating from axial muscles.
We present a case of a patient who developed propriospinal myoclonus 135 minutes after spinal anesthesia.
Arthroscopy under spinal anaesthesia was planned for a patient with meniscopathy. Spinal anaesthesia was performed with 10 mg hyperbaric bupivacaine and 100 mcg morphine. Myoclonic movements in the upper extremities and trunk of the patient started 135 minutes after spinal anaesthesia. Diazepam 10 mg slow bolus followed by 10 mg/30 min infusion was administered and the frequency of myoclonic movements decreased but did not completely disappear. Diazepam infusion was repeated and myoclonic movements disappeared approximately 6 hours after spinal anaesthesia.
In conclusion, anesthesiologists should be aware that this rare condition is a temporary complication with no sequelae.
Keywords: Arthroscopy, Myoclonus, Propriospinal Myoclonus, Spinal Anesthesia
Introduction
Spinal anesthesia is very common in daily anesthesia practice, due to its advantage such as protection from airway complications. Anaesthesiologist may encounter rare but serious neurological complications of spinal anaesthesia. One of these complications is Spinal Myoklonus following Neuroaxiel Anesthesia (SM-NA) and only 23 cases have been reported in the literature so far. SM-NA is a movement disorder originating in the spinal cord and causes transient myoclonic involuntary movements of the extremities or trunk [1].
Spinal myoklonus is of two types, segmental and propriospinal myoklonus. Propriospinal myoclonus is a rare disorder characterized by sudden, shock-like, involuntary jerks that arise from the axial muscles and spread both rostrally and caudally to other myotomes through slow polysynaptic pathways. It can be secondary to spinal cord lesions; additionally, it can develop as an adverse effect to the administration of several drugs, including neuraxial local anesthetics [2].
We aimed to present a patient who underwent spinal anaesthesia for meniscopathy surgery and developed SM-NA. The aim of this case report is to enable anaesthesiologists to recognise SM-NA, which is a rare complication, and to draw attention to the fact that benzodiazepines can be used to suppress symptoms, although they do not provide a complete cure. Informed consent was obtained from the patient.
Case Report
A 34-year-old, 175 cm, 97 kg male patient was diagnosed with meniscopathy and arthroscopy was planned. The patient had a history of inguinal hernia operation under spinal anesthesia 1 year ago, thyroidectomy operation 6 years ago and levothyronine use. Preoperative laboratory values were within normal limits. Standart monitoring (ECG, SpO2, non-invasive blood pressure) was performed. After antisepsis in the sitting position, 10 mg hyperbaric bupivacaine and 100 mcg morphine were administered intrathecally. After intrathecal injection, the sensory block level was evaluated as T6 dermatome and the patient was delivered to surgery. The patient’s vital signs were stable during surgery and no additional medication was administered. After the 135-minute surgical procedure was completed, myoclonic movements started in the patient’s upper extremities and trunk. At this time, the patient was conscious and cooperative. Blood gas and biochemical tests were repeated and no abnormality was found in the new results. The patient was given 2 mg midazolam two times. Myoclonic movements started to be seen in the lower extremities approximately 1 hour later. Neurology was consulted and neurologist recommended diazepam 10 mg slow bolus followed by diazepam 10 mg/30 min infusion and ordered Electroencephalography (EEG) and brain magnetic resonance imaging (MRI) to investigate the etiology. The frequency of myoclonic movements decreased considerably after diazepam. The patient, who was always conscious during this period, was transferred to the Intensive Care Unit (ICU). 10 mg diazepam was infused again in 1 hour and the myoclonic movements stopped completely in ICU. The patient was checked daily until discharge and no abnormal neurologic findings were observed. The patient was followed up by neurology and epileptiform changes were observed in the EEG taken 1 week later. 2 months later, MRI revealed that “the temporal horns of the lateral ventricles were more prominent on the left side in the coronal oblique sections taken from the hippocampus and temporal lobe. The volume of the hippocampus was slightly decreased, more prominent on the left”. The neurologist stated that this structural abnormality was not a factor in the development of myoclonus. The patient who had no neurologic symptoms in the last 3 months was not started any drug treatment by the neurologist.
Discussion
Myoclonus is the involuntary twitching of muscles that is caused by brief electromyographic discharges. Myoclonus can arise from either the central or peripheral nervous system. Central nervous system myoclonus can originate from cortical, subcortical, brainstem and spinal cord. SM is a type of myoclonus originating from the spinal cord [3, 4] and is a very rare complication of spinal anesthesia.
The pathophysiology of SM-NA is not fully understood because there is no research showing that local anesthetics act on spinal neurons to produce myoclonus. Based on the reported cases, the most well-established characteristics of SM-NA are that it occurs frequently with hyperbaric local anesthetics, is more common in women, and its occurrence is unpredictable [1].
SM is classified into two types: segmental and propriospinal. Segmental SM typically originates within a few or several adjacent spinal segments, whereas propriospinal SM refers to myoclonic involuntary movements involving muscles innervated by many different segments. Propriospinal SM is extremely rare than segmental SM [5]. The propriospinal route is a pathway for transmitting stimulation among multiple spinal segments. Abnormal impulses originating from the lumbar spinal cord can ascend and spread upward through this pathway, resulting in myoclonic involuntary movements of the upper extremities and trunk [3, 4]. In our case, myoclonic movements were observed both in the extremities and trunk, so we think it is propriospinal myoclonus. Myoclonus in the trunk (17.4%) is more rare than myoclonus in the extremities (30.4%) [1].
Shiratori et al. reported 23 case reports in their literature review. 16 of these patients were female, suggesting that the incidence of SM-NA differs according to gender. SM-NA has been observed at younger ages in females and at older ages in males [1]. A feature that makes our case different is that our patient was a young male. This may be interpreted that the incidence of SM-NA differs according to age as well as gender.
In most of the cases, SM-NA started within the first 3 hours after spinal anesthesia and usually ended within 12 hours. In our case, it started within 3 hours and ended after 6 hours. In 10 cases, recovery occurred spontaneously, while in 13 cases anticonvulsant drugs were empirically administered [1]. In the drug-treated cases, it is not known whether the drug completely cured SM-NA, because the clinical picture improves spontaneously with the resolution of the effect of the local anesthetic. Nevertheless, it has been reported that benzodiazepines may be effective or semi-effective in the rapid suppression of SM-NA. At first, our patient was tried to be treated with midazolam but no response was obtained. On the recommendation of neurology, diazepam 10 mg slow bolus followed by infusion (10 mg/30 min) was started and the frequency of myoclonus decreased but did not stop completely. After taking diazepam again at a rate of 10 mg/hour, the myoclonus stopped. Meanwhile, approximately 6 hours had passed since spinal anesthesia. The cure achieved after 6 hours may also be related to the dissolution of the effect of the local anesthetic.
It has been reported that no abnormal findings were found in patients’ EEG in the middle of the SM-NA event and after the SM-NA passed [2,6]. In our case, EEG could not be taken at the time of the event but generalized epileptiform changes were observed in the EEG taken 1 h later.
The coexistence of reduced activity in the suprasegmental descending inhibitory pathway, increased excitability of inhibitory interneurons, and the abnormal hyperexcitation produced by the recovery of alpha motor neurons in the anterior horn are the mechanisms of SM-NA generation. When diagnosising of SM-NA, the following conditions causing myoclonus may need to be excluded; myoclonus due to neuraxial opioid high dose therapy and drug-induced dystonic movements. Neuraxial opioids can also cause myoclonus as a side effect, but this side effect is more likely to be seen in long-term or high-dose use [7]. In our case, intrathecal morphine was used, but the dose used (100 mcg) was not high and it was a one-time use.
SM-NA can also be confused with drug-induced dystonic movements. Movements in SM-NA are faster than in dystonia and are lightning-like muscle jerks that usually develop in the extremities. Dystonic movements are characterized by sustained muscle contractions that cause abnormal twisting-like movements and postures involving the trunk and limbs, which can also affect the facial muscles. In our patient, there was no abnormal posture and the facial muscles were not affected. The following drugs have been blamed for the etiology of drug-induced dystonic movements; antihistamines, antimalarials, antiseizure medications, calcium channel blockers, cholinergic agonists, lithium, methylphenidate, metoclopramide, selective serotonin reuptake inhibitors, tricyclic antidepressants [8]. But none of these drugs were used in our patient.
Six of the cases reported as SMNA had previously undergone surgery under spinal anesthesia and did not develop myoclonus. Our patient also underwent inguinal hernie operation under spinal anesthesia 1 year ago and did not experience any complications to spinal anesthesia. The occurrence of SM-NA is unpredictable because there are patients diagnosed with SM-NA who did not have any problems in previous spinal anesthesia experiences, and there are also cases where SM-NA did not recur or recurred in subsequent spinal anesthesia applications. It has been reported that a history of SM-NA is not a contraindication for re-NA, but SM-NA recurrence should occur within 1 year after the first episode. When patients who have undergone SM-NA within the last 1 year undergo a new operation, it is recommended to be prepared for possible SM-NA or to choose an anesthesia method other than neuraxial anesthesia [1].
Conclusion
Spinal myoclonus is a very rare, unusual event that can occur after administration of spinal anesthesia. It is a self-limiting adverse event and usually resolves after the drug wears off.
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 compareable ethical standards.
Conflict of interest
The authors declare that there is no conflict of interest.
References
1. Shiratori T, Hotta K, Satoh M. Spinal myoclonus following neuraxial anesthesia: A literature review. J Anesth. 2019;33(1):140-47.
2. Zamidei L, Bandini M, Michelagnoli G, Campostrini R, Consales G. Propriospinal myoclonus following intrathecal bupivacaine in hip surgery: A case report. Minerva Anestesiol. 2010(4);76:290-93.
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Emine Aslanlar, Ali Sevgili, Elif Eldeniz Demircioğlu, Zuhal Çakıcı, Derviş Güzel, İnci Kara. Propriospinal myoclonus following spinal anesthesia for knee arthroscopy. Ann Clin Anal Med 2025;16(Suppl 1):S74-76
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Botulism from ready-made food
Mirkan Bulğak, Tuna Demirdal
Department of Microbiology, Izmir Katip Celebi University, Ataturk Research and Training Hopital, Izmir, Turkey
DOI: 10.4328/ACAM.22418 Received: 2024-09-24 Accepted: 2024-11-04 Published Online: 2024-11-18 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S77-79
Corresponding Author: Mirkan Bulğak, Department of Microbiology, Izmir Katip Celebi University, Ataturk Research and Training Hopital, Izmir, Turkey. E-mail: mirkanbulgak@gmail.com P: +90 532 792 31 79 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3020-9414
Other Author ORCID ID: Tuna Demirdal, https://orcid.org/0000-0002-9046-5666
Botulism is a fatal illness caused by the botulinum toxin produced by Clostridium botulinum. This report describes two cases of botulism linked to ready-to-eat “mantı” from vacuum-sealed pouches. Both patients, a 54-year-old woman and a 54-year-old man, experienced symptoms including diplopia, blurred vision, dysphagia, and respiratory difficulties after consuming the contaminated food. Both cases were diagnosed promptly and treated with botulism antitoxin, leading to significant symptom improvement and recovery. These cases highlight the need for awareness of botulism risks associated with modern food packaging and emphasize the importance of early diagnosis and treatment.
Keywords: Clostridium Botulinum, Neurotoxin, Ready-Made Foods, Antitoxin, Vacuum-Sealed Packaging
Introduction
Botulism is a flaccid paralysis syndrome caused by botulinum neurotoxin (BoNT) produced by Clostridium botulinum (C. botulinum). However, canned foods are generally shown as the source of botulism, in our two cases, ready-made “mantı” sold in vacuum-sealed pouches was determined to be the source of the disease. Therefore, it was considered worthy of presentation. Informed consent forms were obtained from the patients.
Case Report
A 54-year-old female patient with no known chronic disease came to the emergency room with complaints of having a single black stool, diplopia, blurred vision, difficulty swallowing, and difficulty breathing, which started after eating ready-made manti that she bought from the market with her husband the day before. The patient, who was diagnosed with botulism clinically by infectious diseases consultation in the emergency department, was administered botulinum anti-toxin obtained from the public health institution. No pathological findings were detected in brain imaging, and the patient was admitted to the anesthesia intensive care unit. EEG and EMG examinations performed during hospitalization were normal, and abdominal CT was reported as ‘edema and reactive lymph nodes in the small bowel mesentery, this finding is non-specific and supports infective processes.’ The patient’s airway was kept open, and on the 10th day of hospitalization, the complaints of diplopia, diarrhea, and difficulty breathing completely regressed, and the difficulty in swallowing partially improved. The patient, who was transferred to the infectious diseases ward, was able to swallow solid foods after being monitored in the ward for seven days and was discharged with the recommendation of outpatient clinic control.
After eating ready-made “mantı,” a 54-year-old male patient, who was the spouse of the first case, presented to the emergency department with complaints of green diarrhea three times, fatigue, double vision, blurred vision, and difficulty swallowing. There was no known history of chronic disease. The patient, who was initially diagnosed with botulism in the emergency department, was administered botulinum anti-toxin obtained from the public health institution. No pathology was detected in brain imaging. The patient was admitted to the infectious diseases ward, and no other clinical or laboratory diagnosis was considered during consultations with ophthalmology and neurology specialists during his stay in the ward. The patient, who was fed soft food, was initially given blended food and later transitioned to solid foods. The patient, who experienced mild swallowing difficulties, was discharged at the end of the 14th day with a recommendation for outpatient follow-up.
Discussion
Botulism is a fatal illness caused by the botulinum toxin produced by C. botulinum. This toxin leads to flaccid paralysis by inhibiting the release of acetylcholine at nerve endings, which can result in serious complications such as respiratory failure [1].
The formation of botulinum toxins in foods is usually associated with improperly processed or stored canned foods. However, in recent years, despite modern packaging and storage techniques, attention has been drawn to the risk of botulinum, especially in vacuum-packed or bagged foods [2]. This situation shows that hygienic conditions are of critical importance in the production, packaging, and storage processes of foods. In our cases, the determination of “mantı” sold in sealed bags as the cause of botulinum is important in terms of showing the risk that such foods carry. Diagnosis of botulism can be made through careful evaluation of the patient’s clinical symptoms and history. It is particularly important to keep botulism in mind as a differential diagnosis in patients with a history of consuming ready-made foods. Although gastrointestinal symptoms are observed in many botulism cases, neurological signs are more definitive indicators of the disease. Therefore, promptly diagnosing botulism in patients with double vision, blurred vision, difficulty swallowing, and respiratory problems can help reduce mortality rates [3]. Additionally, laboratory tests and radiological examinations may often be nonspecific; thus, rapid diagnostic processes that align with clinical findings are crucial.
From a treatment perspective, the early administration of antitoxins that neutralize botulinum neurotoxin significantly improves patients’ prognosis. In our cases, it was observed that symptoms greatly diminished with antitoxin treatment. Intensive care monitoring plays a critical role in managing life-threatening symptoms, especially those like difficulty swallowing and respiratory distress. Since complications such as respiratory failure can develop, these patients must be monitored in units equipped to provide mechanical ventilation if needed [4]. Therefore, our first case, who developed respiratory failure, was followed in the intensive care unit until shortness of breath improved, but mechanical ventilation was not required. Thanks to the antitoxin, the patient’s complaints of diplopia and difficulty swallowing also improved, and the blurred vision was completely resolved.
These cases are an important warning that foods sold in sealed bags may also carry a risk of botulism. The food industry must strictly comply with hygiene standards, and consumers must pay attention to the rules for storing and consuming such foods. In addition, rapid interventions for public health in such cases can play a critical role in preventing possible outbreaks. Due to these cases, the provincial Health Directorate and the provincial Agriculture and Forestry Directorate were informed to reach the market selling the food and prevent possible new cases.
Conclusion
Botulism is a rare and potentially fatal illness. In patients with a history of consuming ready-made foods, botulism should be considered in the differential diagnosis. Rapid diagnosis and early treatment play a critical role in the recovery of patients. Botulinum antitoxin accelerates the recovery process by neutralizing the effects of the toxin.
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 compareable ethical standards.
Conflict of interest
The authors declare that there is no conflict of interest.
References
1. Dong M, Masuyer G, Stenmark P. Botulinum and Tetanus Neurotoxins. Annu Rev Biochem. 2019;88:811-37.
2. Dong Y, Wang W, Jiang T, Xu J, Li M, Yan S, et al. A family outbreak of type E botulism caused by contaminated vacuum-packed ambient-stored chili chicken feet in Zhangjiakou, China. Foodborne Pathog Dis. 2022;19(9):613-21.
3. Sobel J. Botulism. Clin Infect Dis. 2005;41(8):1167-73.
4. Rao AK, Sobel J, Chatham-Stephens K, Luquez C. Clinical guidelines for diagnosis and treatment of botulism, 2021. MMWR Recomm Rep. 2021;70(2):1-30.
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Mirkan Bulğak, Tuna Demirdal. Botulism from ready-made food. Ann Clin Anal Med 2025;16(Suppl 1):S77-79
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Tracheal adenoid cystic carcinoma: A case report
Gulen Ece Topaloglu 1, Serife Nilgun Kalac 1, Aydin Yilmaz 1, Mahmut Gulgosteren 2, Nurettin Karaoglanoglu 2, Izzetiye Ebru Cakir 3
1 Department of Pulmonology, Atatürk Chest Diseases and Thoracic Surgery Research and Education Hospital, Ankara, 2 Department of Thoracic Surgery, Ataturk Chest Diseases and Thoracic Surgery Research and Education Hospital, Ankara, 3 Department of Pathology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, Izmir, Turkey
DOI: 10.4328/ACAM.22613 Received: 2025-02-20 Accepted: 2025-03-22 Published Online: 2025-03-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S80-82
Corresponding Author: Gulen Ece Topaloglu, Department of Pulmonology, Atatürk Chest Diseases and Thoracic Surgery Research and Education Hospital, Ankara, Turkey. E-mail: gulen__ece@hotmail.com P: +974 501 272 71 Corresponding Author ORCID ID: https://orcid.org/0000-0002-4660-3830
Other Authors ORCID ID: Serife Nilgun Kalac, https://orcid.org/0009-0005-2897-8574 . Aydin Yilmaz, https://orcid.org/0000-0001-6776-2454 . Mahmut Gulgosteren, https://orcid.org/0000-0003-2065-8574 . Nurettin Karaoglanoglu, https://orcid.org/0000-0003-2827-6044 . Izzetiye Ebru Cakir, https://orcid.org/0000-0001-7959-3491
This study was approved by the Ethics Committee of Chest Diseases and Thoracic Surgery Research and Education Hospital (Date: 2022-01-12, No: 25)
Adenoid cystic carcinoma (ACC) of the trachea is a rare malignancy that often leads to airway obstruction and misdiagnosis as chronic respiratory conditions such as asthma. Due to its slow-growing nature and submucosal infiltration, ACC presents diagnostic and therapeutic challenges. Here, we report the case of a 46-year-old female who was misdiagnosed with bronchial asthma for seven years before being accurately diagnosed with tracheal ACC. The patient underwent a rigid bronchoscopy for airway stabilization, followed by transcarinal tracheal resection and lymph node dissection. Postoperatively, the patient exhibited significant improvement in pulmonary function and was referred for adjuvant radiotherapy. This case highlights the importance of considering alternative diagnoses in patients with persistent respiratory symptoms and underscores the necessity of a multidisciplinary approach for optimal management of tracheal ACC.
Keywords: Adenoid Cystic Carcinoma, Tracheal Tumor, Airway Obstruction, Bronchoscopy, Surgical Resection
Introduction
Tracheal tumors constitute approximately 1% of all respiratory system malignancies. The majority of these tumors are squamous cell carcinomas, while only about 10% are diagnosed as adenoid cystic carcinoma (ACC) [1, 2]. ACC can partially or completely obstruct the airway due to its involvement of the trachea and main bronchi, often leading to misdiagnosis as bronchial asthma and prolonged incorrect management. The optimal treatment for primary tracheal ACC involves surgical resection combined with radiotherapy [1, 2].
In this case report, we present a rare case of tracheal ACC, its diagnostic challenges, and the treatment approach.
Case Report
A 46-year-old female patient was admitted with complaints of wheezing and dyspnea. Her medical history revealed that she had been followed for seven years with a misdiagnosis of bronchial asthma. Over the past six months, her dyspnea had progressively worsened, leading to the use of combination inhaler bronchodilator therapy.
On physical examination, bilateral biphasic diffuse rhonchi were noted. Laboratory tests revealed leukocytosis and an elevated erythrocyte sedimentation rate. The posteroanterior chest radiograph was unremarkable (Figure 1.).
Pulmonary function tests (PFT) showed: FVC: 110% (3.27 L), FEV1: 38% (0.96 L), and FEV1/FVC: 79%, with a negative bronchodilator reversibility test. The flow-volume curve demonstrated flattening of both inspiratory and expiratory limbs (Figure 2.). Fiberoptic bronchoscopy revealed a tumoral mass occluding three-quarters of the tracheal lumen at its distal end. The patient had an oxygen saturation of 78% while receiving 5 L/min of oxygen, was unable to lie supine, and exhibited stridor. To secure the airway, the patient was intubated in the operating room and underwent rigid bronchoscopy with argon plasma coagulation (40 W) for vaporization of the mass. A biopsy taken during the procedure confirmed the diagnosis of adenoid cystic carcinoma.
Chest computed tomography (CT) demonstrated a soft tissue density extending from the distal trachea to the level of the right main bronchus, narrowing the carina from the right anterolateral side. Given the known submucosal spread characteristic of tracheal ACC, endobronchial treatment alone is not curative. Positron emission tomography-computed tomography (PET-CT) revealed pathological metabolic activity within the lesion and mildly increased metabolic activity in bilateral cervical, left jugular, and hilar lymph nodes (Figure 3).
The patient was deemed suitable for surgical intervention and underwent right thoracotomy with transcarinal tracheal resection (3.5 cm) and lymph node dissection. Histopathological examination confirmed adenoid cystic carcinoma with tumor-free surgical margins and reactive lymph nodes. Postoperative PFT results showed improvement: FVC: 80% (2.34 L), FEV1: 73% (1.83 L), FEV1/FVC: 79%. The patient was referred to the radiation oncology department for adjuvant radiotherapy.
Due to its rarity, we present this case to highlight the diagnostic and therapeutic approach to tracheal adenoid cystic carcinoma.
Ethical Approval
This study was approved by the Ethics Committee of Chest Diseases and Thoracic Surgery Research and Education Hospital, Ankara, Turkey (Date: 2022-01-12, No: 25). The study was performed in accordance with the principles stated in the Declaration of Helsinki. Written informed consent was obtained from all participants using appropriate patient consent forms.
Discussion
Adenoid cystic carcinoma of the trachea is a rare malignancy with a slow but persistent growth pattern and a high tendency for perineural invasion. Due to its submucosal spread, it can be challenging to diagnose early, often leading to misclassification as asthma or chronic bronchitis [3-5]. In this case, the patient had been treated for asthma for several years before the correct diagnosis was made. This highlights the importance of considering alternative diagnoses in patients with refractory respiratory symptoms.
Bronchoscopy and imaging techniques, particularly CT and PET-CT, play a crucial role in the diagnosis of tracheal ACC [3, 6-8]. The management of tracheal ACC involves a multidisciplinary approach, with surgical resection being the cornerstone of treatment. However, given the tumor’s tendency for submucosal extension, achieving clear margins can be challenging, and adjuvant radiotherapy is often recommended to reduce recurrence risk [3, 7].
In this case, the patient underwent transcarinal tracheal resection with negative margins, followed by adjuvant radiotherapy. The postoperative improvement in pulmonary function parameters indicated a successful intervention. Long-term follow-up is necessary, as tracheal ACC has a high potential for late recurrence.
Limitation
This case report is limited by its single-patient design, which restricts the generalizability of findings. Additionally, the long-term prognosis of the patient remains uncertain, necessitating extended follow-up. While imaging and histopathological findings support the diagnosis, molecular and genetic analyses were not performed, which could have provided further insights into the tumor’s characteristics and potential targeted therapies.
Conclusion
Tracheal adenoid cystic carcinoma is a rare but significant airway malignancy that can be misdiagnosed as asthma for an extended period, delaying appropriate treatment. This case underscores the importance of thorough clinical evaluation, advanced imaging, and histopathological confirmation in patients with persistent respiratory symptoms. Surgical resection remains the preferred treatment, with adjuvant radiotherapy playing a key role in reducing recurrence risk. Early diagnosis and a multidisciplinary treatment approach are essential for improving patient outcomes.
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 compareable ethical standards.
Conflict of interest
The authors declare that there is no conflict of interest.
References
1. Chen Z, Jiang J, Fan Y, Lu H. Pulmonary adenoid cystic carcinoma: molecular characteristics and literature review. Diagn Pathol. 2023;18(1):1-9.
2. Horio Y, Kuroda H, Masago K, Matsushita H, Sasaki E, Fujiwara Y. Current diagnosis and treatment of salivary gland-type tumors of the lung. Jpn J Clin Oncol. 2024;54(3):229-47.
3. Tan X, Xu T, Shen W, Ai C, Zhang W, Tang X, et al. Primary pulmonary adenoid cystic carcinoma: A clinicopathological study of 64 patients. Thorac Cancer. 2023;15(5):386-93.
4. Huang H-c, Zhao L, Cao X-h, Meng G, Wang Y-j, Wu M. Primary salivary gland tumors of the lung: Two cases date report and literature review. Respir Med Case Rep. 2021;32(1):1-8.
5. Fei Q, Zhao H, Wang Y, Chen Y. Adenoid cystic carcinoma of trachea mimicking a thyroid follicular tumor: A case report and literature review. Radiol Case Rep. 2024;19(12):5653-7.
6. Wu J, Tao Y, Liu Y, Wang Y, Zhang C. 18F-FDG PET/CT of Primary Tracheal Adenoid Cystic Carcinoma. Clin Nucl Med. 2021;46(9):766-7.
7. Wickramasinghe S, Munavvar M, Bittar MN, Jacob D, Nicholson S, Stockwell R, et al. Adenoid cystic carcinoma of the trachea mimicking asthma. Respirol Case Rep. 2023;11(5):1-10.
8. Wang SC, Yin LK, Zhang Y, Xue LM, Ye JD, Tao GY, et al. CT diagnosis and prognosis prediction of tracheal adenoid cystic carcinoma. Eur J Radiol. 2021;140(7):1-8.
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Gulen Ece Topaloglu, Serife Nilgun Kalac, Aydin Yilmaz, Mahmut Gulgosteren, Nurettin Karaoglanoglu, Izzetiye Ebru Cakir. Tracheal adenoid cystic carcinoma: A case report. Ann Clin Anal Med 2025;16(Suppl 1):S80-82
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Radiation and oxidative stress: A mini-review
Huseyin Erdal 1, Turay Cesur 2
1 Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray, 2 Deparment of Radiology, Mamak State Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22411 Received: 2024-09-20 Accepted: 2024-11-04 Published Online: 2024-11-18 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S83-86
Corresponding Author: Huseyin Erdal, Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray, Turkiye. E-mail: herdalyfa@gmail.com P: +90 543 414 08 15 Corresponding Author ORCID ID: https://orcid.org/0000-0003-0786-5077
Other Author ORCID ID: Turay Cesur, https://orcid.org/0000-0002-2726-8045
Radiation, particularly ionizing radiation used in medical imaging and cancer treatments, induces oxidative stress (OS), a key factor in the biological damage it causes. Radiation interacting with biological tissues generates reactive oxygen species (ROS) that can overwhelm the cell’s natural antioxidant defenses. This leads to oxidative damage to essential macromolecules such as DNA, proteins, and lipids, triggering a cascade of harmful cellular events. DNA strand breaks, protein oxidation, and lipid peroxidation are common consequences, contributing to mutations, cellular dysfunction, and apoptosis. These effects play a significant role in both acute radiation injury and long-term health outcomes, such as carcinogenesis and cardiovascular diseases. Given the growing use of radiological procedures in medicine, understanding radiation-induced OS is critical for improving patient safety. Strategies to mitigate oxidative damage, including using antioxidants and radiation dose optimization, are being actively explored. Continued research into the mechanisms of radiation-induced OS is necessary to enhance therapeutic interventions and diagnostic accuracy while minimizing potential risks. This review provides a concise summary of the relationship between radiation and OS.
Keywords: Radiology, Radiation, Oxidative Stress, Reactive Oxygen Species, Oxidative Damage
Introduction
Wilhelm Conrad Roentgen accidentally discovered the X-rays in 1895. This discovery has created a major change not only in the field of physics but also in the field of medicine. Within months of Röntgen’s discovery, X-rays were being used for medical diagnosis (1). Then, Henri Becquerel discovered radioactivity in 1896, followed by Marie and Pierre Curie’s isolation of radium in 1898. Radiation falls into two categories: ionizing and non-ionizing. Non-ionizing radiation (NIR), including microwaves, infrared, ultraviolet, and visible light, can excite atoms but lacks the energy to ionize them (2,3). MRI is one of the most important medical imaging methods in which we use non-ionizing radiation. Ionizing radiation (IR) is, on the other hand, classified into electromagnetic radiation (gamma rays and X-rays) and particle radiation (electrons, protons, neutrons, and alpha particles) (4). They are possessing sufficient energy to ionize atoms. In medicine, IR is crucial for both therapy and diagnostics. It’s used in nuclear medicine for treatments like radionuclide therapy and imaging techniques such as PET and in radiology for CT scans, digital subtraction angiographies (DSAs), and as well as X-ray radiography (5). Moreover, radiotherapy plays a crucial role in cancer treatment, with approximately 80% of cancer patients requiring this form of therapy (6). These advancements have fundamentally transformed how we detect and visualize diseases, as well as how we approach therapeutic intervention (5). But since the discovery of radiation, it has been a double-edged sword (7).
Biological Effects of Radiation
Scientists would gradually discover the biological effects of the radiation. By 1897, epigastric dermatitis was reported as a side effect of X-ray exposure (8). The link between radiation exposure and cancer development wasn’t immediately apparent. This grim connection became evident through the tragic fates of two groundbreaking scientists in the field of radioactivity. Marie Sklodowska-Curie, a Nobel Prize recipient and trailblazer in radiation research, succumbed to aplastic anemia resulting from her prolonged radiation exposure. Similarly, her daughter, Irene Joliot-Curie, who, along with her husband, was awarded a Nobel Prize for their pioneering work on artificial radioactivity, later died from leukemia induced by radiation (9).
Within three decades after the discovery of Roentgen, a wealth of scientific literature emerged, documenting the wide-ranging effects of ionizing radiation on diverse substances and biological systems, from the visibly damaged hands of pioneering radiologists to more insidious consequences such as sterility, bone disease, cancer, and various other illnesses (10, 11). The atomic bombings of Hiroshima and Nagasaki led to extensive studies on radiation effects. Most of the information on the health risks of radiation in healthy populations comes from the life span studies, which were established after the detonation of the atomic bombs in Japan in 1945. Assembled in 1950, these cohorts have been followed for 65 years (12). It showed a direct link exists between radiation dose and solid cancer risk, with children being more vulnerable; high doses increase the risk of heart disease and other non-cancer illnesses; exposure in the womb affected brain development and raised cancer risk; interestingly, no clear increase in birth defects or illnesses was found in survivors’ children; high doses impacted the immune system similarly to aging; while cancer risk increases at moderate to high doses (over 0.1-0.2 Gy), the effects of low doses (under 0.1 Gy) remain uncertain. Several large cohort studies support the life span study’s findings on low-dose radiation effects. These include studies of UK nuclear workers (13), Techa River residents (14), Chornobyl cleanup workers (15), and residents of high natural radiation areas in China (16).
Effects of Oxidative Damage on Macromolecules
Oxidative damage, primarily caused by the excessive generation of reactive oxygen species (ROS), can have profound effects on various macromolecules within cells, including DNA, proteins, and lipids (17, 18). Each of these macromolecules is critical to cellular function, and their damage can lead to significant biological consequences (19). Figure 1.
DNA Damage: ROS can attack the nucleotides within DNA, leading to base modifications, strand breaks, and crosslinking (20). These mutations can interfere with DNA replication and transcription, potentially leading to errors in protein synthesis. If not properly repaired, DNA damage may result in genomic instability, which is a precursor to cancer, aging, and various genetic disorders (21).
Protein Oxidation: Proteins are vulnerable to oxidative damage, particularly in their amino acid residues. This can lead to the alteration of protein structure, loss of enzymatic activity, and impaired cellular signaling pathways (22). The accumulation of oxidized proteins is often associated with neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as impaired immune and metabolic functions.
Lipid Peroxidation: Lipids, especially polyunsaturated fatty acids in cell membranes, are highly susceptible to ROS attack, leading to lipid peroxidation. This process compromises the structural integrity and fluidity of cell membranes, disrupting essential functions such as ion transport, cell signaling, and energy production (23). Lipid peroxidation products can also form toxic aldehydes, further amplifying cellular damage and inflammation.
Carbohydrate Damage: Although less frequently discussed, carbohydrates can also be oxidatively damaged, particularly through reactions that generate advanced glycation end-products (AGEs). These AGEs can impair normal cellular functions by crosslinking with proteins and altering their normal activities, contributing to diabetes complications, cardiovascular diseases, and aging (24). The cumulative oxidative damage to these macromolecules can initiate a cascade of deleterious effects at the cellular level, eventually affecting tissues and organs. This contributes to a range of pathological conditions, including cancer, neurodegeneration, cardiovascular diseases, and chronic inflammation. Understanding these mechanisms underlines the importance of controlling oxidative stress through both intrinsic antioxidant defenses and potential therapeutic interventions.
DNA Damage from Ionizing Radiation: The Role of Oxidative Stress as an Indirect Pathway
The concept that ionizing radiation (IR) can harm genetic material, such as by breaking chromosomes, was recognized before we understood DNA’s structure. Initially, scientists proposed a direct mechanism where high-energy particles or photons directly collided with DNA strands (25). However, later research revealed an indirect pathway involving oxidative stress (OS), which is now believed to cause most (60-70%) of IR-induced DNA damage (26-30). Oxidative stress occurs when there’s an imbalance between oxidant production and antioxidant activity, favoring the former. This OS-mediated indirect mechanism involves the generation of reactive oxygen species (ROS) through IR-induced water radiolysis (4).
Ionizing radiation’s impact on cells is a complex and rapid process. Within a fraction of a second after exposure, the radiation releases electrons that break chemical bonds in cellular molecules. This creates unstable particles called free radicals and ROS. Some DNA damage occurs instantly from direct radiation hits, but most happens indirectly through these newly created particles. Interestingly, the majority of DNA damage takes place within the first 5 minutes after exposure. After this initial burst, the rate of new damage slows down (4, 31). This timing is crucial for scientists studying radiation effects, as they need to measure damage quickly before cells begin their natural repair processes (32). While some ROS are neutralized, those near the cell’s nucleus can be particularly harmful. They can cause severe DNA damage, especially double-strand breaks (DSBs), which are considered the most dangerous type (26-28, 30, 33-36). If not repaired correctly, these DSBs can alter chromosome structure, potentially leading to mutations. Over time, these mutations might contribute to cancer development (37-39).
Biomarkers and Assessment of the IR-Damage
Cells respond to IR-caused DNA damage by modifying a protein called H2AX, creating γ-H2AX. Scientists use this modified protein as a marker to measure the extent of DNA damage. This cellular response is part of the body’s attempt to detect and repair the harm caused by radiation (40).
Radioprotective agents and Anti-oxidant Supplementation
Understanding the process from initial exposure to cellular response helps researchers develop better protective measures against radiation damage and improve treatments for radiation exposure (4). Studies have investigated a variety of antioxidant compounds for their potential to mitigate radiation-induced damage. Research has shown that certain ingredients can reduce lethality or decrease markers of DNA and cellular damage caused by radiation exposure. These include quercetin (41, 42), which has demonstrated protective effects in several studies, and astaxanthin(43), known for its potent antioxidant properties. Zeaxanthin (44), vitamin C (45), and vitamin B12 (46) have also been examined for their radioprotective potential. Additionally, selenium(47), folate (48), and CoQ10 (49, 50) have been the subject of research focusing on their ability to counteract radiation damage. Studies have also explored the benefits of α-lipoic acid and vitamin E in this context. These investigations suggest that these antioxidants might offer protection against radiation-induced cellular harm.
Conclusion Remarks
OS is an important consideration in radiology, particularly in imaging modalities that rely on ionizing radiation, such as X-rays, CT scans, and fluoroscopy. The ionization process leads to the generation of ROS, which can damage cellular components like DNA, proteins, and lipids. Although the body has natural antioxidant defenses, prolonged or excessive exposure to radiation can overwhelm these mechanisms, leading to oxidative damage and potential long-term health risks, including cancer and cardiovascular diseases. The clinical implications highlight the need for optimized protocols to minimize radiation exposure without compromising diagnostic efficacy. This includes employing the principle of ALARA (As Low As Reasonably Achievable), using advanced imaging technologies that require lower doses of radiation, and exploring protective agents that can mitigate oxidative damage. Further research is crucial to better understand the mechanisms of radiation-induced oxidative stress and to develop strategies for safeguarding patients, particularly those requiring repeated imaging. Ultimately, the balance between effective diagnostic imaging and the prevention of OS remains a key objective in the field of radiology. With ongoing advancements, radiologists and healthcare providers can continue to improve patient safety while delivering high-quality diagnostic care.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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3. Sotomayor CG, Gonzalez C, Soto M, Moreno-Bertero N, Opazo C, Ramos B, et al. ionizing radiation-induced oxidative stress in computed tomography-effect of vitamin C on prevention of DNA damage: PREVIR-C randomized controlled trial study protocol. J Clin Med. 2024;13(13).
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Neurotoxic snake bites in Saudi Arabia: Current status analysis
Raed Al Ruwaili 1, Ekramy Elmorsy 2, 3, Asmara Syed 3, Anil Mohan R. Saini 3
1 Department of Internal Medicine, 2 Center for Health Research, 3 Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
DOI: 10.4328/ACAM.22438 Received: 2024-10-05 Accepted: 2024-11-11 Published Online: 2024-11-24 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1):S87-90
Corresponding Author: Anil Mohan R. Saini, Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia. E-mail: Anilmohanrao_saini@yahoo.com P: +9 665 375 01 455 Corresponding Author ORCID ID: https://orcid.org/0009-0009-8165-9520
Other Author ORCID ID: Raed Al Ruwaili, https://orcid.org/0000-0002-2163-9132 . Ekramy Elmorsy, https://orcid.org/0000-0002-7444-2499 . Asmara Syed, https://orcid.org/0000-0002-8895-9069
Saudi Arabia has vast areas of deserts with the availability of different types of venomous snakes. Snake bites continue to be extremely dangerous injuries worldwide and occasionally need critical care. Snake bites have different systemic manifestations including hematotoxic and neurotoxic presentations. Neurotoxic bites are characterized by neurological manifestations with flaccid paralysis of the respiratory muscles which ends fatally by respiratory arrest and death. Neurotoxic snake bites were reported in Saudi Arabia with lower incidence than the hemotoxic bites. Effective handling of an envenomed patient, such as timely hospitalization, ventilator support, and antivenom administration, greatly lowers the risk of neurological complications, which lowers mortality and enhance the functional outcome of survivors.
Keywords: Neurotoxic, Snakes, Bites, Desert, Manifestations
Introduction
Snakes are members of the reptile’s family, which descended from lizards. Their sizes differ significantly, with the smallest measuring only 15 cm and the largest reaching up to 10 m. The majority of species, however, reach an adult height of 1 to 2 m [1]. Snakes have developed extra senses, most likely because their sight and hearing are insufficient. They share some of the same senses as other animals, including smell and sight. In general, temperature controls snake activity and population size. Snakes are rare in colder temperatures but common in tropical areas where they have spread to many different habitats. Certain snakes are exclusively aquatic, some are subterranean, while some spend the majority of their lives on huge forest trees [2].
Snake bites continue to be extremely dangerous injuries worldwide, occasionally need critical care [3]. There is always a chance of getting bitten by a snake, just like with malaria, dengue hemorrhagic fever, TB, and parasitic illnesses. Snake bites were included in the list of neglected tropical illnesses, along with Japanese encephalitis, cholera, and dengue hemorrhagic fever, by the World Health Organization in 2009. Compared to other neglected tropical diseases, snake bites have a far higher death rate [4]. A deadly illness, snakebite envenomation causes between 81 000 to 138 000 deaths worldwide each year [5]. The most vulnerable groups are those who work in agricultural fields, the children, and those who reside in rural areas of poverty [3, 6, 7].
A retrospective study found that youngsters in Saudi Arabia had a higher prevalence of having been bitten by a snake than the global trend [8]. Interestingly, this study showed more severe manifestations of the venomous snakebites in children when compared to adults enrolled in the study [9]. The clinical presentation of the toxic snakebites depends on the type of venomous snake, the quantity of injected venom, and a personal health status and susceptibility. Tissue necrosis, edema, and discomfort are typical local consequences. From minor nausea and vomiting to potentially fatal life-threatening neurotoxicity, cardiotoxic manifestations, renal impairment, or serious hematological consequences. These manifestations can vary widely [10, 11].
Classification of venomous snakes
Every snake that is significant to medicine has one or more sets of upper jaw fangs. These pierce the skin of their prey, allowing the venom to enter the tissues through a closed tube or groove. The Atractaspididae, Elapidae, Hydrophidae, and Viperidae families comprise venomous snakes [12]. Based on the main effects of the venom, snake venom can be categorized mainly as as hematotoxic, neurotoxic, necrotoxic, cardiotoxic, or nephrotoxic. Protein, enzymes, neurotoxins, coagulants, anticoagulants, and compounds having cytotoxic effects are some of the components that make up the venom [13].
Venoms are a complex mixture of poisonous and enzymatic proteins that, depending on the pathophysiological alterations in certain species, cause a variety of clinical symptoms [14, 15]. The Middle East is home to forty-six species of venomous snakes, five of which are found in Saudi Arabia. Three of these families are clinically significant: the Viperidae (which includes Bitis arietans, Cerastes cerastes gasparetti, Echis carinatus sochureki, Echis pyramidium, and Echis coloratus); the Elapidae (which includes Naja haje arabica and Walterinnesia aegeptia); and the Atractaspididae (which includes Atractaspis microlepidota and Atractaspis engaddensis) [13]. Elapidae bites are the most common source of neurotoxic snake bites [3].
Neurotoxic venomous snakes
Elapidae family
Elapidae members are characterized by their front permanently erected fangs in the mouth. Except for the species Emydocephalus, the majority of elapids are venomous [16]. With terrestrial species found in Asia, Australia, Africa, and the Americas and marine forms found in the Pacific and Indian Oceans, elapids are indigenous to tropical and subtropical locations worldwide. The family’s members range widely in size, from 0.18 to 5.85 m in white-lipped snake and king cobra, respectively [1]. Through their hollow fangs, the majority of species channel their neurotoxic venom; others may also contain additional harmful ingredients in different amounts. To inject venom from glands toward the back of the upper jaw, all elapids possess a pair of proteroglyphous fangs [17]. The two primary Elapidae family members in Saudi Arabia are Walterinnesia aegeptia and Naja haje arabica [13].
Neurotoxic Snake venom
The primary neurotoxic effect of Elapidae venom is used to immobilize prey and for defense. Three-finger toxins (3FTx) and PLA2 comprise the majority of the toxins. Other harmful elements found in certain species include cytotoxins and cardiotoxins, which harm cells and induce cardiac problems, respectively. Hemostases, which cause blood to clot or harden, are also present in cobra venom [17].
The capacity of large species, such as cobras and mambas, to inject copious amounts of venom during a single envenomation and/or to strike at a high point close to the victim’s brain, which is susceptible to neurotoxicity, makes them dangerous [18]. Spitting cobras produce cytotoxic venom as opposed to neurotoxic venom. It harms local cells, particularly those in the eyes, which the snakes specifically target. When venom gets in the eye, it can hurt so much that it can induce blindness. If there is no wound that would allow the poisons to enter the bloodstream, it is not fatal when applied topically [19].
Clinical Features of neurotoxic snakebite
The majority of the bites from neurotoxic snakes only had minor local characteristics, such as the fang marks. Rare symptoms include bleeding, edema, and pain. In general, symptoms including flushing, dyspnea, palpitations, lightheadedness, chest tightness, perspiration, and acroparaesthesiae are frequent. These result from overactive sympathetic nervous system and anxiousness [20]. In addition, vomiting, heavy eyelids, blurred vision, hypersalivation, congested conjunctivae, and “gooseflesh” are among the initial symptoms of elapid bites. cramping stomach ache and diarrhea after krait bites [21].
Venoms from elapids are very neurotoxic. Elapid bites cause ptosis and external ophthalmoplegia, which can emerge as soon as 15 minutes after the bite and are the initial signs of paralysis. On occasion, the onset could be postponed for up to ten hours. Subsequently, paralysis occurs in the muscles of the neck, deglutition muscles, tongue, jaws, palate, and voice cords. Respiratory failure is brought on by blockage of the airways or paralysis of the diaphragm and intercostal muscles. The effects of neurotoxic substances can be entirely reversed, either immediately by using antivenom or anticholinesterases, or they can go away on their own in one to seven days [22-24]. It is noteworthy that these neurotoxins do not change consciousness or pass through the blood-brain barrier [24]. Furthermore, bradycardia, tachycardia, hypotension, and arrhythmias are examples of direct cardiac injury that can result from elapid venom. Numerous factors can lead to shock, which can happen for various reasons. Among them are cardiac depression and fear [22].
Limited information was found when the literature on neurogenic snakebites in Saudi Arabia was reviewed. According to one study, a single case of bulbar palsy appeared six hours after the bite and became better one and a half hours after receiving AV infusion. According to snake description, the cobra snake Naja haje arabicus was suggested as the involved snake [24]. Two more case reports, one describing a vegetative state and intracranial hemorrhage [25] and the other imitating brain death with respiratory arrest [26] following neurotoxic snakebites. Alfaifi et al. [7] study, which examined thirteen individuals with neurologic features—defined as altered mental status, respiratory impairment, or ophthalmoplegia—provided the most extensive data regarding neurotoxic snake bites in Saudi Arabia. Three of them showed signs of moderate ptosis, diplopia, or dyspnea. The remaining ten had moderate-to-severe presentations, which included respiratory paralysis, cardiopulmonary arrest, and bewilderment. The most typical neurogenic symptom was altered mental status.
Interestingly, Alfaifi et al.’s article [7] reports that a patient who had Echis coloratus envenomation also had proximal weakness and ophthalmoplegia, indicating the possibility of neurogenic effects from snakes other than elapids in Saudi Arabia including other viperid species. This discovery highlights the necessity for additional investigation into the venom profiles of local snakes and their distinct neurotoxic constituents.
Management of neurotoxic snake bite
First aid
As soon as possible, the patient needs to be reassured and taken to the closest hospital. A splint or sling should be used to immobilize the biting portion. Compression bandages and tourniquets should only be used with caution in cases of severe sea snake or elapid bites if getting to a medical facility would likely take longer than two to three hours but less than an hour [27]. Here, tourniquets and compression assist in postponing the venom’s absorption and the subsequent development of respiratory muscle paralysis. The tourniquet should be just tight enough to obstruct venous and lymphatic flow, but not arterial flow. The rule of thumb is that it should be sufficiently slack to allow a finger to pass under it. Every fifteen minutes, the tourniquet should be removed for thirty seconds to allow the venom to slowly leak into the bloodstream and neutralize it. After administering the first dosage of antivenom, the tourniquet should only be removed [28, 29]. Use sterile cotton gauze to carefully clean the bite wound. Only utilize the intravenous method for medicines if there is incoagulable blood or seeping from puncture wounds [30].
Evaluation in the hospital
If any of the following occur at the bite site and its extension—such as swelling, blistering, or necrosis—the bite is said to have been poisonous. Shock or hypotension, hemorrhage, myoglobinuria, bradycardia, tachycardia, neuroparalytic symptoms, and laboratory evidence of coagulation malfunction are all suggestive manifestations of toxic snake bites [31].
Antivenom therapy
Whether or not to inject antivenom is the most crucial decision in managing a case of snakebite. Research indicates that the advantages of this treatment greatly exceed the possibility of side effects in individuals with severe envenomation [32]. Neurotoxicity manifestation, hypotension, shock, irregular ECG, any other symptom of cardiovascular malfunction, impaired awareness, or generalized rhabdomyolysis are common indications for the delivery of antivenom in situations of neurotoxic bites. As long as systemic indications of envenoming continue, it is virtually never too late to administer anti-venom [31].
The National Antivenom and Vaccine Production Centre, the manufacturer in Saudi Arabia, suggests administering 4-6 vials of polyvalent snake antivenom as an initial dosage, with the option to re-administer it dependent on clinical response [7]. According to reports from Saudi Arabia, neurologic envenoming cases required an average antivenom dose of 22 vials. Re-administration was necessary in up to 39% of treated cases, indicating the possibility of ongoing antivenom therapy being necessary to get the best possible clinical response [7]. Up to 9% of our patients experienced minor and temporary allergic reactions to antivenom in the Saudi investigations [24-26]. The comparatively low incidence of severe allergic reactions supports the continued use of antivenom as the main treatment for snakebite.
Anticholinesterase medication
It is commonly acknowledged that anticholinergics can reverse reversal, which is the inhibition of cholinesterase at the NMJ leading to elevated acetylcholine concentrations, after neurotoxic snake bites. Increased acetylcholine displaces nicotinic receptor competitive antagonists, restoring function of the NMJ, particularly in cases where ophthalmoplegia is present. [25, 33] Alfaifi et al. [25] from Saudi Arabia reported on the application of antivenene and anticholinergic combo therapy for imitating cobra bite-induced brain death. Additionally, Alfaifi et al. [7] reported in their study that three patients arrived at the emergency room with respiratory arrest mimicking brain death, ventricular fibrillation cardiac arrest, and anticholinesterase medication for suspected neurogenic envenomation, while the third case was represented with asystole cardiac arrest. Neostigmine, pyridostigmine, physostigmine were reported to be used for these cases.
Discussion
Conclusion
Saudi Arabia’s diverse snake species pose a serious threat to public health because they can cause a wide range of clinical manifestations, from minor local envenomation to potentially fatal consequences like coagulation disorders, compartment syndrome, respiratory faliure, and even cardiorespiratory arrest. Our research highlights the significance of raising public awareness about lethal snakebites and the need to administer first aid correctly, avoiding the use of ineffective traditional beliefs that could worsen conditions or even prolong death.
It is important to improve the knowledge of the physicians and emergency personnel about the venomous snakes in Saudi Arabia and their pattern of clinical presentations, which may be mild and may extend to a state mimicking brain death, which must be evaluated and investigated to save it from the diagnosis errors the brain death. In addition, they should be aware of the atypical manifestations of certain snakes’ bites and they should know that the venom contains different types of toxins, which may be manifested in different proportions. This emphasizes the significance of early diagnosis and treatment, especially for neurotoxic envenomation, and the necessity for physicians in the area to be knowledgeable about the range of snakebite manifestations.
Additionally, it is critical to address snakebite cases comprehensively and holistically, with the right dosage based on the severity and particular clinical circumstances of each case. Antivenin therapy continues to be based on supportive care and antivenin. Given the high prevalence of coagulopathy and other significant effects in Saudi Arabia, it is imperative to regularly monitor patients, promptly identify issues, perform a thorough neurological evaluation in all suspected cases of snakebites, and take prompt treatment to improve the patient’s prognosis.
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 compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Raed Al Ruwaili, Ekramy Elmorsy, Asmara Syed, Anil Mohan R. Saini. Neurotoxic snake bites in Saudi Arabia: Current status analysis. Ann Clin Anal Med 2025;16(Suppl 1):S87-90
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Thalassemia and heat shock proteins
Fatma Yılmaz
Department of Hematology, Ankara Etlik City Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22538 Received: 2024-12-27 Accepted: 2025-02-04 Published Online: 2025-02-11 Printed: 2025-03-25 Ann Clin Anal Med 2025;16(Suppl 1)
Corresponding Author: Fatma Yilmaz, Department of Hematology, Ankara Etlik City Hospital, Ankara, Turkiye. E-mail: dr.fatmak@hotmail.com P: +90 506 882 38 69 Corresponding Author ORCID ID: https://orcid.org/0000-0001-6112-3950
To the editor:
Thalassemia and Heat Shock Proteins
Thalassemias are hereditary hemoglobinopathies characterized by decreased or absent production of one or more globin chains. They are classified into two main groups, alpha and beta thalassemia. Individuals with beta thalassemia can be classified as major, intermediate, minor, and also as transfusion-dependent or non-transfusion-dependent [1].
The anemia seen in thalassemias is caused by ineffective erythropoiesis and increased hemolysis. The mechanisms of ineffective erythropoiesis include apoptosis and phagocytosis by bone marrow macrophages. One of the mechanisms involved in apoptosis has been shown to involve the sequestration of heat shock proteins found in the cytoplasm of red blood cell precursors [2].
Heat shock proteins (HSP) are compounds that protect the organism from environmental stress and are synthesized at high rates during this time. They play a role in protein folding correctly, correcting misfolding and assembly. HSP-70 heat shock protein is a heat shock protein that plays a role in the differentiation of erythroid precursors and increases the survival time of erythroid precursors by preventing apoptosis via the main transcription factor GATA-binding factor-1 (GATA-1) that plays a role in erythropoiesis [3].
Heat shock protein 27 (HSP27) is a multifunctional protein that plays a role in the inhibition of apoptosis and actin cytoskeletal remodeling. There are also studies suggesting that it plays a role in maintaining serum pro-oxidant and anti-oxidant balance in beta-thalassemia major [4].
There are many studies in the literature showing that heat shock proteins play a role in various diseases. The guiding effects of heat shock proteins in thalassemia patients have also been emphasized in various studies. The relationship between heat shock proteins and hypoxia and tissue damage in thalassemia patients may be guiding in the management of transfusion frequency and transfusion-related complications, especially in transfusion-dependent patients. In studies, it would be more effective in terms of reliability and guidance to evaluate all heat shock proteins (HSP-70, HSP-90, HSP-60, HSP-27, etc.) that affect erythropoiesis and can be used.
References
1. Viprakasit V, Ekwattanakit S. Clinical Classification, Screening and Diagnosis for Thalassemia. Hematol Oncol Clin North Am. 2018;32(2):193-211.
2. Centis F, Tabellini L, Lucarelli G, Buffi O, Tonucci P, Persini B, et al. The importance of erythroid expansion in determining the extent of apoptosis in erythroid precursors in patients with beta-thalassemia major. Blood. 2000;15;96(10):3624-9.
3. Sumera A, Radhakrishnan A, Baba AA, George E. Review: Beta-thalassemia and molecular chaperones. Blood Cells Mol Dis. 2015;54(4):348-52.
4. Ghahremanlu E, Banihashem A, Saber H, Tavallaie S, Mirhosseini N, Ghayour-Mobarhan M, et al. Increased serum heat shock protein 27 antibody titers and prooxidant-antioxidant balance in patients with beta-thalassemia major. Acta Haematol. 2013;129(1):1-9.
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Fatma Yilmaz. Thalassemia and heat shock proteins. Ann Clin Anal Med 2025;16(Suppl 1)
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