April 2025
Clinical characteristics of patients with adrenocortical carcinoma: A single center experience
Perihan Perkin 1, Yusuf Acikgoz 2, Tugba Kos 1
1 Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey, 2 Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA
DOI: 10.4328/ACAM.22055 Received: 2023-12-02 Accepted: 2024-02-22 Published Online: 2024-11-30 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):232-236
Corresponding Author: Perihan Perkin, Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey. E-mail: perihanperkin@gmail.com P: +90 505 884 48 04 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3994-815X
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2023-01-18, No: E2-23-3261)
Aim: Adrenocortical carcinomas (ACC) are rare tumors with an aggressive course. A better understanding of the molecular pathogenesis may lead to the development of more effective therapies in the future. However, there are limited effective treatment options currently.
This study aimed to retrospectively investigate the clinical characteristics of patients diagnosed with adrenocortical carcinoma who were followed at Ankara Numune Training and Research Hospital and Ankara City Hospital between November 2002 and January 2022.
Material and Methods: The medical records of patients diagnosed with ACC and followed at Ankara Numune Education and Research Hospital and Ankara City Hospital between November 2002 and January 2022 were retrospectively reviewed. Metastatic and non-metastatic patients were compared regarding demographic data, clinical parameters, and survival.
Results: Twenty-five patients with a median age of 45 (17-75) were included. Abdominal pain (36%) was the most common presenting symptom. The median tumor diameter was 12 (2-27) cm. In the 18 patients who were initially non-metastatic, the median disease-free survival (DFS) was 57.3 months (95% CI: 15.7-98.9). The median progression-free survival (PFS) for metastatic patients was 8.3 months (95% CI 0-24.6). The overall survival (OS) in patients with metastasis at diagnosis was 16.1 months, while in those without metastasis, it was 98.1 months (p<0.0001).
Discussion: Adjuvant mitotane therapy is an option for high risk cases. Mitotane plus chemotherapy combinations are the current treatment options for metastatic patients. However, further research is needed to develop treatment guidelines due to the disease’s rarity.
Keywords: Adrenocortical Carcinoma, Chemotherapy Options For Adrenocortical Carcinoma, Mitotane
Introduction
Adrenocortical carcinomas (ACC) are rare tumors with an aggressive course and limited effective treatment options for advanced stages. According to the Surveillance, Epidemiology, and End Results (SEER) database, the annual incidence in the United States is 0.72 cases per million, accounting for 0.2% of all cancer deaths [1]. The frequency of ACC follows a bimodal distribution, with peaks in childhood and the 5th-6th decades, and the mean age of occurrence is 46 [2]. The incidence is slightly higher in females, with a ratio of 1.5-2.5/1 compared to males [3].
Clinically, patients commonly (40-60%) present with symptoms related to hormone excess, while non-functional ACCs typically manifest with symptoms related to large masses, such as abdominal pain and early satiety [2, 4].
In terms of diagnosis, most cases of adrenocortical carcinoma present with large tumor sizes, with a mean tumor size ranging from 10 to 13 cm [2, 5]. A tumor size of less than 6 cm is detected in 9-14% of cases, while tumors smaller than 4 cm are found in 3% [5, 6]. Staging can be performed using the World Health Organization (WHO) 2004 classification or its Sullivan modification, the American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging, or the European Network for the Study of Adrenal Tumors (ENSAT) system [7]. While older studies reported higher rates, currently, 25-30% of patients are diagnosed at a metastatic stage, the most common sites of metastasis being the lungs (40-80%), liver (40-90%), and bones (5-20%) [8].
Complete surgical resection is the only curative treatment [9]. For stage 1-3 disease, surgery at an experienced center is the preferred approach [10]However, despite complete resection, local recurrence rates of 19-34% were reported. In a series including 3982 patients, the authors noted that 9% underwent R1 while 10% underwent R2 resection [11]. Mitotane is the only FDA-approved agent for ACC treatment, and adjuvant mitotane treatment showed benefits regarding relapse-free survival (RFS) and overall survival (OS) in patients with stage 1-3 ACC [12]. Therefore, in high-risk cases with a Ki67 value of >20%, a history of incomplete resection, and suspicion of tumor spread due to intraoperative capsular rupture, adjuvant mitotane is recommended [13].
In a retrospective study including 31 patients, it was reported that adding platinum-based chemotherapy to adjuvant mitotane led to a significant increase in RFS and OS in the patients with a Ki67 value >20%, extensive vascular invasion, or tumor thrombus in the vena cava [14]. Also, combinations of mitotane and platinum-based chemotherapy are commonly used for unresectable, recurrent, and metastatic ACC patients.
The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study, which compared etoposide, doxorubicin, cisplatin, mitotane [EDPM] combination with streptozotocin-mitotane combination in metastatic ACC patients concluded that the EDPM combination demonstrated a superior objective response rate [15]. In this trial, the EDPM arm showed better progression-free survival (PFS), but only by 5 months.
Despite these findings, due to the paucity of data in the literature, further research is needed regarding the treatment of ACC.
This study investigated the clinical characteristics of patients diagnosed with ACC and followed at two tertiary care centers.
Material and Methods
The medical records of patients diagnosed with ACC and followed at Ankara Numune Training and Research Hospital and Ankara City Hospital between November 2002 and January 2022 were retrospectively reviewed. The survival status of patients no longer under follow-up was checked through the death notification system (DNS) using their national identification numbers. Eastern Cooperative Oncology Group (ECOG) score was used to assess performance status. The demographic and clinical characteristics, including age, gender, initial tumor stage, baseline performance status, tumor size, side (left vs. right), initial symptoms, and data regarding hormonal activity, were collected and comparatively analyzed. In addition, patients who received adjuvant therapy were determined, and DFS was calculated in these cases. Likewise, PFS and OS were calculated in metastatic patients. We analyzed whether age, gender, side of the tumor, tumor size, and the presence of metastasis at the time of initial diagnosis impacted survival.
Statistical Analysis
Descriptive data were given as means and standard deviations, medians, and ranges [minimum-maximum]. Groups were formed based on gender, symptomatology, disease stage, and other clinical features, and differences between these groups were analyzed. The chi-square test, Student’s t-test, Mann-Whitney U test, and ANOVA were used for primary and comparative statistical analyses. Overall survival and disease-free survival (DFS/PFS) analyses were performed. Kaplan-Meier method was used for survival analyses, including OS, DFS, and PFS. Differences between the groups concerning survival were analyzed using the log-rank test. Cox regression analysis was used to determine factors affecting OS. Hazard ratios and 95% confidence intervals (CI) were calculated. All statistical analyses were performed using the SPSS (Statistical Package for Social Sciences, SPSS v22, IBM, Armonk, NY, US). The level of statistical significance was set at 5%.
Ethical Approval
This study was approved by the Ethics Committee of Ankara Bilkent City Hospital (Date: 2023-01-18, No: E2-23-3261).
Results
The general characteristics of the patients are displayed in Table 1. A total of 25 patients with a median age of 45 (17-75) were included. While 60% (n=15) were female, 40% (n=10) were male. Abdominal pain was the most common presenting symptom, observed in 36% (n=9) of the cohort. The median tumor diameter was 12 (2-27) cm, and the tumor was on the left side in 64% (n=16) of the cases. Hormonal changes were detected in 36% (n=)) of the patients.
The review regarding initial disease stages revealed that 8% (n=2) of the patients had stage 1, 48% (n=12) stage 2, 12% (n=3) stage 3, and 32% (n=8) stage 4 disease. Among the 25 patients, 7 (28%) were metastatic at the initial diagnosis, and 6 of these patients received systemic treatment. Among the 18 non-metastatic patients, 7 received adjuvant chemotherapy. Adjuvant treatment consisted of cisplatin-etoposide in 3 patients and mitotane in 4 patients.
Comparative analyses based on gender showed that hirsutism was more commonly observed in females (27% vs. 0%, p=0.044), while left-sided tumors were significantly more prevalent in males compared to females (90% vs. 47%, p=0.04). There were no other significant differences between female and male patients regarding other parameters (Table 2).
Our retrospective review also revealed that among 18 non-metastatic patients, 10 (56%) experienced recurrence or metastasis during follow-up, and 9 of these patients received systemic treatment. Among the patients with metastatic disease at diagnosis or those who developed recurrence or metastasis during follow-up and received systemic treatment (15 patients), mitotane was the most commonly preferred agent (33%), followed by the cisplatin-etoposide-mitotane combination (26.7%), and cisplatin-etoposide without mitotane (20%). The CAP (cisplatin-doxorubicin-vincristine) and CAP+mitotane were the other treatment regimens preferred in this cohort.
The survival analyses showed that the median OS was 63.7 (95% CI 6.0-121.4) months in the entire group (Figure 1). In the female group, the median OS was 63.7 months, while it was 30.4 months in the male group. However, the difference was not statistically significant. For the 18 patients who were initially non-metastatic, the median DFS was 57.3 (95% CI 15.7-98.9) months. On the other hand, in the metastatic patients, the median PFS was 8.3 (95% CI 0-24.6) months. The most common sites of metastasis were the liver (n=4) and lungs (n=4). In our cohort, the median follow-up duration was 28.4 months, and 9 (36%) died during follow-up. Our analysis also included a search for potential factors affecting OS. This analysis included potential factors such as age, gender, tumor diameter, tumor side (right vs left), and metastasis at the initial diagnosis. This analysis revealed that, among these potential factors, only metastasis at diagnosis was significantly associated with shorter OS: While OS was 16.1 months in initially metastatic patients, it was 98.1 months in those who were non-metastatic at the time of initial diagnosis (p<0.0001).
Discussion
In our study, we examined the general characteristics of the patients diagnosed with ACC, a rare and aggressive disease with a poor prognosis.
In the relevant literature, it was reported that the mean patient age was 46 [2]. We calculated the mean patient age as 45 in our cohort. It was previously reported that ACC was 1.5-2.5 times more frequently diagnosed in women than in men [3, 16]. In line with this finding, in our study, 60% of the patients were female.
Fassnacht et al. noted that the rate of left-sided ACC was 1.2-fold higher than the right-sided disease in their cohort [17]. It was denoted that hormonal hypersecretion symptoms are common in ACC [10, 12]. In our patient group, hormonal hypersecretion was detected in 36% of cases. These findings suggest that all patients should undergo endocrinological assessment before initiation of treatment.
In our cohort, analysis regarding sites of distant metastasis revealed that the most common sites of metastases were the liver and lungs. This finding is also consistent with the literature since the most commonly reported metastatic sites were the liver and lungs, followed by intra-abdominal lymph nodes, adrenal glands, and bones in the existing literature.
Although surgical resection is the primary curative treatment modality in ACC, it is associated with a relatively higher recurrence rate than other common malignancies [18]. Due to insufficient evidence-based data regarding adjuvant therapy, clinical decisions on adjuvant mitotane treatment in patients at high risk of recurrence should be made by an individualized approach. In a meta-analysis including 1249 patients, Tang Y. et al. reported that adjuvant mitotane treatment led to an increase in recurrence-free survival and overall survival in patients with ACC [19]. On the other hand, the ADIUVO study, which investigated the impact of adjuvant mitotane treatment on DFS in 91 low-risk (stage 1-3, R0 resected, Ki-67<10%) ACC patients, concluded that adjuvant mitotane treatment did not lead to an increase in RFS and OS [20].
As per ENSAT guidelines, adjuvant mitotane therapy should be considered in patients with a high risk of recurrence based on disease stage, R0 resection status, Ki-67 value, or mitotic index [14, 21]. Currently, adjuvant mitotane treatment is recommended for those with Ki-67 values between 10% and 20% or mitotic indices higher than 20 under a 50x magnification and those with an intraoperative capsular rupture. On the other hand, according to the guidelines, in cases with a Ki-67 value of higher than 20%, there is a significant risk of extensive vascular invasion or tumor thrombus in the vena cava, and cytotoxic treatments should be preferred over adjuvant mitotane therapy in these patients. However, the decision should be given by an individualized approach. In our cohort, most of our patients were diagnosed before 2015. Therefore, Ki-67 and mitotic index values were not available for all participants, and these parameters were not used while making decisions regarding patient management.
Some studies on the management of metastatic ACC focused on mitotane monotherapy [22]. Although these studies included patients with low tumor burden, they reported a median survival of 6.5 months, similar to untreated patients. Currently, the preferred treatment approach involves combining mitotane with cytotoxic chemotherapy [23]. In an in vitro setting, it was demonstrated that mitotane sensitized the human ACC cells to other chemotherapeutic drugs, possibly by acting as an antagonist to multidrug resistance (MDR) proteins. This finding constitutes the rationale for combination therapy [24, 25]. The First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRM-ACT) study compared the combination of etoposide, doxorubicin, cisplatin, and mitotane [EDPM] with streptozotocin and mitotane in metastatic ACC patients [16, 17]. The EDPM combination showed a superior objective response rate than streptozotocin (23% vs 9%). In this study, the PFS was better in the EDPM arm, albeit by only 5 months [16].
In our patient group, only one patient received this combination therapy since most patients were diagnosed before the publication of these reports [16, 17]. Three patients received cisplatin-etoposide-mitotane, and 2 patients received cisplatin-etoposide. The low number of patients makes it difficult to compare these regimens regarding survival.
Our analysis revealed that the median OS was 63.7 months for the entire patient group. The relatively longer OS in our cohort compared to the published reports can be because approximately half of our patients were at stage 2.
Conclusion
In conclusion, ACC is a rare and aggressive disease with limited treatment options, especially in the metastatic stage. For patients who undergo R0 resection, the recurrence risk should be determined. Adjuvant mitotane treatment should be given in high-risk patients. On the other hand, for metastatic ACC patients, EDPM combination therapy should be considered in patients who can tolerate it. Since there is still insufficient data for composing guidelines, further clinical research is needed to arrive at more concrete conclusions.
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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Can pregnancy, delivery, and early neonatal complications be predicted using the ultrasonographically measured first trimester placental volume? A prospective study
Tevfik Giray Ozkırım 1, Mustafa Torehan Aslan 2, Ozlem Sevinc Ergul 1, Ilke Ozer Aslan 1
1 Department of Obstetrics and Gynecology, 2 Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdag, Turkey
DOI: 10.4328/ACAM.22098 Received: 2024-01-06 Accepted: 2024-03-19 Published Online: 2024-11-24 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):237-241
Corresponding Author: Ilke Ozer Aslan, Department of Obstetrics and Gynecology, Faculty of Medicine, Tekirdağ Namık Kemal University, Tekirdag, Turkey. E-mail: girayozkirim@gmail.com P: +90 505 389 48 00 Corresponding Author ORCID ID: https://orcid.org/0000-0002-3175-8354
Other Authors ORCID ID: Tevfik Giray Ozkırım, https://orcid.org/0009-0007-5201-9626 . Mustafa Torehan Aslan, https://orcid.org/0000-0002-3966-4635 . Ozlem Sevinc Ergul, https://orcid.org/0000-0001-6432-730X
This study was approved by the Ethics Committee of Non-Interventional Clinical Research Tekirdag Namık Kemal Unıversity (Date: 2022-07-26, No: 2022.146.07.13)
Aim: We aimed to determine the relationship between first trimester placental volume and pregnancy, birth, and perinatal complications.
Material and Methods: This prospective observational study was performed between August 2022 and March 2023 at the Department of Obstetrics and Gynecology at Tekirdağ Namık Kemal University Faculty of Medicine. A total of 82 singleton pregnant women at 11 + 0 to 13 + 6 weeks from the last menstrual date or first trimester ultrasonography (USG) were enrolled.
Results: The median age of the patients was 24 (19–35) years. The median placental volume was 22.78 (11.31–35.46) cm3. gestational diabetes mellitus (GDM) developed in nine (11.0%) pregnant women and gestational hypertension (GHT) developed in eight (9.8%). There was a significant positive correlation between the mean placental volume and the maternal weight (r=0.251, p=0.023), gestational age according to the last menstrual period (r=0.572, p<0.001), and gestational age according to USG (r=0.735, p<0.001). There was no significant relationship between the mean placental volume and the birth type (p=0.540), cesarean section indication (p=0.146), admission to the neonatal intensive care unit (ICU) (p=0.733), indication for ICU admission (p=0.520), GDM (p=0.563), and GHT (p=0.527).
Discussion: Although the first trimester placental volume was positively related to maternal weight and gestational age, it was not associated with other variables. However, there is insufficient evidence regarding the role of first trimester placental volume in predicting problems related to pregnancy, delivery, and the early neonatal period.
Keywords: Placental Volume, Ultrasonography, Maternal Weight, Gestational Week, Gestational Diabetes Mellitus
Introduction
The human placenta is a vascular organ that is a combination of embryo/fetal and maternal tissue, to which the fetus is connected by the umbilical cord. The human placental villi begin to emerge 7 to 8 days after fertilization, and a complete placenta is formed by the 3rd month of pregnancy. The placenta grows gradually as the pregnancy progresses [1, 2]. Transportation and endocrine and metabolic functions of the placenta are the main determinants of fetal nutrition and homeostasis [2-4]. It ensures that oxygen and nutrients are delivered to the fetus and waste products are removed to maintain fetal growth [1]. Adequate blood flow from the placenta is an important determinant of fetal development and maternal health [2]. Considering these factors, placental problems are the primary cause of common pregnancy disorders, including recurrent miscarriages, fetal growth restriction, preeclampsia, and stillbirth [1, 5]. The health, functions, and capacity of the placenta are related to its weight. The placental weight at birth is positively related to the birth weight [6]. Since the 1970s [7], two-dimensional (2D) ultrasonography (USG) has been used to evaluate the placental size during early pregnancy. Several studies have revealed that low placental volume in the first trimester is associated with small for gestational age (SGA) fetus, fetal growth restriction, preeclampsia, gestational diabetes mellitus (GDM), and gestational hypertension (GHT) [8-12]. Problems during pregnancy and the early neonatal period create a serious burden on the health system in addition to negatively affecting maternal and infant health. Detection and prevention of possible complications in early pregnancy are necessary to reduce maternal and fetal mortality and morbidity. Demonstrating that the placental thickness, width, and volume on USG in the first trimester can predict the possible obstetric, fetal, and perinatal risks will provide a proactive approach to managing complications. However, the number of studies on this subject is limited. Thus, we aimed to determine the relationship between first trimester placental volume and pregnancy, birth, and perinatal complications.
Material and Methods
82 participants were included in the study. The sample size of this study was determined based on the study by Soongsatitanon et al [9]. Accordingly, a 95% confidence interval (CI) and 95% power were obtained for a sample calculation of 82 participants. G-Power (version 3.1.9.7) was used to calculate the power of the sample size. This prospective observational study was performed between August 2022 and March 2023 at the Department of Obstetrics and Gynecology at Tekirdag Namık Kemal University.
Measuring the placental volume
Placental volume was measured using a 2D transabdominal USG device (DC-8 Exp; Mindray, Shenzhen, China) and transabdominal convex probe (C5-2s probe; Mindray, Shenzhen, China) in patients during their 11 + 0 to 13 + 6 weeks of gestation, by a single operator blinded to all the clinical data. Volumetric imaging of the placenta was performed with the pregnant woman lying in the semi-recumbent position. After confirming the viability and determining the position of the placenta, optimal probe placement was determined for performing a 2D scan of the entire placenta. This was generally chosen as a cross-sectional plane near the placental center. The width, height, and thickness of the placenta were measured. The mean placental volume was estimated using the following convex–concave shell formula: V = (πT/6) × [4H(W − T) + W(W − 4T) − 4T2], where V = volume; W = maximal width; H = height at maximal height; and T = thickness at maximal height [13]. To calculate the placental volume, it is very important to identify the two ends of the placenta, the width of which is used in the calculation process. Another thing to consider is that the interface of the placenta and decidua is set above the placenta, perpendicular to the width. The thickness was measured along the height line from the junction of the placenta and amniotic fluid to the placental edge.
Other tools and definitions
Preeclampsia and GHT were diagnosed in line with the recommendations of the International Society for the Study of Hypertension in Pregnancy [14]. GDM was diagnosed in accordance with the International Association of Diabetes and Pregnancy Study Groups [15] and the World Health Organization criteria. SGA was defined as a birth weight below the 10th percentile for the gestational age and sex of a standard birth weight curve used in the Turkish population [16]. The APGAR score was assessed using the standard tool [17] at the 1st, 5th, and 10th min after birth. Only the 1st and 5th min APGAR scores were used. The umbilical cord venous blood pH was measured using the blood gas analyzer immediately after childbirth.
Statistical analysis
All statistical analyses were performed using SPSS Statistics for Windows (version 25.0; IBM Corp., Armonk, NY, USA). Conformity of the continuous variables to normal distribution was evaluated using the Kolmogorov–Smirnov test. Non-parametric tests were used to analyze the non-normally distributed data. The Mann–Whitney U test was used to compare two independent groups, and the Kruskal–Wallis test was used to compare more than two groups. The relationship between the continuous variables was examined using the Spearman correlation test. The role of continuous numerical variables in predicting GDM and GHT was evaluated using the receiver operating characteristic (ROC) analysis. Statistical significance was set at p < 0.05.
Ethical Approval
This study was approved by the Ethics Committee of Non-Interventional Clinical Research Ethics Committee of Tekirdag Namık Kemal Unıversity (Date: 2022-07-26, No: 2022.146.07.13).
Results
The median age of the patients was 24 (19–35) years. The median gestational age according to the last menstrual period was 26.19 (20.2–38.96) weeks while it was 12.49 ± 0.63 weeks according to USG. The median placental volume was 22.78 (11.31–35.46) cm3. GDM developed in nine (11.0%) pregnant women and GHT developed in eight (9.8%). Forty (48.8%) pregnant women delivered by C/S due to fetal distress (n = 10) or prolonged delivery (n = 10). Nine (11.0%) newborns were admitted to the ICU, and the most common indications were prematurity with respiratory distress syndrome (n = 3) and transient tachypnea (n = 3). All variables related to the pregnancies, births, and newborns and are summarized in Table 1. There was no significant relationship between the mean placental volume and the birth type (p = 0.540), C/S indication (p = 0.146), admission to the neonatal ICU (p = 0.733), indication for ICU admission (p = 0.520), GDM (p = 0.563), and GHT (p = 0.527) (Table 3). There was a significant positive correlation between the mean placental volume and the maternal weight (r = 0.251, p = 0.023), gestational age according to the last menstrual period (r = 0.572, p < 0.001), and gestational age according to USG (r = 0.735, p < 0.001) (Table 2). ROC analysis evaluating the success of the first trimester mean placental volume in predicting the development of GDM and GHT is presented in Table 3, Figure 1 and Figure 2. The mean placental volume measured in the first trimester could not significantly predict the occurrence of GDM [AUC (95% CI) = 0.559 (0.351–0.767), p = 0.568)] and GHT [AUC (95% CI) = 0.432 (0.239–0.626), p = 0.532)].
Discussion
We found that the first trimester placental volume was significantly associated with the maternal body weight and gestational age at the time of volume measurement. There was no significant relationship between the first trimester placental volume and the other variables examined in the study. Obesity is becoming a common problem among pregnant women worldwide and is associated with a number of placenta-mediated obstetric complications such as preeclampsia, macrosomia, intrauterine growth restriction, and stillbirth. In addition to these direct effects, obesity can negatively and indirectly affect the placental health, pregnancy, and birth process by increasing the risk of GDM [20]. The placenta has a key role in programming intrauterine development. Therefore, it is important to know the effects of maternal obesity on placental development. In the present study, a weak, significant, positive correlation was found between the first trimester placental volume and the maternal weight. We found a statistically significant positive correlation between the maternal BMI and body weight, and the fetal and placental weight. Howell and Powell showed that increased levels of maternal adipokine and metabolic hormones associated with body weight can cause an increase in the placental size and function and have long-term metabolic and behavioral consequences on the newborns [19].
We found that placental volume and weight increase as the gestational age increases; this has been reported in previous studies as well [11, 21]. Our study results confirmed that the first trimester gestational age and placental volume were positively correlated. Pala et al. reported that placental volume was statistically significantly positively correlated with gestational age (r = 0.219) and parity (r = 0.228) [11]. Similarly, in another study, there was a similar and significant relationship between gestational age and placental volume [21]. The placental volume increases as the pregnancy progresses because the fetus grows, which in turn increases the transfer of necessary oxygen, nutrients and other important components. Under hormonal influence, the placental volume increases in the later weeks of pregnancy. Thus, the placental volume is expected to increase as the gestational age increases. Furthermore, this volume increase is necessary for the healthy growth of the baby. However, if the increase in placental volume is more or less than it should be, it can cause problems in the growth or health of the fetus. Although the first trimester placental volume did not significantly affect the pregnancy process and outcomes in our study, ensuring the standardization of placental volume and volume increases according to the gestational age, following up women to assess this, and investigating the cause of possible adverse events can contribute to better pregnancy management and outcomes.
One of the main aims of this study was to evaluate the efficacy of first trimester placental volume in predicting the occurrence of GDB and GHT. However, there was no significant relationship between the first trimester placental volume and the development of GDB and GCT. The increased risk of greater fetal birth weight in pregnant women with GDM also carries the risk of increased placental weight [22]. It is believed that this situation may be an indicator of increased delivery of nutrients to the placenta or a direct effect of GDM independently increasing both fetal and placental growth [22]. Results obtained from previous studies using 2D and three-dimensional (3D) USG show that there is no placental growth in the first trimester in pregnant women with GDM; placental growth occurs in the second trimester and later in pregnant women with GDM [10-12]. Wong et al. suggested that placental overgrowth is not evident in pregnant women with GDM due to the limited-term effect of hyperglycemia in the first trimester; however, this effect emerges as pregnancy progresses when the continuous effect of hyperglycemia is seen [12]. They also stated that the high glucose level in the placenta of patients with GDM may cause an increase in the glycogen, DNA, and lipid content in the placenta. While some studies have reported that the first trimester placental volumes in women with GHT are smaller than that in women without GHT [8, 9, 23], others have reported that they are larger [23], and some have stated that there is no significant difference [24]. Our study results also showed that there was insufficient evidence to use first trimester placental volume measurements in predicting the occurrence of GHT and GDM in the later stages of pregnancy.
Evaluation of the placenta via USG makes important contributions, because of its advantages such as ease of application, absence of side effects, and cost-effectiveness. In the present study, we evaluated the relationship between additional parameters, such as the newborn APGAR score, neonatal ICU requirement, gestational age, umbilical cord blood pH, and delivery type, and the first trimester placental volume, which has never been investigated before to the best of our knowledge. However, no significant relationship was found between any of these variables and the first trimester placental volume. The role of first trimester placental volume, measured via USG, in predicting pregnancy problems in the following trimesters, problems related to delivery, and problems in the early neonatal period seems to be limited or unclear.
Limitation
The current study has some limitations. Since our study was conducted at a single center with relatively few participants, the generalizability of its results is limited. Since the incidence of pregnancy complications such as GHT and GDM is relatively low, the relationship with the first trimester placental volume may not have been shown statistically. The main purpose of our study was to identify a parameter that can predict problems that may occur in the later stages of pregnancy and at birth. Therefore, placental volumes in the second and third trimesters, temporal changes in the placental volume, and the effects of these changes on the results were not investigated. Hence, there is a need for future studies that include case groups with and without relevant gestational complications and with a larger sample population, where placental volumes are evaluated not only in the first trimester, but also in the second and third trimesters.
Conclusion
In conclusion, although the first trimester placental volume was positively related to maternal weight and gestational age, it was not associated with maternal age, maternal height, maternal BMI, GDM, GHT, birth type, C/S indication, gestational age at birth baby’s birth weight, APGAR scores at 1 min and 5 min, cord blood pH, admission to the neonatal ICU, and indication for admission to the neonatal ICU. However, there is insufficient evidence regarding the role of first trimester placental volume in predicting problems related to pregnancy, delivery, and the early neonatal period. Thus, more comprehensive studies are required to investigate this.
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. Walker DW, McLean JR. Absence of adrenergic nerves in the human placenta. Nature. 1971;229:344-345.
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4. Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the normal human placenta. Thromb Res. 2004;114(5-6):397-407.
5. Burton GJ, Fowden AL. Thornburg, KL. Placental Origins of Chronic Disease. Physiol Rev. 2016; 96:1509-1565.
6. Janthanaphan M, Kor-Anantakul O, Geater A. Placental weight and its ratio to birth weight in normal pregnancy at Songkhlanagarind Hospital. J Med Assoc Thai. 2006; 89:130-137.
7. Ashwal E, Ali-Gami J, Aviram A, Ronzoni S, Mei-Dan E, Kingdom J, et al. Contribution of second trimester sonographic placental morphology to uterine artery Doppler in the prediction of placenta-mediated pregnancy complications. J Clin Med. 2022;11(22):6759.
8. 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):1247-54.
9. Soongsatitanon A, Phupong V. First trimester 3D ultrasound placental volume for predicting preeclampsia and/or intrauterine growth restriction. J Obstet Gynaecol. 2019;39:474-479.
10. Ehlers E, Talton OO, Schust DJ, Schulz LC. Placental structural abnormalities in gestational diabetes and when they develop: A scoping review. Placenta. 2021;116:58-66.
11. Pala HG, Artunc-Ulkumen B, Koyuncu FM, Bulbul-Baytur Y. Three-dimensional ultrasonographic placental volume in gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2016;29(4):610-4.
12. Wong CH, Chen CP, Sun FJ, Chen CY. Comparison of placental three-dimensional power Doppler indices and volume in the first and the second trimesters of pregnancy complicated by gestational diabetes mellitus. J Matern Fetal Neonatal Med. 2019;32(22):3784-3791.
13. Azpurua H, Funai EF, Coraluzzi LM, Doherty LF, Sasson IE, Kliman M, et al. Determination of placental weight using two-dimensional sonography and volumetric mathematic modeling. Am J Perinatol. 2010;27(2):151-5.
14. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification and diagnosis of the hypertensive disorders of pregnancy: Statement from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy. 2001;20(1):IX-XIV.
15. Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, et al. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care. 2010;33(3):676-82.
16. Tuzun F, Yucesoy E, Baysal B, Kumral A, Duman N, Ozkan H. Comparison of INTERGROWTH-21 and fenton growth standards to assess size at birth and extrauterine growth in very preterm infants. J Matern Fetal Neonatal Med. 2018;31(17):2252-2257.
17. Apgar V, Holaday DA, James LS, Weisbrot, IM, Berrien, C. Evaluation of the newborn infant; second report. J Am Med Assoc. 168(15):1985-1988.
19. Howell KR, Powell TL. Effects of maternal obesity on placental function and fetal development. Reproduction. 2017;153:97-108.
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Download attachments: 10.4328.ACAM.22098
Tevfik Giray Ozkırım, Mustafa Torehan Aslan, Ozlem Sevinc Ergul, Ilke Ozer Aslan. Can pregnancy, delivery, and early neonatal complications be predicted using the ultrasonographically measured first trimester placental volume? A prospective study. Ann Clin Anal Med 2025;16(4):237-241
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Association between insall-salvati index and anterior cruciate ligament tears: A cross-sectional study
Volkan Kızılgöz 1, Sonay Aydın 1, Mecit Kantarcı 2, Nizamettin Koçkara 3, Ali Osman Gülmez 1, Volkan Gür 3
1 Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, 2 Department of Radiology, Faculty of Medicine, Atatürk University, 3 Department of Orthopaedics and Traumatology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
DOI: 10.4328/ACAM.22258 Received: 2024-05-10 Accepted: 2024-11-11 Published Online: 2024-11-24 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):242-246
Corresponding Author: Volkan Kızılgöz, Department of Radiology, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey. E-mail: volkankizilgoz@gmail.com P: +90 505 799 40 13 Corresponding Author ORCID ID: https://orcid.org/0000-0003-3450-711X
Other Authors ORCID ID: Sonay Aydın, https://orcid.org/0000-0002-3812-6333 . Mecit Kantarci, https://orcid.org/0000-0002-1043-6719 . Nizamettin Koçkara, https://orcid.org/0000-0003-1780-0074 . Ali Osman Gülmez, https://orcid.org/0000-0001-7050-1765 . Volkan Gür, https://orcid.org/0000-0003-4736-6555
This study was approved by the Ethics Committee of Clinical Research of Erzincan Binali Yıldırım University (Date: 2023-03-07, No: 2023-06/3)
Aim: There are many studies in the literature presenting morphological predisposing factors of anterior cruciate ligament (ACL) tears. Insall-Salvati index (ISI), which is widely used to measure patellar height, was investigated as a predisposing risk factor for the ruptures of ACL.
Material and Methods: Patellar tendon length (PTL), Patellar length (PL), and anterior tibial translation (ATT) were measured, and ISI values were calculated for the study and control groups. Knee magnetic resonance (MR) images of 33 patients who had undergone ACL reconstruction due to ruptured ACL, which is surgically confirmed (study group), and 90 patients who had undergone meniscus operation with surgically confirmed intact ACL (control group) were re-interpreted by two reviewers in terms of ISI and ATT values. Independent samples T-test was used to compare the results of the study and control groups. Additionally, intraclass correlation coefficient (ICC) values were presented to verify the interobserver difference between reviewers.
Results: PTL, ATT, and ISI values showed a statistically significant difference, and higher values were obtained in the study group than in the control group (p<0,001). There was excellent agreement between reviewers regarding PTL, PL, ISI, and ATT measurements.
Discussion: ISI had been used as an indicator of patellar dislocation. In this research, ISI was investigated to be in a relationship with ACL injuries in operated patients. The results of this study indicated higher ISI values in patients with ACL rupture. High ISI values might be a predisposing factor for ACL rupture and may be used in preventive medicine in terms of ACL injuries.
Keywords: Insall-Salvati Index, Anterior Cruciate Ligament, Patella, Knee Injuries, Knee
Introduction
Anterior cruciate ligament (ACL) rupture is one of the most common injuries of the knee [1]. ACL injuries are particularly encountered more frequently in sports activities that involve jumping, knee rotation, and direction changes [2]. To develop preventive strategies against this injury, the investigators should be aware of the morphological and kinematic background of the function of ACL. In the literature, many morphological [3] and kinematic factors [4] have been investigated to be in a possible relationship with ACL injuries.
The Insall-Salvati index is widely used to indicate height and location anomalies of the patella. It is an easy method to apply and can be measured in lateral knee radiographs, as well as cross-sectional imaging techniques. Magnetic resonance (MR) imaging has the advantage of showing the cartilage and ligamentous structures better. The patellar tendon length (PTL) can reliably be measured on MR images, which provide higher sensitivity for predicting patellar instability compared with the other classic indices applied on radiographic images [5].
Some authors mentioned that during torsion, valgus, varus, flexion, or extension of the knee, translation is increased to prevent further stress on the patella and femur and leads to strain and injury of the ACL [6]. In the literature, patella alta has been hypothesized to be a risk factor for ACL rupture in children and teenagers [7]. Some recent studies indicated that PTL and ISI measurements were higher in ACL-ruptured patients in comparison with non-ruptured individuals [6, 8].
In this study, the authors aimed to verify the relationship between ISI and ACL tears by comparing surgically confirmed ACL-ruptured and ACL-intact patients who have undergone ACL reconstruction surgery and surgery for meniscal injuries, respectively. The interobserver differences of the measurements were also presented to indicate the reliability of the ISI and anterior tibial translation (ATT) values.
Material and Methods
Patients
This study has been approved by the institutional ethics committee, and the consent form from each patient has been waived due to the retrospective nature of the study. Between January 2020 and February 2023, 36 patients with ACL reconstruction surgery and 91 patients who have undergone surgery for meniscus injuries in the orthopedics and traumatology departments of our hospital have been considered to form the study group and the control group, respectively. Therefore, researchers aimed to compare surgically confirmed patient groups in terms of ACL integrity. Patients who were skeletally mature and had non-contact total ACL rupture were included in the study. 2 patients with traumatic ACL rupture (with tibial microfractures and traumatic bone marrow edema) and one patient under 18 years old were excluded from the study group. One patient with motion artifacts whose MR images could not be interpreted confidently in terms of ISI and ATT measurements was excluded from the control group. Patients with abnormalities of the tibial tuberosity (e.g., Osgood-Schlatter, history of osteotomy procedure) and moderate or severe osteodegeneration (Kellgren-Lawrence type 3 and 4) might influence the results and be planned to be excluded from the study. However, none of the patients has been encountered with this condition. After exclusions, 33 patients in the study and 90 patients in the control group were evaluated.
MR imaging protocol
All the patients underwent MR imaging, which was performed by a 1,5 T magnetic resonance machine (Magnetom Aera, Siemens, Erlangen, Germany) with standard (16-channel) knee coils. Turbo spin echo images with different sequences were obtained. The parameters (TR: Time of repetition, TE: Time of echo, NEX: Number of excitations, FOV: Field of View, ST: Slice thickness, VS: Voxel size, ms: milliseconds, mm: millimeters) used in each imaging series were as follows: Sagittal plane T1 weighted images (TR: 1110 ms, TE: 9,7 ms, NEX: 1, FOV: 180 mm, ST: 3 mm, VS: 0,5×0,5×3 mm), sagittal plane fat-saturated proton density imaging (TR: 3060 ms, TE: 38 ms, NEX: 1, FOV: 180 mm, ST: 3 mm, VS: 0,7×0,7×3 mm), coronal plane fat-saturated proton density imaging (TR: 2390 ms, TE: 20 ms, NEX: 2, FOV: 200 mm, ST: 4 mm, VS: 0,6×0,6×4 mm), axial plane proton density weighted fat saturated imaging (TR: 3440 ms, TE: 30 ms, NEX: 2, FOV: 180 mm, ST: 3 mm, VS: 0,6×0,6×3 mm).
Interpretation of the MR images
Two independent reviewers (a radiology resident with 3 years of experience and a radiologist with 18 years of experience) who were unaware of the surgical results and each other re-interpreted the MR images in different monitors. The reviewers used the same picture archiving and communication system (PACS) (Akgün PACS Viewer v7.5, Akgün Software, Ankara, Turkey) to examine the digital imaging and communication in medicine (DICOM) images of the patients, and the image dataset had randomized (including patient and control groups randomly) by another researcher before the examination of the reviewers. Non-fat-suppressed T1 weighted sagittal plane images were used to perform the ISI and ATT measurements to view the anatomical background. The mid-sagittal plane was used to depict the maximum lengths of the patella and patellar tendon. In addition, non-fat-suppressed T1W images provided good anatomical detail to understand the insertions of the patellar tendon into the patella and tibial tuberosity.
ISI and ATT measurements
Patellar tendon length (PTL) was measured as the length of the posterior surface of the patellar tendon from the lower pole of the patella to its insertion on the tibia. Patellar length (PL) was measured as the greatest superoinferior pole-to-pole length. The PTL/PL ratio was calculated as the Insall-Salvati ratio (Figure 1). Anterior tibial translation (ATT) was measured as described by Chiu [9]. The midsagittal plane of the lateral compartment of the knee was used to measure the ATT. The distance between two parallel lines drawn perpendicular to the image frame, the tangent line to the posterior contour of the lateral femoral condyle, and the posterior contour of the proximal tibial condyle in the same image, was measured as the ATT (Figure 2). Each reviewer measured PTL, PT, and ATT twice and noted the average value as the measurement result. The measured values were noted by the reviewers using two decimals after the comma, which was indicated by the PACS system automatically.
Statistical analysis
All statistical analyses were achieved using IBM SPSS Statistics for Windows version 22.0 /IBM Corp., Armonk, NY, USA). The data distribution normality analysis was tested by the Shapiro-Wilk test, and parametric test procedures were applied after the quantitative data showed normal distributions. Box plot analyses are used to show the data distributions of the measured values. Intraclass correlation coefficient (ICC) values were measured to indicate the interobserver differences. According to the ICC values, less than 0,50, 0,50-0,75; 0,75-0,90,>0,90 indicated poor, moderate, good, and excellent agreement, respectively, in terms of ranking the agreement between reviewers as described by Koo and Li [10]. The PTL, PT, ISI, and ATT values were compared between the study and control groups using the independent T-test. The p values <0,05 were accepted to indicate the significance of the difference in all statistical analyses.
Ethical Approval
This study has been approved by the institutional ethics committee (Ethics Committee of Clinical Research of Erzincan Binali Yıldırım University (Date: 2023-03-07, No: 2023-06/3).
Results
Knee MR images of 101 male and 22 female patients were re-interpreted. The mean age was 32,95 ± 10,36 years for the patients involved in this study. 60 right-sided and 63 left-sided knee MR images were included in this investigation. Each operated knee belonged to a different patient, and there was no operated patient for both knees in the period of the study. Table 1 shows the demographic data of the patients involved in the study.
PTL, PL, ISI, and ATT values measured by each reviewer indicated ICC values as 0.990, 0.986, 0.983, and 0.992, respectively, and showed almost perfect agreement between the reviewers (Table 2).
There was a statistically significant difference between the study and control groups according to PTL, ISI, and ATT values (p values were <0.001 for all three parameters). No statistically significant difference was observed regarding the PL measurements (Table 3). The data distributions were presented for PTL, PT, ISI, and ATT values (Figure 3).
Discussion
This study verified the difference between patients with and without ACL rupture in terms of PTL, ISI, and ATT values with high inter-observer agreements. Higher PTL, ISI, and ATT values were measured in patients with ACL injuries. The theoretical background and observations in the past literature encouraged some authors to consider the effect of ISI on ACL rupture and are worth discussing. Degnan et al. hypothesized that the factors that predispose to ACL ruptures may also predispose to relative patella alta. To emphasize this thought, they suggested that females have a higher incidence of ACL injuries and also a higher incidence of patella alta than male individuals. This situation made the authors think that there is a common predisposing factor for both entities [7]. In addition, females have weaker hamstring muscles compared to males, as mentioned in the literature, and a higher strength ratio between the quadriceps and hamstring muscles has been indicated to provide greater strain in the ACL [11-12]. Singerman et al. reported that the subluxation of a high-riding patella might partly be explained by the association between genitofemoral contact and the medial-lateral component of the contact force. In addition, the authors indicated that any procedure that shifts the patella superiorly to the femoral condyles or tibiofemoral joint line would tend to increase this force and, therefore, renders the tendency to subluxation of the patella [13]. The ratio of PTL to PL is a commonly used and reliable index to measure and determine the patellar height [14]. Insall-Salvati ratio was not only applied to consider the patella alta or baja but studied as a distinct parameter to be related to chondromalacia patella by some authors [15]. On the other hand, there are not many studies in the literature using ISI to be in relationship with ACL injuries via MR imaging and presenting interobserver differences between the reviewers.
The factors which play a role in ACL injuries are investigated in many studies. Morphologically, multiple factors have been studied to be in a possible relationship with ACL ruptures, including tibial plateau characteristics, Q angle, alpha angle, femoral intercondylar notch geometry, condylar width, bone to cartilage height, cartilage slope [3, 16]. In addition to the morphological factors, the genetic background was also investigated by some authors [17].
Some papers mention the possible relationship between ISI and ACL injuries, including the PTL and PT values to investigate as distinct parameters. Degnan et al. measured ISI on knee MR images of children who were arthroscopically proven to have ACL tears, and PTL and IS values were significantly higher in the ACL-ruptured group [7]. Akgün et al. measured PTL and PT on the MR images of an adult population, and increased PTL and ISI values were reported in patients with ACL injuries compared with the control group [8]. Güven et al. evaluated the MR images of skeletally matured patients and revealed significantly higher values in patients with ACL injury about PTL, PL, ISI, and ATT values compared with the control group [6]. The results of this current study were very similar to Güven et al. in terms of higher values according to PTL, ISI, and ATT measurements in the study group. Additionally, ICC values showed a high-grade agreement between reviewers, which strengthens the results and underlines this association between ISI and ACL injuries.
On the other hand, there were studies with negative or opposite results in the literature, and it is important to discuss to determine the exact relationship between ISI and ACL tears. Gültekin et al. indicated no significant difference between patients with and without ACL tears according to ISI measurements in their study [18]. Lin et al. used lateral radiographs to compare patients with and without ACL tears and reported significantly lower values of ISI measurements in patients with ACL tears than in the control group [19].
Limitation
There were limitations of the study to discuss before interpreting the results of this investigation. Although all of the patients in the study and control group were surgically confirmed in terms of the integrity of the ACL, the number of patients was relatively small, and larger patient groups are needed to confirm the results of the current study. The mean age difference between the patient and control groups should also be another factor to mention before determining the results. The body mass indexes of the patients, which are known to be related to considering the axial force to the knee, were not taken into account in this study. The male dominance in the study group is also an important issue to discuss and should be kept in mind before the evaluation of the results. In addition, the absence of data explaining the mechanism of ACL rupture in this investigation can also be considered another limitation of the study.
Conclusion
The biomechanical effect and kinematic alterations with higher PTL and ISI should be better understood to rationalize the mechanism behind these results of the study. Negative results should also be considered to reveal the exact relationship between the patellofemoral geometry and the effect of the specific morphological conditions, which might be a predisposing factor for ACL injuries. Many more studies, including statical evaluations with knee imaging and biomechanical models supported by kinetic tests of the knee joint, may be helpful to analyze this relationship further.
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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17. Dlamini SB, Saunders CJ, Laguette MN, Gibbon A, Gamieldien J, Collins M, et al. Application of an in silico approach identifies a genetic locus within ITGB2, and its interactions with HSPG2 and FGF9, to be associated with anterior cruciate ligament rupture risk. Eur J Sport Sci. 2023;23(10):2098-2108.
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Knowledge, attitudes and practices of caregivers towards inhaler use in asthmatic children
Bui-Binh-Bao Son 1, 2, Nguyen-Thi Kim-Hoa 2, Nguyen-Duy Nam-Anh 1, Nguyen-Manh Phu 2, Le-Binh Phuong-Nguyen 1, Ho-Ly Minh-Tien 1, Phan-Thi Bich-Chi 2
1 Department of Pediatrics, Faculty of Medicine and Pharmacy, Hue University, 2 Department of Pediatric Center, Hue Central Hospital, Hue, Viet Nam
DOI: 10.4328/ACAM.22263 Received: 2024-05-15 Accepted: 2024-07-02 Published Online: 2024-12-01 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):247-253
Corresponding Author: Bui-Binh-Bao Son, Department of Pediatrics, Faculty of Medicine and Pharmacy, Hue University, Hue, Viet Nam. E-mail: bbbson@hueuni.edu.vn P: +84 90 350 3368 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7373-8300
Other Authors ORCID ID: Nguyen-Thi Kim-Hoa, https://orcid.org/0000-0003-2525-4368 . Nguyen-Duy Nam-Anh, https://orcid.org/0000-0002-7070-9045 . Nguyen-Manh Phu, https://orcid.org/0009-0005-2694-8718 . Le-Binh Phuong-Nguyen https://orcid.org/0009-0007-6757-7364 . Ho-Ly Minh-Tien, https://orcid.org/0009-0000-4145-2829 . Phan-Thi Bich-Chi, https://orcid.org/0009-0003-0910-0104
This study was approved by the Ethics Committee of Hue University (Date: 2022-10-10, No: 22/NCKH-DHH)
Aim: This study aimed to assess the knowledge, attitudes, and practices (KAPs) of caregivers towards asthma disease, especially in using prescribed inhalers for children with asthma at Hue Central Hospital, Vietnam.
Material and Methods: This was a cross sectional survey based study conducted at the Pediatric Pulmonary Department of Hue Central Hospital. A questionnaire that assessed KAPs regarding inhalers used in asthma was distributed to 278 parents of children who had asthma.
Results: Only 5.0% of the participants correctly answered > 75% of the questions assessing knowledge, 10.8% gave positive responses to > 75% of the questions related to attitudes, whereas 48.6% correctly performed of practices of nebulizer and 8.6% correctly performed of practices of MDI (metered-dose inhaler) with chamber. There was a relationship between knowledge and attitudes toward the use of inhaler (p<0.05). The proportion of caregivers having good practices of nebulizers was higher in the group with good asthmatic knowledge than in the other groups (70.2% compared to 50.4% and 35.2%, p < 0.05), in the group with good asthma practices compared to the other groups (20.8% vs 6.7% and 4.7%, p < 0.05). Good practice of MDI with spacer was found to be better in the group of caregivers of children with a history of asthma than in the group without a history of asthma (13.8% vs. 3.6%, p < 0.05).
Discussion: Although a minority of the caregivers had a good level of knowledge and attitudes, they tended to demonstrate good practices with regard to the use of an inhaler, especially using nebulizer.
Keywords: Knowledge, Attitudes, Practices, Inhaler Use, Childhood Asthma
Introduction
Asthma is one of the most common chronic diseases in the world. The World Health Organization (WHO) estimates that there are currently about 300 million people with asthma worldwide, and with the current increasing trend, it is expected that this number will reach 400 million people with asthma by 2025 [1]. In children, asthma is the most common chronic disease, ranking among the top 20 diseases in disease-adjusted life years in children worldwide [2]. According to the International Study of Asthma and Allergy in Children (ISAAC) from phase I to phase III, the global rate of asthma symptoms in children and adolescents ranged from 11.1-11.6% and from 13.2-13.7% respectively [3]. World data records showed that the death rate due to asthma in children ranged from 0 – 0.7/100.000 people [4]. Many surveys still show that the current level of asthma control in many countries is still below optimal levels, especially in developing countries, increasing the burden of asthma [5, 6]. It is worth mentioning that the appropriate treatment of pediatric asthma patients does not solely rely on accurate evaluation and prompt intervention by healthcare professionals. It is also greatly affected by parental/caregivers’ knowledge, attitudes, and practices (KAPs) regarding the use of inhalers in asthmatic children. Only a few studies have assessed this issue among children with asthma worldwide. The aim of this study was to evaluate the factors affecting knowledge, attitudes and practices of parents/caregivers towards inhaler use in asthmatic children.
Material and Methods
Patients
The study subjects were the parents and direct caregivers of pediatric patients with asthma aged between 1 and 15 years admitted to the Respiratory Department, Pediatric Center, Hue Central Hospital. 285 parents/caregivers were invited to participate in this survey during the study period.
Method
A cross‐sectional non‐interventional survey-based study was conducted at the Respiratory Department, Pediatric Center, Hue Central Hospital between January 2022 and December 2023.
Data collection methods
We developed a questionnaire to assess caregiver KAPS regarding the use of inhalers [Appendix 1]. Knowledge of parents/caregivers regarding reliever and controller medications consists of 22 items, and each correct answer is given a score of 1. A score of ≤ 50% total points was considered as poor, 51-75% total points as fair and > 75% total points as good. Attitudes of parents/caregivers regarding reliever and controller medications consist of 17 items. Each correct answer is given a score of 1. A score of ≤ 50% total points was considered as negative, 51-75% total points as neutral and > 75% total points as positive [7]. The practice of parents/caregivers using nebulizer consists of 8 items. Good practice would be defined if parents/caregivers performed successfully the two critical steps 3 and 4 (*), while other steps might be partially accomplished; not good practice if parents/caregivers did not perform successfully the two critical steps (*), while other steps might be partially accomplished [8]. The practice of parents/caregivers using a metered-dose inhaler (MDI) with spacer consists of 5 items. Good practice would be defined if parents/caregivers correctly performed all critical steps (*); and not good practice if parents/caregivers performed incorrectly one or more critical steps (*) [9-11].
Procedure
Caregivers were notified about the purpose of the study and they were invited voluntarily. After providing written informed consent, they completed the questionnaire through a face-to-face interview with medical doctors. Each child will have only one caregiver who will be interviewed. The inhaler technique was demonstrated by caregivers by face-to-face demonstration.
Statistical analysis
Data were analyzed according to knowledge, attitude and practices about the asthmatic disease and towards inhaler use. All statistical analysis was performed using SPSS v.18.0 (IBM Corp, Armonk, NY).
Ethical approval
This study was approved by the Hue University Ethics Committee (Date: 2022-10-10, No: 22/NCKH-DHH). Consent was obtained from all participants in this study.
Results
Knowledge
General knowledge about asthma medications: most caregivers did not have good knowledge, accounting for 14 (5.0%), the percentage of having fair and poor knowledge were 11.5% and 83.5% respectively. Regarding using reliever asthma medication knowledge, the percentage of having good, fair and poor knowledge accounted for 5.0%, 11.9% and 83.1% respectively. The percentage of having good, fair and poor knowledge of using controller asthma medication were 4.7%, 8.6% and 86.7% respectively.
Attitudes
The percentage of caregivers who had a positive attitude toward the use of asthma medication was 10.8%, whereas 28.1% and 61.2% of the caregivers exhibited fair and negative attitudes, respectively. Regarding the attitude toward the use of reliever asthma medication, the percentage of caregivers who had a positive, fair and poor attitude were 9.4%, 28.1% and 62.6%. These percentages were similar for the caregivers who toward the use of controller asthma medication, with 12.6% caregivers having a positive attitude, 18.7% of them having fair attitudes and the majority of them (68.7%) having negative attitudes.
Practices
The percentage of caregivers who have good practices in the use of nebulizer was 48.6%, whereas 51.4% had bad practices. Regarding practices in the use of MDIs with spacers, there were only 8.6% of caregivers who had good practices and 91.4% of caregivers who had bad practices.
Factors affecting caregivers’ knowledge towards reliever and controller medications
Caregivers’ knowledge about asthma medication was not significantly associated with caregivers’ gender, age, job, education, asthma history of patients and their families, severity of flare-ups, and severity of asthma (p > 0.05) (Table 1).
The proportion of caregivers with good knowledge about medications was significantly lower in the group that received asthma information from relatives compared to the group that did not receive those (0.0% vs. 7.7%, p < 0.05). However, this rate was not correlated with self-searching information on the internet, radio or receiving information from healthcare staff. The percentage of caregivers with good knowledge about medications was higher in the group with good asthma knowledge than in the other groups (15.8% vs 3.8% and 0.0%, p < 0.05); in the group with good asthma attitudes than the other groups (12.5% vs 0.7% and 0.0%, p < 0.05); in the group with good asthma practices than the other groups (9.6% vs 1.1% and 1.6%, p < 0.05) (Table 1).
Factors affecting caregivers’ attitudes towards reliever and controller medications
Caregiver’s attitudes about asthma medications were not significantly associated with caregivers’ gender, job, asthma history of patients and their families, severity of flare-ups, and severity of asthma (p > 0.05); but significantly associated with caregivers’ age and education (p < 0.05) (Table 2).
The proportion of caregivers with good attitudes about medications was significantly lower in the group that received asthma information from relatives compared to the group that did not receive those (8.2% vs. 12.2%, p < 0.05), However, this rate was not correlated with self-searching information on the internet, radio or receiving information from healthcare staff. The proportion of caregivers with good attitudes about medications was significantly higher in the group with good asthma knowledge than in the other groups (24.6% vs 11.5% and 1.1%, p < 0.05); in the group with good asthma attitudes than the other groups (20.2%% vs 6.7% and 0.0%, p < 0.05); in the group with good asthma practices than the other groups (20.8% vs 3.4% and 1.6%, p < 0.05) (Table 2).
Factors affecting caregivers’ practices of using nebulizers and MDIs with spacers
Caregivers’ practices of using nebulizers were not significantly associated with caregivers’ gender, age, job and education, asthma history of patients and their families, severity of flare-ups, and severity of asthma (p > 0.05). However, there was a significant relationship between caregivers’ knowledge and attitudes about reliever medications, caregivers’ attitudes about controller medications and their practice of using nebulizers (p < 0.05) (Table 3).
The proportion of caregivers with good practices of using nebulizer was significantly lower in the group that received asthma information from relatives compared to the group that did not receive those (35.1% vs. 55.8%, p < 0.05). However, this rate was not correlated with self-searching information on the internet, radio or receiving information from healthcare staff. And the proportion of caregivers with good practices of using nebulizer was significantly higher in the group with good asthma knowledge than in the other groups (70.2% vs 50.4% and 35.2%, p < 0.05); in the group with good asthma practices than the other groups (20.8% vs 6.7% and 4.7%, p < 0.05) (Table 3).
Caregivers’ practices of using MDIs with spacers were not significantly associated with caregivers’ gender, age, job, education, asthma information sources, asthma history of patients and their families, severity of flare-ups, and severity of asthma (p > 0.05) (Table 3).
The proportion of caregivers who had good practices of using MDIs with spacers in the group with a history of asthma was significantly higher than the group without a history of asthma (13.8% vs. 3.6%, p < 0.05).
Table 3 also shows that there was a significant relationship between attitudes toward the use of controller medications and practices of MDIs with spacers: 22.9% of the caregivers who had positive attitudes towards the use of controller medications had good practices toward the use of MDIs with spacers, whereas only 5.2% of those who had negative attitudes had positive practices (p<0.05).
Discussion
This study was the first research relating knowledge, attitudes and practices of caregivers towards using inhalers in Vietnamese children. So, there was not any data to compare with. The GINA and the asthma guidelines for the prevention and treatment highlight the value of education and the optimal use of inhaler devices [12]. In this study, the percentage of caregivers who had poor knowledge about general asthma medications, reliever medications and controller medications were very high: 83.5%, 83.1% and 86.7% respectively. Similar results were found in some other researches, such as in China, where results from an asthma-related KAPs survey showed that more than half the parents had a low level of knowledge [13]. In United Arab Emirates, the KAPs survey demonstrated that 52.6% of patients had poor knowledge [14]. In another study in Cairo, the result revealed that more than one-third of the mothers were found to have incomplete knowledge about asthma medications [15].
Our study found that caregivers’ knowledge about asthma medication was not significantly related to caregivers’ gender, age, job, education (p > 0.05). However, the proportion of caregivers with good knowledge about medications was significantly lower in the group that received asthma information from relatives compared to the group that did not receive those (0.0% vs. 7.7%, p < 0.05). These findings had some points which were similar to other studies and had some points which differ from some other studies. According to the study of Al-Ali et al., level of knowledge was not significantly associated with relation to child, marital status, or the age of the parents; but the percentage of parents who had good knowledge was significantly highest among parents of non‑Emirati non-Arab background (16.1%), among those having educational level of university and above (16.6%) and among those being employed (13.6%) [14]. In the study conducted in Riyadh, Saudi Arabia, Al-Otaibi and Al-Ateeq explored that the majority of caregivers received their information about asthma from pediatricians (87%), followed by family physicians (44.3%), written materials (41.1%), and the Internet (40.7%); and suggested that for better control of asthma, more effort is needed to educate caregivers and to enhance their awareness about asthma, at both hospital and community levels [7].
Regarding attitudes, in this study, the percentage of caregivers who had a positive attitude toward the using of asthma medication, reliever asthma medication and controller asthma medication were 10.8%, 9.4% and 12.6%. These findings differed from those of other studies. According to Al-Ali et al., approximately half of participants (49%) had positive attitudes [14]. In the study of Zhao et al., most participants (89.95%) gave positive responses to ≥ 60% of the attitude questions [14]. Our study found that caregiver’s attitudes about asthma medication were not significant associated with relation to child, caregivers’ sex, job, asthma history of patients and their families, the severity of acute asthma attacks, asthma (p> 0.05). However, caregiver’s attitudes about asthma medication were significant associated with caregivers’ age, education (p <0.05). According to Al-Ali et al., attitudes toward the use of inhalers were associated with age of the parents, whereby elderly parents (>40) had more positive attitudes than younger parents (21-30 year-old) [14]. With regards to inhaler practices, the percentage of caregivers who have good practices in the use of nebulizer was 48.6%, whereas 51.4% had bad practices. There were only 8.6% of caregivers who had good practices in the use of MDIs with spacers and 91.4% of caregivers who had bad practices of that. In contrast with Al-Ali et al, the percentage of parents who had good practices in the use of inhaler was 56.2%, and more than two-thirds of participants who were given asthma action plans stated that they were confident about the use of inhaler [14]. According to Deis et al.’ research, parents who were given a written asthma action plan for acute attacks were more confident in managing their child’s asthma exacerbation, and they felt confident in using inhaler [16]. In our study, caregivers’ practices of using nebulizers were not significant associated with relation to child, caregivers’ sex, age, job and education, asthma history of patients and their families, the severity of acute asthma attack, asthma (p > 0.05). Our study differ from the result of Al-Ali et al which demonstrated that the relationship between education level and practices was significant associated [14]. However, our study showed that there was a significant relationship between caregivers’ knowledge and attitudes about reliever medications, caregivers’ attitudes about controller medications and their practice of using nebulizers (p < 0.05). And there was a significant relationship between attitudes toward the use of controller medications and practices of MDI with the chamber. These findings emphasize the importance of providing knowledge, explain more detail asthma disease for caregivers and guide them carefully on how to use inhalers.
Conclusion
Only a minority of the caregivers in this study had a good level of knowledge as well as positive attitudes regarding asthma, and the use of inhalers, and approximately half had good practices in the use of nebulizer and the minority of caregivers had good practices in the use of MDIs with spacers. Moreover, a good level of knowledge and positive attitudes were related to partial good practices. Besides, knowing patient’s asthma history and receiving asthma information from relatives also play an important role in asthma practice. Education and training for caregivers reveal outstanding steps which contribute to treat asthma successfully, especially in practices of using inhaler. It is required that healthcare staff to educate and assess their understanding and practices.
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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7. AlOtaibi E, AlAteeq M. Knowledge and practice of parents and guardians about childhood asthma at King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia. Risk Manag Healthc Policy. 2018;11:67-75.
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Download attachments: 10.4328/ACAM.22263
Bui-Binh-Bao Son, Nguyen-Thi Kim-Hoa, Nguyen-Duy Nam-Anh, Nguyen-Manh Phu, Le-Binh Phuong-Nguyen, Ho-Ly Minh-Tien, Phan-Thi Bich-Chi. Knowledge, attitudes and practices of caregivers towards inhaler use in asthmatic children. Ann Clin Anal Med 2025;16(4):247-253
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Awareness about hypothyroidism among population in the northern border region, Saudi Arabia: A cross-sectional study
Malik Azhar Hussain 1, Riyad Yahia Al Laham 1, Abdulelah Arar S Alruwaili 2, Daher Dakhel D Alenezi 2, Abdulelah Khalid H Alruwaili 2
Nasser Obaylik M Alruwaili 2, Ekramy Elmorsy 3
1 Department of Surgery, 2 Medical Student, 3 Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia
DOI: 10.4328/ACAM.22324 Received: 2024-07-03 Accepted: 2024-08-12 Published Online: 2024-11-25 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):254-259
Corresponding Author: Ekramy Elmorsy, Department of Pathology, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia. E-mail: Ekramy.elmorsy@nbu.edu.sa P: +966 50 127 5835 Corresponding Author ORCID ID: https://orcid.org/0000-0002-7444-2499
Other Authors ORCID ID: Malik Azhar Hussain, https://orcid.org/0009-0007-4612-178X . Riyad Yahia Al Laham, https://orcid.org/0009-0001-0335-9858 . Abdulelah Arar S Alruwaili, https://orcid.org/0009-0005-3616-532X . Daher Dakhel D Alenezi, https://orcid.org/0009-0000-5357-0179 . Abdulelah Khalid H Alruwaili, https://orcid.org/0009-0007-2160-9260 . Nasser Obaylik M Alruwaili, https://orcid.org/0009-0007-7229-8458
This study was approved by the Ethics Committee of Northern Border University (Date: 2023-12-13, No: 118/23/H)
Aim: This study aimed to assess the public awareness about hypothyroidism the Northern Borders Province, Saudi Arabia.
Material and Methods: The study was conducted as a descriptive cross-sectional study enrolling residents aged 18 years and above in the Northern Borders Province, Saudi Arabia, excluding healthcare workers, medical students, and hypothyroid patients. Data were collected via an online questionnaire. It comprised demographic questions and 20 items assessing hypothyroidism awareness on a three-point Likert scale.
Results: After applying the exclusion criteria to 436, we included 392 participants. The sample was predominantly males (53%), unmarried (60%), urban residents (97%), and holding a university degree (71%). The median age of 25 years. The mean knowledge score was 7.38±4.47, with 54.9% demonstrating good knowledge. Female gender, younger age and students were associated with an increase in knowledge of hypothyroidism (p < 0.0001, <0.0001, and 0.029, respectively)
Discussion: The study reveals moderate awareness about hypothyroidism in the Northern Border of Saudi Arabia. Targeted educational interventions to improve understanding of hypothyroidism should be implemented.
Keywords: Awareness, Hypothyroidism, Thyroid Gland, Saudi Arabia
Introduction
Thyroid glands disorders are globally recognized as one of the commonest endocrinal diseases. The thyroid glands are the largest endocrine glands in the body. These glands are placed at the front of the neck, and they are primarily responsible for producing and releasing thyroid hormones. These hormones play an essential role in protein synthesis, basal metabolic rate (BMR), and the growth of tissues and organs [1].
Hypothyroidism is a hormonal disorder, which is caused by a deficiency of thyroid hormones. Clinical primary hypothyroidism is mainly characterized by elevated levels of thyroid-stimulating hormone (TSH) with a parallel decrease in the free thyroxine hormone levels. Mild or subclinical hypothyroidism, often indicates early thyroid dysfunction, is defined by elevated TSH levels, while free thyroxine remains within the normal range. It can result from either iodine deficiency or an autoimmune attack, leading to autoimmune thyroiditis, which is also known as Hashimoto’s disease [2]. The prevalence of overt hypothyroidism ranges from 0-3% in the USA and 3-7% in Europe [3] to a broader range of 6.18% to 47.34% in the Arab region [4]. Thyroid disorders are very common in Saudi Arabia. It shows a high prevalence of 49.76%, among which 39.25% were subclinical hypothyroidism and 5.3% were primary hypothyroidism [5].
Hypothyroidism is manifested clinically in adults via a wide range of symptoms including easy fatigability, lethargy, intolerance to cold, increased body weight, constipation, voice changes, as well as dry skin. However, symptoms may vary based on age, gender, and duration of the disease [6, 7].
In 2010, a study conducted among hypothyroid patients in Chennai’s community hospital endocrine clinics assessed the knowledge of hypothyroidism. It revealed significant gaps in their understanding regarding the terminology, symptoms, and treatment. Some patients held incorrect beliefs, such as the idea that iodized salt could cure hypothyroidism [8].
Similarly, in 2016, a study in India aimed to evaluate awareness about thyroid disorders. Findings indicated that 29.2% of females had never encountered the term “thyroid.” Furthermore, various symptoms were prevalent, with 55.2% of participants believing in alternative therapies for thyroid diseases [9]. In 2021, a study from the Eastern Saudi Arabian province involved 882 participants and explored public awareness about thyroid diseases’ clinical presentation and the predisposing factors. Participants were categorized as having low (44.7%), average (41.2%), or high (14.2%) knowledge, with a mean knowledge score of 8.67 [10]. Another study revealed that 52% had a good understanding of the thyroid gland and its disorders, while 45% had limited knowledge [11].
A significant concern is the presence of iodine deficiency in many parts of the world, which can severely affect the neuropsychiatric development among fetuses and children [12]. Moreover, the potential impact of milder forms of deficient iodine intake during pregnancy on children’s cognitive skills development and their future school performance [13]. Hypothyroidism was shown to increase the risk of several diseases, including coronary insufficiency, kidney and liver diseases including fatty liver, arthritis, associated diabetes mellitus, and higher cancer mortality [14- 16]. Given these factors, it is crucial to assess the general population’s awareness of hypothyroidism. Such studies can enable physicians to focus on specific issues during initial patient interactions and plan future interventions to enhance disease outcomes. Therefore, this study aimed to assess the awareness of hypothyroidism among the public in the Northern Border of Saudi Arabia and to evaluate its determinants. In addition, the demographic factors affecting the level of awareness were evaluated among the respondents.
Material and Methods
Study design, settings and population
A descriptive cross-sectional study was conducted between January and March 2024 among the general population who resided on the northern border of Saudi Arabia, located in the country’s north, bordering Iraq and Jordan. We included participants who resided on the northern border of Saudi Arabia and were aged 18 years and above, excluding healthcare workers, students in the medical field, and patients with personal and/or family history of thyroid disorders. Knowledge of these groups may affect the estimation of real population knowledge.
Data collection tool
A self-administered online questionnaire was used. The survey was easily disseminated via social media and Google Forms. A panel of specialists made revisions to the questionnaire to guarantee its validity. Expert clearance was obtained before a pilot study with 20 participants was carried out. The questionnaire was made more understandable and clearer by using the pilot study’s input. The final analysis does not incorporate the pilot study’s responses.
The questionnaire was in Arabic and divided into two sections: The first section questions assessed the demographic characteristics of the participants, such as age, gender, marital status, occupation, education, nationality, family history of thyroid disorders and personal history of thyroid disorders. The second section evaluates hypothyroidism awareness, which was adopted from a previous study [17]. It contains 20 items on a three-point Likert scale (yes, no, I do not know). It covers the general knowledge (4 items), risk factors (6 items), clinical manifestations (7 items) and management lines (3 items).
Sample size
Epi info was used to compute the sample size. A sample size of 384 was determined by taking a 5% margin of error, a 50% expected proportion, a 95% confidence interval, and a population of 383,051.
Statistical Analysis
The data was cleaned in an Excel sheet and imported to SPSS software version 27 (Statistical Product and Service Solutions, SPSS Inc, Chicago, IL, USA).
Firstly, the consistency of the responses was evaluated via Cronbach alpha test. To calculate the knowledge score, the correct answers were coded 1, while incorrect and insured answers were coded zero. The normality of the score was tested using a histogram and Kolmogorov- Smirnov test and participants who scored ≥ the median (median=10) were considered to have “Good knowledge.”
For continuous data, descriptive statistics were used to calculate the median and interquartile range, and for categorical variables, frequencies with percentages. We employed multiple logistic regression to identify the factors that predicted the knowledge of hypothyroidism. For this investigation, a p-value of less than 0.05 was deemed significant.
Ethical consideration
The study was reviewed and approved by the local bioethics committee of the Northern Border University, Saudi Arabia (Date: 2023-12-13, No: 118/23/H). Each participant received a thorough description of the goals of the research. All participants subsequently provided online informed written consent, confirming their voluntary involvement in the study. It was underlined how morally preferable it is for participants to leave at any time. Regarding participant identities and responses, anonymity and confidentiality were preserved.
Results
After applying the exclusion criteria to 436, the study included 392 participants. Among them, 47% were female and the median age was 25 years. Approximately 97% were Saudi, 60% were unmarried and 97% resided in urban areas. More than a third of participants (39%) were students, 42% were employed, and 19% were not working. Moreover, 29% had education before university, 71% held universities degrees.
Cronbach Alpha showed estimated internal consistency of the responses of 0.89 which is considered a good satisfactory level of the data validity. The overall average of the correct answers to all questions was 40.7%. The highest average of correct answers was shown in the area of general knowledge (52.25%), while the lowest average scores of correct answers were shown in area of diagnosis and treatment (24.6%). Average scores of the correct answers in all survey studied areas are shown in figure (1). The overall scores of the participants was 9.1 (ranging from 4-17). The average scores of the definite areas of general knowledge, risk factors, clinical manifestations, and management lines were 2.9/4, 2.7/6, 2.8/7, and 0.7/3, respectively.
Regarding the general knowledge questions, approximately 47% recognized that reduced levels of thyroid hormone cause hypothyroidism, 37% reported that they can live without the thyroid gland, 5.8% identified that hypothyroidism is not a contagious disease, while only 48% of participants reported that hypothyroidism can affect children. According to the participants’ responses to the risk factors questions, 46% recognized that females are more likely to develop hypothyroidism. Approximately 48%, 51%, 46%, and 45% recognized positive family history of hypothyroidism, low iodine intake, smoking and autoimmune disease as risk factors for developing hypothyroidism, respectively. Regarding symptoms, 46%, 34%, and 60% correctly identified cold intolerance, constipation and swelling neck as a symptom of hypothyroidism. When 45% correctly identified that hypothyroidism can lead to thyroid cancer and 29% recognized that hypothyroidism can lead to infertility. Hypothyroidism related psychiatric and cognitive disorders were identified by only 26 and 43% of the enrolled participants, respectively. Regarding the knowledge of diagnostic and treatment methods, 19% correctly believed a biopsy must not be performed to diagnose hypothyroidism. However, 8.8% knew that thyroid-stimulating oral medication does not cure hypothyroidism and only 11% knew that surgical removal of the thyroid gland is not a cure for hypothyroidism.
Regarding the effect of demographic factors on the level of knowledge about hypothyroidism among the participants, Female gender, younger age and students were associated with an increase in knowledge of hypothyroidism (p < 0.0001, <0.0001, and 0.029, respectively. Residence area, Marital status, and educational level didn’t show a significant association with knowledge of hypothyroidism. Female gender, younger age and students were associated with an increase in knowledge of hypothyroidism (p < 0.0001, <0.0001, and 0.029, respectively).
Discussion
With the continued increase in its prevalence, thyroid disorders are considered the most common endocrine diseases [18]. Thyroid disorders are very common in Saudi Arabia [5]. A study in Jeddah city reported 29.1% hypothyroidism prevalence [19]. Hence, in this study, we assessed the awareness of hypothyroidism and evaluated the determinants of hypothyroidism awareness among the general population in the northern border of Saudi Arabia.
Generally, 54.9% of participants demonstrated a good level of knowledge. A previous study by Almuzaini et al. reported nearly
similar results, showing a good level of knowledge in 57.32% of responders [20]. However, another study by Alzahrani et al., including mostly participants from the Central region, stated a mainly poor level of knowledge among responders [21]. And surprisingly, the level of knowledge among Saudi patients with hypothyroidism was mostly low [22].
The highest level of knowledge was about hypothyroidism transmission; 77% of participants knew that hypothyroidism is not a contagious disease. Moreover, 60% of participants identified neck swelling as a symptom of hypothyroidism. Anterior neck swelling is a common presentation of thyroid disorders; a previous study assessing the thyroid function in patients with anterior neck swelling indicates an association between subclinical hypothyroidism and patients 70-79 years of age [23]. The lowest level of knowledge was reported in the diagnostic and treatment methods, with 11% of participants knowing that surgical removal of the thyroid gland does not cure Hypothyroidism and 8.8% knowing that Thyroid-stimulating oral medication does not cure Hypothyroidism.
We found a significant association between younger ages and knowledge level about hypothyroidism. This was in accordance with Alzahrani et al. who showed significantly higher knowledge in younger age groups than older individuals [21]. However, this differs from what was reported by Almuzaini et al. who reported no significant association between age groups and knowledge level [20]. Moreover, another study assessing the knowledge among hypothyroidism patients in India showed that the low knowledge level was significantly more prevalent in the 41–50 years age group [24]. The higher level of knowledge among the younger age group and students in the current study can be explained by the national programs about hypothyroidism which targets more school children with screening for hypothyroidism, which is expected to improve their awareness about hypothyroidism.
The current study showed a significant difference was found in knowledge level between males and females with higher levels of awareness among females. This may be attributed to the fact that hypothyroidism is more common in females; thus, they might have previous exposure to the disease and its associated complications. In addition to better awareness among mothers about hypothyroidism in the primary healthcare centers they are bringing their newborns for the early screening sampling for hypothyroidism according to the implemented national program. This finding may be different from what was previously reported among the Saudi population with no gender predominance regarding hypothyroidism awareness [20]. However, in another study among Saudi hypothyroidism patients, male patients showed lower levels of knowledge [21].
Regarding employment status, we found a significantly higher knowledge level among students than among employed and unemployed participants. However, No significant difference was found between knowledge level and marital status, educational level, and residence area. Similar results were previously reported regarding educational level, residence and marital status. [20, 21, 25].
Limitation
This study provides a comprehensive overview of the level of awareness of hypothyroidism among the general population on the northern border of Saudi Arabia. However, several limitations must be addressed: Firstly, online questionnaires may bias the response toward younger and more educated individuals. Secondly, self-reported data carry a risk of response bias and inaccuracies. Finally, the small sample size carries a risk of selection bias and limits the generalizability of the findings.
Conclusion
More than half of the participants demonstrated a high level of hypothyroidism knowledge covering areas of clinical manifestations, diagnosis and treatment. Knowledge was significantly associated with younger ages and students. More effort is recommended for better public awareness about hypothyroidism, which is expected to guide the public to seek medical advice at the proper time with better compliance with the physicians’ instruction which is expected to lead to better outcomes of treatment.
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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7. Carlé A, Pedersen IB, Knudsen N, Perrild H, Ovesen L, Andersen S, et al. Hypothyroid symptoms fail to predict thyroid insufficiency in old people: A population-based case-control study. Am J Med. 2016;129(10):1082-92.
8. Kannan S, Mukundan L, Mahadevan S, Sathya A, Kumaravel V, Bhat RV, et al. Knowledge, Awareness and Practices (KAP) among patients with hypothyroidism attending endocrine clinics of community hospitals in Chennai. Thyroid Res Pract. 2010;7(1):11-5.
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11. Alhawiti AM, Albalawi AS, Alghamdi AA. Assessment of public knowledge regarding the differences between hyperthyroidism and hypothyroidism. Egypt J Hosp Med. 2018;70(9):1595–602.
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Download attachments: 10.4328.ACAM.22324
Malik Azhar Hussain, Riyad Yahia Al Laham, Abdulelah Arar S Alruwaili, Daher Dakhel D Alenezi, Abdulelah Khalid H Alruwaili, Nasser Obaylik M Alruwaili, Ekramy Elmorsy. Awareness about hypothyroidism among population in the Northern Border region, Saudi Arabia: A cross-sectional study. Ann Clin Anal Med 2025;16(4):254-259
Citations in Google Scholar: Google Scholar
Multi-centric comparative analysis of the clinical and functional outcomes of two neuromuscular island flaps for fingertip defects: Hetero-digital versus reverse homo-digital
Feridun Arat 1, Burak Kuscu 2, Kadir Ismail Dere 3, Kaan Gurbuz 1
1 Department of Orthopedics and Traumatology, Kayseri City Education and Research Hospital, Kayseri, 2 Department of Orthopedics and Traumatology, Special Bandirma Royal Hospital, Balıkesir, 3 Department of Orthopedics and Traumatology, Faculty of Medicine, Sutcu Imam University, Kahramanmaras, Turkiye
DOI: 10.4328/ACAM.22358 Received: 2024-08-07 Accepted: 2024-09-24 Published Online: 2024-11-23 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):260-264
Corresponding Author: Kaan Gurbuz, Department of Orthopedics and Traumatology, Kayseri City Education and Training Hospital, Kayseri, Turkiye. E-mail: drkagangurbuz@gmail.com P: +90 532 408 65 03 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0144-5517
Other Authors ORCID ID: Feridun Arat, https://orcid.org/0000-0002-7763-8219 . Burak Kuscu, https://orcid.org/0000-0002-1082-2206 . Kadir Ismail Dere, https://orcid.org/0000-0001-7837-6997
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2023-03-17, No: 2023/4248)
Aim: The goal of fingertip injury reconstructions should be mainly to restore the sensation of the tip with similar pulp volume, texture, and tissue preserving the contour. Regarding this aim, many flap techniques have been defined in the literature. Herein this manuscript, aimed to present and compare clinical outcomes of two different local flap procedures, hetero-digital artery island flap, reverse homo-digital artery island flap, widely used for the reconstruction of fingertip defects.
Material and Methods: A 8-year prospectively followed-up, retrospectively statistical analyzed 83 patients undergoing reconstruction of fingertip defects of 2-5 digits by hetero-digital artery island flap (Group 1, n=56), reverse homo-digital artery island flap (Group 2, n=52) was performed. All participants were assessed using the Quick Disability of Arm, Shoulder, and Hand (Q-DASH) score, the cold intolerance symptom severity score (CISS), static 2-point discrimination, the time taken to return to work, and the range of motion (ROM) values for each operated finger joint.
Results: The mean age of patients was 36.9 years with a male-to-female ratio of 2.6:1 and a mean follow-up of 26.72 months. There were no significant differences in average scores for Q-DASH, CISS, static 2-point discrimination, time to return to work, and DIP ROM between the study groups. However, the average ROM values for the PIP and MCP joints were significantly lower in Group 2 compared to Group 1.
Discussion: The use of hetero-digital artery island flap for fingertip reconstruction is a reliable one-stage option in terms of improved ROM of finger joints. However, the surgical experience is of most importance to reduce postoperative morbidity of the procedure. Homo-digital artery island flap can be seen as another attractive option for less experienced surgeons with excellent postoperative results regarding DASH and CISS scores, static 2-point discrimination and time to return to work.
Keywords: Finger, Tip, Defect, Hetero Digital, Homo Digital, Flap
Introduction
The primary objective of fingertip injuries reconstructions should be to reestablish the sensation of the tip by maintaining the form and ensuring equal pulp quantity, texture, and tissue. The literature has described numerous flap strategies that align with this objective [1]. Each technique presented and applied in a therapeutic setting carries its own set of benefits and drawbacks [2]. The two most frequently employed strategies are homo-digital and reverse hetero-digital neuro-vascular island flaps. Each of these two strategies possesses unique qualities. In the case of, the crushing injuries potentially harm the pedicle vessels, and the soft-tissue defect’s shape or subsequent lacerations on the wounded finger limit the flap’s use, homo-digital neuro-vascular island flaps may not be suitable [3]. In such situations, it may be advisable to consider a hetero-digital island flap. This procedure offers substantial coverage of soft tissue from a distant place with a reliable blood supply. Additionally, it can restore sensation in a single operation without compromising the sensitivity of the donor finger. On the other hand, reverse hetero-digital neuro-vascular island flaps might keep digits immobile in positions that are not natural [4]. This can limit joint range of motion and cause stiffness and contractures in both the donor and recipient fingers, as well as pain at the donor finger sites.
This study commences by examining which type of flap application yields the most beneficial outcomes for fingertip injuries. This study’s goal is to compare the two most common procedures in terms of how well they work and how long the flap lasts. The outcomes that will be looked at are static 2-point discrimination, cold intolerance, time to return to work, length of follow-up, defect size, and joint range of motion (ROM).
Material and Methods
The local ethics committee, with the reference number 2023-4258, granted ethics approval. In five tertiary-level hand trauma centers from December 2014 to March 2023, a retrospective statistical review of prospective follow-up data was conducted on 108 patients who underwent reconstruction of the fingertip defects of the second to fourth digits using a hetero-digital neuro-vascular island flap (Group 1, n=56) and a reverse homo-digital neuro-vascular island flap (Group 2, n=52). The study was omitted from thirteen patients due to the absence of data. Before participating in the study, all patients gave their informed consent, meaning they understood the risks and benefits of taking part. The research was also carried out according to the ethical guidelines set out in the Declaration of Helsinki.
The PNB classification system was employed to evaluate all cases in terms of age, gender, etiology of trauma, duration of follow-up, and the severity of the injury [5]. And also, post-operative Quick Disability of Arm, Shoulder, and Hand Score (Q-DASH) [6], post-operative cold intolerance symptom severity score (CISS) [7], post-operative static 2-point discrimination test, ROM value of phalangeal joints and time to return to work were performed.
Reconstruction of the fingertip defect was initiated with local radical debridement and lavage following routine upper extremity preparation and draping. Surgical planning was initiated with a digital Allen’s test and Doppler examination to verify the functionality of the digital arteries of both the donor and recipient digits. A tie-over dressing is employed in all cases to conceal the donor site defect with full-thickness skin obtained from the severed portion or from an alternative appropriate location, if available. All patients were administered antibiotics and analgesics within 24 hours of surgery. All patients were discharged within 24 hours of surgery in this investigation. Following the surgery, 100 mg of acetylsalicylic acid was administered and maintained for a period of one week. In addition to the postoperative restoration of motion, patients must collaborate with a hand therapist to undergo sensory re-education of the affected digit.
Surgical Techniques
Hetero-digital neuro-vascular island flap operative procedure
The radial side of the digit is chosen in all cases as in the representative case presented in Figure 1 since its removal will have minimal influence on grip and pinch activities. The measurements of the flap needed are marked on the ulnar pulp of the chosen donor finger with roughly 2 to 4 mm broader (Figure 1a). The flap frequently necessitates skin harvesting from the donor finger’s distal and middle phalanges. The flap is incised, and a mid-lateral incision is created starting at the flap’s proximal end. The flap is lifted from the distal to the proximal end, and the complete neuro-vascular bundle is elevated in tandem (Figure 1b). Because the vasa vasorum of the artery is the only source of venous outflow for the flap, it is crucial to raise the neuro-vascular bundle with a reasonably thick cuff of surrounding fatty tissue encompassing the vasa vasorum of the artery. Failure to do this will result in flap congestion. To provide appropriate transposition to the recipient digit, one must dissect quite close to the palm, and the other branch of the common digital artery must be separated. To provide proper flap motion, the common digital nerve might be divided along the fascicles. A subcutaneous tunnel can then be used to transfer the flap to the index and the flap is subsequently inserted into the index finger’s recipient defect (Figure 1c-d).
Reverse homo-digital neuro-vascular island flap operative procedure
After determining the defect’s size and shape, a flap is designed and marked along the mid-lateral axis of the proximal phalanx of the same finger showing the defect (Figure 2a). The junction of the dorsal and volar skin in the lateral aspect of the digit forms a line in which a lazy- S skin incision is continued distally after the division of the proximal end of the digital artery which is the enthesis region of the flexor digitorum profundus. The flap is raised in a proximal to distal direction after identification of neuro-vascular bundle with attention not to use the dominant digital artery. The vascular pedicle should be dissected to the level where the flap may easily reach the defect, with a thin cuff of tissue left surrounding that as well (Figure 2b). To preserve a good cuff of subcutaneous tissues around the vascular pedicle to allow adequate venous drainage, it has to be secure. With the division of the lateral digital sheet, the dissection proceeds in a distal to proximal orientation, releasing the digital artery and nerve up to the proximal interphalangeal joint level. Nerve dissection should never be performed more than 3-5mm from the distal interphalangeal joint. After dissection and elevation, the flap is inset into the defect, which can be advanced or rotated 180o to cover the fingertip defect (Figure 2c).
Statistical Analysis
The PASW version 17.0 software (SPSS Inc., Chicago, IL, USA) was employed to analyze the statistics. In order to verify the Gaussian distribution of the continuous variables, Kolmogorov–Smirnov tests were implemented. All continuous variables with a Gaussian distribution were subjected to T-tests. The study used a significance level of p < 0.05 for all statistical comparisons. This means that any result with a p-value less than 0.05 was considered statistically significant. Different statistical tests were used depending on the type of comparison:
The concordance and disparities between intra- and inter-observer measurements of various scoring systems, including Q-DASH, CISS, static 2-point discrimination, and phalangeal joints’ ROM values, were evaluated in the outcomes of all patients using a two-way mixed-effects model. These measurements were assessed using Interclass Coefficients (ICC). It was determined that the intra- and inter-observer measurements were highly reliable (ICC: 0.935–0.986), –good (ICC: 0.879–0.981), excellent (ICC: 0.911–0.686) –outstanding (ICC: 0.927–0.906), excellent (ICC: 0.955–0.946) –good (ICC: 0.843–0.921), and excellent (ICC: 0.955–0.921) –good (ICC: 0.899–0.831), respectively.
Ethical Approval
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2023-03-17 No: 2023/4248).
Results
The average follow-up period was 26.72 ± 2.7 months, and the mean age of all patients was 27.4 ± 5.1 years. Work-related injuries (n = 61) were the most prevalent cause, followed by home-related injuries (n = 25), motor vehicle-related injuries (n = 17), and others (n = 5). The most prevalent presentations were PNB 400 (palmar oblique loss, no nail injury, and no bone injury) in 71 cases, PNB 521 in 19, and PNB 665 in 18 cases, according to the PNB classification system [5]. Two patients in Group 2 experienced complete flap loss as a result of potential iatrogenic pedicle laceration during dissection. Despite the fact that 35 cases (32.4%) were observed to have transient venous congestion, only four patients experienced partial flap loss, which was treated conventionally (Table 1). The mean of the Q-DASH score, CISS score, static 2-point discrimination, duration to return to work, and ROM value of the DIP joint did not differ significantly between the groups (p < 0.05) (Table 2). While the average ROM in the PIP and MCP joints was considerably lower in Group 2 compared to Group 1, this difference was not statistically significant (p > 0.05). Similarly, although Group 2 had lower ROM values than Group 1, this difference was also not statistically significant (p > 0.05). In comparison to the homo-digital neuro-vascular island flap, the hetero-digital neuro-vascular island flap has a statistically significant detrimental effect on the ROM of the donor digit’s DIP, IP, and MCP joints (p < 0.05) (Table 3).
Discussion
The reconstructive strategy for fingertip injuries is determined by the surgeon’s expertise and skills. Naturally, every proficient surgeon chooses their reconstructive approach based on multiple surgical indications and patient-specific considerations. The patient’s sociodemographic, injury type, and severity characteristics are altered by these factors. This research assessed and compared the clinical outcomes of the three most often employed surgical techniques for fingertip injuries. The findings of this study will have a favorable impact on the decision-making process of surgeons.
The vitality of a flap is the paramount result of these two reconstruction procedures, and it varies across different investigations. Roberto et al. found that all neuro-vascular island flaps with different fingers survived in a study of 22 patients [8]. Wang et al. recently reported a 100% survival rate for all hetero-digital neuro-vascular island flaps, used in 14 patients [9]. Regmi et al. conducted a study on the results of 8 clinical trials including the use of the reverse homo-digital neuro-vascular island flaps technique. They found that the average survival rate was 98% [10]. The flap survival rate in our patients was 98.2% for hetero-digital neuro-vascular island flaps and 96.1% for reverse homo-digital neuro-vascular island flaps.
Temporary venous congestion can be identified in nearly all procedures utilized for fingertip injury restorations, occurring at different frequencies. Venous congestion may occur in the early postoperative period, particularly within the first 24 hours, with reverse homo-digital neuro-vascular island flaps. This is likely caused by the rotation of the flap during the insertion of the fingertip defect. In hetero-digital neuro-vascular flaps, venous congestion occurs due to extensive dissection of the pedicle, rather than the inclusion of fatty tissue cuff on the pedicle that contains venae comitantes for proper venous drainage. In our research, postoperative venous congestion was clinically determined in 14 patients of hetero-, and 16 patients of homo-digital neuro-vascular island flaps.
Postoperative neuropathic pain is more prevalent in patients who had a reverse homo-digital neuro-vascular island flap compared to those who received a hetero-digital neuro-vascular island flap. This was seen in a study involving 18 patients. The most significant adverse consequence of the reverse homo-digital neuro-vascular island flap is likely due to compression of the digital nerve following the rotation of the flap to repair the fingertip defect. Kim SK proposed in his article which should keep in mind that retaining a tiny amount of adipose tissue beneath the donor site on the fingertip could potentially reduce neuropathic discomfort associated with this condition [11].
Another important result of fingertip injury healing is the improvement of static 2-point discrimination. Based on the statistical analysis conducted on patients, there is no significant difference observed in 2-point discrimination. However, upon comparing the individual results in each group to the existing literature, it was discovered that they were all comparable [12- 14].
The precise etiology of cold intolerance remains unclear, but alterations in brain and/or vascular pathways have been implicated. The CISS scale spans from zero to one hundred points. The diagnosis of cold intolerance is determined using a cut-off value of 30 points [7], based on the 95 percent confidence interval in a healthy population. Our study found no significant statistical difference between the groups in terms of the CISS. However, patients who underwent hetero-digital neuro-vascular island flap surgery reported fewer complaints, potentially due to the characteristics of the flap. Regarding another aspect, Karjalainen and Jokihaara made the decision not to combine the data on cold intolerance in their review and meta-analysis due to the presence of heterogeneously dispersed data [15].
Due to the fact that stiffness in the hand joints is the most uncertain outcome, it is recommended that thorough postoperative physical therapy be conducted following fingertip damage reconstructions. In this particular study, it was determined that the decreased range of motion (ROM) values of the PIP and MCP joints for Group 1 compared to Group 2 were associated with a longer period of immobilization of these joints as a result of donor site morbidity. It was believed that the flap elevation from a donor site close to the MCP joint, which may restrict the range of motion for MCP and PIP joints, was the cause of the decreased range of motion (ROM) values of PIP and MCP joints for Group 1 compared to Group 2, despite the fact that there was no significant difference between the two groups.
Conclusion
In conclusion, the choice between homo-digital and hetero-digital island flaps for fingertip reconstruction should be based on the specific characteristics of the injury and the desired outcomes. By comparing the clinical effects and long-term results of these techniques, healthcare providers can make informed decisions to optimize patient outcomes in fingertip reconstruction procedures.
Limitation
The primary limitations of this research were the inability to standardize etiological components and the study’s retrospective and uncontrolled nature. Another constraint of the study is the lack of randomization in the selection of cases, as the surgeon applied his favorite procedure to his preferred patient without any random assignment.
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. Chen K, Yang S, Cheng Y, Xiang W, Zhang J, Shen J et al. Reverse homodigital artery versus reverse dorsal homodigital island flaps for fingertip defect repair: A meta-analysis. J Plast Reconstr Aesthet Surg. 2023;82:237-246.
3. Wang S, Yuan C, Ding W, Shen H, Gu J. Repair of finger pulp defect and sensory reconstruction using reverse homodigital artery ısland flap with palmar cutaneous branches of the proper digital nerve. Ann Plast Surg. 2023;90(6):559-563.
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Feridun Arat, Burak Kuscu, Kadir Ismail Dere, Kaan Gurbuz. Multi-centric comparative analysis of the clinical and functional outcomes of two neuromuscular island flaps for finger tip defects: Hetero-digital versus reverse homo-digital. Ann Clin Anal Med 2025;16(4):260-264
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Determinants of colorectal cancer diagnosis delay in Morocco
Fatima Zahra Ben Fouıla 1, 2, 3, Fatima Zahra Meskı 4, Mohammed Adnane Tazı 1, Samia El Hilali 2, 3, Nada Bennani Mechita 2, 3, Majdouline Obtel 2, 3
1 Directorate of Epidemiology and Diseases Control, Ministry of Health and Social Protection, 2 Laboratory of Biostatistics, Clinical Research and Epidemiology (LBRCE), 3 Department of Public Health, Laboratory of Social Medicine, Faculty of Medicine and Pharmacy, Mohamed V University, 4 National School of Public Health, Ministry of Health and Social Protection, Rabat, Morocco
DOI: 10.4328/ACAM.22368 Received: 2024-08-15 Accepted: 2024-10-03 Published Online: 2024-11-28 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):265-271
Corresponding Author: Fatima Zahra Ben Fouila, Department of Public Health, Laboratory of Social Medicine, Faculty of Medicine and Pharmacy, Mohamed V University, Morocco. E-mail: fatima.zahra.benfouila@gmail.com P: +212 614 813 504 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2247-2135
Other Authors ORCID ID: Fatima Zahra Meskı, https://orcid.org/0000-0002-4296-0574 . Mohammed Adnane Tazı, https://orcid.org/0009-0007-0926-4773 . Samia El Hilali, https://orcid.org/0009-0009-2320-873X . Nada Bennani Mechita, https://orcid.org/0000-0001-9893-9312 . Majdouline Obtel, https://orcid.org/ 0000-0002-3357-0603
This study was approved by the Ethics Committee of Biomedical Research at the Faculty of Medicine and Pharmacy of Rabat (Date: 2018-02-28, No: 36/18)
Aim: In Morocco, over the last 10 years, the colon and rectum have remained the third most common localizations of cancer in both sexes. An advanced diagnosis is often correlated with a poorer prognosis and lower survival rates. Additionally, the time to diagnosis is defined as a predictor of stage and survival. Our study aimed to explore the diagnostic delay of colorectal cancer (CRC) and its determinants.
Material and Methods: A retrospective and cross-sectional analytical study was conducted, including all CRC cases admitted to the National Institute of Oncology in Morocco between 2015 and 2016. Sociodemographic, clinical data, as well as data on the care pathway of patients admitted during the 2015–2016 period, were collected. Diagnostic delay was defined as the time interval between the onset of the first symptoms and the date of diagnosis. A quantile regression analysis was applied to determine the factors associated with this delay.
Results: A total of 321 cases of CRC were included. The median diagnostic delay was three months. This delay was longer for rectal cancer than for colon cancer. The median diagnosis delay of CRC was extended by two months in the presence of rectal bleeding (p-value < 0.01).
Discussion: Diagnostic delay was significantly associated with rectal bleeding, despite it being an alarming symptom. This association has been reported in several previous studies.
Keywords: Colorectal Cancer, Delay, Diagnosis, Factors, Morocco
Introduction
Colorectal cancer (CRC) is a major cause of mortality and morbidity globally [1]. It ranks as the third most common cancer and the fourth leading cause of cancer-related deaths worldwide, with 1.4 million new cases and around 700,000 deaths annually [2]. In recent decades, the incidence of CRC has increased significantly. The number of newly diagnosed CRC cases rose from 783,000 in 1990 to 1,361,000 in 2012 [3]. In terms of geographical distribution, the incidence of this cancer has increased in industrialized countries with a medium or high Human Development Index [2].
Mortality is estimated at 694,000 deaths in both sexes, accounting for 8.5% of the total, with more deaths (52%) occurring in the less developed regions of the world, reflecting a poorer prognosis in these regions [3].
In Morocco, according to data from the cancer registry of the Greater Casablanca region (2013-2017) (Available at: https://www.irc.ma/images/Registre_des_Cancers_de_la_Region_du_Grand_Casablanca_2013-2017.pdf), CRC is the third most common cancer in both sexes, representing 7.7% of cases. Its incidence increases with age, with the 65 to 74 age group being the most affected.
Mortality attributable to CRC was estimated at 2,892 deaths (7.8%) in 2022, according to Globocan estimates (Available at: https://gco.iarc.fr/today/fact-sheets-populations).
The Ministry of Health and Social Protection, in collaboration with the Lalla Salma Foundation (FLS), developed a National Cancer Prevention and Control Plan for 2010–2019 (Available at: https://www.contrelecancer.ma/site_media/uploaded_files/PNPCC_-_Axes_strategiques_et_mesures_2010-2019.pdf). The goal of this plan is to reduce cancer-related morbidity and mortality and improve the quality of life for patients and their families.
Diagnosis and treatment are key components of this plan. Research in these areas is crucial for improving quality of care, especially by reducing the time required to access cancer diagnosis and treatment. This delay serves as a critical indicator of care quality and highlights disparities in access. While several studies have investigated delays in managing breast and cervical cancers [4, 5], no research has specifically focused on CRC.
Studies have shown that delays in diagnosis, attributable to both patients and practitioners, are associated with the stage of CRC at the time of diagnosis [6]. Furthermore, survival rates are closely linked to the stage at diagnosis: the five-year survival rate is over 90% for stage I patients but only 10% for those with stage IV CRC [7]. Therefore, reducing diagnostic delays is crucial for improving patient outcomes [8, 9].
In Morocco, where CRC is the third most common cancer in both sexes, there is currently no specific national program, unlike breast and cervical cancers.
This study aimed to describe the delay in the diagnosis of CRC and identify its determinants in patients treated at the National Institute of Oncology Sidi Abdellah (NIO) in Rabat during the 2015–2016 period.
Material and Methods
Design and population of the study
A retrospective, cross-sectional analytical study was conducted at the NIO, the first hospital specializing in cancer care in Morocco, inaugurated in 1983. The NIO receives approximately 6,000 new patients annually from across the Kingdom, making it an ideal location for this study.
The study population comprised all patients admitted to the NIO between January 2015 and December 2016, regardless of their age, residence or stage of CRC.
Study eligibility criteria
Inclusion criteria:
The subjects included in this study were Moroccan nationals, patients admitted for the management of primary CRC and patients with a diagnosis confirmed by pathological examination.
Exclusion criteria:
Subjects were excluded from this study if they had a personal history of other cancers or of their medical record lacked essential data for this study.
Sampling
Kish’s formula was used to calculate the minimum sample size, assuming that 50% of the delays were greater than the median. With an accuracy of 0.05, the minimum required sample size was 246. To account for the high variability in delays and the potential for missing data, the sample size was increased to 365.
Tool and data collection
Information was collected using a data collection sheet, which allowed for the extraction of all relevant medical records for patients who met the inclusion criteria.
Definition of study variables
The collected information included sociodemographic data, clinical data and information on the care pathway.
Diagnostic delay was defined as the time interval between the onset of symptoms and the confirmation of diagnosis through anatomopathological examination.
Management and statistical analysis
The collected data were coded and entered into a pre-established questionnaire developed using Epi Info version 7 software, with input control. Paper-based records were archived with the study documents.
All variables were analyzed after cleaning the database and missing data were reported.
Bivariate analyses were conducted using the Mann-Whitney and Kruskal-Wallis tests. Quantile regression was then performed to identify factors influencing the diagnostic delay.
Data analysis was carried out using Epi Info version 7 and Stata 10 software.
Ethical Approval
This study was approved by the Ethics Committee of Biomedical Research at the Faculty of Medicine and Pharmacy of Rabat (Date: 2018-02-28, No: 36/18).
Results
A total of 321 cases of CRC were included. The median diagnostic delay for CRC was three months (interquartile range: 1.0 – 7.0). When stratified by cancer location, the median delay was two months (interquartile range: 0 to 5 months) for colon cancer and four months (interquartile range: 2 to 10 months) for rectal cancer.
Due to significant variability in the distribution of diagnostic delays (with extreme values), the delays exhibited an asymmetrical distribution in our study population. Consequently, the analysis of diagnostic delay based on sociodemographic, clinical and organisational factors was conducted by comparing medians, with p-values derived from exact tests, such as the Mann-Whitney and Kruskal-Wallis tests.
The analysis revealed a statistically significant difference (p-value < 0.01) in diagnostic delay between patients with colon cancer and those with rectal cancer. Therefore, we conducted further analyses on all data and by cancer location.
The analysis of CRC diagnostic delay according to sociodemographic characteristics revealed a statistically significant association with sex (p = 0.04). The median diagnostic delay was three months for women and four months for men. In addition, there was a statistically significant difference (p = 0.01) in diagnostic delays between patients from rural and urban areas, with median delays of four months and three months, respectively. Smoking and alcoholism were also statistically associated with diagnostic delay (see Table 4).
For other sociodemographic characteristics, no significant dependence on diagnostic time was found, applicable to all cancer locations.
However, among patients with colon cancer, having a family history of cancer was associated with a longer diagnostic delay (p = 0.01) (see Table 1).
Clinical features such as transit disorders, weight loss, general impairment, tenesmus and the number of clinical signs were associated with CRC diagnostic delay regardless of cancer location. The median diagnostic delay was five months for patients with rectorrhagia and two months for those without (see Table 2).
Analysis by location revealed a significant association between diagnostic delay and signs such as rectorrhagia, abdominal pain, transit disorders, weight loss and general deterioration in cases of colon cancer. In contrast, only rectorrhagia was significantly associated with diagnostic delay in rectal cancer cases (see Table 2).
Regarding CRC stage and diagnostic delay, there was a statistically significant difference between median delays for early-stage (I and II) and late-stage (III and IV) diagnoses: two months for stages I/II and four months for stages III/IV (p = 0.04) (see Table 2).
Considering the patient management pathway, the mode of tumor discovery was statistically associated with diagnostic delay. The median diagnostic delay for CRC was four months, excluding patients diagnosed urgently due to complications (see Table 2).
The analysis of factors associated with diagnostic delay, adjusted for significant characteristics identified in the bivariate analysis using quantile regression, revealed a significant association between CRC diagnosis time and factors such as rectorrhagia, transit disorders, weight loss, number of clinical signs and place of endoscopy. Specifically, the median diagnostic delay was statistically longer by two months for patients with rectorrhagia compared to those without (p-value < 0.01), after adjusting for other sociodemographic, clinical and organizational factors (see Table 7). The delay was also extended by about one month in patients who experienced transit problems or weight loss compared to those who did not (p-value < 0.01). Additionally, when patients presented with more than three clinical signs, the median diagnostic delay was reduced by just over one month compared to those with three or fewer signs (p-value < 0.01) (see Table 3).
After stratifying the diagnosis delay by location, rectorrhagia was found to significantly delay the diagnosis of both colon and rectal cancers by approximately three months, after adjusting for other clinical signs. In cases of colon cancer, the diagnosis was faster if complications required emergency intervention. Conversely, the diagnosis of CRC was delayed by two months when patients presented with non-specific signs of colon cancer (see Table 3).
For rectal cancer, tenesmus was significantly associated with a delay in diagnosis, with a median delay of two months in patients presenting this sign (p-value < 0.01) (see Table 3).
Discussion
Diagnosis delay
In this study, diagnostic delay is defined as the time interval between the onset of the first clinical signs and the diagnosis of CRC. The median delay was three months with considerable variability (±7.8 months). This is longer compared to a multicenter study conducted in Spain, which reported a median delay of 36.5 days (interquartile range: 73) [10], and another study in Jordan with an average delay of 5.6 months from symptom onset to the first consultation [11]. In our study, CRC was diagnosed within three months of symptom onset in 50% of cases. The median delay was four months in a study conducted in Spain [12] and 136 days in a cohort from the United Kingdom [13]. It is important to note that a very short diagnostic delay is not necessarily associated with a better prognosis. Torring et al. (2011) demonstrated in a seven-cohort study comprising 11,720 patients that both primary care delay and secondary care are associated with advanced CRC [14].
Paradoxically, in our population, the diagnostic delay was significantly longer for rectal cancer (median time = four months) compared to colon cancer (median time = two months), despite rectal cancer often presenting with more recognizable symptoms. This observation aligns with previous studies [10, 12, 15, 16]. For instance, in Norway, the diagnosis of rectal cancer was delayed by a month compared to colon cancer [17]. This discrepancy might be attributed to patients’ perceptions of proctological examinations. Indeed, a study conducted at Hassan II University Hospital in Fez found that 84% of patients expressed fear or shame regarding this examination [18].
In our study, diagnostic delay was significantly associated with rectal bleeding, despite it being an alarming symptom. This association has been reported in several studies [12, 13, 19]. Previous research suggests that hemorrhoids, which affect 4% to 5% of the adult population [11], cause prolonged diagnostic delays may result from the assumption by patients and/or doctors that rectal bleeding. A longer delay may occur if the patient has both cancer and hemorrhoids. For example, a Danish study found that 63% of CRC patients with rectal bleeding also had hemorrhoids [11]. This may be related to the low positive predictive value of rectal bleeding as a symptom of CRC, ranging from 2.2% to 16%, as reported in a meta-analysis [7]. However, some studies have reported the opposite, noting a shorter diagnostic delay in CRC patients with rectal bleeding [13].
Other clinical signs, such as transit disorders and weight loss for CRC and tenesmus specifically for rectal cancer, were also significantly associated with longer diagnostic times. This, similar to rectal bleeding, could be attributed to the lack of specificity of these symptoms, as several digestive pathologies present with these signs. Some studies report similar findings, while others have not found a significant association [16]. In the absence of a pathognomonic sign for CRC, the risk of late diagnosis remains high, which helps explain the large proportion of late-stage cases observed in our study and in general. Conversely, our results indicated that the presence of multiple signs (more than three) was associated with a faster diagnosis. A previous study has confirmed this association when another one has not found a significant association between the number of clinical signs and diagnosis delay for CRC [12, 13].
The observed effect of clinical signs on the diagnostic delay of CRC partly explains why patients diagnosed through symptom onset and standard diagnostic methods (such as colonoscopy) experienced longer delays compared to those diagnosed during emergency interventions due to obstruction. This relationship between the mode of discovery and diagnostic delay is supported by other studies [12, 20]. Some researchers differentiate their populations based on the mode of tumor discovery [20].
A family history of cancer was found to significantly prolong the median diagnostic delay for colon cancer. This may be attributed to the negative perception of the disease and the fear of being a carrier, influenced by personal experience with a loved one. Although this factor is less studied, some research associates it with the time to treatment, while other studies have not linked it to diagnostic delay [12].
Strengths and limitations of the study
Quantile regression provides a more comprehensive view of variations in diagnostic delays compared to other analytical techniques. Nonetheless, our study has certain limitations. Being retrospective, it is subject to challenges regarding data reliability. Additionally, the lack of information on the timing of the first medical consultation after symptom onset necessitated treating the entire diagnostic period as a whole, without distinguishing delays caused by patients from those attributable to the healthcare system.
Conclusion
In conclusion, the presence of alarming signs often delays the early diagnosis of CRC rather than facilitating it. Therefore, it is recommended to launch extensive awareness campaigns about presumptive signs for both the general population and healthcare professionals. Additionally, enhancing management capabilities and ensuring the availability of diagnostic tools, such as endoscopy and medical imaging, are crucial. Efforts should also focus on implementing an effective screening program targeting individuals at medium risk.
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.22368
Fatima Zahra Ben Fouıla, Fatima Zahra Meskı, Mohammed Adnane Tazı, Samia El Hilali, Nada Bennani Mechita, Majdouline Obtel. Determinants of colorectal cancer diagnosis delay in Morocco. Ann Clin Anal Med 2025;16(4):265-271
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Can the halp score, a new prognostic tool, predict the progression of pseudoexfoliation patients to pseudoexfoliation glaucoma?
Betul Akbulut Yagci 1, Huseyin Erdal 2
1 Deparment of Opthalmology, Aksaray University Training and Research Hospital, 2 Department of Medical Genetics, Faculty of Medicine, Aksaray University, Aksaray, Turkiye
DOI: 10.4328/ACAM.22378 Received: 2024-08-21 Accepted: 2024-11-04 Published Online: 2024-11-27 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):272-275
Corresponding Author: Betul Akbulut Yagci, Deparment of Opthalmology, Aksaray University Training and Research Hospital, Aksaray, Turkiye. E-mail: betul_dr@hotmail.com P: +90 505 946 95 96 Corresponding Author ORCID ID: https://orcid.org/0000-0002-0608-9195
Other Authors ORCID ID: Huseyin Erdal, https://orcid.org/0000-0003-0786-5077
This study was approved by the Ethics Committee of Aksaray University (Date: 2023-06-22, No: 70-SBKAEK)
Aim: The present study aims to investigate the prognostic role of hemoglobin, albumin, lymphocyte, and platelet (HALP) score in pseudoexfoliation syndrome (PEXS) patients and its relationship with pseudoexfoliation glaucoma (PEXG) progression.
Material and Methods: This retrospective study included 58 PEXS and 61 PEXG patients. All groups ‘ demographic information and hemograms, s were collected from the hospital automation system. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), systemic immuno-inflammatory index (SII), systemic inflammatory response index (SIRI), pan-immune inflammation value (PIV), and HALP were calculated to both groups. The results were compared among the groups.
Results: In this study, there were 119 participants in total: 58 patients with PEXS with an average age of 71.3 ± 8.9 years and 61 patients with PEXG with an average age of 71.3 ± 8.9 years (p=0.15). In paired comparisons, it was observed that the NLR, PLR, SII, SIRI, and PIV indices of the groups were not found to be statistically significant (p>0.001). The HALP score value was lower in the PEXG group than the PEXS (4.73 ±1.99 and 6.3 ±2.63, respectively) (p<0.001). The AUC of the HALP score for PEXS and PEXG was 0.696. The optimal cut-off value of HALP to predict PEXG was ≤ 4.23, with 85% sensitivity and 51.7% specificity (95% confidence interval 0,605-0,777, p<0.01).
Discussion: It was found that a lower HALP score was significantly associated with PEXG patients and could be an independent prognostic factor. Although this score alone is not sufficient, this study is important in that it may predict the possibility of developing PEXG.
Keywords: Halp Score, Pseudoexfoliation Glaucoma, Pseudoexfoliation Syndrome
Introduction
Pseudoexfoliation syndrome (PEXS) is an age-related systemic disease affecting the extracellular matrix. It is characterized by the overproduction and accumulation of extracellular elastic fibrillary substance (pseudoexfoliation), particularly in the anterior segment of the eye [1]. The prevalence of PEXS increases with age and varies among countries. For instance, the prevalence of PEXS in individuals over the age of 60 is 25% in Iceland, 20% in Finland, 6.3% in Norway, 4.7% in Germany, 4% in England, and 0% in the Eskimo population, whereas it has been reported as 5-11.2% in Turkey [2- 4]. PEXS is strongly associated with elevated intraocular pressures in up to 44% of patients, leading to the subsequent development of pseudoexfoliation glaucoma (PEXG). It is recognized as the most commonly identified cause of secondary open-angle glaucoma [5]. In Turkey, the prevalence of PEXG patients was 26.8% in individuals over 60 years old [4].
The pathophysiology of PEXS and pseudoexfoliation glaucoma (PEXG) patients have been associated with systemic and ocular inflammation. In the literature, it has been reported that the values of many cytokines and chemokines are high in PEXS/PEXG patients in aqueous humor and serum [6- 8]. Tumor necrosis factor-alpha (TNF-α) and high sensitivity C-reactive protein (hs-CRP) levels, which are considered to be markers of inflammation and peripheral endothelial dysfunction, were also measured to be high in patients with pseudoexfoliation [9].
Recently, increased inflammatory biomarkers calculated by hemogram parameters have been a research topic in ocular inflammation diseases such as PEXS, dry eye disease, and glaucoma [10- 13]. Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) inflammatory indexes were observed to be significantly higher in PEXS and PEXG patients than healthy group [12]. In a study evaluating another inflammatory index marker, the systemic immuno-inflammatory index (SII), it was found that there was an association between higher SII with PEXS and PEXG [14]. These studies suggested that PLR, NLR, and SII may be useful in predicting the prognosis of PEXS patients and progression to PEXG.
The hemoglobin, albumin, lymphocyte, platelet (HALP) score consisting of complete blood count parameters and albumin has been defined as a new inflammatory index. In recent studies, the HALP score has been proven to be a good prognostic indicator in patients such as malignancy and acute ischemic stroke [15- 18]. This inflammatory index has not been previously evaluated in PEXS and PEXG patients associated with systemic inflammation. According to our knowledge, our study is the first to evaluate the association of HALP score with PEXS prognosis and progression to PEXG. Our study aims to investigate the prognostic role of HALP score in PEXS patients and its relationship with PEXG progression.
Material and Methods
A total of 119 patients, of which 61 had PEXG and 58 had PEXS, were diagnosed between March 2022-2023 at Aksaray University Training and Research Hospital’s Ophthalmology Department and were subsequently followed up. Demographic information for both the study and control groups was retrieved from the hospital automation system. The study was approved by the local ethics committee following the Declaration of Helsinki principles, and all participants gave informed written consent.
Patients with PEXS exhibited normal optic nerve head results, a standard visual field, and intraocular pressure (IOP) less than 21 mm Hg, in addition to the characteristic pseudoexfoliative material deposition observed during dilated eye examinations. In contrast, the PEXG group exhibited pseudoexfoliative material, along with evidence of IOP> 21 mm Hg, glaucomatous optic neuropathy, and glaucomatous damage in the visual field.
Exclusion criteria encompassed autoimmune disorders, cardiac diseases, diabetes mellitus, hyperlipidemia, hypertension, acute systemic infections, ocular conditions other than pseudoexfoliation and cataract, recent surgery within the last 3 months, malignancy history, ongoing systemic medications affecting blood parameters (especially steroids), and a history of smoking or alcohol consumption.
The NLR, PLR, SII, systemic inflammatory response index (SIRI), pan-immune inflammation value (PIV), and HALP, respectively, were calculated as follows:
neutrophils ÷lymphocytes
platelets ÷lymphocytes
platelets ×( neutrophils ÷lymphocytes)
(neutrophils ×monocyte)÷lymphocytes
(neutrophils×platelets ×monocytes)÷lymphocytes
(hemoglobins ×albumins ×lymphocytes )÷platelets
Statistical Analyses
The study groups underwent statistical analysis using version 22 of the Statistical Package for the Social Sciences (SPSS). The Kolmogorov-Smirnov test was employed to assess the normality of the data. A t-test was used for comparing continuous variables, presenting results in means and standard deviations. In cases where variables deviated from a normal distribution, the Mann-Whitney U test was utilized for comparison. Statistical significance was determined at a threshold of p<0.05. Receiver operating characteristic curves (ROCs) were created to address the predictive role of HALP.
Ethical Approval
This study was approved by the Ethics Committee of Aksaray University (Date: 2023-06-22, No: 70-SBKAEK).
Results
A total of 119 patients -58 with PEXS and 61 with PEXG- with average ages of 71.3 ± 8.9 years and 71.3 ± 8.9 years, respectively, participated in this study. There were no gender or age-related statistically significant differences between the groups (Table 1). The median and minimum-maximum results of the hemogram parameters, albumin, and inflammatory indexes among both groups are presented in Table 2.
There was no statistically significant distinction between the hemogram parameters and albumin levels of the groups (p>0.05). Furthermore, inflammatory indices for the PEXS and PEXG groups were computed. In paired comparisons, it was detected that the NLR, PLR, SII, SIRI, and PIV indices of the groups were not found to be statistically significant (p>0.001, Table 2). The HALP score value was lower in the PEXG group than in the PEXS (4.73 ±1.99 and 6.3 ±2.63, respectively) (p<0.001) (Table 2). The AUC of the HALP score for PEXS and PEXG was 0.696. The optimal cut-off value of HALP to predict PEXG was ≤ 4.23, with 85% sensitivity and 51.7% specificity (95% confidence interval 0,605-0,777, p<0.01) (Figure 1).
Discussion
This is the first study to examine hemogram and albumin parameters and novel inflammatory indices, including NLR, PLR, SII, SIRI, PIV, and HALP scores together in patients with PEXS and PEXG. In the present study, no significant difference was detected among PEXS and PEXG patients in NLR, PLR, SII, SIRI, and PIV indexes. However, our findings provided evidence for the association between HALP score and PEXG. According to ROC analysis, a cut-off value of 4.23 for HALP was determined to distinguish between PEXS and PEXG. This is the first study, as far as we are aware, to investigate the value of the HALP score to predict the PEXG prognosis of PEXS patients.
In recently, several studies have demonstrated that parameters easily calculated from hemograms are valuable in showing the role of inflammation in some ocular diseases [10, 11, 19, 20]. Among PEX-related inflammatory index studies, Ozgonul et al. detected that NLR and PLR were high in PEX patients and that a high NLR could predict PEXS and PEXG [12]. In the study of Tukenmez Dikmen et al., it was stated that the PEXS group had the highest NLR and SII values, followed by the PEXG and control groups, and there was no difference in PLR values between the groups [14]. In another study, Mirza et al. compared the monocyte count/high-density lipoprotein ratio (MHR) and lymphocyte/monocyte ratio (LMR) indexes in PEX and control groups.
Moreover, it was detected that MHR was higher and LMR was lower in the PEX group than in the healthy group [21]. In the present study, the results of PEXS and PEXG were compared to research the prognostic role of inflammatory indexes in both patients. Although NLR, SII, SIRI, and PIV values were relatively higher in PEXG patients than in PEXS patients, this difference was not found to be statistically significant between the groups.
Current studies have shown that the HALP score can reflect the inflammation condition of patients and has been proven to be an important prognostic indicator for patients with especially tumors [18, 22]. Studies have shown that the HALP score can be evaluated as a negative predictive biomarker for the prognosis of the disease [22, 23]. A meta-analysis, which included a total of 28 studies with 13,038 patients, revealed that pre-treatment, a low HALP score was a dependable and prognostic indicator for survival results in cancer patients [22]. Another study conducted by Bayram et al. reported that the HALP score was lower in severe hyperemesis gravidarum and was significantly different from mild hyperemesis gravidarum. According to the hypothesis of the authors, the HALP score can be a practical, affordable, and easily accessible objective biomarker to predict the existence and severity of hyperemesis gravidarum [23]. In the present study, our findings indicate that the HALP score was significantly lower in patients with PEXG compared to the PEXS patients. PEXS has a strong association with high intraocular pressures in up to 44% of patients, and this situation subsequently leads to the development of PEXG [5]. Therefore, our study indicates that the HALP score can be a negative predictive biomarker in the development of PEXG. In the meantime, we demonstrated that the cut-off value for the HALP score in the ROC curve analysis was 4.23. We hypothesized that the risk of developing PEXG may be higher in PEXS patients below this value.
As far as we are aware, this is the first study to analyze the prognostic significance of the HALP score in patients with PEX. The strength of this study is the use of systemic inflammation biomarkers and HALP score, which are prognosis indicators together to investigate the progression to PEXG.
Limitation
There are some limitations in our study. First, the study is conducted in a single-center setting. Second, this study population is comparatively small.
Conclusion
In conclusion, in our study comparing PEXS and PEXG patients, the inflammatory biomarkers NLR, PLR, SII, SIRI, and PIV and the new biological indicator HALP score were studied together. It was found that a lower HALP score was significantly associated with PEXG patients and could be an independent prognostic factor. Although this score alone is not sufficient, this study is important in that it may predict the possibility of developing PEXG. Larger-scale prospective studies should investigate and validate these predictive inflammatory biomarkers in patients with PEXS and PEXG.
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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6. Yildirim Z, Yildirim F, Ucgun NI, Sepici-Dincel A. The role of the cytokines in the pathogenesis of pseudoexfoliation syndrome. Int J Ophthalmol. 2013;6(1):50-3.
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8. Garweg JG, Zandi S, Pfister IB, Skowronska M, Gerhardt C. Comparison of cytokine profiles in the aqueous humor of eyes with pseudoexfoliation syndrome and glaucoma. PLoS One. 2017;12(8):e0182571.
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10. Ozarslan Ozcan D, Kurtul BE, Ozcan SC, Elbeyli A. Increased systemic immune-inflammation index levels in patients with dry eye disease. Ocul Immunol Inflamm. 2022;30(3):588-92.
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16. Peng D, Zhang CJ, Gong YQ, Hao H, Guan B, Li XS, et al. Prognostic significance of HALP (hemoglobin, albumin, lymphocyte and platelet) in patients with bladder cancer after radical cystectomy. Sci Rep. 2018;8(1):794.
17. Chen XL, Xue L, Wang W, Chen HN, Zhang WH, Liu K, et al. Prognostic significance of the combination of preoperative hemoglobin, albumin, lymphocyte and platelet in patients with gastric carcinoma: A retrospective cohort study. Oncotarget. 2015;6(38):41370-82.
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The effects of lower uterine segment involvement on angiolymphatic invasion, tumor grade, and staging ın patients with early-stage endometroid type endometrial cancer
Yağmur Soykan 1, 2, Asiye Ugras Dikmen 3, Özlem Erdem 4, Mehmet Anıl Onan 1
1 Department of Obstetrics and Gynecology, 2 Department of Medical Biology and Genetics, 3 Department of Public Health, 4 Department of Pathology, Faculty of Medicine, Gazi University, Ankara, Turkey
DOI: 10.4328/ACAM.22389 Received: 2024-08-28 Accepted: 2024-10-21 Published Online: 2024-11-19 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):276-280
Corresponding Author: Yagmur Soykan, Department of Obstetrics and Gynecology, Faculty of Medicine, Gazi University, Ankara, Turkey. E-mail: dr.soykan@hotmail.com P: +90 536 781 40 58 Corresponding Author ORCID ID: https://orcid.org/0000-0003-1053-1115
Other Authors ORCID ID: Asiye Ugras Dikmen, https://orcid.org/0000-0002-3204-7562 . Özlem Erdem, https://orcid.org/0000-0002-5981-4856 . Mehmet Anıl Onan, https://orcid.org/ 0000-0001-7643-1585
This study was approved by the Ethics Committee of Gazi University Hospital (Date: 2017-04-24, No: 185)
Aim: Endometrial cancer (EC) is the most common malignancy of the female reproductive system in developed countries. EC is surgically staged. EC’s most important prognostic factors are stage, grade, lymphovascular space involvement (LVSI), and histologic subtype. We designed this study to determine the predictive value of lower uterine segment involvement (LUSI) in terms of angiolymphatic invasion, tumor grade, and lymph node involvement in patients with early-stage endometrioid type endometrial cancer (EEC).
Material and Methods: The study was performed as a retrospective clinical study in patients with stages 1A and 1B (FIGO 1988) who were operated for EEC (total abdominal hysterectomy + bilateral salpingo-oophorectomy (TAH+BSO) ± lymph node dissection) in the Gynecologic Oncology Clinic of Gazi University Hospital.
Results: Of the 98 patients in the study group, 53 (54.1%) had LUSI, while in the remaining 45 cases (45.9%), LUSI was negative. A statistically significant difference was found between LUSI and pelvic lymph node metastasis (p=0.049). There was a statistically significant difference between LUSI and depth of myometrial invasion (MI) (p=0.03). There was also a statistically significant difference between tumor diameter size and LUSI (p=0.001). However, LUSI was not substantial for other prognostic factors such as LVSI, tumor grade, and age.
Discussion: We showed that lower uterine segment involvement is important for myometrial invasion and pelvic lymph node metastasis and may determine the extent of surgery.
Keywords: Endometrioid-Type Endometrial Cancer, Lower Uterine Segment, Angiolymphatic Invasion, Myometrial Invasion, Endometrial Cancer Staging
Introduction
Endometrial cancer is the most common malignancy of the female reproductive system in developed countries. It is the fourth most common cancer in women after breast, lung, and colorectal cancer [1]. The lifetime risk of developing EC is 2.6%, and the average age of onset is 62 years [2].
Approximately 80% of endometrial cancers diagnosed in developed countries are endometrioid type [3]. Prognosis, recurrence, and survival mainly depend on the surgical stage of the tumor. There are many risk factors for the development of EC, the majority being unmet estrogen and its causes. These include endometrial hyperplasia, polycystic ovary syndrome, obesity, nulliparity, infertility, history of infertility treatment, early menarche-late menopause, and prolonged estrogen exposure such as the use of estrogen therapy without progesterone at menopause. Medical conditions such as diabetes, hypertension, and hypothyroidism have also been shown to be associated with endometrial cancer. Conditions that decrease estrogen exposure or increase progesterone levels (such as oral contraceptives or smoking) have a protective effect [4].
The main complaint in 90% of endometrial cancer patients is abnormal vaginal bleeding, most commonly postmenopausal bleeding. Intermenstrual bleeding or prolonged heavy bleeding in perimenopausal and anovulatory premenopausal patients should also be suspected.
Endocervical curettage and endometrial biopsy should be performed in all patients with suspected endometrial cancer. Planning for definitive treatment is done in case of a positive endometrial biopsy. Stage, grade, lymphovascular area involvement, and histologic subtype are the most important prognostic factors in endometrial cancer. 70-80% of patients with endometrial cancer are stage 1 at the time of diagnosis. Stage 3 and stage 4 cancer are less common. The 5-year survival in stage 1 endometrial cancer is over 90% [5]. The first approach in the treatment of endometrial cancer is surgery. The surgical approach is total abdominal hysterectomy and bilateral salpingo-oophorectomy in the early stage, bilateral pelvic paraaortic lymphadenectomy and omentectomy in selected cases, and debulking in the advanced stage [5]. The therapeutic usefulness of systematic pelvic and paraaortic lymphadenectomy is controversial [5].
Lymphatic drainage of the uterus occurs in the pelvic lymph nodes, inguinal region, and paraaortic lymph nodes via the infundibulopelvic ligament. The frequency of lymph node metastasis in endometrial cancer varies between 7.7-21%. Of this rate, 3.3-12% is pelvic lymph node metastasis only, 2.5-8.8% is both pelvic and paraaortic metastasis, and 0.7-2% is paraaortic metastasis only. As pelvic lymph node involvement increases, paraaortic lymph node involvement also increases [6, 7, 8].
Endometrial carcinoma originates from the uterine corpus and fundus, but lower uterine segment involvement (LUSI) is observed in 3-6% of cases [9].
Tumors originating from the lower uterine segment (LUS) are located between the uterine corpus and cervix and show histologic features of both. Therefore, they sometimes complicate the differential diagnosis of uterine corpus and cervical adenocarcinomas when the primary tumor needs to be identified for further investigation and prognosis [10]. Tumors arising from or involving the LUS also differ from tumors of the uterine corpus by their thin mucosal and myometrial layers and poor hormonal response to estrogen [11].
In some reports, LUS carcinoma does not have the characteristics of type I endometrial cancer. It tends to show characteristics of type II, thought to be due to the thin endometrial layer of the LUS and a weak endometrial response to estrogen [12]. Clinically, type I cases are characterized by irregular menstruation, unmet estrogen, nulliparity, infertility, and a high frequency of PCOS (polycystic ovary syndrome). In contrast, type II cases show weak estrogen and progesterone receptors and p53 mutation expression and have similar features to LUS carcinoma [13, 14-17].
The endometrial layer of LUS carcinoma is similar to the endometrium in cell distribution and histochemistry, but the volume of the endometrium tends to be smaller in LUS [18]. Because the endocervical mucosa histologically transitions gradually to the LUS endometrium, endocervical and endometrial epithelial features show combinations in LUS.
Because cases of endometrial cancer originating from the LUS are rare, few studies have compared the characteristics of LUS tumors with tumors originating from the uterine corpus. There are conflicting reports on the effect of LUS involvement as a prognostic factor in endometrial cancer.
In this study, we aimed to investigate the effects of uterine lower segment involvement on lymph node involvement, myometrial invasion, angiolymphatic invasion, and staging in patients with early-stage endometrioid-type endometrial cancer.
Material and Methods
In cases operated for early-stage endometrioid type endometrial cancer, the predictive value of uterine lower segment involvement on lymph node involvement, myometrial invasion, angiolymphatic invasion, and staging was evaluated. Patients with histologic types other than endometrioid type endometrial cancer (serous, clear cell, undifferentiated, etc.), patients with advanced endometrial cancer, and patients who would not provide reliable data due to incomplete information were not included in the study. All patients who participated in the study were patients who underwent endometrial sampling due to perimenopausal or postmenopausal bleeding preoperatively and were diagnosed with endometrioid type endometrial cancer by pathology. TAH+BSO, bilateral pelvic lymph node dissection and ± paraaortic lymph node dissection were performed. The degree of myometrial invasion, tumor diameter size, histological grade, and cervical metastasis were evaluated by a frozen section of the hysterectomy slice. While only pelvic lymph node dissection was performed in patients with good prognostic data, total pelvic and paraaortic lymph node dissection was performed in the poor prognostic group with grade 3 tumor, myometrial invasion depth >1/2, tumor diameter >2cm, isthmus-cervix invasion, extrauterine disease (abdominal metastasis) invasion. Dissection was performed up to the renal vein level in surgically suitable cases. All materials were analyzed in our hospital’s pathology laboratory. FIGO surgical staging system was used for endometrial cancer staging. FIGO was used for grade classification, and the World Health Organization Classification of Tumors system was used for histological classification. Age, date of operation, type of operation, histological type of tumor, grade of tumor, diameter of tumor, percentage of tumor invasion into myometrium, stage of disease, number/location of lymph nodes removed, number/location of metastatic lymph nodes removed, presence of lymphovascular invasion, LUSI and surgical stage were evaluated.
In patients with LUSI, the depth of uterine myometrial invasion and tumor diameter, grade, and LVSI were evaluated to determine whether they were predictive values for lymph node involvement.
Statistical analysis
The research data were evaluated using the SPSS 17.0 statistical package program. Descriptive statistics were presented as mean, median (min; max), frequency distribution, and percentage. Pearson Chi-Square, Yates Corrected Chi-Square Test, and Fisher’s Test were used as statistical methods. The statistical significance value was accepted as p<0.05.
Ethical Approval
This study was approved by the Ethics Committee of Gazi University Hospital (Date: 2017-04-24, No: 185).
Results
A total of 98 patients were included in the study. Patients underwent TAH+BSO, bilateral pelvic lymph node dissection, ± paraaortic lymph node dissection. The mean age of the patients in the study group was 61.2 (±9.3) years. The final pathology of all patients was endometroid-type adenocarcinoma. 12 (12.2%) patients were grade 1, 65 (66.3%) were grade 2, and 21 (21.4%) were grade 3.
After postoperative histopathologic evaluation, 17 (17.3%) patients were stage 1A, 65 (66.3%) were stage 1B, 7 (7.1%) were stage 3C1, and 8 (8.2%) were stage 3C2. The depth of myometrial invasion was below ½ in 42(42.9%) patients and above ½ in 56(57.1%) patients. Tumor diameter size was below 4 cm in 43(43.9%) patients and above 4 cm in 55(56.1%) patients. LVSI was positive in 25(25.5%) and negative in 72(73.5%) patients.
Of the 98 patients in the study group, 53(54.1%) had LUS involvement, and 45(45.9%) had no LUSI.
Of the 98 patients in the study group, 7 patients underwent only hysterectomy and salpingo-oophorectomy operation due to co-morbid diseases. The mean age of the patients with LUSI was 60.5(±9.19), while the mean age of the patients without LUSI was 62.0(±9.45).
Pelvic lymph node dissection was performed in 20 of 52 patients with LUSI, while pelvic paraaortic lymph node dissection was performed in 32 patients. Of 39 stage 1B patients without LUSI, 12 patients underwent hysterectomy + pelvic lymph node dissection, while 27 patients underwent pelvic + paraaortic lymph node dissection. Lymph node metastasis was detected in 11 patients with LUSI, while pelvic and paraaortic lymph node involvement was detected in 4 patients without LUSI (Table I).
No patients without myometrial involvement were among the 98 patients who participated in the study. A statistically significant difference was found between LUSI and MI depth (p=0.03). A statistically significant difference was also between LUSI and tumor diameter size (p=0.001). A statistically significant difference was found between LUSI and pelvic lymph node metastasis (p=0.049).
There was no statistically significant difference between LUSI, tumor grade, and LVSI (p=0.392 and p=0.852, respectively).
Discussion
Endometrial cancer is the most common gynecologic cancer in women in developed countries. Currently, most patients with endometrial cancer require surgical staging according to the FIGO staging system. Lymphadenectomy is one of the most controversial issues in endometrial cancer surgery[19]. Since lymph node metastasis in endometrial cancer affects the prognosis of the patient, lymphadenectomy has diagnostic value and therapeutic value.
LUS is anatomically located between the uterine corpus and cervix and shows histologic features of both of these parts. The main aim of our study is to perform lymph node surgery in patients with tumors located in the LUS only when necessary.
In our study, the mean age of the patient group with LUSI was 60.5(±9.19), while the mean age of the patient group without LUSI was 62.08(±9.45). Our study found no significant correlation between age and LUSI (p=0.543).
Brown et al. investigated whether LUSI was associated with the depth of MI and showed that LUSI was a determinant for the depth of myometrial invasion (p=0.02)[20]. In our study, LUSI was found to be associated with the depth of myometrial invasion (p=0.030). A study by Phelan et al. investigating whether LUSI was associated with tumor grade showed that LUSI was not a determinant of tumor grade (p=0.20)[21]. Of the 98 patients included in our study, the grade was 1 in 8(15.1%), 2 in 36(67.9%), and 3 in 9(17%) patients (p=0.392). Our study found no significant correlation between tumor grade and LUSI.
In a study by Gemer et al., age, depth of myometrial invasion, tumor grade, depth of myometrial invasion, depth of myometrial invasion lymphovascular area invasion were examined in patients with endometrial cancer with AUS involvement and evaluated whether they had predictive value for LUSI. In a retrospective study of 138 patients, tumor grade (p = 0.002), LVAI (p = 0.01), and depth of MI (p < 0.001) were statistically significant in patients with LUSI [22].
In a study by Erkaya et al., depth of MI, tumor grade, tumor diameter, lymph node metastasis, depth of myometrial invasion, and lymphovascular area invasion were examined in patients with endometrial cancer who had LUSI and evaluated whether they had predictive value for LUSI. In a retrospective study of 139 patients, tumor grade (p<0.0001), LVAI (p<0.001), depth of MI (p<0.001), and tumor diameter (p=0.01) showed a significant correlation in terms of LUSI. They also found that the risk of pelvic and paraaortic lymph node involvement increased in patients with AUS involvement, and this relationship was statistically significant ( p=0.001 and p=0.005, respectively) [23]. In our study, LUSI was found to be associated with MI depth, tumor size, and pelvic lymph node involvement, which is consistent with the literature. However, no significant results were found in terms of LVSI and tumor grade. This may be related to the heterogeneity in tumor grade of the 98 patients included in our study. In addition, the effect of LUSI on survival was investigated in this study by Erkaya et al., but no significant difference was found (p>0.05).
A study by Kizer et al. evaluated whether LUSI is a predictive value for tumor grade and LVSI in endometrial cancer patients. In a retrospective study of 481 patients, LVSI was found to be associated with LUSI. It was reported that LUSI was associated with decreased survival[24]. In our study, LUSI was not found to be statistically significant for LVSI. This may be due to the need for more cases in the study to evaluate the association with LUSI.
A study by Madom et al. evaluated whether LUSI, MI, and LVSI have a predictive value in terms of lymph nodes in endometrial cancer patients. In a retrospective study of 324 patients, LVSI, LUSI, and MI were found to be predictive of lymph node involvement [25].
Of the 97 patients included in our study, 25(25.7%) had LVSI, and 72(74.3%) did not have LVSI. Eight of 25(25.7%) patients with LVSI had lymph node metastasis, while 8 of 72(74.3%) patients without LVSI had lymph node metastasis, and this was statistically significant (p=0.044). Of the 15 patients with lymph node metastases, 7 had LVSI.
LVSI was added to the 2023 FIGO Endometrial cancer staging updated last year, and the disease is considered stage 2 when diffuse LVSI is present.
Conclusion and Limitation
Understanding the prognostic value of LUSI may be useful in planning the extent of surgery, adjuvant treatment, and survival. Prospective studies with more patients are needed for more meaningful results to have the last word on the subject.
The research(thesis study) was presented at the 1st International and 16th National Gynecologic Oncology Congress (November 21st – 25th, 2018) held in Antalya. (Oral Presentation-31).
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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15. Lax SF, Pizer ES, Ronnett BM, Kurman RJ. Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression. Hum Pathol. 1998;29(6):551-558.
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Negative impact of hydroxychloroquine on artificial decidualization in a rat model of pseudopregnancy
Asmaa S. El Naggar 1, Adham R. Mohamed 1, Eman M. Fawzy 1, Shaymaa A. Abdulmalek 2, Eman A. Allam 1
1 Department of Medical Physiology, Faculty of Medicine, 2 Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
DOI: 10.4328/ACAM.22397 Received: 2024-09-08 Accepted: 2024-10-21 Published Online: 2024-11-21 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):281-285
Corresponding Author: Asmaa S. El Naggar, Department of Medical Physiology, Faculty of Medicine, Alexandria University, Alexandria, Egypt. E-mail: asmaa.elnaggar@alexmed.edu.eg P: +20 12 23305252 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9704-0970
Other Authors ORCID ID: Adham R. Mohamed, https://orcid.org/0000-0002-2475-5702 . Eman M. Fawzy, https://orcid.org/0009-0008-1871-5342 . Shaymaa A. Abdulmalek, https://orcid.org/0000-0002-8384-4625 . Eman A. Allam, https://orcid.org/0000-0002-6267-5164
This study was approved by the Ethics Committee of Alexandria Faculty of Medicine (Date: 2021-04-15, No: 0201489)
Aim: The study sought to investigate the possible effects of hydroxychloroquine intake on uterine decidualization in rats.
Material and Methods: Three groups of adult Wistar nulliparous female rats were divided as follows, two groups were administered daily hydroxychloroquine either for 1 week or 4 weeks and one group took a vehicle to act as the negative control. Then, pseudopregnancy and artificial decidualization were induced in all groups. On day 8 of pseudopregnancy, the quantity and quality of artificial decidualization were assessed by decidual weight, decidualization biomarkers, and histologically. In addition, the decidual oxidative stress was assessed.
Results: The results showed that hydroxychloroquine induced oxidative stress and impacted artificial decidualization in rats with prolonged treatment (4 weeks) with hydroxychloroquine but not with short-term treatment (1 week). In the form of a significant decrease in decidual weight, decidual prolactin, and insulin-like growth factor binding protein-1 (IGFBP1), as well as the number of decidual cells under light microscopy.
Discussion: This research suggested that the long-term use of hydroxychloroquine may impair uterine decidualization in rats and accordingly affect pregnancy which contradicts the common concept about its safety during pregnancy.
Keywords: Decidualization, Hydroxychloroquine, Oxidative Stress
Introduction
Endometrial decidualization is a crucial prerequisite for a successful pregnancy that lays the essential foundation for subsequent gestation by preparing the endometrium for embryo reception. It is primarily a progesterone-dependent process during which the endometrial stromal cells (ESCs) multiply and transform into large epithelioid cells, called decidual stromal cells (DSCs) along with other stromal changes [1, 2]. These reprogrammed DSCs have several vital roles for pregnancy success including inflammation suppression, vascular adaptation, tolerance to fetal antigens, etc. [1, 2]. Decidualization spontaneously occurs during each menstrual cycle in the few menstruating species including humans while in rats and most other placental mammals, it only starts after embryo implantation [1]. The crosstalk between a blastocyst and a receptive endometrium in the proper timing has been considered the “black box” of fertility and reproduction. This is when many pregnancies fail, and many developmental disorders are thought to arise. Any disruption in this delicate synchrony or intervention during this critical period can be causally linked to infertility and many obstetric complications [3]. So, a dysfunctional endometrium and/or decidualization is highly suspected as a causal factor in pregnancy complications or even failure [2, 4].
Chloroquine is one of the oldest drugs still widely used in clinical practice along with its analogue hydroxychloroquine (HCQ) which was found to be more effective and less toxic. They have been used to prevent and treat malaria and also in the treatment of autoimmune disorders [5, 6]. Furthermore, they drew interest during the Ebola virus outbreak and again recently during the initial phase of the COVID-19 pandemic based on preliminary research exhibiting potent antiviral effects on severe acute respiratory syndrome coronavirus 2 [5]. Previous research recommended the use of HCQ in the prevention of obstetric complications and protection against fetal death and placental insufficiency in retrospective studies and in vivo models of autoimmune diseases which reported better outcomes with HCQ treatment [7]. Additionally, based on HCQ’s probability to improve prognosis of pregnancy in females with autoimmune disorders, it was proposed that it may also lessen pregnancy complications in non-autoimmune women with risk for placental insufficiency [8]. However, with the expansion of its use, variable posology, and prolonged duration with the lack of a definitive dose-response relationship that determines the minimum effective and toxic doses, its impact on pregnancy, particularly decidualization, remains unclear [5, 9, 10]. In the current study, we aimed to assess whether HCQ intake can affect decidualization positively or negatively through its effect on oxidative stress in an experimental rat model of artificial decidualization.
Material and Methods
Experimental animals
The study was conducted on adult (8-10-week-old) nulliparous female Wistar rats of 150-180 gm body weight range in the animal house of the Medical Physiology Department Faculty of Medicine, Alexandria University. The animals were housed under standard laboratory conditions, at room temperature, and a 12-hour light-dark cycle with unrestricted access to standard chow and water. All experiments followed the Guide for the Care and Use of Laboratory Animals, Faculty of Medicine, Alexandria University (IRB NO: 00007555-FWA NO: 00018699). Additionally, the study was authorized by the Alexandria Faculty of Medicine Ethics Committee.
Experimental design and procedures
Study groups
The rats were divided into three groups of ten rats each at random:
Group I (control decidualization) administered 1 ml of oral vehicle.
Group II (1-week HCQ + decidualization), treated with 40 mg/Kg/day HCQ for one week. HCQ solution was prepared from Hydroxychloroquine sulphate (Hydroquine 200-mg, Minapharm Company, 10th of Ramadan, Egypt).
Group III (4-weeks HCQ + decidualization), received the same daily dose of HCQ for 4 weeks that represents 5 to 6 rat estrous cycles equivalent to about 5 to 6 monthly human cycles.
Artificial decidualization surgery
For artificial decidualization induction, female rats at the proestrus or early estrus phase were allowed to mate with vasectomized males by a 1:1 ratio to induce pseudo-pregnancy. Pseudopregnancy was considered to be on day 1 if sperm or a vaginal plug were found [11]. On the 4th day of pseudo-pregnancy, the rats were anesthetized using mixture of ketamine and xylazine intraperitoneally. Then, artificial decidualization was induced in the right uterine horn by injecting 100μl of sesame oil inside it. On the 8th day of pseudo-pregnancy, the animals were sacrificed [11].
Measurements and laboratory investigations
Serum estrogen and progesterone
After sacrifice, the serum was separated from a posterior vena cava blood sample by centrifugation and samples. Serum estradiol and progesterone levels were assayed by electrochemiluminescence immunoassay on the Roche Cobas e analyzer.
Decidual weight assessment
On the sacrifice day, the rats’ uteri were dissected, and right and left uterine horns were weighed to determine the fold increase in stimulated horn weight which represents decidual weight [12].
Tissue sampling and processing
After weighing, stimulated horns were divided into two parts. One part was stored at -80°C till minced and homogenized to be used for biochemical analysis. While the other part was fixed in 10% formalin for histological examination.
Decidualization biomarkers assessment
Each prolactin and IGFBP1 protein were measured in uterine homogenate by using ELISA kits according to the manufacturer’s instructions (Wuhan Fine Biotech Co., Hubei, China, Cat. No. ER0076 and ER0081respectively). The assay applied the quantitative sandwich enzyme immunoassay technique where the specific protein is bound by the specific monoclonal immobilized antibody and the biotin-conjugated antibody is used as the detection antibody. The results were adjusted to total tissue proteins and presented per milligram of tissue protein.
Oxidative stress evaluation
Total antioxidant capacity (TAC) was assessed using TAC assay kit from Biodiagnostic diagnostic and research reagents, Giza, Egypt (Cat. No. TA 2513,) to measure the reductive power of a sample representing the cumulative effect of antioxidant systems [13]. According to provider instructions, H2O2 was diluted then mixed with the sample or distilled water and incubated. After that, a working reagent was added. Finally, the absorbances were read spectrophotometrically.
Lipid Peroxidation assay kit (Cat. No. MD 2529, Biodiagnostic diagnostic and research reagents, Giza, Egypt) was used to analyze the decidual Malondialdehyde (MDA) content as a measurement of the decidual oxidative-stress levels [13]. In brief, either the samples or the standard was added to trichloroacetic acid and mixed well then centrifuged. The supernatant was added to thiobarbituric acid and heated then cooled. The absorbance of the resultant product was read by spectrophotometer.
Histopathological assessment of decidualization using hematoxylin & eosin (H&E)
Uterine horn samples were fixed in 4% paraformaldehyde, and specimens were placed in a 10% formalin solution, processed, and embedded in paraffin for histological examination. Tissue sections (3-5 Microns thick) were cut with microtome and stained with H&E. Finally, tissue section slides were examined using light microscopy for the histopathologic evaluation magnification.
Statistical analysis
IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp) was used for statistical data analysis. Quantitative data were expressed using the mean and Standard Error of Mean (SEM), and the results were considered of statistical significance at p values ≤0.05. Analysis of variance (ANOVA) test was used for comparison between groups, and the post-hoc test (Tukey) for pairwise comparisons.
Ethical Approval
This study was approved by the Ethics Committee of Alexandria Faculty of Medicine (Date: 2021-04-15, NO: 0201489, IRB NO: 00012098- FWA NO: 00018699).
Results
Effect of HCQ intake on serum estradiol and progesterone
There was no significant difference in the level of serum estradiol (Figure 1A) or progesterone (Figure 1B) between the three studied groups.
Effect of HCQ on artificial decidualization
Decidual weight
There was no statistically significant difference in decidual weight in group II compared to control group I. Prolonged HCQ intake for 4 weeks caused a significant decrease of decidua thickness as compared to control group I and to short-term intake of HCQ in group II (Figure 1C).
Decidualization biomarkers
There was a significant increase in prolactin and IGBP-1 stimulated horn homogenate of group I and group II as compared to the unstimulated horn. On the other hand, in group III, prolactin of the stimulated horn was non-statistically higher than in the unstimulated horn while IGBP-1 in the stimulated horn in group III was significantly lower compared to group I and group II despite being statistically higher than in the unstimulated horn (Figures 1D,1E).
Decidual oxidative stress evaluation after HCQ intake
Stimulated horn MDA level was significantly higher in group III as compared to control group I (Figure 2A). Prolonged intake of HCQ in group III led to a significant decrease in total antioxidant capacity in tissue homogenate of stimulated horn compared to that in groups I and II (Figure 2B).
Results of histopathological assessment of Decidualization
Histopathological examination of the right stimulated horn exhibited the normal decidual reaction with hyperplasia and hypertrophy of endometrial stroma in control group I (Figure 3B). In line with the previous findings, the decidual reaction in group II was apparently normal and may not be affected by short-term intake of HCQ (Figure 3C). On the other hand, long-term treatment with HCQ in group III passively affected the decidualization in the form of fewer decidual cells and glands in addition to the appearance of necrosis, indicating that hydroxychloroquine inhibited this process impaired stromal cells differentiation with a notable decrease in the endometrial thickness (Figure 3D).
Discussion
The safety of CQ and HCQ during pregnancy was reported when used for the treatment of autoimmune and rheumatologic disorders as well as malaria prevention and treatment. Nevertheless, their expanded usage for other nonmalarial disorders has led to longer intake durations and higher daily dosages, resulting in greater cumulative doses and unanticipated adverse effects. Accordingly, many studies have been conducted to assess their safety, study their possible side effects, and determine the safe maximal daily dose [14, 15].
Shu-Wing Ng et al.[2] state that “the primary driver of pregnancy health is the quality of the soil, not the seed”. Decidualization is a sequence of changes in the endometrial stroma including cellular transformation to provide a nutrient-rich uterine suitable environment for embryo implantation and growth [2, 4]. Since decidualization in humans begins during the secretory phase of each monthly menstrual cycle, pregnancy health gets determined even before the blastocyst arrival [2].
In the present study, the working model of artificial decidualization in one uterine horn was chosen to simulate endometrial changes in humans which start regularly each month without dependence on the implanted embryo as a trigger and to focus on the possible effects of HCQ on the quality of the endometrial soil without the seed impact on the decidualization response.
The results of this study indicated that HCQ might adversely affect decidualization response in the model of artificial decidualization mostly due to local uterine factors depending on the duration of intake. It was found that HCQ intake for four weeks and throughout the days of decidualization induction impaired decidualization compared to its intake for only one week and to control. In other words, HCQ intake in group III significantly decreased decidual weight and decidualization biomarkers while there was no statistically significant difference between the studied groups as regards serum female sex hormones. In addition, only in rats administered HCQ for four weeks, histological evaluation of the decidua revealed remarkably impaired cellular differentiation and proliferation with a considerable reduction of the endometrial thickness.
The potential mechanism by which HCQ may impact decidualization is likely multifactorial. Hydroxychloroquine alkalinizes lysosomes inhibiting lysosomal enzymes and interfering with lysosomal activity. Thereby, they affect membrane stability, signaling cascades and transcriptional activity, and inhibit autophagy [16, 17]. Moreover, since HCQ is widely used for chronic autoimmune diseases, it has anti-inflammatory and immunomodulatory effects. However, it can indirectly reduce the anti-inflammatory cytokines and elevate some inflammatory cytokines, thereby presenting a potential risk of immune imbalance and damage in addition to endothelial cell injury and antiangiogenic effects especially with high doses [5, 16]. This effect was reported in previous studies [18, 19]. In other mechanistic studies on the negative effects of HCQ, they were attributed to its induction of apoptosis, inhibition of phospholipase A2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1, and interference with some ion channels [20, 21]. According to Okada et al.[22], all the previous factors could influence the decidualization process and function. Besides, as decidualization is considered a high-energy process because of cellular proliferation and differentiation, it stands to a reason for autophagy to be activated. Consistent with this concept, Mestre et al.[23] observed that decidualized cells showed enhanced autophagic flux, indicating that autophagy plays a role in decidualization.
Other findings by Huybrechts et al.[9] demonstrated a slight increase in the risk of birth defects linked to the use of HCQ during the first trimester, based on the theory that HCQ crosses the placenta and affects DNA synthesis and cell division, increasing the chance of chromosomal abnormalities in rapidly proliferating embryonic cells. The benefits of therapy during pregnancy will probably outweigh this risk for the majority of people with autoimmune rheumatic illnesses since it lowers the disease activity and the associated negative pregnancy outcome [9].
Contrary to our findings, most research on HCQ studied its safety when used for malaria, rheumatic disorders, and autoimmune disorders and suggested it is safe in pregnancy with no increase in the risk of common adverse obstetrical outcomes [9, 10]. Moreover, in spite that pregnant women were excluded from most clinical trials during the COVID-19 pandemic, González et al.[15] in Spain carried out a randomized double-blind clinical trial showed that HCQ intake for 3 days or 11 days is safe for use in postpartum and pregnant females with asymptomatic or mild infection.
Multiple studies were discussed in Arachchillage et al.[7] review which reported better outcomes with HCQ intake in cases of antiphospholipid syndrome. Additionally, Kim et al.[8] proposed that through similar mechanisms, it could be used in non-autoimmune patients. They also pointed to the clinical trials (eight, registered at https://clinicaltrials.gov/) which focused on how HCQ influences the pregnancy among women with either autoimmune diseases, high-risk pregnancies, or an unfavorable pregnancy outcomes history [8].
Another result of the current work was that HCQ administration significantly induced uterine oxidative stress in the stimulated horn in the form of increased MDA and decreased TAC only after prolonged intake for more than four weeks’ duration which may play a role in decidualization response. In support of this idea, some studies reported that it may be due to increased production of reactive oxygen species [19, 21]. Further, Oxidative stress is a major contributor to placental dysfunction and can lead to endothelial dysfunction and an excessive production of anti-angiogenic molecules [24]. On the other hand, Ogunbayo et al.[25] revealed that, within six hours, a single dosage of CQ increased MDA levels and decreased the antioxidant systems enzymes in rabbits blood. Accordingly, the oxidative stress brought on by HCQ might have contributed to its detrimental impact on decidualization.
Conclusion
The current experimental animal study declared that HCQ intake for a long duration may impact uterine decidualization and that the daily dosage and length of exposure are critical risk factors for the usage of HCQ. Further research is necessary to entail the other possible related mechanisms, and implicated pathways affected by HCQ in the decidualization process to address the controversy surrounding the use of HCQ and to improve pregnancy prognosis and outcome in addition to fetal safety with its increased use.
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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Asmaa S. El Naggar, Adham R. Mohamed, Eman M. Fawzy, Shaymaa A. Abdulmalek, Eman A. Allam. Negative impact of hydroxychloroquine on artificial decidualization in a rat model of pseudopregnancy. Ann Clin Anal Med 2025;16(4):281-285
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Relationship between platelet mass index and coronary slow flow phenomenon
Erdoğan Sökmen, Muhammet Salih Ateş
Department of Cardiology, Kırsehir Ahi Evran Education and Research Hospital, Kırsehir, Turkiye
DOI: 10.4328/ACAM.22423 Received: 2024-10-02 Accepted: 2024-11-11 Published Online: 2024-11-18 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):286-291
Corresponding Author: Erdoğan Sökmen, Department of Cardiology, Kırsehir Ahi Evran Education and Research Hospital, Kırsehir, Turkiye. E-mail: erdoganmen@gmail.com P: +90 551 553 99 14 Corresponding Author ORCID ID: https://orcid.org/0000-0002-8170-5912
Other Authors ORCID ID: Muhammet Salih Ateş, https://orcid.org/0000-0003-4099-0064
This study was approved by the Ethics Committee of Necmettin Erbakan University (Date: 2023-12-15, No: 118)
Aim: Coronary slow flow (CSF) is an important clinical entity that may cause anginal symptomatology, acute coronary syndrome or even sudden cardiac death. Its pathogenesis is complex, and previously, several hematological parameters were shown to be independently associated with CSF. Platelet mass index (PMI) is a novel platelet index showing bodily inflammation and thrombogenesis status. Our aim was to assess the relationship between PMI and CSF in anginal patients undergoing coronary angiography.
Material and Methods: Our study is retrospective and a total of 92 patients with CSF and 100 age- and sex- matched subjects with normal coronary flow were included between June 2020 and October 2023. Data regarding demographic, clinical and angiographic characteristics were retrieved from digital hospital database. TIMI frame count (TFC) were calculated by two independent cardiologists blinded to the study protocol. PMI was calculated as platelet count multiplied by mean platelet volume (MPV).
Results: Mean TFC was (43.93±9.56 vs 20.0±4.1, respectively, p<0.001). Respective MPV and PMI of CSF and control groups were 8.64±0.88 fL vs 8.64±0.88 fL (p<0.001) and 2983.5 (2692.5-3217.2) vs 2261.5 (2100-2456) (p<0.001). PMI (rho=0.578, p<0.001) and MPV (rho=0.395, p<0.001) were correlated with CSF. In regression analysis, MPV and PMI were independently associated with CSF. In ROC analysis, MPV cut-off was 80.5 fL with 70% sensitivity and 68% specificity (AUC: 0.755), and PMI cut-off was 2564 with 80% sensitivity and 82% specificity (AUC: 0.866).
Discussion:PMI and MPV are increased in CSF, and PMI and MPV are independently associated with CSFP.
Keywords: Platelet Mass Index, Coronary Slow Flow Phenomenon, Timi Frame Count, Mean Platelet Volume
Introduction
Coronary slow flow phenomenon (CSFP) is characterized by the delayed transmission of contrast dye to the distal part of the coronary arteries without overt stenosis. While its incidence is reported to be between 1% and 7% of all the coronary angiography procedures [1], the exact mechanism by which CSFP occurs is yet to be totally resolved. However, several mechanisms have been put forth as the etiology such as increased microvascular tonus, microvascular inflammation [1, 2] and endothelial dysfunction [3]. It is well known that CSFP is associated with angina pectoris, cardiac arrhythmias, acute coronary syndromes and even sudden cardiac death [1].
Previous studies have shown that platelet indices, such as platelet count, platelet distribution width and mean platelet volume (MPV), are likely to be related with acute coronary syndrome (ACS) and coronary artery disease (CAD) progression [4, 5]. Despite a greater number of studies regarding the association of MPV and CSFP [6, 7], there are some other studies oppose this association, too [8- 10]. In most of the studies, there have been no significant difference with regard to mean platelet counts between the CSFP and control groups, although some reported greater platelet counts in CSFP groups.
Platelet mass index has been proposed as a relatively new platelet and inflammation index, which is calculated by multiplying the MPV with platelet count. As a novel index of both platelet activity and inflammation, PMI has been proposed to have a superior predicting ability compared to lone MPV or platelet count [11, 12]. However, studies on the association of PMI with CAD are scanty. It was reported in a previous study that an increased PMI in psoriasis might be a relevant factor of coronary plaque formation due to close interplay between CAD formation and psoriasis [13]. The preliminary studies regarding PMI were on platelet transfusion in preterm newborns in neonatal intensive care units [14, 15]. There has been a fine balance between MPV and platelet count, where a decreasing platelet counts due to various reasons, for example inflammation, intravascular coagulation or platelet alloimmunization, cause an increase in MPV due to newly-formed younger platelets characterized with greater megakaryocyte cytoplasm. There is, on the other hand, no study investigating the relationship between PMI and CSFP.
In the present study, the relationship of PMI with CSFP was investigated, and our hypothesis was that increased PMI would be observed in patients with CSFP.
Material and Methods
Study designation and patient enrollment
This is a cross-sectional and retrospective study. Coronary angiographic data of 158 patients with CSFP were analyzed retrospectively between June 2020 and October 2023 and, after excluding 66 patients based on our exclusion criteria, a final 92 subjects having CSFP in at least one epicardial coronary artery without a prominent stenosis were included in the study as the CSPF group. Furthermore, 100 subjects with angiographically-depicted normal coronary arteries without any CSFP were selected as controls. All subjects of the study cohort underwent coronary angiography due to anginal chest pain, along with ischemic findings in non-invasive stress tests. The clinical and demographic features of the subjects were retrieved from the hospital digital database.
The exclusion criteria included: a history of acute coronary syndrome; history of rheumatic, hematological, or oncological disease; moderate-to-severe valvular heart disease; chronic inflammation; severe hepatic or kidney disease; and presence of dilated or hypertrophic cardiomyopathy.
Echocardiographic evaluation via Vivid S5 (GE Vingmed Ultrasound AS, Horten, Norway) was implemented in all the study subjects and modified Simpson’s rule was utilized in the calculation of left ventricular ejection fraction (LVEF). The body-mass index (BMI) was computed as subject’s weight divided by the square of his/her height. A BMI >30 kg/m2 was accepted as obesity. Patients with a mean of repeated office blood pressure >140/90 mmHg or on anti-hypertensive therapy were considered to have hypertension. Diabetes mellitus was defined by a fasting blood glucose >126 mg/dL, HgA1c>6.5 or the use of antidiabetic drugs. Hyperlipidemia was defined as: triglycerides >150 mg/dL, low density lipoprotein (LDL) >130 mg/dL, or total cholesterol >200 mg/dL.
Coronary angiographic procedures
Coronary angiography was performed using Judkins technique in each subject with Artis Zee (Siemens Medical, Erlangen, Germany) via femoral or radial access. Angiographic views were recorded at 15 frames per second and two consultant cardiologists blinded to the study data assessed the angiographic views in Axiom workstation (Siemens Medical, Erlangen, Germany).
The diagnosis of CSFP was confirmed using the TIMI frame count (TFC) method. Briefly, the number of total cine-frames for contrast agent to reach the distal part of the left anterior descending artery (LAD), right coronary artery (RCA) and the left circumflex artery (Cx) was determined with the help of frame counter. The distal part of the each major epicardial artery was defined as follows: LAD: distal bifurcation; Cx: artery’s distal bifurcation or obtuse marginal artery’s distal bifurcation on the basis of their length and, RCA: first branch of posterolateral artery [16- 19]. As the course of LAD is longer than both Cx and RCA, a correction was applied using the formula LAD TFC/1.7 to obtain an ultimate corrected LAD TFC (cTFC) (16). Gibson et al.[16] described the TFC normal values as 21.1±1.5 for LAD; 22.2±4.1 for Cx; and, 20.4±3.0 for RCA. The sum of the each TFM for LAD, Cx and RCA was divided by three to end up with the mean TFC. Moreover, we multiplied the TFCs that we counted by two, because the standardized recording rate for the given normal values was 30 frames per second [16]. TFC calculations were performed by 2 consultant cardiologists and if a disagreement occurs between these two cardiologists, a third cardiologist blinded to the study data resolved this conflict. Subjects with greater TFC than the normal values were regarded as having CSFP.
Biochemical and Hematological Parameters
The blood samples were collected from each subject via a venous route before angiography and were analyzed in 10-15 minutes after sampling. An automated analyzer (Roche Hitachi Cobas c8000 autoanalyzer, Roche Diagnostic Corp., Mannheim, Germany) was used to measure serum biochemistry. Moreover, a Beckman Coulter (Miami, FL, USA) was utilized for complete blood count. PMI was computed as platelet count multiplied by
MPV.
Statistical Analysis
The normality of the distribution of the parameters was assessed using the Kolmogorov-Smirnov test. Variables with a normal distribution were expressed as mean ± standard deviation. The variable that are not normally distributed were expressed as median (25th-75th percentiles). Categorical parameters were expressed as counts and percentages. The bivariate analysis of the study parameters was performed using the Chi Square test, Mann-Whitney-U test and independent t test where appropriate. Correlations between the variables were assessed using Pearson or Spearman correlation analysis, as appropriate. We performed a multinominal logistic regression analysis to define the parameters independently associated with CSFP. Finally, receiver operating characteristic (ROC) curve analysis was utilized in order to define the cot-off of PMI to predict CSFP. A p-value was accepted statistically significant when it is <0.05. All the calculations were implemented using the Statistical Package for Social Sciences (SPSS) for Windows, version 29.0 (SPSS Inc., Chicago, IL, USA).
Ethical Approval
The principles of the Declaration of Helsinki were conformed during the performance of this study and local ethics committee of Necmettin Erbakan University approved our protocol (Date: 2023-12-15, No: 118).
Results
The study included 92 patients with CSFP (mean age 58.4±9.2, 85.5% male) and 100 controls with normal epicardial blood flow (mean age 56.5±10.1; 86.6% male). Clinical and demographic features of two groups were presented in Table 1. There were no significant differences between the groups in terms of gender, age, systolic and diastolic pressures, pulse rate, HT, DM, dyslipidemia, smoking, LVEF, glucose, cholesterol levels, urea, creatinine, WBC, hemoglobin, platelet count, and platelet distribution width (p>0.05). However, patients with CSFP were more obese compared with the controls (25.6% vs 20%, respectively, p=0.035). Platecrit, MPV and PMI were significantly greater in the CSFP group as compared with the control group [for platecrit: 0.215±0.043% vs 0.201±0.025, respectively, p=0.022; for MPV: 8.64±0.88 fL vs 8.64±0.88 fL, respectively, p<0.001; for PMI: 2983.5 (2692.5-3217.2) vs 2261.5 (2100-2456), respectively, p<0.001].
As for the angiographic characteristics of the subjects. TFC in all major coronary arteries was higher in the CSFP groups compared with the controls (p<0.001 for all cLAD artery, LCx artery and RCA). Moreover, the mean TFC in CSFP was significantly greater than in the control group (43.93 ± 9.56 vs 20.0 ± 4.1, respectively, p < 0.001) (Table 1).
Correlation analysis shows that TFC was significantly correlated with PMI (rho = 0.578, p < 0.001), MPV (rho = 0.395, p < 0.001) and platecrit (rho = 0.188, p = 0.016) (Table 2).
Table 3 demonstrates univariate and multivariate logistic regression analysis. Smoking [OR: 1.51 (1.10 – 2.21), p = 0.024], obesity [OR: 1.04 (1.01-1.06), p = 0.027], TFC [OR: 6.361 (1.15 – 35.2), p = 0.034], MPV [OR: 1.103 (1.026 – 1.215), p = 0.013] and PMI [OR: 1.407 (1.04 – 2.015), p = 0.026] were found to be independently associated with CSFP. In ROC curve analysis, MPV cut-off was 80.5 fL with 70% sensitivity and 68% specificity (AUC: 0.755) (Figure 1). PMI cut-off was 2564 with 80% sensitivity and 82% specificity (AUC: 0.866) (Figure 2). The AUC for PMI was greater than AUC for MPV.
Discussion
Our study investigated the relationship between PMI and CSFP, and demonstrated the following findings: 1- PMI and MPV were higher in the CSFP group than those of the controls; 2- PMI and MPV significantly correlated with TFC; 3- PMI and MPV were independently associated with CSFP; 4- PMI better predicted CSFP compared with MPV due to its greater AUC. To our knowledge, our study is the first to evaluate the relationship of PMI with CSFP.
The exact principle underlying mechanism of CSFP has still been yet to be totally elucidated. But, a number of hypotheses have been introduced regarding the topic, including endothelial damage caused by high asymmetric dimethyl arginine and decreased nitric oxide level in plasma [20, 21]. Pakdemir et al. [3] demonstrated a diffuse atherosclerotic state in the coronary vasculature with the help of fractional flow reserve. Mangiery et al. [22], on the other hand, performed histopathological examinations on cardiac biopsies and showed traces of microvascular resistance to blood circulation such as fibromuscular hyperplasia, neointimal proliferation, and vessel wall thickening in CSFP patients.
Platelets exert a significant influence over thrombosis and inflammation, and also pathophysiology of various cardiovascular diseases (CVDs) such as stroke, acute coronary syndrome carotid artery disease, pulmonary embolism, CAD [8, 23]. Among the platelet indices which shows the platelet activation is MPV. Larger platelets are more active due to increased number of granules containing prothrombotic and adhesion molecules. MPV represents a critical factor in the emergence of CVDs including CSFP [6, 7]. However, findings of some other studies stand against this association. Kaya et al. [8] performed a study on 76 patients with CSFP and 389 controls and found no independent association of MPV with CSFP. Nurkelam et al. reported that MPV had not been associated with CSFP patients presenting with stable angina pectoris; however, MPS had been associated with CSFP patients presenting with unstabil angina pectoris. Most of the previous studies assessed the MPV and platelet count in the context of hematological indices, and ignored the platelet mass as calculated by the platelet count X MPV. In only one study, Akpınar et al. [23] demonstrated that platecrit, a surrogate marker of platelet mass, is independently associated with CSFP. PMI is another novel parameter representing another surrogate marker of platelet mass. In our current investigation, PMI was also revealed to be significantly associated with CSFP.
Studies on PMI is sparce. Preliminary studies regarding PMI were mainly conducted over the need of platelet transfusion in pediatric patients in neonatal intensive care unit [14, 15]. There seems to be a balance in the PMI, since megakaryocytes expedite platelet production on the expense of larger cytoplasm upon decrease in platelet number for various reasons such as inflammation, intravascular coagulation or platelet alloimmunization, thereby increasing the MPV [14]. In most of the studies regarding the hematological parameters in CSFP reported no association between platelet count and CSFP, and mean platelet numbers are similar between CSFP and the controls [7, 8]. Due to discrepancies in previous studies, sole platelet count or MPV would seem to be a poor clinical predictor of CSFP; and therefore, it would be prudent to hypotheses that PMI as addressed by platelet count X MPV might be more predictive as compared with the platelet count or MPV alone.
There is no clear-cut reference range for PMI. However, it seems that greater PMI is likely to be more predictor. In this regard, Demir et al. [24] showed that PMI could be a more useful predictor of patent ductus arteriosus closure in preterm neonates compared with the platelet count alone. Günday et al. [12] demonstrated that PMI was a more valuable predictor than MPV alone in coronary bypass operations. Unal [13] reported an increased PMI and MPV in his study encompassing psoriatic patients, and concluded that the increase in these parameters may put the psoriasis patients to a more vulnerable state as regards atherosclerotic plaque complications.
Limitation
Among the limitations of the current study are: First, our patient population is relatively small. For this reason, there is a need for future studies encompassing larger cohorts confirm our results. Secondly, we did not perform a prospective study where catheter sizes and amount and administration pressure of contrast dye would be more predictable.
Conclusion
It was demonstrated in the present study that PMI and MPV are increased in patients with CSFP, and PMI and MPV are positively correlated with TFC. Moreover, PMI and MPV are independently associated with CSFP. Further studies are needed to validate our results.
Scientific Responsibility Statement
The authors declare that they are responsible for the article’s scientific content including study design, data collection, analysis and interpretation, writing, some of the main line, or all of the preparation and scientific review of the contents and approval of the final version of the article.
Animal and Human Rights Statement
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or compareable ethical standards.
Funding: None
Conflict of Interest
The authors declare that there is no conflict of interest.
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Erdoğan Sökmen, Muhammet Salih Ateş. Relationship between platelet mass index and coronary slow flow phenomenon. Ann Clin Anal Med 2025;16(4):286-291
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In-depth evaluation of violence against women
Hacı Mehmet Çalışkan 1, Ömer Jaradat 2, Süleyman Ersoy 1, Şafak Taktak 3, Burak Çelik 4
1 Department of Emergency Medicine, Faculty of Medicine, Kirsehir Ahi Evran University, Kirsehir, 2 Department of Emergency Medicine, Kirsehir Training and Research Hospital, Kirsehir, 3 Department of Psychiatry, Faculty of Medicine, Kirsehir Ahi Evran University, Kirsehir, 4 Department of Emergency Medicine, Faculty of Health Science, Fatih Sultan Mehmet Training and Research Hospital, Istanbul, Turkiye
DOI: 10.4328/ACAM.22430 Received: 2024-09-30 Accepted: 2024-11-11 Published Online: 2024-11-26 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):292-297
Corresponding Author: Ömer Jaradat, Department of Emergency Medicine, Kirsehir Training and Research Hospital, Kirsehir, Turkiye. E-mail: dromerjaradat@gmail.com P: +90 553 311 37 44 Corresponding Author ORCID ID: https://orcid.org/0000-0002-6177-710X
Other Authors ORCID ID: Hacı Mehmet Çalışkan, https://orcid.org/0000-0001-7340-420X . Süleyman Ersoy, https://orcid.org/0000-0001-5417-934X . Şafak Taktak, https://orcid.org/0000-0002-9129-2605 . Burak Çelik, https://orcid.org/0000-0002-6746-4083
This study was approved by the Ethics Committee of Ahi Evran University Faculty of Medicine (Date: 2020-02-25, No: 2020-03/24)
Aim: Violence against women is a leading public health issue that poses a threat to every woman’s life. It has a negative physical, psychological, social, cultural, and economic impact on women. The study aimed to examine the nature, location, level of injury, and treatment needs of women who were victims of domestic violence, as well as their previous psychiatric admissions and diagnoses.
Material and Methods: This quantitative study retrospectively reviewed the records of 203 women who were presented to the emergency department for cases of domestic violence. This study examined the forms of domestic violence, forensic records, and medical history of these women.
Results: The mean age of the women was 32.62±11.62 (16–75) years. It was found that 72.4% of them were married, and 8.37% (n = 17) were exposed to violence during pregnancy. Moreover, 93.6% of these victims were exposed to physical violence, and 90.6% had blunt injuries. Most injuries (65.1%) were observed in the head area. Bone fractures were found in 4.9% (n = 10) of the cases, of which 60% were nasal fractures. Although 195 women were treated as outpatients, six required hospitalization, and two women died.
Discussion: Because emergency services are often the first point of contact for women who have been victims of violence, emergency medicine physicians must be able to suspect and diagnose all types of assault. They are usually present more frequently than other healthcare personnel, especially in busy emergency departments.
Keywords: Intimate Partner, Injury, Violence, Women, Trauma
Introduction
Violence against women is a leading public health problem and poses a threat and danger to women’s lives [1]. The World Health Organization (WHO) defines violence as “the intentional use of physical force or power, threatened or actual, against oneself, another person, or against a group or community, which either results in or has a high likelihood of resulting in injury, death, psychological harm, maldevelopment, or deprivation” (available at: https://www.who.int/news-room/fact-sheets/detail/violence-against-women). Violence affects women negatively in a multifaceted way: physically, psychologically, socially, culturally, and economically [2].
Yam stated that 42% of the women killed for any reason were killed by their spouses or people living with them [3]. In a study conducted by the Turkish Prime Ministry General Directorate on the Status of Women in 2009 with a total of 24,048 households across Turkey, it was stated that 39% of women experienced physical violence, 15% experienced sexual violence, and 44% experienced emotional violence at some point in their lives (available at: http://kasaum.ankara.edu.tr/wp-content/uploads/sites/34/2013/11/Aile-ici-siddet-HUNEE-2008-AnaRapor.pdf).
The impact of domestic violence on women makes it a critical health issue that requires identification and intervention. It’s important to recognize that without action, violence against women can result in loss of life (available at: https://www.cdc.gov/violenceprevention/pdf/ipvbook-a.pdf). Violence against women is a preventable health problem. The health sector, particularly emergency department professionals, plays a crucial role as the first point of contact for women who are victims of violence. After family and friends, as well as the police, emergency departments are the most utilized point of contact for women who experience violence [4, 5]. Two previous studies stated that women who were subjected to domestic violence applied to emergency departments three times more commonly compared to other women [6, 7]. Two different studies found that women who were subjected to domestic violence used healthcare services more commonly for a variety of reasons. However, women are unable to express their problems due to various reasons, such as shame from medical personnel, fear of their assailant, and guilt [8, 9].
In this study, we retrospectively examined the forensic reports and medical histories of women who sought a judicial report at the emergency department due to domestic violence. We looked at the demographic data of the women, the type of violence they experienced, requested medical examinations, treatments received, injury scores, need for consultation, number of visits to the psychiatric outpatient clinic, diagnoses received, hospitalization status, and the time between psychiatric admission and marriage date.
Material and Methods
This retrospective study was carried out by examining the files of 203 female cases who applied to Ahi Evran University Faculty of Medicine Training and Research Hospital Emergency Department between 01 July 2018 and 31 December 2019 due to domestic violence. This hospital is the sole tertiary care facility offering psychiatric outpatient services to a population of 400,000.
Identity and demographic data of the cases were obtained from standard forms of domestic violence issued by the Health Directorate. In addition, data about the educational status, marital status, type of domestic violence, and type of injury of the cases were also obtained from these forms. The type of violence, injury type and region, imaging methods performed, the treatment method, the need for consultation, and data on outcome were obtained from the forensic reports issued for the cases. In addition, information about the number of admissions to the psychiatric outpatient clinic in the last ten years, the time of application, the diagnoses received, and hospitalization status in the psychiatric clinic were obtained from the hospital automation system. Missing data were collected by talking with some of the patients via telephone.
Women who arrived at the emergency department due to trauma from falls, car accidents, or altercations with others were not included in the study. Twenty-seven cases were excluded due to missing data. The chi-square, Fisher-Freeman-Halton, and Fisher exact tests were used for univariate analysis of the variables. Statistical analysis was performed using Statistical Package for Social Sciences for Windows (IBM SPSS version 25.0, Armonk, NY, USA) software.
Ethical Approval
This study was approved by the Ethics Committee of Ahi Evran University Faculty of Medicine (Date: 2020-02-25, No: 2020-03/24).
Results
The mean age of women included in the study was 32.62±11.62 years (range: 16-75). 35.5% of the cases were in the 20-30 age group. The least applications were made by those 70 years old and over. 31.5% of the cases were primary school graduates. 72.4% of the cases were married. 93.6% of the cases brought to the emergency room due to domestic violence were subjected to physical violence, 3.9% were subjected to verbal violence, and 2.5% were subjected to sexual violence (Table 1).
50.2% of the cases had previously applied to the emergency department due to domestic violence. 8.37% (n = 17) of the cases were subjected to violence during their pregnancy. While thirteen women were subjected to violence in the first trimester of pregnancy, two women were subjected to violence in the second trimester, and two women were subjected to violence in the third trimester. One of the women who was subjected to violence in the third trimester had a stillbirth within a week.
In terms of injury types, the most common injuries were blunt injuries, with a rate of 90.6%. Bone fractures occurred in 4.9% of cases (n = 10), of which 60% were nasal bone fractures. The most commonly requested radiological imaging method was X-ray, with a rate of 51.2%. In 65.5% of cases (n = 132), injuries were left to secondary healing. The most common consultations requested were neurosurgery and ear, nose, and throat consultations (Table 1). While 195 cases were treated as outpatients in the emergency department and discharged, six cases were hospitalized, and two cases died from domestic violence. The injury score of 91.1% of cases was 1, while the injury score of 2 cases was 6. Emergency room doctors most issued conclusive forensic reports with a rate of 73.8% (Table 1).
In the present study, no statistical relationship was found between the type of injury and age, educational status, marital status, type of violence, and fracture status. However, there was a statistically significant difference between the type of injury and treatment needs (p = 0.000). Most blunt injuries (38.0%) did not require treatment, and 56.5% were left to secondary healing. Primary repairs were performed in 47.4% of penetrating injuries. There was also a statistically significant difference between the type of injury and the outcome (p = 0.010). While 96.7% of blunt injuries were treated as outpatients and discharged, this rate was 89.5% for penetrating injuries (p < 0.010). No patients died from blunt injuries. However, 10.5% of the patients suffering from penetrating injuries died. There was also a statistically significant difference between the abbreviated injury scale and injury type (p = 0.016). While 92.4% of blunt injuries were minor, this rate was only 78.9% for penetrating injuries (Table 2). On the other hand, no significant relationship was found when the same parameters concerning the type of violence (verbal, physical, sexual) were compared.
When the victims were examined in terms of the region of trauma on the body, it was found that 61.5% (n = 125) had trauma in the head region, followed by the upper extremities (38.9%). The least number of injuries were observed in the lower extremities (feet and ankles) (Figure 1).
Significant results were obtained when the victims were examined in terms of the impact areas on the bodies (Table 3). Injuries resulting in death were caused by penetrating injuries to the thorax and abdomen. The present study divided the head into eight separate sections and evaluated. Lesions were observed in 22.4% of the cases on the scalp area, 20.8% of the cases on the neck area, 14.4% of the cases on the cheek and forehead area, 11.2% of the cases on the eye and supraorbital area, 11.2% of the cases on the lip and mouth area, 10.4% of the cases on the nose, 7.2% of the cases on the ear and 2.4% of the cases on the jaw area. Fractures were most commonly observed on the nasal bone, with a rate of 60% (Figure 1).
Since our hospital is the sole provider of psychiatric outpatient services for a population of 400,000, we were able to access ten years’ worth of psychiatric archives. In the present study, we investigated the admission rates of patients in the psychiatry outpatient clinic before and after their marriage. It was found that 16% of the women applied to the psychiatry outpatient clinic before their marriage, and the admission rate of patients after their marriage increased to 51.6%. Thus, it was determined that after their marriage, women applied to psychiatry outpatient clinics three times more often than those before marriage.
In our study, we found that the most common psychiatric diagnosis among women who visited the psychiatric outpatient clinic was anxiety and adjustment disorder, with a rate of 34.9% (n = 71). This was followed by depression, with a rate of 26.1% (n = 53); bipolar affective disorder, with a rate of 3.9% (n = 10); obsessive-compulsive disorder, with a rate of 0.5% (n = 4); and, lastly, schizophrenia, with a rate of 0.5% (n = 2). These diagnoses in the psychiatric outpatient clinic were found to be statistically significant (P = 0.000). On the other hand, 47.3% (n = 96) of patients had no psychiatric diagnosis.
Discussion
Violence against women is increasing in Turkey and globally. According to a 2014 WHO report, one in three women has experienced physical or sexual violence from an intimate partner at least once in their lives [10]. According to the Center for Disease Control estimates, domestic violence against women leads to many health problems (disabilities, sexually transmitted diseases, perinatal complications, HIV, depression, suicide, anxiety, drug-alcohol addiction, post-traumatic stress disorder) and the lack of an established and reliable support system for women who are victims of violence and inadequate legal regulations against violence results in an increase in violence against women (available at: https://www.cdc.gov/violenceprevention/pdf/ipvbook-a.pdf).
In two previous studies conducted in Turkey, the mean age of women who were victims of domestic violence was 34 and 35.7, and the age period where domestic violence was most common was 30-40 [1, 11]. The mean age of the victims included in the present study is consistent with the literature (32.5); however, the age period where domestic violence was most common was found to be 21-30. Muelleman et al. stated that the mean age of women who suffered from intimate partner violence (IPV) was 29, but the mean age of women who applied to health institutions due to non-IPV causes (other traumas) was 32 [12].
In three separate studies conducted in Turkey, the marriage rates of women who were victims of violence were reported to be 91.2% in 2006, 85.6% in 2010, and 79.2% in 2020 [1, 11, 13]. In the present study, 72.4% of the victims were married. This rate is decreasing steadily as more women who suffer from domestic violence get separated from their partners. Almeida et al. stated that almost 50% of women were exposed to at least one form of violence during pregnancy [14]. In three previous studies conducted in Turkey, the ratio of women who were exposed to violence during pregnancy was determined as 3.9%, 7.6%, and 9.7%, respectively [1, 11, 15]. This ratio was 8.37% in the present study. These rates are lower in Turkey, most likely because verbal violence is not considered a type of violence and reported. In addition, Berhanine et al. reported that women who were subjected to violence during pregnancy gave birth to underweight babies or gave birth prematurely three times more commonly compared to those who were not subjected to violence [16].
Consistent with many studies in the literature, women who were subjected to domestic violence were mainly primary school graduates [1, 11, 13]. Canpolat et al. mentioned that 69.8% of the cases they evaluated had been subjected to domestic violence before [11]. In the present study, 50.2% of the cases had been previously admitted to the emergency department due to domestic violence.
In the present study, the most common region of trauma was the head area, with a rate of 61.57%. Muelleman et al. also reported that women who were victims of violence were most commonly injured in the head area (76.37%). Muelleman et al. divided the head area into three regions and reported that the injuries were most commonly on the face area [12]. In the present study, we divided the head area into eight regions to provide a more detailed evaluation. However, when the cases were evaluated by the categorization of Muelleman et al., the most common region of trauma was the face, followed by the scalp and neck area. Similarly, a meta-analysis conducted by Wu et al. also concluded that the most common region of trauma among women who were subjected to violence was the head [17].
Wu et al. stated that Head Neck Facial (HNF) injuries or multiple injuries are important markers for IPV cases, whereas isolated thoracic, abdominal, and pelvic injuries are not specific to IPV. In the same study, it was stated that IPV should be considered in women with HNF injuries with no witnesses or if there are injuries anywhere else in the body. Two studies reported that cases that died due to IPV applied to trauma centers due to similar traumas before they died, which was described as a missed opportunity if no diagnosis had been made during these previous applications. In the present study, two women died due to IPV [12, 17]. One of these cases was a Turkish citizen, and the case had applied to the emergency department twice in the last year due to IPV. The other case was a 23-year-old woman of Afghan nationality who had just come to Turkey. Therefore, patient history could not be obtained.
Two previous studies in the literature reported that maxillofacial trauma was observed in about half of the women subjected to violence. Similarly, head trauma was the most common form of trauma in the present study, and 50% of the cases had maxillofacial trauma [18, 19]. Mulleman et al. reported that fascial region contusion was the most common type of injury in women subjected to violence [12]. In the present study, the most common lesion observed in the cases was blunt trauma in the fascial region.
Although a significant number of domestic violence cases occur each year in Turkey, the rates of emergency room admissions and official registration of these cases are relatively low. Campbell et al. noted that women subjected to IPV used health services more commonly for headaches and other reasons compared to other women [17, 20]. The present study determined that these cases applied to the emergency department with various subjective complaints. Therefore, some cases of domestic violence can only be detected in the emergency room thanks to the attention of doctors and nurses. For this reason, emergency healthcare personnel must consider domestic violence in cases with lesions, especially in the head and facial areas.
Limitation
One of the primary limitations of our study is its retrospective nature and the fact that it was conducted at a single center. Consequently, the potential for bias cannot be discounted.
Conclusion
Violence against women is a degrading act that should be addressed at every level of the healthcare system. This study emphasizes the importance of identifying and finding solutions to this problem. Emergency departments are often the initial point of contact for women who experience violence, so it is crucial to ensure that these departments can diagnose violence and provide the necessary psychological support, counseling, guidance, and security for the victims.
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. Yaman Ş. Acil Servis Hemşirelerinin Kadına Yönelik Aile İçi Şiddete İlişkin Rol ve Sorumlulukları [The Role and Responsibilities of Emergency Nurses Regarding Domestic Violence Against Women]. Fırat Univ Sağlık Bilim Tıp Derg. 2012;26(1):49-54.
3. Yam M. Seen but not heard: Battered women’s perceptions of the ED experience. J Emerg Nurs. 2000;26(5):464-70.
4. Hoffman RM, Ryus C, Tiyyagura G, Jubanyik K. Intimate partner violence screening during COVID-19. PLoS One. 2023;18(4):e0284194.
5. Duchesne E, Nathoo A, Walker M, Bartels SA. Patient and Provider Emergency Care Experiences Related to Intimate Partner Violence: A Systematic Review of the Existing Evidence. Trauma, Violence, & Abuse. 2023;24(5):2901-21.
6. Campbell JC. Health consequences of intimate partner violence. Lancet. 2002;359(9314):1331-6.
7. Feder GS, Hutson M, Ramsay J, Taket AR. Women exposed to intimate partner violence: Expectations and experiences when they encounter health care professionals: A meta-analysis of qualitative studies. Arch Intern Med. 2006;166(1):22-37.
8. Coker AL, Bethea L, Smith PH, Fadden MK, Brandt HM. Missed opportunities: Intimate partner violence in family practice settings. Prev Med. 2002;34(4):445-54.
9. Kothari CL, Rhodes KV. Missed opportunities: Emergency department visits by police-identified victims of intimate partner violence. Ann Emerg Med. 2006;47(2):190-9.
10. Butchart A, Mikton C, Dahlberg LL, Krug EG. Global status report on violence prevention 2014. Inj Prev. 2015;21(3):213.
11. Canpolat Ö, Demir M. Acil Servise Kadına Yönelik Aile İçi Şiddet Nedeniyle Başvuran Vakaların Değerlendirilmesi [Evaluation of Case Applied to Emergency Department Due to Domestic Violence Against Women]. Gazi Sağlık Bilim Derg. 2020;5(1):1-9.
12. Muelleman RL, Lenaghan PA, Pakieser RA. Battered women: Injury locations and types. Ann Emerg Med. 1996;28(5):486-92.
13. Kocacik F, Dogan O. Domestic violence against women in Sivas, Turkey: Survey study. Croat Med J. 2006;47(5):742-9.
14. Almeida FSJ, Coutinho EC, Duarte JC, Chaves CMB, Nelas PAB, Amaral OP, et al. Domestic violence in pregnancy: Prevalence and characteristics of the pregnant woman. J Clin Nurs. 2017;26(15-16):2417-25.
15. Yanikkerem E, Karadaş G, Adigüzel B, Sevil U. Domestic violence during pregnancy in Turkey and responsibility of prenatal healthcare providers. Am J Perinatol. 2006;23(2):93-103.
16. Berhanie E, Gebregziabher D, Berihu H, Gerezgiher A, Kidane G. Intimate partner violence during pregnancy and adverse birth outcomes: A case-control study. Reprod Health. 2019;16(1):22.
17. Wu V, Huff H, Bhandari M. Pattern of physical injury associated with intimate partner violence in women presenting to the emergency department: A systematic review and meta-analysis. Trauma, Violence, & Abuse. 2010;11(2):71-82.
18. Saddki N, Suhaimi AA, Daud R. Maxillofacial injuries associated with intimate partner violence in women. BMC Public Health. 2010;10:268.
19. Rezaee N, Mardani-Hamooleh M. A Qualitative Study of the Health-Related Perceptions of Married Iranian Women Who Have Experienced Domestic Violence. J Forensic Nurs. 2021;17(1):34-42.
20. Campbell J, Jones AS, Dienemann J, Kub J, Schollenberger J, O’Campo P, et al. Intimate partner violence and physical health consequences. Arch Intern Med. 2002;162(10):1157-63.
Download attachments: 10.4328.ACAM.22430
Hacı Mehmet Çalışkan, Ömer Jaradat, Süleyman Ersoy, Şafak Taktak, Burak Çelik. In-depth evaluation of violence against women. Ann Clin Anal Med 2025;16(4):292-297
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Comparing letrozole versus clomiphene citrate for ovulation induction in polycystic ovary syndrome: A retrospective study
Dilay Gok Korucu 1, Sevcan Sarıkaya 1, Melike Unlu 1, Oguzhan Gunenc 1, Muslu Kazım Korez 2
1 Department of Obstetrics and Gynecology, Faculty of Health Sciences, Konya City Hospital, 2 Department of Biostatistics, Faculty of Medicine, Selcuk University, Konya, Turkiye
DOI: 10.4328/ACAM.22434 Received: 2024-10-03 Accepted: 2024-11-11 Published Online: 2024-11-20 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):298-303
Corresponding Author: Dilay Gok Korucu, Department of Obstetrics and Gynecology, Faculty of Health Sciences, Konya City Hospital, Konya, Turkiye. E-mail: dilaygok@yahoo.com P: +90 530 330 11 68 Corresponding Author ORCID ID: https://orcid.org/0000-0002-2340-2075
Other Authors ORCID ID: Sevcan Sarıkaya, https://orcid.org/0000-0002-0922-4671 . Melike Unlu, https://orcid.org/0009-0005-9246-4367 . Oguzhan Gunenc, https://orcid.org/0000-0003-4373-5245 . Muslu Kazım Korez, https://orcid.org/0000-0001-9524-6115
This study was approved by the Ethics Committee of Karatay University Faculty of Medicine (Date: 2024-02-15, No: 2024/027)
Aim: This study compares the effects of clomiphene citrate (CC) and letrozole on pregnancy outcomes in infertile patients with polycystic ovary syndrome (PCOS) and examines the influence of mild hyperprolactinemia on these outcomes. There is limited research examining the effect of mildly elevated prolactin (PRL) levels during ovulation induction cycles in PCOS patients.
Material and Methods: A retrospective analysis was conducted on 226 primary infertile PCOS patients with an infertility duration of 1-3 years. Patients were treated with either CC or letrozole as oral ovulation induction agents. Statistical analysis was performed using R software, applying Welch’s t-test, Student’s t-test, Mann-Whitney U test, Pearson chi-square test, and Fisher-Freeman-Halton test. A p-value of <0.05 was considered statistically significant.
Results: The letrozole group exhibited more mono follicular development compared to the CC group (92.52% vs. 83.54%; RR=1.11 [95% CI, 0.99 to 1.23], p=.037). The mean endometrial thickness was significantly greater in the letrozole group (9.86 ± 2.70 mm) compared to the CC group (8.77 ± 2.68 mm). No significant differences were found in clinical pregnancy rates (29.93% vs. 29.11%; RR=1.03 [95% CI, 0.67 to 1.57], p=.898) and live birth rates (25.85% vs. 22.78%; RR=1.13 [95% CI, 0.70 to 1.85], p=.611) between the two groups. PRL levels did not significantly differ between the clinically pregnant and non-pregnant groups.
Discussion: We found no difference in pregnancy or live birth rates between CC and letrozole. Letrozole increased endometrial thickness and mono-follicular development. Minimal PRL elevation did not affect pregnancy outcomes, suggesting treatment may be unnecessary.
Keywords: Clomiphene, Letrozole, Polycystic Ovary Syndrome, Primary Infertility, Prolactin
Introduction
Infertility is described as the inability to conceive after one year of trying for women under 35 years of age and after six months for women above 35 who do not use any contraception method [1]. Infertility may result from male, female, or combined reasons. Anovulation is the cause of infertility in 25% of couples [2]. The most common cause of anovulation is PCOS. PCOS is a complex disease encompassing metabolic and reproductive disorders. According to the 2023 International Evidence-based Guideline Criteria, to confirm the diagnosis of PCOS, at least two out of the following three criteria must be met: clinical or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology [3]. Management strategies for subfertility linked to PCOS typically focus on lifestyle modifications, drug treatments, surgical interventions, and the use of assisted reproductive technologies. Letrozole should be used as the first-line ovulation induction agent, followed by CC as the second option. Letrozole, a widely used selective non-steroidal third-generation aromatase inhibitor, is primarily utilized for ovulation induction. It acts by inhibiting the secretion of estradiol in the ovaries. Letrozole continues to be used off-label for ovulation induction despite not having approval from the US Food and Drug Administration (FDA) for this specific use [4]. CC has been used for many years as a selective estrogen receptor modulator, it antagonizes the negative effects of estrogen in the hypothalamus and stimulates follicular development as an endogenous gonadotropin [5]. Contrary to the multi-follicular development in CC, mono-follicular development in LE has been shown to reduce the risk of multiple pregnancies [6]. In many studies conducted on PCOS patients, LE is superior to CC regarding ovulation, pregnancy, and live birth [7, 8].
Elevated or reduced PRL levels can lead to infertility by causing anovulation or infrequent ovulation (oligo-ovulation) through mechanisms related to hormonal imbalances, with abnormal PRL activity occurring both in the blood and within ovarian tissues [9, 10]. Hyperprolactinemia was classified into three levels by the Canadian Medical Association: mild (serum PRL levels under 50 ng/mL), moderate (serum PRL levels ranging from 50 to 100 ng/mL), and severe (serum PRL levels exceeding 100 ng/mL) [11].In 30% of patients with PCOS, elevated levels of serum PRL are observed during both the follicular and luteal phases of the menstrual cycle [12, 13]. A meta-analysis investigating PRL concentrations in women with PCOS versus those without shows generally elevated PRL concentrations in women diagnosed with PCOS, proposing that these could serve as a potential diagnostic indicator for PCOS [14].
In this study, we compared the ovulation induction parameters, clinical pregnancy, abortion, and live birth rates in groups using oral ovulation induction agents CC or letrozole in infertile PCOS patients. We also investigated whether mild PRL elevation in PCOS patients affected pregnancy outcomes.
Material and Methods
Patient records were accessed from the computer system and infertility forms in the file archives of the Konya City Hospital IVF unit between the years 2018 and 2022. Due to being a training and research hospital, a general informed consent form is obtained from all patients at the time of application, allowing their data to be used in academic and scientific studies. Age, body mass index (BMI), basal hormone profiles on day 2 of menstruation, dominant follicle size, endometrial thickness on the day of dominant follicle measurement, sperm parameters, clinical pregnancy, live birth, abortion, birth week parameters were compared between the groups using letrozole and CC for ovulation induction.
Inclusion-exclusion criteria
For this study, we included the first treatment cycle of primary infertile patients who had a history of infertility of at least one year but not exceeding three years and who were diagnosed with PCOS according to the Rotterdam criteria and used CC or letrozole as an oral ovulation induction agent. Information about the patients was obtained retrospectively from files and computer records. All patients had confirmed tubal patency via hysterosalpingography (HSG), and normal spermiogram values were observed. PRL levels measured on the 2nd or 3rd day of the menstrual cycle, ranging between 20-50 ng/mL, were considered as mild hyperprolactinemia. In our laboratory, the upper limit of normal PRL levels is deemed to be 20 ng/mL. Hyperprolactinemia treatment was not administered to these patients.
Patients whose BMI exceeds 30 kg/m², those with endometrioma/endometriosis, endometrial pathologies, and mullerian anomaly, detected tubal factors, systemic or immunological diseases, and patients with serum PRL levels of 50 ng/mL were excluded from the study.
Ovulation induction protocol
All patients were assessed on the 2nd or 3rd day of menstruation for basal hormone profile and were screened for persistent cysts using transvaginal ultrasound before starting CC (Klomen, Koçak Farma, Istanbul, Turkey) or letrozole (Femara, Novartis, Istanbul, Turkey) at a dose of 2x50mg or 2×2.5mg. In our infertility clinic, we primarily prefer letrozole as the oral agent. However, when the government does not cover this medication or patients sometimes choose not to use it for various reasons, we prescribe CC, which is covered by the government and is less expensive. After taking the medication for 5 days, patients were instructed to take a 5-day break and then invited to the hospital for folliculometry. When the endometrial thickness reached >7 mm, and the follicle diameter reached at least 20 mm, patients were recommended to engage in sexual intercourse every other day. They were called back to the hospital 15 days later for a pregnancy test. Patients who showed a heartbeat on transvaginal ultrasound were considered to have a clinical pregnancy positive, and those who delivered a live birth weighing 500 grams or more or after 24 weeks were considered to have a live birth.
Statistical analysis
The study was designed to achieve a power of 80% to detect an absolute difference in pregnancy rate between treatment groups using Pearson’s chi-square test at a two-sided significance level of 0.05 and a medium effect size of 0.5. We estimated that the analysis would need a sample size of 75 patients per treatment group, which was increased to 100 to account for a potential 10% dropout rate.
Baseline characteristics were reported as counts (n) and proportions (%), or mean ± standard deviation and median with ranges (minimum-maximum) or inter-quartiles [1st quartile – 3rd quartile]. A Welch’s t-test, student’s t-test, Mann-Whitney U test, Pearson chi-square test, and Fisher-Freeman-Halton test were used to compare the baseline characteristics of the participants between drug groups.
A two-sided p-value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed with R software, version 4.2.1. (The R Foundation for Statistical Computing, Vienna, Austria; https://www.r-project.org).
Ethical Approval
This study was approved by the Ethics Committee of Karatay University Faculty of Medicine (Date: 2024-02-15, No: 2024/027).
Results
Patients who used the LE drug were older than those who used the CC (29.44 ± 5.84 years vs. 26.10 ± 4.86 years, p<.001). The BMI, FSH (follicle-stimulating hormone), and basal estradiol levels of the two trial groups were similar. Compared with patients who received CC, patients who received letrozole demonstrated higher LH (luteinizing hormone) levels (10.97 ± 2.96 IU/mL vs. 9.33 ± 3.21 IU/mL, p<.001) and less PRL levels (28 ng/dl [IQR, 25 – 33] vs. 31 ng/dl [IQR, 25 – 36], p=.005). The mean endometrial thickness was measured at 9.86 ± 2.70 mm for the letrozole group and 8.77 ± 2.68 mm in those receiving CC, and this high measure was statistically significant. The sperm volume was significantly lower in the letrozole group (2.5 ml [IQR, 2 – 3] vs. 3 ml [IQR, 2.5 – 3.35], p=.007). There was no evidence of sperm motility and TPMS (total progressively motile sperm) count between groups. The baseline characteristics of participants are presented in Table 1.
The reproductive outcomes of the study participants are presented in Table 2. The clinical pregnancy (29.93% vs. 29.11%, RR=1.03 [95% CI, 0.67 to 1.57], p=.898) and live birth (25.85% vs. 22.78%, RR=1.13 [95% CI, 0.70 to 1.85], p=.611) rates in the letrozole group were slightly higher than that in the CC group, but the differences were not statistically significant. The patients who received letrozole had more mono follicular development than the patients who received CC (92.52% vs. 83.54%, RR=1.11 [95% CI, 0.99 to 1.23], p=.037). 16.46% (13 out of 79 patients) of patients who received CC and 6.80% (10 out of 147) of those who received letrozole developed multi-follicular growth, therefore letrozole was associated with a 59% (RR=0.41 [95% CI, 0.19 to 0.90], p=.022) reduction in the risk of multi follicular development.
Table 3 compares the characteristics of the groups with and without clinical pregnancy. There was no difference in PRL levels between the groups who did and did not become pregnant (p=0.592).
Discussion
We did not observe any difference in clinical pregnancy and live birth rates between the groups using CC and letrozole in PCOS patients. We concluded that minimal PRL elevation has no adverse effects on clinical pregnancy and live births. Literature includes studies on the impact of elevated PRL levels on IVF outcomes, but there is limited research examining the effect of mildly elevated PRL during ovulation induction cycles in PCOS patients on pregnancy outcomes.
The treatment of infertility due to anovulation in women with PCOS requires a multifaceted approach. According to Balen et al. [15], lifestyle interventions are recommended as the initial treatment, especially for obese patients, to enhance the effectiveness of subsequent therapies. Pharmacologically, CC is commonly used, but letrozole may offer better ovulation and pregnancy rates. For resistant cases, options like bariatric surgery or IVF are considered, though they carry inherent risks.
According to a comprehensive individual participant data (IPD) meta-analysis, letrozole significantly improves live birth and clinical pregnancy rates in women with PCOS compared to CC. Notably, the efficacy of letrozole is further enhanced in women with higher baseline serum total testosterone levels. This finding suggests that letrozole may be particularly beneficial for a subgroup of PCOS patients characterized by higher androgen levels, supporting a more personalized approach to treatment [16].
The management of infertility in women with PCOS continues to evolve, particularly in the context of selecting optimal ovulation induction agents. The studies by Bahawi et al. and Wang et al. [17, 18], along with our data, provide insights into the effectiveness of letrozole and CC in inducing ovulation and achieving pregnancy in PCOS patients. Both Bahawi et al. and our study reported slightly higher pregnancy rates with LE compared to CC, but this was not statistically significant. Wang et al. [18] also noted superior endometrial receptivity in the letrozole group, which could theoretically lead to higher pregnancy rates, though this was not directly compared in our study.
Patients in the Bahawi et al. [17] study required fewer treatment cycles when using letrozole compared to CC, a finding somewhat echoed in our data, where letrozole also demonstrated a higher rate of mono follicular development. This could indicate a more targeted and efficient follicular response with letrozole, reducing the risk of multi-follicular development and its associated complications, such as ovarian hyperstimulation syndrome. The collective findings underscore the potential benefits of letrozole in treating infertility associated with PCOS, particularly in terms of endometrial receptivity and the efficiency of achieving pregnancy. However, the absence of significant differences in live birth rates and the similar overall pregnancy rates observed in our study suggests that both medications remain viable first-line options, with the choice potentially guided by patient-specific factors such as tolerance to medication and specific endocrine profiles.
PRL, traditionally associated with lactation and reproductive functions, also plays a significant role in metabolic regulation, which is particularly relevant in the context of PCOS. Research indicates that PRL levels may influence various metabolic processes in PCOS, affecting glucose and lipid metabolism and overall metabolic homeostasis [19]. PCOS is often accompanied by hormonal imbalances that include not only the well-known issues of hyperandrogenism and insulin resistance but also varied PRL levels. Elevated PRL levels, or hyperprolactinemia, can exacerbate the symptoms of PCOS, including menstrual irregularities and infertility, by impacting ovarian function directly and by altering metabolic functions [19]. Interestingly, while extremely high or deficient PRL levels are linked to adverse metabolic effects, a specific range of elevated PRL levels might be beneficial, potentially enhancing metabolic stability in PCOS patients. This suggests a nuanced role of PRL, where its concentration-dependent effects could either contribute to or mitigate metabolic dysfunctions associated with PCOS [20].
While there are studies in the literature on the impact of elevated PRL levels on IVF outcomes, there is no research on the effect of mild PRL elevation during ovulation induction cycles in patients with PCOS on pregnancy outcomes. A study examines serum PRL level changes during Intracytoplasmic Sperm Injection (ICSI) in 90 patients and their impact on pregnancy rates. Results indicate a significant increase in PRL levels post-ovum pickup, which normalized before embryo transfer and did not affect pregnancy outcomes. A positive correlation was found between early PRL levels and higher-quality embryos, suggesting that early PRL measurements may help predict embryo quality [21].
Another study complementing this research examined the correlation between serum PRL levels and cumulative pregnancy outcomes in in-vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) cycles. The study suggests that higher baseline PRL levels, particularly those below 50 ng/mL, might positively influence the number of oocytes retrieved and embryos and increase the rates of clinical pregnancies and live births. The study explores the potential positive implications of maintaining mildly elevated PRL levels during IVF/ICSI treatments, challenging previous assumptions about the need to suppress high PRL levels [22]. In contrast to these studies, a series of 20,877 patients examined the relationship between PRL levels and live birth in patients without PCOS, indicating that there is a significant relationship between serum PRL levels and live birth rates. Specifically, PRL levels below 14.8 ng/mL positively correlate with higher live birth rates. However, once PRL levels exceed this threshold, the relationship becomes insignificant, suggesting an optimal range for PRL that may influence pregnancy outcomes positively [23].
In our study, when we compared PRL levels between the group with clinical pregnancies and the group without, although the PRL levels were slightly higher in the group with clinical pregnancies (27.70 ± 9.05 ng/mL vs. 28.40 ± 8.92 ng/mL), this difference was not statistically significant (p=0.592).
Limitation
Limitations of the study are: first, it was a retrospective study with a small sample size. Secondly, we recommended coitus every other day, but we did not check for ovulation or whether the patient’s coitus regularly and at the recommended time. Age values were significantly higher in the letrozole group compared to the CC group, which may be one of the reasons for the lack of statistically significant high pregnancy rates in the letrozole group. On the other hand, the reason why PRL levels did not affect pregnancy outcomes may be that the patients in the study did not have very high PRL levels. Therefore, it may not be correct to conclude that high prolactin levels do not affect pregnancy outcomes based on our results.
Conclusion
In conclusion, we observed no difference in clinical pregnancy and live birth rates between groups using CC and letrozole. Consistent with the literature, we found that the group using letrozole had greater endometrial thickness and higher rates of mono follicular development compared to the CC group. Additionally, we discovered that minimal PRL elevation was not statistically significant between the groups who did and did not become pregnant. This research contributes to our understanding of how PRL might affect fertility outcomes. It may assist clinicians in deciding whether or not to treat minimal PRL elevation.
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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15. Balen AH, Morley LC, Misso M, Franks S, Legro RS, Wijeyaratne CN, et al. The management of anovulatory infertility in women with polycystic ovary syndrome: An analysis of the evidence to support the development of global WHO guidance. Hum Reprod Update. 2016;22(6):687-708.
16. Wang R, Li W, Bordewijk EM, Legro RS, Zhang H, Wu X, et al. First-line ovulation induction for polycystic ovary syndrome: An individual participant data meta-analysis. Hum Reprod Update. 2019;25(6):717-32.
17. Bahawi YO, Radwan EM, Khouj MA, Alotaibi RK, Bajuwaiber NA, Baghlaf LF, et al. Pregnancy Rates in Women With Polycystic Ovary Syndrome (PCOS) Using Letrozole Versus Clomiphene Citrate: A Retrospective Record Review. Cureus. 2023;15(7):e42257.
18. Wang L, Lv S, Li F, Bai E, Yang X. Letrozole Versus Clomiphene Citrate and Natural Cycle: Endometrial Receptivity During Implantation Window in Women With Polycystic Ovary Syndrome. Front Endocrinol (Lausanne). 2021;11:532692.
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Dilay Gok Korucu, Sevcan Sarıkaya, Melike Unlu, Oguzhan Gunenc, Muslu Kazım Korez. Comparing letrozole versus clomiphene citrate for ovulation induction in polycystic ovary syndrome: A retrospective study. Ann Clin Anal Med 2025;16(4):298-303
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Effect of bispectral index monitoring on desflurane consumption, extubation and recovery times in anesthesia management for arthroscopic surgery
Sadık Özkavak 1, Hatice Adsan 2, Yeliz Kılıç 3, Pınar Erdaloğlu 1, Nermin Göğüş 4
1 Department of Anesthesiology and Reanimation, Faculty of Health Sciences, Eskişehir City Hospital, Eskişehir, 2 Social Security Institution, The Ministry of Labor and Social Security, Ankara, 3 Department of Anesthesiology and Reanimation, Faculty of Medicine, Osmangazi University, Eskişehir, 4 Department of Anesthesiology and Reanimation, University of Health Sciences, Bilkent City Hospital, Ankara, Turkiye
DOI: 10.4328/ACAM.22446 Received: 2024-10-09 Accepted: 2024-11-18 Published Online: 2024-11-25 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):304-308
Corresponding Author: Sadık Özkavak, Department of Anesthesiology and Reanimation, Faculty of Health Sciences, Eskişehir City Hospital, Eskişehir, Turkiye. E-mail: drsozkavak@hotmail.com P: +90 505 467 05 93 Corresponding Author ORCID ID: https://orcid.org/0009-0002-9977-3945
Other Authors ORCID ID: Hatice Adsan, https://orcid.org/0009-0004-7519-7159 . Yeliz Kılıç, https://orcid.org/0000-0003-1446-7747
Pınar Erdaloğlu, https://orcid.org/0009-0009-4268-9567 . Nermin Göğüş, https://orcid.org/0000-0002-1706-7039
This study was approved by the Ethics Committee of Ankara Numune Trainig and Research Hospital (Date: 2005-09-14, No: 1)
Aim: The bispectral index (BIS) assesses the hypnotic effects of anesthetic agents. It has been reported that the incidence of postoperative cognitive dysfunction is reduced, and wake-up and recovery times are shortened with the use of BIS monitoring. The aim was to evaluate the effect of BIS monitoring on hemodynamic parameters, recovery times, and desflurane consumption in patients who underwent arthroscopic surgery.
Material and Methods: The patients were classified into two groups: the control group, which received standard anesthesia monitoring, and the BIS group, which received both standard and BIS monitoring. The two groups were compared in terms of hemodynamic parameters, desflurane consumption, spontaneous eye-opening time, recovery time, and side effects.
Results: There were no significant differences between the groups in terms of the course of perioperative hemodynamic parameters over time. The groups were comparable regarding side effects, including hypotension, nausea, vomiting, bradycardia, and laryngospasm. Spontaneous eye-opening time and recovery time were shorter in the BIS group. The amount of desflurane consumed per unit time was found to be lower in the BIS group.
Discussion: BIS monitoring shortened desflurane consumption, spontaneous eye-opening, and recovery times, indicating that BIS monitoring can be safely used to monitor the depth of anesthesia by providing ideal inhalation anesthetic titration.
Keywords: Anesthesia Management, Arthroscopy, Bispectral Index Monitoring, Desflurane
Introduction
Balanced anesthesia, in other words, appropriate depth of anesthesia, has three main components: adequate analgesia, hypnosis, and muscle relaxation. As known, very deep anesthesia can cause unwanted hemodynamic changes, while very light anesthesia carries a high risk of awareness [1]. Therefore, monitoring the depth of anesthesia is of great importance during any surgical procedure, particularly for preventing awareness. In this context, the bispectral index (BIS), based on the analysis of the electroencephalogram (EEG) of patients, is the first FDA-approved method to assess the hypnotic effects of anesthetic agents [2]. BIS is a parameter that measures the level of sedation, loss of consciousness, and recall, ranging from 0, an indicator of complete brain inactivity, to 100, an indicator of alertness. BIS values between 40 and 60 represent adequate general anesthesia for surgery and prevent awareness. In addition, the amount of anesthetic drug is reduced, and postoperative alertness becomes better with the use of BIS monitoring. Moreover, it has been reported that wake-up and recovery times are shortened, the incidence of postoperative cognitive dysfunction and delirium is reduced, and hospital costs are decreased without an increase in undesirable clinical responses [3-7].
In this study, the effect of BIS monitoring on hemodynamic parameters, desflurane consumption, wake-up, and recovery times was aimed to be evaluated in patients who underwent elective arthroscopic surgery.
Material and Methods
Patient selection
After obtaining approval from the local ethics committee, adult patients who were scheduled for elective arthroscopic meniscopathy surgery in Ankara Numune Training and Research Hospital were included in the study. All patients were informed about the operation and anesthesia methods preoperatively. The patients were randomly and equally assigned to two groups: the control group, which received standard anesthesia monitoring (non-invasive blood pressure, ECG, SpO2, and EtCO2), and the BIS group, which received both standard and BIS monitoring. The two groups were compared in terms of perioperative hemodynamic parameters, anesthetic inhalation agent (desflurane) consumption, spontaneous eye-opening, and recovery times.
The patients less than 18 years old, who had ≥3 ASA status, central neurological disease, and drug (anticonvulsant) sensitivity that may affect the neurological response, chronic drug (opioid, benzodiazepine, etc.) and alcohol use, and those with mean arterial pressure (MAP) above 60 mmHg and heart rate (HR) below 50 beats/minute were excluded from the study. If the operation lasted less than 20 minutes or more than 60 minutes, data from those patients were also excluded from the statistical analysis.
Anesthesia management
All patients fasted for at least 8 hours before the operation. In order not to affect the BIS value, sedative premedication was not applied. In all patients, 0.9% NaCl infusion was started through the back of the hand, and 0.5 mg atropine was administered. The patients were randomly divided into two groups: the control group, who received standard routine anesthesia, and the BIS group. Standard monitoring included electrocardiogram (ECG), HR, MAP, peripheral oxygen saturation (SpO2), and end-tidal carbon dioxide (EtCO2) values. In addition, BIS values were measured with Aspect Medical system A-2000 and BIS sensor in the BIS group.
All patients were preoxygenated with 100% oxygen for 3 minutes, and initial monitoring values were recorded. During anesthesia induction, a bolus of 2 µg/kg fentanyl and 2 mg/kg propofol was administered. After ensuring sufficient depth of anesthesia, the appropriate laryngeal mask was placed.
For anesthesia maintenance, 4 L/min oxygen-nitrous oxide mixture (40% O2-60% N2O) and 2-6% desflurane were given in the first 5 minutes. Meanwhile, hemodynamic parameters and BIS values were recorded. Then, the 02-N20 mixture was reduced to 2 L/min in both groups. Hemodynamic parameters and BIS values were also noted every 10 minutes from the incision to the end of the surgery. The depth of anesthesia was evaluated according to the changes in hemodynamic parameters in the control group and BIS values (keeping between 40 and 60) in the BIS group. In both groups, 0.5 µg/kg fentanyl was administered 3 minutes before the incision to suppress the sensation related to the surgical incision, and the desflurane flow percentage was increased by an average of 2% (range 2-6%).
In the presence of findings indicating superficial anesthesia (20% increase in systolic pressure compared to the initial value, 20% increase in heart rate in one minute, sweating, tears, significant movement, swallowing, eye-opening, grimacing) or if the BIS value is 60 and above, the anesthetic gas concentration Increased by 25%. If the findings persisted, 0.5-1 µg/kg fentanyl was given.
If the changes in hemodynamic parameters were high or low but the depth of anesthesia was sufficient (that is, the BIS value was between 40 and 60 in the BIS group, and there was no movement in the control group), auxiliary anesthesia drugs were used. If systolic artery pressure was 20% above the baseline value, 0.1 mg IV permanganate was administered. When a 20% decrease in systolic artery pressure compared to the initial value was observed, 10 mg IV ephedrine was administered, and if HR was below 50/min, 0.01-0.02 mg/kg IV atropine was administered.
At the end of the operation, the time for spontaneous eye opening was recorded. In the BIS group, patients were taken to the recovery room when their BIS scores at the end of surgery were above 90 and close to the initial BIS score. Before removing the laryngeal mask, 10 mg IV metoclopramide was administered to prevent postoperative nausea and vomiting, and 100 mg IV tramadol was given to prevent postoperative pain.
In the postoperative period, patients were evaluated every 5 minutes with the Modified Alderete Postanesthetic Recovery Scoring. The patients who reached 13 or higher scores were sent to their clinics.
Statistical analysis
Data analysis was done using the SPSS package program. Continuous variables were shown as mean and standard deviation, while categorical variables were presented as frequency and percentage. The Repeated Measures Analysis of Variance was used to evaluate whether the changes in HR, MAP, SPO2, and ETCO2 levels during the follow-ups, the differences between the groups, and whether the effect of the group on the changes occurring over time was statistically significant. Mann Whitney U test was used to compare the groups in terms of age, spontaneous eye-opening time, and recovery time. Differences in terms of anesthesia duration and amount of desflurane consumed per unit time (ml/min) were examined using Student’s t-test. A value of p<0.05 was considered statistically significant.
Ethical Approval
This study was approved by the Ethics Committee of Ankara Numune Trainig and Research Hospital (Date: 2005-09-14, No: 1).
Results
A total of 40 patients with a mean age of 38.2 years old were randomly and equally assigned to two groups: a control group and the BIS group. The groups were statistically similar in terms of age, gender, ASA status, body mass index, and anesthesia time (p> 0.05).
In both groups, HR, MAP, SpO2, and EtCO2 values were recorded at those times: before induction (baseline), during induction, just after LMA insertion, 10 minutes after LMA insertion, during incision, 10 minutes after incision, after LMA removal, and during recovery (Figure 1A).
In the statistical analysis of HR, The change in HR over time was found to be statistically significant (p< 0.001). In both the control group and BIS group, HR values measured after LMA insertion, at the 10th minute of LMA insertion, and during the incision were significant compared to the baseline values (p< 0.01). There was no statistically significant difference between the groups in terms of the course of HR over time (p= 0.653).
In the statistical analysis of MAP, The change in MAP over time was found to be statistically significant (p< 0.001). In both groups, MAP values measured after LMA insertion, at the 10th minute of LMA insertion, and during the incision were lower and significant compared to the baseline values (p< 0.01). MAP values measured after the incision were found to be similar to the baseline values in both groups (p> 0.05). There was no statistically significant difference between the groups in terms of the course of MAP over time (p= 0.899) (Figure 1B).
In statistical analysis of SpO2, The change in SpO2 over time was found to be borderline statistically significant (p= 0.003). In both groups, there was an increase in SpO2 values during induction and after LMA compared to the initial SpO2 values, but it was not statistically significant (p> 0.01). There was no statistically significant difference between the groups in terms of the course of SpO2 over time (p= 0.604) (Figure 1C).
In statistical analysis of ETCO2 measurements, The change in ETCO2 over time was found to be statistically significant (p< 0.001). In the control group, there was a significant decrease at the 10th minute of LMA insertion, during and after the incision, compared to the baseline ETCO2 values (p< 0.01). The change in ETCO2 values measured in the BIS group was not significant in comparison to the baseline ETCO2 values (p> 0.01). There was no statistically significant difference between the groups in terms of the course of ETCO2 over time (p= 0.675) (Figure 1D).
Both groups were compared with each other in terms of side effects (Table 1). The most frequent side effect was hypotension. Six patients in the control group and four patients in the BIS monitoring group developed hypotension, all of whom were easily treated with adequate fluid support and vasoactive drugs (ephedrine) when necessary. The second most common side effect was nausea/vomiting. Although antiemetic prophylaxis (10 mg IV metoclopramide before LMA removal) was routinely administered, postoperative nausea and vomiting were observed in five patients in the control group and three patients in the BIS group. All of those patients were successfully treated with additional antiemetic medication. Laryngospasm, which developed during LMA removal in one patient in each group, was corrected with pressurized O2.
Finally, the groups were compared in terms of spontaneous eye-opening time, recovery time, and amount of desflurane consumed per unit time (mL/min). Spontaneous eye-opening time and recovery time were shorter in the BIS group (p= 0.041 and p= 0.014, respectively). The amount of desflurane consumed per unit time was found to be lower in the BIS group (p= 0.008) (Table 2).
Discussion
Unpredictable and unwanted responses associated with anesthetic agents carry potential risks for anesthesiologists. Today, there is no ideal anesthetic agent that provides appropriate depth of anesthesia, causes early and rapid recovery, and has a minimal side effect profile. In addition, the exact dosage of anesthetics to be administered remains a great challenge. To date, clinical symptoms such as corneal and eyelash reflexes, pupil size, pupil reaction to light, tearing, eyeball movements, hemodynamic parameters such as blood pressure and heart pulse, and motor response to skin incision have been used to determine the depth of anesthesia. The hemodynamic changes are not sufficient to determine the depth of anesthesia because they can affected by many factors. Over the last two decades, BIS, which shows electrical activity in the deep cortical brain layers, has become increasingly used in the evaluation of the depth of anesthesia [8, 9]. However, there are many studies with conflicting results regarding the benefits of BIS monitoring. It should be stated here that some of those conflicting results are related to inappropriate study designs, including different patient populations and different anesthesia protocols. In the present study, the BIS and control groups consisted of patients with similar clinical and surgical features. The hemodynamic parameters were then compared between the groups. The fact that basic hemodynamic changes in both groups were statistically similar also allowed us to provide more accurate statistical analyses. Burrow et al. also found that patients who underwent BIS monitoring had better respiratory functions and were more alert and more active when they came to the recovery room. Additionally, hemodynamic data in the BIS group were closer to preoperative values compared to other patients [3].
The main focus of our study was whether the use of BIS monitoring was beneficial in three parameters related to anesthesia management, including spontaneous eye-opening time, recovery time, and amount of desflurane consumed per unit time. Besides, side effects related to anesthetics were the other endpoint in the present study. According to the results obtained from the study, BIS monitoring provided significant reductions in spontaneous eye-opening time, recovery time, and amount of desflurane consumed.
The value of BIS in evaluating the depth of anesthesia has been proven by many studies [9, 10-13]. In those works, keeping the BIS values under 60 during anesthesia was reported to be essential for adequate hypnosis and preventing awareness [9, 14]. In parallel, BIS values were between 40 and 60 in all patients, and the course of the BIS values was almost always consistent with the clinical parameters. In addition, all patients in both groups stated that they did not remember anything about the operation when questioned in the postoperative period.
In previous studies, BIS was found to be a good monitoring method to evaluate loss of consciousness caused by different anesthetic agents such as thiopental, propofol, midazolam, and isoflurane [15-17]. We used propofol for anesthesia induction and desflurane for maintenance. In our study, time for spontaneous eye opening was one of the primary endpoints and was found to be significantly reduced in the BIS group compared to the non-BIS group. Similarly, BIS monitoring provided a reduction in time for spontaneous eye-opening in the majority of clinical studies [15, 18-20].
In our study, recovery time was also found to be decreased in the BIS group, consistent with the majority of previous studies [20, 21]. It is well known that recovery time can be affected by the duration of anesthesia. In our study, there was no significant difference between the groups in terms of anesthesia time. Johansen and Sigl reported in their studies that patients’ extubation times were shortened, and hospital costs were reduced by using BIS monitoring [22].
In the literature, several studies reported that the use of BIS caused a decrease in the consumption of anesthetic drugs [21, 23]. Similarly, we found that desflurane consumption was significantly lower in the BIS monitoring group compared with the control group. As known, high-dose desflurane is associated with serious side effects such as airway irritation, cough, and laryngospasm. In our study, only one patient in each group developed laryngospasm during laryngeal mask removal and was treated with pressurized oxygen. Desflurane also causes postoperative nausea and vomiting due to its irritating smell. A meta-analysis showed that the use of BIS monitoring in patients undergoing outpatient anesthesia reduced the likelihood of nausea and vomiting by 38% [23]. In our study, the patients in the BIS monitoring group had developed less postoperative nausea and vomiting, although not statistically significant.
The use of IV fluids and anticholinergics has been recommended to prevent hypotension and bradycardia that may occur during the use of opioids and desflurane [24]. In our study, all cases were given 7 ml/kg of IV fluid and 0.5 mg atropine before the operation. No statistically significant difference was observed between the groups in terms of the development of hypotension and bradycardia. Postoperative pain, nausea, and vomiting are among the most important reasons for delayed patient discharge. Therefore, titrating general anesthetics with BIS monitoring may reduce these side effects and shorten discharge times [23]. However, discharge time was not evaluated in our study.
Conclusion
There was no significant difference between the BIS monitoring group and the standard monitoring group in terms of perioperative hemodynamic parameters and side effects. However, BIS monitoring shortened desflurane consumption, spontaneous eye opening, and recovery times, indicating that BIS monitoring can be safely used to monitor the depth of anesthesia by providing ideal inhalation anesthetic titration.
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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Sadık Özkavak, Hatice Adsan, Yeliz Kılıç, Pınar Erdaloğlu, Nermin Göğüş. Effect of bispectral index monitoring on desflurane consumption, extubation and recovery times in anesthesia management for arthroscopic surgery. Ann Clin Anal Med 2025;16(4):304-308
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The prognostic role of whole blood viscosity and bone marrow fibrosis in predicting survival outcomes in new diagnosis multiple myeloma patients
Mustafa Duran 1, Nermin Keni Begendi 1, Çiğdem Özdemir 2, Sinan Kazan 3, Yiğit Senol 4
1 Department of Internal Medicine Hemathology, Faculty of Medicine, Afyonkarahisar Health Science Unıversity, 2 Department of Pathology, Faculty of Medicine, Afyonkarahisar Health Science Unıversity, 3 Department of Internal Medicine Nephrology, Faculty of Medicine, Afyonkarahisar Health Science Unıversity, 4 Department of Public Health Services, Afyonkarahisar Health Directorate, Afyonkarahisar, Turkiye
DOI: 10.4328/ACAM.22452 Received: 2024-10-12 Accepted: 2024-11-18 Published Online: 2024-11-23 Printed: 2025-04-01 Ann Clin Anal Med 2025;16(4):309-314
Corresponding Author: Mustafa Duran, Department Of Internal Medıcıne Hemathology, Faculty of Medicine, Afyonkarahisar Health Science Unıversity, Afyonkarahisar, Turkiye. E-mail: mistik07@hotmail.com P: +90 505 913 95 77 Corresponding Author ORCID ID: https://orcid.org/0000-0001-9158-8214
Other Authors ORCID ID: Nermin Keni Begendi, https://orcid.org/0000-0002-7570-1552 . Çiğdem Özdemir, https://orcid.org/0000-0001-8500-0744 . Sinan Kazan, https://orcid.org/0000-0001-7290-4680 . Yiğit Senol, https://orcid.org/0000-0002-2220-4595
This study was approved by the Ethics Committee of Afyonkarahisar Health Sciences University, Faculty of Medicine (Date: 2024-05-03, No: 2024/89)
Aim: This study aimed to evaluate the prognostic role of whole blood viscosity and bone marrow fibrosis in predicting survival outcomes and relationships with prognostic predictors, such as international scoring system albumin levels, beta2-microglobulin, total protein, albumin, and lactate dehydrogenase in newly diagnosed multıple myeloma patients.
Material and Methods: We retrospectively evaluated 108 patients diagnosed with multıple myeloma between 2015-2022. Whole blood viscosity was calculated using the Simone formula, incorporating the hematocrit and total protein values. Bone marrow fibrosis was graded as mild ‘2’, significant ‘3’, or advanced. Comparisons of grade 0-3 bone marrow fibrosis and high-low calculated whole blood viscosity groups in terms of overall survival were conducted using the Kaplan-Meier survival curve and log-rank test.
Results: The median follow-up period was 16 months, and 57.4% of patients died during follow-up. The median overall survival was 26 months. The calculated whole blood viscosity (c-WBV) value predicted mortality with 88.7% sensitivity and 45.7% specificity. Patients with a high c-WBV (≥17.14 208 mPa-s) had significantly lower one- and two-year survival rates than those with a low c-WBV (<17.14 208 mPa-s) (p<0.001). Bone marrow fibrosis was inversely related to survival, with higher grades being associated with lower survival rates. The two-year expected survival time, respectively, bone marrow fibrosis 2 and 3 was determined to be 56.7%, 43.6%, 41.4%, and 23.3% (p<0.001).
Discussion: This study highlights the potential of whole blood viscosity and bone marrow fibrosis as prognostic markers in patients with newly diagnosed multiple myeloma patients. Incorporating these parameters into the existing staging systems may enhance prognostic prediction and guide treatment decisions. Further prospective studies are warranted to validate these findings and explore the mechanistic links between whole blood viscosity, bone marrow fibrosis, and MM pathophysiology.
Keywords: Multiple Myeloma, Calculated Whole Blood Viscosity, Bone Marrow Fibrosis, Overall Survival
Introduction
Multiple myeloma (MM) is a blood cancer marked by abnormal plasma cell proliferation inside and outside the bone marrow. It accounts for 1% of all cancers and 10% of hematologic cancers. In 2022, there were 187,952 new cases and 121,388 deaths. MM predominantly affects males over 50, causing complications like renal failure, hypercalcemia, anemia, immune deficits, bone lesions, hyperviscosity syndrome, and neuropathy [1, 2]. Prognostic factors, including the International Scoring System (ISS) and Durie–Salmon classification, guide treatment planning, and life expectancy predictions. ISS uses albumin (alb) and β2-microglobulin (β2mg) to classify MM into three stages, with stage III having a life expectancy of 29 months, half that of stage I [3]. In 2015, the Revised ISS (R-ISS) added serum lactate dehydrogenase (LDH) and chromosomal abnormalities [4]. In 2022, the European Myeloma Network (EMN) introduced R2-ISS, adding the chromosomal abnormality 1q+ and defining four categories [5].
Hemorheology, which examines the flow and deformation of blood and its elements, has been extensively studied in MM patients compared to healthy individuals. The most common irregularities in MM are anemia and elevated erythrocyte sedimentation rate, while leukopenia and thrombocytopenia are less frequent [6]. Hemorheological assessments show increased whole blood and plasma viscosities and decreased erythrocyte deformability in MM patients. A relationship exists between measured plasma viscosity and calculated WBV (c-WBV) [7]. WBV is crucial in MM pathophysiology, influencing thrombotic event risk and clinical management. The IMPEDE-VTE score indicated increased calculated blood viscosity in patients at “intermediate+high” risk. Although low albumin and ISS III suggest potential as predictive markers for WBV, statistical significance was not achieved. Nevertheless, WBV and thrombosis relationships can predict prognosis [8].
Bone marrow fibrosis (BMF) is influenced by nonmalignant, clonal, or nonclonal neoplastic cells, resulting from cytokines and growth factors like FGF, TGF-β, and BMP released by malignant hematopoietic stem cells. Myelofibrosis involves the activation of cellular fibrogenic pathways, causing excessive extracellular matrix deposition. Effector cells facilitate mesenchymal stem cell differentiation and production of extracellular matrix and collagen [9]. Elevated BMF leads to increased apoptosis in the bone marrow niche, impaired cellular proliferation, and increased extramedullary and medullary hematopoiesis. BMF was found in 38% of MM patients, who had a reduced life expectancy of 4.4 to 5 years compared to those with low or no fibrosis [10].
Recently, hemorheological parameters have gained importance in MM and various hematological cancers. WBV is a critical factor, especially relevant in hyperviscosity. Our study retrospectively calculated WBV for MM patients diagnosed at our center, evaluating the results concerning fibrosis, an indicator of the bone marrow microenvironment. We aimed to include WBV as a prognostic parameter in MM patients and explore the correlation between BMF, hemorheological profile, and survival analyses in the literature.
Material and Methods
We retrospectively evaluated 108 MM patients diagnosed between 2015 and 2022 at Afyonkarahisar Health Sciences University Medical Faculty Hospital. The cohort included 65 males and 43 females, all over the age of 18. Exclusion criteria included infectious diseases, end-stage liver failure, rheumatic and autoimmune diseases, non-MM hematological or oncological malignancies, solitary plasmacytomas, and those receiving active chemotherapy and steroid treatment. MM was diagnosed according to its subtypes by bone marrow biopsy.
We assessed hemoglobin concentration (HGB), hematocrit (HCT), platelet count (PLT), total protein (TP), alb, creatinine (Crea), lactate dehydrogenase (LDH), calcium (Ca+2), β2mg, and C-reactive protein (CRP) using the Cobas 6000 analyzer (Roche, Switzerland). The ISS classification was based on serum alb and β2mg at diagnosis: serum alb >3.5 g/dl and β2mg <3.5 mg/l indicated stage 1 (ISS-1); serum β2mg>5.5 mg/l indicated stage 3 (ISS-3); other cases were stage 2 (ISS-2). Total plasma protein levels, measured in g/L via the colorimetric method, were used to calculate WBV using de Simone’s formula: WBV = (0.12 × HCT) + 0.17 x (TP – 2.0). Bone marrow reports were reviewed for fibrosis presence, evaluated with reticulin staining, and graded 0 to 3: 0 normal, 1 loose, 2 focal bundles, and 3 coarse bundles.
Statistical Analysis
Categorical variables are presented as percentages and frequencies. Continuous variables were assessed for normal distribution using visual methods (histograms) and the Shapiro-Wilk test. Normally distributed continuous variables are expressed as mean ± standard deviation (mean ± SD), and non-normally distributed continuous variables are expressed as median (quartile 1-3). The chi-square test and Fisher’s exact test were used to compare categorical variables between groups. The independent samples t-test was used for conditions with normal distribution, and the Mann-Whitney U test was applied for conditions without normal distribution. Receiver operating characteristic (ROC) curves were used to determine the viscosity value that could distinguish between patients who died and those who survived. The Youden index was used to calculate the optimal cutoff value. Comparisons of high- and low-viscosity groups in terms of OS were conducted using the Kaplan-Meier survival curve and log-rank test. All p values were two-sided, and statistical significance was defined as p<0.05. Statistical analyses were performed using the SPSS 26.0 (IBM Corp. 2019 IBM SPSS Statistics for Windows, version 26.0. Armonk, NY: IBM Corp.) package program.
Ethical Approval
This study was approved by the Ethics Committee of Afyonkarahisar Health Sciences University, Faculty of Medicine (Date: 2024-05-03, No: 2024/89).
Results
The study was conducted on 108 patients with MM. The median age of the patients was 68 (Q1-Q3= 65-74.75) years. Of these, 60.2% (n = 65) were male, and 39.8% (n = 43) were female. The median follow-up period was 16 (Q1-Q3= 5-38) months. During follow-up, 57.4% (n= 62) of patients died. The median OS was 26 months (95% CI= 16.2-35.8 months). The general characteristics of the surviving and deceased patients are presented in Table 1.
Receiver operating characteristic (ROC) analysis for viscosity demonstrated that a viscosity value of 17.14 could predict mortality with a sensitivity of 88.7% and specificity of 45.7% (AUC= 0.667, 95% CI= 0.558-0.775, p= 0.003). Figure 1 illustrates the ROC curve of the predictive power of viscosity for mortality. Subjects were categorized into two groups: those with viscosity ≥ 17.14 and those with viscosity < 17.14 and subsequently compared. Of the participants, 74.1% (n = 80) were in the high-WBV group, whereas 25.9% (n = 28) were in the low-viscosity group. Table 2 presents a comparison of the high- and low-viscosity groups.
One- and two-year survival in the high-viscosity group were 59.8% and 40.4%, respectively, while those in the low WBV group were 85.7% and 81.8%, respectively. Overall survival (OS) in the low-WBV group was significantly higher (p<0.001). Figure 2 shows a comparison of survival between the high- and low-viscosity groups.
Upon examination of the effect of reticular fiber degree on survival, no mortality was observed in the cohort with reticular fiber degree “0”. The one- and two-year survival rates for subjects with a reticular fiber degree of “1” were 85.7% and 71.7%, respectively. For those with a reticular fiber degree of “2”, the rates were 56.7% and 43.6%, while for those with a reticular fiber degree of “3”, the rates were 41.4% and 23.3%, respectively. A statistically significant inverse relationship was observed between survival and the degree of reticular fiber (p<0.001). Figure 3 illustrates a comparative analysis of survival among the reticular fiber degree groups.
Discussion
This study provides valuable insights into the prognostic factors affecting survival in patients with MM. The median age of the study cohort was 68 years, and the findings revealed that a significant proportion of patients experienced poor OS, with a median OS of 26 months. The diversity of laboratory findings has identified various prognostic markers, notably through the ISS staging system developed by Greipp, which includes β2-MG and serum albumin. In 2015, the International Myeloma Working Group (IMWG) integrated LDH and cytogenetic features into the ISS [11]. One of the primary observations was the strong association between the ISS stage and patient outcomes. Patients in ISS stage III had significantly worse survival compared to those in earlier stages. Low albumin, high β2mg, elevated LDH, and creatinine levels were found to correlate with increased mortality, emphasizing the importance of these parameters in staging and risk stratification. This is consistent with prior studies that demonstrate the prognostic value in MM, as these markers reflect both tumor burden and the patient’s general health status (Table 1). The correlation of these results with studies in the literature was further supported [12].
The hypercoagulable state in cancer patients is linked to procoagulant factors (thrombin products, and elevated activity of tissue factor, FVII, FVIII, vWF, fibrinogen, procoagulant phospholipids, IL-6, TNF-α, and M proteins.), fibrinolytic, or proteolytic factors from tumor cells and inflammatory cytokines affecting coagulation [13]. MM should be considered separately regarding thrombosis due to elevated M proteins, which slow blood flow through increased contact and friction, raising stasis and thrombosis risk. Plasma proteins significantly influence coagulation by affecting blood properties like viscosity and erythrocyte aggregation, though the exact mechanical connections to disease symptoms are not fully understood. Immunoglobulins, a component of total protein, can alter blood viscosity directly or by increasing erythrocyte aggregation, making calculated WBV (c-WBV) particularly relevant in MM patients [14]. When plasma viscosity is assessed alongside classical risk factors, its predictive value for cardiovascular disease and mortality is highlighted, enhancing the differentiation between cardiovascular events and mortality, starting from the increased thrombosis risk in MM [15].
Increased viscosity leads to intensified inflammation and vascular damage, resulting in elevated NO release, which lowers vascular resistance but can become exhausted and toxic in systemic circulation [16]. Besides, high protein levels, changes in erythrocyte behavior, and increased erythrocyte count also affect slow blood flow, a topic largely studied due to its link with higher thrombotic risk in patients, yet its prognostic and survival evaluation remains underexplored Elevated c-WBV increases the risk of vascular occlusion by slowing blood flow, a crucial factor in thrombosis prognosis [17]. Due to the retrospective nature of the study design, direct WBV calculation was not feasible. Instead, the de Simone formula, a simple and non-invasive method incorporating hematocrit and total protein parameters, was used to calculate c-WBV. While this formula may sufficiently evaluate WBV influenced by these factors, it may not fully account for the effects of erythrocyte aggregation and deformability. The literature review revealed no studies on the relationship between c-WBV and mortality in diseases with dysproteinemia. Although, limited studies have examined the relationship between WBV and mortality. One study demonstrated significantly higher mortality in COVID-19 patients with high WBV compared to those with low WBV, and another large-scale prospective study highlighted the relationship between plasma and blood viscosity and mortality in heart disease patients [18, 19].
This study identified c-WBV as a significant mortality predictor. Increased plasma viscosity, a key WBV component, is linked to thrombotic complications and poor outcomes [20,21]. Our findings showed a significant difference in mortality rates between groups with high (20.18 ± 3.5) and low c-WBV values (p= 0.016) (Table 1). Hemoglobin and total protein values, essential for the Simone formula calculation for c-WBV, were significantly different (p < 0.05). ROC analysis confirmed c-WBV’s predictive power for mortality, with a threshold of 17.14 showing 88.7% sensitivity (AUC = 0.667, p = 0.003) (Figure 1). The low c-WBV group had significantly higher OS (p < 0.001) (Figure 2), with one- and two-year survival rates at 85.7% and 81.8%, respectively, compared to 59.8% and 40.4% in the high c-WBV group (Table 2). Low albumin was significantly associated with high c-WBV, indicating its role as a negative prognostic factor. The total protein value significantly differed in the high c-WBV group (p < 0.001), while hematocrit did not show a significant difference despite its general prognostic value (Table 2). This suggests that hyperproteinemia, often due to elevated immunoglobulin levels, contributes to increased blood viscosity and associated risks. Lower albumin levels in the high-WBV group further link hypoalbuminemia to poor prognosis in MM patients. High c-WBV (≥17.14) values also correlated with higher ISS stage 3 prevalence, likely related to low albumin. No significant correlation was found between c-WBV and β2-MG, calcium, LDH, creatinine, and platelet values (Table 2). Significant relationships were identified between ISS, calcium, LDH, β2-MG, platelet, hematocrit, protein, and albumin values and survival (Table 1) (p < 0.05). Protein value alone predominantly determined the c-WBV value in the evaluation of the relationship with other prognostic markers. Apart from the association with mortality and OS, although not statistically significant, it was observed that the group with high c-WBV (≥17.14) values demonstrated higher prevalence, particularly in ISS stage 3, which appears to be related to the correlation with low albumin. A noteworthy observation is the absence of a significant correlation between β2-MG, calcium, LDH, creatinine, and platelet values, and c-WBV (Table 2). In the analysis of general characteristic features, a significant relationship was identified between ISS, calcium, LDH, β2-MG, PLT, Htc, protein, and albumin values and survival (Table 1) (p < 0.05). Our study revealed that the protein value alone played a predominant role in determining the c-WBV value. There is no consensus on the proper diagnosis and standard interpretation of reticulin staining density (RLD) in MM, and myelofibrosis should not be equated with fibrosis. A lower RLD value in MM may yield a more precise assessment. RLD, reflecting the bone marrow microenvironment, has been linked to decreased OS and mortality in MM, a disease with established survival relationships. It also correlates with various clinical pathological factors [22]. This study found a significant inverse relationship between bone marrow RLD and survival, with higher reticular fiber grades (grades 2 and 3) showing substantially lower two-year survival rates of 43.6% and 23.3%, respectively, compared to 71.7% for grade 1 and no mortality for grade 0. These results suggest that BMF, linked to increased production of fibrogenic cytokines like TGF-β and IL-6 due to tumor burden, is crucial for MM prognosis. The correlation between higher RLD and poor survival underscores the importance of bone marrow microenvironment changes in disease progression. High levels of M protein, related to disease burden, may increase cytokine production associated with fibrosis [23]. A statistically significant difference was found between the RLD-3 group and the high c-WBV group (Table 2). Incorporating c-WBV and RLD into routine clinical assessments could improve risk stratification and guide therapeutic decisions. Addressing hyperviscosity and managing BMF may enhance patient outcomes, warranting future prospective studies to validate these findings and explore targeted interventions for patients with high c-WBV and advanced BMF.
Limitation
Our study was a retrospective, single-center investigation with a limited sample size. A larger, multicenter, prospective study could provide more reliable results. Some patients lacked cytogenetic examination data, but exploring the relationship between cytogenetic results and c-WBV remains feasible and potentially valuable. The relationship between PFS and c-WBV could not be established due to the unavailability of PFS results. Additionally, the inability to determine patients’ causes of death required calculating mortality related to thrombotic events.
Conclusion
The study underscores the pivotal influence of clinical and laboratory markers on MM prognosis and survival, incorporating advanced staging systems like the R-ISS. The retrospective analysis highlights c-WBV as a potential prognostic marker associated with both thrombosis risk and survival outcomes, filling a gap in the literature where no prior studies have examined the relationship between c-WBV and MM prognosis. This study reveals that elevated c-WBV values correlate with decreased survival and increased prognosis in MM beyond their effectiveness in thrombosis and vascular events. Data analyses showed no significant differences among MM subtypes and ISS, with primary determinants being low albumin and increased total protein levels. The findings suggest increased globulin production, inflammation, and the negative impact of elevated cytokines on albumin production as potential explanations. The simplicity of calculating these parameters suggests their broader application, advocating for their automatic inclusion in biochemistry results to enhance accessibility. Early anticoagulant initiation in patients with elevated blood viscosity might positively impact life expectancy and mortality. Additionally, bone marrow RLD, indicative of BMF, was linked to shorter survival in patients with higher fibrosis grades, adding depth to the MM prognostic evaluation. The study suggests that RLD, c-WBV, and key markers like protein levels should be integrated into comprehensive patient prognosis assessments. The research advocates incorporating parameters like c-WBV and RLD into routine clinical evaluations to refine prognostic accuracy and tailor patient management, especially for those at higher risk of adverse outcomes. Future prospective studies are necessary to validate these findings and explore their role in guiding therapeutic decisions. The aim is to enhance hemorheological evaluation by addressing current limitations and providing more comprehensive data with a larger sample size, considering factors like cytogenetic abnormalities.
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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Mustafa Duran, Nermin Keni Begendi, Çiğdem Özdemir, Sinan Kazan, Yiğit Senol. The prognostic role of whole blood viscosity and bone marrow fibrosis in predicting survival outcomes in new diagnosis multiple myeloma patients. Ann Clin Anal Med 2025;16(4):309-314
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