Association of IL-6 rs1800795, but not TNF-α rs1800629, and IL-1ß rs16944 polymorphisms' genotypes with recovery of ischemic stroke patients following thrombolysis.

OBJECTIVES: Inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, and IL-6 can cause brain injury, slow recovery, and adverse effects (ADEs) in ischemic stroke (IS) patients treated with recombinant tissue plasminogen activator (rtPA). We explored the relationship between selected polymorphisms within TNF-α, IL-1ß and IL-6 genes, and post-IS outcome and ADEs in patients treated with rtPA. METHODS: One hundred and sixty-six patients with IS treated with rtPA were included in this study. The modified Rankin Scale (mRS) was used to assess functional recovery 3 months after IS likewise thrombolytic therapy efficacy. Patients were classified into groups with favorable (0-1) or poor recovery based on their mRS score at the ninetieth day post-IS. During hospitalization, ADEs following rtPA were monitored. TNF-α-308 G/A (rs1800629), IL-1ß-511 G/A (rs16944), and IL-6-174 G/C (rs1800795) polymorphisms were genotyped using Real-Time PCR. SPSS software version 22.0 was used for statistical analyses. RESULTS: Patients with the TNF-α-308 G/A GG genotype had a higher mean NIHSS value at admission (12.75 ± 5.176) than those carrying A-allele (10.56 ± 3.979;p = 0.016). Individuals with the CC genotype of the IL-6-174 G/C polymorphism had significantly lower NIHSS scores (8.79 ± 5.053) than those with G-allele (12.06 ± 6.562) 24 hours after rtPA (p = 0.050). Patients with the GG genotype of the IL-6-174 G/C polymorphism had a significantly poorer outcome (p = 0.024; OR = 2.339; 95%CI 1.121-4.880), while patients who were G-allele carriers of the Il-6-174 G/C polymorphism and had the AA genotype of the IL-1ß-511 G/A polymorphism were statistically significantly more likely to experience hemorrhagic transformation (p = 0.046; OR = 2.7273; 95%CI 1.0414-7.1426). CONCLUSION: GG genotype of the IL-6-174 G/C polymorphism is associated with poor recovery after IS treated with rtPA therapy.

The burden of breast, cervical, and colon and rectum cancer in the Balkan countries, 1990-2019 and forecast to 2030.

BACKGROUND: Despite effective prevention and control strategies, in countries of the Balkan region, cancers are the second leading cause of mortality, closely following circulatory system diseases. OBJECTIVE: To describe trends in the burden of breast, cervical, and colon and rectum cancer in the Balkan region and per country between 1990 and 2019, including a forecast to 2030. METHODS: We described the 2019 Global Burden of Disease (GBD) estimates for breast, cervical, and colon and rectum cancers in eleven Balkan countries over the period 1990-2019, including incidence, years lived with disability (YLD), years of life lost (YLL), and disability-adjusted life years (DALYs) rates per 100,000 population and accompanied 95% uncertainty interval. With the Autoregressive Integrated Moving Average, we forecasted these rates per country up to 2030. RESULTS: In the Balkan region, the highest incidence and DALYs rates in the study period were for colon and rectum, and breast cancers. Over the study period, the DALYs rates for breast cancer per 100,000 population were the highest in Serbia (reaching 670.84 in 2019) but the lowest in Albania (reaching 271.24 in 2019). In 2019, the highest incidence of breast cancer (85 /100,000) and highest YLD rate (64 /100,000) were observed in Greece. Romania had the highest incidence rates, YLD rates, DALY rates, and YLL rates of cervical cancer, with respective 20.59%, 23.39% 4.00%, and 3.47% increases for the 1990/2019 period, and the highest forecasted burden for cervical cancer in 2030. The highest incidence rates, YLD rates and DALY rates of colon and rectum cancers were continuously recorded in Croatia (an increase of 130.75%, 48.23%, and 63.28%, respectively), while the highest YLL rates were in Bulgaria (an increase of 63.85%). The YLL rates due to colon and rectum cancers are forecasted to progress by 2030 in all Balkan countries. CONCLUSION: As most of the DALYs burden for breast, cervical, and colon and rectum cancer is due to premature mortality, the numerous country-specific barriers to cancer early detection and quality and care continuum should be a public priority of multi-stakeholder collaboration in the Balkan region.

Preliminary outcomes of five-year survival for ovarian malignancies in profiled Serbian Oncology Centre.

OBJECTIVE: The present study purposed to determine characteristics of ovarian carcinoma and to analyze predictors of survival in patients with ovarian carcinoma. METHOD: A retrospective cohort study was conducted including the patients with diagnosed ovarian carcinoma treated at the Clinic for Operative Oncology, Oncology Institute of Vojvodina in the period from January 2012 to December 2016. Seventy-two women with ovarian carcinoma were included in the analysis. The data about the histological type of tumor, disease stage, treatment, lymphatic infiltration, and surgical procedure were collected retrospectively, using the database of the institution where the research was conducted (BirPis 21 SRC Infonet DOO ‒ Information System Oncology Institute of Vojvodina). Descriptive statistics and multivariate analysis using Cox proportional hazards model were performed. RESULTS: The univariate Cox regression analysis identified histology, tumor grade, FIGO (International Federation of Gynecology and Obstetrics) stage, NACT (Neoadjuvant Chemotherapy), number of therapy cycles, type of surgery, and chemotherapy response as independent predictors of mortality. Finally, the type of tumor and chemotherapy response had an increased hazard ratio for mortality in the multivariate Cox regression model. Herewith, the percentage of high-grade, advanced-stage ovarian cancer patients with complete response to chemotherapy, absence of recurrent disease, and lymphovascular space invasion were significant predictors of survival in patients with ovarian carcinoma. CONCLUSIONS: Herein, emerging data regarding precision medicine and molecular-based personalized treatments are promising and will likely modify the way the authors provide multiple lines of treatments in the near future.

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy.

Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies.

Revisiting type II diabetes mellitus in pregnancy and pregnancy outcomes such as in thyroidology: do you mind?

SUMMARY OBJECTIVE: There is an increase in the prevalence of pre-gestational diabetes in the past decades, mainly due to the increase in the prevalence of obesity in the general population and consequently type 2 diabetes among women of reproductive age. METHODS: This study purposed to describe the delivery characteristics, pregnancy complications, and outcomes among women in Serbia with the pre-gestational type 2 diabetes in the past decade, as well as their pregnancy complications, deliveries, and neonatal outcomes. The study included data from all the pregnant women with pre-gestational type 2 diabetes in Belgrade, Serbia during the period between 2010 and 2020. The final sample consisted of 138 patients. RESULTS: More than half, i.e., 70 (50.7%) had a vaginal delivery, while 48 (34.8%) had elective and 20 (14.5%) had emergency caesarean sections. Throughout the period, there was 1 patient with preeclampsia (0.7%), 5 with pregnancy-induced hypertension (3.6%), 7 had newborns with small for gestational age (5.1%), 28 with macrosomia (20.3%), 12 (8.7%) had preterm births, and one-fifth, i.e., 28 (20.3%) of the newborns had Apgar score under 8. CONCLUSION: The present study revealed that women with type 2 diabetes in pregnancy have a significant burden of pregnancy complications, related to pregnancy, delivery, and newborns.

Hereditary thrombophilia and low -molecular -weight heparin in women: useful determinants, including thyroid dysfunction, incorporating the management of treatment and outcomes of the entity

SUMMARY OBJECTIVE: Our study purposed to examine the complex relationship between low-molecular-weight heparin therapy, multiple pregnancy determinants, and adverse pregnancy outcomes during the third trimester in women with inherited thrombophilia. METHODS: Patients were selected from a prospective cohort of 358 pregnant patients recruited between 2016 and 2018 at the Clinic for Obstetrics and Gynecology, University Clinical Centre of Serbia, Belgrade. RESULTS: Gestational age at delivery (β=-0.081, p=0.014), resistance index of the umbilical artery (β=0.601, p=0.039), and D-dimer (β=0.245, p<0.001) between 36th and 38th weeks of gestation presented the direct predictors for adverse pregnancy outcomes. The model fit was examined using the root mean square error of approximation 0.00 (95%CI 0.00-0.18), the goodness-of-fit index was 0.998, and the adjusted goodness-of-fit index was 0.966. CONCLUSION: There is a need for the introduction of more precise protocols for the assessment of hereditary thrombophilias and the need for the introduction of low-molecular-weight heparin.

Preliminary outcomes of five-year survival for ovarian malignancies in profiled Serbian Oncology Centre

Abstract Objective: The present study purposed to determine characteristics of ovarian carcinoma and to analyze predictors of survival in patients with ovarian carcinoma. Method: A retrospective cohort study was conducted including the patients with diagnosed ovarian carcinoma treated at the Clinic for Operative Oncology, Oncology Institute of Vojvodina in the period from January 2012 to December 2016. Seventy-two women with ovarian carcinoma were included in the analysis. The data about the histological type of tumor, disease stage, treatment, lymphatic infiltration, and surgical procedure were collected retrospectively, using the database of the institution where the research was conducted (BirPis 21 SRC Infonet DOO - Information System Oncology Institute of Vojvodina). Descriptive statistics and multivariate analysis using Cox proportional hazards model were performed. Results: The univariate Cox regression analysis identified histology, tumor grade, FIGO (International Federation of Gynecology and Obstetrics) stage, NACT (Neoadjuvant Chemotherapy), number of therapy cycles, type of surgery, and chemotherapy response as independent predictors of mortality. Finally, the type of tumor and chemotherapy response had an increased hazard ratio for mortality in the multivariate Cox regression model. Herewith, the percentage of high-grade, advanced-stage ovarian cancer patients with complete response to chemotherapy, absence of recurrent disease, and lymphovascular space invasion were significant predictors of survival in patients with ovarian carcinoma. Conclusions: Herein, emerging data regarding precision medicine and molecular-based personalized treatments are promising and will likely modify the way the authors provide multiple lines of treatments in the near future.

Programmed cell death-1 and its ligands: Current knowledge and possibilities in immunotherapy

Abstract Programmed Cell Death-1 (PCD-1) is a key immune checkpoint receptor, which mainly expresses on activated T, B, Dendritic (DC), Natural Killer (NK), and Treg cells. On the surface of activated T-cells, PCD-1 expression is upregulated after the recognition of peripherals antigens by T cells; subsequently, the elevated binding of PD-1 to Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2) becomes a key step for downstream inhibitory signaling. Although the role of PD-L1 has been evaluated more thoroughly by clinical research, and PD-L1 has also been used more widely in the clinical setting, PD-L2 also plays an important role in the negative regulation of T-cells, one of the necessary conditions that lead to immune tolerance. Expression of PD-L1 either in tumors or in infiltrating immune cells has been verified predominantly by Immunohistochemistry (IHC) in a variety of tumors, suggesting a role for the PD-1/PD-L1 axis as a prognostic trait and therapeutic target across multiple histotypes. The complex interplay between these factors plays a major role in the diffusion and clinical application of PD-L1 IHC assays as predictive biomarkers of response to PD-1/PD-L1 inhibitors. Checkpoint blockades are registered for the treatment of various cancers, including gynecological malignancies.

Highlighting early detection of thyroid pathology and gestational diabetes effects on oxidative stress that provokes preterm delivery in thyroidology: Does that ring a bell?

Abstract Objectives: Ad fontes, the status of the thyroid gland, and metabolic disturbance lead to the alteration of oxygenation. In pregnancy, it is particularly crucial to possess all predictive parameters. Methods: This cross-sectional study was conducted at the Clinic of Gynecology and Obstetrics, Clinical Center of Serbia, Belgrade, Serbia, between 2017 and 2021 which study included a total of 99 women who had been admitted for preterm delivery and had undergone thyroid analysis, detected Hashimoto thyroiditis, and Oral Glucose Tolerance Test (OGTT) 40 days after delivery and had pathological Homeostatic Model Assessment for Insulin Response (HOMA IR) indices. In the group of urgent patients with preterm delivery, we looked after not only routine Doppler of the umbilical artery, but we measured specific ratios such as the Cerebroplacental ratio (CP). Results: The mean maternal age was 32.23 ± 5.96 years and the mean gestational age was detected as 35.40 ± 2.39 weeks. The delivery was completed vaginally in 77 women (78%) and surgically in 22 (22%). The Mean APGAR score was 8.44 ± 1.18, the mean birth weight was 2666.87 ± 622.17g and the cases undergoing cesarean section had significantly higher values of pulsatility index (1.85 ± 0.27 vs. 1.34 ± 0.31) and CP (1.22 ± 0.26 vs. 0.47 ± 0.17). Conclusions: The introduction of Doppler sonography for blood flow assessment helps to form a complete clinical description of the patient, particularly in conditions where oxidative stress became provocative by the thyroid gland antibodies and gestational diabetes in Thyroidology.

Biomarkers and Predictors of Adverse Cardiovascular Events in Different Stages of Chronic Kidney Disease.

Chronic kidney disease (CKD) is an important factor that contributes to the increase of all-cause morbidity and mortality in the group of non-communicable diseases, and it is also recognized as a strong and independent risk factor that contributes to cardiovascular disease (CVD). CVDs are a consequence of the action of a large number of risk factors among which are traditional and non-traditional. These risk factors have been the subject of a large number of studies which partially explained the unfavorable cardiovascular (CV) outcome of CKD patients. Therefore, valid studies about clinical and biohumoral predictors are of particular importance, especially in the early stages of renal disease, that is, in patients with creatinine clearance below 60 ml/min/1.73 m2 when preventive measures are most effective. Among potential predictors of adverse CV outcome are biomarkers of inflammation (Interleukin-18-IL-18), oxidative stress (ischemia-modified albumin-IMA; superoxide dismutase-SOD), acute kidney injury (kidney injury molecule-1-KIM-1; neutrophil gelatinase-associated lipocalin-NGAL), and microribonucleic acids (specific microRNA-133a). In this review, we tried to confirm the relationship between risk factors of CKD and CVD and newer, less frequently examined biomarkers with the occurrence of incidental CV events in renal patients.

Knowledge and barriers to early detection of breast cancer among female primary care patients in Serbia.

OBJECTIVES: Breast cancer is the leading cause of cancer mortality among women in Serbia and accounts for 22.8% of total cancer mortality in 2018. This study assessed the knowledge and barriers to early detection of breast cancer in women. METHODS: In March 2019, at the Primary Healthcare Centre Kikinda, Serbia, a 22-item questionnaire was distributed to a series of patients (N = 403, response rate 91.8%) to assess the odds ratio (OR) and 95% confidence interval (CI) between variables explaining knowledge of breast cancer symptoms and risk factors and barriers to screening, and four types of early detection of breast cancer. RESULTS: The majority of patients (85.4%) know that a lump in a breast is a common symptom of breast cancer and that a family history of breast cancer is a risk factor (80.1%); 63.8% of respondents aged ≥ 30 years self-examined their breasts in the past month, 39.1% of patients aged ≥ 40 years had clinical, while 34.4% had ultrasound breast examination in the past year, and 51.1% of patients aged ≥ 50 years had mammography once in the past two years. Patients aged ≥ 40 years retired and those with a positive family history were 84% and 63% less likely not to undergo a clinical breast examination in the past year. Participants over 40 years of age who reported a lack of funds were 2.46 times more likely to miss a clinical breast examination than those who did not have that barrier. Among participants aged 50-69 years, the likelihood of not receiving the mammography increases by 2.82 with an increase in wealth status and it was 65% lower for those who lack information about the available treatment. CONCLUSION: Women under the age of 50 rarely practice breast cancer screening. Study findings can be used to improve breast cancer screening at the primary level.

Distribution of normal and pathological OGTTs among pregnant population and non-pregnant women with PCOS - the cross-sectional study.

ABSTRACT: Both pregnancy, as physiological, and polycystic ovary syndrome (PCOS), as a pathological condition, carry the risk for developing glucose metabolism abnormalities. In this retrospective cross-sectional study, we hypothesized that pregnancy as a physiological condition carries a higher likelihood for abnormal oral glucose tolerance test (OGTT) results than PCOS as a pathological condition.We have compared the prevalence and likelihood ratios for abnormal OGTT results between non-pregnant women with PCOS (Group A) and pregnant women at 24 to 28 weeks of gestation (Group B). Participants of both study groups underwent glucose tolerance testing with 75 g glucose OGTT. During the study period, 7411 women were tested, 3932 women encompassed Group A, and 3479 women comprised Group B.The numbers of yearly tested pregnant women and the corresponding proportion of tested women among all study participants have decreased during the study period, from 766 to 131 and 89.1% to 20.5%, respectively. Group A had a significantly lower prevalence (4.4%) of pathological OGTT results compared to Group B (8.1%). This has resulted in a 45.427 likelihood ratio (P < .001) for abnormal OGTT results in pregnant women compared to non-pregnant women with PCOS.We might conclude that pregnancy could have a more challenging influence on glucose metabolism and that carries higher risks for abnormal glucose metabolism than PCOS. The awareness of obstetricians regarding physiological changes during pregnancy that predisposes abnormal glucose metabolism is decreasing over time and the compliance concerning OGTT testing of pregnant women is decreasing too.

Clinical and ultrasound characteristics of pediatric lateral neck masses.

Lateral neck masses (LNM) often present a diagnostic challenge in the practice of pediatric plastic surgeon. The aim of this study is to investigate the clinical and ultrasound (US) characteristics of pediatric LNM in order to make mutual comparison between their entities and enable the most accurate preoperative diagnosis. A cross-sectional study was conducted among 250 pediatric patients treated by surgical excision or sclerotherapy in our institution in the period from July 2009 to June 2019. Lymphatic malformation was the most frequent congenital LNM (60.9%), while reactive or granulomatous lymphadenitis was the most frequent acquired LNM (47%). Congenital anomalies were significantly more often localized in the upper half of the sternocleidomastoid (SCM) muscle region, and had more often soft consistency than acquired ones. Congenital LNM had a 32.37 (3.44-304.63) times higher likelihood of incorrect (p = 0.002) and 5.86 (1.35-25.48) times higher likelihood of undetermined (p = 0.018) than correct US findings, respectively. Acquired LNM were significantly more often localized in the region behind the SCM muscle and more often had solid US appearance in comparison to the congenital ones. Association of the clinical and US findings is very important in determining the most accurate preoperative diagnosis without exposing the children to unnecessary utilizing ionizing radiation or anesthesia. Although they are mostly benign, extreme caution is necessary due to malignancies which were found in 16.4% of all our patients.

Uptake of Human Papillomavirus Vaccine and Intention to Vaccinate among Healthy Pregnant Women in Serbia: A Cross-Sectional Study on Awareness, Knowledge, and Attitudes.

We aimed to assess awareness, knowledge, and attitudes of healthy pregnant women towards human papillomavirus (HPV), to estimate factors associated with a positive attitude towards HPV immunization and to assess the uptake of the vaccine among their children. A cross-sectional study was conducted at the University Clinic of Gynecology and Obstetrics, Belgrade, Serbia among pregnant women attending their regular gynecological check-ups at the 12th gestational week. Knowledge about HPV and HPV vaccine was assessed using a specifically designed 12-item and 5-item questionnaires. Out of total 265 included women, 79.3% had heard of HPV, and 37.5% knew that HPV vaccine exists. HPV vaccine knowledge score was associated with higher odds for a positive attitude towards vaccination of both female (OR = 4.10, 95% CI 1.50-11.29) and male (OR = 3.71, 95% CI 1.52-9.01) child. The number of children (OR = 1.32, 95% CI 1.04-1.67) and high vaccine knowledge score (OR = 1.64 95% CI 1.13-2.39) were independent predictors associated with willingness to vaccinate child against HPV. The gynecologist was the preferable point of reference for information seeking about the HPV vaccine. Despite relatively high HPV awareness and knowledge among pregnant women in Serbia, about one-third of them are HPV vaccine aware, and are willing to vaccinate their children against HPV.

Awareness and knowledge about HPV infection and HPV vaccination among women undergoing cytology and colposcopy in Serbian cervical cancer counseling center.

PURPOSE: Understanding target groups' awareness and knowledge regarding the human papillomavirus (HPV) and the HPV vaccine is essential for planning the screening and vaccination programs and attaining adequate vaccination coverage. The aim of this study was to estimate awareness and knowledge about HPV infection and the HPV vaccine and to assess factors associated with HPV awareness, HPV vaccine awareness and high HPV-related knowledge among women undergoing cervical cancer screening in Serbia. METHODS: A cross-sectional study was conducted between January and June 2013 at the Obstetrics and Gynecology Clinic "Narodni Front" in Belgrade, Serbia. HPV awareness, HPV vaccine awareness, and HPV-related knowledge of women undergoing cervical cancer screening were estimated by the means of structured, self-administered questionnaire. RESULTS: The median age of respondents was 36.0 years (range 18-65). Of 324 women participating in the study, 196 (60.5%) had heard of HPV while 95 (29.3%) had heard of the HPV vaccine. The median HPV-related knowledge score was 7 (interquartile range 4.8). Type of occupation and having an increasing number of lifetime sexual partners were associated with HPV awareness, while having no children was associated with HPV vaccine awareness. High HPV knowledge score was associated with younger age and type of occupation. CONCLUSIONS: Women undergoing cervical cancer screening in Serbia have moderate awareness of HPV infection and low awareness of HPV vaccine. However, it is promising that those who heard of HPV have high knowledge about it.

The association between IUGR and maternal inherited thrombophilias: A case-control study.

One of the risk factors for vascular obstetric complications, such as intrauterine growth restriction (IUGR), is inherited thrombophilias. Nevertheless, routine screening for thrombophilias is not endorsed in pregnant women due to their low prevalence and conflicting results of published studies regarding the usefulness of screening in these patients. The cause of IUGR remains unknown in almost 1 quarter of cases. There are no published studies evaluating the association of inherited thrombophilias and IUGR in patients with IUGR of unknown origin. Understanding and preventing IUGR is an important public health concern, as IUGR has been associated with fetal mortality and neonatal morbidity, as well as adverse long-standing consequences. This study aimed to evaluate the prevalence of inherited thrombophilias in IUGR of unknown cause and to test the association between the inherited thrombophilias and IUGR of unknown cause.This study included 33 cases of IUGR of unknown cause tested for inherited thrombophilias and 66 controls individually matched for age, ethnicity, and smoking status.Patients with plasminogen activator inhibitor 1 (PAI-1) and methylenetetrahydrofolate reductase (MTHFR) had significantly higher odds for IUGR of unknown cause (P < .001 and P = .002, respectively) with OR 13.546 (CI 95% 3.79-48.37) and 8.139 (CI 95% 2.20-30.10), respectively. A positive association between other inherited thrombophilias (homozygous 20210 prothrombin gene mutation and homozygous factor V Leiden) and IUGR of unknown cause was also found, P = .096, OR 6.106 (CI 95% 0.72-51.30), although it was not statistically significant (P = .096, OR = 6.106, CI 95% 0.72-51.30).Our results indicate that PAI-1 and MTHFR thrombophilias represent risk factors for IUGR of otherwise unidentified cause.