A multicentre, multinational study of clinical characteristics and prognosis of hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is a significant health problem, and the associated mortality rate is increasing. Aim: We aimed to determine the clinical characteristics and prognosis for HCC in member countries of the OncoBridge Study Group. Methods: We recruited 630 patients diagnosed with HCC between 2013 and 2019 from 4 countries (Türkiye, Russia, Georgia, and Greece). Univariate and multivariate analyses were conducted to investigate clinical and laboratory prognostic factors. Receiver operating characteristic (ROC) analysis was used to determine the prognostic value of the neutrophil to lymphocyte ratio (NLR) and alpha-fetoprotein (AFP) value. Results: The 3 most common etiological factors were hepatitis B infection (39.7%), hepatitis C virus infection (17.0%) and non-alcoholic fatty liver disease (9.0%). Median overall survival for the whole group was 25 [95% confidence interval (CI): 15.7-34.2] months. Cut-off values for AFP and NLR were accepted as 200 ng/mL and 3.45, respectively. The area under the ROC curve values for AFP, NLR and NLR+AFP were 0.625 (95% CI: 0.547-0.704), 0.589 (95% CI: 0.512-0.667) and 0.657 (95% CI: 0.583-0.731). From the multivariate analysis, advanced tumour size, lymph node involvement and metastasis (TNM) stage, presence of cirrhosis, high AFP, and high NLR values were associated with poor survival. Conclusion: AFP, NLR, advanced TNM, and presence of cirrhosis may predict prognosis in patients with HCC. Studies involving more countries are needed to corroborate these findings.

Hypermetabolic Axillary Lymph Nodes Associated with COVID-19 Vaccination in Breast Cancer Management.

A 42-year-old female patient diagnosed with invasive ductal breast ca underwent 18F-fluorodeoxyglucose (FDG) positron emission tomography/ computed tomography (PET/CT) scan for staging, 1.5 cm diameter hypermetabolic lesion was observed in the lower inner quadrant of the right breast that was compatible with primary tumor [maximum standardized uptake value (SUVmax): 10.5]. No pathological 18F-FDG uptake was observed in lymph nodes whose fatty hilum was seen in the right axilla. However, in the left axilla and left deep axilla, hypermetabolic lymph nodes with a maksimum diameter of 19 mm and fatty hilum were observed (SUVmax: 8.0). In a detailed CT evaluation, these lymph nodes have thicker walls than the ones in the right axilla. The patient was questioned again and coronavirus disease-2019 (COVID-19) vaccination history (with BNT162b2, COVID-19 mRNA vaccine) was determined that was administrated to the left arm 5 days ago. Tru-cut biopsy was performed from the left aksillary lymph nodes and proved to be reactive lymphoid tissue and there was no primary or metastatic tumor in these axillary lymph node tissues. The patient was given neoadjuvant chemotherapy 4.5 months after the first 18F-FDG PET/CT, and the second was performed for the treatment response evaluation. Significant regression was determined from the findings. The patient underwent right total mastechtomy. She was being followed up with adjuvant chemotherapy and radiotherapy. In conclusion, hypermetabolic lymph nodes in the axillas should be interrogated for vaccination in patients with breast cancer. Hypermetabolic lymph nodes observed on the same side of the vaccinated arm in the 18F-FDG PET/CT scan may be related to vaccine-induced reactive lymph node enlargement. Lymph node metastasis may be excluded, especially if there are hypermetabolic lymph nodes with preserved fatty hilum in the contralateral axilla on the same side as the vaccinated arm. Active lymph nodes reactive to the vaccine become inactive after a while.

Could the Inflammatory Prognostic Index Predict the Efficacy of Regorafenib in Patients with Metastatic Colorectal Cancer?

PURPOSE: To investigate the clinical importance of the inflammatory prognostic index (IPI) in patients with metastatic colorectal cancer treated with regorafenib. METHODS: A retrospective analysis of 65 metastatic CRC patients treated with regorafenib between 2015 and 2020 was performed. The association between NLR, PNLR, IPI, and overall survival (OS) and progression-free survival (PFS) was evaluated. RESULTS: According to the cut-off points, patients were divided into two groups. The patients in the high IPI group showed poorer OS compared to patients in the low IPI groups. The PFS was better in patients with low neutrophil-lymphocyte ratio (NLR) and platelet-neutrophil to lymphocyte ratio (PNLR), and the OS was better in patients with low IPI. CONCLUSION: Among the immune inflammation scores analyzed in mCRC patients receiving regorafenib, NLR and PNLR were the best predictor of recurrence, whereas IPI was the best predictor of long-term survival. After being confirmed by better designed controlled trials, IPI can be used to identify the group of patients who will benefit more from regorafenib treatment.

Focusing on Asthma and Chronic Obstructive Pulmonary Disease with COVID-19.

INTRODUCTION: We aimed to evaluate clinical and laboratory findings of hospitalized asthma and chronic obstructive pulmonary disease (COPD) patients with COVID-19 and demonstrate that they have different symptoms and/or laboratory results and outcomes than COVID-19 patients with comorbidity (CoV-com) and without comorbidity (CoV-alone). METHODOLOGY: The data of the demographic, clinical, laboratory findings of hospitalized CoV-alone, asthma, COPD patients with COVID-19 (CoV-asthma, CoV-COPD, respectively), and CoV-com were analyzed. RESULTS: Out of 1082 patients hospitalized for COVID-19, 585 (54.1%) had CoV-alone, 40 (3.7%) had CoV-asthma, 46 (4.3%) had CoV-COPD and 411 (38%) had CoV-com. Cough, shortness of breath, fever and weakness were the most common four symptoms seen in all COVID-19 patients. Shortness of breath, myalgia, headache symptoms were more common in CoV-asthma than the other groups (p < 0.001, p < 0.01, p < 0.05 respectively). Sputum was more common in CoV-COPD than other groups (p < 0.01). COPD group most frequently had increased values, different from the other groups with CRP>5ng/mL in 91.3%, D-dimer > 0.05mg/dL in 89.1%, troponin > 0.014micg/L in %63.9, INR>1.15 in 52.2%, CK-MB>25U/L in 48.5%, PT>14s in 40.9% of patients (p < 0.05, p < 0.001, p < 0.001, p < 0.001, p < 0.05, p < 0.001, respectively). NT-ProBNP was found to have the highest AUC value and the best differentiating parameter for CoV-asthma from CoV-alone. Typical CT findings were present in 44.4% of CoV-alone, 57.5% of CoV-asthma, 28.3% of CoV-COPD and 38.9% of CoV-com groups. CoV-COPD and CoV-com patients died more frequently than other groups (17.8%, 18.5%). CONCLUSIONS: CoV-asthma and CoV-COPD patients might have different symptoms and laboratory parameters than other COVID-19 patients which can guide the physicians.

PROGRESS STUDY: Progression of chronic kidney disease in children and heat shock proteins.

Various molecular and cellular processes are involved in renal fibrosis, such as oxidative stress, inflammation, endothelial cell injury, and apoptosis. Heat shock proteins (HSPs) are implicated in the progression of chronic kidney disease (CKD). Our aim was to evaluate changes in urine and serum HSP levels over time and their relationships with the clinical parameters of CKD in children. In total, 117 children with CKD and 56 healthy children were examined. The CKD group was followed up prospectively for 24 months. Serum and urine HSP27, HSP40, HSP47, HSP60, HSP70, HSP72, and HSP90 levels and serum anti-HSP60 and anti-HSP70 levels were measured by ELISA at baseline, 12 months, and 24 months. The urine levels of all HSPs and the serum levels of HSP40, HSP47, HSP60, HSP70, anti-HSP60, and anti-HSP70 were higher at baseline in the CKD group than in the control group. Over the months, serum HSP47 and HSP60 levels steadily decreased, whereas HSP90 and anti-HSP60 levels steadily increased. Urine HSP levels were elevated in children with CKD; however, with the exception of HSP90, they decreased over time. In conclusion, our study demonstrates that CKD progression is a complicated process that involves HSPs, but they do not predict CKD progression. The protective role of HSPs against CKD may weaken over time, and HSP90 may have a detrimental effect on the disease course.

Association between ß arrestin 2 and filamin A gene variations with medical treatment response in acromegaly patients.

BACKGROUND: Acromegaly is a disease that occurs as a result of excessive growth hormone caused by pituitary adenomas. Some acromegaly patients show resistance to somatostatin analog (SSA) treatment. Filamin-A (FLNA) and ß-arrestins are thought to play a role in the response to SSAs. We aimed to investigate the relationship between FLNA-rs782079491 and ß-arrestin-2-rs34230287 single-nucleotide polymorphisms and disease risk, as well as treatment response in patients with acromegaly in the Turkish population. METHODS: The genotypes of 110 acromegaly patients and 99 controls were determined by realtime PCR. The genotype distributions were compared with clinical data on the disease. RESULTS: There was no association between the ß-arrestin-2 gene polymorphism and the response to SSA treatment in acromegaly patients. For responder patients to SSAs, the ß-arrestin-2-rs34230287 CT+TT genotype was associated with higher microadenoma as compared with the CC genotype (p = 0.017). The FLNA polymorphism was not observed in the study group. CONCLUSIONS: We showed that there was no association between the polymorphic genotypes of FLNA and ß-arrestin-2 genes with acromegaly disease and SSAs response in the Turkish population. However, there was a relationship between ß-arrestin-2 and some of the clinical characteristics. Furthermore, the CC genotype and the C allele are risk factors associated with tumor growth rate in acromegaly patients.

Prognostic factors in patients with metastatic urothelial carcinoma who have treated with Atezolizumab.

BACKGROUND: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies of patients with metastatic platinum-resistant urothelial carcinoma. However, the response rate of Atezolizumab was modest. In the current study, we evaluated the pretreatment prognostic factors for overall survival in patients with metastatic urothelial carcinoma who have progressed after first-line chemotherapy in the Expanded-Access Program of Atezolizumab. PATIENTS AND METHODS: In this study, we present a retrospective analysis of 113 patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy. Data of the patients was obtained from patient files and hospital records. Eligible patients included metastatic urothelial carcinoma patients treated with at least one course of ATZ. Univariate analysis was used to identify clinical and laboratory factors that significantly impact OS. Variables were retained for multivariate analysis if they had a statistical relationship with OS (p < 0.1), and then included a final model of p < 0.05. RESULTS: The median follow-up duration was 23.5 months. Of the patients, 98 (86.7%) were male and 13.3% were female. The median age was 65 years of age (37-86). In univariate analysis, primary tumor location in the upper tract, increasing absolute neutrophil count (ANC), increasing absolute lymphocyte count, neutrophil-to-lymphocyte ratio (NLR) > 3, liver metastases, baseline creatinine clearance less (GFR) than 60 ml/min, Eastern Cooperative Oncology Group (ECOG) performance status (1 ≥), and hemoglobin levels below 10 mg/dl were all the significantly associated with OS. Three of the five adverse prognostic factors according to the Bellmunt criteria were independent of short survival: liver metastases HR 3.105; 95% CI 1.673-5.761; p < (0.001), ECOG PS (1 ≥) HR 2.184; 95% CI 1.120-4.256; p = 0.022, and Hemoglobin level below 10 mg/dl HR 2.680; 95% CI 1.558-4.608; p < (0.001). In addition, NLR > 3 hazard ratio [HR] 2.092; 95% CI 1.031-4.243; p = 0.041 and GFR less than 60 ml/min HR 1.829; 95% CI 1.1-3.041; p = 0.02, maintained a significant association with OS in multivariate analysis. CONCLUSIONS: This model confirms the Bellmunt model with the addition of NLR > 3 and GFR less than 60 ml/min and can be associated with clinical trials that use immunotherapy in patients with bladder cancer.

Can Albumin Bilirubin Ratio and Inflammatory Prognostic Index Be A New Marker Determining Survival in Metastatic Pancreatic Cancer?

OBJECTIVE: The main purpose of our study is to analyze the predictive and prognostic value of inflammatory prognostic index (IPI (using albumin, CRP, neutrophils and lymphocytes) and albumin / bilirubin ratio in metastatic pancreatic cancer patients in addition to other markers currently used. MATERIALS AND METHODS: Medical records of patients with pancreatic cancer treated in Celal Bayar University Medical Faculty Hospital Medical Oncology Clinic between February 2012 and April 2020 were retrospectively reviewed. Clinicopathologic variables such as age, gender, performance status (PS), treatments, histopathology type, localization of metastasis, comorbidity were recorded by an electronic medical record system. Patients performance status were recorded according to the Eastern Cooperative Oncology Group (ECOG). A total of 110 pancreatic cancer patients were reviewed. The IPI was calculated as C-reactive protein × NLR (neutrophil/lymphocyte ratio)/serum albumin. Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. RESULTS: Median OS of all patients was 6 months. The NLR cut off value we calculated was 3,47. The median OS of 47 (49,4%) patients was 8 months (95 % cl. 8,673- 15,383) with NLR < 3,47 and median OS of 48 (50,6%) patients was 4 months (95 % cl. 4,221-7,523) with NLR ≥ 3,47 (P: 0,001). The cut off value calculated for the IPI was 0,79. The median OS of 24 (25,8 %) patients was 8 months (95 % cl. 7,475-18,814) with IPI < 0,79 andmedian OS of 69 (74,2 %) patients was 5 months (95 % cl. 5,774-9,580) with IPI ≥ 0,79 (P: 0,047). The ABR cut off value we calculated was 5,23. The median OS of 45 (47,3 %) patients was 4 months (95 % cl. 8,879- 15,174) with ABR ≥ 5,23 and median OS of 50 (42,7 %) patients was 9 months (95 % cl. 4,015-7,585) with ABR < 5,23 (p< 0.001) (Figure 1). According to this analyses, presenting with jaundice, peritoneum metastasis, CA19.9 and LDH values higher than cut off, high NLR, high IPI and high ABR were also significantly associated with OS. In multivariate analyses, ABR was an independent prognostic factor in PC. Patients with high ABR (> 5,23) had increases in the risk of death compared with those with low ABR (< 5,23) (HR, 0,305; 95 % CI, 0,176-0,531; p: 0.000). Alongside ABR, CA-19.9 (HR, 2,300; 95 % CI, 1,111-4,764; p: 0,025) and LDH (HR, 3,348; 95 % CI, 1,792-6,253; p: 0.000) were an independent prognostic factor in PC. CONCLUSION: In this study, we demonstrated that both IPI and ABR, which were not evaluated in PC before, are non-invasive, cheap, accessible, and easily formulated parameters in determining the prognosis. Especially the fact that ABR is an independent prognostic indicator in multivariate analysis makes it stronger. Although we are aware that our study is retrospective, we hope that the reliability of these scores will increase if it is done with more patient series and if it is done multicenter.

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences.

BACKGROUND: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies in patients with locally advanced or metastatic platinum-resistant urothelial carcinoma. OBJECTIVE: To compare the real-life experience and data of clinical trials on ATZ treatment in metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy from an expanded access program were retrospectively studied. Data of patients were obtained from their files and hospital records. Safety was evaluated for patients treated with at least one cycle of ATZ. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR). The secondary endpoints are overall survival (OS), progression-free survival (PFS), duration of response, and safety profile of patients. Kaplan-Meier methods were used to calculate median follow-up and estimate PFS and OS. RESULTS AND LIMITATIONS: Data of 115 enrolled patients were analyzed. Most of the patients (92.3%, n = 106) had received chemotherapy regimen only once prior to ATZ. The median follow-up duration was 23.5 mo. The complete response rate, partial response rate, and ORR were 8.7% (n = 10), 20.0% (n = 23), and 28.7% (n = 33), respectively. The median duration of response was 20.4 mo (95% confidence interval [CI], 6.47-28.8). Of the 33 patients who responded to treatment, 60% (n = 20) had an ongoing response at the time of the analysis. PFS and OS with ATZ were 3.8 mo (95% CI, 2.25-5.49) and 9.8 mo (95% CI, 6.7-12.9), respectively. All-cause and any-grade adverse events were observed in 113 (98%) patients. Of the patients, 64% experienced a treatment-related adverse event of any grade and 24 (21.2%) had a grade 3-4 treatment-related adverse event. Limitations of the study included its retrospective design, and determination of treatment response based on clinical notes and local radiographic studies. CONCLUSIONS: In these real-life data, ATZ was effective and well tolerated in patients with metastatic urothelial carcinoma who have progressed with platinum-based first-line chemotherapy. ATZ is an effective and tolerable treatment for patients with locally advanced or metastatic platinum-resistant urothelial carcinoma in our study, similar to previously reported trials. PATIENT SUMMARY: Atezolizumab is effective and well-tolerated in patients with metastatic urothelial cancer who progressed with first-line chemotherapy, consistent with the outcomes of the previous clinical trials in this setting.

SNPs of miR-23b, miR-107 and HMGA2 and their Relations with the Response to Medical Treatment in Acromegaly Patients.

INTRODUCTION: Acromegaly is a chronic disease of increased growth hormone (GH) secretion and elevated insulin-like growth factor-I (IGF-I) levels induced by a pituitary adenoma. HMGA2 (high mobility group A2) and AIP (aryl hydrocarbon receptor-interacting protein) expression levels are related to GH-secreting adenomas, and also a response to Somatostatin Analogs (SSAs). We studied SNPs in miR-107 and miR-23b that related with AIP and HMGA2 genes respectively and control their expression, and also SNP in the 3'UTR of HMGA2 gene. Our aim was to investigate genotype distributions of the studied SNPs, as well as the possible relationship between disease and/or response to SSAs treatment in patients with acromegaly. MATERIAL AND METHODS: Genotypes were determined by qRT-PCR method from DNA materials obtained blood samples of acromegaly patients (141) and healthy individuals (99). The genotype distributions of patients and healthy groups, as well as the relationship between the clinical data of the disease and genotypes were statistically compared. RESULTS: In acromegaly patients with T-allele, p53 expression (p=0.049) was significantly higher. In patients with CT+TT genotype and T-allele who were responder to SSA-treatment Ki-67 index (respectively p=0.019, p=0.020 respectively) was higher. We did not observe the genotypes for miR-23b and miR-107 polymorphisms in the patients and control group of Turkish population. CONCLUSION: The genetic variations of the miRNAs genes related with HMGA2 and AIP genes were not seen in our study. Although there is no relationship between HMGA2-rs1351394 polymorphism and acromegaly disease, T allele was associated with some clinical features related to adenoma in patients with acromegaly.

Assessment of death risk of breast cancer patients with joint frailty models.

OBJECTIVES: To investigate the effects of risk factors on recurrence and death in breast cancer patients, taking into account the dependence between recurrence and death as well as the heterogeneity among individuals. The other aim of this study was to make predictions of death risks with a dynamic model that includes patient's history and different horizons. Methods: The data of 465 patients who had undergone surgery at the Istanbul University Oncology Institute,  Istanbul, Turkey, between 2009 and 2016 were used. For data analysis in this retrospective study, the authors applied the joint frailty model, and the predictions were obtained using dynamic prediction methods that consider the patient's history. The Brier score was used to evaluate the accuracy of the estimations. RESULTS: A positive relationship was found between recurrence and death, and heterogeneity was found among patients (p less than 0.001, p=1.008, p=2.945). The effects of Cerb-B2, tumor type, remaining lymph nodes, neoadjuvant chemotherapy, and surgery type were statistically significant for death and recurrence (p less than 0.05, relative risk [death, recurrence] = [2.5, 11.86], [2.065, 2.798], [1.852, 3.113], [4.211, 9.366], [1.521,1.991]). The Brier score values used in the evaluation of the predictions obtained by the dynamic prediction methods were found to be below 0.30. Conclusion: The use of joint frailty models is recommended for the detection of heterogeneity effects and dependence between recurrence and death. Through models in survival analysis, researchers can obtain more accurate parameter estimates. A significant variance of frailty indicates different death risks for the same characteristics.

Predictors of endoscopic recurrence in resected patients with Crohn's disease in a long-term follow-up cohort: History of multiple previous resections and residual synchronous disease in the remnant intestine.

BACKGROUND/AIMS: This study aimed to determine the predictors of endoscopic recurrence in a cohort of patients with Crohn's disease (CD) with prior intestinal resections. MATERIALS AND METHODS: The charts of the patients with CD were reviewed in a retrospective manner. Eighty-three patients were eligible for the final analysis. Demographic features of these patients and time between resection and colonoscopy, presence of any macroscopic residual disease in the remnant intestine, and postoperative medications were noted. Rutgeerts score was used to define postoperative endoscopic recurrence. RESULTS: The patients' mean age±SD at their final colonoscopy was 42.81±11.99 yr; and 37 of 83 patients (45%) were female. The mean follow-up time between resection and the final colonoscopy was 51.16±51.08 months. A total of 51 of 83 patients (61%) were in endoscopic remission (i0, i1); whereas 32 (39%) had an endoscopic recurrence (i2, i3, i4). History of multiple resections (χ2=6.12; p=0.013) and the presence of any postoperative residual disease in the remnant intestine (χ2=5.86; p=0.015) were risk factors; whereas the regular use of azathioprine (AZA) was significantly more common among patients without recurrence (χ2=4.515; p=0.034). In an age-sex adjusted Cox regression analysis history of multiple resections, presence of any postoperative residual disease proved to be independent risk factor for endoscopic recurrence, whereas the regular use of AZA proved to be ineffective. CONCLUSION: In a retrospective long-term follow-up cohort of resected patients with CD, having multiple resections for CD and the presence of any residual synchronous disease after ileocolonic resection were identified as risk factors for endoscopic recurrence; the latter was never reported in previous studies.

AGT rs699 and AGTR1 rs5186 gene variants are associated with cardiovascular-related phenotypes in atherosclerotic peripheral arterial obstructive disease.

BACKGROUND: Peripheral arterial diseases (PAD) refer to the arterial diseases other than coronary arteries and the aorta. Atherosclerosis is the major cause of PAD. Renin angiotensin aldosterone system (RAAS)-related genes were associated with cardiovascular diseases. Angiotensin II is the pro-inflammatory, proliferative and vasoconstrictor effector of RAAS in the vascular system. AIMS: In this study, we aimed to investigate whether the effects of the angiotensinogen (AGT) rs699 (M268T), angiotensin-converting enzyme (ACE) I/D (rs1799752), angiotensin II receptor type 1 (AGTR1) (A1166C) rs5186, and angiotensin II receptor type 2 (AGTR2) rs35474657 variants were associated with PAD etiology due to atherosclerotic involvement of aorta-iliac and femoro-popliteal artery occlusions. METHODS: AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), AGTR2 rs35474657 gene variants were determined by real-time polymerase chain reaction (RT-PCR) in 63 PAD patients (33 femoro-popliteal, 30 aorta-iliac) and 70 healthy controls. RESULTS: Although there was no significant relationship in the genotype frequencies of AGT rs699, AGTR1 rs5186, ACE I/D (rs1799752), and AGTR2 rs35474657 variants between PAD and control groups (p > 0.05), AGT rs699 TT genotype was significantly associated with fasting glucose (p = 0.023) in PAD patients. Besides, CC genotype of rs699 was significantly related with HDL-cholesterol levels (p = 0.020) in PAD group. Furthermore, AGTR1 rs5186 CC genotype carriers demonstrated significantly higher LDL-cholesterol (p = 0.034) and triglycerides levels (p = 0.007). CONCLUSIONS: This report is the first to show an association between RAAS-related gene variants and their relation with the biochemical characteristics of PAD and suggests that RAAS-associated gene variants may have significant roles in cardiovascular related phenotypes of PAD patients.

Programmed cell death ligand-1 expression in gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Gastroenteropancreatic tumors (GEPNETs) is a heterogeneous disease with variable clinical course. While promising therapeutic options exist for other adult cancers, there are no new molecular-based treatments developed for GEPNETs. One of the main targets of cancer immunotherapy is the Programmed Cell Death Ligand-1 (PD-L1) pathway. Our purpose was to investigate the profile of PD-L1 expression in different organs of GEPNETs and compare the conventional immunohistochemistry (IHC) with the RNA expression analysis via real time polymerase chain reaction (RT-PCR) in order to determine which patients might be appropriate for immune check point-targeted therapy. METHODS: A total of 59 surgically or endoscopically resected GEPNET tissues were retrospectively collected. The expression of PD-L1 and mRNA was evaluated with IHC. RESULTS: The expression of PD-L1 was significantly associated with the high-grade classification (p=0.012). PD-L1 mRNA expression in tumor samples appeared to be higher compared to the corresponding normal tissues. In appendix, stomach and small intestine, the expression of PD-L1 mRNA was higher in the tumor tissues compared to the respective controls. In pancreas and colon, control tissues tend to have a higher PD-L1 mRNA expression compared to tumor tissues. PD-L1 mRNA expression was higher in GEP carcinomas (p=0.0031). CONCLUSION: RT-PCR was found to be more sensitive in detecting PD-L1 expression than conventional IHC. This study may provide an important starting point and useful background information for future research about immunotherapy for appendix, stomach and small intestine neuroendocrine carcinomas.

Orexin/hypocretin receptor, Orx1, gene variants are associated with major depressive disorder.

Objective: Orexins (hypocretins) are neuropeptides expressed in hypothalamic neurons and have regulatory roles in feeding/drinking behaviours, endocrine functions and sleep/wakefulness state. Major depressive disorder (MDD) is a major mood disorder and neurotransmitter dysfunction in hypothalamic neurons may have roles in its formation. Hence, we conducted experiments to determine whether orexin receptor 1 and 2 (Orx1, Orx2) genes were associated with MDD development. Methods: Seventy-five MDD patients and 87 healthy controls were enrolled for the study. Genotyping was carried out with real-time polymerase chain reaction (RT-PCR). Hamilton Rating-Scale for Depression (HRSD) and Beck Depression Inventory (BDI) were utilized to evaluate depressive symptom severity. Results: A significant relation was found in genotype frequencies of Orx1 rs10914456 and rs2271933 variants between MDD patients and controls (p = .009, p = .006). Rs10914456 CC genotype increased MDD risk 3.57 times more than carrying other genotypes (p = .008, OR =3.57;95% CI: 1.39-9.14). However, no association was observed in Orx2 rs2653349 genotypes for MDD development (p > .05). Although statistically not significant, HRSD scores were diminished in MDD subjects carrying rs10914456 CC variants when compared with CT and TT variants (p = .069). Conclusion. This study suggests that, Orx1 rs10914456 and rs2271933 can be associated with MDD development. Hence, Orx1 rs10914456 variants may affect depressive symptom severity.

Urine Levels of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Children with Type 1 Diabetes Mellitus

Objective: Histopathological changes in the kidney in type 1 diabetes mellitus (T1DM) begin before detection of microalbuminuria. Therefore, there is interest in finding a better biomarker for the early detection of diabetic kidney injury. The aim of this present study was to determine whether urinary indicators of fibrosis are detectable early in the development of T1DM in children and if they may predict progressive renal injury. Methods: Urinary matrix metalloproteinase 2 and 9 (MMP2 and MMP9), tissue inhibitor of metalloproteinase 1 and 2 (TIMP1 and TIMP2) and transforming growth factor-ß1 (TGF-ß1) were assessed in 33 patients with T1DM with normal renal functions and in 24 healthy controls. Microalbuminuria was not present in the patient group with the exception of three patients. The results were adjusted to urine creatinine (Cr) and the differences between patients and controls were evaluated. These measurements were repeated after one year and the results were compared with the first year results. Results: Urine MMP2/Cr, MMP9/Cr, TIMP1/Cr, TIMP2/Cr, TGF-ß1/Cr were not different between the patient and control groups (p>0.05). There were also no significant differences between the first and second year results for these biomarkers (p>0.05). None of these parameters were correlated with hemoglobin A1c, body mass index and duration of T1DM. Interestingly, all parameters were negatively correlated to age of onset of T1DM (p<0.05). Conclusion: Our findings suggest that urinary biomarkers of fibrosis do not show an increase in diabetic children without microalbuminuria. The results also indicate that the risk of early fibrosis may increase as age of onset of T1DM decreases.

Variations in Toll-like receptor and nuclear factor-kappa B genes and the risk of glioma.

PURPOSE: Glioblastoma (GBM) is the most aggressive primary brain tumour in the adult nervous system and is associated with a poor prognosis. NF-KB activation is an important driver of the malignant phenotype that confers a negative prognosis in patients with GBM. NF-KB plays a role in Toll-like Receptors (TLR)-induced tumourigenesis. The aim of the present study was to investigate the association of a promoter region polymorphism of NFKB1 gene encoding the p50 subunit of NF-KB, namely -94ins/del ATTG, the most widely discussed the TLR2 Arg753Gln, TLR4Asp299Gly and TLR4Thr399Ile polymorphisms, their combined effects, and the glioma risk. METHODS: A group of 120 Glioma patients and 225 control subjects were screened for these four polymorphisms using the PCR-RFLP method. RESULTS: Statistical analysis indicates that the ins/ins genotype of NFKB -94ins/delATTG (p=0.003), and the AA genotype of TLR4Asp299Gly (p < 0.001) are risk factors for glioma and people carrying the ins allele have an approximately 1.47 times susceptibility risk of glioma whereas GG genotype of TLR2Arg753Gln seems to be protective against glioma (p = 0.002). Combined genotype analysis showed that del/ins-GG genotype of TLR2Arg753Gln-NFKB1, del/ins + GG genotype of TLR4Asp299Gly-NFKB1, del/ins-CC genotype of TLR4Thr399Ile-NFKB1 were risk factors for glioma development. CONCLUSION: NFKB1 -94ins/delATTG and TLR4Asp299Gly polymorphisms are associated with increased glioma cancer risk in a Turkish population.

Increased Expression of Interleukin-18 mRNA is Associated with Carotid Artery Stenosis

Background: Carotid artery stenosis is the atherosclerotic narrowing of the proximal internal carotid artery and one of the primary causes of stroke. Elevated expression of the pleiotropic proinflammatory cytokine interleukin-18 has been demonstrated in human atherosclerotic plaques. Aims: To investigate whether the mRNA expression levels of interleukin-18 and interleukin-18-binding protein and interleukin-18 −137 G/C (rs187238) variants are associated with carotid artery stenosis development. Study Design: Case-control study. Methods: The mRNA expression levels of interleukin-18 and interleukin-18-binding protein and interleukin-18 rs187238 variants were evaluated by quantitative real-time polymerase chain reaction and real-time polymerase chain reaction, respectively, in the peripheral blood mononuclear cells of 70 patients with carotid artery stenosis (36 symptomatic, 34 asymptomatic) and 75 healthy controls. Results: Interleukin-18 mRNA expression was significantly increased in carotid artery stenosis patients compared to that in healthy controls (p=0.01). However, no significant difference was observed between interleukin-18-binding protein mRNA expression levels in patients with carotid artery stenosis and those in controls (p=0.101). Internal carotid artery stenosis severity was significantly higher in symptomatic patients than that in asymptomatic patients (p<0.001). A significant relationship was identified between interleukin-18 expression and internal carotid artery stenosis severity in patients with carotid artery stenosis (p=0.051). Interleukin-18 rs187238 polymorphism genotype frequencies did not significantly differ between patients with carotid artery stenosis and controls (p=0.246). A significant difference was identified between interleukin-18-binding protein gene expression and symptomatic and asymptomatic patients (p=0.026), but there was no difference in interleukin-18 expression between the symptomatic and asymptomatic subgroups (p=0.397). Conclusion: Interleukin-18 mRNA expression may affect carotid artery stenosis etiopathogenesis and internal carotid artery stenosis severity and also may play a mechanistic role in the pathogenesis of carotid artery stenosis, influencing the appearance of symptoms.

The effects of Internet-based exercise compared with supervised group exercise in people with type 2 diabetes: a randomized controlled study.

OBJECTIVES: To compare the effects of Internet-based exercise on glycaemic control, blood lipids, body composition, physical activity level, functional capacity, and quality of life with supervised group exercise in patients with type 2 diabetes. DESIGN: Single-blind, randomized controlled study. SETTING: A Faculty of Health Sciences. SUBJECTS: A total of 65 patients with type 2 diabetes (47 women, 18 men). INTERVENTION: Group A ( n = 22), control group - physical activity counselling once with a brochure. Group B ( n = 22), supervised group-based exercise, three days per week for eight weeks. Group C ( n = 21), Internet-based exercise following the same programme via a website. MAIN MEASURES: Primary outcomes - glycosylated haemoglobin, fasting blood glucose, high-density and low-density lipoprotein, triglyceride, and cholesterol. Secondary outcomes - waist and hip circumferences, body mass index, number of steps, six-minute walking test, and Euro-Quality of Life-5 Dimension. RESULTS: After treatment, glycaemic control (mean change for Group B; Group C; -0.80%, -0.91%, P = 0.003), waist circumference (-4.23 cm, 5.64 cm, P = 0.006), and quality of life (0.26, 0.15, P = 0.013) significantly improved in both training groups compared with the control group. Fasting blood glucose (-46.86 mg/dL, P = 0.009) and hip circumference (-2.7 cm, P = 0.011) were significantly decreased in Group B and total cholesterol (-16.4 mg/dL, P = 0.028), six-minute walking distance (30.5 m, P = 0.01), and number of steps (1258.05, P = 0.023) significantly improved in Group C compared with control group. Group B and Group C changed with equal magnitude. CONCLUSION: In type 2 diabetes, supervised group-based and Internet-based exercise can improve equally glycaemic control, waist circumference, and quality of life, and both are better than simply counselling.

Genetic variants rs1994016 and rs3825807 in ADAMTS7 affect its mRNA expression in atherosclerotic occlusive peripheral arterial disease.

AIM: Peripheral artery disease (PAD) is a vascular disease affecting peripheral circulation. Recently, genome-wide association studies revealed a relationship between single nucleotide polymorphisms (SNPs) in ADAMTS7 (a disintegrin and metalloprotease with thrombospondin motif 7) and atherosclerosis. In this study, we aimed to determine ADAMTS7 expression in peripheral blood mononuclear cells (PBMCs) and the frequency of ADAMTS7 rs1994016 and rs3825807 polymorphisms in a sample of Turkish patients with PAD, and to evaluate the association of matrix metalloproteinase (MMP) levels with PAD development. METHODS: In this case-control study, ADAMTS7mRNA and protein expression was determined using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and western blot, respectively, and rs1994016 and rs3825807 variants in ADAMTS7 were determined by real-time PCR in 115 PAD patients and 116 healthy controls. Plasma levels of nine MMPs were determined using a multiplex immunoassay system. RESULTS: ADAMTS7mRNA levels were significantly higher in PAD patients than in controls (t=-2.75, P=.007). There was no significant difference in the frequencies of rs1994016 and rs3825807 between PAD patients and controls (P>.05). In PAD patients, ADAMTS7mRNA levels were significantly increased for the CC genotype of rs1994016 (t=-2.31, P=.026) and TT genotype of rs3825807 (t=-2.23, P=.032). Furthermore, plasma levels of MMP-1, MMP-3, MMP-7, MMP-10, MMP-12, and MMP-13 were significantly higher in PAD patients than in controls (P<.05). CONCLUSION: This is the first report of the relationship between PAD and ADAMTS7 expression and the effects of the rs1994016 and rs3825807 variants on PAD development. ADAMTS7 may be associated with PAD development.