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Item A Partial Epithelial-Mesenchymal Transition Signature For Highly Aggressive Colorectal Cancer Cells That Survive Under Nutrient Restriction(JOURNAL OF PATHOLOGY, 2024-01-24) Pastorino, Gil A.; Sheraj, Ilir; Oral, Goksu; Gulec Taskiran, Aliye Ezgi; Palmisano, Ralph; Schneider-Stock, ReginePartial epithelial-mesenchymal transition (p-EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p-EMT in starved colorectal cancer (CRC) cells and identify a p-EMT gene signature that can predict prognosis. Functional characterisation of starvation-induced p-EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT-specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease-free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p-EMT genes, a triple-gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation-induced p-EMT was characterised by increased migratory potential and chemoresistance, as well as E-cadherin processing and internalisation. Both gene signature and E-cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high-resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. (c) 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.Item Acute Stroke Management in Türkiye: Intravenous Tissue Plasminogen Activator and Thrombectomy NöroTek: Türkiye Neurology Single Day Study(2023) Arlier, Zulfikar; Can, UfukObjective: To reveal the profile and practice in patients with acute stroke who received intravenous tissue plasminogen activator (IV tPA) and/or neurointerventional therapy in Turkiye. Materials and Methods: On World Stroke Awareness Day, May 10, 2018, 1,790 patients hospitalized in 87 neurology units spread over 30 health regions were evaluated retrospectively and prospectively. Results: Intravenous tPA was administered to 12% of 859 cases of acute ischemic stroke in 45 units participating in the study. In the same period, 8.3% of the cases received neurointerventional treatment. The rate of good prognosis [modified Rankin score (mRS) 0-2] at discharge was 46% in 83 patients who received only IV tPA [age: 67 +/- 12 years; National Institutes of Health Stroke Scale (NIHSS): 12 +/- 6; hospital stay, 24 +/- 29 days]; 35% in 51 patients who underwent thrombectomy (MT) alone (age: 64 +/- 13 years; NIHSS: 14.1 +/- 6.5; length of hospital stay, 33 +/- 31 days), 19% in those who received combined treatment (age: 66 +/- 14 years; NIHSS: 15.6 +/- 5.4; length of hospital stay, 26 +/- 35 days), and 56% of 695 patients who did not receive treatment for revascularization (age: 70 +/- 13 years; NIHSS: 7.6 +/- 7.2; length of hospital stay, 21 +/- 28 days). The symptom-to-door time was 87 +/- 53 minutes in the IV treatment group and 200 +/- 26 minutes in the neurointerventional group. The average door-to-needle time was 66 +/- 49 minutes in the IV tPA group. In the neurothrombectomy group, the door-to-groin time was 103 +/- 90 minutes, and the TICI 2b-3 rate was 70.3%. In 103 patients who received IV tPA, the discharge mRS 0-2 was 41%, while the rate of mRS 0-1 was 28%. In 71 patients who underwent neurothrombectomy, the mRS 0-2 was 31% and mRS 0-1 was 18%. The door-to-groin time was approximately 30 minutes longer if IV tPA was received (125 +/- 107 and 95 +/- 83 minutes, respectively). Symptomatic bleeding rates were 4.8% in IV recipients, 17.6% among those who received only MT, and 15% in combined therapy. Globally, the hemorrhage rate was 6.8% in patients receiving IV tPA and 16.9% in MT. Conclusion: IV thrombolytic and neurointerventional treatment applications in acute ischemic stroke in Turkiye can provide the anticipated results. Heterogeneity has begun to be reduced in our country with the dissemination of the system indicated by the "Directive on Health Services to be Provided to Patients with Acute Stroke."Item The Prognostic Value of the Novel Global Immune-Nutrition-Inflammation Index (GINI) in Stage IIIC Non-Small Cell Lung Cancer Patients Treated with Concurrent Chemoradiotherapy(2023) Topkan, Erkan; Selek, Ugur; Pehlivan, Berrin; Kucuk, Ahmet; Ozturk, Duriye; Ozdemir, Beyza Sirin; Besen, Ali Ayberk; Mertsoylu, Huseyin; 0000-0001-8120-7123; 37760482; AAG-2213-2021Simple Summary: We investigated the prognostic significance of the newly created Global Immune-Nutrition-Inflammation Index (GINI) in IIIC non-small cell lung cancer (NSCLC) patients who received definitive concurrent chemoradiotherapy (CCRT). A total of 802 newly diagnosed stage IIIC NSCLC patients were included. The optimal pre-CCRT GINI cutoff was 1562 (area under the curve: 76.1%; sensitivity: 72.4%; specificity: 68.2%; Youden index: 0.406). GINI >= 1562 was associated with significantly shorter median locoregional progression-free (p < 0.001), progression-free (p < 0.001), and overall survival (p < 0.001) than GINI < 1562. For each survival endpoint, the association between GINI and survival outcomes appeared independent of other confounding variables (p < 0.05 for each). The novel GINI index effectively stratified patients with stage IIIC NSCLSC into two distinct subgroups, demonstrating significant differences in both median and long-term survival rates. Background: We sought to determine the prognostic value of the newly developed Global Immune-Nutrition-Inflammation Index (GINI) in patients with stage IIIC non-small cell lung cancer (NSCLC) who underwent definitive concurrent chemoradiotherapy (CCRT). Methods: This study was conducted on a cohort of 802 newly diagnosed stage IIIC NSCLC patients who underwent CCRT. The novel GINI created first here was defined as follows: GINI = [C-reactive protein x Platelets x Monocytes x Neutrophils] divided by [Albumin x Lymphocytes]. The receiver operating characteristic (ROC) curve analysis was used to determine the optimal pre-CCRT GINI cut-off value that substantially interacts with the locoregional progression-free (LRPFS), progression-free (PFS), and overall survival (OS). Results: The optimal pre-CCRT GINI cutoff was 1562 (AUC: 76.1%; sensitivity: 72.4%; specificity: 68.2%; Youden index: 0.406). Patients presenting with a GINI >= 1562 had substantially shorter median LRPFS (13.3 vs. 18.4 months; p < 0.001), PFS (10.2 vs. 14.3 months; p < 0.001), and OS (19.1 vs. 37.8 months; p < 0.001) durations than those with a GINI < 1562. Results of the multivariate analysis revealed that the pre-CCRT GINI >= 1562 (vs. <1562), T4 tumor (vs. T3), and receiving only 1 cycle of concurrent chemotherapy (vs. 2-3 cycles) were the factors independently associated with poorer LRPS (p < 0.05 for each), PFS (p < 0.05 for each), and OS (p < 0.05 for each). Conclusion: The newly developed GINI index efficiently divided the stage IIIC NSCLSC patients into two subgroups with substantially different median and long-term survival outcomes.Item High Measures of Pre-Chemoradiotherapy Platelet-to-Albumin Ratio Indicates Poor Prognosis in Locally Advanced Pancreatic Cancer Patients(2022) Kucuk, Ahmet; Topkan, Erkan; Selek, Ugur; Haksoyler, Veysel; Mertsoylu, Huseyin; Besen, Ali Ayberk; Pehlivan, Berrin; https://orcid.org/0000-0001-8120-7123; 35444422; AAG-2213-2021Purpose: In a lack of similar research, we meant to retrospectively investigate the prognostic significance of pre-chemoradiotherapy (C-CRT) platelet-to-albumin ratio (PAR) on the survival results of locally advanced unresectable pancreatic adenocarcinoma (LAPC) patients. Patients and Methods: The present analysis included 139 LAPC patients who received C-CRT in total. The utility of pre-C-CRT cutoff(s) reshaping survival data was explored using receiver operating characteristic (ROC) curve analysis. The primary and secondary objectives were the associations between PAR levels and overall survival (OS) and progression-free survival (PFS) outcomes. Results: At a median follow-up of 15.7 months (95% CI: 11.6-19.8), the overall cohort's median and 5-year OS rates were 14.4 months (95% CI: 11.8-17) and 14.7%, respectively, while the corresponding PFS rates were 7.8 months (95% CI: 6.5-9.1) and 11.2%. Because the ROC curve analysis found 4.9 as the optimal PAR cutoff for both OS and PFS [area under the curve (AUC): 75.4%; sensitivity: 72.4%; specificity: 70.3%], we divided the patients into two PAR cohorts: PAR<4.9 (N=60) and PAR>4.9 (N=79). Comparative analysis per PAR group exhibited significantly worse OS (11.2 vs 18.6 months, and 9.8% vs 20.9% at 5 years, P=0.003) and DFS (7 vs 14.3 months, and 7.6% vs 16.2% at 5 years, P=0.001) with PAR>4.9 versus PAR<4.9, respectively. In multivariate analysis, the N0 nodal status, CA 19-9 <= 90 U/mL, and PAR<4.9 were found to be independent predictors of improved OS and PFS. Conclusion: The pre-C-CRT high PAR (>4.9) robustly and independently prognosticated significantly worse OS and PFS results in inoperable LAPC patients who underwent definitive C-CRT.Item Does Lymph Node Ratio (Metastasis/Total Lymph Node Count) Affect Survival And Prognosis In Gastric Cancer?(2022) Topcu, Ramazan; Sahiner, Ibrahim T.; Kendirci, Murat; Erkent, Murathan; Sezikli, Ismail; Tutan, Mehmet B.; https://orcid.org/0000-0002-3592-5092; 35110338; GVS-3968-2022; CAA-2756-2022Objectives: To investigate the influence of the metastatic lymph node/total lymph node ratio (N- ratio) on survival and prognosis in surgically treated gastric carcinomas. Methods: A retrospective review of 73 patients who underwent curative resection at the Department of General Surgery, Hitit University Faculty of Medicine, Turkey. Receiver operating characteristic analysis was used to calculate the cut-off value for the N-ratio of the patients. The N-ratio cut-off value was determined to be 0.32. Patients were divided into 2 groups: below 0.32 (Group 1) and 0.32 and above 0.32 (Group 2). Results: Group 2 patients had a total lymph node mean of 25.10 +/- 13.64 while Group 1 patients had a total lymph node mean of 18.77 +/- 9.36 (p=0.04). In Group 2, the mean of metastatic lymph node was 15.97 +/- 10.30 (p<0.001). The mortality rate of Group 1 was 18% while Group 2 was 51.7%, and were statistically significant (p=0.0039). The estimated survival duration of Group 2 was 24.22 months, and Group 1 was 48.01 months (p=0.001). The mean estimated survival time for the entire group was 40.92 months. We differentiated patients from the development of mortality cut-off value in ROC analysis with 65.2% sensitivity and 72% specificity. This ratio was found to be 0.32, which was statistically significant (p=0.003). Ratios greater than 0.32 raised the risk of mortality by 4.8 times, which was statistically significant (p=0.003). Conclusion: The N-ratio could be a new metric to evaluate prognosis following curative gastrectomy and improve the existing tumor lymph node metastasis staging system.Item Low Pre-Chemoradiotherapy Pan-Immune-Inflammation Value (PIV) Measures Predict Better Survival Outcomes in Locally Advanced Pancreatic Adenocarcinomas(2022) Topkan, Erkan; Selek, Ugur; Kucuk, Ahmet; Pehlivan, Berrin; 0000-0001-8120-7123; 0000-0001-8087-3140; 36158517; AAG-2213-2021Objective: This study sought to determine whether pretreatment pan-immune-inflammation value (PIV) could be used to predict prognosis in patients with locally advanced pancreatic adenocarcinoma (LA-PAC) following definitive concurrent chemoradiotherapy (C-CRT). Methods: The outcomes of 178 LA-PAC patients who received definitive C-CRT were analyzed retrospectively. For all patients, the PIV was calculated using the peripheral blood platelet (P), monocyte (M), neutrophil (N), and lymphocyte (L) counts obtained on the first day of C-CRT: PIV=PxMxN divided by L. The optimum cutoff values for PIV connected to progression-free (PFS) and overall survival (OS) results were sought using receiver operating characteristic (ROC) curve analysis. The OS and PFS differences between the PIV groups constituted the primary and secondary endpoints, respectively. Results: ROC curve analysis indicated that the ideal PIV cutoff was 464 (AUC: 75.9%, sensitivity: 74.1%, specificity: 71.9%), which categorized patients into two groups based on PFS and OS results: low PIV (L-PIV; N = 69) and high PIV (H-PIV; N = 109). According to comparative survival analyses, patients in the L-PIV group had significantly longer median PFS (14.3 vs 7.3 months; HR: 3.04; P < 0.001) and OS (25.9 vs 13.3 months; HR: 2.86; P < 0.001) than those in the H-PIV group. Although none of the H-PIV patients could survive beyond 5 years, the estimated 5-year OS rate was 29.7% in the L-PIV cohort. In multivariate analyses, besides the L-PIV, N0 nodal stage, and CA 19-9 <= 90 U/mL appeared to be the independent predictors of better PFS (P < 0.05 for each) and OS (P < 0.05 for each) results. Conclusion: The present results indicated that pre-C-CRT L-PIV measures were associated with favorable median and long-term PFS and OS results in LA-PAC patients, suggesting that the PIV is a potent and independent novel prognostic biomarker.Item What is the predictive value of preoperative CA 125 level on the survival rate of type 1 endometrial cancer?(2021) Baran, Safak Yilmaz; Alemdaroglu, Songul; Durdag, Gulsen Dogan; Simsek, Seda Yuksel; Bolat, Filiz Aka; Kose, Fatih; Celik, Husnu; 0000-0001-5874-7324; 0000-0003-4335-6659; 0000-0003-3191-9776; 0000-0002-0156-5973; 32979897; AAI-8400-2021; AAK-7016-2021; G-4827-2016; AAL-1923-2021Background/aim: To investigate the utility of preoperative serum cancer antigen 125 (CA 125) levels in type 1 endometrial carcinoma (EC) as a marker for determining poor prognostic factors and survival. Material and methods: All patients with endometrial cancer, who had been treated between 2012 and 2020, were retrospectively reviewed, and finally, 256 patients with type 1 endometrium carcinoma were included in the study. The relationship between the clinicopathological characteristics, CA 125 level, and survival rates were analyzed. The cut-off value for the preoperative serum CA 125 level was defined as 16 IU/L. Results: The median serum CA 125 levels were significantly higher in patients with deep myometrial invasion, lymph node metastasis, lymphovascular space invasion, cervical stromal and adnexal involvement, advanced stage, positive peritoneal cytology, recurrence, and adjuvant therapy requirement. Serum CA 125 cut-off values determined according to clinicopathologic factors ranged from 15.3 to 22.9 IU/L (sensitivity 61%-77%, specificity 52%-73%). The disease-specific survival rate was significantly higher in patients with CA 125 levels < 16 IU/L (P = 0.047). Conclusion: The data showed that choosing a lower threshold value for the CA 125 level (16 IU/L) instead of 35 IU/L, could be more useful in type 1 EC patients with negative prognostic factors.Item The Prognostic Significance of Novel Pancreas Cancer Prognostic Index in Unresectable Locally Advanced Pancreas Cancers Treated with Definitive Concurrent Chemoradiotherapy(2021) Topkan, Erkan; Selek, Ugur; Pehlivan, Berrin; Kucuk, Ahmet; Haksoyler, Veysel; Durankus, Nulifer Kilic; Sezen, Duygu; Bolukbasi, Yasemin; 0000-0001-8087-3140; 0000-0001-8120-7123; 0000-0002-4505-2280; 34511977; O-5474-2014; AAG-2213-2021Purpose: We evaluated the prognostic quality of the novel pancreas cancer prognostic index (PCPI), a combination of CA 19-9 and systemic inflammation response index (SIRI), on the outcomes of locally advanced pancreas adenocarcinoma (LAPAC) patients who received concurrent chemoradiotherapy (C-CRT). Methods: This retrospective analysis covered 152 unresectable LAPAC patients treated from 2007 to 2019. Receiver operating characteristic (ROC) curve analysis was used to define ideal cutoff thresholds for the pretreatment CA 19-9 and SIRI measurements, indivi-dually. The associations between the PCPI groups and progression -free-(PFS) and overall survival (OS) comprised the respective primary and secondary endpoints. Results: The ROC curve analysis distinguished the respective rounded optimal cutoffs at 91 U/m/ L (< versus >= 90) and 1.8 (< versus >= 1.8) for CA 19-9 and SIRI, arranging the study cohort into two significantly different survival groups for each, with resultant four likely groups: Group-1: CA 19-9<90 U/m/L and SIRI<1.8, Group-2: CA 19-9<90 U/m/L but SIRI >= 1.8, Group-3: CA 19-9 >= 90 U/ m/L but SIRI<1.8, and Group-4: CA 19-9 >= 90 U/m/L and SIRI >= 1.8. Since the PFS (P=0.79) and OS (P=0.86) estimates of the groups 2 and 3 were statistically indistinct, we merged them as one group and created the novel three-tiered PCPI: PCPI-1: CA 19-9<90 U/m/L and SIRI<1.8, PCPI-2: CA 19-9<90 U/m/L but SIRI >= 1.8 or CA 19-9 >= 90 U/m/L but SIRI<1.8, and PCPI-3: CA 19-9 >= 90 U/m/L and SIRI >= 1.8, respectively. Comparative analyses unveiled that the PCPI-1 and PCPI-3 groups had the respective best and worst PFS (17.0 versus 7.5 versus 4.4 months; P<0.001) and OS (26.1 versus 15.1 versus 7.4 months; P<0.001) outcomes, while the PCPI-2 group posed in between. The multivariate analysis outcomes confirmed the novel three tired PCPI's independent prognostic significance on either of the PFS [HR: 5.38 (95% confidence interval (CI): 4.96-5.80); P<0.001)] and OS [HR: 5.67 (95% CI: 5.19-6.15); P<0.001] endpoints, separately. Conclusion: The new PCPI introduced here can be used as an independent and reliable prog-nostic indicator to divide LAPAC patients into three subgroups with discrete survival results.Item Prognostic factors of endometrial cancer in elderly patient group and their effects on survival(2021) Alemdaroglu, Songul; Durdag, Gulsen Dogan; Baran, Safak Yilmaz; Simsek, Seda Yuksel; Yetkinel, Selcuk; Yaginc, Didem Alkas; Guler, Ozan Cem; Celik, Husnu; 0000-0003-4335-6659; 34585068; AAI-8400-2021OBJECTIVE: The objective of the study was to investigate the prognostic factors of the elderly group and their effects on survival by examining the histopathological features, surgical treatment protocols, and treatment modalities of patients diagnosed with endometrial cancer (EC). METHODS: The records of 397 EC patients who completed their treatment and follow-up at a single center between 2012 and 2019 were evaluated retrospectively. The patients were evaluated in two groups as <70 years old (n: 301; 75.8%) and >70 years old (n: 96; 24.2%). Following the evaluation of histopathological features and treatment protocols, independent risk factors influencing survival were investigated with the Cox regression model. RESULTS: The incidence of non-endometrioid histology (16.3% vs. 32.3%, p: 0.001), high-grade tumors (50.5% vs. 69.8%; p: 0.001), and >50 myometrial invasion (19.6% vs. 36.5%, p: 0.003) in the >70 age group was more frequent than that in the <70 age group. The independent risk factors on overall survival in the >70 age group were determined as non-endometrioid histology (HR: 5.9; 95% CI: 1.4- 24.7) and lymph node metastasis (HR: 6.4; 95% CI: 1.6-25.0). In the <70 age group, non-endometrioid histology (HR: 11.3; 95% CI: 4.0-32.0) was identified as the only independent risk factor affecting 5-year survival. CONCLUSION: EC, with non-endometrioid histology, which is observed at a higher rate in elderly patients despite equal surgery and adjuvant therapy, is the primary factor that affects survival.Item Neutrophil to lymphocyte ratio, stroke severity and short term clinical outcomes in acute ischemic stroke(2021) Iyigundogdu, Ilkin; Derle, Eda; Kibaroglu, Seda; Can, Ufuk; 0000-0001-7860-040X; 0000-0002-3964-268X; AAJ-2053-2021; AAJ-2956-2021Background: Neutrophil to lymphocyte ratio is an easily evaluated systemic inflammation indicator. However, there are limited reports on neutrophil to lymphocyte ratio and functional outcome in ischemic stroke. In this study, we aimed to evaluate the association of neutrophil to lymphocyte ratio and stroke severity, short term functional outcomes and mortality in patients with acute ischemic stroke. Methods: The clinical data of patients who were > 18 age-old and hospitalized with acute ischemic stroke in Baskent University Hospital, Ankara, Turkey between January 2018 and May 2019 were studied retrospectively. Neutrophil to lymphocyte ratio were measured. The neutrophil to lymphocyte ratio and National Institute of Health Stroke Scale (NIHSS) score at admission, mortality during hospitalization and Modified Rankin Scale (mRS) score at discharge of the patients with acute ischemic stroke were correlated. Results: Among the acute ischemic stroke patients due to the exclusion criteria, the data of 134 patients were evaluated. Median age of the patients were 76 +/- 12.5 years and 82 patients (61.2%) were male. The median NIHSS scores of the patients at admission was 5 +/- 4.5. Mortality during the hospitalization was seen in 8 patients (6%). The median neutrophil to lymphocyte ratio value of the patients at admission were found to be 2.6 +/- 3.4. Neutrophil to lymphocyte ratio and NIHSS scores of the patients at admission, duration of the hospitalization, mRS scores at discharge and mortality during hospitalization were found to be positively correlated. Conclusion: Neutrophil to lymphocyte ratio is a simple and easily measured marker and can be used as a potential indicator for prognosis in acute ischemic stroke. However further prospective multicenter investigations are required to confirm the role of neutrophil to lymphocyte ratio for predicting the prognosis in acute ischemic stroke patients.