Tıp Fakültesi / Faculty of Medicine
Permanent URI for this collectionhttps://hdl.handle.net/11727/1403
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Item First-Line Cemiplimab Monotherapy and Continued Cemiplimab Beyond Progression Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 50% Or More (EMPOWER-Lung 1): 35-Month Follow-Up From A Multicentre, Open-Label, Randomised, Phase 3 Trial(2023) Ozguroglu, Mustafa; Kilickap, Saadettin; Sezer, Ahmet; Gumus, Mahmut; Bondarenko, Igor; Gogishvili, Miranda; Nechaeva, Marina; Schenker, Michael; Cicin, Irfan; Ho, Gwo Fuang; Kulyaba, Yaroslav; Zyuhal, Kasimova; Scheusan, Roxana-Ioana; Garassino, Marina Chiara; He, Xuanyao; Kaul, Manika; Okoye, Emmanuel; Li, Yuntong; Li, Siyu; Pouliot, Jean-Francois; Seebach, Frank; Lowy, Israel; Gullo, Giuseppe; Rietschel, Petra; 37591293Background: Cemiplimab provided significant survival benefit to patients with advanced non-small-cell lung cancer with PD-L1 tumour expression of at least 50% and no actionable biomarkers at 1-year follow-up. In this exploratory analysis, we provide outcomes after 35 months' follow-up and the effect of adding chemotherapy to cemiplimab at the time of disease progression.Methods: EMPOWER-Lung 1 was a multicentre, open-label, randomised, phase 3 trial. We enrolled patients (aged >= 18 years) with histologically confirmed squamous or non-squamous advanced non-small-cell lung cancer with PD-L1 tumour expression of 50% or more. We randomly assigned (1:1) patients to intravenous cemiplimab 350 mg every 3 weeks for up to 108 weeks, or until disease progression, or investigator's choice of chemotherapy. Central randomisation scheme generated by an interactive web response system governed the randomisation process that was stratified by histology and geographical region. Primary endpoints were overall survival and progression free survival, as assessed by a blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumours version 1.1. Patients with disease progression on cemiplimab could continue cemiplimab with the addition of up to four cycles of chemotherapy. We assessed response in these patients by BICR against a new baseline, defined as the last scan before chemotherapy initiation. The primary endpoints were assessed in all randomly assigned participants (ie, intention-to-treat population) and in those with a PD-L1 expression of at least 50%. We assessed adverse events in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT03088540.Findings: Between May 29, 2017, and March 4, 2020, we recruited 712 patients (607 [85%] were male and 105 [15%] were female). We randomly assigned 357 (50%) to cemiplimab and 355 (50%) to chemotherapy. 284 (50%) patients assigned to cemiplimab and 281 (50%) assigned to chemotherapy had verified PD-L1 expression of at least 50%. At 35 months' follow-up, among those with a verified PD-L1 expression of at least 50% median overall survival in the cemiplimab group was 261 months (95% CI 221-318; 149 [52%] of 284 died) versus 133 months (105-162; 188 [67%] of 281 died) in the chemotherapy group (hazard ratio [HR] 057, 95% CI 046-071; p<00001), median progression-free survival was 81 months (95% CI 62-88; 214 events occurred) in the cemiplimab group versus 53 months (43-61; 236 events occurred) in the chemotherapy group (HR 051, 95% CI 042-062; p<00001). Continued cemiplimab plus chemotherapy as second-line therapy (n=64) resulted in a median progression-free survival of 66 months (61-93) and overall survival of 151 months (113-187). The most common grade 3-4 treatment-emergent adverse events were anaemia (15 [4%] of 356 patients in the cemiplimab group vs 60 [17%] of 343 in the control group), neutropenia (three [1%] vs 35 [10%]), and pneumonia (18 [5%] vs 13 [4%]). Treatment-related deaths occurred in ten (3%) of 356 patients treated with cemiplimab (due to autoimmune myocarditis, cardiac failure, cardio-respiratory arrest, cardiopulmonary failure, septic shock, tumour hyperprogression, nephritis, respiratory failure, [n=1 each] and general disorders or unknown [n=2]) and in seven (2%) of 343 patients treated with chemotherapy (due to pneumonia and pulmonary embolism [n=2 each], and cardiac arrest, lung abscess, and myocardial infarction [n=1 each]). The safety profile of cemiplimab at 35 months, and of continued cemiplimab plus chemotherapy, was generally consistent with that previously observed for these treatments, with no new safety signalsINTERPRETATION: At 35 months' follow-up, the survival benefit of cemiplimab for patients with advanced non-small-cell lung cancer was at least as pronounced as at 1 year, affirming its use as first-line monotherapy for this population. Adding chemotherapy to cemiplimab at progression might provide a new second-line treatment for patients with advanced non-small-cell lung cancer.Copyright (c) 2023 Elsevier Ltd. All rights reserved.Item Subconjunctival Bevacizumab in The Impending Recurrent Pterygia(2014) Bayar, Sezin Akca; Kucukerdonmez, Cem; Oner, Ozlem; Akova, Yonca A.; https://orcid.org/0000-0001-5109-755X; 24026871; AAJ-2406-2021The aim of this study is to evaluate the efficacy and safety of subconjunctival bevacizumab injection(s) in the treatment of impending recurrent pterygia. Twenty-three eyes of 23 patients who developed impending recurrence after pterygium surgery with conjunctival autografting and were treated with subconjunctival bevacizumab injection(s) (2.5 mg/0.1 mL) were included in the study. Anterior segment photographs were taken prior to and at 1 week, 1, 3 and 6 months after the injection, and at the end of the follow-up period. Image analysis was performed using an image processing and analysis software program. Recurrence rate and complications were recorded. The mean age and follow-up time of the patients were 51.2 +/- A 6.2 (31-60 years) and 16.8 +/- A 3.1 (12-22 months), respectively. The average number of injections was 2 +/- A 0.78 (1-3). Sixteen eyes required re-injection (two injections in nine eyes, three injections in seven eyes), due to progression of vascularization. There were significant differences between size percentage of lesions before injection and at 1 week, 1, 3 and 6 months after the injection (p < 0.05 for all). Corneal recurrence developed in only one patient and no ocular or systemic side-effects of bevacizumab were observed. Repeated injections of bevacizumab may help to prevent the high recurrence rate of residual impending pterygium, due to its adjuvant role in decreasing lesion size, especially in the first year after surgery.Item Evaluation of Angiopoietin 1 and 2, Vascular Endothelial Growth Factor, and Tumor Necrosis Factor Alpha Levels in Asthmatic Children(2014) Koksal, Burcu Tahire; Ozbek, Ozlem Yilmaz; Bayraktar, Nilufer; Yazici, Ayse Canan; https://orcid.org/0000-0001-9580-7656; https://orcid.org/0000-0003-2974-9579; https://orcid.org/0000-0002-7886-3688; https://orcid.org/0000-0002-3132-242X; 25584916; AAF-2109-2021; AAJ-2034-2021; Y-8758-2018; AAS-6810-2021Asthma is characterized by chronic airway inflammation that is associated with structural changes termed airway remodeling. Recently, cytokines/mediators that augment inflammation have been attracting attention in this field. The aim of this study was to evaluate serum angiopoietin (Ang)-1, Ang-2, vascular endothelial growth factor (VEGF), and tumor necrosis. factor (TNF) alpha values, which have important roles in inflammation, angiogenesis, and remodeling in astlunatic children. We also documented correlations between demographic features, duration of asthma, and pulmonary function test (PFT) parameters. Randomly selected 40 children (20 male and 20 female children, aged 6-16 years) with mild or moderate persistent asthma and 32 healthy children (15 male and 17 female children, aged 6-16 years) enrolled in the study. All asthmatic children had been using inhaled corticosteroids at least for the last 3 months. Serum Ang-1 levels were significantly lower in asthmatic children than those in normal controls. The Ang-1/Ang-2 ratio was also significantly lower in asthmatic children compared with those in normal controls (p < 0.01). However, serum Ang-2, VEGF, and TNF-alpha levels were similar in the two groups. A significant positive correlation was found between VEGF and duration of asthma. No correlation between sewn Aug-I, Ang-2, VEGF values, and PFT parameters was obtained. On the other hand, significant negative correlation was detected between serum TNF-alpha and forced expiratory volume in 1 second. We have shown that serum Aug-1 levels and Ang-1/Ang-2 ratio were significantly reduced and balance was toward Ang-2 in asthmatics children. This process may lead to inflammation, destabilization of blood vessels, and trigger remodeling.Item Brain-Derived Neurotrophic Factor Levels in Children with Asthma and Isolated Chronic Cough(2016) Guc, Belgin Usta; Asilsoy, Suna; Cihan, Fatma Goksin; https://orcid.org/0000-0002-9432-3008; HOH-3400-2023; AAM-7975-2020Studies show that neurogenic inflammation is implicated in the pathogenesis of chronic cough. Neurotrophins (NTs) regulate the synthesis of neuropeptides, which cause neurogenic inflammation. There is growing evidence suggesting their involvement in airway inflammation. The role of the brain-derived neurotrophic factor (BDNF), a member of the NT family, is not clear in chronic cough. The aim of this study was to evaluate the role of BDNF in children with nonspecific isolated chronic cough and to compare the differences between patients with asthma and healthy controls. In this case-control study, we included 30 patients with chronic cough (5-15 years) as the patient group. As the control group, 28 asthma patients under control, 30 children with asthma attacks, and 30 healthy children were included. Serum BDNF levels were measured by ELISA in all groups. The median of BDNF levels was 708.12 pg/mL (155-974) in the patient group, 952.94 pg/mL (220-1,018) in the controlled asthma group, 852.09 pg/mL (355-1,036) in the uncontrolled asthma patients, and 572.65 pg/mL (213-818) in the healthy children group. There were differences in the patient group and control groups regarding the BDNF levels (for the patient group and the controlled asthma group, P = 0.0014; for the patient group and the uncontrolled asthma patients, P = 0.0009; for the patient group and healthy children group, P = 0.05). The BDNF levels of asthma patients were statistically different from healthy children (P = 0.0001). Neurogenic inflammation was implicated in the pathogenesis of chronic cough. In patients with chronic cough, high BDNF levels may support the presence of asthma.Item Cytomegalovirus Infection in Pediatric Renal Transplantation and the Impact of Chemoprophylaxis With (Val-)Ganciclovir(2016) Hoecker, Britta; Zencke, Sebastian; Krupka, Kai; Fichtner, Alexander; Pape, Lars; Dello Strologo, Luca; Guzzo, Isabella; Topaloglu, Rezan; Kranz, Birgitta; Koenig, Jens; Bald, Martin; Webb, Nicholas J. A.; Noyan, Aytul; Dursun, Hasan; Marks, Stephen; Yalcinkaya, Fatos; Thiel, Florian; Billing, Heiko; Pohl, Martin; Fehrenbach, Henry; Bruckner, Thomas; Toeshoff, Burkhard; https://orcid.org/0000-0002-8817-494X; 26736017; AAD-5713-2021; AAB-7105-2020Background. Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection. Methods. We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity. Results. While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R-) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 +/- 3.4 vs. 30.1 +/- 4.7 mL/min per 1.73 m(2) in the preemptive therapy cohort, P < 0.05). CMV replication was associated with amore pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m(2) at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia. Conclusion. Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome.Item Mitochondrial estrogen receptors alter mitochondrial priming and response to endocrine therapy in breast cancer cells(2021) Karakas, Bahriye; Aka, Yeliz; Giray, Asli; Temel, Sehime Gulsum; Acikbas, Ufuk; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur; 34294688Breast cancer is the most common cancer with a high rate of mortality and morbidity among women worldwide. Estrogen receptor status is an important prognostic factor and endocrine therapy is the choice of first-line treatment in ER-positive breast cancer. However, most tumors develop resistance to endocrine therapy. Here we demonstrate that BH3 profiling technology, in particular, dynamic BH3 profiling can predict the response to endocrine therapy agents as well as the development of acquired resistance in breast cancer cells independent of estrogen receptor status. Immunofluorescence analysis and subcellular fractionation experiments revealed distinct ER-alpha and ER-beta subcellular localization patterns in breast cancer cells, including mitochondrial localization of both receptor subtypes. shRNA-mediated depletion of ER-beta in breast cancer cells led to resistance to endocrine therapy agents and selective reconstitution of ER-beta in mitochondria restored sensitivity. Notably, mitochondria-targeted ER-alpha did not restore sensitivity, even conferred further resistance to endocrine therapy agents. In addition, expressing mitochondria-targeted ER-beta in breast cancer cells resulted in decreased mitochondrial respiration alongside increased total ROS and mitochondrial superoxide production. Furthermore, our data demonstrated that mitochondrial ER-beta can be successfully targeted by the selective ER-beta agonist Erteberel. Thus, our findings provide novel findings on mitochondrial estrogen signaling in breast cancer cells and suggest the implementation of the dynamic BH3 technique as a tool to predict acquired endocrine therapy resistance.Item Incidence and outcome of occult uterine sarcoma: A multi-centre study of 18604 operations performed for presumed uterine leiomyoma(2020) Yorganci, Aycag; Meydanli, Mehmet Mutlu; Kadioglu, Nezaket; Taskin, Salih; Kayikcioglu, Fulya; Altin, Duygu; Atasoy, Latife; Haberal, Asuman Nihan; Kinay, Tugba; Akgul, Mehmet Akif; Tapisiz, Omer Lutfi; Evliyaoglu, Ozlem; Tekin, Ozlem Moraloglu; Ortac, U. Firat; Ayhan, Ali; 0000-0001-9852-9911; 0000-0001-7369-5470; 31499285; AAJ-5802-2021; AAK-4587-2021; AAI-8793-2021Item The effect of helicobacter pylori eradication on atrophic gastritis and intestinal metaplasia : a retrospective single center research(2020) Suna, N.; Etik, D.; Ocal, S.; Gunduz, C.; Acikgoz, A.; Bildik, I; Gursoy, A.; Kasgoz, I; Tuleylioglu, H.; Boyacioglu, A.; 0000-0003-3719-9482; 0000-0002-4724-0728; 0000-0001-6234-7788; 33094583; ABH-4817-2020; AAJ-4707-2021; AAI-8822-2021Background and study aims : Gastric cancer (GC) is one of the major causes of cancer-related deaths worldwide. Helicobacter pylori (Hp) plays an important role in gastric carcinogenesis by inducing precancerous changes such as atrophic gastritis (AG) and intestinal metaplasia (IM). In our study, we aim to compare the grade of AG and IM before and after Hp eradication in patients who underwent esophagogastroduodenoscopy (EGD) in our center. Patients and methods : The data of 40.060 patients who underwent EGD for various reasons in our Endoscopy Unit between June 2011 and November 2017 were retrospectively evaluated. The grade of AG and IM before and after Hp eradication of patients meeting the study criteria were compared with each other. In addition, these findings were compared using OLGA and OLGIM staging systems. Results : A total of 175 patients, 89 (50.9%) women and 86 (49.1%) men, were included in the study. The mean age was 55 +/- 12 years. The mean time between two EGD examinations was 38 +/- 14 months. Significant improvement was observed in the grade of AG on corpus and antrum after Hp eradication (P=0.000, P=0.008). In the corpus and antrum, the grade of IM was regressed but this was not significant (P=0.80 and P=0.370 respectively). There was a decrease in OLGA stages after Hp eradication (P=0.000). There was also a reduction in the OLGIM stages, but this was not significant(P=0.341). Conclusion: Our study demonstrates that Hp eradication may reduce the risk of developing GC by providing an improvement in AG and IM which are precancerous changes in GC.Item Epoetin receptor status may alter the outcomes in head and neck cancers treated with radiotherapy and darbepoetin-alpha(2019) Topkan, Erkan; Yildirim, Berna Akkus; 0000-0001-8120-7123; 30414758; AAG-2213-2021Item Therapeutic Potential of Apigenin, a Plant Flavonoid, for Imatinib-Sensitive and Resistant Chronic Myeloid Leukemia Cells(2014) Solmaz, Soner; Gokbulut, Aysun Adan; Cincin, Birsu; Ozdogu, Hakan; Boga, Can; Cakmakoglu, Bedia; Kozanoglu, Ilknur; Baran, YusufDespite the presence of many therapeutic regimens like imatinib and other tyrosine kinase inhibitors, the development of resistance, intolerance, and side effects makes chronic myeloid leukemia (CML) therapy challenging. Thus, there is a need to discover novel drugs for CML patients. In this study, we attempted to assess apigenin, a common plant dietary flavonoid, in terms of its cytotoxic, apoptotic, and cytostatic effects on imatinib-sensitive and resistant Philadelphia-positive CML cells. We analyzed apigenin's effects on cell proliferation, apoptosis, caspase-3 activity, loss of mitochondrial membrane potential, and cell cycle progression in K562 and K562/IMA3 cells. Furthermore, we described genes and gene networks that are modulated in CML in response to apigenin. Results of our study revealed that apigenin has cytotoxic and apoptotic effects on both cell types. We also displayed that apigenin induced G2/M arrest in K562 cells while arresting K562/IMA3 cells in S phase especially at the highest apigenin concentration. The expression analysis identified a set of genes that were regulated by apigenin in K652 and K562/IMA3 cells. Association of modulated genes with biological functional groups identified several networks affected by apigenin including cell survival, proliferation, cell death, cell cycle, and cell signalling pathways.