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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39)(Wolters Kluwer, 2021) Moore, K. N.; Bookman, M.; Sehouli, J.; Miller, A.; Anderson, C.; Scambia, G.; Myers, T.; Robison, K.; Mäenpää, J.; Willmott, L.; Colombo, N.; Thomes-Pepin, J.; Liontos, M.; Gold, M. A.; Garcia, Y.; Sharma, S. K.; Darus, C. J.; Aghajanian, C.; Okamoto, A.; Wu, X.; Safin, R.; Wu, F.; Molinero, L.; Maiya, V.; Khor, V. K.; Lin, Y. G.; Pignata, S.; Taşkıran, Çağatay; Faculty Member; School of Medicine; 134190Purpose: to evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). Methods: this multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1-positive populations. Results: between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1-positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). Conclusion: current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.Publication Open Access Cancer associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition(American Association for Cancer Research (AACR), 2021) Sharbeen, G.; McCarroll, J. A.; Akerman, A.; Kopecky, C.; Youkhana, J.; Kokkinos, J.; Holst, J.; Boyer, C.; Goldstein, D.; Timpson, P.; Cox, T. R.; Pereira, B. A.; Chitty, J. L.; Fey, S. K.; Najumudeen, A. K.; Campbell, A. D.; Sansom, O. J.; Ignacio, R. M. C.; Naim, S.; Liu, J.; Russia, N.; Lee, J.; Chou, A.; Johns, A.; Gill, A. J.; Gonzales-Aloy, E.; Gebski, V.; Guan, Y. F.; Pajic, M.; Turner, N.; Apte, M. V.; Davis, T. P.; Morton, J. P.; Haghighi, K. S.; Kasparian, J.; McLean, B. J.; Setargew, Y. F. I.; Apgi APCGI; Phillips, P. A.; Erkan, Murat Mert; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 214689Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle genesilencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth. Significance: this study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.Publication Open Access ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease(Lippincott Williams and Wilkins (LWW), 2019) Colombo, Nicoletta; Sessa, Christiana; du Bois, Andreas; Ledermann, Jonathan; McCluggage, W. Glenn; McNeish, Iain; Morice, Phillippe; Pignata, Sando; Ray-Coquard, Isabelle; Vergote, Ignace; Baert, Thais; Belaroussi, I.; Dashora, Abhissek; Olbrecht, Siel; Planchamp, Francois; Querleu, Denis; Banerjee, S.; Blecharz, Pawel; Bruchim, Ilan; Cibula, Donald; Concin, Nicole; Davidson, Ben; Devouassoux-Shisheboran, Mojgan; Ferrero, Annamaria; Glasspool, Rosalind; Gonzalez-Martin, Antonio; Heinzelmann-Schwarz, Viola; Joly, Florence; Kim, J. W.; Kridelka, Frederic; Lorusso, Domenika; Mahner, Sven; Mikami, Mikio; Mirza, Mansoor Raza; Nicum, Shibani; O'Donnell, Dearbhaile M.; Pautier, Patricia; Rodolakis, Alexander; Sehouli, Jalid; Singh, N.; Tan, David Shao Peng; Timmerman, D.; Tognon, Germana; van der Velden, Jacobus; Witteveen, Petronella O.; Zeimet, Alain G.; Selçukbiricik, Fatih; Faculty Member; Koç University HospitalThe development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on April 12-14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.Publication Open Access Systematic review of active surveillance for clinically localised prostate cancer to develop recommendations regarding inclusion of intermediate-risk disease, biopsy characteristics at inclusion and monitoring, and surveillance repeat biopsy strategy(Elsevier, 2022) Willemse, Peter-Paul M.; Davis, Niall F.; Grivas, Nikolaos; Zattoni, Fabio; Lardas, Michael; Briers, Erik; Cumberbatch, Marcus G.; De Santis, Maria; Dell'Oglio, Paolo; Donaldson, James F.; Fossati, Nicola; Gandaglia, Giorgio; Gillessen, Silke; Grummet, Jeremy P.; Henry, Ann M.; Liew, Matthew; MacLennan, Steven; Mason, Malcolm D.; Moris, Lisa; Plass, Karin; O'Hanlon, Shane; Omar, Muhammad Imran; Oprea-Lager, Daniela E.; Pang, Karl H.; Paterson, Catherine C.; Ploussard, Guillaume; Rouvière, Olivier; Schoots, Ivo G.; van den Bergh, Roderick C.N.; Van den Broeck, Thomas; van der Kwast, Theodorus H.; van der Poel, Henk G.; Wiegel, Thomas; Yuan, Cathy Yuhong; Cornford, Philip; Mottet, Nicolas; Lam, Thomas B.L.; Tilki, Derya; Other; School of Medicine; Koç University HospitalContext: there is uncertainty regarding the most appropriate criteria for recruitment, monitoring, and reclassification in active surveillance (AS) protocols for localised prostate cancer (PCa). Objective: to perform a qualitative systematic review (SR) to issue recommendations regarding inclusion of intermediate-risk disease, biopsy characteristics at inclusion and monitoring, and repeat biopsy strategy. Evidence acquisition: a protocol-driven, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-adhering SR incorporating AS protocols published from January 1990 to October 2020 was performed. The main outcomes were criteria for inclusion of intermediate-risk disease, monitoring, reclassification, and repeat biopsy strategies (per protocol and/or triggered). Clinical effectiveness data were not assessed. Evidence synthesis: of the 17 011 articles identified, 333 studies incorporating 375 AS protocols, recruiting 264 852 patients, were included. Only a minority of protocols included the use of magnetic resonance imaging (MRI) for recruitment (n = 17), follow-up (n = 47), and reclassification (n = 26). More than 50% of protocols included patients with intermediate or high-risk disease, whilst 44.1% of protocols excluded low-risk patients with more than three positive cores, and 39% of protocols excluded patients with core involvement (CI) >50% per core. Of the protocols, ?80% mandated a confirmatory transrectal ultrasound biopsy; 72% (n = 189) of protocols mandated per-protocol repeat biopsies, with 20% performing this annually and 25% every 2 yr. Only 27 protocols (10.3%) mandated triggered biopsies, with 74% of these protocols defining progression or changes on MRI as triggers for repeat biopsy. Conclusions: for AS protocols in which the use of MRI is not mandatory or absent, we recommend the following: (1) AS can be considered in patients with low-volume International Society of Urological Pathology (ISUP) grade 2 (three or fewer positive cores and cancer involvement ?50% CI per core) or another single element of intermediate-risk disease, and patients with ISUP 3 should be excluded; (2) per-protocol confirmatory prostate biopsies should be performed within 2 yr, and per-protocol surveillance repeat biopsies should be performed at least once every 3 yr for the first 10 yr; and (3) for patients with low-volume, low-risk disease at recruitment, if repeat systematic biopsies reveal more than three positive cores or maximum CI >50% per core, they should be monitored closely for evidence of adverse features (eg, upgrading); patients with ISUP 2 disease with increased core positivity and/or CI to similar thresholds should be reclassified. Patient summary: We examined the literature to issue new recommendations on active surveillance (AS) for managing localised prostate cancer. The recommendations include setting criteria for including men with more aggressive disease (intermediate-risk disease), setting thresholds for close monitoring of men with low-risk but more extensive disease, and determining when to perform repeat biopsies (within 2 yr and 3 yearly thereafter).Publication Open Access Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer(Wiley, 2022) Mendes, Adrianna A.; Lu, Jiayun; Kaur, Harsimar B.; Zheng, Siqun L.; Xu, Jianfeng; Hicks, Jessica; Weiner, Adam B.; Schaeffer, Edward M.; Ross, Ashley E.; Balk, Steven P.; Taplin, Mary-Ellen; Department of Chemical and Biological Engineering; Lack, Nathan Alan; Tekoğlu, Tahsin Emirhan; Faculty Member; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 120842; N/ABackground: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. Methods: an automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. Results: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. Conclusions: the current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. Lay Summary: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.Publication Open Access Feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer during COVID-19 pandemic(BMJ Publishing Group, 2021) Ayhan, Ali; Yılmaz Baran, Şafak; Doğan Durdağ, Gülşen; Akıllı, Hüseyin; Çelik, Hüsnü; Taşkıran, Çağatay; Vatansever, Doğan; Faculty Member; Faculty Member; School of Medicine; 134190; 193687Objective: this study aims to evaluate the effect of the COVID-19 pandemic and related restrictions on patients who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian cancer. Methods: we retrospectively evaluated ovarian cancer patients who underwent HIPEC following complete cytoreductive surgery performed during the outbreak of the COVID-19 pandemic in three different centers specializing in gynecological oncology. All patients who underwent cytoreduction plus HIPEC for a primary, interval, and recurrent surgery were evaluated. Primary outcomes was postoperative 30-day morbidity and mortality. The secondary outcome was infection of patient and/or related staff with COVID-19 during the perioperative or early postoperative period. Results: we performed a total of 35 HIPEC procedures during the pandemic: 15 (42.9%) patients underwent primary/interval surgery, while 20 (57.1%) patients had recurrent disease. Grade 3-4 complications occurred in one patient (2.9%) (chronic renal failure), while mortality did not occur in any patient. Neither the patients nor related staff were infected with the coronavirus during the perioperative or early postoperative period. One patient, who was diagnosed with COVID-19 pneumonia on postoperative day 80 died from the infection. Another patient died on postoperative day 85 due to progressive ovarian cancer, a disorder in vital functions, and organ failure. Conclusion: HIPEC during the COVID-19 pandemic seems a safe and feasible procedure, with acceptable morbidity and mortality rates. Careful selection of patients is important and precautions should be taken before the procedure.Publication Open Access Upper abdominal debulking surgery for ovarian cancer total colectomy, total peritonectomy, and extended upper abdominal debulking surgery(BMJ Publishing Group, 2020) Giray, Burak; Arvas, Macit; Taşkıran, Çağatay; Vatansever, Doğan; Eraslan, Alper; Tanju, Serhan; Balık, Emre; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; 134190; 193687; N/A; N/A; 18758Publication Open Access ESMO-ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease(Oxford University Press (OUP), 2019) Colombo, N.; Sessa, C.; du Bois, A.; Ledermann, J.; McCluggage, W. G.; McNeish, I.; Morice, P.; Pignata, S.; Ray-Coquard, I.; Vergote, I.; Baert, T.; Belaroussi, I.; Dashora, A.; Olbrecht, S.; Planchamp, F.; Querleu, D.; Baert, T.; Banerjee, S.; Belaroussi, I.; Blecharz, P.; Bruchim, I.; Cibula, D.; Colombo, N.; Concin, N.; Davidson, B.; Dashora, A.; Devouassoux-Shisheboran, M.; du Bois, A.; Ferrero, A.; Glasspool, R.; Gonzalez-Martin, A.; Heinzelmann-Schwarz, V.; Joly, F.; Kim, J. W.; Kridelka, F.; Ledermann, J.; Lorusso, D.; Mahner, S.; McCluggage, W. G.; McNeish, I.; Mikami, M.; Mirza, M. R.; Morice, P.; Nicum, S.; Olbrecht, S.; O'Donnell, D. M.; Pautier, P.; Planchamp, F.; Pignata, S.; Querleu, D.; Ray-Coquard, I.; Rodolakis, A.; Sehouli, J.; Selcukbiricik, F.; Sessa, C.; Singh, N.; Tan, D. S. P.; Timmerman, D.; Tognon, G.; van der Velden, J.; Vergote, I.; Witteveen, P. O.; Zeimet, A. G.; Selçukbiricik, Fatih; Faculty Member; Koç University HospitalThe development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on 12-14 April 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.Publication Open Access Experiences of breast cancer survivors during the COVID-19 pandemic: a qualitative study(Springer, 2021) Seven, Memnun; Bağçivan, Gülcan; Paşalak, Şeyma İnciser; Selçukbiricik, Fatih; Faculty Member; PhD Student; Faculty Member; School of Medicine; School of Nursing; Koç University Hospital; 261422; 125009; N/A; N/A; 202015Purpose: this study aimed to explore the impacts of the COVID-19 pandemic on the quality of life of breast cancer survivors. Methods: this qualitative descriptive study included 18 breast cancer survivors who completed cancer treatment within the last five years in Istanbul, Turkey. A directed content analysis was performed using the quality-of-life domains as guiding themes. Results The mean age was 51 +/- 5.9, and the average months since active treatment were 26.5 +/- 9.8 (9-48). Six themes and associated categories are as follows: Physical functioning; Changes in physical activity and weight, new physical symptoms, Role functioning; Work-life, changes in household chores, Emotional functioning; Emotional changes, fear of having the COVID-19 infection, Cognitive Functioning; Risk Perception about the COVID-19 infection, reactions to the COVID-19 pandemic' measures, Social Functioning; Familial relationship changes, social interactions, General Health/Utilization of Healthcare services; Changes in routine follow-ups, changes in diet. Conclusion: breast cancer survivors had different challenges causing new physical and psychological symptoms such as lymphedema, pain, burnout, and anxiety that may have long-term effects on their quality of life.