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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 What is the current role and what are the prospects of the robotic approach in liver surgery?(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Sijberden, J.P.; Hilal, M.A.; Bozkurt, Emre; Koç University HospitalRobotic liver surgery is being applied with increasing frequency. Comparable, and in specific settings superior, perioperative outcomes compared to laparoscopic liver surgery have been reported. In its current form, the most commonly mentioned advantage of robotic surgery is improved dexterity. Important obstacles to its wider implementation in daily clinical practice are the associated costs, technical difficulties, and a scarce amount of evidence. Robotic liver surgery will likely continue to evolve in parallel with technological developments that enhance the robots' abilities. In parallel with the historical development of minimally invasive surgery, the laparoscopic and robotic approaches are now frequently utilized to perform major abdominal surgical procedures. Nevertheless, the role of the robotic approach in liver surgery is still controversial, and a standardized, safe technique has not been defined yet. This review aims to summarize the currently available evidence and prospects of robotic liver surgery. Minimally invasive liver surgery has been extensively associated with benefits, in terms of less blood loss, and lower complication rates, including liver-specific complications such as clinically relevant bile leakage and post hepatectomy liver failure, when compared to open liver surgery. Furthermore, comparable R0 resection rates to open liver surgery have been reported, thus, demonstrating the safety and oncological efficiency of the minimally invasive approach. However, whether robotic liver surgery has merits over laparoscopic liver surgery is still a matter of debate. In the current literature, robotic liver surgery has mainly been associated with non-inferior outcomes compared to laparoscopy, although it is suggested that the robotic approach has a shorter learning curve, lower conversion rates, and less intraoperative blood loss. Robotic surgical systems offer a more realistic image with integrated 3D systems. In addition, the improved dexterity offered by robotic surgical systems can lead to improved intra and postoperative outcomes. In the future, integrated and improved haptic feedback mechanisms, artificial intelligence, and the introduction of more liver-specific dissectors will likely be implemented, further enhancing the robots' abilities.Publication Open Access Autophagy and cancer dormancy(Frontiers, 2021) Akçay, Arzu; Akkoç, Yunus; Peker, Nesibe; Gözüaçık, Devrim; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; N/A; N/A; 40248Metastasis and relapse account for the great majority of cancer-related deaths. Most metastatic lesions are micro metastases that have the capacity to remain in a non-dividing state called "dormancy" for months or even years. Commonly used anticancer drugs generally target actively dividing cancer cells. Therefore, cancer cells that remain in a dormant state evade conventional therapies and contribute to cancer recurrence. Cellular and molecular mechanisms of cancer dormancy are not fully understood. Recent studies indicate that a major cellular stress response mechanism, autophagy, plays an important role in the adaptation, survival and reactivation of dormant cells. In this review article, we will summarize accumulating knowledge about cellular and molecular mechanisms of cancer dormancy, and discuss the role and importance of autophagy in this context.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 Adjuvant chemotherapy for gastric cancer in elderly patients has same benefits as in younger patients(Medknow Publications, 2018) Karaca, Mustafa; Tural, Deniz; Koçoğlu, Hakan; Bilgetekin, İrem; Özet, Ahmet; N/A; Selçukbiricik, Fatih; Faculty Member; School of MedicineObjective: The age-adjusted mortality rate due to gastric cancer was reported to increase with age. This study aims to investigate the results of adjuvant chemotherapy in patients aged 65 years or older comparing with younger patients and focusing on its impact on survival. Materials and Methods: A total of 406 patients with nonmetastatic gastric cancer that consisted of 283 patients younger than 65 years (range: 23-64 years) and 123 patients 65 years of age or older (range: 65-75 years) were retrospectively evaluated. Categorical and continuous variables were summarized using the descriptive statistics and compared with Chi-square and Mann-Whitney U-tests, respectively. Cancer-specific survival rates were estimated by the Kaplan-Meier method. Results: Median age at diagnosis was 58 years (range: 23-75 years). There was no significant difference in gender, tumor localization in the stomach (cardia/noncardia), tumor histology, perineural invasion, lymphovascular invasion, histopathological characteristics of the tumor, and tumor stage between groups. No significant difference was detected in survival between groups. The median survivals were 20.8 months (range: 17-24.6) in patients younger than 65 years and 19.5 months (range: 14.8-24.1) in patients 65 years of age or older (P = 0.9). Conclusions: We showed that adjuvant chemotherapy in elderly patients with gastric cancer has same effectiveness as nonelderly patients. However, further well-designated prospective studies are needed to confirm these findings.Publication Open Access Salvage radiotherapy versus observation for biochemical recurrence following radical prostatectomy for prostate cancer: a matched pair analysis(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Preisser, Felix; Thamm, Reinhard; Pompe, Raisa S.; Chun, Felix K. -H.; Graefen, Markus; Siegmann, Alessandra; Boehmer, Dirk; Budach, Volker; Wiegel, Thomas; Tilki, Derya; Other; School of Medicine; Koç University HospitalSalvage radiotherapy improves oncologic outcomes in prostate cancer patients who develop biochemical recurrence after radical prostatectomy. However, the evidence on hard clinical endpoints is scarce. Within this study, we compare the long-term oncologic outcomes of patients with biochemical recurrence after prostatectomy, who were treated with either salvage radiotherapy or no radiotherapy. Our results show that patients who were treated with salvage radiotherapy after the development of biochemical recurrence following radical prostatectomy had a lower risk of developing metastasis and lower risk of death within the follow-up. These findings further underline the curative potential of salvage radiotherapy in the case of biochemical recurrence after radical prostatectomy, and should be discussed with these patients. Background: Salvage radiotherapy (SRT) improves oncologic outcomes in prostate cancer (PCa) patients who develop biochemical recurrence (BCR) after radical prostatectomy (RP). However, evidence on hard clinical endpoints is scarce. We compare long-term oncologic outcomes of SRT versus no radiotherapy (noRT) in patients with BCR after RP. Patients and methods: within a multi-institutional database, we identified patients with BCR after RP between 1989 and 2016 for PCa. Patients with lymph node invasion, with adjuvant radiotherapy, or with additional androgen deprivation therapy at BCR were excluded. In all patients with SRT, SRT was delivered to the prostatic bed only. Propensity score matching (PSM) was performed to account for differences in pathologic tumor characteristics. Kaplan-Meier analyses and Cox regression models tested the effect of SRT versus no RT on metastasis-free (MFS) and overall survival (OS). Results: of 1832 patients with BCR, 32.9% (n = 603) received SRT without ADT. The median follow-up was 95.9 months. Median total SRT dose was 70.2 Gy. After 1:1 PSM, at 15 years after RP, MFS and OS rates were 84.3 versus 76.9% (p < 0.001) and 85.3 versus 74.4% (p = 0.04) for SRT and noRT, respectively. In multivariable Cox regression models, SRT was an independent predictor for metastasis (HR: 0.37, p < 0.001) and OS (HR: 0.64, p = 0.03). Conclusion: this is the first matched-pair analysis investigating the impact of SRT versus observation only in post-RP recurrent PCa. After compensating for established risk factors, SRT was associated with better long-term MFS and OS. These results on clinical endpoints underline the curative potential of SRT.Publication Open Access Reirradiation of pediatric tumors using hypofractionated stereotactic radiotherapy(Sage, 2017) Gültekin, Melis; Cengiz, Mustafa; Zorlu, Faruk; Yıldız, Ferah; Yazıcı, Gözde; Hürmüz, Pervin; Özyiğit, Gökhan; Akyol, Fadıl; Gürkaynak, Murat; Sezen, Duygu; Faculty Member; School of Medicine; Koç University HospitalBackground: This study aimed to evaluate the efficacy and safety of hypofractionated stereotactic radiotherapy for reirradiation of recurrent pediatric tumors. Methods and Materials: The study included 23 pediatric patients who were reirradiated using hypofractionated stereotactic radiotherapy in the radiation oncology department between January 2008 and November 2013. In total, 33 tumors were treated-27 (82%) cranial and 6 (18%) extracranial. Hypofractionated stereotactic radiotherapy was administered due to recurrent disease in 31 (94%) tumors and residual disease in 2 (6%) tumors. The median total dose was 25 Gy (range: 15-40 Gy), and the median follow-up was 20 months (range: 2-68 months). Results: The 1-year and 2-year local control rates in the entire study population were 42% and 31%, respectively. The median local control time was 11 months (range: 0-54 months) following hypofractionated stereotactic radiotherapy. The patients with tumor response after hypofractionated stereotactic radiotherapy had significantly longer local control than the patients with post-hypofractionated stereotactic radiotherapy tumor progression (21 vs 3 months, P < .001). Tumor volume <1.58 cm(3) was correlated (not significantly) with better local control (23 vs 7 months, P = .064). Conclusion: Reirradiation of pediatric tumors using hypofractionated stereotactic radiotherapy is a safe and effective therapeutic approach. This treatment modality should be considered as a treatment option in selected pediatric patients.Publication Open Access Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells(Spandidos Publications, 2016) Zhang, Wei-Wei; Zhan, Shu-Hui; Geng, Chang-Xin; Sun, Xin; Kleeff, Joerg; Xie, Xiang-Jun; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues. Subsequently, reverse transcription-quantitative polymerase chain reaction and immunoblotting were applied to assess the expression of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, as well as in PSCs. An enzyme-linked immunosorbent assay was used to measure ALCAM levels in cell culture medium stimulated by hypoxia, tumor necrosis factor (TNF)- and transforming growth factor-. Silencing of ALCAM was performed using ALCAM small interfering (si)RNA and immunocytochemistry was used to analyze the inhibition efficiency. An invasion assay and a cell interaction assay were performed to assess the invasive ability and co-cultured adhesive potential of Panc-1 and T3M4 cells, as well as PSCs. Histologically, ALCAM expression was generally weak or absent in pancreatic cancer cells, but was markedly upregulated in PSCs in pancreatic cancer tissues. ALCAM was highly expressed in PSCs from CP tissues and PSCs surrounding pancreatic intraepithelial neoplasias, as well as in pancreatic cancer cells. ALCAM mRNA was highly expressed in PSCs, with a low to moderate expression in T3M4 and Panc-1 cells. Similar to the mRNA expression, immunoblotting demonstrated that ALCAM protein levels were high in PSCs and T3M4 cells, but low in Panc-1 cells. The expression of TNF- increased, while hypoxia decreased the secretion of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, and also in PSCs. Silencing of ALCAM by siRNA revealed no significant alteration in the invasion of pancreatic cancer cells, however, it inhibited the invasive ability of PSCs, and decreased the interaction between Panc-1 cells and PSCs. In conclusion, ALCAM is upregulated in PSCs of pancreatic cancer tissues, suggesting a potential role of ALCAM in regulating pancreatic cancer cell-PSC interactions.Publication Open Access Metabolic reprogramming in adipose tissue during cancer cachexia(Frontiers, 2022) Department of Molecular Biology and Genetics; Weber, Bahar Zehra Camurdanoğlu; Arabacı, Hilal Dilşad; Kır, Serkan; Faculty Member; Department of Molecular Biology and Genetics; Graduate School of Sciences and Engineering; College of Sciences; N/A; N/A; 274185Cancer cachexia is a disorder of energy balance characterized by the wasting of adipose tissue and skeletal muscle resulting in severe weight loss with profound influence on morbidity and mortality. Treatment options for cancer cachexia are still limited. This multifactorial syndrome is associated with changes in several metabolic pathways in adipose tissue which is affected early in the course of cachexia. Adipose depots are involved in energy storage and consumption as well as endocrine functions. In this mini review, we discuss the metabolic reprogramming in all three types of adipose tissues - white, brown, and beige - under the influence of the tumor macro-environment. Alterations in adipose tissue lipolysis, lipogenesis, inflammation and adaptive thermogenesis of beige/brown adipocytes are highlighted. Energy-wasting circuits in adipose tissue impacts whole-body metabolism and particularly skeletal muscle. Targeting of key molecular players involved in the metabolic reprogramming may aid in the development of new treatment strategies for cancer cachexia.