Publications with Fulltext
Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
Browse
90 results
Search Results
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 Hybrid arc: combining forward IMRT and double arc VMAT in locally advanced rectum cancer(Akademi Doktorlar Yayınevi, 2019) Sağlam, Yücel; Alpan, Vildan; Bingölbali, Ayhan; N/A; Bölükbaşı, Yasemin; Sezen, Duygu; Selek, Uğur; Faculty Member; Faculty Member; Faculty Member; School of Medicine; 216814; N/A; 27211To investigate the potential of increasing target dose conformity and organ at risk (OAR) sparing of Hybrid Arc approach for patients with locally advanced rectum cancer (LARC) in comparison to VMAT and inverse IMRT. This study consisted of thirteen patients who had LARC, were treated with VMAT in 25Gy in 5 fractions. Two different new plans for each patient were generated on Pinnacle TPS by inverse IMRT (7 fields) and Hybrid Arc technique (combining forward IMRT (3 fields) with 20% weight and VMAT (double full arcs) with 80% weight). Treatment plans; Hybrid Arc, VMAT and inverse IMRT, were assessed using dose-volume histogram (DVH) parameters of OARs doses for bladder, small bowel, femur heads and penile bulb in male patients' cases. Ad-ditionally, monitor units (MU), conformity index (CI) and homogeneity index (HI) for clinical target volumes (CTV) were compared for all three techniques. Most DVH parameters pertaining to OARs significantly favored Hybrid Arc technique compared to VMAT and inverse IMRT. Hybrid Arc provided significantly improved Bladder DVH parameters in comparison to IMRT & VMAT. The Hybrid technique provided significantly lower small bowel doses in comparison to inverse IMRT and VMAT for all DVH pa-rameters. Mean MU of inverse IMRT was the highest one (MUIMRT= 1803, p= 0.001 vs VMAT; p= 0.023 vs Hybrid Arc). The target dose conformity and homogeneity of VMAT were better than the other two techniques. Hybrid technique combined the advantages of forward IMRT and VMAT for better OAR sparing in comparison to VMAT and inverse IMRT. / Lokal ileri rektum kanserli (LİRK) olgularda, Hibrit Ark yaklaşımının, VMAT ve IMRT ile karşılaştırılarak, hedef doz konformalitesini ve risk altındaki organ (OAR) korumasını arttırma potansiyelini araştırmaktır. Çalışmamıza, 5 fraksiyonda 25 Gy VMAT ile tedavi edilen 13 LİRK’li olgu dahil edilmiştir. Her hasta için, yeni IMRT ve Hibrit Ark tekniği (forward IMRT (3 alanlar: 275 °, 80 °, 180 °) %20 ağırlık ile ve VMAT (çift tam ark: 182°-178°) %80 ağırlık ile birleştiren) kullanılarak yapılan planlar, Pinnacle TPS’de oluşturuldu. Tedavi planları; Hibrit Ark, VMAT ve IMRT, mesane (V25Gy %, V20Gy %, V15Gy %, V10Gy % ve Dort), ince bağırsak (V25Gy cc, V15Gy cc, V10Gy cc, Dmaks and Dort), femur başları (V25Gy %, V15Gy %, Dmax and Dmean) ve erkek olgularda penis bulb (Dmax and Dmean) için OAR dozları doz hacim histogramı (DVH) parametreleri kullanılarak değerlendirildi. Ek olarak, klinik hedef hacimleri (CTV) için monitör birimleri (MU), konformalite indeksi (CI) ve homojenite indeksi (HI) her üç teknik için karşılaştırıldı. OAR’larla ilgili DVH parametrelerinin çoğu, VMAT ve IMRT’ye kıyasla önemli ölçüde Hibrit Ark tekniğinden yanaydı. Hibrit Ark yönteminin, IMRT ve VMAT karşılaştırıldığında, Mesane DVH parametrelerini (V25Gy cc, V15Gy cc, V10Gy cc, Dmax and Dmean) azalttığı gösterilmiştir. Hibrit planlama tekniği, ortalama doz dahil olmak üzere listelenen tüm ince bağırsak DVH parametreleri için, IMRT ve VMAT ile karşılaştırıldığında belirgin şekilde daha düşük dozlar sağlamıştır. Hibrit tekniği, VMAT’a kıyasla V20Gy%, V15Gy %’de daha düşük femur başı dozları olduğu saptanmıştır. Penis bulbusun, ortalama ve maksimum dozları her üç teknik için benzerdir. IMRT’nin ortalama MU değeri en yüksektir (MUIMRT= 1803, p= 0.001 vs VMAT; p= 0.023 vs Hybrid Arc). VMAT’ın hedef doz konformalitesi ve homojenitesi diğer iki teknikten daha iyiydi. (CIVMAT=1.16 vs CIHybrid=1.19, p= 0.003; vs CIIMRT= 1.22, p= 0.001 and HIVMAT= 0.33 vs HIHybrid= 0.36, p= 0.01; vs HIIMRT= 0.37, p= 0.012). Hibrit tekniğinin, VMAT ve IMRT’ye kıyasla, daha iyi OAR koruması için ileri IMRT ve VMAT’ın avantajlarını birleştirmektedir.Publication Open Access The present and future opportunities of the Rare Cancer network: an international consortium for advancement of oncologic care(PAGEpress, 2015) Sio, Terence T.; Mirimanoff, Rene-Olivier; Özyar, Enis; Belkacemi, Yazid; Miller, Robert C.; Villa, Salvador; Thariat, Juliette; Krengli, Marco; Scandolaro, Luciano; Atalar, Banu; Uğurluer, Gamze; Gutierrez Garcia, Beatriz; Ashman, Jonathan B.; Anacak, Yavuz; Onal, Cem; Arat, Mutlu; Sun, Xu Shan; Tesanovic, Dusanka; Lassen-Ramshad, Yasmin; Oksuz, Didem; Dinçbaş, Fazilet; Akyürek, Serap; Kütük, Tuğce; Bölükbaşı, Yasemin; Eren, Gülnihan; Paryani, Nitesh N.; Ahmed, Safia K.; Moretti, Luigi; Merrell, Kenneth W.; Chang, Kenneth; Mayeda, Mark; Arnett, Andrea L.; Habboush, Jacob Y.; Özşahin, Mahmut; N/A; Sezen, Duygu; Faculty Member; School of MedicineTo date, the Rare Cancer Network (RCN) has initiated more than 90 studies and 54 peer-reviewed publications were produced as a result. The Second International Symposium of the Rare Cancer Network recently took place in Istanbul, Turkey on April 17-18, 2015, and update was given on multiple currently ongoing projects, while also giving room for new proposals which will shape the direction of future studies for the group. This companion issue of the RCN Proceedings summarized the findings of this meeting, while also serving as a call for fresh projects and papers which will continue to energize the group and advance the oncologic science. A brief introduction to the principles, history, and vision of the RCN was also included. To review, the academic year of 2014-15 marked an enormous success for the international members of the RCN, with the generation of 8 fully published papers and more than 12 newly proposed topics. By the collective efforts of all RCN members, in the future, we look forward to the upcoming opportunities in continuing to advance the standard of chemo-and radiotherapeutic oncologic care for selected rare tumor topics. The studies of these rare cancers often do not allow the design and execution of prospectively enrolled trials; however, these uncommon malignancies do impact the humankind and add to its suffering globally in significant ways.Publication Open Access Management of nodal disease in advanced-stage ovarian cancer: porta hepatis, celiac, pelvic and paraaortic lymphadenectomy(MRE PRESS, 2022) Taşkıran, Çağatay; Giray, Burak; Vatansever, Doğan; Bilge, Orhan; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; Koç University Hospital; 134190; N/A; 193687; 176833Maximal cytoreduction is considered the most important prognostic factor for ovarian cancer survival. Most ovarian cancer patients are diagnosed at an advanced stage, and more than half of them have upper abdominal involvement. Upper abdominal regions alongside the pelvis should be evaluated systematically as a routine procedure during cytoreductive surgery. Therefore, aggressive procedures are adopted during cytoreductive surgery, including upper abdominal regions, to achieve maximal cytoreduction. It should include the exploration of porta hepatis and celiac lymph nodes. The feasibility of metastatic disease resection at the porta hepatis and celiac lymph nodes has been demonstrated in many studies with acceptable morbidity. Furthermore, ovarian cancer often leads to retroperitoneal lymph nodes metastases in patients with advanced stages of the disease. Data from the literature showed that more than half of the advanced-stage ovarian cancer patients had lymph node involvement. In this manuscript, we reviewed the current literature and aimed to investigate the impact on survival of surgical resection of porta hepatis, celiac regions, and pelvic/paraaortic lymph nodes in patients with advanced-stage ovarian cancer. Resection of metastatic disease at the porta hepatis/celiac lymph nodes to achieve maximal cytoreduction is feasible but with a relatively high rate of morbidity and mortality. Randomized controlled trials indicate that in the absence of suspicious lymph nodes, both during surgery and at imaging, systematic lymphadenectomy seems to provide no survival benefit.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.