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Publication Metadata only Breast cancer screening services: trade-offs in quality, capacity, outreach, and centralization(Springer Nature, 2004) Chick, Stephen E.; Güneş, Evrim D.; Department of Business Administration; Karaesmen, Zeynep Akşin; Faculty Member; Department of Business Administration; College of Administrative Sciences and Economics; 4534This work combines and extends previous work on breast cancer screening models by explicitly incorporating, for the first time, aspects of the dynamics of health care states, program outreach, and the screening volume-quality relationship in a service system model to examine the effect of public health policy and service capacity decisions on public health outcomes. We consider the impact of increasing standards for minimum reading volume to improve quality, expanding outreach with or without decentralization of service facilities, and the potential of queueing due to stochastic effects and limited capacity. The results indicate a strong relation between screening quality and the cost of screening and treatment, and emphasize the importance of accounting for service dynamics when assessing the performance of health care interventions. For breast cancer screening, increasing outreach without improving quality and maintaining capacity results in less benefit than predicted by standard models.Publication Metadata only Collecting duct carcinoma: epidemiology, clinical characteristics and survival(Elsevier Inc., 2023) Panunzio, Andrea; Tappero, Stefano; Hohenhorst, Lukas; Cano Garcia, Cristina; Piccinelli, Mattia; Barletta, Francesco; Tian, Zhe; Tafuri, Alessandro; Briganti, Alberto; De Cobelli, Ottavio; Chun, Felix K.H.; Terrone, Carlo; Kapoor, Anil; Saad, Fred; Shariat, Shahrokh F.; Cerruto, Maria Angela; Antonelli, Alessandro; Karakiewicz, Pierre I.; Tilki, Derya; Other; School of Medicine; Koç University Hospital; N/AIntroduction: Collecting duct carcinoma (CDC) is a rare renal malignancy. We relied on a large population-based cohort to address epidemiology, clinical characteristics, and treatment of CDC patients. We also tested survival in the overall cohort, as well as in stage-specific fashion. Materials and methods: Within Surveillance, Epidemiology, and End Results (2004–2018) database, we identified 399 CDC patients. Based on Kaplan-Meier plots survival estimates, conditional survival rates were derived according to disease stage. Cox regression models tested for predictors of cancer specific mortality (CSM). Results: Overall, 273 (68.4%) patients were male, 236 (59.2%) had T3-4 stages, 148 (37.1%) had lymph node invasion, and 156 (39.1%) had distant metastases at initial diagnosis. Nephrectomy alone was commonest in stage I-II (n = 91/99, 92%) and III (n = 94/116, 81%). Combination of both nephrectomy and systemic therapy was commonest in stage IV (n = 62/172, 36%). In the overall cohort, median cancer specific survival was 18 months. Provided a disease-free interval of 24 months, five-year Kaplan-Meier estimated survival at diagnosis increased from 74.2 to 91.0% in stage I–II, from 31.1 to 65.3% in stage III, and from 6.3 to 34.1% in stage IV. In multivariable Cox regression models addressing CSM, systemic therapy (Hazard Ratio [HR]: 0.47, P = 0.020), nephrectomy (HR: 0.37, P < 0.001) and combination of both (HR: 0.28, P < 0.001) exhibited a strong protective effect. Conclusion: Despite its highly aggressive phenotype and dismal survival, CDC is sensitive to nephrectomy and/or systemic therapy. Moreover, even for advanced stage, a more favorable prognosis can be achieved in patients, who benefit of disease-free interval after diagnosis and initial treatment.Publication Metadata only Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer(2019) Jönsson, Jenny-Maria; Hedenfalk, Ingrid; N/A; Şahin, İrem Durmaz; Faculty Member; School of Medicine; 303825High-grade serous ovarian cancer (HGSOC) is the predominant and most lethal histological type of epithelial ovarian cancer. During the last few years, several new treatment options with PARP inhibitors have emerged. The FDA has approved the PARP inhibitor olaparib (Lynparza™) as maintenance treatment after first-line platinum-containing chemotherapy and olaparib, niraparib (Zejula™) and rucaparib (Rubraca™) are approved as maintenance therapies in the recurrent, platinum-sensitive setting; nevertheless, development of resistance limits their efficacy. In this study, new combinatorial treatment strategies targeting key signaling pathways were explored to enhance the activity of PARP inhibitors in HGSOC. Carboplatin, olaparib, niraparib, the PI3K inhibitor LY294002 and the c-Met inhibitor crizotinib were used for this investigation. PARP inhibitors and carboplatin alone and in combination caused accumulation of DNA double-strand breaks and G2/M cell cycle arrest. In contrast, crizotinib alone or in combination with PARP inhibitors induced accumulation of cells in sub-G1. Crizotinib together with either of the PARP inhibitors was more strongly synergistic than combinations with a PARP inhibitor and carboplatin or the PI3K inhibitor. Sequential combination of crizotinib and a PARP inhibitor resulted in activation of ATM/CHK2 and inhibition of c-Met pathways, contributing to a decrease in RAD51 levels and induction of caspase-3 dependent apoptotic cell death and suggesting that the combination of crizotinib with a PARP inhibitor may be considered and further explored as a new therapeutic strategy in HGSOC.Publication Metadata only Differences in overall survival between clear cell metastatic renal cell carcinoma patients versus population-based controls according to race/ethnicity in the United States(Elsevier Inc., 2023) Cano Garcia, Cristina; Nimer, Nancy; Piccinelli, Mattia Luca; Tappero, Stefano; Panunzio, Andrea; Barletta, Francesco; Incesu, Reha-Baris; Tian, Zhe; Saad, Fred; Kapoor, Anil; Briganti, Alberto; Terrone, Carlo; Shariat, Shahrokh F.; Antonelli, Alessandro; De Cobelli, Ottavio; Kluth, Luis A.; Becker, Andreas; Chun, Felix K.H.; Karakiewicz, Pierre I.; Tilki, Derya; Other; School of Medicine; Koç University Hospital; N/APurpose: To quantify differences in five-year overall survival (OS) between clear cell metastatic renal cell carcinoma (ccmRCC) patients and age- and sex-matched population-based controls, especially when race/ethnicity is considered. Methods: We relied on the Surveillance, Epidemiology and End Results database (2006–2016) to identify newly diagnosed (2006- 2011) ccmRCC patients of either Caucasian, Hispanic, African American, or Asian/Pacific Islander race/ethnicity. For each case, we simulated an age- and sex-matched control (Monte Carlo simulation), relying on Social Security Administration Life Tables with five-year follow-up. We compared OS between ccmRCC patients and controls. Multivariable Cox regression models tested for race/ethnicity effect on OS. Results: Of 3067 ccmRCC patients, 2167 (71%) were Caucasians vs. 488 (16%) Hispanics vs. 216 (7%) African Americans and 196 (6%) Asians/Pacific Islanders. At five years, OS difference between ccmRCC patients vs. population-based controls was greatest in African Americans (11 vs. 94%, Δ = 84%), followed by Hispanics (16 vs. 94%, Δ = 77%), Caucasians (16 vs. 89%, Δ = 73%) and Asians/Pacific Islanders (19 vs. 88%, Δ = 70%). In multivariable Cox regression models, African Americans exhibited highest Hazard Ratio for death (HR 1.3, p= 0.003). Conclusion: Relative to Life Tables’ derived age- and sex-matched controls, ccmRCC patients exhibit drastically worse OS, especially African Americans.Publication Metadata only Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 4/6 inhibitor therapy(BioMed Central Ltd, 2023) Karacin C.; Oksuzoglu B.; Demirci A.; Keskinkılıç M.; Baytemür N.K.; Yılmaz F.; Selvi O.; Erdem D.; Avşar E.; Paksoy N.; Demir N.; Göksu S.S.; Türker S.; Bayram E.; Çelebi A.; Yılmaz H.; Kuzu Ö.F.; Kahraman S.; Gökmen İ.; Sakin A.; Alkan A.; Nayır E.; Uğraklı M.; Acar Ö.; Ertürk İ.; Demir H.; Aslan F.; Sönmez Ö.; Korkmaz T.; Celayir Ö.M.; Karadağ İ.; Kayıkçıoğlu E.; Şakalar T.; Öktem İ.N.; Eren T.; Urul E.; Mocan E.E.; Kalkan Z.; Yıldırım N.; Ergün Y.; Akagündüz B.; Karakaya S.; Kut E.; Teker F.; Demirel B.Ç.; Karaboyun K.; Almuradova E.; Ünal O.Ü.; Oyman A.; Işık D.; Okutur K.; Öztosun B.; Gülbağcı B.B.; Kalender M.E.; Şahin E.; Seyyar M.; Özdemir Ö.; Selçukbiricik F.; Kanıtez M.; Dede İ.; Gümüş M.; Gökmen E.; Yaren A.; Menekşe S.; Ebinç S.; Aksoy S.; İmamoğlu G.İ.; Altınbaş M.; Çetin B.; Uluç B.O.; Er Ö.; Karadurmuş N.; Erdoğan A.P.; Artaç M.; Tanrıverdi Ö.; Çiçin İ.; Şendur M.A.N.; Oktay E.; Bayoğlu İ.V.; Paydaş S.; Aydıner A.; Salim D.K.; Geredeli Ç.; Yavuzşen T.; Doğan M.; Hacıbekiroğlu İ.; N/A; Selçukbiricik, Fatih; Faculty Member; School of Medicine; 202015Background: There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). Methods: A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. Results: The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0–14.0) months in the ET arm of group A, and 5.3 (3.9–6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8–7.7) months in the ET arm of group B, and 5.7 (4.6–6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5–8.0) months in the ET arm of group C and 4.0 (3.5–4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months. Conclusion: Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.Publication Metadata only Five-year outcome and safety in patients treated with immune checkpoint blockade therapies for urothelial carcinoma: experience from real-world clinical practice(Elsevier Inc., 2023) Tural, Deniz; Arslan, Çagatay; Ölmez, Ömer Fatih; Akar, Emre; Erman, Mustafa; Ürün, Yüksel; Erdem, Dilek; Karadurmuş, Nuri; Kılıçkap, Saadettin; Selçukbiricik, Fatih; Faculty Member; School of Medicine; 202015Background: In this study, we report real-world results from the 5-year follow-up data of urothelial carcinoma patients treated with immune checkpoint blockade therapies (ICTs). Patients and Methods: Metastatic urothelial carcinoma patients treated with at least one course of ICT were included in the study. The primary endpoint was overall response rate (ORR), and secondary endpoints were overall survival (OS), progression-free survival (PFS), duration of treatment with ICT, and safety. Median follow-up, PFS, and OS were estimated by using the Kaplan-Meier method. Results: Data of 201 eligible patients were analyzed. The median age of the patients was 66 (37-86) years, and 156 (84.3%) were male. The majority of patients (94.6%) had Eastern Cooperative Oncology Group (ECOG) PS scores of 0 to 1 and primary tumor in the bladder was predominant (87.5%). The median follow-up time was 54 (1.15-65) months. The rate of complete response (CR) to ICT, partial response (PR) rate, and ORR were 10.4% (n = 21), 22.4% (n = 45), and 32.4% (n = 66), respectively. The median duration of response (DOR) was 34.8 months (95% confidence interval [CI], 29.2-42.1). Of the 66 patients who responded to treatment, 28 (42%) had an ongoing response at the time of the analysis. Median PFS and OS were 3.8 (2.6-5.8) months and 9.4 (7.4-11.4) months, respectively. The 5-year PFS and OS rates were 9.8% and 12.8%, respectively. Fifty-eight percent of patients experienced a treatment-related adverse event of any grade, and 33 (16.4%) patients had a grade 3 to 4 adverse event. Conclusion: This 5-year analysis of real-world data confirms the durable response and long-term survival with ICT in metastatic urothelial carcinoma patients.Publication Metadata only Genomic classifiers in personalized prostate cancer radiation therapy approaches: a systematic review and future perspectives based on international consensus(Elsevier Ltd, 2023) Spohn, Simon K.B.; Draulans, Cedric; Kishan, Amar U.; Spratt, Daniel; Ross, Ashley; Maurer, Tobias; Berlin, Alejandro; Blanchard, Pierre; Collins, Sean; Bronsert, Peter; Chen, Ronald; Pra, Alan Dal; de Meerleer, Gert; Eade, Thomas; Haustermans, Karin; Hölscher, Tobias; Höcht, Stefan; Ghadjar, Pirus; Davicioni, Elai; Heck, Matthias; Kerkmeijer, Linda G.W.; Kirste, Simon; Tselis, Nikolaos; Tran, Phuoc T.; Pinkawa, Michael; Pommier, Pascal; Deltas, Constantinos; Schmidt-Hegemann, Nina-Sophie; Wiegel, Thomas; Zilli, Thomas; Tree, Alison C.; Qiu, Xuefeng; Murthy, Vedang; Epstein, Jonathan I.; Graztke, Christian; Gao, Xin; Grosu, Anca L.; Kamran, Sophia C.; Zamboglou, Constantinos; Tilki, Derya; Other; School of Medicine; Koç University Hospital; N/ACurrent risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa.Publication Metadata only In Regard to Hammer et al.(Elsevier Ltd, 2023) Önal, Cem; Oymak, Ezgi; Bölükbaşı, Yasemin; Spratt, Daniel E.; Ward, Matthew C.; Fasola, Carolina E.; White, Richard L.; Bentzen, Søren M.; Khan, Atif J.; Vicini, Frank; Shah, Chirag; Vaidya, Jayant S.; Bulsara, Max; Wenz, Frederik; Sperk, Elena; Massarut, Samuele; Alvarado, Michael; Williams, Norman R.; Brew-Graves, Chris; Bernstein, Marcelle; Holmes, Dennis; Vinante, Lorenzo; Pigorsch, Steffi; Lundgren, Steiner; Uhl, Valery; Joseph, David; Tobias, Jeffrey S.; Sezen, Duygu; Faculty Member; School of Medicine; 170535N/APublication Metadata only Induction of long-lasting regulatory B lymphocytes by modified immune cells in kidney transplant recipients(Wolters Kluwer Health, 2023) Morath, Christian; Schaier, Matthias; Ibrahim, Eman; Wang, Lei; Kleist, Christian; Opelz, Gerhard; Ponath, Gerald; Aly, Mostafa; Alvarez, Cristiam M.; Kälble, Florian; Speer, Claudius; Benning, Louise; Nusshag, Christian; Pego Da Silva, Luiza; Sommerer, Claudia; Hückelhoven-Krauss, Angela; Czock, David; Mehrabi, Arianeb; Schwab, Constantin; Waldherr, Rüdiger; Schnitzler, Paul; Merle, Uta; Tran, Thuong Hien; Scherer, Sabine; Böhmig, Georg A.; Müller-Tidow, Carsten; Reiser, Jochen; Zeier, Martin; Schmitt, Michael; Terness, Peter; Schmitt, Anita; Daniel, Volker; Süsal, Caner; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; 351800Background: We recently demonstrated that donor-derived modified immune cells (MICs)-PBMCs that acquire immunosuppressive properties after a brief treatment-induced specific immunosuppression against the allogeneic donor when administered before kidney transplantation. We found up to a 68-fold increase in CD19 + CD24 hi CD38 hi transitional B lymphocytes compared with transplanted controls. Methods: Ten patients from a phase 1 clinical trial who had received MIC infusions before kidney transplantation were followed to post-transplant day 1080. Results: Patients treated with MICs had a favorable clinical course, showing no donor-specific human leukocyte antigen antibodies or acute rejections. The four patients who had received the highest dose of MICs 7 days before surgery and were on reduced immunosuppressive therapy showed an absence of in vitro lymphocyte reactivity against stimulatory donor blood cells, whereas reactivity against third party cells was preserved. In these patients, numbers of transitional B lymphocytes were 75-fold and seven-fold higher than in 12 long-term survivors on minimal immunosuppression and four operationally tolerant patients, respectively ( P <0.001 for both). In addition, we found significantly higher numbers of other regulatory B lymphocyte subsets and a gene expression signature suggestive of operational tolerance in three of four patients. In MIC-treated patients, in vitro lymphocyte reactivity against donor blood cells was restored after B lymphocyte depletion, suggesting a direct pathophysiologic role of regulatory B lymphocytes in donor-specific unresponsiveness. Conclusions: These results indicate that donor-specific immunosuppression after MIC infusion is long-lasting and associated with a striking increase in regulatory B lymphocytes. Donor-derived MICs appear to be an immunoregulatory cell population that when administered to recipients before transplantation, may exert a beneficial effect on kidney transplants.Publication Metadata only Minimally invasive approaches in metastatic spinal tumor surgery(Turkish Neurosurgery Society, 2015) Dalbayrak, Sedat; Yaman, Onur; Özer, Ali Fahir; Faculty Member; School of Medicine; 1022The surgical treatment of spinal metastases is still controversial. Due to developments in diagnostic imaging there has been a great evolution in minimally invasive surgical techniques for the spinal surgery. Most of the patients with spinal metastases are debilitated and under high risk of major surgical morbidity and mortality. Less perioperative pain, less blood loss, less hospitalization time, protection of the spine biomechanics, fast recovery and less morbidity in medically debilitated patients are the advantages of minimally invasive surgical techniques. Radiotherapy, chemotherapy or combining both treatments are the standard treatment options for spinal tumors following surgery. Standard open approaches are not suitable for some patients due to limited life expectancies, high surgical complication rates and decrease in quality of life. Minimal invasive techniques represent major advance in minimizing approach related morbidity in the treatment of spinal tumors. Because of the evolution of minimally invasive surgical techniques for the spinal surgery, minimally invasive techniques are alternative treatment to standard open approaches for the treatment of metastatic spinal tumors. Due to less complication rates there has been a trend toward the minimalization of spine surgery / Metastatik spinal tümörlerin cerrahi tedavisi halen tartışmalıdır. Gelişen görüntüleme yöntemleri ile spinal cerrahide kullanılan minimal invaziv tekniklerde büyük gelişmeler ortaya çıkmıştır. Spinal metastazı olan hastaların büyük bölümünde genel durum bozukluğu vardır ve cerrahi açıdan yüksek oranda mortalite ve morbidite riski taşırlar. Minimal invaziv tekniklerin belli başlı avantajları; daha az ağrılı olması, daha az kan kaybına neden olması, hastanede kalım süresinin az olması, omurga biyomekaniğinin korunması, iyileşmenin daha çabuk olması ve daha az morbidite oranına sahip olması olarak sıralanabilir. Spinal tümörlerin standart tedavisinde cerrahi sonrası radyoterapi, kemoterapi ya da ikisinin kombinasyonu uygulanmaktadır. Standart açık cerrahiler yaşam beklentisi kısa olan hastalarda yüksek komplikasyon oranları ve yaşam kalitesini düşürmesi nedeniyle uygun değildir. Minimal invaziv tekniklerin bir diğer avantajı spinal tümörlerin tedavisinde işleme bağlı morbiditeyi azaltmasıdır. Komplikasyon oranlarının az olması nedeniyle spinal cerrahide minimal invaziv tekniklere eğilim mevcuttur. Spinal cerrahi için kullanılan minimal invaziv teknik teknolojilerinin artmasıyla beraber spinal metastazlarda minimal invaziv teknikler klasik açık cerrahiye alternatif olarak kullanılmaya başlanmıştır.