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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3
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Publication Metadata only Feasibility of next-generation sequencing of liquid biopsy (circulating tumor DNA) samples and tumor tissue from patients with metastatic prostate cancer in a real-world clinical setting in germany(Elsevier B.V., 2024) Mandel, Philipp; Hoeh, Benedikt; Humke, Clara; Doering, Claudia; Wenzel, Mike; Cano Garcia, Cristina; Fuhr, Nina; Koll, Florestan; Fassl, Anne; Steuber, Thomas; Faull, Iris; Jeroch, Jan; Ebner, Silvana; Schmitt, Christina; Reis, Henning; Köllermann, Jens; Kokkaliaris, Konstantinos D.; Demes, Melanie C.; Chun, Felix K.H.; Wild, Peter J.; Tilki, Derya; School of MedicineBackground and objective: With European Medicines Agency approval of PARP inhibitors in metastatic castration-resistant prostate cancer and ongoing trials in metastatic hormone-sensitive prostate cancer, detection of genetic alterations in BRCA1/2 and other homologous recombination repair genes has gained an important role. Our aim was to investigate the feasibility and comparability of comprehensive next-generation sequencing (NGS) of liquid biopsy (LB; circulating tumor DNA) and tumor tissue (TT) samples in a real-world clinical setting. Methods: The study cohort consisted of 50 patients with metastatic prostate cancer (mPC) who had TT NGS performed for BRCA1/2 alterations and consent for additional LB NGS. The Oncomine Comprehensive Assay v3 (Thermo Fisher Scientific, Waltham, MA, USA) was used for TT NGS. The Guardant360 83-gene assay (Guardant Health, Palo Alto, CA, USA) was used for LB NGS, including all types of somatic alterations, microsatellite instability, and blood tumor mutational burden. We calculated BRCA1/2 alteration rates and the negative percentage agreement (NPA) and positive percentage agreement (PPA) between TT and LB results. Key findings and limitations: TT NGS was successful in 44/50 patients (88%), with pathogenic BRCA1/2 alterations detected in four (9%). LB NGS was successful in all 50 patients (100%), with BRCA1/2 alterations detected in ten (20%). In a subgroup analysis for the 44 patients with successful TT NGS, NPA was 85% and PPA was 50%. The median time between TT sample collection and blood sampling for NGS was 132 wk (IQR 94–186). The limited sample size and differences in the time of NGS assessment are limitations. Conclusions and clinical implications: LB NGS resulted in a higher detection rate for BRCA1/2 alterations in comparison to conventional TT NGS (20% vs 9%). Ideally, BRCA1/2 testing should be based on both approaches to identify all patients with mPC eligible for PARP inhibitor therapy. Patient summary: Our study shows that genetic tests for both tumor tissue and blood samples results in higher rates of detection of BRCA1/2 gene alterations in patients with metastatic prostate cancer.Publication Metadata only EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer—2024 update. Part i: screening, diagnosis, and local treatment with curative intent(Elsevier B.V., 2024) Cornford, Philip; van den Bergh, Roderick C.N.; Briers, Erik; Van den Broeck, Thomas; Brunckhorst, Oliver; Darraugh, Julie; Eberli, Daniel; De Meerleer, Gert; De Santis, Maria; Farolfi, Andrea; Gandaglia, Giorgio; Gillessen, Silke; Grivas, Nikolaos; Henry, Ann M.; Lardas, Michael; van Leenders, Geert J.L.H.; Liew, Matthew; Linares Espinos, Estefania; Oldenburg, Jan; van Oort, Inge M.; Oprea-Lager, Daniela E.; Ploussard, Guillaume; Roberts, Matthew J.; Rouvière, Olivier; Schoots, Ivo G.; Schouten, Natasha; Smith, Emma J.; Stranne, Johan; Wiegel, Thomas; Willemse, Peter-Paul M.; Tilki, Derya; School of MedicineBackground and objective: The European Association of Urology (EAU)-European Association of Nuclear Medicine (EANM)-European Society for Radiotherapy and Oncology (ESTRO)-European Society of Urogenital Radiology (ESUR)-International Society of Urological Pathology (ISUP)-International Society of Geriatric Oncology (SIOG) guidelines provide recommendations for the management of clinically localised prostate cancer (PCa). This paper aims to present a summary of the 2024 version of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on the screening, diagnosis, and treatment of clinically localised PCa. Methods: The panel performed a literature review of all new data published in English, covering the time frame between May 2020 and 2023. The guidelines were updated, and a strength rating for each recommendation was added based on a systematic review of the evidence. Key findings and limitations: A risk-adapted strategy for identifying men who may develop PCa is advised, generally commencing at 50 yr of age and based on individualised life expectancy. The use of multiparametric magnetic resonance imaging in order to avoid unnecessary biopsies is recommended. When a biopsy is considered, a combination of targeted and regional biopsies should be performed. Prostate-specific membrane antigen positron emission tomography imaging is the most sensitive technique for identifying metastatic spread. Active surveillance is the appropriate management for men with low-risk PCa, as well as for selected favourable intermediate-risk patients with International Society of Urological Pathology grade group 2 lesions. Local therapies are addressed, as well as the management of persistent prostate-specific antigen after surgery. A recommendation to consider hypofractionation in intermediate-risk patients is provided. Patients with cN1 PCa should be offered a local treatment combined with long-term intensified hormonal treatment. Conclusions and clinical implications: The evidence in the field of diagnosis, staging, and treatment of localised PCa is evolving rapidly. These PCa guidelines reflect the multidisciplinary nature of PCa management. Patient summary: This article is the summary of the guidelines for “curable” prostate cancer. Prostate cancer is “found” through a multistep risk-based screening process. The objective is to find as many men as possible with a curable cancer. Prostate cancer is curable if it resides in the prostate; it is then classified into low-, intermediary-, and high-risk localised and locally advanced prostate cancer. These risk classes are the basis of the treatments. Low-risk prostate cancer is treated with “active surveillance”, a treatment with excellent prognosis. For low-intermediary-risk active surveillance should also be discussed as an option. In other cases, active treatments, surgery, or radiation treatment should be discussed along with the potential side effects to allow shared decision-making.Publication Metadata only CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization(Elsevier B.V., 2024) Behboudi, Afrouz; Redline, Susan; Lyu, Jing; Wei, Ying; Gottlieb, Daniel J.; Jelic, Sanja; Peker, Yüksel; Çelik, Yeliz; School of MedicineBackground: Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease. Methods: Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed. Findings: Patients with OSA (n = 189; 84% men; age 66 ± 8 years, BMI 28 ± 3.5 kg/m2, AHI 41 ± 23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n = 91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n = 98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes. Interpretation: Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA. Funding: National Institutes of Health/ National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.Publication Metadata only Current standards for training in robot-assisted surgery and endourology: a systematic review(Elsevier B.V., 2024) Basile, Giuseppe; Gallioli, Andrea; Diana, Pietro; Gallagher, Anthony; Larcher, Alessandro; Graefen, Markus; Harke, Nina; Traxer, Olivier; Van Der Poel, Henk; Emiliani, Esteban; Angerri, Oriol; Wagner, Christian; Montorsi, Francesco; Wiklund, Peter; Somani, Bhaskar; Buffi, Nicolò; Mottrie, Alex; Liatsikos, Evangelos; Breda, Alberto; Tilki, Derya; School of MedicineBackground and objective: Different training programs have been developed to improve trainee outcomes in urology. However, evidence on the optimal training methodology is sparse. Our aim was to provide a comprehensive description of the training programs available for urological robotic surgery and endourology, assess their validity, and highlight the fundamental elements of future training pathways. Methods: We systematically reviewed the literature using PubMed/Medline, Embase, and Web of Science databases. The validity of each training model was assessed. The methodological quality of studies on metrics and curricula was graded using the MERSQI scale. The level of evidence (LoE) and level of recommendation for surgical curricula were awarded using the educational Oxford Centre for Evidence-Based Medicine classification. Key findings and limitations: A total of 75 studies were identified. Many simulators have been developed to aid trainees in mastering skills required for both robotic and endourology procedures, but only four demonstrated predictive validity. For assessment of trainee proficiency, we identified 18 in robotics training and six in endourology training; however, the majority are Likert-type scales. Although proficiency-based progression (PBP) curricula demonstrated superior outcomes to traditional training in preclinical settings, only four of six (67%) in robotics and three of nine (33%) in endourology are PBP-based. Among these, the Fundamentals of Robotic Surgery and the SIMULATE curricula have the highest LoE (level 1b). The lack of a quantitative synthesis is the main limitation of our study. Conclusions and clinical implications: Training curricula that integrate simulators and PBP methodology have been introduced to standardize trainee outcomes in robotics and endourology. However, evidence regarding their educational impact remains restricted to preclinical studies. Efforts should be made to expand these training programs to different surgical procedures and assess their clinical impact. Patient summary: Simulation-based training and programs in which progression is based on proficiency represent the new standard of quality for achieving surgical proficiency in urology. Studies have demonstrated the educational impact of these approaches. However, there are still no standardized training pathways for several urology procedures.Publication Metadata only Deciphering the role of rapamycin in modulating decidual senescence: implications for decidual remodeling and implantation failure(SPRINGER/PLENUM PUBLISHERS, 2024) Kendirci-Katirci, Remziye; Sati, Leyla; Özenci, Çiler Çelik; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicinePurpose Physiological decidual senescence promotes embryo implantation, whereas pathological decidual senescence causes many pregnancy pathologies. The aim of this study was to evaluate the effect of rapamycin on decidual cell subpopulations and endometrial function in physiological and induced senescence and to investigate the decidual cell subpopulations present in physiological conditions during early pregnancy and implantation in mice.Methods Control, physiological decidualization (0.5 mM cAMP and 1 mu M MPA added), and induced senescence (0.1 mM HU added) models with and without 200 nM rapamycin treatment were established using a human endometrial stromal cell line, and decidual cell subpopulations were analyzed by immunofluorescence and flow cytometry. The human extravillous trophoblast cell line AC-1M88 was also cultured in decidualization models, and spheroid expansion analysis was performed. In in vivo studies, decidual cell subpopulations were analyzed by immunofluorescence during early mouse pregnancy.ResultsThe results revealed that rapamycin decreased DIO2 and beta-GAL expressions in physiological and induced senescence without FOXO1. Notably, in induced senescence, increased fragmentation was observed in AC-1M88 cells, and rapamycin treatment successfully attenuated the fragmentation of spheroids. We showed that the FOXO1-DIO2 signaling axis can trigger decidual senescence during early gestation and days of implantation in mice.Conclusions Our study underlines the importance of rapamycin in modulating decidual cell subpopulations and endometrial tissue function during decidual senescence. The information obtained may provide insight into the pathologies of pregnancy seen due to decidual senescence and guide better treatment strategies for reproductive problems.Publication Metadata only Impact of age on long-term urinary continence after robotic-assisted radical prostatectomy(MDPI, 2023) Cano Garcia, Cristina; Wenzel, Mike; Humke, Clara; Wittler, Clarissa; Dislich, Julius; Incesu, Reha-Baris; Koellermann, Jens; Steuber, Thomas; Graefen, Markus; Tilki, Derya; Karakiewicz, Pierre I.; Kluth, Luis A.; Preisser, Felix; Chun, Felix K. H.; Mandel, Philipp; Hoeh, Benedikt; Tilki, Derya; School of Medicine; Koç University HospitalAim and Objectives: We aimed to test the impact of age on long-term urinary continence (& GE;12 months) in patients undergoing robotic-assisted radical prostatectomy. Methods and Materials: We relied on an institutional tertiary-care database to identify the patients who underwent robotic-assisted radical prostatectomy between January 2014 and January 2021. Patients were divided into three age groups: age group one (& LE;60 years), age group two (61-69 years) and age group three (& GE;70 years). Multivariable logistic regression models tested the differences between the age groups in the analyses addressing long-term urinary continence after robotic-assisted radical prostatectomy. Results: Of the 201 prostate cancer patients treated with robotic-assisted radical prostatectomy, 49 (24%) were assigned to age group one (& LE;60 years), 93 (46%) to age group two (61-69 years) and 59 (29%) to age group three (& GE;70 years). The three age groups differed according to long-term urinary continence: 90% vs. 84% vs. 69% for, respectively, age group one vs. two vs. three (p = 0.018). In the multivariable logistic regression, age group one (Odds Ratio (OR) 4.73, 95% CI 1.44-18.65, p = 0.015) and 2 (OR 2.94; 95% CI 1.23-7.29; p = 0.017) were independent predictors for urinary continence, compared to age group three. Conclusion: Younger age, especially & LE;60 years, was associated with better urinary continence after robotic-assisted radical prostatectomy. This observation is important at the point of patient education and should be discussed in informed consent.Publication Metadata only External tertiary-care-hospital validation of the epidemiological SEER-based nomogram predicting downgrading in high-risk prostate cancer patients treated with radical prostatectomy(MDPI, 2023) Garcia, Cristina Cano; Wenzel, Mike; Piccinelli, Mattia Luca; Hoeh, Benedikt; Landmann, Lea; Tian, Zhe; Humke, Clara; Incesu, Reha-Baris; Koellermann, Jens; Wild, Peter J.; Wurnschimmel, Christoph; Graefen, Markus; Karakiewicz, Pierre I.; Kluth, Luis A.; Chun, Felix K. H.; Mandel, Philipp; Tilki, Derya; School of Medicine; Koç University HospitalWe aimed to externally validate the SEER-based nomogram used to predict downgrading in biopsied high-risk prostate cancer patients treated with radical prostatectomy (RP) in a contemporary European tertiary-care-hospital cohort. We relied on an institutional tertiary-care database to identify biopsied high-risk prostate cancer patients in the National Comprehensive Cancer Network (NCCN) who underwent RP between January 2014 and December 2022. The model's downgrading performance was evaluated using accuracy and calibration. The net benefit of the nomogram was tested with decision-curve analyses. Overall, 241 biopsied high-risk prostate cancer patients were identified. In total, 51% were downgraded at RP. Moreover, of the 99 patients with a biopsy Gleason pattern of 5, 43% were significantly downgraded to RP Gleason pattern = 4 + 4. The nomogram predicted the downgrading with 72% accuracy. A high level of agreement between the predicted and observed downgrading rates was observed. In the prediction of significant downgrading from a biopsy Gleason pattern of 5 to a RP Gleason pattern = 4 + 4, the accuracy was 71%. Deviations from the ideal predictions were noted for predicted probabilities between 30% and 50%, where the nomogram overestimated the observed rate of significant downgrading. This external validation of the SEER-based nomogram confirmed its ability to predict the downgrading of biopsy high-risk prostate cancer patients and its accurate use for patient counseling in high-volume RP centers.Publication Metadata only Survival of testicular pure embryonal carcinoma vs. mixed germ cell tumor patients across all stages(MDPI, 2023) Cano Garcia, Cristina; Panunzio, Andrea; Tappero, Stefano; Piccinelli, Mattia Luca; Barletta, Francesco; Incesu, Reha-Baris; Law, Kyle W.; Scheipner, Lukas; Tian, Zhe; Saad, Fred; Shariat, Shahrokh F.; Briganti, Alberto; De Cobelli, Ottavio; Terrone, Carlo; Antonelli, Alessandro; Banek, Severine; Kluth, Luis A.; Chun, Felix K. H.; Karakiewicz, Pierre I.; Tilki, Derya; School of Medicine; Koç University HospitalBackground and Objectives: The impact of pure histological subtypes in testicular non-seminoma germ cell tumors on survival, specifically regarding pure embryonal carcinoma, is not well established. Therefore, this study aimed to test for differences between pure embryonal carcinoma and mixed germ cell tumor patients within stages I, II and III in a large population-based database. Materials and Methods: We relied on the Surveillance, Epidemiology and End Results (SEER) database (2004-2019) to identify testicular pure embryonal carcinoma vs. mixed germ cell tumor patients. Cumulative incidence plots depicted cancer-specific mortality that represented the main endpoint of interest. Multivariable competing risks regression models tested for differences between pure embryonal carcinoma and mixed germ cell tumor patients in analyses addressing cancer-specific mortality and adjusted for other-cause mortality. Results: Of 11,223 patients, 2473 (22%) had pure embryonal carcinoma. Pure embryonal carcinoma patients exhibited lower cancer-specific mortality relative to their mixed germ cell tumor counterparts for both stage III (13.9 vs. 19.4%; p < 0.01) and stage II (0.5 vs. 3.4%, p < 0.01), but not in stage I (0.9 vs. 1.6%, p = 0.1). In multivariable competing risks regression models, pure embryonal carcinoma exhibited more favorable cancer-specific mortality than mixed germ cell tumor in stage III (hazard ratio 0.71, p = 0.01) and stage II (hazard ratio 0.11, p < 0.01). Conclusions: Pure embryonal carcinoma exhibits a more favorable cancer-specific mortality profile relative to mixed germ cell tumor in stage II and III testicular cancers. Consequently, the presence of mixed germ cell tumor elements may be interpreted as a risk factor for cancer-specific survival.Publication Metadata only Metabolically healthy obesity: misleading phrase or healthy phenotype?(Elsevier, 2023) Gaipov, Abduzhappar; Kuwabara, Masanari; Hornum, Mads; Raalte, Daniel H. Van; Tanrıöver, Cem; Çöpür, Sidar; Özlüşen, Batu; Akcan, Rüştü Emre; Kanbay, Mehmet; School of MedicineObesity is a heterogenous condition with multiple different phenotypes. Among these a particular subtype exists named as metabolically healthy obesity (MHO). MHO has multiple definitions and its prevalence varies ac-cording to study. The potential mechanisms underlying the pathophysiology of MHO include the different types of adipose tissue and their distribution, the role of hormones, inflammation, diet, the intestinal microbiota and genetic factors. In contrast to the negative metabolic profile associated with metabolically unhealthy obesity (MUO), MHO has relatively favorable metabolic characteristics. Nevertheless, MHO is still associated with many important chronic diseases including cardiovascular disease, hypertension, type 2 diabetes, chronic kidney disease as well as certain types of cancer and has the risk of progression into the unhealthy phenotype. Therefore, it should not be considered as a benign condition. The major therapeutic alternatives include dietary modifi-cations, exercise, bariatric surgery and certain medications including glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and tirzepatide. In this review, we discuss the significance of MHO while comparing this phenotype with MUO.Publication Metadata only Comment on: evaluation of halitosis parameters in patients undergoing head and neck radiotherapy(Wiley, 2023) Somay, Efsun; Topkan, Erkan; Selek, Uğur; School of MedicineN/A