bluuebunny/crossref_metadata_2025_split huggingface dataset:
Programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) expression in bladder cancer (BC): Differences in recurrent, progressive, and metastatic disease.
Authors: Hegele Axel , Wahl Franziska , Rexin Peter , Nimphius W , Hofmann Rainer , Haenze Joerg 
Published: May 2019

e16001 Background: The significance of PD-L1/PD-1 expression in BC is still unclear. In the present study we evaluated the PD-L1/PD-1 expression in tumor tissue (TT) and immune cells (IC) in the primary BC tumor as well as in case of BC recurrence and/or metastasis to detect possible changes in PD-L1/PD-1 expression using immunohistochemstry. Methods: PD-L1/PD-1 expression was determined in histological specimens of 20 pat. with a recurrent non-muscle invasive BC (NMIBC – Cohort 1) as well as in 20 pat. with muscle-invasive BC (MIBC- Cohort 2) treated by radical cystectomy and appearance of metastases during follow up using commercial available assays (E1L3N, Cell Signaling/ Zytomed). Staining intensity was performed using the Cologne Score. PD-L1/PD-1 status was compared between primary tumor and metastatic/recurrent/progressive BC tissue and correlated with clinical data. Results: Cohort 1: In NMIBC (18m,2f) a recurrent tumor occurred after 25 mo (1-114). In the recurrent TT PD-L1 expression was higher compared to primary BC in 15%. In case of progression higher PD-L1 expression was detectable in 42.9%. IC showed higher PD-L1 expression in 50% of recurrent NMIBC and in 42% in case of progression. PD-1 expression on IC rose in 70% in recurrent and 71% in progressive NMIBC without correlation to time interval of appearance. Cohort 2: After curative cystectomy (17m,3f) metastases occurred after a median time of 20.5 mo (0-58). Comparing PD-L1 expression in cystectomy specimens and metastases we found differences in 52.9% (4x down/5x up). Expression of PD-L1 in primary BC tissue correlated significantly with the time to metastasis (p < 0.05). Conclusions: In case of metastasis after cystectomy as well as in recurrent/progressive NMIBC we found distinct variations in PD-L1/PD-1 expression in TT and IC. In MIBC primary PD-L1 status correlates with the time to metastasis. Whether PD-L1/PD-1 status can be helpful for clinical decisions (i.e. adjuvant therapy, instillation therapy) or as prognosticator have to be subject of further study.
Cost-effectiveness of pembrolizumab as second-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma in the United States.
Authors: Zhong Yichen , Lai Yizhen , Li Haojie , Batteson Rachael , Meng Yang , Frenkl Tara L. , Godwin James Luke , Sonpavde Guru 
Published: May 2019

e16010 Background: Pembrolizumab is approved by the US Food and Drug Administration for the treatment of locally advanced or metastatic urothelial carcinoma (mUC) following platinum-based chemotherapy, based on results from KEYNOTE-045. In this randomized phase 3 trial, pembrolizumab significantly prolonged overall survival (OS) vs. chemotherapy in mUC patients (cut-off: Oct 26, 2017). The current analysis evaluates the cost-effectiveness of pembrolizumab vs. standard-of-care chemotherapy (docetaxel or paclitaxel) as second-line (2L) treatment for mUC, from a US payer perspective. Methods: We developed a partitioned-survival model to measure the costs and effectiveness over a 20-year time horizon to capture long-term costs and benefits from the treatments. Clinical efficacy, time on treatment, safety and utility data were derived from KEYNOTE-045. OS and progression-free survival were extrapolated beyond the trial period using piecewise models, i.e., Kaplan-Meier data followed by parametric function. Costs (in 2018 $US) for drug acquisition/administration, disease monitoring, adverse events management and terminal care were included. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of the results. Results: Pembrolizumab resulted in a mean gain of 1.33 life years (LYs) and 1.14 quality-adjusted life-years (QALYs) at an incremental cost of $103,861 vs. chemotherapy. The incremental cost-effectiveness ratios were $91,103/QALY and $78,254/LY. Key drivers of cost-effectiveness were extrapolation methods for OS data, time horizon and utility values. Pembrolizumab had a 72% or 100% probability of being cost-effective vs. chemotherapy at a $100,000 or $150,000 willingness-to-pay threshold, respectively. Conclusions: Pembrolizumab appears to be cost-effective vs. docetaxel or paclitaxel monotherapy as 2L mUC therapy when accounting for durable survival seen in a subset of patients receiving pembrolizumab. The model was established based on robust estimates, with key clinical endpoints directly drawn or derived from patient level data in KEYNOTE-045.
Sequencing chemotherapy and immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (UC): Meet-Uro1 study.
Authors: Bandini Marco , Farè Elena , Raggi Daniele , De Giorgi Ugo , Banna Giuseppe Luigi , Basso Umberto , Losanno Tania , Bersanelli Melissa , Buti Sebastiano , Santini Daniele , Mucciarini Claudia , Tucci Marcello , Tambaro Rosa , Farnesi Azzurra , Ficorella Corrado , Caffo Orazio , Naglieri Emanuele , Pederzoli Filippo , Pignata Sandro , Necchi Andrea ,   Italian Network for Research in Urologic Oncology (Meet-Uro)
Published: May 2019

e16013 Background: Several ICI are now approved in different therapeutic settings of metastatic UC. The identification of the optimal therapeutic sequence that includes standard chemotherapy (CT) use is a key objective of further research, mainly in the first-line (1L) setting. In this study, we analyzed the pathways of treatment post-ICI and focused on the effects of CT post-ICI in both 1L and salvage-line (≥2L) therapy of metastatic UC. Methods: Data from 15 Italian centers were collected. Patients (pts) should have received ICI in any line of treatment for metastatic UC and have experienced a disease progression (PD) according to RECIST 1.1. Cox regression analyses were performed within the subgroups, and adjusted Kaplan-Meier curves analyzed the progression-free survival (PFS) and overall survival (OS) post-ICI PD, according to the treatment line. Results: 278 pts (79 in 1L; 199 ≥2L) were analyzed. In total, after ICI, pts were treated with CT (N = 69), ICI beyond PD (N = 20) or no treatment (N = 189). Features associated with no therapy post-ICI were rapid PD on ICI (p < 0.001) and number of metastatic sites (p = 0.002). The objective response (OR) to CT post-ICI was 23.1% in 1L, and 18.5% in ≥2L. Median PFS was 5 months (m) in 1L and 3m ≥2L, median OS on CT was 13m in 1L and 9m ≥2L. Post-ICI CT was not significantly associated with improved OS in 1L on multivariable analyses (MVA): HR: 0.43 (95%CI: 0.15-1.23), but it was significant in MVA in ≥2L pts (HR: 0.22, 95%CI: 0.10-0.48). The type of previous ICI (combination-ICI vs single-agent ICI, p = 0.789), as well as the OR to previous ICI (p = 0.871) had no effect on OS with sequential CT on MVA. In the total population adjusted by line, median OS post-CT was 17m (range 15-NA), and with ICI beyond PD was 8m (6-NA) (p < 0.001). Conclusions: This large multicentric appraisal indicated that CT post-salvage ICI is endowed with similar activity and efficacy compared to ICI-naïve pts. Conversely, CT administered post-ICI in 1L determined less responses and was not significant on MVA. These effects are likely determined by the inability to rescue pts with rapidly aggressive disease. Shifting to salvage CT at the time of PD on ICI remains the preferable option in all suitable pts.
Impact of timing of adjuvant chemotherapy following radical cystectomy for bladder cancer on patient survival.
Authors: Grunewald Camilla Marisa , Henn Alina , Galsky Matt D. , Plimack Elizabeth R. , Harshman Lauren Christine , Yu Evan Y. , Crabb Simon J. , Pal Sumanta K. , Alva Ajjai Shivaram , Powles Thomas , De Giorgi Ugo , Agarwal Neeraj , Bamias Aristotelis , Ladoire Sylvain , Necchi Andrea , Vaishampayan Ulka N. , Sternberg Cora N. , Bellmunt Joaquim , Baniel Jack , Niegisch Guenter 
Published: May 2019

e16017 Background: Trials of adjuvant chemotherapy following radical cystectomy generally require chemotherapy to start approximately 90 days postoperatively. However, it is unclear, whether the interval between surgery and start of adjuvant therapy (S-AC-interval) impacts the oncological outcome. Methods: Using the Retrospective International Study of Invasive/Advanced Cancer of the Urothelium (RISC) data base, we identified patients who underwent radical cystectomy for muscle invasive bladder cancer and subsequent adjuvant chemotherapy. Uni- and multi-variate analysis of patient characteristics, surgical factors and tumor characteristics regarding their impact on S-AC-interval was performed. Uni- and multivariate analysis of progression-free and overall survival (starting from day 1 of adjuvant chemotherapy) was analysed in relation to SAC interval (both continuous and dichotomous with a cut-off at 90 days), patient characteristics, surgical factors and tumor characteristics by Kaplan-Meier and COX regression analysis. Results: Two hundred thirty-eight eligible patients were identified (83% male, median age: 64 years, 76% T3/T4, 66% pN+, 15% R+, 75% urothelial carcinoma, 71% cisplatin-based adjuvant chemotherapy). Median S-AC-interval was 57 days (range 10-321 days, ≤ 90 days: 87%, 91-120 days: 6%, > 120 days: 7%). S-AC-interval did not have association with any patient/tumor characteristics or surgery related factors (type of surgery, diversion). S-AC-interval did not impact patients´ outcomes when adjuvant chemotherapy was initiated 90 days after surgery. Median PFS and OS in patients with an S-AC-interval of 90 days was 37 and 73 months, respectively, as compared to 24 and 48 months in patients with an S-AC-interval > 90 days. Only differences in PFS reached statistical significance (37 (95% CI 26-48) months vs. 24 (95% CI 12-36) months p = .042; Log Rank test). When analyzed by different multivariate models, the impact of S-AC-interval on PFS and OS was negated by tumor related factors (pathological T-stage and N-stage). Conclusions: An S-AC-interval of below 90 days is likely to be optimal in bladder cancer patients requiring adjuvant therapy. However, regarding prognosis, tumor related pathological factors seem to be more important than the S-AC-interval.
Endogenous DNA damage levels in peripheral blood mononuclear cells in patients with muscle-infiltrating urothelial bladder carcinoma.
Authors: Palacka Patrik , Sestakova Zuzana , Holickova Andrea , Kalavska Katarina , Rejlekova Katarina , Kollárik Boris , Chovanec Michal , Obertova Jana , Sycova-Mila Zuzana , De Angelis Valentina , Slopovsky Jan , Svetlovska Daniela , Mego Michal , Chovanec Miroslav 
Published: May 2019

e16020 Background: Cisplatin-based combination chemotherapy is used as a standard neoadjuvant treatment of patients with muscle-infiltrating urothelial bladder carcinoma (MIUBC). DNA damage represents one of the most important factors contributing to its toxicity. The objective of this prospective study is to evaluate the prognostic value of the endogenous DNA damage level in peripheral blood mononuclear cells (PBMCs) from MIUBC patients before treatment with neoadjuvant chemotherapy. Methods: PBMCs isolated from 25 consecutive MIUBC patients (16 men, 64%) were included into this study. Karnofsky index < 80% was present in 1 patient (4%). DNA damage levels in PBMCs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. Cut-off of 5.25 was used to dichotomize DNA damage level as “high” or “low” based on the previous study. Results: At the median follow-up 12.1 months, 13 patients progressed (52%) and 8 patients (32%) died. The median and IQR (interquartile range) of endogenous DNA damage level was 7.52 (4.07-27.9). Patients with low DNA damage levels had non-significantly better progression free survival (HR = 0.33, 95% CI: 0.09-1.29) and overall survival (HR = 0.64, 95% CI: 0.11-3.87) compared to patients with high DNA damage levels. Conclusions: These data suggest that endogenous DNA damage levels in PBMCs from MIUBC patients may serve as a prognostic marker early identifying patients with poor outcome. This study is supported by VEGA 2/0053/19 and APVV-17-0384.
First-line PD(L)1 inhibitors for platinum-ineligible advanced urothelial carcinoma (aUC).
Authors: Agarwal Archana , Pond Gregory Russell , Gupta Ruby , Ornstein Moshe Chaim , Barata Pedro C. , Garcia Jorge A. , Drakaki Alexandra , Lee Jae-Lyun , Kanesvaran Ravindran , Bilen Mehmet Asim , Lorenzo Felipe R. , Grivas Petros , Hussain Syed A. , Curran Catherine , Sonpavde Guru 
Published: May 2019

e16024 Background: FDA modified the label for 1st-line pembrolizumab or atezolizumab to PD-L1 high cisplatin-ineligible or platinum-ineligible aUC patients (pts) regardless of PD-L1 expression. However, the outcomes when using PD-(L)1 inhibitors for platinum-ineligible pts are unclear. We hypothesized that treatment response and outcomes are comparable to data reported in trials in the 1st line setting of aUC, and conducted a retrospective study to test this hypothesis using data outside the clinical trial setting. Methods: We collected data from 8 institutions for aUC pts with locally advanced unresectable or metastatic UC. The following criteria were used to define pts platinum-ineligible while comorbidities, age and physician discretion were also allowed: Cr Cl < 30 ml/min, ECOG PS 3, Cr Cl 30-59 ml/min and ECOG PS 2. Demographic & clinical variables and outcomes (overall response rate [ORR], overall survival [OS]) were collected. A Cox regression analysis was used to explore associations of baseline variables with response and outcomes. Results: Data were available for 79 pts. Pts received atezolizumab [n = 41], pembrolizumab [n = 28], nivolumab [n = 7] or durvalumab [n = 3]. Median age was 74 years (45-93). Reasons for platinum-ineligibility were: Cr Cl < 30 ml/min (n = 26), ECOG PS 3 (n = 8), ECOG-PS 2 and Cr Cl < 30-59ml/min (n = 14), elderly/co-morbidities (n = 17), and ‘unavailable’ (n = 14). Median OS was 45 weeks (CI 32-80) and ORR was 27.9%: Complete response in 4 pts [5.1%], partial response in 18 pts [22.8%], stable disease in 19 pts [24.1%], progressive disease in 34 pts [43 %]; data for 4 pts [5.1%] was unavailable for best response. Toxicity of any grade and Grade ≥3 was seen in 41.8% and 31.7% of pts, respectively. Hemoglobin (HR = 0.78, 95% CI 0.68 - 0.90, P = 0.001) and liver metastasis (HR = 1.13, 95% CI 0.51 - 2.53, P = 0.036) correlated with OS. Conclusions: The efficacy and toxicities of 1st-line PD-(L)1 inhibitors for platinum-ineligible pts outside clinical trials appear comparable to those reported in trials for unselected cisplatin-ineligible pts. Further validation is required including data based on PD-L1 status and other biomarkers. Platinum-ineligible pts with aUC warrant evaluation of novel safe and effective agents.
Correlation between FGFR mutation and PD-L1 expression of urinary bladder cancers: A real-world based biomarker study.
Authors: Maraz Aniko , Takacs Peter , Lawson Joe , Santiago-Walker Ademi , Pajor Laszlo , Sukosd Farkas , Revesz Janos 
Published: May 2019

e16030 Background: Programmed cell death (PD)-1 / PD-ligand 1 (PD-L1) inhibitors have made a breakthrough mainly in the treatment of PD-L1 positive advanced urothelial bladder cancer (UBC). The effect of Fibroblast Growth Factor Receptor 3 (FGFR3) mutation on the treatment outcomes of PD-L1 treatment still remains unclear. Our goal was to assess the frequency of FGFR mutations in different tumor stages, in relation with PD-L1 status. Methods: Enrolled patients were diagnosed with UBC and underwent radical cystectomy between 2006-2016 at the University of Szeged, Hungary. FGFR3 mutation analysis by targeted next-generation sequencing and PD-L1 (28-8 DAKOR and SP142 VentanaR) tests were carried out from the most infiltrative area of tumors, in T0 cases from the earlier resection samples. The treatment and survival data were collected from the National Health Insurance Fund (NHIF), Hungary. Independence between covariates was tested using chi-square tests, survival analysis was performed using Kaplan-Meier models and Cox proportional hazards regression. Results: 215 of all 310 UBC samples (T0:19 (8.8%); superficial 43(20%); muscle invasive 41(19%); extraorgan 112 (52%)) could be tested for both PD-L1 and FGFR successfully. Pairwise dependency between tumor stage, FGFR3 mutation status and PD-L1 expression were all found to be significant (p < 0.01). In cases of less advanced diseases FGFR mutation was more often detected. We have found that FGFR mutated samples are less likely to be PD-L1 positive than wild type ones. The effect of all covariates on survival was found to be in accordance with the effect of tumor stage. Conclusions: FGFR alteration frequency varied with stage of disease, with higher positivity rates in early stages, but that lower PD-L1 expression was observed in FGFR mutant patients across disease stages.
Adjuvant carboplatin for clinical stage I testicular seminoma in New Zealand centers: Retrospective analysis of efficacy and long-term adverse effects.
Authors: Chandran Elias Aris , Chindewere Aaron Farai , North Richard T. , Jameson Michael B. 
Published: May 2019

e16041 Background: Adjuvant carboplatin reduces relapse risk in clinical stage I (CS1) testicular seminoma, though there is a paucity of long-term safety data. While some studies report that two cycles is more effective than one, there is no randomised trial evidence or consensus on the optimal number of cycles. European guidelines recommend a risk-based approach to consider adjuvant carboplatin in those with either rete testis involvement (RTI) or tumour size > 4cm, and surveillance for other patients. We report long-term outcomes of 2 cycles of adjuvant carboplatin dosed at area under the curve (AUC) of 7 as standard management of CS1 seminoma since 2000. Methods: We performed a retrospective analysis on treatment and outcomes of patients with CS1 seminoma who received adjuvant carboplatin from 2000 to 2016 at the Waikato, Lakes and Bay of Plenty District Health Boards. We also collected information on mortality, causes of death and subsequent malignant neoplasms (SMN). Results: Of 160 patients, median age 39 (range 20-73) years, 154 received 2 cycles of carboplatin: 148 dosed at AUC7 and six at AUC6; another six patients had one cycle of carboplatin AUC7, curtailed due to toxicity in 3 patients. Two relapses occurred: one at 10 months (in hindsight stage 2a at diagnosis) and one at 22 months (died of pulmonary embolism 2 months after achieving complete response with BEP chemotherapy). Neither RTI (present in 21.3%) nor tumour size > 4cm (in 43.1%) were predictive of relapse. No patients died of seminoma. At median follow up of 109 (range 17-209) months, relapse-free survival was 98.7%, overall survival was 97.5% and disease-specific survival was 100%. A SMN occurred in 11 patients (6.9%) at median 96 months and caused 4 deaths (melanoma, myeloma, small cell lung cancer and glioblastoma); 4 patients (2.6%) had a contralateral testicular germ cell tumour (at median 69 months). One patient had persistent grade 1 thrombocytopenia at 46 months. Conclusions: This data adds to the body of evidence that two cycles of carboplatin AUC7 is safe, effective adjuvant treatment for CS1 seminoma. It did not have significant long-term adverse effects in our population.
Prognostic value of serum tumor marker (STM) rate of decline during high-dose chemotherapy (HDCT) and peripheral-blood stem-cell transplant (PBSCT) for relapsed germ-cell tumors (rGCT).
Authors: Adra Nabil , Althouse Sandra K. , Liu Hao , Abonour Rafat , Abu Zaid Mohammad Issam , Cary Clint , Masterson Timothy A. , Foster Richard , Albany Costantine , Hanna Nasser H. , Einhorn Lawrence H. 
Published: May 2019

e16044 Background: Rate of STM decline is prognostic in patients (pts) with metastatic GCT receiving first-line chemotherapy. We investigated the prognostic value of STM decline in pts with rGCT treated with HDCT and PBSCT. Methods: 444 consecutive pts with rGCT were treated with HDCT and PBSCT at Indiana University between 2004-2018. All pts were planned for 2 consecutive HDCT courses. Pts with elevated STM (AFP > 25 and/or hCG > 4.9) were included in this analysis. Slope and half-life (T1/2) were calculated for weekly AFP and hCG values during HDCT starting with peak value during days 1-7 to avoid interference from lysis. T1/2 AFP≤7 days and hCG≤3 days were categorized as satisfactory (SAT); normalization within 7 days was also considered SAT regardless of T1/2. Pts with elevated AFP and hCG must have adequate decline in both to be SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs unsatisfactory (UNSAT) using log-rank test and analyzed using Kaplan-Meier methods. Results: 2-yr PFS for pts with elevated STM at initiation of HDCT (N = 335) was inferior to pts with normal STM (N = 109) [49% vs. 89%; p < 0.001]. Among the 335 pts with elevated STM, 300 had non-seminoma and 35 had seminoma. Median age was 31 (range, 17-58). Primary site: testis (285), mediastinum (25), and retroperitoneum/other (25). Metastatic sites included retroperitoneum (267), lung (226), liver (81), brain (76), and bone (21). At initiation of HDCT, 73 pts had elevated AFP only, 215 had elevated hCG only, and 47 had elevated both AFP and hCG. Median AFP 9 (1-21,347) and hCG 115 (1-178,140). 307 pts (92%) completed 2 planned cycles of HDCT. Overall, 45/335 pts had SAT decline (13 for AFP; 29 for hCG; 3 for both). Pts with SAT STM decline had superior outcomes compared to UNSAT: 2-yr PFS 71% vs 46% (p = 0.004) and 2-yr OS 77% vs 52% (p = 0.004). When evaluating each STM separately, SAT decline in hCG had superior outcomes vs UNSAT: 2-yr PFS 76% vs 47% (p = 0.002). There was statistically non-significant difference in outcomes for AFP: 2-yr PFS 50% vs 43% (p = 0.55). Conclusions: SAT rate of STM decline predicts superior outcomes in pts with rGCT undergoing HDCT and PBSCT. Although UNSAT STM decline does not preclude long-term remissions, these pts are at higher risk of relapse and death.