bluuebunny/crossref_metadata_2025_split huggingface dataset:
Primary urethral cancer: A GETUG French nationwide cohort study.
Authors: Blazevic Ilfad , Flechon Aude , Pignot Geraldine , Mesnard Benoît , Rigaud Jerome , Roumiguié Mathieu , Soulie Michel , Thibault Constance , Crouzet Laurence , Goislard De Monsabert Camille , Lefort Felix , Gross-Goupil Marine , Campedel Lucas , Laramas Mathieu , Martin Elodie , Chaltiel Leonor , Pouessel Damien 
Published: February 2022

430 Background: Primary urethral cancer (PUC) is a rare and heterogeneous malignancy. Due to its scarcity, little data are available on the optimal treatment sequence and survival, especially in metastatic patients. Methods: Data from patients diagnosed with a PUC between 01/01/2000 and 12/31/2018 were retrospectively collected from nine French referral centers. Survival rate were estimated with the Kaplan-Meier method and prognostic factors were analyzed using the Cox proportional hazards model and the log-rank test. In order to increase the statistical power of survival analysis in the metastatic stage, patients with synchronous and metachronous metastatic disease were pooled. Results: We identified 44 (62%) males and 27 (38%) females with a PUC. The most frequent histological types were urothelial carcinomas (40.0%), squamous cell carcinomas (34.3%) and adenocarcinomas (14.3%). Twenty-five (35.2%) patients were diagnosed at a localized stage (≤ T2, N0, M0); 35 (49.3%) at a locally advanced stage (≥ T3 or ≥ N1, M0) and 11 (15.5%) at a distant stage (M1). Twenty-seven patients had a metachronous metastatic cancer. Multimodality therapy was used in 24.0% and 57.1% of the patients with a localized and locally advanced disease, respectively. In the entire cohort, median overall survival (OS) was 52.5 months (IC95% 32.2 – 64.1) and stage at diagnosis was a predictor of OS (p < 0.0001). For the 60 patients with a non-metastatic disease, 39 (65%) had a recurrence or were dead and the median disease-free survival (DFS) was 21.2 months (IC95% 16.8 – 34.5). Nodal involvement was the only factor associated with DFS (HR: 2.03, p = 0.0390). Multimodal treatment compared with unimodal treatment was not significantly associated with DFS (HR: 1.22, p = 0.5419). Regarding survival of the 38 metastatic patients, the median OS was 15.2 months (IC95% 8.2 – 23.5) and the median progression-free survival was 6.4 months (IC95% 4.4 – 9.8). Conclusions: This retrospective study showed an important heterogeneity in terms of histology, stage at diagnosis, and treatment of PUC. In this cohort, the multimodal approach did not show any improvement in survival of non-metastatic patients. This study is one of the few to describe the survival in metastatic patients.
Study EV-103 Cohort H: Antitumor activity of neoadjuvant treatment with enfortumab vedotin monotherapy in patients (pts) with muscle invasive bladder cancer (MIBC) who are cisplatin-ineligible.
Authors: Petrylak Daniel P. , Flaig Thomas W. , Mar Nataliya , Gourdin Theodore Stewart , Srinivas Sandy , Rosenberg Jonathan E. , Guseva Maria , Yu Yao , Narayanan Sujata , Hoimes Christopher J. 
Published: February 2022

435 Background: Up to 25% of all pts diagnosed with urothelial cancer present with muscle-invasive disease for whom the risk of progression or metastasis is substantial. Neoadjuvant chemotherapy prior to radical cystectomy and pelvic lymph node dissection (RC+PLND) has been shown to prolong overall survival for patients who are cisplatin (cis) eligible. The standard of care for cis-ineligible pts undergoing surgery does not include neoadjuvant therapy. Therefore, safe, and effective neoadjuvant therapies are an unmet need for cis-ineligible pts with MIBC. Enfortumab vedotin (EV) is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit locally advanced or metastatic urothelial cancer pts in Phase II and III trials, including cis-ineligible pts. Methods: Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled pts with cis-ineligible cT2-T4aN0M0 MIBC who were eligible for RC+PLND and had an ECOG of 0-2. Pts received 3 cycles of neoadjuvant EV (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to RC+PLND. The primary endpoint of the study was pathological complete response rate (pCRR; ypT0N0) by central review. Key secondary endpoints included pathological downstaging (pDS) rate (yp T0,Tis,Ta,T1,N0) and safety. Results from a preliminary analysis are presented. Results: 22 pts were treated. Pts had cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. 68.2% pts had predominant urothelial cancer; 31.8% had a mixed histology. 19 pts completed all 3 cycles of EV. 21 underwent RC+PLND, and 1 had a partial cystectomy. 36.4% pts had a pCR. pDS was seen in 50.0% pts, with 1 case pending central pathology review. The most common EV treatment-related adverse events (TRAEs) were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). 18.2% pts had Grade ≥3 EV TRAEs. No surgeries were delayed due to EV administration. 3 pts had Grade 5 AEs while on study that were unrelated to EV; in 2 pts these AEs occurred > 30 days after RC+PLND. Conclusions: Observed pCRR after neoadjuvant EV showed promising activity in cis-ineligible pts with MIBC who have a high unmet need. Adverse events were consistent with the known safety profile of EV. This first disclosure of data supports the ongoing Phase II and III programs evaluating EV in MIBC. Clinical trial information: NCT03288545.
Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).
Authors: Grimm Marc-Oliver , Grün Barbara , Niegisch Guenter , Pichler Martin , Roghmann Florian , Schmitz-Dräger Bernd , Baretton Gustavo Bruno , Schmitz Marc , Foller Susan , Leucht Katharina , Schumacher Ulrike , Schostak Martin , Meran Johannes , Loidl Wolfgang C. , Zengerling Friedemann 
Published: February 2022

441 Background: Nivolumab (nivo) is an approved 2nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2nd/3rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant > 20%, p < 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]
Response to neoadjuvant chemotherapy in histologic variants of bladder cancer.
Authors: Viala Caroline , Viala Marie 
Published: February 2022

458 Background: Localized muscle invasive bladder carcinoma is mostly treated with neoadjuvant chemotherapy (NAC) before surgery in order to improve the outcome. Urothelial carcinoma (UC) is the most frequent histological type. Histological variants (pure or mixed) occur in 10% of bladder carcinoma. There is a lack of data on NAC efficacy for these histological subtypes. In this study, we evaluated the histologic response to NAC in the variant population of bladder cancer. Methods: Patients from 2 french hospitals (CHU de Nantes and ICM) treated with NAC for bladder cancer from 2010 to August 2021 were included in this retrospective study. We compared response to NAC between UC and histologic variants (pure or mixed) on cystectomy piece. The histological response was defined by the tumor downstaging after NAC (≤pT1Nx). We also collected the pathological complete response (pCR), which was defined by no residual tumor on the cystectomy piece. Results: 87 patients were included. 31 patients harbored a variant pattern: 7 squamous component, 3 adenocarcinoma component, 5 micropapillary component, 2 sarcomatoid component, 4 neuroendocrine carcinoma, 4 nest, 1 lymphoepithelial carcinoma, 2 giant cell, 1 undifferentiated, 1 micropapilallary and adenocarcinoma component and 1 adenosquamous component; 56 were conventional UC. NAC was MVAC in 77% of patient in the variant group, and 82% in the UC group. Others chemotherapy drugs were used as gemzar cisplatine, and platine etoposide. Downstaging was observed in 55% of patients in the variant group (17/31) and in 59% in the UC group (33/56). The difference was not statistically significant (p <0,44). pCR was observed in 39% of patients in the variant group (12/31) and 43% in the UC group (24/56), the difference was not significant (p< 0.44). Conclusions: NAC can be effective in the histologic variant population of bladder carcinoma, nevertheless these data could be confirmed in a larger cohort.
Real-world treatment patterns, survival outcomes, and health care resource utilization among individuals with nonmuscle-invasive bladder cancer in Canada.
Authors: Jarada Tamer N. , Gotto Geoffrey , Bhindi Bimal , Beaton Natalie , Feroz Tahir , Maier-Downing Teagan , Brenner Darren , Cheung Winson Y. , Boyne Devon J. 
Published: February 2022

470 Background: Real-world evidence pertaining to high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) is limited. We aimed to describe real-world treatment patterns and outcomes of this study population within a Canadian setting. Methods: A retrospective cohort study was conducted by linking various population-based administrative datasets from a large Canadian province. The study population consisted of all individuals ≥ 18 years who were diagnosed with Tis or high-grade Ta/T1 NMIBC in Alberta, Canada between 2010-2019. High-grade disease was defined using the WHO 1973 system. Individuals who initiated BCG therapy were classified as having received adequate induction therapy if they completed 5+ cycles. BCG unresponsive was defined as receipt of TURBT, intravesical chemotherapy, cystectomy, or radiation within 1 year of the last BCG dose. Overall survival (OS), cystectomy-free survival (CFS), progression-free survival (PFS), and healthcare resource utilization (HCRU) were examined from the time of being classified as BCG unresponsive following adequate induction therapy. CFS was defined as time until death or radical cystectomy and PFS was defined as time until death or disease progression. Disease progression was classified using a proxy based on subsequent receipt of cystectomy, systemic therapy, or radiation. Kaplan-Meier survival curves were estimated for OS, CFS, and PFS and the mean number of healthcare encounters within each year of follow-up were estimated for HCRU. Results: 5369 individuals were diagnosed with NMIBC in Alberta between 2010-2019, of whom 2679 (49.9%) had Tis or HG Ta/T1 disease at initial diagnosis. Among individuals with high-risk NMIBC, 1044 (39%) initiated BCG therapy. 885 (84.8%) individuals received 5+ BCG doses. Despite receiving adequate induction treatment, 249 (28.1%) individuals became unresponsive. The mean age at BCG unresponsive was 72.9 years and 213 (58.5%) were males. Among those who were BCG unresponsive, 25.7% underwent radical cystectomy (median time to cystectomy: 4.4 months, IQR: 1.7 to 8.2). Median OS was 50.7 months (95% CI: 37.2-65.5), CFS was 22.4 months (18.9-31.1), and PFS was 14.4 months (11.6-20.9). Within the first year of becoming BCG unresponsive, individuals spent an average of 6.2 days in hospital, had 28.8 visits with healthcare practictitioners, and had 2.2 emergency and 13.6 non-emergency encounters with ambulatory care services. Conclusions: A considerable proportion of individuals with high-risk NMIBC became unresponsive to BCG therapy despite adequate treatment. The time from becomining BCG unresponsive to radical cystectomy was relatively short. These findings highlight an unmet need in this patient population for alternative therapeutic options.
The prognostic impact of preoperative health-related quality life on bladder cancer-specific survival in patients treated with radical cystectomy.
Authors: Westhofen Thilo , Eismann Lennert , Buchner Alexander , Schlenker Boris , Giessen-Jung Clemens , Becker Armin , Stief Christian G. , Kretschmer Alexander 
Published: February 2022

475 Background: Previous studies have shown that baseline health-related quality of life (HRQOL) is a valuable prognostic indicator of survival outcomes for various cancer entities in the metastatic setting, yet there is no evidence on the prognostic value of baseline HRQOL for patients undergoing radical cystectomy (RC) with curative intent. The goal of this study was to evaluate the influence of baseline preoperative HRQOL on cancer specific survival prognosis for patients undergoing RC. Methods: 407 patients with prospectively assessed baseline HRQOL prior RC were included. Patients were stratified by the global health status (GHS) domain of the EORTC QLQ-C30 questionnaire, and good general HRQOL was defined as GHS≥70 based on validated cut-off levels. A 1:2 propensity-score-matched analysis of n=357 patients [n=125 (GHS≥70), n=232 (GHS<70)] was performed. Primary endpoint was cancer-specific survival (CSS), secondary endpoints encompassed overall survival (OS) and recurrence-free survival (RFS). Multivariate Cox regression models were performed to assess prognostic significance of baseline GHS on survival outcomes. Harrell’s discrimination C-index was assessed to calculate the predictive accuracy of the model (p<0.05). Results: Median follow-up was 40.5mo. Patients subcohorts were well-balanced. All baseline QLQ-C30 functioning scales were in favour of the GHS≥70 cohort (each p<0.001). 5-yr CSS (82% vs. 65%; p=0.001), 5-yr OS (76% vs 53%; p=0.001) and 5-yr-RFS (50% vs. 39%; p=0.04) and were significantly increased in the GHS≥70 cohort. GHS≥70 was confirmed as an independent predictor for increased CSS (HR 0.43, 95%CI 0.21–0.89; p=0.028), OS (HR 0.56, 95%CI 0.31–0.90; p=0.031) and RFS (HR 0.52, 95%CI 0.31–0.87; p=0.013) multivariate analysis. Conclusions: Our findings suggest preoperative baseline HRQOL to have a pronounced predictive value for patients undergoing RC with curative intent for bladder cancer. We found baseline good general HRQOL to accurately predict increased CSS, OS and RFS.[Table: see text]
Recombinant humanized Anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma (POLARIS-03 study): Two-year survival update and biomarker analysis.
Authors: Sheng Xinan , Chen Haige , Hu Bin , Yao Xudong , Liu Ziling , Yao Xin , Guo Hongqian , Hu Yi , Ji Zhigang , Luo Hong , Shi Benkang , Liu Jiyan , WU Jin , Zhou Fangjian , He Zhisong , Fan Jinhai , Huang Yiran , Guo Jun ,   Shanghai Junshi Bioscience
Published: February 2022

508 Background: Patients with advanced metastatic urothelial carcinoma (mUC) who experience disease progression after standard therapy have limited treatment options. Toripalimab was approved for the 2nd line treatment of mUC based on a phase II clinical study (POLARIS-03) in Chinese patients with mUC (Clinical trial ID: NCT03113266). Here we report the two-year OS update and biomarker analysis of the study. Methods: Metastatic UC Patients received toripalimab 3 mg/kg Q2W until disease progression, unacceptable toxicity or voluntary withdrawal. Clinical response was assessed every 8 weeks. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated for correlation with clinical response. Results: From May 2017 to September 2019, 204 patients were screened and 151 patients were enrolled from 15 participating centers. By cutoff date of September 8, 2021, no emergent of new safety signal was identified compared with the previous one-year report. By the cutoff date, 91 patients have died, and the median OS was 14.6 months. Whole exome sequencing (WES) was performed on tumor biopsies and paired PBMCs and the results were available from 135 patients. Patients with mutations in chromatin remodelers SMARCA4/PBRM1 or tumor suppressor RB1 were associated with better responses to toripalimab than patients with wild-type genes. The ORR was 30% (6/20) in patients with FGFR2/FGFR3 mutations or FGFR2/FGFR3 gene fusions, and 42% (5/12) in patients with NECTIN4 genomic alternations. The median TMB value was 4.1 mutations per million base pairs (Mb) in the cohort. Using 10 mutations/Mb as the cut off, TMB-high patients (n = 27) had better ORR than TMB low patients(n = 108) (48% versus 22%, p = 0.014). The TMB-high group also showed better PFS (12.9 versus 1.8 months, HR = 0.48 [95% CI:0.31-0.74], p < 0.001) and OS (not reached versus 10.0 months, HR = 0.53 [95% CI:0.32-0.88], p = 0.013) than the TMB low group. Conclusions: Toripalimab has demonstrated a manageable safety profile and encouraging clinical activity in metastatic UC patients refractory to 1st line chemotherapy. WES analysis identified divergent mutations in the study. We report the utility of TMB to predict not only the response rate but also the PFS and OS benefits in patients with mUC in response to an ICI monotherapy. Clinical trial information: NCT03113266.
Characterization of fungal mycobiome in bladder cancer.
Authors: Bukavina Laura , Prunty Megan , Calaway Adam C. , Isali Ilaha , Retuerto Mauricio , Ghannoum Mahmoud , Markt Sarah C. , Sindhani Mohit , Mishra Kirtishri , Ponsky Lee Evan , Abbosh Phillip 
Published: February 2022

542 Background: Bacterial dysbiosis accompanies carcinogenesis in malignancies such as colon, breast and pancreatic cancer. However, the role of fungal mycobiome has not been evaluated in bladder cancer. With the sexual dimorphism that exists within bladder cancer (Bca) prevalence and survival, our study aims to characterize fungal mycobiome composition in Bca. Methods: This is a single site, non-randomized, prospective study of patients with the diagnosis of muscle invasive bladder cancer (MIBC) undergoing cystectomy from September 2020 to May 2021. Stool samples were collected during surgery using aseptic technique. We utilized the ITS1 region from DNA sample extracts, which was amplified in triplicate using primers with high specificity for ascomycete fungi (fluorescently-labeled forward primer ITS1F (CTTGGTCATTTAGAGGAAGTAA) and unlabeled reverse primer ITS2 (GCTGCGTTCTTCATCGATGC). Fungal PCR products were separated on the SCE 9610 capillary DNA sequencer (Spectrumedix LLC, State College, PA) using GenoSpectrum software to convert fluorescent output into electropherograms. Hierarchical clustering by Bray-Curtis distance was performed using hclust2. Mean normalized abundance for each amplicon was calculated from the three PCR replicates of each sample, excluding means below 1%. Results: A total of 29 patients (17 males and 12 females) were enrolled. The median (IQR) age was 74 yo (63-77), males, and 68.5 yo (58-78), females. Per figure 1, Saccharomycecales dominated the fungal community at order level with mean relative abundance of 36.35% females, and 21.20%, males. (Figure 1D) Tremellales was the second most notable order, composing 8.22% and 5.13% of male and female samples. There were no differences seen in alpha and beta diversity (Figure 1C) (Figure 1A, C), notable differences were seen across orders. The greatest difference between sexes in LDA( M:F) were noted in Saccharomycecales (log change -4.686, p=0.001/ padj= 0.01), Tremellales (log change 5.119, p=0.001/padj= 0.01), and Sporidiobolales (log change 4.839, p=0.001 padj= 0.03). (Figure 1B). Female bladder cancer patients demonstrating an increase abundance of Saccharomycecale. When assessing differences in fungal composition in patients with history of neoadjuvant therapy( NAC) (receipt vs none), patients with history of NAC exhibited a 3.48 increase in Saccharomycecale (padj= 0.015 ), 4.81 increase Tremalles (padj= 0.009) and 4.37 increase Pleosporales(padj= 0.009) . Conclusions: Mycobiome is an integral part of gut microbiota, with fungal elements relatively poorly studied. Nevertheless, the association between fungal dysbiosis and carcinogenesis across multiple cancers exists. Our study is the first to characterize fungal profile in bladder cancer patients, stratified by sex and receipt of NAC, with results highlighting key fungal players: Saccharomycecale, Tremallales, Pleosoporales.