bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUB-urothelial durvalumab injection: 1 (SUBDUE-1)—Results from the first nine urothelial cancer patients using a dose-escalation schedule.
Authors: Hayne Dickon , Swarbrick Nicole , McCombie Stephen , Moe Andrew , Hawks Cynthia , Viswambaram Pravin , Conduit Ciara , Liow Elizabeth Chien Hern , Spalding Lisa , Bothe Jarrad , Ferguson Tom , Martin Andrew James , Davis Ian D. , Redfern Andrew David 
Published: February 2022

483 Background: The sub-urothelial administration of checkpoint inhibitors has not been reported. This approach could be safer and more efficacious than systemic delivery for patients with non-muscle-invasive bladder cancer (NMIBC). Methods: This phase 1b study employed a 3+3 dose-escalation design to explore tolerability, safety and immunological efficacy of sub-urothelial durvalumab, a programmed death-ligand 1 (PDL1) monoclonal antibody. Eligible participants had high risk NMIBC or MIBC without prior chemotherapy or immunotherapy (BCG allowed) and were planned for cystectomy. Participants received 25/75/150mg durvalumab diluted in 25mL normal saline injected into the sub-urothelium at 25 locations (25x1mL injections), at least 2 weeks prior to radical cystectomy. Systematic four quadrant cold cup bladder biopsies were taken immediately prior to durvalumab injection and immediately prior to cystectomy. Tumour, if present, was biopsied before and after injection and bladder maps recorded. International Prostate Symptom Index (IPSS) and O’Leary symptom score at various time points and adverse events (AE) as per CTCAE (Version 4) were recorded. Relative changes in immune cell counts (RCI) on bladder biopsy for CD3, CD8, CD68 and CD168 expressing cells are reported (value >1.0 designating increase). Results: Nine participants were recruited; eight male (89%), 1 female; mean age 72 years (range 56 – 82). No dose-limiting toxicities were observed. No evidence of treatment-related effect on IPSS or O’Leary Symptom scores was seen. Fourteen AEs were reported by six (67%) patients: 10 were Grade 1, 3 Grade 2, 1 Grade 3. None were considered immune- or treatment-related by investigators. Transient elevation of peri-operative thyroid stimulating hormone was seen in two subjects, which normalised without intervention. No hepatitis was seen. All patients underwent planned cystectomy. RCI of different immune populations was calculated (see Table). Visible tumour was present in only 4 patients limiting interpretation of RCI. RCI varied significantly between cell types (p=0.008*). RCI numerically increased by dose but did not reach statistical significance (p=0.076**). A numeric increase in monocytes was seen at 150mg dose. RCI of different immune populations by dose of sub-urothelial durvalumab. Conclusions: Sub-urothelial injection of durvalumab was safe at all 3 dose levels without any drug-related adverse events. Immunological studies showed differential effects on immune cells with macrophage population most affected. Further studies investigating the role of 150mg sub-urothelial durvalumab in the management of NMIBC are planned. Clinical trial information: ACTRN12620000063910.[Table: see text]
CIMUC: Chemotherapy following Immune checkpoints inhibitors in patients with locally advanced or metastatic urothelial carcinoma (la/mUC).
Authors: Meynard Lucie , Dinart Derek , Flechon Aude , Saldana Carolina , Lefort Felix , Gravis Gwenaelle , Thiery-Vuillemin Antoine , Cancel Mathilde , Coquan Elodie , Ladoire Sylvain , Maillet Denis , Rolland Frederic , Boughalem Elouen , Martin Sophie , Laramas Mathieu , Crouzet Laurence , Abbar Baptiste , Falkowski Sabrina , Pouessel Damien , Roubaud Guilhem 
Published: February 2022

492 Background: Immune checkpoints inhibitors (ICIs) have recently changed therapeutic landscape of la/mUC. Recent studies suggested an improvement of response to salvage chemotherapy (CT) after ICIs in several cancer types including urothelial carcinoma. We assumed that efficacy of CT rechallenge after ICIs may be improved compared to second-line CT without previous ICIs in patients (pts) with la/mUC. Methods: CIMUC is a French multicentric retrospective study including all pts with la/mUC initiating second or third-line CT from January 1st 2015 to June 30th 2020. Two groups of pts were defined: pts in group 1 (G1) were treated with a second-line CT without previous ICIs; pts in group 2 (G2) were treated with third line CT after ICIs. Primary endpoint was objective response rate (ORR: proportion of patients with complete or partial response, according to RECIST 1.1 criteria) in G2 versus G1. Secondary endpoints were progression-free survival (PFS), defined as time from initiation of second or third-line CT to disease progression or death from any cause, and toxicities. This study is supported by the French Genito Urinary Group (GETUG). Results: 553 pts were included. Baseline characteristics of the 2 groups are summarized in the Table. ORRs were 31% (95%CI [26.5-35.5]) and 29.2% (95%CI [21.9-36.6]) respectively in G1 and G2, without statistically significant difference (p=0.617), even after adjustment for Bellmunt risk factors (p=0.3214). In subgroups analysis, no difference in ORR was observed by type of CT (platinum or taxanes), duration of response (DOR) to first-platinum-based CT (< 12 months or ≥ 12 months) and FGFR-status. We did not identify any predictive factor of OR in G2 in multivariate analysis. Median PFS were 4.6 months (95%CI [3.88; 5.06]) and 4.86 months (95%CI [4.11; 5.45]), respectively in G1 and G2. Grade 3/4 hematologic toxicity occurred in 35% and 22.4%, respectively in G1 and G2. Conclusions: While ORR was not superior in G2 versus G1, pts derive comparable benefit in a further line of treatment (G2) in terms of ORR and PFS. Despite limits inherent to any retrospective study, CIMUC represents one of the largest retrospective studies in this setting.[Table: see text]
Sequential intravesical gemcitabine and docetaxel for BCG-naïve high-risk nonmuscle-invasive bladder cancer.
Authors: McElree Ian Mitchell , Steinberg Ryan L. , Mott Sarah L. , Martin Alexander C. , Richards Jordan , Gellhaus Paul T. , Nepple Kenneth G. , O'Donnell Michael A. , Packiam Vignesh T. 
Published: February 2022

497 Background: Bacillus Calmette-Guerin (BCG) is currently recommended as adjuvant therapy following complete transurethral resection of bladder tumor (TURBT) for high-risk non-muscle invasive bladder cancer (NMIBC). However, continued BCG production shortages have precluded the use of BCG in many urologic practices. Efficacy of sequential intravesical gemcitabine and docetaxel (Gem/Doce) in the BCG failure setting has been reproduced across multiple institutions. In response to the continuing BCG shortage, Gem/Doce has been utilized at our institution in the BCG-naïve setting. We report the outcomes of a large cohort of patients with high-risk BCG-naïve NMIBC treated with Gem/Doce. Methods: We retrospectively identified all patients with BCG-naïve high-risk NMIBC who were treated with Gem/Doce from May 2013 through April 2021. We included patients with intent to receive 6 weekly intravesical instillations of sequential 1 gram gemcitabine and 37.5mg docetaxel after complete TURBT. Monthly maintenance of 2 years was initiated if disease free at first follow-up. The primary outcome was recurrence-free survival (RFS) and efficacy was evaluated in an intention-to-treat manner. Recurrence was defined as pathologically confirmed tumor relapse in the bladder or prostatic urethra. Progression was defined as T-stage increase from Ta or CIS to T1 or development of muscle invasive or metastatic disease. Survival was assessed using the Kaplan-Meier method and log rank test, indexed from the first Gem/Doce instillation. Results: One hundred seven patients with median follow-up of 15 months were included in the analysis. There were 47 with any CIS, 55 with T1 disease, and 7 with micropapillary variant histology. Four patients did not complete a full induction cycle due to hematuria (3) and severe frequency/nocturia (1). 19 patients sustained a recurrence at any point during follow-up. RFS was 89%, 85%, and 82% at 6, 12, and 24 months, respectively. No difference in RFS was seen in patients with or without CIS (p = 0.42). No patients met criteria for either form of disease progression. One patient underwent cystectomy due to end-stage lower urinary tract symptoms, with final pathology pTisN0. No patients died of bladder cancer. Overall survival was 84% at 24 months. 46 patients reported any symptoms during treatment. Common side effects included urinary frequency/urgency (36%), hematuria (11%), and dysuria (8%). Conclusions: In a large cohort of high-risk, BCG-naïve NMIBC patients, Gem/Doce showed excellent efficacy (84% 2-year HG-RFS). These rates are similar to modern treatment naïve cohorts receiving BCG. Prospective comparative analysis of Gem/Doce in BCG-naïve populations is warranted.[Table: see text]
A multicenter real-life U.K. study of use of immunotherapeutic agents in metastatic urothelial cancer.
Authors: Das Prantik , Sharma Anand , Bhandari Ruchir , Lim JunHao , Ghose Aruni , Davies Jessica , Nair Ajith , Vasdev Nikhil , Moldawa Maja , Karimi Ahmad , Ward Colin , Richardson Alison , Singh Sadmeet , Peracha Amjad , Ahmed Shaista 
Published: February 2022

504 Background: First-line chemotherapy for patients with cisplatin-ineligible metastatic urothelial carcinoma (mUC) is associated with short response duration and high toxicity. Pembrolizumab(PEM) and atezolizumab (ATZ) are associated with long-term, durable remissions as a first-line treatment of cisplatin-ineligible, PD-L1-positive patients with mUC. For patients who progressed during or after platinum-based chemotherapy, Immunotherapy also prolongs survival with less toxicity and better quality of life compared with further lines of chemotherapy. There have been no studies directly comparing the effectiveness of PEM to ATZ in mUC patients. Methods: A cohort of 112 patients from 3 UK centres were included. 62, previously untreated cisplatin ineligible mUC patients who showed PDL1 positivity were given either ATZ or PEM once every 3 weeks until progression. 49 patients who had initial platinum based chemotherapy subsequently had ATZ or PEM as second line treatment following their disease progression The primary endpoint was Overall Survival(OS) and secondary endpoints included objective rate(ORR), response duration and safety. Results: The median age was 69 ( Interquartile range 43-91) and 23% were female and 77% were male. Among, patients who received immunotherapy 1st line, 82% had baseline renal impairment(GFR < 60), and 18% had Eastern Cooperative Oncology Group performance status 2. For chemo naïve patients, median OS was 11.5 months for PEM and 5 months for ATZ respectively. ORR was 22 % for ATZ vs 50% for PEM and median duration of treatment was 4.5 and 2.5 months for PEM and ATZ respectively. When used in 2nd line median OS is 7 months for ATZ irrespective of PDL1 status and not reached for PEM yet. Grade 2 and above toxicities were reported in 18 % ATZ patients vs 10% in PEM patients, commonest were pneumonitis, tiredness, hepatitis and dermatitis. No treatment related deaths were reported. Conclusions: This study suggests that pembrolizumab has higher response rate and better survival compared to atezolizumab in cisplatin-ineligible patients with mUC and also in the 2nd line setting after disease progression following platinum based agents. Both agents were well tolerated.
Association of time to second-line (2L) immune-checkpoint inhibitors (ICI) and outcomes with ICIs in patients (pts) with advanced urothelial carcinoma (aUC).
Authors: Makrakis Dimitrios , Talukder Rafee , Dawsey Scott , Carril Lucia , Stewart Tyler F. , Morales-Barrera Rafael , Park Joseph J. , Fulgenzi Claudia Angela Maria , Murgic Jure , Vather-Wu Naomi , de Kouchkovsky Ivan , Devitt Michael Edward , Di Lorenzo Giuseppe , Gupta Kavita , Tripathi Nishita , Zakopoulou Roubini , Tripathi Abhishek , Lu Eric , Grivas Petros , Khaki Ali Raza 
Published: February 2022

505 Background: Current standard therapy for most pts with aUC is first-line (1L) platinum-based chemotherapy followed by ICI maintenance (or 2L if progression). Shorter time on 1L or between therapy lines may be a surrogate of more aggressive disease and poor outcome, but its prognostic role in ICI response is unclear. We hypothesized that shorter time until start of 2L ICI would be associated with worse outcomes in aUC. Methods: We performed a retrospective multi-institution cohort study in pts with aUC treated with 1L platinum-based chemotherapy, who later received 2L ICI. Pts receiving maintenance ICI were excluded. We calculated the time from start of 1L platinum chemotherapy to start of 2L ICI, dichotomizing the exposure into ≤6 months and >6 months. We compared overall response rate (ORR) to 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI between the two populations. ORR was compared among groups using multivariable logistic regression and PFS, OS using cox regression. Analysis was adjusted for calculated Bellmunt score. Results: From a total of 1283 pts, 462 received 1L platinum chemotherapy; among those, 350 received 2L ICI. After exclusions, 270, 269 and 260 pts were included in the ORR, PFS and OS analyses, respectively. Median age was 70 years, 78% men, 75% White, 74% with pure urothelial histology, 21% upper tract, 60% received cisplatin in 1L. Pts with time to 2L ICI ≤6 months had significantly higher Bellmunt scores (32% vs 22% score=2, 9% vs 3% score=3). ORR and PFS were comparable between pts with ≤ and >6 months to 2L ICI. However, OS was significantly longer for pts with >6 months to 2L ICI (median [m]OS 13 vs 7 months, p=0.002), (Table). Conclusions: Among pts with aUC treated with 2L ICI, time to 2L ICI ≤6 months from 1L platinum based chemotherapy was associated with similar ORR and PFS but shorter OS. Limitations include retrospective nature, patient selection, confounding factors. More studies are needed on the impact of platinum resistance in pts with aUC treated with ICIs.[Table: see text]
Survival outcomes with radical cystectomy (RC) in localized clinically node-positive bladder cancer (CNBC).
Authors: Perimbeti Stuthi , Jiang Changchuan , Deng Lei , Jatwani Karan , Kaur Anahat , George Saby , Chatta Gurkamal S. , Gopalakrishnan Dharmesh 
Published: February 2022

520 Background: The role of RC in patients with CNBC remains unclear since most prospective clinical trials excluded them. Our study aims to evaluate overall survival (OS) in patients with CNBC treated with systemic chemotherapy (SC) with or without RC. Methods: We queried the National Cancer Database for adult patients who received SC for localized CNBC during the years 2004 to 2018. Patients with distant metastases, including to non-regional nodes, and those treated with radiation to the bladder or pelvic nodes were excluded. Chi-square and Mann Whitney U tests were used to compare frequency distributions. Cox proportional hazards analysis was employed for multivariate analysis of factors associated with OS. Results: A total of 8464 patients were identified – 3565 (42.1%) underwent RC + SC (RC+), while 4899 (57.9%) received only SC (RC-). Median age at diagnosis was 65y in the RC+ grp vs. 68y in the RC- grp ( P = 0.006). Majority of patients were Caucasian in both grps – 86.9% and 85.1%, respectively. 5y-OS was 34.1% in the RC+ grp vs. 36.1% in the RC- grp ( P = 0.06). On multivariate analysis, factors independently associated with OS were RC+ status (Hazard ratio (HR) 0.81, 95% CI 0.75-0.88, P < 0.001), advanced age (70-85y vs. 18-35y, HR 1.88, 95% CI 1.18-3.01, P < 0.001), female gender (HR 1.20, 95% CI 1.12-1.28, P = 0.001), African American (vs. Caucasian) race (HR 1.24, 95% CI:1.10-1.40, P = 0.0004), ≥ 2 comorbidities (HR 1.67, 95% CI 1.34-1.92, P = 0.001), annual income ( < $30,000 vs > $45,000, HR 1.24, 95% CI 1.13-1.37, P < 0.001), and insurance status (uninsured vs. private, HR 1.39, 1.15-1.67, P < 0.001). Conclusions: In this large retrospective analysis, among patients with localized CNBC who received SC, 5y-OS rates were comparable with or without RC. However, RC was associated with improved OS on multivariate analysis.[Table: see text]
Outcomes according to histological variants of urothelial carcinoma after neoadjuvant chemotherapy in the GETUG-AFU V05 VESPER trial.
Authors: Allory Yves , Culine Stephane , Krucker Clémentine , Harter Valentin , Pfister Christian ,   VESPER Trial Investigators
Published: February 2022

533 Background: The histological variants of urothelial carcinoma (UC) may impact the outcomes after neoadjuvant chemotherapy in muscle invasive bladder cancer (MIBC). Previous studies provided contradictory results because of bias related to their retrospective design. Our aim was to assess pathological response and 3-year (yr) progression free survival (PFS) according to UC variants for patients included within the French prospective Vesper clinical trial (NCT01812369). Methods: 493 patients received dose-dense Methotrexate, Vinblastine, Doxorubicin and Cisplatin (dd-MVAC) or Gemcitabine and Cisplatin (GC) after randomization in the VESPER trial. This ancillary study was restricted to 437 patients treated in neoadjuvant setting. A central pathological review of initial transurethral diagnostic specimens allowed to assess UC variants (if ≥10% tumor area) and the presence of tumor emboli, perineural invasion, and CIS. Results: Slides were available for central review in 303 cases. UC variants were present in 180 patients (59%). Tumor emboli, perineural invasion, and CIS were noticed in 119 (39%), 24 (8%) and 143 (47%) cases. In comparison with pure UC, the presence of UC variants was not associated with different complete pathological response (ypT0N0) (OR 0.78, 95% CI 0.48-1.27) or 3 yr PFS (HR 1.25, 95%CI 0.83-1.86). Tumor emboli were negatively associated with ypT0N0 (OR 0.57, 95%CI 0.35-0.95, p = 0.029), organ confined disease (OR 0.44, 95%CI 0.26-0.75, p = 0.002) and 3 yr PFS (HR 1.81, 95%CI 1.23-2.67, p = 0.003). Perineural invasion were negatively associated with organ confined disease (OR 0.29, 95%CI 0.12-0.68, p = 0.005) and 3 yr PFS (HR 2.54, 95%CI 1.47-4.40, p < 0.001). There was no association for CIS. Conclusions: In the VESPER trial, UC variants were not associated with distinct pathological response or 3 yr PFS after neoadjuvant chemotherapy. Future studies will determine whether molecular subtypes are associated or not with distinct outcome.
Clinical outcomes in advanced urothelial cancer (UC) patients who experienced immune-related adverse events (irAEs) after immune checkpoint inhibitor monotherapy (ICI).
Authors: Sanda Gregory E. , Shabto Julie M. , Goyal Subir , Liu Yuan , Martini Dylan J. , Nazha Bassel , Brown Jacqueline T , Yantorni Lauren Beth , Russler Greta , Caulfield Sarah , Joshi Shreyas S. , Narayan Vikram M. , Kissick Haydn , Ogan Kenneth , Master Viraj A. , Carthon Bradley Curtis , Kucuk Omer , Bilen Mehmet Asim 
Published: February 2022

544 Background: Immune checkpoint inhibitors (ICIs) continue to demonstrate promise in treatment of advanced urothelial carcinoma (UC). Some patients undergoing ICIs experience immune related adverse events (irAEs) and may serve as a marker of response. We investigated the relationship between irAEs and clinical outcomes in UC patients treated with ICIs. Methods: A retrospective study of 70 UC patients treated with ICI monotherapies at Winship Cancer Institute from 2015-2020 was done. Overall survival (OS) and progression-free survival (PFS), defined as time from ICI initiation to death and clinical or radiographic progression, respectively as well as clinical benefit (CB), defined as best radiographic response of complete response, partial response, or stable disease for ≥ 6 months per RECIST v1.1, were used to measure clinical outcomes. Cox proportional hazards and multivariable analyses (MVA) were used to model associations with OS and PFS. Results: Most patients were male (70%) with a median age of 68.7 years (28.0-91.0). Most patients (95%) had urothelial carcinoma and most (81%) received at least 1 prior treatment. One third of patients had ECOG PS greater than or equal to 2. Of patients that experienced an irAE (35%), the most common were dermatologic (12.9%) and arthralgia (0.5%). In addition to significantly longer treatment duration, irAE patients had significantly increased OS (HR:0.38, 95% CI:0.18-0.79, p=0.009), significantly longer PFS (HR:0.27, 95% CI:0.14-0.53, p < 0.001), and significantly greater CB (OR:4.20, 95% CI:1.35-13.06, p=0.013). Patients who experienced dermatologic irAEs had significantly increased OS, PFS, and CB (Table). Conclusions: Our results demonstrate that UC patients undergoing ICI therapy who experience irAEs, especially dermatologic irAEs, had improved clinical outcomes. This suggests that irAEs may serve as a clinical biomarker of advantageous response in patients receiving ICI. Future prospective studies are needed for validation.[Table: see text]
Genomic sequencing for bladder urothelial carcinoma and its clinical implications for immunotherapy.
Authors: Kim Ryul , Lee Jeeyun , Kwon Ghee Young , Hong Jung Yong , Jeong Byong Chang , Park Se Hoon 
Published: February 2022

551 Background: To explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI). Methods: We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, PD-L1 expression was evaluated in a subset of patients (n = 57) including those treated with ICI (n = 8). Results: We identified frequent molecular dysregulations in chromatin regulatory genes ( KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples ( P= 0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among 8 patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment. Conclusions: Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.