bluuebunny/crossref_metadata_2025_split huggingface dataset:
Radical radiotherapy for muscle-invasive bladder cancer: A single centre experience.
Authors: Forster Mayumi , Mehta Ami , Clifford Amy , Needleman Sarah , Mansukhani Sonia , Prentice Mark 
Published: March 2023

519 Background: Muscle-invasive bladder cancer (MIBC) is managed with radical cystectomy or (chemo)radiotherapy ((C)RT), CRT offers the chance of cure alongside organ preservation. Patients presenting with MIBC are often elderly and frail, with comorbidities precluding cystectomy and systemic treatment. We report outcome data for our institution of patients treated with radical (C)RT. Methods: Patients with T2-4N0 MIBC diagnosed between December 2014 and December 2021 were retrospectively identified from the radiotherapy planning system. Baseline demographic, clinical and follow up data were collated from electronic patient records. Results: 54 patients were identified. Mean patient age was 78.5 (range 47 – 94); 51 patients had urothelial cancer and 3 squamous cell carcinoma. 20 patients had evidence of carcinoma in situ (CIS) at diagnosis. 19 patients had neoadjuvant chemotherapy (NACT) (13 patients had cisplatin-gemcitabine, 6 patients had carboplatin-gemcitabine). 12/19 patients completed 3 cycles of NACT, 7 patients received 1-2 cycles. 24/54 patients had concurrent chemotherapy (6 patients receiving mitomycin-5-FU, 17 weekly gemcitabine and 1 weekly cisplatin). 14/24 patients completed concurrent chemotherapy as planned. Of the 24 patients treated with CRT, 18 had NACT. 12 patients received 64 Gy 32 fractions, 2 received 60 Gy 30 fractions, and 40 received 55 Gy 20 fractions. All except 1 patient completed the prescribed course. With a median follow up of 9.4 months (range 0.7-79 months), 3-year overall survival was 43% for all patients; 63% with CRT and 21% with RT alone (log-rank test p=0.0052 HR 3.15 (95% CI 1.48-6.7)). At 3 years 49% were free of recurrence (distant or local); 72% with CRT and 25% with RT alone (log-rank test 0.0079 HR 3.12 (95% CI 1.38-7.01)). 3yr OS and % free of recurrence were not impacted by the presence of CIS. OS was 46% with CIS and 41% without (log-rank test p=0.6649); 3yr % free of recurrence was 43% with CIS and 49% without (log-rank test p=0.4055). Median time to recurrence with CIS was shorter at 13.3 months vs 26.1 months. Conclusions: Radical radiotherapy to the bladder is an effective option for the treatment of MIBC and should be routinely discussed with patients. Patients should be treated with CRT as opposed to RT alone as both OS and RFS are significantly improved. Ensuring patients are fit to receive systemic treatment alongside RT may require prehabilitation in this elderly and more co-morbid group.
Association of biomarkers and response to immune checkpoint inhibitors (ICIs) in patients with metastatic urothelial carcinoma (mUC) with high and low tumor mutation burden (TMB).
Authors: Jindal Tanya , Zhu Xiaolin , Zhang Li , Reyes Kevin R , Deshmukh Prianka , de Kouchkovsky Ivan , Kumar Vipul , Maldonado Edward , Shipp Chase , Kwon Daniel H , Borno Hala , Bose Rohit , Desai Arpita , Aggarwal Rahul Raj , Porten Sima P. , Small Eric Jay , Fong Lawrence , Chou Jonathan , Friedlander Terence W. , Koshkin Vadim S 
Published: March 2023

534 Background: ICIs are frequently used as therapy in mUC, but only a minority of patients (pts) respond to treatment. High TMB is associated with improved outcomes to ICIs. However, much is unknown about biomarkers associated with ICI outcomes in pts with high and low TMB respectively. Methods: We retrospectively identified mUC pts with known TMB status and available next generation sequencing (NGS) results treated with ICI monotherapy at our institution. TMB high was defined as ≥ 10 mutations/Mb, with the rest being TMB low. Somatic alterations present in ≥10% pts ( ARID1A, CCND1, CDKN2A, CDKN2B, ERBB2, FGF3, FGF4, FGF19, FGFR3, KDM6A, MDM2, MLL2, PIK3CA, RB1, TERTp, TP53, TSC1), and presence of DNA damage response (DDR) alterations were assessed as biomarkers of interest. Within the TMB-high and TMB-low pt groups we separately assessed patients based on the presence or absence of these somatic alterations, APOBEC mutational signature and high PD-L1 expression. Log rank test was used to determine differences in overall survival (OS) and progression free survival (PFS) among these groups. P-value ≤0.05 was considered significant. Results: Among 107 mUC pts treated with ICI monotherapy between 12/2014 and 3/2022 who had NGS data (UCSF500, FoundationOne, Strata), 85 pts had TMB data, including 47 TMB high pts and 38 TMB low pts. Among 85 pts with known TMB status, median age was 76 yrs, the majority were male (55, 65%), Caucasian (57, 67%), had pure urothelial histology (46, 55%) and were treated with ICIs in frontline setting (47, 55%). Median OS was 17.2 mos and median PFS was 3.42 mos. In TMB high pts, presence of DDR , MLL2, KDM6A, PIK3CA and TERTp alterations were each associated with improved outcomes, while presence of CDKN2B alterations was associated with inferior outcomes (Table). Among TMB low pts, those with RB1 alterations had shorter mOS (11.3 months vs 17.2 months; p=0.04) compared to wild-type pts. Conclusions: In this single-center retrospective analysis of mUC pts, we identified somatic alterations that were predictive of outcomes with ICI treatment in TMB high and TMB low pts respectively. Further exploration of biomarkers in patients stratified by TMB status is warranted in larger cohorts. [Table: see text]
Assessing the utility of a cell-free tumor (ct)DNA assay (MSK-ACCESS) in patients (pts) with node-positive (N+) muscle-invasive bladder cancer (MIBC) undergoing neoadjuvant chemotherapy (NAC).
Authors: Katims Andrew B , Lenis Andrew T , Shah Ronak H. , Chu Carissa E , Ratna Neha , Regazzi Ashley M , Pietzak Eugene J. , Aggen David H , Funt Samuel A , Teo Min Yuen , Rosenberg Jonathan E. , Bajorin Dean F. , Donahue Timothy F. , Bochner Bernard H. , Berger Michael F. , Solit David B. , Iyer Gopa 
Published: March 2023

544 Background: Circulating ctDNA is associated with disease progression, worse overall survival, and recurrence in pts with bladder cancer. This study correlated targeted exome ctDNA sequencing with pathologic response to NAC and metastatic recurrence in pts with N+ MIBC undergoing radical cystectomy (RC). Methods: We prospectively identified pts with cT2-3N1-2M0 bladder cancer who underwent NAC prior to RC. Node positivity was determined radiographically and/or by node biopsy. Plasma samples were collected pre-NAC, mid-treatment, after NAC completion, and 3 months after RC. Samples were analyzed using MSK-ACCESS, an ultrasensitive ctDNA platform designed to identify somatic mutations in 129 cancer associated genes. Primary bladder tumors were sequenced using targeted exome sequencing. Results: Samples (31) from 9 pts (6 men) were analyzed. Median age was 63 years (IQR 58-69). NAC regimens included gemcitabine and cisplatin alone (78%) or with paclitaxel (22%). Seven (78%) pts had >1 detectable mutation pre-NAC. The most altered genes detected in both tissue and ctDNA included: TERT (88% vs 28%), TP53 (76% vs 40%), ARID1A (43% vs 17%), RB1 (43% vs 15%), KDM6A (43% vs 15%), and ATM (17% vs 17%). Four (45%) pts had complete response (ypT0N0), 1 (11%) had a partial response (ypT1N0), and 4 (33.3%) were non-responders (ypT2N0-3). All non-responders had disease recurrence after RC (median 3 months, range 2-11 months). Of 7 pts with on-treatment MSK-ACCESS, 2 (29%) had detectable ctDNA (1 ypT2N0, 1 ypT0N0). The pt with a PR had detectable ctDNA post-NAC with 1 mutation identified that was not detected at 3 months. All pts with >ypT2N0 had detectable ctDNA post-NAC. Pts with recurrence/non-responders had a significantly higher mutation count 3 months after RC compared to responders, with a median of 7 vs. 0 mutations, respectively. Two pts with CR had detectable ctDNA at 3 months post-RC but have not recurred (Table). Conclusions: Clearance of ctDNA post-NAC correlated with pathologic complete response. Approximately 70% of pts had ctDNA clearance on NAC. All pts with residual disease at RC had detectable ctDNA post-NAC. [Table: see text]
Characterizing the immune phenotype of FGFR3 mutated upper tract urothelial carcinoma (UTUC) using single-cell (sc)RNA-sequencing (seq).
Authors: Katims Andrew B , Kuo Fengshen , Reisz Peter , Tracey Andrew , Thomas Jasmine , Yip Wesley , Merghoub Taha , Bochner Bernard H. , Pietzak Eugene J. , Solit David B. , Hakimi A. Ari , Kim Kwanghee , Coleman Jonathan 
Published: March 2023

558 Background: Fibroblast growth factor 3 (FGFR3) is the most common mutation in UTUC and is altered in approximately 75% of tumors. Tumors harboring FGFR3 mutations (FGFR3-M) have a T-cell impaired tumor microenvironment (TME) which may explain the incomplete response to immune checkpoint blockade. We performed scRNA-seq on 8 untreated tumors to further characterize the T-cell immune phenotype of FGFR3-M tumors. Methods: scRNA-seq (10x Genomics platform) was performed on 8 UTUC tissue specimens from 8 different patients who had not received treatment (chemotherapy or immunotherapy) using an established institutional process. We also performed targeted gene sequencing (MSK-IMPACT) on all samples to identify mutational calls. We assessed the phenotype of defined cell clusters and the immune composition of each sample according to known marker gene expression as well as SingleR prediction. We then performed the gene set enrichment analysis over the differentially expressed genes with the Gene Ontology Biologic Process (GO:BP) to identify unique biologic processes and possible functional state of each immune cluster. Results: Among the 8 samples, 4 (50%) had altered FGFR3 (Table). We identified 19 immune cell clusters (8 T-cell clusters) with unique biologic function. Within the CD4 compartment, FGFR3-M was enriched with exhausted/active CD4 cells characterized with Th17 cell differentiation/immune regulatory function (cluster 4) and yet with lower frequency of naive-like CD4 cells possessing alpha-beta T cell activation functions and lower T-cell receptor (TCR) signaling (cluster 2). Regulatory T cells (cluster 5) were less frequently found in FGFR3-M tumors compared to their wild-type counterpart. In the CD8 compartment, FGFR3-M tumors had higher infiltration specifically in cluster 3 which corresponds to a naïve state with lower exhausted/active markers, lower cytotoxic activity, leukocyte apoptotic process, and alpha-beta T cell differentiation regulation. There was also a lower proportion among cluster 9, a mixture of NK and CD8 cytotoxic cells, which is characterized with response to interleukin (IL)-1, tumor necrosis factor (TNF), and NK cell chemotaxis. Additionally, this cluster had high cytotoxic activity and lower exhausted/active markers. Conclusions: FGFR3 mutated patients have a T-cell phenotype with more active/exhausted Th17-like CD4, lower Treg, and more CD8/cytotoxic cells in naïve state with lower response to IL-1 and TNF. scRNA-seq revealed enrichment of different functional states among T-cell compartments which may lead to improved therapeutic decision making in the future. [Table: see text]
Landscape of genomic alterations (GA) in urothelial bladder carcinoma (UBC) in patients of East Asian and South Asian ancestry.
Authors: Peak Taylor , Spiess Philippe E. , Li Roger , Grivas Petros , Necchi Andrea , Pavlick Dean C. , Huang Richard S.P. , Lin Douglas I. , Danziger Natalie , Jacob Joseph M , Bratslavsky Gennady , Ross Jeffrey S. 
Published: March 2023

567 Background: UBC is the 10th most common cancer worldwide, with more than 550,00 new cases annually (WHO, International Agency for Research on Cancer, 2020). Rates vary by regions of the world, explained in part by the fact that different genetic ancestries demonstrate varying germline genetics, environmental exposures, and social risk factors. Methods: 8,728 UBC samples underwent hybrid capture-based comprehensive genomic profiling (CGP) to determine all classes of genomic alterations (GA), microsatellite instability (MSI) status, tumor mutational burden (TMB), and genomic trinucleotide signature. Predominant genetic ancestry was determined using a SNP-based approach using an algorithm trained on the 1000 Genomes data (Connelly et al. AACR 2018). Ancestry was classified as one of the five following categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Results: Of the cohort, 7,447 (85.3%) were EUR, 541 (6.2%) were AFR, 461 (5.3%) were of AMR, 74 (0.85%) were SAS, and 205 (2.3%) were EAS. Age, gender, genomic signature distributions, and MSI status (range 0.9%-1.5%) were similar in all cohorts. The frequency of TMB >10 mutations/Megabase was similar in all cohorts (range 30.7%-39.1%) as was the median TMB (6.3 mutations/Megabase for all). At 67.6%, TP53 was the most frequent GA in SAS cohort. When compared with the non-SAS cohort, TERT GA were lower in the SAS cohort (58.1% vs 72.6%; p=0.06) as were GA in FGFR3 (9.5% vs 18.5%, p=0.25). In the EAS cohort, at 59.0%, GA in TP53 were the most common. TERT mutations were significantly lower in EAS compared to the non-EAS cohort (54.1% vs 72.9%; p <0.001). When compared with the non-EAS cohort, PIK3CA alterations were significantly less common in the EAS cohort (12.7% vs 22.1%, p =0.005). GA in FGFR3 were similar in the EAS and non-EAS cohorts (16.6% vs 18.4%). There were no significant differences in genomic landscapes identified between the EAS and SAS cohorts when directly compared to one another. Conclusions: The results from this comprehensive genomic analysis of UBC in East Asian and South Asian patients provides important insight into the unique differences in the genomic landscapes that exist on a population level. These findings should motivate future investigators to include more diverse patient populations in clinical trials of targeted agents and immunotherapy strategies.
Real-world treatment patterns and sequencing in patients with locally advanced or metastatic urothelial cancer (la/mUC) in the US.
Authors: Kearney Mairead , Mahmoudpour Hamid , Ike Chiemeka , Modh Ambar , Monzon Sebastian , Fragkogianni Matina , Carson Ken 
Published: March 2023

572 Background: Platinum-based chemotherapy (PBC) is standard first-line (1L) treatment (tx) for patients (pts) with la/mUC. On June 30, 2020, avelumab was approved in the US as 1L maintenance (1LM) for pts without disease progression following PBC. Other novel agents such as enfortumab vedotin were recently approved for second-line (2L) or later tx. Little is known about how to incorporate these agents into the optimal tx sequencing approach. This real-world (RW) study describes the characteristics and tx patterns of pts with la/mUC. Methods: A retrospective cohort of de-identified records of pts with la/mUC was obtained from the Tempus Database. Eligible pts were diagnosed with la/mUC between January 1, 2016 and February 23, 2022. Pts who completed 1L PBC were categorized as 1LM or 2L-treated. 1LM was differentiated from 2L tx based on stated clinical intent of 1LM or initiation of immunotherapy (IO) within 180 days of 1L PBC completion without disease progression. These patients were split into pre and post groups based on when they completed their 1L PBC in relation to avelumab 1LM US approval on June 30, 2020. Results: A total of 821 pts were included from community centers (21%), academic centers (27%), and ASCO CancerLinQ network sites (52%). The median age at diagnosis was 68 years (IQR, 61-75), 73% male, and 63% White. 634 (77%) pts received 1L systemic tx; of those, 62% (395/634) received PBC, 24% (155/634) received IO monotherapy, 7% (45/634) received non-PBC, and 6% (39/634) received other regimens. Tx sequencing for a subgroup of pts who discontinued 1L PBC pre- and post-avelumab 1LM approval is shown (Table). Of those receiving IO (n=84) as subsequent tx post-avelumab approval, 80% (67/84) received IO as 1LM, out of which, 84% (56/67) received avelumab as 1LM. Of the 25 pts who received 2L tx after progression on IO 1LM post-avelumab approval, enfortumab vedotin was the most commonly integrated 2L agent (n=20; 80%). Conclusions: This RW study offers valuable insight into the characteristics of pts with la/mUC treated in routine clinical practice in the US. These tx pattern data are consistent with known and evolving tx paradigms in la/mUC. In subsequent RW studies, clinical data with longer follow-up could provide further insight into the optimal tx sequencing and associated clinical outcomes. [Table: see text]
Impact of neoadjuvant chemotherapy–induced acute kidney injury on oncological outcomes in patients who underwent radical cystectomy: A multicenter retrospective study.
Authors: Fujita Naoki , Momota Masaki , Hatakeyama Shingo , Ito Hiroyuki , Yoneyama Takahiro , Hashimoto Yasuhiro , Yoshikawa Kazuaki , Ohyama Chikara 
Published: March 2023

573 Background: Neoadjuvant chemotherapy (NAC)-induced acute kidney injury (AKI) is a frequent complication in patients with muscle-invasive bladder cancer (MIBC). Although previous studies have reported that AKI during cancer treatment was associated with poor oncological outcomes in several cancers, the impact of NAC-induced AKI on oncological outcomes in patients with MIBC remains unclear. Methods: This retrospective study included 398 patients who received 2-4 cycles of NAC followed by radical cystectomy (RC). AKI was defined according to the KDIGO criteria. Patients were divided into two groups: patients who developed AKI during NAC (AKI group) and patients who did not (non-AKI group). Multivariable Cox-proportional hazards regression analyses were performed to evaluate the impact of NAC-induced AKI on recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Results: The median age and follow-up period were 69 years and 62 months, respectively. Of the 398 patients, 66 (17%) developed AKI during NAC. The rates of <ypT2 and downstage in the AKI group were significantly lower than those in the non-AKI group (38% vs. 53%, P = 0.023; 53% vs. 69%, P = 0.013; respectively). After adjustment for age, performance status, cisplatin-based regimen, tumor grade, pathological T stage, pathological lymph-node involvement, and positive surgical margin, AKI was associated with shorter RFS (hazard ratio [HR] 1.619, P = 0.043), CSS (HR 1.727, P = 0.049), and OS (HR 1.848, P = 0.008). Conclusions: NAC-induced AKI was associated with reduced effects of NAC and poor oncological outcomes in patients who underwent RC.
Overall survival (OS) and efficacy results of second-line treatment in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) treated in the randomized phase II BIONIKK trial.
Authors: Vano Yann-Alexandre , Phan Letuan , Simonaggio Audrey , Bennamoun Mostefa , Pannier Diane , Chevreau Christine , Borchiellini Delphine , Maillet Denis , Gross-Goupil Marine , Laguerre Brigitte , Tournigand Christophe , Barthelemy Philippe , Coquan Elodie , Gravis Gwenaelle , Sun Cheng-Ming , Meylan Maxime , Fridman Wolf-Hervé , Sautès-Fridman Catherine , Elaidi Réza , Oudard Stephane 
Published: March 2023

607 Background: To date, no biomarker of efficacy of nivolumab+/-ipilimumab (N+/-I) or anti-VEGFR TKI has been prospectively validated in mRCC. The BIONIKK trial showed promising objective response rate (ORR) and progression-free survival (PFS) with these treatments in first line (L1) after selection by tumour molecular group. We report OS and efficacy results of the second-line (L2) treatment. Methods: BIONIKK is a French multicentre non-comparative phase II trial, randomising 199 mRCC pts to receive N (58), NI (101) or TKI (40) in L1 according to four molecular groups (ccrcc1-4). ORR and PFS were already reported. With an additional follow-up of ≥20 months, we report OS from randomization and from the start of L2, as well as ORR and PFS with a TKI in L2 by molecular group. Results: With a median follow-up of 42.1 months (40.5-45.2), 86 (43%) patients died: 27/58 (46.5%), 39/101 (39%) and 20/40 (50%) in the N, NI, and TKI arm, respectively. Median OS were 43.4 months (95%CI=31.4-NR) with N, 52.7 months (95%CI=46-NR) with NI and 38.1 months (95%CI=33.2-NR) with TKI (table). 175 (88%) patients discontinued first-line treatment, including 20 deaths, and 129 (74%) received a L2, 38/58 (65.5%), 64/101 (63%), and 27/40 (67.5%) after N, NI and TKI, respectively. The most frequent L2 received after N+/-I was a TKI in 96/102 (94%) pts, including cabozantinib in 49, sunitinib/pazopanib in 32, axitinib in 13, and lenvatinib in 2. N was the most frequent L2 after TKI, 20/27 (74%). ORR with TKI in L2 was 28.5% (10/35) after N, 39% (24/61) after NI and 80% (4/5) after TKI, with marked benefit in ccrcc2 pts (table). The mPFS with TKI in L2 was 8.2 (95%CI=6.9-19.3) after N, 11.4 (95%CI= 8.9-16.8) after NI, and 12.1 (95%CI =11.4-NR) months after TKI, with a higher benefit in ccrcc2 pts (vs. ccrcc1+4, p=0.04). Conversely, ORR and mPFS with N after TKI in ccrcc2-pts were 12.5% (2/16) and 5.4 (2.6-NR) months, respectively. Median OS L2 was reported in the table. The updated ORR and PFS in L1 will presented at the Meeting, as well as PFS2 and efficacy by TKI type in L2. Conclusions: We report for the first-time OS and L2 efficacy results by molecular group in a randomized trial. Molecular selection also has an impact on treatment efficacy in L2. These results, together with those reported in L1, can inform clinicians on the best treatment sequence in L1-2. Clinical trial information: NCT02960906 . [Table: see text]
Prognostic utility of linear segmentation in nonmetastatic renal cell carcinoma: Correlation of overall survival with muscle mass.
Authors: Schmeusser Benjamin , Midenberg Eric , Palacios Arnold Raul , Vettikattu Nikhil , Patil Dattatraya H , Nabavizadeh Reza , Medline Alexandra , Higgins Michelle , Psutka Sarah P. , Ogan Kenneth , Master Viraj A. 
Published: March 2023

617 Background: In renal cell carcinoma (RCC) and other solid organ malignancies, sarcopenia has been associated with decreased survival and increased perioperative complications. Traditional body composition analysis is an expensive and time extensive process. As a modifiable risk factor, more clinic friendly methods to identify patients with low muscle composition is of interest. Linear segmentation on routine imaging has been proposed as a fast, reliable and reproducible alternative. This study assesses the prognostic ability of linear segmentation in patients with nonmetastatic RCC. Methods: Patients that underwent nephrectomy for nonmetastatic RCC from 2005-2021 at an academic referral center were identified. Linear segmentation of the bilateral psoas/paraspinal muscles was completed on preoperative imaging obtained within 60 days of surgery. Cox proportional-hazards analysis was used to determine association between total muscle index and overall survival. Results: 532 (388 clear cell) patients were analyzed and a median total muscle index was 28.6 (25.8-32.5) for women and 33.3 (29.1-36.9) for men. As a binary variable, lower total muscle index was significantly associated with decreased survival in both the full (HR=1.96, 95% CI 1.32-2.90, p<0.001) and clear cell only cohorts (HR=1.78, 95% CI 1.08-2.75, p=0.022). As a continuous variable, unit increases in total muscle index were significantly associated with improved survival in the full cohort (HR=0.95, 95% CI 0.92-0.99, p=0.006) and the clear cell only cohort (HR=0.95, 95% CI 0.92-0.99, p=0.016). Conclusions: Assessment of muscle composition via linear segmentation on routinely obtained preoperative imaging is a clinically feasible technique with prognostic utility in patients with localized RCC. In this cohort of patients with nonmetastatic RCC, linear segmentation demonstrated significant associations with overall survival as a binary and continuous variable. This simplified technique may allow for routine inclusion of body composition into clinical decision making. [Table: see text]