bluuebunny/crossref_metadata_2025_split huggingface dataset:
Associations of education, residence, and travel distance to oncology center on survival outcomes in patients with penile cancer: A tertiary care referral center experience.
Authors: GARG VIKAS , Ray Mukurdipi , Haresh KP , Sahoo Ranjit Kumar , Sharma Atul , Kaushal Seema , Batra Atul 
Published: March 2021

4 Background: Rural residence, educational status & longer travel distance are variably associated with suboptimal cancer treatment and outcomes. There are limited data on impact of these factors on treatment patterns & survival outcomes in penile cancer. Methods: Patients with a histological diagnosis of carcinoma penis during 2015 to 2019 were identified from the database of a large tertiary care center in India. Chart reviews were performed to retrieve demographic, clinicopathological and treatment details. Educational status was categorized as no formal education and any educational attainment, while travel distance was dichotomized at 500 km. Logistic regression analyses were performed to examine the associations with cancer treatments. Relapse free survival (RS) and overall survival (OS) were calculated by plotting Kaplan Meir curves and compared using log rank test. Multivariable Cox regression analysis were used to determine the associations of socioeconomic status and residence on survival outcomes. Results: A total of 100 patients were eligible for the current analysis. The median age was 56 (interquartile [IQR]range, 42-65) years. The median duration of symptoms was 6 (IQR, 4-12) months. Ulcero-proliferative growth (65%) was the most common presenting symptom followed by pain (57%) and dysuria (36%). Most patients had grade 2 tumor (60%), while stage was equally distributed from I-IV. Three-fourths of patients had clinically enlarged inguinal lymph nodes, while, 42 % were pathologically involved. Of all patients, 58% were from rural communities, 44% patient didn’t receive any formal education, and 36% had travelling distance of over 500 km from the hospital. Surgery, radiotherapy, and chemotherapy were administered in 53%, 42% and 24%, respectively. On multivariable logistic regression analysis, lower education, rural residence and longer travel distance were not associated with a lower likelihood of receiving any treatment. At a median follow-up of 50.7 months, median RFS and OS were 59.8 (95% CI, 15.8-NR) and 83.9 (95% CI, 29.2–NR) months, respectively. After adjusting for tumor stage, involvement of lymph nodes, PS, and grade, education status, primary residence (urban vs rural), and distance from the treatment center were not associated with RFS and OS. However, advanced stage was the only factor predictive of worse RFS and OS (Table). Conclusions: Rural residence, educational status and travel time were not associated with treatment administration and survival outcomes in patients with penile cancer treated in a publicly funded tertiary care center in India. [Table: see text]
Reliability, validity, and clinically important differences (CIDs) on the NCCN/FACT Bladder Symptom Index (NFBISI-18) among individuals with locally advanced or metastatic urothelial cancer (UC).
Authors: Peipert John , Chang Jane , Li Si , Di Pietro Alessandra , Cislo Paul , Cappelleri Joseph C , Cella David 
Published: March 2021

408 Background: The NFBlSI-18 is a measure of advanced bladder cancer–specific symptoms composed of a total scale and 3 subscales representing physical disease–related symptoms (DRS-P), emotional disease–related symptoms (DRS-E), treatment side effects (TSE), and function/well-being (F/WB). There is evidence for the reliability and content validity of this instrument, but a full psychometric evaluation of the full 18-item format has not been done. In addition, CIDs have not been estimated. Methods: With the exception of test-retest (TRT) analyses, baseline data (n=651) from the JAVELIN Bladder 100 trial (NCT02603432), which compared maintenance treatment with avelumab + best supportive care (BSC) vs BSC alone in patients with unresectable, locally advanced or metastatic UC that did not progress with first-line platinum-containing chemotherapy, were used for this study. Since we focused on baseline, we did not analyze the TSE. We estimated internal consistency reliability (Cronbach coefficient α), tested convergent validity by estimating Spearman ρ correlations with the EQ-5D-5L utility index (UI) and visual analog score (VAS) scales, and estimated known group validity using age (<65, ≥65 years), ECOG performance status rating (PSR), and number of comorbidities/symptoms (1-9, ≥10) as anchors. We estimated TRT reliability using data from treatment cycles 2-3 with intraclass correlation coefficients (ICCs). To estimate and compare CIDs, we calculated differences in means between categories of the known group anchors for which Cohen’s d was >0.2 (ie, at least a small effect). To provide context for the CIDs, we calculated distributional properties of the scales (1/2 standard deviation [SD], 1 standard error of measurement [SEM]). Results: The table shows the reliability, convergent validity, and CID estimates. Reliability estimates often exceeded thresholds for reliability generally considered acceptable. Cohen’s d for NFBlSI-18 scale score differences between known groups ranged between 0.05 and 0.25 (age), 0.35 and 0.6 (ECOG PSR 0 vs 1), and 0.1 and 0.41 (number of comorbidities/symptoms). Conclusions: This analysis demonstrated that the NFBlSI-18 is a reliable and valid instrument to measure symptoms in patients with advanced UC. The CID estimates can help clinicians and researchers to understand what difference in patient symptoms are clinically meaningful, as measured by NFBlSI-18, to inform clinical practice. [Table: see text]
Germline alterations in cancer susceptibility genes in women with high-risk bladder cancer: Implications for germline testing and clinical management.
Authors: Truong Hong , Sheikh Rania , Khurram Aliya , Kemel Yelena , Lenis Andrew Thomas , Reisz Peter , Joseph Vijai , Goh Alvin , Cha Eugene K. , Donahue Timothy F. , Coleman Jonathan , Pietzak Eugene J. , Bochner Bernard H. , Offit Kenneth , Carlo Maria Isabel 
Published: March 2021

418 Background: Gender differences exist in bladder cancer incidence, stage at diagnosis, and outcomes. Women have lower incidence of bladder cancer but are diagnosed with more advanced disease at presentation. They also have less favorable outcomes even after adjusting for tumor stage and treatment modality. The biologic mechanisms underlying gender disparities in bladder cancer remain unknown. Methods: We leveraged a prospective matched tumor-normal genomic profiling initiative to determine the prevalence and spectrum of pathogenic/likely pathogenic (P/LP) germline variants in women with bladder cancer. Germline DNA was tested for mutations in ≥77 cancer susceptibility genes using next-generation sequencing in 686 patients with bladder cancer. Mutation frequency and clinical characteristics were assessed by gender. Results: A total of 184 (27%) women and 502 (73%) men with bladder cancer underwent germline testing; median age of diagnosis was 66 ± 11.3 and 65 ± 11.3 years, respectively. Twenty-two women (12%) had bladder cancer diagnosis at age ≤ 50 years. Both groups had similar rate of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.5), and disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 54% vs 54%, MIBC 38% vs 39%, and metastatic disease 8% vs 6%, p = 0.7). Women had more non-urothelial carcinoma histology than men (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001). More P/LP germline variants were found in women than men (38 [21%] vs. 70 [14%], p = 0.04). Twenty-eight women (15%) had P/LP variants in DNA-damage repair (DDR) genes; 23 (13%) carried moderate/high penetrance germline mutations, the most common were BRCA1/ 2, CHEK2, NBN, ATM, and MITF. Current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. Nine women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers ( BRCA1/ 2 [5], ATM [2], MLH1 [1], TP53 [1]). Conclusions: Deleterious germline alterations are commonly present in women with high-risk bladder cancer. The presence of germline variants in some genes, such as BRCA1/2, can guide cancer screening and risk-reducing surgeries for patients and their families. Women with high-risk bladder cancer should be evaluated for suitability of germline testing, especially those who desire preservation of uterus and ovaries at the time of radical cystectomy, to rule out the presence of P/LP variants that increase risk of future gynecologic malignancies.
Efficacy of chemohyperthermia (HIVEC) in patients with high-risk nonmuscle invasive bladder cancer (NMIBC) who fail BCG therapy.
Authors: Pignot Geraldine , Doisy Laure , Walz Jochen , Marquette Thibault , Maubon Thomas , Rybikowski Stanislas , Gravis Gwenaelle 
Published: March 2021

456 Background: To evaluate Hyperthermic Intra-Vesical Chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (DFS) rate and bladder preservation rate in patients with high-risk Non-Muscle Invasive Bladder Cancer (NMIBC) who fail BCG therapy or are contraindicated to BCG. Methods: Between June 2016 and October 2019, patients treated with HIVEC for high-risk NMIBC who failed BCG (Fail-BCG) or BCG-naive if BCG contraindicated (N-BCG) have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. Results: Fifty-three patients, median age 72 [39-93] years, were included (n = 29 Fail-BCG and n = 24 N-BCG). The median follow-up was 18 months. The bladder preservation rate was 92.4%. The RFS rate at 12 months was 60.5%. The RFS rate at 12 months for N-BCG and Fail-BCG groups was respectively 70% and 52.2%. Three patients progressed to muscle-invasive disease, all in the Fail-BCG group and all in the very high-risk EORTC group. Two of them experienced metastatic progression and died from bladder cancer. Conclusions: Chemohyperthermia using HIVEC device achieved a RFS rate of 60% at 1 year and enabled a bladder preservation rate of 92%. Given the low risk of progression in the N-BCG group, HIVEC could be a good alternative. Conversely, for patients with very high-risk tumors that fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression to muscle-invasive disease.
Single-cell DNA targeted sequencing (scDNA-seq) to test therapeutic vulnerabilities in urothelial cancer (UC) patient-derived organoids (PDO).
Authors: Shohdy Kyrillus , Liu Weisi , Alonso Alicia , Xiang Jenny , Martin M. Laura , Elemento Olivier , Faltas Bishoy Morris 
Published: March 2021

464 Background: Genomic alterations in FGFR3, PIK3CA, and CDKN2A are common actionable targets in urothelial cancer (UC). We aimed to determine the efficacy of alpelisib, a PIK3CA inhibitor, and abemaciclib, a CDK4/6 inhibitor in bladder cancer patient-derived organoid using single-cell targeted DNA sequencing. Methods: We established a patient-derived UC organoid (PDO) harboring the FGFR3 mutation (p.Y375C), the PIK3CA (p. E452K) mutation, and CDKN2A deletion, which we characterized using whole-genome sequencing. We generated dose-response curves of alpelisib, abemaciclib, and erdafitinib (an FGFR3 inhibitor) in PDO cells to determine the IC50 concentrations. The scDNA-seq (Tapsteri) platform was used to measure changes in the variant allele frequencies (VAF) and clonal fractions post-treatment. The Chi-square test for trend was used to test for linear trend across ordered categories. Results: scDNA-seq was performed after treating PDO cells with 3uM erdafitinib or DMSO. A total of 7000 single cells were obtained (4179 cells treated with erdafitinib vs. 2821 cells treated with DMSO). After removing variants mutated in <50% of cells, we identified 94 clonal variants. As expected, cells harboring FGFR3 Y375C have significantly decreased post erdafitinib treatment compared to DMSO-treated cells (66.05% vs. 82.36%, p<0.0001). We identified mutations in two genes ( RAB31 and SMAD4) that were associated with clonal expansion following FGFR3 inhibition (12% vs. 53% and 13% vs. 26%, respectively). We treated PDO cells with 3uM abemaciclib. We identified three genes harboring SNVs ( RB1, GNAQ, and SMAD4). The SNVs harboring cells were significantly decreased after abemaciclib compared to DMSO (p<0.0001). Then, we treated the cells with 1uM alpelisib for 72 hours alone or combined with abemaciclib (0.1uM). We identified that 100% of cells harbored the PIK3CA mutation E452K at pre-treatment, which limited our ability to detect significant changes in VAF post-treatment. Instead, we analyzed the effect on the FGFR3 Y375C clone. Using trend analysis, there was a significant reduction of FGFR3-mutant cells observed across the three conditions, abemaciclib + alpelisib vs. alpelisib alone vs. DMSO (74% vs. 85% vs. 92%, trend test p<0.0001), suggesting in vitro efficacy of alpelisib alone and significant synergism with the addition of abemaciclib. Conclusions: This study established the feasibility of using scDNA-seq as a promising tool to study the clonal evolution patterns in patient-derived UC organoids. Combined pharmacologic inhibition of CDK4/6 and PIK3CA showed more in vitro sensitivity than PIK3CA inhibition alone.
Characterization of microsatellite instability (dMMR/MSI-H) and mutational landscape in a large contemporary cohort of upper tract urothelial cancer (UTUC) patients.
Authors: Rao Arpit , McGrath Julie Elaine , Xiu Joanne , De Souza Andre Luiz , Gulati Shuchi , Abuali Inas , Sagaram Smitha , Nabhan Chadi , Korn W. Michael , Ryan Charles J. , Heath Elisabeth I. 
Published: March 2021

465 Background: UTUC is a rare genitourinary malignancy and a number of studies, limited by small sample sizes, have attempted to characterize its mutational landscape. Because immunotherapy is commonly used for this disease type, we evaluated the prevalence of microsatellite instability and characterized the mutational landscapes of UTUC in a large contemporary patient cohort. Methods: UTUC tumor samples were analyzed using next generation sequencing (NGS) (NextSeq, 592 gene panel) or whole exome sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Mismatch repair status (deficient [dMMR] or proficient [pMMR]) and microsatellite instability status (MSI-high or stable [MSS]) were detected by immunohistochemistry (IHC), fragment analysis, and NGS. Tumor mutational burden (TMB) was measured by counting all somatic mutations found per tumor (high cutoff ≥ 10 mutations per MB). PD-L1 expression was tested by IHC using PD-L1 antibody clones 22c3 (Agilent; positive cutoff CPS ≥ 10) and SP142 (Ventana; positive cutoff ≥ 5% IC). Pathogenic fusion events were detected using whole transcriptome sequencing (NovaSeq). Statistical significance was determined using the Chi-square test and adjusted for multiple comparison. Results: 538 patients with included – median (range) age 71.5 (30-89) years and 37.5% female/62.5% male. Prevalence of dMMR/MSI-H was 3.9% (21/538) and TMB-high was 22.7% (96/423). Significant molecular differences were not detected in primary vs metastatic disease or in male vs female cases. dMMR/MSI-H tumors had higher frequency of TMB-high compared to MSS tumors (100% vs. 19%, p = 0.00003). dMMR/MSI-H tumors also had a higher frequency than MSS tumors for mutations in genes involved in chromatin remodeling (ASXL 82.4%, CREBBP 60%, SMARCA4 40%, KMT2D 95%, ARIDIA 100%, KMT2A 20%, KMT2C 35.3%, NSD1 20%), DNA-damage repair (FANCG 10%, ATM 45%, ATRX 40%) and other biological pathways (RNF43 10%, PTCH1 21.4%, ERBB3 30%, CDKN2A 25%, TSC2 15%, FLNC 15%, HNF1A 20%, CIC 15%, DNMT3A 17.6%); all adjusted p < 0.05. Pathogenic fusions were detected in 3.8% (17/443) cases, with FGFR3 fusion being the most common, occurring in 2.7% (12/443) cases. PD-L1 positivity was identified in 33.2% (133/400) cases tested by 22c3 antibody and 28.4% (89/313) cases tested by SP142 antibody. No difference was seen in PD-L1 positivity between MSI-H/dMMR vs. MSS tumors. Conclusions: In the largest analysis to date, we found a 3.9% prevalence of dMMR/MSI-high rate in UTUC. All dMMR/MSI-H tumors displayed TMB-high. PD-L1 positivity was comparable between dMMR/MSI-H and MSS tumors. dMMR/MSI-H tumors had a significantly higher rate of mutations in genes involved in chromatin remodeling and DDR biological pathways. These results could inform design of targeted therapy trials in UTUC.
Impact of FGFR2/3 activating genomic alterations on response to enfortumab vedotin in metastatic urothelial carcinoma (mUC).
Authors: Adib Elio , Jain Rohit K. , Skelton William Paul , Freeman Dory , Curran Catherine , Akl Elie W. , Nassar Amin , Ravi Praful , Mantia Charlene , Merchan Jaime R. , Tan Winston , Plastini Trisha M. , Choueiri Toni K. , Sonpavde Guru 
Published: March 2021

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.
Prognostic impact of serum cytokeratin 19 fragments in patient with metastatic urothelial cancer (mUC) treated with first-line chemotherapy.
Authors: Endo Yuki , Kimura Go , Akatsuka Jun , Yanagi Masato , Mikami Hikaru , Takeda Hayato , Hasegawa Hiroya , Toyama Yuka , Ikuma Shunsuke , Nishikawa Yoshihiro , Takasaki Suisen , Hayashi Tatsuro , Kondo Yukihiro 
Published: March 2021

473 Background: Even today, when several immune checkpoint Inhibitors have been approved for the treatment of metastatic urothelial cancer (mUC), cytotoxic chemotherapy (CTC) still remains the mainstay for first-line treatment. We believe that the prognostic factors for the first-line CTC have become more important again and need to be re-analyzed. Current guidelines do not yet provide recommendations for any serum tumor markers in patients with mUC. Previous studies have shown that serum cytokeratin 19 fragments levels (sCK) were correlated with depth of tumor invasion and metastatic burden in patients with bladder cancer. In this study we evaluated whether sCK, and other clinical parameters could predict overall survival (OS) in patients with mUC treated with CTC. Methods: Two hundreds fifty two patients with mUC received CTC from December 2006 to 2016 at our institution. sCK had been measured in 128 patients at diagnosis of mUC. OS rate were analyzed by Kaplan–Meier curves and log–rank test. Multivariate analysis was carried out using the Cox hazards model. Tumor burden (TB) was measured based on Response Evaluation Criteria In Solid Tumor (version 1.1). Results: Of 128 patients, with median age of 72 (44-93), 36 (28%) had lung metastasis, 11 (9%) had bone metastasis, 10 (8%) had liver metastasis (LM). Ninety five (74%) patients received platinum based chemotherapy as a first-line treatment. During the median follow-up period of 19 (1-89) months, 72 patients (70%) had died. A 1-year (1y) OS was 51% and a 2y-OS was 36%. On univariate analysis, performance status (PS) (HR2.0, p<0.005), sCK (HR3.9, p<0.001), CRP (HR4.0, p<0.001), neutrophil-lymphocyte ratio (HR1.9, p<0.049), LM (HR2.0, p=0.042) and TB (HR2.4, p<0.001) were the significant prognostic factors for OS. On multivariate analysis, PS (HR2.0, 95%CI (1.05-3.85) p=0.036 ), sCK (HR3.1, 95%CI (1.3-8.3), p=0.011), and LM (HR3.0, 95%CI (1.06-6.98), p=0.022) were the independent prognostic factors for OS. Based on these 3 factors we divided patients into three groups, good risk (G, 0 factor), intermediate risk (I, 1 factor) and poor risk (P, 2-3 factors). There was a significant difference between the three groups. (G vs I: p<0.001, I vs P: p=0.001). Conclusions: PS, sCK, and LM were the independent prognostic factors for OS in patients with mUC receiving CTC. For the patients in good or intermediate risk with this score, early exposure of ICIs should be performed after CTCs. Treatment strategy should be changed in patients with poor risk since CTC is primary refractory in such population.