bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.
Authors: Lyou Yung , Dorff Tanya B. , Pal Sumanta K. , Yuan Yate-Ching 
Published: March 2021

474 Background: Advanced/metastatic urothelial carcinoma (UC) is a significant public health burden with median overall survival of 15 months. Although, immune checkpoint inhibitors (ICI) have provided an additional second line treatment option, only 15-40% of patients will respond. There has been much effort in determining the mechanisms of immunotherapy resistance and predictive biomarkers to further improve these treatments. Methods: Pre-treatment genomic sequencing data derived from FFPE samples from the IMVIGOR210 clinical trial (n=298) was accessed for analysis. Briefly it was a single arm phase II clinical trial where advanced/metastatic UC patients refractory to platinum chemotherapy treatment received the ICI atezolizumab. This study has been published with detailed methods (PMID: 28950298). The raw sequencing data was pre-processed using standard QC measures and aligned to the human reference genome (hg38). The resulting outputs were then normalized and processed to generate the gene level counts for differential gene expression (DGE). We did DGE analysis comparing patients who had clinical benefit (CR, PR, SD) vs non-clinical benefit (ie. PD) to atezolizumab. The list of differentially expressed genes were then analyzed using various gene ontology, pathway and systems biology tools (IPA, Enrichr, and X2Kweb). Further subset analysis was done using gene-gene correlations (ie. PD-L1 and STAT3) and clinicopathologic features (eg. gender, race, smoking history). Results: Among the 298 patients in this study, there were 25 with CR, 43 with PR, 63 with SD, and 167 with PD based on clinical response to atezolizumab. Subgroup analysis for CR vs PD patients found that approximately 847 genes were differentially expressed with statistical significance (p ≤ 0.05). IPA analysis for this list of differentially expressed genes found among the top signaling pathways were “primary immunodeficiency” and “sirtuin signaling”. Further subset analysis of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb found that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x104). Conclusions: Our results found that when the transcriptional profiles of CR vs PD there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways. Of note it has been reported that STAT3 signaling can modulate immune activity and its expression is correlated with poor prognosis in urothelial carcinoma patients. These results warrant a larger study to see if STAT3 signaling is a potential biomarker for ICI resistance. If validated this may indicate that the STAT3 pathway is a potential therapeutic target to overcome ICI resistance and improve the efficacy of these agents.
TERT promoter mutation as a prognostic marker in patients with advanced urothelial carcinoma treated with immune checkpoint inhibitors.
Authors: de Kouchkovsky Ivan , Zhang Li , Philip Errol , Wright Francis , Kim Daniel Myung , Natesan Divya , Kwon Daniel , Ho Hansen , Ho Son , Chan Emily , Porten Sima P. , Desai Arpita , Huang Franklin W. , Chou Jonathan , Oh David Yoonsuk , Pruthi Raj , Fong Lawrence , Small Eric Jay , Friedlander Terence W. , Koshkin Vadim S 
Published: March 2021

476 Background: Reliable predictive markers are lacking in patients (pts) with locally advanced or metastatic urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICI). We sought to determine whether specific genomic alterations could be used to predict overall survival (OS) in this patient population. Methods: We undertook a retrospective cohort study of pts with aUC who received ICI and underwent genomic profiling by next-generation sequencing (NGS). All patients underwent NGS using commercially available platforms (e.g. Foundation Medicine, Strata, Invitae), or testing on the CLIA-certified institutional panel UCSF500. Associations between the 20 most frequently altered genes and OS were first examined by Cox regression. Genes with a p <0.1 on univariate analysis and relevant clinical variables were then included in a multivariable analysis. Results: We identified 78 pts treated with ICI for aUC with available genomic profiling results. Median age at ICI initiation was 71; the majority of patients had visceral metastases (70.5%), ECOG performance status ≤1 (62.8%) and received ICI in the post-platinum setting (52.6%). Objective response rate in this cohort was 35.9%, median progression free survival was 4.0 months (95% CI 2.6-10.5) and median OS was 17.5 months (95% CI 14.1-NR) from ICI start. The most commonly altered genes were the TERT promoter (TERTp) (61%), TP53 (52%), RB1 (31%), CDKN2A(29%) and CDKN2B (27%). On univariable analysis there was a trend towards longer OS in pts with TERTp mutations (HR 0.53, 95% CI 0.27-1.06, p = 0.07), and shorter OS in pts with CDKN2B mutations (HR 1.91, 95% CI 0.98-3.73, p = 0.06). Both mutations were included in a multivariable analysis. After adjusting for known prognostic variables (ECOG PS, visceral metastases, albumin, hemoglobin, body mass index [BMI], neutrophil to lymphocyte ratio [NLR], and histology), the presence of a TERTp mutation was significantly associated with improved OS (HR 0.30, 95% CI 0.10-0.93, p = 0.04; Table). Conclusions: The presence of a TERTp mutation was an independent predictor of improved OS in a cohort of aUC pts treated with ICI. Other common mutations and clinical variables were not associated with OS on a multivariable analysis. These findings are hypothesis-generating and prospective validation is needed. [Table: see text]
RNA-seq analysis of non-muscular invasive bladder cancer to reveal different gene expression profiles between smoking and non-smoking patients.
Authors: Fu Zhichao , Liu Shenghua , Wang Jianfei , He Ning , Yang Yadong , Xu Tianyuan , Anil Shrestha , Yan Yang , Li Cheng , Zheng Zongtai , Li Xin , Yao Xudong 
Published: March 2021

478 Background: Bladder cancer is the ninth most common malignancy in the world, approximately 75% of patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). Smoking has been established to be a carcinogenic risk factor of bladder cancer. Nevertheless, the detailed relationship between smoking and progression of NMIBC are poorly understood. In this study, we revealed high expressed genes in smoking patients were significantly related to tumor progression in NMIBC patients. Methods: A total of 54 NMIBC patients including 19 never smokers and 35 smokers (current smokers and previous smokers) were enrolled in this study.The gene expression profiles were obtained by RNA-seq and the differentially expressed genes between smoking and non-smoking patients were identified using DESeq2 .The further analysis of the association between genes expression and patient survival in NMIBC cohorts(Jakob et al., 2016)and IMvigor 210 cohorts(Jonathan et al., 2016)by Kaplan-Meier survival estimate. Results: We identified 46 differentially expressed genes (p<0.05) in smoking and non-somking NMIBC patients. IDO1 and KRT14 gene, which related to bladder cancer progression and poor prognosis, was identified significantly higher expressed in somking group compared with non-smoking and they have a logFC of 2.6,3.9 with FDR 1.83E-5,3.40E-5 respectively. The expression of other genes, including KRT6A, CASP14, SERPINA1, MYO3A and IL20RB, were significantly higher in smoking patients compared to non-somking. Notably, survival data analysis from 476 NMIBC cohorts showed that IL20RB had a significant relationship with poor PFS(p = 0.021) and in the Mvigor 210 Cohort including 310 advanced or metastatic urothelial carcinoma patients treated with atezolizumab, we found that the high expression of IL20RB was significantly related to poor OS(p = 0.002). Conclusions: We identified 14 genes related to tumor progression were significantly higher in smoking NMIBC patients than in non-smoking. Among these genes, the expression of IL20RB was related to the poor prognosis of NMIBC, and it may correlates with reduced clinical benefit of immunotherapeutic in patients with urothelial carcinoma.
Characterization of FOXF1 as a novel regulator of nodal metastasis in bladder cancer.
Authors: Mitra Anirban P , Kokorovic Andrea , Miest Tanner , Narayan Vikram M , Sundi Debasish , Lim Amy , Mokkapati Sharada , Dinney Colin P.N. 
Published: March 2021

480 Background: Members of the forkhead transcription factor (FOX) family are important mediators of embryonic development and are known to be altered in a variety of cancers. The functional role of FOXF1 in bladder tumorigenesis and progression has not been clearly characterized thus far. This study investigated the clinical implications of differential FOXF1 expression in bladder cancer, and potential mechanisms by which its alteration can lead to tumor metastasis. Methods: Whole genome expression profiling was performed on paired primary tumors and nodal metastases from a radical cystectomy discovery cohort using Illumina HT12 v3-4 BeadChip arrays to identify FOXF1 as a top differentially expressed gene. Prognostic role of differential FOXF1 expression was validated on two independent cystectomy cohorts. Differential FOXF1 expression was also evaluated in murine orthotopic xenografts. Small interfering RNA was used to knock down FOXF1 in RT112 and UC6 bladder cancer cell lines to develop an in vitro model for assessment of metastatic potential. Next-generation sequencing and hierarchical clustering analysis were used to identify differentially altered genes secondary to FOXF1 knockdown. 186 biologically curated pathways were interrogated with internal validation to elucidate the downstream biologic mechanisms of metastasis. Results: In the discovery cohort, FOXF1 was a top differentially expressed gene with 3.6-fold lower expression in nodal metastases than paired primary tumors (n = 33, p < 0.001). Multivariable analyses in two validation cohorts (total n = 128) indicated that FOXF1 underexpression was associated with worse cancer-specific (p = 0.046) and overall survival (p = 0.006). Murine orthotopic xenografts (n = 13) established from human bladder cancer cell lines (UC3, UC6, UC14) showed FOXF1 underexpression in metastatic deposits compared with primary tumors (p = 0.004). Hierarchical clustering identified 40 differentially expressed genes between FOXF1-knockdown bladder cancer cell lines and their corresponding controls. Biological pathway interrogation showed differential enrichment for genes associated with mitogen-activated protein kinase signaling, focal adhesion and other carcinogenic pathways in FOXF1-knockdown cells compared with controls (normalized enrichment score ≥ 1.3). Conclusions: We identify and characterize FOXF1 as a novel regulatory molecule that potentially drives bladder cancer metastasis. This may be modulated through alterations in intracellular signaling and cellular adhesion. FOXF1 may serve as a prognostic biomarker that can identify patients at impending risk for metastasis who may benefit from more aggressive management.
Patient-centric care in bladder cancer: Virtual simulation to benefit clinical decision-making of oncologists.
Authors: Parikh Kinjal , Topping Donna L. , Dhoble Saee , Cohen Jacob , Kadkhoda Haleh , Kugel Patrick , Van Laar Emily Sherene 
Published: March 2021

492 Background: Immunotherapy (IO) utility in bladder cancer (UC) has expanded into multiple stages of disease. Employing IO optimally requires mastery of clinical trial data, patient eligibility criteria, and interpretation of biomarkers and determination of treatment sequencing. Given the nuanced therapeutic decision-making, education was developed in partnership between Medscape Oncology and Society for Immunotherapy of Cancer (SITC) to assist oncologists in improving their performance surrounding the management of patients with advanced UC. Methods: A virtual patient simulation (VPS) continuing medical education (CME)-certified activity depicting 2 advanced UC cases was made available to oncologist members of Medscape. The cases depicted 1) a patient with newly diagnosed metastatic UC with comorbidities and PDL1+ disease and 2) a patient with advanced UC progressing on platinum therapy with no actionable mutations. The VPS platform captures real-life decision making process of oncologists in an EHR-like format supported by an extensive database of diagnostic and treatment possibilities. Learners were able to interact with patients via video, order lab tests, assess patients, make diagnoses, and order treatments matching the scope and depth of actual practice. Tailored clinical guidance (CG) employing up-to-date evidence-based and faculty recommendations was provided after each decision point. Decisions were collected pre- and post-CG and analyzed using McNemar’s test to determine p-values. Data were collected from 4/28/20 to 7/13/20. Results: Analyses from oncologists (n = 51-66) found significant improvement in performance measured pre- to-post CG: Case 1: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 65% post; p < .001) Prescribing appropriate therapy based on patient- and disease-specific factors (38% pre; 77% post; p < .001) Providing appropriate counseling and follow-up for a patient receiving treatment (65% pre; 80% post; p < .01) Case 2: Ordering appropriate testing to determine patient eligibility for therapy (39% pre; 57% post; p < .01) Prescribing appropriate therapy based on patient- and disease-specific factors (25% pre; 41% post; p < .01) Providing appropriate counseling and follow-up for a patient receiving treatment (71% pre; 82% post; p < .05). Conclusions: This activity demonstrates the value of providing oncologists a simulation platform to practice and master clinical decision-making of the limitless possible diagnostic and therapeutic options in the management of advanced UC. Insights from rationales for each clinical decision point uncover continued gaps for oncologists on guideline recommendations, efficacy outcomes, or molecular implications. They also highlight barriers including limited experience or confidence with IO.
Tumor mutation burden and immune microenvironment analysis of urothelial carcinoma.
Authors: Jia Yuanyuan , He Ning , Yang Yadong , Huang Yuliang , Zhang Xiaoyu , Fu Zhichao , Xu Xiaohong , Cao Jianjun , Wang Jianfei 
Published: March 2021

494 Background: Tumor mutation burden (TMB) has been established as a biomarker for response to immune therapy and prognosis in various cancers. However, the correlation between TMB and immune microenvironment remains unwell studied, especially in urothelial carcinoma. This study was aimed to investigate the relationship between TMB and other immunotherapy related biomarkers, including genetic alterations, APOBEC signature, microsatellite instability (MSI), PD-L1 expression and immune cell infiltration in urothelial carcinoma. Methods: 131 patients with urothelial carcinoma admitted from October 2018 to May 2020 were included. Total DNA was isolated from FFPE or fresh tissues. Mutation profiles, APOBEC signature and MSI scores were obtained by next-generation sequencing based a 642 cancer genes panel assay. PD-L1 expression, CD8+ T-cells and tumor-infiltrating lymphocytes density were evaluated by immunohistochemistry. The correlation was analyzed by Wilcoxon signed-rank test. Results: The mutation landscape showed that TP53 mutation is the most common alterations (n = 64/131, 48.9%), followed by KMT2D alterations (n = 49/131, 37.4%), KDM6A mutations (n = 42/131, 32.1%), MUC17 mutations (n = 42/131, 32.1%). The median TMB was 5.06 Muts/Mb (0-118 Muts/Mb). 2 of 131 patients showed MSI-H, who exhibited a much higher TMB (41, 118 Muts/Mb). Further analysis showed that TMB in the patients with certain gene mutations (such as TP53, KMT2D, KDM6A and MUC17) was significantly higher than those wild type ones (p < 0.05). Meanwhile, the high APOBEC-enrichment group has a higher TMB than the low APOBEC-enrichment group (p = 0.045). Furthermore,we observed that the patients with a higher PD-L1 expression (n = 28/131, 21.4%, at a combined positive score cut-off value of 10) also showed a significantly higher TMB (p = 0.016), and TMB in the patients with higher density of CD8+ T-cells (n = 42/131, 32.1%, at a cut-off value of 5%) was also significantly higher than that of the group with lower density of CD8+ T-cells (p = 0.039). Conclusions: This study provides new insights into the correlation between the TMB and the immune microenvironment in urothelial carcinoma. The result may be a reference to immunotherapy.
The impact of adjuvant chemotherapy on oncologic outcomes of patients with locally advanced bladder adenocarcinoma: An analysis of the National Cancer Database.
Authors: Reddy Akshay G , Sparks Andrew D , Helbig Michael , Whalen Michael Joseph 
Published: March 2021

495 Background: The relatively poor prognosis associated with locally advanced bladder adenocarcinoma necessitates investigation of the utility of adjuvant chemotherapy (AC) and risk stratification of those who would benefit from such systemic therapy. This study seeks to evaluate the oncologic and surgical outcomes of those with locally advanced disease treated with and without AC. Methods: A retrospective cohort analysis was performed using the National Cancer Database from 2006 to 2016. Patients with non-metastatic locally advanced pT3-4 or pT(any)N1-3 primary bladder adenocarcinoma who received AC only or did not receive AC after radical (RC) or partial cystectomy (PC) were included. The AC cohort was further sub-stratified by surgery type (PC versus RC) and disease origin (urachal versus non-urachal subtypes). Survival, oncologic, and surgical outcomes were compared between cohorts. Results: Inclusion criteria identified 79 AC patients and 251 no AC patients. Of the 79 patients who received AC, 23 had PC procedure, 56 had RC procedure, 10 had urachal origin and 69 had non-urachal origin. Receipt of AC was significantly higher in RC relative to PC (27.6% vs 18.1%; p = 0.049). Urachal vs. non-urachal subtype did not impact receipt of AC (25.3% vs 17.5%; p = 0.214), but urachal subtype was associated with improved overall survival compared to non-urachal (47% vs 18%; HR = 0.37; p = 0.04). Although receipt of AC was significantly associated with higher odds of positive margins (46% vs 23%; odds ratio = 2.85; p < 0.01), no difference in overall survival was detected between the AC and no AC cohorts (23% vs 19%; hazards ratio [HR] = 0.98; p = 0.91). Of note, independent of AC, PC was associated with improved survival compared to RC (51% vs 12%; HR = 0.25; p < 0.01). Conclusions: There is no detected survival benefit to the use of a non-standardized AC regimen in locally advanced bladder adenocarcinoma. Within the AC treated population, survival outcomes suggest that urachal subtype may confer survival advantage and that those patients selected for PC tend to have improved survival. Although employing a national dataset, statistical power was limited given the rarity of this disease. Further investigation is warranted on a larger scale in order to assess the impact of AC regimen, afford proper patient selection, and enhance risk stratification for oncologic outcomes.
Cognitive status of prostate cancer (PCa) patients aged 60 years and older after a six-month gonadotropin-releasing hormone agonist (GnRHa) therapy, according to age groups: Secondary analysis of PRISME study.
Authors: Roupret Morgan , Rozet Francois , Hennequin Christophe , Pello Leprince Ringuet Nathalie , Grandoulier Anne-Sophie , Mongiat-Artus Pierre 
Published: March 2021

56 Background: Age is a risk factor for both PCa and cognitive impairment. Moreover, androgen deprivation therapy (ADT) is suspected to alter cognition, but little is known about the cognitive status of men starting ADT. Our purpose was to analyze cognitive status in 3 groups of age ([60-70[, [70-75[ and ≥ 75 years), before and after a 6-month GnRHa therapy. Methods: Between March 2018 and February 2020, a prospective, multicenter, longitudinal, non-interventional study was conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited patients aged 60 years and older, with PCa, initiating a GnRHa therapy. 1000 patients were planned to be included 1:2:1 in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). Cognitive status was evaluated through Mini Mental State Evaluation (MMSE) questionnaire (scores 0-30). Significant differences between groups were concluded in case of non-overlapping of the means 95% CIs, and significant changes in case of means 95% CIs not including 0. An analysis of covariance (ANCOVA) was performed to compare evolution of MMSE global score in subgroups of ages, adjusted on baseline scores (secondary effectiveness analysis). Post-hoc analyses of subgroups of level of education were also provided. Results: The final analysis included 652 patients (full analysis set population). Mean (±SD) age was 72.5±6.2 years. There were 193, 269 and 190 patients, in the [60-70[, [70-75[ and ≥75y age groups, respectively. 95.5% of patients had a Karnofsky score ≥ 80%; 71.6% had at least one comorbidity at baseline,65.0% were receiving at least one concomitant systemic treatment. Main reasons for GnRHa initiation were high risk PCa (65.3%), metastatic stage (18.4%), biochemical recurrence (13.3%). Mean [95% CI] baseline MMSE score was significantly lower in the ≥75y age group (26.2 [25.6-26.8]) than in the [60-70[ (27.9 [27.5-28.3]) and [70-75[ (27.6 [27.3-28.0]) age groups, with significantly more patients with cognitive impairment (MMSE < 26) in the ≥75y (30.9%) than in the [60-70[ (15.3%) and [70-75[ (14.7%) age groups. Baseline MMSE scores were significantly different between all level of education groups: 28.4 [28.0-28.7] in high, 27.2 [26.8-27.7] in middle and 24.7 [23.5-25.9] in low level groups. No significant changes in MMSE scores were observed after a 6-month GnRHa therapy inside age groups or inside level of education groups. Planned ANCOVA analyses found no statistically significant changes of MMSE global score from baseline between age groups. Conclusions: In this large observational cohort of PCa patients aged 60 years and older with prespecified age groups, cognitive status did not change after a 6-month GnRHa therapy, whatever the age group. Clinical trial information: NCT03516110.