bluuebunny/crossref_metadata_2025_split huggingface dataset:
TSC1-mutant bladder cancer expression signature in relation to nuclear localization of TFE3 and potential for targetable dependency.
Authors: Probst Clemens Kemena , Adib Elio , Losko Magdalena , Du Heng , Hirsch Michelle S. , Giannikou Krinio , Kwiatkowski David J. 
Published: June 2022

e16532 Background: Mutation and inactivation of the tumor suppressor gene TSC1 is a recurrent (6-10%) event in bladder cancer, but whether it functions as a driver event for tumor development has been uncertain. Methods: We performed differential gene expression and pathway analyses using RNA-seq data from the curated TCGA TSC1 mutant BLCA (n = 26) and TSC1 wild-type BLCA (n = 382) cohort and compared to an internal cohort of putative TSC1/TSC2-driven tumors (n = 63). Mechanistic studies, as well as RNA-seq and H3K27ac ChIP-seq analyses, were conducted in 2 TSC1 mutant/WT BLCA cell lines. Results: Comparison of The Cancer Genome Atlas (TCGA) TSC1-mutant bladder cancers ( TSC1mBLCA) with TCGA TSC1 wildtype tumors ( TSC1WTBLCA) identified a conserved TSC-associated expression signature, similar to ones seen in syndromic TSC tumors. GSEA and DESeq2 analyses implicated both mTORC1 hyperactivation, as well as activation of lysosomal pathways in TSC1mBLCA. We validated our findings by IHC analysis of a separate cohort of TSC1mBLCA (n = 5), compared to TSC1WTBLCA (n = 5). In addition, we found that TFE3, a transcriptional regulator of lysosomal gene expression, was relatively highly expressed in BLCA (compared to other MiT-TFE genes) and was localized to the nucleus in TSC1mBLCA but not in TSC1WTBLCA. Mechanistic studies of two TSC1mBLCA cell lines and their respective TSC1 addback derivatives, recapitulated the phenotype found in human tumors and demonstrated that TFE3 was both post-translationally modified and predominantly nuclear in TSC1-null cell lines compared to TSC1 addbacks. RNA-seq and H3K27ac ChIP-Seq analyses showed that TSC1mBLCA cell lines retained elements of the TSC-associated expression signature that was seen in TSC1mBLCA tumors, confirming differential activation of TFE3 in response to TSC1 loss. Nuclear localization of TFE3 in TSC1mBLCA cell lines was only partially reversed by rapamycin treatment and was unaffected by treatment of Torin1. SiRNA mediated knockdown of TFE3 significantly decreased cell growth and viability in TSC1mBLCA cell lines and did not result in compensatory upregulation of TFEB and MITF. Conclusions: Our findings indicate that TSC1 mutant bladder tumors retain elements of a conserved transcriptional signature that is characterized by nuclear localization and activation of TFE3. Aberrant TFE3 activation likely contributes to TSC1mBLCA development and may therefore be amenable to targeted therapy.
Five-year survival stratification using “the Cancer Of the Bladder Risk Assessment” (COBRA) score for micropapillary and sarcomatoid urothelial carcinoma of the bladder variants.
Authors: Rivera Carlos , Jabbal Iktej Singh , Yaghi Marita , Saravia Diana , Muruve Nicolas , Ercole Barbara , George Tiffany L. , Nahleh Zeina A. , Arteta-Bulos Rafael Eduardo 
Published: June 2022

e16534 Background: The Cancer of the Bladder Risk Assessment (COBRA) score is a validated risk stratification tool for patients with urothelial carcinoma of the bladder (UCB) after cystectomy. Radical cystectomy with or without neoadjuvant chemotherapy is the standard of care for patients with muscle-invasive bladder cancer (MIBC). Lymph node density and the presence of positive lymph nodes have been demonstrated to be critical prognostic tools. Our goal was to evaluate 5-year overall survival (OS) on UCB variants: micropapillary and sarcomatoid, stratified by COBRA score and the presence of lymph nodes. Methods: We sampled the National Cancer Database (NCDB) for bladder cancer patients diagnosed with de novo micropapillary and sarcomatoid UCB between 2004 and 2018 and treated with radical cystectomy. 5-year Kaplan-Meier survival plots were utilized to assess OS differences amongst different COBRA score groups and stratified by the presence of lymph nodes (LNs). A multivariable Cox regression model was used to compare hazard ratios, adjusting for significantly unbalanced factors. A p-value < 0.05 was considered statistically significant. Results: A total of 1382 patients met the inclusion criteria. The average age was 68.10 + 10.31 years. 75% were male. Micropapillary represented 50.1% of selected histologies, followed by 49.5% sarcomatoid. For all combined histologies, 5-year OS percentage for patients with cystectomy and stratified by COBRA score (0-7) were 66% COBRA 0, 54% COBRA 1, 34% COBRA 2, 29% COBRA3, 15% COBRA > 4) (p < 0.001). 5-year OS for patients with cystectomy stratified by LN status was 54% for LN negative and 24% for LN positive (p < 0.001). Substratification of the cohort according to the presence of LNs and COBRA score have shown a numerical drop in 5-year survival and a notable decrease in median survival amongst compared groups. The risk of death was almost 5 times higher in patients with a high COBRA score (> 4) than in patients with a COBRA score of 0 (HR = 5.15, p < 0.001). Conclusions: COBRA score could contribute to clinical decision-making as a risk stratification tool for patients with UCB variants, micropapillary and sarcomatoid. 5-year OS decreases with higher COBRA scores, and LN status plays a major role in 5-year OS for these two UCB variants.[Table: see text]
Impact of PD-L1 expression on conventional urothelial bladder carcinoma (UCB) genomic alteration (GA) profile.
Authors: Necchi Andrea , Grivas Petros , Spiess Philippe E. , Bratslavsky Gennady , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Graf Ryon , Danziger Natalie , Ross Jeffrey S. 
Published: June 2022

e16535 Background: Immunohistochemistry (IHC) to determine PD-L1 expression level has been used as a biomarker to predict immune checkpoint inhibitors response in UCB. We hypothesized that the GA profiles would differ between UCB featuring high vs negative PD-L1 expression. Methods: 102 cases of advanced UCB with known PD-L1 tumor cell expression underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alteration (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Tumor cell (TC) PD-L1 expression was determined by IHC (Dako 22C3). Only PD-L1 high (H) (≥50% TC expression) and negative (N) (0% TC expression) cases were included in this study. Results: Overall, only 2 (8.3%) of the 24 PD-L1H UCB featured CD274 ( PD-L1) amplification (mean 19 copies) and none of 78 PD-L1N had CD274 amplification (P = .05). The gender, age and GA per tumor frequencies were similar in the groups. When compared with the PD-L1H UBC cases, FGFR3 GA were significantly more frequent in the UBC PD-L1N cases (p = .02). Currently “untargetable” GA that were more frequent in the PD-L1H UBC, but did not reach significance, included TP53, TERT and RB1. MTAP loss, a potential target for PRMT5 and MTA2 inhibitors, were 3X more frequent in the PD-L1N UBC. ERBB2 amplification and ERBB3 and PIK3CA short variant (SV) GA were more frequent in the PD-L1N UBC with differences not reaching significance. The mean gLOH scores were similar in both groups. Other ICPI-associated potential biomarkers, including MSI status, TMB level and GA in PBRM1, STK11 and MDM2 were not significantly different in the groups. For UCB cases where a mutational signature could be determined, 15/33 (45%) of PD-L1H and 34/112 (30%, p = 0.14) of PD-L1N UCB featured an APOBEC gene signature; 79% of PD-L1H and 83% of PD-L1N featured European ancestry (p = 0.61). Conclusions: PD-L1H and PD-L1N subtypes of UCB differ in their genomic profiles. PD-L1N UCB features greater frequencies of potentially “targetable” GA, including FGFR3, ERBB2, ERBB3 and PIK3CA. PD-L1 IHC may thus not only play a role in the selection of ICPI for advanced UCB but also in designing trials that may combine ICPI with targeted therapies.[Table: see text]
Time-of-day infusion of immunotherapy in metastatic urothelial cancer (mUC): Should it be considered to improve survival outcomes?
Authors: Ortego Ignacio , Molina-Cerrillo Javier , Pinto Alvaro , Santoni Matteo , Alonso-Gordoa Teresa , Lopez Criado M. Pilar , Gonzalez-Morales Alejandro , Grande Enrique 
Published: June 2022

e16541 Background: Immune-checkpoint inhibitors (ICIs) are key in the current management of mUC pts. Recent data in melanoma revealed a link in between the circadian rhythm of the immune-system and expected activity with ICIs (Quian et al, Lancet Oncol 2021). In preclinical models naïve CD4 and CD8 T cells in blood have shown to approach nadir levels around 4 P.M., and therefore, to lower adaptative immune responses after that time. We aimed to correlate the activity of single agent ICIs for the systemic treatment of mUC pts depending on the time of administration. Methods: This is a multicenter and retrospective study performed in 3 academic institutions in Spain and 1 in Italy of patients with mUC who initiated treatment with anti-PD1 or anti-PDL1 as 1st or subsequent line. ICIs were administered and managed according to product labelling. Time cut-off as adaptive immune-modulation for ICIs administration was considered after 4:30 PM. We divided pts into those who received at least 20% of their infusions after 4:30 PM and those who received fewer than 20% after that time. Other data such as patient characteristics and adverse-events related to the treatment were also collected. We carried out a survival analysis by a Cox regression model. Results: From 2016, 92 pts were treated with single agent ICIs for mUC. Most of the pts (n = 62; 67.4%) received less than 20% of the doses after 4:30 PM, while a lower proportion (n = 26; 28.3%) received at least 20% of the doses after that time. Median follow-up time of immunotherapy was 8.6 months. 35 (38.0%) and 57 (62.0%) pts received ICIs as 1st and subsequent lines of treatment respectively. There were no differences in the proportion of pts in 1st vs subsequent lines and time of administration, nor other well prognostic baseline factors like PD-L1 expression, or Bajorin or Bellmunt’s scoring. A significant benefit in both PFS (11.38 vs 3.58 months; HR 2.66: 95%CI 1.53-4.63; p = 0.001) and in OS (14.04 vs 6.80 months; HR 2.62: 95%CI 1.48-4.63: p = 0.001) benefited to pts who received less than 20% of the doses after 4:30 PM. Response rate also favored (59.3% vs 16.0%) the earlier administration of the treatments. Neither corticosteroids concomitant use nor immune-related toxicity appeared to impact on these outcomes. Conclusions: Time of the day administration of ICIs may influence the efficacy of ICIs in mUC pts. Although the small size of the sample and the short median follow-up is something to be considered, this data are promising and consistent with the previous studies. Prospective confirmation is needed.
Competing endogenous RNA network features and prostate tumor cell sensitivity to radiotherapy.
Authors: Kutilin Denis S. , Zinkovich Mikhail S. , Gusareva Marina A. , Shevchenko Aleksey N. , Faenson Aleksandr V. , Solntseva Anna A. , Fatkina Natalya B. , Vasilieva Ekaterina O. , Filatova Elena V. , Kosheleva Natalia G , Tolmacheva Ekaterina A. , Martynova Ksenia V. , Gappoeva Madina A. , Udalenkova Irina A. , Khomutenko Irina A. , Rozenko Lyudmila Ya , Pavlyatenko Inna V. , Gvaramiya Astanda K. , Kit Oleg I. 
Published: June 2022

e17008 Background: Radiotherapy (RT) is one of the main treatments for prostate cancer (PC). The effectiveness of RT depends on the initial radioresistance of tumor cells provided by their certain molecular features - the transcriptional activity of genes, miRNAs and long non-coding RNAs (lncRNAs). Together, these indicators form a competing endogenous RNAs network (ceRNAs). The aim of this work was to study the ceRNA features in PC patients with different responses to RT. Methods: The study included 400 patients with PC, 90 of them developed biochemical recurrence after RT (Novalis TX, TFD = 75 Gy). Tumor tissue samples were obtained by biopsy. The RNA fraction was isolated and purified using the RNeasy Plus Universal Kits. Bioinformatic search for miRNAs was performed using a modified TarPmiR algorithm. The miRNA-lncRNA interactions were assessed by bioinformatics. Expression of AKT, ATM, BRIP, BRCA1/2, CDK1, CDKN1B, CCND1/3, EXO1, H2AX, KU70, PTEN, RAD50, RAP80, RIF1, RNF168, TOPB1, TP53, XRCC4, BAX, CASP-8, -3, -9, MDM2, BCL2, RBBP8, EP300 genes, miRNA and lncRNA were determined by RT-qPCR. Differences were assessed using the Mann-Whitney test (Bonferroni correction was used). Results: The expression of CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50 genes in tumor tissues of patients with biochemical recurrence (group 1) was higher (p < 0.005) and the expression of TP53 and BCL2 was lower than the values in tumor tissues in patients without recurrence (group 2). Bioinformatic search for miRNAs targeting the CDK1, CDKN1B, RBBP8, XRCC4, BRCA2, RAD50, TP53 and BCL2 revealed 1725 miRNAs, 78 of which were validated (miRDB) and had a minimum free energy of miRNA-mRNA interaction. Patients in group 1 showed differential expression of miRNAs targeting genes BCL2 (increased miR-139-5p, miR-4446-5p, miR-211-5p); CDK1 (decreased miR-330-3p, miR-5580-3p, miR-429), CDKN1B (decreased miR-6841-3p); RAD50 (decreased miR-433-3p, miR-3691-5p); RBBP8 (decreased miR-130b-3p); TP53 (increased miR-6884-5p, miR-149-3p, miR-6860, miR-4728-5p, let-7b-5p); XRCC4 (decreased miR-4489) and BRCA2 (decreased miR-7151-3p). The interaction of these miRNAs with 160 lncRNAs was mathematically predicted. Patients in group 1 demonstrated increased expression of lncRNAs LINC00641, SCAMP1, MALAT1, MATN1-AS1 (miR-429) , LINC00657 and GAS5 (miR-433-3p), CCAT1 (miR-130b-3p) and reduced expression of S NHG3, DHRS4-AS1 (miR-139-5p) and MAL2 (let-7b-5p). Conclusions: Our study of the ceRNA network features and RT effectiveness for PC established the mechanisms of radioresistance development and its predictors.
Early metabolic syndrome in testicular germ cell tumors : A prospective study from India.
Authors: Pandey Prashant , Dabkara Deepak , Ganguly Sandip , Ghosh Joydeep , Roy Somnath , Mondal Debapriya , Gupta Sujoy , Nair Reena , Biswas Bivas 
Published: June 2022

e17010 Background: Metabolic syndrome (MS) is a known complication in patients of testicular germ cell tumors . Early metabolic syndrome is not well-defined and literature on the same is scarce. Methods: This is a single institutional prospective cohort study of patients with testicular germ cell tumors from Jan’2020 to June 2021 with a minimum follow-up of 6 months after treatment completion. Patients were evaluated for MS as per NCEP ATP (National Cholesterol Education Program Adult Treatment Plan) III criteria and partial MS was defined if any one abnormal criteria was present. Clinicopathologic and treatment characteristics were correlated with development of MS. Results: Thirty-six (25 nonseminomatous tumor and 11 seminoma) were included with median age of 29 yrs (range: 18-44). Treatment protocol was - platinum based chemotherapy [BEP (n = 7), EP(n = 18),VIP(n = 4) ]in 81% (n = 29/36), single agent carboplatin in 8% (n = 3/36), and surveillance only in 11% (n = 4/36) patients. Incidence of complete metabolic syndrome noted in 42% (n = 15) and partial metabolic syndrome in 36% (n = 13) of patients after median follow-up of 13.2 months (range-6-22). Deranged parameters detected were - high serum triglyceride (≥150 mg/dl) in 64% (n = 23/36), low serum HDL cholesterol (< 40 mg/dl) in 53% (n = 19/36), high blood pressure (≥130/85 mm of Hg) in 47% (n = 17/36), high waist circumference (> 110 cm) in 6% (n = 2/36) and high fasting plasma glucose (≥5.6 mmol/L) in 22% (n = 8/36) of patients. Median weight gain was 5 Kg (range: 2-14). The median time to development of metabolic syndrome was 143 days (range: 90-461). Hypogonadism (testosterone < 433ng/dl.) showed positive correlation (degree of freedom = 0.3143) and C-reactive protein showed negative correlation (degree of freedom -0.3090) with MS, respectively. Conclusions: Majority of Testicular germ cell tumor patients (n = 28, 78%) had features of early MS, irrespective of treatment modalities. Patients with hypogonadism are more likely to develop early MS. Larger prospective studies are warranted to assess the incidence of early MS in patients with testicular germ cell tumors and to formulate appropriate health intervention to mitigate its significant long-term effects on mortality and morbidity.
What is the impact of ischemic heart disease on PSA testing?
Authors: Panzone John , Welch Christopher , Wu Maximillian S , Jacob Joseph M , Shapiro Oleg , Basnet Alina , Bratslavsky Gennady , Goldberg Hanan 
Published: June 2022

e17014 Background: Prostate Specific Antigen (PSA) testing can improve early prostate cancer detection. However, numerous factors can influence patients’ willingness and ability to undergo PSA testing. Methods: We performed a cross-sectional study investigating the impact of various degrees of ischemic heart disease (IHD) on PSA testing. We assessed 3,822 male respondents aged 55-75 from the 2018 year of the National Health Interview Survey (NHIS). Men were stratified according to the degree of IHD (none, history of angina pectoris (AP), history of myocardial infarction (MI), or history of neither, but with a diagnosis of IHD). Multivariable logistic regression analysis was used to assess the relationship between IHD and being tested for PSA, adjusting for known cofounders. Results: Multivariable logistic regression demonstrated that males with a history of IHD (no MI or AP) were more likely to have ever been PSA tested than males without IHD (p = 0.012, OR = 1.630, 95% CI 1.115-2.383), as seen in Table. Additionally, older age (p < 0.001), having a partner (vs. no partner p < 0.001), homosexual sexual orientation (vs. heterosexual orientation p = 0.007), and a history of cancer (vs. no history p < 0.001) all increased likelihood of being PSA tested. In contrast, Asian race (vs. White, p = 0.001), and being a current smoker (vs. no smoking history, p < 0.001) decreased the likelihood. Interestingly, males with a history of a symptomatic IHD (MI or AP) were not shown to be more likely to undergo PSA testing. Conclusions: Our results suggest that males with non-symptomatic IHD are more likely to be PSA tested. Males with symptomatic IHD do not seem to undergo more PSA screening, perhaps due to lower suggested life expectancy. Awareness of discrepancies in PSA testing in men with IHD should be raised. Table - Multivariable logistic regression analyses demonstrating relationships with likelihood of being PSA tested.[Table: see text]
Predictive significance of tumor-associated miRNA-21 and -221 expression in patients with prostate cancer.
Authors: Tryfonyuk Liliya , Borikun Tetiana , Zadvornyi Taras , Rossylna Olha , Pavlukovich Natalia 
Published: June 2022

e17015 Background: It is thought that the occurrence and progression of tumors, such as prostate cancer (PCа), may be due to decreased levels of tumor-inhibiting microRNAs and/or overexpression of oncogenic microRNAs, but their specificity and role in tumor progression are contradictory. That is why the study of the possibility of using miRNAs as prognostic markers is especially relevant. Objective: to investigate the features of tumor -associated microRNAs-21 and -221 expression in PCa tissue with different risk of progression and to determine the relationship of their indicators with the molecular profile of tumors. Methods: The study was conducted on the clinical material of 60 patients with PCa stage II-III, who were treated in Rivne Regional Hospital and Rivne oncological center during 2018-2021 years. Determination of the risk of PCa progression was performed by D'Amico et al. (1998). Immunohistochemical study of Ki-67 expression (clone MIB -1) and androgen receptors (AR) (clone 441) were performed on paraffin sections of tumor tissue using the Ultra Vision LP Detection System (Thermo Scientific, USA). Determination of microRNA-21 and -221 levels were determined using real-time quantitative PCR. Statistical processing of the results was performed using GraphPad Prism 8. Results: It is determined that a characteristic feature of PCa with a low risk of progression by D'Amico et al . are low expression of oncogenic miRNA-21 and -221 in tumor tissue. In particular, in the PCa samples of high risk of progression (n = 30) the level of miRNA-21 was 3.2 times (p < 0.05), and miRNA-221 was 1.35 times (p < 0.05) higher compared to tumor tissue of patients with low progression (n = 30). The existence of a direct correlation between the expression of miRNA-21 and the proliferative activity of PCa (ρ = 0.63; p < 0.05) is shown. We found that the expression of miRNA-221 is associated with a high level of AR expression (ρ = 0.43; p < 0.05) . Conclusions: The obtained data indicate the relationship of tumor -associated microRNA-21 and -221 with the risk of tumor progression and such molecular biological characteristics of tumors as proliferative activity and receptor status, which indicates the prospects for their further study as additional markers for predicting of PCa course.
Real-world treatment patterns in the U.S. and trends pre-post CARD trial among patients with metastatic castration-resistant prostate cancer.
Authors: Ghantoji Shashank , Yu Channing , Sawhney Amrita , Byrne Clare , Tang Jackson , Runeckles Kyle , Patel Jeetvan 
Published: June 2022

e17024 Background: Numerous treatments with different mechanisms of action are approved for metastatic castration-resistant prostate cancer (mCRPC). The sequencing for management of these patients has been evolving post availability of trials such as the CARD trial, looking at clinical outcomes post androgen receptor pathway inhibitor (ARPI) and docetaxel. This study examined real-world treatment patterns and sequencing among United States patients with mCRPC. Methods: This retrospective cohort study used Flatiron Health electronic health record data from Jan 1, 2013 to June 30, 2020 (study period). Included patients were male aged ≥18 years, had a confirmed diagnosis of mCRPC within the study period, and received ≥1 systemic therapy post-mCRPC diagnosis. Index date was the date of first-line (1L) therapy initiation post-mCRPC diagnosis. Patient characteristics and treatment patterns were evaluated descriptively. Across analyses, treatments were grouped as follows: ARPI (abiraterone, enzalutamide), taxane (docetaxel, cabazitaxel), sipuleucel-T, radium-223, targeted therapy (TT; olaparib, rucaparib), mitoxantrone, combo therapy (any combination regimen containing ≥1 of the preceding therapies), and other (any other therapy or combination of therapies). Results: 2,588 patients were included in the study; mean±SD age was 72±8 years and 66% were White. The most common 1L therapy was ARPI (63%), followed by taxane (11%), combo therapy (11%), radium-223 (6%), sipuleucel-T (6%), and other therapy (2%). No patient received TT or mitoxantrone alone in 1L. Median time to next treatment post-1L was longest for combo therapy (8.1 months) and ARPI (7.6 months) and shortest for sipuleucel-T (3.4 months). The most common sequence of treatment for mCRPC patients was 1L ARPI to another ARPI at second-line (2L) (29%); taxane and combo therapy (both 14%) were the next most common (Table). Treatment patterns were similar pre- and post- read-out of the CARD trial. Conclusions: The majority of mCRPC patients who receive 1L ARPI will receive another at 2L rather than switching to an alternative type of treatment.[Table: see text]