bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular subtype variation within metastasis of urothelial carcinoma.
Authors: Kozubenko Alla , Arora Sonali , Montgomery Robert B. , Wright Jonathan L. , Lam Hung-Ming , Hsieh Andrew Caleb 
Published: March 2021

471 Background: Molecular subtyping of cancer based on gene expression is a new prognostic tool with potential to guide treatment in the future. Urothelial carcinoma is one such cancer for which numerous molecular subtyping systems have been developed, but the diversity of these systems has hindered their clinical application. Recently, a consensus classification system was derived from six independent systems, defining six molecular classes with distinct oncogenic mechanisms and mutations (Kamoun A, et al. 2020). Considering the high heterogeneity in urothelial carcinoma, we hypothesized that molecular subtype variation may occur between primary and metastatic samples. We further evaluated whether variation in subtype was associated with any unique patient characteristics. Methods: As part of the University of Washington Bladder Cancer Rapid Autopsy Program (BCRAP), primary and metastatic tumor tissue samples were acquired from 14 deceased patients with urothelial carcinoma within 6 hours of death. Patient history was collected and deidentified for analysis. RNA exome sequencing was used for assigning molecular subtype for each of the 61 tumor samples, using the consensus and six comprising systems. Results: Molecular subtype variation within metastatic tumors according to any classification system was detected in 8 out of 14 patients, independent of histologic morphologies. Amongst the patients with variation, on average 2.1 out of 7 classification systems identified a major difference in subtype between sites. Patients with variation (mean age 70 years (SD 7 years)) were older than those without variation (mean age 59 years (SD 11 years), P = 0.04). Furthermore, patients with variation tended to have decreased survival from diagnosis and received less chemotherapy, although these were not statistically significant (p > 0.05). Conclusions: Molecular subtype variation within metastasis is relatively common amongst BCRAP patients with urothelial carcinoma. Older patients are more likely to have variation, possibly due to a higher tumor mutation burden. Potential variation must be taken into account when considering prognosis and developing a recommended drug regimen specific to molecular subtypes.
Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar immune microenvironment as compared to conventional UC.
Authors: Kossai Myriam , Radulescu Camélia , Adam Julien , Dziegielewski Anaïs , Signolle Nicolas , Sibony Mathilde , Lebret Thierry , Allory Yves , Rouanne Mathieu 
Published: March 2021

477 Background:Plasmacytoid urothelial carcinoma (UC) is a rare pathological variant of UC with low chemotherapeutic sensitivity and dismal outcomes. The molecular and immune profiles of such tumors remain poorly investigated. Herein, we investigated the phenotypical features of a cohort of plasmacytoid UC (n = 32) by comparison to a control group of conventional high-grade UC with matched clinicopathological characteristics (n = 30). Methods: Histopathological analysis included the following antibodies: p63, GATA3, CK5/6, CK20 and HER2. In addition, the density of intra-tumor CD8+ lymphocytes, and PD-L1 expression in tumor (TC) and immune cells (IC) were evaluated. Clinical data were collected. Results: Plasmacytoid UC expressed GATA3 (97% vs 86% p = 0.18), CK20 (59% vs 36% p = 0.08) markers and showed a significantly higher rate of HER2 overexpression (2+ and 3+ score: 25% vs 0%, p < 0.01) compared to controls. A significantly lower expression of CK5/6 (22% vs 56%, p < 0.05) and p63 (41% vs 80%, p < 0.05) was observed in plasmacytoid UC compared to controls. The density of tumor-infiltrating CD8+ cells was similar between plasmacytoid and conventional UC (p = 0.5). PD-L1 expression on IC was similar compared to conventional UC (p = 0.3). Overall survival at 5 years was significantly lower among patients with plasmacytoid UC compared to patients with conventional UC (p = 0.02). Conclusions: Together, our study demonstrated that plasmacytoid UC belong to the luminal subtype and display a rather inflamed microenvironment similar to conventional UC. These data support the inclusion of plasmacytoid variant of UC in clinical trials evaluating immune checkpoint inhibitors monotherapy or combination immunotherapeutic strategies.
Novel synthetic lethality (SL) anti-cancer drug target in urothelial bladder cancer (UCB) based on MTAP genomic loss: Incidence and correlations in standard of care (SOC).
Authors: Bratslavsky Gennady , Jacob Joseph M , Necchi Andrea , Grivas Petros , Danziger Natalie , Sokol Ethan , Madison Russell , Ramkissoon Shakti H. , Graf Ryon , Mata Douglas A , Decker Brennan James , Ross Jeffrey S. 
Published: March 2021

485 Background: When UCB presents or progresses to chemorefractory metastatic disease, the search for new therapy targets is paramount. Targeting PRMT5 arginine methyltransferase accumulation in tumors with MTAP (methylthioadenosine Phosphorylase) genomic loss has been proposed as a new SL based anti-tumor strategy and under consideration for development for UCB. We sought to evaluate the incidence of patients with candidate SL and correlate to treatment-guiding biomarkers currently evaluated in SOC. Methods: 2,683 cases of clinically advanced UCB underwent hybrid-capture based comprehensive genomic profiling in a standard of care setting using the F1CDx FDA-approved assay to evaluate all classes of genomic alterations (GA) among 324 genes. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 650 (24%) of UCB feature MTAP loss (MTAP-) (Table). The gene and age distributions were similar MTAP intact (MTAP+) and MTAP- UCB. The GA/tumor was higher in MTAP- UCB likely reflecting the significant GA co-deletions of CDKN2A/ B at the 9p21 locus. Of potential therapeutic targets, FGFR3 and PTEN GA were more frequent in the MTAP- UCB. In contrast, biomarkers of immunotherapy (IO) response included higher frequencies of high TMB and high PD-L1 IHC staining in the MTAP+ UCB. Conclusions: When compared with MATP+ UCB, MTAP- UCB differs in genomic signatures including an increase in potential for targeted therapies but a lower potential for IO drug benefit. Thus, the genomic landscape in MTAP- UCB may play a significant role in the design of clinical trials incorporating SL strategies when targeting PRMT5 in MTAP deficient tumors. [Table: see text]
Association between tumor mutational burden (TMB) and immune-related adverse events (irAEs) in patients (pts) with metastatic urothelial carcinoma (mUC) during checkpoint immunotherapy.
Authors: Akl Elie W. , Nuzzo Pier Vitale , Adib Elio , Nassar Amin , Alaiwi Sarah Abou , Ravi Praful , Mantia Charlene , Sonpavde Guru 
Published: March 2021

489 Background: Immune checkpoint inhibition (ICI) has greatly improved clinical outcomes for pts with mUC and other cancers. ICI is associated with a class of AEs, deemed irAEs due to immune activation. Nonetheless, biomarkers associated with irAE are still lacking. We hypothesized that the immune response against neoantigens is partly responsible for irAEs and investigated the association between irAEs, TMB and response to ICI. Methods: We identified patients with mUC at Dana Farber Cancer Institute who were treated with ICI (monotherapy or combination) and had available tumor sequencing data through Oncopanel. TMB was calculated using the number of non-synonymous exonic mutations per megabase. The severity of irAEs was graded using CTCAE v.5.0. Mann-Whitney U test was performed to identify association between TMB, incidence and grade of irAEs. A cut-off of 10/mb was assigned for TMB. Fisher’s exact test was used to evaluate the radiologic response between pts with and without irAEs and low vs. high TMB. Multivariable linear regression was used to assess the relationship between TMB, irAEs and response. p-values were adjusted using Benjamini-Hochberg method. Results: Of 101 pts with mUC who met the inclusion criteria, 32 (32%) reported irAEs. 6 (6%) were grade (G)1, 20 (20%) were G2, and 6 (6%) were G3. Median(m) time on therapy was 84 days for pts without irAEs and 88 days for pts with irAEs. Pts with irAEs had higher mTMB (15.4/mb) compared to pts with no irAEs (9.8) ( p = 0.01). In pts on monotherapy (93), those with irAEs (n=27) had a higher mTMB (15.13/mb) compared to pts with no irAEs (n=66) (mTMB = 10.20/mb) ( p = 0.01). Out of 94 pts with radiological data, response was achieved in 16 (50%) pts with irAE vs 10 (16%) pts with no irAE ( p < 0.001). When both irAE and response were included in a multivariable regression, the association between irAE and TMB was not significant ( p = 0.4). Pts with both irAE and high TMB had a response rate of 56% which was significantly higher than those with either irAE but low TMB (28.6%) or high TMB but no irAE (21.2 %) or low TMB and no irAE (10.3%) (Chi-square test p = 0.002; FDR corrected p-values for individual comparisons in Table). There was no association between TMB and irAE grade. Conclusions: Higher TMB was associated with higher incidence of irAEs in pts with mUC on ICIs. Moreover, pts with both high TMB and irAEs exhibited better response rates than those with only high TMB or irAEs, suggesting that they may provide complementary tumor and host characteristics. Further evaluation in mUC is needed to confirm this relationship between TMB, irAEs and response in a larger cohort and explore specific mutational signatures that may be associated with irAEs. [Table: see text]
Impact of primary tumor location, histology, and host factors on objective response to immune checkpoint inhibitors in metastatic urothelial carcinoma.
Authors: Dawsey Scott , Khan Mohammad Siddique , Radakovich Nathan , Wei Wei , Mian Omar Y. , Ornstein Moshe Chaim , Gilligan Timothy D. , Gupta Shilpa 
Published: March 2021

493 Background: Factors affecting response to immune checkpoint inhibitor (ICI) are poorly understood in metastatic urothelial carcinoma (mUC). While tumor PD-L1 status is often used as a biomarker, it is not always predictive and ICI also benefits patients (pts) with PD-L1 negative tumors. Therefore, we sought to study the effect of some host and disease-related variables like gender, ethnicity, body mass index (BMI), platelet to lymphocyte ratio (PLR), and neutrophil to lymphocyte ration (NLR) on objective responses in pts with mUC treated with ICI. Methods: We performed a retrospective analysis of adult pts with mUC who received ≥2 cycles of ICI (pembrolizumab or atezolizumab) at the Cleveland Clinic from 2015 to 2020. Tumor and host-related factors evaluated are listed in the table below. We focused on meaningful treatment response, so only partial response (PR) and complete response (CR) were included as responders, while stable disease (SD) and progressive disease (PD) were counted as non-responders. Analysis was carried out with Fisher’s exact test and Wilcoxon rank sum test as applicable. Results: A total of 124 pts with mUC that received ICI were included. Gender did not correlate with response (p>0.99) or duration of response (p=0.37). Ethnicity did not correlation with response (p=0.78) or duration of response (p=0.24). Histology (UC, mixed variant histology or non UC) did not correlate with response (p=0.13) or duration of response (p=0.87). Location of primary malignancy (upper tract versus lower tract) did not correlate with response (p>0.99) or duration of response (p=0.36). BMI (p=0.23), PLR (p=0.9), and NLR (p=0.9) did not correlate with objective response. Conclusions: In our single center experience of pts with mUC treated with ICI, host factors (gender, ethnicity, histology, BMI, NLR, PLR) and location of primary tumor did not correlate with treatment response or duration of response. Although there were few African Americans represented in this study as commonly seen for minority representation, it is encouraging that no significant differences in responses were observed. The role of BMI and gender in response to ICI treatment in mUC was not observed. While there are limitations of a retrospective analysis, our study warrants investigation into predictive factors of response to ICI in mUC. Ongoing work integrating radiomics and pathomics will further our understanding and develop potential predictive biomarkers of response to ICI in mUC. [Table: see text]
Role of CA 125, CA19-9 and CEA in predicting outcome following neoadjuvant chemotherapy in muscle invasive bladder cancer.
Authors: Ahmadi Hamed , Ladi Seyedian Seyedeh Sanam , Reddy Sharath , Nguyen Charles , Bhanvadia Sumeet , Schuckman Anne K. , Djaladat Hooman , Daneshmand Siamak 
Published: March 2021

496 Background: We have previously shown the prognostic value of three tumor markers (TMs) including Carbohydrate Antigen 125 (CA-125), Carbohydrate Antigen 19-9 (CA 19-9) and Carcinoembryonic Antigen (CEA) in muscle invasive bladder cancer (MIBC). Current report presents an update on TM levels before and after neoadjuvant chemotherapy (NAC) and their association with oncological outcomes. Methods: Serum levels of three TMs were prospectively measured in patients with MIBC who underwent NAC between 2011 and 2019. Rate of pathological upstaging (Path-U) and recurrence-free (RFS) was compared between patients with: (1) Elevated versus normal pre-NAC TM (2) Elevated versus normal post-NAC TM, and (3) Elevated pre-NAC TMs with normalized post-NAC TMs (TM responders) versus persistently elevated post-NAC TMs (TM non responders). Results: Of a total of 199 patients, 63 patients had both pre- and post-NAC TMs. 33/63 (52%) patients had elevated pre-NAC TM of whom, 15/33 (45%) were TM responders. Patients with elevated pre-NAC TM had significantly higher rate of Path-U compared to those with normal pre-NAC TM (62% vs. 22.5%, respectively; P < 0.001). There was no significant difference in Path-U in the other two comparison groups. Patients with elevated pre- and post-NAC TM had significantly lower RFS. Compared to TM responders, TM non responders had significantly higher rate of recurrence (70% vs 34%) and shorter median time to recurrence (4.2 months vs 13.5 months) (P = 0.03). In six patients with recurrence who had complete post cystectomy TM, TM recurrence preceded clinical recurrence by median of 1.2 months (IQR 0.8 – 2.4 months). Conclusions: Elevated TM prior to NAC is associated with pathologic upstaging. TM elevation pre- or post-NAC predicts a worse outcome. Post-cystectomy TM might play a role in earlier detection of recurrence.
Phase II/III clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS) patients.
Authors: Chamie Karim , Chang Sam , Gonzalgo Mark L. , Kramolowsky Eugene V. , Sexton Wade J. , Reddy Sandeep K. , Bhar Paul , Garner Chad , Soon-Shiong Patrick 
Published: March 2021

510 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL-15RαFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase Ib data in BCG-naive patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. An open-label, 3 cohort multicenter phase II/III study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. We report here the interim analysis of Cohort A, BCG-unresponsive (CIS) [with or without Ta or T1 disease], as of December 2020 data cutoff. Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A of this phase II/III study is incidence of complete response (CR) of CIS at any time. Results: To date, 80 patients have enrolled in cohort A of this phase II/III trial. Evaluable analysis at this time shows CR rate at any time of 72% (N=51/71); for patients achieving CR, the probability of maintaining a CR for 12 months is 59%, with a median duration of complete response of 19.2 (7.6, 26.4) months. Low-grade treatment related AEs include dysuria, hematuria, and pollakiurua (all 16%), urgency (14%), and bladder spasm (8%), all other AEs were seen at 6% or less. A total of 9 subjects experienced at least 1 treatment emergent SAE (Severe Adverse event), the SAE rate is 1% for any given AE. No treatment emergent SAE’s were considered treatment related. No immune related SAE’s have been seen. To date, 10/80 (12.5%) patients proceeded to cystectomy in this BCG unresponsive population. Conclusions:With a CR rate of 72%, N-803 has met its primary endpoint with 59% probability of CR patients maintaining CR for at least 12 months. With the observed strong efficacy and an SAE rate of 1%, N-803 represents a novel treatment option for BCG unresponsive CIS with a favorable benefit:risk ratio, in a therapeutically challenging disease. Clinical trial information: NCT03022825.
Cardiac risk factors and events in patients with prostate cancer commencing androgen deprivation therapy: Analysis from a tertiary care center in the Middle East.
Authors: Hassan Mona , Telvizian Talar , Abohelwa Mostafa , Skouri Hadi , Mukherji Deborah 
Published: March 2021

73 Background: Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer, improving symptoms and prolonging survival. There is an association between ADT use and cardiovascular events, particularly in men with pre-existing risk factors. There are no definite guidelines to stratify patients based on cardiovascular risk prior to ADT initiation. This is the first study on cardiac risks and events in patients on ADT from Lebanon and the Middle East region, a population known to have a high prevalence of cardiovascular risk factors. Methods: A retrospective chart review of 236 patients with prostate cancer who received ADT therapy at a tertiary care center in Lebanon was performed. 167 had a full set of data and were included in analysis. Cardiovascular risk factors at baseline and cardiovascular events on ADT were reviewed. Results: The median age of our cohort was 68, range 48-92 years. The majority of patients had stage 4 diseases at diagnosis (49.8%) with a median duration of 12 months on ADT. In our cohort 24.4% had body mass index > 30, 52.1% had smoking history, 27.4% were diabetic, 28.8 % had history of coronary artery disease, 10.6% had heart failure history and 54.6% had hypertension. Less than half of the patients had a documented lipid profile at baseline. Twenty two patients (9.5%) had documented cardiac events following ADT initiation. Conclusions: In this cohort of patients from the Middle East we found that one third of the population had established coronary artery disease at baseline and 9.5% had documented cardiac events on ADT initiation. Our study highlights the gaps in cardiovascular risk assessment for this high risk group of patients with prostate cancer. Risk and resource-stratified algorithms are needed before starting ADT therapy for optimal cardiovascular health. Increased awareness, collaboration and referral mechanisms between oncologists, urologist and cardiologists are also needed.
Impact of treatment and frailty on elder-relevant physical function outcomes in older adults with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Yang Helen , Breunis Henriette , Timilshina Narhari , Kim Seungyeon , Alibhai Shabbir M.H. 
Published: March 2021

76 Background: Maintenance of physical function is a key consideration in treatment decision-making for older adults with metastatic cancer, many of whom are frail. However, physical function outcomes with treatment, and effects of frailty, have not been adequately explored in the mCRPC setting. We evaluated the effects of frailty status and treatment with docetaxel (CHEMO), abiraterone (ABI), enzalutamide (ENZA), and radium 223 (RAD) on elder-relevant physical function outcomes in older men with mCRPC. Methods: Men aged 65+ were enrolled in this multicenter prospective observational cohort study. Daily function was evaluated with the OARS instrumental activities of daily living (IADL). Objective physical function was assessed by grip strength and the Short Physical Performance Battery (SPPB). Falls were documented during interviews. We also collected FACT-G physical well-being (PWB) and functional well-being (FWB) subscales. Assessments were performed at baseline, 3 months, and 6 months. We identified frailty status with a validated frailty index. Mixed effects regression models were used to examine the difference in primary outcomes over time by treatment group or frailty status adjusted for baseline characteristics. Factors associated with falls within 6 months of treatment initiation were determined with logistic regression. Results: A total of 70, 38, 67, and 23 men starting CHEMO, ABI, ENZA, and RAD were included. Mean age, education, race, number of medications, and BMI were similar at baseline between treatment groups. In treatment-stratified analyses without considering frailty, no significant changes over time were reported for any physical function outcome. Frailty was significantly associated with lower IADL function (p < 0.0001), worse grip strength (p < 0.0001), worse SPPB score (p < 0.0001), worse PWB (p < 0.0001), and worse FWB (p < 0.0001) at baseline. In frailty-stratified analyses, grip strength (p = 0.0345) worsened, but SPPB (p = 0.0147) improved significantly over time. Also, changes in SPPB (p = 0.0394) and PWB scores (p = 0.0269) over time differed by frailty status, where frail cohorts had greater improvement over time in both scores. Frailty and treatment type were not predictors of falls whereas prior falls history (OR: 3.52, 95% CI: 1.40-8.86) and age (OR: 1.07, 95% CI: 1.01-1.14) were significant predictors. Conclusions: Frail older men receiving treatment for mCRPC have worse IADL function, grip strength, SPPB scores, PWB, and FWB at baseline. Although grip strength worsened over time, they had greater improvement in SPPB scores and PWB over time than fit patients. Contrary to our hypothesis, most older adults do not experience significant worsening in elder-relevant physical function outcomes over time regardless of treatment. The impact of frailty requires further study.