bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of pretreatment immune cell infiltration in muscle invasive bladder cancer treated with definitive chemoradiation: Analysis of NRG RTOG 0524 and 0712.
Authors: Deek Matthew Pierre , Shetty Amol , Song Yang , Efstathiou Jason A. , Feng Felix Y , Shipley William U. , Simko Jeff , Mouw Kent William , Miyamoto David Tomoaki , Pollack Alan , Michaelson Dror Dror , Zietman Anthony L. , Coen John , Dahl Douglas M. , Jani Ashesh B. , Souhami Luis , Chang Brian K. , Lee R. Jeffrey , Pugh Stephanie L. , Tran Phuoc T. 
Published: June 2023

4523 Background: Chemoradiation therapy (CRT) is an organ conserving approach in the treatment of locally advanced bladder cancer. Chemoradiation is thought to potentially result in immunogenic stimulation, and bladder cancer is often a tumor with high immune cell infiltration. Thus, we aimed to profile the tumor immune microenvironment of bladder cancer and identify prognostic immune biomarkers for CRT response by profiling tumor samples from NRG/RTOG 0524 and 0712, two prospective trials of CRT in muscle invasive bladder cancer (MIBC). Methods: Pretreatment tissue samples from both trials were profiled using Cofactor Genomics ImmunoPrism, an RNA sequencing assay that uses gene expression profiles to quantify immune cell populations in the tumor microenvironment (TME). Differential gene expression was estimated for different immune cell type proportions across samples. Kaplan-Meier survival analysis and log rank tests were performed to evaluate differences in overall survival (OS) stratified by genes influenced by immune cell proportions or genes associated with immune response signatures. Results: A total of 70 samples (43 from RTOG 0524 and 27 from RTOG 0712) underwent analysis using the ImmunoPrism assay. Immune cell proportions were as follows: CD8 T cells: median 1.2%, CD4 T cells: median 0.8%, Treg cells: median 9.2%, CD19 B cells: median 5.1%, M2 macrophages: median 0.8%, M1 macrophages: median 0%. Unbiased clustering based on gene expression profiles driven by immune cell proportions demonstrated two groups: cluster 1 with a low percentage of immune cells and shorter OS (median 31 months) and cluster 2 with a high percentage of immune cells and longer OS (median 101 months, p = 0.036). Higher expression of genes associated with T cell infiltration ( CD8A and ICOS) was associated with improved OS (104 vs 35 months, p = 0.028, HR = 0.48 (0.25 – 0.94), p = 0.031) as was higher expression of IDO1, which is associated with the interferon gamma pathway (104 vs 35 months, p = 0.042, HR = 0.49 (0.24 – 0.99), p = 0.046). Conclusions: Bladder tumors have a wide range of immune cell infiltration in the TME. Increased immune cell proportions are prognostic for OS following CRT, as well as a higher expression of genes associated with T cell infiltration interferon gamma signaling. These findings have implications for the integration of immunotherapy in the definitive management of MIBC; and can be explored further in the ongoing NRG/SWOG 1806 trial.
A phase I/II study to evaluate the safety, pharmacodynamics, and efficacy of entinostat in combination with atezolizumab and bevacizumab in patients with renal cell carcinoma.
Authors: Pili Roberto , Haas Naomi B. , Monk Paul , Logan Theodore F. , Narayan Vivek , Burney Heather , Adra Nabil 
Published: June 2023

4526 Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we conducted a Phase I/II clinical study with the HDAC inhibitor entinostat in combination with the immune check point inhibitor atezolizumab and the VEGF inhibitor bevacizumab in RCC pts, either treatment naïve or previously treated with immune checkpoint inhibitors. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a Phase I/II clinical trial. This clinical study was composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. Due to unforeseen circumstances, enrollment was halted during Stage I of the Phase II portion. In the Phase I dose finding cohorts, according to the 3+3 standard design, pts received oral entinostat at 1 mg (dose level or dl1), 3 mg (dl 2), or 5 mg (dl 3) every 7 days, continuously, with atezolizumab at a dose of 1,200 mg/kg mg IV every three weeks in combination with bevacizumab at a dose of 15 mg/kg IV every 3 weeks. Phase II patients were split into two distinct cohorts: Cohort A (no prior treatments with PD-1 or PD-L1 inhibitors) and Cohort B (at least one prior treatment with a PD-1 or PD-L1 inhibitor for metastatic disease). Pts treated at dl3 were included in the Phase II efficacy analyses. Results: 31 pts (18 and 13 pts during Phase I and II, respectively) were enrolled. Phase I was completed with the following DLTs: hypertension (3) in dl1, encephalopathy and hyponatremia (dl2), pneumonitis and pruritis (dl3). Dl3 was established as the recommended phase II dose. The most common treatment-related toxicities were thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. A total of 21 grade≥3 events were observed. Nine pts achieved a partial response in Cohort A and one patient in Cohort B with an ORR 60% (CI 32.3-83.7) and 33.3% (28.2-56.4), respectively. According to Simon’s optimal two-stage design, the ORR met the Stage I primary objective. The median PFS was 13.7 months (CI 8.7-21.3) in Cohort A and 9.8 months (CI 1.3-NE) in Cohort B. We have collected blood samples to conduct several correlative studies on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and atezolizumab plus bevacizumab is relatively well tolerated and may be active in pts with ccRCC. Clinical trial information: NCT03024437 .
Head-to-head effectiveness and safety of pembrolizumab plus axitinib vs. nivolumab plus ipilimumab in metastatic renal cell carcinoma in the United States.
Authors: Aran Dvir , Granot-Hershkovitz Einat , Amar-Farkash Shlomit , Rosenberg-Katz Keren 
Published: June 2023

4532 Background: Two main first-line combination therapies for metastatic renal cell carcinoma (mRCC) are pembrolizumab plus axitinib (P+A) and nivolumab plus ipilimumab (N+I). No head-to-head clinical trial comparing these treatments has been performed, and the available real-world data (RWD) on their effectiveness is limited. Here, we used RWD to compare the overall survival and posttreatment hospitalization rates of mRCC patients receiving P+A vs. N+I. Methods: We included mRCC patients treated with N+I or P+A between 6/2018 and 3/2022, utilizing data from Elevance Health administrative claims and clinical data from AIM Cancer Care Quality Program. Inverse probability of treatment weighting (IPTW) was used to adjust for age, sex, socioeconomic deprivation index (SDI), ECOG performance status (PS), Charlson Comorbidity Index (CCI), and metastatic sites. Real-world overall survival (rwOS) was defined from first treatment until death or last claim and was estimated using weighted Kaplan-Meier method. Favorable risk was defined based on PS (<2) and with a treatment initiated less than 1 year from diagnosis. Results: We identified 764 mRCC patients, of them 483 were treated with N+I (63%). The P+A group was slightly older (p=0.08), while other features were similar in both groups. Survival analysis using IPTW showed a borderline significant advantage of P+A vs. N+I (p-value=0.07). Inspection of the Kaplan-Meier curves suggested that P+A provides short-term survival benefit: 12-month rwOS was 86% for P+A vs. 77.8% for N+I (p<0.001), while at 24-months, where power was lower, the curves almost converged (rwOS: 68% in P+A vs. 65% in N+I; p=0.52). In a subset of patients with favorable risk (N=69 P+A, N=68 N+I), the P+A survival improvement extended to at least 24-months (p=0.06). Finally, the N+I group had significantly higher rates of posttreatment hospitalizations (3-months after treatment initiation) compared to the P+A group (31.9% vs. 19.6%; p-value<0.001). Conclusions: Our retrospective cohort study suggests that P+A may provide short-term survival benefits over N+I, and this benefit is extended in patients with favorable risk. P+A is also associated with fewer post-treatment hospitalizations. We argue that the higher toxicity of N+I may explain its lower short-term effectiveness and may also explain its lower effectiveness in patients with favorable risk. [Table: see text]
Health-related quality of life (HR-QOL) measures in renal cell carcinoma (RCC): Patient-reported relevance of items of the FKSI-19, EORTC QLQ-C30, and EQ-5D.
Authors: Bergerot Cristiane Decat , Mercier Benjamin D , Castro Daniela V. , Bergerot Paulo Gustavo , Toms Charlotte , Ali Adil A , Philip Errol James , Lages Dr. Paulo Sergio , Mota Augusto C. A. , Hutson Thomas E. , Grünwald Viktor , Bex Axel , Psutka Sarah P. , Rini Brian I. , Plimack Elizabeth R. , Master Viraj A. , Albiges Laurence , Choueiri Toni K. , Pal Sumanta Kumar , Powles Thomas 
Published: June 2023

4540 Background: Given the need to balance both quantity and quality of life among patients with advanced cancer, developing a robust, relevant, and consensus-driven patient-focused measurement strategy is a necessity. Our study expands upon previous findings (Bergerot et al., The Oncologist 2023) in evaluating the perceived relevance of questions on the FKSI-19, EORTC QLQ-C30, and EQ-5D among patients with RCC. Methods: Eligible patients were diagnosed with RCC and asked to evaluate the relevance of each question of the FKSI-19, EORTC QLQ-C30, and EQ-5D (items rated as relevant vs non-relevant). Patients also responded to 2 open-ended questions regarding topics not covered by these measures and their perception of wearable technologies. Questions identified as meaningful required ≥66% “relevant” ratings. Descriptive statistics were collated, and open-ended questions were analyzed by 2 independent reviewers (CB, PB). Results: 116 patients were recruited from Brazil and the US. Most (69%) were male with a median age of 64 (32-88) years. 83% were diagnosed with advanced disease, and 75% received immunotherapy and/or targeted therapy as primary treatment. Few items across surveys were identified as meaningful including 8/19 FKSI-19 questions (lack of energy, fatigue, appetite, sleeping, worry, able to work, enjoyment and quality of life), 3/30 EORTC QLQ-C30 questions (tired, overall health and quality of life), and 0/5 EQ-5D questions. Patients suggested items pertaining to treatment side effects, emotional symptoms, physical function, social/family support, and financial distress should be included. Notably, 58% of patients were open to using wearable devices to assess HRQOL. Conclusions: Our multi-institutional international study confirms findings from our single-institution pilot data suggesting that HRQOL measures for RCC require substantial refinement. These data will inform development of a novel-RCC specific HRQOL tool in a joint effort between experts and patients.
Biomarkers of response to first-line nivolumab therapy in patients with advanced renal cell carcinoma (RCC) enrolled in the HCRN GU16-260 trial.
Authors: El Ahmar Nourhan , Matar Sayed , Jegede Opeyemi , Savla Varunika , Bagheri Sheshdeh Aseman , Ghandour Fatme , Denize Thomas , West Destiny , Choueiri Toni K. , Catalano Paul J. , Braun David A. , Haas Naomi B. , Hammers Hans J. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Wu Catherine J. , McDermott David F. , Atkins Michael B. , Signoretti Sabina 
Published: June 2023

4549 Background: The HCRN GU16-260 study showed that nivolumab (nivo) monotherapy is active in treatment-naïve patients (pts) with RCC. Although efficacy correlated with tumor cell (TC) PD-L1 expression, more clinically relevant biomarkers are needed. We previously showed that levels of CD8+ tumor-infiltrating lymphocytes (TIL) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+ TIM3- LAG3-) were associated with response to nivo in previously treated clear cell RCC (ccRCC) pts (Pignon, 2019; Ficial, 2021). Here, we sought to validate these findings in the first-line setting. Methods: Primary tumor tissues from pts with ccRCC (n= 67) and non-ccRCC (n= 13) were analyzed by multiparametric immunofluorescence (IF), and the density of CD8+PD-1+TIM-3-LAG-3- TIL was quantified by image analysis. The correlation of the log-transformed biomarkers with objective response rate (ORR) and progression-free survival (PFS) was assessed in the ccRCC cohort and the combined (ccRCC + non-ccRCC) cohort (n=80) using Cox or logistic regression analysis, or Chi-square/Fisher’s exact test (as appropriate) for statistical inference – alpha level was set at 5% (1-sided). Results: In both the ccRCC and the combined cohort, density of CD8+PD-1+TIM-3-LAG-3- TIL (IF biomarker) measured as continuous variable was associated with ORR (ccRCC: OR = 1.54, p = 0.017; combined: OR = 1.35, p = 0.040) and PFS (ccRCC: HR = 0.79, p = 0.015; combined: HR = 0.85, p = 0.016). At a cutoff optimized for maximum sensitivity for ORR, ccRCC patients with a high (61/67) vs low (6/67) IF biomarker had higher ORR (44.3% vs. 0% p = 0.039) and longer median PFS (10.9 months vs. 4.2 months, p = 0.016). Of note, when combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated the clinical outcomes of ccRCC pts. Conclusions: High levels of CD8+ PD1+ TIM-3-LAG-3- TILs were associated with response to first-line nivo in pts with advanced RCC and the combination with TC PD-L1 status further separated the outcomes of pts with ccRCC, validating our previous findings. Further investigations into the role of myeloid inflammation as determinant of clinical outcome to nivo therapy are ongoing. Clinical trial information: NCT03117309 . [Table: see text]
Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Gebrael Georges , Saad Eddy , Labaki Chris , Saliby Renee Maria , Sayegh Nicolas , Wells J Connor , Semaan Karl , Eid Marc , Takemura Kosuke , Ernst Matthew Scott , Lemelin Audreylie , Basappa Naveen S. , Wood Lori , Powles Thomas , Ernst D. Scott , Kapoor Anil , Xie Wanling , Agarwal Neeraj , Heng Daniel Yick Chin , Choueiri Toni K. 
Published: June 2023

4555 Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p>0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p>0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]
Kidney cancer mortality in the United States between 1999 and 2020: An observational analysis of outcomes by gender, race, and ethnicity.
Authors: Abdallah Nour , Jani Chinmay , Mouchati Christian , Chrysafi Pavlina , Singh Harpreet , McKay Rana R. 
Published: June 2023

4563 Background: Kidney cancer (KC) is one of the leading causes of cancer mortality, with recent data showing an increase in incidence and mortality worldwide. Gender, racial, and ethnic disparities can impact KC outcomes. Studies investigating the outcomes of diverse patient populations spanning the cytokine, targeted therapy and immunotherapy eras have been limited. This study aims to investigate trends in age-adjusted mortality rates (ASMR) by gender, race, and ethnicity in the US at national and state levels. Methods: We utilized the Center for Disease Control Wonder database to extract national and state-wide KC mortality data (ICD-10 C64) from 1999-2020. ASMR and 95% confidence intervals (CI) were extracted based on gender, race and ethnicity reported per 100,000 population. To evaluate the difference between metro and non-metro regions, we divided the national trends based on 2013 Urban NCHS Urban-Rural scheme. Joinpoint regression analysis was performed to evaluate trends. Results: In total, 284,224 KC deaths were reported over twenty years, with an overall decrease in ASMR in recent years. Males had significantly higher ASMR throughout the study period, with a lower decrease than females. Amongst racial groups, American Indians (AI) had the highest mortality in 1999 (5.7). However, due to the smaller decrease of ASMR in Whites compared to Non-Whites, Whites showed the highest ASMR (3.9) in 2020. According to ethnicity, Non-Hispanics Whites (NHW) had significantly higher ASMR than Hispanics in 1999 (4.0 vs. 3.5) and 2020 (3.5 vs. 3.0) with a similar rate of decline (-11.4% vs. -12.5%). State-wise, ASMR decreased in all states except Utah (+45.8%), Arkansas (+18.4%), Hawaii (+15.4%), Montana (+5.3), Kansas (+2.7) and Nevada (+2.6). Interestingly, non-metro regions showed higher ASMR throughout the study period. Also, while there was a steep decline in ASMR (15%) in metro regions, only a minimal decline (-4.7%) was observed in non-metro regions. Conclusions: Over the last two decades, there has been a decrease in the ASMRs across all genders, races and ethnicities and in most states in the USA. The decrease in ASMR is likely multifactorial, related to earlier detection and improved treatments. However, differences in outcomes by gender, race, and ethnicity persist, highlighting the need for strategies to better understand the etiology of differences and mitigate disparities across social determinants of health across gender, racial, and ethnic groups. [Table: see text]
Mismatch repair deficiency and microsatellite instability-high in urothelial carcinoma: A systematic review and meta-analysis.
Authors: Chandran Elias , Iannantuono Giovanni Maria , Akbulut Dilara , Atiq Saad Omar , Gurram Sandeep , Teo Min Yuen , Coleman Jonathan , Sinaii Ninet , Apolo Andrea B. 
Published: June 2023

4570 Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a small subset of urothelial carcinoma (UC) and confer a sensitivity to immunotherapy in multiple solid tumors. Due to the rarity of this patient subset in UC, there is a lack of prospective data on their prevalence or of clinical outcomes with immunotherapy and other treatment modalities. Methods: We performed a systematic review with the objectives of estimating the prevalence of dMMR and MSI-H in urothelial bladder cancer (BC) and upper tract urothelial carcinoma (UTUC) apart from estimating survival and clinical outcomes of treatment. We searched for published prospective and retrospective studies, review articles, case reports, case series, conference proceedings, letters, commentaries, and editorials on dMMR and MSI-H in BC and UTUC published up to 10/26/2022 in PubMed, Cochrane CENTRAL, Embase and Web of Science: Core Collection databases. The study protocol is registered on the PROSPERO database (CRD42022365690). Prevalence data were analyzed using meta-analysis with random-effects models and are reported here. Results: A total of 1,750 studies were screened, of which 125 were included. Thirty-six studies (including 5,113 patients) reported frequencies of dMMR, and 42 studies (including 21,291 patients) reported on MSI-H. Of the total included patients, sex was reported in 11,225, with 72.6% being male and 27.4% female. Age ranged from 17-97 years. Reported primary site was BC in 64.4%, UTUC in 16.3% and not stated in 19.3%. Disease stage reported in 5,341 patients was M0 in 75.0% and M1 in 25.0%. Of the M0 patients, tumor stage data were available in 3,149 patients: Ta-T1 in 33.6% and T2-T4 in 66.4%. The pooled weighted prevalence of dMMR in UC patients was 6% (95% CI 5-8%). The breakdown for BC and UTUC were 2% (95% CI 1-3%) and 9% (95% CI 7-12%), respectively. The three most frequent MMR protein loss patterns in UC, BC and UTUC are shown in the table. Out of 42 studies reporting MSI status, 21 used polymerase chain reaction (PCR) and 21 used next-generation sequencing (NGS). Pooled weighted prevalence of MSI-H in UC was 3% (95% CI 2-3%). In BC, the prevalence was 1% (95% CI 1-1%) and in UTUC, it was 11% (95% CI 8-13%). Conclusions: dMMR and MSI-H were observed more frequently in UTUC than BC. Further analysis on survival and clinical outcomes of dMMR/MSI-H UC with different treatment modalities is ongoing. Additionally, clinical trials in dMMR and/or MSI-H UC are in development to study immunotherapeutic strategies to improve outcomes in both early and advanced stages for this small but important subset of patients. [Table: see text]