bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of VEGFR-TKI plus immune checkpoint inhibitor (ICI) in metastatic renal cell carcinoma (mRCC) patients with favorable IMDC prognosis.
Authors: Ciccarese Chiara , Iacovelli Roberto , Bria Emilio , Schinzari Giovanni , Rossi Ernesto , Astore Serena , Cannella Maria Antonella , D'Angelo Tatiana , Cicala Carlo Maria , Maratta Maria Grazia , Tortora Giampaolo 
Published: March 2021

318 Background: Combinations of a PD-1/PD-L1 immune checkpoint inhibitor (ICI) with a VEGFR-TKI as front-line/treatment-naïve therapy significantly improve the outcome of metastatic renal cell carcinoma (mRCC) patients. The benefit of these combinations is well evident in IMDC intermediate- and poor-risk population, while it is unclear in the subgroup of mRCC patients with favorable prognosis. We performed a meta-analysis with the aim to evaluate whether the addition of ICIs to VEGFR-TKIs is able to improve the outcome compared to VEGFR-TKIs alone in mRCC patients with favorable IMDC prognosis. Methods: This meta-analysis searched MEDLINE/PubMed, the Cochrane Library and ASCO Meeting abstracts for phase II or III randomized clinical trials (RCTs) testing the combination of VEGFR-TKI+ICI in mRCC. Data extraction was conducted according to the PRISMA statement. The hazard ratios (HRs) for PFS and OS with the relative 95% CIs were extracted from each study. Summary HRs was calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. Results: Three RCTs were selected for the final analysis, with a total of 605 patients (306 treated with VEGFR-TKI+ICI combinations and 299 who received sunitinib in the control arms). The combination of VEGFR-TKI+ICI improved PFS compared to sunitinib, with a 30% reduction of the risk of progression (fixed-effect, HR=0.70; p = 0.003). However, VEGFR-TKI+ICI combinations did not significantly prolong OS (fixed-effect; HR = 0.94; 95% CI 0.62–1.43; p = 0.77). Conclusions: Our analysis demonstrates a PFS benefit without an OS advantage for VEGFR-TKI+ICI combinations as first-line therapy for mRCC patients with favourable prognosis according to IMDC. Longer follow-up is required to definitely confirm the best therapy for treatment-naïve mRCC patients with favorable prognosis. [Table: see text]
Phase I with expansion clinical trial of seleno-l-methionine (SLM) in combination with axitinib in patients with relapsed clear cell renal cell carcinoma (ccRCC): Bench to bedside.
Authors: Zakharia Yousef , Reis Ryan , Garje Rohan , Swami Umang , Born Janelle M , Brown James A. , Nepple Kenneth Gerard , Abuqayas Bashar , Rajput Maheen , Bellizzi Andrew , Sieren Jessica C , Rustum Youcef M. 
Published: March 2021

322 Background: Hypoxia induced factor 1α/2α (HIFs) and vascular endothelial growth factor (VEGF) are overexpressed in ccRCC and associated with increased tumor angiogenesis, vascular instability and drug resistance. In xenografts, high dose SLM resulted in sustained down regulation of HIFs, normalization of tumor vasculature that resulted in increased drug delivery, and therapeutic synergy with anti-VEGF therapeutic. These effects were highly SLM dose, sequence, and schedule dependent. Methods: After completion of the escalating phase I (3+3) trial, the non-toxic SLM dose of 4000μg was administered orally twice daily (BID) for 14 days, followed by once daily in combination with axitinib 5 mg BID. The primary endpoint is safety and the secondary end point include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). To assess the potential effects of SLM on tumor vascular function, dual energy computed tomography (DECT) was conducted at baseline, day 14 of SLM, and at 3 months of SLM + axitinib. Results: Thirty subjects are screened. Of whom 25 have efficacy data (3 subjects screen failure, 1 withdrew, 1 taken off study prior to first scan due to progression with brain lesions likely present prior to study entry). 13/25 (52%) have confirmed response (CR/PR). Two subjects had CR lasting for at least 35 and 44 months, 6 subjects achieved stable disease (SD) lasting at least 6 months accounting for disease control rate (DCR) of 76%, mPFS is 9.5 months. 5/30 patients have sarcomatoid features, all of which are evaluable for efficacy with 1 PR achieved (20%). In the 20 patients without sarcomatoid features, 12/20 achieved PR (60%). The most prevalent adverse events (AE) included fatigue, diarrhea, anorexia, nausea, hoarseness, weight loss, and hypertension. No deaths nor grade 4 toxicities observed. The blood selenium concentrations achieved in the 4000μg SLM dose cohorts are similar to those determined molecularly and therapeutically synergistic with axitinib in xenografts and are being achieved clinically without significant toxicity. DECT data demonstrated increased iodine uptake by tumor lesions, but not in normal tissues, on day 14 SLM treatment and decreased in these same lesions at 3 months of SLM/axitinib. Conclusions: Blood selenium concentrations and duration of treatment seem to be critical determinants of response. Pre and concurrent treatment with SLM enhance the ORR and PFS of axitinib, with no additional toxicity. Currently documented responses are similar across IMDC risk groups. Clinical trial information: NCT02535533 .
Angiogenic and T-effector subgroups identified by gene expression profiling (GEP) and propensity for PBRM1 and BAP1 alterations in clear cell renal cell carcinoma (ccRCC).
Authors: Barata Pedro C. , Gulati Shuchi , Elliott Andrew , Rao Arpit , Hammers Hans J. , Quinn David I. , Gartrell Benjamin Adam , Zibelman Matthew R. , Wei Shuanzeng , Geynisman Daniel M. , Zhang Tian , Darabi Sourat , Dawson Nancy Ann , Hauke Ralph J. , Poorman Kelsey Anne , Nabhan Chadi , Ryan Charles J. , Heath Elisabeth I. 
Published: March 2021

343 Background: With the emergence of multiple active treatment options in RCC, predictive biomarkers for optimal treatment selection are lacking. Gene expression data from IMmotion151 and Javelin Renal 101 clinical trials generated anti-angiogenic and immune signatures that warrant further validation. We aimed to describe the genomic and gene expression profiles in a multi-institutional database of patients with ccRCC, and its association with other biomarkers of interest. Methods: Whole transcriptome sequencing was performed for ccRCC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) from February 2019 to September 2020. Tumor GEP and hierarchical clustering based on the validated 66-gene signature (D’Costa et al, 2020) were used to identify patient subgroups. Samples from both primary tumors and metastatic sites were included. Results: A total of 316 patients with ccRCC, median age 62 (range 32-90), 71.8% men, were included. Tissue samples were obtained from primary tumor (46.5%), lung (12.3%), bone (9.5%), liver (4.7%) and other metastatic sites (27%). Gene expression analysis identified angiogenic, mixed and T-effector subgroups in 24.1%, 51.3% and 24.7%, respectively. Patients with angiogenic subgroup tumors compared to those with T-effector subgroup tumors were more likely to be older (63 versus 60 years, p=0.035), female (40.8% versus 16.7%, p=0.0009) and more frequently found in pancreatic/small bowel metastases (75% versus 12.5%, p=0.0103). Biomarkers of potential response to immunotherapy such as PD-L1 (p=0.0021), TMB (not significant), and dMMR/MSI-H status (not significant) were more frequent in the T-effector subgroup. PBRM1 mutations were more common in the angiogenic subgroup (62.0% vs 37.5%, p=0.0034) while BAP1 mutations were more common in the T-effector subgroup (18.6% versus 3.0%, p= 0.0035). Immune cell population abundance (e.g. NK cells, monocytes) and immune checkpoint gene expression (TIM-3, PD-L1, PD-L2, CTLA4) were also increased in the T-effector subgroup. Conclusions: Our hierarchical clustering results based on the 66-gene expression signature were concordant with results from prior studies. Patient subgroups identified by evaluation of angiogenic and T-effector signature scores exhibit significantly different mutations and immune profiles. These findings require prospective validation in future biomarker-selected clinical trials.
Assessing the impact of the COVID-19 pandemic on patients with genitourinary malignancies.
Authors: Borno Hala , Zhang Sylvia , Gomez Scarlett Lin , Kaplan Celia , Miaskowski Christine , Hong Julian , Idossa Dame , Bailey Adina , Small Eric Jay 
Published: March 2021

38 Background: The COVID-19 pandemic has vast implications on the health system. Patients with a cancer diagnosis may face greater challenges in the context of the current COVID-19 pandemic. Methods: We sought to assess the impact of the COVID-19 pandemic among patients with genitourinary malignancies. We performed a cross-sectional survey study at a Comprehensive Cancer Center during the current pandemic. Results: A total of 86 participants were recruited to the study to date, 72.1% had prostate, 19.8% had kidney, and 12.8% had bladder cancer. A subset (n = 5) had more than one primary tumor. The mean time from diagnosis was 6.47 years (std dev 6.01, range from 0 to 27 years). Overall, 73% reported having metastatic disease and prior treatment with surgery (62%), radiation (71%), or systemic therapy (68%), with 68.6% currently receiving cancer treatment. In the study, 78.9% of patients were >65 years of age and 88.2% were White. The majority of participants had a bachelor’s degree or higher level of education (74.4%), were legally married (82.6%), were homeowners (91.9%), and reported an annual household income of >$100,000 (56.0%). Among respondents, 7% reported loss/change of health insurance and 30% reported a decrease in household income. Among patients with reduced household income, 23% reported a reduction of more than 50%. In this study, 28% of patients reported that the pandemic impacted their cancer treatment. Overall 7% reported decrease in frequency of labs, 11% reported a delay in obtaining a scan, 5% reported treatment delays, and 96% reported use of telemedicine (video or telephone) visit. Overall, 59% reported fear of hospitalization, 23% reported delays in seeking medical care, and 16% reported missing required medications. Conclusions: The negative impact of the COVID-19 pandemic on patients with genitourinary malignancies is extensive. Ongoing research is evaluating the impact across socio-demographically groups and examine clinical outcomes associated with delays in care and medication non-adherence.
Impact of equal access healthcare on race disparities in bladder cancer.
Authors: Kotha Nikhil V. , Kumar Abhishek , Qiao Edmund M. , Cherry Daniel R. , Nalawade Vinit , Kader A. Karim , McKay Rana R. , Stewart Tyler Francis , Rose Brent S. 
Published: March 2021

399 Background: Outcomes in bladder cancer are disproportionately worse for black patients compared to white patients. We hypothesize these disparities arise in part due to differences in access to healthcare and therefore may be mitigated in an equal access healthcare system, such as the Veterans Affairs’ (VA) system. Here, we examine outcomes by race for patients with bladder cancer within the VA system and then compare these outcomes to those in the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We performed a retrospective cohort study using VA Informatics and Computing Infrastructure (VINCI) and SEER. We included all patients diagnosed with bladder cancer, American Joint Committee on Cancer (AJCC) stage 0-4 diagnosed between 2000 and 2018. Endpoints of overall survival (OS), bladder cancer-specific survival (BCS), and non-bladder cancer-specific survival (NCS) were evaluated in multivariable Cox and Fine-Gray models. Results: Using the VA dataset, we identified 36322 veterans (9.0% black, 91.0% white) with bladder cancer. Black veterans were more likely to have more comorbidities, reside in zip codes with lower median income and education levels, and present with higher stage disease (AJCC stages 2-4) than white veterans (23.3% vs 19%). In multivariable models accounting for disease stage among other covariables, there were no statistically significant differences in any survival endpoint (Table). Using the SEER dataset, we identified 130998 patients (5.9% black, 94.1% white) with bladder cancer. In similar multivariable models, SEER’s black patients had statistically significant inferior outcomes in all survival endpoints compared to SEER’s white patients (Table). Conclusions: While racial disparities for patients with bladder cancer in the SEER database were observed, no differences in survival outcomes between black and white patients were observed in the VA healthcare system. Of note, black veterans presented with more advanced stage, suggesting a delay in diagnosis or a more aggressive cancer phenotype compared to white patients. Our findings underscore the need to bridge healthcare disparities across diverse racial groups. Our study highlights the beneficial impact of an equal access healthcare system in reducing financial and social barriers to healthcare to counteract racial health disparities. Further research is required to delineate these disparities and guide appropriate screening strategies. [Table: see text]
Combinatorial biomarkers to predict responses to immune checkpoint therapy in metastatic urothelial cancer.
Authors: Goswami Sangeeta , Chen Yulong , Anandhan Swetha , Szabo Peter M , Basu Sreyashi , Blando Jorge M , Liu Wenbin , Zhang Jan , Natarajan Seanu , Xiong Liangwen , Guan Baoxiang , Singh Shalini , Saci Abdel , Allison James Patrick , Galsky Matt D. , Sharma Padmanee 
Published: March 2021

488 Background: Immune checkpoint therapy can produce durable anti-tumor responses in metastatic urothelial carcinoma (mUCC); however, the responses are not universal. Despite multiple approvals of immune checkpoint therapy in mUCC, we lack predictive biomarkers to guide patient selection. Therefore, there is a critical need to develop clinically useful biomarkers to refine patient selection. The single biomarker studies either focused on tumor mutations or immune response biomarkers, which may limit predictive power due to lack of integration between cancer cell biology and immune cell responses. The identification of biomarkers may require interrogation of both the tumor mutational status and the immune microenvironment. Methods: We performed retrospective multi-platform immuno-genomic analyses of pre-treatment tumor tissues in a discovery cohort (n = 31). Next, we tested the clinical relevance of ARID1A mutation and pre-treatment CXCL13 expression in two independent confirmatory cohorts (CheckMate275 and IMvigor210). Additionally, we performed reverse translational studies using murine model of bladder cancer to demonstrate direct association of the biomarkers in anti-PD-(L)-1 mediated anti-tumor immunity. Results: We identified genomic mutation of AT-rich interactive domain-containing protein 1A ( ARID1A) in tumor cells and expression of immune cytokine CXCL13 in the pre-treatment tumor tissues as two predictors of clinical responses. We found that ARID1A mutation and expression of CXCL13 in the baseline tumor tissues correlated with improved overall survival (OS) in both confirmatory cohorts (CheckMate275, CXCL13 data, n = 217; ARID1A data, n = 139, and IMvigor210, CXCL13 data, n = 348; ARID1A data, n = 275). Further, reverse translational studies revealed that CXCL13−/− tumor-bearing mice were resistant to immune checkpoint therapy whereas ARID1A knockdown enhanced sensitivity to immune checkpoint therapy in a murine model of bladder cancer. We then interrogated CXCL13 expression plus ARID1A mutation as a combination biomarker in predicting response to immune checkpoint therapy in CheckMate275 and IMvigor210. Combination of the 2 biomarkers in baseline tumor tissues showed improved OS compared to either single biomarker. Conclusions: Cumulatively, this study revealed that the combination of CXCL13 plus ARID1A mutation may improve patient selection in mUCC for immune checkpoint therapy.
The potential role of frailty in modifying quality-of-life related outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel, abiraterone, enzalutamine, and radium 223.
Authors: Kim Seungyeon , Breunis Henriette , Timilshina Narhari , Yang Helen , Alibhai Shabbir M.H. 
Published: March 2021

63 Background: As the arsenal of therapeutic agents for mCRPC expands, frailty-informed care is emerging as a strategy for tailoring management decisions. Yet, data to guide this approach and to ascertain its impact on the mood, fatigue, pain, and quality of life (QoL) experienced by older men with mCRPC remain lacking. We examined patient-reported outcomes, stratified by a validated frailty index (FI), for mCRPC treatment with docetaxel chemotherapy (CHEMO), abiraterone (ABI), enzalutamide (ENZA), or radium 223 (RAD). Methods: Older (aged 65+) men starting one of four approved therapies for mCRPC were enrolled in a multicenter prospective cohort study. Assessing their mood, fatigue, pain, and QoL with PHQ-9, ESAS tiredness, ESAS pain, and FACT-G total as well as subscale scores, we used linear mixed effect models to determine change in each outcome over time (0, 3, 6 months). At end of treatment, we administered the Decisional Regret Scale. We then constructed a FI from 34 variables that span laboratory abnormalities, geriatric syndromes, instrumental activities of daily living, social support, as well as emotional, cognitive, and physical deficits. Following established cut-offs, we categorized patients as non-, pre-, and frail, then performed stratified linear mixed effects regression analyses to identify differences in outcomes by frailty status. Results: A total of 198 men (mean age 75.1) starting CHEMO (n = 70), ABI (n = 38), ENZA (n = 67), and RAD (n = 29) were included, of which 9.6%, 1.5%, 5.6%, and 2.5%, respectively, were determined frail. Frailty correlated only modestly with age (Pearson r = 0.27). Independent of frailty status, patients across treatment cohorts were similar in terms of baseline QoL-related measures, with the exceptions of mood (p = 0.033) and pain (p = 0.034). Over time, no significant change in QoL was reported, although all four therapies resulted in generally low levels of decisional regret and similar trends of improved pain but worsened mood (p = 0.006 and 0.02, respectively). At baseline, frailty status correlated with worse FACT-G total (p < 0.001) and functional well-being (p < 0.001), as well as worse depression scores (p < 0.001). According to FI-stratified analysis, frail patients experienced similar QoL-related outcomes to fit patients for all measures aside from mood (p < 0.001). Contrary to our hypotheses, frailty was not associated with significant worsening in emotional well-being or functional well-being in response to mCRPC treatment. Conclusions: Of the older men receiving care for mCRPC, frail patients may experience generally similar trends in QoL as fit patients. Interestingly, frailty status, rather than treatment modality, may play more of a contributory role to changes in QoL-related outcomes over time.
Comparative analysis of sarcopenia induced by long-term abiraterone (A) versus enzalutamide (E) therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Naimi Mahdi Farzad , Khan Maira , Briones Carvajal Juan Rodrigo , Emmenegger Urban 
Published: March 2021

69 Background: Androgen deprivation therapy induces osteosarcopenia, which in turn is associated with prostate cancer related morbidity, mortality and health expenditures. Although bone and skeletal muscle health are interconnected at multiple levels, clinical guidelines focus on the prevention and management of osteoporosis while largely ignoring skeletal muscle health. Due to the paucity of studies investigating the impact of A or E therapy on skeletal muscle loss, we decided to compare the effects of the two agents on sarcopenia development among men with mCRPC. Methods: In this retrospective single-centre study we identified a total of 58 mCRPC patients (pts) who (i) had received treatment with A (n = 29) or E (n = 29) for > 1.5 years, (ii) had an available routine abdominopelvic CT scan at baseline, and (iii) had at least one follow-up CT scan 12 and/or 24 months after treatment initiation. Using the contour tool of the eUnity imaging platform, we obtained the total contour area of the left and right psoas muscle at the inferior endplate of L3 in order to calculate the Psoas Muscle Index (PMI; defined as the total contour area divided by patients’ height in meters) as a measure of sarcopenia. Results: The median age of men undergoing A or E therapy was 75 (range 70-79) versus 69 (67-75) years (p = 0.09), with A use for first line mCRPC therapy in 65.5% of pts, and of E in 69.0% of pts. The median time on A was 30.3 (95%CI 27.2-46.0) months, compared to 42.8 (27.4-49.9) months for men on E (p = 0.96). Using a PMI cut-off for sarcopenia of < 5.7, the rate of sarcopenia increased from 34.5% at baseline to 39.3% at 24 months in pts undergoing A therapy (p = 0.71); the median PMI of A pts at baseline was 6.79 (95%CI 5.48-7.22) and steadily decreased to 5.86 (5.46-6.42) at 24 months (p = 0.0002). As for E, the rate of sarcopenia increased from 24.1% to 39.3% after 24 months of treatment (p = 0.21), with a concurrent PMI decrease from 6.73 (95%CI 5.87-7.64) to 6.32 (5.25-6.90; p = 0.001). There were no significant PMI differences between the A and E cohorts at baseline, month 12, or month 24. Furthermore, the presence versus absence of baseline sarcopenia was not significantly associated with the time on A or E therapy (p = 0.15 and p = 0.54, respectively). Conclusions: A sizeable number of men with mCRPC are sarcopenic at start of A or E therapy. In addition, the use of both agents is associated with an increase in the rate of sarcopenia, and with significant PMI decreases over time. The sarcopenia-inducing potential of A and E is comparable, while baseline sarcopenia seems not to predict time on A or E.