bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient perspectives on the impact of immune therapy on comorbid conditions in kidney cancer.
Authors: Vaishampayan Ulka N. , Staehler Michael D. , Pal Sumanta Monty , Zipperer Emma , Vaishampayan Neil , Shah Neha , Battle Dena 
Published: March 2023

640 Background: Immune based regimen has rapidly become the mainstay of frontline therapy in advanced RCC. The median survival is in the range of 48-55 months and long term remissions are feasible. The impact of the therapy on other health conditions has not been studied. The immune therapy toxicities can potentially be long lasting and life changing. With the conversion of advanced RCC to a chronic disease, awareness and management of these conditions is important. With the use of immune checkpoint therapy in the adjuvant setting has made this information even more critical. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Multiple responses from the same patient were prohibited via anonymized IP address tracking. The comorbid conditions were collected and patient perspective on changes to any medical conditions was evaluated in the survey questionnaire. Results: Patients with metastatic disease being treated with systemic therapy were included in this survey. A total of 1062 patients responded to the survey of which 399 patients self identified as being metastatic and 289 reported to be treated with immune based systemic therapy. The table includes patient characteristics. 85% respondents were from the United States. The most common condition that developed after starting immune based therapy was thyroid dysfunction as seen in 81 patients, followed by hypertension (Htn) in 50 pts, chronic kidney disease in 23 pts, heart disease in 10 patients and diabetes mellitus (DM) in 13 pts. Immune disorders developed in 26 (10%) patients. Conclusions: There is a noteworthy incidence of medical conditions emerging as a result of immune checkpoint inhibitor therapies in RCC. This information would be a starting point for studying the long term effects of immune therapy and would lead towards development of survivorship programs for renal cancer. [Table: see text]
Consideration for reclassification of pathologically upstaged T3a renal cell carcinomas.
Authors: Puri Dhruv , Wang Luke , Meagher Margaret F , Shah Aastha , Ghassemzadeh Saeed , Liu Franklin , Nguyen Mimi , Dhanji Sohail , Hakimi Kevin , Nasseri Ryan , Javier-Desloges Juan , McKay Rana R. , Derweesh Ithaar H 
Published: March 2023

644 Background: Pathological upstaging to pT3a disease can occur after the surgical treatment of clinical T1 and T2 Renal Cell Carcinomas (RCCs), and this upstaging has been previously shown to be associated with poorer outcomes. With an intent to delve deeper into the disparateness in outcomes of pT3a disease, we investigated the survival of patients with an initial clinical stage of cT1, cT2 and cT3a. Methods: Using the National Cancer Database (NCDB), patients with RCC were categorized by pathological and clinical staging of RCC according to the American Joint Committee on Cancer Guidelines (AJCC). The primary outcome was measured as overall survival (OS) at the end of follow up. Five-year survival rates and Kaplan-Meier Analysis assessed the differences between cT1 → pT3a, cT2 → pT2, cT2 → pT3a, and cT3a → pT3a. Multivariable cox regression (MVA) assessed predictors OS with age, sex, ethnicity, Charlson Score, socioeconomic status, geography, tumor size histology and grade, lymph node metastasis, surgical margins, and surgery type (partial versus radical nephrectomy) as covariates. Results: 53908 patients were analyzed (10789 cT1 → pT3a, 22183 cT2 → pT2, 9676 cT2 → pT3a, 11260 cT3a → pT3a, mean follow up 62.3 months). Of all pT3a patients, 64.5% were upstaged from cT1-2. MVA for OS demonstrated Hispanic ethnicity to be protective (hazard ratio [HR]=0.88, P<0.001) and revealed different histologic risks. MVA for OS demonstrated that cT2 → pT3a (HR=1.33, P<0.001, cT1 → pT3a [ref]) and cT3a → pT3a (HR=1.35, P<0.001, cT1 → pT3a [ref]) were associated with worsened OS, and that cT1 → pT3a and cT2 → pT2 (HR=0.96, P<0.052, cT1 → pT3a [ref]) were associated with improved OS. Kaplan-Meier analysis revealed a difference in 5 year overall survival as well (cT1→pT3a 72%, cT2→pT2 77%, cT2→pT3a 61%, and cT3a→pT3a 59%, p < 0.001). Conclusions: Patients with cT1 upstaged to pT3a have similar outcomes to cT2 staged to pT2 and better outcomes than cT2 upstaged with the latter’s outcomes being more like cT3a staged to pT3a. The TNM staging system from AJCC for RCCs should consider these outcomes and adjust the grouping for RCCs accordingly.
Does the time-of-day administration of immune checkpoint inhibitors affect efficacy in patients with metastatic renal cell carcinoma? A single-center study.
Authors: Fernandez-Mañas Laia , Gonzalez Aguado Laura , Aversa Caterina , Ferrer-Mileo Laura , Garcia de Herreros Marta , Jiménez Natalia , Febrer Albert , Vernet Roger , García-Esteve Samuel , Mellado Begona , Reig Torras Oscar 
Published: March 2023

681 Background: Immune checkpoint inhibitors (ICI) are the standard of care for metastatic renal cell carcinoma (mRCC). Circadian rhythm drives organisms to properly predict and react to cyclical changes in the environment, and also affects the adaptive immune response. Here, we study the relationship between time-of-day ICI administration and outcomes in mRCC patients (pts). Methods: This is a single-center retrospective study of ICI-treated mRCC pts diagnosed from January 2014 to March 2022. Day and time of each ICI infusion (inf) for each pt were obtained from the pharmacy records. Proportion of ICI inf administered after 4:30 pm (ICI430) was calculated based on a prior publication (Quian, Lancet Oncol 2021). The primary outcome was overall survival (OS), and secondary endpoints were time on treatment (TOT), time to next treatment (TNT), and overall response rate (ORR). The proportion of ICI430 as a continuous variable, and the dichotomized data (≥20% and ≥50%) were correlated with OS, TOT and TNT by Kaplan-Meier analysis and Cox regression, and with ORR by logistic regression. Results: Overall, 104 pts and 1763 inf were analyzed (Table). 48 pts were treated with 1st line (1L) ICI. 903 inf were administered (median 12 inf per pt, 1 - 111), 146 (15.6%) after 4:30 pm. 12 (25%) and 2 (4.2%) pts received ≥ 20% and ≥ 50% ICI430. Due to the small number of events (5 deaths and 15 progressions), of ICI430, and heterogeneity of treatments in 1L, we focus on pts treated with 2nd line (2L) ICI. 56 pts were treated with ICI in ≥2L. 860 inf were administered (median 8 inf per pt, 1 - 123), 180 (20.9%) after 4:30 pm. 15 (34.1%) and 9 (20.5%) pts received ≥20% and ≥50% ICI430. Pts who received ≥20% after 4:30pm, received fewer inf (7 vs. 16, p=0.022), had a worse TOT (4.3 vs. 9 m, HR 2.5, p=0.013), a trend to a worse TNT (6.3 vs. 10.5 m, HR 1.9, p=0.06) and a worse OS (16.9 vs. 56.1 m, HR 3.1, p=0.01). Similar results were obtained when using ≥ 50% ICI430 as the cut-off (TOT, 2 vs. 9m, p=0.007; TNT 4.7 vs. 10.5m, p=0.05; OS 16.9 vs. 36.6m, p=0.1), as well as higher frequency of progressive disease (85.7 vs. 21.9%, p=0.006). A significant association with OS (HR 1.02, p=0.03) was shown when analyzing ICI430 as a continuous variable, meaning a 16% increase in the risk of death for each 10% increment of ICI inf after 4:30 pm. Conclusions: Administration of ≥2L ICI after 4:30 pm is associated with poor overall survival. Our results could have a direct impact on pt survival and organization of outpatient clinics, but further research is needed. [Table: see text]
Immune checkpoint inhibitors in the peri-operative setting in renal cell carcinoma: A meta-analysis of the randomized clinical trials.
Authors: Esteban Villarrubia Jorge , Carril-Ajuria Lucía , Carretero-González Alberto , Romero Ferreiro Carmen , Álvarez Pablo , Ruiz-Vico Maria , Castellano Daniel , de Velasco Guillermo 
Published: March 2023

682 Background: Localized and oligometastatic resectable renal cell carcinoma (RCC) have moderate to high rates of relapse after surgery and evidence regarding the efficacy of perioperative treatments is conflicting. The risk of relapse varies across studies and there is a need to define the benefit/risk of immune checkpoint inhibitors (ICI) in this setting to optimize their use. Methods: A meta-analysis of the randomized phase 3 trials of peri-operative treatment with anti-PD-1/PD-L1 agents or anti-PD1/antiCTL4 in combination was conducted. The primary outcomes of interest were disease-free survival (DFS) and overall survival (OS). Secondary outcomes of interest were the proportion of grade 3-4 adverse events (AE) according to CTCAE 5.0. Subgroup analyses were performed according to clinically relevant characteristics. Statistical heterogeneity assumption was evaluated by the χ²-based Cochran’s Q test and quantified with the I² statistic. All statistical analyses were performed using Stata software (StataCorp LLC), version 16. Results: Published results of 4 phase 3 trials were included, involving 3393 patients. 1695 patients received ICI (anti-PD1: 900 patients; anti-PD-L1 390 patients, antiPD1/anti-CTLA4 405 patients) while 1712 received no active treatment (1297 placebo, 415 observation). ICI did not show to increase DFS (Hazard ratio (HR) 0.84 95% CI 0.69-1.03 p 0.10) or OS (HR 0.73 95% CI 0.40-1.34 p 0.31). High-grade AEs were 2.6 times more frequent in the immunotherapy arm (OR 2.64 95% CI 1.54 – 4.68 p < 0.001) while high grade treatment-related AEs were 8 times more frequent in the experimental arm (OR 8.60 95% CI 3.23-22.91 p < 0.001). Interestingly, subgroup analyses showed statistically significant differences favoring the experimental arm in females (HR 0.72 95% CI 0.55-0.93 p 0.01), in patients with sarcomatoid differentiation (HR 0.59 95% CI 0.403-0.88 p 0.010) and PD-L1 positive tumors (HR 0.74 95% CI 0.61-0.90 p 0.003). No significant effect was found in patients according to age, type of nephrectomy (radical vs. partial), and stage (M1 without evidence of disease vs M0 patients). Conclusions: The introduction of anti-PD-(L)1 +/- anti-CTLA-4 agents in the adjuvant setting of RCC might benefit selected RCC patients, although with increased toxicity. Longer follow-up of the conducted studies is needed to establish a potential benefit in long-term survival.
Real-world prostate-specific antigen (PSA) response and disease progression among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) initiated on apalutamide (APA).
Authors: Lowentritt Benjamin H , Du Shawn , Rossi Carmine , Kinkead Frederic , Waters Dexter , Moore Bronwyn , Lefebvre Patrick , Pilon Dominic , Muser Erik 
Published: March 2023

69 Background: For patients with nmCRPC, APA with androgen deprivation therapy is an important therapeutic option with demonstrated efficacy in improving metastasis-free survival (MFS), and other clinical outcomes. However, there is limited real-world information on these outcomes among patients with nmCRPC treated with APA. This study describes PSA response and MFS among patients with nmCRPC treated with APA in the United States as compared to the SPARTAN registrational trial. Methods: Clinical data from 2/2017 to 4/2022 collected from 77 community-based urology practices were used to evaluate patients with nmCRPC who received ≥1 APA dispensation (index date being the date of first dispensation). Patients were excluded if they had previously used another next-generation antiandrogen or had <12 months of pre-index clinical activity. PSA response was evaluated while on treatment and was defined as a post-index ≥90% decline (PSA90) in PSA from baseline (using the closest PSA value within 13 weeks prior to or on the index date) and was reported in patients with ≥1 post-index PSA test result by 3 months, 6 months, 12 months and overall. Disease progression was evaluated as MFS and defined as the time from index date to the occurrence of metastasis or death, whichever occurred first. Disease progression was described using Kaplan-Meier (KM) analysis by 6-month increments up to 24 months post-index. Results: A total of 406 patients with nmCRPC (mean age 78.8 years, 73% white, mean baseline PSA 9.0 ng/mL) were identified. Among 96 patients with available data, the mean (median) baseline PSA doubling time was 9.9 (7.5) months. The mean (median) treatment duration was 434 (305) days. PSA90 rates were 40% by 3 months, 51% by 6 months, 56% by 12 months, and 58% overall. KM rates for MFS were 95% at 6 months, 90% at 12 months, 82% at 18 months, and 75% at 24 months. PSA response and MFS for real-world patients were consistent with those observed from the SPARTAN trial. Conclusions: This real-world study of patients with nmCRPC demonstrates that APA treatment resulted in early, deep PSA responses, consistent with the SPARTAN trial. Moreover, MFS observed in the real-world was similar to that of the SPARTAN trial. [Table: see text]
Assessment of surgical complications in patients with metastatic clear cell renal cell carcinoma (mccRCC) receiving perioperative cabozantinib and nivolumab on Cyto-KIK clinical trial.
Authors: Runcie Karie , Ornstein Moshe Chaim , Saraiya Biren , Krishnamurthi Venkatesh , Lee Byron H , Anderson Christopher B. , DeCastro Guarionex Joel , McKiernan James M. , Dallos Matthew , Mayer Tina M. , Marron Melanie , Kulik Alexandria , Singer Eric A. , Stein Mark N. 
Published: March 2023

691 Background: The perioperative safety of cabozantinib and nivolumab in mccRCC, and the optimal timing to hold cabozantinib prior to surgery, are unknown. Methods: In this phase 2 trial, patients with mccRCC are given cabozantinib (40mg daily) and nivolumab (480mg q4 weeks) for 12 weeks prior to cytoreductive nephrectomy. Post-operatively, patients resume treatment with cabozantinib and nivolumab until disease progression. A 3+3 design was used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabozantinib and nephrectomy. Evaluable patients completed at least 10 of 14 cabozantinib doses prior to the pre-specified period of stopping pre-operative cabozantinib. Surgical complications assessed using the Clavien-Dindo classification system is a secondary endpoint of this study. Results: 16 patients have been enrolled and 14 completed nephrectomy to date. 12 (75%) of patients are male, 4 (25%) female, ages 44-77 years old with median age at diagnosis 58.5 years old. BMIs ranged from 17.8 kg/m2 to 39.3 kg/m2 with median BMI of 28.7kg/m2. 63% of patients were classified by IMDC as intermediate-risk and 37% as poor-risk disease. Dose reductions of cabozantinib occurred in 14% of patients who completed nephrectomy and cabozantinib held in 42% of nephrectomy patients during the course of treatment. Three evaluable patients completed nephrectomy within the 21-day interval and 5 within the 14-day interval after discontinuation of cabozantinib. There were no treatment-related surgical complications in patients who completed nephrectomy and there were no delays in resuming combination systemic therapy after surgery. Conclusions: Combination cabozantinib and nivolumab can be safely administered up to 14 days prior to cytoreductive nephrectomy. Clinical Trial Information: NCT04322955 Clinical trial information: NCT04322955 .
Efficacy of immune-checkpoint inhibitor (ICI) combination as a first-line (1L) therapy in metastatic renal cell carcinoma (mRCC) with sarcomatoid histology: A systematic review and meta-analysis.
Authors: Siddiqi Rabbia , Kumar Gaurav , Ijaz Hafsah , Naqvi Syed Arsalan Ahmed , Ayaz Ahsan , Riaz Zaryab Bin , Bryce Alan Haruo , Ho Thai Huu , Riaz Irbaz Bin , Singh Parminder 
Published: March 2023

692 Background: Sarcomatoid mRCC exhibits poor prognosis and limited response to vascular endothelial growth factor pathway inhibition. Therefore, we assessed the efficacy of ICI combination therapy in this patient population using data from contemporary trials. Methods: MEDLINE and EMBASE were searched to identify phase III randomized controlled trials (RCTs) comparing the efficacy of ICI combinations with sunitinib monotherapy in patients with sarcomatoid mRCC. Patient important outcomes of interest included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR). Precomputed hazard ratios (HR) with 95% confidence intervals (CI) for survival outcomes and binary outcome data for response rates (expressed as relative risk [RR] were meta-analyzed using a DerSimonian-Lairds random-effects method. Mixed treatment comparisons among different ICI combinations were made using a network-meta-analysis within the Bayesian framework. The surface under the cumulative ranking curves (SUCRA) were computed to assess the relative treatment rankings. Results: Six RCTs with a total of 618 patients were considered eligible for inclusion. ICI combination therapy was significantly associated with improved OS (HR: 0.56; 95% CI: 0.43-0.72) and PFS (HR: 0.50; 0.40-0.62), increased ORR (RR: 2.42; 1.92-3.06), and CR (RR: 4.23; 2.00-8.93) when compared to sunitinib in patients with sarcomatoid mRCC (Table). The results were consistent with Hartung-Knapp adjustment. Mixed treatment comparisons using current data revealed no statistically significant differences among different ICI combinations. However, the combination of nivolumab-ipilimumab was consistently ranked higher (rank 2 for OS, ORR, and CR) and may potentially be more efficacious than other counterparts. Conclusions: Current evidence suggests improved survival, delayed disease progression and increased response rates with the use of ICI combination therapy in patients with sarcomatoid mRCC. [Table: see text]
Association of mitochondrial metabolic activity and immune pathways with disease stage in renal cell carcinoma.
Authors: Gulati Shuchi , Shamsaei Behrouz , Vemuri Bhargav , Yang Juechen , Secic Dina , Bischoff Megan , Figueroa Julio A Landero , Plas David R. , Cunningham Tom , Meller Jarek , Czyzyk-Krzeska Maria F. 
Published: March 2023

722 Background: Previous large scale genomic studies have described somatic alterations that affect tumor progression. However, metabolic and immune pathway changes that occur with advancing disease stage are not well characterized. Herein, we performed transcriptomic profiling of clear-cell renal carcinoma (ccRCC) tumors across clinical stages to define these changes. Methods: TCGA Firehose Legacy cohort was used to determine differential gene expression between stage 3 ccRCCs from patients who remained disease free (S3DF) vs. those who relapsed (S3RL) within two years of nephrectomy. Single cell RNA-seq (scRNAseq) analysis was performed on primary ccRCCs from nine patients (stage 1 n=4, stage 3 n=4, metastatic n=1). Seurat V4 package and module score was used to analyze patterns of gene expression associated with tumor progression at the single cell level. Results: Transcriptomic comparison of ccRCCs from TCGA Firehose Legacy cohort revealed induction of genes encoding mitochondrial respiratory complexes and mitochondrial ribosomal proteins (MRPs) and decrease in expression of immune genes in S3RL as compared to S3DF tumors. Using a set of 23 differentially regulated mitochondrial and immune genes we established a transcriptomic signature that stratified patients into those at risk of relapse vs. not. ScRNA-seq data analysis determined increased expression of mitochondrial respiratory complexes’ gene-sets, and decreased levels of glycolytic genes and HIF targets during tumor progression from stage-I to metastatic. This was supported by spatial transcriptomics of cancer cells, which revealed clusters of cells with high mitochondrial activity and decreased MHC class I and II gene expression. Conclusions: The data support a model of progressive metabolic reprogramming from glycolysis and HIF-regulated pathways to mitochondrial respiration in parallel with diminished immune expression of antigens on cancer cells with advancing disease stage in ccRCC. Identification of targetable mitochondrial vulnerability could be a therapeutic option in patients who progress on immune checkpoint inhibitors.
Time interval between radium-223 (223Ra) therapy and Lutetium-177–prostate-specific membrane antigen (177Lu-PSMA) treatment and outcomes in the RALU study.
Authors: Rahbar Kambiz , Essler Markus , Eiber Matthias , la Fougère Christian , Prasad Vikas , Pabst Kim M. , Fendler Wolfgang Peter , Rassek Philipp , Hasa Ergela , Dittmann Helmut , Bundschuh Ralph A. , Kurtinecz Milena , Schmall Anja , Verholen Frank , Sartor A. Oliver 
Published: March 2023

73 Background: 223Ra and 177Lu-PSMA-617 both prolong overall survival (OS) in different mCRPC settings. The observational, retrospective study, RALU, investigated safety and clinical outcomes of sequential 223Ra/177Lu-PSMA therapy in patients (pts) with mCRPC. This analysis evaluated the association of time interval between 223Ra and 177Lu-PSMA treatments and safety and OS outcomes of 177Lu-PSMA. Methods: Retrospective data were collected from 2021–22 in German nuclear medicine centers for all pts receiving 177Lu-PSMA with prior history of 223Ra therapy. Time intervals were <6 months (mo) (Group [Grp]1) or ≥6 mo (Grp 2) from last 223Ra dose to first 177Lu-PSMA dose. Results: 42 pts received 177Lu-PSMA within 6 mo after 223Ra (Grp 1) and 90 pts received 223Ra ≥6 mo prior to 177Lu-PSMA (Grp 2). Baseline characteristics prior to 177Lu-PSMA therapy were, respectively: median ages 72 and 74 years; 57% and 63% with Eastern Cooperative Oncology Group performance status (ECOG PS) 1, 43% and 37% with ECOG PS 2; median prostate-specific antigen (PSA) values were 366 and 268 ng/ml, and median alkaline phosphatase (ALP) values were 133 and 149 U/L; 40% and 64% received ≥4 life prolonging therapies before starting 177Lu-PSMA. All pts had prior 223Ra; 57% and 77% received 6 223Ra injections; other prior therapies were abiraterone (60%, 77%), enzalutamide (50%, 78%), docetaxel (71%, 76%) and cabazitaxel (17%, 26%). Prior to 177Lu-PSMA, 24% and 29% of pts had visceral metastases. 45% and 52% of pts received ≥4 177Lu-PSMA cycles. From 177Lu-PSMA start to ≤30 days post last dose, 71% and 82% of pts had treatment-emergent adverse events (TEAEs) of any grade; most common were fatigue (12%, 7%), nausea (12%, 8%) and dry mouth (7%, 18%); 36% and 24% of pts had grade 3–4 TEAEs; excluding laboratory abnormalities, osteonecrosis of the jaw was the most frequent grade 3–4 TEAE (5%, 2%). Grade 3–4 laboratory abnormalities (177Lu-PSMA start to ≤90 days post last dose) are shown; treatment-related deaths were reported for 2% and 4% of pts. AEs led to treatment delays in 10% and 9% of pts. Median OS from start of 177Lu-PSMA was 12.0 mo (95% CI, 8.8–19.9) in Grp 1 and 13.2 mo (95% CI, 10.0–15.9) in Grp 2. During 177Lu-PSMA therapy, PSA response ≥50% occurred in 53% and 39% and ALP response ≥30% in 28% and 14% of pts, respectively. Conclusions: In this real-world setting, treating pts with 177Lu-PSMA within 6 mo of completing 223Ra was clinically feasible and well tolerated: no safety signals or concerns were seen. OS outcomes were similar in pts receiving 177Lu-PSMA <6 mo vs. pts receiving it ≥6 mo after completing 223Ra. [Table: see text]