bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastrointestinal metastases in renal cell carcinoma: A retrospective multicenter GETUG (Groupe d’Etude des Tumeurs Uro-Genitales) study.
Authors: Carneiro Florian , Vinceneux Armelle , Larroquette Mathieu , Rony Maelle , Carril Lucia , Laguerre Brigitte , Blazevic Ilfad , Barthelemy Philippe , Teyssonneau Diego , Goujon Morgan , Linassier Claude , Thiery-Vuillemin Antoine , Roubaud Guilhem , Mourey Loic , Albiges Laurence , Gravis Gwenaelle , Gross-Goupil Marine , Cancel Mathilde 
Published: January 2024

391 Background: Among patients with renal cell carcinoma (RCC), bone and visceral metastases have a poor prognosis, while endocrine gland metastases have a more favorable prognosis. Gastrointestinal metastases (GIMs) are rare, and their prognosis is still poorly understood. Objectives: To report clinical presentations, patients’ characteristics, therapeutic strategies, and prognosis of GIMs from RCC. Methods: We retrospectively collected data from RCC patients presenting GIMs, in 10 French GETUG centers, between 2000 and 2021. Results: We identified 74 patients with 87 GIMs, mostly gastric or duodenal. The median age at GIM diagnosis was 69 years and 76% of the patients already had other metastases. GIMs occurred after a median of 5.4 years (IC95%=[4.2-7.1]) and 1.9 years (IC95%=[1.2-3.8]) from RCC diagnosis and first metastasis, respectively. GIMs were symptomatic in 52 patients (70%), with anemia in 41 patients (55%) and/or gastrointestinal bleeding in 31 patients (42%). Only 22 asymptomatic patients (30%) were fortuitously diagnosed. The management of GIMs consisted of systemic treatment only in 29 GIMs (33%), local treatment only in 23 GIMs (26%), and both local and systemic treatment in 18 GIMs (21%). For 17 GIMs (20%), there was no therapeutic modification. After diagnosis of GIM, median overall survival was 19 months. Conclusions: We report the largest retrospective cohort of GIMs in RCC patients. They should be suspected in case of anemia or gastrointestinal bleeding in any patient with a history of RCC. Their management varies widely depending on their location in the digestive tract and whether they are symptomatic.
Real world evidence comparison of first-line (1L) immune-oncology(IO)/tyrosine kinase inhibitor (TKI) vs. IO/IO combination therapy in renal cell carcinoma (RCC).
Authors: Bolan Patrick , Hui Gavin , Low Yen , Gombar Saurabh , Fan Alice C. , Parikh Divya Ahuja , Shah Sumit , Srinivas Sandy , Khaki Ali Raza 
Published: January 2024

402 Background: IO/IO and IO/TKI are the preferred first-line combinations for treatment of RCC. While these combinations have been superior to sunitinib, no head-to-head clinical trials have been completed, which leaves uncertainty about the preferred combination. Here, we have leveraged ASCO Cancerlinq data to compare overall survival for RCC patients (pts) receiving first line IO/IO vs. IO/TKI combinations. We hypothesized that IO/IO and IO/TKI would have similar survival. Methods: We performed a retrospective cohort study comparing IO/IO vs IO/TKI therapy for pts with metastatic RCC. We used the Atropos health platform, which is a commercial platform and queried ASCO CancerLinq data for this study. We identified pts with kidney cancer who received IO/IO or IO/TKI combinations between 2019 and 2023. For our primary analysis, we included only pts with ICD10 code consistent with clear cell [cc]RCC, but also did a secondary analysis including all pts with kidney cancer. The IO/TKI pts received either avelumab/axitinib, pembrolizumab/axitinib, nivolumab/cabozantinib, pembrolizumab/lenvatinib, or atezolizumab/cabozantinib within two weeks of each other. The IO/IO pts were identified as pts receiving ipilimumab and nivolumab within 2 weeks of each other without interceding TKI. We conducted a survival analysis of time to death using Cox proportional hazards regression to compare the two groups. The analysis was performed under three different confounder adjustment scenarios: without adjustment, with basic matching on sex and age, and with high dimensional propensity score (hdPS) using inverse probability of treatment weighting. Results: A total of 584 pts (286 IO/IO and 296 IO/TKI) with kidney cancer and 146 with ccRCC (75 IO/IO and 71 IO/TKI) were included. Mean age was 63-65 years and 30-35% female sex across groups. Table shows the restricted mean survival time (RMST) and HR for the Cox models. In the ccRCC cohort, 20 pts with IO/IO and 7 with IO/TKI died with RMST of 947 and 1071 days, respectively (hdPS HR 0.35, p=0.03). In the RCC cohort, 76 pts with IO/IO vs 49 with IO/TKI died with RMST 1126 vs 1017 (hdPS HR 0.61, p=0.04). Conclusions: In this exploratory, hypothesis-generating analysis of CancerLinq data, pts treated with IO/TKI had longer OS vs those treated with IO/IO. Limitations include the retrospective nature of the study, low power, lack of randomization, and potential unmeasured confounding factors (e.g., confounding by indication). Further investigation and prospective validation are needed to confirm these findings. [Table: see text]
Retrospective study assessing the use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers to reduce toxicity from tyrosine kinase inhibitors in metastatic renal cell carcinoma.
Authors: Miller Theodore Joseph , Maddukuri Ashok , Elias Michael , Wheelden Megan , Trivedi Naman , Zhu Junjia , Joshi Monika 
Published: January 2024

411 Background: The main toxicities associated with tyrosine-kinase inhibitors (TKIs) in the treatment of renal cell carcinoma (RCC) are proteinuria and hypertension. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have established reno-protective and anti-hypertensive effects and can help with toxicity in mRCC. We hypothesize that use of ACEIs/ARBs is an effective method to decrease the degree of proteinuria and hypertension in patients treated with TKIs for metastatic/advanced renal cell carcinoma (mRCC). Methods: Single Institution retrospective study; mRCC patients (pts) who received TKI and ACEIs/ARBs and had urine protein measurements available at baseline and at 4-6 wk follow up post ACEs/ARBs were included in the analysis. Primary endpoints included improvement in grade of proteinuria and BP in mRCC pts on TKI treatment at baseline and with addition of ACEIs/ARBs. Secondary endpoints included number of dose interruptions (DI), BUN and creatinine changes. Paired statistical tests were used to compare the selected outcome variables between baseline and post ACE/ARB measures: for example, nonparametric Wilcoxon Signed-rank test for paired quantitative data and McNemar test for paired binary data. Results: Out of 71 screened patients between 2020-2023, N of 22 mRCC (N=22, 72.7% male, 77.3% white; 9% Hispanic; N=14 for TKI+ immunotherapy; N=8 TKI alone) pts were selected. ACEIs/ARBs treatment was associated with significantly reduced levels of proteinuria at 4–6wk follow-up. At baseline vs. follow-up, pts were found to have significantly lower proteinuria overall after ACEI/ARBs (p=0.0147), and 45.4% of pts had clinically insignificant proteinuria vs. 22.7% at baseline. Additionally, DI rates for TKI were significantly lower for pts placed on ACEIs/ARBs, with an 81% chance that pts with prior DI would not experience similar event in the follow-up period (p=0.003). Reductions in BP, creatinine, and TKI dosing were seen but not statistically significant (p>0.05 for all measures). Conclusions: In our small study, degree of proteinuria was notably reduced with administration of ACEIs/ARBs. Further findings show fewer DI of TKIs with ACEIs/ARBs use. Our findings suggest a potential role for ACEIs/ARBs in managing toxicity in patients undergoing TKI based therapy for mRCC. Future studies are needed to evaluate the use of ACE/ARB from the time of initiation of TKI based therapy to reduce the toxicities and improve the adherence to mRCC treatment which may result in better outcomes.
Impact of timing of immunotherapy and cytoreductive nephrectomy on outcomes in metastatic renal cell carcinoma: Results from the CKCis database.
Authors: Park Changsu , Ghosh Sunita , Moria Feras Ayman , Wood Lori , Bjarnason Georg A. , Bhindi Bimal , Heng Daniel Yick Chin , Castonguay Vincent , Pouliot Frederic , Kollmannsberger Christian K. , Bosse Dominick , Basappa Naveen S. , Finelli Antonio , Fallah-rad Nazanin , Breau Rodney H. , Lalani Aly-Khan A. , Tanguay Simon , Graham Jeffrey , Saleh Ramy R. 
Published: January 2024

416 Background: Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC but its role and timing are not well-understood in the era of immunotherapy. The primary objective of this study is to assess patient outcomes in patients who received ST only, CN followed by ST (CN-ST) and ST followed by CN (ST-CN). Methods: The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST for mRCC between January 2014 to June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression free survival (PFS), after adjusting for IMDC risk group. Complications of ST and CN for these cohorts were collected. Results: A total of 588 patients were included in this study. 331 patients received ST only, 215 patients received CN-ST and 42 patients received at least one dose of ST prior to CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST and metastatic sites are reported and globally well-balanced. OS analysis favoured patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13-0.68) and CN-ST (HR 0.68, CI 0.47-0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26-0.77) and CN-ST (HR 0.9, CI 0.68-1.17). The most common cause of ST delay or cessation was treatment toxicity, followed by progression of disease. The most common perioperative complication was bleeding, followed by infection. Conclusions: This study examined baseline features and outcomes associated with the use and timing of CN and ST using real world data through the CKCis database. Patients selected to receive CN after ST seem to have improved outcomes. There were no appreciable differences in ST toxicity or perioperative complications across groups. Limitations include the small number of patients in the CN-ST group and residual confounding and selection bias that may influence the outcomes in patients undergoing CN.
Nucleosome profiling at AR binding sites (ARBS) to provide a prognostic tool for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dai Chao , Zhu Lisha , Fettke Heidi , Gan Shuang , Du Pan , Jia Shidong , Azad Arun 
Published: January 2024

42 Background: Prostate cancer is the second leading cause of cancer death for men in the U.S., and metastatic castration-resistant prostate cancer (mCRPC) is the most advanced form. In previous work, we have reported prognostic significance of PTEN-PI3K-AKT pathway and DNA damage response aberrations detected in cell-free DNA (cfDNA) of mCRPC. Here we utilized nucleosome profiling pattern at androgen receptor (AR) binding sites to further investigate AR signaling pathway dysregulation of mCRPC. Methods: Using the next-generation sequencing PredicineScore liquid biopsy assay (low-pass whole genome sequencing, LP-WGS), we profiled cfDNA fragment coverage centered around AR binding sites (ARBS). For 118 mCRPC patient samples, we quantified sample-level ARBS nucleosome profiling abnormality score (ARBS score) by comparing its centric fragment coverage with normal plasma background using standard Z-score. ARBS score was correlated with clinical outcomes including PSA response rate (PSA RR), progression-free survival and overall survival (OS). Results: By comparing ARBS nucleosome profiling and normal plasma background, we found that mCRPC plasma samples had significant ARBS nucleosome depletion, reflective of transcription factor binding and persistent AR signaling. Notably, ARBS nucleosome depletion was prostate cancer specific, and did not occur in other examined cancer types. ARBS score was highly correlated with tumor fraction (R=0.82), indicating that high tumor fraction mCRPC sample had higher AR binding. Importantly, we found that high ARBS score (>2) in pre-treatment samples (n=86) was associated with significantly shorter OS and lower PSA RR compared with low ARBS (≤2) group for patients receiving AR pathway inhibitor (ARPI) or taxane chemotherapy (13.4 vs. 19.4 months, p=7.3×10-3, 45.7% vs. 77.5%, p=5.2×10-3). By integrating genome-wide DNA methylation profiling, we further found that ARBS was hypo-methylated in mCRPC patients, and identified a strong negative correlation between DNA methylation beta value and ARBS score (R=-0.83). Conclusions: ARBS nucleosome profiling abnormality inferred from LP-WGS can serve as a key prognostic tool for mCRPC patients. Patients with high ARBS score had worse clinical outcomes, highlighting the potential clinical utility of cfDNA fragmentomics analysis for mCRPC patient stratification. Integration of mutation, copy number variation and fragmentomics profiling of ARBS may further enhance our understanding of molecular aberrations and treatment outcomes in mCRPC.
A phase II study of neoadjuvant tislelizumab and axitinib in patients with locally advanced non-metastatic clear cell renal cell carcinoma (accRCC).
Authors: Zhang Shun , JI Changwei , Liu Guangxiang , Guo Hongqian 
Published: January 2024

420 Background: PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors improves survival in patients with advanced renal cell carcinoma (RCC), but the role of perioperative application in patients with localized RCC has not been established. In this phase II trial, we investigate the safety and role of tislelizumab and axitinib in downsizing tumors in patients with non-metastatic clear cell RCC prior to surgical resection. Methods: In this investigator-initiated study, 20 patients with high-risk non-metastatic ccRCC (clinical stage T2a-4 and/or N1, M0 lesions) were enrolled to receive 12 weeks of neoadjuvant ticelizumab and axitinib prior to nephrectomy. The primary endpoint was the objective response rate (complete and partial response) after neoadjuvant treatment according to RECIST v1.1. Secondary endpoints were disease-free survival (DFS), overall survival (OS), surgical outcome and safety. Results: By September 2023,13 eligible pts were enrolled. 11 pts have completed neoadjuvant therapy, with a median age of 60 (range 45-73) years, among whom 9 pts underwent surgery as planned without any delay. One patient progressed during treatment and received further systemic therapy. In 9 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 55.5%. The median reduction of primary renal tumor size was 26.2% (range 12.5-45%). Pathologic results showed that one patient (11.1%) achieved a complete response (CR) by RECIST 1.1 and four patients achieved a partial response (PR). One patient who was considered unresectable became resectable at the end of treatment. Two patients were converted from radical to partial nephrectomy. The most common neoadjuvant therapy-related AEs were hematologic toxicity, hypothyroidism, nausea, vomiting, decreased appetite, fatigue, diarrhea, and elevated ALT/AST. There were no Gr4/Gr5 TRAEs. No direct intraoperative complications and no drug-related surgical complications postoperatively. Conclusions: As a neoadjuvant therapy for accRCC, the combination of tislelizumab and axitinib has clinical efficacy and a manageable safety profile. Clinical trial information: NCT05172440 .
Key parameters that influence surgical strategy in localised kidney cancer.
Authors: Pikul Maksym , Heidenreich Axel , Stakhovsky Eduard , Semko Sofiya , Pfister David A. , Voylenko Oleg , Paffenholz Pia , Kononenko Oleksii , Vitruk Iuriy , Stakhovskyi Oleksandr 
Published: January 2024

423 Background: The goal of this studywas to select the key factors affecting choice between radical nephrectomy (RN) and partial nephrectomy (PN) for patients with localized RCC based on clinical and nephrometry data. Methods: A special retrospective cohort study was conducted in National Cancer Institute of Ukraine, which results were further validated on patient dataset in urological department of University Clinic of Cologne. The Institutional Review Boards and the local ethics committees of both high-volume centres approved the study. The main nephrometry parameters of tumor location in the kidney were analysed according to the R.E.N.A.L nephrometry score. The remaining functional parenchymal volume (RFPV) was calculated using the special formula. To determine the relationship between the risk of RN or PN, the multivariate predictive modelling method containing 12 parameters was used (Artificial Neural Networks [ANN]). Data validation based on referential centre experience using ROC-curve analysis to detect clinical applicability of the null hypothesis was performed. Results: Based on the analysis, for polary and laterally located tumors, the risk of RN was conditioned only by RFPV. The average critical value of RFPV for polar lesions was X6crit = 58% (in X6 < X6crit, RN was predicted); for lateral tumors - X6crit = 67% (in X6 < X6crit, RN was predicted). For medial location, the risk of RN only depended on the tumor size. Average critical value of the tumor size in the medial location was X7crit = 38 mm (in X7 > X7crit, RN was predicted). Based on the ROC curve comparison, there were no statistically significant differences between the AUCLin_12 and AUCMLP_3 (p = 0.12); thus, the reduced amount of the factor indicators from 12 to 3 did not worsen the model predictive qualities. Designed during primary analysis hypothesis was successfully validated in a referent centre on the cohort of 300 patients. Out of the cohort - 14 (4.6%) patients experienced false positive/negative outcome, which resulted in a radical/partial nephrectomy out of the hypothesis margins. Predictive model is characterized by high sensitivity (95.2%) and specificity (95.4%) in selecting patients for partial nephrectomy. Conclusions: For the polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67% respectively serve as PN indications. However, for the medial lesions, the primary PN indication is a tumor size less than 38 mm.
Cytoreductive nephrectomy in patients with metastatic renal cell carcinoma treated with immunotherapy: A systematic review and meta-analysis.
Authors: Zhao Fengnian , Chen Junru , Liu Haoyang , Zeng Hao 
Published: January 2024

427 Background: lmmunotherapy is changing the treatment of patients with metastatic renal cell carcinoma (mRCC). In recent years, many immune checkpoint inhibitors (ICls) have been introduced, and ICl-combination therapies have changed the treatment landscape for patients with mRCC. However, the role of cytoreductive nephrectomy (CN) in patients with mRCC receiving ICls is not clear. We aimed to assess the role of ICl-combination therapies in patients receiving /not receiving CN. Methods: PubMed, Embase, and Cochrane Library databases were searched for English-language clinical trials, cohort studies, and case-control studies evaluating OS in patients with mRCC who underwent /did not undergo CN (end-of-search date: 1 April 2023). The hazard ratio [HR] and 95% confidence interval [CI] for OS obtained by multivariate analysis were extracted and aggregated. Meta-analysis was performed using Review manager 5.4.1, and p<0.05 was defined as a statistical significance. Results: Eleven studies met the eligibility criteria. Receiving CN+ICI combination therapy was associated with significantly better OS than patients receiving ICI combination therapy alone (HR: 0.56，95% CI: 0.46-0.69, P < 0.001). In subgroup analyses, thinking about the number of lines for immunotherapy, CN provided OS benefit when immunotherapy was used as either first-line (HR: 0.54, 95% CI: 0.41-0.70, P < 0.001) or non-first-line treatment (HR: 0.59, 95% CI: 0.44-0.81, P = 0.001). In terms of tumor pathologic type, CN also provided OS benefit no matter the pathologic type was only clear cell renal cell carcinoma (ccRCC) (HR: 0.52, 95% CI: 0.28-0.95, P = 0.03) or not (HR: 0.54, 95% CI: 0.39-0.75, P < 0.001). For the choice of drugs, CN provided OS benefits with nivolumab/nivolumab + ipilimumab (HR: 0.50, 95% CI: 0.32-0.79, P = 0.003) or immunotherapy combined with tyrosine kinase inhibitors (HR: 0.59, 95% CI: 0.48-0.73, P < 0.001). About the timing of CN, CN also provided OS benefit when performing before immunotherapy (HR: 0.63, 95% CI: 0.54-0.73, P < 0.001) or no strictly restricted (HR: 0.49, 95% CI: 0.33-0.74, P = 0.0007). Conclusions: CN brings good effect on OS in mRCC patients treated with ICI-combination therapies. In ICI-combination therapy era, the role of CN still deserves attention.
Outcomes and prognostic factors of first-line combination of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in TFE3-rearranged renal cell carcinoma.
Authors: Zhao Junjie , Tang Yanfeng , Hu Xu , Chen Junru , Liu Haoyang , Liu Haolin , Liang Jiayu , Zhang Xingming , Zhao Jinge , Shen Pengfei , Liu Zhenhua , Sun Guangxi , Zeng Hao 
Published: January 2024

429 Background: Due to the rarity of TFE3-rearranged renal cell carcinoma ( TFE3-rRCC) and the poor understanding of its underlying mechanisms, the clinical treatment landscape in TFE3-rRCC is largely undefined. Hence, the optimal therapy for TFE3-rRCC remains to be determined. The diversity of fusion partners leads to the high heterogeneity of TFE3-rRCC, yet no studies have compared responses of patients with different fusion partners to systemic treatment. Methods: Data were collected retrospectively from our institution. Patients with metastatic TFE3-rRCC were eligible. Kaplan-Meier survival analysis and univariate and multivariate analysis were performed to compare survival outcomes. RNA-seq was performed to determine fusion partners and explore the transcriptomic features. Results: A total of 38 patients with metastatic TFE3-rRCC were enrolled in this study. The fusion partners were identified in 33 (87%) patients. Patients receiving first-line ICI plus TKI had longer PFS than those not receiving first-line ICI plus TKI (median PFS: 11.5 vs. 5.1 months, P=0.098). Subgroup analysis demonstrated that patients with ASPSCR1-TFE3 fusion significantly benefited from ICI plus TKI (PFS HR: 0.068, 95% CI: 0.008-0.609, P=0.016), whereas no improvement in PFS was observed in patients with other fusions. Univariate and multivariate cox regression analysis further demonstrated that besides IMDC risk score, ASPSCR1-TFE3 fusion could also serve as an independent prognostic factor for PFS in patients receiving first-line ICI plus TKI. Among patients receiving ICI plus TKI, those with ASPSCR1-TFE3 fusion had longer PFS than those with other fusions (median PFS: not reached vs. 6.5 months, P=0.01). Transcriptomic data revealed that ASPSCR1-TFE3 fusion rearranged RCC harbored higher angiogenesis activity. Additionally, decreased infiltration of immunosuppressive M2-phenotype macrophages and Tregs was observed in tumors with ASPSCR1-TFE3 fusion. Conclusions: Metastatic TFE3-rearranged RCC patients with ASPSCR1-TFE3 fusion could benefit from ICI plus TKI. Higher angiogenesis activity and decreased infiltration of immunosuppressive cells were observed in tumors with ASPSCR1-TFE3 fusions, which may explain the clinical outcome.