bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hospital-level quality indicators for kidney cancer surgery: A Veteran’s Affairs national health system validation of concept.
Authors: Aguilar Palacios Diego , Wilson Brigid , Saarela Olli , Ascha Mustafa , Song Sunah , DeWitt-Foy Molly Elmer , Lawson Keith , Barnholtz-Sloan Jill , Finelli Antonio , Campbell Steven , Abouassaly Robert 
Published: February 2020

667 Background: Validation and implementation of quality indicators (QIs) for oncological surgical care is imperative in national health care systems. However, QIs must be adjusted for significant case-mix variations among hospitals and to capture disparate patient outcomes. Here, we explore and validate a compound quality score (CQS) as a metric for hospital-level quality of care in kidney cancer patients. Methods: Kidney cancer patients (n = 8233) treated at the VA (2005-2015) were identified. Two previously described and validated process QIs were explored: the proportion of patients with a) T1a tumors undergoing partial nephrectomy; and b) T1-T2 tumors undergoing minimally invasive radical nephrectomy. Demographics, comorbidity, tumor characteristics and treatment year were used for case-mix adjustment using indirect standardization / multivariable regression models. The predicted vs observed ratio of cases was calculated to generate each QI score. CQS represents the sum of both QIs scores. Ninety-six hospitals were benchmarked by CQS and patient-level outcomes were regressed on CQS levels to assess for length of stay (LOS), 30 days complications/readmission, 90 days overall mortality and total cost of surgical admission. Results: CQS identified 25, 33 and 38 hospitals with higher, lower and average performance, respectively. Total CQS score was independently associated with LOS [β = -0.04, p< 0.01, predicted LOS 0.84 days shorter for CQS = 2 vs. CQS = -2], 30 days surgical complications [OR = 0.88, p < 0.01] or 30 days medical complications [OR = 0.93, p < 0.01] and total cost of surgical admission [β = -0.014, p< 0.01, predicted 12% lower cost for CQS = 2 vs. CQS = -2]. No association was found between CQS and 30 day readmissions or 90 days mortality (all p>0.05), although low event rates were observed (8.9% and 1.7%, respectively). Conclusions : Variability in quality of surgical care at a hospital-level can be captured with the CQS among kidney cancer patients. CQS is associated with length of stay, post-operative complications and total cost of surgical admission. Quality indicators should be used to identify, audit and implement quality improvement strategies across health systems.
Association of checkpoint inhibitor monotherapy with less cardiac toxicity than combination therapy.
Authors: Cone Eugene Blanchard , Reese Stephen , Marchese Maya , Nabi Junaid , Kilbridge Kerry L. , Trinh Quoc-Dien 
Published: February 2020

671 Background: Immune checkpoint inhibitors (ICIs) demonstrate impressive clinical benefit across a variety of cancers. NCCN guidelines for several cancers including renal cell carcinoma now support ICI monotherapy and combination therapy with ipilimumab. Cardiac toxicity is a rare but catastrophic adverse event associated with ICIs. We sought to define the comparative cardiac risk profile of ICI combination versus monotherapy in a real world setting. Methods: We used VigiBase, the World Health Organization database of case safety reports, which collects data from more than 130 countries to identify drug-associated adverse events. Using Medical Dictionary for Regulatory Activities terminology, we identified cardiac adverse events (AE) related to monotherapy (nivolumab, ipilimumab, pembrolizumab) or combination therapy (ipilimumab/nivolumab). To explore a possible relationship we used the reporting odds ratio (ROR), a surrogate measure of association using all other reactions as non-cases. A lower bound of a 95% confidence interval of ROR > 1 reflects a disproportionality signal that more AEs are observed than expected due to chance. Results: We found 7,644, 25,016, and 14,681, and 5,191 AEs for ipilimumab, nivolumab, pembrolizumab, and combination therapy respectively. No signal existed for overall cardiac events, but combination therapy was associated with significantly higher odds of pericarditis or myocarditis (ROR 6.9, 95% CI 5.7—8.3) versus pembrolizumab (5.6, 4.9—6.4), nivolumab (5.1, 4.6-5.7), or ipilimumab monotherapy (1.9, 1.4-2.7). Pericarditis and myocarditis with combination therapy was fatal for 23% of reported AEs, compared to 14%, 14%, and 20% for ipilimumab, nivolumab, and pembrolizumab (p = 0.003) respectively. Conclusions: Using validated pharmacovigilance methodology, we found significantly increased odds of myocarditis and pericarditis for all ICI, with the highest odds for combination therapy. These adverse events were often fatal. Further research is needed to identify patients at high risk for immunotherapy related cardiac toxicity.
Second-line VEGF TKI after IO combination therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Stukalin Igor , Dudani Shaan , Wells Connor , Gan Chun Loo , Pal Sumanta K. , Dizman Nazli , Powles Thomas , Donskov Frede , Wood Lori , Bakouny Ziad , Kollmannsberger Christian K. , Basappa Naveen S. , Hansen Aaron Richard , de Velasco Guillermo , Beuselinck Benoit , Canil Christina M. , Vaishampayan Ulka N. , Agarwal Neeraj , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2020

684 Background: Immuno-Oncology (IO) combinations are standard of care first-line treatment for metastatic renal cell carcinoma (mRCC). Data on therapy with vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) post-progression on IO-combination therapy are limited. Methods: Using the IMDC, a retrospective analysis was done on mRCC patients treated with second-line VEGF TKIs after receiving IO combination therapy. Patients received first-line ipilimumab+nivolumab (IOIO) or anti-PD(L)1+anti-VEGF (IOVE). Baseline variables and second-line IMDC risk factors were collected. Overall response rates (ORR), time to treatment failure (TTF) and overall survival (OS) were determined. Multivariable Cox regression analysis was performed. Results: 142 patients were included. 75 patients received IOIO and 67 received IOVE pretreatment. The ORR of 2nd line therapy was 17/46 (37%) and 7/57 (12%) in the IOIO and IOVE pretreated groups, respectively (p<0.01). 2nd-line TTF was 5.4 months (95% CI 4.1-8.3) for the IOIO- and 4.6 months (95% CI 3.7-5.8) for the IOVE-pretreated group (p=0.37). 2nd-line median OS was 17.2 months (95% CI 10.8-35.1) and 11.8 months (95% CI 9.9-21.3) for the prior IOIO and IOVE groups, respectively (p=0.13). The hazard ratio adjusted by IMDC for IOVE vs IOIO pretreatment was 1.22 (95% CI 0.73-2.07, p=0.45) for 2nd line TTF and 1.43 (95% CI 0.74-2.8, p=0.29) for 2nd line OS. Conclusions: VEGF TKIs show activity after combination IO therapy. Response rates are higher in patients treated with VEGF TKIs after first-line IOIO compared to after IOVE. In patients with VEGF TKI after IOIO or IOVE, no difference in OS and TTF was observed.[Table: see text]
Individualized dosing schedule of sunitinib switched through plasma concentration monitoring in patients with metastatic renal cell carcinoma.
Authors: Zhu Xudong , Zhang Xingming , Zhang Haoran , Ni Yuchao , Dai Jindong , Sun Guangxi , Zhu Sha , Chen Junru , Zhao Jinge , Wang Zhipeng , Zeng Hao 
Published: February 2020

694 Background: The aim of this study was to investigate the survival benefit and safety of switched dosing schedules for sunitinib in Chinese patients with metastatic renal cell carcinoma through plasma concentration monitoring. Methods: One hundred and twelve patients with mRCC were enrolled who were treated with Sunitinib. Patients were classified into 3 groups: switched dosing schedule through plasma concentration monitoring (4/2-2/1 schedule, 4/2-2/1-individualized and 2/1-individualized schedule), switched dosing schedule empirically due to severe adverse events (AEs)(4/2-2/1 schedule) and dosing schedule without switching (initial 4/2 or 2/1 schedule).The blood samples of patients in monitoring group were collected at different medication points consecutively within one or two course of treatment. In monitoring group, dosing schedule was switched according to plasma concentration curve. For patients whose dosing schedule was switched empirically, the switching was from 4/2 to 2/1 schedule because of intolerance to initial 4/2 schedule. The survival benefit and safety were compared among these 3 groups. Results: From plasma concentration curves, dosing schedules were switched in 17 patients. The dosing schedule was switched from 4/2 to 2/1 in 37 patients empirically, while 58 patients were administrated with a 4/2 or 2/1 schedule without switching. Among the monitoring, empirical and initial group, the median PFS was 30.0,20.0 and 9.0 months,respectively(P = 0.001), and the median OS was not-reach, 37.0, and 18.0 months, respectively (p = 0.004). Moreover, patients with a switched schedule through monitoring had better tolerance after switching. The incidence of grade 3/4 AEs fell from 88.2% to 41.2% (p = 0.001).In empirical group, the incidence of grade 3/4 AEs fell from 73.0% to 37.8% (p = 0.001). Conclusions: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with switched schedules by monitoring could achieve a better survival benefit.
Endoscopic Ultra Sound-guided RadioFrequency Ablation (EUSRFA) as focal treatment for pancreatic metastases from renal cell carcinoma: A monocentric experience.
Authors: Chanez Brice , Caillol Fabrice , Ratone Jean-Philippe , Bories Erwan , Pesenti Christian , Pignot Geraldine , Brunelle Serge , Walz Jochen , Thomassin Jeanne , Salem Naji , Giovannini Marc , Gravis Gwenaelle 
Published: February 2020

695 Background: Pancreatic metastases (PM) from renal cell carcinoma (RCC) are rare but associated with long survival. The usual management of PM is surgery or tyrosine kinase inhibitor (TKI) with sides effects. Endoscopic radiofrequency ablation (EUSRFA) is an innovative approach to focally treat deep metastasis and could be a relevant technic to control PM from RCC. Methods: This analysis addressed the local control and toxicity in patients treated by EUSRFA for progressive PM from RCC. EUSRFA was done with a linear EUS scope and a 19 G needle delivering short ablation time. Response was assessed by CT-scan using both size and contrast enhancement of the PM treated every 2 to 3 months. Results: 8 pts from Paoli-Calmettes Institute (France) were treated between May 2017 and August 2019. Age was 70.5y [61-75], 5/8 female, ECOG 0-1 (100%). The median time from diagnosis to PM was 14.5 years [9.35-22.18], median number of PM was 2 [1-3], 6/8 was documented by histology and all were classified as progressive before EUSRFA. PM localizations was: head in 40%, body 40% and average size was 14 mm [4 - 35]. 75% of pts (6/8) had other mRCC spread, 5/8 had received systemic treatment and 2 were on therapy at EUSRFA time. 3 pts had EUSRFA as the only treatment for RCCm. We performed 18 EUSRFA procedures over 16 PM. Patient received in median 2 EUSRFA sessions [1-3]. Follow up of 22.4 months [2.3-42.6], 50% of treated PM was evaluated as complete response, 17.5% as partial response and 20% as stable disease at the last CT-scan evaluation. 2 pts were considered as progressive disease and PM focal control was 87.5%. One patient treated with TKI during EURFA developed a paraduodenal abscess 2 months after EUSRFA. Another patient with biliary prothesis developed hepatic abscesses few days after EUSRFA. No other acute side effects were experienced. Interestingly, all PM treated with diameter of < 20mm was locally control versus only 75% of PM> 20mm. Conclusions: Though larger studies have to corroborate our data, EUSRFA is feasible and displays a good local control for PM. It could be a valuable option, less morbid than pancreas resection, for well selected patients with progressive PM.
Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma (S/R RCC) to reveal potential determinants of poor prognosis and response to immune checkpoint inhibitors (ICI).
Authors: Bakouny Ziad , Braun David A. , Shukla Sachet A. , Pan Wenting , Gao Xin , Hou Yue , Flaifel Abdallah , Nassar Amin , Abou Alaiwi Sarah , Flippot Ronan , Steinharter John A. , Nuzzo Pier Vitale , Ishii Yuko , Ross-Macdonald Petra , Lee Gwo-Shu Mary , McDermott David F. , Heng Daniel Yick Chin , Signoretti Sabina , Van Allen Eliezer Mendel , Choueiri Toni K. 
Published: February 2020

715 Background: S/R RCC are highly aggressive tumors but recent pilot clinical data have suggested that these tumors respond well to ICI. Our aim was to perform integrative molecular characterization of S/R RCC tumors in order to characterize potential features that underlie their poor prognosis and responses to ICI. Methods: We compared genomic (1), transcriptomic (2) and immune microenvironment (3) data between S/R and non-S/R tumors. (1) S/R patients from 3 cohorts [N = 209]: The Cancer Genome Atlas [TCGA], CheckMate 010/025 & panel sequencing from Dana-Farber/Harvard Cancer Center [DF/HCC]. (2) RNA-seq on S/R from 2 cohorts [N = 98]: TCGA & CheckMate 010/025. (3) Immunofluorescence for CD8+ T cells [N = 17] & Immunohistochemistry for PD-L1 expression on tumor cells [N = 118] from CheckMate 010/025. Overall Response Rate (ORR), Progression Free Survival (PFS), and Overall Survival (OS) in S/R RCC was compared between ICI and non-ICI in clinical cohorts (Table). Results: S/R tumors were significantly enriched in mutations in BAP1, NF2, RELN, and MUTYH, deletions of CDKN2A/B & amplifications of EZH2 (q < 0.05) compared to non-S/R tumors. Gene Set Enrichment Analysis showed upregulation of epithelial-mesenchymal transition, immune pathways, and proliferation programs compared to non-S/R tumors in both RNA-seq cohorts independently (q < 0.25). S/R tumors exhibited greater infiltration by CD8+ T cells at the tumor margin (p = 0.048) and PD-L1 expression on tumor cells (43.2% vs 21.0%, p < 0.01) compared to non-S/R. S/R had improved ORR, PFS, and OS on ICI vs. non-ICI (Table). Conclusions: S/R RCC tumors have distinctive molecular features that may account for their association with poor prognosis and outcomes on ICI.[Table: see text]
AGAP2-AS1 as a potential marker for development of distant metastases in surgically treated low-risk clear cell renal cell carcinoma.
Authors: Nakken Sigrid , Eikrem Øystein , Marti Hans-Peter , Beisland Christian , Bostad Leif , Scherer Andreas , Flatberg Arnar , Beisvag Vidar , Strauss Philipp 
Published: February 2020

732 Background: Historically, 30 % of patients with localized kidney cancer develop distant metastases during follow-up. There is an urgent need to improve the individual risk assessment for clear cell renal cell carcinoma (ccRCC) patients. We therefore aim to characterize the gene expression profile of low-risk patients both with and without progressive disease to define predictive outcome candidate markers. Methods: Formalin-fixed tissue blocks from ccRCC patients (n=24, eight progressors and 16 non-progressors) with a low Leibovich score were collected. Patients had a mean age of 65 years (5 females and 19 males). The non-progressors were matched 2:1 to the progressors for gender, age, pT tumor stage, size, Fuhrman grade, and eGFR. Total RNA was extracted(miRNeasy FFPE Kit, Qiagen) and sequenced (TruSeq RNA Access Library Kit, Illumina). RNA-seq results were analyzed by ingenuity pathway analysis, K Nearest Neighbors algorithm, and survival analysis. Results: 1167 differentially expressed genes (abs.FC≥2, p≤0.05) were detected. Progressors overexpressed genes related to cancer, B-cell infiltration and other immune-system related pathways. Principal component analyses and hierarchical clustering depicted a systematic transcriptomic difference between progressors and non-progressors. Combinations of up to 10 genes were evaluated as classifiers. The AGAP2-AS1 mRNA classified 23 out of 24 samples correctly, without the need for a larger gene panel. The trend of expression was confirmed with RT-PCR.The correlation between sample status as either progressor or non-progressor and AGAP2-AS1 level was R2 =0.69, p <0.01. Patients were split into groups based on AGAP2-AS1 expression (cut-off log2cpm>1), where higher expression correlated with shorter survival; Wilcoxon (p<0.0001),Log-rank test (p<0.0001), Hazard ratio; 9.24E-11. Immunohistochemistry of AGAP2, USP10 and KI-67 confirmed results from the mRNA level. Conclusions: RNA-seq results show a transcriptomic difference between low-risk ccRCC progressors and low-risk non-progressors. AGAP2-AS1 may serve as a potential classifier for the identification of low-risk progressors.
Identification of genomic aberrations associated with overall survival in metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Kessel Adam , Tran Summer , Rivers Zachary , Hahn Andrew W , Nussenzveig Roberto , Rathi Nityam , Maughan Benjamin Louis , Sirohi Deepika , Stenehjem David D. , Agarwal Neeraj 
Published: February 2020

745 Background: Tumor comprehensive genomic profiling (CGP) in addition to risk stratification by IMDC criteria may aid in improving risk stratification. The objective of this study was to assess the prognostic impact of somatic mutations in addition to IMDC risk criteria. Methods: All patients with mccRCC treated with first line with VEGFR-TKI with CGP data available through a CLIA certified lab were included. Kaplan-Meier methodology and Cox proportional hazard ratios were used to test the association of overall survival with genomic alterations present in at least 7% of the population in this dataset. Genomic data were correlated with outcome by univariate analysis and subsequent multivariate testing, integrating genomic data with IMDC risk criteria. Results: A total of 58 patients met eligibly. The presence of any mutation in VHL, PBRM1, and MLL2 were prognostic in terms of overall survival (Table). The mutation status for these three prognostic genes was added to the IMDC risk model to test for the prognostic correlation. The mutations status of these 3 genes significantly correlated with overall survival (VHL: 0.32 [95% CI 0.11-0.95], PBRM1: 0.36 [0.14-0.96], and MLL2: 7.60 [1.35-24.6]) independent of the IMDC risk criteria. Conclusions: In mccRCC, VHL, PBRM1, and MLL2 mutations each predict overall survival independent of IMDC criteria. Further studies are warranted to assess alterations with low prevalence in this data set. Upon external validation, these data provide the rationale for integration of mutation status of these three genes in to the IMDC risk criteria.[Table: see text]
Multicenter comparison of outcomes for clinical and pathologic T3a renal cell carcinoma.
Authors: Bradshaw Aaron , Ghali Fady , Miller Nathan , Keiner Cathrine , Dutt Raksha , Meagher Margaret , Yim Kendrick , Patel Devin , Uzzo Robert Guy , Lane Brian R. , Capitanio Umberto , Derweesh Ithaar 
Published: February 2020

758 Background: The identification of venous thrombus in patients with renal cell carcinoma (RCC) is particularly challenging, with a substantial number upstaged to pathologic T3a following intervention. We compared survival outcomes between patients with initial cT3a status versus those upstaged to pT3a. Methods: This is a retrospective, multicenter analysis of patients with cT3a or pT3a RCC who underwent operative management. Primary outcome was recurrence-free survival (RFS). Secondary outcomes were overall survival (OS) and cancer-specific survival (CSS). Cox regression multivariable analysis (MVA) was utilized for primary outcome. Kaplan-Meier analyses (KMA) were conducted to describe RFS, OS, and CSS with log-rank test comparing clinical and upstaged pathologic T3a groups. Results: 770 patients were analyzed (cT3a 184, pT3a 586, median follow-up 28 months). Average pathologic tumor size was smaller in pT3a (7.2 cm vs 8.7 cm, p < 0.01), with no significant differences in clinical variables. A similar proportion underwent radical nephrectomy (vs. partial) (89.7% cT3a and 85.0% pT3a, p = 0.11) with no significant different in positive margin rate (3.8% cT3a, 4.8% pT3a, p = 0.23). However, a higher proportion of patients with cT3a disease were pathologically node positive (19.0% vs. 10.8%, p < 0.01) and demonstrated a higher rate of recurrence (cT3a 51.1% vs. pT3a 34.1%, p < 0.01) despite shorter mean follow-up (cT3a 33.0 vs. pT3a 50.7 mo, p < 0.01). MVA for RFS revealed cT3a staging (pT3a referent, HR 1.72, p < 0.01), positive margins (HR 2.85, p < 0.01), and clear cell histology (HR 1.68, p < 0.01) to be independently associated with higher recurrence rate, while partial nephrectomy (radical referent, HR 0.259, p < 0.01) was associated with a decreased rate. KMA revealed 5-year RFS of 34.4% and 60.6% for cT3a and pT3a respectively (p < 0.01). KMA for secondary outcomes revealed 5-year OS rates of 56.7% and 62.0% (p = 0.02) and 5-year CSS of 74.4% and 67.7% for cT3a and pT3a respectively (p = 0.01). Conclusions: Patients with cT3a RCC have poorer oncologic outcomes than those with upstaged pT3a RCC. Suspected venous involvement on pre-operative imaging may indicate more aggressive or advanced disease than that found during surgery.
ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastasized castration-resistant prostate cancer (mCRPC): A multicenter phase I study.
Authors: Vermunt Marit , Robbrecht Debbie , Devriese Lot , Janssen Julie , Keessen Marianne , Eskens Ferry , Beijnen Jos H. , Mehra Niven , Bergman Andre M. 
Published: February 2020

79 Background: ModraDoc006 is a novel formulation of docetaxel and to enhance bioavailability, this tablet is co-administered with ritonavir (r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The safety, anti-tumor activity and pharmacokinetics (PK) of ModraDoc006/r were investigated by dose-escalation in patients with mCRPC, to propose a recommended phase 2 dose (RP2D). Methods: Progressive mCRPC patients, who were treatment naïve or previously treated with either abiraterone or enzalutamide, received a maximum of 30 weekly cycles of ModraDoc006/r in a bi-daily once weekly (BIDW) schedule. Plasma docetaxel concentrations were determined at the first 2 cycles up to 48h after intake of ModraDoc006/r. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Serum Prostate Specific Antigen (PSA) levels were assessed every 6 weeks. Results: 23 patients were included, of whom 20 were evaluable for safety and PK. In 5 patients, the initial 30-20/100-100 dose was explored, with observation of one dose limiting toxicity (DLT) (grade 3 alanine aminotransferase increase). The next dose level of 30-20/200-200 resulted in 2 DLTs in 6 patients (grade 3 diarrhea and mucositis). Subsequently, two intermediate dose levels: 30-20/200-100 and 20-20/200-100 were explored in 6 and 3 patients. At the 30-20/200-100 dose, an adequate docetaxel exposure was achieved and 1 DLT (grade 3 diarrhea) was observed, with no DLTs at the 20-20/200-100 dose. Common treatment-related AEs (occurring in > 30% of all patients) were diarrhea, nausea, vomiting, anorexia and fatigue. Five patients completed the maximum of 30 weekly treatments. In 10 patients, evaluable for anti-tumor activity after treatment with ≥9 cycles, 4 confirmed and 2 non-confirmed PSA responses ( > 50% decrease) were observed. Conclusions: The RP2D of BIDW ModraDoc006/r in mCRPC was established as 30-20/200-100 mg. These results are encouraging for further development of ModraDoc006/r as a convenient, safe and effective alternative to IV docetaxel for mCRPC patients. A phase 2b study is currently being conducted. Clinical trial information: NCT03136640.