bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: Nationwide survey in Japan.
Authors: Inamoto Teruo , Azuma Haruhito , Oya Mototsugu , Hamada Yoko , Akaza Hideyuki 
Published: March 2019

565 Background: The average age of the patients (pts) with renal cell carcinoma (RCC) are getting older year by year, hence the baseline comorbidity should be considered when pts have tyrosine kinase inhibitor treatments. However, the safety and efficacy data of these agents in pts with cardiovascular disease (CVD) are limited. In this study, we analyzed the data which were prospectively collected practical use of sorafenib amongst all RCC pts in Japan, and investigated whether baseline comorbidity of CVD would provide any affection for the safety and efficacy on sorafenib treatment using propensity-matched analysis. Methods: A total of 3,255 pts with advanced RCC were enrolled and 770 pts selected by propensity score were matched for CVD (n=385) and non-CVD pts (n=385). Dose modification, tumor response, progression free survival (PFS), and adverse events (AEs) were analyzed. Results: After matching the patient’s demographics were well balanced except for BMI (22.47 ± 3.37 vs. 23.13 ± 3.59, p=0.019) between non-CVD and CVD group, respectively. The median starting dose (800mg vs. 800mg), median daily dose (484.8mg vs. 500mg), and median duration of treatment (7.26 months vs. 7.89 months) were not significantly different. Objective response rate (CR+PR) was comparable in both groups (27.1 and 29.4%). The hazard ratio (HR) of overall PFS was similar between two groups (HR: 1.005, 95% CI: 0.838-1.206). When stratified according to IMDC risk classification, the risk of PFS was not significantly different in any IMDC risk groups (favorable; HR: 0.883, 95% CI: 0.600-1.300, intermediate; HR: 1.11, 95% CI: 0.885-1.3920, and poor ; HR 0.972, 95% CI: 0.513-1.842). Safety was analyzed for 766 pts, and any grade AEs observed ≥20% were hand-foot skin reaction (59.5%), hypertension (40.0%), rash (26.9%), lipase/amylase increased (26.5%), and diarrhea (24.2%). The frequency of any grade AEs were similar between the groups, but lipase/ amylase increased was significantly higher in CVD group than that in non-CVD group (p=0.0042). Conclusions: The present study suggests that sorafenib can be used with clinical benefit for RCC pts regardless of baseline cardiovascular comorbidities. Clinical trial information: NCT01411423.
Identification of differentially expressed genes to predict radioresistant prostate carcinomas.
Authors: Nestler Tim , Wittersheim Maike , Hellmich Martin , Pfister David J. K. P. , Odenthal Margarete , Büttner Reinhard , Schäfer Stephan , Heidenreich Axel 
Published: March 2019

57 Background: Although relapses after radiotherapy are common in prostate cancer (PCa) patients, there are no clinical models or markers to identify patients at high risk for radioresistance. So far, only in vitro studies and xenograft models have been performed to identify gene expression patterns associated with radioresistance. However, studies which address the protein pattern to predict radioresistance in humans are completely missing. In order to determine potential biomarkers for radioresistance, we compared protein expression profiles of radioresistant PCa patients with PCa of primary prostatectomized patients. Methods: Two study groups consisting of: I) 30 patients who were treated by salvage prostatectomy and II) 94 patients treated by primary prostatectomy were formed. Tissue microarrays were constructed and immunostained for 15 proteins which are suggested to be associated with radioresistance by in vitro findings. Kruskal-Wallis test was used for multiple group comparison and followed by Dunn-Bonferroni-Test to detect intergroup differences. Cohen’s d was used to calculate the intergroup effect size. Results: Most proteins studied did not show any relevant differences between radioresistant PCa and primary PCa, except for two (AR and AKR1C3). On comparing immunostaining patterns between radioresistant PCa and primary PCa separated by Gleason risk groups, we observed only AR (androgen receptor) to be most expressed in radioresistant PCa (89.7%) and, in 87.8% of primary PCa of the high-risk group ( > 7a) (p = 0.851, Cohen’s d = 0.05), while only 67.3% PCa of the low-risk group (≤7a) (p = 0.017, Cohen’s d = 0.55) were positive. Considering the highest Gleason pattern per patient, only AKR1C3 (Aldo-Keto Reductase Family 1 Member C3) was seen to be similarly expressed in radiation-resistant PCa and patients with Gleason patterns 4 and 5 (p = 0.827, Cohen’s d = 0.05 and p = 0.893, Cohen’s d = 0.10) as compared to Gleason pattern 3 (p = 0.20, Cohen’s d = 0.69) in primary PCa. Conclusions: This is the first study evaluating protein expression profiles to predict radioresistance in PCa, where AR and AKR1C3 were identified to be the most promising protein markers.
Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients.
Authors: Xu Wen-Hao , Qu Yuan-Yuan , Wang Jun , Zhang Hai-Liang , Ye Dingwei 
Published: March 2019

571 Background: Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of CD36 in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients. Methods: Real-Time qPCR was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of CD36 expression were compared with χ2-test. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by MRI. Pearson’s correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and CD36 expression respectively. Cox regression analysis were developed to address the influence of independent factors on prognostic value. Gene Set Enrichment Analysis (GSEA) was performed to select related genes and pathways from TCGA database. Results: In the current study, we demonstrated that CD36 mRNA was highly expressed in ccRCC tissues, and was found significantly increased in patients with advanced TNM stage ( p= 0.003, p< 0.001, p< 0.001), and high VAT% ( p= 0.004). Pearson’s correlation coefficient indicated CD36 amplification positively correlated with BMI ( r= 0.117, p= 0.025), VAT% ( r= 0.465, p< 0.001), while negatively with SAT ( r= -0.296, p= 0.002). Furthermore, ccRCC patients with elevated CD36 expression held shorter PFS and OS, with HR of 4.873 (3.300-7.196, p< 0.001) and 4.610 (2.956-7.189, p< 0.001). In 104 cases whose MRI scans were available, VAT was significantly correlated with poor PFS and OS. Significant genes were obtained from GSEA, and CD36 was found involved in the most significant pathways including fatty acid metabolism, angiogenesis and TGF-β signaling pathways. Conclusions: In conclusion, our study first reveal that elevated CD36 mRNA expression is positively correlated to distribution of abdominal adipose, particularly VAT%, which, in addition, notably predicts poor prognosis in ccRCC patients.
Outcomes of patients with metastatic clear cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.
Authors: Shah Amishi Yogesh , Kotecha Ritesh , Lemke Emily , Chandramohan Anuradha , Chaim Joshua , Msaouel Pavlos , Xiao Lianchun , Gao Jianjun , Campbell Matthew T , Zurita Amado J. , Wang Jennifer , Corn Paul Gettys , Jonasch Eric , Motzer Robert J. , Sharma Padmanee , Voss Martin Henner , Tannir Nizar M. 
Published: March 2019

575 Background: Immune checkpoint inhibitors (ICI) are being increasingly utilized in front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) VEGFR-TKI therapy after 1L ICI therapy. Methods: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists’ review using RECIST v1.1. Descriptive statistics and Kaplan-Meier method were utilized. Results: 70 patients were included in the analysis. Median age at mccRCC diagnosis was 59 years old; 8 patients (11%) had IMDC favorable-risk score, 48 (69%) had intermediate-risk score, and 14 (20%) had poor-risk score. As 1L therapy, 12 patients (17%) received anti-PD-(L)1 monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab, and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib, and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete remission (CR), 27 patients (39.7%) a partial response (PR), and 36 patients (52.9%) stable disease (SD), adding to a 94% disease control rate (DCR). Median progression-free survival (mPFS) was 13.2 months (95% CI: 10.1, NA). Estimated 1-yr overall survival (OS) probability was 79.6% (95% CI: 70.2 – 90.3). Median duration of 2L TKI therapy was 10.1 months. In total, 45.7% of subjects required a dose reduction, and 27% of patients discontinued treatment due to toxicity. Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy following 1L ICI, we observed 2L antitumor activity and tolerance comparable to historical data for first-line TKI. Further studies are needed to evaluate optimal strategies and sequencing of therapies in mccRCC.
Are immune checkpoint inhibitors (ICI) a valid option for papillary renal cell carcinoma (pRCC)? A multicenter retrospective study.
Authors: De Vries-Brilland Manon , Gross-Goupil Marine , Boughalem Elouen , Beuselinck Benoit , Thibault Constance , Chevreau Christine , Ladoire Sylvain , Barthelemy Philippe , Negrier Sylvie , Borchiellini Delphine , Huillard Olivier , Geoffrois Lionnel , Gravis Gwenaelle , Saldana Carolina , Thiery-Vuillemin Antoine , Seegers Valérie , Escudier Bernard , Ravaud Alain , Albiges Laurence 
Published: March 2019

582 Background: pRCC is the most common non-clear cell RCC (nccRCC) and represents up to 15% of RCC. Pivotal studies evaluating ICI mostly excluded nccRCC. Therefore the efficacy of ICI in pRCC remains to be demonstrated. Methods: We retrospectively investigated the activity and safety of PD-1/PD-L1 inhibitors (PD-1i) specifically in patients (pts) with metastatic pRCC from 15 centers in France and Belgium. Pts baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). Results: From 02/2016 to 09/2018, 50 pRCC pts treated with PD-1i were included. Median age was 63 years (range: 27-84), 36 (72%) were male. Histology included 14 (28%) type 1 pRCC, 30 (60%) type 2 pRCC, 6 (12%) unclassified pRCC. PD-1i was used in first line setting in 5 pts (10%), in second line in 29 pts (58%) and in third line or beyond in 16 pts (32%). IMDC risk group at PD-1i start was 22% good, 44% intermediate and 33% poor. ICI used were PD-1 inhibitors in 47 pts (94%) and PD-L1 inhibitors in 3 pts (6%). PD-1 in was used as monotherapy in 94% of pts. With a median follow up of 10.7 months (95% Confidence Interval (CI): 6.8-14.8), the median TTF was 3.7 months (95% CI: 3.1, 10.1). In type 1, the median TTF was 7.1 months (95% CI: 3.2-NA) and 3.2 months (95% CI: 2.9-NA) in type 2. Median treatment duration was 3.2 months (range: 0.4-24.5, IQR: 2.4-6.4). Among the 45 pts evaluable for ORR, best response was complete response/partial response in 8 pts (16%), stable disease in 13 pts (26%) and progressive disease in 24 pts (48%). ORR was 25% in type 1 pRCC and 15% in type 2 pRCC. Median OS was 17.6 months (95% CI 11.4- not reached). TRAEs of grade 3-4 were noted in 6 patients (12%) which led to treatment discontinuation, no grade 5 were observed. Conclusions: This retrospective study is the largest cohort of metastatic pRCC treated with PD-1i to date. PD-1i exhibit limited activity in this pRCC population, with better TTF and ORR in type 1 pRCC. Our findings underline the need for further prospective clinical trials evaluating ICI combinations in pts with pRCC.
Sites of metastasis (mets) and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim 
Published: March 2019

585 Background: Cabo is approved for the treatment for mRCC. We investigated the association of sites of mets and clinical outcomes (CO) in mRCC pts treated with cabo. Methods: We performed a retrospective analysis of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from first dose of cabo to date of death and clinical or radiographic progression, respectively. Objective response was defined as a complete response (CR) or partial response (PR). Sites of mets were obtained from radiology and clinic notes and included bone, lymph node, brain, lung, and liver. Univariate analysis (UVA) and multivariate analysis (MVA) was performed using Cox proportional hazard or logistic regression model. Results: The median age was 63 years and most (68%) were males. The majority of pts (79%) had ccRCC and 48% received at least 2 prior systemic treatments. The distribution of mets were: bone (42%), lymph node (69%), brain (6%), lung (83%), and liver (40%). The UVA and MVA of association between sites of mets and CO are presented in Table. Pts with bone mets had significantly longer OS in UVA and trended towards longer OS and PFS in MVA compared to pts without bone mets. Conclusions: Bone mets may be a prognostic factor for improved CO in mRCC pts treated with cabo. Larger studies are needed to validate the results of this study. UVA and MVA† of bone metastases and CO. [Table: see text]
Neoadjuvant durvalumab +/- tremelimumab affects the expression of immune checkpoint (IC) molecules on myeloid derived suppressor cells (MDSC) in patients (pts) with locally advanced renal cell carcinoma (RCC).
Authors: Fallah Jaleh , Diaz-Montero C. Marcela , Rayman Patricia A. , Wei Wei (Auston) , Wood Laura S. , Martin Allison , Allman Kimberly D , Gilligan Timothy D. , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I. 
Published: March 2019

587 Background: In a single arm, open label phase 1b clinical trial the safety of neoadjuvant durvalumab +/- tremelimumab was studied in pts with (w) locally advanced RCC. Expression of IC molecules on immunomodulatory cells in peripheral blood (PB) and tumor (T) and the association w treatment (tx) was investigated. Methods: Pts with ≥ T2bN0-1M0 RCC received either durvalumab or combination durvalumab + tremelimumab prior to surgery. Blood samples were drawn prior to neoadjuvant tx, prior to surgery, and approximately 30 days after surgery before adjuvant tx. The percentage of MDSC (CD33+/HLADR-) and subtypes in PB and T and expression of PD1, PD-L1, and V-domain Ig suppressor of T cell activation (VISTA) were measured. MDSC subtypes included polymorphonuclear (PMN; CD15+/CD14-), monocytic (M; CD15-/CD14+) and uncommitted (UC; CD15-/CD14-). Linear mixed model was used for each MDSC subtype to estimate and compare cohorts over time. Results: Eighteen pts were enrolled: 4 women and 14 men, median age 62, 17 pts had T3-4 and 4 pts had N1 disease. Six pts received 1 dose of durvalumab and 12 pts received 1 dose of durvalumab + tremelimumab before surgery. Tx-related grade 3 adverse events (per CTCAE, v5.0) included thrombocytopenia, bilateral lower extremity weakness, hyperglycemia, chest pain, and diabetic ketoacidosis.One pt had grade 4 elevated lipase. One pt had sudden death from a non-drug related cardiac event 9 days after receiving combination therapy prior to surgery. PB and T samples from 17 pts were available. Expression of VISTA on M-MDSC and UC-MDSC were positively correlated in PB and T (Spearman’s rho = 0.61; P=0.03 for both). VISTA expression on UC-MDSC in PB was significantly higher in pts who received durvalumab monotherapy compared to those treated w durvalumab + tremelimumab (P=0.04). Frequencies of PD-L1 expression on M-MDSC and UC-MDSC in PB decreased significantly from pre- to post-neoadjuvant tx (P < 0.01). Conclusions: Neoadjuvant durvalumab + tremelimumab in pts w locally advanced RCC is feasible and affects the expression of IC molecules (PD-L1 and VISTA) on M-MDSC and UC-MDSC. Clinical trial information: NCT02762006.
Efficacy of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients (pts) with refractory metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W , Drake Charles G. , Denmeade Samuel R. , Zakharia Yousef , Maughan Benjamin Louis , Kennedy Eugene Paul , Link Charles J. , Vahanian Nicholas N. , Hammers Hans J. , Agarwal Neeraj 
Published: March 2019

590 Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity. A previous report demonstrated that HAR is well tolerated in pts with mRCC (2017 GUASCO, abstract: 528). Herein, we report the efficacy of HAR immunotherapy in mRCC. Methods: Pts with refractory clear-cell mRCC were eligible for this phase 1 dose-escalation trial. Concomitant treatment (Rx) with other approved agents was permitted after initial 2 months (m) of HAR monotherapy. The trial followed a standard 3+3 design with cells injected intradermally weekly for 4 weeks then biweekly injections for 10 immunizations (150 x106cells then escalated to 300 x106cells). Co-primary objectives were safety and efficacy. Results: A total of 18 patients were enrolled (4 low dose, 14 high dose) between 06/2015 to 07/2016. Patients received a median of 1 systemic Rx prior to HAR immunotherapy, with 8 patients receiving 2 or more prior agents. IMDC risk categories at the time of initial metastatic disease were: favorable risk (33%), intermediate risk (66%), poor risk (0%). The ORR was 0% with a disease control rate of 50%. Median PFS for patients treated with HAR immunotherapy was 2.0 months (m) (range 1.7-30.3 m). For patients receiving the low dose HAR, median overall survival (OS) was 14.2 m (range 3.6-21.6 m), while median OS for high dose HAR was 25.3 m (5.8-29.3 m). At the time of data cutoff in 09/2018, 7 patients were still living. Detailed clinical data will be presented in the meeting. Conclusions: HAR immunotherapy in refractory mRCC was well tolerated and demonstrated potential efficacy for OS similar to currently approved salvage-line Rx. With a unique mechanism of action, HAR immunotherapy may be a candidate for inclusion in novel combinatorial regimens being developed in salvage therapy setting in pts with mRCC. Clinical trial information: NCT02035358.
The association of rising serum uric acid levels with survival in renal cell carcinoma.
Authors: Yim Kendrick , Bindayi Ahmet , McKay Rana R. , Mehrazin Reza , Raheem Omer , Field Charles , Bloch Aaron , Wake Robert , Ryan Stephen , Patterson Anthony , Derweesh Ithaar 
Published: March 2019

608 Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative and postoperative SUA levels between 8/2005-8/2014. Increased SUA was defined as > 7mg/dL for males and > 5.7 mg/dL for females. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. Results: 905 patients were analyzed. Decreased/stable SUA levels were noted in 675(74.6%) and increased SUA levels were noted in 230(25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs 18.3%, p = 0.004). Increased SUA had significantly greater de novo CKD (38.7% vs. 18.4%, p < 0.001) and proteinuria (30.9% vs. 20.7%, p = 0.002). KMA demonstrated improved 5-year OS for patients with decreased/stable SUA compared to increased SUA for stage I, (93% vs. 60%), stage II (87% vs. 50%), and stage III (88% vs. 62%) RCC (all p < 0.001). MVA revealed that increasing BMI (OR 1.05, p = 0.009), statin use (OR 0.11, p < 0.001), dyslipidemia (OR 2.66, p = 0.004), stage III/IV cancer (OR 1.89, p = 0.015 and OR = 10.78, p < 0.001), and postoperative de novo CKD stage 3 (OR 5.95, p < 0.001) were predictors for increased postoperative SUA levels. MVA revealed increasing BMI (OR 1.09, p = 0.002), increasing SUA (OR = 4.70, p < 0.001), stage IV RCC (OR = 7.7, p < 0.001, and de novo CKD stage 3 (OR 7.07, p < 0.001) to be independent risk factors for worsened all-cause mortality. Conclusions: Increasing SUA post operatively was associated with worsened outcomes in RCC patients. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite.
Duration of treatment (DOT) with targeted therapies (TT) or immunotherapy (IO) in PBRM1 mutated metastatic renal cell carcinoma (mRCC).
Authors: Dizman Nazli , Bergerot Paulo Gustavo , Bergerot Cristiane Decat , Hsu Joann , Pal Sumanta K. 
Published: March 2019

622 Background: Current evidence indicates improved outcome with IO in mRCC patients (pts) with PBRM1 loss of function mutations (Miao et al., Nature, 2018). We seek to demonstrate an association between PBRM1 mutation and treatment duration with IO and TT in a retrospective cohort. Methods: Consecutive patients with mRCC who had genomic profiling in the course of routine clinical care were identified from an institutional database. GP assessments included testing either tissue or blood with 1 of the 3 CLIA certified commercial panels (Foundation Medicine, Cambridge, MA; Ashion Analytics, Phoenix, AZ; Guardant Health, Redwood City, CA). Information regarding systemic treatment was collected. Median DOT with first targeted therapy and first immunotherapy received was calculated for each patient. DOT was compared across treatment groups in PBRM1+ and PBRM1- patients. Only PBRM1 mutations with functional significance documented in COSMIC were considered. Results: Among 104 pts (72:32 M:F) with mRCC, 82 pts received TT, 35 pts received IO, and 45 pts received both. GP was performed in blood and tissue in 84 and 63 pts, respective, and 25 pts (24%) with PBRM1 mutations were identified. Among PBRM1+ pts, median DOT was 8.8 months (95% CI, 7.6-9.6) mos and 2.3 mos (95% CI, 1.7 – 2.8) mos with TT and IO, respectively (p=0.049). Among PBRM1- pts, median DOT was 5.5 mos and 2.8 mos with TT and IO, respectively (p=0.544). There were 11 PBRM1+ pts and 34 PBRM- pts who received both TT and IO. The ratio of DOT on IO to DOT on TT (DOTIO/TT) was higher in PBRM1- pts than PBRM1+ pts (0.76 versus 0.37 respectively, p=0.014). Conclusions: We failed to replicate the results from Miao et al, suggesting clinical benefit with IO in PBRM1 mutated patients. PBRM1 mutation did appear to predict benefit with TT versus IO. Although limited by sample size, the contrasting results of the current study with literature highlight the importance of clinical validation in a large and prospective setting.