bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cabozantinib for the treatment of patients with metastatic variant histology renal cell carcinoma (vhRCC): A retrospective study.
Authors: Campbell Matthew T. , Bilen Mehmet Asim , Duran Cihan , Altinmakas Emre , Lim Zita Dubauskas , Jonasch Eric , Tannir Nizar M. 
Published: March 2017

478 Background: Cabozantinib (C) prolongs overall survival (OS) and progression-free survival (PFS) in patients with metastatic clear-cell renal cell carcinoma (ccRCC) that progressed on first-line VEGFR-TKI. No standard of care systemic therapy exists for the management of patients with metastatic vhRCC. Methods: This is a retrospective, IRB approved study of patients with vhRCC who received C at MD Anderson Cancer Center from January 2014 till June 2016. Information collected from the medical records included the baseline characteristics, toxicity, dose reductions, and OS. A blinded radiologist assessed the radiographic response using RECIST v1.1. Descriptive statistics, the Kaplan Meier method and the log rank test were applied using Microsoft Excel and GraphPad Prism version 6 software. Results: Median PFS was 8.1 months (mos) (95% CI: 5.8-17.8), and median OS was 22.7 mos (95% CI:11-NR), median follow up 13.3 months (95% CI: 9.6-17) . There were no significant differences detected between patients with papillary versus non-papillary histologies with respect to PFS or OS. At last follow-up, 7 patients remain on treatment with median time on therapy for all patients of 17.7 months. There were 2 confirmed PRs (both P) for a 12% ORR, 2 unconfirmed PRs (1 chr, 1 sarc), 10 of 17 (59%) with stable disease, and 5 of 19 with progressive disease (26%), for a disease control rate of 14 of 19 (74%). Of 15 patients who started C at 60 mg/d, 10 (67%) required dose reduction due to toxicity. Multiple patients required treatment breaks but none discontinued therapy due to toxicity. Conclusions: In this retrospective study, cabozantinib produced a clinically meaningful benefit in patients with metastatic vhRCC, the majority of whom had PD on prior VEGFR-TKIs. Prospective trials of cabozantinib in vhRCC are warranted.[Table: see text]
CHEK2 mutation in renal cell carcinoma (RCC): Single center experience.
Authors: Huszno Joanna , Mazur Magdalena , Nowara Elzbieta , Grzybowska Ewa 
Published: March 2017

480 Background: Renal cell cancer (RCC) accounts for about 4% of all the adult malignancies. RCC occurs in both sporadic and heritable forms. Genetic mutations have been identified as the cause of inherited cancer risk in 1% to 2% of RCC cases overall. In some studies, variant I157T of CHEK2 gene were found to be associated with increased risk of clear cell renal cancer. The aim of this study was to evaluate the association between CHEK2 mutation and RCC in our centre. Methods: We reviewed the medical records of 43 clear cell renal cancer patients (pts) who were diagnosed and treated in COI in Gliwice. Mutation profile was assessed by RFLP-PCR technique. In Poland, there are three polymorphic variants of CHEK2 1100delC, IVS2+1G →A (premature protein truncation), and a common missense variant (I157T) (substitution of an isoleucine for a threonine). We evaluated the presence of CHEK2 mutation in clear cell carcinoma. Results: In our study CHEK2 mutation (variant I157T) was detected in 7% pts. The median age of pts was 57 years (range from 34 to 74). Most of the patients were women (87%). All CHEK2 mutation carriers were women and were >65 years old. Cancer in family history were reported in 80% pts. Most frequently were: breast cancer (33%), gynecological cancers (33%), gastrointestinal cancers (27%), and renal cell carcinoma (20%). There was also described lung cancer in family history (7%). The most frequent cancers in family history in CHEK2 mutation carriers were: breast cancer and gynecological cancers. 20% of pts had other cancers in their history (breast cancer, ovarian cancer, and contralateral renal cell carcinoma). Contralateral renal cell carcinoma was reported in CHEK2 mutation carrier. All pts had nephrectomy due to RCC and all had clear cell renal cancer in histopathologic examination. All CHEK2 mutation carriers had higher grade (grade 3) and capsular invasion. 5% of CHEK2 mutation carriers had TP53 (c.[215G>C])polymorphism. Conclusions: Variant I157T of CHEK2 gene were found to be associated with increased risk of cancer in family history (breast cancer, gynecological cancer), and renal cancer of contralateral kidney. Factors associated with CHEK2 mutation carriers were higher histologic grade (G3) and elderly age.
ABCB1, CYP3A5*3, and CYP3A4*1B SNPs and risk of toxicity with sunitinib treatment for mRCC.
Authors: Bassanelli Maria , Felici Alessandra , Milella Michele , Giannarelli Diana , Giacinti Silvana , Gentile Giovanna , Carlini Paolo , Cognetti Francesco , Roberto Michela , Poti Giulia , Macrini Serena , Aschelter Anna Maria , Simmaco Maurizio , Marchetti Paolo 
Published: March 2017

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.
Determinants of treatment in patients with stage IV renal cell carcinoma.
Authors: Hollenbeak Christopher S. , Schaefer Eric W. , Doan Justin , Raman Jay D. 
Published: March 2017

486 Background: Although there have been significant advances in the detection and treatment of renal cell carcinoma (RCC), many elderly patients—particularly those with stage IV disease—likely receive no treatment. The purpose of this research was to study treatment patterns for elderly patients with stage IV RCC and determine patient and disease characteristics associated with receiving no treatment. Methods: Data from the Surveillance Epidemiology and End Results (SEER) and Medicare linked data set were analyzed. We identified 949 stage IV RCC patients over age 65 years diagnosed between 2007 and 2011. Surgery was identified using Medicare Part A and B claims, and use of systemic therapy was identified from Part D claims in addition to Part A and B claims. Treatment approach, including no treatment, was modeled using multinomial logistic regression controlling for several patient and disease characteristics, allowing us to identify significant risk factors for no treatment. We also performed landmark analyses at 3 and 6 months to account for early death as a potential cause for no treatment. Results: Of the 949 patients with stage IV RCC, 26.2% received surgery and 34.1% received systemic therapy within 6 months of diagnosis. Of 324 patients who received systemic therapy, most received sunitinib (57.1%), temsirolimus (21.3%), or sorafenib (12.3%). Over half of patients (51.2%) had no evidence of receiving surgery or systemic therapy. Of the 618 patients who survived at least 3 months, 38.3% received no treatment within 3 months, and among the 447 patients who survived at least 6 months, 26.6% received no treatment within 6 months. Older patients and those with a higher Charlson Comorbidity Index had lower odds of being treated with surgery, systemic therapy, or both; married patients had higher odds of being treated. These results were largely sustained in 3- and 6-month landmark analyses. Conclusions: Many elderly patients with stage IV RCC did not receive surgery or systemic therapy despite surviving at least 6 months from diagnosis. Several factors appear to be associated with this phenomenon. Further investigation should determine reasons why physicians and/or patients are reluctant to use systemic therapy in patients.
BAP1 tumor predisposition syndrome: Preliminary data from a laboratory-based multigene panel testing cohort.
Authors: Horton Carrie , LaDuca Holly , Reineke Patrick 
Published: March 2017

490 Background: Germline mutations in BAP1 have recently been shown to cause a tumor predisposition syndrome characterized by renal cell carcinoma (RCC), uveal melanoma, cutaneous melanoma, and mesothelioma. However, mutations have thus far been identified in highly enriched cohorts and the tumor spectrum among individuals with a broader phenotype undergoing multi-gene panel testing (MGPT) has not been described. Other genes associated with familial RCC have been established, such as FLCN (Birt-Hogg Dube syndrome) and VHL (von Hippel Lindau), but the proportion of BAP1 mutations in individuals with RCC is not yet known. Here we aim to describe the clinical features of individuals with BAP1 mutations identified from a clinical laboratory cohort, and to estimate the frequency of BAP1 mutations in individuals with kidney cancer. Methods: Since May 2015, a total of 6956 tests have been ordered that include BAP1 at our diagnostic laboratory. Retrospective data review yielded molecular and clinical details for individuals with identified mutations. Results: Thirteen individuals with BAP1 mutations have been identified. Cancer diagnoses in probands and family members consist of breast cancer (reported in 69.2% of kindreds), RCC (61.5%), melanoma (61.5%), mesothelioma (46.2%), lung cancer (46.2%), non-melanoma skin cancer (30.8%), and cholangiocarcinoma (15.4%). Among probands with kidney cancer undergoing MGPT (n = 1012), there is no difference in mutation rate of BAP1 compared to VHL (n = 3; OR 2.01 p = 0.51) or FLCN (n = 10; OR 0.598 p = 0.45). Conclusions: Cancer histories in our laboratory-selected cohort of BAP1 mutation carriers are consistent with those reported in the clinical literature, lending credence to the notion that BAP1 tumor predisposition syndrome is highly penetrant and consists of a constellation of several core cancers. The observation of breast, lung, non-melanoma skin cancer, and cholangiocarcinoma has also been reported in the literature and warrants further study. Our results suggest that BAP1 mutations are found at a similar frequency as other well-known kidney cancer genes, supporting its position as an important differential when considering genetic testing for RCC.
Impact of rural/urban residence on relative survival (RS) in patients with kidney cancer: An analysis of 14576 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Hackl Monika , Rauchenwald Michael 
Published: March 2017

491 Background: Access to medical diagnostics and treatment might be limited for patients living in rural areas compared to urban residents. To evaluate the potential impact of urban/rural residence, we analyzed trends in RS for patients diagnosed with kidney cancer between 1998 and 2009 in Austria. Methods: All patients with kidney cancer aged ≥18 years, diagnosed from 1998-2009 were derived from the ANCR (n=14,576). Patients were categorized into two groups: rural (n=7,537) and urban (n=7,039) based on a complex algorithm considering infrastructure, commuter interrelations, accessibility of centers, and tourism at the time of diagnosis. Relative survival was calculated based on complete follow-up until December 31st, 2014. Poisson regression modeling was used to evaluate survival differences between the two groups and to calculate the relative excess risk of dying (RER). Analyses were performed for the total patient population and primary metastatic patients (M+). Results: Distribution of sex, age, stage of disease, year of diagnosis, and surgical treatment did not differ between rural and urban patients. Five-year RS was 74% for rural compared to 73% for urban patients (RER for rural: 0.88, 95% CI 0.81-0.95). In M+ patients, 5-year RS was 14% for both residence groups. On multivariate analysis, residence remained as an independent predictor for survival in the overall kidney cancer population (RER of rural patients 0.87, 95% CI 0.81-0.94). For M+ patients the RER was 0.90 ( 95% CI 0.81-1.00). For patients without surgery, rural patients were even stronger benefited in their survival than urban patients (overall population: RER 0.81, 95% CI 0.74-0.89; M+ patients: RER 0.84, 95% CI 0.73-0.97) wherereas in surgical patients RS did not differ between rural and urban patients. Conclusions: An advantage in RS was observed for kidney cancer patients living in rural areas. This advantage was evident in metastatic and non-metastatic patients, especially in patients who did not undergo surgery for (metastatic) kidney cancer. These results suggest that access to medical health care for kidney cancer patients in Austria is not limited by rural residence.
Management of renal masses in an octogenarian cohort: Is there a right approach?
Authors: Nawlo Jude , Tang Dominic H. , Chipollini Juan , Gilbert Scott Michael , Poch Michael Adam , Sexton Wade Jeffers , Pow-Sang Julio , Spiess Philippe E. 
Published: March 2017

497 Background: Although several guidelines outline management options for patients with renal masses, few studies describe treatment strategies and outcomes in octogenarians. We sought to review outcomes in this population managed with active surveillance (AS), partial nephrectomy (PN), or radical nephrectomy (RN). Methods: Data were collected on 113 octogenarian patients referred for management of renal masses at Moffitt Cancer Center between 2000 and 2013. Patients were treated with AS, PN, or RN. Univariate and multivariable Cox regression models measured association of management modality and survival. Kaplan-Meier survival analysis was used for overall survival and log-rank tests were used to compare survival curves. Covariates include age, Eastern Cooperative Oncology Group (ECOG) score, clinical and pathologic stage, tumor size, creatinine, creatinine clearance, and overall survival. Results: Out of 113 patients, 27 (22%) underwent AS, 33 (26.8%) underwent PN, and 53 (43%) underwent RN. The mean age was 83 years (range, 80-92). AS patients had a higher mean age (84 years) than PN patients (81.9 years), but not with RN patients (83 years) (p=0.008). At a median follow-up of 30.6 months (IQR 9.9-56), 13 (48%), 10 (30.3%), and 29 (54.7%) patients died from any cause in AS, PN, and RN patients respectively. PN patients tended to have a longer median overall survival at 81 months versus 55.8 and 57 months for AS and RN respectively, but this did not reach statistical significance on univariate (p=0.588) or multivariate analysis (p=0.29). On subgroup analysis of cT1a patients, there was also no difference in overall survival among treatment arms on univariate (p=0.654) and multivariate analysis (p=0.47). At 1 year follow-up, there was no difference in creatinine levels between treatment arms (p=0.331). However, mean creatinine clearance was lower in RN patients (35.8 ml/min) compared to AS (50.7 ml/min) and PN (48.1 ml/min) (p=0.024). Conclusions: Active treatment with PN and RN may not provide a survival advantage among octogenarians. Renal function was inferior in RN patients but comparable between AS and PN patients at 1 year follow-up.
Whole blood mRNA expression for prognosis of metastatic clear cell renal carcinoma (mCCRCC).
Authors: Giridhar Karthik , Hillman David W. , Sosa Carlos , Dalpiaz Candace Lee , Costello Brian Addis , Quevedo Fernando , Pitot Henry C. , Dronca Roxana Stefania , Ertz Donna , Cheville John C. , Donkena Krishna , Kohli Manish 
Published: March 2017

500 Background: The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score is based on clinical parameters and has several limitations. We analyzed whole blood mRNA expression in mCCRCC patients (pts) and compared it to MSKCC for predicting overall survival (OS). Methods: A prospective collection of whole blood in PAXgene RNA tubes from mCCRCC pts was performed between 2011 and 2015 with uniform processing. A discovery set (DS) of 19 randomly selected pt samples was used to generate whole transcriptome RNA sequencing and signatures describing differential gene expression patterns associated with OS. We calculated the fragment per kilobase of transcript per million (FPKM) of each transcript and gene to identify correlations between the differentially expressed genes and MSKCC score. Candidate genes were selected based on statistical significance (p<0.05) and associations with OS. In an independent validation set (VS) of 47 pts with mCCRCC, we used the nCounter Analysis System (NanoString Technologies, Seattle, WA, USA) to quantify gene transcript expression selected from the DS. Cox regression and Kaplan-Meier analysis were used for association of candidate mRNAs in the VS with OS (time of metastatic recurrence to death or last follow-up). We compared our gene signature to the MSKCC prognostic score for poor versus good survival. Results: In the DS, at a median follow-up of 4.13 years (yrs) (range: 1.3-4.5), 11 patients had died. We identified eighteen genes in the DS with statistically significant differential gene expression patterns and ability to discriminate patient OS. In the VS at a median follow-up of 4.9 yrs (range: 0.1-11.3), twenty-five patients had died. We confirmed two of the eighteen selected genes that had strong prognostic significance: BAG1 [hazard ratio (HR) 0.31, p=0.007] and NOP56 [HR 0.28, p=0.004]. Comparing OS between good and poor outcome groups for these 2 scores, our two-gene panel had higher prognostic ability (HR 20.07, p <0.0001) than the MSKCC prognostic score (HR 3.19, p 0.04). Conclusions: Prognostic value of using whole blood mRNA gene profiling in mCCRCC is feasible and should be prospectively confirmed in larger studies.
Impact of cytoreductive nephretomy on timing of systemic therapy in metastatic kidney cancer.
Authors: Macleod Liam Connor , Dash Atreya , Schade George , Harper Jonathan D. , Lin Daniel W. , Tykodi Scott S. , Gore John L. 
Published: March 2017

503 Background: High rates of disease control with systemic therapy (ST) in the post-cytokine era for metastatic renal cell carcinoma (mRCC) cause apprehension that cytoreductive nephrectomy (CN) may delay effective therapy. We therefore evaluated factors associated with early mortality and time to ST after CN. We hypothesized markers of poor performance status and morbid CN would be associated with postoperative mortality and therapeutic delays. Methods: The National Cancer Database was screened for adult mRCC cases having CN followed by ST, years 2006-2013. We classified a delay in systemic therapy as interval > 45 days (median time to ST in the cohort). Multivariable logistic regression was performed, identifying factors associated with perioperative mortality and delays to initiation of ST. Results: Of 10,913 patients with initial CN (45% of mRCC), 30- and 90-day mortality were 3% and 11%, respectively. 6,362 later received ST (87% targeted therapy, 13% immunotherapy), median start was 45 days post-operatively (IQR 9-72), with 73% receiving ST within 30 days of CN. Multivariable factors associated with 30-day mortality included, older age, (OR 2.3, 95% CI 1.5-3.5 for those >75 [referent < 55 years]), Charlson index >0 (OR 1.3, 95% CI 1.0-1.6), lack of insurance (OR 1.9, 95% CI 1.2-2.8 [referent private payer]), node-positive disease (OR 1.4 95% CI 1.1-1.7), length of stay > 90th percentile (> 10 days, OR 3.2, 95% CI 2.0-5.3), larger tumor size (T4 lesion OR 1.7, 95% CI 1.2-2.5 [referent T1]). Delayed ST was associated with travel burden > 50 miles (OR 1.2, 95% CI 1.0-1.4), concurrent metastasectomy (OR 1.3, 95% CI 1.2-1.5), and length of stay > 90th percentile (OR 1.5, 95% CI 1.1-2.3). Conclusions: These data suggest that markers of frailty, more progressive disease, and surgical morbidity may contribute to surgical-related deaths or hinder patients receiving potentially disease-controlling therapy when treated with initial CN in mRCC. Going forward, existing surgical prognostic models could incorporate risks of surgical-related mortality and delay to ST when considering CN.
Pattern of glycosylphosphatidylinositol-anchored 80 kD protein (GPI-80) expression in peripheral blood as a marker for myeloid-derived suppressor cells (MDSCs) in metastatic renal cell cancer (mRCC) patients.
Authors: Kato Tomoyuki , Takeda Yuji , Kurota Yuta , Ito Hiromi , Araki Akemi , Nara Hidetoshi , Asao Hironobu , Tsuchiya Norihiko 
Published: March 2017

504 Background: Metastatic renal cell cancer (mRCC) patients are afflicted with the immunosuppressed condition, and myeloid-derived suppressor cells (MDSCs) are considered to be associated with this condition. MDSCs are difficult to detect in peripheral blood as their cell structures are not uniform, resembling both neutrophils and monocytes. GPI-80 is known as a regulator of Mac-1 (CD11b/CD18) and closely related with neutrophilic maturation. In this study, we investigated whether the pattern of GPI-80 expression could serve as a useful marker for the detection of MDSCs in peripheral blood among mRCC patients. Methods: This study was approved by the Ethics Committee of Yamagata University’s Faculty of Medicine. Peripheral blood samples, collected from 12 mRCC patients before treatment and 12 healthy volunteers, were stained with several differentiation markers such as CD11b, CD16, CD15, CD33, and GPI-80. The samples were examined using flow cytometry to detect unusual differentiation of myeloid cells. To investigate the immunosuppressive function of GPI-80 positive cells, reactive oxygen species (ROS) was measured, and T cell proliferation assay was performed. Results: The coefficient of variation (CV) of GPI-80 was significantly augmented in the CD16hi neutrophil cell population (p = 0.0001). The mean fluorescence intensity (MFI) of GPI-80 was significantly increased in the CD33hi monocyte cell population (p = 0.0074) in the peripheral blood cells of mRCC patients. Furthermore, the GPI-80 CV in the CD16hi population was inversely correlated with the proliferative ability of T cells (p = 0.0214), and the GPI-80 MFI of the CD33hi population was correlated with ROS production (p = 0.0497). Conclusions: These results showed that the pattern of GPI-80 expression in peripheral blood cells is a simple and useful marker for unusual differentiation, which is linked to MDSC functions among mRCC patients. Further studies are, however, required to identify the role of GPI-80 as a prognostic or predictive marker in such patients.