bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incorporation of PBRM1, BAP1, TP53 mutation status into the Memorial Sloan Kettering Cancer Center (MSKCC) risk model: A genomically annotated tool to improve stratification of patients (pts) with advanced renal cell carcinoma (RCC).
Authors: Voss Martin Henner , Cheng Yuan , Marker Mahtab , Kuo Fengshen , Choueiri Toni K. , Hsieh James J , Reising Albert , Motzer Robert J. , Hakimi A. Ari 
Published: February 2018

639 Background: The MSKCC risk model, an established prognostic tool fo r metastatic RCC, integrates clinical + laboratory data, but is ignorant to tumor genomics. Mutations in BAP1, PBRM1, TP53, cumulatively found in over 50% of pts, have prognostic value in RCC. We sought to study the use of integrating mutation status into the MSKCC model using two large clinical trial datasets. Methods: Pts had received first line sunitinib or pazopanib on the phase III COMPARZ (training set, n = 357) or the phase II RECORD3 trial (validation set, n = 130). Genes were evaluated by next generation sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) in the training set. An annotated model was constructed combining the original clinical variables and mutation status for the 3 genes. We compared risk group assignment and concordance index (c-index) for the original vs. new model in training and validation set. Results: Mutation status for each gene: BAP1, TP53 and PBRM1 independently correlated with OS on MVA (p≤0.0035). Comparing the original (clinical only) to the annotated (clinical + genomics) model, risk categories changed in 139 pts (39%). The C-index was improved with integration of genomic information (0.595 original model - > 0.628 new model). The independent validation cohort confirmed improvement of c-index for predicting OS with integration of genomic data (c-index 0.622 original model - > 0.641 new model). Conclusions: Mutation status for BAP1, PBRM1, and TP53 has prognostic value in pts with advanced RCC. The annotated risk model alters risk status in over 1/3 of pts and improves accuracy of estimating outcomes in patients receiving first-line therapy. Clinical trial information: NCT00720941. [Table: see text]
CD73 expression in primary and metastatic renal cell carcinoma (RCC).
Authors: Tripathi Abhishek , Johnston Sarah E , Zhao Yan D , Hassan Oudai , Thompson Linda F , Lalani Aly-Khan A. , Wei Xiao X. , Giannakis Marios , Signoretti Sabina , Choueiri Toni K. , Harshman Lauren Christine 
Published: February 2018

643 Background: Agents targeting the PD-1 pathway have improved outcomes in RCC. CD73 may be an additional mechanism which tumors can exploit for immune evasion. It is regulated by hypoxia inducible factor (HIF) and converts AMP to adenosine. The resulting increase in extracellular adenosine can inhibit T-cell effector function. We evaluated CD73 expression in primary and metastatic tumor samples in patients with RCC. Methods: A commercial TMA (US Biomax) consisting of 31 primary clear cell RCC samples (2 with sarcomatoid features) with 8 matched and 1 unmatched metastases was used to assess CD73 expression. A genitourinary pathologist (OH) confirmed pathology and grade. Immunohistochemistry (IHC) was performed using a monoclonal anti-CD73 antibody (Cell Signaling; D7F9A). A combined score (CS: % of cells positive x intensity) was employed to quantify CD73 expression. Expression levels between matched primary and metastatic tissue was compared using Wilcoxon signed-rank test. Correlation of CD73 expression (CS > 0) in primary tumor with baseline clinical and pathologic characteristics was assessed using Kruskal-Wallis and Fisher's exact tests. Overall survival (OS) was estimated using the Kaplan-Meier method. Comparison between CD73 expression groups used log rank test. Results: CD73 expression was seen in 19% (n = 6) of primary and 66.7% (n = 6) of metastatic samples. Among matched primary and metastatic samples (n = 8 each), median CS was 25 (Q1-Q3:0-105) in metastatic samples while none of the corresponding primary samples demonstrated CD73 expression (median CS = 0, p = 0.062). CD73 expression in primary tumor samples did not correlate with baseline clinical or pathologic features. Five-year OS was 50% in patients who expressed CD73 in primary tumors compared to 84% in those who did not (p = 0.26). Conclusions: We observed a numerical increase in CD73 expression in metastatic tissue compared to primary RCC samples and worse 5 year OS. The small number of samples has limited statistical significance. Further studies are needed to examine the impact of CD73 expression on outcomes in RCC patients treated with currently approved checkpoint inhibitors and the investigational CD73 antagonists that are in early phases of development.
Efficacy of treatment beyond third-line (3L) in metastatic clear-cell renal cell carcinoma (mccRCC).
Authors: Guida Annalisa , Le Teuff Gwénaël , Silva Carolina Alveosta , Colomba Blameble Emeline , Salviat Flore , Baciarello Giulia , Derosa Lisa , Loriot Yohann , Fizazi Karim , Di Palma Mario , Massard Christophe , Escudier Bernard , Albiges Laurence 
Published: February 2018

647 Background: During the last decade, 10 agents have been approved for the treatment of patients (pts) with mccRCC, and guidelines have been developed up to 3L. The aim of the study is to describe the potential benefit of therapies beyond 3L in clinical practice Methods: Retrospective data analysis was performed using IGRECC (Institut Gustave Roussy REnal Cell Carcinoma) database to describe clinical features and outcomes beyond 3L in mccRCC. Kaplan Meier estimation was applied for progression free survival (PFS) and overall survival (OS) Results: Between 2005 and 2016, 825 (80%) pts had mccRCC and were treated with targeted therapies, of which 517 (63%) had 2L, 271 (33%) had 3L, 145 (18%) had 4L and 75 (9%) had 5L of therapy. Baseline characteristics and treatments are displayed in Table 1. With a median follow-up of 29 months (mo) (min: 20 max: 51), for patients receiving 4L, the median PFS is 5 mo (95%CI 4 – 6) and the median OS is 15.5 mo (95%CI 12 – 21). Pts with International Metastatic Renal Cell Cancer Database Consortium (IMDC) score favourable (18%), intermediate (59%), and poor risk (23%) at 4L initiation had a median OS of 24 mo (95%CI 11 – NR), 16 mo (95%CI 12.6 – 24), and 8 mo (95%CI 6 – 15), respectively (p < 0.0036). Partial response (PR) and stable disease (SD) were achieved in 13% and 56% of 122 evaluable pts. With a median follow-up of 16 mo (min: 13 max: 37) in 5L, the median PFS is 4.5 mo (95%CI 3 – 6) and the median OS is 19.5 mo (95%CI 11 - 28). Pts with a poor IMDC score risk at 5L initiation (33%) had a median OS of 7 mo (95%CI 3 – 10) (p < 0.0001). PR and SD were achieved in 16% and 52% of 55 evaluable pts in 5L Conclusions: The approved agents remain active as 4L or 5L options for mccRCC in pts who can reach this situation. Interestingly, both PFS and OS appear to be very similar in 4L and 5L as compared to 3L. Therefore, we believe that selected pts may derive benefit from these treatments beyond the barriers of regulatory or reimbursement approval [Table: see text]
Gut microbiome composition and response to sunitinib in metastatic renal cell carcinoma (mRCC).
Authors: Gong Jun , Dizman Nazli , Poroyko Valeriy , Won Haejung , Bergerot Cristiane Decat , Bergerot Paulo Gustavo , Maia Manuel C. , Hsu Joann , Frankel Paul Henry , Jones Jeremy , Salgia Ravi , Pal Sumanta K. 
Published: February 2018

657 Background: Recent evidence supports a link between stool microbiome composition and immunotherapy response. However, it is unclear how the microbiome may influence clinical outcome in mRCC where vascular endothelial growth factor-targeted therapies remains a standard of care. Methods: Five consecutive stool samples were collected at baseline and at weeks 2, 3, 4 and 12 of treatment with sunitinib in patients (pts) with mRCC. In responders (R: complete/partial response and stable disease) and non-responders (P: primary progression), gut microbiota composition was assessed through extraction of microbial DNA where 16s RNA gene tags (v4) were generated by PCR amplification and sequenced using MiSeq (Illumina). Sequence reads were processed by Mothur software, assembled in Operational Taxonomic Units (OTUs), taxonomically annotated to the genus level, and used to construct Bray-Curtis dissimilarity matrix. The similarity of samples was visualized by principle coordinate (PCo) analysis and further confirmed by k-means clustering and ANOSIM tests. Differentially abundant taxa were determined by METASTATS. Results: Stool bacteriomic profiling identified 25,304 OTUs attributable to 165 genera from 8 phyla in 4 of 6 pts evaluable for response. PCo analysis revealed clear separation of R and P (accounting for 28.9 % of dataset variation) where subsequent k-means clustering confirmed the difference of microbiota in 2 clusters that perfectly align with R and P groups. The significance of this separation was confirmed by ANOSIM analysis (p = 0.005). Analysis of microbiota composition in P and R groups revealed 14 differentially abundant taxonomic units at the genus level. Of those at ≥1% abundance, Bacteroides, Barnesiella and Phascolarctobacterium were elevated in R, while Bifidobacterium and Dorea were elevated in P (p < 0.01 for all). Of those at < 1% abundance, Lactococcus, Sporobacter, Acidaminococcus, Actinomyces, and Asaccharobacter were elevated in P (p < 0.01 for all). Conclusions: Although limited by sample size, we report the first in-human study to suggest a link between microbiota and response to sunitinib as we identified a significant discrepancy in stool bacteriomic distribution between P and R.
Impact of intravenous acetaminophen on outcomes following radical nephrectomy.
Authors: Zlatev Dimitar V. , Friedlander David F. , Tinay Ilker , Wang Ye , Pucheril Daniel , Chung Benjamin I. , Chang Steven Lee 
Published: February 2018

663 Background: Intravenous acetaminophen (IVA) was approved for use in the United States (US) for moderate to severe pain in 2010. The role of postoperative IVA following radical nephrectomy (RN) is of particular interest given the potential nephrotoxic and bleeding risks associated with other non-opioid alternatives such as parenteral non-steroidal anti-inflammatory drugs. However, given the relatively high cost of IVA versus other pain medications, the benefit of IVA in the postoperative period is unclear. We sought to determine if the use of postoperative IVA is associated with improved outcomes following RN. Methods: Using the Premier Hospital Database (Premier, Inc., Charlotte, NC), we retrospectively identified patients who underwent RN for a diagnosis of kidney cancer or renal mass in the US between 2011 and 2015. To limit confounding, only elective procedures and those with no complications (Clavien Classification of Surgical Complications score of 0) were included for analysis. Analysis was furthermore limited to patients of surgeons who either uniformly used or never used postoperative IVA. Chargemaster data for each patient was reviewed to determine use of IVA and narcotic pain medications postoperatively. Multivariable logistic regression was used to assess the relationship between postoperative IVA and the odds of a prolonged length of stay (LOS, top quartile). Multivariable quantile regression was used to determine the association of postoperative IVA with the use of narcotic pain medications (measured by morphine equivalents) and direct index hospitalization costs. Results: Among our cohort of 9,809 patients undergoing RN, 1,147 (11.7%) received postoperative IVA. The use of postoperative IVA was associated with a 64% decreased odds of prolonged LOS (OR 0.36, 95% CI: 0.19 to 0.69, p < 0.05). There was no significant impact of postoperative IVA on the use of narcotic pain medications or direct costs during the index hospitalization ($12,567 vs. $12,533, p > 0.05). Conclusions: The use of IVA following RN is associated with a reduced length of stay, no change in use of narcotic pain medications, and no increase in hospitalization costs.
Defining individual recurrence risk following surgery for high risk non-metastatic renal cell carcinoma.
Authors: Abel Edwin J , Raman Jay D. , Shapiro Daniel D , Chan Wilson , Allen Glenn O. , Patil Dattatraya , Master Viraj A. 
Published: February 2018

664 Background: Current models to estimate renal cell carcinoma (RCC) recurrence risk following surgery are derived from populations containing primarily low-risk patients. The objective of this study was to evaluate risk factors for recurrence among high risk non-metastatic RCC patients following attempted curative surgery. Methods: Data from 3 independent centers was analyzed for consecutive ≥ pT3a RCC patients without evidence of lymph node or distant metastases who were treated surgically from 2000-2016. Univariate and multivariate Cox proportional hazard models were used to evaluate associations of common clinical and pathological variables with recurrence risk. A risk model was constructed using independent predictors and recurrence risk was evaluated using Kaplan-Meier analysis. Results: Of 771 patients, 190 (24.6%) had RCC recurrence following attempted curative surgery at median 10.2 months (IQR 4.4-20.7). Median overall follow-up interval was 21.4 months (IQR 6.6-53.5). After multivariate Cox proportional hazard analysis, significant associations with RCC recurrence were not identified with: age, gender, race, systemic symptoms, local symptoms, pT stage, perinephric fat invasion, tumor thrombus, sinus fat invasion, serum hemoglobin, or serum albumin. Independent predictors included grade 4 HR 3.27 (95% CI 2.17, 4.92); tumor diameter > 7cm HR 1.70 (95% CI 1.18, 2.45), tumor necrosis HR 1.47 (95% CI 1.06, 2.02), and sarcomatoid/ rhabdoid features HR 1.86 (95% CI 1.12, 3.09) An unweighted risk model was created by assigning one point for each independent predictor. Estimated 3-year recurrence risk was 14%, 25%, 40%, 49%, and 69% for patients with 0,1,2,3 and 4 risk factors (p < 0.001) respectively. Conclusions: Independent predictors of recurrence for high risk non-metastatic RCC include: tumor diameter, necrosis, nuclear grade 4, and sarcomatoid/ rhabdoid features. This model may be used to estimate individual risk in RCC adjuvant therapy clinical trials.
Germline pathogenic variants in patients with pheochromocytoma.
Authors: Yao Shirley A , Wiley Elizabeth A , Susswein Lisa R. , Marshall Megan L. , Carter Natalie J. , McGill Anna K. , Klein Rachel T. , Wang Ying , Hruska Kathleen S. 
Published: February 2018

668 Background: Approximately 25% of pheochromocytomas (PCC) have a hereditary basis, and germline variants in the SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 genes have been associated with a predisposition to PCC and paraganglioma (PGL). Multi-gene hereditary cancer panel testing for PCC has become increasingly more common than single-gene testing algorithms. Identification of a pathogenic or likely pathogenic variant (PV/LPV) in one of these genes has important implications for surveillance in patients and their family members. Here we describe the spectrum of PV/LPV variants identified in individuals with PCC. Methods: We performed a retrospective review of clinical and molecular data for all individuals diagnosed with PCC who underwent panel testing through BioReference Laboratories that included at least SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, VHL, FH, RET, MEN1, and NF1 between January 2016 and February 2017. Results: Seventy-nine individuals underwent testing due to a personal (n = 76) or family (n = 3) history of PCC. The positive yield was 14% (11/79). The majority of PV/LPV were in SDHB (n = 4; 36%), followed by RET (n = 2, 18%), with the remaining variants being identified in SDHA (1), SDHC (1), VHL (1), TMEM127 (1), and MAX (1). Approximately half (6/11) of those with a PV/LPV had a non-syndromic presentation of a unilateral PCC with no reported family history of PCC or PGL. The average age at tumor diagnosis was lower for probands testing positive than those without PV/LPV (34y±14 vs 44y±16). Conclusions: Our data support previous recommendations that patients with apparently sporadic, non-syndromic PCC be considered for genetic testing. Panel testing is a useful tool for identifying individuals with hereditary PCC.
Analysis of an online tool to explore evolving practice patterns in renal cell carcinoma (RCC).
Authors: Kim Won , Rosenthal Kristen , Hutson Thomas E. , Motzer Robert J. , Plimack Elizabeth R. , Obholz Kevin , Vinther Angelique , Rini Brian I. 
Published: February 2018

674 Background: The complex and rapidly evolving treatment (Tx) landscape for advanced RCC poses challenges for healthcare providers (HCPs), particularly those in community settings, to make Tx decisions. To better understand current RCC Tx patterns, we analyzed patient (pt) cases entered by HCPs in an online tool developed by 5 experienced RCC experts from leading academic institutions. Methods: The tool, developed in 2016 and updated in 2017, includes over 500 case variations based on key factors defined by the experts. HCPs enter pt information and their intended Tx plan; the tool provides expert Tx recommendations for the pt case entered, followed by a survey to determine if the recommendations changed the HCP Tx plan. This analysis compares intended Tx of HCPs vs expert recommendations for 1027 cases entered into the tool (2016, n = 470; 2017, n = 557). Pearson chi-squared and Fischer’s Exact tests were used for analyses. Results: There was substantial Tx variation between HCPs and experts. In the first-line setting, 65% of HCPs vs 81% of experts selected sunitinib or pazopanib in both 2016 and 2017 (P = .0014). After disease progression (PD) on a first-line TKI, experts selected nivolumab (nivo) as second-line Tx more often than HCPs (98% vs 26% in 2016, P < .0001; 89% vs 37% in 2017, P < .0001). There were significant changes in practice patterns from 2016 to 2017 for both experts and HCPs in pts who received 2 prior lines of Tx. After PD on a first-line TKI and then nivo, experts recommended cabozantinib as the TKI of choice in 76% of cases in 2017 vs 40% in 2016. After PD on a first-line TKI and then either axitinib or everolimus, experts selected nivo more often than HCPs (84% vs 30%, respectively; P = .002) in 2016; however, expert and HCP Tx plans were not significantly different in 2017 (100% vs 70%, respectively; P = .08). Of the survey respondents, 46% of HCPs who differed from experts in their Tx selection indicated that the tool changed their intended Tx. Conclusions: Practice patterns between experts and HCPs differed substantially in pts with Tx-refractory RCC. Given that expert recommendations often changed the Tx plan of HCPs, the potential of an online tool to improve clinical outcomes in pts with advanced RCC warrants further investigation.
Cost-effectiveness of sunitinib or pazopanib for metastatic renal cell carcinoma in Brazil: A public health system perspective.
Authors: Sasse Andre Deeke , Carvalho Adriana Camargo 
Published: February 2018

680 Background: The first-line treatment with tyrosine kinase inhibitors results in significant clinical benefits for patients with metastatic renal cell carcinoma (mRCC). However, in Brazilian public health system Interferon still remains as standard treatment. In an innovative way, the Brazilian Society of Clinical Oncology made a price negotiation directly with the pharmaceutical company, aiming to propose a formal request for the incorporation of these technologies to the National Committee for Health Technology Incorporation (CONITEC). Our objective was to estimate the cost-effectiveness of Sunitinib or Pazopanib versus Interferon in patients with mRCC, under the perspective of the Brazilian public health system. Methods: A cost-effectiveness analysis was conducted using a Markov model over a lifetime horizon. The model considers three health states: 1st-line treatment, disease progression and death. Transition probabilities were extracted from randomized studies. Costs of standard treatment, complications, and surveillance were obtained from Brazilian public hospitals. Sunitinib and Pazopanib prices were those negotiated with the manufacturing companies. Benefits are presented in life-years (LY) and costs in USD. The relation between costs and benefits were used to present the incremental cost-effectiveness ratio (ICER) per life-year saved. Results: Patients with mRCC treated with Interferon were projected to have 1.92 LY with a total cost of $2,000. Sunitinib or Pazopanib were projected to increase the life expectancy to 2.84 LY, with a total cost of $19,584 (Sunitinib) and $19,646 (Pazopanib). The ICERs for Sunitinib and Pazopanib were estimated at $18,565 and $18,634 per LY respectively. Conclusions: Using the discount prices, at a willingness-to-pay (WTP) threshold of $25,615 per LY (three times gross domestic product per capita), both Pazopanib and Sunitinib are cost-effective strategies compared to Interferon. Potential impacts of targeted therapies for mRCC on the overall health care expenditures need to be assessed in a budget impact analysis. A formal request for the incorporation of these technologies to the CONITEC is in progress.
Liver-directed therapy (LDT) for metastatic renal cell carcinoma (mRCC): Single center experience.
Authors: Raychaudhuri Ruben , Bylow Kathryn A. , Lea William , Byun John , Zellmer Timothy , Burfeind John D. , Riese Matthew John , Kilari Deepak 
Published: February 2018

681 Background: Liver metastases arising from RCC are common and signify a poor prognosis. Given the negative impact of liver metastases on overall survival (OS) and quality of life, it is reasonable to to consider therapies directly targeting these lesions in select patients. Little is known about how minimally invasive LDT affects outcomes in patients with mRCC. Methods: Nine patients with mRCC underwent LDT for liver-dominant or liver-only metastatic disease between 2005 and 2015. Retrospective chart review was performed under an IRB protocol to identify patient and disease characteristics, imaging response, and time to next systemic treatment, OS and toxicities. Patients were seen in clinic at one month post-LDT to monitor for toxicities. Imaging was obtained within 2 months prior to treatment and at 3 and 6 months following LDT. Results: Each patient underwent a median of 2.3 procedures. A total of 18 transarterial chemoembolizations (TACE) and 5 yttrium-90 radioembolizations were performed. 2 patients had metastatic disease confined to the liver, and 7 had liver-dominant disease. 7 had multifocal disease involving < 25% of the liver, and 2 had multifocal disease involving > 25% of the liver. 8/9 patients received prior systemic therapies, receiving a median of 3 (0-4) distinct treatments. 4/9 patients were undergoing systemic therapy at the time of LDT, 1 patient declined further treatment, and the median time to initiation of the next systemic therapy in the remaining patients was 3 months (range 2-4 months). Median OS from first line systemic therapy was 39 months, 95% CI [25.9-53.3], and the median OS from the first LDT was 22 months (from 5-45 months). Follow-up imaging post-LDT showed PR or SD in 88% of cases at 3 months and 44% of cases at 6 months. At one month post-procedure, 8/9 patients maintained performance status, and only one patient experienced CTCAE grade 3-4 toxicity. Conclusions: The median OS in RCC patients with liver disease and systemic therapy alone is 14.3 months. The improved median OS of 39 months with LDT in our unmatched and heavily pretreated cohort suggests a role for LDT. LDT is generally well tolerated and should be considered for patients with liver-dominant mRCC with good performance status.