bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of social demographics and African-American race on outcomes in testicular cancer: Analysis of 75,902 patients in the National Cancer database.
Authors: Nichols Craig R. , Jeldres Claudio , Pham Khanh , Daneshmand Siamak , Kollmannsberger Christian K. , Hayes-Lattin Brandon M. , Odem-Davis Katherine , Wolff Erika , Porter Christopher R. 
Published: February 2017

391 Background: While there have been substantial advances in treatment and outcomes in testicular cancer, most of the data are derived from large institutionals or clinical trials. Testicular germ cell tumors are uncommon (8,000 new patients annually in US). The incidence among patients (pts) of African origins is extremely low. Most of the conclusions regarding outcomes are based on Caucasian pts from research institutions. Information about modern outcomes in non-Caucasian races is scant and little is known about the influence of various social demographic parameters on presentation patterns and survival. Using this population-based database available through the NCDB, we sought to better understand social and racial variations in outcomes. Methods: Within the NCDB, 75,902 testicular cancer pts were available for review. Tools available through the NCDB were utilized for analysis. Herein, we evaluated social demographics (insurance type, educational achievement, annual income, type of treating institution) and racial/ethnic characteristics as they pertained to stage at presentation and survival. Results: 75,902 pts were available from the timeframe of 1998 through 2011 for aggregation of social demographic features as well as racial/ethnic characteristics. Overall survival was available on 48573 pts through 2006. Racial-ethnic breakdown at presentation was 84.1% (n=63,867) Caucasian and African-American 2.7% (n=2,083). Overall, insurance type, education (% without high school degree), income (< $ 30000 to >$46,000) and type of treating hospital were analyzed using univariate and multivariate models. Full details will be presented. Conclusions: Unfavorable presentations and outcomes in testicular cancer are seen by race and social demographics. In depth analytics are being performed to characterize the variations as related to biological/genetic differences and/or differences in social demographics. In this very large cohort, the National Cancer database demonstrates a 2-fold risk increase in death in African American pts relative to Caucasian pts with similar stage at presentation.
Validation and genomic interrogation of the MET variant rs11762213 as a predictor of adverse outcomes in clear cell renal cell carcinoma.
Authors: Hakimi A. Ari , Ostrovnaya Irina , Jacobsen Anders , Coleman Jonathan A. , Russo Paul , Mano Roy , Sankin Alexander , Motzer Robert John , Purdue Mark , Pomerantz Mark , Freedman Matthew L , Choueiri Toni K. , Hsieh James , Klein Robert J. 
Published: February 2017

395 Background: The exonic single nucleotide variant rs11762213 located in the METoncogene has recently been identified as a prognostic marker in clear cell renal cell carcinoma (ccRCC) (Schutz et al, Lancet Oncol 2013). We sought to validate this finding and explore the biologic implications using The Cancer Genome Atlas (TCGA) cohort. Methods: The variant call file (VCF) and expression data was available for 272 patients. We then extracted the data for rs11762213 as follows for the "normal" sample: allelic fraction for variant allele > 80% is homozygous variant while allelic fraction for variant allele 30% to 70% is heterozygous. Paired tumor-normal materials, genomic data (whole exome, RNAseq, and DNA methylation) and clinical information were acquired from publically available TCGA datasets. Kaplan-Meier method was used to estimate the survival probabilities. Cancer specific survival (CSS) was analyzed using the competing risk method and Cox proportional hazard regression was used for analysis of time to recurrence. Multivariate competing risk models were also fitted in the TCGA cohort in order to adjust for the Mayo Clinic SSIGN score. Results: Overall, the variant allele of rs11762213 was detected in 10.3% of the cohort and was associated with higher nuclear grade (p=0.03) and trended toward higher clinical stage (p=0.07). After adjusting for the prognostic SSIGN score, the risk allele remained a significant predictor for adverse cancer specific survival (CSS; p<0.0001; Odds Ratio [OR] 3.88, 95% confidence interval [CI] 1.99-7.56) and time to recurrence (TTR; p=0.003; OR 2.97; 95% CI 1.44-6.2). RNA sequencing data for MET did not reveal differences in tumor mRNA expression when stratified by risk allele, but did show differences in the normal kidney expression (p=0.02) in a smaller cohort (n=61). Conclusions: The exonic MET variant rs11762213 is an independent predictor of adverse CSS and TTR in ccRCC and could be integrated into clinical practice for prognostic stratification. Gene expression analysis suggests that inherited variation at MET influences expression of the gene in normal kidney tissue. Further external validation and biological interrogation is necessary.
Comprehensive kinase profiling to classify clear cell (cc)-renal cell carcinoma (RCC).
Authors: Mehta Amitkumar N. , Willey Christopher Douglas , Anderson Joshua , Welaya Karim Youssry , Chen Dongquan , Ghatalia Pooja , Madan Ankit , Sudarshan Sunil , Naik Gurudatta , Grizzle William E. , Choueiri Toni K. , Sonpavde Guru 
Published: February 2017

409 Background: Comprehensive high throughput functional kinase activity in localized cc-RCC tumors may assist in devising a classification system and help identify potential therapeutic targets. Methods: Patients (pts) with localized tumors undergoing surgery with minimum follow-up of 18 months underwent kinomics of fresh frozen cc-RCC tumors and matched normal renal tissue using the PamStation12 high-content phospho-peptide substrate microarray system (PamGene). The protein tyrosine kinome (PTK) and serine/threonine kinome (STK) PamChips were used to measure global kinase activity. Advanced network modeling of altered phospho-peptides was performed using MetaCore while upstream kinase prediction scoring was based off of phosphonet (phosphonet.ca). Both unsupervised analyses and supervised analyses of kinomics were done guided by tumor recurrence. Kinomics of tumor and matched normal tissue were compared. Results: Of 41 evaluable pts, the median age was 61 and pathologic stage was 1, 2, 3 and 4 in 19, 1, 20 and 1 pts, respectively. Unsupervised clustering analyses of tumor kinomics showed 3 groups: A (N=12), B (N=16), C (N=13). Potential driver kinases implicated were PFTK1, PKG1 and SRC in groups A, B, and C, respectively. Network modeling of these groups identified many Process Mappings including, but not limited to Inflammation pathways (A), translation initiation (B) and immune response and cell adhesion pathways(C). 5 of 9 pts who progressed were classified as Group C, 1 progressor was in Group B, and 3 were in Group A. Supervised analysis showed decreased CDK1, RSK1-4, ERK1-2, PKG2 and AKT2 kinase activity in those who progressed compared to others. 12 tumors showed increased PIM1 and MAPKAPK3, and decreased JNK2 and CDK1 compared to adjacent normal tissue. Conclusions: Comprehensive kinomics of localized cc-RCC was used to classify tumors based on unsupervised clustering, which appeared to confer differential long-term outcomes while supervised analysis also identified potential pathways related to recurrence. Kinases amplified in renal tumors compared to adjacent normal renal tissue were also identified. Significant heterogeneity of kinases was found with no single dominant kinase across all analyses.
Deep sequencing of sarcomatoid renal cell carcinoma (sRCC) and identification of aurora kinases and mTOR as potential therapeutic targets.
Authors: Pal Sumanta Kumar , Tong Tommy , He Miaoling , Wu Huiqing , Liu Xueli , Nelson Rebecca A. , Wu Xiwei , Signoretti Sabina , Choueiri Toni K. , Jones Jeremy 
Published: February 2017

411 Background: The presence of sarc elements in pts with RCC portends a poor prognosis. Some studies have focused on epithelial-to-mesenchymal transition (EMT) as a driver of sarc ccRCC; however, the potential role of other targetable entities is unknown. Methods: From an institutional database, we identified 13 pts with metastatic sarc ccRCC and 13 pts with metastatic ccRCC lacking sarc elements matched by age and risk group. All patients had available FFPE tissue derived from nephrectomy. For a limited sample of 5 pts with sarc ccRCC, RNA sequencing was performed on microdissected cc, sarc, and benign renal cortical sections from FFPE blocks. Reads were aligned to hg19 genome with Tophat v2.0. IHC was used to explore expression of implicated genes in the entire matched cohort of 26 pts. Results: With respect to RNA sequencing analysis for 5 pts with sarc ccRCC, reads had between 4% and 24% exon coverage. Hierarchical clustering demonstrated that most samples were clustered by patient, not by disease state (i.e., sarc vs non-sarc), suggesting that inter-patient variation is large. However, comparisons between cc and sarc components for these 5 pts demonstrated a significant increase in cell growth pathways, with the most highly enriched gene ontology pathways being M-phase, cell cycle, mitosis and aurora kinase pathways. No EMT-related pathways were found to be enriched. IHC assessments of VEGF and mTOR pathways were performed, given their purported role in RCC cell growth. While no differences were noted in pVEGFR2, higher pS6K staining was noted in both the sarc and non-sarc components of pts with sarc ccRCC relative to pS6K staining in tumor tissue derived from ccRCC pts lacking sarc elements (p<0.05 for both). No differences in EMT marker expression were noted (specifically, E-cad, N-cad and Twist); IHC assessments for aurora kinases A and B will be reported. Conclusions: Although cytotoxic agents and VEGF-directed therapies have been explored in sarc ccRCC, the finding of mTOR pathway activity underscores the need to examine mTOR inhibitors in this disease. Furthermore, emerging agents targeting aurora kinases may have a role in sarc ccRCC.
High-dose interleukin-2 registry, PROCLAIM: Modern data on toxicities and outcomes.
Authors: Lowder James N , Aung Sandra , Wong Michael K.K. , Daniels Gregory A. , Kaufman Howard , McDermott David F. , Morse Michael 
Published: February 2017

430 Background: High dose interleukin-2 is an FDA-approved treatment for metastatic melanoma (mM) and renal cell carcinoma (mRCC) that consistently delivers durable CRs in up to 10% of patients. Concerns of treatment related toxicities are a major barrier to IL-2 administration. Nonsystematic reviews show that HD IL-2 therapy is safe, however treatment protocols have evolved to a series of best practices within over 60 HD IL-2 centers in the US. Methods: In order to capture current practices and generate modern data on toxicities and outcomes, PROCLAIM, a HD IL-2 observational database, was initiated in 2011. One goal of the registry is to survey real world HD IL-2 clinical experience used in the treatment of patients with mM, mRCC or other metastatic malignancies. A retrospective cohort was initiated for hypothesis generation and to inform the prospective cohort which has currently > 470 patients enrolled. We report here on the retrospective data comprising 267 patients (mRCC,97) treated between 2007-2012. Results: Analysis of the retrospective data show that no deaths were reported, compared to the historic mortality rate of 4% (n=255 mRCC)(Fyfe,1995). Toxicites are acute and abate rapidly after cessation of IL-2. Center-specific reasons for stopping dosing to end a cycle, as well as tolerance of elevated creatinine levels varied significantly. There were striking differences between the median number of doses administered per cycle per center, clustering around 4-6 vs. 8-14. There appears to be a trend towards higher and more durable responses with higher dose density per cycle. Conclusions: HD IL-2 can be a safe and effective immunotherapy that can be given over a short duration and delivers consistent durable therapeutic responses. The rapid resolution of its toxicities allows for its use with other therapies either in sequence or in combination; trials are currently in progress.
Growth kinetics and outcomes of cT1b renal masses under active surveillance.
Authors: Mehrazin Reza , Smaldone Marc C. , Kutikov Alexander , Tomaszewski Jeffrey J. , Li Tianyu , Viterbo Rosalia , Greenberg Richard E. , Chen David Y. T. , Uzzo Robert G. 
Published: February 2017

440 Background: The natural history of untreated T1b renal masses is poorly understood. We assessed the growth kinetics and outcomes of ≥cT1b cortical renal tumors which continue to remain on radiographic AS compared to those who underwent definitive surgery after a period of AS. Methods: Prospectively maintained, renal tumor database was reviewed to identify enhancing solid and cystic masses managed expectantly from 2000-2012. cT1a masses, transitional cell carcinoma or those suspected for metastatic disease were excluded from analysis. Localized tumors > 4.0 cm (≥T1b) that were radiographically followed for > 6 months were included for analysis. Clinical and pathological records were reviewed to determine tumor growth rate and clinical outcomes in those remained on AS or those who underwent delayed intervention. Mean for tumor size on presentation, annual linear tumor growth rate (LGR), Charlson comorbidity index (CCI), and follow-up (FU) were calculated. Chi−square test & Logistic regression were used for uni- and multi-variable analyses. Results: Of 457 pts managed with AS, 67 cT1b tumors (in 63 patients) were identified. 43 pts (67%) were managed solely with AS, while 21 pts (33%) progressed to intervention. The median age at presentation pts managed with AS and intervention was 77 and 60 yrs respectively (p=0.0002), while no difference was observed in median CCI (3 vs. 2, p=0.6). No difference was observed in tumor size at presentation between pts managed with AS and those undergoing delayed intervention (5.9 vs. 5.4 cm, p=0.8). In contrast, the mean LGR significantly differed between pts managed expectantly and pts progressed to intervention (0.37 vs. 0.73 cm/yr; p=0.02). On MVA, age (OR=0.9,CI:0.8−0.98) and LGR (OR=11,CI:1.8−60) were significant predictors of surgical intervention. With a mean FU period of 38.9 ± 24.0 months (6−105), 9 pts died (14%) from other cause and no pt progressed to metastatic disease. Conclusions: Localized cT1b≥ renal masses show comparable growth rates to small tumors managed expectantly with low rates of progression to metastatic disease with short term follow up. An initial period of AS to determine tumor growth kinetics is a reasonable option in select pts with significant competing risks and limited life expectancy.
Phase I study of pazopanib in combination with interferon alfa in patients with advanced renal cell carcinoma (RCC) and other primary tumors: A Spanish Oncology Genitourinary Group (SOGUG) study.
Authors: Garcia del Muro Xavier , Duran Ignacio , García-Donas Jesús , Rodriguez-Moreno Juan Francisco , Gil-Martin Marta 
Published: February 2017

450 Background: Pazopanib is a VEGF receptor inhibitor active in the treatment of advanced RCC treatment, and Interferon has been a long-standing treatment option for metastatic RCC with a modest overall survival benefit. The purpose of this study is to assess the feasibility and safety of the combination of pazopanib and interferon in the treatment of advanced RCC and other tumor types. Methods: This is a phase I study of the combination of pazopanib and interferon alfa-2A. It has been developed in a 3+3 standard escalating design with cohorts of 3-6 patients (pts) to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD). Pazopanib is given po daily and interferon is given subcutaneously 3 times a week. Dose levels 1, 2, 3, 4 and 5 corresponded to pazopanib 400, 600, 800, 800 and 800 mg per day plus interferon 3, 3, 3, 6 and 9 million U. Patients with previously treated RCC and also other primary tumors could be included. Results: 19 pts were included and treated in 4 dose levels. Patients’ median age was 60 years old, 13 men and 6 women. Six of them were diagnosed with RCC; other pts presented metastatic tumors as ovarian carcinoma, peritoneal mesothelioma, breast cancer (2), liposarcoma, breast angiosarcoma, uterine sarcomas (3), endometrial carcinoma (3) and melanoma. MTD was reached at level 4, and the RD was Pazopanib 800mg with IFN 3MUI. Three pts experienced DLT, one in level 2 and two in level 4: grade 4 transaminitis, grade 3 transaminitis and grade 3 liver hematoma, respectively. Other toxicities (grade 3 and 4) included anemia, neutropenia, thrombocytopenia, asthenia, arthromialgia, anorexia, diarrhea and Raynaud’s syndrome. Additional mild but common toxicities were fever and proteinuria. One partial response was observed in a uterine sarcoma patient. In RCC, 4 pts achieved stable disease lasting a median of 5 cycles. Conclusions: Combination of pazopanib and interferon alfa is feasible and safe, allowing administration of active doses of both agents. A phase II study to assess this combination activity in RCC is assured. Clinical trial information: NCT01513187.
Multicenter phase II clinical trial of everolimus in Japanese patients with unresectable or metastatic renal cell carcinoma (mRCC) after failure of treatment with first-line tyrosine kinase inhibitor (TKI) therapy.
Authors: Ozono Seiichiro , Oyama Masafumi , Nozawa Masahiro , Fujimoto Kiyohide , Kishida Ken , Tokuda Noriaki , Kimura Go , Nishimura Kazuo , Matsubara Akio , Matsuyama Hideyasu , Sugiyama Takayuki , Kamba Tomomi , Kume Haruki , Masumori Naoya , Oya Mototsugu , Kanayama Hiro-Omi , Naito Seiji , Hinotsu Shiro , Shimozuma Kojiro , Akaza Hideyuki 
Published: February 2017

455 Background: Everolimus has shown the efficacy and the safety in the phase III trial (RECORD-1) in patients with mRCC after failure of Vascular Endothelial Growth Factor Receptor-TKI. However, 26% of patients received two TKIs (sunitinib and sorafenib) as previous therapy in RECORD-1. In addition, as pre-treatment before TKI, 65% of patients received cytokine therapy and 13% of patients received chemotherapy. Therefore, there is still no clear evidence of everolimus as second line setting after failure of 1st-line TKI therapy. Methods: This study is an open-label, multi-center, single-arm, phase II trial. Primary endpoint is progression-free survival (PFS), and secondary endpoints are overall survival, objective response rate, time-to-treatment-failure, safety and quality of life (EORTC QLQ-C30, FKSI-DRS, EQ-5D). Key eligibility criteria are RCC with clear cell component, patients who received one TKI as first line therapy, patients who did not receive cytokine and chemotherapy and ECOG performance status 0-1. Results: 57 patients were enrolled from 02/11 to 12/12. Median age was 63 years, common sites of metastasis were lung (32.7%) and bone (12.2%), 79.6% had previous nephrectomy, previous TKI therapy were sunitinib (69.4%), sorafenib (22.4%) and axitinib (8.2%). Median PFS was 4.4 months (95% confidence interval: 3.7-6.0). 8.2% had partial response and 57.1% had stable disease according to RECIST v.1.0. The incidence of adverse events (AEs) of all grades was 95.9%. Major AEs were stomatitis (49.0%), hypertriglyceridemia (26.5%) and hypercholesterolemia (24.5%). Serious AEs were stomatitis (10.2%), interstitial lung disease (6.1%) and rash (6.1%). There were no treatment related deaths. All QOL scores were not changed at 2 months, while dyspnea and global health scores of EORTC QLQ-C30 and FKSI-DRS score were worsened at 4 months. Conclusions: This study is a first report of everolimus as second line setting after failure of 1st-line TKI. Further study and long-term follow-up would be warranted. Clinical trial information: UMIN000004742.
Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Neeraj , Parikh Kinjal , Tantravahi Srinivas Kiran , Crispin Hilda , Van Atta Joan , Batten Julia Anne , Sageser Daniel , Samlowski Wolfram E. , Grossmann Kenneth F. , Wang Junfeng , Stenehjem David D. 
Published: February 2017

461 Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB ( OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2. Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer. Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table. Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC pts. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling pts for treatment with HD IL-2. [Table: see text]