bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide profiling of histone 3 lysine 36 trimethylation in clear cell renal cell carcinoma.
Authors: Ho Thai Huu , Lee Jeong-Heon , Nateras Rafael Nunez , Castle Erik P. , Stanton Melissa L. , Joseph Richard Wayne , Bryce Alan H. , Carballido Estrella M. , Parker Alexander S. , Zhang Zhiguo , Ordog Tamas 
Published: February 2017

464 Background: Although the von Hippel-Lindau (VHL) tumor suppressor gene is mutated in 60% of ccRCC, deletion of VHL in mice is insufficient for tumorigenesis. Sequencing of ccRCC tumors identified mutations in SETD2, a histone H3 lysine 36 (H3K36) trimethyltransferase. We hypothesize that loss of SETD2 methyltransferase activity alters the genome wide pattern of H3K36 trimethylation (H3K36me3) in ccRCC, and contributes to the cancer phenotype. Methods: To generate a genome-wide profile of H3K36me3 in frozen nephrectomy samples and RCC cell lines, we optimized a chromatin immunoprecipitation (ChIP) protocol for the isolation of DNA associated with H3K36me3. H3K36me3 is associated with open chromatin and an H3K36me3-specific antibody was used for immunoprecipitation of endogenous H3K36me3-bound DNA. ChIP PCR primers were optimized for active genes, such as actin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and a “gene desert” on chromosome 12 (negative control). ChIP libraries were then generated from 3 paired uninvolved kidney and RCC and 2 RCC cell lines. In order to identify H3K36Me3 upregulated regions in uninvolved kidney and RCC, reads from the ChIP sequencing were mapped to the human genome using Burrows-Wheeler Aligner and SICER algorithms. Results: Using ChIP PCR, we found that active genomic regions were enriched 15-30 fold over the negative controls indicating that the quality and yield of immunoprecipitated DNA/chromatin complexes from frozen tissue was sufficient for ChIP sequencing. A preliminary ChIP sequencing analysis of RCC cell lines and frozen ccRCC tissue indicates that H3K36me3 enriched DNA sequences were mapped to exons (31.3%) compared to introns (13.5%, p<0.001), consistent with the role of H3K36me3 in transcription. Conclusions: Genomic regions enriched for H3K36Me3 binding were identified from patient-derived tissue and RCC cell lines. Current efforts are focused on comparing the H3K36me3 profiles between matched tumor and uninvolved kidney ChIP libraries to generate a genome wide map of dysregulated H3K36me3 modifications.
Searching for circulating microRNAs in genitourinary tumors.
Authors: Medina Villaamil Vanessa , Aparicio Gallego Guadalupe , Veiga Francisco Gomez , Valladares Ayerbes Manuel , Quindós Varela Maria , Fernandez Nunez Natalia , Molina Diaz Aurea , Santamarina Cainzos Isabel , Anton Aparicio Luis Miguel 
Published: February 2017

468 Background: Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information in genitourinary tumors (GT). The aim of this work was identify aberrantly expressed miRNAs potentially useful for CTC detection in blood samples from patients with GT to assess their potential clinical significance, and to gain a greater understanding of the mechanisms driving tumor progression. Methods: We examined blood levels of 92 microRNAs in 113 metastatic patients: prostate (mP), renal cell carcinoma (mRCC), bladder tumors (mB) and healthy volunteers (HV) (N=18) using SYBR-green-based microRNA RT-qPCR arrays (Exiqon). Array design was made by literature review and bioinformatics approach using free databases. Relative Expression Software Tool (REST) and SPPS 21.0 were used to data processing and analysis. Results: microRNAs differential expressed between tumors and HV (only up-regulated miRNAs are shown in Table). Conclusions: microRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. These results suggest that our bioinformatic approach is an useful high-throughput method to identified tumors-associated miRNAs. The selected miRNAs should be further evaluated for their potential as markers for CTC detection, prognosis and therapeutic outcome. Further studies of precision and sensitivity on these markers in this GT population will clarify its role as novel stable blood-based markers. [Table: see text]
CCP score and risk stratification for prostate cancer patients at biopsy.
Authors: Crawford E. David , Shore Neal , Scardino Peter T. , Davis John W. , Tward Jonathan D. , Harrison Lowndes , Moyes Kelsey , Fitzgerald Lisa , Stone Steven , Brawer Michael K. 
Published: February 2017

47 Background: New prognostic markers for prostate cancer play an important role in addressing the controversies of over diagnosis and treatment. The cell cycle progression score (CCP) (Prolaris, Myriad Genetic Laboratories, Inc.) is a new RNA-based marker, which improved the prediction of prostate cancer aggressiveness in eight separate cohorts. Each one-unit increase in CCP score corresponds with approximately a doubling of the risk of the studied event (recurrence or death from prostate cancer). In this analysis, we characterized the CCP score distribution from our initial CCP signature commercial testing. Methods: Our current laboratory database was evaluated for patients whose biopsy was analyzed with the CCP test and whose clinicopathologic data was collected by the ordering physician. Formalin fixed, prostate biopsy tissue from 1,648 patients diagnosed with adenocarcinoma ordered by more than 300 physicians were analyzed. The CCP score was calculated by measuring the RNA expression of 31 cell cycle progression genes normalized to 15 housekeeping genes. Results: Of the 1,648 samples that contained sufficient carcinoma (more than 0.5mm linear extent), 1,604 (97.3%) provided quality RNA for analysis. This retrospective analysis showed a normal distribution for the CCP score ranging from −2.9 to 3.1. Correlation with Gleason score was r=0.35. A relative classification of cancer aggressiveness based on CCP of approximately1,200 patients from multiple cohorts was developed to interpret how the patient’s CCP score compared to that of patients within the same AUA risk category. The thresholds between each of the five intervals are one unit of CCP score apart, with the "consistent" interval centered at the median CCP score. Based on the CCP score, 27.9% of men had a less aggressive cancer compared to the clinicopathologic prediction and were assigned to a lower risk group while 27.6% of patients had a more aggressive cancer. Conclusions: The CCP signature test is a novel assay that can improve risk stratification for men with prostate adenocarcinoma independent of the Gleason score and prostate-specific antigen level. Over 50% of men initially tested in the commercial assay were assigned to a different risk category than predicted by clinicopathologic features alone.
Biomarker analysis from a phase III trial (GOLD) of dovitinib (Dov) versus sorafenib (Sor) in patients with metastatic renal cell carcinoma after one prior VEGF pathway–targeted therapy and one prior mTOR inhibitor therapy.
Authors: Escudier Bernard J. , Porta Camillo , Squires Matthew , Szczylik Cezary , Kollmannsberger Christian K. , Melichar Bohuslav , Rha Sun Young , Esteban Emilio , Bjarnason Georg A. , Vogelzang Nicholas J. , Sternberg Cora N. , Shi Michael , Marker Mathab , Motzer Robert John 
Published: February 2017

473 Background: In the GOLD trial, Dov did not improve progression-free survival (PFS) or overall survival (OS) over Sor. An exploratory objective of the study was to investigate plasma and tumor biomarkers to predict outcome. Methods: Plasma samples were obtained longitudinally throughout the study, and biomarkers were assessed by immunoassay. Primary archival tumor samples were assessed by immunohistochemistry. Log-rank tests, stratified by baseline MSKCC risk group, for difference in Kaplan-Meier curves between biomarker category (low/high based on </≥ median baseline values) within treatment arm were performed. Hazard ratios (HRs) were estimated from Cox proportional hazards models. Results: Plasma samples were available from 561 patients (Dov, n = 281; Sor, n = 280), and tumor samples were available from 341 patients (Dov, n = 181; Sor, n = 160). Baseline plasma biomarker levels were not predictive of Dov or Sor PFS or OS. However, strong prognostic effects, particularly for OS, were observed. High baseline cKIT and low baseline FGF2, HGF, PlGF, sVEGFR1, VEGFA, and VEGFD were associated with better OS for both Dov and Sor (Table). Changes from baseline in a number of plasma biomarkers were observed following treatment with Dov and Sor, consistent with VEGFR/FGFR inhibitory effects. Prognostic effects were also observed for low FGFR2 (PFS) and low FGF2 (OS) expression in archival tumors. Conclusions: Baseline plasma biomarkers are prognostic but not predictive in the third-line setting. Clinical trial information: NCT01223027. [Table: see text]
The impact of body mass index on treatment recommendations for patients with intermediate risk prostate cancer.
Authors: Yamoah Kosj , Whittemore Alice S. , Malkowicz S. Bruce , Spangler Elaine , Kattan Michael W. , Dicker Adam , Rebbeck Timothy R. 
Published: February 2017

48 Background: To evaluate the clinical utility of body mass index (BMI) in predicting adverse pathologic outcomes, hence the need for radiation therapy (RT) following radical prostatectomy (RP) for men with organ-confined prostate cancer. Methods: We compared BMI and preoperative risk factors to adverse pathologic risk factors (RP-risk) that dictate the use of RT following RP. Multivariate analysis was used to determine whether BMI provides clinically relevant information in predicting RP-risk for additional RT as well as biochemical outcome. Results: Patients with elevated BMI had higher RP-risk (p=0.002). Specifically, extraprostatic extension, p less than 0.001; positive surgical margins, p=0.005; and a trend towards worse seminal vesicle invasion, p=0.08. Elevated BMI did not correlate with preoperative risk groupings (p=0.38). However, in patients with intermediate-risk disease BMI greater than 29kg/m2 was strongly associated with higher RP-risk (p=0.03) and higher rate of pathologic upgrading of tumors (p<0.004). Intermediate risk patients with BMI greater than 29kg/m2had a two-fold increased risk of requiring RT following RP based on greater than or equal to two adverse pathologic factors (15% vs. 34%). After controlling for known preoperative risk factors, BMI was an independent predictor of RP-risk for additional RT (p=0.006) and biochemical recurrence (p=0.03). Conclusions: BMI of greater than 29kg/m2 is an independent predictor of adverse RP-risk requiring additional RT, particularly in patients with intermediate risk disease. This select group of patients may be best treated with definitive radiation therapy to prevent the additional toxicity from adjuvant or salvage RT following RP. We propose including BMI in clinical decision-making for appropriate treatment recommendation for patients with intermediate risk prostate cancer.
Long-term clinical and toxicity outcomes of hypofractionated intensity-modulated radiation therapy for clinically localized prostate cancer.
Authors: Kotecha Rupesh , Weller Michael A. , Marwaha Gaurav , Hearn Jason , Kupelian Patrick , Reddy Chandana A. , Ciezki Jay P. , Stephans Kevin L. , Tendulkar Rahul D. 
Published: February 2017

49 Background: As an alternative to dose-escalated conventionally fractionated radiotherapy, hypofractionation capitalizes on the unique radiobiology of prostate cancer cells. This study reports the long-term clinical outcomes and late treatment-related toxicities in patients with clinically localized prostate adenocarcinoma treated with hypofractionated radiation therapy at a single tertiary-care institution. Methods: Between 1996 and 2008, 822 patients were treated with hypofractionated intensity modulated radiation therapy (IMRT) (70 Gy in 2.5 Gy/fraction) directed to the prostate gland with or without coverage of the seminal vesicles over a 5.5 week period. Actuarial rates of biochemical relapse free survival by the nadir + 2 definition (bRFS), distant metastasis free survival (DMFS), and overall survival (OS) were calculated using the Kaplan-Meier method. Acute and late genitourinary (GU) and gastrointestinal (GI) toxicity outcomes were available and measured according to the National Cancer Institute Common Toxicity Criteria (v3) in 773 (94%) of the patients. Results: The median follow-up was 8.5 years (range: 0-14.2 years). The overall 10-year bRFS, DMFS, and OS rates were 69.6%, 86.4%, and 71.7%, respectively. By National Comprehensive Cancer Network (NCCN) low-, intermediate-, and high-risk groups, the 10-year bRFS rates were 86.9%, 74.1%, and 41.3%, respectively. The rate of grade 2 or worse late genitourinary (GU) and gastrointestinal (GI) toxicity rates were 17.2% and 5.6 %. Only 1.4% of patients experienced late equal to or greater than grade 3 GU toxicity and 1.0% experienced late greater than or equal to grade 3 GI toxicity. Of those who had any toxicity during the follow-up period, 47% and 65% of patients experienced resolution or improvement in their GU and GI symptoms, respectively. Conclusions: Hypofractionated IMRT for localized prostate cancer provides excellent long-term relapse-free survival rates that are comparable to historical studies using conventional fractionation. With modern IMRT and image guidance, HFRT has an acceptably low incidence of late GU and GI toxicities, and appears to be a suitable treatment alternative to conventional fractionation.
A weighted-adjusted indirect comparison of everolimus (EVE) versus axitinib (AXI) in second-line metastatic renal cell carcinoma (mRCC) patients who previously failed sunitinib therapy.
Authors: Sherman Steven A. , Wang Xufang , Amzal Billy , Casciano Roman , Gao Haitao , Stergiopoulos Sotirios G. , Calvo Emiliano 
Published: February 2017

491 Background: Both EVE and AXI have been approved for second-line treatment of mRCC after VEGFR-TKI therapy failure. No head-to-head clinical trial has compared clinical outcomes between EVE and AXI in this setting. This study aims to compare progression free survival (PFS) from two phase III clinical trials among mRCC patients with SUN as their only prior antineoplastic therapy and subsequently treated with EVE in the RECORD-1 trial vs. AXI in the AXIS trial, after adjusting for cross-trial differences. Methods: A weighted-adjusted indirect comparison using patient-level data from RECORD-1 and summary data from the AXIS trial publication was performed to align baseline characteristics from both trials and compare PFS (central review). A subset of N=43 second-line SUN -refractory mRCC patients treated with EVE were identified in RECORD-1 to correspond to a similar subset of patients (N=194) treated with AXI in AXIS. Logistic regression was used to identify factors predicting PFS in RECORD-1. The RECORD-1 subset was weighted to align the distributions of these key factors (i.e., MSKCC risk, gender, and time on prior SUN) with the AXIS subset. Weights were calculated for each patient using the following equation: Wi = [Pi (AAXIS)/Pi (ARECORD-1)] * [Pi (BAXIS)/Pi (BRECORD-1)] * [Pi (CAXIS)/Pi (CRECORD-1)], where A=Gender, B=MSKCC risk, and C=time on prior SUN. A weighted median PFS estimate with 95% bootstrap confidence interval (CI) and corresponding Kaplan-Meier (KM) curve were derived for EVE patients. Results: After weighting, the three key baseline characteristics were mostly comparable between the two studies, with the exception of MSKCC where a higher proportion of poor risk patients was evident in RECORD-1 (42%) vs. AXIS (33%). A median PFS of 5.1 months (95% CI: 3.6-10.7) was observed for weighted EVE patients compared to 4.8 months (95% CI: 4.5-6.4) reported in AXIS. Conclusions: The PFS estimates suggest similar efficacy between EVE and AXI in SUN-refractory mRCC patients. Further research is needed to confirm these results, which should be interpreted as those from an observational study.
Second-line prescribing preferences (PPrefs) of U.S.-based medical oncologists’ (MOs) following first-line TKI in patients with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Ryan Charles J. , Green Mark R. , Britton Susan L. , Buettner Arden , Lankford Maria , Neely Douglas 
Published: February 2017

492 Background: During 2013 we assessed PPrefs for 2nd line therapy among 294 MOs based on age and outcome with 1st line TKI management for mccRCC using a validated, proprietary, live, case-based market research tool. A core case scenario with 3 1st line therapy outcomes - objective response; stable disease (SD); progressive disease (PD) -was constructed. Data were acquired using blinded audience response technology. Research support sources were double blinded. Methods: Core case–43 y.o.with recurrent disease in lung and bone 4 years after nephrectomy for ccRCC. PS 1. No brain mets. CrCl 79 ml/min. Scenarios tested (S1, S2, etc.): S1: 9 month objective PR with sunitinib/pazopanib 1st line. S2: 4 months stable disease with pazopanib 1st line. S3: Progression at 8 weeks with sunitinib 1st line. Results: Data from events 1 - 3 are shown in Table. Conclusions: Majority of 2nd line prescribing is mTOR-based with everolimus preferred over temsirolimus. Use of a TKI as 1st salvage after 1st line TKI is preferred by 38–51% of MOs when 1st line response is an extended objective PR. There is very limited preference for sequential TKIs when the best initial response is SD for < 6 months or PD as best response. Current no specific TKI is the dominant PPrefs among MOs in this 1st salvage setting. [Table: see text]
Sequential treatment of advanced or metastatic renal cell carcinoma (mRCC): What is effective? Data from the German RCC registry.
Authors: Mueller Lothar , Goebell Peter J. , Lueck A. , Overkamp Friedrich , Vogt Michele , Marschner Norbert 
Published: February 2017

499 Background: In addition to Bevacizumab+Interferon, current treatment options of mRCC imply two major intracellular modes of action and thus classes of therapies: the four approved tyrosine kinase inhibitors (TKI) Sunitinib, Sorafenib, Pazopanib, Axitinib and the two inhibitors of the mammalian target of rapamycin (mTOR) Temsirolimus, Everolimus (EVE). With their availability efficacy of sequential treatment has become a central question of clinical research. While clinical trials recruit highly selected patients (pts) and usually focus on a single line of therapy, collected data of clinical registries may represent all patients and all sequential therapies. Methods: Starting in 12/2007 the registry aims to enrol a total of 1500 patients from more than 120 oncology and urology outpatient centres collecting data on all systemic treatments, outcome, patient and tumour characteristics. Here, the effectiveness of two 1st – 2nd-line sequential treatments, TKI–TKI vs TKI–EVE, was investigated with a multivariate cox proportional hazards model considering potential confounding variables (age, comorbidity, body mass index (BMI), duration of 1st-line therapy, Motzer’s score and type of sequential treatment). Results: At the time of analysis, 481 pts had received sequential 1st- and 2nd-line treatment between 2007 and 2012. In total, 70% of pts received 1st-line TKI-treatment. 46% of these pts received the sequential treatment TKI–TKI, 25% received TKI–EVE. In the multivariate analysis, high BMI (HR 0.946, 95% CI 0.9018-0.9923, p<.05) and a long duration of 1st-line-therapy (HR 0.9967, 95% CI 0.9956-0.9979, p<.001) had a significant positive impact on OS, whereas high risk Motzer`s score (HR 8.9992, 95% CI 2.4231-33.4228, p<.01) had a significant negative impact on OS. However, the type of sequential treatment had no impact on OS (HR 1.0658, 95% CI0.6463-1.7576, p=0.802). Conclusions: The RCC Registry provides an overview of the current treatment reality in routine medical practice. TKI are the most frequently applied 1st-line treatments, followed by TKI or mTOR inhibitors. Our data show no difference concerning the effectiveness of the sequential treatment TKI–TKI vs TKI–EVE.
Long-term quality of life in high-risk prostate cancer: Results of a phase III randomized trial.
Authors: Nabid Abdenour , Carrier Nathalie , Martin André-Guy , Bahary Jean-Paul , Souhami Luis , Duclos Marie , Vincent François , Vass Sylvie , Bahoric Boris , Archambault Robert , Lemaire Céline 
Published: February 2017

5 Background: To evaluate long-term quality of life (QOL) in 630 patients with high-risk prostate cancer (HRPC) treated in a prospective randomized phase III trial (PCS IV clinical trials, Gov. # NCT 00223171). Methods: Patients were randomized to radiotherapy (RT) plus 36 or 18 months of androgen deprivation therapy (ADT). QOL was assessed by two validated tools: EORTC30 (30 items) and PR25 (25 items). The 55 items were regrouped into 21 scales: 15 for EORTC30 and six for PR25. All items and scales scores were linearly transformed to a 0 to 100 points scale. A p value less than 0.01 was considered statistically significant and a difference between groups in mean scores of greater than or equal to 10 points as clinically relevant. Patient-reported outcomes were filled out before treatments, every six months during ADT, four months after and then once a year for five years. All items and scales scores were analysed with general linear model with repeated measures to evaluate changes between groups and over time periods. Results: Three hundred ten patients were randomized to 36 months and 320 to 18 months of ADT, with a median follow-up of 79 months, there was no difference in survival outcomes. The global adherence to QOL questionnaires was 72.4% (10,052 out of 13,880). When comparing the two groups, 6 out of 21 scales (physical, emotional, and social functioning, fatigue, hormonal treatment-related symptoms, and sexual active) and 14 out of 55 items (trouble with long walks, stay in bed during the day, weakness, tenseness, worry, irritable, depressed, close to a toilet, blood in stools, hot flushes, enlarged breasts, interested in sex, sexually active, enjoyable sex) were statistically significant (p< 0.01) in favor of the 18 months ADT group. None of the 21 scales reached clinical relevance (mean scores greater than or equal to 10 points) sexual active being the highest score with 9.0 points of difference. For the 14 statistically significant items, interest in sex with 9.9 points and sexually active with 8.1 points were close to clinical relevance and hot flushes with 24 points and enjoyable sex with 18 points had important clinical relevance at 42 months. Conclusions: In HRPC treated with RT and ADT, reducing the duration of ADT from 36 to 18 months improves QOL, without a negative impact on survival. Source of Funding: AstraZeneca Pharmaceuticals grant. Clinical trial information: PCS IV clinical trials, Gov. # NCT 00223171.