bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of germ-line genetic variation in the NK3 homeobox 1 gene with overall survival in advanced-stage castrate-resistant prostate cancer (CRPC).
Authors: Kohli Manish , McDonnell Shannon , Bevan Graham , Riska Shaun M. , Costello Brian Addis , Longenbach Sherri , Dronca Roxana Stefania , Moynihan Timothy Jerome , Pitot Henry Clement , Quevedo Fernando , Cerhan James Robert 
Published: February 2017

75 Background: We investigated the association of germline variation in ten candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with overall survival (OS) in a cohort of metastatic CRPC stage patients. Methods: Patients (N=497) were enrolled at the time of androgen deprivation therapy failure for D2 stage prostate cancer. Candidate genes were selected from the literature and pilot studies. Genes were tagged using SNPs from HapMap with minor allele frequency (MAF) of >5% and r2≥0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was OS, defined as time from development of CRPC to death. Principle components analysis was used for gene-levels tests. To account for multiple testing we calculated the false discovery rate (FDR). For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression and adjusted for age and Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 497 Caucasian subjects. The median age of the CRPC cohort was 71 years (range 43,93). The GS distribution was 51% subjects with GS≥8; 32% with GS7 and 17% with GS<7. After a median follow up of 2.1 years (IQ range: 1.2-3.6), 297 subjects had died. In unadjusted gene level analyses, NKX3-1 (p=0.04; FDR=0.03) was associated with OS. After adjusting for age and GS the result remained significant (p=0.03). Two of the 5 genotyped SNPs in this gene were associated with OS after adjustment for age and GS: rs10503733 (dominant model p=0.03, HR=0.77; 95 CI=0.60-0.98; A>C; MAF = 0.22) and rs7005368 (dominant model p=0.05, HR=1.38, 95CI=1.0-1.92; G>A; MAF=0.07). Both SNPs are in Hardy Weinberg Equilibrium and in complete LD (D'=1), although r2 is low (r2=0.025) due to different allele frequencies. Conclusions: Variation in the homeobox NKX-1 gene, a prostate specific tumor suppressor gene involved in prostate development and carcinogenesis is significantly associated with OS in CRPC after accounting for age and GS. Further validation is needed to develop these as prognostic biomarkers.
Relationship of oral glycine with radiation-induced HIF1-alpha and tumor growth delay in a prostate cancer xenograft.
Authors: Kessler Elizabeth Riley , Su Lih-Jen , Yang Xiaoping , Altunbas Cem , Flaig Thomas W. , Li Chuan-Yuan , Kavanagh Brian D. 
Published: February 2017

81 Background: Preclinical studies have shown that nitric oxide (NO) is produced by upregulation of inducible nitric oxide synthase (iNOS) in activated macrophages recruited to the site of cytotoxic injury from radiation or chemotherapy. NO stabilizes hypoxia-inducible factor 1-alpha (HIF1α), leading to increased vascular endothelial growth factor, thus promoting tumor angiogenesis as a recovery mechanism from the initial cytotoxic insult. Because glycine (G) suppresses macrophage activation, we hypothesized that dietary supplementation with G would inhibit HIF1α expression and enhance tumor growth delay by preventing recovery angiogenesis. Methods: PC3 cells were transfected with a HIF1α-inducible luciferase reporter and grown as nude mice xenografts. As tumors grew to 100mm3, mice were continued in 1 of 4 conditions: 1) control (C) diet ; 2) a 5%G diet; 3) C diet with ad libitum drinking water treated with L-NAME (500mg/L), an iNOS inhibitor; or 4) C diet with a single injection of carrageenan (2mg/500uL), a selective macrophagicidal agent. After 3 days tumors were irradiated with 0 Gy (sham) or 6 Gy using a 160kV source. Tumor growth and quantitative bioluminescence data were then collected (n = 4 mice/group). Results: HIF1α expression as assessed by bioluminescence increased more than two fold 4-6 days after 6 Gy (p<0.05) in the C diet group but did not significantly increase in either the L-NAME, 5%G , or carrageenan groups. Tumor growth curves for the 6 Gy L-NAME and 5%G diet groups showed a corresponding statistically significant growth delay compared to 6 Gy C diet. No clear difference in bioluminescence or growth was noted in any 0 Gy cohort. Conclusions: The results support the hypothesis that radiation injury indirectly upregulates HIF1α via an iNOS dependent pathway. Inhibition of this pathway can enhance in vivo radiation-induced tumor growth delay and can be achieved via dietary supplementation with G. Thus, dietary G supplementation might have a clinical role for patients treated with radiotherapy for prostate cancer as a non-toxic means of achieving radiosensitization.
Intermediate versus short-course hormone therapy and mortality in men with high-risk prostate cancer treated with radiation therapy.
Authors: Nanda Akash , Chen Ming-Hui , Moran Brian Joseph , Braccioforte Michelle H. , D'Amico Anthony Victor 
Published: February 2017

83 Background: Radiation therapy (RT) plus 28-36 months of hormonal therapy (HT) is standard-of-care for men with high-risk prostate cancer (HRPC) based on randomized trials comparing these HT durations to 4-6 months. However, it is unknown whether shorter durations of HT may also decrease mortality. We evaluate the impact of intermediate-course HT on the risk of all-cause mortality (ACM) in men with HRPC treated with RT. Methods: The study cohort comprised 554 men with HRPC (PSA > 20; Gleason score 8 or higher; or clinical stage T2c or higher) consecutively treated at the Chicago Prostate Cancer Center between 1997 and 2007. All men received brachytherapy with or without external beam RT and HT of intermediate (> 6 to 24; median 12 months) or short (up to 6; median 4 months) duration. A Cox regression multivariable analysis was performed assessing whether intermediate compared to short-course HT was associated with a decreased risk of ACM, adjusting for age, year and type of RT, treatment propensity score, and known PC prognostic factors. Results: After a median follow up of 4.3 years a total of 64 (11.6%) men died. Intermediate compared to short-course HT was associated with a significantly decreased risk of ACM (adjusted hazard ratio 0.44, 95% confidence interval 0.20 - 0.94, P = 0.03). Other significant covariates are shown in the table. The 5-year estimates of ACM for intermediate versus short-course HT were 7.0% and 15.7%, respectively. Conclusions: In men with HRPC treated with RT, a median HT duration of 12 months was associated with a significantly decreased risk of ACM when compared to a median HT duration of 4 months. This raises the hypothesis that HT durations shorter than 28-36 months may be sufficient to decrease mortality in men with HRPC. The ongoing RADAR trial by the Trans Tasman Radiation Oncology Group comparing 18 to 6 months of HT may provide level I evidence to validate this hypothesis. [Table: see text]
Is there a withdrawal syndrome with abiraterone acetate (AA)?
Authors: Albiges Laurence , Auclin Edouard , Rousseau Benoit , Boughalem Elouen , Levy Antonin , Loriot Yohann , Di Palma Mario , Massard Christophe , Fizazi Karim 
Published: February 2017

89 Background: The withdrawal syndrome phenomenon in prostate cancer is defined as a subset of patients (pts) who experience decreasing prostate-specific antigen (PSA) values with or without clinical improvement from the withdrawal of androgen receptor (AR) inhibitors or steroids used as endocrine therapies in castration-resistant prostate cancer (CRPC). In view of its steroidal backbone and structural similarity to progesterone, abiraterone acetate (AA) might act as an AR agonist in certain subsets of CRPC. So far, this phenomenon has not been reported with AA. The aim of this study was to assess the incidence and clinical meaning of such a PSA decrease in pts after AA discontinuation Methods: A retrospective review of 218 consecutive pts treated with AA for metastatic CRPC received after docetaxel between 01/2009 and 08/2012 was conducted in two French centers. PSA values were evaluated before, during and at the end of AA treatment. We retrospectively collected PSA values performed after AA discontinuation (at 4 weeks) and until further treatment or death. Pts were typically kept on prednisone at AA discontinuation. Results: Amongst 218 consecutive patients, 66 pts (30%) were assessed for PSA follow-up after AA discontinuation; reasons for no assessment were mostly: immediate chemotherapy (13%), death (21%); ongoing AA (23%), non evaluated (14%). Amongst the 66 pts, AA therapy was associated with a PSA decrease in 65% pts. Median AA treatment duration was 5.1 months[1.5-39.9]. Twenty-one out of 66 pts (32%) had a PSA decrease when measured at AA disruption and 4 weeks afterwards. The median PSA decrease was 19% [3-68%]. A PSA decrease of greater than 50% was observed in 4 pts (19%). The median duration before progression was 5.5 weeks [1.7-54]. Two of the 4 pts with a PSA decrease>50% exhibited clinical benefit. PSA decrease duration in the 4 pts was7.1 wks [1.1-11.5]. Conclusions: A serum PSA decrease occurred in 32% of pts after AA discontinuation. PSA decrease greater than 50% was observed in 6% of pts with a potential clinical benefit. This event was usually of minor magnitude and short-term. Physiopathological explanations for this observation remain unclear and may be related to the direct activity of AA on the AR.
Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Final quality-of-life (QOL) results with safety data from the United Kingdom (UK) Early Access Programme (EAP) (NCT01254279).
Authors: Bahl Amit , Masson Susan , Malik Zafar I. , Birtle Alison J. , Sundar Santhanam , Jones Robert J. , James Nicholas David , Mason Malcolm David , Bottomley David , Lydon Anna , Chowdhury Simon , Wylie James , De Bono Johann Sebastian 
Published: February 2017

91 Background: Several drugs can now improve survival in mCRPC after docetaxel, including cabazitaxel, a next generation taxane. TROPIC (NCT00417079) showed an overall survival benefit of 2.4 months for cabazitaxel compared with mitoxantrone for mCRPC. The UK EAP provided patients access to cabazitaxel; detailed QOL and safety data were recorded. Interim analysis suggested improvements in QOL, particularly pain scores and a good safety profile. We report final QOL and updated safety data. Methods: 108 patients recruited at 12 centres received cabazitaxel 25mg/m2intravenously every 3 weeks with oral prednisolone 10mg daily. EQ-5D questionnaires and health state visual analogue scale (VAS) were completed at baseline, at alternate cycles and at 30 days post treatment. Safety assessments followed each cycle. Results: According to EQ-5D and VAS scores, QOL was stable with an overall trend towards improvement in patients who continued treatment. Paired ‘within patient’ analyses also support this trend. Improved pain was noted more frequently than deterioration at all time points and pain scores were at least stable in 96% of patients at cycle 10. A median of 6 cycles were given. 34 patients (31%) received 10 or more cycles. Grade 3/4 adverse events were uncommon, the most frequent being fatigue (9.3%), diarrhoea (2.8%) and neutropenic sepsis (1.9%). 85% received prophylactic granulocyte colony stimulating factor. Conclusions: Almost 1/3 of patients completed 10 or more cycles in the UK EAP. QOL was stable with trends to improved EQ-5D and VAS scores. Improved or stable pain was observed in the majority of patients continuing therapy. The UK EAP provides the first data on QOL benefit with cabazitaxel in mCRPC post docetaxel and demonstrates manageable toxicity. Final safety data will be available for presentation. Clinical trial information: NCT01254279. [Table: see text]
Trans-Pacific variation in outcomes for men treated with primary androgen deprivation therapy for localized prostate cancer.
Authors: Cooperberg Matthew R. , Hinotsu Shiro , Namiki Mikio , Carroll Peter , Akaza Hideyuki 
Published: February 2017

92 Background: Primary androgen deprivation therapy (PADT) is endorsed as an option for monotherapy for localized prostate cancer by guidelines in Asia but not in the United States (US) or Europe. PADT use is common, however, in both the US and Japan. Prior studies on either side of the Pacific have reported disparate outcomes for PADT; we aimed to explore these differences in a direct comparison study. Methods: Data were drawn from the US community-based CaPSURE registry and from J-CaP, comprising men in Japan treated with PADT. 1934 men treated with PADT were included from CaPSURE, and 16,300 treated in J-CaP. Risk adjustment was based on the validated Japan Cancer of the Prostate Risk Assessment (J-CAPRA) score. Cox proportional hazards regression was used to assess prostate cancer-specific mortality (CSM), adjusting for age, J-CAPRA, year of diagnosis, and treatment type (combined androgen blockade [CAB] vs. castration (medical or surgical) monotherapy). Results: Men treated with PADT in J-CaP were older than those in CaPSURE (mean age 75.0 vs. 72.7, p<0.001), and had higher risk disease (mean J-CAPRA score 3.0 vs. 2.1, p<0.001). They were more likely to be treated with CAB: 67.1% vs. 44.5% (p<0.001). In the Cox model, the hazard ratio (HR) for PCSM was 0.31 for J-CaP compared to CaPSURE, 95% CI 0.25–0.40. In J-CaP, CAB improved survival compared to castration alone (HR 0.81, 95% CI 0.66–1.0), but this effect was not observed in CaPSURE (HR 0.96, 95% CI 0.69–1.34). For all-cause mortality, the HR for J-CaP was 0.27 (95% CI 0.24–0.30). Conclusions: Adjusting for multiple factors including disease risk and type of androgen ablation, men treated with PADT in Japan compared to the US have more than 3-fold lower CSM and 4-fold better overall survival. CAB improved outcomes compared to castration alone in J-CaP but not in CaPSURE. These findings support existing guidelines both encouraging PADT in Asia and discouraging its use in the West. The reasons for these substantial differences likely include both genetic and dietary/environmental factors, as well as potential confounding variables such as comorbidities. Such factors may explain varying biology of prostate cancer on both sides of the Pacific.
REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy.
Authors: Perol Maurice , Ciuleanu Tudor-Eliade , Arrieta Oscar , Prabhash Kumar , Syrigos Konstantinos N. , Göksel Tuncay , Park Keunchil , Kowalyszyn Ruben Dario , Pikiel Joanna , Czyzewicz Grzegorz , Orlov Sergey , Lewanski Conrad R. , Alexandris Ekaterine , Zimmerman Annamaria , Chouaki Nadia , John William J. , Yurasov Sergey , Garon Edward B. 
Published: February 2017

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.
Prognosis of metastatic internal mammary sentinel nodes (IMSN) in breast cancer.
Authors: Avisar Eli , Libson Shai , Perez Eduardo 
Published: February 2017

103 Background: The presence of positive internal mammary nodes has historically been associated with a significant worse prognosis. Recent studies have also demonstrated a worse prognosis associated with drainage to the internal mammary nodes. Intense search for those nodes, biopsy, appropriate staging and modern treatment for positive IMSN might improve outcome. We sought to study the prognosis of pathologically positive IMSN at our institution. Methods: A retrospective analysis of a prospectively collected database including all breast cancer patients identified with an IMSN that was biopsied between 2005 and 2012 was performed. Demographics, histologic markers, patterns of recurrence as well as survival data were collected. Univariate and multivariate analysis were performed. Results: Thirteen of 82 patients with a biopsied IMSN were metastatic (16%). In 8 of those (62%), the biopsy resulted in a change in staging. In all cases of positive IMSN additional radiation to the internal mammary chain was added. Eighteen percent (18%) of positive nodes did not show drainage to the internal mammary basin during Lymphoscintigraphy. There was no statistical difference in regional and distant recurrences between the patients with positive IMSN and those with negative IMSN. Furthermore there was no difference in disease specific survival. Conclusions: Intense search for IMSN presence and biopsy of those nodes is associated with changes in staging and treatment for metastatic IMSN. In our study, pathologically positive IMSN were associated with a non- inferior prognosis than negative IMSN.
Crowdsourcing the collateral damage from breast cancer treatment.
Authors: Love Susan M. , Obidegwu Amaka , Fischetti Christine A 
Published: February 2017

110 Background: Survivorship research focuses on quality of life after cancer treatment, but is usually initiated by providers and lacks the voice of the patient. In an effort to explore the patient perspective, we convened a collaboration of advocacy groups to “crowdsource” women’s questions regarding collateral damage from breast cancer treatment. These concerns will be incorporated into the Health of Women [HOW] Study, an ongoing, online cohort study open to anyone aged 18 or older. Methods: Emails to current HOW participants were sent out July 2013 to solicit questions. In October 2013, a new webpage was designed to collect responses; we then partnered with other advocacy organizations and began collecting responses, which were then categorized to guide questionnaire development. Results: Sixteen advocacy organizations came together to support this project. Emails to current HOW participants resulted in 1,191 responses. The website landing page resulted in 5,099 responses. Overall, 16.8% of respondents complained of fatigue, 16.3% of memory problems, 15.7% of anxiety and/or depression, and 14.0% of numbness/neuropathy. Other less frequently reported problems included problems with nail growth, vision, hearing, urinary tract infections, and allergy-like symptoms. Conclusions: We received an overwhelming number of responses about collateral damage. Many of the issues are known side effects, while others are less commonly reported. We will next compare responses to previously validated questionnaires, develop a comprehensive collateral damage questionnaire for inclusion in the HOW Study, and generate a report for publication to be distributed to participants and the medical community.
Understanding potential communication gaps between oncologists and patients with advanced breast cancer: A survey of oncologists.
Authors: Brufsky Adam , Citron Marc L. , Percassi Deana 
Published: February 2017

124 Background: About 232,670 cases of breast cancer will be diagnosed in the US in 2014, of which 86,088 (37%) will be metastatic advanced breast cancer (ABC). The 2013 Global Count Us, Know Us, Join Us survey found that 53% of US women with ABC wanted more time to discuss their needs during clinic visits, and 60% believe their cancer treatment options are limited. To better understand unmet patient needs and potential communication gaps with physicians, surveys were developed for women with ABC, their caregivers, and oncologists. The oncologists’ survey results are presented. Methods: The Make Your Dialogue Count survey for oncologists has 32 items. Responses are single or multiple response numeric text or rated on a 4-point Likert scale. Harris Poll conducted this online survey from June through July 2014 among randomly selected, licensed US medical oncologists who treat ≥ 5 women with ABC per month. Responses for geographic region and number of years in practice by sex were weighted to match actual proportions in the population. Results: By July 15, 2014, 228 oncologists responded. At initial diagnosis, showing care and compassion was very important to 79% of oncologists; helping patients cope with diagnosis (62%) and manage cancer symptoms (56%) and discussing expected treatment response (57%) and side effects (51%) were also very important. Most oncologists (88%) revealed that treating women with ABC has a negative emotional toll. Although 81% of oncologists believe it to be unprofessional to let their emotion affect treatment recommendations, 26% reported that their emotions kept them from providing some information. Notably, 31% of oncologists reported that in certain situations, they have not discussed with patients that ABC is incurable. Conclusions: Caring for terminally ill patients has an emotional impact on oncologists. For some, their emotions have influenced what treatments they recommend and what information they impart. Our findings show that oncologists are compassionate and share disease- and treatment-related information and highlight the need to develop communication strategies that facilitate exchange between oncologists and their patients with ABC.