bluuebunny/crossref_metadata_2025_split huggingface dataset:
The DASH Study: A phase 1b study of dalantercept plus sorafenib in advanced hepatocellular carcinoma.
Authors: Abou-Alfa Ghassan K. , Miksad Rebecca A. , Gutierrez Martin , Tejani Mohamedtaki Abdulaziz , Sharma Manish , Sun Weijing , Henderson Charles A. , Baron Ari David , Olowokure Olugbenga Olanrele , Pearsall R. Scott , Wilson Dawn , Korth Chris , Sherman Matthew L. , Pandya Shuchi Sumant 
Published: February 2017

TPS495 Background: The activin receptor-like kinase (ALK1) pathway is a novel target in angiogenesis that promotes blood vessel maturation and stabilization. ALK1 binds to the ligand bone morphogenetic protein 9 (BMP9) which is overexpressed in hepatocellular carcinoma (HCC) compared to normal hepatocytes. Dalantercept is an ALK1 receptor fusion protein that binds BMP9 and acts as a ligand trap. Sorafenib, a multi-kinase and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI), is the standard therapy for advanced HCC. In a preclinical model of HCC, simultaneous blockade of ALK1 and VEGF signaling with dalantercept and sorafenib resulted in additive tumor growth inhibition. In a completed Phase 1 study in thirty-seven subjects with solid tumors, dalantercept monotherapy demonstrated preliminary anti-tumor activity and a safety profile that was generally non-overlapping with VEGFR TKIs. Methods: An open label, multi-center, dose escalating, phase 1b study to evaluate dalantercept plus sorafenib in subjects with advanced HCC is ongoing. The primary endpoint includes the evaluation of the safety and tolerability of dalantercept plus sorafenib and determination of the recommended phase 2 dose levels of the combination. Secondary endpoints include assessments of the pharmacokinetic profile of the combination, preliminary activity including response rate using RECIST 1.1 and time to progression, and pharmacodynamic biomarkers in the serum and tissue including ALK1 and BMP9 expression. In the first two cohorts of 3-6 subjects each, the dalantercept dose levels will be 0.6 and 0.9 mg/kg, respectively, administered subcutaneously (SC) every 3 weeks in combination with sorafenib 400 mg PO once daily. In cohort three, 3-6 subjects will receive dalantercept dose level 0.9 mg/kg SC every 3 weeks with sorafenib 400 mg PO twice daily. Patient safety data through day 22 will be evaluated prior to escalation to the next cohort. An expansion cohort will enroll 10-20 subjects at or below the maximum tolerated dose level. Key eligibility criteria: histologically confirmed advanced HCC, Child-Pugh A liver disease, ECOG performance status of 0-1, and no prior systemic therapy in the advanced setting. Clinical trial information: NCT02024087.
Phase II trial of temsirolimus (TEM) plus sorafenib (SOR) in hepatocellular carcinoma (HCC).
Authors: Kelley Robin Kate , Nimeiri Halla Sayed , Gordan John Dozier , Hwang Jimmy , McWhirter Ryan M. , Kanakamedala Advaita , Atreya Chloe Evelyn , Kulik Laura , Kircher Sheetal , Mulcahy Mary Frances , Benson Al Bowen , Venook Alan P. 
Published: February 2017

TPS501 Background: The multikinase inhibitor SOR prolongs survival in patients with HCC not amenable to curative therapies. In HCC preclinical models, the combination of SOR with an inhibitor of the mammalian target of rapamycin (mTOR) pathway is synergistic, though single-agent mTOR inhibition did not improve survival in HCC patients after failure of SOR in a phase III trial. We previously completed a phase I study of the mTOR inhibitor TEM combined with SOR in 25 HCC patients which identified the maximum tolerated dose as TEM 10 mg IV weekly and SOR 200 mg PO BID. This two-center, phase II study was developed to examine the efficacy of the combination and to explore candidate biomarkers. The study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support, with activation October 2012. Methods: The study is registered on ClinicalTrials.gov (NCT01687673). Design: Single-arm, one stage phase II trial. Primary endpoint: Time to progression (TTP) by RECIST 1.1. Other endpoints: Progression-free survival, response rate, overall survival, proportion with alpha fetoprotein decline ≥ 50%, toxicity, hepatitis B virus reactivation rate, and exploratory biomarkers including mTOR pathway protein expression in tumor, circulating tumor cells, and blood and tumor micro-RNA profiles. Sample size: 25 evaluable patients are required to detect a difference between the null hypothesis of median TTP < 3 months versus alternate hypothesis of median TTP ≥ 6 months (a clinically-meaningful outcome in advanced HCC), with 1-sided significance level of 10% and power 88% under the exact test. Main eligibility criteria: HCC not amenable to curative therapies, histologically-confirmed, ≥ 1 untreated, radiographically-measurable site of disease. No prior systemic therapy. ECOG ≤ 1. Child-Pugh score ≤ 7 with bilirubin ≤ 2 mg/dL. Treatment and procedures: TEM 10 mg IVweekly plus SOR 200 mg PO BID in 28-day cycles, with collection of archival tumor samples and blood samples at baseline, on treatment, and at progression. Accrual:Sixteen of 25 planned evaluable patients have enrolled. An interim analysis for safety after 30% enrollment met pre-specified target to continue. Clinical trial information: NCT01687673.
A phase I dose-escalation trial of TH-302 with nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Olszanski Anthony J. , Wang-Gillam Andrea , Kwak Eunice Lee , Nazzal Kamal , Mehdi Fazal , Borad Mitesh J. 
Published: February 2017

TPS505 Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m2) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18F-FDG PET, CA19–9 response rate (defined as >50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.
Folfoxiri with or without cetuximab as first-line treatment of patients with non-resectable liver, only metastatic colorectal cancer and KRAS/NRAS wild type (FOCULM study).
Authors: Deng Yanhong , Wang Lei , Liu Guanjian , Hu Huabin , Cai Yue 
Published: February 2017

TPS798 Background: For liver limited metastatic colorectal cancers, complete resection of liver metastases is the only potentially curative treatment and can significantly improve overall survival. The current goal of medical treatment for colorectal cancer with initially unresectable liver metastases is to maximize the rate of secondary resection. This phase II study is to explore whether cetuximab in combination with FOLFOXIRI as first treatment could improve radical resectability in patients with KRAS/NRAS wild-type, unresectable liver - only metastases of colorectal cancer. Methods: The primary aim is to evaluate the percentage of patients who had a curative liver treatment following protocol treatment, i.e., liver metastases that can be completely resected and/or ablated with no evidence of residual malignant disease. Secondary aims include safty, objective response rate, overall survival, progression free survival, quality of life and an assessment of predictive molecular markers of response. 138 cases of patients met inclusion criteria and enrolled in the trial will be randomized to two therapy groups: experimental arm A (Chemotherapy with FOLFOXIRI + Cetuximab) or standard arm B (Chemotherapy with FOLFOXIRI). All patients will receive the study treatment regimen every 2 weeks, and a total of the maximum of 8 cycles. CT scan or MRI of the abdomen will be performed after 2 or 3 cycles of therapy to assess clinical response and resectability of liver metastases by multidisciplinary team including hepatic surgeon. If liver metastases are not deemed to be resectable at this assessment, but tumor assessment demonstrates stable disease or partial response, therapy will continue with re-assessment for clinical response and resectability after the next cycle. Clinical trial information: NCT02063529.
Evaluation of the contribution of individual gene groups to a 17-gene prognostic prostate cancer signature.
Authors: Knezevic Dejan , Lu Ruixiao , Burke Emily , Rothney Megan , Zhang Nan , Febbo Phillip G. , Lawrence H. Jeffrey 
Published: February 2017

101 Background: A 17-gene biopsy-based RT-PCR assay (Oncotype DX Prostate Assay) has been validated as a predictor of adverse pathology and biochemical recurrence (BCR) in clinically very low to intermediate-risk prostate cancer patients. The assay measures expression of 12 cancer and 5 reference genes that are combined to calculate a Genomic Prostate Score (GPS; scaled 0-100), providing a biologic measure of tumor aggressiveness. The cancer genes represent four biological pathways: androgen signaling, stromal response, cellular organization and proliferation. We examined the effects of variation in quantitative expression of individual gene groups on GPS results and prediction of clinical risk. Methods: The first 3,500 tumor specimens processed in the Genomic Health Inc.’s reference laboratory were included. Expression of individual genes was measured and expression of the four gene groups and GPS calculated. For each gene group, GPS of patients with the lowest 5% expression levels were contrasted with GPS of patients with highest 5% expression levels. Results: Percentages of NCCN very low, low and intermediate patients were 28%, 37%, 30%; median age was 65. Mean and median GPS were 24.6 (SD 12.0) and 23 (range 0-90). Individual gene groups exhibited wide expression ranges (e.g. proliferation-16-fold difference (FD) vs. cellular organization > 8000 FD). Large differences in expression of each gene group were reflected in GPS values and, based on a prior clinical validation study, translate into large differences in BCR risk (Table). Conclusions: Each of the four gene groups show large variations in expression, meaningfully affect the GPS, and contribute to the prediction of PCa aggressiveness. [Table: see text]
IHC versus FISH for the detection of ERG rearrangements in prostate cancer.
Authors: Pestova Ekaterina , Zhang Ying , Barbanera William , Kaiser-Walters Kelly A. , Du Jing , Liu Ping , Buckingham Lela , Colpitts Tracey 
Published: February 2017

102 Background: ERG rearrangements are present in about 50% of all prostatic adenocarcinomas (CaP). Using ERG break-apart fluorescence in situ hybridization (FISH) probes, several classes of ERG rearrangement patterns have been described: Edel, Esplit, and 2+Edel. Class ERG 2+Edel was reported to be associated with lethal disease and significantly worse clinical outcome in CaP, while prognostic significance of other classes of ERG rearrangements and of ERG protein expression remains controversial. In this study, we found that IHC cannot discriminate between various forms of ERG rearrangements including 2+Edel, while FISH can. Methods: Formalin fixed paraffin embedded (FFPE) histological specimens from 52 Radical Prostatectomy (RP) cases were used. FISH analysis was performed using Abbott Molecular dual-color break-apart probes for the 5' and 3' regions of the ERG gene. Percent of overall ERG abnormalities and percent of Class 2+Edel per specimen were calculated. ERG expression was evaluated using DAKO FLEX Monoclonal Rabbit Anti-Human ERG Clone EP111. For each slide, H scores (H score =intensity X percentage of positive cells) from both tumor areas and benign prostate epithelium areas were assigned. The IHC score was defined as “H score from tumor minus H score from benign prostate epithelium”. IHC score > 0 was considered positive. Statistical analysis was conducted using JMP 10. Results: Of the 52 RP cases, 9 had the ERG 2+Edel rearrangement (cutoff >2%), 25 had Edel or Esplit rearrangements (cutoff >45%), and 27 had no ERG rearrangements by FISH. The overall Percent Agreement (OPA) between the ERG IHC and FISH (any class of ERG rearrangements) was 90% with 95% Confidence Interval (CI) (79%, 96%). However, for the ERG 2+Edel group, the OPA between the ERG IHC and FISH 2+Edel was 71%, and 62% of IHC positives were false positive. Thus IHC does not discriminate between the 2+Edel, Esplit or Edel forms of ERG while FISH identifies each class of rearrangement. Conclusions: IHC assay allows the detection of overall ERG abnormalities, however it does not discriminate ERG Class 2+Edel, which is consistently reported to be of prognostic significance. Further studies are required to confirm prognostic utility of ERG rearrangements and protein expression in CaP.
Long-term bother profiles in patients with locally advanced prostate cancer treated with radiotherapy compared to men with localized prostate cancer treated with high-dose radiotherapy.
Authors: Lilleby Wolfgang 
Published: February 2017

104 Background: We compared the long-term the bother profiles in patients with prostate cancer (T1-3 M0) consecutively referred to the OUS to definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RT+IMRT) (N=90) or radiotherapy to the prostatic gland only (RAD) (N=180), applied with adjuvant androgen deprivation in all patients. Methods: After 36months 206 (76%) of the eligible men (RT+IMRT = 64 and RAD = 142) had completed the UCLA-PCI questionnaire at baseline, 12, 24 and 36 months. The bother scores were adjusted for significant differences in quality of life measured by the SF-12 instrument. Differences in the mean scores between the treatment groups were evaluated by the Mann-Whitney U test for skewed samples. Patients were similar in age and by the distribution of prognostic risk factors in both cohorts. Results: The longitudinal bother mean scores up to 36 months post-treatment for the main domains are reported. Significantly more RAD patients had less urinary bother at baseline compared to RT+IMRT patients. In both groups sexual bother was significantly increased over time. Thus, at 36 months mean scores for urinary, bowel and sexual bother appeared to be stable in both groups. However, despite of increased bowel bother at one year (p= 0.02) in the RT+IMRT group, bowel bother score improved in these patients compared to RAD at last observation (p= 0.25). Conclusions: The long-term bother profiles are similar in the RT+IMRT and RAD groups at 36 months follow-up. Modern radiotherapeutic techniques allow targeting of high-risk patients. Differences in organ function and bother can only be accomplished for by long-term health care assessment.
Association of neutrophil count with overall survival in localized prostate cancer.
Authors: Taussky Daniel , Bahig Houda , Delouya Guila , Bodson-Clermont Paule , Soulieres Denis 
Published: February 2017

121 Background: Systemic inflammation has been linked to worse outcome in metastatic prostate cancer. This study analyzes the influence of complete blood count (CBC) on outcome after curative radiotherapy for localized prostate cancer. Methods: We reviewed our institutional database of patients with localized prostate cancer treated with either definitive external beam radiotherapy (EBRT) or brachytherapy from September 2001- June 2014. Data on pre-treatment CBC such as hemoglobin (Hgb), mean corpuscular volume(MCV) and platelet count (PLT) were available in 1,021 pts, neutrophil/lymphocyte ratio (NLR) in 1,015 pts. Univariate and multivariate cox proportional hazards models were used to analyze the influence of complete blood count parameters on overall and recurrence free survival (PSA nadir + 2 ng/mL). A p<0.05 was considered statistically significant. Results: Median follow-up was 44 months. 55 patients had biochemical recurrence and 68 patients died.On univariate analysis, increasing risk of biochemical recurrence was associated with a combination of all known risk factors as defined by the Cancer of the Prostate Risk Assessment (CAPRA) score, but not by age. When adjusting for age (p=0.009), CAPRA remained significant (p=0.0003) but no comorbidity or CBC. On univariate analysis for overall survival, CAPRA (p=0.0001) and neutrophil count (p=0.04, HR1.16, 1.01-1.34) as well as a cardiac history (p=0.009) were associated with increased risk of overall mortality. The first multivariate model was adjusted for age and included the CAPRA, comorbidity and CBC variables: age (p=0.006) and CAPRA (p=0.008) were prognostic, neutrophil count was borderline significant (p=0.056, HR 1.17, 0.99-1.37). In a second multivariate model without adjusting for age, neutrophil count was a significant prognostic factor for overall survival (p=0.032, HR 1.18, 1.01-1.38) as well as the CAPRA (p=0.005, HR 1.18, 1.05-1.33). Conclusions: In this testing cohort, neutrophil count was an independent risk factor for increased overall mortality in patients with localized prostate cancer. The influence of age on this prognostic factor will be further studied. A validation cohort is needed to corroborate these results.
Definitive treatment of localized prostate cancer: Time and geographic trends.
Authors: Tward Jonathan D. , Burt Lindsay , Shrieve Dennis C. 
Published: February 2017

132 Background: Numerous definitive treatment options exist for localized prostate cancer. We evaluated how the distribution of treatments varied by geographic location and over time in a contemporary US population database. Methods: All subjects with NCCN clinical risk-stratifiable localized prostate cancer between the years 2004 and 2011 were identified in the Surveillance Epidemiology and End-Results Database. Descriptive statistics evaluating the relative distribution of therapies by geographic region and over time were performed. Results: There were 290,631 evaluable subjects identified. The Table shows trends in treatment over time for combined low, intermediate, high, and very high risk prostate cancer. The use of brachytherapy has been significantly declining between 2004 and 2011, and no definitive therapy has been increasing. In 2010-2011, regional prostatectomy use varied from a low of 18% (Rural Georgia) to a high of 57% (Iowa). No definitive therapy rates varied between 12% (Hawaii) and 35% (Rural Georgia). Analyses of regional variation at the State County level reveals significant variability in the ratio of subjects receiving surgery to radiation (e.g., State of Utah surgery:radiation ratio 0.25 (Beaver County) versus 3.06 (Toole County). Conclusions: There is marked regional variation of practice at both the county and state levels for localized prostate cancer definitive therapy. The use of radiotherapy has been declining between the years 2004 and 2011, and appears to be offset by increases in no definitive therapy. Prostatectomy rates remained stable. [Table: see text]
Racial/ethnic variation in a common genetic alteration in prostate cancer.
Authors: Sesterhenn Isabell , Young Denise , Chen Yongmei , Petrovics Gyorgy , Cullen Jennifer , Kagan Jacob , Srivastava Sudhir , Rosner Inger L. , McLeod David G. , Dobi Albert , Srivastava Shiv 
Published: February 2017

14 Background: The molecular basis of racial/ethnic differences in the detection and outcomes of the carcinoma of the prostate (CaP) needs to be better defined to improve biomarkers and identify appropriate therapeutic targets. ETS-related gene fusions in proto-oncogenes (ERG, ETV1) are among the most common early oncogenic alterations described in CaP. Studies have highlighted the racial/ethnic variation in ERG fusion and ERG oncoprotein expression frequencies showing: the highest frequencies in Caucasian (CA) men, the lowest frequencies in Asian men, and intermediate frequencies in African American (AA) men. These differences persisted when patients were carefully matched for age and clinico-pathologic features. Building on previous work, the current study was conducted to evaluate ERG expression frequencies in a large cohort of AA and CA CaP patients. Methods: Patients enrolled at the Walter Reed National Military Medical Center who consented to provide radical prostatectomy (RP) specimens to the CPDR Tissue Bank and Clinical Database were evaluated. The current study included 443 AA and 696 CA patients. ERG oncoprotein expression was detected by immunohistochemistry using the 9FY mouse monoclonal anti-ERG antibody and was correlated with clinico-pathologic features and CaP outcomes. Results: Lower frequencies of ERG in the index tumors of AA men as compared to CA men (28.4% vs. 51.5%, p < 0.0001) were observed. Furthermore, AA men with higher grade CaP (Gleason 8-10) had even lower ERG frequency (16%), suggesting distinct molecular biologic features in aggressive CaP for AA men. A trend with age was observed for both racial groups, with younger CA showing higher ERG frequencies. At least one focus of ERG positive PIN was present in prostates with ERG positive tumors. In both CA and AA patients, a very low frequency (8%) of ERG expression was noted in anterior index tumors compared to posterior tumors. Conclusions: This study lends increasing support to differences of the most common early genomic alteration (ERG) between AA and CA CaP patients. The study also underscores the importance of identifying new or improving existing biomarkers with consideration of patient race/ethnicity.