bluuebunny/crossref_metadata_2025_split huggingface dataset:
Masitinib in nonresectable pancreatic cancer: Results of a phase III randomized placebo-controlled trial.
Authors: Deplanque Gael , Demarchi Martin , Hebbar Mohamed , Flynn Patrick J. , Melichar Bohuslav , Atkins James , Ruszniewski Philippe , Raymond Eric , Hermine Olivier , Hammel Pascal 
Published: February 2017

158 Background: Masitinib is a selective c-Kit inhibitor that efficiently inhibits mast cell function. Increased mast cell activity in the tumor microenvironment has been linked to poor prognosis in pancreatic cancer (PC) patients. Methods: In a randomized (1:1 ratio), double-blind, international phase III trial, chemo-naïve PC patients (n=348) received either masitinib (9 mg/kg/day) in combination with gemcitabine (1000 mg/m2/wk) (M+G) or placebo plus gemcitabine (P+G). Primary endpoint was overall survival (OS). An ancillary pharmacogenomic study, based on RNA extracted from whole blood prior to treatment, was conducted in a subset of patients. Results: In the overall population median OS was not significantly improved in the M+G arm as compared with the P+G arm (median OS: 7.7 vs. 7.0 months, respectively; p=0.74, HR=0.90 [0.71; 1.14]). However, M+G treatment led to a significant survival advantage in two subpopulations. First, in patients with ‘pain’ at baseline (defined as a VAS score >20 mm on a 100 mm scale) (44% of patients with pain intensity data available) median OS was significantly increased from 5.4 months in the P+G arm to 8.1 months in the M+G arm (p=0.010; HR:0.61 [0.42; 0.88]); OS rates at 12 and 18 months were respectively, 32.2% and 18.2% in the M+G arm vs. 17.8% and 7.8% in the P+G arm. Second, in patients with a specific deleterious genomic biomarker (GBM) consisting of a limited number of genes (66% of patients with genetic data available), median OS was significantly increased in the M+G arm as compared with the P+G arm (11.0 vs. 5.0 months, respectively) (p=0.000038; HR=0.29 [0.17; 0.51]); OS rates at 12 and 18 months were respectively, 41.4% and 18.5% in the M+G arm vs. 11.1% and 4.2% in the P+G arm. In patients without pain (defined as VAS <5 mm and no need for opioid analgesics), median OS was 15.4 months in the P+G arm. In patients without the deleterious GBM, median OS in the P+G arm was 14.3 months. In these two patient populations M+G treatment was contraindicated. The general safety profile of the M+G combination regimen was acceptable. Conclusions: Masitinib in combination with gemcitabine provides a significant survival advantage over gemcitabine monotherapy in PC patients with ‘pain’ and patients with a specific GBM. Clinical trial information: NCT00789633.
Alteration of microbiota in esophagitis and Barrett's esophagus and further modification by PPI treatment.
Authors: Half Elizabeth E. , Amir Itay , Gophna Uri , Konikoff Fred M. 
Published: February 2017

16 Background: Gastroesophageal reflux can cause inflammation, metaplasia, dysplasia and cancer of the esophagus. The incidence of esophageal adenocarcinoma (EAC) has increased almost six fold in the past 30 yrs despite the increased use of Proton Pump Inhibitors (PPIs) to treat reflux. Recently, erosive esophagitis has been shown to increase the risk of EAC relative to patients with normal esophagus (NE). The reason for this remains unknown. Aim: To determine whether the microbiota of gastric refluxate and esophageal biopsies differs between patients with heartburn and NE vs. patients with abnormal esophageal mucosa [esophagitis or Barrett's esophagus (BE)] and to elucidate the effect of PPIs on bacterial communities. Methods: Gastric fluid and esophageal biopsies were collected during endoscopy from 13 BE/esophagitis patients and from 7 with NE. To reveal how PPIs alter the microbiota, samples were obtained from 8 of the patients (2 NE, 4 esophagitis and 2 with BE), before and after 8 weeks of PPI therapy. DNA was extracted and 16S rRNA gene pyrosequencing of microbial communities was performed. Results: Significant differences in the composition of gastric fluid bacteria, but not the esophagus-associated microbiota, were found between patients with heartburn and NE vs. patients with esophagitis and/or BE. Notably, Enterobacteriaceae (specifically Escherichia and Enterobacter) were significantly enriched in gastric fluid of patients with BE/esophagitis (P=0.01) compared to NE. PPIs had a remarkable effect on microbial communities both in the stomach and the esophagus. In gastric fluid, Moraxellaceae were decreased (P=0.016), whereas Erysipelotrichaceae were increased (P=0.031) following PPI treatment. Esophageal biopsies revealed genera belonging to the Microccocaceae, known to be opportunistic human pathogens, which increased following PPIs (P =0.031). Conclusions: Gastric fluid microbiota is modified in heartburn patients with esophagitis and/or Barrett's esophagus compared to patients with normal esophagus. PPI treatment markedly alters gastric and esophageal microbial populations. These modified bacterial communities may predispose to inflammation, dysplasia and cancer.
The association between statin use and hepatocellular cancer outcome.
Authors: Chae Young Kwang , Kaseb Ahmed Omar , Mohamed Hesham , Sahin Ibrahim Halil , Khalil Mohamed Fahd , Li Donghui , Abbruzzese James L. , Hassan Manal 
Published: February 2017

165 Background: Preclinical evidence supports anti-tumoral activity of statins. Several observational studies have shown inverse association between statin use and hepatocellular cancer (HCC) incidence. However, little is known as to whether statins can delay the progression of HCC. Therefore, we investigated the association between statin use and the outcome of patients with HCC. Methods: 644 patients diagnosed with pathologically confirmed HCC were followed up from 2000 till 2011. Survival analysis was done using Cox regression model. Results: The mean age of the HCC cohort was 63.1 years (SD, ±11.5). 73.4% were men and 65.5% were Caucasians. 70.7% were diagnosed at TNM stage III and IV. 52.6% had no evidence of hepatitis B or C virus infection. 81.7% had local and systemic therapy, while 18.3% underwent surgical resection. The median survival of HCC patients was 19.2 months. 10.7% of patients reported statin use. We observed significant difference in overall survival between statin non-users and users; the median overall survival (95% CI) were 18.5 (16.4-20.5) months and 25.4 (19.8-31.1) months, respectively (log rank test p = 0.04). 30% mortality reduction was observed in statin users versus non-users (HR = 0.7, 95% CI, 0.5-0.9). This significant association was also observed in patients who received systemic and local therapy (p = 0.04). HCC patient without liver cirrhosis showed 40% mortality reduction (HR = 0.6, 95% CI, 0.4-0.9, P = 0.04) while patient with liver cirrhosis did not. History of hepatitis did not affect the association. Even after controlling for various clinical variables including age, sex, race, staging, HCV, HBV, liver cirrhosis, treatment, alcohol use and diabetes, statin use was still associated with favorable overall survival in HCC patients (HR = 0.7, 95% CI, 0.5-0.9, P=0.03). Conclusions: This is the largest study to date to evaluate the effect of statins on the outcomes of HCC patients. We found that statin use may reduce the risk of death in patients with HCC. Validation of our finding is warranted in a large prospective study.
Prognostic impact of lymph node retrieval and ratio in gastric cancer: A single-center U.S. experience.
Authors: Wong Joyce , Rahman Shams , Saeed Nadia , Lin Hui-Yi , Almhanna Khaldoun , Shridhar Ravi , Hoffe Sarah , Meredith Kenneth 
Published: February 2017

17 Background: Recommendations for extended lymphadenectomy in gastric cancer is thought to be associated with improved overall survival (OS), although defining adequate lymphadenectomy remains controversial. Methods: A single-institution, prospectively-maintained database of patients referred for surgical care of gastric cancer was reviewed. Patients were stratified by number of examined lymph nodes (eLN): <5, 6-10, 11-15, and >15 and positive LNs (LN+) stratified by 0, 1-2, 3-6, 7-15, and >15. Lymph node ratio (LN+:eLN) was evaluated, stratified by 0, 0.01-0.2, 0.21-0.5, and >0.5. Disease-free-survival (DFS) and OS were the primary endpoints, determined by Kaplan-Meier analyses. Results: From 1997-2012, 222 patients were included; most were male (N=122, 55%) with median age 67 (range 17-92) years. Of 220 (99%) patients surgically explored, 164 (74%) ultimately underwent resection. Median OS of the entire cohort was 22 months. Gender, ethnicity, and smoking status did not impact OS. Pathologic factors such as perineural invasion, lymphovascular invasion, and poor differentiation adversely affected OS, P<0.05. A median 14 lymph nodes (LN) were retrieved (range 0-45), with a median of one positive LN (range 0-31). No OS or disease-free survival (DFS) difference was observed when comparing <5, 6-10, 11-15, and >15 eLN, P=0.30. LN+ affected both OS and DFS: median OS was 52 months for 0 LN+ and decreased to 21 months with 1-2 LN+, 34 months 3-6 LN+, 25 months 7-15 LN+, and 11.5 months with >15 LN+. Similarly, median DFS decreased from 35 months with 0 LN+ to 19 months with 1-2 LN+, 9 months with 3-6 LN+, 13.5 months with 7-15 LN+, and 7.5 months with >15 LN+. Lymph node ratio demonstrated worse median OS with increasing ratio: 49 months for ratio of 0, 37 months for 0.01-0.2, 27 months for 0.21-0.5, and 12 months for >0.5, P<0.0001. DFS was similar: 35months for ratio of 0, 22 months for 0.01-0.2, 13 months for 0.21-0.5, and 7 months for >0.5, P<0.0001. Conclusions: Extent of lymphadenectomy does not impact OS or DFS. Presence of LN+ adversely impacts OS and DFS. Lymph node ratio may be a better prognostic indicator than number of eLN or LN+ in gastric cancer.
Comparison of HER-2 expression in diagnostic biopsies and surgical specimens of gastric and esophageal adenocarcinoma: Influence of neoadjuvant chemotherapy.
Authors: Watson Sarah , Validire Pierre , Cervera Pascale , Zorkani Nabila , Scriva Aurelie , Lemay Frederic , Garcia Marie Line , Bennamoun Mostefa , Tournigand Christophe , Ropert Stanislas , Svrcek Magali , Louvet Christophe 
Published: February 2017

18 Background: HER-2 is overexpressed in 15 to 20% of gastric and esophageal adenocarcinoma (ADK), and is a target for trastuzumab in metastatic patients (Bang YJ et al, Lancet 2010). The main objective of this study was to compare HER-2 expression between diagnostic biopsies and surgical specimens of gastric ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens and biopsies of patients operated on with a curative aim in two French hospitals (Institut Mutualiste Montsouris and Saint-Antoine hospital) between 2004 and 2011 were collected; two cohorts treated or not with a NAC were constituted. Blind HER-2 analyses on biopsies and on surgical specimens were performed using IHC and ISH methods, with two independent pathological readings. HER-2 overexpression was defined by a score 3+ in IHC, or by a score 2+ in IHC with a positive ISH test. Results: Paired samples of 201 patients wereanalyzed. HER-2 overexpression rates were 16.4% on biopsies and 19.4% on surgical specimens. HER-2 positive tumors were mainly cardial or esophageal tumors, with a well-differentiated, intestinal histological type. Surgical specimens seemed to allow better identification of HER-2 positive tumors than diagnostic biopsies for patients that had not received NAC (13.5% of HER-2 positivity on biopsies versus 24.3% on surgical specimens), whereas this trend was reversed for patients with NAC (18.1% of HER-2 positivity on biopsies versus 16.5% on surgical specimens). HER-2 status differed between biopsies and surgical specimens in 10% of patients. Conclusions: The determination of HER-2 status on biopsies provides results that completed those obtained with the analysis of surgical specimens. Analyzed only on surgical specimens, HER-2 status is underestimated in particular after NAC. This study suggests the interest of repeating HER-2 evaluations to optimize the identification of patients that can benefit from trastuzumab treatment.
Inhibition of cMET in an experimental model of pancreatic cancer.
Authors: Lang Sven A. , Brandes Franziska , Geissler Edward K. 
Published: February 2017

185 Background: In human pancreatic cancer, expression of cMET is associated with poor survival. So far, activation/expression of cMET by hepatocyte growth factor (HGF) has been shown to induce proliferation and motility in cancer cells. Therefore, we hypothesized that inhibition of cMET in human pancreatic cancer cell lines impairs oncogenic signaling and tumor growth. Methods: Pancreatic cancer cell lines (HPAF-II, MiaPaCa2, L3.6pl, BxPC3, Panc02) and the cMET inhibitor INC280 (Novartis Oncology, Basel) were used. MiaPaCa2 and L3.6pl pancreatic cancer cells were grown with gemcitabine up to 500 and 250 nM, respectively (then called MiaPaCa2(G500) and L3.6pl(G250)). MTT and Boyden Chamber assays were used to determine effects of INC280 on growth and motility of cells in vitro. Expression of growth factor receptors, activation of signaling intermediates and expression of transcription factors were assessed by Western blotting. Finally, in vitro results were validated in an orthotopic tumor model using L3.6pl pancreatic cancer cell line. Results: All pancreatic cancer cell lines showed expression of cMET. In vitro treatment of cancer cells with INC280 led to a minor, dose-dependent inhibition of growth even when cells were supplemented with HGF. In contrast, migration assays showed a significant reduction of cancer cell motility upon INC280 when cells were stimulated with HGF (P<0.05). Regarding oncogenic signaling, INC280 led to inhibition of HGF-induced phosphorylation of AKT, ERK and FAK. In addition, c-Myc expression was diminished in cancer cells. Interestingly, gemcitabine resistant cell line MiaPaCa2(G500) showed higher cMET expression levels compared to the normal MiaPaCa2. Stimulation of MiaPaCa2(G500) with HGF led to strong induction of oncogenic signaling and tumor cell motility, an effect that was significantly diminished by INC280. Moreover, results from in vivo experiments show that therapy with INC280 (10 mg/kg/d) significantly reduces tumor growth as determined by final tumor weight (P<0.05). Conclusions: In pancreatic cancer cell lines, targeting cMET with INC280 abrogates oncogenic signaling in vitro and impairs tumor growth in vivo. Therefore, the concept of cMET inhibition warrants further preclinical evaluation.
Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary study Circe 07 of the LAP 07 trial.
Authors: Huguet Florence , Bidard François-Clément , Louvet Christophe , Mineur Laurent , Bouche Olivier , Chibaudel Benoist , Artru Pascal , Desseigne Françoise , Bachet Jean-Baptiste , Gasmi Mohamed , Nguyen Suzanne , Wander Lionel , Mathiot Claire , Pierga Jean-Yves , Hammel Pascal 
Published: February 2017

188 Background: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At time of diagnosis, 30% of patients present with a locally advanced unresectable but non metastatic carcinoma (LAPC). Theoretically, patients with micrometastatic dissemination at diagnosis should benefit from systemic treatments, whereas radiation therapy should be favored in the others. Based on the hypothesis that circulating tumor cells (CTC) count is a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. Methods: LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of gemcitabine-based chemotherapy whether to administrate a chemoradiotherapy could increase overall survival versus continuation of chemotherapy alone. A subgroup of patients included in LAP 07 trial were prospectively screened for CTC before the start of the chemotherapy and after two months of treatment, using the CellSearch technique. Clinico-pathological characteristics and survival of patients were obtained prospectively and were correlated with CTC detection. Results: Seventy-nine patients were included in this ancillary study. One or more CTC/7.5ml were detected in 5% of patients before treatment and in 9% of patients after two months of chemotherapy (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (p=0.04), and with shorter overall survival in multivariable analysis (RR=2.5, p=0.01), together with anemia (p=0.005). Conclusions: The evaluation of micrometastatic disease using CTC detection appears as a promising tool which could help to personalize treatment modalities in LAPC patients. Clinical trial information: CDR0000589283.
Phosphorylated ERK (pERK) as biomarker in patients with advanced pancreatic cancer treated with erlotinib within a randomized phase III trial (AIO-PK0104).
Authors: Boeck Stefan Hubert , Ormanns Steffen , Laubender Ruediger Paul , Jung Andreas , Siveke Jens T , Haas Michael , Neumann Jens , Vehling-Kaiser Ursula , Winkelmann Cornelia , Fischer von Weikersthal Ludwig , Clemens Michael R. , Gauler Thomas C. , Marten Angela , Klein Stefan , Kojouharoff Georgi , Geissler Michael , Greten Tim F , Kirchner Thomas , Heinemann Volker 
Published: February 2017

189 Background: Validated biomarkers for patients (pts) with advanced pancreatic cancer (APC) treated with anti-EGFR drugs have not yet been defined. pERK represents the downstream target of the RAS-RAF-MEK cascade. Methods: Within AIO-PK0104 281 pts with APC were randomized between gemcitabine/erlotinib followed by capecitabine and capecitabine/erlotinib followed by gemcitabine. Archival formalin fixed paraffin embedded (FFPE) tumor tissue for central pERK analysis by immunohistochemistry (IHC) was available from 153 pts. Within a retrospective subgroup analysis, pERK data (either as dichotomous or continuous variable) were correlated with AIO-PK0104 biomarker results on KRAS mutation status and EGFR expression and with efficacy study endpoints using a Cox regression model. Results: A semi-quantitative immunohistochemistry scoring system considering cytoplasmic and nuclear pERK expression (staining intensity & % of positive cells) was developed (score 0-12). FFPE samples with a score of 6-12 were defined a pERKhigh. 98/153 pts were classified as pERKhigh and 55/153 pts as pERKlow, respectively. The median pERK score was 7 (range 0-12). No significant correlation of pERK with baseline characteristics like stage of disease, gender, age, KPS or CA 19-9 was detected. Median OS in pERKhigh pts was estimated with 5.7 months and with 6.2 months in pERKlow pts (HR 1.29, 95% CI 0.90-1.83, p=0.16). However, when analysing pERK as continuous variable, a significant association between the pERK score and OS was found (HR 1.06, 95% CI 1.0-1.12, p [log rank]=0.050, p [likelihood ratio]=0.047), indicating an increase in the hazard for death by a factor of 1.06 for each score level of pERK expression. There was no correlation of pERK expression with the objective disease control rate (OR 0.99, p=0.91) or the occurrence of skin rash (OR 0.93, p=0.41). Pts with a KRAS mutation had a similar rate of pERKhigh expression compared to patients with KRAS wildtype (61% vs 71%, p=0.32). Conclusions: pERK expression may have an impact on OS of APC pts treated with the anti-EGFR agent erlotinib. Prospective validation of these results is recommended. Clinical trial information: NCT00440167.
Molecular profiling (MP)-selected therapy for the treatment of patients with advanced pancreaticobiliary cancer (PBC).
Authors: Epelbaum Ron , Shacham-Shmueli Einat , Geva Ravit , Hubert Ayala 
Published: February 2017

195 Background: For patients (pts) with advanced PBC who are able to pursue additional therapy, treatment selection is often empiric and clinical benefits are usually modest. Our goal was to study clinical outcomes of MP-guided treatment in advanced PBC. Methods: This retrospective analysis included pts with advanced PBC whose tissue samples underwent MP (IHC, microarray [MA], and sequencing analyses) using Target Now (Caris Life Sciences, Irving, TX). These pts received ≥1 lines of therapy for advanced PBC before their treatment was guided by MP. The MP-guided therapy was considered to have clinical benefit if the TTP ratio between the longest TTP on MP-guided therapy and the TTP on the last therapy pre-MP was ≥1.3. Results: Out of 20 pts included in the analysis, 16 had advanced cancer of the pancreas. Median age was 59 yrs (range: 30-81), 85% were male, and 60% had PS of 1. Pts had 1-4 treatment regimens (median: 1) prior to MP. MP identified 1-7 (median: 4) actionable targets per pt. The most commonly identified targets by IHC were: negative or low TS (80%), high TOPO1 (70%), negative or low ERCC1 (52%), and high SPARC (40%). In all 14 pts that had MA results, multiple actionable targets were identified. Of 14 pts with KRAS sequencing analysis, 10 pts (71%) had mutations. Post-MP, pts had 1-4 (median: 1) treatment regimens, most commonly FOLFIRI/XELIRI, FOLFOX/XELOX, capecitabine, and nab-paclitaxel. The total number of regimens post-MP was 33, of which 29 were evaluable for decision impact analysis. In 24 (83%) of cases, treatment decision was modified due to the MP results. Out of the 20 pts, 4 received ≤1 cycle of MP-guided therapy during rapidly progressing disease and were excluded from the clinical outcome analysis. Of the 16 evaluable pts, 6 (37.5%) had a TTP ratio of ≥1.3 (one-sided exact binomial test vs a null hypothesis of ≤15% with TTP ratio ≥1.3, P=0.0056; therefore the null hypothesis is rejected). Conclusions: In our retrospective analysis of a small, yet well-defined, cohort of pts with advanced PBC, MP often influenced treatment decisions and over a third of pts experienced a longer TTP (compared to the last regimen pre-MP), highlighting the promise in MP for treatment selection.
HER2 testing in esophageal adenocarcinoma (EAC) using parallel tissue-based methods.
Authors: Yoon Harry H. , Shi Qian , Sukov William R. , Sattler Christopher A. , Wiktor Anne E. , Wu Tsung-Teh , Diasio Robert B. , Jenkins Robert B. , Sinicrope Frank A. 
Published: February 2017

2 Background: Testing for HER2 in EAC has become routine given its ability to predict benefit from HER2-targeted therapy. HER2 protein analysis by immunohistochemistry (IHC) is more rapid and generally less expensive than assessment of gene amplification by fluorescence in situ hybridization (FISH). However, the accuracy of IHC for predicting HER2 amplification has not been examined in a large EAC cohort. Methods: Surgical EAC specimens were examined from 675 patients who underwent curative resection at a single institution without preoperative therapy. Tumors were located in the esophagus (47%) or gastroesophageal junction (53%); most were node-positive (73%). Every tumor was evaluated by IHC in parallel with FISH in a blinded manner using FDA-approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0 or 1+; equivocal, 2+; positive, 3+). Gene amplification by FISH was defined as a HER2/CEP17ratio ≥ 2. Results: HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and 4% of IHC 0-1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value (PPV) of a positive IHC test (3+) was 89% (79/89 [95% CI 82%-95%]), and the negative predictive value of a negative IHC test (0-1+) was 96% (401/417 [94%-98%]). Importantly, the PPV of an equivocal IHC score (2+) for detecting HER2 amplification was 13% (22/169 [8%-18%]). Conclusions: In the largest study to date comparing HER2 testing methods in EAC, a negative IHC result (0 or 1+) nearly excludes the presence of gene amplification by FISH. Whereas a positive IHC result (3+) strongly predicts for the presence of amplification, an equivocal IHC result (2+) is a weak predictor. These findings in EAC support a HER2 testing algorithm where IHC is used for initial screening and FISH testing is restricted to cases with equivocal IHC results. [Table: see text]