bluuebunny/crossref_metadata_2025_split huggingface dataset:
ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma.
Authors: Laforest Anais , Aparicio Thomas , Zaanan Aziz , pittella Silva Fabio , Didelot Audrey , Desbeaux Aurelien , Le Corre Delphine , Benhaim Leonor , Pallier Karine , Aust Daniela Ellen , Pistorius Steffen , Blons Helene , Svrcek Magali , Laurent-Puig Pierre 
Published: February 2017

205 Background: Small bowel adenocarcinoma (SBA) is an aggressive tumor responsible for poor outcomes with an expected median OS at 5 years inferior to 30%. Because of its low incidence, few prospective studies have been performed leading to insufficient knowledge and absence of standard of care. Aiming to better understand the small bowel carcinogenesis process we screened for somatic mutations a large data set of patients in more than 740 mutational hotspots among 46 genes. Methods: In total, 83 SBA cases were selected from 2 European databases. The sequencing was performed using the Ion 316 Chip. We additionally looked into MSI status and ERBB2 expression (immunochemistry and FISH). Results: Tumors were mostly located in the duodenum (47%) and stage ≥ 3 (63%). Among the 46 genes investigated, 8 were mutated in more than 5% of the cases: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF, and FBXW7. Compelling mutations (7 cases) and amplifications (3 cases) 12% of the patients had an ERBB2 alteration. In this group, ERBB2 alterations were positively associated with dMMR status (p=0.006) and APC mutations (p=0.02) but negatively associated with p53 mutations (p=0.038). Interestingly, ERBB2 mutations were mainly detected within tumors derived from the foregut while ERBB2 amplifications were limited those derived from the midgut. Conclusions: This study describes the first large screening of somatic mutations in SBA using next generation sequencing. ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumor location. In most cases patients harbored the same p.L755S-ERBB2 mutation. In clinical practice, this study may suggest that more than 10% of the patients with SBA could be treated using anti-ERBB2-targeted agents.[Table: see text]
A phase II trial of low-dose multiagent chemotherapy with gemcitabine, docetaxel, capecitabine, and cisplatin (GTX-C) in patients with metastatic pancreatic cancer.
Authors: Le Dung T. , Laheru Daniel A. , Purtell Katrina , Uram Jennifer N. , Wang Hao , Lawrence Susie , Foreman Ellen-Lilly , David Jacob Joseph , Parkinson Rose , Savage Dionne T , Donehower Ross C. , Rasheed Zeshaan , Zheng Lei , Azad Nilofer Saba , Cosgrove David , De Jesus-Acosta Ana , Browner Ilene , Diaz Luis A. 
Published: February 2017

213 Background: Multiagent chemotherapy with three agents has been shown to delay the emergence of resistance and extend survival in patients with metastatic pancreatic adenocarcinoma. Four drug regimens, even at low doses, may further improve survival by simultaneously targeting multiple non-redundant oncogenic pathways. Methods: A phase II study of GTX-C (capecitabine 500 mg bid on days 1-14, and the combination of gemcitabine 500 mg/m2 (10 mg/m2/min), docetaxel 20 mg/m2 and cisplatin 20 mg/m2 on days 4 and 11) was initiated in newly diagnosed untreated metastatic pancreatic cancer patients. The primary endpoint was progression-free survival rate at 6 months; the regimen would be considered active if the 6-month PFS rate was >75% and inactive if < 50%. Results: Twenty-nine patients were enrolled and 10 patients remain on GTX-C treatment at the time of this report. All patients were ECOG 0 or 1. Eighty-six percent of patients had evidence of liver metastases and 25% had biliary stents in place at time of study enrollment. Median CA19-9 was 6,159 U/mL (37-154,323 U/mL). Median length of follow-up was 9.0 months. Grade 3/4 related adverse events included: nausea/vomiting (7%), transaminitis (10%), anemia (14%), thrombocytopenia (24%), and neutropenia (55%). However, febrile neutropenia occurred in only 3 patients (10%) and not until cycles 6, 14, and 15. PFS rate at 6 months was 76.4% (95% CI: 54.6% - 88.7%). The partial response (PR) rate was 50%, stable disease (SD) rate was 39% and the disease control rate (DCR) was 89%. CA19-9 declines of >80% occurred in 77% of patients with measurable levels. Estimated median PFS was 8.4 months (95% CI: 6.1-10.6 months) and OS was 13.9 months (95% CI: 10.0-17.2 months) at the time of this submission. Updated results will be reported at GI ASCO 2014. Conclusions: GTX-C is highly active and well-tolerated in patients with metastatic pancreatic cancer and should be tested in a larger, comparative study. Clinical trial information: NCT01459614.
The effect and mechanism of M402 on gemcitabine uptake into pancreatic tumors.
Authors: Schultes Birgit Corinna , Chu Chia Lin , Long Alison , Sun Elaine , Kurtagic Elma , Beccati Daniela , Pradines Joel , Miller Paul , Ryan David P. , Flaherty Keith , Roach James , Kaundinya Ganesh Venkataraman 
Published: February 2017

215 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which has been attributed to high interstitial pressure and poor drug delivery. In nonclinical studies, M402 affected multiple growth factors, adhesion molecules, and chemokines, inhibiting tumor progression, metastasis, and angiogenesis by clearing heparin-binding factors from the tumor microenvironment. We hypothesized that M402 could modulate tumor-stroma interactions in an orthotopic pancreatic cancer model (rich in desmoplasia), decreasing the fibrotic response and in turn increasing tumor perfusion and drug delivery. Methods: Capan-2 human PDAC cells were injected into the pancreata of nude mice. M402 (40 mg/kg/day, s.c.) or saline began Week 5. Gemcitabine (GEM; 30 mg/kg, i.p. biweekly) started Week 7. At different time points, primary tumors were analyzed for mRNA arrays, immunohistochemistry (ECM components, CD31), and functional tumor vasculature. GEM tumor uptake was evaluated by quantifying the incorporation of dFdC into tumor DNA by LC-MS/MS. M402 tumor uptake was visualized using HyLite-750-labeled drug in a Xenogen system. Results: M402 readily targeted pancreatic tumors with long residence time. Alone and particularly in combination with GEM, M402 significantly reduced tumor size and fibrosis, which was accompanied by down-regulation of SHH, PDGF, and TGF-β signaling in stromal cells. Tumors treated with M402 or M402+GEM showed perfusion and microvessel penetration into the tumor centers while vehicle or GEM treated tumors exhibited limited tortuous vessels surrounding the tumor rim. This translated into increased GEM incorporation into the tumor DNA when mice were pre-treated with M402 vs. saline (10.9±5.5 vs. 6.7±1.8 pg of dFdC/µg dG, respectively; p=0.037). Conclusions: M402 appears to inhibit stromal activation within the tumor microenvironment. Reduction in desmoplasia led to improved tumor perfusion, delivery of GEM, and tumor shrinkage. These and other promising nonclinical data support the rationale for the ongoing Phase 1/2 study evaluating the safety and tolerability of M402 in combination with nab-paclitaxel and GEM in patients with metastatic pancreatic cancer.
Functional BRM promoter polymorphisms, pancreatic adenocarcinoma risk, and survival.
Authors: Segedi Maja , Anderson Laura N , Espin-Garcia Osvaldo , Borgida Ayelet , Bianco Teresa , Cheng Dangxiao , Chen Zhuo , Patel Devalben , Brown M Catherine , Hung Rayjean J , Cotterchio Michelle , Gallinger Steven , Xu Wei , Reisman David , Liu Geoffrey , Cleary Sean P. 
Published: February 2017

222 Background: Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM -1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex (PMID:23524580). BRM suppression can be reversed pharmacologically (PMID: 21478905). Our group and others have reported associations with lung, head and neck, and hepatocellular cancer risk (PMIDs: 21478907, 23322154, 23359823). We have also reported associations with lung and esophageal cancer prognosis (ASCO 2013; abstr 11057 and 4077). In this analysis, we assessed risk and survival associations with pancreatic cancer. Methods: A population-based case-control study was conducted in Ontario with 623 histologically-confirmed pancreatic adenocarcinoma cases and 1192 age/gender distribution-matched controls (PMID: 23908141). Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Results: Median age was 65 years; 52% were male; 53% had received a curative resection; Stage I (8%), II (55%), III (14%), IV (23%); 79% received chemotherapy; 83% had died. In the risk analysis, the adjusted odds ratios were 1.01 (95%CI:0.1-2.0) and 0.96 (95%CI:0.7-1.3) for the homozygous variants of BRM-741 and BRM-1321, respectively, when each was compared to wildtype; adjusted odds ratio of double-homozygotes was 1.11 (95%CI:0.80-1.53) when compared to the double-wildtype. In contrast for the survival analysis, the hazard ratios (adjusted for age, stage, receipt of curative surgery, receipt of chemotherapy, and packyears) were 2.19 (95%CI: 1.9-2.5) for BRM-741 and 1.94 (95%CI: 1.7-2.2) for BRM-1321, per each unit increase in variant alleles. Compared with the double-wildtype, the adjusted hazard ratio for carrying no, one, and two homozygous (double-homozygous) variants were 2.14 (95%CI:1.6-2.8), 4.17 (95%CI:3.0-5.7), and 8.03 (95%CI: 5.7-11.4), respectively. Conclusions: Two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.
Phase II study of induction therapy with gemcitabine and nab-paclitaxel followed by consolidation with mFOLFIRINOX in patients with metastatic pancreatic cancer.
Authors: Ramanathan Ramesh K. , Lee Peter , Seng John E. , Anthony Stephen Patrick , Rosen Peter J. , Mena Raul R. , Picozzi Vincent J. , Sachdev Jasgit C. , Larson Tim , Korn Ronald , Jameson Gayle S. , Stoll Amy C. , Von Hoff Daniel D. , Leach Joseph W. 
Published: February 2017

224 Background: FOLFIRINOX or NabP-Gem are now standard mPC regimens.The optimal sequence is not known.This phase II study evaluated the feasibility of NabP-Gem followed by FOLFIRINOX. Methods: Eligible pts had evidence of untreated mPC, ECOG 0-1 and adequate organ function. Pts received Nab-P (125 mg/m2) and Gem (1000 mg/ m2) weekly x 3 (Induction ) every 4 weeks for upto 6 cycles. FOLFIRINOX, q2 weeks (Consolidation regimen) was initiated after 6 cycles of the Induction regimen, or earlier in case of progression, and given for a maximum of 6 months (12 cycles). mFOLFIRINOX (NEJM, 364:1817-25: 2011) has been modified with growth factor prophylaxis and omission of bolus 5FU. One endpoint is to increase 1 year survival to > 70%, (n=30, 95% CI is +/- 20%). Results: Accrual goals have been met (n=31). The M/F ratio is 55%/45%, median is 66 years. In 23 pts with elevated baseline CA19-9 levels treated with NabP-Gem, 83% had a > 90% decrease. The response rate with the NabP-Gem regimen is 43%. Selected therapy related Grade > 3 adverse events during the course of both NabP-Gem and FOLFIRINOX therapy are: neutropenia (39%), fatigue (32%), anemia (19%), thrombocytopenia (16%), thromboembolic events (3%), peripheral neuropathy (16%), leukopenia (16%), nausea (3%), vomiting (3%), diarrhea (7%), and neutropenic fever (3%). During the course of NabP-Gem, 14 dose reductions and four dose delays were seen. Two pts had early progression at cycle 4 or less and were switched to the Consolidation regimen. Seventy one % (22/31) of pts went on to receive FOLFIRINOX (4 pts still on study), 4 received FOLFIRI, and one pt received FOLFOX as Consolidation therapy. One-year survival is projected to be 50-60%. Conclusions: The induction NabP-Gem regimen shows evidence of substantial activity similar to published reports (JCO.29:4548-54: 2011). The induction-consolidation strategy is feasible in selected patients. Cumulative side effects predominantly fatigue and neuropathy will require appropriate dose reductions or treatment breaks. (Supported by the Seena Magowitz foundation). Clinical trial information: NCT01488552.
In vitro chemotherapy profiling of well-differentiated midgut neuroendocrine tumors (NETs) based on individual patient tumor biomarkers analysis.
Authors: Wang Yi-Zarn , Carrasquillo Jean P. , Carimi Alexis , McCord Elizabeth , Chester Maria M. , Ramirez Robert , Boudreaux J Philip , Woltering Eugene , Raines Daniel , Anthony Lowell Brian 
Published: February 2017

235 Background: Midgut neuroendocrine tumors (NETs) are rare malignancies with indolent clinical courses. In general, they are well differentiated with most tumor cells in the G0 phase of the cell cycle, consistent with the poor response rate of NETs to chemotherapy in vivo. We hypothesize that insults, such as surgery, can drive NET cells from G0 into S phase and that biomarker analysis of individual patient tumors harvested and grown in the lab will provide useful practical guide for future intra and post operative adjuvant therapy. Methods: 97 well-differentiated midgut NET patients underwent cytoreductive surgery at our institution between 5/2012 and 10/2012. 148 surgical specimens were collected and submitted to a single commercial lab for processing. Primary tumors, lymph nodes and liver metastases were harvested and cultured. Their RNAs were then extracted to analyze the expressivity a total of 88 different biomarkers. Based on our patients specific tumor biomarker expressivity and known correlations between 36 anti-neoplastic agents with their linked biomarkers, recommendations were reported as clinically benefit or lacking such benefit. Results: A total of 148 specimens from 97 patients were tested. In four of the 97 patients, no clinically beneficial chemotherapy agent could be identified. Among the remaining 93 patients, the top three agents that are most likely to be clinically beneficial are: Fluorouracil, Cisplatin and Carboplatin. These were reported to be clinically beneficial in 135/148 (91.2%), 103/148 (69.6%), and 103/148 (69.6%) patients respectively. Conclusions: Midgut NETs are slow growing tumors which are chemotherapeutically inert owing to the fact that most of the tumor cells are in G0 cell cycle. Surgical insult drives NET cells into active synthetic phase where they begin to express biomarkers specific to their tumor cells. Analysis of these biomarkers guides further potential beneficial therapy based on the current known associations among biomarkers and chemotherapy agents. These results must then be compared and confirmed against a direct in-vitro chemo sensitivity assessment conducted simultaneously on the same patients.
Association of long-term regular aspirin use with reduction of gastric cancer risk: A nationwide cohort study.
Authors: Kim Young-Il , Kim So Young , Park Jong-Hyock , Cho Soo-Jeong , Lee Jun Ho , Kim Young Woo , Choi Il Ju 
Published: February 2017

24 Background: Aspirin use has been associated with a decreased incidence and mortality of various gastrointestinal malignancies. In this study, we evaluated the association between aspirin use and gastric cancer risk. Methods: We randomly selected 200,000 patients with hypertension or type 2 diabetes from the Korean National Health Insurance claim database at 2004. Of these, 3,907 patients who used aspirin regularly (aspirin users) and 7,808 patients who did not use aspirin (aspirin non-users) were selected by 1:2 frequency matching (age, sex, co-morbid illnesses, and starting time of follow-up), and assessed gastric cancer incidence during the followed-up periods from January 2004 to December 2010. Results: In the matched cohort, the incidence rates of gastric cancer were 0.8% (31/3,907) in aspirin users and 1.1% (86/7,808) in aspirin non-users, but the cumulative incidence rates were not significantly different between aspirin users and non-users (P=0.11, log-rank test). Although there was no statistical significance, a multivariate analysis showed that aspirin use was associated with reduced gastric cancer risk (adjusted hazard ratio [AHR], 0.71; 95% confidential interval [CI], 0.47–1.08; P=0.11). However, duration of aspirin use was significantly associated with the reduction of gastric cancer risk (overall AHR, 0.85; 95% CI 0.73–1.00, P=0.04), especially in patients that used aspirin for more than 3 years (AHR, 0.40; 95% CI, 0.16–0.98; P=0.04). Conclusions: Long-term regular aspiri n use is significantly associated with reduced gastric cancer risk.
Phase II trial of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma (HCC).
Authors: He Aiwu Ruth , Tesfaye Anteneh , Smith Daniel , Marshall John , Pishvaian Michael J. , Smaglo Brandon George , Weiner Louis M. , Dorsch-Vogel Karen , Wang Hongkun 
Published: February 2017

240 Background: The combination of the imidazotetrazine derivative temozolomide (TMZ) and poly(ADP-ribose) polymerase inhibitor veliparib (ABT-888) has shown in vivo activity against a variety of tumor types through the alkylating effects of TMZ and DNA repair inhibition by ABT-888. To date, no studies have examined the combination of TMZ and ABT-888 in treating advanced HCC refractory to sorafenib. Methods: This is a single arm Phase II trial. Eligible HCC patients have Child Pugh A/B cirrhosis and have failed prior treatment with sorafenib either through intolerance or disease progression. All patients have received ABT-888 40 mg daily on days 1-7 and Temozolomide 150 mg/m2 daily on days 1-5 in 28 day cycles for a maximum of 6 cycles. Tumor response is analyzed every 2 cycles using RECIST criteria. The primary endpoint is time to disease progression. The trial is being conducted using a modified Simon’s two-stage design optimal design as implemented by Hanfelt, et al. Results: The trial is currently in Simon Stage 1 with 16 patients recruited: 9 patients have stopped the study due to disease progression, 3 patients are still on protocol, and 4 patients stopped the study for reasons other than disease progression. 7 patients had disease progression at two months, 1 patient had cancer progression at 4 months, and 1 patient had disease progression at 16 months. Median time to progression in these 9 patients was 56 days (range 42-486 days). The four patients that stopped the study prematurely were for the following reasons: hiccups/dehydration, Mallory-Weiss tear secondary to refractory nausea, intraperitoneal bleeding from exophytic HCC lesion, and development of hepatorenal syndrome in a paracentesis-dependent patient. The most common grade 3 toxicities in this cohort so far have been nausea/vomiting (in 2 subjects), and anemia/thrombocytopenia (in 2 subjects). Defects in DNA repair pathways are being tested from the liver biopsy in the patient who had response to TMZ and ABT-888 for 16 months. Conclusions: The combination of TMZ and ABT-888 is fairly tolerated in patients with advanced HCC. So far, the treatment did not show activities in majority of patients with advanced HCC. Clinical trial information: NCT01205828.
Angiogenesis genotyping, LDH serum levels, and treatment efficacy for advanced hepatocellular carcinoma patients receiving sorafenib.
Authors: Faloppi Luca , Scartozzi Mario , Bianconi Maristella , Loretelli Cristian , Svegliati Baroni Gianluca , Toniutto Pierluigi , De Minicis Samuele , Bitetto Davide , Mandolesi Alessandra , Giampieri Riccardo , Del Prete Michela , Bittoni Alessandro , Bearzi Italo , Benedetti Antonio , Cascinu Stefano 
Published: February 2017

245 Background: Previous reports suggested that angiogenesis genotyping predicts clinical outcome for HCC patients receiving sorafenib. However gene profiling techniques may not be available in the clinical practice, thus resulting in lack of selection. LDH serum levels, a marker of tumour-driven hypoxia and angiogenesis, demonstrated to play a prognostic role in patients undergoing anti-angiogenetic therapy in different tumour types. Our study evaluated whether angiogenesis genotyping correlates with LDH levels in HCC patients receiving sorafenib with the final aim to provide clinicians with a readily available marker for the clinical management of these patients. Methods: 82 HCC patients treated with sorafenib were included. Tumour samples were tested for VEGF-A/C and VEGFR-1/2/3 SNPs. The LDH cut off value (407 U/l) was set after ROC analysis. Patients were divided into two groups according to the LDH pre-treatment levels and subsequently classified for LDH pre- and post-treatment variations (increased vs. decreased). Results: In patients with LDH values ≤ or > 407 U/l mPFS and mOS were respectively 6.7 vs. 1.9 months (p=0.0006) and 13.2 vs. 4.9 months (p=0.0002). Patients with decreased LDH values after treatment experienced an improved mPFS and mOS compared to those with increased LDH levels (mPFS: 6.8 vs. 2.9 months, p=0.0087, mOS: 21 vs. 8.6 months, p=0.0035). As previously reported VEGF-A (rs2010963) and VEGF-C (rs4604006) genotyping predicted improved clinical outcome and in the present series also significantly correlated with low LDH pre-treatment levels (respectively: p=0.027; p=0.016) and with decreased LDH levels after treatment (respectively: p=0.012; p=0.015). Conclusions: VEGF-A (rs2010963) and VEGF-C (rs4604006), low LDH pre-treatment levels and decreased LDH levels after treatment seem to be concordant in determining clinical outcome in this setting. Our observations suggest that these genotypes are likely to affect tumour angiogenesis with subsequent LDH levels modifications as a result of sorafenib treatment. We believe that these findings may be relevant for a better prognostic stratification of advanced HCC patients receiving sorafenib.
Effect of inflammation-associated cytokines of biliary tract cancer on chemoresistance and therapeutic implications.
Authors: Kobayashi Shogo , Nagano Hiroaki , Yamada Daisaku , Ishii Hideshi , Tomimaru Yoshito , Hama Naoki , Wada Hiroshi , Kawamoto Koichi , Eguchi Hidetoshi , Doki Yuichiro , Mori Masaki 
Published: February 2017

247 Background: Biliary tract cancer (BTC) is well-known to be commonly suffered from inflammations; cholangitis and/or liver abscess. The author previously showed interleukin-6 (IL-6) worked on anti-apoptotic process in BTC. Herein, we focused on inflammation-associated cytokines including not only IL-6 but also transforming growth factor-beta 1 (TGF-β1), and investigated the working processes, their relationship to chemoresistance, and therapeutic implications. Methods: We employed resected specimens and BTC cell lines. We evaluated IL-6/TGF-β1 expression, invasion, endothelial-mesenchymal transition (EMT), and chemoresistance to gemcitabine, with or without silencing of PI3K/Akt, MAPK, STAT, and Smad pathways. Results: Resected specimens expressed IL6 and TGF-β1 staining at the invasion front by immunohistochemical staining. In BTC cell lines, spontaneous expression of IL-6/TGF-β1 was related to malignant potencies such as EMT and chemoresistance. Rh IL-6/TGF-β1 induced invasion, EMT, and chemoresistance. Smad4 among cell signaling pathways functioned in a dominant manner; inhibition of Smad4 pathway reduced invasion, and reversed EMT and chemoresistance, in both rh IL-6/TGF-β1-treated cells, and we confirmed these results using SMAD4 siRNA. And, our established gemcitabine-resistant cells expressed high level of IL-6/TGF-β1, and promoted EMT. Inhibition of Smad4 also reversed chemoresistance in gemcitabine-resistant cells. We confirmed N-cadherin and Smad4 expression at the invasion front by immunohistochemistry. Conclusions: IL-6 and TGF-β1 resulted in chemoresistance, and inhibition of Smad4 would reverse chemoresistance in BTC.