bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRM promoter insertion/deletion polymorphisms in hepatocellular carcinoma risk and survival.
Authors: Wong Kit Man , Liu Geoffrey , Lee Jonghun John , Espin-Garcia Osvaldo , Brhane Yonathan , Cheng Dangxiao , Chen Zhuo , Patel Devalben , Brown Catherine , Wong Amy , Reisman David , Xu Wei , Knox Jennifer J. , Cleary Sean P. , Hung Rayjean J 
Published: February 2017

225 Background: MEF2D and HDAC9 regulate the expression of BRM, the catalytic subunit of SWI/SNF (chromatin remodeling complex). MEF2D binding sites are created in the BRM promoter by two germline insertion/deletion polymorphisms (BRM-741, BRM-1321), which mediate epigenetic silencing. We recently identified BRM as a potential drug target and a susceptibility gene for lung and head and neck cancers, while others reported its association with HCC risk in Asians. BRM also correlates with prognosis in lung and esophageal cancers (ASCO 2013; abstracts 11057, 4077). In this analysis, we assessed the effects of the BRM promoter variants on risk and overall survival (OS) in HCC from a North American centre (Toronto). Methods: We conducted a case-control study with 266 histologically confirmed HCC cases and 536 age/sex distribution-matched healthy controls. Survival of the cases was obtained from medical records. Association between the BRM polymorphisms and HCC risk was analyzed by multivariate logistic regression adjusted for age, sex, race, smoking and BMI; their impact on OS was evaluated by Cox proportional hazard regression adjusted for age, sex, treatment intent and Hepatitis B status. Results: Median age was 62 years; 83% were male. Hepatitis B and C infections affected 34% and 31% of cases, respectively. 83% of patients were Child Pugh A at diagnosis, and 66% received initial curative therapy (surgical resection rate 32%). There were 13% deaths at a median follow-up of 24.1 months. There was no significant association between BRM polymorphisms and HCC risk: the adjusted risk odds ratios of the homozygous BRM variants, relative to wild-type, were 0.87 (95% CI: 0.53-1.45; BRM-741) and 1.01 (95% CI: 0.78-1.29; BRM-1321), and 0.94 (95% CI: 0.48-1.86) for the double homozygotes vs. double wild-type. The adjusted hazard ratios for OS were 5.77 (95% CI: 2.9-11.5; BRM-741) and 4.09 (95% CI: 2.2-7.5; BRM-1321) for each variant allele; the double homozygotes were also highly associated with OS compared to double wild-type (p<0.0001). Conclusions: Two functional BRM promoter polymorphisms did not increase the risk of HCC. However, they were strongly associated with OS despite short median follow-up. SPC and RH are co-senior authors.
Development and validation of a scoring system using insulin-like growth factor to assess hepatic reserve in hepatocellular carcinoma.
Authors: Kaseb Ahmed Omar , Xiao Lianchun , Yoon Jung-Hwan , Hassan Manal , Lee Jeong-Hoon , Lee Hyo-Suk , Chae Young Kwang , Abbruzzese James L. , Morris Jeffrey 
Published: February 2017

231 Background: The Child-Turcotte-Pugh (CTP) score fails to accurately predict survival in hepatocellular carcinoma (HCC), yet remains the standard tool for assessing the liver reserve and guiding therapeutic decisions. CTP relies partially on subjective clinical grading of encephalopathy and ascites. Since liver production of insulin-like growth factor-1 (IGF-1) is significantly reduced in chronic liver diseases and HCC, we hypothesized that IGF-1 could be a valid surrogate for hepatic reserve to replace the subjective parameters in CTP score. Methods: We tested plasma IGF-1 in the training set (n=310). Recursive partitioning identified three optimal IGF-1 ranges that correlated with survival: >50 ng/mL = 1 point; 26-50 ng/mL = 2 points; and <26 ng/mL = 3 points. We modified the CTP score by replacing ascites and encephalopathy with plasma IGF-1, subjected both scores to log-rank analysis, and quantified the prognostic values with C-statistics to compare the scores’ performance. We prospectively validated the score in 150 patients from MDACC; in addition to 180 patients from Korea. Results: The IGF score significantly predicted OS of all classes (p<0·001). In the training cohort, C-indices for CTP and IGF scores were 0·57 and 0·61, respectively (p=0·003 per the U-statistic). Similarly, C-indices in MDACC validation cohort were 0·56 and 0·63 (p=0·02 per the U-statistic), and in Korean cohort were 0·58 and 0·60 (p=0·03 per the U-statistic). Conclusions: The new IGF score is simple and blood-based, and validated well on multiple independent HCC cohorts. It could identify a subpopulation of patients who may benefit from active therapy because of their preserved hepatic reserve, as distinct from patients for whom therapy can be deferred or avoided.
Use of decoy receptor 3 to block gemcitabine-induced apoptosis via binding with TRAIL in pancreatic cancer.
Authors: Wang Wei , Lin Wenjie , Zhuang Xin , Wang Qingda , Luo Jinbing 
Published: February 2017

238 Background: Most of human pancreatic cancer cell lines are resistant to chemotherapeutics-induced apoptosis including gemcitabine. This study is to address the role of decoy receptor3 (DcR3) in pancreatic cancer resistant to chemotherapeutics. Methods: siRNA targeted for DcR3 was used to down-regulate DcR3 expression in pancreatic cancer cells. On exploring for the pathway of DcR3 blocking Gemcitabine-induced apoptosis, up or down-regulated DcR3 level of pancreatic cancer cells were treated with Gemcitabine and apoptosis susceptibility was evaluated with apoptosis analysis. To investigate whether DcR3 is involved in TRAIL, FasL or LIGHT-mediated apoptosis, PARP and apoptotic cells staining were determined under different DcR3 level. Through ELISA-like binding analysis, immunoprecipitation and FACS, TRAIL binding with DcR3 was tested. In vivo experiment, it is to investigate whether down-regulation of DcR3 affects gemcitabine-induced apoptosis and tumor growth delay. Results: It demonstrates that DcR3 down-regulation sensitizes cells to gemcitabine-induced apoptosis and additional DcR3 level can impair gemcitabine-induced apoptosis in both of cells. It is proved that DcR3 blocks gemcitabine-induced apoptosis via binding with TRAIL which was thought not to bind with DcR3 previously. Furthermore, Regulation of DcR3 changes the amount of membrane-bound TRAIL which is correlated with gemcitabine-stimulation. In vivo experiment of AsPC-1 xenografts, stable down-regulation of DcR3 significantly enhances gemcitabine-induced apoptosis and tumor growth delay. Conclusions: DcR3 may play important role resistant to gemcitabine-induced apoptosis via binding with TRAIL in some of pancreatic cancer cells lines. Targeting DcR3 represents a promising strategy to enhance the anti-tumor activity of chemo-agent in pancreatic cancer, which has important clinical implications.
A phase Ib/IIa study of NEO-102: A therapeutic antibody to treat pancreatic and colorectal cancers.
Authors: Patel Sandip Pravin , Morse Michael , Beg Muhammad Shaalan , Azad Nilofer Saba , Beatson Melony A. , Mavroukakis Sharon , Arlen Philip M. 
Published: February 2017

243 Background: We have developed a chimeric monoclonal antibody (ab) that targets a variant of MUC5AC that is expressed specifically by human pancreatic (P) and colorectal (C) tumors with minimal reactivity to normal GI mucosa. In the phase (ph) I trial of the initial formulation NEO-101, 5/19 patients (pts) had stable disease (SD) after completing their 1st course of treatment (tx) (4 doses) and overall survival (OS) of >12 months (mos) observed in 3 C and 2 P pts despite disease progression on standard (std) of care tx regimens. The current study utilizes NEO-102, a glycoengineered form of NEO-101 with improved stability and decreased RBC agglutination. Methods: A Ph Ib/IIa open label, multi-center dose-escalation clinical trial with NEO-102 is enrolling pts with advanced P and C cancer refractory to std therapy. Primary objective: measure efficacy by analysis of CT scans pre- and post-therapy using RECIST criteria, OS, clinical laboratory tests, and physical examinations. Secondary objectives: a.determine safety and tolerability of escalating doses of NEO-102; b. assess pharmacokinetics (PK) and select immune responses to the ab at each dose level. Analyses of pt PBMCs for ADCC and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome, and for correlation with clinical benefit. Results: Safety analysis has been performed on 3 pts enrolled in the first cohort at the dose level of 1.5 mg/kg IV q2weeks. There were no dose limiting toxicities (DLT) observed. In this cohort, one of the pts is evaluable for SD at 4 mos. The other 2 pts are scheduled for restaging scans. Pts are currently being accrued at the 2 mg/kg dose level. Conclusions: Preliminary results with NEO-102 ab have demonstrated signs of clinical activity based on stabilization of disease in heavily pretreated pts with P and C cancer. Safety has been established at the 1.5 mg/kg dose level and patients are currently being accrued to the 2 mg/kg dose level. If no DLT is observed at the current dose level, we plan to escalate to 3mg/kg and 4mg/kg respectively. Immune biomarker analyses are underway to correlate PBMC ADCC and cytokine profile with tx response. Clinical trial information: NCT01040000.
First-in-human fractal methodology for modeling the hepatic arterial tree and tumor microvasculature for 90Y-microsphere brachytherapy.
Authors: Kennedy Andrew S. , Clipp Rachel , Christensen David 
Published: February 2017

248 Background: 90Y-microsphere therapy (radioembolization) is an effective and safe brachytherapy procedure for control of unresectable primary and metastatic hepatic malignancies. To advance this treatment approach, a method is proposed which enables complex modeling of the hepatic arterial route, and the tumor microvascular bed in which the radioactive particles will become permanently embedded. Methods: Prior work from our group included hepatic vessel measurements from patients undergoing 90Y-microsphere therapy including geometry, pressure, velocity and waveforms prior to and during microsphere deposition in real time. A computation particle-fluid dynamics model was built for proximal hepatic arteries of 900 microns, which is the limit of current imaging technology. Fractal methods were programmed in C++ for simulations of both normal liver and tumor arterial trees. Our goal was to produce sufficient generations to achieve daughter arterioles of 50 micron diameter in tumors where microspheres typically lodge in clusters. Results: Normal liver and tumor artery trees were created, with malignant vessels employing a random generator at each node resulting in corkscrew, bifurcation and/or trifurcation daughter vessel pattern. Three key variables were: asymmetry ratio of radii of daughter vessels; power law of the type of flow present in vessels (turbulent or laminar); and area ratio, which is the area between daughters and parent vessel. Simulations of up to 250 generations resulted in successful modeling of 50 micron diameter normal and tumor arterioles. Impedance in each vessel (modulus and phase shift) was tested with a large variety of vessel geometries. Conclusions: Fractal methods were used to develop a software tool that can represent the microvasculature of human liver and different organs, and can account for disease states, such as liver tumors. This is accomplished using corkscrew, bifurcating, trifurcating and randomized structured trees. Predictive modeling may now be possible for radioactive or non-radioactive microspheres exiting from a catheter in the hepatic artery to its final position in a tumor end arteriole, or for systemic therapies.
Identification of aberrant DNA methylation profiles in non-tumor liver tissues of patients with non-B, non-C hepatocellular carcinoma.
Authors: Utsunomiya Toru , Shimada Mitsuo , Imura Satoru , Morine Yuji , Ikemoto Tetsuya , Arakawa Yusuke , Kanamoto Mami , Iwahashi Shuichi , Saito Yu , Ishikawa Daichi , Mikami Chie , Chengzhan Zhu , Tajima Atsusi , Imoto Issei 
Published: February 2017

249 Background: Percentage of patients with non-B non-C (NBNC) hepatocellular carcinoma (HCC) is rapidly increasing in Japan. We have previously shown that miRNA expression profiles in non-tumor liver tissues of patients with NBNC-HCC are different from those of patients with HBV-HCC and HCV-HCC. Moreover, we have recently reported that specific miRNA expression profiles in non-tumor liver tissues can predict a risk of multicentric recurrence after hepatectomy for HCC (Hepatol Res, 2013). In this study, we performed the genome-wide analysis of aberrant DNA methylation in non-tumor liver tissues of patients with NBNC-HCC. Methods: We divided the 23 patients, who underwent hepatectomy, into 3 groups; NBNC (HBcAb-, n=7), NBNC (HBcAb+, n=8), and normal control (NC, n=8). We analyzed DNA methylation status in fresh-frozen non-tumor liver tissues using Infinium Human Methylation 450 Bead Chip (illumina). Gene-expression levels of several identified genes were analyzed by quantitative RT-PCR to validate the correlation between DNA methylation status and gene-expressions. Results: We identified 87 differentially methylated genes in HBcAb- liver tissues, and 603 genes in HBcAb+ liver tissues in comparison to NC liver tissues (Beta value>0.2, P<0.05). Thirty CpG sites were commonly hyper- or hypo-methylated in both HBcAb- and HBcAb+ livers. High percentages of aberrant DNA methylation were observed in gene body. One hypermethylated gene (Lrig1, an intestinal stem cell marker that functions as a tumor suppressor) was confirmed to be down-regulated in its gene-expression level by quantitative RT-PCR. One hypomethylated gene (LEF1, a molecule enhancing hepatocarcinogenesis though Wnt/beta-catenin signaling) was also confirmed to be up-regulated. Ingenuity Pathway Analysisrevealed the association of Wnt/beta-catenin signaling with aberrant DNA methylation status. Conclusions: Genome-wide analysis of aberrant DNA methylation in non-tumor liver tissues may provide not only molecular mechanisms of epigenetic modulation during hepatocarcinogenesis but also early molecular diagnosis in patients with NBNC-HCC.
A single-arm phase II trial of gemcitabine, oxaliplatin, and panitumumab in KRAS wild-type advanced biliary tract cancer.
Authors: Noel Marcus Smith , Allen Jill N. , Abrams Thomas Adam , Yurgelun Matthew , Faris Jason Edward , Goyal Lipika , Clark Jeffrey W. , Blaszkowsky Lawrence Scott , Murphy Janet E. , Zheng Hui , Khorana Alok A. , Connolly Gregory Clayton , Hyrien Ollivier , Ng Kimmie , Borger Darrell R. , Iafrate Anthony John , Hezel Aram F. , Zhu Andrew X. 
Published: February 2017

255 Background: Biliary Tract Cancer (BTC) encompasses a group of aggressive, genetically heterogeneous tumors with limited systemic treatment options. Currently platinum and gemcitabine-based therapy is the standard first-line treatment. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRASwild-type genetic subtypes of colon cancer. Methods: Patients with histologically confirmed, previously untreated unresectable or metastatic KRAS wild type biliary tract or gallbladder adenocarcinoma with ECOG performance status (PS) 0-2 were eligible. Patients were treated with Panitumumab 6mg/kg, Gemcitabine (GEM) 1000 mg/m2 (10 mg/m2/min), Oxaliplatin (OX) 85 mg/m2on days 1 and 15 of each 28 day cycle. The primary objective was to determine the objective response rate (ORR) by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression free survival (PFS), and overall survival. Results: Of the 38 patients screened, 31 patients were found to have KRAS wild type genotype and enrolled. The median age was 61 years old, 55% males, 100% of patients had an ECOG PS of <1. Twenty-five patients had intrahepatic cholangiocarcinoma, and 3 each had extrahepatic and gall bladder carcinoma. Twenty-eight patients completed at least 2 cycles of therapy and were evaluable for response. The ORR was 50% (95% CI 23.8-76.2). With a median follow-up of 11 months, median PFS was 10.5 months (95% CI, 3.8 - 23.9 months) and median OS was 24.8 months (95% CI, 9.0 months-no upper bound). The most common grade 3 toxicities were fatigue 23%, anemia 23%, neuropathy 16%, elevated AST/ALT 16%, hyponatremia 13%, nausea 13%, rash 10%, neutropenia 7%, and hypomagnesemia 7%. Grade 4 toxicities included leukopenia 10%, and 1 case (3%) each of gallbladder perforation, hematoma, anemia, hyperkalemia, hyponatremia and hypokalemia. Conclusions: Completed analysis of this phase II study of GEMOX-panitumumab for KRAS wild type advanced BTC reveals encouraging results with promising response rates and PFS. The toxicity profiles were expected and manageable. Further investigation of this regimen and anti-EGFR therapy is warranted. Clinical trial information: NCT01308840.
FOLFOX and nab-paclitaxel (nab-P) for advanced pancreatic cancer: A phase I study.
Authors: Safran Howard , Charpentier Kevin , Perez Kimberly , Mantripragada Kalyan , Austin Trevor Clark , Nadeem Omar , Lombardo Alise , Houlihan Lindsay , Fontes-Borts Lucia , Kolberg Irene , Mitchell Kristen , Rosati Kayla 
Published: February 2017

258 Background: FOLFIRINOX improves survival in advanced pancreatic cancer, however the contribution of irinotecan is uncertain. The addition of irinotecan to gemcitabine was not superior to gemcitabine alone in pancreatic cancer, however nab-P demonstrates a survival benefit. This phase I study was designed to evaluate the maximum tolerated dose (MTD) of the addition of nab-P to fluorouracil, leucovorin, oxaliplatin (FOLFOX-A). Methods: Patients with metastatic or locally advanced pancreatic adenocarcinoma without prior treatment received oxaliplatin, 85 mg/m2, leucovorin 400 mg/m2 and 5-FU 2400 mg/m2 with 3 dose levels of nab-P (125, 150 and 175 mg/m2) every 2 weeks. Pegfilgrastim was required during the first 2 cycles. Dose limiting toxicities (DLTs) were defined in the first 2 cycles of treatment. Results: Fifteen patients were entered: Dose level 1 (n=6), dose level 2 (N=6), dose level 3 (N=3). The median age was 64 (35-81). Ten patients had metastatic and 5 had locally advanced disease. DLTs of nausea and fatigue occurred in 2 of 3 patients at dose level 3. Two patients developed grade 3 neuropathy after >= 10 cycles of treatment. One patient had grade 3/4 neutropenia. Eight of fifteen patients (53%) had a partial response. Conclusions: The MTD of nab-P is 150mg/m2 every 2 weeks with FOLFOX. Cumulative peripheral neuropathy, similar to other FOLFOX regimens, is the most significant toxicity generally occurring after >= 10 cycles of treatment. FOLFOX-A has substantial activity and may represent a promising regimen in pancreatic cancer. Patients are currently being accrued to an expansion phase utilizing dose level 2. Supported by the Davis and Browning families and LIFEcycle. Clinical trial information: NCT01744353.
Cost-effectiveness of metal stents in pancreatic cancer.
Authors: Montero Alberto J. , Meckley Lisa M. , Anene Ayanna M. , Bentley Tanya G.K. , Ortendahl Jesse D. , Martinez Jose M. 
Published: February 2017

260 Background: American Society for Gastrointestinal Endoscopy guidelines recommend endoscopic metal stent placement for pancreatic carcinoma patients with biliary obstruction and estimated life expectancy of >6 months. Because life expectancy of many such patients has until now been <6 months, plastic stents are frequently placed. Recent phase III trials demonstrated that compared with current standards of care, treatment with chemotherapy regimens FOLFIRINOX and gemcitabine/nab-paclitaxel significantly prolonged overall survival (OS) well beyond the 6-month range. Given this prolonged survival, we evaluated the cost effectiveness of initial metal versus plastic stent placement in pancreatic adenocarcinoma patients with biliary obstruction. Methods: A Markov cohort model was developed to project lifetime health-related outcomes, costs, quality-adjusted life years (QALYs), and cost effectiveness of metal compared with plastic stents. Patients entered the model with locally advanced cancer and underwent endoscopic retrograde cholangiopancreatography with metal or plastic stent placement. Patients were at risk of complications, stent migration or occlusion with subsequent stent placement, progression to metastatic cancer, and death. Published sources were used to estimate clinical, cost, utility, and event rate inputs, and results were presented from the 3rd party payer perspective in 2012 U.S. dollars/QALY. In sensitivity analyses, overall survival was varied from 6-24 months to assess the impact of uncertainty in estimates on model outcomes. Results: Patients with metal stents had lower costs and greater overall and quality-adjusted survival. Placement of metal stents saved approximately $1,500 per patient over a lifetime, improving OS by 0.07 months and quality-adjusted survival by 0.10 months. These findings were robust in sensitivity analyses varying the length of survival for patients with pancreatic cancer. Conclusions: This model demonstrates that placement of metal biliary stents at initial onset of obstructive jaundice in patients with stage III/IV pancreatic adenocarcinoma is cost saving and improves survival when compared with use of plastic stents.
Development and validation of a treatment decision model for optimal delivery of liver stereotactic body radiation therapy (SBRT): Photons versus protons.
Authors: Gandhi Saumil J , Liang Xing , Ding Xuanfeng , Zhu Timothy C , Ben-Josef Edgar , Plastaras John Peter , Metz James M. , Both Stefan , Apisarnthanarax Smith 
Published: February 2017

264 Background: Treatment of liver tumors with SBRT provides excellent local control rates, but is often limited by liver dose constraints. Protons offer potential for more liver sparing, but clinical situations where protons may be superior to photons are not well described. We developed and validated a treatment decision model to determine whether patients with liver tumors of certain sizes and locations are more suited for photon vs proton SBRT. Methods: Six spherical mock tumors from 1-6 cm in diameter were contoured on axial CT images of one patient at each of 4 locations (24 total tumors): peripheral/dome, caudal, left medial, central. We generated photon and proton plans (48 plans) to deliver 50 Gy* in 5 fractions with ~135% dose max within the gross tumor volume. Mean liver dose was constrained to < 14 Gy and at least 700 cc received < 15 Gy. Using these plans, we developed a hypothesis-generating model to predict the optimal modality for maximal liver sparing based on tumor size and location. We validated this model in 10 actual liver tumor patients by generating and comparing photon and proton plans. Results: Proton plans spared significantly more liver volume and decreased mean liver dose, particularly for tumors ≥ 3 cm in the dome or central locations− peripheral/dome: 134 ± 21 cc (p = 0.03), 912 cGy vs 1303 cGy (p = 0.01); central: 108 ± 4 cc (p < 0.01), 1179 cGy vs 1454 cGy (p < 0.01). Our model correctly predicted the optimal SBRT modality for all 10 patients. There was a significant increase in the volume of liver spared (176 ± 21 cc, p < 0.01) and decrease in mean liver dose (841 cGy vs 1223 cGy, p < 0.01) with protons for patients with dome or central tumors ≥ 3 cm. As predicted, in patients with tumors < 3 cm at any location or caudal and left medial tumors of any size, there was no significant difference in liver sparing between photon and proton SBRT (33 ± 18 cc, p = 0.13). Conclusions: Tumor size and location are important determining factors in generating deliverable liver SBRT plans. When feasible, protons should be considered as the radiation modality of choice for dome or central tumors ≥ 3 cm to allow maximal liver sparing and potentially reduce radiation toxicity. *All doses are in Gy (RBE).