bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes of endoscopic resection for early gastric cancer: Appropriate surveillance strategy based on the incidence and patterns of local, metachronous, and extragastric recurrence.
Authors: Kim Eun Ran , Kim Jae J. , Min Byung-Hoon , Min Yang Won , Lee Jun Haeng , Kim Jae Gyu , Rhee Poong-Lyul
Published: February 2017

2

Background: Endoscopic resection (ER) has been accepted as standard treatment of EGC. However, data about long-term outcomes especially related with recurrence have not yet been enough and appropriate surveillance strategy is not established. We evaluated the patterns and risk factors of recurrence, through evaluating the long-term outcomes of ER for treatment of EGCs comparing conventional and expanded indication criteria. Methods: We performed a retrospective review of prospectively and consecutively collected database of 1,855 EGCs in 1,803 patients [1,409 lesions in the conventional indication (CI) and 446 lesions in expanded indication (EI)] underwent ER for EGCs from April 2000 to June 2011. Results: Local recurrence was occurred from five tumors (0.35%) in the CI group and one tumor (0.22%) in the EI group. The median local recurrence interval was 13.5 months (range 2-34 months). 48 (3.1%) patients developed metachronous EGCs during follow up period. The median duration until metachronous recurrence was occurred, was 27.3 months (range, 12.25-115.29 months). There was not significantly different between metachronous group and non-metachronouos group except sex and histologic differentiation. Extragastric recurrence of tumor occurred from two patients in each of the CI and EI group. The extragastric recurrence interval was 62 months in the CI group and 48 months in the EI group. At that time, endoscopic examination showed no evidence of local recurrence around ESD scar area. Conclusions: The expanded indication of ER for EGCs showed acceptable long-term outcomes. More than 5 years of close follow up is needed and CT should be performed together with endoscopy for surveillance of recurrence after ER for EGC in the conventional indication group as well as the expanded indication group.
Genome-wide DNA methylation profiling of gastrointestinal neuroendocrine tumors to identify hypermethylation of mTOR, Wnt, and Notch pathways in GI NET pathogenesis.
Authors: Karpathakis Anna , Dibra Harpreet , Morris Tiffany , Oukrife Dahmane , Pipinikas Christodoulos P , Pearce Kerra , Francis Joshua , Pericleous Marinos , Mandair Dalvinder , Feber Andrew , Toumpanakis Christos , Luong Tu Vinh , Meyerson Matthew , Caplin Martyn E , Beck Stephan , Thirlwell Christina
Published: February 2017

212

Background: Aberrant DNA methylation is known to play an important role in the pathogenesis of many human cancers, however little is known about its role in gastrointestinal neuroendocrine tumours (GI NET) development. We report the first unbiased genome-wide DNA methylation analysis of a large cohort of GI NETs, aiming to identify key methylation variable positions (MVPs) specific to GI NETs which may contribute to tumorigenesis and metastatic progression. Methods: Illumina Infinium Human Methylation 450 Array analysis was performed on 56 cases of GI NET DNA extracted from macrodissected tumour (n=67) and normal (n=29) specimens. Tumours were gastrointestinal primaries (n=39) or metastases (liver, mesenteric, omental or lymph node, n=28) of low (n=35), intermediate (n=17) or high grade (n=3)(unknown grade n=12). Data analysis was performed using the "ChAMP" custom pipeline and pathway analyses were performed using "GREAT," "WebGestalt," and "GSEA" web tools. A Bonferroni adjusted significance threshold value of p<0.05 was used throughout. Results: In order to identify and validate a GI NET specific methylation signature our cohort was divided into a discovery set (31 cases) and validation set (25 cases). Comparison of primary GI NET tumours with normal small bowel identified a total of 77,916 MVPs, including 1,666 sites hypermethylated by over 30% in tumour compared to normal tissue. Application of the profile to the validation set correctly identified 85% of samples. Tumours demonstrated global hypomethylation relative to normal tissue. Gene ontology analysis identified methylation of multiple cancer related pathways (including the Wnt, mTOR and Notch pathways) as a feature of hepatic metastases of GI NET primaries. Increasing RASSF1 promoter hypermethylation was associated with higher tumour grade. Conclusions: This study is the first comprehensive analysis of the epigenetic profile of GI NETs and identifies potential novel biomarkers and therapeutic targets. We are currently performing integrated analysis of epigenomic, genomic and transcriptomic data to further define the pathways involved in GI NET pathogenesis.
Profiling of a global cohort of 1,250 neuroendocrine tumors to identify multiple potential drug targets.
Authors: Astsaturov Igor A. , Cohen Steven J. , Engstrom Paul F. , Gatalica Zoran , Bender Ryan P. , Basu Gargi Dan , Millis Sherri Z.
Published: February 2017

214

Background: Identification of new drug targets may extend treatment options for NET, regardless of histologic classification or primary organ site. Methods: 1,250 cases of infradiaphragmatic neuroendocrine tumors (all grades and sites) were identified among >50,000 cases profiled in a CLIA certified laboratory. Biomarker profiling utilized multiple platforms: gene sequencing (next generation sequencing, Sanger or pyrosequencing), gene copy number by in-situ hybridization, and protein expression by immunohistochemistry. The results are shown relative to the total number of tests performed. Results: Overall, drug therapy-relevant alterations were identified in 1,130 of 1,250 (90%) of cases. Low or absent (0 or 1+ by IHC) MGMT, a biomarker of sensitivity to alkylating agents, was found in 130/219 pancreatic cases (59%), and in 450/991 (45%) of non-pancreatic NET. Low or absent (0 or 1+ by IHC) expression of RRM1, a biomarker of gemcitabine sensitivity, was found in 813/1,100 of NET (74%) and low or absent thymidine synthase, TS, a biomarker of fluoropyrimidine sensitivity, was shown for 793/1,096 (72%) of NET by IHC. Sequencing of tumors showed oncogenic mutations in BRAF (4/369 (V600E in 3 and G596R in 1), CTNNB1 (2/150), KIT (3/281), EGFR (1/178), FGFR2 (1/150), GNAS (1/150), HRAS (2/150), PIK3CA (6/343), RB (2/150) VHL (1/150), KRAS (10/125), NRAS (2/274), and APC (2/150) and amplifications of EGFR (46/686) and MET (4/236). Ki67 status and correlation between the site of origin and biomarkers will be presented. Therapies guided by mechanism-based biomarkers produced durable responses in documented cases: partial response (PR) >1 year to imatinib in a patient with KIT-mutant metastatic NET, and in cases of MGMTlow/TSlowtreated with streptozocine or temizolomide plus fluoropyrimidine chemotherapy, thus supporting the clinical relevance of target profiling in NET. Conclusions: Comprehensive multiplatform profiling of a large series (n=1,250) of NET, despite low frequency of individual biomarkers, identified clinically relevant targets in the majority of patients. Our results provide the basis for future clinical trials to assess the efficacy of biomarker-based therapy for NET.
Clinical deployment of automatic treatment planning for pancreas SBRT patients.
Authors: Moore Joseph A. , Yang Wuyang , Evans Kim , Dholakia Avani Satish , Koong Albert , Chang Daniel Tandel , Goodman Karyn A. , Herman Joseph M. , McNutt Todd R.
Published: February 2017

219

Background: To clinically utilize an SQL relational database of prior treated patients to generate objectives for future treatment plans. A database approach allows for more rapid planning by starting with a better initial solution and improves safety by providing good known achievable dose values for the initial optimization. The use of a database allows for trending of dose, structure and toxicity data. Methods: A database of fifty-three patients from three institutions is populated with dose and structure data via an automatic script within the treatment planning system. For each new patient, overlap volume histograms (OVHs) are generated to describe the relationship between targets and critical structures. To aid in database consistency, a renaming interface is used which maps known alternative structure names to common names in the database. To ensure all required structures are present, the user is prompted with the names of missing structures. This interface allows selection of machine, energy and commonly used beam sets. The database is queried for all prior patients with the same or closer relationship between the target and each critical structure. The dose objectives reported are the lowest achievable dose from all patients as difficult or harder to plan as determined by OVH. Queried dose objectives are automatically loaded into the treatment planning system and optimized. A protocol quality tool is developed to quickly assess how well plans adhere to specified protocols. Results: Twenty-seven SBRT patients have been planned and clinically approved using the automatic planning tool and future patients continue to be added to the database. OVH computation required approximately 2 minutes, while typical plan optimization required 2.5 minutes. If auto-planned patients require even one fewer optimization to achieve an acceptable plan, total planning time is reduced. Safety is improved by reducing the number of protocol violations from 35% to 6% for one objective. Conclusions: Automatic treatment planning allows for rapid planning while reducing normal tissue dose to known achievable values. The continued addition of patients to the database allows for improvement of the automatically selected planning objectives.
Analysis of prognostic factors in locally advanced and metastatic pancreatic cancer treated with gemcitabine or gemcitabine and S-1 chemotherapy using individual patient data from three randomized studies.
Authors: Nakai Yousuke , Okusaka Takuji , Ikari Takaaki , Isayama Hiroyuki , Furuse Junji , Ishii Hiroshi , Imai Shogo , Okamura Shota , Hamada Chikuma
Published: February 2017

223

Background: Both gemcitabine (GEM) and S-1, an oral fluoropyrimidine, are shown efficacy for advanced and resected pancreatic cancer (PC). However PC has one of the poorest outcomes in various cancers. In this pooled analysis, the prognostic factors in locally advanced and metastatic PC were evaluated using individual patient data from three randomized studies (Phase III: GEST, randomized phase II: JACCRO PC-01 and GEMSAP). Methods: Patients (pts) were treated with GEM alone or GEM and S-1 (GS) chemotherapy for advanced PC. Evaluated prognostic factors were standard laboratory data, tumor marker (CA19-9, CEA), clinical and pathological indices and treatment related outcomes e.g. efficacy and safety. To identify the optimal cutoff value to divide continuous data into binomial data, maximized log likelihood value for the model were evaluated and the validity of the model was evaluated by the martingale residuals. The Cox proportional hazards model was performed for overall survival. Results: 770 pts were included in this analysis (389 pts were treated by GEM and 381 pts were GS) and 738 events for survival were observed (95.8%). In continuous data, baseline WBC, AST, CA19-9 and CRP were detected as independent prognostic factors and the cutoff values were identified. The results of multivariate analysis and cutoff value were shown in the table. Conclusions: In our analysis, treatment, extent of disease, target lesion, WBC, AST, CA19-9 and CRP were detected as independent prognostic factors and cutoff values were estimated in continuous data. The further examination is necessary, but these data may help future studies. [Table: see text]
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

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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

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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

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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).
Efficacy of octreotide LAR (OCT) in patients (pts) with advanced neuroendocrine tumors (NET): A post hoc analysis of the placebo (PBO) arm of the phase III RADIANT-2 study with updated survival data.
Authors: Strosberg Jonathan R. , Yao James C. , Bajetta Emilio , Aout Mounir , Bakker Bert , Hainsworth John D. , Ruszniewski Philippe B. , Van Cutsem Eric , Oberg Kjell E. , Pavel Marianne E.
Published: February 2017

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Background: In pts with metastatic midgut NET, OCT showed antitumor activity and significantly extended time to tumor progression (TTP) vs PBO (PROMID trial, Rinke et al. 2009). We present a post hoc analysis assessing efficacy of OCT (30 mg q28d) in the PBO+ OCT arm of the phase III RADIANT-2 study. Methods: For this post hoc analysis, progression-free survival (PFS by central review, cutoff Apr 2, 2010) and overall survival (OS, cutoff Jun 13, 2013) in the PBO + OCT arm were estimated by prior somatostatin analogue (SSA) use and primary tumor location subgroups using the Kaplan-Meier (KM) method. Results: 213 pts were randomized to PBO + OCT (median age, 60 yrs; male, 58%; WHO PS: 0/1/2 in 66%/29%/5% pts; >80% had well-differentiated disease). Of these, 47 (22%) were SSA naïve (foregut, 32%; midgut, 51%; hindgut, 4%; not classified or missing, 13%) and 166 (78%) had received SSA (foregut, 10%; midgut, 72%; hindgut, 11%; not classified or missing, 7%) prior to study entry. Median PFS (95% CI) for pts who were SSA naïve vs who had received SSA was 13.6 (8.2-22.7) mos vs 11.1 (8.4-14.2) mos. By primary tumor location, median PFS (95% CI) in SSA naïve pts vs who received SSA was 5.7 (2.8-27.8) mos vs 8.7 (2.8-13.9) mos for foregut, 22.2 (8.3-29.5) mos vs 12.0 (8.4-17.7) mos for midgut, and not-reached (NR; 4.7-NR) vs 6.6 (3.0-13.0) mos for hindgut. OS analysis is in table. Conclusions: This post hoc analysis of the PBO + OCT arm of the RADIANT-2 study showed a PFS of 13.6 mos in SSA naïve pts treated with OCT. While the RADIANT-2 study PBO arm differs from PROMID in patient population and method of assessment of tumor progression, the data from this post hoc analysis provide additional evidence of the antiproliferative effect of OCT in NET. Clinical trial information: NCT00412061. [Table: see text]
Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in advanced pancreatic cancer patients.
Authors: Shinohara Akira , Okuyama Hiroyuki , Kuwahara Akiko , Kobayashi Misaki , Takahashi Hideaki , Ohno Izumi , Shimizu Satoshi , Mitsunaga Shuichi , Saitoh Shinichiro , Ikeda Masafumi
Published: February 2017

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Background: Erlotinib has been reported to be associated with a high incidence of skin toxicities, such as acneiform rash, paronychia and xerosis. The aim of this study was to evaluate the efficacy of prophylactic minocycline treatment for the skin toxicities induced by erlotinib, as compared to deferred minocycline treatment. Methods: The study subjects were patients with advanced pancreatic cancer receiving treatment with erlotinib plus gemcitabine. In the prophylactic minocycline group, oral minocycline was administered at the dose of 200 mg/daily during the chemotherapy prior to the emergence of any skin toxicities, while in the deferred minocycline group, oral minocycline treatment at 200mg/daily was initiated after the emergence of grade 2-3 of skin toxicities. In both groups, heparinoids were administered during the chemotherapy and topical steroid therapy was initiated after the emergence of the skin toxicities. Results: A total of 96 patients were enrolled, of which 44 received prophylactic minocycline treatment and 52 received deferred minocycline treatment. The incidence rate of acneiform rash and xerosis of any grade during the first 6 weeks of chemotherapy was significantly reduced in the prophylactic minocycline treatment group as compared with that in the deferred minocycline treatment group (47.7% vs. 80.8%; p<0.001; 2.3% vs. 19.2%; p=0.01); on the other hand, no significant difference in the incidence rate of paronychia of any grade was observed between the two groups. Univariate and multivariate analyses identified prophylactic minocycline treatment and female gender as significant independent factors associated with the incidence of acneiform rash of any grade (odds ratio [OR], 0.20; 95%CI, 0.08 to 0.49; p<0.001; OR, 0.30; 95% CI, 0.11 to 0.87; p=0.03). Conclusions: Prophylactic minocycline treatment significantly reduced the incidence of acneiform rash and xerosis, but not that of paronychia, induced by erlotinib in advanced pancreatic cancer patients. Prophylactic minocycline treatment is recommended for the management of erlotinib-related acneiform rash and xerosis.
Cost-effectiveness of routine laparoscopic ultrasound for the assessment of resectability of gallbladder cancer.
Authors: Jayakrishnan Thejus T. , Nadeem Hasan , Groeschl Ryan Thomas , Zacharias Anthony J , Gamblin T. Clark , Turaga Kiran
Published: February 2017

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Background: In addition to a diagnostic laparoscopy (DL), aroutine laparoscopic ultrasound (LUS) has been proposed to identify undetected hepatic metastases and/or anatomically advanced disease in patients with T2 or higher gall bladder cancer (GBC) planned for surgical resection. It was hypothesized that a routine LUS is not a cost-effective strategy for these patients. Methods: Decision tree modeling was undertaken to compare DL-LUS vs. DL at the time of definitive resection of GBC (with no prior cholecystectomy). Costs in US dollars (payers’ perspective), quality-adjusted-life-weeks (QALWs) and incremental-cost-effectiveness-ratios (ICER) were calculated (horizon: 6 weeks, willingness-to-pay: $1,000/QALW or $50,000/ QALY). Results: DL-LUS was cost effective at the base case scenario (costs: $30,838 for DL vs. $30,791 for DL-LUS and effectiveness 3.81 QALWs DL vs. 3.82 QALW DL-LUS, resulting in a cost reduction of $9,220 per quality adjusted life week gained (or $479,469 per QALY). DL-LUS became less cost effective as the cost of ultrasound increased (threshold: $163.18) or the probability of exclusion from resection decreased (threshold 0.29) (Table represents the results of univariate analyses). Conclusions: Routine LUS with diagnostic laparoscopy for the assessment of resectability and exclusion of metastases is cost effective for patients with GBC. Until improvements in pre-operative imaging occur to decrease the probability of exclusion, this appears to be a feasible strategy. [Table: see text]
Association between preoperative neutrophil-lymphocyte ratio (NLR) and clinical outcomes in patients with gastric cancer.
Authors: Suzuki Akihiro , Takano Ryotaro , Takahashi Osamu , Taketa Takashi , Shimodaira Yuhsuke , Sudo Kazuki , Shiozaki Hironori , Ohigashi Seiji , Onodera Hisashi
Published: February 2017

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Background: The neutrophil-lymphocyte ratio (NLR) is related to inflammatory status of patients with some cancers. We hypothesize that preoperative NLR is associated with clinical outcomes in patients with gastric adenocarcinoma. Methods: We identified 458 gastric cancer patients who had curative gastrectomy at our institute between 2000 and 2009. All patients had baseline staging including blood test, CT scan and an endoscopic biopsy. Multiple statistical methods were used to analyze clinical outcomes. Results: Most patients were men and most had stage I. The median follow-up time was 74.8 months (95% C.I; 69.5-80.2). The estimated overall survival (OS) and recurrence-free survival (RFS) rate at 5 years were 76.1 +/- 2.1% and 78.6 +/- 2.2%, respectively. We divided 2 groups by NLR that cut off point was 4. In the stage I patients, the median OS and RFS of high and low NLR patients were not different (p=0.63, p=0.92, respectively). However, in stage II, III and IV patients, RFS of those were significantly different (p=0.027). In multivariate analyses, age (p<0.001) and baseline stage (p<0.001) was an independent prognosis factor for OS, and high NLR (p=0.005) and baseline stage (p<0.001) was an independent risk factor for RFS. High NLR had tendency to be associated with poor OS (p=0.069) in multivariate analysis. Conclusions: A high preoperative NLR may be a useful biomarker to predict a poor prognosis patient with gastric cancer before surgery.
Gastric cancer (GC) in California Cancer Registry (CCR): One disease, many faces.
Authors: Barzi Afsaneh , Stern Mariana C. , Zhang Juanjuan , Lenz Heinz-Josef , Iqbal Syma , Liu Lihua
Published: February 2017

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Background: In the US there are approximately 21,000 newly diagnosed GCs with California having the highest number of reported cases per year. Given the disparity in the incidence of the disease among Asians and Hispanics we conducted an analysis of GCs in the CCR to assess the differences in the presentation and outcome of the reported cases from 2000 to 2010. Methods: We identified 26,645 GCs inclusive of Asian, Hispanic, and non-Hispanic whites (NHW); 20% of our population is Asian and 30% of is Hispanic. We examined the tumor characteristics (demographics, stage, anatomical subsite), age adjusted incidence rates (AAIR), and survival among Asian and Hispanic patients as compared to NHW. Results: AAIR per 100,000 individuals is 5.87 (95% CI: 5.77-5.97) for NHW, 11.74 (95% CI: 11.46-12.02) for Hispanics and 13.31 (95% CI: 12.96-13.66) for Asians. Among Asians, Koreans have the highest rate and lowest median age of presentation (67ys). In the patients with known stage of the disease (82%) most patients present with stage IV (38%) with no differences in the stage of presentation among different racial/ethnic groups. The male/female (M/F) ratio is different among different racial/ethnic groups. M/F among NHWs is 2.2, followed by 1.8 in Hispanics, and 1.6 in Asians. Among NHW proximal GC (cardia and fundus) is the most common site of presentation (44%), whereas in Asians and Hispanics proximal GC are reported in 14% and 18% respectively. Hazard ratios from Cox regression models adjusted for age, gender, socioeconomic status, nativity, stage, anatomical subsite, and type of treatment received, showed that being of Mexican origin is associated with greater risk of cancer death compared to being NHW (HR = 1.3; 95% CI = 1.2-1.4; p<0.001). In contrast Koreans have better survival than NHW (HR = 0.9; 95% CI = 0.8-0.9; p=0.003). Prognostic factors for death from gastric cancer included age > 65 and immigration status, with immigrants doing better than US born. Conclusions: The observed disparity in the incidence, presentation, and outcome of GC in CCR suggests possible different etiologies that may have implications for the diagnosis and treatment of GC and deserve further exploration.
Benefit of chemotherapy (ctx) in elderly patients (pts) with advanced pancreatic adenocarcinoma (PC): A population-based analysis.
Authors: Teo MinYuen , Deady Sandra , Sharp Linda , McDermott Raymond S.
Published: February 2017

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Background: Benefit of ctx in elderly PC is unclear as they are under-represented in trials and most reports are retrospective series from academic centres. This population based study sought to examine the role of ctx in the elderly PC. Methods: Pts with diagnosis of PC between 1998 and 2010 inclusive who did not receive radical resection were identified from National Cancer Registry of Ireland database. Pts were divided into two age groups: ≥70 vs <70, and stratified based on metastatic status: M0 vs M1. Median overall survival (OS) was estimated with Kaplan-Meier method and hazard ratios (HR) with Cox regressional analysis. Results: A total of 4,509 pts were identified, of whom 2,875 (64%) were ≥70 yrs. For the entire group, 16% were staged M0, 42% were staged M1 and 42% didn't have documented staging (Mx). 16% received ctx, 5% chemoradiotherapy (crt) and 79% no cancer directed therapies. More pts ≥70 were Mx compared to <70 (48% vs 30%, p<.01); Mx pts were less likely to receive treatment than M0/M1 (88% vs 73% vs 73%, p<.01). Pts ≥70 were also less likely to receive any treatment (p<.01) (Table). Comparing the ≥70 and <70 groups, median OS (in months) for M0 who received ctx were 6.0 vs 7.3 (HR 1.28 [95% confidence interval 0.85-1.89], p=.24); received crt were 7.0 vs 9.7 (HR 0.95 [0.42-1.88] p=.89) and no treatment were 3.0 vs 3.5 (HR 1.03 [0.84-1.29] p=.75); median OS for M1 who received ctx were 2.4 vs 3.4 (HR 1.21 [0.97-1.49] p=.09), crt were 4.3 vs 6.0 (HR 1.69 [0.89-3.03] p = .11) and none were 1.2 vs 1.4 (HR 1.11 [1.00 – 1.24] p=.06). Regardless of age or M stage, cxt and crt conferred superior OS as compared to no treatment (Table). Conclusions: We observed a disparity in diagnostics and delivery of treatment to older pts with PC. Pts ≥70 who were treated benefited similarly to younger pts. Such therapeutic nihilism should be addressed in a systematic fashion. [Table: see text]