bluuebunny/crossref_metadata_2025_split huggingface dataset:
What studies are appropriate and necessary for staging gastric cancer? Results of a RAND/UCLA expert panel.
Authors: Dixon Matthew , Cardoso Roberta , Tinmouth Jill , Helyer Lucy K. , Law Calvin , Swallow Carol Jane , Paszat Lawrence Frank , McLeod Robin S. , Seevaratnam Rajini , Mahar Alyson L. , Coburn Natalie G. 
Published: February 2017

15 Background: The approach for staging gastric cancer (GC) patients has not been well defined, resulting in widespread heterogeneity in the application of pre-operative staging modalities. Methods: A multi-disciplinary expert panel of 16 physicians from 6 countries scored 84 scenarios using the RAND/UCLA Appropriateness Methodology. Appropriateness was scored from 1 (highly inappropriate) to 9 (highly appropriate). Median appropriateness scores (AS) from 1-3 were considered inappropriate, 4-6 uncertain, and 7-9, appropriate. Agreement was reached when 11 of 16 panelists scored the scenario similarly. If a scenario was agreed to be appropriate, it was given a necessity score (NS) in the same manner. AS and NS are reported if agreed upon. Results: TNM staging should be determined pre-operatively (AS 7.0-9.0; NS 7.0-9.0). Pre-operative radiological assessment should include a computed tomography (CT)−abdomen, CT−pelvis, and should be performed with a multi−detector CT scanner with 5 mm slices (AS 8.0−9.0; NS 7.0−9.0). A CT Chest may be performed (AS 7.5). The utility of a chest radiograph was indeterminate. All patients should have a pre-operative esophagogastroduodenoscopy (EGD). The endoscopist should biopsy the tumor; document its size, description, location, distance from the GE junction, and any GE junction, esophageal or duodenal involvement. If the EGD report is unclear, the surgeon should repeat it to confirm tumor location (AS 7.5-9.0, NS 7.0−9.0). Endoscopic ultrasound is appropriate prior to endoscopic resection, but not surgical resection (AS 9.0). Diagnostic laparoscopy (DL) should be performed prior to resection of cT3,4 lesions, or multi−visceral resections. DL should include visual inspection of the stomach, diaphragm, liver, and ovaries (AS 8.0−9.0, NS 7.0−9.0). Conclusions: The Gastric Cancer Processes of Care expert panel has made recommendations regarding pre−operative staging modalities in an effort to standardize work up. Standardization could lead to more accurate staging and allocation towards optimal stage−specific treatments.
Low 18f-fluorodeoxyglucose uptake on positron emission tomography as a prognostic factor for stage I and II pancreatic cancer.
Authors: Pimiento Jose Mario , Boutrid Hinda , Weber Jill M. , Razzaque Saqib , Farma Jeffrey M. , Kim Richard D. , Hodul Pamela Joy , Shridhar Ravi , Hoffe Sarah E. , Almhanna Khaldoun , Chuong Michael D. , Chen Dung-Tsa , Springett Gregory M. , Eikman Edward , Klapman Jason , Jong Park , Karl Richard C. , Malafa Mokenge Peter 
Published: February 2017

159 Background: Metabolic activity as defined by the uptake of 18F-fluorodeoxyglucose (FDG) on Positron Emission Tomography (PET) has proven beneficial as a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early pancreatic cancer. Methods: Using a comprehensive pancreatic adenocarcinoma database, we identified patients with early stage pancreatic cancer (I-II) who underwent pancreatectomy for cancer and had PET scan performed as part of their preoperative evaluation from 2004 to 2010. Patients were divided by the median primary tumor standard uptake value (SUVmax) into two groups: high and low FDG uptake. The primary outcomes were overall survival (OS) and disease free survival (DFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using Fisher's exact and chi-square. Results: We identified 105 patients with resected stage I and II pancreatic cancer who had PET scans as part of their preoperative evaluation. 51 patients had low FDG uptake while 54 patients had high FDG uptake. The median age at diagnosis was 69 (24-89) years, 57% of the patients were male. 84 (81%) patients had PET avid tumors, while 20 (19%) patients did not. The median SUVmax was 5.1. High FDG uptake correlated with pathologic stage (p=0.012). Median follow-up was 12.3 (0-56) months. Patients with low FDG uptake had a significantly better median OS than patients with high FDG uptake (27 vs. 16 months; p=0.036). Recurrence occurred in 64 (60%) patients. Patients with low FDG uptake had significantly longer median DFS than patients with high FDG uptake (14 vs. 12 months; p=0.049). Conclusions: Low 18F-fluorodeoxyglucose uptake in PET scans for stage I and II pancreatic cancer correlates with improved overall survival and disease free survival. This observation supports the concept that glucose metabolic pathways are important in pancreatic cancer biology, and that PET scan activity can be used as a prognostic biomarker after pancreatectomy for pancreatic cancer.
Utilization of hepatocellular carcinoma surveillance in the United States.
Authors: Harris Samar , Yopp Adam C. , Tiro Jasmin A , Beg Muhammad Shaalan , Skinner Celette Sugg , Lee William M , Singal Amit G 
Published: February 2017

174 Background: Surveillance for hepatocellular carcinoma is recommended in high-risk patients, but several studies have suggested it is being underutilized.The aim of this study is to quantify utilization rates for HCC surveillance among patients with cirrhosis and summarize patterns of association between utilization rates and patient and clinic characteristics. Methods: A systematic literature review using the Medline database and national meeting abstracts identified all cohort studies that described HCC surveillance rates among at-risk patients in the United States. Two investigators independently extracted data on patient populations, study methods, and results. A pooled surveillance rate with 95% confidence intervals was calculated. Pre-specified subgroup analysis was performed to find correlates of surveillance utilization. Results: We identified 9 studies that met all inclusion criteria. There were a variety of definitions for surveillance among the studies, with only 4 assessing surveillance every 6-12 months as recommended by the AASLD guidelines. The pooled surveillance rate was 18.4% (95% CI 17.8% - 19.0%). Surveillance rates were significantly higher among patients followed in gastroenterology clinics compared to those followed in primary care clinics (51.7% vs. 16.9%, p< 0.001). Elderly, non-Caucasians, and people of low socioeconomic status had lower surveillance rates than their counterparts. Current studies fail to identify specific reasons for the underutilization of HCC surveillance. Conclusions: Utilization rates for HCC surveillance are low, although they are significantly higher among patients followed in subspecialty clinics. Appropriate intervention targets to increase surveillance rates and reduce socio-demographic disparities have not been identified to date, and this should be a primary goal for future studies.
Value of preoperative biopsy and radiological assessment for the diagnosis of mixed hepatocellular cholangiocarcinoma (HCC-CC).
Authors: Bouattour Mohamed , Wassermann Johanna , Guedj Nathalie , Paradis Valerie , Dreyer Chantal , Castera Laurent , Vilgrain Valérie , Faivre Sandrine J. , Raymond Eric 
Published: February 2017

176 Background: Mixed tumors with hepatocellular and cholangiocarcinoma component (HCC-CC) are rare variants of primary liver tumors. In this study, we aimed to describe clinical, radiological and histopathological features of patients with resected HCC-CC. Methods: From 2000 to 2010, patients (pts) with diagnosis of mixed HCC-CC based on surgical specimen were identified from our database. Demographic, clinical, radiological and pathological data were analyzed retrospectively, along with outcome after resection. Results: Among 18 pts, 6 men (33%) and 12 women (67%) were identified. The median age was 64 years (range 38- 75). Nine pts (50%) had at least one risk factor for chronic liver disease including alcohol consumption (6), NASH (3) and HBV infection (2). Twelve (67%) and 6 pts (33%) underwent major and minor hepatic resections respectively. The positive predictive value of radiological and pathological diagnosis was reviewed. Imaging by CT scan and/or MRI suggested characteristics of HCC and CC in 5 and 6 pts respectively. In 3 pts imaging showed combined features of HCC and CC while it was atypical in 4 cases. Preoperative biopsy was performed in 10 pts and analyzed using only morphological features. Biopsy sample was non contributive in 2 cases and concluded to CC, HCC and mixed HCC-CC in 5, 2 and 1 cases respectively. This contrasted with examination of resection specimen showing evidence of HCC combined with CC phenotype. Immunostaining on resection specimens showed the presence of differentiation markers for both hepatocytes and biliairy cancer cells (CK7 +, CK19 +, anti-hepatocyte +, and glypican +). Non tumor liver analysis showed normal underlying liver, non extensive fibrosis ≤ F2, extensive fibrosis > F2 without cirrhosis and cirrhosis in 2, 3, 7 and 6 specimens respectively. With more than 6 months follow-up (range 6 -59 months) the recurrence rate was higher than 50%. Conclusions: Mixed HCC-CC are not accurately identified by preoperative biopsy using only morphological features and CT scan/MRI assessment. Following resection, mixed HCC-CC behave more like CC than HCC.
Relationship of STAT3-mediated treatment resistance on activated MAPK signaling in pancreatic cancer.
Authors: Nagathihalli Nagaraj S. , Beesetty Yugandhar , Shi Chanjuan , Merchant Nipun B. 
Published: February 2017

181 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult human malignancies to treat due to its intrinsic (de novo) and extrinsic (acquired) chemoresistance. We have previously identified constitutively activated STAT3 as a mediator of treatment resistance. Src or EGFR activate STAT3 and promote STAT3 mediated tumor progression and mediate communication within the tumor microenvironment (TME). The purpose of this study was to further understand the molecular mechanisms of stromal-mediated chemoresistance in PDAC to generate new and promising targeted therapies. Methods: We characterized the expression of total and activated STAT3 and MAPK proteins in human pancreatic tissues (n=106), PDAC cell lines (n=9) and in PanIn lesions, primary PDAC and liver metastasis cell lines generated from tumors established in genetically engineered mice. Effects of STAT3 and MAPK inhibition (drug or siRNA) were assessed for phosphorylation of STAT3, Src, MAPK, EGFR and GSK3β and expression of cyclin-D1, SPARC, VEGF, fibronectin, CD31 and tumorigenicity in vitro and in vivo. Results: STAT3 activation is necessary for the malignant phenotype and affects survival in PDAC. In both human and mouse PDAC cell lines and tissues, there is an inverse correlation between activation of STAT3 on MAPK and GSK3β signaling. Inhibition of STAT3 reciprocally activated MAPK, GSK3β, Src and EGFR which led to subsequent reactivation of STAT3. Targeting both STAT3 and MAPK inhibited activation of STAT3, MAPK, GSK3β, Src, EGFR and cyclin-D1. Combined inhibition of STAT3 and MAPK overcame STAT3 mediated resistance and resulted in synergistic inhibition of tumorigenicity as well as inhibition of the tumor stroma, angiogenesis and hypoxia within the TME. Conclusions: The mechanism of STAT3-mediated treatment resistance is dependent on activation of MAPK signaling which in turn leads to reactivation of multiple oncogenic signaling pathways. Combined inhibition of STAT3 and MAPK overcomes therapeutic resistance, targets the TME and reduces tumorigenicity in PDAC. Targeting STAT3 and MAPK is a potent treatment regimen and may be a novel approach to enhance drug delivery and improve therapeutic response in PDAC.
Prevalence of risk factors among patients with hepatocellular carcinoma (HCC) and the general population in an employer group database.
Authors: Doan QuynhChau Diem , Beiderbeck Annette , Qian Qingshan 
Published: February 2017

190 Background: Most US studies evaluating risk factors for HCC have used data from hospitals, cancer registries, or Veterans Affairs database. These data sources have small patient populations and limited generalizability. Methods: This study investigated the association between HCC and potential risk factors [hepatitis B and C virus (HBV, HCV), diabetes, alcoholism, cirrhosis, obesity, liver disease, dyslipidemia, hemochromatosis, and hypothyroidism] and compared to the general (non-HCC) population of ~60 million lives from an employer group database. A retrospective cohort analysis was conducted using the Marketscan Research Database from Thomason Reuters. Case patients had an ICD-9 diagnosis for HCC between 1/1/2001 – 12/31/2009 (index date) but no HCC diagnosis during 1-year prior to index date. Randomly selected control patients did not have HCC diagnosis, were matched 3:1 ratio and enrolled during same time period as matched case patients, and matched for age (+/− 1 year), gender, and geographical region. All patients were 18 - 65 years old and did not have any cancer diagnosis (except HCC for case patients). Data from 1-year prior to index date were used to identify risk factors. Demographic variables and prevalence of risk factors were analyzed using descriptive statistics. Multiple logistic regression was used to predict the odds of developing HCC compared to non-HCC patients for these risk factors. Results: The study included 1,208 case and 3,624 control patients. Mean age of cases and controls was 54 years and 67% were male. In unadjusted multiple logistic regression models, the risk for HCC was 48-fold and 135-fold increased for patients with HBV and HCV, respectively [95% confidence interval (CI): 6.2 – 374.4 for HBV, 31.5 – 580.8 for HCV]. Diabetes increased the risk for HCC by 3.85 (95% CI 2.5 – 5.9). Alcoholic cirrhosis and nonalcoholic (NA) fatty liver disease/NA steatohepatitis increased the risk for HCC by nearly 200-fold. Conclusions: Using a larger database, these study findings were consistent with previous research and provided further evidence that the risk of HCC is greatly increased in individuals diagnosed with hepatitis, diabetes, liver disease, and alcoholism.
Spanish registry and screening program for families at high risk of pancreatic adenocarcinoma.
Authors: Guillen-Ponce Carmen , Mocci Evelina , Marquez Mirari , Earl Julie , Guerrero Carmen T , Salazar Maria Teresa , Calcedo Maria Celia , Real Francisco X , Malats Nuria , Carrato Alfredo 
Published: February 2017

192 Background: 5-10% of pancreatic cancer (PC) cases show familial aggregation. 20% of these correspond to syndromes: Peutz Jeghers, hereditary pancreatitis, familial multiple melanoma, breast and ovarian cancer (HBOC) and others. Familial pancreatic cancer (FPC) is defined as: ≥2 first degree relatives with PC and with no other known syndromes. FPC seems to have autosomal dominant inheritance, but the genetic cause is unknown. Methods: The objectives are: 1) To develop the first FPC Spanish Registry, connecting different groups interested in this disease 2) To study inheritance, phenotypic and molecular characteristics of the FPC, and families with early PC 3) To establish a strategy for early detection of PC in high-risk individuals and to implement it 4) To characterize preneoplastic lesions and diagnosed PC by monitoring high-risk individuals. 16 Spanish hospitals are participating. This study has two components: 1) Cohort to identify families with FPC and hereditary PC. Sources for the families are the PanGen-ES Study, a case-control study of PC which identifies families through a questionnaire on family history of cancer, and Genetic Counseling Units, 2) Cohort of high-risk families. The latter will be followed up by endoscopic ultrasound (EUS) and CT ± abdominal magnetic resonance imaging. In addition, circulating tumor cells (CTC) in peripheral blood will be determined. Results: The assessment of family history of the 421 cases included in the PanGen Study has identified 32 (7.6%) families with FPC and 52 patients with PC ≤ 50 years (12.4%). In addition, the 190 families presenting PC aggregation with other neoplasms are being further evaluated. At this time we have obtained clinical data and blood samples to carry out molecular studies of 23 individuals: 17 belonging to 3 families with FPC, and 6 members of 2 families with an HBOC with some cases of pancreatic cancer. 18 relatives at risk began a follow-up with EUS and CT, with no detection of any suspicious pancreatic lesion; also CTC have not been detected. Conclusions: This initiative will permit to know more about FPC and will serve to evaluate protocols and PC markers in screening the high-risk population, and promote connections with other international groups.
Endobiliary jumbo forceps biopsy as a technique for diagnosing bile duct malignancies.
Authors: Hsu Michael H. , Tummuru Rajeev , Patil Abhitabh 
Published: February 2017

197 Background: Pancreaticobiliary cancers are difficult to diagnose early and have a high associated mortality. Current methods of obtaining pathologic specimens from a biliary stricture include fine-needle aspiration, brush cytology, and endobiliary forceps biopsy. Among these forceps biopsy is the best, but is frequently limited by its low sensitivity (56%). The goal of this study is to evaluate the diagnostic yield and safety of jumbo forceps biopsies taken from the bile duct. Methods: All patients who presented to a single, tertiary academic referral center from July 2009 to July 2010 with a non-anastomotic biliary stricture were studied. This resulted in 9 patients with common bile duct strictures – 3 male and 6 female (ages 29-83, mean 61). All subjects underwent ERCP by the same gastroenterologist with endobiliary jumbo forceps biopsy using the Boston Scientific Radial Jaw 4 jumbo biopsy forceps. Specimens obtained were compared to available specimens obtained via fine needle aspiration, cytologic brushing or surgical resection. Patients with benign results were followed clinically for 1 year. Results: Three patients had benign biliary strictures as determined by clinical follow-up or surgical resection specimen. Jumbo forceps biopsy diagnosed a benign entity in 100% of these cases. Among the remaining 6 patients with malignant strictures, jumbo biopsy diagnosed a malignancy in 83% of cases. Tissue obtained was deemed adequate for histologic evaluation in 8 of 9 patients. The exception was recognized at the time of the procedure and was attributed to the technical inability to adequately open the biopsy forceps within the bile duct. Of the technically successful cases, 100% yielded an accurate histologic diagnosis as determined by concordant alternative sampling or clinical follow-up. In the 90 days following jumbo forceps biopsy, there were no adverse events such as bleeding, cholangitis, pancreatitis, perforation, peritonitis, or need for hospitalization. Conclusions: In our limited study, the use of jumbo forceps biopsies is safe and, when technically feasible, has a very high yield in evaluating biliary strictures. Larger studies are needed to confirm our findings.
Acquired resistance to combination therapy with lapatinib and MEK 1/2 inhibitor GSK1120212 in an in vivo murine model of pancreatic cancer.
Authors: Lindberg James M. , Walters Dustin M , Adair Sara J , Cowan Catharine R , Stokes Jayme B , Borgman Cheryl A , Stelow Edward B , Lowrey Bryce T , Chopivsky Maria E , Parsons J Thomas , Bauer Todd W. 
Published: February 2017

208 Background: Mutations of the oncogene KRAS and activation of cell-surface receptor tyrosine kinases are important and preserved mechanisms of tumorgenicity in pancreatic cancer. Dual inhibition of the downstream KRAS effector MEK 1/2 and tyrosine kinases EGFR and Her2 results in effective inhibition of patient-derived tumor growth in a murine orthotopic transplantation model. Because combinatorial therapies are moving rapidly into clinical trials, we sought to develop a model of acquired tumor resistance to this combination therapy. Methods: Patient-derived pancreatic tumor xenografts MAD 09-366 (KRAS mut), MAD 08-608 (KRAS mut) and MAD 08-738 (KRAS wt) were implanted orthotopically in nude mice and treated with combination lapatinib (EGFR/Her2 inhibitor) and GSK1120212 (MEK1/2 inhibitor) and tumor volume was measured by MRI. Following 4-6wks of treatment, tumors were reimplanted in second and third generation mice and retreated. Tumors were evaluated by phospho-RTK and phospho-MAPKinase array. Results: Acquired resistance developed in all three tumor xenografts. Treated tumors demonstrated a relative volume decrease in the original (F0) generation. All second re-implantation (F2) tumors, demonstrated relative tumor volume increases despite treatment. A comparison of pre-treatment mean tumor volumes showed a significant decrease in tumor size from the F0 to F2 generations suggesting selection for slower growing tumors. Array data demonstrated increased activation of FGFR1, VEGFR1/3, GSK-3β, p38, and Akt in resistant tumors as compared to their pre-treatment controls. These may represent mechanisms of tumor resistance and warrant further investigation. Conclusions: Repeated tumor exposure in vivo to combination treatment with GSK1120212 and lapatinib was used to develop a preclinical, orthotopic murine model of acquired drug resistance in patient-derived pancreatic cancers. This model provides the opportunity to define the mechanism of resistance in an appropriate tumor microenvironment and to develop alternative strategies for treating tumors resistant to this and other emerging therapies.
Metabolomic signature of esophageal cancer.
Authors: Davis Vanessa Wylie , Schiller Dan E. , Sawyer Michael B. 
Published: February 2017

21 Background: Esophageal cancer is a pervasive malignancy, and early detection combined with newer therapeutic targets could alter the landscape of this condition. Metabolomic profiling offers one such innovative opportunity. We applied metabolomic techniques to identify urinary metabolites uniquely associated with this condition. Methods: Urine samples from patients with histologically confirmed esophageal cancer (n=66) and healthy volunteers (n=25) were collected and examined using 1H-NMR spectroscopy. Targeted profiling of spectra using Chenomx NMR Suite 7.0 software permitted detection and quantification of 66 distinct metabolites. Unsupervised (principal component analysis, PCA) and supervised (partial least-squares discriminant analysis, PLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra of esophageal cancer patients and healthy volunteers using SIMCA-P (version 11, Umetrics, Umeå, Sweden). Results: Significant differences were found when comparing concentrations of 59 metabolites in urines of healthy volunteers and esophageal cancer patients. Those metabolites contributing most class discriminating information included choline, urea, 2-aminobutyrate, and 3-hydoxybutyrate. Clear distinctions between patients with esophageal cancer and healthy controls were noted when PLS-DA was applied to the data set. Model parameters for both goodness of fit R2, and predictive capability Q2, were high (R2 = 0.867; Q2 = 0.732). Model validity was tested using response permutation and results were suggestive of excellent predictive power (see Figure). Conclusions: Urinary metabolomics identified a discrete signature associated with esophageal cancer compared to healthy controls. This profile has the potential to aid in diagnosis and development of new therapeutic targets.