bluuebunny/crossref_metadata_2025_split huggingface dataset:
Malignant progression in intraductal papillary mucinous neoplasms of the pancreas: Results of 157 patients selected for radiographic surveillance.
Authors: LaFemina Jennifer , Gaujoux Sebastien , D'Angelica Michael Ian , Jarnagin William R. , Katabi Nora , Do Kinh Gian , Brennan Murray F. , Allen Peter J 
Published: February 2017

152 Background: Natural history studies suggest that intraductal papillary mucinous neoplasm (IPMN) is a field defect of pancreatic ductal instability. The risk of malignancy is well known, but it is unclear if the radiographic abnormality is the predominant site at which this progression occurs. This study analyzes the prevalence and site of pancreatic ductal adenocarcinoma (PDAC) progression in patients initially selected for radiographic surveillance. Methods: Patients evaluated for pancreatic cystic lesions between 1995-2010 were reviewed. Patients were included if they were followed for > 6 months for a cystic lesion with either a documented cyst fluid CEA >/= 200 ng/mL or pathologic confirmation of an IPMN. Results: Of the 157 patients initially selected for surveillance, 97 (62%) eventually underwent resection. The median length of surveillance prior to operation was 15 mo (range: 6-193 mo). Pathologically confirmed carcinoma in situ (high grade dysplasia, n=22) or invasive carcinoma (n=18) was identified in 40 patients. Of the 18 patients who were found to have invasive carcinoma, 10 had main duct IPMN (56%), 5 had branch duct (28%), and 3 had combined (17%). Four of the 18 patients who developed invasive cancer during surveillance (22% of those resected for carcinoma and 3% of those followed) developed PDAC in a region of the gland distinct from the radiographically identified lesion for which surveillance was recommended. Invasive carcinoma was diagnosed a median of 24 mo after the original IPMN diagnosis. During follow-up (median = 8 months from the cancer diagnosis), 1 patient died of disease, 2 are cancer-free, and 1 patient is alive with recurrence. Conclusions: In this study, 11% of patients with IPMN initially selected for surveillance developed invasive disease; 22% of those tumors arose in an area of the gland distinct from the initially identified lesion. Diagnostic and operative strategies for IPMN should consider the cancer risk in the entire gland. [Table: see text]
The association between metabolic syndrome and primary liver cancer: A meta-analysis.
Authors: Jinjuvadia Raxitkumar , Njei Basile M. , Ditah Ivo C. 
Published: February 2017

175 Background: The Metabolic syndrome (MetS) and/or its individual components have been liked to the development of cancer. Recent studies have suggested a similar link to Primary Liver Cancer (PLC). The mechanism for the development of cancer in this group of patients remains unclear. The aim of this study was to evaluate the direction and magnitude of the association between the MetS and PLC. Methods: Two reviewers independently conducted a systemic search of the PubMed, OvidSP and Cochrane Library databases from January 1980 to July 2011. Search terms included ‘Metabolic syndrome’, ‘insulin resistance syndrome’ combined with ‘hepatocellular carcinoma’, ‘liver cancer’ and ‘GI malignancy’. No language restriction was applied to the search. Only studies reporting an effect measure for the association between MetS and PLC were eligible for inclusion. Metabolic syndrome was defined according to NCEP/ATP III, IDF, AHA and WHO guidelines. Identified articles were reviewed for additional references. Combined analysis including all studies was done using a random effects model. Publication bias was assessed using the Begg and Egger’s tests, with a visual inspection of funnel plot. All analyses were performed using Comprehensive Meta-Analysis version 2 software. Results: Five studies (4 cohort and 1 case-control) including 863,714 participants were included in the analysis. The age range of participants was between 20 and 88 years. The combined analysis showed an overall 74% increase risk of PLC in cases with MetS (RR: 1.74, 95% CI: 1.36-2.24). After excluding the single case-control study from analysis, the overall risk ratio remained statistically significant (RR: 1.62, 95% CI: 1.22-2.15). Funnel plot inspection, Begg and Egger’s tests showed no evidence of publication bias, whether in the combined or subgroup analysis. Conclusions: Though studies are scarce, currently available epidemiologic data is suggestive of positive association with significantly higher risk of liver cancer among patients with metabolic syndrome. More studies are required before reaching conclusive statement regarding this association. Further better-designed studies with good quality data with definitely aid in strengthening this association.
Use of DARPP-32 to increase interactions between EGFR and ERBB3 and to promote gastric cancer resistance to gefitinib.
Authors: Zhu Shoumin , Belkhiri Abbes , Zaika Alexander , El-Rifai Wael 
Published: February 2017

18 Background: Dopamine and cAMP-regulated phosphoprotein, Mr 32000 (DARPP−32), is overexpressed during gastric carcinogenesis. Gefitinib is a specific and effective EGFR inhibitor that has shown antitumor activity in clinical trials against gastrointestinal cancers. Gastric tumors can become resistant to gefitinib. However, molecular mechanisms that mediate resistance to gefitinib remain poorly understood. Methods: The expression of DARPP−32 in the multi-step carcinogenesis cascade was examined using IHC analysis. Cell survival was determined by clonogenic survival and ATP−Glo assays. Apoptosis was assessed by Annexin-V and immunoblot analyses. The association between DARPP−32 and EGFR was evaluated by immunofluorescence and co-IP assays. Results: The composite expression score progressively increased significantly from normal or gastritis to adenocarcinoma (p<0.001). Overexpression of DARPP−32 in MKN-28 cells blocked gefitinib-induced apoptosis and increased the drug’s IC50 10−fold, compared to that of control cells (P<0.01). And DARPP-32 expressing MKN−28 cells had activated the PI3K-AKT pathway as compared to control cells. The three−way co-IP experiments demonstrated the existence of DARPP-32, EGFR, and ERBB3 in the same protein complex. DARPP-32 enhanced EGFR-ERBB3 heterodimerization promoting phosphorylation of ERBB3, and then activated the PI3K-AKT pathway. Following treatment with gefitinib (25 μM) overnight, MKN−28 cells expressing DARPP-32 displayed stable protein levels of EGFR. The knockdown of endogenous DARPP-32 by DARPP-32 shRNA in SNU-16 cell lines reversed these signaling effects and increased sensitivity to gefitinib (p<0.01). Conclusions: Our results suggest that DARPP-32 overexpression may participate in the progression to neoplasia. DARPP-32 also plays a role in increasing the stability of EGFR protein; DARPP-32 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between EGFR and ERBB3 and activating PI3K–AKT signaling. DARPP-32 may have potential as a predictive biomarker in gastric cancer prognosis and clinical response to treatment.
Variable expression of somatostatin receptor type 2 in metastatic midgut carcinoid.
Authors: Liu Eric H. , Revetta Frank , Merchant Nipun B. , Washington Mary Kay , Shi Chanjuan 
Published: February 2017

189 Background: Somatostatin receptor type 2 (SSTR2) is frequently highly expressed in carcinoid tumors of the midgut. The presence of the receptor is the basis of imaging and therapeutics. Because of the high dependence of clinical care on SSTR2, we evaluated the immunohistochemical staining of specimens and correlated with clinical parameters. Methods: A tissue microarray (TMA) of 1 mm cores from paraffin embedded specimens of surgically resected midgut carcinoid were created with primary, lymph node, and liver metastatic lesions. These sections were stained by immunohistochemistry with anti-SSTR2 antibody, and scored on staining intensity. Sections were evaluated by membrane (0-none, 1 – weak, 2 – partial, 3- complete) and cytoplasmic (strong vs. weak) staining. Results: Thirty-five patient samples were included in the TMA. There were a total of 62 cores embedded: 21 primary lesions, 26 lymph node metastases, and 15 liver metastases. The total disease burden was captured in 17 patients, and specimens from all three sites were captured in 6 patients. Of the thirty-five patients, 6 had consistently weak SSTR2 staining (17% either 0 or 1). One of these cases had an intermediate grade tumor with Ki67 >20%. Of the patients where more than one location was captured, 19/21 (90%) had consistent SSTR2 staining at all sites. Most cases had strong staining in the membrane (69%) while a minority had strong cytoplasmic staining (31%). Of the patients with weak SSTR2 membrane staining, 2 still had positive octreoscans. Clinically, most patients had good outcomes and 94% are still alive. Eight cases had carcinoid carcinomatosis (23%). Of the six with weak membrane staining, three had carcinomatosis (50%), while only 5/30 (17%) with strong membrane staining had carcinomatosis. Conclusions: While the majority of small bowel carcinoids and their metastatic lesions have strong SSTR2 staining, not all do. However, even in cases with low amounts of SSTR2 on the membrane, the tumors can still be detected on octreoscan, demonstrating the effect of receptor turnover. The loss of SSTR2 may be associated with more advanced disease, but is not completely predictive.
A phase Ib trial of IPI-926, a hedgehog pathway inhibitor, plus gemcitabine in patients with metastatic pancreatic cancer.
Authors: Richards Donald Anthony , Stephenson Joe , Wolpin Brian M. , Becerra Carlos , Hamm John Turner , Messersmith Wells A. , Devens Shannon , Cushing Jill , Schmalbach Tess , Fuchs Charles S. 
Published: February 2017

213 Background: IPI-926 is a novel, natural product-derived small molecule that targets the Hedgehog (Hh) pathway by inhibiting smoothened. In preclinical models of pancreatic cancer, repressing activation of the Hh pathway diminishes tumor-associated desmoplasia and improves chemotherapy delivery. Methods: This is the final report of the Phase 1b portion of a Phase 1b/2 trial evaluating the safety and efficacy of IPI-926 plus gemcitabine. Eligible patients (pts) with untreated metastatic pancreatic cancer and ECOG status 0-1 were administered oral IPI-926 daily (QD) for 28-day cycles, in 3 to 6 pt dose cohorts. Gemcitabine (1,000 mg/m2) was administered IV weekly for 3 weeks with 1 week off. DLTs were evaluated during Cycle 1. Results: 16 pts (median age 69 years; range 58-86) were enrolled at IPI-926 doses of 110, 130 or 160 mg QD (single agent MTD). Pts received a median of 5 cycles (1-13). Two pts remain on trial. No IPI-926-related serious AEs have been observed. One DLT of Grade 3 AST increase was observed (130 mg dose cohort) and was asymptomatic; it resolved with dose interruption, and did not recur with dose reduction. The most common AEs occurring were fatigue (75% total, 6% ≥ Grade 3), thrombocytopenia (63%, 25%), anemia (56%, 13%), nausea (50%, 0%), diarrhea (44%, 0%), vomiting (44%, 0%), peripheral edema (44%, 0%), pyrexia (44%, 0%), and AST increase (44%, 13%). Dose reductions of IPI-926 occurred in 3 (19%) pts. Dose reductions of gemcitabine occurred in 11 (69%) pts, primarily for thrombocytopenia (9 pts). One pt (6%) discontinued due to an AE (microangiopathic hemolytic anemia). Five (31%) radiographic partial responses were observed (1/3 at 110 mg, 2/6 at 130 mg, 2/7 at 160 mg). Median progression-free survival is > 7 months. 74% of pts were alive 6 months after study entry. Conclusions: IPI-926 plus gemcitabine is well tolerated in pts with untreated metastatic pancreatic cancer, with evidence of activity and no unexpected toxicity. Complete Phase 1b data, including final overall survival, will be presented. Clinical evaluation of this combination continues in the randomized, double-blind, placebo-controlled Phase 2 portion of the trial.
Paradoxical cross-talk between the Stat3 and MAPK pathways in CCL25-CCR9 mediated pancreatic cancer growth and proliferation.
Authors: Le Maithao N. , Shen Xiaoming , Lee Wendy , Duldulao Marjun Philip , Garcia-Aguilar Julio , Kim Joseph 
Published: February 2017

231 Background: Chemokine receptors have been shown to regulate the progression of several malignancies. Signal transducer and activator of transcription 3 (Stat3) may contribute to the invasive phenotype of several human cancers, but its upstream signals have not been well characterized. Our objective was to investigate the relationship between the CCL25-CCR9 axis and Stat3 signaling in pancreatic cancer cells. Methods: We exposed two established human pancreatic cancer cell lines PANC-1 and MIAPaCa-2 to the cytokine CCL25 (800 ug/uL for 20 min) and measured the activation of Stat3 (phosho-Stat3) by Western blot assay. Stattic, a small molecule Stat3 inhibitor, was used (20uM) to antagonize Stat3 signaling. We also measured activation level of extracellular signal-regulated kinase (phospho-ERK) following CCL25 exposure and used UO126 (10uM), a small molecule MEK inhibitor, to antagonize the MAPK pathway. Changes in cell proliferation were measured by CellTiter Glo Fluorescence assay. Results: Constitutive phosphorylation of Stat3 was observed in both pancreatic cancer cell lines. Exposure of MIAPaCa-2 to CCL25 further increased phospho-Stat3 levels on Western blot assay. We also observed a concomitant increase in phospho-ERK levels with exposure to CCL25 in both cell lines. Exposure of pancreatic cancer cells to CCL25 significantly increased cell proliferation. To determine the mechanism of CCR9-mediated cell proliferation, we used stattic and UO126 to specifically inhibit Stat3 and MEK activation, respectively. Interestingly, pre-treatment with stattic prior to CCL25 exposure resulted in a paradoxical enhancement of phospho-ERK levels. Conversely, inhibition of the MAPK pathway with UO126 led to a paradoxical enhancement of phospho-Stat3 levels. Conclusions: Our results demonstrate that CCL25 activates Stat3 and MAPK pathways to contribute to pancreatic cancer proliferation. We also show potential cross-talk between Stat3 and MAPK pathways, wherein antagonism of one pathway resulted in paradoxical activation of the other pathway. Our findings suggest that therapeutic targeting of downstream pathways may require a multi-drug approach.
Use of PG545, a heparanase inhibitor, to inhibit pancreatic cancer tumor cell proliferation and migration in vitro and in vivo.
Authors: Ostapoff Katherine , Awasthi Niranjan , Schwarz Roderich , Brekken Rolf A. 
Published: February 2017

234 Background: Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy, as result there is an ongoing search to find novel effective strategies. Resistance is due in part to the high proportion of stromal tissue within the primary tumor. This intricate ECM (extracellular matrix) includes heparan-sulfate glycosaminoglycans which participate in tumor progression, angiogenesis and metastasis. PG545 is a heparanase inhibitor developed to target these pathways. Methods: In vitro cell viability assays were performed using WST-1 reagent and migration was evaluated using T- scratch assay. Animal survival experiments were performed by intraperitoneal injection of AsPC-1 (0.75 x 10^6) cells. In vivo tumor growth experiments were performed by orthotopic injection of PanO2-HY (5x10^5) cells. Results: PG545 significantly inhibited proliferation of tumor cells (AsPC-1 and PanO2) and fibroblasts (WI-38). PG545 caused only a modest inhibition in endothelial cell (HUVECs) proliferation. Migration was significantly inhibited by 1 µM PG545 in AsPC-1 and PanO2 after 12 hours. In a metastatic model of pancreatic cancer, treatment with PG545 (10 mg/kg 1st week, 5 mg/kg 2nd week) improved survival (35 days) compared to saline (22 days) and gemcitabine (28 days). In an immunocompetent orthotopic model, mice treated with PG545 (5 mg/kg twice weekly) had significantly decreased tumor weights after 3 weeks of therapy (p=0.002). Total metastatic events were also reduced in PG545 compared to gemcitabine and control treatment in the PanO2 model. Conclusions: PG545 inhibits tumor cell proliferation and migration in vitro and prolongs survival and inhibits tumor growth in vivo. Additionally it inhibits metastasis in vivo. Further studies are underway to elucidate the mechanism of inhibition and changes to pancreatic tumor microenvironment.
Usefulness of circulating tumor cell detection for the diagnosis of malignant pancreatic head tumors: A pilot study.
Authors: Coget Julien , Blanchard France , Lamy Aude , Toure Emmanuel , Chiavelli Helene , Basile Paul , Di Fiore Frédéric , iwanicki-Caron Isabelle , Michel Pierre , Lemoine Francoise , Sabourin Jean-Christophe 
Published: February 2017

235 Background: Pancreatic adenocarcinomas account for 90% of pancreatic malignancies. It is often diagnosed at an unresectable stage (at a metastatic and / or at a locoregional invasion stage). Histological diagnosis is mandatory to establish palliative chemotherapy. Endoscopic ultrasound-guided fine needle aspiration (EUGA) of pancreatic tumors is a difficult gesture, not without risk. Furthermore, it frequently provides pauci-cellular, hemorrhagic or necrotic material unsuitable for precise histologic diagnosis. Techniques for detecting circulating tumor cells (CTC) have been recently developed to highlight the presence of malignant cells circulating in peripheral blood. Screencells technology is based on the separation of CTCs from other circulating cells by blood filtration through a polycarbonate membrane with 7m pores. The aims of this pilot study were 1) to compare the results of detections CTC to EUGA, 2) to assess the feasibility and the contribution of this innovative technique in the care of a limited series of patients. Methods: A sample of peripheral venous blood was performed in 15 patients with a suspicious CT scan of a pancreatic head tumoral lesion, before the completion of an EUGA. 4 ml of blood were filtered using ScreencellsCyto columns. After Giemsa staining, a pathologist analyzed each filter. Cells visualized on the filter under light microscopy were considered as tumoral if they met the following morphological criteria: anisocytosis, anisokaryosis, nuclear diameter>7m, nuclear membrane irregularitie, large nucleolus. Results: The malignant feature of the pancreatic lesion could be histologically assessed after liver biopsy for two patients. EUGA showed malignancy in 10 cases. CTC presence was identified in 7 patients with tumoral histological diagnosis. Conclusions: This study demonstrates the feasibility of CTC detection in patients with pancreatic head tumor. The identification of CTCs could facilitate patient care, thus avoiding difficult and potentially dangerous EUGA. A prospective trial is needed to confirm the positive predictive value of this biomarker and to evaluate its contribution in the diagnosis procedure of such tumors.
Overall survival with everolimus, sunitinib, and placebo for advanced pancreatic neuroendocrine tumors: A matching-adjusted indirect comparison of randomized trials.
Authors: Signorovitch James , Swallow Elyse , Kantor Evan , Wang Xufang , Metrakos Peter 
Published: February 2017

237 Background: Everolimus and sunitinib are approved in the US and EU for treating advanced pancreatic neuroendocrine tumors (pNET). No randomized trial has directly compared these treatments for pNET. This study indirectly compared overall survival (OS) with everolimus vs. 1) placebo and 2) sunitinib. Methods: Individual patient data were used from the RADIANT-3 trial of everolimus 10 mg/day vs. placebo (cutoff: April 4, 2010); published summary data were used from the A6181111 trial of sunitinib 37.5 mg/day vs. placebo (cutoff: June 1, 2010). To adjust for cross-trial differences, RADIANT-3 patients were subjected to exclusion criteria used in A6181111 and then re-weighted to match A6181111 in terms of baseline demographics, performance status, time since diagnosis, disease sites, distant metastases and prior therapy. After matching, OS was compared between balanced trial populations for everolimus in RADIANT-3 vs. 1) the placebo arm in A6181111, which had access to sunitinib after early stopping, and 2) the sunitinib arm in A6181111. Progression-free survival (PFS) was also assessed, but was confounded by early stopping of A6181111. Results: Analyses included 394 patients from RADIANT-3 (after excluding 15 with worse performance status than allowed in A6181111 and 1 with missing baseline data) and all 171 patients in A6181111. Before matching, patients in RADIANT-3 had better performance status, more prior use of somatostatin analogues and less prior use of systemic chemotherapy. After matching, these and all other baseline characteristics were well-balanced between trials. Everolimus was associated with prolonged OS vs. placebo in A6181111 (hazard ratio [HR] for death = 0.61, 95% CI = 0.38-0.98, p=0.04). No statistically significant difference was observed with everolimus vs. sunitinib in OS (HR for death = 0.81, 95%CI=0.49-1.31) or in PFS (HR for progression = 0.84, 95% CI=0.46-1.53). Conclusions: After adjusting for cross-trial differences, treatment of advanced pNET with everolimus was associated with prolonged OS compared to treatment with placebo.
Efficacy of gemcitabine as second-line therapy after S-1 therapy failure in advanced pancreatic carcinoma.
Authors: Fukahori Masaru 
Published: February 2017

248 Background: Gemcitabine (GEM) and GEM-containing combination chemotherapy have been established as standard first-line therapies for advanced pancreatic carcinoma (APC). In the GEST study, a phase III clinical trial that compared the results for GEM, S-1, and GEM+S-1 therapies, there was no significant difference between overall survival (OS) for GEM and GEM+S-1; S-1 and GEM had similar efficacies as first-line treatment for APC. Therefore, S-1 is expected to be used as first-line therapy. In our study, we have evaluated the efficacy and outcomes of second-line GEM therapy after S-1 therapy failure in APC. Methods: We retrospectively examined the data for 27 patients (pts) with APC refractory to first-line S-1 therapy. All the pts had undergone second-line GEM therapy during October 2000–February 2009 at National Cancer Center Hospital after first-line S-1 therapy. Tumor responses were analyzed using Response Evaluation Criteria in Solid Tumors. The Kaplan-Meier method was used to evaluate tumor progression and survival. Results: The Eastern Cooperative Oncology Group Performance Status was 0 or 1. The male:female ratio was 16:11 and median age was 62 years (range, 42–75 years). Four pts (14%) exhibited a partial response to second-line GEM therapy, 11 (40%) showed stable disease, and 12 (44%) showed progressive disease. Grade 3 adverse events for second-line GEM therapy were neutropenia in 2 pts and upper gastrointestinal hemorrhage in 1 pt. Grade 4 adverse events were not observed. The median progression-free survival was 77 days (95% confidence interval, 33–121 days) and the median OS after second-line GEM therapy was 240 days (95% confidence interval, 156–324 days). Conclusions: Although this study had a small sample population and retrospective design, the results indicate that GEM has good antitumor activity with tolerable toxicity. Second-line GEM therapy was found to be effective after first-line S-1 therapy failure in APC.