bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pancreatic injury, genetic variation of PNPLA3, and risk of pancreatic cancer.
Authors: Aly Mohammed , Sahin Ibrahim Halil , Li Donghui , Khalil Mohamed Fahd , Chang Ping , Fogelman David R. , Javle Milind M. , Abbruzzese James L. , Hassan Manal 
Published: February 2017

141 Background: Similar to primary liver cancer, obesity, diabetes mellitus and hepatitis B virus infection have been associated with increased risk of pancreatic cancer (PC) development. A genome-wide association study has reported that a polymorphic variant of the patatin-like phospholipase domain containing 3 (PNPLA3) gene was associated with a higher susceptibility to fatty liver and liver cancer. The relationship between this variation and PC has not been previously examined. We investigated the correlation in the degree of organ damage between the liver and the pancreas in patients with PC. In addition, we examined the effect of PNPLA3genetic variation (rs738409: C>G) on PC development. Methods: Using resources of our case-control study in MD Anderson Cancer Center, we analyzed 544 pathologically confirmed PC patients and 498 healthy controls. Cases and controls were frequency matched by age, gender, and race. Multivariate logistic regression analysis was performed to adjust for the confounding factors. Medical records of PC patients were reviewed for pancreatic and liver fatty changes. Results: We found that 18.8% of PC patients had evidence of pancreatic steatosis, fibrosis, or pancreatitis. Fatty liver was observed in 14.5% of PC patients which was frequently detected in patients with pancreatitis (p=0.002). A significant correlation between pancreatitis and cirrhosis was observed in PC patients with a prior history of obesity but not in patients without a history of obesity (p=0.001). On the other hand, we observed no significant association between PNPLA3 genotype and risk of PC. The adjusted odds ratio (OR) was 1.4 (95% confidence interval [CI], 0.7-2.7) for the homozygous variant GG genotype compared with the CC/CG genotypes. Conclusions: We concluded that despite the similarities between the liver and the pancreas, genetic susceptibility to fatty infiltration and its effect on cancer development may differ between the two organs. Evaluation and assessment of nonalcoholic fatty pancreatic disease (NAFPD) in PC patients and genetic susceptibility of NAFPD may be warranted in future research.
Effect of the revised AJCC staging (7th edition) on prognostic stratification in patients with surgically resected esophageal squamous cell carcinoma.
Authors: Minella Gloria Terase , Luketich James D. , Davison Jon M. , Winger Dan , Levy Ryan M. , Gibson Michael K. , Pennathur Arjun , Nason Katie Sue 
Published: February 2017

15 Background: Historically, the AJCC esophageal staging system separated patients into prognostic groups based on tumor, node, and metastasis (TNM) classifications. In 2010, the 7th edition (AJCC 7) significantly modified esophageal squamous cell cancer (ESCC) staging by separating ESCC from adenocarcinoma, incorporating tumor grade and location for node negative cancers, and stratifying by the number of involved regional nodes for node positive cancers. Our study aim was to determine whether AJCC 7 stage groupings provide improved survival prognostication compared to 6th edition (AJCC 6). Methods: We abstracted pathology and survival for 150 consecutive ESCC patients who underwent esophagectomy (1994-2012); 44 patients received induction therapy. AJCC 6 and AJCC 7 stages were assigned and overall survival analyzed from esophagectomy to death or most recent alive contact and censored at 60 months. Discriminatory ability and homogeneity within subgroups was assessed with Kaplan-Meier curves and monotonicity comparisons were evaluated with linear trend chi-squared tests. Overall survival was compared using Cox regression and Akaike Information Criterion (AIC) used to assess model fit. Results: Compared to AJCC 6, AJCC 7 upstaged 32 patients from IIa to IIb and 1 patient from IIb to IIIa and downstaged 3 patients from stage IIa to Ib. AJCC 7 subclassified 42 AJCC 6 stage III patients (17 IIIa, 10 IIIb and 15 IIIC). Median overall survival was 19 months. Kaplan-Meier log-rank statistic indicated stronger differentiation in AJCC 7 (19.8 vs 29.7). Cox regression likelihood (19.5 vs 26.1), AIC (618.1 vs 611.6), and linear trend chi-squared at 24- (17.5 vs 24.3) and 60-months (13.3 vs 17.3), were all superior for AJCC 7 stage groupings (AJCC 6 vs AJCC 7, respectively). Conclusions: AJCC 7 stage groupings demonstrate superior homogeneity, discriminatory ability and monotonicity compared to AJCC 6. Incorporating the extent of nodal disease, tumor location and tumor grade into the revised AJCC 7 stage classification improves prognostic stratification of surgically resected ESCC patients, including patients who received induction therapy.
Effect of venous involvement on survival in locally advanced pancreatic cancer.
Authors: Hewitt Kelly C. , Madden Jesse L , Christensen Joslin C , Mulvihill Sean J. , Scaife Courtney L. 
Published: February 2017

153 Background: Locally advanced pancreatic cancer is defined as tumor that extends beyond the pancreas into surrounding structures. Borderline resectable disease usually includes a description of superior mesenteric vein (SMV) or portal vein (PV) involvement, while the AJCC staging no longer includes venous involvement in the staging system. We reviewed our institutional cancer database to determine if venous involvement affects overall survival and should be included in pancreatic ductal adenocarcinoma (PDA) staging. Methods: A retrospective review was performed of all patients with stage II or III PDA identified through our institutional prospective Clinical Cancer Research Database, between 2007-2012. Patients with superior mesenteric artery (SMA) or celiac artery and/or venous (SMV or PV) involvement were compared to those without. Vascular involvement was defined as either vessel encasement or abutment on endoscopic ultrasound or CT imaging. Survival analysis was performed using the Kaplan-Meier method with log-rank test for comparison of survival curves. Results: A total of 194 patients were identified as having stage II or stage III pancreatic adenocarcinoma, with 85 having evidence of vascular involvement. In our patient population we found that in patients with stage IIA and IIB disease PV or SMV involvement did not portend statistically worse survival (median survival 14 months v 15 months p=0.63). In stage III patients survival was actually longer in patients with PV or SMV involvement, but this was not statistically significant (median survival 13 months v 7.9 months p=.066). When comparing those with PV or SMV involvement versus those with celiac axis or superior mesenteric artery (SMA) involvement in all patients with locally advanced pancreatic cancer (stage II or III), those with celiac or SMA involvement did significantly worse (mean survival 14 months v. 7.9 months p<0.001). Conclusions: Venous involvement does not portend a worse survival in patients with stage II and III pancreatic cancer. The addition of venous involvement to the current AJCC staging scheme would not provide additional survival information.
Diagnostic discrepancies between second-opinion and referring pathology reports of neuroendocrine tumors.
Authors: Lin Hillary , Longacre Teri A. , Khandelwal Vilay H. , Balise Raymond R. , Kunz Pamela L. 
Published: February 2017

154 Background: Neuroendocrine tumors (NETs) are rare malignancies that can arise from neuroendocrine cells throughout the body, most commonly in the lungs, gastrointestinal tract, and pancreas. The nomenclature and histologic classification schemes for NETs have historically been heterogeneous and inconsistent. Klimstra, et al published a set of NET pathology guidelines in 2010. We undertook a systematic evaluation of discrepancies between referring versus second-opinion NET pathology reports using these guidelines as our reference. Methods: We developed a cohort ofall NET cases seen at Stanford University Hospital between April 1998 and February 2012 with available Stanford and referring pathology reports for the same specimen to identify the discrepancies between their clinical diagnoses. Results: Of 141 cases, primary sites were identified as 39 (28%) pancreas, 21 (15%) small intestine, 49 (35%) other NET sites, and 32 (22%) unknown or missing. Most reports agreed on a diagnosis of NET, although twelve different terms were used to describe the NET diagnosis. There were 24 cases (17%) with major discrepancies by histologic description (NET vs. not NET). Grade, mitotic index (MI), and Ki67 were among the variables examined; they were missing from the majority of cases in one or both reports, yet more likely to be included in the Stanford report. Grade was not reported (NR) in one or both reports in 124 cases (88%); of the 17 cases reporting grade in both reports, 3 had major discrepancies. MI was NR in one or both reports in 105 cases (74%); of the 36 cases reporting MI in both reports, 5 had major discrepancies. Ki67 was NR in one or both reports in 127 cases (90%); of the 14 cases reporting Ki67 in both reports, 3 had major discrepancies. Conclusions: Clinically relevant differences were frequently found between Stanford and referring pathology reports for NETs. Our results suggest that it is beneficial for NET cases to be reviewed by NET pathology experts given the potential to impact treatment. Future studies of NET pathology discrepancies are warranted to allow additional time for adoption of the 2010 guidelines.
Performance of a novel TNM staging system for pancreatic neuroendocrine tumors versus the current AJCC staging system.
Authors: Qadan Motaz , Ma Yifei , Visser Brendan C. , Norton Jeffrey A. , Poultsides George A. 
Published: February 2017

156 Background: Adopting a unified staging system for pancreatic neuroendocrine tumors (PNET) has been challenging. Currently, the American Joint Committee on Cancer (AJCC) recommends the use of the pancreatic adenocarcinoma staging system for PNET. We sought to validate this recommendation on a large administrative population database. Methods: Surveillance, Epidemiology, and End Results (SEER) data were used to identify patients with PNET (excluding patients with large cell, small cell, or mixed endocrine-exocrine carcinoma) who underwent curative-intent surgical resection from 1983 to 2008. The discriminatory ability of the AJCC system (recorded by SEER since 2004) was examined and a new TNM system was devised utilizing extent of disease variables. Results: Of 1,202 patients identified, 51% were female. Median age was 55 years (range, 9-93). Lymph node metastasis (present in 43% of patients) was associated with worse overall survival (OS) after resection (10-year OS, 50% vs 63%, p<.0001), as was the presence of distant metastasis (present in 24% of patients, 10-year OS, 35% vs 63%, p<.0001).The current AJCC system (available in 412 patients) distinguished overall survival adequately only between stages I and II, but not between II and III, or III and IV (Table). By modifying the T stage to be based only on size (0-1 cm, 1-2 cm, 2-4 cm, and > 4 cm) and by revising the grouping allocation, we propose a novel TNM system with improved discriminatory ability (Table). Conclusions: In this study validating the current AJCC staging system for PNET, we found stages II, III, and IV to perform similarly. We propose a simplified TNM system that better discriminates between outcomes. [Table: see text]
The natural history of preoperative indeterminate pulmonary nodules in patients with resectable pancreatic adenocarcinoma.
Authors: Nguyen Dennis C. , Chang Stephanie , Gongfu Zhou , Wang-Gillam Andrea , Linehan David , Hawkins William G , Strasberg Steven M , Menias Christine , Raptis Constantine , Fields Ryan C. 
Published: February 2017

161 Background: Preoperative abdominal imaging often detects indeterminate pulmonary nodules (IPN) in patients with resectable pancreatic adenocarcinoma. The natural history of IPN in this setting is not well characterized. Methods: Patients with adenocarcinoma of the head of the pancreas who underwent pancreaticoduodenectomy (PD) were queried from a prospectively maintained database. Pre- and postoperative imaging was reviewed and IPN characterized and analyzed for associations with nodule progression and overall survival (OS). Results: 463 patients underwent PD for adenocarcinoma of the head of the pancreas from 2000-2010. Of these, 329 (71%) had reviewable pre-operative imaging. 48 patients (15%) had pre-operative IPN (non-calcified) identified with follow-up imaging available for review. The only pre-operative factor associated with the presence of IPN was increasing age (68 v. 64 years; p=0.003). 8 patients (12%) had new or enlarging nodules, of whom 5 (7%) had confirmed pulmonary metastatic adenocarcinoma. There was no difference in OS between patients with or without pre-operative IPN (2-year OS 41% v. 38%, respectively; p=0.37). Further, no radiographic criteria of IPN (including # of, size of, bilateral, calcified, solid, spiculated, smooth, lobular, or ground-glass nodules) was associated with OS. On follow-up, new or enlarging nodules were not associated with OS. Conclusions: IPN are often found in patients undergoing PD for pancreatic adenocarcinoma. The majority of IPN remain stable on post-operative imaging. Neither the presence of IPN nor nodule characteristics was associated with OS. These data do not support the routine additional workup of pre-operative IPN in patients with resectable adenocarcinoma of the head of the pancreas; however, larger studies are needed to further characterize the significance of IPN in the preoperative evaluation of patients with pancreatic adenocarcinoma.
Usefulness of peripheral regulatory T-cells induced by Notch signaling pathway-driven indoleamine 2, 3-dioxygenase positive dendritic cell as a biomarker for the decision for IPMN surgical indications.
Authors: Ikemoto Tetsuya , Shimada Mitsuo , Utsunomiya Toru , Morine Yuji , Imura Satoru , Mori Hiroki , Arakawa Yusuke , Kanamoto Mami , Iwahashi Shu-ichi , Yamada Shinichiro , Asanoma Michihito 
Published: February 2017

181 Background: This study was performed to elucidate the expression of the Notch signaling pathway regulated by dendetric cell (DC) and their correlations to clinicopathological factors of intraductal papillary mucinous neoplasms (IPMNs) as a new biomarker for surgical indications. We already reported that regulatory T cells (Tregs) play an important role in tumor immunity (Pancreas 2006, ASCO-GI 2009), however, the whole mechanism of control of peripheral Tregs remains unclear. It is reported that Indoleamine 2, 3-dioxygenase (IDO) induces active Treg from naïve CD4+Tcells through dendritic cells. Otherwise, we also reported that the Notch signaling pathway is involved in tumor growth and DC function (JI 2010). Thus we focused that Indoleamine 2,3-deoxygenase(IDO)-Treg axis driven by Notch signaling in IPMNs. Methods: Peripheral blood samples and resected specimens from 20 patients with IPMN were evaluated. All patients were pathologically diagnosed with IPMN. Resected specimens were immunohistochemically evaluated (anti-Notch1, anti-Notch2, anti-Notch2-intracellular domain and anti-IDO antibody staining) and compared to clinicopathological factors. Peripheral Treg populations were analyzed with an automated flow cytometer. Results: Disease-free survival was significantly worse in the Notch1 high-expression group (P<0.05). Notch2 family expressions were higher in intraductal papillary mucinous carcinoma (IPMC) than in intraductal papillary mucinous adenoma (IPMA) (Notch2, P< 0.05; Notch2-intracellular domain, P < 0.05). Jagged1 and IDO expressions were significantly higher in IPMC than in IPMA (P < 0.05) and was significantly related to recurrence. The Treg population in peripheral blood was higher in patients with IPMC than in those with IPMA (P < 0.01). Conclusions: Notch signaling, especially Jagged1 expression, regulated by IDO+DC reflects IPMN aggressiveness. Our data strongly suggest that peripheral Treg induced by Notch signaling pathway driven IDO+DC may be a nobel biomarker for the decision for IPMN surgical indications.
Identification of a bona-fide biomarker of microRNA in serum exosomes to predict recurrence of hepatocellular carcinoma after liver transplantation.
Authors: Sugimachi Keishi , Matsumura Tae , Ishibashi Masahisa , Akiyoshi Sayuri , Shirabe Ken , Maehara Yoshihiko , Mimori Koshi 
Published: February 2017

183 Background: The predictive biomarker for the recurrence of hepatocellular carcinoma (HCC) has great benefit on the selection of treatment options including liver transplantation (LT) for HCC. Micro RNA (miR), a class of small non-coding RNA molecule, affect crucial processes in cancer development and offer great potential as biomarkers for cancer due to their remarkable stability in blood. The objective of this study is to identify specific miRs in exosomes of HCC recurrence from the serum and bone marrow of the patients and validate these molecules as novel biomarkers for HCC recurrence. Methods: We employed microarray-based profiling of miR expression from exosome in serum and bone marrow of the patient with HCC to define a biomarker that distinguishes between patients with and without HCC recurrence after liver transplantation or hepatic resection. This was followed by a real-time semi-quantitative PCR validation in a separate cohort of 63 HCC patients who underwent living related LT. Results: We found that 4 miRs which were differentialy (>2 folds) expressed in the serum exosome with HCC cases that had recurrence after LT compared to those without recurrence. They were associated with tumor aggressiveness of HCC in the validated cohort series. To disclose the original cell fraction of each identified miR in bone marrow, we divided bone marrow cells into 3 fractions by cell surface markers, such as CD14+ (macrophage), CD14-/CD45- (lymphocyte) and CD14-/CD45-/EpCAM+ (epithelial cell), then we performed microRNA microarray in each fraction. The increased expression of miR-150, miR-135a, and miR-1225-5p were observed in the CD14-/CD45+ fraction of bone marrow of HCC cases with recurrence, which suggested the association of CD4+ lymphocyte impairment and tumor recurrence. Conclusions: Circulating miR in serum exosome has potential as a novel biomarker to predict recurrence of HCC. MiR profiling of serum and bone marrow may help to clarify the mechanism of recurrence of HCC. The identified miR/gene axis indicated that the disruption of the immune systems after LT should provoke the recurrence of HCC in the future.
Preclinical evidence of ET-743 as a potential chemotherapy option for the treatment of biliary carcinoma.
Authors: Leone Francesco , Peraldo-Neia Caterina , Cavalloni Giuliana , Soster Marco , Gammaitoni Loretta , MarchiÃƒÂ² Serena , Aglietta Massimo 
Published: February 2017

193 Background: The standard chemotherapy for unresectablebiliary tract carcinoma (BTC) is based on gemcitabine and platinum compounds. However, these combinations have not been shown to be effective in improving long-term survival. Thus, there is a real need to find new strategies that would impact in a significant way on clinical outcome. Ecteinascidin-743 (ET-743), a compound isolated from the marine tunicate Ecteinascidia turbinata. ET-743, is approved for the treatment of ovarian cancer and soft tissue sarcoma. Phase II and III clinical trials are ongoing for the treatment of different solid tumors. No preclinical data are available about the efficacy of ET-743 in BTC. In a phase I study, one patient received ET-743 plus capecitabine and experienced a long lasting complete metabolic response. Here, we investigated the antitumor activity of ET-743 in preclinical BTC models. Methods: Four BTC cell lines TFK1, EGI-1, HuH28 and TGBC1 were used to evaluate the effect of ET-743 on proliferation, cell cycle, apoptosis and on the activation of DNA damage proteins. The effect on proliferation was also investigated on a primary cell culture of a gallbladder carcinoma (GBC) resistant to gemcitabine and oxaliplatin. On the same cells, the inhibition of VEGF secretion mediated by ET-743 was analyzed by ELISA. The anti-tumor activity of ET-743 was tested on EGI-1 xenografts in NOD/SCID mice. Results: In vitro, ET-743 is able to markedly reduce cell proliferation of BTC cell lines through cell cycle blockage on G0/G1 phase and to inhibit the growth of primary cell culture derived from GBC patient. Moreover, ET-743 promotes apoptosis by caspase 3 activation, activates proteins involved in DNA damage and reduces VEGF secretion. In the in vivo model, ET-743 is able to slow tumor growth in BTC xenograft. The mechanism of anti-tumor activity involves DNA damage, the induction of hypoxia transcription factor-1, and angiogenesis inhibition. ET-743 has no significant effect on apoptosis in vivo. Conclusions: These data suggest that ET-743 could represent an alternative chemotherapy for BTC treatment and encourage the development of clinical trials of ET-743 in BTC patients.
Sequence dependence of MEK inhibitor AZD6244 combined with gemcitabine for treatment of biliary cancer.
Authors: Xu Junyao , Knox Jennifer J. , Ibrahimov Emin , Chen Eric Xueyu , Serra Stefano , Tsao Ming Sound , Cao Pinjiang , Vines Douglass , Green David E , McNamara Mairead Geraldine , Hedley David W 
Published: February 2017

196 Background: MEK inhibition has clinical activity against biliary tract cancers, and might therefore be successfully combined with gemcitabine; one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the ERK pathway has a major role driving cell cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 in vitro and in vivo. Methods: Two biliary tract cancer cell lines and 4 xenografts established from patients were used in this study. In vitro, cell cycle effects of AZD6244 and their impact on gemcitabine sensitivity were detected by Flow cytometry, EdU uptake assay, MTS assay and Clonogenic survival assay. In vivo, tumor-bearing SCID mice were treated for 48hr with AZD6244 and then monitored for 48hr off treatment. Plasma and tumor drug levels were assessed by LC-MS. The time course for recovery of ERK signaling, cell cycle distribution and cell proliferation were measured by Immunofluorescence staining, Flow cytometry, EdU uptake assay and 18F-FLT PET imaging. Based on these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary tract cancer models. Results: DNA synthesis was suppressed during treatment with AZD6244, and re-entry into S-phase was delayed by 15hr in vitro and 48hr post-treatment in vivo. Concurrent treatment showed antagonistic effect (IC50=2.02±0.91uM) compared to gemcitabine alone (IC50=0.09±0.04uM) whereas when gemcitabine treatment was delayed for 24 hr after AZD6244 removal, enhanced cytotoxic effect was observed (IC50=0.051± 0.012uM). Consistantly, strong schedule dependence was seen in all four biliary cancer models tested: combined treatment with AZD6244 plus gemcitabine exerts enhanced antitumor effect when gemcitabine is given following a 48hr interruption in AZD6244 dosing, rather than concurrently. Conclusions: The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols.