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BackgroundIn patients with unresectable hilar malignant biliary obstruction (MBO), bilateral metal stent placement is recommended. However, treatment selection between partially stent-in-stent (SIS) and side-by-side (SBS) methods is still controversial.StudyClinical outcomes of bilateral metal stent placement by SBS and SIS methods for hilar MBO were retrospectively studied in four Japanese centers. While large-cell-type uncovered metal stents were placed above the papilla in SIS, braided-type uncovered metal stents were placed across the papilla in SBS.ResultsA total of 64 patients with hilar MBO (40 SIS and 24 SBS) were included in the analysis. Technical success rate was 100% in SIS and 96% in SBS. Functional success rate was 93% in SIS and 96% in SBS. Early adverse event rates were higher in SBS (46%) than in SIS (23%), though not statistically significant (P = 0.09). Post-procedure pancreatitis was exclusively observed in SBS group (29%). Recurrent biliary obstruction rates were 48% and 43%, and the median time to recurrent biliary obstruction was 169 and 205 days in SIS and SBS, respectively.ConclusionsOther than a trend to higher adverse event rates including post-procedure pancreatitis in SBS, clinical outcomes of SIS and SBS methods were comparable in patients with unresectable hilar MBO.

Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal neoplasms, is characterized by an expanded stroma with marked fibrosis (desmoplasia). We previously generated pancreas epithelium-specific TGF-β receptor type II (Tgfbr2) knockout mice in the context of Kras activation (mice referred to herein as Kras+Tgfbr2KO mice) and found that they developed aggressive PDAC that recapitulated the histological manifestations of the human disease. The mouse PDAC tissue showed strong expression of connective tissue growth factor (Ctgf), a profibrotic and tumor-promoting factor, especially in the tumor-stromal border area, suggesting an active tumor-stromal interaction. Here we show that the PDAC cells in Kras+Tgfbr2KO mice secreted much higher levels of several Cxc chemokines compared with mouse pancreatic intraepithelial neoplasia cells, which are preinvasive. The Cxc chemokines induced Ctgf expression in the pancreatic stromal fibroblasts, not in the PDAC cells themselves. Subcutaneous grafting studies revealed that the fibroblasts enhanced growth of PDAC cell allografts, which was attenuated by Cxcr2 inhibition. Moreover, treating the Kras+Tgfbr2KO mice with the CXCR2 inhibitor reduced tumor progression. The decreased tumor progression correlated with reduced Ctgf expression and angiogenesis and increased overall survival. Taken together, our data indicate that tumor-stromal interactions via a Cxcr2-dependent chemokine and Ctgf axis can regulate PDAC progression. Further, our results suggest that inhibiting tumor-stromal interactions might be a promising therapeutic strategy for PDAC.

Background Intraductal papillary mucinous neoplasm (IPMN) is recognized as a precursor lesion to pancreatic cancer, a unique pathological entity. IPMN has subtypes with different clinical characteristics. However, the molecular mechanisms of cancer progression from IPMN remain largely unknown. In this study we examined the differences in genetic alteration(s) among the IPMN subtypes. Methods Surgically resected IPMNs ( n  = 25) were classified into four subtypes by hematoxylin and eosin (H&E) and mucin immunostaining. Mutations in KRAS , BRAF , and PIK3CA genes and expression of CDKN2A, TP53, SMAD4, phospho-ERK, and phospho-SMAD1/5/8 proteins were examined. Results There were 11 gastric, 11 intestinal, one pancreatobiliary, and two oncocytic types in this study. We then compared the two major subtypes, gastric-type and intestinal-type IPMN. Gastric-type IPMN showed a significantly higher incidence of KRAS mutations (9/11, 81.8%) compared with intestinal type (3/11, 27.3%; p  < 0.05), although the intestinal type showed a higher grade of dysplasia than gastric type ( p  < 0.01). All cases with KRAS mutations showed phospho-ERK immunostaining. In contrast, intestinal type (9/11, 81.8%) showed more frequent SMAD1/5/8 phosphorylation compared with gastric-type IPMN (3/11, 27.3%; p  < 0.05%). Conclusions There may be distinct mechanisms of pancreatic cancer progression in the different subtypes of IPMN. In particular, KRAS mutation and bone morphogenetic protein-SMAD signaling status may be crucial diverging steps for the two representative pathways to pancreatic cancer in IPMN patients.

Background Diabetes mellitus (DM) has long been recognized as a risk factor for pancreatic cancer (PaC) and recently has attracted attention as a manifestation of PaC. Diabetes is expected to be a clue for the early detection of PaC; however, no effective screening strategy has been established. Methods Forty diabetic patients with PaC were identified and compared with 120 diabetic patients without any malignancies. We analyzed risk factors for and early signs of PaC, focusing on the DM-onset age. Results As there were peaks at 40–45 years and 60–65 years in the distribution of DM-onset age, we analyzed the clinical characteristics of and risk factors for PaC according to DM-onset age: i.e., early-onset (<55 years) and late-onset (≥55 years). PaC was diagnosed within 2 years of DM onset (new-onset) in 0 % of the patients with early-onset DM, and in 33 % of those with late-onset DM. The mean duration of DM in patients with early-onset DM with PaC was longer than that in the late-onset patients (26 vs. 9 years; P  < 0.01). A family history of DM (odds ratio [OR] 3.60) and use of insulin (OR 3.52) were significant risk factors in patients with early-onset DM, while the onset age of DM (OR 1.12) and multiple diabetic patients in the family (OR 6.13) were risk factors in those with late-onset DM. Body weight loss and exacerbation of DM were seen 12 months prior to PaC diagnosis in both groups. Conclusions Our study revealed specific risk factors for and similar early signs of PaC in early-onset and late-onset DM. Thus, we could develop a screening strategy, combining these risk factors specific for DM-onset age with early signs of disease.

Background Gallbladder cancer (GBC) is the most common type of cancer with the worst prognosis among the bile duct cancers. There still remains a clear need for effective mechanism-based novel therapeutic approaches. A crosstalk between mitogen-activated protein kinase (MAPK) and the mammalian target of Rapamycin (mTOR) signaling pathways has been reported in several cancers. We hypothesized that targeting both pathways in combination will be a potent therapeutic for GBC. Methods Expression of phospho-ERK and phospho-S6rp protein were evaluated by immunostaining in surgically resected GBC specimens ( n  = 30). GBC cell lines and a xenograft model were treated with CI-1040, an inhibitor of MEK (mitogen-activated protein kinase kinase) and RAD001, an inhibitor of mTOR, alone or in combination, and then, we examined the cell proliferation and tumor growth, cell cycle status, and apoptosis. Results Analysis of human GBC tissues demonstrated that MAPK and mTOR signaling pathways were frequently coordinately dysregulated in one third of them. The combination therapy inhibited both signaling pathways and subsequently inhibited human GBC cell proliferation in vitro and xenograft tumor growth in vivo. Compared to the single treatment, the combination therapy significantly induced cell cycle arrest and apoptosis with decreased cyclin D1 expression. Conclusions The double blockade of MAPK and mTOR signaling pathways inhibits the signal crosstalk and shows anti-tumor activity, which can be a potent therapeutic for GBC, especially for the patients with hyperactivated signaling of both pathways.

Background Cholecystectomy after endoscopic sphincterotomy for bile duct stones with concomitant gallstones is known to reduce late biliary complications. Endoscopic papillary balloon dilation for bile duct stones develops fewer late biliary complications than endoscopic sphincterotomy, but no randomized controlled trials have been conducted about the role of cholecystectomy after endoscopic papillary balloon dilation. Therefore, we conducted this propensity score-matched analysis to compare cholecystectomy and wait-and-see approach after endoscopic papillary balloon dilation. Methods Propensity score matching extracted 147 pairs of patients with cholecystectomy after endoscopic papillary balloon dilation and with gallbladder left in situ with stones (wait-and-see) from 725 patients who underwent endoscopic papillary balloon dilation for bile duct stones. Late biliary complications such as recurrent bile duct stones and cholecystitis were evaluated. Cumulative incidence of late biliary complications was calculated treating death without biliary complications as a competing risk, and its prognostic factor was evaluated. Results The rates of late biliary complications were 5.4 and 25.2 % in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see groups: Recurrent bile duct stones rates were 4.1 and 19.0 %, and cholecystitis rates were 0.7 and 6.1 %. The cumulative incidences of biliary complications in the cholecystectomy after endoscopic papillary balloon dilation and wait-and-see approach were 3.1 versus 13.0 % at 1 year and 5.7 versus 28.0 % at 5 year after endoscopic papillary balloon dilation ( p  = 0.008). Subdistribution hazard ratio of late biliary complications in the wait-and-see group was 5.1 ( p  = 0.020). Conclusion Cholecystectomy after endoscopic papillary balloon dilation for choledocholithiasis was associated with fewer late biliary complications. Prophylactic cholecystectomy should be offered to all surgically fit patients after endoscopic papillary balloon dilation for bile duct stones with concomitant gallstones.

Purpose The role of local renin-angiotensin system (RAS) as a target for the treatment of pancreatic cancer has been increasingly reported, but the addition of candesartan, one of angiotensin system inhibitors (ASIs), to gemcitabine in our prospective trial failed to demonstrate activity against pancreatic cancer. The aim of this study was to explore subgroups that would benefit from the inhibition of RAS by the use of ASIs. Methods Consecutive patients with advanced pancreatic cancer receiving gemcitabine-based chemotherapy were retrospectively studied. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were estimated by a Cox proportional hazards model. Interactions between the use of ASIs and each subgroup were tested. Results Between 2001 and 2013, 349 patients received gemcitabine-based chemotherapy for advanced pancreatic cancer; 232 were metastatic, 210 received gemcitabine monotherapy, 108 took ASIs, 166 were never smokers and 188 were diabetic. The median PFS and OS were 4.9 and 11.2 months, respectively. When the effects of the use of ASIs were evaluated by a Cox proportional hazard model, there were two subgroups with P interaction <0.10 both in PFS and OS: never smokers and gemcitabine monotherapy. HRs for PFS and OS by the inhibition of RAS were 0.71 ( P  = 0.021) and 0.68 ( P  = 0.014) in never smokers and 0.70 ( P  = 0.027) and 0.77 ( P  = 0.124) in patients receiving gemcitabine monotherapy. Conclusion The inhibition of RAS in advanced pancreatic cancer might improve clinical outcomes in cases without a history of smoking or in cases receiving gemcitabine monotherapy.

Background/Aims: The role of endoscopic preoperative biliary drainage (PBD) for pancreatic head cancer is controversial because of the high incidence of stent occlusion before surgery. This study was performed to evaluate the feasibility and safety of PBD using a fully covered self-expandable metallic stent (FCSEMS). Patients and Methods: This multicenter prospective study involved 26 patients treated for pancreatic head cancer with distal bile duct obstruction from April 2011 to March 2013. An FCSEMS was endoscopically placed in 24 patients. Among these, 7 patients were diagnosed with unresectable cancer, and 17 underwent surgery at a median of 18 days after FCSEMS placement. The main outcome measure was preoperative and postoperative adverse events. Results: Two adverse events (cholecystitis and insufficient resolution of jaundice) occurred between FCSEMS placement and surgery (12%). Postoperative adverse events occurred in eight patients (47%). The cumulative incidence of stent-related adverse events 4 and 8 weeks after FCSEMS placement among the 24 patients who underwent this procedure were 19%. Conclusions: PBD using an FCSEMS is feasible in patients with resectable pancreatic head cancer. Placement of an FCSEMS can be an alternative PBD technique when surgery without delay is impossible. A larger randomized controlled trial is warranted.