PurposeThe aim of this multicenter retrospective study was to evaluate the impact of statin use on clinical outcomes in patients with unresectable pancreatic cancer (PC) receiving gemcitabine plus nab-paclitaxel (GnP) in a large Japanese cohort.Materials and MethodsWe retrospectively reviewed the medical records including data on the use of concomitant medications in patients with unresectable PC receiving GnP between January 2015 and January 2019 at 10 hospitals. Prognostic factors for progression-free survival (PFS) and overall survival (OS) were evaluated.ResultsA total of 1682 patients were included in the analysis; of which 322 patients (19%) received statins and 1360 (81%) did not receive statin. The median PFS and OS were 7.5 versus 7.3 months (P = 0.87) and 15.1 versus 14.4 months (P = 0.48) in cases with and without statin use. The use of statin was not associated with PFS (hazard ratio, 1.01; 95% confidence interval, 0.85-1.18, P = 0.93) or OS (hazard ratio, 1.05; 95% confidence interval, 0.91-1.21, P = 0.47) in the multivariable analyses. PFS and OS did not significantly differ by liposolubility of statins, either.ConclusionsStain use was not associated with PFS or OS in patients with unresectable PC receiving GnP.

Supplementary Figure 3-2 PDF file - 172K, Gemcitabine-induced expression of EGFR ligands was dependent on active MAPK signaling in the lung cancer cells

Supplementary Figure 3-1 PDF file - 354K, Gemcitabine-induced expression of EGFR ligands was dependent on active MAPK signaling in the PDAC cells

Supplementary Table 1 PDF file - 108K, Adding erlotinib to gemcitabine synergistically inhibited the growth of mouse and human PDAC cells

Supplementary Figure 2 PDF file - 97K, MEK inhibition reduced the gemcitabine-induced activation of EGFR and ErbB2 in the PDAC cells

Supplementary Materials PDF file - 91K, Supplementary Methods and Figure Legends

Supplementary Figure 1 PDF file - 186K, Exogenous EGF rescued gemcitabine-induced apoptosis in vitro

Supplementary Figure 5 PDF file - 1755K, Gemcitabine-induced EGFR/ErbB2-MAPK signal activation was a common phenomenon in PDAC and lung cancer cells irrespective of KRAS mutation status and gemcitabine sensitivity.

Supplementary Figure 4 PDF file - 177K, The effect of erlotinib was mainly through the inhibition of MAPK signaling

Background In 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. Study Clinical 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. Results A 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. Conclusions Other 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.

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.

Background and Objectives: Endoscopic ultrasound-guided biliary drainage (EUS-BD), first reported as an alternative to percutaneous transhepatic BD in failed endoscopic retrograde cholangiography, is sometimes performed as reintervention for transpapillary stent dysfunction such as in patients with new onset gastric outlet obstruction, but direct conversion to EUS-BD can potentially have a risk of leakage of infected bile. The aim of this study is to evaluate the safety and efficacy of conversion to EUS-BD using a temporary endoscopic nasobiliary drainage (ENBD) tube placement as a reintervention for prior BD. Patients and Methods: Sixteen patients with prior BD for malignant biliary obstruction undergoing conversion to EUS-BD using a temporary ENBD tube placement were studied. Technical and clinical success rate and adverse events were evaluated. Results: The major reason for conversion to EUS-BD was recurrent cholangitis due to duodenobiliary reflux (n = 13). In 14 patients with an indwelling covered metal or plastic stent, the stents were removed before temporary ENBD placement. After a median duration of 6 days, subsequent conversion to EUS-BD using a covered metal stent was performed, which was technically and clinically successful in all 16 patients (14 hepaticogastrostomy and 2 choledochoduodenostomy). Adverse events were observed in 3 patients (19%): one bleeding, one cholecystitis, and one cholangitis. No bile leak, peritonitis, or sepsis was observed. Conclusions: Conversion to EUS-BD using temporary ENBD tube placement in patients with prior BD was technically feasible and relatively safe without infectious complications related to bile leakage.

Objectives Pancreatic cancer is reported to be highly associated with thromboembolism (TE). The aim of this analysis is to clarify risk factors for TE and its clinical impact in Japanese patients with pancreatic cancer.Methods Data on consecutive pancreatic cancer patients receiving systemic chemotherapy between August 1999 and July 2015 were retrospectively studied. Both symptomatic and asymptomatic, arterial and venous TEs were included in the analysis. Risk factors for TE development were analyzed using a proportional hazards model with death without TE as a competing risk. The impact of TE on survival was also evaluated using a time-dependent covariate multiple Cox model.Results A total of 475 patients were included in the analysis, and 57 TEs (12%) were identified: 45 venous TEs and 12 arterial TEs. The median time to TE was 169 days and the median survival from TE was 65 days. Liver metastasis was the only significant risk factor for TE (subdistribution hazards ratio, 2.15; P = 0.01), and TE was significantly associated with poor prognosis (hazards ratio, 3.31; P < 0.01).Conclusions Thromboembolism was not uncommon in Japanese patients receiving chemotherapy for advanced pancreatic cancer and was associated with poor prognosis. Liver metastasis was the risk factor for TE.

OBJECTIVE:To predict the duration of steroid maintenance therapy required to achieve good prognosis in patients with autoimmune pancreatitis. PATIENTS AND METHODS:The study sample comprised 21 patients with autoimmune pancreatitis who met the following criteria: (1) they received steroid therapy (ST) for at least 3 years without clinical relapse; and (2) immunoglobulin (Ig) G<1600 mg/dL was observed in the past year with a prednisolone maintenance dose ≤5 mg. All patients could be diagnosed with international consensus diagnostic criteria. Patients were prospectively followed up after tapering and cessation of steroids. Clinical relapse was defined as the need to resume ST. Serological relapse was defined as having an IgG level of >1600 mg/dL. RESULTS:During the 43-month (range, 19 to 48 mo) follow-up period, clinical relapse occurred in 10 patients: pancreatic lesion in 4; coronary lesion in 2; submandibular lesion in 1; both pulmonary and renal lesions in 1; pulmonary, retroperitoneal, and submandibular lesions in 1; and bronchial asthma in 1. Serological relapse was observed in 12 patients. Although clinical and serological relapse occurred concomitantly in 3 patients, serological relapse preceded clinical relapse in 4 patients. Five patients experienced serological relapse alone, and no clinical or serological relapse occurred in 6 patients. According to Cox proportional hazard analysis, the duration of ST before tapering was a significant predictive parameter (hazard ratio, 0.969/month; 95% confidence interval, 0.940-0.998; P=0.038). CONCLUSIONS:ST cessation resulted in a high rate of clinical relapses, even in patients with long-term maintenance therapy. Therefore, it appears desirable to continue steroid maintenance therapy for a period >3 years to prevent relapse.

BACKGROUND AND AIMS:In EUS-guided FNA (EUS-FNA), small-caliber needles are preferable for optimal cytologic yield, whereas large ones are preferable when histologic specimens are needed. Because of the rigidity and friction induced by its large caliber, however, technical limitation does exist in a 19-gauge FNA needle. Recent development of miniature biopsy forceps enables EUS-guided through-the-needle forceps biopsy (EUS-TTNFB). The aim of this study is to evaluate safety and efficacy of EUS-TTNFB.METHODS:Eighteen sessions of EUS-TTNFB in 17 patients with solid lesions were performed by using a 0.75-mm biopsy forceps through a 19-gauge FNA needle. Technical feasibility, safety, and diagnostic yield of EUS-TTNFB were retrospectively studied.RESULTS:A total of 49 passes, a median of 3 passes per session, were performed, and the needle puncture, advancement and removal of the biopsy forceps, and subsequent EUS-FNA were technically successful in all patients. No adverse events were observed other than one case with hyperamylasemia without pancreatitis. Macroscopic histologic core by EUS-TTNFB was obtained at a rate of 71% per pass. The tissue acquisition rate by EUS-TTNFB alone was 67% per pass and 100% per session. When EUS-TTNFB and subsequent EUS-FNA were combined, the tissue acquisition rate was 94% per pass. The accuracy of combined EUS-TTNFB and EUS-FNA to diagnose malignancy was 88% per pass and 94% per session. With a single pass of EUS-TTNFB and EUS-FNA, the tissue acquisition rate was 89%, and the accuracy to diagnose malignancy was 83%.CONCLUSIONS:EUS-TTNFB was safe and technically feasible and provided additional tissue acquisition with a single puncture of a 19-gauge FNA needle.

218 Background: Thromboembolism (TE) is common in cancer patients, and pancreatic cancer is reported to be highly associated with TE. The aim of this analysis is to clarify risk factors for TE and its clinical impact in pancreatic cancer patients. Methods: Data on consecutive pancreatic cancer patients receiving systemic chemotherapy between August 1999 and July 2015 were retrospectively studied. The diagnosis of TE was made on CT scan either performed for suspicious symptoms of TE or for evaluation of chemotherapy response, and TE was classified into two groups: arterial events including coronary artery disease (CAD), cerebrovascular disease and other artery thrombosis, and venous events including deep vein thrombosis/pulmonary embolism (DVT/PE), portal vein thrombosis (PVT) and IVC thrombosis. Overall survival and time to TE (TTE) were calculated by Kaplan-Meier analysis. Risk factors for TE development were analyzed using a Cox proportional hazards model. To evaluate the impact of TE on survival, multivariate analyses were performed using a time-dependent covariate multiple Cox model. Results: A total of 475 patients (195 female, a median age of 67 years) were analyzed. TE was identified in 57 patients (12%). Venous TE were 45 (79%) including DVT/PE 24(42%), IVC thrombosis 2 (4%), PVT 19 (33%). Arterial TE were 12 (21%) including cerebrovascular infarction 9 (16%), CAD 2 (4%) respectively. The median TTE was 169 days (95% CI, 75-203). Liver metastasis was the only significant risk factor for TE in the multivariate analysis (OR 2.01, 95%CI 1.12-3.47, P = 0.012). The median survival from TE development was 57 days (95% CI, 37-65) and TE was significantly associated with poor prognosis (HR 3.31, 95%CI 2.72-5.27, P< 0.01) in the time-dependent covariate analysis. Conclusions: TE was not uncommon in pancreatic cancer patients receiving chemotherapy and was associated with poor prognosis. Whether the prophylaxis for TE can improve survival should be further investigated, especially in high risk patients such as patients with liver metastasis.

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.

Background/Aims: Endoscopic papillary balloon dilation (EPBD) is a possible alternative to endoscopic sphincterotomy (EST) for common bile duct (CBD) stones. To date, 10- and 8-mm EPBD have not been fully compared. Patients and Methods: Patients who underwent EPBD for CBD stones at two Japanese tertiary care centers between May 1994 and January 2014 were identified. Matched pairs with 10- and 8-mm EPBD were generated. Short- and long-term outcomes were compared between the two groups. Results: A total of 869 patients were identified (61 and 808 patients for 10- and 8-mm EPBD, respectively), and 61 well-balanced pairs were generated. The rate of complete stone removal within a single session was higher in the 10-mm EPBD group than in the 8-mm EPBD group (69% vs. 44%, P < 0.001), and use of lithotripsy was less frequent in the 10-mm EPBD group (23% vs. 56%, P < 0.001). The rates of post-ERCP pancreatitis were similar between the 10- and 8-mm EPBD groups (11% vs. 8%). Cumulative biliary complication-free rates were not statistically different between the two groups: 88% [95% confidence interval (CI): 79–97%] and 94% (95% CI: 88–100%) at 1 year and 69% (95% CI: 56–85%) and 80% (95% CI: 69–93%) at 2 years in the 10- and 8-mm EPBD groups, respectively. In the 10-mm EPBD group, ascending cholangitis was not observed, and pneumobilia was found in 5% of cases during the follow-up period. Conclusions: EPBD using a 10-mm balloon for CBD stones is safe and more effective than 8-mm EPBD. The sphincter function is highly preserved after 10-mm EPBD.