Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer.

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.

Retrospective Comparative Study of Side-by-Side and Stent-in-Stent Metal Stent Placement for Hilar Malignant Biliary Obstruction.

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.

Preoperative biliary drainage using a fully covered self-expandable metallic stent for pancreatic head cancer: A prospective feasibility study.

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.

Thromboembolisms in Advanced Pancreatic Cancer: A Retrospective Analysis of 475 Patients.

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.

Conversion to endoscopic ultrasound-guided biliary drainage by temporary nasobiliary drainage placement in patients with prior biliary stenting.

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.

Antireflux Metal Stent as a First-Line Metal Stent for Distal Malignant Biliary Obstruction: A Pilot Study.

BACKGROUND/AIMS: In distal malignant biliary obstruction, an antireflux metal stent (ARMS) with a funnel-shaped valve is effective as a reintervention for metal stent occlusion caused by reflux. This study sought to evaluate the feasibility of this ARMS as a first-line metal stent. METHODS: Patients with nonresectable distal malignant biliary obstruction were identified between April and December 2014 at three Japanese tertiary centers. We retrospectively evaluated recurrent biliary obstruction and adverse events after ARMS placement. RESULTS: In total, 20 consecutive patients were included. The most common cause of biliary obstruction was pancreatic cancer (75%). Overall, recurrent biliary obstruction was observed in seven patients (35%), with a median time to recurrent biliary obstruction of 246 days (range, 11 to 246 days). Stent occlusion occurred in five patients (25%), the causes of which were sludge and food impaction in three and two patients, respectively. Stent migration occurred in two patients (10%). The rate of adverse events associated with ARMS was 25%: pancreatitis occurred in three patients, cholecystitis in one and liver abscess in one. No patients experienced nonocclusion cholangitis. CONCLUSIONS: The ARMS as a first-line biliary drainage procedure was feasible. Because the ARMS did not fully prevent stent dysfunction due to reflux, further investigation is warranted.

A pilot study of EUS-guided through-the-needle forceps biopsy (with video).

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.

A potent therapeutics for gallbladder cancer by combinatorial inhibition of the MAPK and mTOR signaling networks.

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.

Antireflux metal stent with an antimigration system for distal malignant biliary obstruction: a feasibility pilot study.

An antireflux metal stent (ARMS) for distal malignant biliary obstruction has been reported to be useful, but the effectiveness of a flared-end structure to prevent migration on ARMS remains unclear. To evaluate the feasibility of a newly designed ARMS with both ends flared, 8 patients with covered metal stent occlusion due to sludge or food impaction were enrolled. ARMS were placed successfully after endoscopic removal of the occluded stents in all patients, and no procedure-related complication was observed. The median time to recurrent biliary obstruction was 71 days. ARMS occlusion occurred in 3 (38%) patients (sludge in 2 patients and hemobilia in 1). ARMS migration occurred in 1 (13%) patient. As a late complication, cholecystitis occurred in 1 (13%) patient. In conclusion, our newly designed ARMS with an antimigration system was technically feasible and safe, and a further investigation is warranted to evaluate the effectiveness of the current antimigration system.

Pancreatic cancer with malignant ascites: clinical features and outcomes.

OBJECTIVES: Malignant ascites (MA) caused by peritoneal carcinomatosis is not uncommon in patients with pancreatic cancer. However, the clinical features and outcomes in these patients remain to be elucidated. METHODS: Baseline characteristics and overall survival (OS) of consecutive patients with advanced pancreatic cancer who presented with MA were retrospectively evaluated. RESULTS: Of 494 patients with advanced pancreatic cancer, 73 (15%) presented with MA. Patients with synchronous MA (n = 21), compared with those with metachronous MA (n = 52), had better performance status (P = 0.02), smaller amount of ascites (P < 0.01), and higher chance of receiving chemotherapy (57% vs 17%, P < 0.01), and resulted in longer OS (115 vs 42 days, P < 0.01). Overall survival was significantly longer in patients receiving chemotherapy than in those with best supportive care alone (124 vs 50 days, P < 0.01). In a multivariate analysis, chemotherapy was prognostic in addition to performance status, CRP, and small amount of MA; the hazard ratio of chemotherapy was 0.46, compared with best supportive care alone (P = 0.02). CONCLUSIONS: Although the prognosis of pancreatic cancer patients with MA remains poor, selected patients may be candidate for chemotherapy, regardless of the timing of appearance of MA.

Risk factors for post-ERCP pancreatitis in wire-guided cannulation for therapeutic biliary ERCP.

BACKGROUND: Wire-guided cannulation (WGC) was reported to decrease post-ERCP pancreatitis (PEP), but risk factors for PEP in WGC are not fully elucidated. OBJECTIVE: To evaluate the incidence and risk factors of PEP in WGC. DESIGN: Single-center retrospective study. SETTING: Academic center. PATIENTS: A total of 800 consecutive patients with a native papilla. INTERVENTIONS: Biliary therapeutic ERCP by using WGC. MAIN OUTCOME MEASUREMENTS: The rate of PEP and its risk factors. RESULTS: Biliary cannulation was successful by using WGC alone in 70.5%, and the final cannulation rate was 96.1%. Unintentional guidewire insertion and contrast material injection into the pancreatic duct (PD) during cannulation occurred in 55.3% and 21.8%, respectively. The incidence of PEP was 9.5% (mild 5.6%, moderate 2.9%, severe 1.0%). Multivariate analysis revealed a common bile duct (CBD) diameter of <9 mm (odds ratio [OR] 2.03; P = .006) and unintentional guidewire insertion into the PD (OR 2.25; P = .014) as risk factors for PEP. PD opacification was not a risk factor for PEP (OR 1.15; P = .642), but the incremental increase of the PEP rate was seen in patients with CBDs <9 mm: 4.6% without any PD manipulation, 8.3% with contrast material alone, 16.9% with guidewire alone, and 22.1% with both contrast material and guidewire. LIMITATIONS: Retrospective design in a single center. CONCLUSION: Unintentional PD manipulation was not uncommon in WGC. Guidewire insertion into the PD and a small CBD were risk factors for PEP in biliary therapeutic ERCP with the use of WGC.

The inhibition of renin-angiotensin system in advanced pancreatic cancer: an exploratory analysis in 349 patients.

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.

Clinical outcomes of secondary gastroduodenal self-expandable metallic stent placement by stent-in-stent technique for malignant gastric outlet obstruction.

BACKGROUND AND AIM: To evaluate the efficacy and safety of secondary gastroduodenal stent placement after first stent dysfunction for malignant gastric outlet obstruction. METHODS: We conducted a retrospective analysis to investigate the efficacy and safety of secondary stent-in-stent gastroduodenal stent placement. RESULTS: Among 260 patients who had been treated with first gastroduodenal stent placement for malignant gastric outlet obstruction, 29 patients (11.2%) were treated with secondary gastroduodenal stent placement because of first stent dysfunction. Pancreatic cancer was the major primary cancer (55.2%). A WallFlex duodenal stent was the most frequently inserted stent both as a first stent (75.9%) and as a secondary stent (62.1%). There were 22 patients (75.9%) that received gastroduodenal stents at the bending site (supraduodenal angle or infraduodenal angle). Technical and clinical success rates were 100% and 86.2%, respectively. Median eating period was 3.0 months, and median survival time was 3.5 months. As for related complications, gastrointestinal perforation, insufficient stent expansion, tumor ingrowth, tumor overgrowth, and cholangitis were experienced in 13.8% (four cases), 6.9% (two cases), 6.9% (two cases), 3.4% (one case), and 3.4% (one case), respectively. CONCLUSION: Secondary gastroduodenal stent placement might be effective for managing first stent dysfunction in malignant gastric outlet obstruction. However, gastrointestinal perforation was the major complication.

A phase I trial of gemcitabine, S-1 and LV combination (GSL) therapy in advanced pancreatic cancer.

PURPOSE: In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL). METHODS: Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m(2) over 30 min on day 1, and oral S-1 at a dose of 40 mg/m(2) twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1-7, every 2 weeks. A standard "3 + 3" phase I dose escalation design was utilized. RESULTS: Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥ 50 % decline. CONCLUSIONS: RD of gemcitabine in GSL was determined as 1,000 mg/m(2). GSL was well tolerable and showed promising results in advanced pancreatic cancer.

Intravenous and intraperitoneal paclitaxel with S-1 for refractory pancreatic cancer with malignant ascites: an interim analysis.

OBJECTIVES: Here, we reported an interim analysis of feasibility and safety in the first 10 cases of 30 cases in a phase II trial of intravenous and intraperitoneal paclitaxel combined with S-1 for gemcitabine-refractory pancreatic cancer with malignant ascites. METHODS: Paclitaxel was administered intravenously at 50 mg/m2 and intraperitoneally at 20 mg/m2 on days 1 and 8 every 3 weeks, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, followed by 7-day rest. RESULTS: Between April 2011 and February 2012, ten patients were enrolled. A partial response was achieved in two patients (20%) and a disease control rate of 50%. The median time to progression and overall survival were 2.1 and 3.4 months, respectively. Malignant ascites was completely resolved in two patients (20%). Major grade 3/4 adverse events were myelosuppression including neutropenia (50%) and catheter-related infection (10%). CONCLUSIONS: This novel combination chemotherapy was feasible and showed promising results in pancreatic cancer patients with malignant ascites (clinical trial registration number: UMIN000005306).

Incidence of malignancies in patients with IgG4-related disease.

OBJECTIVE: It has been discussed whether IgG4-related disease (IgG4-RD), including autoimmune pancreatitis (AIP), is associated with malignancy; however, the issue has not been clarified. METHODS: We analyzed 113 patients with IgG4-RD in whom malignancy was not diagnosed at the time of IgG4-RD onset and the follow-up period was longer than six months. A total of 95 patients had AIP. The mean follow-up period was 73 months. The incidence of the observed malignancies was compared with the expected incidence in an age- and sex-matched general Japanese population based on the Vital Statistics of Japan. RESULTS: There were 15 malignancies (lung cancer in five patients, pancreatic cancer in two patients, gastric cancer in two patients, bile duct cancer in one patient, renal cancer in one patient, breast cancer in one patient, tongue cancer in one patient, malignant melanoma in one patient and acute myeloid leukemia in one patient) in 14 patients during the follow-up period. The calculated standardized incidence rate of the total malignancies was not significant, that is, 1.04 (95% CI 0.57-1.75). CONCLUSION: The incidence of total malignancies in IgG4-RD patients is similar to that observed in the general population. At present, it is reasonable to conclude that IgG4-RD is not associated with an increased incidence of total malignancies.

High single-session success rate of endoscopic bilateral stent-in-stent placement with modified large cell Niti-S stents for malignant hilar biliary obstruction.

BACKGROUND: Endoscopic bilateral self-expandable metallic stent (SEMS) placement in a stent-in-stent method for malignant hilar biliary obstruction is technically challenging. Technical difficulties in the initial placement and reinterventions for stent occlusion are disadvantages inherent to this stent-in-stent method. We previously reported the feasibility of Niti-S large cell D-type biliary stents (LCD). This multicenter prospective consecutive study evaluated the efficacy of bilateral SEMS placement using modified LCD with large and uniform cells, a slimmer delivery system and high radial force. PATIENTS AND METHODS: From July 2010 to June 2011, 26 consecutive patients with unresectable malignant hilar biliary obstruction underwent endoscopic bilateral placement of modified LCD in a stent-in-stent method at three tertiary hospitals. Ten patients had gallbladder cancer, eight had cholangiocarcinoma, four had lymph node metastasis, two had intrahepatic cholangiocarcinoma, and two had liver metastasis. RESULTS: Single-session and final technical success rate was 96% and 100%, respectively. Functional success rate was 89%. Stent occlusion occurred in 11 patients (42%) because of sludge (n = 7) or tumor ingrowth (n = 4). Endoscopic bilateral reintervention was technically easy and successful: six patients had stent clearance by balloon sweeping and five had plastic stent placement. According to Kaplan-Meier analysis, median survival and stent patency were 220 days and 157 days, respectively. CONCLUSIONS: Modified LCD achieved a high technical success rate both in the initial stent-in-stent placement and in bilateral reinterventions in patients with malignant hilar biliary obstruction.