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Background and Aims We previously reported preliminary safety results for a new method, endoscopic detachable snare ligation (EDSL), for diverticular hemorrhage. This method does not need endoscope removal to attach a ligation device after detection of the bleeding site. The aim of the present study was to evaluate the efficacy and safety of EDSL in a larger patient population. Methods This prospective study was conducted in 12 institutions. Patients suspected of having diverticular hemorrhage without serious systemic disease were enrolled. The primary endpoint was early (within 30 days) recurrent bleeding rate in patients treated with EDSL. The secondary endpoints were overall early recurrent bleeding rate in patients with definite diverticular bleeding and adverse events in patients treated with EDSL. Results From June 2015 to March 2017, bleeding diverticula were detected in 123 of 205 enrolled patients (60%), of whom 101 (82%) were treated with EDSL. Most patients (20/22) in whom EDSL was not successful were treated with clipping. The early recurrent bleeding rate was 7.9% (95% confidence interval, 2.6%-13.2%; 8/101) in patients who could be treated with EDSL. The median total endoscopic and EDSL procedure time was 40 minutes (interquartile range, 15-71) and 4 minutes (interquartile range, 1-7), respectively. Two mild adverse events, colonic diverticulitis and temporary abdominal pain, were observed. Conclusion EDSL was confirmed to be useful and safe for treatment of colonic diverticular hemorrhage. (Clinical trial registration number: UMIN 000001858.)

Background and study aims: Colonic diverticular hemorrhage is the most common cause of lower intestinal bleeding. We tried to develop a convenient and reliable hemostatic method, endoscopic detachable snare ligation (EDSL), to treat diverticular hemorrhage and retrospectively explored its safety and efficacy. Patients and methods: The definitive bleeding diverticulum was ligated with a detachable snare, instead of a rubber band, in a procedure similar to endoscopic band ligation. Removal of the scope to attach a ligation device and reinsertion for treatment are not needed in this method. Results: From November 2013 to September 2014, EDSL was used to treat 8 patients with colonic diverticular hemorrhage. The mean procedure time required for hemostasis after identification of the bleeding diverticulum was 5 ± 2 minutes. Sustained hemostasis was achieved in 7 patients (88 %), and early rebleeding occurred in 1 patient, in whom the applied suction seemed inadequate. No complications occurred in any patient. Conclusions: EDSL may be a safe and effective treatment for colonic diverticular hemorrhage. However, additional studies are warranted to confirm these initial exploratory data.

Combination therapy with replicative oncolytic viruses is a recent topic in innovative cancer therapy, but few studies have examined the efficacy of oncolytic adenovirus plus replication-deficient adenovirus carrying a suicide gene. We aim to evaluate whether an E1A, E1B double-restricted oncolytic adenovirus, AxdAdB-3, can improve the efficacy for gallbladder cancers (GBCs) of the replication-deficient adenovirus-based herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) therapy directed by the carcinoembryonic antigen (CEA) promoter. Cytopathic effects of AxdAdB-3 plus AxCEAprTK (an adenovirus expressing HSVtk directed by CEA promoter) or AxCAHSVtk (an adenovirus expressing HSVtk directed by a nonspecific CAG promoter) with GCV administration were examined in several GBC lines and normal cells. Efficacy in vivo was tested in severe combined immunodeficiency disease mice with GBC xenografts. Addition of AxdAdB-3 (1 multiplicity of infection, MOI) significantly enhanced the cytopathic effects of AxCEAprTK (10 MOI)/GCV on GBC cells. The augmented effect was attributable to the replication of the AxCEAprTK and also to the enhanced CEA promoter activity, which was presumably transactivated by E1A. In normal cells, AxdAdB-3 (20 MOI) plus AxCEAprTK (200 MOI)/GCV was not cytopathic, whereas AxdAdB-3 (1 MOI) plus AxCAHSVtk (10 MOI)/GCV was significantly toxic. Low-dose AxdAdB-3 (2 x 10(7) PFU, plaque-forming unit) plus AxCEAprTK (2 x 10(8) PFU)/GCV significantly suppressed the growth of GBC xenografts as compared with either AxdAdB-3 (2 x 10(7) PFU)/GCV or AxCEAprTK (2 x 10(9) PFU)/GCV alone. E1A, E1B double-restricted replicating adenovirus at low dose significantly augmented the efficacy of CEA promoter-directed HSVtk/GCV therapy without obvious toxicity to normal cells, suggesting a potential use of this combination for treating GBC and other CEA-producing malignancies.

Purpose: Cancers of biliary system represent highly malignant diseases of dismal prognosis. We have previously introduced AxdAdB3, an E1A, E1B double-restricted oncolytic adenovirus, which showed excellent oncolytic efficacy for approximately half of the biliary cancer lines with an enhanced safety to normal cells. The purpose of this study was to evaluate whether RGD-fiber modification (AxdAdB3-F/RGD), which enables integrin-dependent infection, can improve the infectivity and efficacy of AxdAdB3 for biliary cancers.Experimental Design: Expressions of adenoviral receptors, coxsackievirus adenovirus receptor (CAR) and integrins (αvβ3 and αvβ5), were compared with the level of infectivity of LacZ-expressing replication-defective adenoviruses with wild-type fibers or RGD-modified fibers in a panel of biliary cancer cell lines in vitro. Viral replication and cytotoxicity in vitro of AxdAdB3-F/RGD, a novel E1A, E1B double-restricted replication-selective adenovirus with RGD-modified fibers, were compared with those of its parent virus, AxdAdB3, in various biliary cancer cells and in normal cells. In vivo antitumor effects of these oncolytic viruses were compared in a xenograft tumor model.Results: Expression of CAR significantly correlated with the adenovirus infectivity, whereas integrin αvβ5 was abundantly expressed in almost all biliary cancer cells. Whereas AxdAdB3 effectively replicated and lysed only the biliary cancer cells with a preserved expression of CAR, AxdAdB3-F/RGD exhibited efficient replication and potent oncolysis in both CAR-positive and CAR-negative biliary cancer cells. AxdAdB3-F/RGD showed attenuated replication and little cytopathy in human normal cells (i.e., hepatocytes, WI-38 cells) as well as AxdAdB3. Furthermore, in nude mice with s.c. xenografts of CAR-deficient human biliary cancer, i.t. AxdAdB3-F/RGD therapy caused a marked inhibition of tumor growth.Conclusions: The RGD-fiber modification strategy enhanced the infectivity, replication, and oncolytic effects of the E1A, E1B double-restricted oncolytic adenovirus for CAR-deficient biliary cancers. In addition, it preserved the merit of excellent safety of the double-restricted virus for normal cells. These results suggest a potential use of this agent for the treatment of biliary cancers.

Advanced gallbladder cancer (GBC) is one of the most difficult cancers to be cured by cmT~nt therapies and new treatments, such as gene therapy, are necessary, but little has been studied Recent studies have introduced E1B mntam adenoviruses fad) focusing on tmnor-specific replication, and clinical results have been promising. We have constructed AxdAdB-3, a E1 double-mutant Ad with a mutant EIA and E1B-55kD deletion and reported on its efficacy for GBC as well as enhanced safety m normal cells. ALMS: We aimed to study the combined effects of this Ad and chemotherapy with 5-fluoronracil (5-FU) on GBC in vivo, METHODS: We compared the replication and the cytopathic effects of AxdAdB-3 in several lines of GBC and prima~y normal cells with those of wild-t3~?e Ad The efficacy in vivo was examined in nude mice with subcataneously implanted or intraperitoneally disseminated GBC Mice were separated into the following groups; contrd, Ad monotherapy, 5-FU monotherapy, and combination therapy of Ad and 5-FU. Ad was intratumorally injected ~br subeutaneons xenografis and intraperitoneally injected for disseminated GBC with or wtdmut intraperitoneal injection of 5FU. RESULTS: Axcka-dB-3 replicated and caused oncolysis as efficient]y as wild-type Ad in several GBC cell lines, whereas it replicated much less effectively in normal cells and had only' a mild cytopathic eitect unlike wild-type Ad in vitro. Furthermore, cytotoxicity of Ax&a-dB-3 in normal cells was milder than AxE1AdB, a E1B55kD deleted Ad. AxdAdB-3 significantly suppressed the growth of subeutaneous GBC xenogmfis and also showed eft~:ctiveness in the treatment of peritoneaily disseminated GBC with significantly prolonged survival Combination therapy with 5-FU further regressed the subcutaneous GBC xenografts and significantly prolonged the survival of mice with disseminated GBC. CONCLUSIONS: E1 double-mntant Ad effectively and selectively replicated and caused oncolysis in GBC in vitro and in vivo with reduced negative eflects on normal cells, Combination therapy wifh 5-FU further enhanced its efficacy in vivo, suggesting a synergistic therapeutic effects of the virotherapy and chemotherapy for GBC.