Does endoscopic sphincterotomy contribute to the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis after endoscopic biliary stenting for malignant biliary obstruction? A multicenter prospective cohort study.

BACKGROUND: There is no consensus on the necessity of endoscopic sphincterotomy (ES) to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) after endoscopic stenting in patients with malignant biliary obstruction. We investigated the incidence of PEP after endoscopic biliary stenting for malignant biliary obstruction with or without ES in a multicenter prospective cohort study. METHODS: We enrolled 807 patients who underwent endoscopic biliary stenting for malignant biliary obstruction with a native papilla at 36 hospitals between April 2017 and March 2018. The incidence of PEP in patients with or without ES was compared for subgroups based on stent type, placement method, and patient background. Univariate and multivariate analysis was performed to investigate the incidence of PEP in all stenting patients. RESULTS: Plastic and metal stents (MS) were inserted in 598 and 209 patients, respectively. The incidence of PEP in patients with or without ES was 7.9% and 7.4%, respectively among all stenting patients. The incidences of PEP with or without ES in plastic stent insertion patients, patients with MS insertion, stent insertions across the papilla, stent insertions across the papilla in patients without main pancreatic duct obstruction, and fully covered MS insertions across the papilla were compared. There was no overall significant difference in the incidence of PEP between those with or without ES. Multivariate logistic regression analysis for the incidence of PEP in all stenting patients revealed obstruction of the main pancreatic duct at the pancreatic head and epinephrine spraying on the papilla were significant factors; there was no significant difference in the incidence of PEP between patients with or without ES. CONCLUSION: Endoscopic sphincterotomy may not contribute to the prevention of PEP after endoscopic biliary stenting for malignant biliary obstruction, even in cases of insertion with a fully covered MS across the papilla.

Optimal treatment strategies for hepatic portal venous gas: A retrospective assessment.

BACKGROUND: Hepatic portal venous gas (HPVG) generally indicates poor prognoses in patients with serious intestinal damage. Although surgical removal of the damaged portion is effective, some patients can recover with conservative treatments. AIM: To establish an optimal treatment strategy for HPVG, we attempted to generate computed tomography (CT)-based criteria for determining surgical indication, and explored reliable prognostic factors in non-surgical cases. METHODS: Thirty-four cases of HPVG (patients aged 34-99 years) were included. Necessity for surgery had been determined mainly by CT findings (i.e. free-air, embolism, lack of contrast enhancement of the intestinal wall, and intestinal pneumatosis). The clinical data, including treatment outcomes, were analyzed separately for the surgical cases and non-surgical cases. RESULTS: Laparotomy was performed in eight cases (surgical cases). Seven patients (87.5%) survived but one (12.5%) died. In each case, severe intestinal damage was confirmed during surgery, and the necrotic portion, if present, was removed. Non-occlusive mesenteric ischemia was the most common cause (n = 4). Twenty-six cases were treated conservatively (non-surgical cases). Surgical treatments had been required for twelve but were abandoned because of the patients' poor general conditions. Surprisingly, however, three (25%) of the twelve inoperable patients survived. The remaining 14 of the 26 cases were diagnosed originally as being sufficiently cured by conservative treatments, and only one patient (7%) died. Comparative analyses of the fatal (n = 10) and recovery (n = 16) cases revealed that ascites, peritoneal irritation signs, and shock were significantly more frequent in the fatal cases. The mortality was 90% if two or all of these three clinical findings were detected. CONCLUSION: HPVG related to intestinal necrosis requires surgery, and our CT-based criteria are probably useful to determine the surgical indication. In non-surgical cases, ascites, peritoneal irritation signs and shock were closely associated with poor prognoses, and are applicable as predictors of patients' prognoses.

A new gastropod associated with a deep-sea whale carcass from São Paulo Ridge, Southwest Atlantic.

An unfamiliar gastropod was collected from a deep-sea whale carcass at the base of the São Paulo Ridge in the Southwest Atlantic by the manned research submersible Shinkai 6500, and is here described as a new species of the abyssochrysoidean genus Rubyspira, R. brasiliensis sp. nov., following morphological and molecular phylogenetic examinations. There are only two other known species in the genus, which occur together in the Monterey Submarine Canyon off California. The present new species was shown by the molecular analysis to be closer to one of the Californian species than the other. It was found aggregated on and around a whale carcass at a depth of 4204 m, which represents the deepest record of whale- fall ecosystems ever discovered.

Morphological and molecular diversity of rissoellids (Mollusca, Gastropoda, Heterobranchia) from the Northwest Pacific island of Hokkaido, Japan.

This study deals with four species of marine microgastropods of the family Rissoellidae. Rissoella elatior (Golikov, Gulbin Sirenko, 1987), R. golikovi (Gulbin, 1979), R. japonica n. sp., and Rissoella sp. 1 were collected in different locations around the island of Hokkaido, Japan. Light and scanning electron microscopy (SEM) were used to study the general morphology of the shell and radula, and a region of the mitochondrial cytochrome c oxidase subunit I (COI) gene was amplified for 26 specimens. Rissoella elatior is morphologically characterized by a highly asymmetrical radula with a deep notch encircled by 10-13 minute secondary cusps on the left dorsal margin of the central tooth. Rissoella golikovi is characterized by a skeneiform shell and possession of three teeth per row on the radula. Rissoella japonica n. sp. shows five teeth per row on the radula; central tooth higher than wide; lateral and marginal teeth narrow with an outer lateral projection at the base; all teeth presenting numerous small cusps on the cutting edge. Rissoella sp. 1 is distinguished from R. japonica n. sp. in having i) very short oral lobes, ii) a mantle with a large, black patch and whitish blotches inside, and iii) different color patterns associated with the visceral mass. Although Rissoella sp. 1 probably represents an undescribed species, additional specimens are needed to complete its description. This study represents a first molecular approach to the family Rissoellidae. Studies of traditional morphological characters indicated four species, the addition of COI data raised the count to eight potential species, suggesting the occurrence of cryptic species among rissoellids.

Use of endoscopic balloon dilation for benign esophageal stenosis in children: our 11 year experience.

Endoscopic balloon dilation (EBD) is an established therapy for esophageal stenosis. To assess its usefulness in children, we reviewed 11 years of pediatric cases of EBD in our hospital. Over the last 11 years, EBD was performed on 14 pediatric patients (10 boys and four girls; 7 months-11 years) at our hospital. All EBD sessions were performed under general anesthesia and fluoroscopic monitoring. The sessions were repeated every week or alternate weeks until resolution of dysphagia or development of smooth endoscope passage. Stenosis was resolved in 14 of 14 patients (100%). None of the patients (0%) showed recurrence of stenosis. As for postoperative complications, mediastinitis occurred only in one patient (7.1%). The median number of session repeats for an individual patient was three (range 1-10). EBD is a safe and effective therapeutic modality for esophageal stenosis in children.

MAFB is dispensable for the fetal testis morphogenesis and the maintenance of spermatogenesis in adult mice.

The transcription factor MAFB is an important regulator of the development and differentiation of various organs and tissues. Previous studies have shown that MAFB is expressed in embryonic and adult mouse testes and is expected to act as the downstream target of retinoic acid (RA) to initiate spermatogenesis. However, its exact localization and function remain unclear. Here, we localized MAFB expression in embryonic and adult testes and analyzed its gene function using Mafb-deficient mice. We found that MAFB and c-MAF are the only large MAF transcription factors expressed in testes, while MAFA and NRL are not. MAFB was localized in Leydig and Sertoli cells at embryonic day (E) 18.5 but in Leydig cells, Sertoli cells, and pachytene spermatocytes in adults. Mafb-deficient testes at E18.5 showed fully formed seminiferous tubules with no abnormal structure or differences in testicular somatic cell numbers compared with those of control wild-type mice. Additionally, the expression levels of genes related to development and function of testicular cells were unchanged between genotypes. In adults, the expression of MAFB in Sertoli cells was shown to be stage specific and induced by RA. By generating Mafbfl/fl CAG-CreER™ (Mafb-cKO) mice, in which Cre recombinase was activated upon tamoxifen treatment, we found that the neonatal cKO mice died shortly upon Mafb deletion, but adult cKO mice were alive upon deletion. Adult cKO mice were fertile, and spermatogenesis maintenance was normal, as indicated by histological analysis, hormone levels, and germ cell stage-specific markers. Moreover, there were no differences in the proportion of seminiferous stages between cKO mice and controls. However, RNA-Seq analysis of cKO Sertoli cells revealed that the down-regulated genes were related to immune function and phagocytosis activity but not spermatogenesis. In conclusion, we found that MAFB is dispensable for fetal testis morphogenesis and spermatogenesis maintenance in adult mice, despite the significant gene expression in different cell types, but MAFB might be critical for phagocytosis activity of Sertoli cells.

Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial.

OBJECTIVES: The requirements of biliary stents used in the palliation of malignant biliary obstruction are a long duration of patency and minimal adverse effects. Covered self-expandable metal stents (SEMSs) have been shown to prevent tumor ingrowth, which is the most frequent complication of uncovered SEMSs. However, because they are prone to migration, the superiority of covered SEMS has yet to be convincingly demonstrated. The aim of this study was to evaluate the superiority of covered over uncovered SEMSs in the palliation of distal biliary obstruction due to unresectable pancreatic carcinoma, using both stent types with relatively low axial force and uncovered flared ends to prevent their migration. METHODS: From April 2009 to December 2010, 120 patients who were admitted to 22 tertiary-care centers because of distal biliary obstruction from unresectable pancreatic carcinomas were enrolled in this prospective randomized multicenter study. Patients were randomly assigned to receive a covered or uncovered SEMS deployed at the site of the biliary stricture during endoscopic retrograde cholangiopancreatography. Stent patency time, patient survival time, patient survival time without stent dysfunction (time to stent dysfunction or patient death), cause of stent dysfunction (ingrowth, overgrowth, migration, or sludge formation), and serious adverse events were compared between covered and uncovered SEMS groups. RESULTS: Patient survival time in the two groups did not significantly differ (median: 285 and 223 days, respectively; P=0.68). Patient survival time without stent dysfunction was significantly longer in the covered than in the uncovered SEMS group (median: 187 vs. 132 days; P=0.043). Stent patency was also significantly longer in the covered than in the uncovered SEMS group (mean±s.d.: 219.3±159.1 vs. 166.9±124.9 days; P=0.047). Reintervention for stent dysfunction was performed in 14 of 60 patients with covered SEMSs (23%) and in 22 of 60 patients with uncovered SEMSs (37%; P=0.08). Stent dysfunction was caused by tumor ingrowth, tumor overgrowth, and sludge formation in 0 (0%), 3 (5%), and 11 (18%) patients in the covered SEMSs group, and in 15 (25%), 2 (3%), and 6 (10%) patients in the uncovered SEMSs group, respectively. Stent migration was not observed in either group. Rates of tumor overgrowth and sludge formation did not significantly differ between the two groups, whereas the rate of tumor ingrowth was significantly lower in the covered than in the uncovered SEMS group (P<0.01). Acute pancreatitis occurred in only one patient in the covered SEMS group. Acute cholecystitis occurred in one patient in the covered SEMS group and in two patients in the uncovered SEMS group. There was no significant difference between the two groups in the incidence of serious adverse events. CONCLUSIONS: By preventing tumor ingrowth and migration, covered SEMSs with an anti-migration system had a longer duration of patency than uncovered SEMSs, which recommends their use in the palliative treatment of patients with biliary obstruction due to pancreatic carcinomas.

[A case of endocrine carcinoma of the cecum treated with CDDP/VP-16].

A 41-year-old man was admitted to our hospital because of multiple liver tumors. Colonoscopy showed a mass lesion in the cecum. He was given a diagnosis of endocrine cell carcinoma by immunostaining technique, and received chemotherapy of CAPOX regimen for 3 courses. After that, he underwent second-line chemotherapy of EP(CDDP/VP-16)regimen due to deterioration of his performance status(PS), and his tumor marker NSE. He then showed dramatically improved PS, and improvement in the size of liver mets and NSE(4. 3mg/mL).

Biliary complications in donors for living donor liver transplantation.

OBJECTIVES: With the increasing number of living donor liver transplantations, biliary complications in donors have emerged as a major postoperative problem. The aim of the present study was to characterize the features of the biliary complications that occur in donors. METHODS: The study subjects comprised 731 consecutive patients who donated liver grafts (434 right-lobe and 297 left-lobe grafts) for transplantation at Kyoto University Hospital from July 1999 to December 2006. Donors whose biliary complications could not be cured by conservative therapy were referred for endoscopic treatment. RESULTS: Postoperative biliary complications occurred in 55 (7.5%) donors. Initially, 48 of these 55 donors had biliary leakage and 7 had biliary stricture. Subsequently, 5 of 48 donors with leakage developed biliary stricture. The respective incidences of biliary leakage and overall biliary complications were significantly higher among donors of right-lobe grafts (9.9% and 11.1%) than among donors of left-lobe grafts (1.7% and 2.4%). Among 55 donors with biliary complications, 24 were cured by conservative therapy, and 1 was converted to surgical repair due to ileus. Endoscopic treatment was successful in 24 of 30 (80%) donors treated by endoscopic retrograde cholangiography, while the remaining 6 (20%) patients underwent surgery due to difficulties with cannulation (N = 2), excessive biliary leakage (N = 2), or complete biliary obstruction (N = 2). CONCLUSIONS: Donors of right-lobe grafts have a significantly higher incidence of biliary complications than donors of left-lobe grafts. When conservative therapy fails, endoscopic treatment is effective for these complications, and should be attempted as the first-line therapy before surgical repair.

Restoration of RUNX3 enhances transforming growth factor-beta-dependent p21 expression in a biliary tract cancer cell line.

RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region commonly inactivated by deletion and methylation in various human tumors. To elucidate the role of RUNX3 in transforming growth factor (TGF)-beta signaling in biliary tract cancer, we transfected Mz-ChA-2 cells, which do not express RUNX3 but have intact TGF-beta type II receptor and SMAD4 genes, with the RUNX3 expression plasmid pcDNA3.1/RUNX3 or with the vector pcDNA3.1 as a control. Four Mz-ChA-2/RUNX3 clones and one control clone were obtained. Although TGF-beta1 only slightly inhibited growth of the control cells, growth inhibition and TGF-beta-dependent G(1) arrest were significantly enhanced in the RUNX3-transfected clones. None of the clones, however, exhibited apoptosis. The slightly increased TGF-beta1-induced p21 expression in the control clone was strongly enhanced in the RUNX3-transfected clones, and was accompanied by augmented decreases in the expression of cyclins D1 and E. When RUNX3 small interfering RNA was added, TGF-beta-dependent induction of p21 was reduced in the RUNX3-transfected clones. Xenografts of the clones in nude mice demonstrated that tumorigenicity was significantly decreased in the RUNX3-transfected clones in inverse proportion to the expression levels of RUNX3. Based on these results, RUNX3 is involved in TGF-beta-induced expression of p21 and the resulting induction of TGF-beta-dependent G(1) arrest.

Endoscopic treatment of biliary complications after right-lobe living-donor liver transplantation with duct-to-duct biliary anastomosis.

BACKGROUND/PURPOSE: The aims of this study were to characterize the features of the biliary complications that occur after right-lobe living-donor liver transplantation (RL-LDLT) with duct-to-duct biliary anastomosis, and to evaluate the efficacy of treating biliary complications endoscopically. METHODS: The records of 273 consecutive patients who underwent RL-LDLT with duct-to-duct biliary anastomosis from July 1999 through July 2005 at Kyoto University Hospital were reviewed to determine the overall incidence of postoperative biliary complications and the outcome of endoscopic repair of those complications. RESULTS: Biliary complications occurred in 93 (34.1%) of the patients. These complications were: 80 biliary strictures (75 anastomotic and 5 nonanastomotic) and 16 biliary leakages (5 patients with biliary leakage also had a biliary stricture); most (72%) of the anastomotic strictures were complex (i.e., fork-shaped or trident-shaped). The strictures and leakages were repaired by the endoscopic placement of multiple inside stents above the sphincter of Oddi, and by nasobiliary drainage, respectively. The procedure was successful in repairing 51 (68.0%) of the anastomotic strictures and 8 (50.0%) of the biliary leakages. CONCLUSIONS: Endoscopic stenting of the bile ducts is efficacious in treating biliary complications related to RL-LDLT with duct-to-duct biliary anastomosis and the stenting should be attempted before surgical revision of strictures and leakages.

Possible involvement of RUNX3 silencing in the peritoneal metastases of gastric cancers.

PURPOSE: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray. EXPERIMENTAL DESIGN AND RESULTS: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-beta (TGF-beta)-induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of approximately 21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified approximately 28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-beta signaling pathway. CONCLUSION: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

Frequent loss of RUNX3 gene expression in human bile duct and pancreatic cancer cell lines.

RUNX3, a Runt domain transcription factor involved in TGF-beta signaling, is a candidate tumor-suppressor gene localized in 1p36, a region commonly deleted in a wide variety of human tumors, including those of the stomach, bile duct, and pancreas. Recently, frequent inactivation of RUNX3 has been demonstrated in human gastric carcinomas. In this study, to examine the involvement of RUNX3 abnormalities in tumorigenesis of bile duct as well as pancreatic cancers, we investigated not only the expression but also methylation status of RUNX3 in 10 human bile duct and 12 pancreatic cancer cell lines. Seven (70%) of the bile duct and nine (75%) of the pancreatic cancer cell lines exhibited no expression of RUNX3 by both Northern blot analysis and the reverse transcriptase polymerase chain reaction. All of the 16 cell lines that did not express RUNX3 also showed methylation of the promoter CpG island of the gene, whereas the six cell lines that showed RUNX3 expression were not methylated or only partially methylated in the RUNX3 promoter region. Moreover, treatment with the methylation inhibitor 5'-aza-2'-deoxycitidine activated RUNX3 mRNA expression in all of 16 cancer cell lines that originally lacked RUNX3 expression. Finally, hemizygous deletion of RUNX3, as detected by fluorescence in situ hybridization, was found in 15 of the 16 cancer cell lines that lacked RUNX3 expression. These data suggest that the inactivation of RUNX3 plays an important role in bile duct and pancreatic carcinogenesis, and that methylation is a common mechanism by which the gene is inactivated.

Endoscopic management of biliary strictures after duct-to-duct biliary reconstruction in right-lobe living-donor liver transplantation.

BACKGROUND: The aims of this study were to characterize the features of the biliary strictures that occur after duct-to-duct biliary reconstruction during right-lobe living-donor liver transplantation (LDLT) and to evaluate the feasibility of correcting such stricture endoscopically by inserting an "inside stent," that is, a short internal stent, above the sphincter of Oddi. METHODS: Biliary stricture occurred in 26 (35.6%) of 73 consecutive patients who underwent right-lobe LDLT with duct-to-duct biliary reconstruction from July 1999 through October 2001 and survived for more than 3 months. Of the 26 patients who had biliary stricture, 22 were referred for endoscopic retrograde cholangiography (ERC) and 4 for percutaneous cholangiography. RESULTS: ERC disclosed biliary stricture in 19 (86.4%) of the 22 patients who underwent the procedure. One patient had an unbranched stricture, 16 had a fork-shaped stricture, 1 had a trident-shaped stricture, and 1 had a stricture with more than three branches. Fourteen (73.7%) of the patients with strictures were treated endoscopically by inserting inside stents ranging from 7 F to 12 F in size, three underwent a Roux-en-Y hepaticojejunostomy to repair their stricture, and two were closely observed as outpatients. Of the 14 patients who were treated with the inside-stent, only 1 had acute cholangitis immediately after the procedure and underwent a Roux-en-Y hepaticojejunostomy. The other 13 patients who were treated with the inside stent have not required surgical repair for as long as an average of 586 days. CONCLUSION: Endoscopic placement of an inside stent is useful for treating biliary strictures in patients who have undergone right-lobe LDLT with duct-to-duct reconstruction.

A role of Helicobacter pylori infection in the development of duodenal ulcer after adult living-related liver transplantation.

Gastrointestinal bleeding caused by peptic ulcer disease is one of the serious complications of living-related liver transplantation (LRLT). The aim of this study was to clarify the factors involved in peptic ulcer formation in adult LRLT recipients. Forty consecutive adult LRLT recipients without a history of peptic ulcer disease were studied. Twenty-five patients (62.5%) tested positive for Helicobacter pylori. After LRLT, duodenal ulcer (DU) developed in six patients, and all of them tested positive for H. pylori. In contrast, none of the H. pylori-negative patients developed DU. Preoperative serum gastrin levels in patients with DU were significantly higher than in those without DU, irrespective of H. pylori infection. Preoperative pepsinogen I levels in patients with DU were significantly higher than in those without DU with H. pylori infection. These data suggest involvement of H. pylori infection in the development of DU after LRLT. Eradication of H. pylori may prevent the development of DU after LRLT particularly in patients with hypergastrinemia and high serum pepsinogen I.

Endoscopic management of postoperative biliary complications in donors for living donor liver transplantation.

BACKGROUND & AIMS: Biliary leakage and stricture are serious complications that occur in donors whose liver is resected for living donor transplantation. We assessed the usefulness of endoscopic nasobiliary drainage and endoscopic biliary stenting, respectively, in repairing biliary leakage and stricture. METHODS: Between July 1999 and December 2001, a total of 276 donors underwent liver resection (left side, 118; right side, 158) for living donor transplantation at Kyoto University Hospital. Seven (2.5%) donors developed biliary leakage, which required endoscopic nasobiliary drainage; 3 of these donors also had biliary stricture. RESULTS: All 7 patients who developed biliary leakage were the right-lobe donors. Endoscopic retrograde cholangiography identified the site of the biliary leakage in all 7 of the donors. In 6 of these donors, the biliary leakage resolved within an average of 15 days after an endoscopic nasobiliary drainage tube was placed. In the seventh donor, the biliary leakage resolved after percutaneous transhepatic biliary drainage was performed. Three patients developed biliary stricture that required endoscopic biliary stenting. The angles between common hepatic duct and the left hepatic duct were more acute in patients with stricture than in those without stricture (62 degrees vs. 119 degrees). CONCLUSIONS: Biliary complications requiring endoscopic treatment developed exclusively in donors for right-lobe living donor transplantation. Endoscopic retrograde cholangiography is a favorable modality for diagnosing and treating postoperative biliary complications in donors for living donor liver transplantation.