Search

We previously found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) exerts cytoprotective and pro-angiogenic functions via G-protein coupled receptor 15 (GPR15). TME5 is comprised of three S-S bonds that divide it into three loops: A (TME5A), B (TME5B), and C (TME5C). Herein we identified the minimum structure of TME5 that produces favorable effects in vascular endothelial cells (ECs). We found that TME5C, composed of 19 amino acids, but not TME5A or TME5B, stimulated the proliferation of human umbilical vein endothelial cells (HUVECs) and human hepatic sinusoidal endothelial cells (HHSECs). Matrigel plug assays showed that TME5C stimulates in vivo angiogenesis. In addition, TME5C counteracted calcineurin inhibitor-induced apoptosis and vascular permeability in HUVECs and HHSECs. Western blot analysis indicated that exposure of either HUVECs or HHSECs to TME5C increased the levels of anti-apoptotic myeloid cell leukemia-1 protein in association with the activation of signal transduction pathways, including extracellular signal-regulated kinase, AKT, and mitogen-activated protein kinase p38. Importantly, TME5C did not affect the coagulation pathway in vitro The cytoprotective function of TME5C was mediated by cell surface-expressed GPR15, as TME5C was not able to protect vascular ECs isolated from Gpr15 knock-out (KO) mice. Strikingly, TME5C successfully ameliorated sinusoidal obstruction syndrome in a murine model by counteracting the reduction of sinusoidal EC numbers. Taken together, the cytoprotective and pro-angiogenetic functions of TM are preserved in TME5C. The use of TME5C may be a promising treatment strategy to prevent or treat lethal complications, such as sinusoidal obstruction syndrome, whose pathogenesis is based on endothelial insults., (Copyright © 2018 Ferrata Storti Foundation.)

Background: In our process of standardizing laparoscopic right hemihepatectomy (Lap-RH), we found several advantages of the laparoscopic caudate lobe first approach by using a unique laparoscopic caudodorsal view., Methods: Between April 2012 and October 2017, 21 patients underwent pure Lap-RH at our hospital. The mean patient age was 62 years (range 36-75 years), and there were more male than female patients (66.7%). Of 21 patients, 11 had hepatocellular carcinoma, eight had metastatic tumor, and the other two had focal nodular hyperplasia and refractory liver abscess. All 21 patients had Child-Pugh class A liver function. The surgical technique was recorded on video., Results: The mean operative time was 409 min (range 241-522 min), and the mean blood loss was 279 g (range 0-1,010 g). No procedure was converted to open surgery. With regard to postoperative complications, one patient had bile leakage from the stump of the main Glissonean branch and another patient had abscess formation in the subphrenic space. No postoperative bleeding, hepatic failure, and mortality occurred., Conclusions: Our standardized procedure of Lap-RH using the unique laparoscopic caudodorsal view is not only feasible but also confers a true advantage of the laparoscopic approach., (© 2018 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

The International Summit on Laparoscopic Pancreatic Resection (ISLPR) was held in Coimbatore, India, on 7th and 8th of October 2016 and thirty international experts who regularly perform laparoscopic pancreatic resections participated in ISPLR from four continents, i.e., South and North America, Europe and Asia. Prior to ISLPR, the first conversation among the experts was made online on August 26th, 2016 and the structures of ISPLR were developed. The aims of ISPLR were; i) to identify indications and optimal case selection criteria for minimally invasive pancreatic resection (MIPR) in the setting of both benign and malignant diseases; ii) standardization of techniques to increase the safety of MIPR; iii) identification of common problems faced during MIPR and developing associated management strategies; iv) development of clinical protocols to allow early identification of complications and develop the accompanying management plan to minimize morbidity and mortality. As a process for interactive discussion, the experts were requested to complete an online questionnaire consisting of 65 questions about the various technical aspects of laparoscopic pancreatic resections. Two further web-based meetings were conducted prior to ISPLR. Through further discussion during ISPLR, we have created productive statements regarding the topics of Disease, Implementation, Patients, Techniques, and Instrumentations (DIPTI) and hereby publish them as "Coimbatore Summit Statements"., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Anatomical hepatectomy is an ideal curative treatment for hepatocellular carcinoma (HCC). We have standardized our laparoscopic anatomical hepatectomy (LAH) procedure, gradually extending its indications. In the present study, we describe our experience and the perioperative and oncological outcomes of LAH for HCC compared to those of open anatomical hepatectomy (OAH) during the gradual introduction of LAH., Methods: Seventy patients with primary HCC underwent anatomical hepatectomy in our institution from November 2008 to April 2014. As we gained experience with LAH, our indications for choosing LAH over OAH gradually expanded. Ultimately, 40 and 30 patients underwent LAH and OAH, respectively. Perioperative and oncological outcomes were compared between the two groups., Results: There were no significant differences in age, sex, background of liver disease, liver function, tumor size, tumor number, or type of liver resection between the two groups. Major complications and mortality rates were similar between the LAH and OAH groups (12.5% vs. 20%; p = 0.582, and 0% vs. 3.3%; p = 0.429, respectively). The median follow-up time after surgery was 40.5 months in the LAH group and 32.9 months in the OAH group (p = 0.835). The 1-, 3-, and 5-year overall survival rates were 89.9, 84.7, and 70.9%, in the LAH group, and 89.8, 68.0, and 63.1% in the OAH group, respectively (p = 0.255). The 1-, 3-, and 5-year disease-free survival rates were 79.5, 58.0, and 42.5%, in the LAH group, and 72.4, 56.1, and 50.4% in the OAH group, respectively (p = 0.980)., Conclusions: Through gradual introduction of LAH, we obtained comparable results to those achieved with OAH. LAH can be a feasible surgical treatment for primary HCC, with good oncological outcomes.

To collect big data for further research to improve treatment outcomes in patients with colorectal liver metastasis (CRLM), the Joint Committee for Nationwide Survey on CRLM was established by the Japanese Society for Cancer of the Colon and Rectum and the Japanese Society of Hepato-Biliary-Pancreatic Surgery. The joint committee initiated data collection since 2014. The data of 4,237 patients newly diagnosed with CRLM between 2005 and 2007 were registered from 134 departments of 127 institutions (64%) among 209 departments (from 201 institutions) that agreed to participate in this study. Finally, 3,820 patients were enrolled in this report after a quality management process by the joint committee. We report the comprehensive data obtained from 3,820 patients, clinicopathological findings, treatment strategies, prognoses, and implementation status of chemotherapy. The joint committee is prospectively collecting data of patients newly diagnosed with CRLM after 2013 and will provide these raw data, including data of patients diagnosed between 2005 and 2007, to researchers who will conduct meaningful studies that meet the aim of the joint committee., (© 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Thrombomodulin (TM), an endothelial protein with anti-coagulant activity, is composed of 5 domains, D1-D5. Recombinant human soluble TM (TMα) consisting of D1-D3, which is generated in CHO cells, suppresses inflammatory and nociceptive signals by inactivating high mobility group box 1 (HMGB1), one of damage-associated molecular patterns. TMα sequesters HMGB1 with the lectin-like D1 and promotes its degradation by thrombin binding to the EGF-like D2. We prepared TM's D123, D1 and D2 by the protein expression system of yeast, and evaluated their effects on HMGB1 degradation in vitro and on the allodynia caused by HMGB1 in distinct redox forms in mice in vivo. TMα and TM's D123, but not D1, promoted the thrombin-dependent degradation of all-thiol (at-HMGB1) and disulfide HMGB1 (ds-HMGB1), an effect mimicked by TM's D2, though to a lesser extent. Intraplantar administration of TMα and TM's D123, but not D1, D2 or D1 plus D2, strongly prevented the mechanical allodynia caused by intraplantar at-HMGB1, ds-HMGB1 or lipopolysaccharide in mice. Our data suggest that, apart from the role of D3, TMα and TM's D123 require both lectin-like D1 capable of sequestering HMGB1 and EGF-like D2 responsible for thrombin-dependent degradation of HMGB1, in abolishing the allodynia caused by exogenous or endogenous HMGB1., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: We retrospectively investigated the operative outcomes of patients who underwent distal pancreatectomy (DP) for invasive pancreatic ductal adenocarcinoma (PDAC) located at the body and tail., Methods: Data from 395 patients with PDAC who underwent DP with margin-negative resection (R0 or R1) were collected from seven high-volume centers in Japan from 2001 to 2012. Among them, 72 patients underwent DP with en-bloc celiac axis resection (DP-CAR). The remaining 323 patients underwent conventional DP with splenectomy (DP-S). To determine the efficacy of DP-CAR, clinicopathological data were compared between the DP-CAR and the DP-S groups., Results: The DP-S group consisted mainly of patients with resectable disease (93%), and conversely, all patients in the DP-CAR group had borderline resectable or unresectable disease. The overall morbidity was significantly higher in the DP-CAR group than in the DP-S group (63% vs 47%, respectively; P = 0.017). The median survival time (MST) of the DP-CAR group was significantly shorter than that of the DP-S group (17.5 vs 28.6 months, respectively; P = 0.004). However, the MST of patients in the DP-CAR group (n = 61, 85%) who received adjuvant therapy was significantly longer than that of patients in the DP-S group (n = 65, 20%) who underwent R1 resection (21.9 vs 16.7 months, respectively; P = 0.024)., Conclusion: DP-CAR followed by adjuvant chemotherapy provided an acceptable overall survival rate in patients with highly advanced PDAC, but should be performed with great caution because of high morbidity. Patients with a high risk of positive surgical margins with DP-S may be candidates for DP-CAR., (Copyright © 2017 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: This study evaluated individual risks of malignancy and proposed a nomogram for predicting malignancy of branch duct type intraductal papillary mucinous neoplasms (BD-IPMNs) using the large database for IPMN., Background: Although consensus guidelines list several malignancy predicting factors in patients with BD-IPMN, those variables have different predictability and individual quantitative prediction of malignancy risk is limited., Methods: Clinicopathological factors predictive of malignancy were retrospectively analyzed in 2525 patients with biopsy proven BD-IPMN at 22 tertiary hospitals in Korea and Japan. The patients with main duct dilatation >10 mm and inaccurate information were excluded., Results: The study cohort consisted of 2258 patients. Malignant IPMNs were defined as those with high grade dysplasia and associated invasive carcinoma. Of 2258 patients, 986 (43.7%) had low, 443 (19.6%) had intermediate, 398 (17.6%) had high grade dysplasia, and 431 (19.1%) had invasive carcinoma. To construct and validate the nomogram, patients were randomly allocated into training and validation sets, with fixed ratios of benign and malignant lesions. Multiple logistic regression analysis resulted in five variables (cyst size, duct dilatation, mural nodule, serum CA19-9, and CEA) being selected to construct the nomogram. In the validation set, this nomogram showed excellent discrimination power through a 1000 times bootstrapped calibration test., Conclusion: A nomogram predicting malignancy in patients with BD-IPMN was constructed using a logistic regression model. This nomogram may be useful in identifying patients at risk of malignancy and for selecting optimal treatment methods. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.

Background: Recombinant human soluble thrombomodulin (TM-α) has been shown to be useful in the treatment of disseminated intravascular coagulation (DIC) in a heparin-controlled study, and has been available for clinical use in Japan since 2008. However, use of TM-α for obstetrical DIC has not yet been established, so efficacy and safety were analyzed in 117 obstetrical DIC patients identified from post-marketing surveillance., Materials and Methods: From June 2010 to March 2012, the cases of 117 patients with obstetrical DIC treated with TM-α were registered., Results: In the majority of cases, the underlying disease was DIC-type postpartum hemorrhage (n=43) or placental abruption (n=37). Mean (±standard deviation) obstetrical DIC score was 10.6±4.9. Mean duration of TM-α administration was 2.2±1.7days. The most commonly used concomitant anticoagulants were antithrombin (n=60) and gabexate mesilate (n=37). Concomitantly used blood components products included red blood cell concentrate (n=72), fresh frozen plasma (n=70), and platelet concentrate (n=31). Hemostatic test result profiles revealed significant improvement of fibrinogen/fibrin degradation products, D-dimer, fibrinogen, prothrombin time and activated partial thromboplastin time. Efficacies of TM-α as evaluated by "The efficacy evaluation criteria for DIC in obstetrics" at 24h, 48h and the day after last administration of TM-α were 72.3%, 82.4% and 90.2%, respectively. Total bleeding adverse drug reactions occurred in 6 patients (5.1%)., Conclusions: This surveillance confirmed the safety and efficacy of TM-α in clinical practice. These findings thus indicated that the efficacy of TM-α is comparable to that of previously investigated obstetrical DIC pharmacotherapies., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Even though most patients who undergo resection of pancreatic adenocarcinoma have T3 disease with extra-pancreatic tumor extension, T3 disease is not currently classified by tumor size. The aim of this study was to modify the current TNM classification of pancreatic adenocarcinoma to reflect the influence of tumor size., Methods: A total of 847 consecutive pancreatectomy patients were recruited from multiple centers. Optimum tumor size cutoff values were calculated by receiver operating characteristics analysis for tumors limited to the pancreas (T1/2) and for T3 tumors. In our modified TNM classification, stage II was divided into stages IIA (T3aN0M0), IIB (T3bN0M0), and IIC (T1-3bN1M0) using tumor size cutoff values. The usefulness of the new classification was compared with that of the current classification using Akaike's information criterion (AIC)., Results: The optimum tumor size cutoff value distinguishing T1 and T2 was 2 cm, while T3 was divided into T3a and T3b at a tumor size of 3 cm. The median survival time of the stages IIA, IIB, and IIC were 44.7, 27.6, and 20.3 months, respectively. There were significant differences of survival between stages IIA and IIB (P = 0.02) and between stages IIB and IIC (P = 0.03). The new classification showed better performance compared with the current classification based on the AIC value., Conclusions: This proposed new TNM classification reflects the influence of tumor size in patients with extra-pancreatic tumor extension (T3 disease), and the classification is useful for predicting mortality.

Objectives: Patients with bipolar disorder often suffer from cognitive impairment that significantly influences their functional outcome. However, it remains unknown whether lithium has a central role in cognition and functional outcome. We examined whether cognition and functional outcome were predicted by demographic and clinical variables, including the response to lithium, in lithium-treated patients with bipolar disorder., Methods: We evaluated 96 lithium-treated euthymic patients with bipolar disorder and 196 age- and-gender-matched healthy controls, using the Brief Assessment of Cognition in Schizophrenia (BACS). The patients were also assessed using the Social Functioning Scale (SFS) and "The Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" (Alda) scale, which was evaluated as either a continuous measure of the total scale or a dichotomous criterion., Results: Multiple regression analysis revealed two key findings: first, that the premorbid intelligence quotient, age, and number of mood episodes were predictors of the BACS composite score; and, second, that the BACS composite score, negative symptoms, and continuous measure on the total Alda scale (but not its dichotomy) predicted the total SFS score. Structural equation modeling (SEM) was used to confirm these findings, and additionally revealed that the Alda scale was significantly associated with negative symptoms and also the number of mood episodes, regardless of how it was evaluated., Conclusions: SEM delineated how demographic and clinical variables, cognitive performance, and response to lithium treatment were causally associated with, and converged on, social function. The putative role of the Alda scale for social function warrants further study., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We present a resected case of annular pancreas in which Wirsung's duct encircled the duodenum and continued directly to the main pancreatic duct in the body and tail. Furthermore, Wirsung's duct coursed along the right side of the lower bile duct near the major duodenal papilla. Histologically, the islets of Langerhans in the annular pancreas were irregular in shape and were characterized by a striking abundance of pancreatic polypeptide (PP)-positive cells. The PP-rich area that encircled the duodenum was fused with the PP-poor area in the head of the pancreas. The following embryological hypothesis is proposed. The tip of the ventral pancreatic anlage adhered to the duodenal wall and stretched to form a ring during clockwise rotation. The rotation was incomplete, and the pancreatic duct did not cross over the lower bile duct. Since there was adequate ventral anlage in the lower part of the head of the pancreas, fusion between the ducts of the ventral and dorsal anlagen did not occur. The tip of the ventral anlage overgrew and adhered to the dorsal anlage, and the annular duct fused with the main duct of the dorsal anlage.

Thrombomodulin (TM) exerts anti-inflammatory functions. We previously found that recombinant human soluble TM alleviated murine graft-versus-host disease (GVHD). Nevertheless, it is unclear how TM mediates its anti-inflammatory functions in GVHD. Here, we identified G-protein coupled receptor 15 (GPR15) expressed on T cells as a receptor/sensor of TM. The fifth region of epidermal growth factor-like domain of TM (TME5) bound GPR15 in vitro. TME5 prolonged survival of mice undergoing acute GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). TME5 increased regulatory T cells (Tregs) but decreased Th 1 proportions in targeted organs. TME5 suppressed allo-reaction in vitro in association with an increase in the number of induced Tregs. However, the anti-inflammatory function of TME5 was abolished when GPR15 knockout T cells were used as donor T cells. We further found that TME5 suppressed production of IL-6 in T cells, which probably facilitated differentiation of Tregs. Moreover, TME5 reduced activation of bone marrow-derived dendritic cells (BMDCs) and hampered function of BMDCs in inducing allo-reaction in vivo and in vitro. Our findings suggested that inducing Tregs as well as blocking activation of DCs in vivo by using TME5 is a potential therapeutic option for preventing GVHD in allo-HSCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Thrombomodulin (TM) stimulates angiogenesis and protects vascular endothelial cells (ECs) via its fifth epidermal growth factor-like region (TME5); however, the cell surface receptor that mediates the pro-survival signaling activated by TM has remained unknown. We applied pull-down assay followed by MALDI-TOF MS and western blot analysis, and identified G-protein coupled receptor 15 (GPR15) as a binding partner of TME5. TME5 rescued growth inhibition and apoptosis caused by calcineurin inhibitor FK506 in vascular ECs isolated from wild type (WT) C57BL/6 mice. On the other hand, TME5 failed to protect ECs isolated from GPR15 knockout (GPR15 KO) mice from FK506-caused vascular injury. TME5 induced activation of extracellular signal-regulated kinase (ERK) and increased level of anti-apoptotic proteins in a GPR15 dependent manner. In addition, in vivo Matrigel plug angiogenesis assay found that TME5 stimulated angiogenesis in mice. TME5 promoted endothelial migration in vitro. Furthermore, TME5 increased production of NO in association with activated endothelial NO synthase (eNOS) in ECs. All these pro-angiogenesis functions of TME5 were abolished by knockout of GPR15. Our findings suggest that GPR15 plays an important role in mediating cytoprotective function as well as angiogenesis of TM.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall, usually forming an abnormally long common channel. In PBM, since the long common channel defeats the effect of the sphincter of Oddi, pancreatobiliary reflux frequently occurs, resulting in high rates of biliary tract cancers. We present the case of a 68-year-old female with advanced gallbladder cancer concomitant with bile duct cancer associated with PBM without biliary dilatation that had an extremely rare configuration showing a connecting duct without a long common channel. Pancreatography in the selectively cannulated main pancreatic duct showed the terminal portion of the common bile duct via an abnormal connecting duct. Cholangiography in the selectively cannulated lower bile duct showed the main and accessory pancreatic ducts via the connecting duct. The bile amylase level was markedly elevated. This case of a rare configuration of PBM with a connecting duct without a long common channel is the first such reported case in the English literature.

Background: We previously identified 25 intraoperative findings during laparoscopic cholecystectomy (LC) as potential indicators of surgical difficulty per nominal group technique. This study aimed to build a consensus among expert LC surgeons on the impact of each item on surgical difficulty., Methods: Surgeons from Japan, Korea, and Taiwan (n = 554) participated in a Delphi process and graded the 25 items on a seven-stage scale (range, 0-6). Consensus was defined as (1) the interquartile range (IQR) of overall responses ≤2 and (2) ≥66% of the responses concentrated within a median ± 1 after stratification by workplace and LC experience level., Results: Response rates for the first and the second-round Delphi were 92.6% and 90.3%, respectively. Final consensus was reached for all the 25 items. 'Diffuse scarring in the Calot's triangle area' in the 'Factors related to inflammation of the gallbladder' category had the strongest impact on surgical difficulty (median, 5; IQR, 1). Surgeons agreed that the surgical difficulty increases as more fibrotic change and scarring develop. The median point for each item was set as the difficulty score., Conclusions: A Delphi consensus was reached among expert LC surgeons on the impact of intraoperative findings on surgical difficulty., (© 2017 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IκBα, nuclear translocation of NF-κB and release of pro-inflammatory cytokines in macrophages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-κB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis.

Introduction: We employed a safe approach during laparoscopic splenectomy by first mobilizing the pancreatic tail and then dissecting the splenic vessels at the splenic hilum before mobilizing the spleen., Materials and Surgical Technique: Patients were placed in the lithotomy position, and only the upper body was twisted to the right side. Five trocars were placed. After the bursa omentalis was opened, an avascular layer was identified behind the pancreas. This avascular layer was bluntly dissected, and the pancreatic tail was isolated from the retroperitoneum. The tissue surrounding the splenic hilum was dissected by a handling tape that was placed around the pancreatic tail. Because the spleen remained connected to the retroperitoneum with the splenorenal ligament, a good operative view of the splenic hilum was obtained with proper extension. After sufficient space was secured between the pancreatic tail and the spleen, the splenic vessels were divided with a linear stapler. The spleen was detached in the final stage., Discussion: The current standardized procedure is highly recommended for a safe laparoscopic splenectomy., (© 2016 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Objective: To evaluate the clinical efficacy and tolerability of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel combined with S-1, "an oral fluoropyrimidine derivative containing tegafur, gimestat, and otastat potassium" in chemotherapy-naive pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis., Background: PDAC patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis. An effective treatment strategy remains elusive., Methods: Paclitaxel was administered i.v. at 50 mg/m and i.p. at 20 mg/m on days 1 and 8. S-1 was administered at 80 mg/m/d for 14 consecutive days, followed by 7 days of rest. The primary endpoint was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect and safety (UMIN000009446)., Results: Thirty-three patients who were pathologically diagnosed with the presence of peritoneal dissemination (n = 22) and/or positive peritoneal cytology (n = 11) without other organ metastasis were enrolled. The tumor was located at the pancreatic head in 7 patients and the body/tail in 26 patients. The median survival time was 16.3 (11.47-22.57) months, and the 1-year survival rate was 62%. The response rate and disease control rate in assessable patients were 36% and 82%, respectively. OS in 8 patients who underwent conversion surgery was significantly higher than that of nonsurgical patients (n = 25, P = 0.0062). Grade 3/4 hematologic toxicities occurred in 42% of the patients and nonhematologic adverse events in 18%. One patient died of thrombosis in the superior mesenteric artery., Conclusions: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis.

Background: Generally, surgeons' perceptions of surgical safety are based on experience and institutional policy. Our recent pilot survey demonstrated that the acceptable duration of surgery and criteria for open conversion during laparoscopic cholecystectomy (LC) vary among workplaces., Methods: A web-based survey was distributed to 554 expert LC surgeons in Japan, Korea, and Taiwan. The questionnaire covered LC experience, safety measures and recognition of landmarks, decision-making regarding conversion to open/partial cholecystectomy and the implications of this decision. Overall responses were compared among nations, and then stratified by LC experience level (lifetime cases 200-499, 500-999, and ≥1,000)., Results: The response rate was 92.6% (513/554); 67 surgeons with ≤199 LCs were excluded, and responses from 446 surgeons were analyzed. We observed significant differences among nations on almost all questions. Differences that remained after stratification by LC experience were on questions related to acceptable duration of surgery, adoption rates of intraoperative cholangiography, the "critical view of safety" technique, identification of Rouvière's sulcus, recognition of the SS-Inner layer theory, and intraoperative judgment to abandon conventional LC., Conclusions: Even among experts, surgeons' perceptions during LC are workplace-dependent. A novel grading system of surgical difficulty and standardized LC procedures are paramount to generate high-level evidence., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Enduring cognitive impairment in patients with schizophrenia represents a global health burden. The Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and the Japanese Adult Reading Test were administered to 288 patients with chronic schizophrenia and 308 unrelated healthy control subjects. The Japanese version of self-reported Social Functioning Scale (SFS) was administered to a subpopulation of 157 patients with schizophrenia. In patients with schizophrenia, premorbid IQ and age were significantly related to most of the BACS subdomains, composite score, and intra-individual variability of BACS subdomains, whereas negative symptoms were significantly related to all BACS indices. Dosages of the first-generation antipsychotics had a significant negative impact on Tower of London task and intra-individual variability of BACS subdomains. The relationship of symbol coding with age was significantly lower in patients than in healthy control subjects. Multiple regression analysis revealed that negative symptoms were significantly negatively related to the total SFS scale, whereas better performance of token motor task was associated with higher total SFS. The present study revealed the role of premorbid IQ, age, and negative symptoms in predicting cognitive performance, and the significant correlation of negative symptoms and token motor task with social function in patients with schizophrenia., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Primary liver cancer is the fifth most common cancer worldwide. Apart from liver transplantation, surgical resection has been accepted as the effective local treatment for hepatocellular carcinoma (HCC), one of the most common primary liver cancers. Recent technological innovations including navigation technology and intraoperative real-time fluorescence guidance have been utilized for liver resections in clinical practice. With respect to liver resection techniques, the laparoscopic approach has been increasingly gaining popularity as one of the minimally-invasive treatments of HCC. These technological innovations and technical advancements are expected to further improve the safety and efficacy of liver resections.

Background: Among young residents, there seems to be a decreasing desire to become surgeons, resulting in a decrease in the number of surgeons. There is concern regarding a shortage of hepatobiliary pancreatic (HBP) surgery residents in Japan. A questionnaire survey was designed to assess the work motivations of Japanese gastrointestinal (GI) and HBP surgeons., Methods: Questionnaires assessing seven domains related to motivation (aptitude, satisfaction/dissatisfaction, knowledge/skill, evaluation/approval, self-management, community/expectation from other parties, and emotion) were sent to GI and HBP surgeons throughout Japan. Differences between HBP and GI surgeons were analyzed., Results: Responses were received from 27 institutions in Japan between May and August 2014. Mid-career and senior HBP surgeons (11-20 years after graduation) working in university hospitals were significantly less satisfied with their work than GI surgeons (P = 0.036). Evaluation/approval factors were significantly lower in senior HBP surgeons than in GI surgeons 16-20 years after graduation (P = 0.048)., Conclusions: The future satisfaction of young residents seeking to become HBP surgeons should be enhanced, providing an appealing workplace for young residents and preventing discontinuation by mid-career and senior surgeons., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Although surgical resection is the only curative strategy for pancreatic cancer, the prognosis of patients with pancreatic cancer remains poor. Recently, neoadjuvant treatment has been frequently employed as a promising treatment. Here, the mid-term results of neoadjuvant chemoradiotherapy(NACRT)using S-1, which has been performed in our hospital since 2008, are reported., Methods: Seventy-nine patients with resectable or borderline resectable pancreatic ductal adenocarcinoma, who had been intended to undergo NACRT treatment using S-1, were enrolled. The NACRT comprised radiotherapy( 1.8 Gy×28 days)and full-dose twice-daily oral S-1 given on the same days as the radiotherapy. The results of the NACRT and pancreatectomy and the patients' prognoses were evaluated., Results: Fifty-five patients(69.6%)underwent pancreatectomy, with no case of mortality. The curative resection rate was 94.5%. Postoperative adjuvant chemotherapy was administered in 46 patients(83.6%). The 3-year survival rates of all 79 patients and 55 pancreatectomy patients were 40.1% and 50.4%, respectively., Conclusion: NACRT using S-1 was found to be feasible, and good mid-term outcomes were obtained. However, analysis of the long-term outcomes and comparisons with other novel anti-cancer drugs are still required.

Background: Serious complications continue to occur in laparoscopic cholecystectomy (LC). The commonly used indicators of surgical difficulty such as the duration of surgery are insufficient because they are surgeon and institution dependent. We aimed to identify appropriate indicators of surgical difficulty during LC., Methods: A total of 26 Japanese expert LC surgeons discussed using the nominal group technique (NGT) to generate a list of intraoperative findings that contribute to surgical difficulty. Thereafter, a survey was circulated to 61 experts in Japan, Korea, and Taiwan. The questionnaire addressed LC experience, surgical strategy, and perceptions of 30 intraoperative findings listed by the NGT., Results: The response rate of the survey was 100%. There was a statistically significant difference among nations regarding the duration of surgery and adoption rate of safety measures and recognition of landmarks. The criteria for conversion to an open or subtotal cholecystectomy were at the discretion of each surgeon. In contrast, perceptions of the impact of 30 intraoperative findings on surgical difficulty (categorized by factors related to inflammation and additional findings of the gallbladder and other intra-abdominal factors) were consistent among surgeons., Conclusions: Intraoperative findings are objective and considered to be appropriate indicators of surgical difficulty during LC., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

An incorrect approach to the critical view of safety can cause bile duct and/or vascular injury. However, only superficial anatomical features have been proposed as surgical landmarks to initiate laparoscopic cholecystectomy (LC) safely in previous reports. Accordingly, we have proposed a novel surgical anatomical definition of the gallbladder wall, in which the subserosal (SS) layer is divided into the inner layer of the SS (SS-Inner) layer consisting of vasculature and fibrous tissue, and the outer layer of the SS (SS-Outer) layer consisting of abundant fat tissue. By dissecting the gallbladder along the SS-Inner layer after exposure at a safe region, bile duct and/or vascular injury can be avoided, even in cholecystitis cases. Furthermore, recognition of this surgical anatomy reveals several aspects. In cholecystitis cases associated with severe fibrotic change, completion of LC by dissecting along the SS-Inner layer is impossible, resulting in abandonment of regular LC. An abscess in the liver bed associated with acute cholecystitis usually forms in the SS-Outer layer, thus, the gallbladder can be dissected easily. In the dome-down technique, the right hepatic duct is endangered by whole-layer dissection, in which the SS-Outer layer is also removed. The proposed procedure should become the universal standard for LC., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: The aim of this study was to reappraise the clinical role of total pancreatectomy with curative intent in patients with pancreatic ductal adenocarcinoma (PDAC)., Methods: In 2001 to 2011 database from 7 institutions in Japan, 45 (3.1%) of 1451 patients with PDAC underwent total pancreatectomy (TP group), and 885 patients underwent pancreaticoduodenectomy (PD group). A matched-pairs group consisted of 45 patients matched for age, sex, year, resectability status, and neoadjuvant therapy (matched-PD group). Clinicopathological data, overall survival, and disease-free survival were compared between groups., Results: Clinical features of the TP group revealed higher-stage disease, greater surgical stress, a higher frequency of lymph node metastasis, and a lower adjuvant chemotherapy completion rate compared with the PD group (P < 0.05). Overall survival and disease-free survival in the TP group were significantly worse than those in the PD group (P < 0.05). Multivariate analysis revealed resectability status, neoadjuvant therapy, blood transfusion, lymph node metastasis, and adjuvant therapy to be significant prognostic factors. No differences in mortality and morbidity rates were observed between the 2 groups. A matched-pairs analysis revealed similar surgical outcomes and overall survival., Conclusions: The surgical outcome of total pancreatectomy for patients with PDAC is acceptable. When margin-negative resection is expected, total pancreatectomy should not be abandoned in the modern era.

Background: Several studies have demonstrated that postoperative complications after pancreatectomy for pancreatic cancer adversely affect survival. The impact on survival of a pancreatic fistula according to the classification of the International Study Group for Pancreatic Surgery has not been fully evaluated. The aim of this multicenter, observational study was to evaluate the impact of pancreatic fistula on pancreatic cancer patients who had undergone pancreatectomy., Methods: Between 2001 and 2012, 1,397 patients who underwent pancreatectomy for pancreatic cancer at 7 high-volume centers in Japan were reviewed retrospectively. The impact of pancreatic fistula on survival was evaluated by univariate and multivariate analysis., Results: Pancreatic fistula occurred in 327 of 1,397 patients (23.4%) and was classified based on the International Study Group for Pancreatic Surgery as follows: grade A in 9.9%, grade B in 10.6%, and grade C in 2.9% of the patients. Median survival time in no fistula/grade A, grade B, and grade C were 23.6, 26.0, and 9.0 months, respectively. There was no significant difference in overall survival between patients with no fistula/grade A and those with grade B (P = .403); in contrast, overall survival in patients with grade C was worse than in patients without grade C (P < .001). The multivariate Cox proportional hazard analysis demonstrated that grade C pancreatic fistula was an independent prognostic factor (hazard ratio 1.59; 95% confidence interval, 1.03-2.45; P = .035)., Conclusion: Grade B pancreatic fistula after pancreatectomy does not adversely affect long-term survival, but a grade C pancreatic fistula has a negative impact on long-term survival of patients with pancreatic cancer., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine optimal settings for airway pressure (AWP), pneumoperitoneum pressure (PPP), and central venous pressure (CVP) in pure laparoscopic hepatectomy., Background: High PPP is often employed to control bleeding from the hepatic vein during pure laparoscopic hepatectomy; however, there is a risk of pulmonary gas embolism. We noted that decreases in AWP were often effective., Methods: After establishing carbon dioxide pneumoperitoneum in 6 male piglets and maintaining PPP at 25 mmHg, CVP was measured 3 times at each of 9 levels of airway pressure, which was increased in increments of 5 cmH2O from 0 to 40 cmH2O. CVP was measured in the same manner by maintaining PPP at 20, 15, 10, 5, and 0 mmHg, and in laparotomy. Correlation and regression analyses were performed among airway pressure, CVP, and pneumoperitoneum pressure., Results: Positive correlations were observed between AWP and CVP and between PPP and CVP (P < 0.001). Under high airway pressure, CVP was persistently higher than pneumoperitoneum pressure. Under low airway pressure, CVP did not increase or often decreased when PPP was higher than CVP., Conclusions: By increasing pneumoperitoneum pressure, bleeding from the hepatic vein cannot be controlled under high airway pressure, but can be controlled under low airway pressure. However, under low airway pressure, the risk of pulmonary gas embolism increases when PPP is higher than CVP. We consider that reducing AWP is also effective for controlling bleeding from the hepatic vein and safer than increasing pneumoperitoneum pressure.

LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins regulate leukocyte trafficking in health and disease by binding primarily to IgSF ligand ICAM-1 and ICAM-2 on endothelial cells. Here we have shown that the anti-coagulant molecule thrombomodulin (TM), found on the surface of endothelial cells, functions as a potentially new ligand for leukocyte integrins. We generated a recombinant extracellular domain of human TM and Fc fusion protein (TM-domains 123-Fc), and showed that pheripheral blood mononuclear cells (PBMCs) bind to TM-domains 123-Fc dependent upon integrin activation. We then demonstrated that αL integrin-blocking mAb, αM integrin-blocking mAb, and β2 integrin-blocking mAb inhibited the binding of PBMCs to TM-domains 123-Fc. Furthermore, we show that the serine/threonine-rich domain (domain 3) of TM is required for the interaction with the LFA-1 (αLβ2) and Mac-1 (αMβ2) integrins to occur on PBMCs. These results demonstrate that the LFA-1 and Mac-1 integrins on leukocytes bind to TM, thereby establishing the molecular and structural basis underlying LFA-1 and Mac-1 integrin interaction with TM on endothelial cells. In fact, integrin-TM interactions might be involved in the dynamic regulation of leukocyte adhesion with endothelial cells., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The optimal therapeutic strategy for very elderly pancreatic cancer patients remains to be determined. The aim of this study was to clarify the role of pancreatic resection in patients 80 years of age or older., Methods: A retrospective multicenter analysis of 1401 patients who had undergone pancreatic resection for pancreatic cancer was performed. The patients aged ≥ 80 years (n = 99) were compared with a control group <80 years of age (n = 1302)., Results: There were no significant differences in the postoperative complications and mortality between the two groups. However, the prognosis of octogenarians was poorer than that of younger patients for both resectable and borderline resectable tumors. Importantly, there were few long-term survivors in the elderly group, especially among those with borderline resectable pancreatic cancer. A multivariate analysis of the prognostic factors in the very elderly patients indicated that the completion of adjuvant chemotherapy was the only significant factor. In addition, preoperative albumin level was the only independent risk factor for a failure to complete adjuvant chemotherapy., Conclusion: This study demonstrates that the postoperative prognosis in octogenarian patients was not good as that in younger patients possibly due to less frequent completion of adjuvant chemotherapy., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: This study aimed to evaluate the impact of preoperative biliary drainage (PBD) on the long-term survival of patients with pancreatic ductal adenocarcinoma (PDAC) who underwent pancreaticoduodenectomy (PD)., Methods: A multicenter observational study was performed using a common database of patients with resected PDAC from seven high-volume surgical institutions in Japan., Results: Of 932 patients who underwent PD for PDAC, 573 (62 %) underwent PBD, including 407 (44 %) who underwent endoscopic biliary drainage (EBD) and 166 (18 %) who underwent percutaneous transhepatic biliary drainage (PTBD). The patients who did not undergo PBD and those who underwent EBD had a significantly better overall survival than those who underwent PTBD, with median survival times of 25.7 months (P < 0.001), 22.3 months (P = 0.001), and 16.7 months, respectively. Multivariate analysis showed that seven clinicopathologic factors, including the use of PTBD but not EBD, were independently associated with poorer overall survival. Furthermore, patients who underwent PTBD more frequently experienced peritoneal recurrence (23 %) than those who underwent EBD (10 %; P < 0.001) and those who did not undergo PBD (11 %; P = 0.001). Multivariate analysis demonstrated that the independent risk factors for peritoneal recurrence included surgical margin status (P < 0.001) and use of PTBD (P = 0.004)., Conclusions: Use of PTBD, but not EBD, was associated with a poorer prognosis, with an increased rate of peritoneal recurrence among patients who underwent PD for PDAC.

Background/objective: Although surgical resection remains the only chance for cure in patients with pancreatic ductal adenocarcinoma (PDAC), postoperative early recurrence (ER) is frequently encountered. The purpose of this study is to determine the preoperative predictive factors for ER after upfront surgical resection., Methods: Between 2001 and 2012, 968 patients who underwent upfront surgery with R0 or R1 resection for PDAC at seven high-volume centers in Japan were retrospectively reviewed. ER was defined as relapse within 6 months after surgery. Study analysis stratified by resectable (R) and borderline resectable (BR) PDACs was conducted according to the National Comprehensive Cancer Network guidelines., Results: ER occurred in 239 patients (25%) with a median survival time (MST) of 8.8 months. Modified Glasgow prognostic score = 2 (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.05-3.95; P = 0.044), preoperative CA19-9 ≥300 U/ml (OR 1.94, 1.29-2.90; P = 0.003), and tumor size ≥30 mm (OR 1.72, 1.16-2.56; P = 0.006), were identified as preoperative independent predictive risk factors for ER in patients with R-PDAC. In the R-PDAC patients, MST was 35.5, 26.3, and 15.9 months in patients with 0, 1 and ≥2 risk factors, respectively. There were significant differences in overall survival between the three groups (P < 0.001). No preoperative risk factors were identified in BR-PDAC patients with a high rate of ER (39%)., Conclusions: There is a high-risk subset for ER even in patients with R-PDAC and a simple risk scoring system is useful for prediction of ER., (Copyright © 2015 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Background: The aim of the present study was to clarify the surgical outcome and long-term prognosis of laparoscopic liver resection (LLR) compared with conventional open liver resection (OLR) in patients with colorectal liver metastases (CRLM)., Methods: A one-to-two propensity score matching (PSM) analysis was applied. Covariates (P < 0.2) used for PSM estimation included preoperative levels of CEA and CA19-9; primary tumor differentiation; primary pathological lymph node metastasis; number, size, location, and distribution of CRLM; existence of extrahepatic metastasis; extent of hepatic resection; total bilirubin and prothrombin activity levels; and preoperative chemotherapy. Perioperative data and long-term survival were compared., Results: From 2005 to 2010, 1,331 patients with hepatic resection for CRLM were enrolled. By PSM, 171 LLR and 342 OLR patients showed similar preoperative clinical characteristics. Median estimated blood loss (163 g vs 415 g, P < 0.001) and median postoperative hospital stay (12 days vs 14 days; P < 0.001) were significantly reduced in the LLR group. Morbidity and mortality were similar. Five-year rates of recurrence-free, overall, and disease-specific survival did not differ significantly. The R0 resection rate was similar., Conclusions: In selected CRLM patients, LLR is strongly associated with lower blood loss and shorter hospital stay and has equivalent long-term survival comparable with OLR., (© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The aim of this study was to evaluate the validity of preoperative resectability status, as defined by the National Comprehensive Cancer Network (NCCN), from the viewpoint of overall survival., Methods: A total of consecutive 704 patients with pancreatic head carcinoma who underwent pancreatoduodenectomy with upfront surgery at seven Japanese hospitals between 2001 and 2012 were evaluated retrospectively. According to the NCCN definition of preoperative resectability status, tumors were divided into resectable tumors without vascular contact (R group), resectable tumors with portal or superior mesenteric vein (PV/SMV) contact of ≦180° (R-PV group), borderline resectable(BR) tumors with PV/SMV contact of >180° (BR-PV group), and BR tumors with arterial contact (BR-A group). The relationship between the NCCN definition of preoperative resectability status and overall survival was analyzed., Results: Of the 704 patients, 389, 114, 145, and 56 were classified into the R group, the R-PV group, the BR-PV group, and the BR-A group, respectively. Overall survival of the BR-PV and BR-A groups was significantly worse than that of the R group and R-PV groups (P < 0.05), although there was no significant difference in overall survival between the R group and the R-PV group (P = 0.310). Multivariate analysis revealed that PV/SMV contact of >180° (P = 0.008) and arterial contact (P < 0.001) were independent prognostic factors of overall survival., Conclusion: From the viewpoint of overall survival, the NCCN definition of preoperative resectability status was valid.

Background: An aberrant right posterior sectoral hepatic duct (PHD) draining into extrahepatic bile duct, gallbladder or cystic duct directly is a common and critical anomaly during cholecystectomy. This study aimed to investigate the frequency of aberrant PHD and describe why PHD is critical., Methods: In 753 consecutive patients who underwent laparoscopic cholecystectomy (LC) using our standardized procedure over 9 years, we reinvestigated whether an aberrant PHD was present using preoperative images. A PHD joining the common bile duct through the cranial side of the hilar plate was defined as the supraportal type, and one passing through the caudal side of the right portal vein was defined as the infraportal type., Results: Fifty-one (6.8%) patients had aberrant PHD. All of them had the infraportal type, and the cystic duct drained into aberrant PHD in 10 (1.3%) and aberrant PHD drained into the cystic duct in six (0.8%). These 16 most dangerous anomalies were diagnosed before surgery. In all patients with aberrant PHD, LC was completed without any complications., Conclusions: It seems possible to identify most aberrant PHD by attention to the infraportal-type PHD, and injury to them can be avoided by exposing a critical view using an appropriate procedure., (© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The prognosis of pancreatic cancer patients with metastatic para-aortic lymph node (PALN) has been reported to be extremely poor. In general, PALN metastasis has been considered as a contraindication for pancreatic resection. The aim of this study was to reevaluate the postoperative prognostic value of PALN metastasis in pancreatic cancer and to determine the validity of pancreatic surgery., Methods: Retrospective multicenter analysis of 882 patients who have undergone curative-intent pancreatic resection with pathological evaluation of PALNs for pancreatic ductal adenocarcinoma between 2001 and 2012 was conducted. Clinicopathological data and outcomes were evaluated with univariate and multivariate analysis., Results: In total, 102 (12.4 %) patients had positive metastasis in PALN. Patients with metastatic PALN had significantly poorer survival than those without (17 vs. 23 months; p < 0.001). Multivariable analysis of 822 patients identified adjuvant chemotherapy, primary tumor status, regional lymph node metastasis, portal vein invasion, pre- and post-operative serum CA19-9 levels, and tumor grade as independent prognostic factors. In contrast, PALN metastasis did not have a significant prognostic value. Furthermore, the multivariate prognostic analysis in patients with PALN metastasis revealed that adjuvant chemotherapy and the number of metastatic PALN were significantly associated with long-term survival. Lung metastasis as initial recurrence was observed more often in patients with PALN metastasis in comparison with those without., Conclusions: Some pancreatic cancer patients with metastatic PALN may survive for longer than expected after pancreatectomy. Adjuvant chemotherapy and the number of metastatic PALN were critical factors for long-term survival of those patients.

Background/aims: To determine the recommended dose (RD) for full-dose S-1 and low-dose gemcitabine combined with radiotherapy in patients with non-metastatic advanced pancreatic cancer., Methodology: Adult patients with non-metastatic advanced pancreatic cancer (Union for International Cancer Control T stage 3 or 4) were eligible. The weekly intravenous gemcitabine (level 0-1: 200 mg/ml,level 2: 300 mg/m on Days 1, 8, 15, 22, 29, 36) dose was escalated starting from level 1 in a 3+3 design along with full dose twice-daily oral S-1 (level 0: 60 mg/m2/day, level 1-2: 80 mg/ml/day), and was administered on the same days as radiotherapy (1.8 Gy x 28 days)., Results: Eight patients were included in this study. A dose-limiting toxicity (DLT) (grade 4 neutropenia) was observed in one of the first three patients in level 1, and three additional patients received the level 1 dose without any severe adverse events. DLTs (grade 3/4 neutropenia) were then observed in the first two patients given level 2 dose. Therefore, level 1 was designated as the RD. Common grade 3/4 toxicities included neutropenia (62.5%), anorexia (37.5%), and pneumonitis (12.5%)., Conclusions: The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Japanese clinical practice guidelines on how to deal with PBM were made in 2012, representing a world first. According to the 2013 revision to the diagnostic criteria for PBM, in addition to direct cholangiography, diagnosis can be made by magnetic resonance cholangiopancreatography (MRCP), 3-dimensional drip infusion cholangiography computed tomography, endoscopic ultrasonography (US), or multiplanar reconstruction images by multidetector row computed tomography. In PBM, the common channel is so long that sphincter action does not affect the pancreaticobiliary junction, and pancreatic juice frequently refluxes into the biliary tract. Persistence of refluxed pancreatic juice injures epithelium of the biliary tract and promotes cancer development, resulting in higher rates of carcinogenesis in the biliary tract. In a nationwide survey, biliary cancer was detected in 21.6% of adult patients with congenital biliary dilatation (bile duct cancer, 32.1% vs. gallbladder cancer, 62.3%) and in 42.4% of PBM patients without biliary dilatation (bile duct cancer, 7.3% vs. gallbladder cancer, 88.1%). Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of pancreaticobiliary ducts, a common channel ≥6 mm long, and occlusion of communication during contraction of the sphincter. Once the diagnosis of PBM is established, immediate prophylactic surgery is recommended. However, the surgical strategy for PBM without biliary dilatation remains controversial. To detect PBM without biliary dilatation early, MRCP is recommended for patients showing gallbladder wall thickening on screening US under suspicion of PBM.

Objective: The objective of the present study was to reappraise the clinical value of peritoneal washing cytology (CY) in 984 pancreatic ductal adenocarcinoma patients who underwent margin-negative resection., Methods: In a 2001-2011 database from seven high-volume surgical institutions in Japan, 69 patients (7%) had positive CY (CY+ group) indicative of M1 disease and 915 patients had negative CY (CY- group). Clinicopathological data and survival were compared between groups., Results: Significant correlations between CY+ and high CA19-9 level, pancreatic body and tail cancer, lymph node metastasis, and a lower frequency of R0 resection were observed. Overall survival (OS) of CY+ patients was significantly worse than that of CY- patients (median survival time [MST], 16 vs. 25 months; 3-year OS rate, 6 vs. 37%; p < 0.001). CY+ patients had a significantly higher rate of post-operative peritoneal carcinomatosis than CY- patients (48 vs. 21%; p < 0.001). Administration of adjuvant chemotherapy did not provide a favorable survival outcome to CY+ patients. The current study showed that patients with M1 disease had acceptable MST after margin-negative resection and a high incidence of peritoneal carcinomatosis within 3 years after surgery, resulting in decreased long-term survival. The development of a new strategy to control peritoneal carcinomatosis when surgical resection is performed in such patients is required.