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Background: Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. Methods: This retrospective multi‐institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. Results: Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19–9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un‐matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p < 0.001). Conclusion: Postoperative AT might benefit selected patients with invasive IPMC, especially those at high risk of poor survival. NAT might improve the survivability of BR invasive IPMC. Any treatment for recurrence after surgery for invasive IPMC might improve survival. [ABSTRACT FROM AUTHOR]

Background: Although surgical resection is the only curative treatment for biliary tract cancer, in some cases, the disease is diagnosed as unresectable at initial presentation. There are few reports of conversion surgery after the initial treatment for unresectable locally advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of conversion surgery in patients with initially unresectable locally advanced biliary tract cancer. Methods: We retrospectively collected clinical data from groups of patients in multiple centers belonging to the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery and Korean Association of Hepato‐Biliary‐Pancreatic Surgery. We analyzed two groups of prognostic factors (pretreatment and surgical factors) and their relation to the treatment outcomes. Results: A total of 56 patients with initially unresectable locally advanced biliary tract cancer were enrolled in this study of which 55 (98.2%) patients received chemotherapy, and 16 (28.6%) patients received additional radiation therapy. The median time from the start of the initial treatment to resection was 6.4 months. Severe postoperative complications of Clavien‐Dindo grade III or higher occurred in 34 patients (60.7%), and postoperative mortality occurred in five patients (8.9%). Postoperative histological results revealed CR in eight patients (14.3%). The median survival time from the start of the initial treatment in all 56 patients who underwent conversion surgery was 37.7 months, the 3‐year survival rate was 53.9%, and the 5‐year survival rate was 39.1%. Conclusions: Conversion surgery for initially unresectable locally advanced biliary tract cancer may lead to longer survival in selected patients. However, more precise preoperative safety evaluation and careful postoperative management are required. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis. Neoadjuvant chemotherapy is an effective PDAC treatment option, but chemotherapy causes unfavorable side effects. Glucocorticoids (e.g., dexamethasone [DEX]) are administered to reduce side effects of chemotherapy for solid tumors, including pancreatic cancer. Glucocorticoids have both beneficial and detrimental effects, however. We investigated the functional changes and gene‐expression profile alterations induced by DEX in PDAC cells. PDAC cells were treated with DEX, and the cell proliferation, migration, invasion, and chemosensitivity to gemcitabine (GEM) were evaluated. The results demonstrated decreased cell proliferative capacity, increased cell migration and invasion, and decreased sensitivity to GEM. A comprehensive genetic analysis revealed marked increases in ECM1 and KRT6A in DEX‐treated PDAC cells. We evaluated the effects of ECM1 and KRT6A expression by using PDAC cells transfected with those genes. Neither ECM1 nor KRT6A changed the cells' proliferation, but each enhanced cell migration and invasion. ECM1 decreased sensitivity to GEM. We also assessed the clinicopathological significance of the expressions of ECM1 and KRT6A in 130 cases of PDAC. An immunohistochemical analysis showed that KRT6A expression dominated the poorly differentiated areas. High expressions of these two proteins in PDAC were associated with a poorer prognosis. Our results thus demonstrated that DEX treatment changed PDAC cells' functions, resulting in decreased cell proliferation, increased cell migration and invasion, and decreased sensitivity to GEM. The molecular mechanisms of these changes involve ECM1 and KRT6A, whose expressions are induced by DEX. [ABSTRACT FROM AUTHOR]

Background: Diagnosing biliary tract cancer is difficult because endoscopic retrograde cholangiopancreatography (ERCP) is performed fluoroscopically, and the sensitivity of bile cytology is low. Liquid biopsy of bile using targeted sequencing is expected to improve diagnosis and treatment, but few studies have been conducted. In this study, we examined whether liquid biopsy of bile improves the diagnostic sensitivity of biliary strictures. Methods: A total of 72 patients with biliary strictures who underwent ERCP at Chiba University Hospital between April 2018 and March 2021 were examined. Of these, 43 and 29 were clinically and pathologically diagnosed as having malignant and benign biliary strictures, respectively. We performed targeted sequencing of bile obtained from these patients, and the sensitivity of this method was compared with that of bile cytology. Detection of at least one oncogenic mutation was defined as having malignancy. Results: The sensitivity of bile cytology was 27.9%, whereas that of genomic analysis was 46.5%. Comparing bile cytology alone with the combination of cytology and genomic analysis, the latter was more sensitive (53.5%, p <.001). Among the 43 patients with malignant biliary strictures, mutations with FDA‐approved drugs were detected in 11 (26%). Conclusions: Liquid biopsy of bile can potentially diagnose malignancy and detect therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Tokyo Guidelines 2018 (TG18) recommend early laparoscopic cholecystectomy (LC) for low‐risk acute cholecystitis (AC); however, some patients undergo delayed LC (DLC) after conservative treatment. DLC, influenced by chronic inflammation, is a difficult procedure. Previous studies on LC difficulty lacked objective measures. Recently, TG18 introduced a novel 25 findings difficulty score, which objectively assesses intraoperative factors. The purpose of this study was to use the difficulty score proposed in TG18 to identify and investigate the predictors of preoperative high‐difficulty cases of DLC for AC. Methods: We retrospectively reviewed 100 patients with DLC after conservative AC treatment. The surgical difficulty of DLC was evaluated using a difficulty score. Based on previous studies, the highest scores in each category were categorized as grades A–C. Results: The severity of AC was mild in 51 patients and moderate in 49. Surgical outcomes revealed a distribution of difficulty scores, with grade C indicating high difficulty, showing significant differences in operative time, blood loss, achieving a critical view of safety, bailout procedures, and postoperative hospital stay compared with grades A and B. Regarding the preoperative risk factors, multivariate analysis identified age >61 years (p =.008), body mass index >27.0 kg/m2 (p =.007), and gallbladder wall thickness >6.2 mm (p =.001) as independent risk factors for grade C in DLC. Conclusion: The difficulty score proposed in TG18 provides an objective framework for evaluating surgical difficulty, allowing for more accurate risk assessments and improved preoperative planning in DLC for AC. [ABSTRACT FROM AUTHOR]

Background & Aims: Notch1 activation promotes ICC progression and is associated with chemoresistance; however, therapies directly targeting Notch1 showed severe adverse effects. Notch1 activation is mediated by ADAM10, a molecular scissor that separates the target protein from its substrates in the cell membrane. Tspan15 regulates ADAM10 function, but the role of Tspan15 in ICC progression is unclear. Methods: Tspan15, ADAM10, and Notch1 expression and activation in fresh surgical specimens from 80 ICC patients and ICC cells were evaluated by immunohistochemistry, RT‐PCR, western blotting, and flow cytometry. Results: Tspan15 expression was increased in ICC compared with adjacent liver tissue, and high Tspan15 expression was an independent factor for poor prognosis. In ICC with high Tspan15 expression, vascular invasion, lymph node metastasis, and haematogenous recurrence were increased. Tspan15 was co‐expressed with ADAM10 in ICC, and associated with the expression of stemness and EMT markers. In ICC cells, Tspan15 induced ADAM10 activation by mediating the translocation of activated m‐ADAM10 from the cytoplasm to the surface of the cell membrane, which further activated Notch1 by separating the intracellular domain of Notch1 from its extracellular domain, leading to enhancement of CSC‐like properties and EMT. This signalling was associated with enhanced chemoresistance against gemcitabine and cisplatin. Inhibition of Tspan15 or ADAM10 is a promising therapeutic strategy in ICC, as Tspan15 or ADAM10 knockdown or treatment with ADAM10 inhibitor reduced chemoresistance and invasiveness by suppressing Notch1‐mediated CSC‐like properties and EMT. Conclusions: Tspan15‐ADAM10‐Notch1 signalling is associated with aggressive tumour progression and poor prognosis in ICC. [ABSTRACT FROM AUTHOR]

Background: Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of unknown etiology that affects the intra‐ and extrahepatic bile ducts. The present study examined the utility of a bile proteome analysis using a high‐sensitivity mass spectrometer to comprehensively screen for novel PSC biomarkers. Methods: Bile endoscopically collected from patients with PSC, common bile duct stones, and biliary tract cancer were subjected to high‐precision liquid chromatography/mass spectrometry. Some of the proteins specifically up‐regulated in the bile of the PSC group were re‐examined by an enzyme‐linked immunosorbent assay. Results: A total of 8094 proteins were successfully identified and 332 were specifically up‐regulated in the PSC group. The bioinformatics analysis showed that proteins involved in the proliferation and activation of diverse inflammatory cells were up‐regulated in the PSC group. A receiver operating characteristic curve analysis showed good area under the curve values for interleukin‐8 and annexin A1 (ANXA1) (0.836 and 0.914, respectively). Immunostaining for ANXA1 revealed its strong expression in inflammatory cells infiltrating the peripheral biliary tract in PSC livers. Conclusion: A bile proteome analysis is a useful tool for elucidating the pathogenesis of PSC and developing new diagnostic approaches. Therefore, ANXA1 has potential as a bile biomarker for PSC. [ABSTRACT FROM AUTHOR]

Background: In monarchE and Postoperative Therapy with Endocrine and TS‐1 (POTENT) trials, abemaciclib and S‐1 have, respectively, shown to be effective as adjuvant therapies for luminal breast cancer (BC), although whether patients who meet the criteria are at high risk of recurrence compared to non‐eligible patients is still unknown. Here, we investigated recurrence risk according to the criteria of each trial in Japanese patients. Methods: We reviewed the records of 992 patients who received surgery at Chiba University Hospital for stage I–III BC from January 2017 to May 2022 and selected 553 analytic cohort patients and retrospectively analyzed the relapse‐free survival of the patients as the primary endpoint. High‐recurrence risk was defined according to monarchE trial and POTENT trial. Results: The 5‐year RFS for monarchE cohort 1 and cohort 2 eligible patients were 77.78% and 89.33%, respectively, which were significantly lower than monarchE non‐eligible patients (98.31%; p < 0.0001). However, the 5‐year RFS rate for POTENT eligible patients (90.51%) was lower than for POTENT non‐eligible patients (98.75%; p = 0.0001); excluding those who met the monarchE criteria, the prognosis of POTENT eligible patients had no significant differences from the prognosis of patients with POTENT non‐eligible BC (p = 0.3100). Conclusion: MonarchE criteria accurately identify patients who are prone to relapse. Moreover, although POTENT criteria also suggested a reasonable capacity for recurrence prediction, there was no significant difference in recurrence between POTENT non‐eligible patients and the patients who were POTENT but not monarchE eligible. This might offer justification for reconsidering the use of S‐1 in monarchE non‐eligible patients. [ABSTRACT FROM AUTHOR]

Aim: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late‐onset hepatic failure (LOHF) admitted to our unit over a 32‐year period to clarify the nature of Japanese patients with FH and LOHF. Methods: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. Results: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. Conclusions: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult‐to‐treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT. [ABSTRACT FROM AUTHOR]

Infection with certain viruses is an important cause of cancer. The Pan‐Cancer Analysis of Whole Genomes (PCAWG) Consortium recently analyzed the whole‐genome sequencing (WGS) data from 2656 cases across 21 cancer types, and indicated that Epstein–Barr virus (EBV) is detected in many different cancer cases at a higher frequency than previously reported. However, whether EBV‐positive cancer cases detected by WGS‐based screening correspond to those detected by conventional histopathological techniques is still unclear. In this study, to elucidate the involvement of EBV in various cancers, we reanalyzed the WGS data of the PCAWG cohort combined with the analysis of clinical samples of gastric and pancreatic cancer in our cohort. Based on EBV copy number in each case, we classified tumors into three subgroups: EBV‐High, EBV‐Low, and EBV‐Negative. The EBV‐High subgroup was found to be EBV‐positive in the cancer cells themselves, whereas the EBV‐Low subgroup was EBV‐positive in the surrounding lymphocytes. Further, the EBV‐Low subgroup showed a significantly worse prognosis for both gastric cancer and across cancer types. In summary, we classified tumors based on EBV copy number and found a unique cancer subgroup, EBV‐positive in the surrounding lymphocytes, which was associated with a poor prognosis. [ABSTRACT FROM AUTHOR]

Background & Aims: TRIM27 is stabilized by binding to USP7 and mediates tumour progression in several cancers; however, the roles of TRIM27‐USP7 complex on STAT3 activation in HCC are unknown. Methods: Regulations and functions of TRIM27 for activating STAT3 in HCC were assessed using 207 HCC samples or HCC cells. Results: TRIM27 expression was increased in some cases of HCC. High TRIM27 expression was an independent predictor for poor prognosis in HCC after surgery. It was correlated with the expression of EpCAM, vimentin, MMP‐9, and activation of STAT3 in HCC. TRIM27 expression was correlated with USP7 expression, and HCC with high TRIM27 expression together with high USP7 expression showed enhanced STAT3 activation, resulting in poorer prognosis. p‐JAK1 expression was correlated with STAT3 activation in HCC with high TRIM27 expression. In vitro, USP7 knockdown decreased TRIM27 expression, suggesting that USP7 was essential for TRIM27 stabilization. Knocking down of TRIM27 or USP7 suppressed STAT3 activation and overexpression of TRIM27 accelerated STAT3 activation; therefore, the formation of TRIM27‐USP7 complex was needed for STAT3 activation, which led to aggressive tumour proliferation and invasion by enhancing EMT and CSC‐like property. Binding of JAK1 to TRIM27‐USP7 complex was confirmed in vitro. Deletion of TRIM27‐USP7 complex by USP7 inhibitor significantly inhibited tumour cell invasion by suppressing STAT3 activation. Conclusions: TRIM27 is stabilized by binding to USP7 and is related to aggressive tumour progression in HCC via STAT3 activation, resulting in poor prognosis after operation. Therefore, TRIM27‐USP7 complex is a useful prognostic predictor and a promising therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

At the periphery of the cyst, the right adrenal gland adhered with the liver, and some small bile ductules were just entering into the adrenal tissue (C). We encountered a case of adenocarcinoma derived from adrenohepatic fusion-related cyst (AHF-RC). Fragmented adrenal tissues were multifocally observed around the cyst, and the lining cells showed immunophenotypes of the true epithelium, which supported the existence of AHF-RC prior to the carcinogenesis. [Extracted from the article]

Background/Purpose: Whether organ‐preserving pancreatic surgery has an advantage in postoperative short‐ and long‐term outcomes or not is still unknown because only small case series studies have been available to date. In this multicenter retrospective study, we aimed to elucidate the clinical advantage and disadvantage of organ‐preserving pancreatectomy among patients with low‐grade malignant pancreatic tumors and benign pancreatic diseases. Methods: We included patients diagnosed with benign or low‐malignant pancreatic tumor who underwent pancreaticoduodenectomy (PD) in 621 cases, duodenum‐preserving pancreatic head resection (DPPHR) in 31 cases, middle pancreatectomy (MP) in 148 cases, distal pancreatectomy (DP) in 814 cases, and spleen‐preserving distal pancreatectomy (SPDP) in 259 cases between January 1, 2013, and December 31, 2017. Preoperative backgrounds, surgical outcomes and pre‐ and postoperative (3, 6, 12, 24, and 36 months) nutritional status were compared between these procedures. Results: In terms of short‐term outcomes, the incidence of pancreatic fistula in patients who underwent MP was significantly higher than in patients with standard pancreatectomy. As for the long‐term pancreatic functions in the cases of head or body lesion, both exocrine and endocrine functions after MP were significantly favorable compared with the PD group from 3 to 36 months after surgery. In pancreatic body or tail lesion, significant advantage of endocrine function, but not exocrine function, was found in the MP group compared to standard DP at all time points. Conclusions: MP may contribute to the improvement of postoperative quality of life for patients with pancreatic body low‐malignant tumors, rather than PD or DP; however, reducing the incidence of short‐term complications such as pancreatic fistula is a future challenge. [ABSTRACT FROM AUTHOR]

Glycoproteins produced by tumor cells are involved in cancer progression, metastasis, and the immune response, and serve as possible therapeutic targets. Considering the dismal outcomes of pancreatic ductal adenocarcinoma (PDAC) due to its unique tumor microenvironment, which is characterized by low antitumor T‐cell infiltration, we hypothesized that tumor‐derived glycoproteins may serve as regulating the tumor microenvironment. We used glycoproteomics with tandem mass tag labeling to investigate the culture media of three human PDAC cell lines, and attempted to identify the key secreted proteins from PDAC cells. Among the identified glycoproteins, prosaposin (PSAP) was investigated for its functional contribution to PDAC progression. PSAP is highly expressed in various PDAC cell lines; however, knockdown of intrinsic PSAP expression did not affect the proliferation and migration capacities. Based on the immunohistochemistry of resected human PDAC tissues, high PSAP expression was associated with poor prognosis in patients with PDAC. Notably, tumors with high PSAP expression showed significantly lower CD8+ T‐cell infiltration than those with low PSAP expression. Furthermore, PSAP stimulation decreased the proportion of CD8+ T cells in peripheral blood monocytes. Finally, in an orthotopic transplantation model, the number of CD8+ T cells in the PSAP shRNA groups was significantly increased, resulting in a decreased tumor volume compared with that in the control shRNA group. PSAP suppresses CD8+ T‐cell infiltration, leading to the promotion of PDAC progression. However, further studies are warranted to determine whether this study contributes to the development of a novel immunomodulating therapy for PDAC. [ABSTRACT FROM AUTHOR]

Background/Purpose: In the present study we aimed to prospectively assess the current prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) after total pancreatectomy (TP). Methods: Between August 2015 and December 2017, we prospectively collected data from 68 Japanese centers on 148 consecutive patients who underwent TP whose computed tomography (CT) attenuation values were evaluated for 12 months. We defined post‐TP NAFLD as a liver parenchyma CT value of less than 40 Hounsfield units (HU). Data on perioperative variables were retrieved from all patients and evaluated using univariate and multivariate analyses to identify the perioperative risk factors of NAFLD. Results: In this prospective cohort study, supplementation of pancreatic exocrine enzymes was provided to all 148 patients, and 97% of them were treated with high‐titer pancrelipase (median dosage: 1800 mg) postoperatively. Indeed, 29 patients (19.6%) developed NAFLD within a year after TP. Multivariate analysis revealed that female sex (P =.002), higher body mass index (BMI) (P =.001), and postoperative diarrhea (P =.038) were independent risk factors for post‐TP NAFLD. However, post‐TP NAFLD ameliorated in 11 patients (37.9%) at 12 months after surgery. Conclusions: Among patients with risk factors such as female sex, higher BMI, and postoperative diarrhea, attention should be paid to the occurrence of NAFLD after TP. [ABSTRACT FROM AUTHOR]

Background: Although the most important goal in surgery for perihilar cholangiocarcinoma (PHC) is to achieve tumor‐free proximal ductal margins, little is known about the implications of confluence patterns of the left intrahepatic bile ducts for the proximal ductal margin status in right hepatectomy (RH) for PHC. Methods: Of 203 patients who underwent surgical resection for PHC with curative intent, confluence patterns of the left intrahepatic bile duct were evaluated in 94 consecutive patients who underwent RH, and they were classified into the following two types: normal type: the bile duct of segment 4 (B4) drained into the common trunk of the bile ducts of segment 2 (B2) and segment 3 (B3) at the right side of the umbilical portion of the left portal vein to form the left hepatic duct; and hepatic confluence type: B2 entered the common trunk of B3 and B4 at the hepatic confluence or B4 entered the common trunk of B2 and B3 at the hepatic confluence. The proximal ductal margin status following RH was compared between the two types of confluence patterns. Results: Of 94 consecutive patients, 69 (73%) were the normal type, and 25 (27%) were the hepatic confluence type. There were no significant differences in patients' characteristics, surgical characteristics, surgical outcomes, and histopathological features between the two groups. However, in patients with Bismuth‐Corlette type II and IIIa PHC, the achievement rates of negative proximal ductal margins at the first dividing line were significantly higher in the hepatic confluence type group than in the normal type group (16/16 [100%] vs 34/52 [65%], respectively; P =.007). Conclusions: Confluence patterns of the left intrahepatic bile ducts might affect proximal ductal margin status in RH for PHC. [ABSTRACT FROM AUTHOR]

Background/Purpose: The objective of this study was to determine the frequency and predictors of biliary tract cancer (BTC) with deficient DNA mismatch repair (dMMR) in Japan. Methods: Immunostaining and microsatellite instability analysis were performed for mismatch repair‐related proteins in tissue specimens from 662 patients who underwent surgery for BTC between 2001 and 2017 to identify dMMR‐BTC. We compared dMMR‐BTC and proficient MMR (pMMR)‐BTC based on patient demographics, pathological features, and host immune responses characterized by the percentage of stromal tumor infiltrating lymphocytes (sTIL percentage) and tertiary lymphoid structures (TLS). Results: The incidence of dMMR‐BTC was 2.3%. Significant predictors of dMMR‐BTC were its primary lesion being intrahepatic cholangiocarcinoma (odds ratio [OR] 6.34, P =.004), presence of signet ring cell component (OR 35.62, P <.001), sTIL percentage ≥40% (OR 3.43, P =.038), and presence of TLS (OR 22.22, P <.001). The sensitivity, specificity, and negative likelihood ratio for any one or more of these four variables to be positive were 93.3%, 57.8%, and 0.12, respectively. Conclusion: Evaluation of histopathological findings and host immune response based on conventional histochemical staining is useful for efficient and inexpensive diagnostic screening of dMMR‐BTC patients. [ABSTRACT FROM AUTHOR]

Background & Aims: LGR5 enhances Wnt‐β‐catenin signalling; however, involvement of LGR5 or Wnt‐β‐catenin signalling in ICC progression has not been reported. Methods: Functions and regulations of LGR5‐mediated β‐catenin activation in ICC progression were evaluated using surgical specimens collected from 61 ICC patients or 2 ICC cell lines. Results: LGR5 expression was increased in some cases of ICC. It was positively correlated with β‐catenin activation, OLFM4 expression and STAT3 activation, and negatively correlated with GRIM19 expression in ICC, thereby enhancing cancer stem cell (CSC)‐like property and EMT. High LGR5 expression was an independent factor for poor prognosis in ICC after operation. In vitro, Wnt inhibition by IWP‐2 suppressed β‐catenin activation, OLFM4 expression and STAT3 activation. IWP‐2 treatment decreased expression of EpCAM, CD133, vimentin and increased E‐cadherin expression. The rate of mesenchymal cells was decreased and cell invasiveness was suppressed after IWP‐2 treatment, suggesting that Wnt‐β‐catenin signalling enhanced CSC‐like property and EMT by activating STAT3. In addition, LGR5 knockdown inhibited β‐catenin activation, resulting in suppression of β‐catenin‐induced STAT3 activation through inhibition of OLFM4‐GRIM19 cascade. As these results, LGR5 knockdown suppressed CSC‐like property and EMT. Therefore, LGR5 was a key regulator for β‐catenin activation, and β‐catenin was unable to be activated without LGR5. Conclusions: LGR5 is essential for β‐catenin activation induced by Wnt signalling. Activated β‐catenin further activates STAT3 and enhances CSC‐like property and EMT, leading to aggressive tumour progression and poor prognosis in patients with ICC. Therefore, LGR5 is an excellent prognostic predictor and a promising therapeutic target for ICC. [ABSTRACT FROM AUTHOR]

Background: Hepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors. Methods: Eight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations. Results: The eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two. A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy. Conclusions: These guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence. [ABSTRACT FROM AUTHOR]

Background and Aim: Postoperative hemorrhage is a rare but potentially lethal complication of hepatobiliary and pancreatic surgeries. This study aimed to retrospectively evaluate the clinical outcome of patients with delayed postoperative hemorrhage and compare the results according to the surgical procedure. Methods: Overall, 4220 patients underwent surgery for hepatobiliary and pancreatic diseases. Delayed postoperative hemorrhage (observed more than 24 h postoperatively) occurred in 62 patients. Of these, 61 underwent interventional radiology to achieve hemostasis. Patients' clinical data were analyzed retrospectively. The chi‐squared or Fisher's exact test was used in data analysis. Results: A total of 62 patients (1.5%) developed delayed postoperative hemorrhage; 61 (1.4%) of them underwent interventional radiology to achieve hemostasis. Median duration from surgery to interventional radiology was 19 days (range: 5–252 days). Sentinel bleeding was detected in 31 patients; Clinical success was achieved in 54 patients (88.5%) by interventional radiology. Overall mortality rate was 26.2%. Causes of 16 in‐hospital deaths were uncontrollable hemorrhage (n = 4) and worsening of general condition after hemostasis (n = 12). Mortality rates were 50.0% (11/22) and 12.8% (5/39) after hepatobiliary surgery and pancreatic resection, respectively. Mortality rate was significantly higher after hepatobiliary surgery than after pancreatic surgery (P = 0.002). Conclusions: Interventional radiology can be successfully performed to achieve hemostasis for delayed hemorrhage after hepatobiliary and pancreatic surgeries. Because successful interventional radiology does not necessarily lead to survival, particularly after hepatobiliary surgery, meticulous attention to prevent surgical complications and intensive treatments before and after interventional radiology are required to improve outcomes. [ABSTRACT FROM AUTHOR]

Krüppel‐like factor 5 (KLF5) plays an oncogenic role and has diverse functions in cancer cells. However, correlation between KLF5 and clinical outcome has not been determined in patients with colorectal cancer and colorectal liver metastasis. Herein, we analyzed 65 patients with colorectal cancer who developed colorectal liver metastasis. Clinical effects were assessed through immunohistochemical analysis of primary colorectal cancer lesions and metastatic liver lesions. High expression of KLF5 in these tissues correlated with the presence of vascular invasion, elevated serum carbohydrate antigen 19‐9 levels, large diameters of metastatic liver tumors, and poor prognosis following surgery. Multivariate analyses revealed that high expression of KLF5 was an independent prognostic factor. Increased expression of KLF5 in both colorectal cancer primaries and colorectal liver metastasis was significantly associated with shorter overall survival time and time to surgical failure. Krüppel‐like factor 5 expression positively correlated with Ki‐67 and c‐Myc expression in colorectal cancer tissues. In vitro experiments with colon cancer cell lines showed that siRNA knockdown of KLF5 inhibited cell proliferation. Western blot analyses revealed that knockdown of KLF5 expression reduced cyclin D1 and c‐Myc expression. It also impaired the stem cell‐like properties of cancer cells in tumorsphere formation assays. Furthermore, anoikis assay indicated that KLF5 contributed to anoikis resistance. High KLF5 expression is associated with poor prognosis in patients with colorectal cancer and liver metastasis by promoting cell proliferation and cancer stem cell‐like properties. [ABSTRACT FROM AUTHOR]

Neoplastic cells directly and deeply invaded the adjacent organs including regional lymph node (d), duodenal wall (e), and vascular wall of the superior mesenteric vein (f), which indicated locally aggressive behaviors gl The patient was followed up without additional therapy including adjuvant chemotherapy. Here, we describe a rare case of solid serous neoplasm (SN) of the pancreas with locally aggressive behaviors. Based on these findings, the tumor was thought to be locally aggressive neoplasm, especially pancreatic neuroendocrine neoplasm, solid pseudopapillary neoplasm or acinar cell carcinoma. [Extracted from the article]

Background: In Japan, strategies for preoperative management of perihilar cholangiocarcinoma (PHC) have evolved over the last decade; the operative mortality has significantly reduced to <5%. Methods: A questionnaire was sent to 10 institutions based on their case volume. Questionnaire was based on: (1) preoperative biliary drainage, (2) bile replacement, (3) role of synbiotics, (4) remnant liver volume enhancement, (5) predicted remnant liver function, (6) imaging, (7) nutrition, and (8) role of Inchinkoto. Results: The median case volume was 226 (range 105–889) cases, respectively. Eight institutions preferred endoscopic nasobiliary drainage and two preferred endoscopic biliary stenting for biliary drainage. Nine used bile replacement within 2–3 days of biliary drainage. Four used synbiotics preoperatively. The median cutoff value for future remnant liver volume and serum total bilirubin, at which portal vein embolization (PVE) is done, is <40% and <4 mg/dl. The median interval between PVE and surgery was 3–4 weeks. To predict remnant liver function, indocyanine green retention (n = 8) and clearance rate (n = 2) were mainly used. Five used Inchinkoto to improve liver function. Nine used multidetector computed tomography and direct cholangiography for surgical planning. Conclusion: With appropriate preoperative management of PHC, surgical morbidity and mortality can be reduced. This survey can provide recommendations to improve PHC perioperative outcomes. [ABSTRACT FROM AUTHOR]

Background: Although multidetector-row computed tomography (MDCT) before biliary drainage is useful for the assessment of the resectability of perihilar cholangiocarcinoma (PHC), the impact of biliary drainage on MDCT images before surgical resection for PHC has been poorly studied, and its possible consequences for R0 resection of PHC remain unclear. This study was performed to compare the surgical outcomes of patients with PHC who underwent MDCT before versus after biliary drainage.Methods: All consecutive patients who underwent major hepatectomy extending to segment 1 with extrahepatic bile duct resection for PHC from 2009 to 2016 were retrospectively evaluated. R0 resection was defined as no residual cancer at all surgical margins. Patients with pathological stage IV PHC were excluded.Results: Of 142 patients who underwent major hepatectomy, 108 were eligible for this study. Of these 108 patients, 64 (59%) and 44 (41%) underwent MDCT before and after biliary drainage, respectively. The total bilirubin concentration at presentation was lower in patients who underwent MDCT before than after biliary drainage (4.1 ± 5.9 vs. 8.0 ± 7.1 mg/ml, respectively; p = 0.002). Although there were no significant differences in the surgical characteristics or pathological stages between the two groups, R0 resection was more frequently achieved in patients who underwent MDCT before than after biliary drainage [46/64 (72%) vs. 22/44 (50%), respectively; p = 0.03]. On multivariate analysis, MDCT before biliary drainage was independently associated with R0 resection of PHC (risk ratio: 2.38, 95% CI 1.05-5.41; p = 0.04).Conclusions: In selected patients, MDCT should be performed before biliary drainage to achieve R0 resection of PHC. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition ( EMT) and mesenchymal-epithelial transition ( MET) contribute to cancer metastasis of pancreatic ductal adenocarcinoma ( PDAC). We explored the role of grainyhead-like 2 ( GRHL2), a suppressor of EMT, in the progression of PDAC. Expressions of GRHL2 were assessed using surgically resected PDAC tissues by immunohistochemistry analysis, and in vitro using human and mouse PDAC cells. Effects on epithelial plasticity and stemness of GRHL2 were examined in vitro using liver metastatic PDAC cells ( CFPAC-1) with GRHL2 knockdown by specific si RNAs. GRHL2 has a significantly positive correlation with E-cadherin and CD133 in 155 resected human primary PDAC tissues. GRHL2 is highly expressed in liver metastatic cells than in primary invasive cells of both human and mouse PDAC, accompanied by a positive correlation with E-cadherin expression. GRHL2 knockdown CFPAC-1 cells demonstrated morphological changes into mesenchymal appearances and reduced proliferation through EMT. Notably, knockdown studies followed by flow cytometry analysis for a subpopulation of CD133+ showed that GRHL2 facilitates CFPAC-1 cells to maintain stem-like characters including self-renewal capacity and anoikis resistance. GRHL2 regulates epithelial plasticity along with stemness in PDAC, both of which are crucial for metastasis, implicating the possibility of GRHL2 as a therapeutic target for PDAC liver metastasis. [ABSTRACT FROM AUTHOR]

Background The aim of the present study was to assess recent trends in pancreaticoduodenectomy ( PD) and the role of institutional standardization on the development of postoperative complications in 3,378 patients who underwent PD in Japan. Methods Data were collected from 3,378 patients who underwent PD in 2006, 2010 and 2014 at 53 institutions. A standardized institution ( SI) was defined as one that implements ≥7 of 13 quality initiatives according to departmental policy. There were 1,223 patients in the SI group and 2,155 in the non- SI group. Clinical parameters were compared over time, and between groups. Risk factors for morbidity and mortality were assessed by logistic regression analysis with a mixed-effects model. Results The number of patients who underwent PD in SIs increased from 16.5% in 2006 to 46.4% in 2014. The SI group experienced an improved process of care and a lower frequency of severe complications vs. the non- SI group ( P < 0.001). Multivariate analysis revealed that the SI group was associated with a lower incidence of delayed gastric emptying (odds ratio −0.499, P = 0.008) and incisional surgical site infection (odds ratio −0.999, P < 0.001). Conclusion Standardization of care in PD may be important in reducing post- PD complications, and is a critical element for improving clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: In the present study, we conducted a multicenter nationwide survey to investigate the effects of preoperative fluorine‐18‐fluorodeoxyglucose (FDG) positron emission tomography (PET) on the prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT). Methods: From 16 Japanese LT centers, data were collected on 182 recipients with HCC who underwent living donor liver transplantation (LDLT) between February 2005 and November 2013. PET‐positive status was defined as increased uptake of FDG in the tumor compared to the surrounding non‐tumor liver tissue. The median follow‐up after LDLT was 54.5 months (range 1–125 months). Results: Postoperative HCC recurrence occurred in 23 patients. Multivariate analysis revealed that exceeding the Milan criteria (MC), alpha‐fetoprotein (AFP) level ≥115 ng/ml, and PET‐positive status were significant and independent risk factors for recurrence. In the over‐MC group, a subgroup of patients with AFP level <115 ng/ml and PET‐negative status (n = 22) had a significantly lower 5‐year recurrence rate than the other patients (n = 27, 19% vs. 53%, P = 0.019). Conclusions: These results suggest that preoperative FDG‐PET status offers additional information on HCC recurrence risk after LT. Over‐MC patients with PET‐negative status and lower AFP level may achieve successful outcome comparable to that of within‐MC patients. Highlight To elucidate the efficacy of preoperative FDG‐PET in predicting HCC recurrence after living donor liver transplantation, Takada and colleagues investigated data of 182 recipients from 16 centers. Patients exceeding the Milan criteria with PET‐negative status and lower AFP levels achieved favorable outcomes comparable with those of patients within the Milan criteria. [ABSTRACT FROM AUTHOR]

Background: The prognosis of advanced hepatocellular carcinoma (HCC) is poor because of its rapid progression. Peroxisome proliferator‐activated receptor‐gamma (PPARγ) is known to inhibit tumor growth in vitro; however, the behavior of PPARγ in clinical cases of HCC remains uncertain. Methods: Surgical specimens were collected from 104 HCC patients. The anti‐neoplastic effects of PPARγ were evaluated. Results: PPARγ and its ligand expression were increased in some cases of HCC. When HCC patients were divided into two groups, tumor size was larger in patients with low PPARγ expression. Moreover, low PPARγ expression in HCC was an independent predictor of poorer prognosis. PPARγ expression was positively correlated with PPARγ activation and negatively correlated with NF‐κB activation in HCC. PPARγ activation inhibited cell proliferation by inducing cell cycle arrest, through increased expression of p27(kip1) and decreased expression of cyclin D1 and interleukin‐8. When HCC cells were treated with PPARγ ligands, PPARγ activation was increased and cell proliferation was inhibited in a dose‐dependent manner. In contrast, PPARγ ligands negatively regulated NF‐κB activation. Conclusions: Activation of PPARγ induces cell cycle arrest and inhibits tumor progression by negatively regulating NF‐κB activation in HCC. Therefore, PPARγ is an important endogenous regulator of HCC progression, and is a potential therapeutic target for HCC. Highlight Nojima and colleagues set out to elucidate the behavior of PPARγ, which is known to inhibit tumor growth in vitro, in clinical cases of hepatocellular carcinoma. Increased PPARγ ligands enhanced the expression and activation of PPARγ, showing anti‐neoplastic effects by inducing cell cycle arrest through the inhibition of NF‐γB activation. [ABSTRACT FROM AUTHOR]

Background: Diffusion-weighted magnetic resonance imaging (DW-MRI) is utilized as a method of oncologic imaging for predicting treatment outcomes. This study explored the role of DW-MRI in the treatment of patients with resected pancreatic cancer by comparing apparent diffusion coefficient (ADC) values with clinicopathological findings and survival rates.Materials and Methods: Records of 54 patients in whom DW-MRI at 1.5T was performed (b values: 0 and 1000 mm(2) /s) before macroscopically curative resection were analyzed. ADC values were then calculated and compared with clinicopathological factors including age, gender, serum carcinoembryonic antigen levels, serum carbohydrate antigen 19-9 levels, lymph node metastasis, primary tumoral location, size, differentiation, resectability, and pT stage. A survival analysis of clinicopathological factors and ADC values was performed using the Kaplan-Meier method, and the results were evaluated with the log-rank test. Prognostic significance was assessed using the Cox proportional hazard model.Results: Significant associations were found between tumor differentiation and ADC values (P = 0.001). In a univariate analysis of overall survival, tumor differentiation (P = 0.037) and ADC values (P = 0.002) were identified as significant prognostic factors. However, age, gender, carcinoembryonic antigen levels, carbohydrate antigen 19-9 levels, lymph node metastasis, primary tumoral location, size, resectability, and pT stage were not associated with overall survival. In a multivariate analysis of overall survival, only ADC values were identified as significant prognostic factors (hazard ratio 2.293, 95% confidence interval 1.147-4.585, P = 0.019).Conclusion: ADC values were found to be associated with prognosis in patients with resected pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background and Aim Whether an antiviral interferon ( IFN)-based therapy ( IBT) after curative treatment of hepatocellular carcinoma ( HCC) improves the prognosis in patients with hepatitis C virus ( HCV)-related HCC remains to be elucidated. Methods A total of 178 patients within the Milan criteria underwent curative treatment for HCV-related HCC. Both the time to beyond the Milan criteria ( TTBMC) and overall survival ( OS) were compared between the sustained virologic response ( SVR) ( IFN with SVR, n = 22), non- SVR ( IFN without SVR, n = 19), and non- IBT (control, n = 82) groups using propensity score matching analysis. Prognostic factors to predict survival were also determined by the Cox proportional-hazards model. Results TTBMC in the IFN with SVR group was significantly longer than those in the control and IFN without SVR groups ( P < 0.001 and P = 0.006, respectively), although no significant difference existed between the IFN without SVR and control groups. Similarly, OS of the IFN with SVR group was significantly longer than that of the control and IFN without SVR groups ( P < 0.001 and P = 0.029, respectively), although no significant difference existed between the IFN without SVR and control groups. The Cox proportional-hazards model identified SVR as an independent prognostic factor in these patients. The IFN with SVR group showed a 0.096-fold decrease in mortality risk compared with the control group (95% confidence intervals = 0.023-0.405; P = 0.001). Conclusion Elimination of HCV after curative treatment of patients with HCC within the Milan criteria inhibits recurrence and contributes to a preferential prognosis. [ABSTRACT FROM AUTHOR]

Background: The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. Methods: Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence‐based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. Results: The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. Conclusions: This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full‐text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary‐tract2.html. [ABSTRACT FROM AUTHOR]

Background: The 3rd English edition of the Japanese classification of the biliary tract cancers (JC) is now available in this journal. The primary aim of this revision is to provide all clinicians and researchers with a common language of cancer staging at an international level. On the other hand, there are several important issues that should be solved for the optimization of the staging system. Methods: Revision concepts and major revision points of the 3rd English edition of the JC were reviewed. Furthermore, comparing with the 7th edition of staging system developed by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC), distinctive points in the JC was discussed. Results: In this edition of the JC, the same stage groupings as those in the UICC/AJCC staging system were basically adopted. T, N, and M categories were also identical in principle with those in the UICC/AJCC staging system, although slight modifications were proposed as the “Japanese rules”. As distinctive points, perihilar cholangiocarcinomas and ampullary region carcinomas were clearly defined. Intraepithelial tumor was discriminated from invasive carcinoma at ductal resection margins. Classifications of site‐specific surgical margin status remained in this edition. Histological classification was based on that in the former editions of the JC, but adopted some parts of the World Health Organization classification. Conclusions: The JC now share its staging system of the biliary tact carcinomas with the UICC/AJCC staging system. Future validation of the “Japanese rules” could provide important evidence to make globally standardized staging system. © Japanese Society of Hepato‐Biliary‐Pancreatic Surgery [ABSTRACT FROM AUTHOR]

Background: Full understanding of the hilar anatomy is crucial for successful surgical resection of perihilar cholangiocarcinoma (PHC). Methods: The three-dimensional positional relationship between the left hepatic artery (LHA) and the umbilical portion of the left portal vein (UP) was evaluated using multidetector-row computed tomography (CT) in 58 consecutive patients who underwent right-sided hepatectomy for Bismuth-Corlette IIIa or IV tumors. The positional relationship of the LHA related to UP was classified into the following three types: L-UP type, LHA runs into the left lateral section (LLS) from the left caudal side of the UP; R-UP type, LHA runs into the LLS from the right cranial side of the UP; and combined type, one branch of the LHA runs into the LLS from the right cranial side of the UP, and the other from the left caudal side of the UP. Results: L-UP-type LHA was observed in 53 cases (91.4 %), R-UP type in three cases (5.2 %), and combined type in two cases (3.4 %). No cancer involvement of the LHA was seen in any cases with L-UP type. In one case with R-UP type (one of three; 33.3 %) and one case with combined type (one of two, 50 %), cancer invasion to the LHA was observed at the right side of the UP, requiring combined resection of the involved LHA. Conclusions: R-UP-type LHA running just along the left hepatic duct may be easily involved by right-side predominant PHC when extending to the left hepatic duct. Hepatobiliary surgeons should recognize this anatomical variant and carefully evaluate the running courses of LHA to successfully perform R0 resection in right-sided hepatectomy for PHC. [ABSTRACT FROM AUTHOR]

Background: The possibility of resection for locally advanced pancreatic ductal adenocarcinoma (PDAC) with involvement of hepatic or superior mesenteric artery is low. The treatment strategy for these locally advanced PDAC needs to be elucidated. Methods: We retrospectively reviewed the medical records of 107 patients undergoing pancreaticoduodenectomy for PDAC between 2007 and 2012. Among these patients, seven patients who had unresectable PDAC because of cancer involvement of hepatic artery underwent preoperative hepatic arterial embolization and subsequent pancreaticoduodenectomy combined with resection of hepatic artery without reconstruction (PDCAR). We specifically focused on these seven patients to clarify the benefit and drawback of PDCAR. Results: Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on 1 day after hepatic arterial embolization increased, but returned to baseline before pancreaticoduodenectomy. There was no arterial embolization‐related complication before surgery. Serum ALT and AST levels increased 1 day after surgery, but thereafter returned to baseline. Although postoperative morbidity such as hepatic infarction was observed in one case, there were no in‐hospital deaths. The median survival time was 12.6 months and 5‐year survival rate was 19%. Conclusion: Preoperative hepatic arterial embolization and subsequent PDCAR might be a feasible procedure in selected patients with unresectable locally advanced PDAC with hepatic artery involvement. [ABSTRACT FROM AUTHOR]

Surgical resection is the only hope for cure in patients with pancreatic cancer. To improve the resectability and achieve better prognosis of this lethal disease, extended resection for pancreatic cancer has been applied. We have performed portal vein resection aggressively for pancreatic cancer with portal vein invasion. We also established a method of portal vein reconstruction using the left renal vein graft for tumors widely extended to the portal vein. Our data show similar survival between patients with portal vein obstruction and those without invasion. We also show that portal vein reconstruction using the left renal vein graft can be performed safely without severe liver damage. With video, we introduce our surgical technique for portal vein resection and reconstruction, especially focusing on the usage of the left renal vein graft, providing several tips for a safe and successful procedure. [ABSTRACT FROM AUTHOR]

Background: Preoperative diagnosis of solid pseudopapillary neoplasm of the pancreas (SPN) remains difficult and optimal surgical management for SPN has yet to be fully defined. Methods: Retrospective analysis was undertaken of all 10 patients (six women, four men) who underwent surgery for SPN between 2001 and 2013. Results: Mean age was 26 years (range, 16–33 years) for women, and 50 years (range, 35–76 years) for men. Although large SPN showed typical imaging findings, small SPN (≤3.0 cm) appears as almost entirely solid tumors. Endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) was performed in six patients with atypical findings of SPN for differentiation from other pancreatic neoplasms. Definitive preoperative cytological diagnosis was achieved in all patients who underwent EUS‐FNA. All 10 patients underwent surgical exploration. One patient with portal vein invasion and multiple lung metastases underwent pancreaticoduodenectomy combined with portal vein resection and reconstruction, followed by two pulmonary resections. This patient remains alive as of 34 months after the initial operation. Conclusions: Endoscopic ultrasound‐guided fine‐needle aspiration is useful for definitive preoperative diagnosis of SPN. As long‐term survival after surgical resection can be achieved even in patients with locally advanced and metastatic SPN, aggressive surgical resection should be performed. [ABSTRACT FROM AUTHOR]

Background: Recently, the Liver Cancer Study Group of Japan (LCSGJ) staging system for intrahepatic cholangiocarcinoma (ICC) was followed by a proposal of the American Committee on Cancer (AJCC)/International Union Against Cancer (UICC) system. The present study aimed to assess the accuracy of both systems to predict survival after curative resection for mass‐forming ICC and to establish a new staging system based on survival analysis results. The present study was conducted as a project study of the Japanese Society of Hepato‐Biliary‐Pancreatic Surgery. Methods: Clinical data from 233 patients who underwent curative resection for mass‐forming ICC were retrospectively reviewed. Survival analysis was performed to identify predictors of postoperative outcomes, and a new staging system was established. The survival stratification of our proposed system was compared with two previous staging systems. Results: A N0M0 cohort analysis demonstrated that tumor size, tumor number, and vascular invasion were independently associated with survival after curative resection for mass‐forming ICC, whereas serosal and periductal invasion were not. Of patients with nodal metastases, patients with T4 tumor had significantly lower overall survival rate than patients with T1, T2, or T3 tumor. Thus, we proposed a new staging system as follows: serosal invasion was excluded from the LCSGJ T categories, and patients with nodal metastases were divided into stage IVA or IVB according to T classification. The new system better stratified survival after curative resection for mass‐forming ICC than the two previous systems. Conclusions: The AJCC/UICC staging system failed to stratify the Japanese patients with mass‐forming ICC. The new staging system provided better survival prediction in the patients who underwent curative resection for mass‐forming ICC, although further studies are necessary to evaluate the impact of tumor size on survival. [ABSTRACT FROM AUTHOR]

Background and Aim Preoperative assessment of longitudinal extension of cholangiocarcinoma ( CCA) is essential for making decisions concerning surgical resection and selecting operative procedures. We evaluated the accuracy of peroral video-cholangioscopy ( PVCS) in diagnosing longitudinal extension of CCA. Methods Patients with CCA who underwent preoperative PVCS were considered for this study. We evaluated the accuracy of PVCS in diagnosing longitudinal extension of perihilar cholangiocarcinoma ( PCCA) and distal extrahepatic cholangiocarcinoma ( DCCA) to the secondary biliary radicles and confluence of the hepatic ducts, respectively, on the hepatic side and to the intrapancreatic common bile duct on the papillary side. Diagnostic accuracy was determined by comparing the results with those of histopathological analyses of surgical specimens. Results Forty-three consecutive patients were enrolled. The cholangioscope could not be advanced into the hepatic side ineight of the 25 patients with PCCA and in five of the 18 patients with DCCA. The accuracy of PVCS in diagnosing longitudinal extension of CCA on the hepatic and papillary sides was 82.4% and 92.0%, respectively, in patients with PCCA and 92.3% and 100%, respectively, in patients with DCCA. PVCS accurately detected longitudinal extension of CCA to the hepatic and papillary sides that was not detected previously by endoscopic retrograde cholangiography in 20.0% and 11.6% patients, respectively. Conclusions PVCS proved useful for the preoperative assessment of longitudinal extension of CCA. Therefore, it can aid surgeons in deciding surgical resectability and selecting operative procedures. This, in turn, may impact overall patient prognosis. [ABSTRACT FROM AUTHOR]

Purpose: Hepatectomy of segments 4a and 5 (S4a+5) is the recommended treatment for pT2 gallbladder cancer. However, gallbladder bed resection is also occasionally used. Using nationwide data from the Japanese Biliary Tract Cancer Registry and a questionnaire survey, we retrospectively compared these 2 methods of treatment. Method: The study involved 85 patients with pT2, pN0 gallbladder cancer (55 treated with gallbladder bed resection, and 30, with S4a+5 hepatectomy). The prognosis and mode of tumor recurrence following treatment were analyzed retrospectively, with overall survival as the endpoint. Results: The 5-year survival rate did not differ significantly between the 2 groups. Univariate analysis showed that bile duct resection and perineural tumor invasion were significant prognostic factors, but the extent of hepatectomy, location of the major intramural tumor, regional lymph node excision, and histological type were not. Multivariate analysis identified perineural tumor invasion as a significant prognostic factor. Recurrence occurred most frequently in both lobes than S4a+5 of the liver following gallbladder bed resection. Conclusion: In the present study of cases of Japanese Biliary Tract Cancer Registry, it was not possible to conclude that S4a+5 hepatectomy was superior to gallbladder bed resection. [ABSTRACT FROM AUTHOR]

Background/purpose: The aim of this study is to examine the effects of biliary drainage on hepatic microcirculation and Kupffer cell activity in the liver with obstructive jaundice. Methods: Common bile duct ligation and division was performed on C57BL/6 mice to induce obstructive jaundice. Seven or 14 days after surgery, some mice underwent biliary drainage. Three days after biliary drainage, sinusoidal perfusion, leukocyte rolling and sticking in the postsinusoidal venules, and the diameters of sinusoids containing blood flow were evaluated using intravital microscopy. Kupffer cell phagocytic activity was estimated as the ratio of Kupffer cells that phagocytosed fluorescent-labeled particles to sinusoids containing blood flow. Results: Sinusoidal perfusion after biliary drainage was significantly increased compared with that in livers with obstructive jaundice, but remained decreased compared with controls. Although the number of rolling leukocytes and sticking leukocytes was significantly decreased, the diameters of sinusoids remained reduced, associated with an increase in Kupffer cell phagocytic activity compared with controls even after biliary drainage. Conclusions: Leukocyte-endothelial cell interaction is ameliorated but sinusoids remain narrowed due to swelling of activated Kupffer cells; this might cause deterioration of hepatic microcirculation during the early phase of biliary drainage. [ABSTRACT FROM AUTHOR]

Background/purpose: The aim of this study was to clarify the prognostic factors of intrahepatic cholangiocarcinoma (ICC) following hepatectomy and to examine the impact of lymph node metastasis on survival. This study was therefore carried out as a Project Study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Methods: Three hundred and forty-one patients who underwent hepatectomy for ICC between 1995 and 2004 at the 9 institutions of the Medical University Hospitals were analyzed retrospectively. Multivariate regression analyses and a Kaplan-Meyer analysis were performed to identify prognostic factors. Results: Pathological lymph node metastasis was one of the significant factors affecting overall survival (hazard ratio 2.10, p < 0.001) based on the multivariate analysis. Among the patients who underwent extended lymphadenectomy beyond the hepatoduodenal ligament, the median survival of 121 patients with nodal involvement was 12.2 months. Only seven patients with nodal involvement have survived for more than 4 years. Conclusions: In the present study, preoperative carbohydrate antigen (CA) 19-9, intrahepatic metastasis, and nodal involvement were the significant independent predictors of poor prognosis by multivariate analysis. Further prospective studies may thus be needed to confirm these findings, because this study has a limitation in that it was a retrospective study with multicenter data collection. [ABSTRACT FROM AUTHOR]

Objective: To develop a clinical and prognostic scoring system predictive of survival after resection of intrahepatic cholangiocarcinomas (ICC). Patients: Two hundred and one consecutive ICC patients (83 from Essen, Germany, 54 from New York, USA and 64 from Chiba, Japan). The scoring systems were developed utilizing the data set from Essen University and then applied to the data sets from Mount Sinai Medical Center and Chiba University for validation. Eighteen potential prognostic factors were evaluated. Statistical analysis included multivariable regression analyses with the Cox proportional hazard model, power analysis, internal validation with structural equation modelling bootstrapping and external validation. The prognostic scoring model was based mainly in pathological and demographical variables, whereas the clinical scoring model was based mainly in radiological and demographical variables. Results: Gender ( P=0.0086), UICC stage ( P=0.0140) and R-class ( P=0.0016) were predictive of survival for the prognostic scoring model, while gender ( P=0.0023), CA 19-9 levels ( P=0.0153) and macrovascular invasion ( P=0.0067) were predictive of survival for the clinical scoring model. Prognostic points were assigned as follows: female:male=1:2 points, UICC (I–II):UICC (III–IV)=1:2 points and R0:R1=1:2 points. Clinical points were allocated as follows: female:male=1:2 points, CA 19-9 (<100 U/ml):CA 19-9 (≥100 U/ml)=1:2 points and no macrovascular invasion:macrovascular invasion=1:2 points. Prognostic groups with 3–4, 5 and 6 points ( P=0.000001) and clinical groups with 3–4 and 5–6 points ( P=0.0103) achieved statistically significant difference. Conclusions: We propose a clinical and prognostic scoring system predictive of long-term survival after surgical resections for ICC. [ABSTRACT FROM AUTHOR]

Tumors with copious mucin production within the intra- or extrahepatic bile ducts have been reported as mucin-producing bile duct tumors (MPBTs). Because mucin produced by these tumors causes recurrent cholangitis and obstructive jaundice, surgical resection should be indicated even if these tumors are regarded as benign. In order to choose the appropriate surgical procedure, exact preoperative assessment of tumor location and cancer extension is important, especially evaluation of the extent of superficial spreading through cholangioscopic observation and biopsy. In principle, MPBTs should be resected in a manner similar to that employed for other types of bile duct carcinomas. That is, major hepatectomy with or without extrahepatic bile duct resection or pancreaticoduodenectomy should be chosen as the surgical procedure, and intraoperative frozen section at the stumps of the bile duct is essential. On the other hand, when precise diagnosis is completed preoperatively and the lesion is diagnosed as adenoma or carcinoma with invasion confined to the ductal wall and limited superficial spreading, limited resections preserving organ functions as much as possible can be considered as a choice among surgical procedures. All ten patients with MPBT resected at our institution according to these strategies are still alive without tumor recurrence, with a median survival of 48.0 months. [ABSTRACT FROM AUTHOR]

Background/Purpose: Intraductal papillary mucinous neoplasm of the bile duct (IPMN-B) is considered an uncommon tumor. The purpose of this study was to evaluate the diagnostic utility of endoscopic cholangiography (ERC) with subsequent peroral cholangioscopy (POCS) and/or intraductal ultrasonography (IDUS) for this tumor. Methods: From December 1991 to November 2006, a retrospective analysis was made of eight patients with IPMN-B. Their clinical features and the endoscopic diagnostic strategy for POCS and IDUS were reviewed. Results: In all the patients, ERC failed to show papillary tumors, due to coexisting mucin or biliary sludge. POCS was carried out after ERC and it showed the presence and locations of papillary tumors in all patients, except for one with a tumor in the peripheral intrahepatic bile duct (B3). IDUS was performed in seven of the eight patients; in five of these patients, intraductal protruding tumors were clearly visualized, whereas flat tumors were not identified in the remaining two patients. In one of the eight patients, endoscopic nasobiliary drainage did not remove the huge amount of mucin. Hence, this patient required subsequent percutaneous biliary drainage. Six of the eight patients underwent surgical treatment; five patients underwent a hepatic resection with or without extrahepatic bile duct resection and one underwent a pancreaticoduodenectomy. Five of the six operated patients are still alive; one patient died of gastric cancer 90 months after the operation (mean follow-up period, 45.3 months). The two remaining patients, who were considered inoperable due to major medical comorbidities, died of liver failure and cholangitis 3 and 6 months, respectively, after stent placement. Conclusion: ERC failed to delineate intraductal papillary tumors, due to coexisting mucin. The presence and location of papillary tumors were correctly diagnosed by both POCS and IDUS, but POCS may be better than IDUS to diagnose the extent of the tumor. [ABSTRACT FROM AUTHOR]