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A 73-year-old man with mixed-type intraductal papillary mucinous neoplasm of the pancreas body was followed up for 14 years. Based on imaging findings, the intraductal papillary mucinous neoplasm of the pancreas met the high-risk stigmata, and new hepatic masses were suspected to be intraductal papillary neoplasms of the bile duct. With a diagnosis of intraductal papillary mucinous neoplasm of the pancreas and intraductal papillary neoplasm of the bile duct, the patient had undergone left lateral hepatectomy and distal pancreatectomy. Based on pathology, the pancreatic specimen was diagnosed as a high-grade intraductal papillary mucinous neoplasm of the pancreas, and the hepatic specimen was diagnosed as an intraductal papillary neoplasm of the bile duct and hepatocellular carcinoma. The intraductal papillary neoplasms of the bile duct and hepatocellular carcinoma were adjacent to each other. Fifteen months after surgery, recurrence in the remnant pancreas was detected. The patient had undergone residual total pancreatectomy, with no recurrence thirty months after the second resection. This case demonstrates that second surgery for metachronous high-risk lesions in the remnant pancreas of patients with intraductal papillary mucinous neoplasm of the pancreas and intraductal papillary neoplasm of the bile duct may also be considered to improve survival.

Background/aim Few studies have established a definite conclusion regarding the limitation of surgical treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage B and C hepatocellular carcinoma (HCC). Patients and methods A retrospective analysis was performed on 717 consecutive patients who underwent initial hepatectomy for HCC. Results Reductive hepatectomy was performed in 103 patients, with a median survival time (MST) of 18.0 months. Total bilirubin and albumin levels were identified as independent prognostic factors. The predictive score of these factors ranged from 0 to 2. Subsequent local treatment was performed in 91.0, 75.0, and 25.0% of patients who scored 0, 1, and 2, respectively. The MST for patients with a score of 0, 1, and 2 was 20.1, 14.8, and 2.7 months, respectively, with a significant difference. Conclusion Patients with BCLC stage B and C could be properly treated with reductive hepatectomy and subsequent local treatments.

Purpose This study retrospectively investigated relationships among risk factors and post-hepatectomy surgical site infection (SSI) and other complications in patients who underwent hepatectomy for hepatocellular carcinoma (HCC). Methods We included 334 patients who underwent hepatectomies for liver cancers between January 2011 and December 2015 in this study. We evaluated risk factors for SSI and other post-hepatectomy complication, including demographic factors, preoperative factors, and preoperative intervention including oral management, perioperative factors, and length of hospital stay, with univariate and multivariate analyses. The oral management intervention included self-care instructions, extraction of infected teeth, removal of dental plaques and calculus (scaling), professional mechanical teeth cleaning, removal of tongue coating, and cleaning of dentures. SSI was defined in accordance with the guideline issued by the Centers for Disease Control and Prevention; it included purulent discharge from any incision or organ space within 30 days postoperatively, with or without microbiological evidence. Complications of grade II or greater, according to the Clavien-Dindo classification, were regarded as postoperative complications. Results We found bacterial infection of ascites (Odds ratio (OR) = 13.72), lack of preoperative oral management intervention (OR = 10.17), and severe liver fibrosis (OR = 2.76) to be associated with SSI and severe liver fibrosis (OR = 2.28), hypoalbuminemia (OR = 2.02), blood transfusion (OR = 1.86), and longer operation time (OR = 1.80) to be associated with postoperative complications. Conclusions Preoperative oral management may reduce the risk of SSI in patients with HCC who undergo hepatectomy.

Background: Pancreaticoduodenectomy (PD) is a standardized strategy for patients with middle and distal bile duct cancers. The aim of this study was to compare clinicopathological features of bile duct segmental resection (BDR) with PD in patients with extrahepatic cholangiocarcinoma. Methods: Consecutive cases with extrahepatic cholangiocarcinoma who underwent BDR (n = 21) or PD (n = 84) with achievement of R0 or R1 resection in Kobe University Hospital between January 2000 and December 2016 were enrolled in the present study. Results: Patients who underwent PD were significantly younger than those receiving BDR. The frequency of preoperative jaundice, biliary drainage and cholangitis was not significantly different between the two groups. The duration of surgery was longer and there was more intraoperative bleeding in the PD than in the BDR group (553 vs. 421 min, and 770 vs. 402 mL; both PClavien-Dindo IIIa) were observed in the PD group (46% vs. 10%, P

Resecting liver tumors located in Couinaud's segment VII is challenging; the efficacy and safety of laparoscopic liver resection for segment VII lesions compared to open liver resection remain unclear.Medical records of 84 patients who underwent liver resection of segment VII at Kobe University Hospital and Hyogo Cancer Center between 2010 and 2021 were retrospectively analyzed. Surgical outcomes were compared between laparoscopic liver resection and open liver resection groups using propensity matching analysis.Thirty-one and 53 patients underwent laparoscopic liver resection and open liver resection, respectively. After propensity matching, 29 patients were included in each group. The laparoscopic liver resection group had a significantly longer operation time (407 vs. 305 min, P = 0.002), lower blood loss (100 vs. 230 mL, P = 0.004), and higher postoperative alanine aminotransferase levels (436 vs. 252 IU/L, P = 0.008) than the open liver resection group. In patients with liver cirrhosis, the proportion of patients with postoperative liver-specific complications was higher in the laparoscopic liver resection group than in the open liver resection group (57% vs 11%, P = 0.049), although there was no significant difference in postoperative liver-specific complication rates between the groups in patients without liver cirrhosis.For liver resection of segment VII, laparoscopic liver resection led to higher postoperative liver damage than open liver resection. Open liver resection may be better for patients with liver cirrhosis to avoid postoperative liver-specific complications. Laparoscopic liver resection could be an acceptable procedure for patients without liver cirrhosis, with some merits such as less blood loss.

Resected bile duct cancers often relapse during postoperative follow-up. The aim of this study was to detect predictors of early recurrence in patients with extrahepatic bile duct cancer.Consecutive cases (n = 162) of extrahepatic bile duct cancer in which R0 or R1 resection was achieved in Kobe University Hospital between 2000 and 2016 were divided into three groups [early recurrence (ER), within 6 months of surgery, late recurrence (LR), and no recurrence (NR)] and their clinicopathological features were compared.Twenty-two patients (14%) developed ER and 69 (43%) developed LR after surgery. The rates of lymph node metastasis and residual cancer status were similar in all three groups. Liver metastasis was more common in the ER group than in the LR group (59% vs. 32%, p = 0.02). ER had a significantly worse prognosis than LR and NR (7% vs. 44% vs. 85% at 1 year, p 0.01, respectively). Multivariate analysis showed that age 75 years, serum CA19-9 1008 U/ml and perineural invasion were independent predictors of early recurrence.High serum CA19-9 values ( 1008 U/ml) were an independent predictor of early recurrence. Neoadjuvant therapy and aggressive adjuvant therapy may be beneficial for patients who show highly elevated CA19-9 values before surgery.

This study aimed to evaluate the clinical relevance of hepatectomy for Barcelona Clinic Liver Cancer (BCLC) stages B and C advanced hepatocellular carcinoma (HCC). A total of 314 patients (149 and 165 BCLC stages B and C, respectively) who underwent hepatectomy were included. Complete hepatectomy (without residual tumors after hepatectomy) and reductive hepatectomy (apparent residual tumors after hepatectomy) were performed for 212 and 102 patients, respectively. Short-term operative and postoperative outcomes, as well as long-term outcomes, were evaluated. The median survival times of patients with stage B disease undergoing complete hepatectomy and reductive hepatectomy were 48.9 and 20.1 months, respectively (p = 0.0075), whereas those of patients with stage C disease were 19.5 and 17.6 months, respectively (p = 0.0140). The 3-year overall survival rates of patients with stage B disease undergoing reductive hepatectomy with and without subsequent local treatments after surgery were 47.5% and 0%, respectively, whereas those of patients with stage C diseases were 18.6% and 0%, respectively. Survival benefits are obvious for both BCLC stages B and C HCC when complete hepatectomy can be performed safely. Reductive hepatectomy is also acceptable for BCLC stages B and C when subsequent local treatment for remnant liver tumors can be performed safely after reductive hepatectomy. Without subsequent local treatment, reductive hepatectomy has little clinical relevance. Thus, a cautious approach to patient selection is required for this aggressive strategy.

Objective This study aimed to determine whether retrocolic alimentary tract reconstruction is noninferior to antecolic reconstruction in terms of DGE incidence after pancreatoduodenectomy (PD) and investigated patients' postoperative nutritional status. Summary of background data The influence of the route of alimentary tract reconstruction on DGE after PD is controversial. Methods Patients from 9 participating institutions scheduled for PD were randomly allocated to the retrocolic or antecolic reconstruction groups. The primary outcome was incidence of DGE, defined according to the 2007 version of the International Study Group for Pancreatic Surgery definition. Noninferiority would be indicated if the incidence of DGE in the retrocolic group did not exceed that in the antecolic group by a margin of 10%. Patients' postoperative nutrition data were compared as secondary outcomes. Results Total, 109 and 103 patients were allocated to the retrocolic and antecolic reconstruction group, respectively (n = 212). Baseline characteristics were similar between both groups. DGE occurred in 17 (15.6%) and 13 (12.6%) patients in the retrocolic and antecolic group, respectively (risk difference; 2.97%, 95% confidence interval; -6.3% to 12.6%, which exceeded the specified margin of 10%). There were no differences in the incidence of other postoperative complications and in the duration of hospitalization. Postoperative nutritional indices were similar between both groups. Conclusions This trial could not demonstrate the noninferiority of retrocolic to antecolic alimentary tract reconstruction in terms of DGE incidence. The alimentary tract should not be reconstructed via the retrocolic route after PD, to prevent DGE.

This study aims to validate Japanese diagnostic criteria for acute-on-chronic liver failure (ACLF) and confirm the feasibility of performing transplantation.We included 60 patients with acute liver injury. Demographic and clinical features were retrospectively collected, and the primary outcome was compared among 4 types: acute liver failure (ALF) with hepatic coma (n = 23), ALF without hepatic coma (n = 12), acute liver injury (n = 20), and ACLF (n = 5). Moreover, 80 transplanted patients were enrolled to compare the difficulty of transplantation between ALF (n = 8) vs non-ALF (n = 72) patients.Seven patients in the ALF with hepatic coma group and 1 patient in the ACLF with hepatic coma group were transplanted. Ten patients who could not be registered for transplantation died. In univariate analysis, liver failure type (P.0001), total bilirubin level (P = .05), and prothrombin time internationalized ratio (P.0001) were associated with patient survival. In multivariate analysis, liver failure type was associated with patient survival (P.0001). The respective 1-, 3-, and 5-year patient survival rates were 45.9%, 45.9%, and 45.9% for ALF patients with hepatic coma; 100.0%, 100.0%, and 100.0% for ALF patients without hepatic coma and acute liver injury; and 80.0%, 80.0%, and 80.0% for ACLF patients (P.0001). Chronic liver disease did not affect operation time (P = .46) and bleeding volume (P = .49).Patients diagnosed with ACLF via Japanese criteria presented significantly higher survival rates than ALF patients with hepatic coma.

The prognostic impact of pancreatic ductal adenocarcinoma (PDAC) invasion to the splenic vessel is controversial. The aim of this study was to assess the clinical value of pathological and radiological splenic vessel invasion in PDACs of the body and tail. Medical records of patients with resectable PDAC of the body and tail who underwent distal pancreatectomy between 2003 and 2016 at the Kobe University Hospital were retrospectively analyzed. Overall, 68 patients (29 female and 39 male patients) were enrolled. Pathologically determined splenic vein invasion (p-SV) and splenic artery invasion (p-SA) were identified in 21 (30.9%) and 5 (7.4%) patients, respectively. The p-SV (but not p-SA) was an independent prognostic factor in multivariate analysis (p = 0.009). On analysis of recurrence patterns, patients with PDAC positive for p-SV were at a higher risk for liver metastasis (p = 0.022); however, the associations were not significant for other recurrence patterns. Liver metastasis occurred earlier in patients who were positive for p-SV (p = 0.015). Preoperative computed tomography effectively diagnosed pathological vessel invasion (SV: sensitivity, 95.2%, specificity, 72.3%; SA: sensitivity, 100%, specificity, 84.1%). Radiological SV invasion remained significant in multivariate analysis regarding postoperative survival (p = 0.007), and was also associated with early liver metastases (p = 0.008). Pathological/radiological SV invasion were independent adverse prognostic factors associated with early liver metastasis in patients with PDAC of the body/tail. Assessment of these findings may be useful in determining optimal therapeutic options in these patients.

We compared surgical outcomes, with a focus on tumor characteristics, of laparoscopic repeat hepatectomy (LRH) and open repeat hepatectomy (ORH) to identify recurrent hepatocellular carcinoma (HCC) cases where the LRH procedure would be more favorable than ORH. Eighty-one HCC patients who underwent repeat hepatectomy in our hospital from 2008 to 2019 were retrospectively analyzed in this study. Of these patients, 30 and 51 patients underwent LRH and ORH, respectively. We analyzed surgical outcomes of LRH and ORH, focusing on tumor characteristics such as tumor size, location, distance from major vessels, and contralateral or ipsilateral tumor recurrence to determine what factors could affect surgical outcomes. Subsequently, using a propensity-matched cohort, we compared the impact of those factors on LRH and ORH outcomes. In the entire cohort, the LRH operation time was significantly shorter in contralateral recurrent HCC cases than in ipsilateral recurrent HCC cases (252 vs. 398 min, P = 0.008); however, such a difference was not observed in the ORH operation time. We subsequently compared the surgical outcomes, in terms of the location of tumor recurrence, between the LRH and ORH groups in a propensity-matched cohort. In total, 23 patients were included in each of these groups. We found that the LRH procedure had significantly shorter operative time than the ORH procedure in the contralateral recurrent HCC cases (253 vs. 391 min, P = 0.018); however, we did not observe such a difference in the ipsilateral recurrent HCC cases (372 vs. 333 min, P = 0.669). LRH had lower blood loss, similar postoperative complications and shorter hospital stay than ORH in both contralateral and ipsilateral recurrent HCC cases. LRH is likely considered a more favorable approach than ORH in treating patients with contralateral recurrent HCC.

Although surgical resection is the first-line treatment for biliary tract cancer(BTC), elderly patients often have underlying diseases and decreased cardiopulmonary function that place them at a high risk of undergoing surgery. We examined the safety and efficacy of surgical resection in elderly BTC patients. Among the BTC cases that underwent surgical resection at Kobe University Hospital from 2009 to 2015, the safety and prognosis ofthose aged 75 years or older(Group 1)were compared to those younger than 75 years(Group 2)at the time ofsurgery. Fifty-two patients with perihilar cholangiocarcinoma( Bp), 29 patients with intrahepatic cholangiocarcinoma(ICC), and 40 patients with ampulla ofVater cancer(AV) were included. There was no significant difference between the 2 groups with respect to complications of Grade Ⅲor above, while surgery-related death was more common in Bp and ICC ofGroup 1. The median survival ofGroup 1 following hepatectomy for Bp and ICC(22 months)was significantly shorter than that of Group 2(40 months)(p=0.023). There was no significant difference in overall survival of Group 1 and Group 2 patients with AV(p=0.094). Surgical resection for BP and ICC for elderly patients has a higher risk of hepatectomy; therefore, precise assessment of oncologic and patient risk factors should be performed. As we can expect to achieve similar prognoses between non-elderly and elderly patients with AV, aggressive treatments should be considered for elderly patients with AV.

Background: This study evaluated the prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases who can undergo hepatectomy. Methods: A total of 32 patients who underwent hepatectomy for HCC with extrahepatic metastases, including lymph node and/or distant metastases were recruited for this study. Results: Fourteen patients had lymph node metastasis only, 16 had distant metastasis only, and 2 had both metastasis types during preoperative diagnosis. The 3-year overall survival (OS) rate of all patients was 17.9%, and the median survival time (MST) was 11.8 months. Univariate analysis revealed that intrahepatic maximal tumor size, intrahepatic tumor number, and intrahepatic tumor control after hepatectomy were significant factors influencing OS (p < 0.05). Multivariate analysis revealed that independent risk factors for OS were intrahepatic maximal tumor size and intrahepatic tumor number (p < 0.05). The MST and 3-year OS rate of patients with maximal tumor size Conclusions: Hepatectomy is not recommended for HCC patients with extrahepatic metastasis with ≥3 intrahepatic tumors, even when all intrahepatic tumors can be eliminated via hepatectomy. Aggressive surgery may be justified for HCC patients with ≤2 intrahepatic tumors and maximal tumor size

Background The present study aimed to assess the clinical features of patients who received lenvatinib treatment for unresectable hepatocellular carcinoma (HCC). Methods The clinical characteristics, adverse events, and radiological responses were evaluated for 51 consecutive patients. Results Of the study subjects, 37 patients had Child–Pugh class A (CPA) liver function, and 14 patients had Child–Pugh class B (CPB) liver function. The overall response rates in the CPA and CPB groups were 42.9% and 25.0%, respectively, and disease control rates were 82.9% and 83.3%, respectively, without significant difference (p = 0.2621 and 0.9697). There was no significant difference between CPA and CPB groups regarding the incidence of adverse events, except for hepatic coma. No significant difference was observed in the relative dose intensity between the CPA and CPB groups, for the first month, 1–2 months, or 2–3 months (p = 0.2368, 0.9368, and 0.9293). Conclusion The comparable outcomes between the CPA and CPB groups suggest the acceptability of lenvatinib treatment in patients with impaired liver function, at least in the acute phase. With careful follow-up, the dose can be relatively intensified, even in patients with impaired liver function and this may contribute to offering comparable treatment.

Background The albumin-bilirubin (ALBI) grade, stratified from the ALBI score, may have prognostic value in patients with hepatocellular carcinoma. We aim to evaluate the prognostic abilities of the ALBI score/grade among living-donor liver transplantation patients. Methods We retrospectively collected data of 81 patients who underwent living-donor liver transplant at Kobe University Hospital between June 2000 and October 2018. The efficacy of the ALBI score/grade as a prognostic factor was assessed and compared with that of the well-established Model for End-Stage Liver Disease (MELD) score. Main findings Multivariate analysis indicated that recipient age (P = .003), donor age (P = .003), ALBI score ≥ -1.28 (P = .002), and ALBI grade III (P = .004) were independently associated with post-transplant survival. A high MELD score was not associated with post-transplant survival in univariate or multivariate analyses. Although there was no significant difference in the overall survival rate relative to recipient and donor age, ALBI score/grade was significantly associated with the 1- and 5-year survival rates (P = .023, P = .005). ALBI scores specifically detected fatal complications of post-transplant graft dysfunction (P = .031) and infection (P = .020). Conclusion ALBI score/grade predicted patient survival more precisely than the MELD score did, suggesting that it is a more useful prognostic factor compared to the MELD score in living-donor liver transplantation cases.

BACKGROUND Acute cholecystitis (AC) after cardiovascular surgery (CS) tends to have a serious postoperative course; however, there are few reports of AC after CS. In this study, we investigated the clinical features of AC after CS. METHOD Of 26 patients who underwent surgery for AC after CS between 2001 and 2018 were investigated. Of these patients, the severity of AC, onset time, surgical outcomes, and postoperative pathological findings were evaluated. RESULTS Grade III accounted for 46% (12/26) of the AC after CS patients. Gallbladder drainage did not produce sufficient outcomes in all CS cases. The postoperative hospital days of AC after CS were extended (31/21 days, P = 0.07) and the postoperative pathologic findings revealed a higher rate of gangrenous cholecystitis (88/41%, P

IntroductionIn-vivo fluorescence imaging techniques using indocyanine green (ICG) to identify liver tumours and hepatic segment boundaries have been recently developed. The purpose of this study is to evaluate the efficacy of fusion ICG-fluorescence imaging for navigation during hepatectomy.Methods and analysisThis will be an exploratory single-arm clinical trial; patients with liver tumours will undergo hepatectomy using the ICG-fluorescence imaging system. In total, 110 patients with liver tumours scheduled for elective hepatectomy will be included in this study. Preoperatively, ICG will be intravenously injected at a dose of 0.5 mg/kg body weight within 2 days. To detect liver tumours intraoperatively, the hepatic surface will be initially observed using the ICG-fluorescence imaging system. After identifying and clamping the portal pedicle corresponding to the hepatic segments, including the liver tumours to be resected, additional ICG will be injected intravenously at a dose of 0.5 mg/kg body weight to identify the boundaries of the hepatic segments. The primary outcome measure will be the success or failure of the ICG-fluorescence imaging system in identifying hepatic segments. The secondary outcomes will be the success or failure in identifying liver tumours, liver function indicators, operative time, blood loss, rate of postoperative complications and recurrence-free survival. The findings obtained through this study are expected to help to establish the utility of ICG-fluorescence imaging systems, and therefore contribute to prognostic outcome improvements in patients undergoing hepatectomy for various causes.Ethics and disseminationThe protocol has been approved by the Kobe University Clinical Research Ethical Committee. The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations.Trial registration numberUMIN000031054 and jRCT1051180070

A 47-year-old woman who had unresectable locally advanced gallbladder cancer(GBC)accompanied with liverinvasion, duodenum invasion, transverse colon invasion, and surrounding lymphatic metastasis received 5 courses of chemotherapy with gemcitabine plus cisplatin. Afterthe chemotherapy, imaging showed down-staging of the GBC, indicating tumor shrinkage. The initial laparoscopic examination revealed no peritoneal seeding or distant metastasis. Subsequently, we performed cholecystectomy with a partial hepatectomy at the gallbladder bed. Malignant findings were not observed in the histopathological examination and the pathological diagnosis was CR with pT0N0M0, Stage 0. The patient was discharged on day 11 after the operation. There has been no recurrence at 14 months after surgery. Although the prognosis of advanced GBC with local invasion is generally poor, chemotherapy might be an effective treatment for patients with initially unresectable locally advanced gallbladder carcinoma.

We assessed the predictive value of the preoperative neutrophil-to-lymphocyte ratio (NLR) in patients who underwent a two-stage treatment combining reductive surgery and percutaneous isolated hepatic perfusion for multiple hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT).Forty-two patients underwent the two-stage treatment between January 2000 and December 2014 at Kobe University Hospital (Hyogo, Japan). The NLR was calculated from lymphocyte and neutrophil counts in the preoperative routine blood test. Clinical data and overall survival were compared statistically and multivariate analysis was done to identify prognostic factors.The median survival of patients with a preoperative NLR 2.3 was 14.9 months (n = 13), whereas that of patients with a preoperative NLR ≤ 2.3 was 26.1 months (n = 29; P = 0.022). A preoperative NLR 2.3 was an independent prognostic factor in patients with multiple HCC with PVTT [hazard ratio (HR) 2.329; 95 % confidence interval (CI) 1.058-5.667; P = 0.036].Based on the results of this study, an elevated preoperative NLR is an independent predictive risk factor for patients undergoing two-stage treatment for multiple HCC with PVTT.

Although the first-line treatment for hepatocellular carcinoma(HCC)is hepatectomy, extreme elderly(80 years or older) patients often tend to have a variety of underlying diseases and decreased cardiopulmonary function, which means that surgery involves a high risk. In this case, we examined the safety and efficacy of hepatectomy performed in an extreme elderly patient with HCC. Of the patients with HCC that underwent initial hepatectomy at Kobe University Hospital(n=348)between 2009 and 2015, 23 patients aged 80 years or older at the time of surgery(Group 1, n=23)and those younger than 80 years at the time(Group 2, n=325)were compared, based on parameters related to safety and prognosis. We did not identify differences between the 2 groups with respect to blood loss and operating time. Intraoperative blood transfusion was more common in Group 1. There was no significant difference between the 2 groups with respect to complications of Grade Ⅲ or higher. The median survival of Group 2 patients following hepatectomy(42 months)was better than that of Group 1 patients(34 months), but there was no significant difference between the 2 groups(p=0.429). Furthermore, when the same parameters were compared after adjusting for and matching propensity scores, there were no significant differences in complications, hospitalization periods, and prognosis between the 2 groups. Through proper assessment of oncologic factors and patient risk factors, hepatectomy can be performed safely and effectively even for extreme elderly patients with HCC. If there is no other disease regulating the prognosis, we can expect to achieve similar prognosis in non-extreme elderly patients. Hence, treatments should not be limited solely based on a patient being extremely elderly; rather, proactive treatments should be considered.

The patient was a 63-year-old man with hepatitis C. He discontinued combination therapy containing interferon and ribavirin because of the development of skin symptoms. A screening examination showed multiple early-stage hepatocellular carcinomas. He refused treatment and was followed up as an outpatient. During follow-up, his PIVKA-Ⅱ level remarkably elevated to 59,994mAU/mL. Computed tomography(CT)showed an enlarged tumor with portal invasion(vp2)in segment 8 and intrahepaticmetastasis. We performed right and partial hepatectomy. Three months later, CT showed multiple lung metastases. We initiated the daily administration of 800 mg of sorafenib. However, 6 months after hepatectomy, the lung metastases increased in size and number. We considered the therapeutic effect as progressive disease(PD)according to the RECIST criteria. We then initiated administering 120 mg of regorafenib daily as second-line therapy. In a course of the treatment containing sorafenib and regorafenib, the dose was reduced due to hand-foot skin reactions. 8.5 months after hepatectomy, the lung metastases significantly decreased in size. One year after hepatectomy, almost complete response(CR) was obtained, and no intrahepatic recurrence was found.

A 71-year-old woman underwent right nephrectomy for the treatment of clear cell renal cell carcinoma at the age of 53. After 15 years, surgical removal of a solitary tumor was performed in the right adrenal gland and thyroid gland; both were diagnosed as metastases of renal cell carcinoma. Eighteen years after the initial resection, computed tomography(CT) showed multiple hypervascular tumors spreading across the entire area of the pancreas. She was referred to our hospital, and endoscopic ultrasound-guided fine needle aspiration biopsy(EUS-FNA)revealed that they were metastases from the renal cell carcinoma. Total pancreatectomy and splenectomy were performed, and the patient remains alive and well with no evidence of recurrent disease 7 months after the pancreatectomy. Furthermore, her blood glucose level is well controlled with insulin therapy.

BACKGROUND Lactate production is exacerbated by surgical stress. We sought to determine whether branched-chain amino acid (BCAA) supplementation could decrease blood lactate levels in patients undergoing hepatectomy. METHODS A total of 275 consecutive patients who underwent hepatectomy of ≥2 segments were retrospectively reviewed. Blood lactate levels in patients treated with BCAA supplementation before hepatectomy (December 2011 to December 2016) were compared with levels in patients who were not pretreated (January 2008 to November 2011). RESULTS Postoperative lactate levels were significantly lower in patients who received preoperative BCAA supplementation than in those who did not (2.6 vs 3.4 mmol/L; P < .001). Intraoperative blood lactate levels, which were evaluated after induction of general anesthesia, were also lower in those who received BCAA supplementation than in those who did not (1.1 vs 1.5 mmol/L, respectively; P < .001). A multiple regression analysis revealed that preoperative BCAA supplementation was independently associated with decreased postoperative and intraoperative lactate levels (P = .030 and P < .001, respectively). CONCLUSION Preoperative BCAA supplementation decreased intraoperative and postoperative blood lactate levels in patients undergoing major hepatectomy.

Background Progression of portal vein tumor thrombus directly affects the prognosis and treatment for patients with hepatocellular carcinoma; there are no data on the growth velocity of portal vein tumor thrombus. We analyzed the growth velocity of portal vein tumor thrombus and its risk factors to propose the best timing of surgical treatment for hepatocellular carcinoma with portal vein tumor thrombus. Methods We retrospectively collected data on 57 hepatocellular carcinoma patients with portal vein tumor thrombus who underwent computed tomography twice preoperatively and hepatectomy between 2005 and 2015. To calculate the growth velocity of portal vein tumor thrombus, migration lengths of portal vein tumor thrombus were divided by the number of days. To identify risk factors for rapid growth of portal vein tumor thrombus, patients were classified according to the velocity: rapid (≥ 1.0 mm/day, n = 23) and slow ( Results Median survival times of patients with portal vein tumor thrombus that invaded the ipsilateral second portal branch, ipsilateral first portal branch, and portal trunk were 42.9, 11.7, and 12.3 months, respectively. The average growth velocity of portal vein tumor thrombus was 0.9 ± 1.0 mm/day. Median estimated times required from ipsilateral second portal branch to ipsilateral first portal branch and ipsilateral first portal branch to portal trunk were 8.2 and 11.5 days, respectively. Liver fibrosis, alpha-fetoprotein, and extent of portal vein tumor thrombus were independent risk factors for rapid progression of portal vein tumor thrombus. Proteins induced by vitamin K absence or antagonist II, extent of portal vein tumor thrombus, and liver fibrosis, not rapid growth of portal vein tumor thrombus, were independent prognostic factors. Conclusion An understanding of the rapid progression of portal vein tumor thrombus and its risk factors can be helpful in deciding an appropriate timing of surgical treatment for hepatocellular carcinoma with portal vein tumor thrombus.

We report a case of bilobar multiple hepatocellular carcinoma(HCC)with peritoneal dissemination successfullytreated by dual treatment with reductive surgeryplus percutaneous isolated hepatic perfusion(PIHP). A 73-year-old man had sudden abdominal pain and was diagnosed bilobar multiple HCC through some examinations. The abdominal CT scan demonstrated onlya peritoneal dissemination under the liver. We performed partial hepatectomyof the lateral segment and the Spiegel lobe, and resected a peritoneal dissemination. Subsequently, we underwent PIHP twice. The tumor marker was normalized, and CT images demonstrated complete response according to the RECIST. Dual treatment is considered to be a unique therapeutic modalityfor severe advanced HCC.

A 72-year-old woman had severe watery diarrhea and weight loss. Computed tomography demonstrated a 55mm tumor in pancreatic tail with enlargement of para-aortic lymph nodes. There was no apparent liver metastasis. Endoscopic ultrasound demonstrated a well-circumscribed heterogenous tumor, which was diagnosed neuroendocrine tumor by endoscopic ultrasound-guided fine needle aspiration biopsy. For suspected VIPoma with para-aortic lymph node involvement, distal pancreatectomy and para-aortic lymphadenectomy was performed. The tumor was diagnosed as VIPoma by immunohistochemistry. The diarrhea improved after surgery. No evidence of recurrence was detected after a follow-up of 11 months.

A 69-year-old woman who was identified the tumor of the pancreas tail by CT scan for postoperative inspection of breast cancer. Pancreas tail cancer with para-aortic lymph node metastases was diagnosed by close inspection. She consulted a different hospital to receive their second opinion. She was diagnosed of sarcoidosis from points with lymphadenopathy in hilar region and para-aorta for 3 years and uveitis. The patient was referred to our institution for treatment. We performed distal pancreatectomy in March, 2014. No.16 lymph nodes were cancer-negative, but lymph nodes around the pancreas were cancer positive. Abdominal CT, 9 months after surgery, showed lymph node swelling. We recommended a definitive diagnosis by EUS-FNA, but she refused the inspection. She was checked by CT scan regularly afterwards and is alive without recurrence 39 months after the operation. Diagnosis for lymph node metastases is difficult for a malignant tumor when the sarcoidosis coexisted.

IntroductionMultimodal treatment prolongs the survival of patients with biliary tract cancer (BTC). However, the chemotherapy choices for this disease are few, and completing each chemotherapy session is important. Adjuvant chemotherapy has been attempted for BTC, but has only had a 75% completion rate. Body weight loss and cholangitis are reasons for the interruption of chemotherapy. Previous reports suggested that nutritional intervention with omega-3 fatty acids maintained body weight and improved the completion rate for chemotherapy. Moreover, omega-3 fatty acids have an anti-inflammatory effect. Therefore, we theorised that omega-3 fatty acids would improve the completion rate of adjuvant chemotherapy in patients with BTC. The aim of this study is thus to evaluate the effectiveness of omega-3 fatty acids for patients planning adjuvant chemotherapy for BTC.Method and analysisThis study is a single-centre, open-label, single-arm, historically controlled study with a planned enrolment of 55 participants. Protocol treatment consists of four courses of S-1 adjuvant chemotherapy and an oral omega-3 fatty acid pharmaceutic adjuvant (LOTRIGA 2 g (Takeda Pharmaceutical Co.)), which includes 2 g of omega-3 fatty acids from day 1 until day 168 of the treatment period. The primary endpoint is the completion rate of four total courses of S-1. Secondary endpoints are postoperative cholangitis, time to recurrence or distant metastasis, changes in nutritional index, changes in the lymphocyte blast transformation test induced by phytohaemagglutinin, and concanavalin A and diamine oxidase serum activity during adjuvant chemotherapy. All adverse events will be evaluated.Ethics and disseminationThis protocol was approved by the Institutional Review Board of Kobe University Hospital. The findings from this study will be presented at national and international conferences and published in peer-reviewed journals.Trial registration numberUMIN000031247.

Recent progress in medical technology, perioperative management, and surgical technique has contributed greatly to the safety of hepatobiliary surgery. In particular, imaging techniques, including intraoperative imaging, have played a major role in advancing the success of these operations. Precise assessment of biliary anatomy before and during surgery reduces biliary complications. More than 42% of the population is reported to have anatomical variations of the biliary tree. If a biliary anatomical variation is suspected before surgery, confirmatory intraoperative cholangiography (IOC) is recommended. Using radiography and iodinated contrast medium, IOC was first reported by Mirizzi in 1937 and has been widely used to define the biliary tree in surgery for benign and malignant diseases. However, radiographic IOC has several drawbacks; it exposes patients and medical staff to radiation, it requires a large C-arm machine for fluoroscopy and an attendant to operate it, and it requires special techniques to generate 3-dimensional (3D) images. Intraoperative ultrasonography, specifically, contrast-enhanced intraoperative ultrasonic cholangiography (CE-IOUSC), can address these issues. Intraoperative ultrasonography has become an essential tool for the identification of intrahepatic vessels, tumor location, and definition of surgical margins for safe and effective hepatic surgery. Its diagnostic accuracy has been enhanced by the introduction of intravascular ultrasound contrast agents. However, it is still limited in visualization of nondilated bile ducts.

Posthepatectomy liver failure (PHLF) is a major complication after hepatectomy. As there was no standardized definition, the International Study Group of Liver Surgery (ISGLS) defined PHLF as increased international normalized ratio and hyperbilirubinemia on or after postoperative day 5 in 2010. We evaluated the impact of the ISGLS definition of PHLF on hepatocellular carcinoma (HCC) patients. We retrospectively analyzed 210 consecutive HCC patients who underwent curative hepatectomy at our facility from 2005 to 2010. The median follow-up period after hepatectomy was 35.2 months. Thirty-nine (18.6 %) patients fulfilled the ISGLS definition of PHLF. Overall survival (OS) rates at 1, 3, and 5 years in patients with/without PHLF were 69.1/93.5, 45.1/72.5, and 45.1/57.8 %, respectively (P = 0.002). Recurrence-free survival (RFS) rates at 1, 3, and 5 years in patients with/without PHLF were 40.9/65.9, 15.7/38.3, and 15.7/20.3 %, respectively (P = 0.003). Multivariate analysis revealed that PHLF was significantly associated with both OS (P = 0.047) and RFS (P = 0.019). Extent of resection (P

A 44-year-old woman underwent surgical resection and received preoperative and postoperative chemotherapy for conventional osteosarcoma in the right fibular head. Three years later, follow-up PET-CT revealed accumulation ofFDG in the tail ofthe pancreas. Contrast-enhanced computed tomography showed a 13mm well-circumscribed hypovascular tumor. EUS showed a heterogeneous solid tumor, which was diagnosed as metastasis ofosteosarcoma to the pancreas. Laparoscopic spleen preserving distal pancreatectomy(LAP-SPDP)was performed. Pathologically, the tumor was diagnosed as metastasis ofconventional osteosarcoma to the pancreas. Cells from pancreas islet tissue were detected in the tumor, suggesting invasion ofthe tumor into the pancreatic body and surrounding adipose tissue. Although postoperative chemotherapy was administered, lung metastasis was detected 1.1 years after surgery. Laparoscopic partial resection of the lung metastasis was performed, and the patient is still alive. Metastasis ofosteosarcoma to the pancreas is rare, and there is no report oflaparoscopic approach as a treatment. Herein, we report a case with several references.

A 66-year-old woman presented to the Department of Gynecology in our institution in 2005 with peritoneal recurrence of ovarian fibrosarcoma. Originally, combined modality therapy including repeated surgical resection and somatic chemotherapy was performed. A peritoneal recurrence was found near the pancreatic head. She was referred to our department in October 2015, and underwent pancreaticoduodenectomy. The tumor was severely adhesive to the portal vein and combined portal venous resection was performed. Histological examination of tumor specimens revealed tumor invasion to the adjacent pancreatic parenchyma and portal vein. No evidence of recurrence was detected after a follow-up of 8 months. We suggest that in cases with peritoneal recurrence of ovarian tumors, radical resection might be considered, taking into account the biologic behavior of the tumor.

Patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) invading the portal trunk (Vp4) are poor surgical candidates because of the technical difficulties involved. To overcome the limitations, we developed a technique of back-flow thrombectomy (BFT) based on the inherent portal hemodynamics and the macroscopic form of PVTT. Forty-six patients with multiple HCC and Vp4 PVTT underwent hepatectomy with tumor thrombectomy. We used the BFT to treat 24 patients, 18 of whom had PVTT in the contralateral second portal branch. The form of PVTT was classified macroscopically into the floating and expansive types. The rate of complete removal by BFT of PVTT in the contralateral second portal branch was 89%. The patency rates at the thrombectomy site in all 46 patients and in the 24 BFT patients, 3 months after hepatectomy were 93 and 90%, respectively. The median OS of all 46 patients was 15 months, with 1- and 3-year OS rates of 58.5 and 17.1%, respectively. The median OS of the 24 patients treated with BFT vs. the 22 not treated with BFT was 14 and 15 months, respectively. BFT can expand the therapeutic time window for patients with HCC and deep-seated PVTT and may improve their survival.

Alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) are frequently used as tumor markers in hepatocellular carcinoma (HCC). The authors hypothesized different patient populations with varying tumor sizes would influence the predictive power of tumor markers for survival in HCC patients. The authors investigated the influence of tumor size on predictive powers of AFP and DCP. 181 patients underwent hepatectomy for HCC from 2003 to 2008 at Kobe University Hospital. Tumor markers were measured before and at 1 month post-hepatectomy. The Cox proportional-hazards model revealed that preoperative serum AFP was associated with survival; its effects depended on tumor size. Hazard ratios (HRs) for preoperative AFP were maximum for medium-sized HCC, and for DCP, HRs were maximum in small-sized tumors. Post-hepatectomy, both tumor markers were associated with survival, revealing significant interactions with tumor size. HRs for postoperative AFP were greater than 1 for relatively wide range tumors (3-11 cm). HRs for postoperative DCP increased with tumor size, with a strong prognostic predictive power for tumors5 cm. The predictive power of serum tumor markers varied by tumor size in HCC patients. By selecting the appropriate tumor marker, its predictive power can be improved.

BACKGROUND Portal vein thrombus (PVT) has been an absolute contraindication for liver transplantation because of technical difficulties and inadequate vessel graft supply. With recent surgical innovations many difficulties have been overcome and PVT is no longer a contraindication to liver transplantation. MATERIAL AND METHODS From June 2000 to December 2014, 72 patients underwent living donor liver transplantation at Kobe University Hospital, with a focus on the high-grade PVT cases and analysis of modified PV reconstruction technique and clinical course. RESULTS Four recipients (5.6%) developed Yerdel classification grade III PVT and 2 recipients (2.8%) developed grade IV PVT. There were no statistically significant differences between the severity of PVT grades by sex (p=0.77), recipient age (p=0.49), model for end-stage liver disease (MELD) score (p=0.68), graft-recipient weight ratio (GWRW) (p=0.15), graft type of right or left lobe (p=0.55), original liver disease (p=0.09), or intra-operative bleeding (p=0.21). Four grade III recipients were anastomosed with SMV, and 2 grade IV recipients were anastomosed with coronary vein, both of which were interpositioned with vein grafts. Only 1 recipient had died of hepatocellular carcinoma recurrence by 1.5 years after liver transplantation, and all 5 remaining severe PVT recipients survived. Overall 1- and 5-year survival rates for grade 0, I, and II recipients were 78.8% and 62.4%, respectively; 75.0% and 75.0%, respectively, for grade III recipients; and 100% and 100%, respectively, for grade IV recipients (p=0.54). CONCLUSIONS High-grade PVT had comparable survival without the recurrence of PVT after living donor liver transplantation.

We have developed a novel insertion method, a non-trocar technique (NTT), for laparoscopic radiofrequency ablation, whereby an ablation needle, guided by a 14.8-mm echo probe (PVM-787LA; Toshiba, Tokyo, Japan), accurately and easily punctures the target tumor in the liver. By existing methods, an ablation needle is inserted into the abdominal cavity through a puncture hole away from the echo probe because of the presence of a 15-mm trocar. Under such circumstances, fitting and sliding an ablation needle along the groove of the probe into the abdominal cavity is difficult because of the longitudinal dissociation between the needle and the probe. To avoid this dissociation, an echo probe is inserted directly through the small incision from which the 12-mm trocar is withdrawn and an ablation needle is introduced directly into the abdominal cavity through a puncture hole adjacent to and slid along the groove of the probe.

Purpose: This study was designed to determine whether DNA methylation biomarkers are associated with recurrence and survival in colon cancer patients. Experimental Design: A retrospective analysis of 82 patients who received curative surgical resection for American Joint Committee on Cancer (AJCC) high-risk stage II or III colon cancer (1999–2007) was conducted. DNA methylation status was quantitatively evaluated by the pyrosequencing method. We preselected three tumor suppressor genes and one locus of interest; CHFR, ID4, RECK, and MINT1. Mean methylation levels of multiple CpG sites in the promoter regions were used for analysis; 15% or more was defined as methylation positive. The association of recurrence-free survival (RFS) and overall survival (OS) with methylation status was analyzed by the log-rank test, Kaplan–Meier method, and Cox proportional hazards model. Results: Methylation levels of ID4, MINT1, and RECK did not correlate with RFS or OS. CHFR was methylation positive in 63% patients. When methylation status was dichotomized (negative or low: Conclusions: The extent of CHFR promoter methylation correlates with RFS, indicating it is a promising epigenetic marker for recurrence. Clin Cancer Res; 17(13); 4531–40. ©2011 AACR.

Purpose: To show whether single nucleotide polymorphisms (SNP) of drug metabolic genes were associated with toxicity of 2′,2′-difluoro 2′-deoxycytidine (gemcitabine)–based chemoradiotherapy and overall survival (OS) of patients with pancreatic cancer. Experimental Design: We evaluated 17 SNPs of the CDA, dCK, DCTD, RRM1, hCNT1, hCNT2, hCNT3, and hENT1 genes in 154 patients with potentially resectable pancreatic adenocarcinoma who were enrolled in clinical trials at The University of Texas M.D. Anderson Cancer Center (Houston, TX) from February 1999 to January 2006, with follow-up until April 2009. Patients received neoadjuvant concurrent gemcitabine and radiation therapy with or without gemcitabine-cisplatin induction therapy. The association of genotypes with toxicity or OS was tested, respectively, by logistic regression and Cox regression analysis. Results: None of the 17 SNPs, individually, had a significant association with OS. A combined genotype effect of CDA A-76C, dCK C-1205T, DCTD T-47C, hCNT3 C-69T, hENT1 T-549C, and hENT1 C913T on OS was observed. Patients carrying 0 to 1 (n = 43), 2 to 3 (n = 77), or 4 to 6 (n = 30) variant alleles had median survival time of 31.5, 21.4, and 17.5 months, respectively. The hazard ratio of dying was 1.71 (95% confidence interval, 1.06-2.76) and 3.16 (95% confidence interval, 1.77-5.63) for patients carrying two to three or four to six at-risk genotypes (P = 0.028 and P < 0.001), respectively, after adjusting for clinical predictors. CDA C111T, dCK C-1205T, dCK A9846G, and hCNT3 A25G, individually and jointly, had a significant association with neutropenia toxicity. Conclusions: These observations suggest that polymorphic variations of drug metabolic genes were associated with toxicity of gemcitabine-based therapy and OS of patients with resectable pancreatic cancer. Clin Cancer Res; 16(1); 320–29

Radiographic intraoperative cholangiography (R-IOC) has been widely used to reduce the incidence of biliary complications in living donor hepatectomy (LDH), but it has some drawbacks including radiation exposure and difficulty with handling a C-arm machine for generating 3D images and delineating thin caudate branches. We recently developed contrast-enhanced intraoperative ultrasonic cholangiography (CE-IOUSC) as a tool for biliary navigation in hepatobiliary surgery. We compared the feasibility and usefulness of CE-IOUSC and R-IOC in LDH for visualizing the biliary system and facilitating bile duct division. Seven consecutive patients who underwent LDH using CE-IOUSC and R-IOC between January 2013 and December 2015 in our institute were enrolled. The detectability of each hepatic duct, biliary configuration types, and caudate branches around the cutting point of the hepatic duct was compared. The detectability of each hepatic duct and biliary configuration types was 100%, 100%, 86%, and 100% in drip infusion cholangiography-computed tomography, R-IOC, and 3D/2D CE-IOUSC, respectively. 2D CE-IOUSC could detect caudate branches draining into the cutting side of the hepatic duct, similar to R-IOC (p

A 69-year-old woman was admitted to a nearby clinic complaining of abdominal pain. Abdominal CT showed a 10 cm diameter huge cystic lesion in the body and tail of the pancreas. The patient was referred to our institution for treatment. Endoscopic ultrasonography (EUS) revealed a cystic mass with a solid lesion. Endoscopic retrograde pancreatography(ERP) demonstrated mucous at the opening of the papilla of Vater and dilatation of the pancreatic duct with a solid nodule. Contrast radiography revealed a fistula from the tumor to the jejunum. A biopsy specimen from the lesion showed adenocarcinoma. Intraoperative findings showed a tumor occupying the pancreas body and tail with suspected invasion to the stomach, jejunum, and transverse colon. We performed distal pancreatectomy with partial resection of stomach, jejunum, and colon. Pathological findings showed an invasive type of IPMC, with invasion to the subserosal layer of the stomach and colon and the mucous layer of the jejunum. While IPMC is recognized as a slow growing malignancy, some cases of invasive carcinoma with fistulation into adjacent organs have been reported. To our knowledge, a case of IPMC penetrating to 3 adjacent organs is rare.

A 38-year-old man underwent right hepatectomy for a huge hepatocellular carcinoma(HCC)in the right hepatic lobe. Four months later, recurrent and metastatic disease were observed in the remnant liver and right lung, respectively. We performed a hepatectomy for the recurrent lesion because transcatheter arterial chemoembolization (TACE) was not effective. After surgery, we initiated sorafenib treatment for the lung metastases. One year later, the lung metastases worsened and metastases were observed in the mediastinal lymph nodes, and both metastatic lesions were resected. Seven months later, para-aortic lymph nodal metastasis was observed and dissected. Three months later, metastasis to the supraclavicular lymph node was observed. We performed particle radiation therapy and a complete response was achieved. One year later, metastases in both lungs were observed and resected. Despite continued sorafenib administration throughout the clinical course, a metastasis to the left adrenal gland was observed. This lesion was extirpated because no other recurrent lesions were detected. At 4 years and 6 months after the first operation, no other recurrences have occurred. Currently, sorafenib is the initial drug of choice for HCC with extrahepatic metastases. It is possible to improve the prognosis of patients with HCC and extrahepatic metastases by applying surgical treatment during the course of sorafenib administration.

We previously reported that hepatitis C virus (HCV) infection induces Bax-triggered, mitochondrion-mediated apoptosis by using the HCV J6/JFH1 strain and Huh-7.5 cells. However, it was still unclear how HCV-induced Bax activation. In this study, we showed that the HCV-induced activation and mitochondrial accumulation of Bax were significantly attenuated by treatment with a general antioxidant, N-acetyl cysteine (NAC), or a specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, with the result suggesting that the reactive oxygen species (ROS)/JNK signalling pathway is upstream of Bax activation in HCV-induced apoptosis. We also demonstrated that HCV infection transcriptionally activated the gene for the pro-apoptotic protein Bim and the protein expression of three major splice variants of Bim (BimEL, BimL and BimS). The HCV-induced increase in the Bim mRNA and protein levels was significantly counteracted by treatment with NAC or SP600125, suggesting that the ROS/JNK signalling pathway is involved in Bim upregulation. Moreover, HCV infection led to a marked accumulation of Bim on the mitochondria to facilitate its interaction with Bax. On the other hand, downregulation of Bim by siRNA (small interfering RNA) significantly prevented HCV-mediated activation of Bax and caspase 3. Taken together, these observations suggest that HCV-induced ROS/JNK signalling transcriptionally activates Bim expression, which leads to Bax activation and apoptosis induction.

The N-terminal 198 residues of NS3 (NS3-N) of Hepatitis C virus (HCV) subtype 1b obtained from 29 patients, as well as full-length NS3 (NS3-Full), were analysed for their subcellular localization, interaction with the tumour suppressor p53 and serine protease activity in the presence and absence of the viral cofactor NS4A. Based on the subcellular-localization patterns in the absence of NS4A, NS3-N sequences were classified into three groups, with each group exhibiting either dot-like, diffuse or a mixed type of localization. Chimeric NS3-Full sequences, each consisting of an individual NS3-N and a shared C-terminal sequence, showed the same localization patterns as those of the respective NS3-N. Site-directed mutagenesis experiments revealed that a single or a few amino acid substitutions at a particular position(s) of NS3-N altered the localization pattern. Interestingly, NS3 of the dot-like type, either NS3-N or NS3-Full, interacted with p53 more strongly than that of the diffuse type, in both the presence and the absence of NS4A. Moreover, NS3-N of the dot-like type suppressed trans-activating activity of p53 more strongly than that of the diffuse type. Serine protease activity did not differ significantly between the two types of NS3. In HCV RNA replicon-harbouring cells, physical interaction between NS3 and p53 was observed consistently and p53-mediated transcriptional activation was suppressed significantly compared with HCV RNA-negative control cells. Our results collectively suggest the possibility that NS3 plays an important role in the hepatocarcinogenesis of HCV by interacting differentially with p53 in an NS3 sequence-dependent manner.

The N-terminal domain of NS3 of hepatitis C virus (HCV) possesses serine protease activity, which is essential for virus replication. This portion is also implicated in malignant transformation of hepatocytes. We previously demonstrated that an N-terminal portion of NS3 formed a complex with the tumor suppressor p53 and suppressed actinomycin D-induced apoptosis. We report here that single-point mutations of NS3 at position 106 from Leu to Ala (L106A), and position 43 from Phe to Ala (F43A) to a lesser extent, significantly impaired complex formation with p53. Moreover, the L106A mutation impaired an otherwise more distinct anti-apoptotic activity of NS3. F43A and L106A mutations also inhibited serine protease activity of NS3. These results collectively suggest the possibility that Leu106 and Phe43 are involved in p53 interaction and serine protease activity, and therefore, can be a good target for certain low-molecular-weight compound(s) to inhibit both oncogenic and replicative abilities of HCV.

The NS3 protein of hepatitis C virus (HCV) has a serine protease activity in its N-terminal region, which plays a crucial role in virus replication. This region has also been reported to interact not only with its viral cofactor NS4A, but also with a number of host-cell proteins, which suggests a multifunctional feature of NS3. By means of yeast two-hybrid screening using an N-terminal region of NS3 as bait, a human cDNA encoding a region of ELKS-δ, a member of a novel family of proteins involved in intracellular transport and secretory pathways, was molecularly cloned. Using co-immunoprecipitation, GST pull-down and confocal and immunoelectron microscopic analyses, it was shown that full-length NS3 interacted physically with full-length ELKS-δ and its splice variant, ELKS-α, both in the absence and presence of NS4A, in cultured human cells, including Huh-7 cells harbouring an HCV subgenomic RNA replicon. The degree of binding to ELKS-δ varied with different sequences of the N-terminal 180 residues of NS3. Interestingly, NS3, either full-length or N-terminal fragments, enhanced secretion of secreted alkaline phosphatase (SEAP) from the cells, and the increase in SEAP secretion correlated well with the degree of binding between NS3 and ELKS-δ. Taken together, these results suggest the possibility that NS3 plays a role in modulating host-cell functions such as intracellular transport and secretion through its binding to ELKS-δ and ELKS-α, which may facilitate the virus life cycle and/or mediate the pathogenesis of HCV.

RNA interference (RNAi) is a phenomenon in which small interfering RNA (siRNA), an RNA duplex 21 to 23 nucleotides (nt) long, or short hairpin RNA (shRNA) resembling siRNA, mediates degradation of the target RNA molecule in a sequence-specific manner. RNAi is now expected to be a useful therapeutic strategy for hepatitis C virus (HCV) infection. In the present study we compared the efficacy of a number of shRNAs directed against different target regions of the HCV genome, such as 5′-untranslated region (5′UTR) (nt 286 to 304), Core (nt 371 to 389), NS3–1 (nt 2052 to 2060), NS3–2 (nt 2104 to 2122), and NS5B (nt 7326 to 7344), all of which except for NS5B are conserved among most, if not all, HCV subtype 1b (HCV-1b) isolates in Japan. We utilized two methods to express shRNAs, one utilizing an expression plasmid (pAVU6+27) and the other utilizing a recombinant lentivirus harboring the pAVU6+27-derived expression cassette. Although 5′UTR has been considered to be the most suitable region for therapeutic siRNA and/or shRNA because of its extremely high degree of sequence conservation, we observed only a faint suppression of an HCV subgenomic replicon by shRNA against 5′UTR. In both plasmid- and lentivirus-mediated expression systems, shRNAs against NS3–1 and NS5B suppressed most efficiently the replication of the HCV replicon without suppressing host cellular gene expression. Synthetic siRNA against NS3–1 also inhibited replication of the HCV replicon in a dose-dependent manner. Taken together, the present results imply the possibility that the recombinant lentivirus expressing shRNA against NS3–1 would be a useful tool to inhibit HCV-1b infection.

The patient was a 79-year-old man diagnosed with a single 9.3-cm hepatocellular carcinoma (HCC) in the medial segment of the liver, and left iliac bone metastasis. Initially, the patient was treated with a hepatic arterial infusion of low-dose FP (cisplatin/5-fluorouracil) at another hospital. Here, the patient received particle therapy for the left iliac bone metastasis at a total dose of 52.8 Gy in 4 fractions. Subsequently, he underwent medial segmentectomy of the liver to treat the primary HCC. Eleven months later, the first intrahepatic recurrence occurred, and the tumor was treated with percutaneous radiofrequency ablation (RFA). A second intrahepatic recurrence was detected 39 months later, which was also treated with percutaneous RFA. The patient remains well, with no evidence of tumor recurrence.

A 67-year-old man was admitted to our hospital with a complaint of epigastric discomfort. A 29-mm hypovascular tumor was detected in the head of the pancreas by abdominal computed tomography imaging. As the superior mesenteric artery (SMA) was also involved, we diagnosed the tumor as unresectable pancreatic cancer. With S-1 chemotherapy, a radiological partial response was seen. After 4 courses of chemotherapy, a subtotal-stomach-preserving-pancreatoduodenectomy with dissection of the nerve plexus surrounding the SMA was performed. Although the tissue surrounding the SMA was hard, invasion of the SMA was not detected. Microscopic investigation revealed a few moderately differentiated adenocarcinoma cells in the fibrous tissue and the nerve fibers of pancreas. No cancer cells were found at the edges of the surgical specimen. The patient underwent R0 resection and a pathological evaluation showed Grade III tumor according to the Evans classification. After surgery, S-1 was interrupted because of diarrhea and local recurrence appeared 4 months postoperatively. For improving the prognosis of patients with pancreatic cancers, surgical intervention is often performed in patients with initially unresectable pancreatic cancers who have "long-term" favorable responses to chemotherapy or chemoradiotherapy. However, because of the possibility of relatively good prognosis with nonsurgical treatment for such patients and also the demerits of surgical stress, it is important to carefully consider the adjuvant surgery option.

Here, we report a case of Hassab's operation for left-sided portal hypertension after pancreatoduodenectomy. A 69-year old man underwent pancreatoduodenectomy for pancreatic cancer in 2006 in which the splenic vein was ligated near the portal vein and then divided. The patient suffered repeated episodes of anemia between 2010 and 2013. However, we could not identify the bleeding site at that time. In 2011, local recurrence was detected. Disease progression occurred despite chemotherapy treatment, which was then discontinued. The left-sided portal hypertension gradually progressed, and the collateral vessels became dilated. In 2014, he was examined in our department for gastrointestinal bleeding. An upper gastrointestinal endoscopy revealed bleeding from gastric varices. Gastrointestinal bleeding ceased after endoscopic injection sclerotherapy ( EIS) was performed; however, the bleeding recurred. Balloon retrograde transvenous occlusion (BRTO) could not be performed because blood flow was not detected within the gastro-renal shunt. An emergency surgery was performed. Surgical splenectomy and devascularization (Hassab's operation) were performed. After surgery, the gastric body varices and gastrointestinal anastomosis disappeared and the bleeding did not occur. He is currently receiving outpatient treatment.

Recently, the indications for particle beam therapy have been expanded to include metastatic liver tumors. However, its adverse effects on the treated liver are unclear, and the possibility of local recurrence after treatment should not be ignored. A 65-year-old man with advanced rectal carcinoma underwent low anterior resection. Resectable metastatic liver tumors were detected after adjuvant chemotherapy; however, he opted to undergo particle beam therapy. Nine months after treatment, a local recurrence was detected around the treated area, and central bisegmentectomy of the liver was performed as a salvage operation. The operation was technically complicated owing to severe adhesions and inflammatory changes in the liver parenchyma around the treated area. Pathological examination revealed advanced liver fibrosis at the treated area, in contrast with normal parenchyma in the untreated area. Although the procedure requires advanced surgical techniques, salvage surgery is a feasible option for recurrent liver tumors after particle beam therapy.