Toshifumi Wakai

Radical second resection provides survival benefit for patients with T2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy

Port site recurrence or peritoneal seeding is a fatal complication following laparoscopic cholecystectomy for gallbladder carcinoma. The aims of this retrospective analysis were to determine the association of gallbladder perforation during laparoscopic cholecystectomy with port site/peritoneal recurrence and to determine the role of radical second resection in the management of gallbladder carcinoma first diagnosed after laparoscopic cholecystectomy. A total of 28 patients undergoing laparoscopic cholecystectomy for gallbladder carcinoma were analyzed, of whom 10 had a radical second resection. Five patients had recurrences; port site/peritoneum recurrence in 3 and distant metastasis in 2. The incidence of port site/peritoneal recurrence was higher in patients with gallbladder perforation (3/7, 43%) than in those without (0/21, 0%) (p = 0.011). The outcome after laparoscopic cholecystectomy was worse in 7 patients with gallbladder perforation (cumulative 5-year survival of 43%) than in those without (cumulative 5-year survival of 100%) (p <0.001). Among 13 patients with a pT2 tumor, the outcome after radical second resection (cumulative 5-year survival of 100%) was better than that after laparoscopic cholecystectomy alone (cumulative 5-year survival of 50%) (p = 0.039), although there was no survival benefit of radical second resection in the 15 patients with a pT1 tumor (p = 0.65). In conclusion, gallbladder perforation during laparoscopic cholecystectomy is associated with port site/peritoneal recurrence and worse patient survival. Radical second resection may be beneficial for patients with pT2 gallbladder carcinoma first discovered after laparoscopic cholecystectomy.

Depth of Subserosal Invasion Predicts Long-Term Survival After Resection in Patients With T2 Gallbladder Carcinoma

AbstractBackground: This study aimed to identify a subgroup of patients with inapparent T2 gallbladder carcinoma who may be best suited for radical second resection. Methods: A retrospective analysis was conducted of 126 patients with pathologic stage T2 (pT2) gallbladder carcinoma (51 with clinically evident tumor and 75 with inapparent tumor). Depth of subserosal invasion was measured histologically in each gallbladder specimen. The median follow-up period was 113 months. Results: In all 126 patients, depth of subserosal invasion was the strongest independent prognostic factor by univariate (P < .0001) and multivariate (relative risk, 9.27; P < .0001) analyses. Among the 75 patients with inapparent tumor, the outcome after resection was significantly better in patients who had undergone radical second resection than in patients who had undergone cholecystectomy alone (P = .0006). When depth of subserosal invasion was divided into ≤2 vs. >2 mm, the effectiveness of radical second resection remained only in patients with subserosal invasion >2 mm (P = .0004). Conclusions:Depth of subserosal invasion best predicts postresectional long-term survival of pT2 gallbladder carcinoma patients. Among patients with inapparent pT2 tumors, those with subserosal invasion >2 mm are good candidates for radical second resection.Background: This study aimed to identify a subgroup of patients with inapparent T2 gallbladder carcinoma who may be best suited for radical second resection. Methods: A retrospective analysis was conducted of 126 patients with pathologic stage T2 (pT2) gallbladder carcinoma (51 with clinically evident tumor and 75 with inapparent tumor). Depth of subserosal invasion was measured histologically in each gallbladder specimen. The median follow-up period was 113 months. Results: In all 126 patients, depth of subserosal invasion was the strongest independent prognostic factor by univariate (P < .0001) and multivariate (relative risk, 9.27; P < .0001) analyses. Among the 75 patients with inapparent tumor, the outcome after resection was significantly better in patients who had undergone radical second resection than in patients who had undergone cholecystectomy alone (P = .0006). When depth of subserosal invasion was divided into ≤2 vs. >2 mm, the effectiveness of radical second resection remained only in patients with subserosal invasion >2 mm (P = .0004). Conclusions:Depth of subserosal invasion best predicts postresectional long-term survival of pT2 gallbladder carcinoma patients. Among patients with inapparent pT2 tumors, those with subserosal invasion >2 mm are good candidates for radical second resection.

Preoperative predictors of vascular invasion in hepatocellular carcinoma

AIMS Vascular invasion is an established adverse prognostic factor in hepatocellular carcinoma (HCC). The aim of the current study was to identify the preoperative predictors of vascular invasion in patients undergoing partial hepatectomy for HCC. METHODS A retrospective analysis of 227 consecutive patients who underwent partial hepatectomy for HCC was conducted. Vascular invasion was defined as gross or microscopic involvement of the vessels (portal vein or hepatic vein) within the peritumoral liver tissue. RESULTS Seventy-six (33%) patients had vascular invasion. Among the preoperative factors, only the tumour size (relative risk, 16.78; p<0.01) and the serum alpha-fetoprotein (AFP) level (relative risk, 3.57; p<0.01) independently predicted vascular invasion. As the tumour size increased, the incidence of vascular invasion increased: < or =2 cm, 3%; 2.1-3 cm, 20%; 3.1-5 cm, 38%; and > 5 cm, 65%. The incidence of vascular invasion was 32% in patients with serum AFP levels < or =1000 ng/mL, compared to 61% in patients with higher serum AFP levels (p<0.01). Patients with both tumours >5 cm and serum AFP levels >1000 ng/mL had an 82% incidence of vascular invasion. CONCLUSIONS The tumour size and serum AFP level, alone or in combination, are useful in predicting the presence or absence of vascular invasion before hepatectomy for HCC.

Risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts

The aim of this study was to elucidate the risk of subsequent biliary malignancy in patients undergoing cyst excision for congenital choledochal cysts.

Reduced NKG2D ligand expression in hepatocellular carcinoma correlates with early recurrence

BACKGROUND & AIMS The activating receptor natural killer group 2, member D (NKG2D) and its ligands play a crucial role in immune response to tumors. NKG2D ligand expression in tumors has been shown to be associated with tumor eradication and superior patient survival, but the involvement of NKG2D ligands in the immune response against hepatocellular carcinoma (HCC) still remains to be elucidated. METHODS We investigated the expression of NKG2D ligands in HCC tissues collected from 54 patients and HCC cell lines. We also examined the proteasome expression and the effect of inhibition of proteasome activity on NKG2D ligand expression in HCC tissues and cell lines. RESULTS In dysplastic nodules (DN), well-differentiated (well-HCC), and moderately-differentiated HCCs (mod-HCC), UL16-binding protein (ULBP) 1 was expressed predominantly in tumor cells, but not in poorly-differentiated HCCs (poor-HCC). Remarkably, recurrence-free survival of patients with ULBP1-negative HCC was significantly shorter than that of patients with ULBP1-positive HCC (p=0.006). Cox regression analysis revealed that loss of ULBP1 expression was an independent predictor of early recurrence (p=0.008). We confirmed that ULBP1 was expressed in the well- and mod-HCC cell lines, but not in the poor-HCC cell line KYN-2. However, inhibition of proteasome activity resulted in significant up-regulation of ULBP1 expression in KYN-2. Moreover, we found that 20S proteasome expression was more abundant in KYN-2 than that in the well- and mod-HCC cell lines. CONCLUSIONS ULBP1 is prevalently expressed in DN to mod-HCC, but loss of its expression correlates with tumor progression and early recurrence.

p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

p62/Sqstm1 is a multifunctional protein involved in cell survival, growth and death, that is degraded by autophagy. Amplification of the p62/Sqstm1 gene, and aberrant accumulation and phosphorylation of p62/Sqstm1, have been implicated in tumour development. Herein, we reveal the molecular mechanism of p62/Sqstm1-dependent malignant progression, and suggest that molecular targeting of p62/Sqstm1 represents a potential chemotherapeutic approach against hepatocellular carcinoma (HCC). Phosphorylation of p62/Sqstm1 at Ser349 directs glucose to the glucuronate pathway, and glutamine towards glutathione synthesis through activation of the transcription factor Nrf2. These changes provide HCC cells with tolerance to anti-cancer drugs and proliferation potency. Phosphorylated p62/Sqstm1 accumulates in tumour regions positive for hepatitis C virus (HCV). An inhibitor of phosphorylated p62-dependent Nrf2 activation suppresses the proliferation and anticancer agent tolerance of HCC. Our data indicate that this Nrf2 inhibitor could be used to make cancer cells less resistant to anticancer drugs, especially in HCV-positive HCC patients.

Surgical Outcomes for Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

BackgroundThe present study investigated outcomes following surgical resection of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD).MethodsPatients (n = 225) undergoing resection for HCC were divided into three groups: hepatitis C viral group (n = 147), hepatitis B viral group (n = 61), and NAFLD group (n = 17). Clinicopathological characteristics and surgical outcomes were analyzed retrospectively.ResultsPatients in the NAFLD group were older (P < 0.001), with a higher body mass index (P < 0.001) and larger tumors (P = 0.002) than patients who were positive for hepatitis viral markers. Eight patients in the NAFLD group were found to have nonalcoholic steatohepatitis (NASH) histologically. Postoperative morbidity and 30-day mortality rates were significantly higher in the NAFLD group (59% and 12%, respectively) than in the hepatitis C viral (31% and 0.7%, respectively) and hepatitis B viral (28% and 3.3%; P = 0.043 and P = 0.016, respectively) groups. All deaths in the NAFLD group were in patients with NASH-related cirrhosis who had undergone right hemihepatectomy. Survival after resection was comparable among the three groups (P = 0.391), but patients with NAFLD showed better disease-free survival on univariate (P = 0.048) and multivariate (P = 0.020) analyses.ConclusionsSurgical resection may provide a survival benefit for patients with NAFLD-related HCC. Patients with NASH-related cirrhosis undergoing major hepatic resection should be treated carefully.

Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition

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.

Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy

Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.

Assessment of lymph node status in gallbladder cancer: location, number, or ratio of positive nodes

BackgroundAssessment of lymph node status is a critical issue in the surgical management of gallbladder cancer. The aim of this study was to compare the anatomical location of positive nodes, number of positive nodes, and lymph node ratio (LNR) as prognostic predictors in gallbladder cancer.MethodsWe conducted a retrospective analysis of 135 patients with gallbladder cancer who underwent a radical resection with regional lymphadenectomy. A total of 2,245 regional lymph nodes were retrieved (median, 14 per patient). The location of positive nodes was classified according to the AJCC staging manual (7th edition). ‘Optimal’ cutoff values were determined for the number of positive nodes and LNR based on maximal χ2 scores calculated with the Cox proportional hazards regression model.ResultsLymph node metastasis was found histologically in 59 (44%) patients. The ‘optimal’ cutoff values for the number of positive nodes and LNR were determined to be three nodes and 10%, respectively. Univariate analysis identified location of positive nodes (pN0, pN1, pN2; P < 0.001), number of positive nodes (0, 1 to 3, ≥4; P < 0.001), and LNR (0%, 0 to 10%, >10%; P < 0.001) as significant prognostic factors. Multivariate analysis identified number of positive nodes as an independent prognostic factor ( P = 0.004); however, location of positive nodes and LNR failed to remain as an independent variable.ConclusionsThe number of positive lymph nodes better predicts patient outcome after resection than either the location of positive lymph nodes or LNR in gallbladder cancer. Dividing the number of positive lymph nodes into three categories (0, 1 to 3, or ≥4) is valid for stratifying patients based on the prognosis after resection.