Correlation between the complex of small heat shock proteins (HSPBs) and the progression in patients with hepatocellular carcinoma.

Small heat shock proteins (HSPBs) regulate various cell functions. We previously reported that HSPB1, HSPB6, and HSPB8 each suppress the progression of hepatocellular carcinoma (HCC). The heterooligomerization of HSPs is speculated to be crucial for functional activities. Here, we investigated the relationship between the complex of HSPBs and the progression of HCC. HSPB1/HSPB6 complex and HSPB1/HSPB8 complex, but not HSPB6/HSPB8 complex, were observed in both HSPB6-overexpressing human HCC-derived HuH-7 cells and resected human HCC tumor tissue. Differentiation, stage, tumor size, and vein invasion of HCC were inversely related to the presence of HSPB complexes in the HCC tissue. Our results strongly suggest that the HSPB complex formation plays a suppressive role in the HCC progression.

Identification of the suitable candidates for EOB-MRI with the high risk of the presence of non-hypervascular hypointense nodules in patients with HCV infection.

OBJECTIVES: Non-hypervascular hypointense nodules (NHHNs) depicted by gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) have a high likelihood of progressing to hepatocellular carcinoma (HCC). The presence of NHHNs is a strong risk factor for HCC development in patients with chronic hepatitis C virus (HCV) infection after the achievement of sustained virologic response (SVR). However, it is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection. We therefore explored serum markers that potentially indicate the presence of NHHNs. METHODS: Three serum markers, alpha-fetoprotein (AFP), FIB-4 index, and Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi), were measured in 481 patients with HCV infection and no history of HCC who underwent EOB-MRI. The associations between these serum marker levels and the presence of NHHNs were investigated. RESULTS: All three markers were associated with the presence of NHHNs. M2BPGi predicted the presence of NHHNs more accurately than AFP and FBB-4 index; M2BPGi had the highest area under the receiver operating characteristic curve. Multivariate analysis identified male gender and high M2BPGi as factors associated with the presence of NHHNs. When patients were stratified by the degree of liver fibrosis, M2BPGi increased with the progression of fibrosis. In addition, NHHNs were more prevalently detected in patients with higher M2BPGi (COI > 3.46) in patients with similar fibrosis degree. CONCLUSIONS: M2BPGi is a serum marker that potentially identifies HCV patients with high risk of the presence of NHHNs, for whom EOB-MRI should be considered. KEY POINTS: • Non-hypervascular hypointense nodule on EOB-DTPA-enhanced MRI is pre-HCC nodule with high likelihood of progressing to HCC, which is a strong predictor for HCC that develops after the eradication of HCV in patients with HCV infection. • It is difficult for all patients with HCV infection to undergo EOB-MRI for NHHN detection due to limited access, limited availability of MRI equipment, and high costs. • Serum Wisteria floribunda agglutinin-positive Mac-2 binding protein glycan isomer (M2BPGi) levels effectively indicate the presence of NHHNs and can be used to identify patients with high risk of their presence, for whom EOB-DTPA-enhanced MRI should be considered.

Outcome of Hepatocellular Carcinoma Detected During Surveillance: Comparing USA and Japan.

BACKGROUND & AIMS: Differences in outcomes of hepatocellular carcinoma (HCC) between countries have been largely attributed to variation in the conduct of surveillance and subsequent HCC treatment eligibility. However, differences in outcomes among those detected under surveillance have not been well described. We compared characteristics and prognosis between patients with surveillance-detected HCC from the United States (US) and Japan. METHODS: Patients in whom initial HCC was detected under surveillance between January 2006 and December 2015 from two centers in the US and two from Japan were included. Survival was compared between patients from the US and Japan using multivariable Cox regression analysis and propensity-score matched analysis. We performed subgroup analyses by liver disease etiology, tumor stage, and type of HCC treatment. RESULTS: Of 3788 HCC patients, 1797 (47.4%) were diagnosed under surveillance, 715 from the US and 1082 from Japan. Patients from the US diagnosed under surveillance had worse liver dysfunction and larger tumor burden than those from Japan. In multivariate analysis, US patients with surveillance-detected HCC had significantly worse survival than those from Japan (HR 1.17, 95% CI 1.00-1.35), which was also observed in propensity-score matched analysis. However, this difference was no longer significant after adjusting for treatment type (HR 1.07, 95% CI 0.92-1.25). When stratified by treatment type, survival was comparable between the two countries except lower survival among patients who underwent resection in the US versus Japan. CONCLUSIONS: Prognosis of patients with surveillance-detected HCC is poorer in the US than Japan, primarily driven by differences in treatment delivery. Studies are necessary to elucidate reasons for these differences.

Prediction of early recurrence of hepatocellular carcinoma after resection using digital pathology images assessed by machine learning.

Hepatocellular carcinoma (HCC) is a representative primary liver cancer caused by long-term and repetitive liver injury. Surgical resection is generally selected as the radical cure treatment. Because the early recurrence of HCC after resection is associated with low overall survival, the prediction of recurrence after resection is clinically important. However, the pathological characteristics of the early recurrence of HCC have not yet been elucidated. We attempted to predict the early recurrence of HCC after resection based on digital pathologic images of hematoxylin and eosin-stained specimens and machine learning applying a support vector machine (SVM). The 158 HCC patients meeting the Milan criteria who underwent surgical resection were included in this study. The patients were categorized into three groups: Group I, patients with HCC recurrence within 1 year after resection (16 for training and 23 for test); Group II, patients with HCC recurrence between 1 and 2 years after resection (22 and 28); and Group III, patients with no HCC recurrence within 4 years after resection (31 and 38). The SVM-based prediction method separated the three groups with 89.9% (80/89) accuracy. Prediction of Groups I was consistent for all cases, while Group II was predicted to be Group III in one case, and Group III was predicted to be Group II in 8 cases. The use of digital pathology and machine learning could be used for highly accurate prediction of HCC recurrence after surgical resection, especially that for early recurrence. Currently, in most cases after HCC resection, regular blood tests and diagnostic imaging are used for follow-up observation; however, the use of digital pathology coupled with machine learning offers potential as a method for objective postoprative follow-up observation.

Short- and Long-Term Outcomes of Transabdominal Preperitoneal, Open Mesh Plug and Open Tissue Inguinal Hernia Repair.

BACKGROUND: There have been few comparisons of the postoperative outcomes of transabdominal preperitoneal (TAPP), open mesh plug (mesh plug) and open tissue (tissue) hernia repair. The objectives of this study were to compare these repair methods. METHODS: This was a retrospective study of 1813 inguinal hernia patients between January 2008 and December 2016. Of these patients, 474 underwent TAPP repair, 1293 underwent mesh plug repair, and 46 underwent tissue repair. The short-term and long-term outcomes determined by questionnaire were compared among the three groups. In addition, risk factors for patient dissatisfaction were assessed. RESULTS: In the TAPP group, the postoperative complications rate was the lowest at 4.6% (7.4% and 6.5% in the mesh plug and the tissue groups, respectively, P = 0.07), and recurrence rate was lower compared to the mesh plug group (0.8% vs. 3.3%, P = 0.002). As long-term outcomes, 92%, 88% and 75% of patients were satisfied in the TAPP, mesh plug and tissue groups, respectively (P = 0.03). The rate of patients with numbness was 3.1% in the TAPP group, 5.2% in the mesh plug group and 14% in the tissue group (P = 0.04). Predictive independent risk factors for patient dissatisfaction were complications (OR: 3.99, 95% CI: 1.35-11.8, P = 0.012) and infection (OR: 16.9, 95% CI: 1.25-229, P = 0.003). CONCLUSIONS: TAPP repair is superior to mesh plug and tissue repairs in terms of complications, satisfaction and numbness, as determined by questionnaire. Complications and infection were independently associated with the patient dissatisfaction.

Human equilibrative nucleoside transporter-1 expression is a predictor in patients with resected pancreatic cancer treated with adjuvant S-1 chemotherapy.

The high expression of human equilibrative nucleoside transporter-1 (hENT1) and the low expression of dihydropyrimidine dehydrogenase (DPD) are reported to predict a favorable prognosis in patients treated with gemcitabine (GEM) and 5-fluorouracil (5FU) as the adjuvant setting, respectively. The expression of hENT1 and DPD were analyzed in patients registered in the JASPAC 01 trial, which showed a better survival of S-1 over GEM as adjuvant chemotherapy after resection for pancreatic cancer, and their possible roles for predicting treatment outcomes and selecting a chemotherapeutic agent were investigated. Intensity of hENT1 and DPD expression was categorized into no, weak, moderate or strong by immunohistochemistry staining, and the patients were classified into high (strong/moderate) and low (no/weak) groups. Specimens were available for 326 of 377 (86.5%) patients. High expression of hENT1 and DPD was detected in 100 (30.7%) and 63 (19.3%) of 326 patients, respectively. In the S-1 arm, the median overall survival (OS) with low hENT1, 58.0 months, was significantly better than that with high hENT1, 30.9 months (hazard ratio 1.75, P = 0.007). In contrast, there were no significant differences in OS between DPD low and high groups in the S-1 arm and neither the expression levels of hENT1 nor DPD revealed a relationship with treatment outcomes in the GEM arm. The present study did not show that the DPD and hENT1 are useful biomarkers for choosing S-1 or GEM as adjuvant chemotherapy. However, hENT1 expression is a significant prognostic factor for survival in the S-1 arm.

Liver Resection for Multiple Hepatocellular Carcinomas: A Japanese Nationwide Survey.

OBJECTIVE: The aim of the study was to evaluate the survival benefits of liver resection (LR) compared with transarterial chemoembolization (TACE) for patients with multiple hepatocellular carcinomas (HCCs). BACKGROUND: Despite significant improvements in diagnostic imaging and the widespread application of screening programs, some patients with HCC continue to present with multiple tumors. The surgical indications for multiple HCCs remain controversial. METHODS: Among 77,268 patients with HCC reported in a Japanese nationwide survey, 27,164 patients had multiple HCCs. The exclusion criteria were Child-Pugh B/C, treatment other than LR and TACE, >3 tumors, and insufficient available data. Ultimately, 3246 patients (LR: n = 1944, TACE: n = 1302) were included. The survival benefit of LR for patients multiple HCCs was evaluated by using propensity score matching analysis. RESULTS: The study group of 2178 patients (LR: n = 1089, TACE: n = 1089) seemed to be well matched. The overall survival rate in the LR group was 60.0% at 5 years, which was higher than that in the TACE group (41.6%, P < 0.001). Among patients with a tumor size of 30 mm or more, LR showed a survival benefit over TACE at 5 years (53.0% vs 32.7%, P < 0.001). The multivariate analysis indicated that age, serum albumin level, serum alpha-fetoprotein (AFP) level, macrovascular invasion, tumor size, and TACE were independent predictors of poor prognosis in multiple HCCs. CONCLUSIONS: LR could offer better long-term survival than TACE for patients with multiple HCCs (up to 3 tumors). If patients have good liver function (Child-Pugh A), LR is recommended, even for those with multiple HCCs with tumor sizes of 30 mm or more.

Lower bile duct metastasis from rectal cancer after surgery for liver metastasis and intrahepatic bile duct metastasis: a case report.

BACKGROUND: Biliary metastasis of colorectal cancer is a manifestation of metastatic liver carcinoma, and is often difficult to differentiate from cholangiocarcinoma. Further, lower bile duct metastasis of colorectal cancer is rare. We report the case of a 74-year-old woman who underwent pylorus-preserving pancreatoduodenectomy for lower bile duct metastasis of rectal cancer. CASE PRESENTATION: The patient had undergone laparoscopic low anterior resection for rectal cancer (pT3N0M0 stage IIA) 6 years ago, laparoscopic anterior liver resection for liver metastasis (Couinaud segment V) 3 years ago, and left and caudal lobectomy with extrahepatic bile duct resection for left intrahepatic bile duct metastasis 6 months ago. A follow-up examination showed a 15 mm mass in the common bile duct, for which she underwent pylorus-preserving pancreatoduodenectomy. Histological and immunohistological examination of the specimens revealed similar cytokeratin (CK) expression patterns, which were negative for CK7 and positive for CK20. Therefore, the definitive diagnosis was metastasis from rectal cancer. CONCLUSIONS: In summary, we encountered a case of lower bile duct metastasis from rectal cancer, which is often difficult to differentiate from cholangiocarcinoma. In such patients, CK7 and CK20 expression patterns are important in differentiating the two. The mechanism of metastasis in this case was considered to be through cancer cell implantation from lymphatic spread, or through distant metastasis of the primary cancer.

Circulating microRNA-1246 as a possible biomarker for early tumor recurrence of hepatocellular carcinoma.

AIMS: Early tumor recurrence (ETR) after hepatic resection is a crucial predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify clinically significant serum microRNAs (miRNAs) involved in the ETR of HCC. METHODS: We compared expression profiles of circulating miRNAs from serum samples between five HCC patients with ETR (recurrence within 12 months after hepatectomy) and five HCC patients without recurrence using microarray analysis of miRNA. The identified miRNA associated with ETR was further verified in 121 HCC patients, 73 liver disease patients, and 15 health controls by real-time quantitative reverse transcription-polymerase chain reaction (PCR). RESULTS: Of the approximately 2000 miRNAs analyzed, we identified 15 miRNAs for which expression levels correlated significantly with ETR. Of these miRNAs, we further investigated expression of miRNA-1246 (miR-1246). Quantitative PCR confirmed that miR-1246 was upregulated in HCC with ETR, compared to the level in HCC without ETR (P < 0.001). Serum miR-1246 showed a receiver operating characteristic curve area of 0.762, with 77.4% specificity and 54.1% sensitivity in discriminating HCC patients with ETR from HCC patients without ETR. Altered expression of miR-1246 was associated with aggressive tumor characteristics, including tumor-node-metastasis classification (P = 0.0413), tumor differentiation (P = 0.0419), and portal vein invasion (P = 0.0394). Moreover, multivariate Cox regression analysis identified serum miR-1246 level as an independent risk factor for overall survival (hazard ratio, 2.784; 95% confidence interval, 1.528-5.071; P = 0.0008). CONCLUSION: Circulating miR-1246 in serum has strong potential as a novel ETR and prognostic biomarker for HCC.

Comparison of end-to-end anastomosis and interposition graft during pancreatoduodenectomy with portal vein reconstruction for pancreatic ductal adenocarcinoma.

PURPOSE: Many studies report that pancreatoduodenectomy (PD) with portal-superior mesenteric vein resection and reconstruction (PVR) is not a contraindication to extended tumor resection for pancreatic ductal adenocarcinoma. However, the clinical benefit of an interposition graft for PVR still remains controversial. METHODS: Between January 2001 and December 2017, 199 patients with pancreatic cancer underwent PD either with or without PVR, and their medical records were reviewed retrospectively, paying specific attention to the PVR methods and the long-term outcome. RESULTS: Among the 122 patients with PVR, 97 (79.5%) underwent end-to-end anastomosis and 25 (20.5%) had an interposition graft using the right external iliac vein (REIV). The 2-year and 5-year survival rates of the no-PVR group (54.2% and 30.8%, respectively) were longer than both the end-to-end anastomosis group (24.5% and 13.7%) and the interposition graft group (32% and 10.0%) (p < 0.001). However, there was no significant difference in the survival between the end-to-end anastomosis group and the interposition graft group (p = 0.963). A multivariate analysis indicated that the level of preoperative serum albumin < 3.5 g/dL (risk ratio (RR) 2.08, 95% confidence interval (CI) 1.26 to 3.43; p = 0.004), and postoperative adjuvant chemotherapy (RR 1.82, 95% CI 1.19 to 2.79; p = 0.006) were independently associated with overall survival after PVR. CONCLUSIONS: An interposition graft using the REIV for PVR following PD is safe and effective. There was no significant prognostic difference between PD with end-to-end anastomosis and with an interposition graft in patients with pancreatic ductal adenocarcinoma.

Adverse oncological outcome of surgical site infection after liver resection for colorectal liver metastases.

PURPOSES: Postoperative complications are associated with poor overall and cancer-specific survival after resection of various types of cancer, including primary colorectal cancer. However, the oncological impact of surgical site infection (SSI) after liver resection for colorectal liver metastases (CLM) is unclear. The aim of this study was to investigate the oncological impact of SSI after liver resection for CLM. METHODS: We reviewed data from 367 consecutive patients treated by curative liver resection for CLM between 1994 and 2015. Patients who underwent simultaneous resection of colorectal cancer and synchronous liver metastases (n = 86) were excluded from the analysis. Short- and long-term outcomes were analyzed. RESULTS: SSI developed in 18 (6.4%) of the 281 patients in the analytic cohort (SSI group). The remaining 93.6% (n = 263) did not suffer this complication (no-SSI group). The operative duration was significantly longer in the SSI group than in the No-SSI group (p = 0.002). The overall survival rates 5 years after liver resection for CLM were 33.3% in the SSI group vs. 50.7% in the No-SSI group (p = 0.043). Multivariate analysis indicated that a liver tumor size ≥ 5 cm, R1 resection, and SSI were independently associated with overall survival after liver resection. CONCLUSIONS: SSI after liver resection for CLM is associated with adverse oncological outcomes.

The Prognostic Impact of the Lymphocyte-to-Monocyte Ratio in Resected Pancreatic Head Adenocarcinoma.

OBJECTIVE: Although the prognostic significance of systematic inflammation-based scores, such as the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR), and the prognostic nutritional index (PNI), has been explored in pancreatic cancers, few reports have investigated the lymphocyte-to-monocyte ratio (LMR). We aimed to retrospectively investigate the prognostic value of the preoperative LMR in patients with resectable pancreatic head cancer (PHC). METHODS: From 2005 to 2016, 165 patients underwent pancreatoduodenectomy for PHC. All samples of peripheral blood were collected within 2 weeks prior to surgery. The best cutoff values of the LMR for predicting survival were determined by using a minimum p value approach (cut-off value: 2.8). The clinicopathological features of LMR <2.8 (n = 25) and ≥2.8 (n = 140) were compared. RESULTS: Patients with LMR ≥2.8 showed significantly lower NLR and PLR, and significantly higher PNI. Levels of CEA and CA19-9 were similar, and the pathological findings were comparable between the groups. The overall survival of patients with LMR ≥2.8 (66.2% at 1 year) was superior to that of patients with LMR <2.8 (36.1% at 1 year, p = 0.015). Multivariate analysis identified LMR <2.8 (hazard ratio 1.72, 95% CI 1.02-2.89, p = 0.042), lymphatic and venous invasion and positive surgical margin as independent prognostic factors. CONCLUSIONS: LMR may carry important prognostic information for patients with resectable PHC. Preoperative LMR may be considered for use in risk stratification for individual patients with PHC.

Clinical Effect of Water-Soluble Contrast Agents for Small Bowel Obstruction in the Virgin Abdomen.

BACKGROUND: Several studies have investigated the diagnostic and therapeutic role of water-soluble contrast agents (WSCAs) in adhesive small bowel obstruction (SBO). However, the clinical effect of WSCA for SBO without previous intraabdominal operation (i.e., virgin abdomen, VA) is unclear. The aim of this study was to clarify the clinical effect of WSCA for SBO in the VA. METHODS: Between January 2008 and December 2015, 838 consecutive patients with SBO were initially managed with WSCA and were included in the study. Abdominal X-rays were taken 5 h after administration of 100 ml WSCA and classified into complete/incomplete obstruction groups. The medical records of the patients with SBO were retrospectively analyzed and divided into two groups of patients with VA or non-VA. RESULTS: A total of 44 and 794 VA and non-VA patients were identified, respectively. Six VA patients (13%) and 121 non-VA patients (15%) were classified with complete obstruction (p = 1.000) and subjected to operative exploration on the same day. There were no significant differences in the duration of nasogastric tube decompression (2.2 versus 2.5 days, p = 0.400) and intervals until the initiation of oral intake (2.4 versus 2.6 days, p = 0.553) between the VA and non-VA groups. The overall operative rate was 16% in the VA and 17% in the non-VA groups (p = 1.000). Compared with non-VA, VA was associated with shorter hospital stays (9.6 versus 11.3 days, p = 0.006). CONCLUSIONS: WSCA for SBO in the VA is as effective as in non-VA patients in terms of a therapeutic strategy.

Differences in the impact of prognostic factors for hepatocellular carcinoma over time.

The aim of the present study was to evaluate the prognostic significance of serum markers that reflect tumor progression, liver function, or liver fibrosis in patients with hepatocellular carcinoma (HCC), focusing on how their impact changes over time after diagnosis. Alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), albumin-bilirubin (ALBI) score, aspartate aminotransferase to platelet ratio index (APRI), and FIB-4 index were measured at the time of initial non-recurrent HCC diagnosis in 1669 patients between 1997 and 2016. Survival rates after diagnosis were compared after stratifying patients by these markers. Time-dependent receiver-operating characteristics (ROC) analysis was carried out to assess how these markers predict patient survival or death. Serum AFP and DCP levels, ALBI score, and APRI and FIB-4 index were strongly correlated with HCC progression, liver function, and degree of liver fibrosis, respectively. Survival rates after diagnosis were significantly different when patients were stratified by these markers. In the time-dependent ROC analysis, AFP and DCP had a high prognostic impact within 3 years of diagnosis but the impact decreased thereafter. In contrast, APRI and FIB-4 index had higher prognostic impact 10 years after diagnosis. ALBI score had a high prognostic impact throughout the study period. Time-dependent ROC analysis clearly showed changes in the prognostic importance of serum markers based on the duration after diagnosis. Whereas the prognostic impact of tumor progression markers was strong in the short term, liver fibrosis markers had higher prognostic impact long after diagnosis. Liver function had constant prognostic impact on patient survival after diagnosis.

Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01).

BACKGROUND: Although adjuvant chemotherapy with gemcitabine is standard care for resected pancreatic cancer, S-1 has shown non-inferiority to gemcitabine for advanced disease. We aimed to investigate the non-inferiority of S-1 to gemcitabine as adjuvant chemotherapy for pancreatic cancer in terms of overall survival. METHODS: We did a randomised, open-label, multicentre, non-inferiority phase 3 trial undertaken at 33 hospitals in Japan. Patients who had histologically proven invasive ductal carcinoma of the pancreas, pathologically documented stage I-III, and no local residual or microscopic residual tumour, and were aged 20 years or older were eligible. Patients with resected pancreatic cancer were randomly assigned (in a 1:1 ratio) to receive gemcitabine (1000 mg/m(2), intravenously administered on days 1, 8, and 15, every 4 weeks [one cycle], for up to six cycles) or S-1 (40 mg, 50 mg, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14 day rest, every 6 weeks [one cycle], for up to four cycles) at the data centre by a modified minimisation method, balancing residual tumour status, nodal status, and institutions. The primary outcome was overall survival in the two treatment groups, assessed in the per-protocol population, excluding ineligible patients and those not receiving the allocated treatment. The protocol prespecified that the superiority of S-1 with respect to overall survival was also to be assessed in the per-protocol population by a log-rank test, if the non-inferiority of S-1 was verified. We estimated overall and relapse-free survival using the Kaplan-Meier methods, and assessed non-inferiority of S-1 to gemcitabine using the Cox proportional hazard model. The expected hazard ratio (HR) for mortality was 0.87 with a non-inferiority margin of 1.25 (power 80%; one-sided type I error 2.5%). This trial is registered at UMIN CTR (UMIN000000655). FINDINGS: 385 patients were randomly assigned to treatment between April 11, 2007, and June 29, 2010 (193 to the gemcitabine group and 192 to the S-1 group). Of these, three were exlcuded because of ineligibility and five did not receive chemotherapy. The per-protocol population therefore consisted of 190 patients in the gemcitabine group and 187 patients in the S-1 group. On Sept 15, 2012, following the recommendation from the independent data and safety monitoring committee, this study was discontinued because the prespecified criteria for early discontinuation were met at the interim analysis for efficacy, when all the protocol treatments had been finished. Analysis with the follow-up data on Jan 15, 2016, showed HR of mortality was 0.57 (95% CI 0.44-0.72, pnon-inferiority<0.0001, p<0.0001 for superiority), associated with 5-year overall survival of 24.4% (18.6-30.8) in the gemcitabine group and 44.1% (36.9-51.1) in the S-1 group. Grade 3 or 4 leucopenia, neutropenia, aspartate aminotransferase, and alanine aminotransferase were observed more frequently in the gemcitabine group, whereas stomatitis and diarrhoea were more frequently experienced in the S-1 group. INTERPRETATION: Adjuvant chemotherapy with S-1 can be a new standard care for resected pancreatic cancer in Japanese patients. These results should be assessed in non-Asian patients. FUNDING: Pharma Valley Center, Shizuoka Industrial Foundation, Taiho Pharmaceutical.

Heat shock protein 22 (HSPB8) reduces the migration of hepatocellular carcinoma cells through the suppression of the phosphoinositide 3-kinase (PI3K)/AKT pathway.

Small heat shock proteins (HSPs) regulate a variety of cell functions. Among them, HSP22 and HSP20 are recognized to be ubiquitously expressed in various tissues. With regard to hepatocellular carcinoma (HCC) cells, we previously reported that phosphorylated HSP20 plays a suppressive role in transforming growth factor (TGF)-α-induced cell migration and invasion. In the present study, we investigated whether or not HSP22 is implicated in HCC cell migration. We detected HSP22 protein expression both in human HCC tumor (189.9±68.4ng/mg protein) and the adjacent non-tumor liver tissues (167.9±94.6ng/mg protein). The cases of low-quantity HSP22 protein level group (88.3≧ng/mg protein, the optimum cut-off value of HSP22) were increased in tumor tissues compared with the adjacent non-tumor tissues. The migration of human HCC-derived HuH-7 cells stimulated by TGF-α or hepatocyte growth factor (HGF) was significantly enhanced by the knockdown of HSP22 expression. Down-regulation of HSP22 protein in the cells markedly strengthened the AKT phosphorylation induced by TGF-α or HGF. Inhibitors of the phosphoinositide 3-kinase (PI3K)/AKT pathway, which suppressed the TGF-α-induced migration, significantly reduced the amplification by HSP22 knockdown. PI3K but not AKT was coimmunoprecipitated with HSP22 in HuH-7 cells. In addition, in human HCC tissues, a significantly lower HSP22 protein level in tumor tissues than in adjacent non-tumor tissues was observed more frequently in cases of moderately or poorly differentiated HCC than well-differentiated HCC. Taken together, our results strongly suggest that HSP22 represses HCC progression, especially HCC cell migration, by the down-regulation of the PI3K/AKT signaling pathway.

Preoperative radiographic vascular involvement score predicts the prognosis of resected pancreatic head adenocarcinoma.

BACKGROUND: Operative indications for pancreatic head adenocarcinoma (PHC) with vascular invasion remain unclear. We aimed to develop a new prognostic model focusing on preoperative portal/superior mesenteric vein (PV/SMV) and superior mesenteric artery (SMA) invasiveness. METHODS: From 2005 to 2012, 103 patients underwent pancreatoduodenectomy for PHC. The CT findings for both PV/SMV and SMA invasion were evaluated separately [PV/SMV, none (score 0), unilateral narrowing (score 1), bilateral narrowing/stenosis (score 2); SMA, none or <90° (score 0), ≥90° (score 3)]. The total score defined the preoperative vascular involvement score (VI score); VI scores 0 (n = 39), 1 (n = 32), 2 (n = 17) and ≥3 (n = 15) were compared. RESULTS: PV/SMV resection was performed in 1 (3%), 29 (91%), 16 (94%) and 13 (87%) cases of VI scores 0, 1, 2 and ≥3, respectively (P < 0.001). No patients with VI scores ≥3 had margin-negative resection; pathologically curative resection was achieved in 37 of 39 (95%), 27 of 32 (84%) and 13 of 17 (76%) patients with VI scores of 0, 1 and 2, respectively (P < 0.001). The survival rate and median survival time (MST) were reduced with an increasing VI score (MST, 40.9, 16.5, 8.9 and 6.3 months, respectively). The comparison of each survival curve revealed significant differences (P < 0.005), except when comparing VI scores 1 and 2 (P = 0.134). CONCLUSIONS: Higher VI score predicts shorter survival. Proposed scoring system may be useful for determining the choice between undergoing neoadjuvant treatment, or upfront resection with adjuvant treatment.

Postoperative complications following aggressive repeat hepatectomy for colorectal liver metastasis have adverse oncological outcomes.

PURPOSES: Repeat hepatectomy remains the only curative treatment for recurrent colorectal liver metastasis (CLM) after primary hepatectomy. However, the repeat resection rate is still low, and there is insufficient data on the outcomes after repeat hepatectomy. The aim of this study was to investigate the feasibility and prognostic benefit of aggressive repeat hepatectomy for recurrent CLM. METHODS: Data were reviewed from 282 consecutive patients who underwent primary curative hepatectomy for CLM between January 1994 and March 2015. The short- and long-term outcomes were analyzed. RESULTS: One hundred ninety-three patients (68 %) developed recurrence, and repeat hepatectomy was conducted in 62 patients. Overall, 62 s, 11 third, 4 fourth, and 1 fifth hepatectomies were performed. The postoperative morbidity and mortality rates were low (11.5 and 1.3 %, respectively). The overall survival rates at 3 and 5 years after primary hepatectomy for CLM in the repeat hepatectomy group were 79.5 and 57.4 %, respectively. A multivariate analysis indicated that postoperative complications were independently associated with overall survival after repeat hepatectomy. CONCLUSIONS: Repeat hepatectomy for CLM is feasible, with acceptable rates of perioperative morbidity and mortality, and the potential for long-term survival. However, postoperative complications following aggressive repeat hepatectomy for CLM are associated with adverse oncological outcomes.

A preoperative predictive scoring system to predict the ability to achieve the critical view of safety during laparoscopic cholecystectomy for acute cholecystitis.

PURPOSE: The aim of this study was to develop a preoperative scoring system to predict the ability to achieve the critical view of safety (CVS) in patients undergoing emergency laparoscopic cholecystectomy (LC) for acute cholecystitis (AC). METHODS: A retrospective review of patients who underwent LC for AC between 2012 and 2015 was performed. The achievement or failure of creating the CVS was judged by operative records, video recordings, and interviews of the surgeons. Independent preoperative variables associated with failure were determined by multivariate logistic regression analysis and a prediction scoring system created. RESULTS: A C-reactive protein (CRP) >5.5 mg/dl, gallstone impaction, and symptom onset to operation >72 h were identified as independently correlated risk factors for the failure to achieve the CVS. A preoperative risk scoring system for the failure to create the CVS (0-5 points) was constructed using these 3 factors: CRP >5.5 mg/dl (2 points), gallstone impaction (1 points), and time from symptom onset to operation >72 h (2 points). When monitoring the frequency of patients who had a failure to create the CVS at each score, the incidence of failure increased as the score increased (P<0.001). CONCLUSIONS: Using only three preoperative factors, the proposed scoring system provides an objective evaluation of the likelihood that CVS can be achieved in patients undergoing emergency LC for AC.

Serum WFA+ -M2BP levels as a prognostic factor in patients with early hepatocellular carcinoma undergoing curative resection.

BACKGROUND & AIMS: Serum tumour markers for hepatocellular carcinoma (HCC) have less prognostic significance in early stage. Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA(+) -M2BP) levels are reportedly associated with hepatocarcinogenic potential in patients with chronic liver diseases. We investigated the prognostic significance of pretreatment serum WFA(+) -M2BP levels in patients with early-stage HCC. METHODS: A total of 240 patients who underwent hepatic resection for naïve Barcelona Clinic Liver Cancer (BCLC) class 0 or A HCC were analysed. WFA(+) -M2BP and tumour markers for HCC were measured from serum obtained just prior to treatment. Post-operative recurrence and survival rates were compared according to these serum markers, tumour stage and Child-Pugh class. RESULTS: There was an association between serum WFA(+) -M2BP levels and the fibrosis grade of resected noncancerous liver tissue, whereas no association was found between WFA(+) -M2BP levels and tumour progression or liver function. In a multivariate analysis, pretreatment serum WFA(+) -M2BP level was associated with recurrence and survival, respectively, independent of HCC progression or fibrosis grade of resected noncancerous liver tissue. Recurrence rates after hepatic resection were significantly higher in patients with a pretreatment serum WFA(+) -M2BP ≥ 3.00 than those with a pretreatment serum WFA(+) -M2BP < 3.00 (P = 0.0038). Survival rates were lower in patients with a pretreatment serum WFA(+) -M2BP ≥ 3.00 than those with a pretreatment serum WFA(+) -M2BP < 3.00 (P = 0.0187). CONCLUSIONS: Serum WFA(+) -M2BP level is a prognostic factor for recurrence and survival, in addition to tumour progression and liver function, in patients with early-stage HCC treated with curative hepatic resection.