Antithrombin attenuates the progression of hepatocellular carcinoma by regulating neutrophil/interleukin-8 signaling.

AIM: Inflammation plays an important role in hepatocellular carcinoma (HCC) progression. Here, we examined whether antithrombin (AT) plays a role in attenuating HCC progression, via its anti-inflammatory effects. METHODS: HCCs were developed in AT-insufficient (AT+/- ) mice and wild-type (AT+/+ ) mice treated with diethyl nitrosamine and carbon tetrachloride. AT was administered to AT+/- mice. The development of HCC was compared between the three groups. In vitro study, migration assay was performed. The association of the prognosis of patients with HCC and plasma AT values was clinically examined. RESULTS: AT suppressed the release of interleukin (IL)-8 from lipopolysaccharide (LPS)-stimulated human neutrophils in vitro. Huh-7 cells that were co-cultured with neutrophils and stimulated with LPS showed significantly enhanced migration; however, Huh-7 cells co-cultured with LPS/AT-stimulated neutrophils showed significantly decreased migration. Moreover, the addition of anti-IL-8 antibodies to LPS-stimulated Huh-7 cells co-cultured with neutrophils also suppressed migration. AT+/- mice (AT plasma activity: 64%) promoted liver cancer, as compared with wild-type mice (AT plasma activity: 135%); AT administration attenuated liver cancer in AT+/- mice. Patients with HCC with a preoperative AT level of ≥70% showed better outcomes after liver resection, as compared with those with an AT level of <70%. IL-8 expression and neutrophil infiltration in HCC tissues were negatively correlated with the AT level. CONCLUSIONS: AT attenuates HCC progression by regulating neutrophil/IL-8 signaling.

Antithrombin Insufficiency Promotes Susceptibility to Liver Tumorigenesis.

BACKGROUND: Antithrombin (AT) is not only a major regulator of hemostasis, but it shows anti-inflammatory properties as well. We aimed to investigate whether AT-insufficient mice increase susceptibility to liver tumorigenesis. METHODS: We induced the development of liver tumor in AT-insufficient (AT+/-) mice and wild-type (AT+/+) mice by treating them with diethylnitrosamine (DEN) and CCl4. The development of liver tumors and liver inflammation were compared between these mouse groups. Following this, AT was administered to the AT-insufficient mice treated with DEN and CCl4. RESULTS: Tumor size and the number of DEN and CCl4-induced liver tumors significantly increased in AT-insufficient mice compared with the wild-type mice. Serum transaminase levels, cell death, and the expression of cleaved caspase-3 in liver were increased in AT+/-. Furthermore, hepatic neutrophil infiltrations and serum interleukin 6 and tumor necrosis factor-α levels were significantly elevated in AT-insufficient mice. The levels of 8-OHdG, oxidative DNA damage marker, in liver were significantly increased in AT-insufficient mice. Administration of AT led to a significant decrease in DEN- and CCl4-induced liver injury and inflammation in AT-insufficient mice, compared with the wild-type group. CONCLUSIONS: AT insufficiency led to increased susceptibility to liver tumorigenesis by increasing hepatic inflammation.

Prediction of recurrence following hepatectomy in patients with hepatitis C virus infection-related hepatocellular carcinoma who achieved a sustained virological response.

AIM: The risk of hepatitis C virus infection-related hepatocellular carcinoma (HCC) is lower, with a better prognosis, in patients who achieve a sustained virological response (SVR) than in those who do not. We aimed to identify risk factors of post-hepatectomy HCC recurrence in patients who achieved a SVR. METHODS: This retrospective study included 349 HCC patients who underwent an initial radical hepatectomy at our institution between January 2005 and December 2014. Sixty-eight patients had achieved a SVR (the SVR group) and 281 patients had not (the non-SVR group). Clinical characteristics and long-term outcomes were compared between the two groups. Univariate and multivariate analyses identified variables associated with recurrence-free survival in the SVR group. RESULTS: Post-hepatectomy overall and recurrence-free survival rates were significantly higher in the SVR group than the non-SVR group (P < 0.01 and <0.05, respectively). Univariate analysis of post-hepatectomy recurrence-free survival in the SVR group revealed multiple significant factors: aspartate aminotransferase, 25 IU/L or more (P = 0.01); indocyanine green retention rate at 15 min, 20.0% or less (P < 0.05); hepatic vascular invasion (P < 0.05); and an interval of months or less between achieving a SVR and hepatectomy (P < 0.01). Multivariate analysis confirmed an interval of 30 months or less between achieving a SVR and hepatectomy as an independent prognostic factor of recurrence-free survival (hazard ratio, 2.30; 95.0% confidence interval, 1.04-5.13; P < 0.05). CONCLUSION: The interval between achieving a SVR and hepatectomy is an important predictor of recurrence in hepatitis C virus infection-related HCC patients who achieved a SVR.

Prognostic significance of antithrombin III levels for outcomes in patients with hepatocellular carcinoma after curative hepatectomy.

BACKGROUND: Although several studies have shown that serum antithrombin III (ATIII) has anti-inflammatory effects, the prognostic value of ATIII in HCC is unknown. We investigated the influence of preoperative ATIII levels on the outcome of patients who underwent hepatectomy for hepatocellular carcinoma (HCC). METHODS: Data from 440 patients (314 patients with ATIII ≥ 70 % and 126 patients with ATIII <70 %) who underwent curative hepatectomy for HCC were retrospectively collected and analyzed. To overcome bias due to the different distribution of covariates for the 2 groups, propensity score matching was performed on the patients, and outcomes were compared. RESULTS: The propensity score analysis revealed that 65 patients with ATIII of ≥ 70 % (group 1) and 65 patients with ATIII of <70 % (group 2) had the same preoperative and operative characteristics (excluding the ATIII level). The overall survival rate and the disease-free survival rate was significantly higher in group 1 than in group 2 (P = 0.005 and 0.011, respectively). Multivariate analysis showed that ATIII was a significant favorable factor for overall survival and disease-free survival of patients with HCC after curative hepatectomy. CONCLUSIONS: The prognosis of patients with HCC was found to be associated with preoperative antithrombin III levels. ATIII may be useful for predicting outcomes of patients with HCC after curative hepatectomy.

[A case of breast cancer with multiple hepatic metastasis successfully treated with S-1/PTX and S-1 chemotherapy].

The case is a woman in her 50's. A total glandectomy was performed for her breast cancer on August 8, 1998, and subsequently chemotherapy(5'-DFUR, CMF, uracil.tegafur, CEF, and docetaxel)as well as radiation therapy and surgical resection have been performed for local recurrence. With multiple hepatic metastasis recognized in September, 2007, chemotherapy combined with S-1/paclitaxel(PTX)has been performed. In view of the side effects such as reduction in appetite and leukocyte, the dosage has been reduced as of the second course of treatment. With the disappearance of hepatic metastasis on CT, 6 courses of S-1monotherapy have been performed after completing 6 courses of chemotherapy combined with S-1/ PTX. As of March, 2009, the therapeutic effect shows that continuous CR and outpatient follow-up have been performed while maintaining QOL. Since any chemotherapy after thirdline treatment for recurrent breast cancer has not been established yet, chemotherapy combined with S-1/PTX is considered to be one of the regimens and therefore, the second and thirdphase clinical tests ahead are expected to bring better outcomes.

Significance of the Glasgow Prognostic Score for patients with colorectal liver metastasis.

BACKGROUND: Systemic inflammation and nutritional status are strongly associated with tumor progression. Inflammation-based prognostic scores, such as the Glasgow Prognostic Score (GPS), reflect these states and are predictive in patients with several types of advanced cancers. The aim of this study was to evaluate the significance of GPS in patients with colorectal liver metastasis (CRLM). PATIENTS AND METHODS: Study subjects were 134 patients with CRLM who underwent initial radical liver resection at Hiroshima University Hospital between January 2000 and December 2013. Univariate and multivariate analyses were performed to identify variables associated with overall and recurrence-free survival following liver resection in two groups based on GPS. RESULTS: There was no significant relationship between overall survival and GPS. Recurrence-free survival was significantly poorer in patients with GPS 1-2 than in those with GPS 0 (p < 0.01). In multivariate analysis for recurrence-free survival, moderate histologic differentiation, carcinoembryonic antigen level ≥10 ng/mL, and GPS 1-2 were identified as independent prognostic factors. CONCLUSION: We suggest that GPS is an important predictor of recurrence following liver resection in patients with CRLM, and it should be considered one of the evaluation criteria for liver resection.

Predictive Independent Factors for Extrahepatic Metastasis of Hepatocellular Carcinoma Following Curative Hepatectomy.

AIM: The aim of this study was to investigate the prognostic factors associated with extrahepatic metastasis of primary hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively analyzed 559 patients with HCC who underwent curative hepatectomy. We divided the patients into no recurrence (NoR), intrahepatic early recurrence (IHER), intrahepatic late recurrence (IHLR), and extrahepatic recurrence (EHR) groups. We compared the non-metastatic group (IHLR and NoR) with the metastatic group (IHER and EHR) and also compared IHER with EHR to determine risk factors for EHR. RESULTS: There were 252, 163, 109, and 35 patients with NoR, IHER, IHLR, and EHR, respectively. For the EHR group, the independent risk factor was vascular invasion. The EHR group had better liver function and worse tumor factors. CONCLUSION: Vascular invasion is predictive of extrahepatic metastasis of HCC.

Application of endobronchial ultrasonography in laparoscopic liver segmentectomy in an animal model.

INTRODUCTION: This study investigated whether laparoscopic ultrasound-guided segment staining and real-time ultrasound-guided hepatectomy, with endobronchial ultrasonography equipped with a guide sheath, would be useful for laparoscopic liver segmentectomy in a porcine model. MATERIAL AND SURGICAL TECHNIQUE: The abdominal cavity (in two pigs) was reached via a 12-mm umbilical trocar. An artificial tumor was created by radiofrequency ablation within the intended resection area. Portal vein puncture and staining were performed by the endobronchial ultrasonography-guided method. The targeted portal branch was successfully visualized and punctured with a needle through an equipped guide sheath. After targeted segment staining, the liver parenchyma was resected with a bipolar energy device; the regional Glisson's sheath was ligated and cut, and a surgical specimen was extracted. Real-time endobronchial ultrasonography from the cut surface provided information vital for preserving the surgical margin. All procedures were performed laparoscopically. DISCUSSION: This study demonstrated the technical feasibility of laparoscopic ultrasound-guided portal vein staining and safe surgical resection during laparoscopic liver segmentectomy.

Hepatectomy after down-staging of hepatocellular carcinoma with portal vein tumor thrombus using chemoradiotherapy: A retrospective cohort study.

BACKGROUND: This study evaluates the survival benefit and safety of hepatectomy after down-staging by 3-dimensional conformal radiation therapy (3D-CRT) for major portal vein tumor thrombus (PVTT) combined with hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC). METHODS: Fifty-two patients with unresectable advanced HCC treated with HAIC combined with 3D-CRT for PVTT, from January 2002 to March 2015, were analyzed in this retrospective study. Hepatectomy was offered to patients if, based on radiologic findings, all gross lesions were considered resectable. The safety of hepatectomy was investigated and overall survival (OS) was compared between the resection group (n = 7) and non-resection group (n = 43). RESULTS: OS was significantly higher in the resection group than in the non-resection group. Results of multivariate analysis identified conversion to surgery (hazard ratio, 0.35; 95% confidence interval, 0.10-0.99; P = 0.048) as an independent factor influencing OS. There were no serious postoperative complications and no case of mortality in patients who underwent hepatectomy. CONCLUSIONS: Our findings suggest that hepatectomy after down-staging by 3D-CRT for PVTT combined with HAIC for advanced HCC is safe and results in good long term outcome.

Evaluation of the risk factors and prognostic factors of hepatectomy for hepatocellular carcinoma in patients aged 80 years or more.

BACKGROUND: The risk factors of postoperative complications and prognostic factors of hepatocellular carcinoma in patients aged ≥80 years have not yet been defined. We aimed to identify these factors in this patient population. METHODS: This single-center, retrospective cohort study included 625 patients who underwent curative hepatectomy from January 2004 to December 2013. Elderly patients were defined as those aged ≥80 years. Clinicopathological data and outcomes after hepatectomy for 60 elderly patients and 565 non-elderly patients were compared. RESULTS: The elderly group had more comorbidities than the non-elderly group. Liver function, surgical data, tumor factors, the incidence of postoperative complications, disease-free survival rate, and overall survival rate did not differ significantly between the two groups. Results of multivariate analysis showed that the levels of cholinesterase, total cholesterol, and hemoglobin A1c were predictors of complications in the elderly group. The Child-Pugh grade, protein induced in vitamin K absence or antagonists-II level, and multiple tumors were significantly associated with disease-free survival. CONCLUSIONS: Although elderly patients had more comorbidities, their postoperative complications and prognosis were comparable to those of the non-elderly patients. Hepatectomy may be justified for elderly patients, but it is important to evaluate levels of cholinesterase, total cholesterol, and hemoglobin A1c preoperatively.

Efficacy of repeat hepatectomy for recurrence following curative hepatectomy for colorectal liver metastases: A Retrospective Cohort Study of 128 patients.

BACKGROUND: Despite improvements in surgery and chemotherapy, most patients develop recurrence after initial hepatectomy for colorectal liver metastasis (CRLM). Following initial hepatectomy for CRLM, patterns and surgical management of recurrence have not been widely reported. MATERIALS AND METHODS: We identified 128 patients who underwent hepatic resection for CRLM between January 2000 and December 2012. Demographics, operative data, site of recurrence, and long-term survival data were collected and analyzed. Patients were stratified into 3 groups based on their site of recurrence as intrahepatic, intra- and extrahepatic, and extrahepatic. In addition, the influence of potential factors on overall survival (OS) in patients with only liver relapse was analyzed through univariate and multivariate analysis. RESULTS: After curative initial hepatectomy, 87 (68.0%) patients had a recurrence: 33 in the intrahepatic group, 11 in the intra- and extrahepatic group, and 43 in the extrahepatic group. The OS for the intra- and extrahepatic group was significantly lower than that for the intrahepatic group. In the intrahepatic group, disease-free interval (DFI) < 12 months and non-repeat hepatectomy were independent poor prognostic factors. Carcinoembryonic antigen (CEA) at the time of hepatectomy was significantly higher in DFI < 12 group than in the DFI ≥ 12 group. CONCLUSION: Patterns of recurrence following initial hepatectomy for CRLM have important implications for OS. In the intrahepatic recurrence group, short DFI was correlated with high CEA at hepatectomy, and was a poor prognostic factor.