Kiyokazu Hiwatashi

Surgical resection versus radiofrequency ablation for small hepatocellular carcinomas within the Milan criteria

BACKGROUND/PURPOSE It has been reported that hepatic resection may be preferable to other modalities for the treatment of small hepatocellular carcinomas (HCCs), by contributing to improved overall and disease-free survival. Ablation techniques such as radiofrequency ablation (RFA) have also been used as therapy for small HCCs; however, few studies have compared the two treatments based on long-term outcomes. The effectiveness of hepatic resection and RFA for small nodular HCCs within the Milan criteria were compared. METHODS A retrospective cohort study was performed with 278 consecutive patients who underwent curative hepatic resection (n = 123) or initial RFA percutaneously (n = 110) or surgically (thoracoscopic-, laparoscopic-, and open-approaches; n = 45) for HCC. The selection criteria for treatment were based on uniform criteria. Mortality related to therapy and 3- and 5-year overall and disease-free survivals were analyzed. RESULTS The model for endstage liver disease (MELD) scores for all patients in the series were less than 13. There were no therapy-related mortalities in either the hepatic resection or RFA groups. The incidence of death within 1 year after therapy (1.6 and 1.9%, respectively) was similar in the hepatic resection and RFA groups. The group that underwent hepatic resection showed a trend towards better survival (P = 0.06) and showed significantly better disease-free survival (P = 0.02) compared with the RFA group, although differences in liver functional reserve existed. The advantage of hepatic resection was more evident for patients with single tumors and patients with grade A liver damage. In contrast, patients with multinodular tumors survived longer when treated with RFA, regardless of the grade of liver damage. Further analysis showed that surgical RFA could potentially have survival benefits similar to those of hepatic resection for single tumors, and that surgical RFA had the highest efficacy for treating multinodular tumors. CONCLUSIONS In patients with small HCCs within the Milan criteria, hepatic resection should still be employed for those patients with a single tumor and well-preserved liver function. RFA should be chosen for patients with an unresectable single tumor or those with multinodular tumors, regardless of the grade of liver damage. In order to increase long-term oncological control, surgical RFA seems preferable to percutaneous RFA, if the patients condition allows them to tolerate surgery.

Interleukin 8 in Human Hepatocellular Carcinoma Correlates With Cancer Cell Invasion of Vessels But Not With Tumor Angiogenesis

BackgroundAngiogenic factor seems necessary for the development of hepatocellular carcinoma (HCC), which is a hypervascular malignancy. This study examined the expression of interleukin (IL)-8, a potent angiogenic factor, in HCC samples.MethodsWe measured IL−8 expression by using reverse transcriptase-polymerase chain reaction in clinical HCC tissues from 45 patients who underwent surgical resection. We then assessed correlations between IL−8 expression and microvessel growth or clinicopathologic factors. We also elucidated the in vitro effect of IL−8 on HepG2 development by using fluorometric assays of proliferation, chemotaxis, and invasion.ResultsThe expression of IL−8 did not significantly correlate with the microvessel count in HCC tissues, but the incidence of microscopic vessel invasion was significantly higher in IL−8–positive than in IL−8–negative tissues. Thus, more IL−8 was expressed in HCCs at pathologic stage III/IV than in those at stage I/II. Assays in vitro showed that IL−8 stimulates HepG2 chemotactic and invasive activities rather than cell proliferation.ConclusionsThe expression of IL−8 in human HCC has more relevance to metastatic potential, such as vessel invasion, than to angiogenesis or cell proliferation.

A novel function of the receptor for advanced glycation end-products (RAGE) in association with tumorigenesis and tumor differentiation of HCC.

BackgroundThe expression of the receptor for advanced glycation end products (RAGE) has an impact on the mechanisms giving rise to characteristic features of various cancer cells. The purpose of this study was to elucidate the clinicopathological relevance of the level of RAGE expression in patients with hepatocellular carcinoma (HCC) and to explore the effect of RAGE expression on the characteristic features of HCC.MethodsThe expression of RAGE was assessed in paired cancer and noncancerous tissues with HCC, using reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. The quantitative RT-PCR data were analyzed in association with the clinicopathological factors of the patients with HCC. In in vitro experiments, the survival of RAGE-transfected Cos7 and mock-transfected Cos7 cells was compared under hypoxic conditions. In addition, after reducing RAGE levels in RAGE-transfected Cos7 cells by siRNA, similar experiments were performed.ResultsThe expression of RAGE mRNA was lower in normal liver than in hepatitis and highest in HCC. Furthermore, in HCC, it was high in well- and moderately differentiated tumors but declined as tumors dedifferentiated to poorly differentiated HCC. Furthermore, HCC lines resistant to hypoxia were found to have higher levels of RAGE expression, and RAGE transfectant also showed significantly prolonged survival under hypoxia.ConclusionsOur results suggest that HCC during the early stage of tumorigenesis with less blood supply may acquire resistance to stringent hypoxic milieu by hypoxia-induced RAGE expression.

Clinical implication of ZEB-1 and E-cadherin expression in hepatocellular carcinoma (HCC)

BackgroundWhile recent research has shown that expression of ZEB-1 in a variety of tumors has a crucial impact on patient survival, there is little information regarding ZEB-1 expression in hepatocellular carcinoma (HCC). This study investigated the co-expression of ZEB-1 and E-cadherin in HCC by immunohistochemistry and evaluated its association with clinical factors, including patient prognosis.MethodsA total of 108 patients with primary HCC treated by curative hepatectomy were enrolled. ZEB-1 expression was immunohistochemically categorized as positive if at least 1% cancer cells exhibited nuclear staining. E-cadherin expression was divided into preserved and reduced expression groups and correlations between ZEB-1 and E-cadherin expression and clinical factors were then evaluated.ResultsWith respect to ZEB-1 expression, 23 patients were classified into the positive group and 85 into the negative group. Reduced E-cadherin expression was seen in 44 patients and preserved expression in the remaining 64 patients. ZEB-1 positivity was significantly associated with reduced expression of E-cadherin (p = 0.027). Moreover, significant associations were found between ZEB-1 expression and venous invasion and TNM stage. ZEB-1 positivity was associated with poorer prognosis (p = 0.025). Reduced E-cadherin expression was significantly associated with intrahepatic metastasis and poorer prognosis (p = 0.047). In particular, patients with both ZEB-1 positivity and reduced E-cadherin expression had a poorer prognosis (p = 0.005). Regardless of E-cadherin status, ZEB-1 was not a significant prognostic factor by multivariate analysis. There was no statistical difference in overall survival when E-cadherin expression was reduced in the ZEB-1 positive group (p = 0.24).ConclusionsPositive ZEB-1 expression and loss of E-cadherin expression are correlated with poor prognosis in HCC patients and malignancy of ZEB-1 positive tumors involves EMT.

Expression of receptor for advanced glycation end products (RAGE) is related to prognosis in patients with esophageal squamous cell carcinoma.

The receptor for advanced glycation end products (RAGE), known as a multiligand receptor for certain stress-associated factors, has been considered to affect the characteristic differences of various cancer cells. We analyzed the expression and clinicopathological significance of RAGE in esophageal squamous cell carcinoma. We investigated immunohistochemically the relationship between RAGE expression and clinicopathological factors, including prognosis, in surgical specimens of primary tumors in 216 patients with esophageal squamous cell carcinoma. Prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazard regression model). The positive expression rate of RAGE was 50%. RAGE expression was negatively correlated with depth of invasion and venous invasion. Moreover, tumors with positive RAGE expression exhibited better prognosis than those with negative RAGE expression (5-year survival, 52% vs. 32%, respectively). Multivariate analysis indicated that the positive expression of RAGE was an independent prognostic factor, along with tumor depth and nodal metastasis. Our findings suggest that loss of RAGE expression may play an important role in the progression of esophageal squamous cell carcinoma. Evaluation of the expression of RAGE could be useful for determining the tumor properties, including those associated with prognosis, in patients with esophageal squamous cell carcinoma.

Roxithromycin Inhibits Constitutive Activation of Nuclear Factor κB by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma

Purpose: Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470. Experimental Design: Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17. Results: Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor κB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg. Conclusions: Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor κB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.

Anatomical Laparoscopic Hepatectomy for Hepatocellular Carcinoma Using Indocyanine Green Fluorescence Imaging

PURPOSE It is important to minimize surgical invasiveness in the therapy of patients with hepatocellular carcinoma (HCC), and consequently laparoscopic hepatic resection is widely performed. However, most anatomical resections, except left lateral sectionectomy, remain difficult technically, and laparoscopy-assisted procedures have been introduced as an alternative approach because of the safety and curative success of the operation. We reported previously pure laparoscopic subsegmentectomy of the liver using puncture of the portal branch under percutaneous ultrasound (US) with artificial ascites. Herein, we describe pure anatomical laparoscopic segmentectomy using the puncture method with indocyanine green (ICG) injection under laparoscopic US. PATIENTS AND METHODS Pure laparoscopic segmentectomy was planned for 2 patients with HCC of the liver. Identification of the segment was performed by ICG injection for optical imaging using near-infrared fluorescence under laparoscopic US guidance. RESULTS The procedures were completed successfully, and the postoperative courses were uneventful. CONCLUSIONS Pure laparoscopic segmentectomy for HCC with a conventional puncture technique by ICG injection under laparoscopic US is considered to be a useful procedure featuring both low invasiveness and curative success.

Prognostication by inflammation-based score in patients with locally advanced pancreatic cancer treated with chemoradiotherapy

BACKGROUND An association between inflammatory/immunonutritional status and patient prognosis has been reported in various types of cancer. The aim of this study was to evaluate the utility of inflammatory/immunonutritional factors as therapeutic predictors for patients with locally advanced pancreatic cancer treated with chemoradiotherapy (CRT). METHODS Ninety-six patients with histologically proven locally advanced pancreatic adenocarcinoma who underwent CRT were enrolled in this study. We evaluated significance of inflammation-based factors as predictors of therapeutic effect and prognosis. RESULTS The median progression free survival (PFS) and overall survival (OS) of all patients was 10 and 18 months, respectively. A Glasgow prognostic score (GPS) of 2 and plasma fibrinogen levels ≥ 400 mg/dL were independent predictors of poor PFS and OS. A prognostic nutritional index (PNI) ≥ 45 was a predictor of a significantly better reduction rate of the primary tumor. The prognosis between patients with GPS 0/1 and fibrinogen <400 mg/dL, GPS 2 or fibrinogen ≥400 mg/dL, and GPS 2 and fibrinogen ≥400 mg/dL were significantly different. Patients with GPS 2 and/or plasma fibrinogen ≥ 400 mg/dL had significantly higher incidence of metastasis within 6 months after CRT. CONCLUSIONS GPS, fibrinogen, PNI are useful therapeutic and prognostic predictors in patients with locally advanced pancreatic cancer treated with CRT.

The Evaluation of Liver Function and Surgical Influence by ICGR15 after Chemotherapy for Colorectal Liver Metastases

Background; Approximately 60% of patients with colorectal cancer develop liver metastasis at some point after diagnosis. The aim of this study is to investigate whether the evaluation of ICGR15 preoperatively is a useful clinical indicator of hepatic injury following chemotherapy and to investigate the influence of multiple chemotherapies on liver function. Results; Mean ICGR15 values were higher in patients ≥65 years (P = 0.047) and in patients with ≥3 cycles (P = 0.022) and ≥6 cycles (P = 0.001) of systemic chemotherapy. ICGR15 values tended to be higher in patients with postoperative complications (P = 0.085). Patients receiving systemic chemotherapy for ≥6 cycles had higher levels of AST (P = 0.003), ALT (P = 0.015), and alkaline phosphatase (ALP) (P = 0.041). Patients receiving systemic chemotherapy for ≥3 cycles had higher levels of AST (P = 0.015) and ALP (P = 0.015). Conclusions; Because the pathological diagnosis is usually established only after operation, preoperative evaluation such as the identification of sinusoidal injury is difficult. Based on this study, higher ICGR15 values may provide an indication of surgical complications and be a predictor of liver dysfunction following frequent cycles of chemotherapy. Hepatectomy should be performed with the utmost care in such patients, and the number of cycles of preoperative chemotherapy should probably be as low as possible.

Problems of Long Survival Following Surgery in Patients with NonBNonC-HCC: Comparison with HBV and HCV Related-HCC.

Background: The number of patients with hepatocellular carcinoma (HCC) in the absence of both hepatitis B virus surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) (NBNC-HCC) has been rapidly increasing in Japan. The objective of this study was to compare the clinical and pathological characteristics between patients with the NBNC-HCC, those with HBsAg positive HCC (B-related HCC) and HCVAb positive HCC (C-related HCC). A better understanding will facilitate the development of postoperative strategies to better manage patients with NBNC-HCC. Methods: Consecutive 219 patients with primary HCC: (B-related, n=35; C-related, n = 104; NBNC, n = 80) were treated by hepatic resection or ablation. Clinicopathological characteristics including postoperative course were retrospectively compared between the three groups. Results: When comparing within stage I and II, the NBNC-HCC group had improved recurrence free survival (RFS) compared to the C-related HCC (p = 0.013) but had not been good overall survival (OS). Moreover, the NBNC-HCC group showed higher rate of death due to other cancers and cardiovascular disease (p = 0.011) compared to the C-related HCC. Multivariate analysis revealed that the only prognostic factor for RFS in the NBNC-HCC group was high serum total bilirubin. Conclusions: In the patients with the NBNC-HCC, elevated serum bilirubin could predict poor RFS after surgery. Furthermore, patients must be carefully followed-up not only for HCC but also for the occurrence of other critical diseases including multiple other cancers.