[Resection of cholangiolocellular carcinoma successfully responding to neoadjuvant hepatic arterial infusion chemotherapy - report of a case].

A 78-year-old man who had hepatitis C was examined by computed tomography(CT)because of prostate cancer, and was found to have a liver tumor 8. 0 cm in size at S4/S8. The view of the liver tumor was enhanced by CTHA image and washed out by CTAP image. It was suspected to have invaded the RHV and MHV. The pathological examination of the liver biopsy sample revealed cholangiocellular carcinoma or cholangiolocellular carcinoma. Hepatic arterial infusion chemotherapy with gemcitabine and cisplatin was performed. The size of the tumor reduced to 6. 0 cm and the invasion to the RHV was no longer evident. Hepatic resection for the middle two segments was performed after 3 months of chemotherapy. After a histological examination of the resected specimen, the patient was given the final diagnosis of cholangiolocellular carcinoma. Over 50% of the tumor was estimated as necrosis by chemotherapy, indicating that the gemcitabine and cisplatin regimen was remarkably effective. The patient is alive with no evidence of recurrence.

Hepatocyte growth factor as well as vascular endothelial growth factor gene induction effectively promotes liver regeneration after hepatectomy in Solt-Farber rats.

BACKGROUND/AIMS: Hepatic oval cells play an important role in liver regeneration when proliferation of mature hepatocytes is inhibited. The aim of this study was to examine the effect of hepatocyte growth factor (HGF), or vascular endothelial growth factor (VEGF) on proliferation of oval cells in the Solt-Farber rat model. METHODOLOGY: One hour after 70% partial hepatectomy, 2-acetyl-aminofluorene-induced damaged rats were infected intravenously with recombinant adenoviral vectors, encoding rat HGF or human VEGF, or Escherichia coli beta-galactosidase as a control. RESULTS: The plasma HGF concentrations in the HGF-transferred rats were elevated compared with the other groups at 4 and 7 days after hepatectomy. Oval cells were confirmed by positive staining of both cytokeratin-19 and alpha-fetoprotein. Oval cells around the portal tracts in the HGF or VEGF-transferred rats increased in number compared with the control rats at 7 and 9 days after hepatectomy. The proliferating cell nuclear antigen labeling indices of oval cells and the hepatic regeneration rate after hepatectomy were significantly augmented by the HGF or VEGF treatment. Moreover, cyclin E expression was elevated in the HGF-treated rats. CONCLUSIONS: In the Solt-Farber rat model, HGF or VEGF gene injection effectively promoted liver regeneration after hepatectomy mainly with increased proliferation of hepatic oval cells.

Tissue factor is a useful prognostic factor of recurrence in hepatocellular carcinoma in 5-year survivors.

BACKGROUND/AIMS: Tissue factor (TF) is a transmembrane glycoprotein involved in initiating blood coagulation. TF has recently been reported to play an important role in tumor metastasis. The aim of this study was to evaluate the role and the prognostic value of TF in hepatocellular carcinoma (HCC) in long-term survivors. METHODOLOGY: Among 275 patients who underwent curative hepatectomy for HCC, 62 patients who survived more than 5 years after surgery were retrospectively studied. TF expression was immunohistochemically examined. RESULTS: TF was positive in 39 of the 62 patients. In patients with TF expression, the serum albumin level was significantly lower and capsular infiltration, tumor thrombus in the portal vein, and intrahepatic metastasis were more frequently shown than those without TF expression. The recurrence-free rate was significantly higher in the patients whose tissue stained negative for TF than in those whose tissue stained positive for TF. Multivariate analysis showed TF expression to be a significant and independent risk factor for recurrence. Concerning the recurrence pattern, all 23 patients with intrahepatic metastasis were TF-positive, whereas 3 out of 5 patients with multicentric carcinogenesis were TF-positive. CONCLUSIONS: TF expression is closely associated with the tumor invasion and metastasis, and may serve as a useful prognostic factor of recurrence in HCC in 5-year survivors.

Predictive factors affecting early recurrence after hepatectomy for hepatocellular carcinoma in 5-year survivors.

BACKGROUND/AIMS: This study was undertaken to establish a therapeutic strategy for long-term recurrence-free survival in hepatocellular carcinoma (HCC) patients treated by hepatectomy by determining the factors that predict intrahepatic recurrence. METHODOLOGY: This study included 72 patients who survived more than 5 years after hepatectomy for HCC. Based on the interval between hepatectomy and intrahepatic recurrence, they were classified into 3 groups: those with early recurrence within 2 years after surgery (n=15), those with recurrence between 2 and 5 years (n=18), and those without recurrence within 5 years (n=39). Twenty-six parameters concerning host-related, tumor-related, treatment-related factors, and postoperative levels of serum transaminases were evaluated. RESULTS: Among host-related and tumor-related factors, serum albumin level, serum levels of transaminases, indocyanine green retention rate at 15 minutes, tumor number, intrahepatic metastasis and TNM stage were determined to be significantly different between the patients with recurrence within 5 years and those without recurrence. Among treatment-related factors, curability was highly associated with recurrence. The period until increase in the levels of transaminases after surgery was significantly shorter in patients with recurrence compared to the patients without recurrence. CONCLUSIONS: Curative operation minimizing intrahepatic metastasis and postoperative anti-inflammatory treatment lowering the occurrence of multicentric carcinogenesis are useful therapeutic strategies for achieving long-term recurrence-free survival for HCC patients treated with surgery.

Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients.

OBJECTIVES: Immature microvessels, which are not covered by pericytes, are irregular and leaky. We hypothesized that tumor cells can penetrate immature microvessels more easily than mature microvessels. In this study, we investigated the maturation of angiogenesis by the immunohistochemical staining of colorectal cancer specimens and determined the correlation between the microvessel count or the maturity of microvessels and clinicopathological variables. METHODS: Ninety-two surgical specimens from our department were used. Double immunostaining of endothelial cells with anti-CD34 antibody and pericytes with anti-alpha-smooth muscle actin antibody was performed. The microvessel density (MVD) and microvessel pericyte coverage index (MPI) as an index of microvessel maturation were evaluated. RESULTS: The MVD showed a significant positive correlation with tumor size, depth of invasion and Dukes' stage. The MPI showed a significant positive correlation with the histological differentiation of the tumor tissues and distant metastasis at the time of operation. The high MVD group (> or =26.0, n = 50) tended to have a poorer prognosis than the low MVD group (<26.0, n = 42) (p = 0.097). Next, the 50 patients in the high MVD group were classified into two subgroups of high MPI (> or =78.1%, n = 25) and low MPI (<78.1%, n = 25). MPI showed a significant negative correlation with hematogenous metastasis, and the low MPI group demonstrated a significantly poorer survival than the high MPI group (p = 0.040). CONCLUSIONS: These findings demonstrate that immature neovascularization was observed in poorly differentiated tumors and was correlated with metastasis, resulting in a poorer prognosis. Taken together, not only microvessel density but also vascular maturation were crucial factors for colorectal cancer patients.

Simultaneous transfer of vascular endothelial growth factor and hepatocyte growth factor genes effectively promotes liver regeneration after hepatectomy in cirrhotic rats.

BACKGROUND/AIMS: Liver regeneration in a cirrhotic liver is unsatisfactory. In the course of liver regeneration, non-parenchymal cells such as sinusoidal endothelial cells as well as hepatocytes increase in number while the liver structure and physiological functions are maintained. The aim of this study was to examine whether sufficient liver regeneration could be obtained by the simultaneous, preoperative injection of recombinant adenoviral vectors encoding human vascular endothelial growth factor (VEGF), a potent mitogen for sinusoidal endothelial cells, (pAxCAVEGF) and rat hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, (pAxCAHGF) in 70% hepatectomized cirrhotic rats. METHODOLOGY: Forty-eight hours before 70% hepatectomy, dimethylnitrosamine-induced cirrhotic rats were infused intravenously with pAxCAVEGF or with pAxCAVEGF and pAxCAHGF, or with a control virus encoding Escherichia coli beta-galactosidase (pAxCALacZ). RESULTS: Strong VEGF mRNA expressions were shown in the livers of VEGF and VEGF/HGF-treated animals. The plasma HGF concentrations in the VEGF/HGF-treated rats were elevated compared with the other groups. Proliferating cell nuclear antigen immunostaining showed increased labeling indices of hepatocytes in the VEGF/HGF-treated rats at 24 and 48 h after hepatectomy. PCNA labeling indices of SECs were increased in the VEGF and VEGF/HGF-treated rats compared with the control animals at 24 and 48 h after hepatectomy. Moreover, the hepatic regeneration rate after hepatectomy was significantly augmented by the VEGF and VEGF/HGF treatment. CONCLUSIONS: Simultaneous preoperative injection of recombinant adenoviral vectors encoding VEGF and HGF effectively stimulates liver regeneration in cirrhotic rats.

Interleukin-6 augments hepatocyte growth factor-induced liver regeneration; involvement of STAT3 activation.

BACKGROUND/AIMS: In liver regeneration, quiescent hepatocytes need to be primed before they can fully respond to growth factors such as hepatocyte growth factor (HGF). Recently, interleukin-6 (IL-6) has been shown to play an important role in initiating liver regeneration via activating signal transducer and activator of transcription 3 (STAT3). We therefore investigated the effect of IL-6 on liver regeneration and examined STAT3 activation following IL-6 and/or HGF treatment in rats. METHODOLOGY: The animals underwent portal branch ligation (PBL) of the left lateral and median branches. They were intravenously treated with either IL-6 (500 microg/kg), HGF (50 microg/kg), both, or vehicle alone on and every 12 h after PBL. The degree of compensatory hypertrophy in unoccluded lobes was examined by measuring the wet weight ratios of the unoccluded lobes to the whole liver and the 5-bromo-2'-deoxyuridine labeling index of hepatocytes in each group. STAT3 expression in regenerating liver was examined by Western blotting and immunohistochemistry. RESULTS: Coadministration of IL-6 and HGF most effectively increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. HGF as well as IL-6-treated animals showed moderate STAT3 activation in hepatocytes throughout the experiment. CONCLUSIONS: IL-6 augmented HGF-induced liver regeneration and hepatocellular replication. Liver regeneration stimulated by HGF treatment may be closely involved with STAT3 activation in a different manner induced by IL-6 treatment.

Vascular endothelial growth factor reduces mural cell coverage of endothelial cells and induces sprouting rather than luminal division in an HT1080 tumour angiogenesis model.

Vascular endothelial growth factor (VEGF) plays a central role in tumour angiogenesis. In a mouse intramuscular tumour model using VEGF-transfected HT1080 human fibrosarcoma, we investigated the morphological features and patterns of remodelling in size-matched tumours. Compared with the control tumours (C group), the VEGF-transfected tumours (V group) showed vigorous neovascularization with larger vessels. Fenestrations and disruptions of endothelia were specific to the V group. Three types of vascular remodelling, i.e. sprouting, luminal division and intussusceptive microvascular growth, were present in both groups. Morphometric analyses revealed that mural cell coverage of the endothelial cells was significantly smaller in the V group compared with that in the C group (V group, 28.2 +/- 18.6%; C group, 41.6 +/- 21.1%; P < 0.0001). To determine the prevalence of remodelling patterns, the occurrences of abluminal and luminal processes on endothelial cell surfaces were quantified. Abluminal processes are defined as cytoplasmic protrusions of the abluminal membrane of endothelial cells, which can vary from tiny spurs to solid sprouts of the cell. On the other hand, luminal processes are defined as intraluminal protrusions of the endothelial cell membrane, including various membranous changes from filiform processes to rather thick cytoplasmic bulges. An abluminal process is thought to represent an initial morphological change in sprouting type angiogenesis, and a luminal process to be a sign of implementation of luminal division. The frequency of abluminal processes was significantly higher in the V group than in the C group (V group, 0.243 +/- 0.138/microm; C group, 0.114 +/- 0.101/microm; P < 0.0001). In contrast, the number of luminal processes on the endothelial cells per micrometre was statistically comparable between the groups (V group, 0.285 +/- 0.252/microm; C group, 0.309 +/- 0.236/microm, P = 0.381). These results indicate that sprouting is the main mode of VEGF-induced tumour angiogenesis.

Expressions of molecules associated with hepatocyte growth factor activation after hepatectomy in liver cirrhosis.

BACKGROUND/AIMS: The activation pathway of hepatocyte growth factor (HGF), including HGF activator (HGFA) and HGFA inhibitor-1, 2 (HAI-1, 2), has recently been clarified. The present study examined mRNA expressions of HGF, HGFA and HAI-1 following partial hepatectomy in normal and cirrhotic rats. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of dimethylnitrosamine. Two weeks after, the cirrhotic and normal rats underwent 70% hepatectomy and the liver regeneration rate, DNA synthesis of hepatocytes, plasma HGF level, and mRNA expressions of HGF, HGFA, and HAI-1 in the liver, spleen, and lung were examined at different times. RESULTS: Liver regeneration in the cirrhotic rats was deteriorated with a later peak of hepatocellular DNA synthesis. Hepatic HGF mRNA and splenic HAI-1 mRNA were upregulated and liver HGFA mRNA was downregulated in the cirrhotic rats. CONCLUSIONS: Insufficient HGF activation both by a reduced expression of hepatic HGFA and an increased expression of splenic HAI-1 may be one of the reasons for the impaired liver regeneration in cirrhosis.

Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance.

BACKGROUND/AIMS: We analyzed the expressions of hexokinase II (HK II), a key enzyme in glycolysis, and VEGF in hepatocellular carcinoma (HCC) and metastatic liver cancer in relation to tumor vascularity, and the participation of hypoxia-inducible factor-1 (HIF-1) was studied. METHODS: A real-time quantitative reverse transcription-polymerase chain reaction was performed to examine the HK II and VEGF mRNA expression. Expression of HIF-1 alpha and HK II protein, and microvessel density (MVD) were examined immunohistochemically. RESULTS: MVD was significantly higher in HCCs than in metastatic liver cancers, and VEGF mRNA expression was positively correlated only with MVD of HCCs. HK II mRNA expression was significantly higher in metastatic liver cancers, however, some cases of HCC pretreated with transcatheter arterial embolization (TAE) showed marked HK II mRNA expression. Both HIF-1 alpha and HK II protein expressions were co-localized in the cancer cells near necrosis, and the intensity of HIF-1 alpha protein expression was significantly correlated with HK II mRNA expression in both tumors. CONCLUSIONS: These results suggest that, in metastatic liver cancers, glycolysis induced by HIF-1 is the predominant energy source under the hypoxic environment and, at least in some TAE-pretreated HCC cases, cancer cells obtain energy for growth by switching the metabolic profile to glycolysis through HIF-1.