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The optimal type of surgery (e.g., anatomic or non-anatomic resection) or radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) is still under debate despite numerous comparative studies based on overall survival. This debate continues not only because these endpoints are influenced by non-surgical factors, such as liver function, but because the definition of non-anatomic resection for HCC has remained unclear. The optimal surgery could be logically determined based on the mechanism of local intrahepatic metastasis, that is, the drainage of tumour blood flow (TBF), because HCC spreads locally through tumour blood flowing to the peri-tumourous liver parenchyma. Since TBF is clearly demonstrated by CT scan under hepatic arteriography, the surgical margin can be determined individually based on the drainage of TBF without deteriorating local curability. Controversy regarding RFA and surgery does not result from the curability of treatment itself but from the lack of scientific evidence on safety margins. Based on proper concepts and self-evident truths, an algorithm of loco-regional treatment for HCC is proposed., (© 2020 S. Karger AG, Basel.)

A 66-year-old man presented with recurrences in the peritoneum 3 years after heavy particle beam therapy with hepatocellular carcinoma(HCC)and underwent laparoscopic surgery.Five months after surgery, a new peritoneal dissemination found in the vicinity of the colon hepatic flexure area by CT examination, and laparoscopic resection was planned again.Indocyanine green(ICG)0.5 mg/kg was administered on the day before surgery.ICG imaging by the PINPOINT®system revealed 2 small ICG accumulation sites in the diaphragm, as well as the main lesion, and each lesion was excised laparoscopically.All lesions were diagnosed as peritoneal dissemination of HCC, and the postoperative course was uneventful.Although new dissemination nodules were appeared 6 months after surgery, he underwent laparoscopic surgery again and survives.In PINPOINT fluorescence mode, high-definition white-light image and fluorescence image was combined, and it was easy to determine the cut line but also to visualize the small lesion difficult to identify in the visible light mode.It was suggested that the PINPOINT®system might be useful in cases of HCC peritoneal dissemination.

A 61-year-old man untreated with hepatitis C virus presented to our hospital.He was diagnosed advanced hepatocellular carcinoma(HCC)with portal vein tumor thrombosis(PVTT).The hazy tumor was located in the left lobe, and the tumor thrombus extended into the left portal vein.The patient received stereotactic body radiotherapy(SBRT, 48 Gy/4 Fr)for PVTT. The extended left lobectomy with thrombectomy was performed 12 days after SBRT.Resected specimen was diagnosed histopathologically as a poorly differentiated HCC, vp1, and no viable tumor cells in the tumor thrombosis.The patient's postoperative course was uneventful, and hepatic arterial infusion chemotherapy was started 1 month after the operation.He remains free of recurrence 5 years after the hepatectomy.Multidisciplinary therapy including preoperative SBRT was feasible and might be a treatment option for HCC with PVTT.

Background: Recurrence patterns after hepatic resection has been poorly understood in view of tumor blood flow drainage (TBFD) area. Our goal was to clarify the recurrence patterns after anatomical versus nonanatomical hepatic resection for hepatocellular carcinoma (HCC)., Methods: A total of 424 consecutive patients with HCC, who were treated by curative resection (R0) at our hospital from 2001 to 2012, were evaluated. Among these, we compared the outcomes of the anatomical resection group (AR group, n = 243) and the nonanatomical resection group (NR group, n = 181). We performed an analysis of the recurrence patterns of HCC based on the preoperative CT during hepatic arteriography in these 424 patients., Results: Preoperative liver function was better in the AR group than the NR group (P < 0.001), and tumor size was larger in the AR group than the NR group (P < 0.001). HCC recurrence was recorded in 145 patients (59.7 %) of the AR group and 102 patients (56.4 %) of the NR group with no significant differences between the two groups (P = 0.590). The incidences of extrahepatic and intrahepatic recurrence (solitary/multiple) were similar between the two groups. In addition, the rate of recurrences by local dissemination, either recurrences in the same subsegment in the NR group or recurrences in the TBFD area in the AR group, was sufficiently low (1.4 %) as to be considered negligible., Conclusions: The incidence and patterns of HCC recurrence were similar between the anatomical and nonanatomical resection. Recurrence by local dissemination may be considered to be negligible in both surgical methods.

Background: The optimal surgical resection method in patients with HCC to minimize the risk of local recurrence has not yet been determined. The aim of this study was to compare the prognosis following anatomical versus non-anatomical hepatic resection for hepatocellular carcinoma (HCC)., Methods: Consecutive patients with HCC without macroscopic vascular invasion, treated by curative resection between 1981 and 2012 at Osaka Medical Centre, were included in this retrospective study. The outcomes of patients selected by propensity score matching were compared., Results: Some 1102 patients were included, 577 in the anatomical and 525 in the non-anatomical resection group. By propensity score matching, 329 patients were selected into each group. Demographic, preoperative and tumour variables were similar between the propensity score-matched groups, including tumour size, tumour multiplicity, α-fetoprotein level and 15-min indocyanine green retention rate at 15 min. The incidence of microvascular invasion was higher in the matched anatomical resection group (P = 0·048). Stratified analysis of recurrence-free and overall survival rates revealed no statistically significant differences between the two propensity score-matched groups (P = 0·704 and P = 0·381 respectively). There was also no significant difference in the early recurrence rate within 2 years after resection between these groups (P = 0·726). Subset analysis of the early recurrence-free survival rate in patients with and without microvascular invasion revealed no significant differences between the groups (P = 0·312 and P = 0·479 respectively)., Conclusion: The resection method had no impact on the risk of HCC recurrence or survival., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

A 70s man with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT) (Vp-HCC) in the main trunk (Vp4) was referred to our hospital. He was negative for hepatitis C virus (HCV) and hepatitis B virus (HBV), and his liver function was well preserved. The main tumor was in the right lobe and exceeded 10 cm in diameter. There were no intrahepatic metastases to the left lobe. The patient underwent stereotactic body radiation therapy (SBRT) (48 Gy/4 fractions) to the area of the PVTT. Six days after SBRT, the patient underwent right lobectomy for removal of PVTT. The postoperative course was uneventful, and low-dose 5-fluorouracil and cisplatin(FP)intra-arterial chemotherapy was administered for 3 months. Histopathological findings for the tumor indicated a poorly differentiated HCC, vp4, with moderate to severe tumor necrosis or degeneration in the area that received SBRT. Tumor markers (alpha-fetoprotein [AFP], proteins induced by vitamin K absence [PIVKA-II]) decreased within the normal range, and there was no apparent HCC recurrence 6 months after the hepatectomy. Multidisciplinary treatment combined with preoperative SBRT and radical resection for Vp-HCC was feasible and effective in this case.

We report a case of hemobilia developing after RFA for hepatocellular carcinoma. A 75-year-old woman with hepatitis C was diagnosed as hepatocellular carcinoma (d=15 mm) located in subsegment 7. Laboratory data on admission are AFP 37.3 ng/mL, PIVKA-II 20 mAU/mL, GOT/GPT 84/52 IU/L, T-Bil 1.1 mg/dL, Alb 3.8 g/dL, Plt 8.9x104/microL, and PT 11.8 seconds (INR 1.28) "Child classification A". Under general anesthesia, percutaneous RFA (Cool-tip radionics 10 minutes) was performed. Tumor appeared to be well treated, but on day 5 after the procedure, the patient had sudden upper abdominal pain, followed by the elevation of total bilirubin conc. (3.3 mg/dL) and decrease of Hb. Abdominal ultrasonography showed a debris-like shadow in the gall bladder. Hemobilia was confirmed because endoscopic examination revealed blood contaminated bile from the papilla Vater. Since spontaneous thrombolysis is known to occur in the bile, the patient was only followed by MRI. Symptoms were subsided in a week without any treatment. Obstructive jaundice due to hemobilia is a rare complication of RFA, and may be followed without any treatment.

Background: The authors reported previously the beneficial effects of interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for patients with advanced hepatocellular carcinoma (HCC) who have tumor thrombi in the major portal branches. In this report, the authors describe the results from IFN/5-FU chemotherapy for patients who underwent palliative hepatic resection for advanced HCC with tumor thrombus in the main trunk of the portal vein and multiple nodules in the whole liver. In addition, they evaluated the correlation between the response to such therapy and expression of IFN-alpha type 2 receptor (IFNAR2)., Methods: From October 1999 to December 2004, 30 patients with advanced HCC, tumor thrombi in the main trunk of the portal vein, and multiple nodules in the whole liver (Vp4 and grade 3 intrahepatic metastases) were recruited for this study. They underwent palliative hepatic resection followed by at least 2 courses of IFN/5-FU. IFNAR2 expression levels were determined by immunohistochemistry., Results: No major treatment-related complications were noted. An objective response was noted in 10 patients (33.3%) and included a complete response in 6 patients (20%), a partial response in 4 patients (13.3%), no response in 1 patient (3.3%), and progressive disease in 19 patients (63.4%). IFNAR2 expression was detected in 20 of 30 patients (66.7%). There was a significant difference in overall survival between patients with positive and negative IFNAR2 expression cases (P<.0025), and a significant correlation was observed between IFNAR2 expression and response to IFN/5-FU combination therapy (P=.0199)., Conclusions: Adjunct IFN/5-FU therapy is a promising modality for patients with advanced HCC, tumor thrombi in the major trunk, and multiple nodules after palliative hepatic resection. The results from this study indicated that the response to such therapy seemed to be correlated with IFNAR2 expression., (Copyright (c) 2007 American Cancer Society.)

We recently reported that interferon-alpha (IFN-alpha) and 5-fluorouracil (5-FU) combination therapy in advanced hepatocellular carcinoma (HCC) achieved excellent clinical results. However, the mechanism underlying this combination therapy remains to be elucidated. In this study, we examined the anti-tumor effects of IFN-alpha and 5-FU combination therapy in vivo and aimed to reveal its anti-angiogenic effects by investigating the expression of vascular endothelial growth factor (VEGF) and angiopoietins (Ang-1 and Ang-2). Human HCC cells, HuH7, were subcutaneously injected in nude mice. Ten days later, groups of mice received treatment with IFN-alpha alone, 5-FU alone, or with a combination of IFN-alpha and 5-FU for four weeks. Immunohistochemical examinations of proliferating cell nuclear antigen (PCNA), cell differentiation antigen 34 (CD34), Ang-1, -2 and VEGF, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and quantification of VEGF, Ang-1 and-2 mRNA using real-time RT-PCR were performed. Results showed that IFN-alpha and 5-FU combination therapy significantly inhibited the growth of human HCC cells compared with the control group or single agent treatment. The combination therapy decreased PCNA-positive cells as well as microvessel density (MVD) and induced apoptosis of (TUNEL-positive cells) more than other treatment groups. Immunohistochemical analysis revealed that the combination therapy significantly decreased the expression of VEGF and Ang-2 and increased that of Ang-1. The ANG2/ANG1 mRNA expression ratio was significantly lower in the combination therapy group. In conclusion, our results suggested that IFN-alpha and 5-FU combination therapy has anti-proliferative and anti-angiogenic effects and can induce apoptosis in vivo. The synergistic and anti-angiogenic effects may in part be attributable to the regulation of Ang-1, -2 and VEGF.

We report two cases of hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) and lymph node (LN) metastases successfully treated by hepatic arterial infusion of 5-fluorouracil (5-FU) combined with systemic injection of interferon (IFN)-alpha following hepatic resection for the liver tumor. Complete remission was obtained. Case 1 was a 51-year-old man who had HCC in the right lobe of the liver with PVTT and multiple intrahepatic metastases. He also had abdominal and mediastinal LN metastases. Case 2 was a 53-year-old man who had diffuse-type HCC in the right lobe of the liver with PVTT and intrahepatic metastases. A chest computed tomography scan revealed lymph nodes enlarged to 1.0 cm from the mediastinum to the left supraclavicular space. Both patients underwent the hepatectomy to reduce the tumor volumes and remove the PVTT to relieve portal vein obstruction. Following the surgery, the patients underwent IFN-alpha/5-FU combination therapy. Three months after this combined therapy, tumor markers (both alpha-fetoprotein and protein induced by vitamin K absence or antagonist II) returned to the normal range and residual tumors in the liver disappeared. The patients are alive without any recurrence more than 1 year after initial treatment. IFN-alpha/5-FU combined therapy following hepatic resection is a promising modality for the treatment of advanced HCC with LN metastasis.

We experienced a patient who received successful treatment for multiple hepatocellular carcinoma (HCC) nodules, with tumor thrombi in the major portal branches, with intraarterial 5-fluorouracil perfusion chemotherapy combined with subcutaneous interferon-alpha administration. The patient was a 50-year-old man with hepatitis C virus and HCC. The tumors consisted of a 5-cm main nodule in the right lobe (segment 8) and multiple intrahepatic metastases. The tumor also involved portal vein thrombosis throughout the right portal branch. After two cycles of interferon-alpha/5-fluorouracil combination chemotherapy, tumor markers demonstrated a decreasing tendency. Nine months after the initiation of this therapy, the tumors were limited to the right lobe and were surgically removed by S8 subsegmentectomy, S5 partial hepatectomy, and portal thrombectomy. The serum levels of both alpha-fetoprotein and protein induced by vitamin K absence II fell to normal levels after hepatic resection. Fifty-eight months after the first treatment, he is alive with several recurrent nodules in the liver. In conclusion, the interferon-alpha/5-fluorouracil combination therapy is a useful treatment for HCC in patients who have multiple intrahepatic metastases and portal vein thrombosis. In addition to this therapy, combined modality therapy including, for example, surgical resection, can sometimes have a dramatic therapeutic effect, shown by tumor markers reverting to normal levels.

Background: Little is known about the metastatic pattern in patients with extrahepatic metastasis after the removal of primary hepatocellular carcinoma (HCC). The aim of the present study was to determine the clinicopathologic characteristics and prognosis of patients with extrahepatic metastasis from HCC according to the recurrence pattern., Methods: Among the patients who underwent hepatic resection for HCC between 1981 and 2001, 80 patients had no recurrence; 221 patients had intrahepatic recurrence, and 47 patients experienced extrahepatic metastasis within a mean follow-up period of 4.8 +/- 3.7 years (+/-SD; range, 2-15 years). The pattern of extrahepatic metastasis after hepatic resection was divided into pattern I (first recurrence in the liver and then spread outside the liver after repetitive intrahepatic recurrences and repetitive locoregional treatments), pattern II (simultaneous recognition of intrahepatic and extrahepatic recurrences), and pattern III (extrahepatic, but no intrahepatic, lesions at first recurrence)., Results: There were significant differences in proportions of patients with invasion of the portal vein, hepatic vein, or inferior vena cava, intrahepatic metastases, and tumor stage between patients with intra- and extrahepatic metastases. The disease-free survival and extrahepatic metastasis-free survival in pattern I were better than pattern II. Survival after extrahepatic metastasis did not correlate with the 3 patterns., Conclusion: Although long-term overall survival was better in patients with pattern I of extrahepatic recurrences, prognosis was poor in all patterns once extrahepatic metastasis developed.

Background/aims: Several studies have reported the efficacy of combination therapy of interferon (IFN) alpha and 5-fluorouracil (5-FU) for hepatocellular carcinoma (HCC). However, the mechanism underlying the clinical anti-tumor effects of this treatment is not well understood. The aim of this study was to determine the role of Fas/FasL signaling in the anti-tumor effect of this combination therapy., Methods and Results: We used six human hepatoma cell lines, three of which are known Fas-expressing cells. Growth of Fas-positive hepatoma cell lines was inhibited by an agonistic anti-Fas antibody in a dose-dependent manner, and these effects were enhanced by IFNalpha or 5-FU alone, but even more so by combination therapy using both agents. Annexin-V assay implicated apoptosis as the main mechanism underlying these growth inhibitory effects, although changes in Fas expression regulated by IFNalpha and/or 5-FU did not correlate with increased apoptosis. Caspase-3 activation was exclusively increased by IFNalpha/5-FU combination treatment, which was compatible with enhancement of the synergistic apoptotic effect, and other caspases and apoptotic factors (FLIP, BCL-xl, and Bax) were also regulated by IFNalpha/5-FU. 51Cr-release assay revealed that pretreatment with IFN activated cytotoxicity of peripheral blood mononuclear cells (PBMCs) against HCC cells. The largest interaction was observed when both PBMC and HCC cells were pretreated with the combination of IFNalpha/5-FU. These cytotoxicities were markedly inhibited by a neutralizing anti-Fas antibody., Conclusions: Our results indicated that IFNalpha/5-FU combination treatment enhances the induction of apoptosis and the cytotoxic effect of PBMCs via the Fas/FasL pathway. The Fas/FasL pathway seems, at least in part, to contribute to the anti-tumor effects of IFNalpha/5-FU against HCCs.

Background/aims: The prognosis of hepatocellular carcinoma (HCC) invading the major branches of the portal vein (Vp3) is extremely poor. Recently, we reported the efficacy of combination therapy with subcutaneous interferon (IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3. In this study, this therapy was applied for resectable advanced HCC (Vp3) as a postoperative adjuvant., Methodology: Patients with HCC and tumor thrombi either in the major or first branch of portal vein were included (n=30). Fifteen consecutive patients with HCC and Vp3 were treated with at least 3 cycles of a combination therapy consisting of continuous arterial infusion of 5-FU (300 mg/mm3/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN (5 MIU, 3 times/week, 4 weeks) as a postoperative adjuvant therapy following hepatic resection. Another 15 patients who underwent hepatic resection with no IFN/5-FU chemotherapy acted as controls., Results: The results were as follows in the IFN/5-FU adjuvant treatment group; disease-free survival (n=11, 5-55 months), survival with recurrence (n=2, 9, 48 months), cancer death (n=1, 18 months), death from other causes but no recurrence (n=l, 22 months). The 1-year survival rate was 100% in patients treated with IFN/5-FU, and 41% in those without IFN/5-FU historical controls (n=15). There was a significant difference in disease-free and overall survival rates between the two groups (p = 0.0033 and 0.0031)., Conclusions: Combination therapy with subcutaneous IFN and intra-arterial perfusion of 5-FU seems to be a promising postoperative adjuvant treatment modality for resectable HCC with Vp3.

Background/aims: Extracellular matrix-degrading matrix metalloproteinases (MMPs) are invariably up-regulated in epithelial cancers and are key agonists of angiogenesis, invasion and metastasis. Recent studies have shown high levels of various MMPs, including MT1-MMP, MMP-1, MMP-2 and MMP-9, and their involvement in tumor progression in human hepatocellular carcinoma (HCC). However, the expression and role of MT3-MMP in HCC remains unclear., Methodology: We examined the immunohistochemical expression of MT3-MMP in surgically resected HCCs (n=58), hepatitis C virus (HCV) and hepatitis B virus (HBV)-related chronic hepatitis (n=34) and cirrhosis (n=24)., Results: MT3-MMP expression was observed in all non-cancerous liver tissues. In HCCs, 52% (30/58) of patients showed high MT3-MMP expression while the remaining 48% (28/58) of patients showed low expression. A clinicopathological survey demonstrated a significant correlation between high MT3-MMP expression and capsular invasion of carcinoma (p = 0.034) although there was no correlation between high MT3-MMP expression in HCC and overall survival or disease-free survival., Conclusions: MT3-MMP was expressed not only in chronic hepatitis and liver cirrhosis, but also in HCC, and high MT3-MMP expression correlated significantly with capsular invasion of carcinoma.

We present a case of a 70-year-old man with an anamnesis of intra-cerebral bleeding that resulted in right half of the body paralysis and right diaphragm paralysis, The present clinical history indicated hepatocellular carcinoma (HCC) caused by hepatitis C and liver cirrhosis during a regular hospital visit, and the patient had a total of 4 TAEs enforced from three years before. A 4 x 3.5 cm neoplasm at the left adrenal was detected by CT inspection this time. The diagnosis was a metastatic adrenal gland tumor from HCC. Since HCC is controlled by TAE, the metastatic lesions were not found in other organs and were isolated, of 10 cm or less in size. Hence, laparoscopic adrenalectomy was performed in March, 2006. He started having a meal from the 2nd day after the operation. He left the hospital on the 9th day. Pathologial diagnosis was a metastatic adrenal gland tumor from moderately differentiated hepatocellular carcinoma. When observing the adaptation standard strictly to the high-risk case, it was thought that the metastatic tumor extraction under laparoscopic surgery could become a low stress cure in consideration of QOL being useful as a local treatment for cancer.

We report a case of advanced hepatocellular carcinoma (HCC). A 73-year-old man with positive HBV and HCV underwent a partial hepatectomy (S6 and S5) twice and transcatheter arterial (chemo) embolization (TAE) four times, thereafter. During these treatments, HCC became intractable and the patient complained of general fatigue. The liver function was Child's classification A, and serum AFP was 6,737 ng/ml. Abdominal CT scan revealed recurrent lesions in the right hepatic lobe and left adrenal gland. The catheter for hepatic arterial infusion chemotherapy was inserted from the left femoral artery. Arterial chemotherapy with 5-fluorouracil (5-FU 750 mg) and cisplatin (CDDP 10 mg) was performed every two weeks. During 6 courses of this regimen, a significant side effect did not appear. Abdominal CT revealed no change in size, but serum AFP decreased up to 794 ng/ml and the general fatigue subsided. After 2 months, serum AFP began to increase and became 1454 ng/ml. The regimen of arterial chemotherapy was changed to epirubicin (EPI 40 mg every two weeks) and UFT-E (300 mg/day for four weeks), followed by a week off. An appetite loss (grade 2) appeared, but it could be well controlled. Serum AFP decreased again, up to 54 ng/ml. A good QOL was kept for about one year after the initiation of hepatic arterial infusion chemotherapy.

Background: Hepatocellular carcinoma (HCC) is a hypervascular tumor and angiogenesis plays an important role in its progression. Angiogenesis is regulated by a balance between pro and antiangiogenic molecules. The aim of this study was to investigate the expressions of angiogenic factors and elucidate their roles in angiogenesis in HCC., Methods: We investigated immunohistochemical expression of vascular endothelial growth factor (VEGF), angiopoietins (Ang-1 and Ang-2), hypoxia-induced factor-1alpha (HIF-1alpha) and thrombospondin-1 (TSP-1) in 60 specimens of surgically resected HCC. We investigated the relationship between their expressions and clinicopathological factors or prognosis., Results: Ang-2 staining had a significant correlation with the grade of differentiation of HCC cells (P=0.0082). VEGF and Ang-2 expression correlated positively with microvessel density (MVD) (P=0.0061 and 0.0374, respectively). MVD of well-differentiated HCC were significantly lower than those of moderately and poorly differentiated HCC. The disease-free survival time of patients with high Ang-2 and/or HIF-1alpha expression was significantly shorter than that of the low expression group (P=0.0278 and 0.0374, respectively)., Conclusion: Our study showed that the expression of VEGF and Ang-2 correlated with MVD. Strong Ang-2 expression and/or high nuclear expression of HIF-1alpha is a significant predictive factor for recurrence after curative resection in HCC patients.

Background: Hepatoma-derived growth factor (HDGF) is involved in hepatocarcinogenesis, as well as in liver development and regeneration. This study investigated the correlation of HDGF expression with differentiation and prognosis of hepatocellular carcinoma (HCC)., Methods: HDGF expression in 100 patients with HCC (81 men and 19 women) with ages ranging from 34 to 81 years (median, 61 years) receiving surgical treatment was analyzed by immunohistochemistry. HDGF messenger RNA expression was evaluated in 10 cases by reverse transcription-polymerase chain reaction. The immunostaining pattern in HCCs was categorized as a positive HDGF index (showing positive staining in >90% of tumor cells in both nucleus and cytoplasm) or a negative HDGF index (all others)., Results: Twenty-seven cases (27%) showed a positive and 73 (73%) showed a negative HDGF index. HDGF messenger RNA expression was significantly higher in four cases with a positive HDGF index than in six with a negative index. Cases with well-differentiated histological characteristics showed a higher rate of positive HDGF index than those with a poorly differentiated subtype. Univariate and multivariate analysis revealed significantly poorer disease-free and overall survivals in patients with a positive HDGF index compared with patients with a negative index., Conclusions: These findings suggest the potential utility of HDGF immunohistochemistry in determining the prognosis of HCC.

A 56-year-old male was admitted to our hospital for hepatoma with portal vein thrombus and multiple intrahepatic metastases. He underwent an extended left lobectomy and a partial resection of the liver in May 2002. After two weeks from the surgery, he received intra arterial 5-FU infusion chemotherapy combined with subcutaneous interferon-alpha injection to treat the lesions in the residual liver. Four months after the surgery, hepatic vein tumor thrombus appeared in the remnant liver and it extended to the inferior caval vein. And another 4 months later, multiple pulmonary metastases were detected with computed tomography and they grew rapidly in the view of their sizes and numbers. Because the combined therapy of 5-FU/interferon-alpha was not effective to distant metastases, we started a new regimen of oral administration of TS-1 and a subcutaneous interferon-alpha injection. After 1 treatment cool, hepatic vein thrombus was markedly reduced the size and vascularity in the CT. Multiple pulmonary metastases also decreased in their sizes and numbers. No adverse effect was seen during this treatment. It was suggested that a combination therapy of TS-1 and interferon-alpha may be one of the most effective treatment modalities against advanced HCC with distant metastasis.

We previously reported the beneficial effects of combination therapy of interferon (IFN)-alpha/5-fluorouracil (FU) for advanced hepatocellular carcinoma (HCC) with tumour thrombi in the major portal branches. This report describes the results of longer follow-up and includes more than double the number of patients relative to the original report, and evaluates the role of IFN-alpha/type 2 interferon receptor (IFNAR2) expression on the response to the combination therapy. The study subjects were 55 patients with advanced HCC and tumour thrombi in the major branches of the portal vein (Vp3 or 4). They were treated with at least two courses of IFN-alpha/5-FU without major complication. In the 55 patients, 24 (43.6%) showed objective response (eight (14.5%) showed complete response, 16 (29.1%) partial response), four (7.3%) showed no response, and 27 (49.1%) showed progressive disease. Immunohistochemically, IFNAR2 expression was detected in nine out of 13 (69.2%) patients. There was significant difference in the time-to-progression survival (P = 0.0002) and the overall survival (P < 0.0001) between IFNAR2-positive and -negative cases. There was a significant correlation between IFNAR2 expression and response to IFN-alpha/5-FU combination therapy in univariate analysis (P = 0.0070). IFN-alpha/5-FU combination therapy is a promising modality for advanced HCC with tumour thrombi in the major portal branches and could significantly depend on IFNAR2 expression.

Several studies reported that Id (Inhibitor of DNA binding or Differentiation) proteins, helix-loop-helix transcription factors, have important roles in differentiation, cell cycle and angiogenesis in various cells. However, the role of Id proteins in hepatocellular carcinoma (HCC) remains unclear. We examined the immunohistochemical expression of Id1, Id2 and Id3 proteins in 54 surgically resected HCCs with surrounding HCV or HBV-related chronic hepatitis (n=30) and liver cirrhosis (n=24). All non-cancerous livers exhibited immunoreactivity for Id proteins and the expression increased from chronic hepatitis to cirrhosis. In HCCs (n=45), well-differentiated tumors mostly exhibited strong or moderate immunostaining for all Id proteins, while proportion of the samples with weak or no expression increased with tumor dedifferentiation and frequently observed in poorly (66.7, 93.3 and 93.3% respectively for Id1, 2, 3) or undifferentiated (100% for all Ids) HCCs. Clinicopathological survey demonstrated a significant correlation between Id1, 2 and 3 expression and differentiation of carcinoma (p=0.0044, 0.0014 and 0.0014, respectively) although univariate analysis indicated that high expression of Id1 was significant predictive factor for longer disease-free survival of the patients (p=0.047). A similar tendency was also observed with Id2 and Id3. The present study demonstrate high expression of Id1, 2 and 3 in well-differentiated HCC and low expression in advanced dedifferentiated HCC, in contrast to its continuous expression during breast, prostate and colon carcinogenesis. These findings suggested that Id1, 2 and 3 might play a role in the early stages of hepatocarcinogenesis, but not in the development of advanced carcinoma, and might consequently be related to HCC dedifferentiation.

Purpose: Intra- and extrahepatic recurrence is common, even after curative resection for hepatocellular carcinoma (HCC), suggesting preoperative or intraoperative tumor cell dissemination. Reverse transcription - polymerase chain reaction (RT-PCR) for alpha-fetoprotein (AFP) is used to detect circulating liver cancer cells. We previously developed a quantitative method that allows estimation of the AFP mRNA level by real-time PCR. In the present study, we used this method to measure the AFP mRNA level before and after resection of HCC, then correlated the findings with various clinicopathological characteristics and prognosis., Methods: We prospectively examined peripheral blood samples from 38 patients with HCC, and bone marrow aspirate from 25 of these patients. As a control, we examined bone marrow from 20 patients with benign diseases. The follow-up period ranged from 32 to 66 months. Real-time RT-PCR was used to detect AFP mRNA levels in the samples., Results: AFP was expressed in 9 (23.7%) of the 38 peripheral blood samples. The detection of AFP mRNA was significantly correlated with extrahepatic metastasis after primary surgery, and a shorter disease-free survival time (P = 0.0245 each). Bone marrow samples were defined as positive if they expressed AFP mRNA at levels higher than the maximum expressed level in the controls, because only 1 (5%) of the 20 control bone marrow samples had low AFP mRNA expression. Using this cutoff level, 12 (48%) of the 25 patients with HCC had positivity for AFP mRNA. The results of bone marrow RT-PCR did not correlate with the clinocopathological characteristics of prognosis., Conclusions: Using real-time PCR to measure the AFP mRNA level in blood, but not bone marrow, could be useful for predicting postoperative tumor recurrence.

Purpose: Our purpose was to explore the contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of IFNalpha and 5-fluorouracil (5-FU) combination therapy for hepatocellular carcinoma (HCC)., Experimental Design: Susceptibility of HCC cell lines to TRAIL and/or 5-FU was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effects of 5-FU, IFNalpha, or both on the expression of TRAIL receptors (R1, R2, R3, and R4) on HCC cells or TRAIL in peripheral blood mononuclear cells (PBMC) were examined by flow cytometry. IFNalpha-induced cytotoxic effects of PBMC on HCC cell lines were examined by (51)Cr release assay. TRAIL expression in peripheral blood mononuclear cells and liver tissue from patients was examined by real-time reverse transcription-PCR or immunohistochemistry., Results: HLE and HepG2 were sensitive to TRAIL, but HuH7, PLC/PRF/5, and HLF were resistant. 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines. TRAIL receptors on HCC cells were up-regulated by 5-FU, and IFNalpha induced TRAIL on CD4(+) T cells, CD14(+) monocytes, and CD56(+) NK cells. Treatment of effector cells by IFNalpha and target HCC cells by 5-FU enhanced the cytotoxicity of CD14(+) monocytes and CD56(+) NK cells against HCC cells via a TRAIL-mediated pathway. TRAIL mRNA overexpression was noted in PBMC of HCC patients who clinically responded to IFNalpha/5-FU combination therapy, and TRAIL(+) mononuclear cells were found in cancer tissue of a responder., Conclusion: Our results suggest that modulation of TRAIL/TRAIL receptor-mediated cytotoxic pathway might partially contribute to the anti-HCC effect of IFNalpha and 5-FU combination therapy.

To investigate the effect of biochemical modulation on antitumor activity shown by the combination of 5-Fluorouracil (5-FU) and interferon-alpha (IFN-alpha), experimental therapy was performed on human hepatocellular carcinoma cell (HuH7, PLC/PLF/5) xenografts inoculated into nude mice, using 5-FU and IFN-alpha, either alone or in combination. These agents showed antitumor activity in different degrees. Although IFN-alpha, given as 100,000 units/mouse/3 times/week subcutaneously x 6, and 5-FU, given as 0.5 mg/mouse/3 times/week intraperitoneally, showed addititive antitumor effect against HuH7 and PLC/PLF/5, the activities of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), orotate phosphoribosyltransferase (OPRT), uridine phosphorylase (UP) and uridine kinase (UK) were not significantly influenced in the tumors treated with the 5-FU/IFN-alpha combination, compared with those treated with 5-FU or IFN-alpha alone. This suggested that antitumor activity of 5-FU and IFN-alpha in combination was not significantly involved in 5-FU metabolism in two human hepatocellular carcinoma cell lines examined.

A 52-year-old male was admitted to our hospital with huge hepatoma of the right lobe. He underwent a right lobectomy of the liver in July 1999. After five months from the surgery, multiple recurrences in the liver and lung were revealed with Computed tomography (CT). TAE was performed for intrahepatic recurrence and a combination therapy, consisting of UFT and interferon-alpha, was started for pulmonary metastasis. Then 5-FU/CDDP/interferon-alpha therapy was given in 2001 and TS-1/interferon-beta therapy was given thereafter in 2002. Consequently, the patient survived for 31 months with no disturbance in quality of life. No intrahepatic recurrence was also detected during the survival period. It was suggested that a good prognosis may be expected, even in the HCC case with distant metastasis after hepatic resection, if the primary cite was curatively treated.

Purpose: The prognosis of hepatocellular carcinoma (HCC) is very poor, particularly in patients with tumors that have invaded the major branches of the portal vein. Combination chemotherapy with intra-arterial 5-fluorouracil and subcutaneous interferon-alpha has shown promising results for such advanced HCC, but it is important to develop the ability to accurately predict chemotherapeutic responses., Experimental Design: We analyzed the expression of 3,080 genes using a polymerase chain reaction-based array in 20 HCC patients who were treated with combination chemotherapy after reduction surgery. After unsupervised analyses, a supervised classification method for predicting chemotherapeutic responses was constructed. To minimize the number of predictive genes, we used a random permutation test to select only significant (P < 0.01) genes. A leave-one-out cross-validation confirmed the gene selection. We also prepared an additional 11 cases for validation of predictive performance., Results: Hierarchical clustering analysis and principal component analysis with all 3,080 genes revealed distinct gene expression patterns in responders (those with complete response or partial response) and nonresponders (those with stable disease or progressive disease) to the combination chemotherapy. Using a weighted-voting classification method with either all genes or only significant genes as assessed by permutation testing, the objective responses to treatment were correctly predicted in 17 of 20 cases (accuracy, 85%; positive predictive value, 100%; negative predictive value, 80%). Moreover, patients in the validation dataset could be classified into two distinct prognostic groups using 63 predictive genes., Conclusions: Molecular analysis of 63 genes can predict the response of patients with advanced HCC and major portal vein tumor thrombi to combination chemotherapy with 5-fluorouracil and interferon-alpha.

Background/aims: Hepatocellular carcinoma (HCC) has a very poor prognosis, due to the high incidence of tumor recurrence. As the current morphological indicators are often insufficient for therapeutic decisions, we sought to identify additional biologic indicators for early recurrence., Methods: We analyzed gene expression using a PCR-based array of 3,072 genes in 100 HCC patients. Informative genes predicting early intrahepatic recurrence were selected by random permutation testing, and a weighted voting prediction method was constructed. Following estimation of prediction accuracy, a multivariate Cox analysis was performed., Results: By permutation testing, we selected 92 genes demonstrated distinct expression patterns differing significantly between recurrence cases and recurrence-free cases. Our prediction method, using the 20 top-ranked genes, correctly predicted the early intrahepatic recurrence for 29 of 40 cases within the validation group, and the odds ratio was 6.8 (95%CI 1.7-27.5, P = 0.010). The 2-year recurrence rates in the patients with the good signature and those with the poor signature were 29.4 and 73.9%, respectively. Multivariate Cox analysis revealed that molecular-signature was an independent indicator for recurrence (hazard ratio 3.82, 95%CI 1.44-10.10, P = 0.007)., Conclusions: Our molecular-based prediction method using 20 genes is clinically useful to predict early recurrence of HCC.

Previously we reported combined chemo-immunotherapy, using interferon (IFN)-alpha and 5-fluorouracil (5-FU) for patients with advanced hepatocellular carcinoma (HCC), and this regimen improved the prognosis. Recently, we experienced an HCC patient who died of severe interstitial pneumonia during the combined IFN-alpha and 5-FU therapy. This is the first report of the occurrence of interstitial pneumonia during combined IFN-alpha and 5-FU treatment. A 60-year-old-man was admitted to Osaka University Hospital to receive systemic chemo-immunotherapy for recurrent HCC. In the second week of the chemo-immunotherapy, he showed a decreased level of consciousness, and respiratory insufficiency. Emergency roentgenogram revealed diffuse infiltration in both lungs. Respiratory dysfunction due to interstitial pneumonia was suspected, and steroid pulse therapy was started. However, the patient showed respiratory failure, and he died 32 days after the start of the therapy. Autopsy findings showed atelectasis in the bilateral lungs, which showed elastic hard solidity and a dark red color; esophageal varices were also shown, and there was cirrhosis with a large tumor in the liver. Microscopically, the alveolar wall showed marked fibrous thickness and moderate inflammatory change, which is consistent with acute interstitial pneumonia, and the acute pulmonary change was suspected to have been the cause of death. The association of IFN with the development of interstitial pneumonia has been reported. However, the prognosis of IFN-induced interstitial pneumonia has mostly been favorable when the medication was discontinued. It has been postulated that interstitial pneumonia induced by the combination of IFN and 5-FU may be therapy-resistant. The combination of IFN-alpha and 5-FU is a useful therapy for patients with advanced HCC, such as that with portal vein invasion or multiple metastatic foci. Thus, interstitial pneumonia in these patients should be carefully managed.

Objective: The purpose of this study was to separately measure the arterial and portal venous tissue blood flow (TBF) of hepatocellular carcinoma (HCC) with a noninvasive method using xenon inhalation CT (xenon-CT) and to differentiate between well-differentiated HCCs and moderately and poorly differentiated HCCs., Materials and Methods: Total, arterial and portal venous TBFs of 38 surgically proven HCC nodules from 38 patients were measured by means of xenon-CT. Serial abdominal CT scans were obtained before and after inhalation of nonradioactive xenon gas. TBF was computed using the Fick principle, after which the correlation between TBF and pathologic features of the tumors was determined., Results: Total, arterial, and portal venous TBFs of HCC were 125.7 +/- 59.9 mL/min/100g, 102.5 +/- 37.3, and 22.2 +/- 11.4, respectively, and the corresponding findings for hepatic parenchyma were 67.3 +/- 13.1, 25.2 +/-9.6, and 42.4 +/- 11.0. Total and arterial TBFs of HCC were significantly higher than those of the hepatic parenchyma (P < 0.01), whereas portal venous TBF of HCC was significantly lower than that of hepatic parenchyma (P < 0.01). Arterial TBF of moderately or poorly differentiated HCC (120.4 +/- 38.2) was significantly higher than that of well-differentiated HCC (60.4 +/- 43.5) (P < 0.01)., Conclusions: Arterial and portal venous TBFs of HCC could be measured separately, noninvasively, and safely with xenon-CT. Correlation between TBF and pathologic features of tumors indicate that xenon-CT can be used to differentiate between well-differentiated HCCs and moderately and poorly differentiated HCCs.

Many trials using DNA microarrays have been reported for various human malignancies, but an efficient molecular diagnostic system has yet to be established. Here, we adopted a high throughput quantitative PCR-array system based on adaptor-tagged competitive PCR (ATAC-PCR), as a novel technique for gene expression profiling of hepatocellular carcinoma (HCC). This PCR-array contained 3,072 genes derived from three different cDNA libraries, including 298 additional known genes suspected to be involved in hepatocarcinogenesis. Using this PCR-array with 20 pairs of liver tissues (20 HCC, 20 surrounding nontumor liver), we identified a total of 117 genes differing in expression levels in the two liver tissues. Hierarchical clustering analysis and principal component analysis with these genes revealed distinct gene expression patterns in the HBV-positive group and the HCV-positive groups. Among 117 genes, only 7 (GPAA1, TMEM9, FACL4, ADFP, MAWBP, PACE4, FOS) were common to both groups. In conclusion, this PCR-array analysis with an appropriate set of genes is considered useful for gene expression profiling of HCC, and we identified some genes which may play a common key role in hepatocarcinogenesis.

A novel gene, p73, encoding a protein with significant homology to p53 and showing functional similarities to p53, was identified at chromosome 1p36, at which tumor suppressor gene of hepatocellular carcinoma (HCC) is supposed to be. Involvement of p73 in hepatocarcinogenesis is controversial and clinical value of p73 alterations remains obscure. We investigated allelic status of p73 in 63 patients with HCC. Loss of heterozygosity (LOH) in p73 was analyzed by PCR-RFLP analysis. The results were compared with LOH on chromosome 1p surrounding p73 locus, mutations of p53 and p73, and clinicopathologic characteristics. LOH on p73 was observed in 33% of informative tumors. LOH in p73 was not always observed between the regions with LOH on chromosome 1p examined despite the significant association of LOH in p73 with LOH on chromosome 1p. No mutations were detected in p73. Tumors with LOH in p73 were more frequently detected in liver without cirrhosis than that with cirrhosis. There was no significant statistic association between the presence of LOH in p73 and six different clinicopathologic characteristics such as age, sex, histological type, T stage, tumor diameter, and virus status. Disease-free survival rates of the patients with LOH in p73 were significantly poorer than those without LOH in p73. Multivariate analysis indicated that presence of LOH in p73 was independent prognostic factor in patients with HCC. These findings suggested that p73 might play some role in tumor progression of HCC even though p73 should not be considered a candidate gene on chromosome 1p of HCC and does not function as a tumor suppressor gene like p53. Identifying the patients with LOH of p73 in tumors could be useful to predict early recurrence and to stratify the patients who need adjuvant therapy after operation.

Akt, a down-stream target of phosphatidylinositol-3 kinase, plays multiple roles in carcinogenesis. To elucidate its role in hepatocarcinogenesis, we immunohistochemically investigated the expression of Akt protein (Akt1 and Akt2) in tumor and non-tumor tissues from 56 patients with hepatocellular carcinoma (HCC). High expression of Akt2 in HCC tissues was detected in 21 cases (38%) while Akt1 expression was moderate or less in all cases. Low expression of Akt2 was associated with histopathological differentiation, portal invasion and number of tumor nodules (p=0.026, 0.023, and 0.001, respectively). Univariate analysis showed that Akt2, histopathological differentiation, and portal vein invasion were significant prognostic factors (p=0.001, 0.028, and 0.006, respectively). Multivariate analysis revealed that in addition to histopathological differentiation, Akt2 was an independent prognostic marker (risk ratio for cancer relapse, 6.35, p=0.012). In contrast, Akt1 expression did not correlate with any clinicopathological features. Our findings suggest that Akt2, but not Akt1, is a novel independent predictor for the development and progression of HCC.

Background: The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor, but promising effects of chemotherapies combined with interferon (IFN) have been reported., Methods: To develop more effective combination therapies for HCC, we compared the antiproliferative effects of IFN-alpha and IFN-beta in combination with various cytotoxic drugs on hepatoma cell lines using MTT assay and isobologram analysis., Results: IFN-beta was more potent than IFN-alpha in inhibiting the cell growth of all cell lines (P <.05, two-way ANOVA). PLC/PRF/5 was more sensitive to either IFN, than HLE and HuH7. Cell growth of all cell lines was inhibited in a dose-dependent manner by 5-fluorouracil (5-FU), cisplatin (CDDP), and doxorubicin (DOX), but the sensitivities of these cells were considerably different. As for IFN-alpha, synergistic effects were observed when combined with 5-FU and DOX on PLC/PRF/5 cells only, whereas IFN-beta showed synergistic effects with 5-FU and CDDP on HuH7 and PLC/PRF/5 cell lines., Conclusion: The spectra of the antiproliferative activity and synergistic effect of IFN-beta when combined with anticancer drugs are more potent than those of IFN-alpha. Combinations of IFN-beta and anticancer drugs may provide a better treatment of HCC when combinations with IFN-alpha are ineffective.

Background/aims: Hepatocellular carcinoma (HCC) usually develops following chronic liver inflammation caused by hepatitis C or B virus. Through expression profiling in a rare type of HCC, for which the causes are unknown, we sought to find key genes responsible for each step of hepatocarcinogenesis in the absence of viral influence., Methods: We used 68 non-B, non-C liver tissues (20 HCC, 17 non-tumor, 31 normal liver) for expression profiling with PCR-array carrying 3072 genes known to be expressed in liver tissues. To select the differentially expressed genes, we performed random permutation testing. A weighted voting classification algorithm was used to confirm the reliability of gene selection. We then compared these genes with the results of previous expression profiling studies., Results: A total of 220 differentially expressed genes were selected by random permutation tests. The classification accuracies using these genes were 91.8, 92.0 and 100.0% by a leave-one-out cross-validation, an additional PCR-array dataset and a Stanford DNA microarray dataset, respectively. By comparing our results with previous reports on virus-infected HCC, four genes (ALB, A2M, ECHS1 and IGFBP3) were commonly selected in some studies., Conclusions: The 220 differentially expressed genes selected by PCR-array are potentially responsible for hepatocarcinogenesis in the absence of viral influence.

For the difficulty of the giving sufficient dose because of the poor liver function and low sensitivity for the anti-cancer agents, the chemotherapy may not play a central role for the hepatocellular carcinoma (HCC) patients with liver cirrhosis. However, the chemotherapy must be the one of important possibility as a multimodal treatment for the advanced HCC, for which hepatic resection, TAE and other general therapy would not be effective. The intraarterial perfusion chemotherapy is common as a chemotherapy for HCC and it is not difficult to maintain; the effective rate is not sufficient. Recently, the combination therapy with subcutaneous IFN-alpha and intraarterial 5-FU showed a outstanding effective rate for intractable HCC with Vp3. For the further advance of the HCC treatment and prognosis, this therapy might be the promising treatment modality and expected of the development.

A 55-year-old female was admitted to our hospital for a third recurrence of hepatoma. She was treated with transcatheter arterial embolization (TAE) in April and November 1996. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed multiple tumors of S4/S8 and S7 in the liver. After the third TAE using SMANCS, Lipiodol and Spongel, abdominal CT revealed insufficient Lipiodol retention and the in efficacy of this treatment. A right lobectomy of the liver was performed for the TAE resistant multiple recurrence of HCC. After the surgery, the patient survived for over 5 years with no recurrence. It appears that this surgery may be a useful modality for TAE resistant multiple recurrence hepatoma in cases of good liver function and lesions limited to the hemi lobe.

The prognosis of advanced hepatocellular carcinoma (HCC) is extremely poor. Patient 1 was a 43-year-old male with major portal tumor thrombi. He received combination therapy consisting of continuous arterial infusion (MTX 30 mg/m2, day 1, CDDP/5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Patient 2 was a 66-year-old male with major hepatic venous tumor thrombi. He received combination therapy consisting of continuous arterial infusion (5-FU 6 mg/m2: 250 mg/m2, day 1-14) and subcutaneous injection of IFN-alpha (500 x 10(4) U, 3 times a week, 4 weeks). Decrease in tumor was observed in both patients markers and marked regression of tumor was observed in both patients. They are still in complete response. This combination therapy is an effective strategy for advanced HCC.

The patient is a 75-year-old male. Abdominal ultrasound tomography in June 2002 revealed hepatocellular carcinoma with intrahepatic metastasis (IM3) and tumor thrombi (Vp4, Vv3) at S4 in the major portal and hepatic vein. From July 2002, he received hepatic arterial infusion therapy (FAP: 5-fluorouracil, CDDP and adriamycin) for these lesions. In December 2002, these lesions had disappeared completely after 6 sessions of arterial infusion therapy. The patient is still alive with no recurrence after 2 years since the beginning of this treatment. Recently, we treated 9 patients with combined arterial infusion chemotherapy (FAP), and the response rate (CR and PR) was 44% and no major side effect was observed. In conclusion, some patients may obtain longer survival through this treatment, even in cases of advanced HCC with tumor thrombus in the major trunks of portal vein and/or hepatic vein.

The aim of this study was to quantitatively measure tissue blood flow (TBF) in hepatocellular carcinoma (HCC) by a noninvasive method using xenon (Xe) inhalation/CT scans and to correlate the measured TBF with histological features. TBF was measured in HCC with xenon-enhanced CT (xenon/CT) in 20 patients. In 15 patients with HCC diagnosed as hypervascular tumors by conventional CT, TBF of the tumors was significantly higher than that of noncancerous liver tissue (151.1 +/- 20 vs 42.6 +/- 20 ml/min/100 g). Histologically, these tumors were diagnosed as moderately-to-poorly differentiated HCC. In contrast, in five patients with hypovascular HCC, TBF of HCC was almost comparable to that of the noncancerous regions (45.3 +/- 6 vs 48.3 +/- 6 ml/min/100 g). All these tumors were well-differentiated HCC. In conclusions, the measured values of TBF correlate with the clinicopathologic features of liver tumors and nontumorous liver tissue in patients with HCC.

Background/aims: The prognosis of hepatocellular carcinoma (HCC) is poor because of frequent intrahepatic metastasis (IM) or multicentric carcinogenesis (MC). We compared the effectiveness of loss of heterozygosity (LOH) analysis in the diagnosis of these two forms with that of histopathological diagnosis., Methods: Using LOH analysis of 15 specific DNA microsatellite loci, tumor clonality was assessed in 37 cases., Results: LOH was observed in 30% of seven solitary tumors. According to these results, the selected threshold to diagnose MC was a difference in the LOH status at more than 30% of the analyzed loci, when comparing two samples in the same liver. In nine multiple HCCs, identical genetic and histopathological diagnoses were found in four (IM: 2, MC: 2). Of 21 recurrent tumors, 19 showed LOH for at least one marker. IM and MC were genetically diagnosed in five and ten patients, respectively. Genetic and histopathological diagnoses were identical in ten of 19 patients (IM: 5. MC: 5). Five genetic MC were histopathologically diagnosed as IM (3) and 'undetermined' (2)., Conclusions: Genetic diagnosis by LOH analysis may be more strict and specific than histopathological diagnosis in the differential diagnosis of IM and MC.

Purpose and Experimental Design: CDC25 genes are cell cycle-activating phosphatases that positively regulate the activity of cyclin-dependent kinase. CDC25A and CDC25B, being oncogenes, are overexpressed in a variety of human malignancies. To investigate the potential roles of CDC25s in hepatocellular carcinoma (HCC), expression of CDC25A and CDC25B was examined in human HCC samples., Results: Reverse transcription-PCR showed that overexpression of CDC25A and CDC25B mRNAs was found in 9 of 13 (69%) and 4 of 13 (31%) HCCs, respectively. Immunohistochemistry of 59 HCCs showed marked increase in CDC25A expression, but not CDC25B, in HCC compared with noncancer tissues, and high expression of CDC25A in 33 of 59 (56%) HCCs. Overexpression of CDC25A in HCC was confirmed by Western blot analysis. High expression of CDC25A was associated with dedifferentiated phenotype and portal vein invasion (P = 0.001 and 0.031, respectively), and expression of CDC25A correlated well with proliferating cell nuclear antigen labeling index (P = 0.005). Univariate analysis indicated that high expression of CDC25A and proliferating cell nuclear antigen were both significant predictive factors for shorter disease-free survival (P = 0.004 and 0.039, respectively). Multivariate analysis indicated that CDC25A was an independent prognostic marker for disease-free survival (risk ratio for cancer relapse, 2.98; P = 0.029), even when analyzed with several clinicopathologic factors. On the other hand, expression of CDC25B did not correlate with any clinicopathological features., Conclusion: Our findings suggest that CDC25A, but not CDC25B, could be used as an independent prognostic marker for HCC. Our data would also contribute to forward understanding of tumor biology of HCC that is associated with cell cycle regulation.

Purpose: Valosin-containing protein (VCP; also known as p97) has been shown to be associated with antiapoptotic function and metastasis via activation of the nuclear factor-kappaB signaling pathway. In this study, association of VCP expression with recurrence of hepatocellular carcinoma (HCC) and patient survival was examined., Patients and Methods: VCP expression in 170 patients (139 male and 31 female) with ages ranging from 31 to 81 years (median, 61 years) was analyzed by quantitative reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, in which staining intensity in tumor cells was categorized as weaker (level 1) or equal to or stronger (level 2) than that in endothelial cells., Results: Immunohistochemically, 57 patients (35.2%) showed level 1, and 105 patients (64.8%) showed level 2, VCP expression. Quantitative RT-PCR analysis revealed higher VCP mRNA expression in level 2 patients (n = 7) than level 1 (n = 4) (P <.05). Patients with VCP-level 2 HCC showed higher rate of portal vein invasion in the tumor (P <.01) and poorer disease-free and overall survival (P <.0001 and P <.05, respectively) compared with level 1 patients. Multivariate analysis revealed VCP expression level, tumor multiplicity, and degree of fibrosis in the noncancerous liver tissue to be independent prognosticators for disease-free and overall survival. VCP level was an indicator for disease-free survival in each early- (I and II) and advanced- (III and IV) stage group of pathologic tumor-node-metastasis classification (P <.001 and P <.01, respectively)., Conclusion: VCP expression level has prognostic significance for disease-free and overall survival of patients with HCC.

The prognosis of hepatocellular carcinoma(HCC) invading the major branches of the portal vein(Vp3 or 4) is extremely poor. Recently, we reported the efficacy of the combination therapy with subcutaneous interferon(IFN)-alpha and intra-arterial 5-FU for intractable HCC with Vp3 or Vp4. Forty-eight consecutive patients with HCC and Vp3 or 4 were treated with the combination therapy consisting of continuous arterial infusion of 5-FU(450-500 mg/day, 5 days/week, for the initial 2 weeks) and subcutaneous injection of IFN(5 MIU, 3 times/week, 4 weeks). The treatment outcome of these cases was very good. In addition, it is considered direct antitumor effect, the angiogenesis depression effect, and the indirect antitumor effect through immunocompetent cell, may concerned, as the mechanism. In conclusion, combination therapy with subcutaneous IFN and intra-arterial 5-FU is therefore a promising treatment modality for intractable HCC with Vp3 or 4.

The patient was 63-year-old male. Abdominal CT revealed a tumor at S2/S3, which led to a diagnosis of hepatocellular carcinoma, in April 1998. On April 15, 1998 transcathetereal arterial embolization was performed and on May 11, 1998 percutaneous ethanol injection therapy was given, but a viable lesion remained. On July 2, 1998, partial resection of S2/S3 was performed. There was an intrahepapic metastatic lesion at Glisson's site of the main tumor, which was suspected of implantation. In December 2000, the patient had a high AFP level, and a recurrent tumor was observed at S3 on abdominal CT. In June 2001, S3 subsegmentectomy was performed, because the recurrent tumor existed in the Glisson S3 area.

Background: Previous studies have shown that ets-2, a transcription factor, is linked to carcinoma progression. In the present study, we investigated the expression and clinical significance of ets-2 in hepatocellular carcinoma (HCC) and malignant transformation of the liver., Materials and Methods: The expression of ets-2 was immunohistochemically investigated with 91 HCC, 46 noncancerous lesions, 8 atypical adenomatous hyperplasias and 14 normal liver controls., Results: The ets-2 labeling index (LI) in normal liver was significantly lower than in noncancerous lesion (p<0.0001). The LI in atypical adenomatous hyperplasia tended to be higher than in noncancerous lesion (p=.0779). In HCC, the LI was significantly lower (p<0.0001) than that in noncancerous lesion and atypical adenomatous hyperplasia. In HCC, the ets-2 expression level was significantly lower in cases with advanced stage (p=0.0085), large size (p=0.0441), high proliferating activity (p<0.0001), poor differentiation (p=0.0005), the presence of portal invasion (p=0.0009) and intrahepatic metastasis (p=0.0236) and shorter disease-free survival (p=0.0372)., Conclusion: These findings suggest that ets-2 plays an important role predominantly in malignant transformation of the liver.

Background: The prognosis of hepatocellular carcinoma (HCC) invading into the major branches of the portal vein (Vp3) is extremely poor., Methods: Eleven consecutive patients with HCC and Vp3 were treated with 2-6 cycles of a "basic" combination therapy consisting of continuous arterial infusion of 5-fluorouracil (450-500 mg/day, for the initial 2 weeks) and subcutaneous injection of interferon-alpha (5 million international units, 3 times/week, 4 weeks). In the first 3 patients, methotrexate (90 mg/day 1 of every week), cisplatin (10 mg/day), and leucovorin (30 mg/days 2 and 3 of every week) also were administered for the initial 2 weeks ("full" regimen)., Results: In 8 (73%) of 11 patients, an objective response (complete response [CR] or partial response [PR]) was observed with marked regression of tumor and decrease in tumor markers. The use of the full regimen was associated with objective response in all patients; instead, they developed thrombocytopenia or leukopenia. In the subsequent 8 patients with basic regimen, 5 patients showed CR (2 cases) or PR (3 cases; objective response rate, 63%), and leukopenia was observed only in 1 patient., Conclusions: Simple combination therapy with subcutaneous interferon-alpha and intraarterial 5-fluorouracil therefore is a promising treatment modality for intractable HCC with Vp3.