Clinical outcome of esophageal varices after hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with major portal vein tumor thrombus

Aim: To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). Methods: The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra‐arterial 5‐FU with interferon‐α (5‐FU/IFN) in 23 patients and low‐dose cisplatin plus 5‐FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. Results: The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5‐FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5‐FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P < 0.001), metastasis from HCC (HR = 11.469, P = 0.001), ascites (HR = 8.825, P = 0.003) and low serum albumin (HR = 4.953, P = 0.026) as determinants of overall survival. RT for portal vein tumor thrombosis tended to reduce the aggravation rate for EV in patients with these risk factors. Conclusions: Hepatocellular carcinoma disease control was the most significant and independent factor for aggravation of EV and overall survival in HCC patients with major portal vein tumor thrombosis treated with HAIC.     

Intra‐arterial 5‐fluorouracil/interferon combination therapy for hepatocellular carcinoma with portal vein tumor thrombosis and extrahepatic metastases

Background and Aims: We investigated the efficacy of intra‐arterial 5‐fluorouracil (5‐FU) and systemic interferon (IFN)‐α (5‐FU‐IFN) in the treatment of hepatocellular carcinoma (HCC) with portal vein tumor thrombosis in the first branch or trunk (Vp3/4) and extrahepatic metastases. Methods: We examined 17 HCC patients with Vp3/4 and extrahepatic metastases (meta group) and 31 HCC patients with Vp3/4 (non‐meta group). Baseline intrahepatic tumor factors and the hepatic reserve were similar between groups. The extrahepatic metastases of the meta group were not considered prognostic factors. Following the administration of 5‐FU/IFN to all patients, we compared the survival rates, response, time to progression (TTP), and safety between groups. Results: For intrahepatic HCC, complete response, partial response, stable disease, progressive disease, and drop out were observed in no (0%), one (6%), seven (41%), nine (53%), and no (0%) patients of the meta group, and in five (16%), seven (23%), 13 (42%), five (16%) and one (3%) patient of the non‐meta group, respectively. The response rate was significantly lower in the meta group (6% vs 39%, P = 0.018). The median TTP of intrahepatic HCC and the median survival time were significantly shorter in the meta group than in the non‐meta group (1.6 vs 6.3 months, P = 0.0001, and 3.9 months vs 10.5 months, P < 0.0001, respectively). The multivariate analysis showed that the absence of extrahepatic metastases was a significant and independent determinant of both TTP of intrahepatic HCC (P < 0.001) and overall survival (P < 0.001). No patient died of extrahepatic HCC‐related disease. Conclusions: The efficacy of 5‐FU/IFN for advanced HCC with Vp3/4 and extrahepatic metastases was markedly limited.     

Hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic interferon-α for advanced hepatocellular carcinoma in combination with or without three-dimensional conformal radiotherapy to venous tumor thrombosis in hepatic vein or inferior vena cava

Aim: We investigated the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5‐fluorouracil (5‐FU) and systemic interferon (IFN)‐α (HAIC‐5‐FU/IFN) for advanced hepatocellular carcinoma (HCC) with venous tumor thrombosis (VTT) in the hepatic vein trunk (Vv2) or inferior vena cava (Vv3). Methods: Thirty‐three patients with HCC/Vv2/3 underwent HAIC with 5‐FU (500 mg/body weight/day, into hepatic artery on days 1–5 on the first and second weeks) and IFN‐α (recombinant IFN‐α‐2b 3 000 000 U or natural IFN‐α 5 000 000 U, intramuscularly on days 1, 3 and 5 of each week). Three‐dimensional conformal radiotherapy (3D‐CRT) was used in combination with HAIC‐5‐FU/IFN in 14 of 33 patients to reduce VTT. Result: The median survival time (MST) was 7.9 months, and 1‐ and 2‐year survival rates were 30% and 20%, respectively. Evaluation of intrahepatic response after two cycles of HAIC‐5‐FU/IFN showed complete response (CR) in three (9%) and partial response (PR) in seven (21%), with an objective response rate of 30%. Multivariate analysis identified reduction of VTT (P = 0.0006), size of largest tumor (P = 0.013) and intrahepatic response CR/PR (P = 0.030) as determinants of survival. CR/PR correlated significantly with tumor liver occupying rate (P = 0.016) and hepatitis C virus Ab (P = 0.010). Reduction of VTT correlated significantly with radiotherapy (P = 0.021) and platelet count (P = 0.015). Radiotherapy‐related reduction in VTT significantly improved survival of 16 patients with Vv3 and non‐CR/PR response of HAIC‐5‐FU/IFN (P = 0.028). Conclusion: As for advanced HCC with VTT of Vv2/3, HAIC‐5‐FU/IFN responsive patients could obtain favorable survival. Despite ineffective HAIC‐5‐FU/IFN, the combination with effective radiotherapy to VTT might improve patients' prognosis.     

CD34和VEGF在肝癌组织中的表达及与肿瘤血管生成的相关性

目的探讨CD34和血管内皮生长因子（VEGF）在肝细胞肝癌（HCC）组织中的表达及微血管密度（MVD）的临床病理意义。方法应用链霉素扰生物素蛋白-过氧化物酶法（S—P法）对50例HCC患者进行肿瘤血管生成免疫组织化学检测。对CD34阳性血管进行MVD计数．对VEGF进行半定量计数，并分析与HCC的临床病理特征的关系及意义。结果CD34在HCC组织中呈广泛、窦隙状表达，MVD值在有汇管区癌栓和肝内转移者高于无汇管区癌栓和无肝内转移者（P〈0．05），VEGF表达的阳性率在有汇管区癌栓和肝内转移者明显高于元汇管区癌栓及无肝内转移者（P〈0．05）。MVD值在VEGF阳性组和阴性组之间差异有显著性（P〈0．05）。结论HCC中MVD值和VEGF阳性表达率明显增高，由自分泌和旁分泌产生的VEGF通过促进HCC肿瘤血管生成而促进HCC的生长和转移。     

Observation of microvascular casts of human hepatocellular carcinoma by scanning electron microscopy

The microcirculation of hepatocellular carcinomas (HCCs) and surrounding tissue was observed three-dimensionally by scanning electron microscopy of vascular casts made from 10 livers at autopsy. The livers were perfusion-washed and cast with resin through both the hepatic artery and portal vein branches. The HCCs observed ranged from several millimeters to 3 cm in size. A vascular plexus proliferated around the HCC nodules in all cases. Both portal vein and hepatic artery branches proliferated markedly to form the plexus in 5 patients. These vessels communicated directly with the blood sinuses of the HCCs as feeder vessels. HCC cells replaced normal cells while maintaining the liver’s trabecular structure in 2 cases. At the borders of these HCCs, there was direct communication between the hepatic sinusoids and the tumor blood sinuses. Efferent vessels of the tumors were generally difficult to identify but vessels resembling hepatic vein branches were detected in one 4-mm HCC nodule after microdissection. Thus, HCC was demonstrated to be supplied not only by the hepatic artery but also by the portal vein and hepatic sinusoids. This may be one of the reasons why cancer cells survive in the tumor margins and daughter nodules after transcatheter arterial embolization of HCC.     

Multicentric occurrence of hepatocellular carcinoma: diagnosis and clinical significance

To evaluate current knowledge on the multicentric occurrence (MO) of hepatocellular carcinoma (HCC) and its clinical significance was the purpose of this review. The criteria for MO of HCC are defined as follows: (1) the recurrent tumor consists of well differentiated HCC occurring in a different hepatic segment from moderately or poorly differentiated preexisting HCC, (2) both the primary and recurrent tumors are well differentiated HCC, (3) the recurrent tumors contain regions of dysplastic nodules in peripheral areas and, (4) multiple HCCs, indicating the “nodule‐in‐nodule” form, in which nodules consisting of moderately or poorly differentiated HCC cells are contained in a nodule of well differentiated HCC cells. However, these criteria assume rare or no metastasis of well differentiated HCC, and are also not applicable to cases in which some HCCs of multicentric origin are rapidly dedifferentiated, presenting morphologic features of moderately or poorly differentiated tumors. Diagnostic methods, besides histopathologic methods, for determining multicentric origin in multiple HCCs in the liver, or recurrent tumor(s) of HCC, include clonal analysis of the integration pattern of hepatitis B virus (HBV) DNA in HBV carrier patients, and analysis of thep53 mutation patterns or loss of heterozygosity of chromosomal DNA. The prognosis of patients with MO of HCC after curative resection is significantly better than that of patients with intrahepatic HCC metastasis. Moreover, the Liver Cancer Study Group of Japan has reported that patients with hepatic resection for small‐sized HCCs showed higher survival rates than a nonsurgical treatment group. Consequently, HCC with MO, whether this is synchronous or metachronous, should be surgically removed as the treatment of first choice.     

Observation of microvascular casts of human hepatocellular carcinoma by scanning electron microscopy.

The microcirculation of hepatocellular carcinomas (HCCs) and surrounding tissue was observed three-dimensionally by scanning electron microscopy of vascular casts made from 10 livers at autopsy. The livers were perfusion-washed and cast with resin through both the hepatic artery and portal vein branches. The HCCs observed ranged from several millimeters to 3 cm in size. A vascular plexus proliferated around the HCC nodules in all cases. Both portal vein and hepatic artery branches proliferated markedly to form the plexus in 5 patients. These vessels communicated directly with the blood sinuses of the HCCs as feeder vessels. HCC cells replaced normal cells while maintaining the liver's trabecular structure in 2 cases. At the borders of these HCCs, there was direct communication between the hepatic sinusoids and the tumor blood sinuses. Efferent vessels of the tumors were generally difficult to identify but vessels resembling hepatic vein branches were detected in one 4-mm HCC nodule after microdissection. Thus, HCC was demonstrated to be supplied not only by the hepatic artery but also by the portal vein and hepatic sinusoids. This may be one of the reasons why cancer cells survive in the tumor margins and daughter nodules after transcatheter arterial embolization of HCC.     

Huge focal nodular hyperplasia difficult to distinguish from well-differentiated hepatocellular carcinoma

We present a 43‐year‐old man with huge focal nodular hyperplasia (FNH) that was difficult to distinguish from well‐differentiated hepatocellular carcinoma (HCC). He previously had abnormal portal vein circulation due to hypoplasia of the intrahepatic portal vein, which was treated with a superior mesenteric vein–inferior vena cava shunt. Laboratory findings included predominantly indirect hyperbilirubinemia with concomitant elevation in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and ammonia. Serum α‐fetoprotein and des‐γ‐carboxy prothrombin were slightly elevated. Multidetector‐row computed tomography detected the primary tumor in the left liver lobe, which partially showed a central stellate scar. Gd ethoxybenzyl diethylenetriamine pentaacetic acid‐enhanced magnetic resonance imaging showed some low‐intensity areas in the tumor in the hepatocyte phase. 99mTc‐galactosyl human serum albumin scintigraphy showed normal intake of agent in the tumor. We could not rule out well‐differentiated HCC. Extended left hepatectomy was performed. Final histopathological findings showed that most of the tumor was FNH against a background of portal vein hypoplasia with moderate atypia and hemorrhage. And immunohistochemical analysis revealed high expression of organic anion transporter (OATP) 1B3 and low expression of multidrug resistance‐associated protein (MRP) 2 in a part of the tumor. The patient has remained alive with no hepatic lesion for 1 year after surgery. We describe a case of huge FNH that was difficult to distinguish from well‐differentiated HCC even by current fully preoperative imaging technology and demonstrate the effectiveness of curative surgical resection.     

Predictors of hepatic venous trunk invasion and prognostic factors in patients with hepatocellular carcinomas that had come into contact with the trunk of major hepatic veins

Purpose

In this study, we tried to identify the preoperative predictors of hepatic venous trunk invasion and the prognostic factors in patients with hepatocellular carcinoma (HCC) that had come into contact with the trunk of a major hepatic vein over a distance of 1.0?cm or more.

Methods

Forty patients who had such HCCs resected were entered into this study and predictors of hepatic venous trunk invasion and prognostic factors were evaluated by univariate and multivariate analyses.

Results and Conclusions

A combined resection of the HCC and the venous trunk was performed in 29 patients. Hepatic venous trunk invasion was observed in 12 patients, including 2 with inferior vena cava tumor thrombus. A stepwise logistic regression analysis indicated that tumors larger than or equal to 7?cm in diameter and tumors showing a poorly differentiated histological grade were independent predictors of hepatic venous trunk invasion. The survival of patients without venous trunk invasion was significantly better than that for patients with venous trunk invasion (P = 0.048). A univariate analysis revealed that Child–Pugh classification B (P = 0.002), a high des-γ-carboxy prothrombin concentration (≧400?mAU/ml, P = 0.023), a large HCC (≧5.0?cm in diameter, P = 0.002), the presence of portal vein invasion (P < 0.001), the presence of venous trunk invasion (P = 0.048), the presence of intrahepatic metastasis (P < 0.001), and poorly differentiated HCC (P = 0.006) correlated with a worse overall survival after hepatic resection. In a multivariate analysis, however, only the presence of intrahepatic metastasis (P = 0.037, relative risk 8.25) was an independent predictor of poor overall survival.

Conclusions

Large tumors (≥7?cm in diameter) and poorly differentiated HCCs were more likely to be associated with hepatic venous trunk invasion and intrahepatic metastasis was an independent prognostic factor in patients with HCC that had come into contact with the trunk of a major hepatic vein.

     

Predictive factors for intrahepatic cholangiocarcinoma recurrence in the liver following surgery

Background We performed hepatectomy without lymph node (LN) dissection for intrahepatic cholangiocarcinoma (ICC) limited to the peripheral region of the liver, and hepatectomy with extrahepatic bile duct resection and regional LN dissection for any types of ICC extending to the hepatic hilum. Surgical outcomes were evaluated to elucidate the prognostic factors that influence patient survival with respect to intrahepatic recurrence. Methods Forty-one patients underwent resection of ICC with no macroscopic evidence of residual cancer. Results Significant risk factors for poorer survival included preoperative jaundice (P = 0.0115), serum CA19-9 levels >37 U/ml (P = 0.0089), tumor diameter >4.5 cm (P = 0.017), ICC extending to the hepatic hilum (P = 0.0065), mass-forming with periductal-infiltrating type (P = 0.003), poorly differentiated adenocarcinoma, portal vein involvement (P = 0.0785), LN metastasis at initial hepatectomy (P < 0.0001), and positive surgical margin (P = 0.023). Intrahepatic recurrence, which was the predominant manner of recurrence, was detected in 20 patients (74.1%). Patients with intrahepatic recurrence had a significantly high incidence of high serum CA19-9 levels (>37 U/ml; P = 0.0006), preoperative jaundice (P = 0.0262), ICC extended to the hepatic hilum (P = 0.0349), large tumors (>4.5 cm; P = 0.0351), portal vein involvement (P = 0.0423), and LN metastasis at initial hepatectomy (P = 0.009) compared with disease-free patients. The multiple logistic regression analysis revealed that preoperative CA19-9 elevation and obstructive jaundice influenced intrahepatic recurrence of ICC. Conclusions Although LN metastasis is a significant prognostic factor, the most obvious recurrence pattern after surgery was intrahepatic recurrence, which could be predicted preoperatively by a combination of elevated serum CA19-9 levels and manifestation of obstructive jaundice.     

Overexpression of EphA2, MMP‐9, and MVD‐CD34 in hepatocellular carcinoma: Implications for tumor progression and prognosis

Aim: To investigate the expression of erythropoietin‐producing hepatocellular (Eph)A2 receptor, matrix metalloproteinase (MMP)‐9, and angiogenesis in hepatocellular carcinoma (HCC), in order to reveal their expression correlations with tumor invasion, metastasis, and prognosis. Methods: From January 2000 to June 2003, 129 specimens of resected tumors from the patients with HCC were obtained. Corresponding pericarcinomatous liver tissues were also obtained and selected as a control group. Expressions of EphA2, MMP‐9, and CD34 were detected with immunohistochemical staining. Microvascular density (MVD) was calculated with counting of CD34‐positive vascular endothelial cells. Results: The expressions of EphA2, MMP‐9, and MVD in the HCC tissues were significantly higher than those in the pericarcinomatous liver tissues (P < 0.01). Statistical analysis showed there were significant correlations between the expressions of EphA2, MMP‐9 and MVD in some classicclinicopathological parameters (i.e. tumor nodule, vein invasion, tumor, node, metastasis stages, extrahepatic metastasis; P < 0.05). The correlation between EphA2 and MMP‐9 expression was positive (r = 0.625, P = 0.011). Tumor MVD was closely associated with EphA2 (r = 0.281, P = 0.01) and MMP‐9 (r = 0.319, P < 0.01) expressions. In particular, EphA2, MMP‐9, and MVD expressions levels were found to be independent prognostic factors after HCC resection. Conclusions: Overexpressions of EphA2 and MMP‐9 relate to tumor progression, metastasis, and prognosis in HCC. The present study suggests that EphA2 is associated with key mediators of angiogenesis and invasion.     

Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus

Purpose: Both platelet-derived endothelial cell growth factor (PD-ECGF) and vascular endothelial growth factor (VEGF) are known to promote the development of new blood vessels, which are fundamental to tumor growth and metastasis. We aimed at evaluating the gene expression of PD-ECGF and VEGF in hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). Patients and methods: Surgical specimens (28 HCC, 28 nontumorous liver tissues and 18 PVTT) were studied by Northern blot analysis. The levels of PD-ECGF mRNA and VEGF mRNA expression were measured by densitometric scanning of the autoradiographs, and they were normalized to the level of expression of an internal control (glyceraldehyde-phosphate dehydrogenase) mRNA. Results: The expression rates of PD-ECGF mRNA in PVTT, HCC and nontumorous liver tissues were 77.8% (14/18), 67.9% (19/28) and 35.7% (10/28), being 88.9% (16/18), 75.0% (21/28) and 17.9% (5/28) respectively for VEGF mRNA. The expressions of PD-ECGF mRNA and VEGF mRNA were higher in HCC with PVTT than when PVTT was absent (P < 0.05). The PVTT was more often seen in patients with positive expression of both PD-ECGF mRNA and VEGF mRNA in HCC than in patients who were positive for only one of these factors or negative for both (P < 0.05). Conclusion: Both PD-ECGF and VEGF correlated well with the formation of PVTT of HCC. Received: 20 June 1999 / Accepted: 20 July 1999     

Angioechographic evaluation of tumor thrombi and the effect of transcatheter arterial embolization in patients with hepatocellular carcinoma

Background: Background: Transcatheter arterial embolization (TAE) is considered to be relatively ineffective in the treatment of portal and/or hepatic vein tumor thrombi associated with hepatocellular carcinoma (HCC). However, we have seen patients with a positively enhanced tumor thrombus on angioechography where necrosis has occurred after TAE. In this study, we compared the angioechographic enhancement of tumor thrombi with the effect of TAE to assess the use of this method in predicting the efficacy of TAE, and in predicting survival. Methods: Angioechography, using a small amount of CO₂ gas injected into the hepatic artery, was performed before TAE in 41 HCC patients with tumor thrombi of the portal vein (PVTT; n= 35) or hepatic vein (HVTT; n= 6). The relationship between the enhancement of the thrombi and the efficacy of TAE was investigated by follow-up ultrasonography. Results: All 13 PVTT that decreased in size had shown positive enhancement (PE) before treatment (P < 0.001), while 6 of the 7 cases (86%) in which the lesions increased in size had shown negative enhancement (NE). The survival of patients with PE was significantly longer than that of patients with NE (P < 0.005). Multivariate analysis identified two clinical variables associated with survival, angioechographic findings of PVTT, and age. There were no correlations between enhancement and HVTT. Conclusions: Determination of enhancement of PVTT on angioechography was useful in predicting the efficacy of TAE treatment of HCC and the survival time. Angioechography may be valuable in treatment decisions for HCC patients with PVTT, especially as a guide to the effectiveness of TAE. Received: March 1, 2001 / Accepted: November 2, 2001     

Contrast-enhanced ultrasonography using Sonazoid to evaluate changes in hepatic hemodynamics in acute liver injury

Background and Aims: Disturbances in hepatic microcirculation are believed to be involved in the mechanisms regulating the progression of acute liver injury (ALI). Evaluation of hepatic hemodynamics in patients with acute liver injury might be helpful in understanding the extent of the intrahepatic microcirculatory disturbances. Therefore, we investigated whether contrast‐enhanced ultrasonography (CEUS) is useful to evaluate the changes in hepatic hemodynamics in patients with ALI. Methods: CEUS was performed in 21 patients with ALI and coagulopathy. Participants were injected with 0.0075 mL Sonazoid/kg body weight, and time‐intensity curves were simultaneously recorded for the hepatic and portal veins. The data were compared with those of 10 healthy volunteers. Results: The arrival time of Sonazoid in the hepatic vein was similar to that in the portal vein in the patients, whereas the arrival time in the hepatic vein was delayed relative to that in the portal vain in the controls (interval between the hepatic and portal vein arrival times, control vs patients 6.74 ± 3.07 s vs 1.13 ± 1.07 s, P < 0.001). Repeated examination revealed that the interval between the hepatic and portal vein arrival times was extended by improvements in hepatic function. The early arrival of Sonazoid in the hepatic vein in the patients is likely to reflect the formation of intrahepatic shunts as a result of hepatic microcirculatory disturbances. Conclusion: CEUS using Sonazoid is a useful method to estimate the changes in hepatic hemodynamics in patients with ALI.     

HBcrAg is a predictor of post‐treatment recurrence of hepatocellular carcinoma during antiviral therapy

Background/Aims: The recurrence rate of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV‐related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence. Methods: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC. Results: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2–7.4) years. In multivariate analysis, serum HBcrAg levels ≥4.8log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94–41.4) and portal vein invasion (3.94, 1.25–12.4) were independent factors for HCC recurrence. The recurrence‐free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC. Conclusion: HBcrAg is a predictor of the post‐treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence.     

Portal venous invasion: the single most independent risk factor for immediate postoperative recurrence of hepatocellular carcinoma

Background and Aim: Despite improvements of treatment in hepatocellular carcinoma (HCC), the recurrence rate after curative hepatic resection still remains remarkably high. An immediate recurrence of HCC after surgery is frustrating. We tried to clarify risks of immediate postoperative recurrence of HCC; that is, within 4 months after curative hepatic resection. Methods: A total of 167 patients with HCC underwent hepatic resection; 60 had immediate postoperative recurrences (IPR group), and 107 had disease‐free survival for more than 5 years (DFS group). Variables were compared between the two groups. Results: Univariate analysis showed the following variables were significant risk factors for immediate postoperative recurrence of HCC: male sex, elevated serum aspartate aminotransferase level, greater amount of blood loss, longer operation time, worse tumor differentiation, higher tumor node metastasis stage, and presence of any of the following: intrahepatic metastasis, tumor‐rupture, portal venous invasion, or microvascular invasion. In multivariate analysis, only portal venous invasion was a significant risk factor (odds ratio = 3.2, P = 0.03, standard error = 0.5, Logistic regression analysis). Conclusions: Portal venous invasion may be the most significant risk factor for immediate postoperative recurrence of HCC. However, accurate assessment of this risk factor may require histological examination, limiting its utility as a preoperative predictor. Further research is necessary to definitively identify preoperative predictors.     

<Emphasis Type="Italic">Lens culinaris</Emphasis> agglutinin-reactive α-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma

Background We histopathologically examined Lens culinaris agglutinin-reactive α-fetoprotein (AFP-L3)-positive hepatocellular carcinoma (HCC) and protein induced by vitamin K absence (PIVKA) II-positive HCC to clarify the efficacy of these markers for predicting a poor prognosis. Methods Serum AFP-L3 and PIVKA II was measured in 110 HCC patients. AFP-L3 was measured by lectin-affinity electrophoresis coupled with antibody-affinity blotting, and PIVKA II by using a high-sensitivity kit. The growth type, capsule formation, capsule infiltration, portal vein invasion, intrahepatic metastasis and histological tumor grade were evaluated pathologically. Results Thirty-eight (35%) HCC patients were AFP-L3-positive, and 63 (57%) were PIVKA II-positive. In AFP-L3-positive HCC, the frequencies of an infiltrative growth type (positive : negative = 66% : 42%, P = 0.027) and a poorly differentiated type (positive : negative = 32% : 6%, P < 0.001) were significantly higher than in AFP-L3-negative HCC. In PIVKA II-positive HCC, the frequencies of an infiltrative growth type (positive : negative = 62% : 28%, P < 0.001), vascular invasion (positive : negative = 63% : 26%, P < 0.001), and intrahepatic metastasis (positive : negative = 38% : 4%, P < 0.001) were significantly higher than in PIVKA II-negative HCC. In both AFP-L3- and PIVKA II-positive HCC, the frequency of a poorly differentiated growth type was significantly higher than in HCC positive for either AFP-L3 or PIVKA II or HCC negative for both AFP-L3 and PIVKA II (both positive : either positive : both negative = 37% : 12% : 0%; P = 0.014, P < 0.001, respectively). Conclusions AFP-L3 was related to progression from moderately differentiated to poorly differentiated HCC, whereas PIVKA II was more specific to vascular invasion. PIVKA II is therefore likely to be a useful indicator of vascular invasion.     

Carbon dioxide‐based portography: An alternative to conventional imaging with the use of iodinated contrast medium

Background and Aim: To clarify the efficacy of carbon dioxide (CO₂) as a contrast material to evaluate portal vein images by percutaneous transhepatic portography (PTP). Methods: Twenty patients (38–76 years; male 13, female 7) with chronic liver diseases were the subjects of this prospective study. Portal venous opacification by PTP was compared between CO₂‐based images and iodinated contrast medium (ICM)‐based images by two independent reviewers, according to the three‐grade scoring; 0 for none, 1 for weak and 2 for sufficient. Results: Total scores of extrahepatic portal veins (137 for CO₂, 93 for ICM), collateral vessels (64 for CO₂, 60 for ICM) and intrahepatic portal veins (69 for CO₂, 76 for ICM) were not statistically significant between CO₂‐based and ICM‐based images (P = 0.0623). Sufficient opacification of superior mesenteric vein was more frequent on CO₂‐based images (none 0, weak 4, sufficient 16) than ICM‐based images (none 19, weak 0, sufficient 1; P < 0.0001). The score was not statistically significant between CO₂‐based and ICM‐based images in portal trunk, splenic vein, inferior mesenteric vein and other collateral vessels. Although opacification grade in the intrahepatic left portal vein was not statistically significant between CO₂‐based and ICM‐based images (P = 0.1515), weak opacification was significantly frequent on CO₂‐based images (weak 10, sufficient 10) compared to ICM‐based images (weak 0, sufficient 20; P = 0.0003) in the intrahepatic right portal vein. Inter‐reviewer agreement was excellent between the two reviewers for CO₂‐based images (kappa = 0.913) and ICM‐based images (kappa = 0.924). Conclusions: Carbon dioxide may be a first‐line contrast material for evaluating portal vein images by PTP.     

Expression of 8‐hydroxy‐2′‐deoxyguanosine in chronic liver disease and hepatocellular carcinoma

Abstract: Reactive oxygen species may be involved in the progression of chronic liver disease and the occurrence of hepatocellular carcinoma (HCC). To clarify whether clinicopathological findings in liver diseases are related to oxidative DNA damage, hepatic expression of the 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) was examined in 75 liver disease patients, which included 32 chronic hepatitis (CH), 13 liver cirrhosis (LC) and 30 HCC patients. The CH patients had higher 8‐OHdG‐positive hepatocytes than LC (P<0.05). In CH and LC, the number of 8‐OHdG‐positive hepatocytes was correlated with alanine aminotransferase and asparate aminotransferase (P<0.01 and P<0.05, respectively). Of 30 HCC cases, 25 cases (83%) showed stronger immunoreactivity than non‐cancerous counterparts. The patients with poorly differentiated HCC had a larger tumor size and higher levels of AFP, and exhibited higher labeling indices of PCNA‐, TUNEL‐ and 8‐OHdG‐positive cells than those with well and moderately differentiated HCC. Our findings suggest that oxidative DNA damage is increased in association with necroinflammation in chronic liver disease and determination of 8‐OHdG is useful in assessing high‐grade malignancy in HCC.     

Intrahepatic dissemination of hepatocellular carcinoma after local ablation therapy

Background/Purpose

We aimed to clarify the histological features of and risk factors for intrahepatic dissemination after local ablation therapy (LAT) for hepatocellular carcinoma (HCC).

Methods

Between April 1992 and December 2005, 192 HCC patients underwent hepatic resection at our department, among whom were 17 patients who had local recurrences after LAT. Eight of these 17 patients had intrahepatic dissemination. The clinical and histological characteristics of these 8 surgically treated patients with intrahepatic dissemination were investigated.

Results

Histologically, numerous intrahepatic metastases were observed, mainly in the same section as the treated tumor, together with main or sectional portal vein tumor thrombi. Before the ablation therapy, the average tumor diameter was 2.1 cm, and 62.5% of the tumors were adjacent to the main or sectional portal vein. In terms of therapeutic factors, 25% of the patients had a prior needle biopsy and 62.5% had insufficient safety margins.

Conclusions

LAT for HCCs (even those less than 3 cm in diameter) adjacent less than 5 mm to the main or sectional portal vein possibly promotes intrahepatic dissemination.