Hiroshi Kasugai

Validation of a New Prognostic Staging System for Hepatocellular Carcinoma: the JIS Score Compared With the CLIP Score

The Japan Integrated Staging score (JIS score), which combines the Child‐Turcotte‐Pugh classification and tumor‐node‐metastasis staging, has been proposed as a better prognostic staging system for hepatocellular carcinoma (HCC) than the Cancer of the Liver Italian Program (CLIP) scoring system. In this study, validation was performed among a larger patient population. A total of 4,525 consecutive patients with HCC who had been diagnosed at five institutions were included. Stratification ability, prognostic predictive power, and reproducibility were analyzed and compared with results from the CLIP scoring system. Only 45% (1,951 of 4,525) of all patients were categorized as early stage HCC according to JIS score (0 or 1), whereas 63% (2,878 of 4,525) of the patients were categorized as having a CLIP score of 0 or 1. Significant differences in survival curves were not observed among CLIP scores 3 to 6. In contrast, survival curves showed significant differences among all the JIS scores. The same JIS scoring subgroups showed a similar prognosis, and good internal reproducibility was observed in each of the institutions. Multivariate analysis of the prognosis in all 4,525 patients proved the JIS score to be the best prognostic factor. Furthermore, the Akaike information criteria proved that the JIS scoring system was statistically a better model for predicting outcome than the CLIP scoring system. In conclusion, the stratification ability and prognostic predictive power of the JIS score were much better than that of the CLIP score and were simple to obtain and remember. (HEPATOLOGY 2004; 40:1396–1405.)

A new approach to chemoembolization therapy for hepatoma using ethiodized oil, cisplatin, and gelatin sponge

This article reports on a new approach to hepatic arterial chemoembolization therapy using ethiodized oil (Lipiodol, Ultra Fluide), cisplatin, and gelatin sponge (Gelfoam, Upjohn, Kalamazoo, MI) for hepatocellular carcinoma (HCC). The anticancer effects of this therapy on 20 patients who underwent subsequent hepatic resection were evaluated mainly by histologic examination. All main tumors were reduced in size following this therapy. It is notable that in 65% of the patients the tumor size was reduced to less than 50% of that before therapy. All the values of serum α‐fetoprotein (AFP) in the patients who exhibited pretreatment levels exceeding 100 ng/ml dropped by more than 50%, and in 55% of them it fell below 20 ng/ml. The concentration of platinum in the tumor tissue was significantly higher than that in the nontumorous tissue. In 15 of 20 patients (75%), the main nodules were completely necrotic. Thirteen of the patients had daughter nodules and/or small intrahepatic metastases (Group A); nine had tumor emboli in the portal (hepatic) vein (Group B); 17 had intracapsular invasions (Group C); and ten had extracapsular invasions (Group D). The ratios of patients with completely necrotic cancer cells in Group A were nine of 13 (69%); in Group B, seven of nine (78%); in Group C, 11/17 (65%); and in Group D, four of 10 (40%). In eight of the 20 patients (40%) no viable cancer cells were recognized at any foci. Lesions other than those with extracapsular invasion could be considerably eliminated with this form of therapy. It is expected that this method will become the therapy of choice not only for palliative treatment but also for preoperative treatment.

Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil

The therapeutic effectiveness of transcatheter arterial embolization (TAE) with intraarterial infusion of cisplatin/ethiodized oil mixture in treatment of resectable and unresectable hepatocellular carcinoma was compared with TAE with intraarterial infusion of doxorubicin mixed with and without ethiodized oil. The series included 97 patients with unresectable hepatocellular carcinoma and 40 patients with resectable hepatocellular carcinoma. With TAE using doxorubicin infusion, a partial response of the tumor was seen in only 11%, and the 2-yr survival was calculated to be only 5%. Histologic examination of the specimens obtained by hepatectomy also showed that this treatment was relatively ineffective in daughter tumor and portal tumor thrombi. In contrast, TAE with infusion of cisplatin/ethiodized oil mixture significantly increased the rate of partial response (38%), and significantly prolonged the 2-yr survival (45%). Histologically this treatment gave severe necrosis in daughter tumors (69%) and tumor thrombi (78%) as well as main tumor (75%). This treatment was significantly better than TAE with doxorubicin and ethiodized oil infusion in terms of the tumor regression and histologic responses of main tumor and portal vein tumor thrombi, but not in terms of the 2-yr survival. However, 2 patients (8%) died within 4 wk of the latter treatment, whereas no deaths were reported after the former treatment. Therefore, TAE combined with intraarterial infusion of cisplatin/ethiodized oil mixture may be a safe and useful treatment modality for hepatocellular carcinoma.

Multicenter prospective analysis of newly diagnosed hepatocellular carcinoma with respect to the percentage of Lens culinaris agglutinin-reactive α-fetoprotein1

Background and Aim: The Lens culinaris agglutinin‐reactive fraction of α‐fetoprotein (AFP‐L3) has been reported to be a highly useful marker for hepatocellular carcinoma (HCC) compared with a conventional serum AFP concentration, which allows earlier detection of HCC compared with using other imaging modalities and predicting prognosis after therapy. A collaborative prospective study involving nine Japanese hospitals was conducted to analyze the relationships between the tumor characteristics of a HCC patient and the percentage of AFP‐L3/AFP total at the initial detection.

Diagnostic Accuracy of Imaging for Liver Cirrhosis Compared to Histologically Proven Liver Cirrhosis

Objective: To evaluate the diagnostic accuracy of liver cirrhosis by imaging modalities, including CT, MRI and US, compared to results obtained from histopathological diagnoses of resected specimens. Materials and Methods: CT, MRI and US examinations of 142 patients with chronic liver disease who underwent surgery for complicated hepatocellular carcinoma (<3 cm in diameter) in 10 institutions were blindly reviewed in a multicenter study by three radiologists experienced in CT, MRI and US. The images were evaluated for five imaging parameters (irregular or nodular liver surface, blunt liver edge, liver parenchymal abnormalities, liver morphological changes and manifestations of portal hypertension) using a severity scale. The diagnostic imaging impression score was also calculated. Patients were histologically classified into chronic hepatitis (CH; n = 54), liver cirrhosis (LC; n = 71) and pre-cirrhosis (P-LC; n = 17) by three pathologists, independently, who reviewed the resected liver specimens. The results of the three imaging methods were compared to those from histological diagnoses, and a multivariate analysis (stepwise forward logistic regression analysis) was performed to identify independent predictive signs of cirrhosis. The diagnostic efficacies for LC and early cirrhosis were also compared among CT, MRI and US using a receiver-operating characteristic (ROC) curve analysis. Results: The differences in the five imaging parameters evaluated by CT, MRI and US between LC and CH were statistically significant (p < 0.001) except for the manifestations of portal hypertension on US. Irregular or nodular surface, blunt edge or morphological changes in the liver were selected as the best predictive signs for cirrhosis on US whereas liver parenchymal abnormalities, manifestations of portal hypertension and morphological changes in the liver were the best predictive signs on MRI and CT by multivariate analysis. The predictive diagnostic accuracy, sensitivity and specificity in discriminating LC from CH based on the best predictive signs were 71.9, 77.1 and 67.6% by CT; 67.9, 67.5 and 68.3% by MRI, and 66.0, 38.4 (lower than CT and MRI, p =0.001) and 88.8% (higher than CT and MRI, p =0.001)by US. According to the imaging impression scoring system, diagnostic accuracy, sensitivity and specificity were 67.0, 84.3 and 52.9% by CT; 70.3, 86.7 and 53.9% by MRI, and 64.0, 52.4 (lower than CT and MRI, p =0.0001) and 73.5% (higher than CT and MRI, p < 0.003) by US. ROC analysis showed that MRI and CT were slightly superior to US in the diagnosis of LC but no statistically significant difference was found between them. For the pathological diagnosis of P-LC, cirrhosis was diagnosed in 59.5, 46.7 and 41.7% of the P-LC cases by US, CT and MRI, respectively, with no significant difference among these methods. Conclusion: US, CT and MRI had different independent predictive signs for the diagnosis of LC. MRI and CT were slightly superior to US in predicting cirrhosis, especially regarding sensitivity. Noninvasive imaging techniques play an important role in the diagnosis of cirrhosis, especially in the evaluation of P-LC.

Severe Complications of Radiofrequency Ablation Therapy for Hepatocellular Carcinoma: An Analysis of 3,891 Ablations in 2,614 Patients

Objective: To clarify information on and frequency of complications as well as mortality rate after radiofrequency ablation (RFA) for hepatocellular carcinoma.Methods: The results of a questionnaire obtained mainly from members of the Osaka Liver Cancer Study Group at 43 departments of 38 facilities were analyzed in order to clarify the current status of RFA, and information on and frequency of complications and death occurring after RFA. Results: Between January 1999 and May 2002, a total of 3,891 RFA therapies were performed percutaneously in 2,542 patients, laparoscopically in 23, and operatively in 49 (2,614 patients in total). Complications were observed in 207 of 2,614 patients (7.9%), and 9 (0.3%) died within 3 months after RFA. Among these 9 nonsurvivors, 3 had liver failure, 3 rapid progression and sarcomatous changes, 1 biliary injury, 1 gastrointestinal bleeding, and 1 acute myocardial infarction. The departments that treated larger numbers of patients per month had a smaller number of complications and deaths. Conclusion: It is possible that complications of RFA can be reduced by gathering experience.

Regional therapy in the management of intrahepatic recurrence after surgery for hepatoma.

The significance of regional therapy against the intrahepatic recurrence for hepatocellular carcinoma (HCC) was evaluated. During the past 6 years, 101 patients who had radical operations for HCC (liver cirrhosis, 75%; chronic hepatitis, 22%) were followed. Forty-seven patients (47%) had recurrences; the liver was the site of first recurrence in 43 patients and distant site recurrence in four patients. In the patients where the liver was the recurrent site, 33 patients (77%) received regional therapies for an aggregate total of 60 times. Transcatheter arterial chemoembolization was chosen as the first preferred therapy against recurrence in the liver in 30 of 33 patients (91%). Postrecurrence survival of the patients treated with regional therapy was significantly better than disease-free survival (p less than 0.001). Disease-free survival after surgery, postrecurrence survival, and postsurgery survival were compared in the patients treated with regional therapy and untreated patients. Fifty per cent survival after recurrence of the treated patients was 27 months, and that of the untreated patients was 3 months. Postrecurrence survival (p less than 0.001) and postsurgery survival (p less than 0.01) of the treated patients were significantly better than those of the untreated patients. To obtain successful long-term survival after surgery for the cirrhotic patients with HCC, it is necessary to repeat active regional therapies against the recurrent liver.

Effect of vitamin K2 on the recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is characterized by frequent recurrence, even after curative treatment. Vitamin K2, which has been reported to reduce HCC development, may be effective in preventing HCC recurrence. Patients who underwent curative ablation or resection of HCC were randomly assigned to receive placebo, 45 mg/day, or 90 mg/day vitamin K2 in double‐blind fashion. HCC recurrence was surveyed every 12 weeks with dynamic computed tomography/magnetic resonance imaging, with HCC‐specific tumor markers monitored every 4 weeks. The primary aim was to confirm the superiority of active drug to placebo concerning disease‐free survival (DFS), and the secondary aim was to evaluate dose‐response relationship. Disease occurrence and death from any cause were treated as events. Hazard ratios (HRs) for disease occurrence and death were calculated using a Cox proportional hazards model. Enrollment was commenced in March 2004. DFS was assessed in 548 patients, including 181 in the placebo group, 182 in the 45‐mg/day group, and 185 in the 90‐mg/day group. Disease occurrence or death was diagnosed in 58, 52, and 76 patients in the respective groups. The second interim analysis indicated that vitamin K2 did not prevent disease occurrence or death, with an HR of 1.150 (95% confidence interval: 0.843‐1.570, one‐sided; P = 0.811) between the placebo and combined active‐drug groups, and the study was discontinued in March 2007.

Transarterial chemotherapy alone versus transarterial chemoembolization for hepatocellular carcinoma: A randomized phase III trial

BACKGROUND/AIMS Transcatheter arterial chemoembolization (TACE) is a combination of transarterial infusion chemotherapy (TAI) and embolization, and has been widely used to treat patients with hepatocellular carcinoma (HCC). However, since the impact of adding embolization on the survival of patients treated with TAI had never been evaluated in a phase III study, we conducted a multi-center, open-label trial comparing TACE and TAI to assess the effect of adding embolization on survival. METHODS Patients with newly diagnosed unresectable HCC were randomly assigned to either a TACE group or a TAI group. Zinostatin stimalamer was injected into the hepatic artery, together with gelatin sponge in the TACE group and without gelatin sponge in the TAI group. Treatment was repeated when follow-up computed tomography showed the appearance of new lesions in the liver or re-growth of previously treated tumors. RESULTS Seventy-nine patients were assigned to the TACE group, and 82 were assigned to the TAI group. The two groups were comparable with respect to their baseline characteristics. At the time of the analysis, 51 patients in the TACE group and 58 in the TAI group had died. The median overall survival time was 646 days in the TACE group and 679days in the TAI group (p=0.383). CONCLUSIONS The results of this study suggest that treatment intensification by adding embolization did not increase survival over TAI with zinostatin stimalamer alone in patients with HCC.

Cell features and patterns in fine-needle aspirates of hepatocellular carcinoma

The values of the cytologic features of individual cells and cellular patterns in aspirated materials in the diagnosis of 49 hepatocellular carcinomas (HCC) were investigated. Excellent cytologic specimens were obtained by percutaneous aspiration biopsy with a heparinized fine 22‐gauge needle. In the well‐differentiated type of HCC, a correct diagnosis of malignancy was difficult from the cytologic features of individual cells because of their resemblance to normal hepatocytes. In contrast, in moderately differentiated and poorly differentiated types of HCC, a correct diagnosis of malignancy was easily made from the features of individual cells, but there was little or no cytologic evidence of the hepatic origin of the cells. Comparison of histologic and cytologic findings in aspirated materials obtained from the same patients showed that the cellular patterns seen in cytologic specimens faithfully reflected the histologic structures of HCC. Various characteristic cellular patterns were recognized only in specimens obtained from patients with HCC, but not in those from patients with benign liver diseases. These cellular patterns were very useful not only for diagnosis of malignancy, but also for identification of the hepatic origin of cells. A combination of the features of individual cells and of characteristic cellular patterns raised the diagnostic rates for well‐, moderately, and poorly differentiated types of HCC to 90.5%, 100%, and 100%, respectively. Cancer 58:321–328, 1986.