Shuichiro Shiina

An Experimental Study in Dogs

In order to evaluate a possible therapy for hypersplenism, an experiment with animals was done. In nine dogs, 0.6 ml/kg body weight of 5% ethanolamine oleate was injected percutaneously into the spleen under ultrasound guidance. The injection was repeated three times at intervals of 1 week. Three do

Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma

IntroductionThe Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations.MethodsThe working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements.ResultsParticipants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference.

Radiofrequency Ablation for Hepatocellular Carcinoma: 10-Year Outcome and Prognostic Factors

OBJECTIVES:Radiofrequency ablation (RFA) is widely performed for hepatocellular carcinoma (HCC). However, there has been no report on 10-year outcome of RFA. The objective of this study was to report a 10-year consecutive case series at a tertiary referral center.METHODS:We performed 2,982 RFA treatments on 1,170 primary HCC patients and analyzed a collected database.RESULTS:Final computed tomography images showed complete tumor ablation in 2,964 (99.4%) of 2,982 treatments performed for the 1,170 primary HCC patients. With a median follow-up of 38.2 months, 5- and 10-year survival rates were 60.2% (95% confidence interval (CI): 56.7–63.9%) and 27.3% (95% CI: 21.5–34.7%), respectively. Multivariate analysis demonstrated that age, antibody to hepatitis C virus (anti-HCV), Child-Pugh class, tumor size, tumor number, serum des-γ-carboxy-prothrombin (DCP) level, and serum lectin-reactive α-fetoprotein level (AFP-L3) were significantly related to survival. Five- and 10-year local tumor progression rates were both 3.2% (95% CI: 2.1–4.3%). Serum DCP level alone was significantly related to local tumor progression. Five- and 10-year distant recurrence rates were 74.8% (95% CI: 71.8–77.8%) and 80.8% (95% CI: 77.4–84.3%), respectively. Anti-HCV, Child-Pugh class, platelet count, tumor size, tumor number, serum AFP level, and serum DCP level were significantly related to distant recurrence. There were 67 complications (2.2%) and 1 death (0.03%).CONCLUSIONS:RFA could be locally curative for HCC, resulting in survival for as long as 10 years, and was a safe procedure. RFA might be a first-line treatment for selected patients with early-stage HCC.

Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study

Histopathologic examination was done on 18 cases after percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma. In eight cases, the lesion was treated by PEIT alone; in the other ten cases, PEIT was combined with transcatheter arterial embolization. The lesion was completely necrotic in 13 cases, 90% necrotic in four cases, and 70% necrotic in the rest. In addition, PEIT seemed to be effective against intercapsular, extracapsular, and vascular invasions. In the four cases of incomplete necrosis, the viable cancer tissue remained in small tumor nodules around the main tumor, in portions isolated by septa, or along the edge of the lesion. Therefore, ethanol should be injected not only into the center of the lesion, but also into sites close to its edge. Ethanol did not damage noncancerous liver parenchyma distant from injected sites. Local dissemination of the cancer cells was not found in any case. Therefore, PEIT seems to be a valuable therapy and may be an alternative to surgery in some cases.

Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography

Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV‐RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow‐up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person‐year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM ≤10 kPa, of 16.7 (95% confidence interval [CI], 3.71‐75.2; P < 0.001) when LSM 10.1‐15 kPa, 20.9 (95% CI, 4.43‐98.8; P < 0.001) when LSM 15.1‐20 kPa, 25.6 (95%CI, 5.21‐126.1; P < 0.001) when LSM 20.1‐25 kPa, and 45.5 (95% CI, 9.75‐212.3; P < 0.001) when LSM >25 kPa. Conclusions: This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development. (HEPATOLOGY 2009.)

Interferon Therapy after Tumor Ablation Improves Prognosis in Patients with Hepatocellular Carcinoma Associated with Hepatitis C Virus

Context Hepatocellular carcinoma often follows hepatitis C virus infection. Currently available treatments for hepatocellular carcinoma are unsatisfactory. Percutaneous ethanol injection therapy into tumor nodules shows some promise, but recurrence rates are high. Contribution In a carefully selected group of 74 patients with multicentric hepatocellular carcinoma, mild hepatitis C, and mild cirrhosis, patients randomly assigned to receive interferon in addition to ethanol injections showed improved survival at 5 and 7 years, particularly among patients with a sustained virologic response. Cautions Combined treatment of multicentric hepatocellular carcinoma offers the possibility of enhanced survival for carefully selected patients; this study is small, however, and enrolled only patients with low virus levels and mild cirrhosis. The Editors Chronic hepatitis C virus (HCV) infection is a common, frequently asymptomatic disease. Despite the clinically quiescent course of HCV infection, it may slowly progress to cirrhosis and, eventually, to hepatocellular carcinoma (1, 2). Cirrhosis is a major risk factor for the development of hepatocellular carcinoma (3, 4), and 70% to 80% of patients with hepatocellular carcinoma in Japan have HCV infection (5). Current strategies for treating hepatocellular carcinoma include surgical resection, transarterial embolization, percutaneous ethanol injection therapy, radiofrequency wave ablation, and chemotherapy (6-9). Recent studies have shown that percutaneous ethanol injection therapy is effective for hepatocellular carcinoma when the tumors are small (<3 to 5 cm in diameter) and limited in number; survival rates are similar to those obtained with surgery (10-12). Five-year survival rates, however, are poor (30% to 60% for both hepatectomy and percutaneous ethanol injection therapy). Poor prognosis may be the result of the high incidence of tumor recurrence; the cumulative recurrence rate at 5 years is 60% to 100% (10-13). Several studies have evaluated the factors that contribute to the recurrence of hepatocellular carcinoma (12, 13). Occasionally, early recurrence develops adjacent to the treated lesion (local recurrence, 6% to 33% depending on tumor size) (14), but most tumors (80% to 90%) recur at different sites (15). Because hepatocellular carcinoma recurrence and decompensation of underlying liver disease are major problems after medical or surgical treatment, liver transplantation is another option for treating small, unresectable hepatocellular carcinomas in patients with cirrhosis. Studies report 5-year survival rates as high as 75% with liver transplantation (16-18). Interferon therapy has beneficial effects in chronic HCV infection (19, 20). In long-term follow-up studies, sustained virologic responders have remained in remission with normal liver function and improved histologic features of inflammation; in some of these responders, fibrosis even regresses (21, 22). Recently, the frequency of hepatocellular carcinoma in patients receiving interferon therapy has substantially decreased, especially in patients with sustained virologic and biochemical responses (23-25). This decreased frequency has occurred even in patients with cirrhosis (25, 26). Our study evaluated whether complete ablation of neoplastic nodules and administration of antiviral therapy could increase survival rates. Methods Study Design Our prospective study was designed by an eight-member committee in December 1992. The Ethics Committee of the University of Tokyo approved the study. We obtained informed consent from each patient in accordance with the Helsinki declaration. Patients with compensated cirrhosis, three or fewer nodules of hepatocellular carcinoma, and low HCV RNA loads were recruited after complete ablation of the lesions. Eligibility Criteria Inclusion Criteria Hepatitis C virus infection was diagnosed on the basis of identification of anti-HCV antibody using the passive hemagglutination test (Dinabbot, Tokyo, Japan) or enzyme-linked immunosorbent assay (ELISA; Ortho Diagnostic Systems, Tokyo, Japan). Hepatitis C virus RNA was identified by reverse transcriptase polymerase chain reaction (RT-PCR). The serum HCV RNA level was measured by competitive reverse transcriptase (CRT)-PCR according to the method of Kato and colleagues (27); HCV genotype was determined by the method of Okamoto and colleagues (28). Hepatocellular carcinoma was suspected on the basis of several imaging methods, including abdominal ultrasonography, dynamic computed tomography (CT), magnetic resonance imaging (MRI), and arteriography. We confirmed the diagnosis by histologic examination of tumor biopsy specimens obtained from all patients. Evaluation was based on the criteria of the International Working Party (29). In addition, we obtained and evaluated biopsy specimens from non-neoplastic lesions according to the methods of Desmet and colleagues (30). Hepatocellular carcinoma was treated with percutaneous ethanol injection therapy (7, 8, 10). Real-time linear-array scanners were used with 3.5-MHz transducers for the sonographic guidance of needles [21-gauge with a 15-cm or 20-cm needle; Hanako, Tokyo, Japan] into the tumors. Two to 10 mL of 99.5% ethanol was injected into each lesion. Ethanol injection was repeated several times at different sessions. Complete destruction of the nodules was confirmed on dynamic CT 1 month after ethanol injection according to the following criteria: 1) The destructive area was larger than the area of the tumor nodule shown on pretreatment dynamic CT and 2) dynamic CT showed no early-phase contrast enhancement of nodules (7, 8, 10). Inclusion criteria were as follows: 1) hepatocellular carcinoma with three or fewer lesions [verified by histologic examination] and dynamic CTconfirmed complete ablation of hepatocellular carcinoma lesions by percutaneous ethanol injection therapy, 2) detection of HCV RNA by RT-PCR and an HCV RNA load of 2 106 copies/mL or less by CRT-PCR (the cutoff value was based on unpublished data indicating that interferon treatment was effective in patients with HCV RNA loads of 105 copies/50 L of serum by CRT-PCR [27]], 3) platelet count of 50 109 cells/L, 4) leukocyte count of 3 109 cells/L or greater, 5) compensated cirrhosis in ChildPugh stage A, 6) age younger than 70 years, 7) no previous treatment with interferon, and 8) submission of informed consent. Exclusion Criteria Exclusion criteria were as follows: 1) liver diseases due to other causes, such as hepatitis B or primary biliary cirrhosis; 2) HCV RNA load of 2 106 copies/mL or greater by CRT-PCR; 3) severe comorbid diseases, such as heart disease, lung disease, or diabetes mellitus; 4) decompensated cirrhosis in ChildPugh stage B or C; and 5) failure to obtain informed consent. Randomization Patients who enrolled in the study were randomly assigned in a 2:1 ratio to the interferon group or the control group by the controller. We assigned patients to the treatment group or control group by using a randomization list. Interferon Therapy and Follow-up of Patients Interferon Therapy We started interferon therapy with natural interferon- (Sumitomo Pharmaceuticals, Tokyo, Japan) 2 to 3 months after tumor ablation was confirmed. Patients received 6 million U of interferon by intramuscular injection three times weekly for 48 weeks as outpatients. If patients could not tolerate this dose, the interferon dose was reduced to 3 million U. If HCV RNA in serum was still detected by RT-PCR (detection limit, 102 copies/mL) after 24 weeks of interferon therapy and serum alanine aminotransferase (ALT) levels were higher than pretreatment ALT levels, therapy was discontinued. Criteria for Interferon Response We defined the efficacy of interferon therapy virologically and biochemically. Patients who were negative for HCV RNA (as determined by RT-PCR; detection limit, 102 copies/mL) more than 6 months after the completion of interferon therapy were classified as showing a sustained virologic response. Patients with persistently normal ALT levels after the completion of interferon therapy were classified as showing a sustained biochemical response; patients with abnormal ALT levels were classified as showing a nonsustained biochemical response. Follow-up Patients attended a monthly medical consultation at the University of Tokyo Hospital outpatient clinic. Blood biochemical measures, including -fetoprotein (AFP) tumor markers, were measured every 1 to 2 months; ultrasonography was performed every 2 to 3 months; and dynamic CT was performed every 6 months. Recurrence of hepatocellular carcinoma was detected by the finding of abnormal nodules with low or high echogenic appearance on abdominal ultrasonography or by the finding of abnormal density on dynamic CT. The diagnosis was confirmed histologically through ultrasonography-guided fine-needle biopsy of the tumor. Recurrent nodules were divided into two categories [14, 15]: 1) local recurrence, in which the nodule appeared adjacent to the previously treated nodules, suggesting that residual tumor cells had not been completely ablated by percutaneous ethanol injection therapy, or 2) new foci developing at a distant site. New foci of hepatocellular carcinoma, as well as local recurrent nodules at tumor, node, metastasis (TNM) stage I, II, and III, were mainly treated by a second course of percutaneous ethanol injection therapy; local recurrent nodules at TNM stage IV were treated with transarterial chemoembolization or chemotherapy. New development of hepatocellular carcinoma and survival of the patients (tumor recurrence rate and survival rate) were analyzed in relation to the time interval after initial treatment. Statistical Analysis When estimating the sample size, we assumed that 5-year survival in the control group would be 40% according to the data of our previous unpublished study. We predicted that 5-year survival would be increased by 35% as a result of treatment

Radiofrequency ablation for hepatocellular carcinoma in so‐called high‐risk locations

We evaluated the efficacy and safety of radiofrequency (RF) ablation for hepatocellular carcinoma (HCC) in presumably high‐risk locations. Between February 1999 and December 2001, we performed RF ablation on 1,419 nodules in 636 consecutive HCC patients, of which 231 nodules in 207 patients were in high‐risk locations, defined as less than 5 mm from a large vessel or an extrahepatic organ. Eighty‐one patients had a nodule adjacent to a large vessel, 145 patients had a nodule adjacent to an extrahepatic organ, of whom 19 also had one adjacent to a large vessel. Early complications and local tumor progression were analyzed with regard to the location of each nodule. The mean nodule diameter and average number per patient were 27 mm and 2.3, respectively. Early complications, within 30 days after ablation, occurred in 12 of 207 patients (5.8 %) with a nodule in a high‐risk location and in 15 of 429 patients (3.5 %) without (P = .1776). There was no significant difference in local tumor progression rate between nodules in high‐risk locations (1 year: 2.1%, 2 years: 3.1%, 3 years: 3.1%) and those elsewhere (1 year: 0.6%, 2 years: 1.7%, 3 years: 2.5%) (P = .2745). In conclusion, HCC nodules adjacent to a large vessel or extrahepatic organ were treated with RF ablation without compromising the efficacy of the procedure. However, even though without significant difference, some complications occurred at risky locations and need to be carefully considered. (HEPATOLOGY 2006;43:1101–1108.)

Proposal of a new prognostic model for hepatocellular carcinoma: an analysis of 403 patients

Background: The prognosis of hepatocellular carcinoma (HCC) is highly dependent on tumour extension and liver function. Recently, two new prognostic scoring systems—the CLIP score, developed by Italian investigators and the BCLC score, developed in Barcelona—have been widely used to assess prognosis in patients presenting with hepatocellular carcinoma. Each system has its own relative limitations. Aims: To create a new prognostic scoring system which is simple, easy to calculate, and suitable for estimating prognosis during radical treatment of early HCC. Methods: A total of 403 consecutive patients with HCC treated by percutaneous ablation at the Department of Gastroenterology, University of Tokyo Hospital, between 1990 and 1997 were used as the training sample to identify prognostic factors for our patients and used to develop the Tokyo score. As a testing sample, 203 independent patients who underwent hepatectomy at the Department of Hepato-Biliary-Pancreatic Surgery were studied. Prognostic factors were analysed by univariate and multivariate Cox proportional hazard regression. Results: The Tokyo score consists of four factors: serum albumin, bilirubin, and size and number of tumours. Five year survival was 78.7%, 62.1%, 40.0%, 27.7%, and 14.3% for Tokyo scores 0, 1, 2, 3, and 4–6, respectively. The discriminatory ability of the Tokyo score was internally validated by bootstrap methods. The Tokyo score, CLIP score, and BCLC staging were compared by Akaike information criterion and Harrell’s c index among training and testing samples. In the testing sample, the predictive ability of the Tokyo score was equal to CLIP and better than BCLC staging. Conclusions: The Tokyo score is a simple system which provides good prediction of prognosis for Japanese patients with HCC requiring radical therapy.

Nonsurgical treatment of hepatocellular carcinoma: From percutaneous ethanol injection therapy and percutaneous microwave coagulation therapy to radiofrequency ablation

Treatment of hepatocellular carcinoma (HCC) is different from that of other solid tumors, in that surgery plays a limited role while nonsurgical therapies are very instrumental. At our institute, 90% of previously untreated patients have received image-guided percutaneous tumor ablations, such as percutaneous ethanol injection therapy (PEIT), percutaneous microwave coagulation therapy (PMCT) and radiofrequency ablation (RFA). We performed PEIT in 756 patients with HCC. Their survival rates were 89% at 1 year, 64% at 3 years, 39% at 5 years, and 18% at 10 years. With PMCT, survival rates of 122 new patients with HCC were 90% at 1 year, 87% at 2 years, and 68% at 3 years. We performed RFA in 324 patients. RFA required fewer treatment sessions and a shorter hospital stay than PEIT or PMCT to achieve complete necrosis of the lesions. By virtue of their local curability, minimal effect on liver function, and easy repeatability for recurrence, image-guided percutaneous tumor ablations, especially RFA, will be increasingly important in the treatment of HCC.

Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors.

Despite significant advances in the treatment of intrahepatic lesions, the prognosis for patients with hepatocellular carcinoma (HCC) who have extrahepatic metastasis remains poor. The objective of this study was to further elucidate the clinical course and prognostic determinants of patients with this disease.