Disappearance of perihepatic lymph node enlargement after hepatitis C viral eradication with direct-acting antivirals.

Perihepatic lymph node enlargement (PLNE) which has been shown to be negatively associated with hepatocellular carcinoma (HCC) occurrence is frequently observed in chronic liver disease; however, changes in the state of perihepatic lymph nodes after eradication of hepatitis C virus (HCV) have not been investigated yet. We aimed to evaluate this issue. We enrolled 472 patients with chronic HCV infection who achieved viral eradication with direct-acting antivirals (DAA). We investigated whether the status of perihepatic lymph nodes changed before and after HCV eradication (primary endpoint). We also evaluated the association between PLNE and clinical findings such as liver fibrosis or hepatocellular injury before HCV eradication (secondary endpoint). Perihepatic lymph node enlargement was detected in 164 of 472 (34.7%) patients before DAA treatment. Surprisingly, disappearance of PLNE was observed in 23.8% (39 patients) of all PLNE-positive patients after eradication of HCV. Disappearance of PLNE was not associated with baseline clinical parameters or changing rates of clinical findings before and after DAA treatment. At baseline, presence of PLNE was significantly associated with a lower serum HCV-RNA level (P = .03), a higher serum AST level (P = .004) and a higher ALT level (P < .001) after adjustment for sex and age. In conclusion, PLNEs became undetectable after DAA treatment in 23.8% of PLNE-positive patients. Further study with a longer follow-up period is needed to clarify the clinical importance of this phenomenon especially in relationship with the risk of HCC development.

Association between hospital volume and in-hospital mortality following radiofrequency ablation for hepatocellular carcinoma.

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive treatment for hepatocellular carcinoma (HCC). There is increasing evidence of an association between increasing hospital volume and lower postoperative mortality for many surgical procedures, but this is difficult to establish with minimally invasive treatments, where postoperative mortality is low. The aim of this study was to investigate the relationship between hospital volume and in-hospital mortality following RFA using a Japanese nationwide database. METHODS: Data from the Diagnostic Procedure Combination database were analysed from 1 July 2010 to 31 March 2012. Multivariable logistic regression was used to analyse the relationship between hospital volume and in-hospital mortality following RFA, with adjustment for patient background. RESULTS: Some 36 675 patients with HCC were identified in the database. The overall in-hospital mortality rate from RFA was 0·31 per cent. In-hospital mortality was significantly higher in low-volume than high-volume hospitals (odds ratio 2·57, 95 per cent c.i. 1·61 to 4·09; P < 0·001). Higher in-hospital mortality was significantly associated with older age and a higher Charlson Co-morbidity Index score. CONCLUSION: RFA for HCC was associated with acceptably low mortality in Japan, but in-hospital mortality following RFA was affected by hospital procedural volume.

Sharpin promotes hepatocellular carcinoma progression via transactivation of Versican expression.

Sharpin (Shank-associated RH domain-interacting protein, also known as SIPL1) is a multifunctional molecule that participates in various biological settings, including nuclear factor-κB signaling activation and tumor suppressor gene inhibition. Sharpin is upregulated in various types of cancers, including hepatocellular carcinoma (HCC), and is implicated in tumor progression. However, the exact roles of Sharpin in tumorigenesis and tumor progression remain largely unknown. Here we report novel mechanisms of HCC progression through Sharpin overexpression. In our study, Sharpin was upregulated in human HCC tissues. Increased Sharpin expression enhanced hepatoma cell invasion, whereas decrease in Sharpin expression by RNA interference inhibited invasion. Microarray analysis identified that Versican, a chondroitin sulfate proteoglycan that plays crucial roles in tumor progression and invasion, was also upregulated in Sharpin-expressing stable cells. Versican expression increased in the majority of HCC tissues and knocking down of Versican greatly attenuated hepatoma cell invasion. Sharpin expression resulted in a significant induction of Versican transcription synergistically with Wnt/ß-catenin pathway activation. Furthermore, Sharpin-overexpressing cells had high tumorigenic properties in vivo. These results demonstrate that Sharpin promotes Versican expression synergistically with the Wnt/ß-catenin pathway, potentially contributing to HCC development. A Sharpin/Versican axis could be an attractive therapeutic target for this currently untreatable cancer.

Influence of anti-HBc seropositivity on the risk of hepatocellular carcinoma in HCV-infected patients after adjusting for confounding factors.

It is controversial whether past hepatitis B virus infection constitutes an additional risk of hepatocellular carcinoma (HCC) among patients with hepatitis C virus (HCV). The incidence of HCC between 1994 and 2004 was analysed among 1262 patients who were only positive for HCV. The cumulative incidence of HCC was assessed by Kaplan-Meier analysis and the difference between two groups was assessed by the log-rank test. The effect of anti-HBc positivity on the risk of HCC was assessed with multivariate Cox proportional analysis. Anti-HBc was positive in 522 (41.4%) patients. The proportion of male patients (56.7 vs 46.8%, P < 0.001) and mean age (60.8 vs 56.9 years, P < 0.001) were significantly higher in the anti-HBc positive group. HCC developed in 339 patients (mean follow-up 7.0 years), with cumulative incidence rates at 3, 5 and 10 years of 12.7, 24.5 and 41.9% in the anti-HBc positive group and 10.6, 17.7 and 33.4% in the negative group, respectively (P = 0.005). However, anti-HBc seropositivity did not reach statistical significance in multivariate analysis including age and gender (hazard ratio, 1.06; 95% CI, 0.85-1.31; P = 0.63). Anti-HBc positivity and HCC incidence were confounded by male gender and older age.

Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH.

BACKGROUND AND AIMS: Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not been fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. METHODS: 62 patients with naive HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm(2) in males, >90 cm(2) in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients' background, tumour-related factors and liver function-related factors. RESULTS: The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm(2), p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. CONCLUSIONS: Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.

Percutaneous radiofrequency ablation of liver cancer in the hepatic dome using the intrapleural fluid infusion technique.

BACKGROUND: Intrapleural fluid infusion improves ultrasonographic visualization of tumours in the hepatic dome. The aim of this study was to assess the safety and long-term efficacy of ultrasonographically guided percutaneous radiofrequency ablation for tumours in the hepatic dome with intrapleural infusion. METHODS: Of 2575 patients with hepatocellular carcinoma or hepatic metastases treated with radiofrequency ablation, intrapleural fluid infusion was performed in 587 patients for tumours in the hepatic dome. After the tip of a 14-G metallic needle was positioned in the pleural cavity under ultrasonographic guidance, 500-1000 ml of 5 per cent glucose solution was infused in 5-15 min. Radiofrequency ablation was performed using an internally cooled electrode. Long-term results were evaluated in 347 patients with a single hepatocellular carcinoma who were naive to any treatment. RESULTS: Intrapleural fluid infusion was successfully performed in all 587 patients. The major complication rate on a per tumour basis was similar for patients treated with and without intrapleural infusion (1.6 versus 1.6 per cent; P = 0.924). The overall and recurrence-free survival were both similar for naive patients with a single hepatocellular carcinoma treated with and without intrapleural infusion (P = 0.429 and P = 0.109 respectively). Intrapleural infusion was not associated with lower overall survival in multivariable analysis. CONCLUSION: With intrapleural fluid infusion, radiofrequency ablation for tumours in the hepatic dome was safe and effective, resulting in satisfactory overall and recurrence-free survival.

Artificial ascites technique for percutaneous radiofrequency ablation of liver cancer adjacent to the gastrointestinal tract.

BACKGROUND: Percutaneous radiofrequency ablation (RFA) of liver tumours adjacent to the gastrointestinal tract is controversial. This study assessed the value of an intraperitoneal water infusion (artificial ascites) technique for percutaneous RFA of such tumours. METHODS: Before ablation in 52 patients (55 treatments, 58 tumours), between 250 and 3000 (mean 681) ml 5 per cent glucose solution was infused into the abdominal cavity using a 14-G needle, with the aim of preventing thermal injury by separating the liver from the gastrointestinal tract. RESULTS: There were no adverse events associated with the artificial ascites technique. In 43 (78 per cent) of the 55 treatments, the liver and gastrointestinal tract were separated successfully. In the other 12 treatments, in which the separation was not confirmed by real-time ultrasonography, there was one case of perforation of the ascending colon after RFA; adhesion of the liver and colon resulting from previous laparotomy may have been related to the injury. CONCLUSION: Production of artificial ascites can be undertaken safely, making RFA safe and effective for hepatic tumours adjacent to the gastrointestinal tract. In patients with possible postoperative adhesions, confirmation of separation of the liver from surrounding organs is mandatory to avoid thermal injury.

Extrahepatic biliary obstruction after percutaneous tumour ablation for hepatocellular carcinoma: aetiology and successful treatment with endoscopic papillary balloon dilatation.

BACKGROUND AND AIMS: Percutaneous tumour ablation (PTA), such as ethanol injection and radiofrequency ablation, is now recognised as a primary treatment for hepatocellular carcinoma (HCC). Although PTA is a relatively safe procedure, it can cause biliary obstruction as a rare complication. As patients with cirrhosis undergoing surgery or endoscopic retrograde cholangiopancreatography/sphincterotomy have a high mortality rate from bleeding, we adopted the use of endoscopic papillary balloon dilatation (EPBD) in these patients and now report the results. We retrospectively analysed the incidence of biliary obstruction after PTA and the efficacy of treatment with EPBD. PATIENTS AND METHODS: A total of 1043 patients with HCC were treated by PTA, of whom 538 were treated with transarterial embolisation with up to eight years of follow up. RESULTS: There were 17 (1.6%) cases of hilar obstruction due to tumour progression and 35 (3.4%) cases of extrahepatic obstruction. Apart from the expected causes of biliary obstruction (haemobilia n = 11, gallstones n = 11, and three miscellaneous causes), we found that 10 patients had obstruction due to biliary casts. This is the first description of biliary casts after percutaneous tumour ablation therapy. Extrahepatic biliary obstruction by procedure related haemobilia occurred within three days of PTA while other causes occurred between 0 and 17 (average 4.9) months. Biliary casts occurred more frequently after ethanol injection than after radiofrequency ablation. EPBD successfully dissipated biliary obstruction in 33 of 35 cases, while two died due to hepatic failure despite successful drainage. CONCLUSIONS: Extrahepatic biliary obstruction is an uncommon complication after PTA for HCC, and can be safely and effectively treated with EPBD, despite impaired liver function.

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.

Benefit of interferon therapy in hepatocellular carcinoma prevention for individual patients with chronic hepatitis C.

BACKGROUND: An increase in the incidence of hepatocellular carcinoma (HCC) in Japan since the 1980s suggests an imminent outbreak in other countries where viral spread occurred more recently. Interferon therapy for chronic hepatitis C, in general, has been shown to prevent HCC. AIMS: To determine the scale of benefit in individual patients. SUBJECTS: Histologically proven chronic hepatitis C patients in the Inhibition of Hepatocarcinogenesis by Interferon Therapy (IHIT) cohort (Ann Intern Med 1999;131:174), as updated in March 2003. METHODS: The lifetime risk for HCC was calculated based on HCC incidence rates, stratified by sex, age, fibrosis stage, and outcome of interferon therapy. The gain in HCC free survival was defined as the difference between expected HCC free survival with sustained virological response and that without. RESULTS: The gain in HCC free survival was greater when a patient was younger and fibrosis was more advanced. For example, a 30 year old male with F3 fibrosis gained 12.4 years by attaining sustained response while a patient with F1 fibrosis older than 60 years gained less than one year. For a treatment protocol with a given sustained response rate, prior estimation of the gain can be obtained by multiplying the calculated HCC free survival for responders by the response rate. CONCLUSIONS: The gain in HCC free survival may serve as an indicator of the benefit of interferon therapy in terms of HCC prevention and be useful in the consideration of indication and selection of treatment protocol for individual patients.

Hepatocellular carcinoma depicted as hypoattenuation on CT hepatic arteriography (CTA) and hyperattenuation on CT during arterial portography (CTAP).

We report a 68-year-old man with three nodules of hepatocellular carcinoma (HCC) in a cirrhotic liver; the largest nodule was 3.0cm in diameter. The nodules showed hypoattenuation on computed tomography (CT) hepatic arteriography (CTA) and hyperattenuation on CT during arterial portography (CTAP), indicating that the dominant vascularity of the HCC nodules may have been the portal vein. A biopsy specimen obtained from the nodules showed well differentiated HCC (Edmondson-Steiner grade I). The imaging findings of the nodules on both CTA and CTAP are unusual, in spite of the rather large size, so this seemed suggestive of the hemodynamic properties of relatively large nodules of well differentiated HCC.

[Percutaneous tumor ablation therapy for the advanced stage of HCC].

We have performed percutaneous tumor ablation (PTA) including percutaneous ethanol injection therapy (PEIT) for 90% of the patients with hepatocellular carcinoma. Until December 1998, the 793 patients received PTA, 5 years survival rate reached 39.8%. Excluding the patients with Child C whose hepatic function were extremely low, 5 years survival rate reached to the level of 41.2%. Since 5 years survival rate in stage IV-A reached 24.4%, the patients of stage IV-A may be considered to have an indication for PTA. We have confirmed the effectiveness of the local treatment including radiotherapy for advanced hepatocellular carcinoma with portal vein invasion. We are attempting to perform PTA for the extra-hepatic lesions that had no indication of other treatment. However the indication of PTA is limited by the presence of diffuse nodules, exacerbation of the hepatic function, or tumor invasion to portal vein, bile duct, inferior vena cava.

Pleural lavage cytology immediately after thoracotomy and before closure of the thoracic cavity for lung cancer without pleural effusion and dissemination: clinicopathologic and prognostic analysis.

BACKGROUND: The significance of intraoperative pleural lavage cytology (PLC) in lung cancer patients without malignant effusion remains undetermined in terms of staging, prognosis, and local management. METHODS: PLC was performed both after thoractomy and before closure of the thoracic cavity in 325 patients with lung cancer without malignant pleurisy. RESULTS: According to the PLC results (positive [+] or negative [-] after thoracotomy/before closure), the patients were classified as follows: group A (-/-), 262 patients; group B (+/-), 19; group C (-/+), 22; and group D (+/+), 22. In comparison with group A, group C showed more advanced stage with aggressive nodal involvement, and group D showed more advanced lung cancer related to pleural and nodal involvement, whereas group B showed characteristics similar to those of group A. The rate of pleural recurrence in group D was the highest (26%). In particular, pleural recurrence was seen in the patients with a relatively large number of adenocarcinoma cells in PLC after thoractomy. The patients in groups C and D, especially those with adenocarcinoma, showed poorer prognosis, but in a multivariate analysis, PLC status was not an independent prognostic factor. CONCLUSIONS: PLC status after thoractomy provides useful information in the detection of high-risk subgroup for pleural recurrence. Although PLC status is closely associated with survival, its prognostic value is not independent.

bcl-2 oncoprotein in surgically resected non-small cell lung cancer: possibly favorable prognostic factor in association with low incidence of distant metastasis.

BACKGROUND: The bcl-2 oncoprotein serves a regulatory function in permitting several cell types to die in an apoptotic process. Its overexpression probably plays a role in tumorigenesis and tumor development. The aim of this study was to determine the clinicopathological and prognostic significance of the bcl-2 oncoprotein in patients with nonsmall cell lung cancer (NSCLC). METHODS: Immunostaining for bcl-2 oncoprotein was performed on 182 operable NSCLCs. RESULTS: Thirty-six patients (19.8%) showed a positive immunostaining for bcl-2 oncoprotein. Histologically, its incidence was higher in squamous cell carcinomas (29.6%). Its expression status was inversely correlated with tumor development-associated parameters such as tumor stage in NSCLCs, especially in squamous cell carcinomas, bcl-2 positive patients with NSCLCs, especially squamous cell carcinomas, showed better overall survival and disease-free survival (DFS). In a multivariate analysis, this oncoprotein status had prognostic value in DFS for NSCLCs and in overall survival for squamous cell carcinomas. The recurrence of bcl-2 positive NSCLCs was significantly uncommon in distant extrathoracic organs. CONCLUSIONS: The expression of bcl-2 oncoprotein in NSCLCs may be an early event of tumor development, especially in squamous cell carcinomas, and may be of importance in determining tumor progression and prognosis.

Estimation of serum level of pS2 protein in patients with lung adenocarcinoma.

We measured pS2 protein in the serum of patients with adenocarcinoma and non-adenocarcinoma types of lung cancer, non-cancerous lung lesions, and the control sera. Although the serum pS2 protein level in patients with lung adenocarcinoma was significantly higher than that in patients with other diseases, as well in control samples, it had little clinical value as a screening tumor marker because the levels in control samples showed a wide range of variation. However, analysis according to the histological subtype of lung adenocarcinoma, ordinary and bronchioloalveolar, revealed a high serum level of pS2 protein in several patients with advanced stage disease in the former, and mucus-producing goblet cell subtypes in the latter, which showed strong pS2 protein expression in tissues, whose serum levels diminished to the control level after resection. Thus, the serum levels of pS2 protein may be a useful marker of tumor burden in selected patients with lung adenocarcinoma.

[Percutaneous ethanol injection therapy for small hepatocellular carcinoma].

Hepatocellular carcinoma is different from other solid tumors. Because of concomitant cirrhosis or multiple lesions, most hepatocellular carcinoma is unresectable. Still worse, hepatocellular carcinoma frequently recurs after surgical resection; the 5-year cumulative recurrence rate is 70-90% even after curative hepatectomy. The situation is similar in small hepatocellular carcinoma 2 cm or less in diameter. Thus, non-surgical treatment plays an important role. At present, we think that percutaneous ethanol injection therapy (PEIT) is best for the treatment of hepatocellular carcinoma because of its local curativity, minimal adverse effect on liver function, and the easy feasibility of repeated treatment for recurrence. We have recently treated about 85% of hepatocellular carcinoma cases by PEIT and have achieved satisfactory long-term results. Here we describe our results in PEIT for small hepatocellular carcinoma. By the end of December 1995, we performed PEIT on 410 patients with hepatocellular carcinoma. Among them, 140 patients were diagnosed as having small hepatocellular carcinoma 2 cm or less in diameter. The 1-, 3-, 5-, 7-, and 10-year survival rates of the 140 patients were 93%, 73%, 55%, 51%, and 32%, respectively. Furthermore, in 83 patients who had a single, small hepatocellular carcinoma 2 cm or less in diameter, the 1-, 3-, 5-, 7-, and 10-year survival rates were 92%, 82%, 72%, 66%, and 66%, respectively. Thus PEIT achieved satisfactory long-term survival rates in the treatment of small hepatocellular carcinoma.