Prognostic grade for resecting hepatocellular carcinoma: multicentre retrospective study.

BACKGROUND: Surgical treatment for hepatocellular carcinoma (HCC) is advancing, but a robust prediction model for survival after resection is not available. The aim of this study was to propose a prognostic grading system for resection of HCC. METHODS: This was a retrospective, multicentre study of patients who underwent first resection of HCC with curative intent between 2000 and 2007. Patients were divided randomly by a cross-validation method into training and validation sets. Prognostic factors were identified using a Cox proportional hazards model. The predictive model was built by decision-tree analysis to define the resection grades, and subsequently validated. RESULTS: A total of 16 931 patients from 795 hospitals were included. In the training set (8465 patients), four surgical grades were classified based on prognosis: grade A1 (1236 patients, 14.6 per cent; single tumour 3 cm or smaller and anatomical R0 resection); grade A2 (3614, 42.7 per cent; single tumour larger than 3 cm, or non-anatomical R0 resection); grade B (2277, 26.9 per cent; multiple tumours, or vascular invasion, and R0 resection); and grade C (1338, 15.8 per cent; multiple tumours with vascular invasion and R0 resection, or R1 resection). Five-year survival rates were 73.9 per cent (hazard ratio (HR) 1.00), 64.7 per cent (HR 1.51, 95 per cent c.i. 1.29 to 1.78), 50.6 per cent (HR 2.53, 2.15 to 2.98), and 34.8 per cent (HR 4.60, 3.90 to 5.42) for grades A1, A2, B, and C respectively. In the validation set (8466 patients), the grades had equivalent reproducibility for both overall and recurrence-free survival (all P < 0.001). CONCLUSION: This grade is used to predict prognosis of patients undergoing resection of HCC.

Significance of the surgical hepatic resection margin in patients with a single hepatocellular carcinoma.

BACKGROUND: The impact of a wide surgical margin on the outcome of patients with hepatocellular carcinoma (HCC) has not been evaluated in relation to the type of liver resection performed, anatomical or non-anatomical. The aim of this study was to evaluate the impact of surgical margin status on outcomes in patients undergoing anatomical or non-anatomical resection for solitary HCC. METHODS: Data from patients with solitary HCC who had undergone non-anatomical partial resection (Hr0 group) or anatomical resection of one Couinaud segment (HrS group) between 2000 and 2007 were extracted from a nationwide survey database in Japan. Overall and recurrence-free survival associated with the surgical margin status and width were evaluated in the two groups. RESULTS: A total of 4457 patients were included in the Hr0 group and 3507 in the HrS group. A microscopically positive surgical margin was associated with poor overall survival in both groups. A negative but 0-mm surgical margin was associated with poorer overall and recurrence-free survival than a wider margin only in the Hr0 group. In the HrS group, the width of the surgical margin was not associated with patient outcome. CONCLUSION: Anatomical resection with a negative 0-mm surgical margin may be acceptable. Non-anatomical resection with a negative 0-mm margin was associated with a less favourable survival outcome.

ANTECEDENTES: El impacto de un margen quirúrgico (surgical margin, SM) amplio en el resultado de pacientes con carcinoma hepatocelular (hepatocellular carcinoma, HCC) no ha sido evaluado en relación con el tipo de resección hepática realizada: anatómica o no anatómica. El objetivo del presente estudio fue evaluar el impacto del estado del SM en los resultados en pacientes sometidos a resección anatómica o no anatómica por un HCC solitario. MÉTODOS: Los datos de pacientes con un HCC solitario sometidos a resección parcial no anatómica (grupo Hr0) o resección anatómica de un segmento de Couinaud (grupo HrS) entre 2000 y 2007 se obtuvieron a partir de una base de datos nacional de Japón. En los grupos Hr0 y HrS se evaluaron la supervivencia global y la supervivencia libre de recidiva asociadas al estado microscópico del SM y a la amplitud del SM. RESULTADOS: Se incluyeron un total de 4.457 pacientes en el grupo Hr0 y 3.507 en el grupo HrS. Un SM microscópico positivo se asoció con una pobre supervivencia global en ambos grupos. Un SM negativo, pero a una distancia de 0 mm se asoció con una peor supervivencia global y libre de recidiva en comparación con aquellos asociados a un SM más amplio, solo en el grupo Hr0. En el grupo HrS, la amplitud del SM no se asoció con los resultados del paciente. CONCLUSIÓN: La resección anatómica con un SM negativo a una distancia de 0 mm puede ser aceptable. La resección no anatómica con un SM negativo a una distancia de 0 mm se asoció con resultados de supervivencia menos favorables.

Lenalidomide enhances the function of chimeric antigen receptor T cells against the epidermal growth factor receptor variant III by enhancing immune synapses.

The epidermal growth factor receptor variant III (EGFRvIII) is exclusively expressed on the cell surface in ~50% of glioblastoma multiforme (GBM). This variant strongly and persistently activates the phosphatidylinositol 3-kinase-Akt signaling pathway in a ligand-independent manner resulting in enhanced tumorigenicity, cellular motility and resistance to chemoradiotherapy. Our group generated a recombinant single-chain variable fragment (scFv) antibody specific to the EGFRvIII, referred to as 3C10-scFv. In the current study, we constructed a lentiviral vector transducing the chimeric antigen receptor (CAR) that consisted of 3C10-scFv, CD3ζ, CD28 and 4-1BB (3C10-CAR). The 3C10-CAR-transduced peripheral blood mononuclear cells (PBMCs) and CD3(+) T cells specifically lysed the glioma cells that express EGFRvIII. Moreover, we demonstrated that CAR CD3(+) T cells migrated to the intracranial xenograft of GBM in the mice treated with 3C10-CAR PBMCs. An important and novel finding of our study was that a thalidomide derivative lenalidomide induced 3C10-CAR PBMC proliferation and enhanced the persistent antitumor effect of the cells in vivo. Lenalidomide also exhibited enhanced immunological synapses between the effector cells and the target cells as determined by CD11a and F-actin polymerization. Collectively, lentiviral-mediated transduction of CAR effectors targeting the EGFRvIII showed specific efficacy, and lenalidomide even intensified CAR cell therapy by enhanced formation of immunological synapses.

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.

Power Doppler signals after percutaneous ethanol injection therapy for hepatocellular carcinoma predict local recurrence of tumors: a prospective study using 199 consecutive patients.

BACKGROUND/AIMS: This study was prospectively conducted to elucidate the relationship between pre-/post-treatment power Doppler signals of hepatocellular carcinoma (HCC) and local recurrence. METHODS: One hundred ninety-nine consecutive patients with 359 HCC lesions receiving percutaneous ethanol injection therapy (PEIT) as a first-line option were enrolled. Arterial power Doppler signals in the tumor were found in 130 nodules, but not detected in 229. After confirmation of complete tumor necrosis on dynamic CT, Doppler signals in nodules were re-evaluated. Patients received periodical examinations to detect HCC recurrence. RESULTS: Local HCC recurrence was observed in 36 lesions; 22%(28/130) of the pretreatment signal positive lesions, in contrast to 3.5% (8/229) of the pretreatment signal negative lesions (P < 0.01). Out of 130 signal positive nodules, signals disappeared in 120 (92%) after PEIT, but were present in ten (8%). During the 25-month follow up, local recurrence was detected in 19 (16%) from the former, in contrast to nine (90%) from the latter (P < 0.001). Uni- and multivariate Cox analysis revealed that the presence of pre-/post-treatment power Doppler signals, histological differentiation and tumor number were independent factors for local recurrence. However, 3-year recurrence rate of new lesions was 51%, but no predictors were identified. CONCLUSIONS: Residual Doppler signals in tumor after PEIT were related to the local HCC recurrence.

Thoracoscopic thermal ablation therapy for hepatocellular carcinoma located beneath the diaphragm.

BACKGROUND AND STUDY AIMS: Percutaneous interstitial thermal ablation therapy effectively treats hepatocellular carcinoma (HCC) that can be visualized on percutaneous ultrasonography. However, when the tumor is located just under the top of the diaphragm, visualization can be difficult with conventional ultrasonographic examination. There are also problems concerning complete tumor ablation. We performed thoracoscopic thermal ablation therapy for HCC located just beneath the diaphragm in nine patients with advanced liver cirrhosis. PATIENTS AND METHODS: Eight patients underwent thoracoscopic microwave coagulation therapy, and one patient underwent thoracoscopic radiofrequency ablation therapy. RESULTS: Despite the poor hepatic reserve, postoperative recovery after thoracoscopic thermal ablation therapy was rapid in all patients, without deterioration of hepatic function. CONCLUSIONS: This preliminary study suggests that the new technique of thoracoscopic thermal ablation therapy is a less invasive optional therapy for HCC located in segments VII or VIII in cirrhotic 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 ethanol injection therapy for liver tumors.

Percutaneous ethanol injection therapy (PEIT) has been widely practiced in the treatment of liver tumors, especially of hepatocellular carcinoma (HCC). Histopathologic examinations, findings in imaging modalities and serum tumor marker levels have shown a remarkable anticancer effect of this procedure. In addition, PEIT has achieved considerably high long-term survival rates. For small HCC, PEIT has been generally accepted as an alternative to surgery. Here we will describe PEIT from the viewpoints of patient selection, technique, various evaluation procedures of efficacy, long-term results, side effects and complications, and relationship with other therapies.

Des-gamma-carboxy prothrombin as a useful predisposing factor for the development of portal venous invasion in patients with hepatocellular carcinoma: a prospective analysis of 227 patients.

BACKGROUND: Portal venous invasion (PVI) in patients with hepatocellular carcinoma (HCC) is an important factor affecting prognosis. The objective of this study was to elucidate predisposing factors for the development of PVI. METHODS: Two hundred twenty-seven patients with HCC who did not show PVI and who received percutaneous ethanol injection therapy and/or microwave coagulation therapy at the time of their first hospital admission were enrolled between 1994 and 1996. After their HCC was treated, the patients were followed for a mean of 19 months. For the detection of HCC recurrence and/or development of PVI, ultrasonography was performed every 3 months, a computed tomography (CT) scan was performed every 6 months, and the biochemical parameters of the patients were measured every month. PVI was defined as protrusion of the tumor into the first and/or second branch or into the main trunk of the portal vein. RESULTS: Of the 227 patients, 24 (11%) later developed PVI. Tabular analysis was performed on these 24 patients and indicated that tumor size, albumin, total bilirubin, prothrombin time, alpha-fetoprotein (AFP) level, and des-gamma-carboxy prothrombin (DCP) level differed significantly between the time of initial admission and the time of PVI development. A univariate analysis performed on the 227 patients indicated that an increase in the numbers of tumors, the histologic tumor grade (differentiation), the AFP level, and the DCP level at the time of initial diagnosis of HCC had a significant correlation with the later development of PVI; and a stepwise, multivariate Cox regression analysis revealed that the DCP level was the strongest predisposing factor (P < 0.0010; risk ratio = 5.65) followed by the histologic grade of tumor differentiation. CONCLUSIONS: The results suggest that the serum DCP level is the most useful predisposing clinical parameter for the development of PVI.

Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus-an analysis of 236 consecutive patients with a single lesion.

Patients with hepatocellular carcinoma (HCC) frequently experience intrahepatic HCC recurrence even after complete ablation of primary lesions. Because the oncogenic process may be different for hepatitis B viral (B-viral) and hepatitis C viral (C-viral) HCC, the present study was conducted to elucidate the factors contributing to HCC recurrence with respect to the infected hepatitis virus. Two hundred thirty-six patients with a single HCC lesion who underwent complete ablation of the tumor by PEIT and/or PMCT or surgical resection at Tokyo University and its affiliated hospitals from 1993 to 1997 were enrolled. The patients were classified into 3 groups: the B-viral group, C-viral group, and NBNC group. After complete removal of tumors, the patients were followed for a mean period of 39 months. The factors contributing to HCC recurrence were analyzed by univariate and multivariate analysis using the Cox proportional hazard model. The rate of intrahepatic recurrence in enrolled patients at 1, 3, and 5 years was 19%, 50%, and 64%, respectively. The intrahepatic recurrence rate in C-viral and B-viral HCC was higher than that in the NBNC-related HCC. Fibrosis staging, pathological grading of HCC, and serum AFP levels were significantly linked to intrahepatic recurrence by univariate analysis, and fibrosis staging was strongest in the multivariate analysis for C-viral HCC (P = .004). In contrast, fibrosis staging did not affect the recurrence in B-viral (P = .51) and NBNC-related (P = .77) HCC. Risk factors for HCC recurrence differed according to the infected viral state.