Influence of HIV-related immunodeficiency on the risk of hepatocellular carcinoma.

OBJECTIVE: To investigate HIV-related immunodeficiency as a risk factor for hepatocellular carcinoma (HCC) among persons infected with HIV, while controlling for the effect of frequent coinfection with hepatitis C and B viruses. DESIGN: A case-control study nested in the Swiss HIV Cohort Study. METHODS: Twenty-six HCC patients were identified in the Swiss HIV Cohort Study or through linkage with Swiss Cancer Registries, and were individually matched to 251 controls according to Swiss HIV Cohort Study centre, sex, HIV-transmission category, age and year at enrollment. Odds ratios and corresponding confidence intervals were estimated by conditional logistic regression. RESULTS: All HCC patients were positive for hepatitis B surface antigen or antibodies against hepatitis C virus. HCC patients included 14 injection drug users (three positive for hepatitis B surface antigen and 13 for antibodies against hepatitis C virus) and 12 men having sex with men/heterosexual/other (11 positive for hepatitis B surface antigen, three for antibodies against hepatitis C virus), revealing a strong relationship between HIV transmission route and hepatitis viral type. Latest CD4+ cell count [Odds ratio (OR) per 100 cells/mul decrease = 1.33, 95% confidence interval (CI) 1.06-1.68] and CD4+ cell count percentage (OR per 10% decrease = 1.65, 95% CI 1.01-2.71) were significantly associated with HCC. The effects of CD4+ cell count were concentrated among men having sex with men/heterosexual/other rather than injecting drug users. Highly active antiretroviral therapy use was not significantly associated with HCC risk (OR for ever versus never = 0.59, 95% confidence interval 0.18-1.91). CONCLUSION: Lower CD4+ cell counts increased the risk for HCC among persons infected with HIV, an effect that was particularly evident for hepatitis B virus-related HCC arising in non-injecting drug users.

Continuous sunitinib treatment in patients with unresectable hepatocellular carcinoma (HCC): A multicenter phase II trial (SAKK 77/06 and SASL 23)

Background: Sunitinib (SU) is a multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenetic activity. Evidence for clinical activity in HCC was reported in 2 phase II trials [Zhu et al and Faivre et al, ASCO 2007] using either a 37.5 or a 50 mg daily dose in a 4 weeks on, 2 weeks off regimen. The objective of this trial was to demonstrate antitumor activity of continuous SU treatment in patients (pts) with HCC. Methods: Key eligibility criteria included unresectable or metastatic HCC, no prior systemic anticancer treatment, measurable disease and Child- Pugh A or B liver dysfunction. Pts received 37.5 mg SU daily until progression or unacceptable toxicity. The primary endpoint was progression free survival at 12 weeks (PFS12) defined as 'success' if the patient was alive and without tumor progression assessed by 12 weeks (±7 days) after registration. A PFS12 of _20% was considered uninteresting and promising if _40%. Using the Simon-two minimax stage design with 90% power and 5% significance the sample size was 45 pts. Secondary endpoints included safety assessments, measurement of serum cobalamin levels and tumor density. Results: From September 2007 to August 2008 45 pts, mostly male (87%), were enrolled in 10 centers. Median age was 63 years, 89% had Child-Pugh A and 47% had distant metastases. Median largest lesion diameter was 84mm (range: 18-280) and 18% had prior TACE. Reasons for stopping therapy were: PD 60%, symptomatic deterioration 16%, toxicity 11%, death 2% (due to tumor), and other reasons 4%; 7% remain on therapy. PFS12 was rated as success in 15 pts (33%) (95% CI: 20%, 49%) and failure in 27 (60%); 3 were not evaluable (due to refusal). Over the whole trial period 1 CR and 40% SD as best response were achieved. Median PFS, duration of disease stabilization, TTP and OS were 2.8, 3.2, 2.8 and 9.3 months, respectively. Grade 3 and 4 adverse events were infrequent and all deaths due to the tumor. Conclusions: Continuous SU treatment with 37.5 mg/d daily is feasible and demonstrates moderate activity in pts with advanced HCC and mild to moderately impaired liver dysfunction. Under this trial design the therapy is considered promising (>13 PFS12 successes).

Thymostimulin versus placebo for palliative treatment of locally advanced or metastasised hepatocellular carcinoma: a phase III clinical trial.

BACKGROUND: Thymostimulin is a thymic peptide fraction with immune-mediated cytotoxicity against hepatocellular carcinoma (HCC) in vitro and palliative efficacy in advanced HCC in two independent phase II trials. The aim of this study was to assess the efficacy of thymostimulin in a phase III trial. METHODS: The study was designed as a prospective randomised, placebo-controlled, double-blind, multicenter clinical phase III trial. Between 10/2002 and 03/2005, 135 patients with locally advanced or metastasised HCC (Karnofsky >or=60%/Child-Pugh <or= 12) were randomised to receive thymostimulin 75 mg s.c. 5x/week or placebo stratified according to liver function. Primary endpoint was twelve-month survival, secondary endpoints overall survival (OS), time to progression (TTP), tumor response, safety and quality of life. A subgroup analysis according to liver function, KPS and tumor stage (Okuda, CLIP and BCLC) formed part of the protocol. RESULTS: Twelve-month survival was 28% [95%CI 17-41; treatment] and 32% [95%CI 19-44; control] with no significant differences in median OS (5.0 [95% CI 3.7-6.3] vs. 5.2 [95% CI 3.5-6.9] months; p = 0.87, HR = 1.04 [95% CI 0.7-1.6]) or TTP (5.3 [95%CI 2.0-8.6] vs. 2.9 [95%CI 2.6-3.1] months; p = 0.60, HR = 1.13 [95% CI 0.7-1.8]). Adjustment for liver function, Karnofsky status or tumor stage did not affect results. While quality of life was similar in both groups, fewer patients on thymostimulin suffered from accumulating ascites and renal failure. CONCLUSIONS: In our phase III trial, we found no evidence of any benefit to thymostimulin in the treatment of advanced HCC and there is therefore no justification for its use as single-agent treatment. The effect of thymostimulin on hepato-renal function requires further confirmation. TRIAL REGISTRATION: Current Controlled Trials ISRCTN64487365.

Pathogenesis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours worldwide. The major aetiologies and risk factors for the development of HCC are well defined and some of the multiple steps involved in hepatocarcinogenesis have been elucidated in recent years. However, no clear picture of how and in what sequence these factors interact at the molecular level has emerged yet. Malignant transformation of hepatocytes may occur as a consequence of various aetiologies, such as chronic viral hepatitis, alcohol, and metabolic disorders, in the context of increased cellular turnover induced by chronic liver injury, regeneration and cirrhosis. Activation of cellular oncogenes, inactivation of tumour suppressor genes, genomic instability, including DNA mismatch repair defects and impaired chromosomal segregation, overexpression of growth and angiogenic factors, and telomerase activation may contribute to the development of HCC. Overall, HCCs are genetically very heterogeneous tumours. New technologies, including gene expression profiling and proteomic analyses, should allow us to further elucidate the molecular events underlying HCC development and identify novel diagnostic markers as well as therapeutic targets.

Prise en charge du carcinome hépatocettulaire en 2010 [Management of hepatocellular carcinoma]

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide and its incidence has increased over the last years in most developed countries. The majority of HCCs occur in the context of liver cirrhosis. Therefore, patients with cirrhosis and those with hepatitis B virus infection should enter a surveillance program. Detection of a focal liver lesion by ultrasound should be followed by further investigations to confirm the diagnosis and to permit staging. A number of curative and palliative treatment options are available today. The choice of treatment will depend on the tumor stage, liver function and the presence of portal hypertension as well as the general condition of the patient. A multidisciplinary approach is mandatory to offer to each patient the best treatment.

Reply [to: Duberg AS, Hultcrantz R. Misleading figures on trends in mortality from hepatocellular carcinoma in Europe]

Author reply to: Duberg AS, Hultcrantz R. Misleading figures on trends in mortality from hepatocellular carcinoma in Europe. Hepatology. 2009;49(1):336. doi: 10.1002/hep.22671. PMID: 19035339.

Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma.

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is the most frequent form of primary liver cancer and chronic infection with hepatitis C virus is one of the main risk factors for HCC. This study analyses the characteristics of the patients with chronic hepatitis C participating in the Swiss Hepatitis C Cohort Study who developed HCC. METHODS: Analysis of the database of the Swiss Hepatitis C Cohort Study, a multicentre study that is being carried out in eight major Swiss hospitals since the year 2000. Patients with chronic hepatitis C and HCC were regrouped and compared to the patients without HCC. RESULTS: Among the 3,390 patients of the cohort, 130 developed an HCC. Age was one of the determining factors. Cirrhosis and its complications ascites and porto-systemic encephalopathy were associated with HCC. Males presented a higher risk for HCC than females. Alcohol consumption was associated with HCC. Diabetes mellitus was an important risk factor, especially in patients with low fibrosis. Patients with Hepatitis C genotype 2 had significantly less HCC than patients with other genotypes. A low socioeconomic status (income, education, profession) was associated with HCC. CONCLUSIONS: Beside the expected characteristics (age, gender, cirrhosis, alcohol), these data stress the role of diabetes mellitus and reveal the importance of low socioeconomic status as a risk factor for HCC in Swiss patients infected with hepatitis C virus. This vulnerable population should be closely monitored.

Pancréatite aiguë clinique après chimio-embolisation sélective d'un carcinome hépatocellulaire [Acute clinical pancreatitis following selective transcatheter arterial chemoembolization of hepatocellular carcinoma]

Acute pancreatitis can complicate non-selective transcatheter arterial embolization of hepatocellular carcinoma with an incidence ranging from 1,7% (acute clinical pancreatitis) to 40% (biological pancreatitis). This complication is thought to be related to embolization of extrahepatic arterial collaterals.We report herein a case of acute clinical pancreatitis developing within 24 hours after a second course of selective transcatheter arterial chemo-embolization into the proper hepatic artery. Neither anatomical arterial variation nor particular risk factor for acute pancreatitis could be identified. This complication is unusual after selective arterial embolization. Because it may clinically mimick a postembolization syndrome, dosage of serum pancreatic enzymes should be performed systematically in case of abdominal pain following chemoembolization.

Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data.

The incidence of hepatocellular carcinoma (HCC) is increasing in Western countries. Although several clinical factors have been identified, many individuals never develop HCC, suggesting a genetic susceptibility. However, to date, only a few single-nucleotide polymorphisms have been reproducibly shown to be linked to HCC onset. A variant (rs738409 C>G, encoding for p.I148M) in the PNPLA3 gene is associated with liver damage in chronic liver diseases. Interestingly, several studies have reported that the minor rs738409[G] allele is more represented in HCC cases in chronic hepatitis C (CHC) and alcoholic liver disease (ALD). However, a significant association with HCC related to CHC has not been consistently observed, and the strength of the association between rs738409 and HCC remains unclear. We performed a meta-analysis of individual participant data including 2,503 European patients with cirrhosis to assess the association between rs738409 and HCC, particularly in ALD and CHC. We found that rs738409 was strongly associated with overall HCC (odds ratio [OR] per G allele, additive model=1.77; 95% confidence interval [CI]: 1.42-2.19; P=2.78 × 10(-7) ). This association was more pronounced in ALD (OR=2.20; 95% CI: 1.80-2.67; P=4.71 × 10(-15) ) than in CHC patients (OR=1.55; 95% CI: 1.03-2.34; P=3.52 × 10(-2) ). After adjustment for age, sex, and body mass index, the variant remained strongly associated with HCC. Conclusion: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

Trends in mortality from hepatocellular carcinoma in Europe, 1980-2004.

Upward trends in mortality from hepatocellular carcinoma (HCC) were recently reported in the United States and Japan. Comprehensive analyses of most recent data for European countries are not available. Age-standardized (world standard) HCC rates per 100,000 (at all ages, at age 20-44, and age 45-59 years) were computed for 23 European countries over the period 1980-2004 using data from the World Health Organization. Joinpoint regression analysis was used to identify significant changes in trends, and annual percent change were computed. Male overall mortality from HCC increased in Austria, Germany, Switzerland, and other western countries, while it significantly decreased over recent years in countries such as France and Italy, which had large upward trends until the mid-1990s. In the early 2000s, among countries allowing distinction between HCC and other liver cancers, the highest HCC rates in men were in France (6.8/100,000), Italy (6.7), and Switzerland (5.9), whereas the lowest ones were in Norway (1.0), Ireland (0.8), and Sweden (0.7). In women, a slight increase in overall HCC mortality was observed in Spain and Switzerland, while mortality decreased in several other European countries, particularly since the mid-1990s. In the early 2000s, female HCC mortality rates were highest in Italy (1.9/100,000), Switzerland (1.8), and Spain (1.5) and lowest in Greece, Ireland, and Sweden (0.3). In most countries, trends at age 45-59 years were consistent with overall ones, whereas they were more favorable at age 20-44 years in both sexes. CONCLUSION: HCC mortality remains largely variable across Europe. Favorable trends were observed in several European countries mainly over the last decade, particularly in women and in young adults.

Patient with hepatocellular carcinoma related to prior acute arsenic intoxication and occult HBV: epidemiological, clinical and therapeutic results after 14 years of follow-up

Little is known about the long-term survivors of acute arsenic intoxication. We present here a clinical case report of a man with chronic hepatitis B virus (HBV) infection who developed hepatocellular carcinoma four years after acute arsenic poisoning. HBsAg was detected in serum in 1990 when he voluntarily donated blood. In 1991, the patient suffered from severe psychological depression that led him to attempt suicide by massive ingestion of an arsenic-containing rodenticide. He survived with polyneuropathy and paralysis of the lower limbs, and has been wheelchair-bound since then. During participation in a follow-up study conducted among HBV carriers, abdominal ultrasound detected a two-centimeter liver mass consistent with hepatocellular carcinoma. The tumor was confirmed by computed tomography (CT) and magnetic resonance image (MRI). Because of his significant comorbidity, the patient received palliative treatment with transarterial lipiodol chemoembolization (TACE) on three occasions (1996, 1997 and 1999). At his most recent visit in May 2005, the patient was asymptomatic, liver enzymes were normal and the tumor was in remission on ultrasound.

Elevated hepatocyte paraffin 1 and neprilysin expression in hepatocellular carcinoma are correlated with longer survival

Résumé de l'article Le carcinome hépatocellulaire reste une tumeur maligne de mauvais pronostic. Le but de cette étude rétrospective est d'étudier l'expression immunohistochimique semi-quantitative d'Hep Par 1 (hepatocyte paraffin 1) et de CD 10 (CALLA ou neprilysin) et leur valeur pronostique sur un collectif de 97 patients avec un carcinome hépatocellulaire traité à visée curative. Hep Par 1 réagit avec un épitope spécifique de l'hépatocyte au niveau de la membrane mitochondriale et se présente sous forme d'un marquage cytoplasmique diffus d'intensité variable, le foie non tumoral exprimant un marquage granulaire servant de contrôle interne positif. Le CD 10 correspond ä une metallopeptidase de la membrane cellulaire participant au processus de sécrétion hormonale et l'immunoréaction colore spécifiquement la portion luminale des canalicules biliaires du foie non tumoral, qui sert ainsi de contrôle interne positif. Le foie tumoral exprime ou non un marquage canaliculaire (CD 10 can), similaire au foie non tumoral, ou cytoplasmique (CD 10 cyt). Le marquage immunohistochimique est quantifié pour les 3 différents marqueurs (Hep Par 1, CD10 can et CD10 cyt) en fonction du pourcentage de cellules tumorales positives (score de 0 à 3 établi pour chaque marqueur immunohistochimique). L'élaboration d'un score combiné immunohistochimique (CIS) est obtenu en additionnant les scores d'Hep Par 1 et de CD10 con et en soustrayant le score de CD10 cyt. Dans l'analyse univariée, la survie globale des patients est prolongée de manière significative en cas de forte expression tumorale par Hep Par 1 (p=0,0005) et CD10 can (p=0,02). Dans l'analyse multivariée, la combinaison du CIS avec les autres paramètres histopathologiques pronostiques classiques du carcinome hépatocellulaire comme la taille tumorale, l'invasion vasculaire, la multifocalité de la tumeur et le grade tumoral montre que le score immunohistochimique combiné (CIS) reste le facteur pronostique le plus important (p=0,001). Les patients avec un CIS bas (<4) avec une survie moyenne de 17 mois ont 3,5 fois plus de risque de décès comparés à ceux avec un CIS élevé (>4) avec une survie moyenne de plus de 80 mois. En conclusion, une expression immunohistochimique élevée d'Hep Par 1 et de CD10 can en l'absence d'expression de CD10 cyt sont des facteurs pronostiques favorables pour les patients présentant un carcinome hépatocellulaire. La combinaison des marqueurs immunohistochimiques dans un score combiné pourrait être utilisé dans la prise en charge des patients avec un hépatocarcinome àvisée curative. Toutefois des études prospectives restent nécessaires pour confirmer l'utilité pronostique du CIS.