Transarterial chemoembolization and sorafenib in hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is considered as the standard therapy for patients with intermediate-stage hepatocellular carcinoma. However, given the high heterogeneity of this population, no common strategy or protocol standardization has been defined yet. In the last few years TACE treatment has been combined with sorafenib systemic therapy, reporting overall positive results both in terms of safety and efficacy. This systematic review presents and critically discusses the evidence available on the use of TACE in combination (concomitant or sequential) with sorafenib, focusing also on clinical trials currently ongoing to better define an optimal therapeutic strategy for this group of patients.

Management of HCC.

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal neoplasia, the management of which has significantly improved during the last few years. A better knowledge of the natural history of the tumor and the development of staging systems that stratify patients according to the characteristics of the tumor, the liver disease, and the performance status, such as the BCLC (Barcelona Clinic Liver Cancer) system, have led to a better prediction of prognosis and to a most appropriate treatment approach. Today curative therapies (resection, transplantation, ablation) can improve survival in patients diagnosed at an early HCC stage and offer a potential long-term cure. Patients with intermediate stage HCC benefit from chemoembolization and those diagnosed at advanced stage benefit from sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects. In this article we review the current management in HCC and the new advances in this field.

Non-invasive diagnosis of hepatocellular carcinoma ≤ 2 cm in cirrhosis. Diagnostic accuracy assessing fat, capsule and signal intensity at dynamic MRI.

BACKGROUND & AIMS: To prospectively assess the diagnostic accuracy of the incorporation of additional magnetic resonance imaging (MRI) parameters in those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5 and 20mm, detected during surveillance in patients with cirrhosis. METHODS: Between November 2003 and January 2010, we prospectively included 159 cirrhotic patients with a newly detected solitary nodule between 5 and 20mm in diameter by screening ultrasonography (US). Hepatic MRI and fine-needle biopsy were performed in all patients. RESULTS: Final diagnoses were hepatocellular carcinoma (HCC) (n=103), other malignant lesions (intrahepatic cholangiocarcinoma/metastases) (n=4), and benign lesions (n=52). The specific enhancement pattern (arterial enhancement followed by washout) yielded a sensitivity and specificity of 58.3% and 96.4%, respectively. Peritumoral capsule was present in 43 HCC and in 2 non-HCC lesions. Intralesional fat was detected in 24 nodules; 5 nodules were non-HCC. Finally, the presence of both capsule and fat was observed in 10 cases, all of them HCC (100% specificity), but all of them also displayed the specific enhancement pattern, thus adding no sensitivity or specificity. CONCLUSIONS: Conclusive non-invasive diagnosis of HCC in cirrhosis should be based only on the contrast enhancement pattern, while other characteristics at MRI do not increase the diagnostic accuracy.

Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design.

BACKGROUND & AIMS: Transarterial chemoembolisation (TACE) improves survival of properly selected patients with hepatocellular carcinoma (HCC). Drug eluting beads (DEB) provide a calibrated and homogenous procedure while increasing efficacy. Outcome data applying this technology is lacking, and this is instrumental for clinical decision-making and for trial design. We evaluated the survival of HCC patients treated with DEB-TACE following a strict selection (preserved liver function, absence of symptoms, extrahepatic spread or vascular invasion). METHODS: We registered baseline characteristics, the development of treatment-related adverse events, and the overall survival of all HCC patients treated by DEB-TACE from February 2004 to June 2010. RESULTS: One hundred and four patients were treated with DEB-TACE. All but one were cirrhotic, 62.5% HCV+, 95% Child-Pugh A, 41 BCLC-A and 63 BCLC-B. Causes of DEB-TACE treatment in BCLC-A patients were: 35 unfeasible ablation, and six post-treatment recurrences. After a median follow-up of 24.5 months, 38 patients had died, two patients had received transplantation and 24 had received sorafenib because of untreatable tumour progression. Median survival of the cohort was 48.6 months (95% CI: 36.9-61.2), while it was 54.2 months in BCLC stage A and 47.7 months in stage B. Median survival after censoring follow-up at time of transplant/sorafenib was 47.7 (95%CI: 37.9-57.5) months. CONCLUSIONS: These data validate the safety of DEB-TACE and show that the survival expectancy applying current selection criteria and technique is better than that previously reported. A 50% survival at 4 years should be considered when suggesting treatment for patients fitting into controversial scenarios such as expanded criteria for transplantation/resection for multifocal HCC.

Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma.

BACKGROUND AND AIMS: Conventional pathological analysis fails to achieve sufficient sensitivity and specificity for the diagnosis of hepatocellular carcinoma (HCC) in small nodules. Immunohistochemical staining for glypican 3 (GPC3), heat shock protein 70 (HSP70) and glutamine synthetase (GS) has been suggested to allow a confident diagnosis but no prospective study has established the diagnostic accuracy of this approach. The aim of this study is to assess prospectively the diagnostic accuracy of a panel of markers (GPC3, HSP70, GS) for the diagnosis of HCC in patients with cirrhosis with a small (5-20 mm) nodule detected by ultrasound screening. METHODS: Sixty patients with cirrhosis with a single nodule 5-20 mm newly detected by ultrasound were included in the study. Contrast-enhanced ultrasound, magnetic resonance and fine needle biopsy of the nodule (gold standard) were performed; the biopsy was repeated in case of diagnostic failures. Three consecutive sections of the first biopsy sample with meaningful material were stained with antibodies against GPC3, HSP70 and GS. RESULTS: Forty patients were diagnosed with HCC. The sensitivity and specificity for HCC diagnosis were: GPC3 57.5% and 95%, HSP70 57.5% and 85%, GS 50% and 90%, respectively. The sensitivity and specificity of the different combinations were: GPC3+HSP70 40% and 100%; GPC3+GS 35% and 100%; HSP70+GS 35% and 100%; GPC3+HSP70+GS 25% and 100%. When at least two of the markers were positive (regardless of which), the sensitivity and specificity were 60% and 100%, respectively. Conventional pathological analysis yielded three false negative results, but the addition of this panel only correctly classified one of these cases as HCC. CONCLUSION: These data within a prospective study establish the clinical usefulness of this panel of markers for the diagnosis of early HCC. However, the panel only slightly increases the diagnostic accuracy in an expert setting.

Treatment of early hepatocellular carcinoma: Towards personalized therapy.

In recent years, the wide implementation of surveillance programs has led to diagnose HCC at earlier stages, when curative options can be applied. In order to obtain the best results, treatment indication should take into account the estimation of baseline life expectancy. Patients at an early stage are those with single HCC or up to three nodules <3 cm with preserved liver function (Child-Pugh A-B) and no cancer related symptoms. These patients should be evaluated for any of the therapies that can offer complete responses with potential long-term cure, as reflected by a 5 years survival superior to 50-70%. These include surgical resection, liver transplantation and ablation. We briefly reviewed therapeutic management for early HCC, taking into account that any recommendation should be delivered in the clinical setting and based on an individualised evaluation of each patient.

[Primary cardiac sarcoma. Description of a case]. / Sarcoma primitive del cuore. Descrizione di un caso.

Primary cardiac tumors are rare events. We describe here a case of undifferentiated pleomorphic sarcoma (so-called pleomorphic malignant fibrous histiocytoma) obliterating mostly the left side and the anterior wall of pericardium in a 84-year-old man admitted for mild dyspnea at rest. The diagnosis was suspected after excluding the lung origin of the mass (observed by plain chest radiography) by thorax computed tomography but it was confirmed only by cardiac-gated magnetic resonance imaging and transthoracic biopsy. Considering both patient's age and comorbidity, and local extension of the lesion, after counseling with cardiac surgeons and oncologists, the patient was treated only by conservative medical therapy. The patient died 6 months after the diagnosis due to a superior vena cava syndrome as an effect of infiltration and obstruction of superior vena cava by the tumor at the site of vein entry in the right atrium. This case is an example of a primary cardiac tumor that causes relative myocardial sufferance both by infiltration and by limitation of normal heart diastolic function.

Type III intestinal metaplasia, Helicobacter pylori infection and gastric carcinoma risk index in an Italian series of 1750 patients.

BACKGROUND/AIMS: To evaluate the utility of 2 biopsies of antrum and gastric body on routine endoscopy for the assessment of type III intestinal metaplasia (IM-3) and Helicobacter pylori (Hp), 1750 patients (pts) (895 males; 855 females) were considered from June'98 to June'00. METHODOLOGY: Specimens were graded 0 to 3 for atrophy, IM-3 and Hp. 610 pts treated previously with antibiotics or not eligible for biopsy were excluded from initial 2360 pts. RESULTS: IM-3 was found in 118 pts (6.7%), 100 pts (5.7%) only in the antrum. 10 of 355 pts (2.8%) with normal endoscopy and 47 of 702 (6.6%) with non-erosive endoscopic gastritis resulted IM-3 positive in the antrum. 709 pts (40.5%) were positive for Hp in antrum and/or corpus. The presence of Hp and IM-3 in the antrum was not correlated (p=0.99; Spearman test). A positive correlation (p=0.000) between duodenal ulcer and Hp was found when antral Hp positivity was taken into account. The gastric carcinoma risk index (GCRI) was found in 358 pts (20.4%); in this group 131 pts (36.6%) were Hp positive, 81 pts (22.65%) had IM-3 only in the antrum, 184 pts (51.4%) had atrophy. CONCLUSIONS: The incidence of IM-3 is low (6.7%) in routine endoscopy. Normal endoscopy doesn't exclude the presence of IM-3. Biopsy is necessary to discover IM-3 in the antrum in 5.3% of pts with normal or aspecific endoscopic gastritis. Application of the GCRI might be useful for identifying a group of patients carrying a higher risk for gastric carcinoma.

Hyperhomocysteinaemia in chronic liver diseases: role of disease stage, vitamin status and methylenetetrahydrofolate reductase genetics.

BACKGROUND/AIMS: The liver plays a key role in sulphur aminoacid metabolism hence, homocysteine metabolism may be impaired in chronic liver diseases. The aim of this study was to investigate, in patients affected by chronic liver diseases, (1) the prevalence of hyperhomocysteinaemia and (2) the role of its determinants such as the stage and the aetiology of disease, vitamin status, genetic documented alterations (methylenetetrahydrofolate reductase deficiency) and presence/absence of documented malignant evolution (hepatocellular carcinoma). MATERIAL AND METHODS: One hundred and thirty patients with chronic liver disease (34 with chronic active hepatitis, 12 with fatty liver and 88 with liver cirrhosis) and 50 healthy age-matched control subjects were included into the study. RESULTS: Hyperhomocysteinaemia was defined as homocysteine plasma levels greater than 12.6 micromol/l. Hyperhomocysteinaemia prevalence in liver cirrhosis group was 40.9%, significantly higher (all P<0.01) with respect to controls (12%), chronic active hepatitis (14.7%) and fatty liver (25%) groups and increased with Child-Pugh stage [Child A: 22.2%, Child B (50%); Child C (58.3%)]. In chronic-active hepatitis and liver cirrhosis, the prevalence of subjects with methylenetetrahydrofolate reductase C677-->T mutation (both as CT and as TT) and hyperhomocysteinaemia results in significantly higher levels with respect to controls. Methylenetetrahydrofolate reductase C677-->T mutation and disease stage showed to be the most important predictive factors of hyperhomocysteinaemia in liver cirrhosis whereas the influence of homocysteine-related vitamin status seems to have a secondary role. CONCLUSIONS: In conclusion hyperhomocysteinaemia is highly prevalent in liver cirrhosis but not in other chronic liver diseases; it may contribute to fibrogenesis and vascular complication of liver cirrhosis.

A role for homocysteine increase in haemolysis of megaloblastic anaemias due to vitamin B(12) and folate deficiency: results from an in vitro experience.

Megaloblastic anaemias (MA) are frequently associated with haemolysis. The pathogenesis of these finding is not clear, but it is thought to depend on the greater destruction of abnormal and fragile megaloblastic erythrocytes. Vitamin B(12) and folate deficiencies are the commonest cause of MA; these deficiencies may simultaneously induce a significant alteration in homocysteine metabolism leading to hyperhomocysteinemia. Blood cells have enzymes involved in homocysteine metabolism. Considering the possible effects of hyperhomocysteinemia in erythrocyte toxicity (due to oxidative damage and/or to interaction with sulfhydryl residues of structural and enzymatic proteins), the aim of our study was to evaluate (1) the homocysteine blood cells production in patients with MA due to vitamin B(12) and folate deficiency and (2) the possible role and mechanism of hyperhomocysteinemia in MA haemolysis. After incubation at 37 degrees C, blood samples from MA patients showed higher and significant levels of Hcy, LDH, lipid peroxidation parameters (MDA), and ghost protein-bound Hcy than controls. Haemolysis (%) was higher in MA patients than controls and was significantly correlated with Hcy accumulation in the medium, lipid peroxidation indices and ghost protein-bound Hcy. No significant (or significantly lower) alterations through time in considered parameters were observed in the corresponding samples incubated at 4 degrees C or in samples incubated with methionine-free medium (lower Hcy production). Our data, deriving from an in vitro experience, suggest a possible role of Hcy accumulation due to vitamin B(12) and folate deficiencies in haemolysis associated to MA due to vitamin deficiency.