Percutaneous radiofrequency thermal ablation for hepatocellular carcinoma.

BACKGROUND: Radiofrequency thermal ablation is the first therapeutic option in percutaneous treatment of hepatocellular carcinoma but data on its long-term efficacy and safety are not conclusive. AIM: This study reports a prospective survey on radiofrequency thermal ablation in north-east Italy. METHODS: Data were collected on 401 patients with hepatocellular carcinoma (males 301, mean age: 68 years) treated by radiofrequency thermal ablation in 13 centres. Indication to treatment was: single nodule not eligible for surgery in 77% of patients, 2-3 nodes in 18% and multiple lesions in 5%. Mean size was 3 cm (1-8 cm). Treatment response was assessed at 1 month by spiral computerized tomography and then with ultrasound examination and new spiral computerized tomography. RESULTS: Complete response was obtained in 67% of patients and in 27% response was 75-99%. Complete response raised to 77% in lesions smaller than 3 cm. The morbidity rate was 34%; the mortality was 0.5%, seeding was observed in four patients. Ten patients presented an unexpected rapid disease progression. CONCLUSION: The above data show that by radiofrequency thermal ablation, complete response can be achieved only in about two-third of the cases, clearly less than expected, and that, beyond seeding, unexpected progression can be observed.

[Initial experience with clotiapine in the treatment of heroin addiction]. / Prima esperienza con clotiapina nel trattamento dell'eroinomane.

Experience in treating heroin addicts with a major neuroleptic, Chlothiapin (Entumin Sandoz) is described. Treatment was begun on 16 cases and completed on 12. Slight signs of asthenia appeared in three cases. All patients completing the treatment achieved a normal sleeping pattern and reduced anxiety. Thus after a 7 day course patients could be transferred to a specialist drug addiction centre.

[Relationships between clinico-therapeutic parameters and immunological status in patients with lung cancer]. / Rapporti tra parametri clinico-terapeutici e stato immunitario nel paziente portatore di cancro del polmone. Analisi di 150 casi.

150 patients with lung cancer have been studied from the immunological point of view: the two years that elapsed between the study and processing of the data permitted an evaluation of the prognosis in terms of immunology also. This study has been carried out in vivo by means of skin tests (BCG, PPD, Candida, Varidase, CCB, Mumps, BNCB) and in vitro with lymphocyte blastization in the presence of PHA and dependent antibody cytotoxicity. Serum factors which can interfere with lymphocyte cytotoxicity have also been studied. Peri- and intra-tumour lymphocyte infiltration and the lymph node activation stage have been analyzed in patients who underwent surgery. A real depression of the cell mediated immunity observed in the negative response to skin tests has been found. The study of in vitro parameters showed a deficient blast response in 86% of the cases examined, decreased cytotoxicity in 62% and the presence of inhibiting serum factors in 53%. No correlation was observed between positivity to skin tests, normal response to PHA, normal concentration of inhibiting serum factors on the one hand and survival on the other. The only finding which seems to be correlated with survival is lymphocyte infiltration; its peri- and intrastromal presence on the neoplasia may be associated with a significantly better prognosis.

Liver cell surface localization of hepatitis B antigen and of immunoglobulins in acute and chronic hepatitis and in liver cirrhosis.

This paper describes immunofluorescence studies on liver cell surface localization of hepatitis B surface antigen (HBsAg) and of IgG in acute and chronic hepatitis and in cirrhosis. In acute hepatitis B, HBsAg was found at the surface of hepatocytes in an early phase of the disease, but not during the recovery. This finding is consistent with the hypothesis that immune reactions to HBsAg may be responsible for the liver cell lysis. In HBsAg-positive chronic hepatitis and cirrhosis the antigen was found in the cytoplasm, but not on the surface of the hepatocytes, while in HBsAg-negative cases the antigen could not be detected in the liver cells. Both in HBsAg-positive and in HBsAg-negative chronic active hepatitis (CAH) and cryptogenic cirrhosis IgG bound to the membrane of the hepatocytes could be detected, suggesting a role of antibodies in the pathogenesis of the disease.

Blood-transmitted and clotting-factor-transmitted non-A, non-B hepatitis. Clinical differences and evolution.

In a prospective study of post-transfusion hepatitis (PTH) in open-heart surgery patients, non-A, non-B hepatitis was diagnosed by exclusion criteria in 100 patients (14.1%). The frequency of hepatitis was significantly higher (56.9%; p less than 0.001) in patients receiving blood units and clotting-factor concentrates of commercial origin, which were administered for the occurrence of bleeding complications during surgery, as compared to patients treated with blood units alone (10.3%). When clinical features of hepatitis at presentation were compared in the two groups of patients, a shorter incubation period (p less than 0.05) and a higher prevalence of jaundice (p less than 0.01) were found in patients receiving blood and clotting-factors. Persistence of abnormal alanine aminotransferase (ALT) levels after 12 months from onset were found in more than 70% of patients in both groups. Late biochemical remission, however, was observed in 21% of patients receiving blood units alone, but in none of those who received clotting factors. All these latter patients had histologic features of active liver disease during the chronic phase of the illness, as compared to only 46% of patients receiving blood units alone (p = 0.02). Our results show significant differences in the clinical course of non-A, non-B hepatitis transmitted by blood as compared to clotting factors, supporting the hypothesis of different etiological non-A, non-B agents.

Virus replication and liver disease in chronic hepatitis B virus infection.

Recent studies on the natural history of chronic hepatitis B virus infection have provided evidence for a close temporal relationship between the phase of active virus replication and development of liver lesions. To assess the role that virus replication plays in this phase in determining the severity of the liver disease, we studied serum levels of virus-specific DNA-polymerase activity and hepatitis Be antigen/antibody status in 48 chronic carriers of the hepatitis B surface antigen found positive for the hepatitis B core antigen in the liver. There was a remarkably evident inverse correlation between virus replication activity and liver disease activity, patients with minimal histological changes having the highest DNA-polymerase levels (mean +/- SD: 3879 +/- 2557 cpm) and those with severe chronic active hepatitis the lowest enzyme levels (419 +/- 246 cpm), while cases of chronic persistent hepatitis and of mild chronic active hepatitis had intermediate levels. Serum hepatitis Be antigen was detected in 31/32 patients with milder liver lesions and in 11/16 with severe liver lesions; the remaining five cases were anti-HBe-positive despite the presence of the core antigen in the liver. Serum levels of virus replication markers closely correlated with the distribution pattern of the core antigen in the liver. These findings indicate that in chronic hepatitis B the severity of liver disease is not directly related to levels of virus replication, thus suggesting a predominant role of host immune mechanisms.

Detection by immunofluorescence of an antigen-antibody system in patients with acute and chronic non-A, non-B hepatitis.

An antigen-antibody system has been identified by immunofluorescence in patients with non-A, non-B hepatitis. The non-A, non-B antigen was localized in the hepatocyte nuclei of liver biopsies from patients with acute post-transfusion or sporadic non-A, non-B hepatitis and in those from patients with chronic post-transfusion non-A, non-B hepatitis, the percentage of positive cells being most prominent in patients receiving immunosuppressive treatment. Absence of the antigen in normal livers and in livers from patients with type B hepatitis infection indicated its specific association with non-A, non-B infection. Antibody reacting with the nuclear antigen became detectable in serum during post-transfusion acute non-A, non-B hepatitis in 11 out of 15 cases; it was absent before transfusion. Six out of 12 cases of sporadic acute non-A, non-B hepatitis were also found to produce the antibody, which was repeatedly found to be absent during the acute phase in five patients with type A and in eight with type B hepatitis. The non-A, non-B antibody, mainly an IgM antibody, persisted in serum for prolonged periods of time after onset, both in patients showing biochemical resolution of their illness and in those who continued to have liver damage after the acute phase. Accordingly, eight out of nine patients with chronic non-A, non-B hepatitis were found positive for the antibody in serum, seven at the time the non-A, non-B antigen was detected in their liver. Thus this non-A, non-B associated antigen-antibody system shares remarkable similarities of behaviour with the "core" system of the hepatitis B virus.

Ultrastructural changes in the liver of patients with chronic non-A, non-B hepatitis.

Electron microscopy examination of liver biopsies from 8 patients with chronic non-A, non-B hepatitis revealed ultrastructural changes similar to those previously described in chimpanzees with experimentally induced acute non-A, non-B hepatitis. These changes consisted of intranuclear clusters of electron-dense, 15-27-nm particles that were detected in five out of the eight patients and of circular cytoplasmic structures that were present in seven cases. Other cytoplasmic abnormalities found in our patients related to the presence of curved membranes apparently developing from apposition of two cisternae of endoplasmic reticulum. In contrast with what has been reported in infected chimpanzees, the nuclear and cytoplasmic changes were not mutually exclusive in our patients, but coexisted in four of them.

In-vitro cell-mediated cytotoxicity for autologous liver cells in chronic non-A, non-B hepatitis.

To investigate the possible mechanisms of liver cell injury in chronic non-A, non-B (NANB) hepatitis, peripheral blood lymphocytes (PBL) from 16 patients with chronic NANB hepatitis were incubated with autologous hepatocytes in a microcytotoxicity assay. Significant cytotoxicity was demonstrated in 11 patients. T-enriched lymphocytes exhibited significantly greater cytotoxicity than non-T enriched cells. No significant inhibition of cytotoxicity was observed following preincubation of the liver cells with either monoclonal or polyclonal anti-HBc, or monoclonal anti-HBs, or addition of either purified HBsAg or recombinant HBcAg to the culture, indicating that there was no detectable cross-reactivity in this system between hepatitis B virus (HBV) and NANB-associated antigen(s). Preincubation of the patients' hepatocytes with polyclonal IgG purified from a serum of a patient who recovered from an acute NANB hepatitis, did not significantly alter cytotoxicity. Liver cell surface-bound IgG was detected by immunofluorescence in only two of the patients, a finding consistent with existing evidence of poor antibody responses to both liver membrane and NANB-associated antigens. Control experiments using PBL from allogeneic normal donors exhibited normal cytotoxicity for the patients' hepatocytes supporting the hypothesis that antibody-dependent cell-mediated cytotoxicity (ADCC) is unlikely to play a significant role in this clinical setting.

Concurrent hepatitis B and C virus infection and risk of hepatocellular carcinoma in cirrhosis. A prospective study.

BACKGROUND: Patients with cirrhosis have a high risk of hepatocellular carcinoma (HCC) but it is unclear how the etiology of liver disease influences tumor development. The authors evaluated hepatitis B and C virus (HBV, HCV) infection in cirrhosis in relation to the risk of HCC. METHODS: Two hundred and ninety consecutive cirrhotic patients were followed prospectively with periodic ultrasound examination. At entry, patients were tested for markers of HBV and HCV to assess relation to tumor development during follow-up. RESULTS: Twenty and five-tenths percent of patients were hepatitis B surface antigen (HBsAg) positive and 68.9% were positive for HCV antibodies. Previous alcohol abuse was present in 26.2%. During follow-up (46.3 +/- 21.4 months), HCC developed in 32 patients (11.0%) (annual incidence approximately 3%) including 19.6% of HBsAg-positive patients, 12.2% of HCV antibody positive patients and 14.4% of patients with a history of alcohol abuse. The highest rate of HCC was in patients with dual HBsAg and anti-HCV positivity with or without previous alcohol abuse, whereas the lowest incidence (0%) was in cases without risk factors. By univariate analysis, age older than 59 years (P < 0.005), longer duration of cirrhosis (P < 0.005), serum alpha-fetoprotein levels higher than 20 ng/ml (P < 0.05), and dual HBsAg and HCV positivity (P < 0.02) appeared to be associated with HCC. By multivariate analysis, age (P < 0.01), positivity for HBsAg and HCV antibodies (P < 0.05), male sex (P < 0.05), and previous alcohol abuse (P < 0.08) were independently related to tumor appearance. CONCLUSIONS: These results, although confirming that male sex and previous alcohol abuse are risk factors for hepatocellular carcinoma in cirrhosis, indicate that concurrent hepatitis B and C virus infection determines the highest risk of developing hepatocellular carcinoma.

[Frequency of antigen associated to hepatitis due to virus B (HBAg) and of antibody (HBAc) in healthy subjects and during of course of acute and chronic hepatitis. Radioimmunologic study]. / Frequenza dell'antigene associato all'epatite da virus B (HBAg) e dell'anticorpo (HBAc) in soggetti sani e in corso di epatite acuta e cronica. Studio radioimmunologico

Among the several methods employed for the detection of hepatitis B antigen (HBAg) and hepatitis B antibody (HBAb), radioimmunoassay is considered to be the most sensitive and specific. This paper describes a radioimmunoprecipitation test (RIP) for HBAg and HBAb standardized in our laboratory; it consists of a double-antibody precipitation test in a micro-titer system employing 125I-labeled HBAg. The test is compared with double immunodiffusion (ID) and with counterimmunoelectrophoresis (CEP) in the detection of HBAg and HBAb in healthy persons and in patients with acute and chronic liver disease. RIP is 20,000 times more sensitive than ID and 2,500 times than CEP when HBAg is tested, and 40,000 times more sensitive than ID and 10,000 times than CEP for the antibody detection. Moreover the method is reproducible and specific for HBAg and HBAb. With this test the frequency of HBAg in healthy persons was 0% in subjects without any known contact with antigenic material, 0.80% in hospital personnel and 1.17% in high risk personnel (laboratory technicians, blood products workers, ecc.). In acute viral hepatitis the frequency of HBAg was 90% at the admittance to the hospital and 70% at the dimission, while CEP detected a frequency of 85% and 20% respectively. In chronic liver disease the frequency of HBAg with the RIP method was 83.3% in chronic persistent hepatitis, 42.8% in chronic aggressive hepatitis, 23% in cryptogenic cirrhosis and 16.6% in alcoholic cirrhosis. The frequency of HBAb detected with RIP was 4.50% in subjects without any known contact with antigenic material, 6.45% in hospital personnel, 0.41% in high risk personnel, 20% in acute viral hepatitis at the admittance to the hospital and 50% at the discharge, 25% in chronic persistent hepatitis, 14.2% in chronic aggressive hepatitis, 15.3% in cryptogenic cirrhosis and 50% in alcoholic cirrhosis. The high frequency of antibody in healthy persons with no history of hepatitis or parenteral exposure to blood transfusion suggests a widespread diffusion of hepatitis B infection and the possibility of a nonparenteral route transmission. The frequency of HBAg and HBAb in chronic liver disease as detected by a very sensitive method rises the question of a possible role of hepatitis B virus in the pathogenesis of the disease.

Hepatitis C virus antibody response in acute and chronic non-A, non-B hepatitis.

Patients with post-transfusion, community-acquired or hemodialysis-acquired non-A, non-B hepatitis (NANBH) were tested for antibody to hepatitis C virus (HCV) during acute-phase and resolving or chronicized illness. HCV appears to be involved in most cases of post-transfusion and hemodialysis-acquired NANBH, but only in 40% of community-acquired NANBH. Second generation HCV antibody assays are more specific and sensitive, favoring early detection of HCV seroconversion and identification of HCV-antibody-positive individuals years after exposure to the virus.

Space-occupying lesions of the liver detected by ultrasonography and their relation to hepatocellular carcinoma in cirrhosis.

Fifty-four patients with cirrhosis, found to have a space-occupying lesion in the liver by ultrasound (US), underwent US-assisted biopsy of the lesion and were then followed prospectively to define outcome and survival. Histologic examination revealed hepatocellular carcinoma in 26 patients, while five had liver cell dysplasia without hepatocellular carcinoma and 23 had no evidence of tumor or of dysplasia. All five patients with an initial diagnosis of dysplasia developed hepatocellular carcinoma during follow-up and their survival curve was similar to that of patients with liver cancer and significantly worse than that of patients without dysplasia or tumor. There were five false-negative cases of hepatocellular carcinoma among the patients with negative histology. Overall, US-assisted liver biopsy diagnosed malignancy with a sensitivity of 72%, which increased to 86% when dysplasia was considered a pre-neoplastic lesion.

Suppressor cell activity in viral and non-viral chronic active hepatitis.

Suppressor cell function was studied in twenty-nine patients with chronic active hepatitis (CAH) in relation to possible aetiological causes and activity of liver disease. All fifteen patients with evidence of viral aetiology (ten HBsAg-positive CAH and five non-A, non-B CAH) showed normal suppressor cell function independently of severity of liver damage. In contrast, fourteen patients with HBsAg-negative CAH, including four cases with circulating antibodies to the hepatitis B virus, demonstrated a significant reduction in supprpessor cell activity compared to control subjects. No significant difference was found in this group between cases with and without circulating autoantibodies. In four out of five HBsAg-negative patients tested serially suppressor cell defect correlated with disease activity suggesting an abnormality in the regulation rather than a depletion of suppressor cells. These results suggest that different mechanisms are responsible for autoimmunity to the liver in virus and non-virus-related CAH.

Prospective study of posttransfusion hepatitis in cardiac surgery patients receiving only blood or also blood products.

The incidence, etiology and risk factors of posttransfusion (PT) hepatitis were evaluated in a prospective study of 297 consecutive open-heart surgery patients. PT hepatitis occurred in 63 (21.2%) patients with a significantly higher hepatitis attack rate in 51 recipients of commercial clotting factor concentrates (56.8%) compared to 246 recipients of blood units from single volunteer donors (13.8% p less than 0.001). Among the concentrates, Prothrombin-complex showed the highest relative hepatitis risk (24) while in patients receiving only blood, the incidence PT hepatitis was correlated with the blood volume transfused. Of the 63 patients with PT hepatitis, 2 (3%) had hepatitis B, 8 (13%) showed evidence of cytomegalovirus infection and 53 (84%) had non-A, non-B hepatitis. These results show that in Italy, as elsewhere, non-A, non-B PT hepatitis is frequent, particularly when commercial blood products are used.