Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Anti-mitochondrial M5 type antibody represents one of the serological markers for anti-phospholipid syndrome distinct from anti-cardiolipin and anti-beta2-glycoprotein I antibodies.

The aim of this study was to characterize the antigen specificity and to evaluate the diagnostic and prognostic value of anti-mitochondrial M5 type antibodies (AMA M5). Fifty-eight patients selected on the basis of their AMA M5 positivity were investigated in relationship to their clinical and serological profile. Cross-absorption studies, Western blotting and immunoprecipitation analysis were carried out for AMA M5 antigen specificity characterization. Most patients had a diagnosis of systemic lupus erythematosus (SLE) (65.5%) or of primary anti-phospholipid syndrome (PAPS) (24%); all the patients were positive for IgG or IgM anti-cardiolipin (anti-CL) antibodies and 49% of them also displayed lupus anticoagulant (LA) activity. Anti-beta2-glycoprotein I (beta2-GPI) IgG were detectable in 30/38 sera (78.9%) and IgM in 34/38 (89.4%). While anti-CL and anti-beta2-GPI IgG antibodies were significantly associated with history of thrombosis and fetal loss, AMA M5 displayed a statistical association only for thrombocytopenia and recurrent fetal loss. Absorption with human beta2-GPI both in free solution or in solid phase as well as with CL liposomes or CL/beta2-GPI liposome complexes did not affect AMA M5 fluorescence. While AMA M5 activity is absorbed by whole mitochondrial preparations, no specific reactivities against several human, bovine and rat mitochondrial proteins could be detected in Western blotting and immunoprecipitation studies. AMA M5 appear to be detectable in both primary and secondary APS, displaying a strong association with the presence of thrombocytopenia and fetal loss. Although strictly related to anti-phospholipid antibodies, AMA M5, anti-CL and anti-beta2-GPI antibodies represent distinct serological markers of the APS.

Diversity of antinuclear antibody responses in hepatocellular carcinoma.

BACKGROUND/AIMS: The development of antinuclear antibodies (ANA) in malignancies has been described but its mechanism is still not understood. The aim of this study was to examine ANA specificities in hepatocellular carcinoma to further understand autoimmunity in cancer. METHODS: Two hundred and four hepatocellular carcinoma patients were compared with 68 chronic hepatitis C, with 126 chronic hepatitis B and with 30 alcoholic liver cirrhosis patients, as well as with 87 healthy donors. Indirect immunofluorescence, immunoblotting, and immunoprecipitation were used to study ANA reactivities. RESULTS: Hepatocellular carcinoma had a significantly higher frequency of ANA using HEp-2 cells as substrate (31%) than chronic hepatitis C (10%), chronic hepatitis B (9.5%), alcoholic liver cirrhosis (10%) or healthy donors (4.5%). A great diversity of ANA specificities was found in hepatocellular carcinoma. Three hepatoma sera had antibodies that co-localized with non-snRNP splicing factor SC35, suggesting that the antigenic targets might be involved in mRNA splicing. We identified antibodies to two known nuclear autoantigens: fibrillarin and p330d/CENP-F. These autoantigens are involved in the 5' processing of precursor ribosomal RNA transcripts and in mitotic functions, respectively. CONCLUSIONS: Diversity was found in the autoantibody specificity, in contrast to the specific subsets of autoantibodies seen in several systemic rheumatic autoimmune diseases. Our data suggest that immune response in hepatocellular carcinoma targets important proteins involved in cellular biosynthetic or proliferative functions.

Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and -negative primary biliary cirrhosis.

Reports from North America and Northern Europe have suggested that antimitochondrial antibody (AMA) negative primary biliary cirrhosis (PBC) is a distinct chronic cholestatic liver disease with high prevalence of serum non-organ-specific autoantibodies other than AMA. To evaluate if such a peculiar serum immunoreactivity is associated with clinically relevant characteristics, we reviewed our experience with 297 Italian patients who have had a clinical and histological diagnosis of PBC and were regularly followed-up at our Center from June 1974 to June 1994. AMA-negative and AMA-positive patients were compared in terms of biochemical and clinical features, and clinical outcome of the disease. At presentation, 30 of 297 patients (10%) tested negative for AMA by indirect immunofluorescence. Six of them tested positive for antimitochondrial M2 antibodies (AMA-M2) by immunoblotting analysis, therefore, diagnosis of AMA-negative PBC was made in 24 patients (8%). At the initial visit, AMA-negative and AMA-positive patients were similar in terms of biochemical and clinical features. Antinuclear and anti-smooth-muscle antibodies (ANA and ASMA) were more frequently positive in the AMA-negative patients (71% vs. 31%, and 37% vs. 9%; both P = .0002). Incidence of complications of cirrhosis and development of liver failure resulting in death or referral for liver transplantation did not differ significantly between the two populations. In conclusion, data from this historical cohort study suggest that the distinct serological features of AMA-negative PBC are not associated with substantial differences in the clinical spectrum or course of the disease.

Immune response to cyclin B1 in hepatocellular carcinoma.

Proteins expressed by plasmids encoding human cyclins and cyclin-dependent kinase 2 (CDK2) were used as antigens in immunoblotting. Fifteen of 100 patients with hepatocellular carcinoma (HCC) were found to have autoantibodies reactive with cyclin B1 and with a 40-kd degradation product of cyclin B1-glutathione-S-transferase (GST) fusion protein. Only one serum was found to react with cyclin A and another single serum with CDK2 but no antibodies were detected to cyclin D1 and E. The basis for autoimmune responses to cyclin B1 in HCC are unknown at the present time but the possibilities might include aberrations in cyclin B1 regulation leading to altered product or its expression which resulted in stimulation of immune reactions.

Tauroursodeoxycholic acid for treatment of primary biliary cirrhosis. A dose-response study.

Tauroursodeoxycholic acid, a highly hydrophilic bile acid, may be of therapeutic value for chronic cholestatic liver diseases. We performed a dose-response study on 24 patients with primary biliary cirrhosis who were randomly assigned to receive 500, 1000, or 1500 mg daily of tauroursodeoxycholic acid for six months. Biliary enrichment with ursodeoxycholic acid ranged from 15% to 48% and was not related with the dose. Serum liver enzyme levels decreased significantly after the first month of treatment with all the three doses. No significant difference among the three doses was found, although further reduction over time occurred with 1000 and 1500mg daily. Plasma total and HDL cholesterol significantly decreased in patients administered the two higher doses. Diarrhea was the only side effect. In conclusion, a dose of about 10mg/kg body wt/day of tauroursodeoxycholic acid should be used for long-term studies in patients with primary biliary cirrhosis.

Comparison of protocols for depleting anti-E. coli antibody in immunoblotting of recombinant antigens.

A common problem in immunoblotting for the detection of specific antibodies to recombinant proteins synthesized in E. coli is the presence of contaminating antibodies to E. coli proteins. Four protocols for the efficient depletion of anti-E. coli antibodies from human sera are provided and their uses are discussed.

Hepatitis C virus and hepatocellular carcinoma.

Epidemiological evidence indicates that HCV plays an important role in the pathogenesis of many cases of hepatocellular carcinoma (HCC) in both hemispheres. In southern European countries the proportion of HCCs attributable to HCV is high, whilst in the USA this fraction is definitely smaller. These differences cannot be explained merely on the basis of the different prevalences of HCV in the corresponding general populations. Thought the mechanisms of HCV-related carcinogenesis are still obscure, it is clear that HCV alone or in conjunction with other environmental risk factors such as alcohol consumption or HBV infection can contribute to the epidemiological and clinical heterogeneity of HCC. Preliminary data indicate that HCV-related tumors arise in older patients, have a less aggressive course, and are more often associated with cirrhosis than HBV-related tumors.

Autoimmunity to the cell cycle-dependent centromere protein p330d/CENP-F in disorders associated with cell proliferation.

p330d/CENP-F is a novel proliferation-associated and cell cycle-dependent centromere autoantigen which appears to play a very important role in mitotic progression. As an initial step in exploring the clinical and biological significance of autoantibodies to this protein, we evaluated the clinical histories of 26 patients producing these antibodies. The antibodies were detected by both indirect immunofluorescence microscopy (IIF) and Western blotting. All the sera contained anti-p330d/CENP-F IgG antibodies, with an average titer by IIF of 1:6,917 (range 1:160 to 1:20,480). Most of the patients had disorders associated with abnormal or increased cell proliferation at the time the anti-p330d/CENP-F antibodies were detected. These included cancers of various types (14), chronic liver disease (3), chronic rejection of renal allografts (2), and Crohn's disease (1). The average IIF titer of the anti-p330d/CENP-F antibodies in the patients with cancer, 1:10,103, was significantly higher than the average titer in non-cancer patients, 1:3,200 (P = 0.008). Autoimmunity to p330d/CENP-F appeared not to be associated with rheumatic diseases, in particular scleroderma, since only three of the 26 patients had rheumatic disease and the antibodies were not detected by IIF in a group of 351 patients with scleroderma and related disorders. Our findings, although retrospective and limited to a relatively small number of patients, point to the hypothesis that autoimmunity to p330d/CENP-F could be related to events involving increased or abnormal cell proliferation.

Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon alpha-2a.

The occurrence of thyroid abnormalities and the appearance of organ- and non-organ-specific autoantibodies during long-term recombinant interferon alpha-2a (IFN-alpha) therapy were studied in 86 and 51 consecutive outpatients with hepatitis C and B virus-related chronic active hepatitis (CAH-HCV and CAH-HBV), respectively. Most patients had longstanding community-acquired hepatitis. At baseline, 9.3% of CAH-HCV and 3.9% of CAH-HBV patients showed clinical and/or biochemical signs of thyroid dysfunction. The remaining patients were euthyroid, although anti-thyroid autoantibodies were found in 33/78 (42.3%) of CAH-HCV and in 5/49 (10.2%) of CAH-HBV patients. During IFN-alpha treatment, increased anti-thyroid autoantibody levels were seen in 40% of CAH-HCV initially negative patients, while they became detectable in no more than 10% of CAH-HBV patients. Interferon-alpha-induced hypo- or hyperthyroidism was recorded in 12 of 35 CAH-HCV patients treated for 12 months (34.3%). Only one CAH-HBV patient developed hyperthyroidism. High titers of anti-nuclear autoantibodies (ANA) were recorded at enrollment in 5/36 (13.8%) of CAH-HCV and in 3/16 (18.7%) of CAH-HBV patients. Only one CAH-HCV patient displayed anti-parietal cell antibodies (PCA). After IFN-alpha treatment, ANA were found in 10/28 (35.7%) and PCA in 2/28 (7.1%) of CAH-HCV patients, while an additional CAH-HBV patient developed PCA, but not ANA. However, no signs of systemic autoimmune disease were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of preclinical hepatocellular carcinoma in patients with cirrhosis.

The association between hepatocellular carcinoma (HCC) and cirrhosis provides a formidable means for prospectively studying patients who are at risk of HCC. Early diagnosis of HCC is possible not only due to knowledge of the risk factors for this tumor, but also because HCC has a very long phase of intrahepatic growth and tends to grow as a solitary mass. Early diagnosis is also possible because sensitive and relatively inexpensive diagnostic tools are available. Several prospective studies of Oriental and Western patients with cirrhosis now in progress have led to the identification of many patients with small tumors. However, in the face of this evidence that screening high-risk patients may increase the yield of subclinical small tumors, no firm conclusion has yet been reached on whether early diagnosis of HCC may also increase the number of operable patients and reduce the mortality rate for this tumor.

Hepatitis C virus and hepatocellular carcinoma.

Epidemiological, clinical and laboratory data point to a role of hepatitis C virus infection in hepatocellular carcinoma. The connection appears to be indirect and to be mediated by cirrhosis. Thus, geographical differences can be observed, based on the locally prevalent etiological factors for cirrhosis. In the end, prospective studies of hepatitis C virus infected persons will be needed to elucidate the role of this agent in liver cancer.