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ABSTRACT: In patients with advanced fibrosis, primary end points of long-term or possibly indefinite antiviral therapy are sustained inhibition of viral replication and avoidance of emergence of resistance. In lamivudine-treated patients, the strongest predictor of emergence of YMDD mutations is baseline hepatitis B virus (HBV) DNA viral load. We aimed to verify whether abatement of viraemia by a short course of pegylated interferon (PEG-IFN-alpha2a) treatment before lamivudine treatment could prevent the emergence of lamivudine-associated mutations during long-term therapy.
A total of 14 patients with hepatitis B e antigen (HBeAg)-negative infection (3 lamivudine-experienced and 11 lamivudine-naive), with moderate/high viraemia (>10(6) copies/ml) and with Ishak stage 4-6 at liver biopsy were sequentially treated with 180 microg PEG-IFN-alpha2a for a period long enough to reach HBV DNA levels < or =10(3) copies/ml or have a decrease of 3 log(10) copies/ml from baseline. Lamivudine was then added to PEG-IFN-alpha2a treatment for 1 month and finally continued as monotherapy for 2 years or until viral breakthrough.
Baseline HBV DNA (mean +/-se 2.3 x 10(7) +/-7.2 x 10(7) copies/ml) decreased with PEG-IFN-alpha2a treatment to target value in mean +/-se 3.7 +/-1.3 months. None of the 11 lamivudine-naive patients developed genotypic resistance and were still HBV-DNA-negative after a mean +/-se observation period of 23 +/-2 months, whereas the three lamivudine-experienced patients developed YMDD mutations after 6, 9 and 12 months of lamivudine monotherapy (P=0.003, Fisher's exact test).
In lamivudine-naive patients, abatement of HBV DNA<10(3) copies/ml by pretreatment with PEG-IFN-alpha2a completely prevents the emergence of YMDD mutants after 24 months of lamivudine monotherapy. This sequential schedule can optimize the use of a well tolerated, effective and inexpensive drug, such as lamivudine, in highly viraemic HBV patients.
Antiviral therapy 01/2009; 14(8):1081-7. · 3.16 Impact Factor
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ABSTRACT: Experimental and clinical evidence indicates that estrogens have a relevant role in the pathogenesis of cancer of hormone-sensitive organs. Estrogen receptors (ERs) are present in liver cells. Normal liver expresses almost exclusively wild-type ERs derived from the full-length transcript of the gene. During progression of liver disease to hepatocellular carcinoma, variant forms of ERs have been demonstrated that greatly influence the course of the disease and the possibility of palliative treatment. Peritumoral cirrhotic tissue of patients with hepatocellular carcinoma, especially males, expresses a variant form of ER (vER) with an exon 5 deletion. In hepatocellular carcinoma, vER largely predominates and sometimes becomes the only form expressed. That the occurrence of vER alone is limited almost exclusively to males suggests that it could be one of the molecular events that eventually lead to the preferential development of hepatocellular carcinoma in males. In addition, the presence of vER appears most frequently in patients infected with the hepatitis B virus. The growth rate of hepatocellular carcinoma in patients with vER is also significantly higher than that in patients with tumors expressing wtER.
Annals of the New York Academy of Sciences 01/2006; 963(1):37 - 45. · 3.15 Impact Factor
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Mauro Manno,
Calogero Cammà,
Filippo Schepis,
Fabio Bassi,
Roberta Gelmini,
Francesco Giannini,
Francesca Miselli,
Antonella Grottola, Ilva Ferretti,
Chiara Vecchi,
Marisa De Palma,
Erica Villa
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ABSTRACT: Increased morbidity and mortality from liver disease have been reported in chronic hepatitis B surface antigen (HBsAg) carriers, but data on survival are equivocal. To assess the impact of hepatitis B virus (HBV) infection on survival and liver-related complications, we re-evaluated, after a mean follow-up of 30 years, a cohort of 296 blood donors excluded from donation 30 years ago when HBsAg screening became mandatory.
Clinical and ultrasound examination and biochemical and virologic tests were performed. The cause of death was recorded and survival was compared with a control population of 157 HBV-negative blood donors selected at baseline.
Thirty-two (10.8%) cases and 14 controls (8.9%) ( P = 0.625) had died; 3 of 32 (9.3%) and 1 of 14 (7.1%) deaths were liver-related. Hepatocellular carcinoma (HCC) caused death in 2 of 296 and 1 of 157 subjects (0.6% in each group). Alcohol-induced cirrhosis occured in the remaining subject. By Cox regression analysis, survival was independently predicted by older age, abnormal gamma-glutamyl transpeptidase (GGT) levels, and presence of medical comorbidities at baseline. Unequivocal liver disease was found in 4 carriers only. No disease decompensation occurred during follow-up. Fifty-nine (32.2%) carriers cleared HBsAg (yearly incidence, 1.0%). Full-length serum HBV DNA was present in 32.2% of persistently HBsAg-positive individuals (average titer always <10 5 copies/mL).
Over a 30-year period, chronic HBV carrier blood donors from Northern Italy did not develop clinically significant liver disease, hepatocellular cancer, or other liver-related morbidity or mortality at a higher rate than uninfected controls. The presence of medical comorbidities, older age at diagnosis, and abnormal GGT levels were independent predictors of death among chronic HBV carriers.
Gastroenterology 09/2004; 127(3):756-63. · 11.68 Impact Factor
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ABSTRACT: Several scoring systems to evaluate patients with hepatocellular carcinoma (HCC) exist. A good scoring system should provide information on prognosis and guide therapeutic decisions. The presence of variant liver estrogen receptor (ER) transcripts in the tumor has been shown to be the strongest negative predictor of survival in HCC. The aim of this study was to compare the predictive value of the commonly applied clinical scoring systems for survival of patients with HCC with that of the evaluation of ER in patients with HCC (molecular scoring system). Materials and
HCC was staged according to the Okuda classification, Barcelona Clinic Liver Cancer classification, Italian classification system (CLIP), French classification, and ER status in 96 patients. Analysis of survival was performed according to the Kaplan-Maier test and was made for each classification system and ER. A comparison between classifications was made by univariate and multivariate analysis.
Among the clinical classification systems, only the CLIP was able to identify patient populations with good, intermediate, and poor prognosis. On multivariate analysis, ER classification was shown to be the best predictive classification for survival of patients with HCC (P <.0001). This difference was the result of a better allocation of patients with ominous prognosis (variant ER) having nevertheless good clinical score.
The evaluation of the presence of wild-type or variant ER transcripts in the tumor is the best predictor of survival in patients with HCC. Its accuracy in discriminating patients with good or unfavorable prognosis is significantly greater than that of the commonly used scoring systems for the staging of HCC.
Journal of Clinical Oncology 03/2003; 21(3):441-6. · 18.37 Impact Factor
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ABSTRACT: The liver presents estrogen receptors alpha and beta. As for breast cancer, a variant form of estrogen receptor alpha transcript (ER) has been described in hepatocellular carcinoma (HCC). It is derived by an exon 5-deleted transcript (vER), which lacks the hormone-binding domain of the receptor but, being intact in the DNA-binding domain, maintains constitutive transcriptional activity. HCCs presenting vER have an extremely aggressive clinical course and are unresponsive to the antiestrogen tamoxifen. On the other hand, megestrol, a drug able to block both the wild type and the variant form of ER, influence the clinical course of HCC presenting vER. The presence of vER is associated with elevated cancer cell proliferation rate.
Molecular and Cellular Endocrinology 08/2002; 193(1-2):65-9. · 4.19 Impact Factor
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ABSTRACT: Experimental and clinical evidence indicates that estrogens have a relevant role in the pathogenesis of cancer of hormone-sensitive organs. Estrogen receptors (ERs) are present in liver cells. Normal liver expresses almost exclusively wild-type ERs derived from the full-length transcript of the gene. During progression of liver disease to hepatocellular carcinoma, variant forms of ERs have been demonstrated that greatly influence the course of the disease and the possibility of palliative treatment. Peritumoral cirrhotic tissue of patients with hepatocellular carcinoma, especially males, expresses a variant form of ER (vER) with an exon 5 deletion. In hepatocellular carcinoma, vER largely predominates and sometimes becomes the only form expressed. That the occurrence of vER alone is limited almost exclusively to males suggests that it could be one of the molecular events that eventually lead to the preferential development of hepatocellular carcinoma in males. In addition, the presence of vER appears most frequently in patients infected with the hepatitis B virus. The growth rate of hepatocellular carcinoma in patients with vER is also significantly higher than that in patients with tumors expressing wtER.
Annals of the New York Academy of Sciences 07/2002; 963:37-45. · 3.15 Impact Factor
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ABSTRACT: Endometrial adenocarcinoma is a typical estrogen-dependent neoplasia. The molecular mechanisms underlying carcinogenesis in the endometrium are still largely unknown. Recently, estrogen receptor (ER) mRNA splicing variants have been investigated in several normal and neoplastic human tissues. It has been suggested that the variant receptors compete with the wild-type receptors and thereby modulate the effects of estrogens and related steroids.
To investigate the possible expression of the ER alpha mRNA variant-type lacking exon 5 (ERDelta5) in endometrial adenocarcinoma and peritumoral tissues, non-neoplastic endometrium of healthy women served as control.
The study included 16 patients divided in two groups. The first group (n=6) was submitted to hysteroscopy and endometrial biopsy for metrorrhage, showing normal proliferative (n=2) or secretory (n=4) endometrium, the second group (n=10) included patients submitted to hysterectomy for endometrial adenocarcinoma (stages Ib-IIIb). In this latter group, specimens from peritumoral tissues were also analyzed (n=3). Characterization of the variant and wild-type alpha estrogen receptor transcripts was performed by RT-PCR with primers located in exons 4 and 6, followed by southern hybridization with probes directed to a specific 29 nucleotide sequence of exon 6, internal to the amplified fragments.
The ER alpha mRNA variant was co-expressed with the wild-type ER in five or six samples of non-neoplastic endometrium and in 10/10 cases of adenocarcinoma, with a more intense hybridization signal corresponding to the wild-type 439bp band compared to the variant-type 300bp band. Specimens from peritumoral tissue also expressed the variant ERDelta5 along with wild-type ER.
The presence of alpha mRNA variant lacking exon 5 in both normal and endometrial adenocarcinoma do not support a major role of variant estrogens receptors in the biology of endometrial cancer.
European Journal of Obstetrics & Gynecology and Reproductive Biology 05/2002; 102(1):92-5. · 1.97 Impact Factor
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ABSTRACT: Clinical course in hepatocellular carcinoma may be very different. We prospectively evaluated 96 patients with hepatocellular carcinoma unsuitable for radical therapy to investigate factors that could influence survival. Clinical, pathologic, and molecular data of patients were analyzed by univariate and multivariate analysis. The overall actuarial probability of survival at year 1, 2, 3, 4, 5, and 6 was 72%, 41%, 38%, 24%, 20%, and 9%. At univariate analysis, alpha-fetoprotein (AFP) (P = .0082); alkaline phosphatase (P = .0281); bilirubin (P = .0076); etiology (P = .0001); increment of tumor mass at month 3 (P = .0051); type of estrogen receptor (ER) in the tumor (P = .0000); prothrombin time (P = .0003); and portal vein thrombosis (P = .0000) had prognostic significance. At multivariate analysis, only type of ER (P = .0000) and bilirubin (P = .0030) showed independent predictive value for mortality. Survival was significantly longer in patients with wild-type estrogen receptors (P = .0000). Cumulative probability of survival at year 1, 2, 3, 4, 5, and 6 was 94%, 66%, 52%, 43%, 35%, and 18% for wild-type and 51%, 21%, 16%, and 9% for variant estrogen receptors (no patients alive after 4 years). Hepatitis B surface antigen (HBsAg)-positive patients with variant ERs had a median survival of 8 months versus 45 months in anti–hepatitis C virus–positive patients with wild-type ERs (P = .0001). In conclusion, (1) the presence of variant liver ER transcripts in the tumor was the strongest negative predictor of survival in inoperable hepatocellular carcinoma; (2) their presence was associated with spontaneous survival significantly worse than in patients with wild-type estrogen receptors; and (3) HBsAg-positive patients with variant receptors were characterized by the worst survival.
Hepatology 07/2000; 32(2):233 - 238. · 11.66 Impact Factor
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Digestive Diseases and Sciences 01/1983; 28(4):381-381. · 2.12 Impact Factor
