Radiofrequency thermal ablation (RFA) destroys tumoral tissue generating a local necrosis followed by marked inflammatory response with a dense T-cell infiltrate. In this study, we tested whether hepatocellular carcinoma thermal ablation can induce or enhance T-cell responses specific for hepatocellular carcinoma-associated antigens. Peripheral blood mononuclear cells derived from 20 patients with hepatocellular carcinoma were stimulated before and a month after RFA treatment with autologous hepatocellular carcinoma-derived protein lysates obtained before and immediately after RFA treatment. The effect of thermal ablation on memory T-cell responses to recall antigens [tetanus toxoid, protein purified derivative (PPD), Escherichia coli] was also assessed. T-cell reactivity was analyzed in an IFN-; enzymelinked immunospot assay and by intracellular IFN-; staining. Treatment was followed by a significant increase of patients responsive either to tumor antigens derived from both the untreated hepatocellular carcinoma tissue (P < 0.05) and the necrotic tumor (P < 0.01) and by a higher frequency of circulating tumor-specific T cells. T-cell responses to recall antigens were also significantly augmented. Phenotypic analysis of circulating T and natural killer cells showed an increased expression of activation and cytotoxic surface markers. However, tumor-specific T-cell responses were not associated with protection from hepatocellular carcinoma relapse. Evidence of tumor immune escape was provided in one patient by the evidence that a new nodule of hepatocellular carcinoma recurrence was not recognized by T cells obtained at the time of RFA. In conclusion, RFA treatment generates the local conditions for activating the tumorspecific T-cell response. Although this effect is not sufficient for controlling hepatocellular carcinoma, it may represent the basis for the development of an adjuvant immunotherapy in patients undergoing RFA for primary and secondary liver

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A better restoration of HCV-specific CD8 function was detectable after SVR in patients with acute hepatitis than in those with chronic disease. Thus, the difficulty in achieving a complete restoration of the antiviral T cell function should be considered in the design of immunomodulatory therapies.

AimsTo compare steady-state nelfinavir (NFV) pharmacokinetics in pregnant and nonpregnant HIV-infected women. MethodsTwenty-five pregnant HIV-infected women were selected from an ongoing observational study evaluating the pharmacokinetics of antiretroviral agents during pregnancy. Twenty of them were in the third and five in the second trimester. Data for the control group of 21 HIV-infected nonpregnant women were taken from a previous multicentre pharmacokinetic trial. All the participating women achieved steady-state plasma concentrations while on a highly active antiretroviral therapy (HA ART) regimen including NFV (1250 mg bid) and two nucleoside reverse transcriptase inhibitors (N RTIs). Blood samples for NFV measurement were collected predose ( C trough ) and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 h post dose. ResultsDuring the third trimester of pregnancy NFV AUC 0 − 12 h median (range) values were 25.76 (12.61-42.74) µ g h − 1 ml − 1 , and were 32. 49 (19.16-63.81) µ g h − 1 ml − 1 in the control group [mean difference − 9.30 µ g h − 1 ml − 1 ; 95% confidence interval (CI) − 15.76, − 2.83; P < 0.05). Median oral clearance (CL/F) was significantly higher in pregnant women than in the control group (48.5 l h − 1 , range 29.3-99.1 l h − 1 vs. 38.5 l h − 1 , range 19.6-65.2 l h − 1 ; mean difference 12.6 l h − 1 ; 95% CI 3.3, 21.9) but the difference disappeared when CL/F was adjusted for body weight. C trough was significantly ( P < 0.01) lower in pregnant compared with nonpregnant women (median 0.8 µ g ml − 1 , range 0-2.6 µ g ml − 1 vs. 1.5 µ g ml − 1 , range 0.5-4.9 µ g ml − 1 ; mean difference − 1.0 µ g ml − 1 ; 95% CI − 1.7, − 0.31). The median elimination half-life of NFV observed during pregnancy was 3.7 h (range 1.4-6.6 h), compared with 5.2 (range 3.1-10.1 h) in the control group (mean difference − 1.7; 95% CI − 2.8, − 0.51). ConclusionsOur results indicate that women in the later stages of pregnancy may be exposed to subtherapeutic concentrations of NFV. Thus, adjustments in drug dosage or frequency of administration may be required. P. Villani et al. 31062 :3 Br J Clin Pharmacol

We investigated the parental origin of the extra chromosome 14 and of the two chromosomes 14 of the euploid cell line, in a case of fetal mosaicism 46,XX/47,XX+14 diagnosed at amniocentesis. Molecular analysis of five polymorphic loci of the short tandem repeat type was performed. Markers D14S43 and D14S49 showed the presence of maternal uniparental disomy of chromosome 14 in the apparently normal cell line. The distribution of the markers analysed along the chromosome suggests maternal heterodisomy with a large isodisomic segment in the telomeric region, possibly caused by meiotic crossing-over.