Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: a pilot clinical study

BACKGROUND/AIMS: Experimental studies have shown synergy between radiofrequency (RF) ablation and adjuvant chemotherapy in animal tumour models. We aimed to assess safety and efficacy of doxorubicin-eluting bead (DEB)-enhanced RF ablation in the treatment of human hepatocellular carcinoma (HCC). METHODS: Twenty patients with single HCC ranging 3.3-7.0cm (mean, 5.0cm+/-1.4) showing evidence of residual viable tumour after standard RF ablation underwent intraarterial DEB administration (50-125mg doxorubicin; mean, 60.2mg+/-21.8). Follow-up period ranged 6-20 months (mean, 12 months+/-5). RESULTS: No major complication occurred. No deterioration of liver function was observed. The volume of treatment-induced necrosis - as measured on imaging - increased from 48.1cm(3)+/-35.7 after RF ablation to 75.5cm(3)+/-52.4 after DEB administration, with an increase of 60.9%+/-39.0. The enhanced effect resulted in confirmed complete response (CR) of the target lesion in 12 (60%) of 20 patients. Incomplete response with persistence of <10% of initial tumour volume was observed in 6 (30%) of 20 patients, and local tumour progression in 2 (10%) of 20. CONCLUSIONS: Intraarterial DEB administration substantially enhances the effect of RF ablation. DEB-enhanced RF ablation is safe and results in a high rate of CR in patients refractory to standard RF treatment.     

Comparison between a second and a third generation parathyroid hormone assay in hemodialysis patients

Objective

Third generation parathyroid hormone (PTH) assays are new generation assays that do not recognize the PTH_7–84 fragment whereas second generation assays detect both PTH_1–84 and PTH_7–84 fragments. Despite the excellent correlation between both assays in chronic renal failure (CRF) subjects, the mean PTH levels are typically 50% lower with the third compared to the second generation assays. The assessment of third generation PTH assays has not been extensively studied in hemodialysis subjects. The purpose of our study was to compare a third generation PTH assay to a second generation one in a population of hemodialysis subjects.

Materials and methods

92 haemodialysis subjects (36 women and 56 men) with a mean age of 67±12.9 years were included in this study. Anthropometric and clinical parameters (Body Mass Index (BMI) and blood pressure) were measured. Second and third generation PTH assays (Cis biomedical and Diasorin respectively) were performed in each subject. In addition, the following biochemical tests were measured: 25-hydroxyvitamin D (25-(OH)D), 1,25-hydroxyvitamin D (1,25-(OH)₂D), crosslaps and alkaline phosphatase.

Results

The mean second and third generation PTHs are respectively 211±205 pg/ml and 151±164 pg/ml. The mean third generation PTH values are 28.4% lower compared to the second generation ones. Both methods are strongly correlated (r = 0.923, p < 0.001). This correlation persisted without any significant difference after controlling for gender, age, BMI and Blood Pressure. However, the difference between both methods increases when baseline PTH increases. Each of the second and third generation method is significantly correlated with hemodialysis duration (p < 0.01), crosslaps (p < 0.001), alkaline phosphatase (p < 0.05), but not with age, BMI, Blood Pressure, 25-(OH)D or 1,25-(OH) ₂D levels.

Conclusion

Our results show that both second and third generation PTH methods are strongly correlated in hemodialysis patients mainly when PTH values are low. However, the difference between both methods increases when PTH values are high. More research is needed to establish which method is the gold standard when PTH values are high.     

Chronic administration of venlafaxine fails to attenuate 5-HT1A receptor function at the level of receptor-G protein interaction

In this study venlafaxine was administered to rats at a low, moderate or high dose; for comparison, the selective serotonin reuptake inhibitor (SSRI) sertraline and the tricyclic antidepressant (TCA) amitriptyline were also included. We evaluated, using quantitative autoradiography, the effect of these antidepressant treatments on [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT, a measure of the capacity of 5-HT1A receptors to activate G proteins. Chronic administration of amitriptyline resulted in a marked increase in 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus which was accompanied by an increase in 5-HT1A receptor number. 5-HT1A receptor-stimulated [35S]GTPgammaS binding in the hippocampus was also increased by chronic treatment with the highest dose of venlafaxine; 5-HT1A receptor number, however, was not significantly altered. In serotonergic cell body areas (i.e. dorsal and median raphe nuclei), 5-HT1A receptor-stimulated [35S]GTPgammaS binding was not altered by chronic administration of amitriptyline, sertraline or venlafaxine. Chronic TCA treatment does not desensitize somatodendritic 5-HT1A autoreceptor function. However, the lack of effect of chronic sertraline treatment on 5-HT1A receptor-stimulated [35S]GTPgammaS binding is in contrast to what has been observed previously following chronic administration of the SSRI fluoxetine, and suggests that different SSRIs may regulate somatodendritic 5-HT1A autoreceptor function differently depending on their pharmacology. Our data also suggest that the desensitization of somatodendritic 5-HT1A autoreceptors observed in electrophysiological studies following chronic venlafaxine administration is not at the level of receptor-G protein interaction. The hypothermic response in vivo to acute injection of 8-OH-DPAT was significantly attenuated following chronic treatment with venlafaxine or sertraline, but not amitriptyline.     

"Candidatus Neoehrlichia mikurensis," Anaplasma phagocytophilum, and lyme disease spirochetes in questing european vector ticks and in feeding ticks removed from people

To estimate the likelihood of people coming into contact with the recently described tick-borne agent "Candidatus Neoehrlichia mikurensis," we compared its prevalence to those of Lyme disease spirochetes and Anaplasma phagocytophilum in questing adult Ixodes ricinus ticks collected in various Central European sites and examined ticks, which had been removed from people, for the presence of these pathogens. Whereas spirochetes infected questing adult ticks most frequently (22.3%), fewer than a third as many ticks were infected by "Ca. Neoehrlichia mikurensis" (6.2%), and about a sixth harbored A. phagocytophilum (3.9%). On average, every twelfth encounter of a person with an I. ricinus tick (8.1%) may bear the risk of acquiring "Ca. Neoehrlichia mikurensis." Although a fifth of the people (20%) had removed at least one tick infected by "Ca. Neoehrlichia mikurensis," none displayed symptoms described for this pathogen, suggesting that its transmission may not be immediate and/or that immunocompetent individuals may not be affected. Because immunosuppressed patients may be at a particular risk of developing symptoms, it should be considered that "Ca. Neoehrlichia mikurensis" appears to be the second most common pathogen in I. ricinus ticks. In our survey, only Borrelia afzelii appears to infect Central European vector ticks more frequently.     

Role of the chemokine receptors CXCR3 and CCR4 in human pulmonary fibrosis

RATIONALE: The chemokine receptors CXCR3 and CCR4 have recently been described as playing a pivotal role in the mouse model of bleomycin-induced fibrosis. OBJECTIVES: To evaluate the role of these receptors in human idiopathic pulmonary fibrosis (IPF). METHODS: We studied 57 patients: 18 with IPF, 17 with non-IPF (nIPF), 12 with sarcoidosis, and 10 healthy control subjects. MEASUREMENTS: We evaluated the expression of CXCR3 and CCR4 in blood and bronchoalveolar lavage (BAL) T lymphocytes by flow cytometry and the chemokine CXCL10, CXCL11 and CCL17 BAL concentration by singular immunoassay. MAIN RESULTS: Patients with IPF had a significantly lower CXCR3 and a higher CCR4 expression on BAL CD4 T cells compared with the other groups. Among patients with IPF, those treated with corticosteroids exhibited higher CXCR3 and lower CCR4 expression compared with untreated patients. CXCR3 expression correlated with BAL lymphocytes and CCR4 with BAL neutrophils and eosinophils. CXCL10 levels correlated with the expression of CXCR3 on BAL CD4 cells. CXCL11 was undetectable in almost all patients, whereas CCL17 was primarily detectable in patients with IPF. The percentage of BAL CCR4CD4 cells negatively correlated with DL(CO). The changes in the total lung capacity, VC, and of the alveolar-arterial PO2 gradient in patients with IPF and those with nIPF 6 to 12 mo after the first evaluation were associated with CD4CXCR3 percentage on BAL cells. CONCLUSIONS: We found an imbalance in CXCR3/CCR4 expression on BAL CD4 lymphocytes and reduced CXCL10 BAL levels in patients with IPF, suggesting a pivotal role of these molecules in IPF.     

Blood dendritic cells generated with Flt3 ligand and CD40 ligand prime CD8+ T cells efficiently in cancer patients

Flt3 ligand mobilizes dendritic cells (DCs) into blood, allowing generation in vivo of large numbers of DCs for immunotherapy. These immature DCs can be rapidly activated by soluble CD40 ligand (CD40L). We developed a novel overnight method using these cytokines to produce DCs for cancer immunotherapy. Flt3 ligand-mobilized DCs (FLDCs) were isolated, activated with CD40L, loaded with antigenic peptides from influenza matrix protein, hepatitis B core antigen, NY-ESO-1, MAGE-A4, and MAGE-A10, and injected into patients with resected melanoma. Three injections were given at 4-week intervals. Study end points included antigen-specific immune responses (skin reactions to peptides alone or peptide-pulsed FLDCs; circulating T-cell responses), safety, and toxicity. No patient had a measurable tumor. Six patients were entered. FLDCs were obtained, enriched, and cultured under Good Manufacturing Practice grade conditions. Overnight culture with soluble CD40L caused marked up-regulation of activation markers (CD83 and HLA-DR). These FLDCs were functional and able to stimulate antigen-specific T cells in vitro. No significant adverse events were attributable to FLDCs. Peptide-pulsed FLDCs caused strong local skin reactions up to 60 mm diameter with intense perivascular infiltration of T cells, exceeding those seen in our previous peptide-based protocols. Antigen-specific blood T-cell responses were induced, including responses to an antigen for which the patients were naive (hepatitis B core antigen) and MAGE-A10. MAGE-A10-specific T cells with a skewed T-cell receptor repertoire were detected in 1 patient in blood ex vivo and from tumor biopsies. Vaccination with FLDCs pulsed with peptides is safe and primes immune responses to cancer antigens.     

A missense mutation in PIK3R5 gene in a family with ataxia and oculomotor apraxia

Autosomal recessive ataxias are heterogeneous group of disorders characterized by cerebellar atrophy and peripheral sensorimotor neuropathy. Molecular characterization of this group of disorders identified a number of genes contributing to these overlapping phenotypes. Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive form of ataxia caused by mutations in the SETX gene. We report on a consanguineous family with autosomal recessive inheritance and clinical characteristics of AOA2, and no mutations in the SETX gene. We mapped the AOA locus in this family to chromosome 17p12-p13. Sequencing of all genes in the refined region identified a homozygous missense mutation in PIK3R5 that was absent in 477 normal controls. Our characterization of the PIK3R5 protein and findings suggest that it may play a role in the development of the cerebellum and vermis.