Multivariable time-dependent analysis of the impact of azacitidine in patients with lower-risk myelodysplastic syndrome and unfavorable specific lower-risk score.

Scoring systems for lower-risk myelodysplastic syndrome (LR-MDS) recognize patients with a poorer than expected outcome. This study retrospectively analyzes the role of azacitidine in LR-MDS with adverse risk score and compared to an historical cohort treated with best supportive care or erythropoiesis-stimulating agents. Overall response to AZA was 40%. One and 2-year probabilities of survival were 62% and 45% for AZA vs. 25% and 11% (P=10(-4)). In a multivariable time-dependent analysis, response to AZA (CR/PR/HI) was associated with an improved survival (HR=0.234, 95% CI, 0.063-0.0863; P=0.029). Thrombocytopenia (<50 × 10(9)L(-1)) is confirmed as an adverse parameter in LR-MDS (HR=1.649, 95% CI, 1.012-2.687; P=0.045).

Effectiveness and safety of different azacitidine dosage regimens in patients with myelodysplastic syndromes or acute myeloid leukemia.

We investigated the effectiveness and tolerability of azacitidine in patients with World Health Organization-defined myelodysplastic syndromes, or acute myeloid leukemia with 20-30% bone marrow blasts. Patients were treated with azacitidine, with one of three dosage regimens: for 5 days (AZA 5); 7 days including a 2-day break (AZA 5-2-2); or 7 days (AZA 7); all 28-day cycles. Overall response rates were 39.4%, 67.9%, and 51.3%, respectively, and median overall survival (OS) durations were 13.2, 19.1, and 14.9 months. Neutropenia was the most common grade 3-4 adverse event. These results suggest better effectiveness-tolerability profiles for 7-day schedules.

Immunogenicity and reactogenicity of a booster dose of a novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine given to toddlers of 13-14 months of age with antibody persistence up to 31 months of age.

BACKGROUND: A combined Haemophilus influenzae type b and Neisseria meningitidis serogroup C tetanus toxoid conjugate vaccine (Hib-MenC-TT) may be a convenient alternative to separate Hib and MenC conjugate vaccines. METHODS: Healthy infants randomized in a previous study for priming at 2, 4, and 6 months: Hib-MenC-TT primed group, 3 doses of Hib-MenC-TT + DTPa-HBV-IPV (N = 87); MenC-TT primed group, 2 doses of MenC-TT (NeisVac-C; Baxter Healthcare SA, Zuürich, Switzerland) + 3 doses of DTPa/Hib containing vaccines (N = 178); MenC-CRM primed group, 3 doses of MenC-CRM197(Meningitec; Wyeth Corporation Delaware, Madison, NJ) + DTPa-HBV-IPV/Hib (N = 93). At 13-14 months of age, Hib-MenC-TT and MenC-TT primed groups received a Hib-MenC-TT booster dose and the MenC-CRM primed group a booster dose of DTPa-HBV-IPV/Hib. Blood samples were taken before and at 1 and 18 months postbooster. RESULTS: Before the booster dose, persistence of anti-polyribosyl ribitol phosphate (PRP) antibody concentration > or =0.15 microg/mL in the Hib-MenC-TT (96.4%) and MenC-TT (96.1%) primed groups and of MenC bactericidal titers > or =1:8 in the Hib-MenC-TT primed group (96.3%) was statistically significantly higher than in the MenC-CRM primed group (86.4% and 85.4%, respectively). One month after the Hib-MenC-TT booster, 99.2% subjects in the Hib-MenC-TT primed + MenC-TT primed pooled groups had anti-PRP levels > or =1 microg/mL, and 99.6% had SBA-MenC titers > or =1:128. The Hib-MenC-TT booster tended to be less reactogenic than the DTPa-HBV-IPV/Hib control and no serious adverse events related to vaccination were reported. Eighteen months after boosting with Hib-MenC-TT, SBA-MenC titers > or =1:8 persisted in 92.7% subjects and anti-PRP > or =0.15 microg/mL persisted in 99.4%. CONCLUSIONS: Primary immunization with 3 doses of Hib-MenC-TT coadministered with DTPa-HBV-IPV induced antibodies that persisted up to the second year of life. The Hib-MenC-TT booster administered to primed toddlers induced robust and persistent antibody responses to both the Hib and MenC components and had an acceptable safety profile.

Two year follow-up of immunological response in mite-allergic children treated with sublingual immunotherapy. Comparison with subcutaneous administration.

Although the efficacy of allergen-specific sublingual immunotherapy (SLIT) is now accepted, the underlying mechanisms remain elusive. Such mechanisms are better documented in the case of subcutaneous immunotherapy (SCIT). In order to understand the T-lymphocyte response in patients receiving SLIT, we compared children with respiratory disease monosensitized to Dermatophagoides pteronyssinus receiving SLIT or SCIT over a 2-yr period. Peripheral blood was obtained before beginning immunotherapy, and after 3 months, 1 yr and 2 yr. Total IgE, specific IgE and IgG4 to D. pteronyssinus were determined in serum. T-cell markers (CD3, CD4, CD8, CD25) and intracellular cytokine production (TNF-alpha, IL-2, IL-4 and IFN-gamma) were determined in peripheral blood mononuclear cells (PBMC) by flow cytometry. No differences between SCIT and SLIT were detected in the clinical variables or in the subjective evaluation. Although an increase in specific IgE and IgG4 was only detected in SCIT, a significant decrease in the specific IgE/IgG4 ratio was found in both groups. SCIT and SLIT experienced an increase in the CD4/CD8 ratio over time, but an increase in the CD4(+)CD25(+) and a decrease in the CD8(+)CD25(+) subsets were only found with SCIT. A slight shift from a Th2 to a Th1 pattern, measured by the IFN-gamma/IL-4 ratio, was only detected in the CD4 T cells with SCIT. A decrease in both groups was found in TNF-alpha and IL-2 production over time. Children with respiratory allergic diseases receiving SCIT or SLIT had a different immunologic response in peripheral blood during treatment, though the clinical improvement was similar. Whether SLIT induces a mucosal protective response should be studied.

Immunogenicity and reactogenicity of primary immunization with a novel combined Haemophilus influenzae Type b and Neisseria meningitidis Serogroup C-tetanus toxoid conjugate vaccine coadministered with a Diphtheria-tetanus-acellular Pertussis-hepatitis B-inactivated poliovirus vaccine at 2, 4 and 6 months.

BACKGROUND: This phase II study evaluated the immunogenicity and reactogenicity of primary vaccination with a novel Hib-MenC conjugate vaccine (GlaxoSmithKline [GSK] Biologicals) coadministered with DTPa-HBV-IPV (GSK Biologicals) at 2, 4 and 6 months. METHODS: Healthy infants were randomized to receive Hib-MenC coadministered with DTPa-HBV-IPV (N = 117) or MenC-CRM (Wyeth) coadministered with DTPa-HBV-IPV/Hib (GSK Biologicals; N = 120) at 2, 4 and 6 months. Antibody concentrations were measured before vaccination and after doses 2 and 3. Solicited local and general symptoms, unsolicited symptoms and serious adverse events (SAEs) were recorded. RESULTS: All subjects in the Hib-MenC group had seroprotective titers of anti-PRP antibodies (>or=0.15 microg/mL) and SBA-MenC titers (>or=1:8) 1 month after the third dose. These responses were noninferior to those seen in the control group, in which a 99.1% seroprotection rate was observed for both Hib and MenC. At that time, anti-PRP and SBA-MenC GMTs were significantly higher in the Hib-MenC group (12.8 microg/mL and 2467.1 microg/mL, respectively) than in the control group (3.8 microg/mL and 1833.7 microg/mL). High seroprotection rates were already observed after the second dose of Hib-MenC; 96.4% and 100% of subjects were seroprotected to Hib and MenC, respectively. Immune responses to coadministered antigens were unimpaired; seroprotection/vaccine response rates >or=96.5% were recorded postdose 3 in the Hib-MenC group. No differences in reactogenicity were seen between the 2 study groups. CONCLUSIONS: Coadministration of a Hib-MenC conjugate vaccine with DTPa-HBV-IPV is well tolerated and immunogenic, and does not impair the immune response to any of the coadministered antigens.

Immunogenicity and reactogenicity of primary immunization with a hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B vaccine coadministered with two doses of a meningococcal C-tetanus toxoid conjugate vaccine.

BACKGROUND: This study evaluated the concurrent use of meningococcal C tetanus conjugate (MenC-TT) vaccine (NeisVac-C) with DTaP-based combinations, according to 2 vaccination schedules, one of which included hepatitis B vaccination at birth (Trial DTaP-HBV-IPV/Hib-097). METHODS: Healthy infants were randomized to receive either DTaP-HBV-IPV/Hib (Infanrix hexa) at 2, 4, and 6 months (N = 115) or HBV at birth followed by DTaP-HBV-IPV/Hib at 2 and 6 months and DTaP-IPV/Hib (Infanrix-IPV Hib) at 4 months (N = 115). In both groups 2 doses of MenC-TT conjugate were coadministered at 2 and 4 months, and compared with 3 doses of MenC-CRM197 conjugate (Meningitec) coadministered at 2, 4, and 6 months with DTaP-HBV-IPV/Hib (N = 120). Antibody concentrations were measured at 2, 6 and 7 months. Solicited local and general symptoms, unsolicited symptoms, and serious adverse events (SAEs) were recorded. RESULTS: All MenC-TT recipients had seroprotective concentrations of anti-PRP antibodies (> or = 0.15 microg/mL) 1 month after the third vaccine dose and all had SBA-MenC titers > or = 1:8 after the second dose of MenC-TT. These responses were noninferior to those seen after 3 doses of DTaP-HBV-IPV/Hib and MenC-CRM. Anti-PRP antibody GMCs were significantly higher in MenC-TT than MenC-CRM vaccinees (7.9, 7.3, 3.8 microg/mL, respectively). Immune responses to all other coadministered antigens were unimpaired, with seroprotection/seropositivity rates > or = 98.1% in MenC-TT vaccinees. All schedules studied were well tolerated, with no differences in reactogenicity between the study groups. CONCLUSIONS: Coadministration of DTaP-HBV-IPV/Hib or DTaP-IPV/Hib with 2 doses of MenC-TT conjugate vaccine is safe, well tolerated, and immunogenic, with no impairment of the response to the coadministered antigens.

Cytokine production, activation marker, and skin homing receptor in children with atopic dermatitis and bronchial asthma.

T cells are known to develop a critical role in the pathogenesis of atopic dermatitis (AD) and bronchial asthma. T cells involved in AD express the skin homing receptor CLA, but no lung homing receptor has been identified in bronchial asthma. We compared different cell markers and the cytokine production in T cells from children with AD or bronchial asthma. We studied the involvement of CLA+ and CLA- T-cell subpopulations in these diseases. We studied 20 children with acute AD lesions, 15 with mild persistent asthma, and 15 non-atopic controls. All patients were sensitized to house dust mite (DP) and evaluated during the acute phase. Total and specific IgE were measured by immunoassay and the expression of different cell markers and the cytokine production was analyzed by flow cytometry in peripheral blood mononuclear cells. Total IgE was significantly higher in AD children and IgE to DP in the asthmatic children. There was a significant increase in CD25+ CD4+ cells in asthmatic children and in HLA-DR+ CD4+ and HLA-DR+ CD8+ cells in AD. In the CD4+ subsets, there was an increase in IL-13, IL-5 and TNF-alpha in AD compared to controls, a decrease in IFN-gamma in asthmatic children compared to controls, and an increase in IL-13, IL5, IL2, TNF-alpha, and IFN-gamma in the AD compared to asthmatic children. Changes in cytokine production were mainly detected in CLA+ cells in AD and in CLA- cells in asthma. Differences exist in total and specific IgE, activation markers, and cytokine patterns between AD children and children with asthma, with the former expressing a Th2 pattern whereas in asthmatic children we only detected a decrease in IFN-gamma. Moreover, the subpopulations (CLA+ vs. CLA-) expressing these changes were different, indicating that the underlying mechanisms in the two diseases are not exactly the same.

Improvement of toxic epidermal necrolysis after the early administration of a single high dose of intravenous immunoglobulin.

BACKGROUND: Toxic epidermal necrolysis (TEN) is a severe disease often induced by drugs. Treatment is controversial, although intravenous immunoglobulins (IVIGs) have been effective. OBJECTIVE: To report the case of a child with TEN after lamotrigine treatment, who improved 24 hours after IVIG administration. METHODS: Sequential blood and blister fluid samples were obtained for flow cytometry and reverse transcriptase-polymerase chain reaction analyses. RESULTS: The first blood sample, taken before IVIG administration, showed normal levels of lymphocyte subsets and CLA (4.0%) but high levels of activated lymphocytes (CD69) (18.0%). After treatment, the CLA+, CD69+, and memory cells increased until day 7, decreasing to normal values at days 15 and 30. In the blister fluid samples, taken on day 1, there were high levels of CD8+ (70.2%; CD4/CD8 ratio, 1:5), CLA+ (18.8%), and CD69+ (70%) cells, decreasing 24 hours after IVIG administration. In the blood samples, there was a Th1 cytokine pattern initially, tending to Th0 with time. Perforin, granzyme B, and Fas ligand were only observed before IVIG administration. CONCLUSIONS: A single high dose of IVIG interrupted the progression of skin disease and reduced the expression of the apoptotic markers. The immunologic changes, first seen in blister fluid and remaining several days in peripheral blood, indicate that T cells were first recruited to the skin and then recirculated to blood.

Immediate allergy to tetanus toxoid vaccine: determination of immunoglobulin E and immunoglobulin G antibodies to allergenic proteins.

BACKGROUND: Adverse reactions to tetanus toxoid (TT) vaccine are mostly mild and limited to the injection site. However, immunoglobulin (Ig)E-mediated reactions may occur, and the incidence of anaphylactic responses to TT immunization is 0.001%. When TT induces an allergic reaction, the potential causative agents can be TT antigens, thimerosal or aluminum phosphate. OBJECTIVE: We studied four children who developed immediate urticaria after TT vaccine, soon after the reaction and 5 years later. METHODS: Skin tests were performed separately with TT vaccine and two vaccine components, thimerosal and aluminum phosphate, and the diagnosis was confirmed by provocation test. IgE and IgG antibodies to TT and their specificities were determined. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting were performed to characterize the antigenic proteins. RESULTS: All four children were immediate skin test-positive to TT, but negative to thimerosal and aluminum phosphate; 3 developed a reaction after intramuscular provocation using increasing doses of TT vaccine; and 1 refused to be tested. All these tests were negative in five controls, all of whom received TT vaccine and developed only local swelling at the site of application 24 hours after vaccine administration. After 5 years the IgG antibodies were still high in all cases and the IgE antibody values fell by 50%. Patients allergic to TT vaccine produced IgE and IgG antibodies, which decreased at different rates but remained for at least 5 years. The pattern of antibody decrease was confirmed by radioallergosorbent test, enzyme-linked immunoadsorbent assay, or immunoblotting assay. IgE and IgG antibodies recognized two proteins derived from TT, of 150 and 50 kDa, corresponding to the intracellular form and to a chain of the extracellular form of the tetanus neurotoxin. CONCLUSIONS: In children with immediate allergic reactions to TT vaccine, antibodies may persist for at least 5 years, requiring evaluation by skin and/or in vitro tests before subsequent treatment.

Disfagia pseudotumoral tuberculosa: reporte de caso clínico / Tuberculosa pseudotumorlike disfagia: report of clinical case

Analiza que la tuberculosis esofágica es una entidad clínica rara. Esta puede ser sitio excepcional de una reactivación tuberculosa o más frecuentemente puede coexistir con la tuberculosis mediastinal extraesofágica. Debido a que clínicamente simula a la neoplasia esofágica, pero difiere en su tratamiento, su diagnóstico correcto es crucial. Presentamos un caso de tuberculosis de reactivación esofágica sin otros signos radiográficos visibles de actividad tuberculosa. La disfagia progresiva y los hallazgos endoscópicos-radiológicos sugerían cáncer esofágico por lo que se decidió el procedimiento quirúrgico: resección-anatomosis. El examen patológico de la pieza anátomo-quirúrgica reveló granulomas con bacilos ácido-resistentes en la pared del esófago y tuberculosis caseosa ganglionar periesofágica...