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  • 1
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 58, No. 12 ( 2014-12), p. 7164-7170
    Abstract: Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day ( P 〈 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration ( C max ) and area under the concentration-time curve from 0 to 6 h (AUC 0–6 ) were 2.77 mg/liter and 9.71 mg·h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg·h/liter, respectively, for biweekly administration. There were no differences in the C max with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the C max reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the C max and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2014
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    SSG: 12
    SSG: 15,3
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  • 2
    In: Blood, American Society of Hematology, Vol. 123, No. 13 ( 2014-03-27), p. 2034-2043
    Abstract: Activating mutations in PLCG1 are a frequent finding in tumoral CTCL samples. This raises the possibility of targeted therapies against PLCG1 signaling pathway, using calcineurin inhibitors.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 3
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 43, No. 11 ( 2011-11), p. 1098-1103
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2011
    detail.hit.zdb_id: 1494946-5
    SSG: 12
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  • 4
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 4478-4478
    Abstract: Abstract 4478 Background: The optimal therapy after transformation of follicular lymphoma into diffuse large B-cell lymphoma (DLBCL) is unknown. Most of retrospective registry data and phase II studies suggest a potential benefit of high-dose therapy and autologous transplantation (HDT-ASCT) for patients with transformed lymphoma (TL). Addition of rituximab to CHOP chemotherapy could improve survival in TL. However, the effect of prior rituximab-based therapy upon the efficacy of subsequent autologous stell cell transplantation (ASCT) in TL is still unknown. Patients and methods: We have identified the patients with follicular lymphoma who developed confirmed histological transformation to DLBCL treated with HDT-ASCT included in the Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL-TAMO) Spanish registry between October 1994 and March 2011. Patients were divided into two groups, according to whether rituximab-based regimens were given (n = 28, ‘R+’ group) or not (n = 22, ‘R-’ group) at the time of transformation. Kaplan-Meier survival curves were estimated, and differences in survival curves between groups were assessed using the log-rank test. Results: Fifty patients (23 women) with a histological diagnosis of TL who underwent HDT-ASCT were included. Median age at transplantation was 55 years (range 32–70). Patients had received a median of 2 (range 1–5) chemotherapy regimens prior to ASCT. Median time from diagnosis of follicular lymphoma to transformation was 49 months (range 8–135). Age-adjusted International Prognostic Index (IPI) was 2 or 3 in 11 patients (22%). Disease status prior to ASCT was first complete remission in 4 patients (8%), second CR in 56% and active diseasein 14%: sensitive disease in 11 (22%) and refractory disease in 3 (6%) patients. Conditioning regimen consisted of BEAM in 92% of patients, BEAC in 4%, and cyclophosphamide /TBI in 4%. With a median follow-up of 61 months, estimated overall survival (OS) and progression-free survival (PFS) at 5 years after ASCT were 56.5% and 51.3%, respectively. No patients died of transplant-related mortality. Thirteen patients experienced relapse or progression after HD-ASCT; nine of these patients have died because of disease progression. By multivariate analysis three variables significantly influenced both OS and PFS: number of regimens prior to ASCT, disease status at transplant and achievement of response after HD-ASCT. Age-adjusted IPI at transformation had significant influence only on OS. Patients who did not receive rituximab-based regimens had similar characteristics to patients who received rituximab at transformation. Patients in the R+ group had similar 5-year PFS (48.2% vs 48.4%, P = 0.359) and 5-year overall survival (OS) (66.4% vs 67.2%, P = 0.607) compared to patients in the R- group (Figures 1 and 2). Eight out of 28 “R+” patients had not received rituximab prior to transformation; these patients had better PFS (69% vs 38%, p = 0.912) and OS at 5 years (74.1% vs 54.5%) compared to the 20 patients who were treated with rituximab prior to transformation, but the difference did not reach statistical significance (p 〉 0.1). Patients treated with rituximab-based regimens at any time prior HDT-ASCT had similar OS (70% versus 63.8% at 5 years, P = 0.697) and PFS (50% versus 44% at 5 years, P = 0.445) than patients who received chemotherapy alone before ASCT. Conclusion: Our results show that HDT-ASCT remains a valuable therapeutic choice for patients with histological confirmed TL since it allows a long-term disease control in a significant proportion of patients. The addition of rituximab to conventional chemotherapy after transformation does not appear to improve the outcomes of subsequent ASCT, although larger prospective studies are required. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    American Society for Microbiology ; 2012
    In:  Antimicrobial Agents and Chemotherapy Vol. 56, No. 5 ( 2012-05), p. 2357-2363
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 56, No. 5 ( 2012-05), p. 2357-2363
    Abstract: For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum ( C max ) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin C max was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P 〈 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different C max results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender ( P 〈 0.001) and the time to maximum concentration of drug in serum ( T max ) at 2 h ( P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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  • 6
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3142-3142
    Abstract: Abstract 3142 Background: Recent studies indicate that the use of highly effective rituximab (R)-containing primary therapy in Diffuse Large B-cell Lymphoma (DLBCL) makes it more difficult to salvage patients who are refractory or who relapse. To date, peripheral-blood autologous stem-cell transplantation (PBASCT) is the reference treatment for these patients, but the impact of previous exposure to R on the ulterior results of ASCT is still unknown. Patients and methods: We have retrospectively analysed 252 patients (pts) with DLBCL or grade 3B follicular lymphoma with relapsed or refractory disease after at least one rituximab-containing regimen (“R+” group) who received PBASCT in 17 GELTAMO centers, in comparison to a control group of 127 patients who received APBSCT as salvage therapy without previous exposure to rituximab (“R-” group). Patients with refractory disease at transplant were excluded from the analysis. Results: No significant differences between R+ and R- groups were found with respect to age-adjusted IPI at transplant, disease status at salvage therapy and at transplant, nor number or prior chemotherapy regimens. More patients in the R+ group were ≥60 years (30% vs 19%, p=.02). Complete response (CR) (69% v 70%) and overall response (84% v 83%) rates to PBASCT were similar in R+ and R- groups. In multivariate analysis, factors with significant influence on CR rates were: age-adjusted IPI at diagnosis ( 〈 2), number of prior chemotherapy lines ( 〈 3), and disease status at transplant (CR). Median follow-up was 35 (1–130) and 121 (2–214) months in the R+ and R- groups, respectively. Patients in the R+ group had a significantly better progression-free survival (PFS) (63% v 48% at 5 years, p=.041) and a non-significantly better overall survival (OS) (71% v 61% at 5 years, p=.098) as compared with patients in the R- group. In multivariate analysis, independent factors with favourable influence on both PFS and OS were disease status at salvage therapy (first partial response or late relapse, in comparison to primary refractory disease or early relapse), previous exposure to R, and age 〈 60 years, whereas the number of previous chemotherapy lines ( 〈 3) influenced only PFS. Conclusions: Our results show that, in patients with chemosensitive relapsed or refractory aggressive B-cell lymphoma, PBASCT is at least as effective in patients pre-treated with R-containing therapy as compared to R-naive patients. Thus, PBASCT in still the reference treatment for these patients in the rituximab era. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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