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1.
Front Immunol ; 10: 1879, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507582

RESUMO

Recent data revealed the importance of immune reconstitution (IR) for the evaluation of possible biomarkers in National Institutes of Health (NIH)-defined chronic graft-vs.-host disease (cGVHD) and its clinical aspects. In this large pediatric study (n = 146), we have analyzed whether cellular and humoral parameters of IR in the long-term follow-up (FU) with a special emphasis on B-cell reconstitution correlate with NIH-defined cGVHD criteria. HYPOTHESIS: we were especially interested in whether meaningful cGVHD biomarkers could be defined in a large pediatric cohort. We here demonstrate for the first time in a highly homogenous pediatric patient cohort that both cGVHD (n = 38) and its activity were associated with the perturbation of the B-cell compartment, including low frequencies of CD19+CD27+ memory B-cells and increased frequencies of circulating CD19+CD21low B-cells, a well-known hyperactivated B-cell subset frequently found elevated in chronic infection and autoimmunity. Notably, resolution of cGVHD correlated with expansion of CD19+CD27+ memory B-cells and normalization of CD19+CD21low B-cell frequencies. Moreover, we found that the severity of cGVHD had an impact on parameters of IR and that severe cGVHD was associated with increased CD19+CD21low B-cell frequencies. When comparing the clinical characteristics of the active and non-active cGVHD patients (in detail at time of analyses), we found a correlation between activity and a higher overall severity of cGVHD, which means that in the active cGVHD patient group were more patients with a higher disease burden of cGVHD-despite similar risk profiles for cGVHD. Our data also provide solid evidence that the time point of analysis regarding both hematopoietic stem cell transplantation (HSCT) FU and cGVHD disease activity may be of critical importance for the detailed investigation of pediatric cohorts. Finally, we have proven that the differences in risk factors and patterns of IR, with cGVHD as its main confounding factor, between malignant and non-malignant diseases, are important to be considered in future studies aiming at identification of novel biomarkers for cGVHD.

2.
J Clin Oncol ; 37(25): 2246-2256, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31283407

RESUMO

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS: Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS: A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION: Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31319153

RESUMO

Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.

4.
Am J Hematol ; 94(8): 880-890, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31095771

RESUMO

Severe infections (SI) significantly impact on non-relapse mortality after hematopoietic stem cell transplantation (HSCT). We assessed 432 children and adolescents with acute lymphoblastic leukemia (ALL) after total body irradiation based myeloablative HSCT within the multicenter ALL-BFM-SCT 2003 trial for SI grade 3 or higher according to common terminology criteria for adverse events. A total 172 patients experienced at least one SI. Transplantation from matched unrelated donors (MUD) was associated with any type of SI in the pre-engraftment period (hazard ratio [HR]: 2.57; P < .001), and with any SI between day +30 and + 100 (HR: 2.91; P = .011). Bacterial (HR: 2.24; P = .041) and fungal infections (HR: 4.06; P = .057) occurred more often in the pre-engraftment phase and viral infections more often before day +30 (HR: 2.66; P = .007) or between day +30 and + 100 (HR: 3.89; P = .002) after HSCT from MUD as compared to matched sibling donors. Chronic GvHD was an independent risk factor for any type of SI after day +100 (HR: 2.57; P < .002). We conclude that allogeneic HSCT from MUD in children and adolescents with pediatric ALL is associated with higher infection rates, which seems attributable to an intensified GvHD prophylaxis including serotherapy and methotrexate.

5.
J Exp Anal Behav ; 111(3): 493-507, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31038215

RESUMO

Two experiments examined interactions between the effects of food and water motivating operations (MOs) on the food- and water-reinforced operant behavior of mice. In Experiment 1, mice responded for sucrose pellets and then water reinforcement under four different MOs: food deprivation, water deprivation, concurrent food and water deprivation, and no deprivation. The most responding for pellets occurred under food deprivation and the most responding for water occurred under water deprivation. Concurrent food and water deprivation decreased responding for both reinforcers. Nevertheless, water deprivation alone increased pellet-reinforced responding and food deprivation alone likewise increased water-reinforced responding relative to no deprivation. Experiment 2 demonstrated that presession food during concurrent food and water deprivation increased in-session responding for water relative to sessions where no presession food was provided. Conversely, presession water during concurrent food and water deprivation did not increase in-session responding for pellets. These results suggest that a) the reinforcing value of a single stimulus can be affected by multiple MOs, b) a single MO can affect the reinforcing value of multiple stimuli, and c) reinforcing events can also function as MOs. We consider implications for theory and practice and suggest strategies for further basic research on MOs.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31089287

RESUMO

Although allogeneic hematopoietic stem-cell transplantation (HSCT) provides high cure rates for children with high-risk acute lymphoblastic leukaemia (ALL), relapses remain the main cause of treatment failure. Whereas donor killer cell immunoglobulin-like receptor (KIR) genotype was shown to impact on relapse incidence in adult myeloid leukaemia similar studies in paediatric ALL are largely missing. Effect of donor KIR genotype on transplant outcome was evaluated in 317 children receiving a first myeloablative HSCT from an HLA-matched unrelated donor or sibling within the prospective ALL-SCT-BFM-2003 trial. Analysis of donor KIR gene polymorphism revealed that centromeric presence and telomeric absence of KIR B haplotypes was associated with reduced relapse risk. A centromeric/telomeric KIR score (ct-KIR score) integrating these observations correlated with relapse risk (hazard ratio (HR) 0.58; P = 0.002) while it had no impact on graft-versus-host disease or non-relapse mortality. In multivariable analyses ct-KIR score was associated with reduced relapse risk (HR 0.58; P = 0.003) and a trend towards improved event-free survival (HR 0.76; P = 0.059). This effect proved independent of MRD level prior to HSCT. Our data suggest that in children with ALL undergoing HSCT after myeloablative conditioning, donor selection based on KIR genotyping holds promise to improve clinical outcome by decreasing relapse risk and prolonged event-free survival.

7.
Pediatr Blood Cancer ; 66(7): e27691, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30825249

RESUMO

Rothia mucilaginosa is part of the oral and upper respiratory tract flora. Usually, this gram-positive coccus is not pathogenic; however, in the setting of immunosuppressed hosts, it can cause life-threatening infections as an opportunistic pathogen. Among a cohort of 1511 hematologic-oncologic patients at a pediatric tertiary care cancer center, we identified five cancer patients (0.35%) within a period of 10 years having a proven Rothia mucilaginosa bacteremia (1 culture positive: n = 3/5; > 1 culture positive: n = 2/5). With prompt and adequate antibiotic treatment, infection resolved rapidly before recovery of neutrophils and without any sequelae, suggesting that Rothia mucilaginosa bacteremia without organ involvement is not exceptionally problematic in pediatric cancer patients.

8.
Clin J Oncol Nurs ; 23(2): 181-190, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30880807

RESUMO

BACKGROUND: Many factors can interfere with a patient's ability to cope with a new cancer diagnosis. The method of education delivery may improve satisfaction with teaching and reduce anxiety. Structured DVD education combined with other teaching methods has shown positive results. However, few such studies have included family members. OBJECTIVES: The purpose of this study was to evaluate the impact of structured DVD education versus standard one-on-one education on satisfaction with teaching and on anxiety among patients newly diagnosed with leukemia and lymphoma and their families. METHODS: A post-test randomized controlled trial study design evaluated the effects of structured DVD education compared to standard one-on-one education. FINDINGS: Family members in the intervention group had higher satisfaction with teaching than those in the control group; this difference was found to be statistically significant.

9.
Curr Oncol Rep ; 20(9): 74, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30074106

RESUMO

PURPOSE OF REVIEW: Allogeneic hematopoetic stem cell transplantation (HSCT) is a curative option for children and adolescents with high-risk leukemia. Although acute complications were reduced during the last decade, considerable late effects are still limiting the overall success rate. This article emphasizes the specific pediatric aspects of long-term aftercare following myeloablative HSCT and provides an organ-based overview that covers main clinical patterns, incidence, and risk factors enhanced by current references and screening guidelines. RECENT FINDINGS: In the last years, several attempts were made to separate pediatric outcome data from findings in adults. It turned out that not only the indication for but also the time and the procedures of HSCT substantially differ. Nearly any organ might be affected after the complex transplantation process and includes endocrinopathies, musculoskeletal disorders, cardiopulmonary complications, and secondary malignancies. Patients after HSCT in childhood have a high risk for developing a wide range of late sequelae and may benefit from regular screening and early intervention. The occurrence and patterns of late effects depend on the intensity and severity of conditioning and are strongly associated with patient's age at transplant and beginning of complications.

10.
Br J Haematol ; 183(1): 104-109, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30028016

RESUMO

Osteonecrosis (ON) was prospectively assessed in 557 children and adolescents in the Berlin-Frankfurt-Münster Stem Cell Transplantation in children with acute lymphoblastic leukaemia 2003 trial. Median age at haematopoietic stem cell transplantation (HSCT) was 10·3 years (range 0·5-26). Cumulative incidence of symptomatic ON (sON) was 9% at 5 years (standard deviation 1%), median time from HSCT to diagnosis of sON was 12·4 months (range 1-126). Multivariate analysis identified age at HSCT [10-15 years vs. <10 years: hazard ratio (HR) 3·73, P = 0·009; >15 years vs. <10 years: HR 5·46, P = 0·001], diagnosis of sON prior to HSCT and chronic graft-versus-host disease (yes versus no: HR 2·696, P = 0·015) as significant independent risk factors for the development of sON.

11.
Biol Blood Marrow Transplant ; 24(9): 1848-1855, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29772352

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is beneficial for pediatric patients with relapsed or (very) high-risk acute lymphoblastic leukemia (ALL) in remission. A total of 1115 consecutive patients were included in the ALL SCT 2003 BFM study and the ALL SCT 2007 I-BFM study and were stratified according to relapse risk (standard versus high versus very high risk of relapse) and donor type (matched sibling versus matched donor versus mismatched donor). A total of 148 patients (60% boys; median age, 8.7 years; B cell precursor ALL, 75%) were transplanted from mismatched donors, which was defined as either less than 9/10 HLA-compatible donors or less than 5/6 unrelated cord blood after myeloablative conditioning regimen (total body irradiation based, 67%) for high relapse risk (HRR; n = 42) or very HRR (VHRR) disease (n = 106). The stem cell source was either bone marrow (n = 31), unmanipulated peripheral stem cells (n = 28), T cell ex vivo depleted peripheral stem cells (n = 59), or cord blood (n = 25). The median follow-up was 5.1 years. The 4-year rates of overall survival (OS) and event-free survival were 56% ± 4% and 52% ± 4%, respectively, for the entire cohort. Patients transplanted from mismatched donors for HRR disease obtained remarkable 4-year OS and event-free survival values of 82% ± 6% and 80% ± 6%, respectively, whereas VHRR patients obtained values of 45% ± 5% and 42% ± 5% (P < .001), respectively. The cumulative incidence of relapse was 29% ± 4% and that of nonrelapse mortality 19% ± 3%. The cumulative incidence of limited and extensive chronic graft-versus-host disease was 13% ± 3% and 15% ± 4%, respectively, among the 120 patients living beyond day 100. Multivariate analysis showed that OS was lower for transplanted VHRR patients (P = .002; hazard ratio [HR], 3.62; 95% confidence interval [CI], 1.60 to 8.20) and for patients beyond second complete remission (CR2) versus first complete remission (P < .001; HR, 3.68; 95% CI, 1.79 to 7.56); relapse occurred more frequently in patients with VHRR disease (P = .026; HR, 3.30; 95% CI, 1.16 to 9.60) and for those beyond CR2 (P = .005; HR, 4.16; 95% CI, 1.52 to 10.59). Nonrelapse mortality was not significantly higher for cytomegalovirus-positive recipients receiving cytomegalovirus-negative grafts (P = .12; HR, 1.96; 95% CI, .84 to 4.58). HSCT with a mismatched donor is feasible in pediatric ALL patients but leads to inferior results compared with HSCT with better matched donors, at least for patients transplanted for VHRR disease. The results are strongly affected by disease status. The main cause of treatment failure is still relapse, highlighting the urgent need for interventional strategies after HSCT for patients with residual leukemia before and/or after transplantation.

13.
Med Hypotheses ; 114: 49-54, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29602464

RESUMO

Urinary tract infections (UTIs) are the most common bacterial infections seen in the community, especially amongst females. The widespread use of antibiotics has led to the increased occurrence of E. coli resistant isolates worldwide. A promising non-antibiotic approach is the use of probiotic lactobacilli strains. This paper hypothesizes that Lactobacillus spp. containing products are able to prevent recurrent urinary tract infections in females. Using the keywords [lactobacillus OR lactobacilli OR probiotic] and [urinary tract infection OR UTI OR cystitis], a preliminary search on the PubMed, Ovid, Google Scholar and ClinicalTrials.gov database yielded 1,647 papers published in English between 1-Jan-1960 and 1-May-2017. 9 clinical trials with a total of 726 patients were reviewed. Different lactobacilli strains (in either oral or suppository formulation) were utilized and they demonstrated varying efficacy in the prevention of recurrent UTIs. Using a random-effects model, pooled risk ratio of at least one recurrent UTI episode during the entire study duration was 0.684 (95% CI 0.438 to 0.929, p < 0.001), per-protocol analysis. However, key limitations include significant inter-study variability and the limited duration of follow-up of most studies. Our hypothesis on the chemoprophylactic effects of probiotics for UTIs is plausible and supported by current data. Lactobacillus rhamnosus GR1 and Lactobacillus reuteri RC14 were the most commonly studied lactobacilli strains. Further and more robust randomized controlled trials with standardized lactobacilli strains and formulation are required for confirmation of effects.


Assuntos
Lactobacillus , Probióticos/uso terapêutico , Infecções Urinárias/microbiologia , Infecções Urinárias/prevenção & controle , Antibacterianos/uso terapêutico , Escherichia coli , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Biol Blood Marrow Transplant ; 24(8): 1629-1642, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29548831

RESUMO

Outcome data were collected from the European Society for Blood and Marrow Transplantation registry on 373 children from 120 centers with relapsed leukemia (214 with acute lymphoblastic leukemia [ALL] and 159 with acute myelogenous leukemia [AML]) who underwent second allogeneic hematopoietic stem cell transplantation (HSCT) between 2004 and 2013. Overall survival (OS) was 38% at 2 years and 29% at 5 years, and leukemia-free survival (LFS) was 30% at 2 years and 25% at 5 years. Median follow-up after second HSCT was 36.4 months in the ALL group and 50.2 months in the AML group. In the ALL group, OS was 43% at 2 years and 33% at 5 years, and LFS was 34% at 2 years and 31% at 5 years. In the AML group, OS was 32% at 2 years and 24% at 5 years, and LFS was 24% at 2 years and 17% at 5 years. The 2-year nonrelapse mortality (NRM) rate was 22% in the ALL group and 18% in the AML group. Favorable prognostic factors (P < .05) for OS and LFS included >12 months between transplantations and chronic graft-versus-host disease after the first HSCT (in both groups), complete response before the second HSCT (ALL group only), and age >12 years (AML group only). Findings were more consistent over time in the ALL group, with no significant differences between 2-year and 5-year rates of relapse, NRM, and LFS. Children with relapsed acute leukemias have a substantial likelihood of long-term survival following second HSCT. Given the many novel targeted and immunomodulation therapies currently under development, it is important to identify specific patient subpopulations that may benefit from a second HSCT compared with those better suited to new approaches.

15.
N Engl J Med ; 378(5): 439-448, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29385370

RESUMO

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Anticorpos Monoclonais Humanizados/administração & dosagem , Antígenos CD19 , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Indução de Remissão , Análise de Sobrevida , Adulto Jovem
16.
Br J Haematol ; 180(1): 82-89, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29193007

RESUMO

Relapse remains the major cause of treatment failure in children with high-risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem-cell transplantation (allo-SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo-SCT enrolled in the Berlin-Frankfurt-Munster (BFM) ALL-SCT-BFM 2003 and ALL-SCT-BFM international 2007 studies. Median time from allo-SCT to relapse was 7·7 months; median follow-up from relapse after allo-SCT until last follow-up was 3·4 years. The 3-year event-free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo-SCT, 26% of the children underwent a second allo-SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo-SCT hold promise to improve outcome in children with post allo-SCT relapse.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Retratamento , Terapia de Salvação , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
17.
Ther Drug Monit ; 40(1): 84-92, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29189665

RESUMO

BACKGROUND: Busulfan (Bu) is an alkylating agent used as part of the conditioning regimen in pediatric patients before hematopoietic stem cell transplantation. Despite intravenous (IV) administration and dosing recommendations based on age and weight, reports have revealed interindividual variability in Bu pharmacokinetics and the outcomes of hematopoietic stem cell transplantation. In this context, adjusting doses to Bu's narrow therapeutic window is advised. We aimed to assess the utility of therapeutic drug monitoring (TDM) of Bu in children, the reliability of Bu quantification methods, and its stability in plasma when stored for up to 5 years. METHODS: Eighteen patients from our TDM center (252 samples) were included. All of them received a 2-hour Bu IV infusion 4 times daily for a total of 16 doses. The first dose of Bu was age/weight-based, and the subsequent doses were adjusted from third or fifth dose onward based on the estimated first dose pharmacokinetic parameters to target steady-state concentrations (Css) of 600-900 ng/mL. The performance of our unit's high-performance liquid chromatography with tandem mass spectrometry method was assessed using a quality control (QC, 35 series) chart. International, multicenter, cross-validation test (n = 21) was conducted to validate different analytical methods. To assess Bu stability, regression analyses and Bland-Altman plots were performed on measurements at repeated time points on samples stored at -80°C for up to 5 years. RESULTS: We observed a 4.2-fold interindividual variability in Bu Css after the first dose, with only 28% of children having a Css within the target range. During the 4 days of conditioning, 83% of children had their doses modified according to TDM recommendations. This achieved a Css within the target range in 75% of the children. Routine QC measurements were generally within the ±15% range around theoretical values, showing the optimal robustness of our center's analytical method. Two of the 21 Bu TDM centers returned inadequate results during cross-validation testing; both used a UV detection method. Storage at -80°C led to a fall in Bu content of 14.9% ± 13.4% at 2-4 years and of 20% ± 5% by 5 years (roverall = 0.92). CONCLUSIONS: We conclude that TDM is an effective method of achieving targeted Bu levels in children. QC programs are crucial to monitoring and maintaining the quality of an analytical method.


Assuntos
Bussulfano/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Alquilantes/sangue , Alquilantes/farmacocinética , Bussulfano/sangue , Criança , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Estabilidade de Medicamentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Controle de Qualidade , Reprodutibilidade dos Testes , Fatores de Tempo
18.
J Affect Disord ; 228: 13-19, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29197739

RESUMO

INTRODUCTION: Some preclinical and clinical studies have demonstrated the positive impact of probiotic supplementation on depressive symptoms. This paper aims to provide an updated meta-analysis on the topic. METHODS: Using the keywords [probiotics OR gut OR microflora OR microbiome OR bacteria OR yeast OR yoghurt OR lactobacillus OR bifidobacterium] AND [mood OR depression OR MDD OR suicide], a preliminary search on the PubMed, Ovid, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group (CCDANTR) and Cochrane Field for Complementary Medicine database yielded 917 papers published in English between 1-Jan-1960 and 1-June-2017. RESULTS: 10 clinical trials with a total of 1349 patients were reviewed, comparing the use of probiotics to placebo controls. There was no significant difference in mood between the treatment and placebo group post-intervention as the standardized mean difference (SMD) was -0.128 (95% CI -0.261 to 0.00463, P=0.059). A separate subgroup analysis of studies conducted in healthy versus depressed individuals found significant improvements in the moods of individuals with mild to moderate depressive symptoms (SMD -0.684, 95% CI -1.296 to -0.0712, P=0.029) and non-significant effects in healthy individuals (SMD -0.0999, 95% CI -0.235 to 0.0348, P=0.146). LIMITATIONS: Inter-study discrepancies with respect to probiotic dosing, bacterial strains and strain combinations limit the comparability of current clinical trials. Furthermore, majority of existing RCTs were conducted in healthy individuals, making it difficult to extrapolate the results to depressed individuals. CONCLUSION: Probiotic supplementation has an overall insignificant effect on mood. Future studies should be conducted on more patients with clinically diagnosed depression.


Assuntos
Depressão/terapia , Probióticos/uso terapêutico , Afeto , Bifidobacterium , Microbioma Gastrointestinal , Humanos , Lactobacillus
19.
Oncotarget ; 8(53): 90852-90867, 2017 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-29207608

RESUMO

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacity were associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).

20.
J Law Med Ethics ; 45(1_suppl): 11-15, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28661300

RESUMO

This paper highlights the need to apply an equity lens when assessing the impact of preemption and related legal doctrines on community health. Community autonomy to set and pursue public health priorities is an essential part of achieving health equity. Unfortunately, the priorities of organized industry interest groups often conflict with health equity goals. These groups have a history of successfully using law to limit community autonomy to pursue public health measures, most notably through preemption and related legal doctrines. We examine this phenomenon using two examples. First, we look at dental association efforts to block the spread of dental therapists in Indian Country. Native dental therapists have been improving the oral health of native people in Alaska for over a decade; yet the national and state dental associations have sought with mixed success to leverage state and federal laws to hinder other tribal governments from utilizing these providers. We compare these efforts with a restaurant association-led movement to limit what municipal governments can do to address food-based health inequities, focusing on a "model" ALEC bill that started in Ohio. Finally, we discuss how municipalities and Tribes are fighting back and continuing to pursue health equity for their communities.


Assuntos
Governo Local , Saúde Pública , Prioridades em Saúde , Humanos
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