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1.
Leukemia ; 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31578451

RESUMO

AML SCT-BFM 2007 was the first hematopoietic stem cell transplantation (HCT) trial in Germany to comply with the European Clinical Trials Directive, and aimed to standardize pediatric HCT for acute myeloid leukemia (AML) across centers in Germany, Austria, and the Czech Republic. Children with high-risk features and a good early response achieving a complete first remission (CR-1) and those in CR-2 after a first relapse were stratified to receive HCT from a matched donor after myeloablative conditioning consisting of busulfan, cyclophosphamide, and melphalan. Four-year EFS and OS were 61 and 70%. Cumulative incidence of relapse (CIR) was 22%. TRM was 15% and correlated with age reaching 9% (SE 3%) in children younger than 12 years and 31% (SE 9%) in older children and adolescents. Children with poorly responding primary disease or relapse were allocated to receive early HCT after a cytoreductive regimen with fludarabine, amsacrine, and cytarabine, followed by reduced intensity conditioning and prophylactic donor lymphocyte infusions. Four-year EFS and OS were 49 and 53%. CIR was 38% and TRM 11%. For patients with primary poor response disease, early use of RIC HCT followed by prophylactic DLI can induce long-term remissions in more than 50% (EFS 46% (SE 9%)).

2.
Mol Genet Metab ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31375398

RESUMO

OBJECTIVE: To provide recommendations for managing hypersensitivity adverse events (HAEs) to an injectable enzyme substitution therapy (pegvaliase, a PEGylated phenylalanine ammonia lyase enzyme) in adult patients with phenylketonuria (PKU). METHODS: Eight European academic immunology experts with a broad range of experience in hypersensitivity, anaphylaxis, and/or drug reactions, and two geneticists from the USA with pegvaliase experience convened for two advisory board meetings. Efficacy, safety, and immunological profile of pegvaliase were discussed with the objective of developing recommendations for the clinical management of HAEs associated with pegvaliase treatment. RESULTS: Based on available immunogenicity data, it was concluded that pegvaliase induces a Type III hypersensitivity reaction, causing HAEs with peak event rates during induction/titration and a decline over time during maintenance therapy. The decline in HAEs with longer duration of therapy was considered to likely be driven by anti-drug antibody affinity maturation, reduced immune complex formation, and decreased complement activation over time. Immunology and PKU experts unanimously supported that the use of an induction, titration, and maintenance dosing regimen and implementation of several risk mitigation strategies contributed to the improvement of tolerability over time. Key risk mitigation strategies utilized in the Phase 3 clinical trials such as premedication with H1-receptor antagonists, allowance for a longer titration period after an HAE, patient education, and requirement to carry auto-injectable adrenaline (epinephrine) should be continued in clinical practice. A tool for administration of auto-injectable adrenaline in patients using pegvaliase was suggested. It was added that after the occurrence of a severe HAE a temporary dose reduction is more likely to improve tolerability than treatment interruption. CONCLUSIONS: Overall, it was agreed that pegvaliase has a generally tolerable safety profile in adults with PKU. Importantly, the risk mitigation strategies utilized in the clinical trials were considered to support the continued use of key strategies for management in the commercial setting, such as a slow induction/titration dosing paradigm and premedication with H1-receptor antagonists. However, physicians and patients need to be aware of the risk of HAEs associated with pegvaliase; presence of a trained observer during early treatment may be beneficial in certain circumstances, and a requirement to carry auto-injectable adrenaline is recommended. Because pegvaliase offers the possibility to normalize diet, while maintaining blood phenylalanine within the recommended therapeutic range, safe use of this medication in the clinical setting is important. Ongoing monitoring of long-term clinical safety of patients on pegvaliase treatment in the commercial setting was recommended.

3.
J Cancer Res Clin Oncol ; 145(11): 2779-2791, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446489

RESUMO

PURPOSE: To evaluate serum procalcitonin (PCT) and C-reactive protein (CRP) as diagnostic biomarkers of transplant-related adverse events (TRAE) in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: This study analyzed PCT and CRP levels of 214 pediatric patients with a median age of 8.5 years (0.4-17.8 years) undergoing allogeneic HSCT with respect to major TRAE. RESULTS: 26 patients (12.1%) did not experience TRAE (control group), and 188 (87.9%) experienced median 2 (range 1-4) TRAE. Median CRP and PCT were highly and significantly increased during sepsis/SIRS and bacteremia (17.24 mg/dl | 6.30 ng/ml; p < 0.0001 vs. prior values), graft rejection (14.73 mg/dl | 3.20 ng/ml; p < 0.0001), and liver GvHD (6.88 mg/dl | 2.29 ng/ml; p < 0.01). Strong CRP increases and slight/minimal/no PCT increases occurred during fungemia (8.85 mg/dl | 0.72 ng/ml; p < 0.001), intestinal GvHD (8.73 mg/dl | 1.06 ng/ml; p < 0.0001), VOD (10.84 mg/dl | 0.59 ng/ml; p < 0.01), mucositis (8.84 mg/dl | 0.81 ng/ml; p < 0.0001), and viremia (3.62 mg/dl; p < 0.0001 | 0.43 ng/ml; below normal limit). During skin GvHD, CRP and PCT were slightly increased (2.03 mg/dl | 0.93 ng/ml; p < 0.0001). CONCLUSIONS: CRP and PCT did not show congruent changes during TRAE. PCT was a clinically relevant marker for the early detection and differentiation of severe mucositis and sepsis/SIRS and bacteremia during the critical neutropenic period after HSCT. PCT helped to discriminate acute intestinal GvHD from adenovirus viremia and liver GvHD from hepatic VOD. Thus, PCT may be a valuable parameter to enable a prompt and appropriate treatment during these complications, improving patient outcomes.


Assuntos
Bacteriemia/diagnóstico , Proteína C-Reativa/análise , Rejeição de Enxerto/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pró-Calcitonina/sangue , Sepse/diagnóstico , Adolescente , Bacteriemia/sangue , Bacteriemia/etiologia , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Diagnóstico Precoce , Feminino , Seguimentos , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Sepse/sangue , Sepse/etiologia , Transplante Homólogo
4.
Bone Marrow Transplant ; 54(11): 1847-1858, 2019 Nov.
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.

5.
Mol Ther ; 27(5): 933-946, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30879952

RESUMO

Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.

6.
Pediatr Nephrol ; 34(7): 1269-1275, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30843115

RESUMO

BACKGROUND: During the last two decades, there has been a worldwide increase in frequency and severity of infections with Clostridium difficile (CDI). Solid organ transplant (SOT) recipients receiving immunosuppressing medications are especially at risk. METHODS: We collected data from immunocompromised pediatric patients, including kidney and liver transplant recipients, at our tertiary pediatric care center in Germany. For this, we performed a retrospective review of institutional databases and analyzed data from all children who underwent diagnostic tests for CDI in a 3-year study period. RESULTS: A total of 797 diagnostic tests in 343 patients were performed. We found 104 infection episodes in 69 patients (42% female, ages 12 days-20 years). Children after SOT accounted for 20% of all detected CDI patients in our series. Median time of CDI onset after transplantation was 588 days. Overall antibiotic exposure was identified as the major risk factor, particularly in immunocompromised children after SOT (exposure in > 95% of all cases). CONCLUSIONS: The occurrence of CDI in the pediatric SOT population contributes to a greater length of stay and higher hospital charges. However, only very few severe complications from CDI were observed in our cohort. A potentially fulminant course of CDI can be prevented in most cases if timely diagnosis and treatment are carried out.

7.
Int J Mol Sci ; 19(9)2018 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-30149650

RESUMO

The application of autologous mesenchymal stem cells (MSC) for the treatment of bone defects requires two invasive procedures and several weeks of ex vivo cell expansion. To overcome these limitations, the administration of allogeneic MSC may be attractive, because they are anticipated to be immunoprivileged. Because preclinical studies using various animal models are conflicting with respect to the efficacy of allogeneic MSC, we investigated whether autologous and allogeneic human MSC (hMSC) are equally effective in regenerating bone in a humanized mouse model resembling the human immune system. Applying autologous and allogeneic hMSC in critically sized femoral defects, we found that allogeneic hMSC elicited a mild immune response early after implantation, whereas early angiogenic processes were similar in both treatments. At later healing time points, the transplantation of allogeneic hMSC resulted in less bone formation than autologous hMSC, associated with a reduced expression of the osteogenic factor Runx2 and impaired angiogenesis. We found by species-specific staining for collagen-type-1α2 that MSCs of either source did not synthesize new bone matrix, indicating an indirect contribution of transplanted hMSC to bone regeneration. In conclusion, our data suggest that the application of autologous hMSC is superior to that of allogeneic cells for bone defect treatment.

8.
J Hepatol ; 69(4): 961-965, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29935200

RESUMO

Progressive familial intrahepatic cholestasis 2 is an autosomal-recessive disorder caused by mutations in the ABCB11 gene, which encodes the bile salt export pump (BSEP). Recurrence of BSEP deficiency after liver transplantation is caused by the development of anti-BSEP antibodies. Antibody-induced BSEP deficiency is typically treated by increasing immunosuppressive therapy. We report, in a child, the first case of allogeneic haematopoietic stem cell transplantation for antibody-induced BSEP deficiency that was refractory to intensive pharmacological immunosuppression and immunoadsorption. After haematopoietic stem cell transplantation, anti-BSEP antibodies were cleared from the patient's serum and later from the canalicular space of the liver graft.

9.
Int J Phytoremediation ; 20(6): 574-580, 2018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29688048

RESUMO

Multielement-contaminated agricultural land requires the adaptation of agronomic practices to meet legal requirements for safe biomass production. The incorporation of bioenergy plants with, at least, moderate phytoextraction capacity into crop rotations with cereals can affect trace elements (TE) phytoavailability and, simultaneously, constitute economic revenues for farmers outside the food or forage sector. Hence, in a crop rotation pot study sunflower (Helianthus annuus L.), modified for high biomass and TE accumulation by chemical mutagenesis, was compared to winter oilseed rape (Brassica napus L.) as pre-crop. On two agricultural soils with different TE loads, the crops´ potential for phytoextraction and for impacts on TE uptake by subsequent winter wheat (Triticum aestivum L.) was studied. The results showed that rape tolerated high-level mixed contamination with metals (Cd, Pb and Zn) and As more than sunflower. In both soils, labile metals concentration increased and soil acidity remained high following sunflower. Furthermore, enhanced grain As accumulation in subsequent wheat was observed. By contrast, soil acidity and Cd or Zn accumulation of subsequent wheat decreased following rape. In the short term, moderate phytoextraction was superimposed by nutrient use or rhizosphere effects of pre-crops, which should be carefully monitored when designing crop rotations for contaminated land.

10.
J Invest Dermatol ; 138(5): 1157-1165, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29203359

RESUMO

Inherited forms of epidermolysis bullosa are blistering diseases of the skin and mucosa resulting from various gene mutations. Transplantation of bone marrow-derived stem cells might be a promising systemic treatment for severe dystrophic or junctional epidermolysis bullosa, but many key questions remain unresolved. Two open questions of clinical interest are whether systemically transplanted bone marrow-derived stem cells of mesodermal origin might be able to transdifferentiate into keratinocytes with an ectodermal phenotype and whether these cells are also capable of repairing a specific intraepidermal gene defect. To address these questions, we transplanted bone marrow-derived stem cells into mice with a blistering disease exclusively localized to the epidermis resulting from a functional knockout of desmoglein-3 (Dsg3). We found that Dsg3+ donor-derived cells migrate into the recipient epidermis. However, these cells failed to restore the missing Dsg3 mRNA and DSG3 protein expression in the transplanted Dsg3-/- mice. The donor-derived cells found in the epidermis preserved their CD45+ hematopoietic origin, and no transdifferentiation into integrin α6+ keratinocytes or integrin α6+/CD34+ epidermal stem cells occurred. Our results indicate that bone marrow-derived stem cells preserve their mesodermal fate after systemic transplantation and are not capable of treating patients with epidermolysis bullosa with an intraepidermal skin defect.

11.
Br J Haematol ; 180(1): 90-99, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29205259

RESUMO

Poor graft function (PGF) is a severe complication of haematopoietic stem cell transplantation (HSCT) and administration of donor stem cell boosts (SCBs) represents a therapeutic option. We report 50 paediatric patients with PGF who received 61 boosts with CD34+ selected peripheral blood stem cells (PBSC) after transplantation from matched unrelated (n = 25) or mismatched related (n = 25) donors. Within 8 weeks, a significant increase in median neutrophil counts (0·6 vs. 1·516 × 109 /l, P < 0·05) and a decrease in red blood cell and platelet transfusion requirement (median frequencies 1 and 7 vs. 0, P < 0·0001 and <0·001), were observed, and 78·8% of patients resolved one or two of their cytopenias. 36·5% had a complete haematological response. Median lymphocyte counts for CD3+ , CD3+ CD4+ , CD19+ and CD56+ increased 8·3-, 14·2-, 22.- and 1·6-fold. The rate of de novo acute graft-versus-host disease (GvHD) grade I-III was only 6% and resolved completely. No GvHD grade IV or chronic GvHD occurred. Patients who responded to SCB displayed a trend toward better overall survival (OS) (P = 0·07). Thus, administration of CD34+ selected SCBs from alternative donors is safe and effective. Further studies are warranted to clarify the impact on immune reconstitution and survival.


Assuntos
Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Adolescente , Adulto , Antígenos CD34/metabolismo , Linhagem da Célula , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/etiologia , Hematopoese , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Lactente , Masculino , Prognóstico , Retratamento , Estudos Retrospectivos , Quimeras de Transplante , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
12.
Blood ; 130(24): 2682-2688, 2017 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-28974505

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is caused by biallelic deleterious mutations in CECR1 DADA2 results in variable autoinflammation and vasculopathy (recurrent fevers, livedo reticularis, polyarteritis nodosa, lacunar ischemic strokes, and intracranial hemorrhages), immunodeficiency and bone marrow failure. Tumor necrosis factor-α blockade is the treatment of choice for the autoinflammation and vascular manifestations. Hematopoietic stem cell transplantation (HSCT) represents a potential definitive treatment. We present a cohort of 14 patients from 6 countries who received HSCT for DADA2. Indication for HSCT was bone marrow dysfunction or immunodeficiency. Six of 14 patients had vasculitis pre-HSCT. The median age at HSCT was 7.5 years. Conditioning regimens were myeloablative (9) and reduced intensity (5). Donors were HLA-matched sibling (n = 1), HLA-matched unrelated (n = 9), HLA-mismatched unrelated (n = 3), and HLA haploidentical sibling (n = 1). All patients are alive and well with no new vascular events and resolution of hematological and immunological phenotype at a median follow-up of 18 months (range, 5 months to 13 years). Plasma ADA2 enzyme activity normalized in those tested post-HSCT (7/7), as early as day +14 (myeloid engraftment). Post-HSCT hematological autoimmunity (cytopenias) was reported in 4 patients, acute graft-versus-host disease grade 1 in 2, grade 2 in 3, and grade 3-4 in 1, and moderate chronic graft-versus-host disease in 1 patient. In conclusion, in 14 patients, HSCT was an effective and definitive treatment of DADA2.


Assuntos
Adenosina Desaminase/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Adenosina Desaminase/sangue , Adenosina Desaminase/metabolismo , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Síndromes de Imunodeficiência/enzimologia , Lactente , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Fenótipo , Condicionamento Pré-Transplante/métodos
13.
Hum Mutat ; 38(11): 1511-1520, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28762252

RESUMO

Metachromatic leukodystrophy (MLD) is an autosomal-recessive lysosomal storage disease caused by mutations in the ARSA gene leading to arylsulfatase A (ARSA) deficiency and causing sulfatide accumulation. Main symptoms of the disease are progressive demyelination, neurological dysfunction, and reduced life expectancy. To date, more than 200 different ARSA variants have been reported in MLD patients. Here, we report the biochemical characterization of seven novel pathogenic variants (c.98T > C, c.195delC, c.229G > C, c.545C > G, c.674A > G, c.852T > A, and c.1274A > G), which were found when sequencing a cohort of 31 German MLD families. For that purpose, the ARSA cDNAs carrying the respective mutations inserted by site-directed mutagenesis were cloned into a MigR1 (MSCV, IRES, GFP, retrovirus-1) vector. The constructs were overexpressed using retroviral gene transfer in immortalized, human multipotent mesenchymal stromal cells prepared from a patient deficient in ARSA activity (late infantile MLD). In this novel ARSA-/- cell system, the seven ARSA mutants showed ARSA activity of less than 10% when compared with wild type, which is evidence for the pathogenicity of all seven variants. In conclusion, the system of ARSA-/- -immortalized MSC turned out to be a helpful novel tool for the biochemical characterization of ARSA variants.


Assuntos
Cerebrosídeo Sulfatase/genética , Cerebrosídeo Sulfatase/metabolismo , Variação Genética , Células-Tronco Mesenquimais/enzimologia , Adolescente , Alelos , Linhagem Celular Transformada , Criança , Análise Mutacional de DNA , Ativação Enzimática , Éxons , Feminino , Citometria de Fluxo , Expressão Gênica , Genótipo , Humanos , Imunofenotipagem , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/enzimologia , Leucodistrofia Metacromática/genética , Masculino , Mutagênese Sítio-Dirigida , Mutação , Fases de Leitura Aberta , Plasmídeos/genética , Adulto Jovem
14.
Sci Total Environ ; 599-600: 1388-1398, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28531917

RESUMO

Gentle remediation options (GRO), i.e. in situ stabilisation, (aided) phytoextraction and (aided) phytostabilisation, were implemented at ten European sites contaminated with trace elements (TE) from various anthropogenic sources: mining, atmospheric fallout, landfill leachates, wood preservatives, dredged-sediments, and dumped wastes. To assess the performance of the GRO options, topsoil was collected from each field trial, potted, and cultivated with lettuce (Lactuca sativa L.) for 48days. Shoot dry weight (DW) yield, photosynthesis efficiency and major element and TE concentrations in the soil pore water and lettuce shoots were measured. GRO implementation had a limited effect on TE concentrations in the soil pore water, although use of multivariate Co-inertia Analysis revealed a clear amelioration effect in phytomanaged soils. Phytomanagement increased shoot DW yield at all industrial and mine sites, whereas in agricultural soils improvements were produced in one out of five sites. Photosynthesis efficiency was less sensitive than changes in shoot biomass and did not discriminate changes in soil conditions. Based on lettuce shoot DW yield, compost amendment followed by phytoextraction yielded better results than phytostabilisation; moreover shoot ionome data proved that, depending on initial soil conditions, recurrent compost application may be required to maintain crop production with common shoot nutrient concentrations.

15.
Pediatr Blood Cancer ; 64(11)2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28453885

RESUMO

Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B-cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.


Assuntos
Anticorpos Biespecíficos/efeitos adversos , Antígenos CD19/metabolismo , Linhagem da Célula , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/efeitos adversos , Criança , Feminino , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteína de Leucina Linfoide-Mieloide/genética , Recidiva Local de Neoplasia/epidemiologia , Neoplasia Residual/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico
16.
J Cancer Res Clin Oncol ; 143(7): 1281-1292, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28258343

RESUMO

PURPOSE: Paediatric recipients of haematopoietic stem cell transplantation (HSCT) have a high risk for invasive fungal infections. Posaconazole oral suspension has proven to be effective in antifungal prophylaxis in adult and paediatric patients. A new posaconazole tablet formulation with absorption independent of the gastric conditions was approved by the FDA in 2013. This is the first report on the use of posaconazole tablets in paediatric patients. METHODS: This single-centre study included 63 paediatric patients with haemato-oncological malignancies who received posaconazole for antifungal prophylaxis after HSCT. They were analysed for efficacy, feasibility and the safety of posaconazole. Out of 63 patients, 31 received posaconazole oral suspension and 32 received posaconazole tablets up to 200 days after transplantation. Analyses of the posaconazole trough levels were determined. RESULTS: No possible, probable or proven invasive fungal infection was observed in either group. Posaconazole trough levels were significantly higher in the tablet group than in the suspension group at all analysed time points. Drug-related adverse events were similarly low in both groups. CONCLUSIONS: Posaconazole tablets are effective in preventing invasive fungal infections in paediatric patients. As early as day 3 after starting posaconazole tablets, over 50% of the posaconazole trough levels were >500 ng/mL, while this was observed on day 14 after start with posaconazole suspension. The administration of posaconazole tablets was safe, effective and feasible as antifungal prophylaxis in paediatric patients after HSCT.


Assuntos
Antifúngicos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Micoses/prevenção & controle , Triazóis/administração & dosagem , Administração Oral , Adolescente , Antifúngicos/efeitos adversos , Antifúngicos/farmacocinética , Criança , Pré-Escolar , Feminino , Neoplasias Hematológicas/cirurgia , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Masculino , Micoses/imunologia , Comprimidos , Triazóis/efeitos adversos , Triazóis/farmacocinética
17.
Am J Hum Genet ; 100(2): 281-296, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132690

RESUMO

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.


Assuntos
Anormalidades Musculoesqueléticas/genética , N-Acetilglucosaminiltransferases/genética , Osteocondrodisplasias/genética , Alelos , Linhagem Celular , Linhagem Celular Tumoral , Condroitina/sangue , Condroitina/urina , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Glicosaminoglicanos/metabolismo , Humanos , Anormalidades Musculoesqueléticas/diagnóstico , Mutação de Sentido Incorreto , Osteocondrodisplasias/diagnóstico , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética
18.
Cytotherapy ; 18(10): 1345-7, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27519523
19.
JAMA Neurol ; 73(9): 1133-40, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27400410

RESUMO

IMPORTANCE: Allogeneic hematopoietic stem cell transplantation (HSCT) has been the only treatment option clinically available during the last 20 years for juvenile metachromatic leukodystrophy (MLD), reported with variable outcome and without comparison with the natural course of the disease. OBJECTIVE: To compare the long-term outcome of patients who underwent allogeneic HSCT with control patients who did not among a cohort with juvenile MLD. DESIGN, SETTING, AND PARTICIPANTS: Patients with juvenile MLD born between 1975 and 2009 and who received HSCT at a median age of 7 years (age range, 1.5-18.2 years) and nontransplanted patients with juvenile MLD born between 1967 and 2007 were included in this case-control study. The median follow-up after HSCT was 7.5 years (range, 3.0-19.7 years). Patients underwent HSCT at 3 German centers between 1991 and 2012. The analysis was done between July 2014 and August 2015. MAIN OUTCOMES AND MEASURES: Survival and transplantation-related mortality, loss of gross motor function (Gross Motor Function Classification in MLD), loss of any language function, and magnetic resonance imaging (MRI) severity score for cerebral changes. To explore prognostic factors at baseline, patients who underwent HSCT (hereafter, transplanted patients) were a priori divided into stable vs progressive disease, according to gross motor and cognitive function. RESULTS: Participants were 24 transplanted patients (11 boys, 13 girls) and 41 control patients (22 boys, 19 girls) who did not receive transplantation (hereafter, nontransplanted patients) with juvenile MLD. Among the transplanted patients, 4 children died of transplantation-related mortality, and 2 additional children died of rapid MLD progression 1.5 and 8.6 years after HSCT, resulting in a 5-year survival of 79% (19 of 24). Among the nontransplanted patients, 5-year survival after disease onset was 100% (41 of 41). However, 11 died of MLD progression, resulting in similar overall survival within the observation period. Nine of the long-term survivors after HSCT had disease progression, while 11 showed stable disease. Compared with the nontransplanted patients, the transplanted patients were less likely to lose their gross motor or language function and demonstrated significantly lower MRI severity scores at the latest examination. Patients after HSCT were more likely to have a stable disease course when undergoing HSCT at an early stage with no or only mild gross motor deficits (Gross Motor Function Classification in MLD level 0 or 1) and an IQ of at least 85, when age at disease onset was older than 4 years, or when MRI severity scores were low (preferably ≤17). CONCLUSIONS AND RELEVANCE: Among patients with juvenile MLD, patients who underwent HSCT had a better gross motor and language outcome and lower MRI severity scores compared with nontransplanted patients. Transplantation at a presymptomatic or early symptomatic stage of juvenile MLD is associated with a reasonable chance for disease stabilization.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucodistrofia Metacromática/cirurgia , Resultado do Tratamento , Adolescente , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/cirurgia , Feminino , Humanos , Lactente , Leucodistrofia Metacromática/complicações , Leucodistrofia Metacromática/diagnóstico por imagem , Leucodistrofia Metacromática/mortalidade , Imagem por Ressonância Magnética , Masculino , Transplante Homólogo/métodos , Adulto Jovem
20.
Orphanet J Rare Dis ; 11(1): 93, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27392569

RESUMO

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for young Hurler patients. Despite halting of neurocognitive decline and improvement of life expectancy, the beneficial effect on the skeletal system is limited. As orthopedic complications are one of the most disabling factors following HSCT, this points to the need for new treatment strategies. The study summarizes musculoskeletal manifestations in 19 transplanted Hurler patients. METHODS: Data were obtained retrospectively. Patients' charts for physical examinations of the joint range of motion (JROM) of shoulders, elbows, hips and knees were reviewed. Radiographic evaluations of thorax, spine, pelvis and hands were performed. MRI scans of the craniocervical junction were analyzed to determine odontoid hypoplasia and the prevalence of craniocervical stenosis. RESULTS: Nineteen Hurler patients (10 females, 9 males) with an average age of 8.1 years (range 2.5-23.8) at the latest follow-up, who underwent allogenic HSCT between 1991 and 2012, were assessed after an average follow-up period of 6.4 years (range 0.7-22.5). Seventeen patients achieved long-term engraftment, two developed graft failures. The majority of patients showed a steady state or improvements in the mobility of knees (31 %/63 %), hips (47 %/40 %) and elbows (56 %/38 %). However, shoulder abduction was impaired in ¾ of patients and showed the highest rate of progression (31 %). In patients with graft failure, progressive restrictions in JROM were noted. Assessments of the craniocervical junction by MRI showed stable or improved diameters in 67 % of patients. Correction or stabilization of odontoid hypoplasia was found in 64 %. However thoracolumbar kyphosis, scoliosis, hip dysplasia and genua valga were progressive despite HSCT. At the last follow up, 47 % of patients were partially wheelchair dependent, 10 % wheelchair bound and 25 % regularly experienced pain in the spine, hips and lower extremities due to orthopedic problems. CONCLUSION: Joint mobility, odontoid hypoplasia and craniocervical stenosis might stabilize or even improve in Hurler patients following HSCT. However, despite the beneficial effects on some musculoskeletal manifestations, skeletal complications are frequently observed and the overall burden of orthopedic disease is significant. Frequent multi-disciplinary follow-up in a specialized center are essential. Novel therapeutic approaches (e.g. anti-inflammatory drugs) are needed to improve musculoskeletal outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I/patologia , Mucopolissacaridose I/terapia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/patologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Luxação do Quadril/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Mucopolissacaridose I/complicações , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
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