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Front Immunol ; 8: 449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507545


Typical features of dyskeratosis congenita (DC) resulting from excessive telomere shortening include bone marrow failure (BMF), mucosal fragility, and pulmonary or liver fibrosis. In more severe cases, immune deficiency and recurring infections can add to disease severity. RTEL1 deficiency has recently been described as a major genetic etiology, but the molecular basis and clinical consequences of RTEL1-associated DC are incompletely characterized. We report our observations in a cohort of six patients: five with novel biallelic RTEL1 mutations p.Trp456Cys, p.Ile425Thr, p.Cys1244ProfsX17, p.Pro884_Gln885ins53X13, and one with novel heterozygous mutation p.Val796AlafsX4. The most unifying features were hypocellular BMF in 6/6 and B-/NK-cell lymphopenia in 5/6 patients. In addition, three patients with homozygous mutations p.Trp456Cys or p.Ile425Thr also suffered from immunodeficiency, cerebellar hypoplasia, and enteropathy, consistent with Hoyeraal-Hreidarsson syndrome. Chromosomal breakage resembling a homologous recombination defect was detected in patient-derived fibroblasts but not in hematopoietic compartment. Notably, in both cellular compartments, differential expression of 1243aa and 1219/1300aa RTEL1 isoforms was observed. In fibroblasts, response to ionizing irradiation and non-homologous end joining were not impaired. Telomeric circles did not accumulate in patient-derived primary cells and lymphoblastoid cell lines, implying alternative pathomechanisms for telomeric loss. Overall, RTEL1-deficient cells exhibited a phenotype of replicative exhaustion, spontaneous apoptosis and senescence. Specifically, CD34+ cells failed to expand in vitro, B-cell development was compromised, and T-cells did not proliferate in long-term culture. Finally, we report on the natural history and outcome of our patients. While two patients died from infections, hematopoietic stem cell transplantation (HSCT) resulted in sustained engraftment in two patients. Whether chemotherapy negatively impacts on the course and onset of other DC-related symptoms remains open at present. Early-onset lung disease occurred in one of our patients after HSCT. In conclusion, RTEL deficiency can show a heterogeneous clinical picture ranging from mild hypocellular BMF with B/NK cell lymphopenia to early-onset, very severe, and rapidly progressing cellular deficiency.

J Neurooncol ; 124(1): 65-74, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25672644


Pediatric tumors of the central nervous system composed of oligoid tumor cells showing diffuse leptomeningeal spread without a primary mass lesion seem to represent a novel tumor entity. The terms "diffuse leptomeningeal glioneural tumor" or-preferably-"disseminated oligodendroglial-like leptomeningeal tumor of childhood" (DOGLT) were proposed. Four patients were identified with clinico-neuropathologic findings compatible with DOGLT and a mean follow-up time of 54 months was determined. Seven different biopsies obtained from the four patients were histologically evaluated. Clinical course, diagnostic measures, histopathologic and radiologic features and treatment suggestions were recorded, on the basis of which diagnostic and therapeutic algorithm was proposed. Patients with DOGLT presented with hydrocephalus as first symptom, requiring neurosurgical therapy. Open arachnoid biopsy was necessary to confirm diagnosis. The oligoid cells in a desmoplastic or focally myxoid matrix showed OLIG2-, MAP2-, S-100 and rare HuC/HuD protein-immunopositivity. IDH1 (R132H)- and CD99-immunohistochemistry was negative in all patients. None of the evaluable biopsies of three patients showed chromosome 1p/19q deletion, neither as isolated nor combined allelic loss. Chemotherapy according to the SIOP-LGG 2004 standard induction and consolidation protocol resulted in complete response and partial response, respectively, in 50 % of the patients. However, after discontinuation of chemotherapy, two patients experienced tumor progression and one of them succumbed to the disease after 19 months. Radiological criteria as well as preliminary treatment results are presented after observation of four clinical cases. Prognosis and long-term clinical courses remain to be observed.

Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Oligodendroglioma/diagnóstico , Oligodendroglioma/terapia , Criança , Pré-Escolar , Progressão da Doença , Evolução Fatal , Humanos , Lactente , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/patologia , Oligodendroglioma/diagnóstico por imagem , Oligodendroglioma/patologia , Radiografia , Resultado do Tratamento
Cancer Cell ; 22(4): 425-37, 2012 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-23079654


Glioblastoma (GBM) is a brain tumor that carries a dismal prognosis and displays considerable heterogeneity. We have recently identified recurrent H3F3A mutations affecting two critical amino acids (K27 and G34) of histone H3.3 in one-third of pediatric GBM. Here, we show that each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern, and that they are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup. Three further epigenetic subgroups were enriched for hallmark genetic events of adult GBM and/or established transcriptomic signatures. We also demonstrate that the two H3F3A mutations give rise to GBMs in separate anatomic compartments, with differential regulation of transcription factors OLIG1, OLIG2, and FOXG1, possibly reflecting different cellular origins.

Neoplasias Encefálicas/genética , Epigênese Genética , Glioblastoma/genética , Histonas/genética , Isocitrato Desidrogenase/genética , Mutação , Adulto , Neoplasias Encefálicas/patologia , Criança , Metilação de DNA , Glioblastoma/patologia , Humanos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transcriptoma
Pediatr Transplant ; 16(5): 471-9, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22584038


HSCT is an established treatment option for some children with life-threatening diseases, but complications remain a major cause of morbidity and mortality. This retrospective data analysis addresses the surgical issues of children with HSCT-related complications. Between 2002 and 2008, HSCT was performed in 240 children for leukemias/lymphomas (n=135), solid tumors (n=59), immunodeficiencies (n=20), lipid storage diseases (n=10), autoimmune diseases (n=9), and others (n=7). HSCT-related complications requiring surgery occurred in 24 cases (10%) and most often in the leukemias/lymphomas group (18/24 cases): HC (cystoscopic irrigation, n=7), pulmonary aspergilloses (resection, n=7), bone necroses (core decompression, n=3), GvHD bowel (colostomy/PEG, n=2), ICH (drainage, n=2), bilateral kidney abscess (nephrectomies/renal transplantation, n=1), aspergillosis of the maxillary sinus (decompression, n=1), and post-traumatic wound healing disorder (meshed skin transplantation, n=1). Survival was 50% in the group with surgery and 62% in the group without (p=0.275). Even though this difference was not statistically significant, surgical intervention should be encouraged in all cases to achieve favorable results.

Cistite/cirurgia , Doença Enxerto-Hospedeiro/cirurgia , Transplante de Células-Tronco Hematopoéticas , Hemorragias Intracranianas/cirurgia , Micoses/cirurgia , Osteonecrose/cirurgia , Complicações Pós-Operatórias/cirurgia , Adolescente , Adulto , Criança , Pré-Escolar , Cistite/epidemiologia , Cistite/etiologia , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Incidência , Lactente , Recém-Nascido , Hemorragias Intracranianas/epidemiologia , Hemorragias Intracranianas/etiologia , Modelos Logísticos , Masculino , Micoses/epidemiologia , Micoses/etiologia , Razão de Chances , Osteonecrose/epidemiologia , Osteonecrose/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
Anticancer Res ; 25(5): 3585-90, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16101184


Large phase III studies have identified limited survival benefits with chemotherapy in high-grade glioma. However, numerous clinical trials have been published previously with smaller patient numbers and no control groups. A small positive effect could be missed this way, resulting in premature rejection of possible beneficial treatment. In order to perform a treatment arm summarizing analysis (TASA), a database was created summarizing treatments published between January 1976 and June 2002. In this database, one record represents a cohort of patients treated in the same way. Various patient cohort characteristics such as median age, and outcome measures including median overall survival times (mOS), were documented. Two-hundred and twenty publications were documented with a total number of 17,213 cases treated in 337 treatment groups. There was a statistically significant relationship between the distribution of histological grades (p<0.001) and the outcome, and a better outcome in younger patient populations (p<0.01). However, the known influence of the median Karnowsky performance scale could not be confirmed in this database. The extent of surgery showed a positive influence only when excluding relapse studies, while the positive effect of radiation was clear in all subgroups (p<0.05). Clinical studies that included nitrosurea in the treatment had a significantly better outcome than those with platinum drugs or without chemotherapy. We conclude that TASA, representing a novel way to perform a meta-analysis, is valid since it confirms the known treatment effects and, therefore, has the potential to provide new insights by combining information from different clinical treatment studies.

Neoplasias Encefálicas/terapia , Glioma/terapia , Fatores Etários , Idoso , Neoplasias Encefálicas/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Bases de Dados Factuais , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Resultado do Tratamento