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1.
Pediatr Blood Cancer ; : e28184, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31994322

RESUMO

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X-linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21-year-old patient with fatal Epstein-Barr virus infection-associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.

3.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
4.
Blood ; 131(26): 2877-2890, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29720485

RESUMO

Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature.


Assuntos
Histiócitos/patologia , Histiocitose Sinusal/diagnóstico , Histiocitose Sinusal/terapia , Corticosteroides/uso terapêutico , Biópsia , Gerenciamento Clínico , Predisposição Genética para Doença , Histiócitos/metabolismo , Histiocitose Sinusal/genética , Histiocitose Sinusal/patologia , Humanos , Imunoterapia , Mutação , Guias de Prática Clínica como Assunto , Prognóstico , Radioterapia
5.
J Pediatr Hematol Oncol ; 40(6): 438-444, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29794643

RESUMO

Posttransplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation. A common site for PTLD development is the gastrointestinal (GI) tract. The purpose of this study was to evaluate the incidence, clinical features, and overall survival of pediatric patients with GI-PTLD, and to assess whether major surgical interventions increased mortality. Records of pediatric transplant patients who developed GI-PTLD between January 2000 and June 2015 were retrospectively reviewed at our institution. Of 814 patients who received solid organ transplants, 34 (4%) developed GI-PTLD. Lung and multiorgan transplants had the highest incidence of GI-PTLD (both 11%). Patients often had multisite GI involvement (47%). Within the first year of transplantation, 38% of the 34 patients developed GI-PTLD. Of the patients with Epstein-Barr Virus-positive disease, 12/22 (55%) presented in the first 12 months of transplantation, compared with only 1/12 (8%) of the patients with Epstein-Barr Virus-negative disease (P=0.002). Major surgical interventions were required in 41% of patients; overall survival rate for these surgical patients was 71%, compared with 60% for patients not requiring major surgical interventions (P=0.49). Despite multimodal treatments, overall survival remains poor for patients with GI-PTLD; however, major surgical intervention did not significantly impact overall survival in this cohort.


Assuntos
Gastroenteropatias , Transtornos Linfoproliferativos , Transplante de Órgãos/efeitos adversos , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Gastroenteropatias/etiologia , Gastroenteropatias/mortalidade , Gastroenteropatias/patologia , Humanos , Incidência , Lactente , Recém-Nascido , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
6.
Mediterr J Hematol Infect Dis ; 10(1): e2018020, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29531657

RESUMO

Background: The incidence and biology of non-Hodgkin lymphoma (NHL) vary according to age. Some data suggest that the impact of age in pediatric and adolescent NHL patients depends on the histological subtype. Objectives: We aimed to analyze the impact of age at diagnosis on clinical characteristics and treatment-related toxicity in children and adolescents with NHL. Methods: Retrospective review of medical records of children and adolescents diagnosed with NHL at the Hospital for Sick Children, Toronto, between January 1995 and December 2008. Results: 164 children were diagnosed with NHL during the study period, with a median age at diagnosis of 10 years. With a median follow-up of 6.2 years, 5-year OS in patients aged <15 and 15-18 years was 89± 2% vs 82% ± 6%, respectively (P = 0.30), and 5-year EFS was 84% ± 3% vs. 77% ± 7% (P= 0.37). In Burkitt's lymphoma (BL) and lymphoblastic lymphoma (LL) there was a trend towards better outcomes in children compared to adolescents, with EFS of 91% ± 4% vs. 75% ± 15%, respectively in BL (P= 0.17), and 82% ± 7% vs. 51.4% ± 2% respectively in LL (P= 0.16). Late effects occurred in 21 patients (12.8%). Conclusions: Children with NHL aged < 15 years tend to have better survival rates and similar long-term toxicity than adolescents aged 15-18 years.

7.
Br J Haematol ; 179(5): 739-747, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29082519

RESUMO

Treatment with dose-adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA-EPOCH-R) has become the standard of care for primary mediastinal B-cell lymphoma (PMBCL) at many institutions despite limited data in the multi-centre setting. We report a large, multi-centre retrospective analysis of children and adults with PMBCL treated with DA-EPOCH-R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA-EPOCH-R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA-EPOCH-R. Radiation therapy was administered in 14·9% of patients. With median follow-up of 22·6 months, the estimated 3-year event-free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3-91·5] and overall survival was 95·4% (95% CI 91·8-99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy-five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG-PET) scan at the completion of DA-EPOCH-R, defined as Deauville score 1-3. Negative FDG-PET at end-of-therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA-EPOCH-R for the treatment of PMBCL in children and adults. Patients with a positive end-of-therapy FDG-PET scan have an inferior outcome.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Mediastino/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/radioterapia , Masculino , Neoplasias do Mediastino/diagnóstico por imagem , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/radioterapia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Trombose/induzido quimicamente , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Adulto Jovem
8.
J Pediatr ; 189: 72-78.e3, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28807357

RESUMO

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Adolescente , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Masculino , Reprodutibilidade dos Testes
9.
Pediatr Blood Cancer ; 64(2): 302-305, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27577695

RESUMO

To study the prevalence of pediatric cancer patients who have underlying inherited bone marrow failure syndrome (IBMFS), we retrospectively reviewed the medical records of newly diagnosed pediatric cancer patients at The Hospital for Sick Children from June 2009 to May 2010, focusing on clinical, laboratory, and treatment-related findings which may indicate underlying IBMFS. We found five (1.8%) patients out of 276 who had two or more findings suggestive of IBMFS. We conclude that a small fraction of patients with cancer have clinical features that indicate investigations to rule out underlying IBMFSs. A prospective study is needed to determine their prevalence.


Assuntos
Doenças da Medula Óssea/diagnóstico , Neoplasias/complicações , Adolescente , Doenças da Medula Óssea/etiologia , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Neoplasias/patologia , Prognóstico , Estudos Retrospectivos
10.
Pediatr Blood Cancer ; 63(11): 1915-21, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27392123

RESUMO

BACKGROUND: ZNF384 gene rearrangements with multiple partner genes are recurrent in acute leukemia and are most often associated with a precursor B cell immunophenotype. The overall incidence of this genetic category of leukemia is uncertain. PROCEDURE: Patients with ZNF384 gene rearrangements from a cohort of 240 precursor B cell acute lymphoblastic leukemia (ALL) pediatric patients over a 3.5-year time period were characterized with detailed cytogenetic, FISH, genomic, and clinical analyses. RESULTS: Seven of the 240 patients were identified to have ZNF384 gene rearrangements including partner genes TCF3 (four patients), EWSR1 (one patient), EP300 (one patient), and the novel gene partner ARID1B (one patient). The translocations were confirmed by FISH analysis and with RNA sequencing for the EP300 and ARID1B partner genes. Genomic microarray analysis showed an average of 2.7 copy number alterations in each case with no evidence of imbalance at the translocation breakpoints. Six of the patients with ZNF384 gene rearrangements had precursor B cell ALL with a CD10- immunophenotype and myeloid-associated antigens. One of the patients also had myeloperoxidase expression and was diagnosed as mixed phenotype B/myeloid acute leukemia. None of the patients have relapsed with event-free survival ranging from 6 years 2 months to 9 years 2 months. CONCLUSIONS: This study suggests that the frequency of ZNF384 gene rearrangement in pediatric precursor B cell ALL is approximately 3%. The ARID1B gene, commonly mutated in multiple types of cancer, was identified as an additional ZNF384 gene fusion partner.


Assuntos
Proteínas de Ligação a DNA/genética , Fusão Gênica , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transativadores/genética , Fatores de Transcrição/genética , Translocação Genética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise de Sequência de RNA
11.
Mediterr J Hematol Infect Dis ; 8(1): e2016033, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27413525

RESUMO

BACKGROUND: Bone is the most common organ of involvement in patients with Langerhans cell histiocytosis (LCH), which is often painful and associated with significant morbidity from pathological fractures. Current first-line treatments include chemotherapy and steroids that are effective but often associated with adverse effects, whereas the disease may reactivate despite an initial response to first-line agents. Bisphosphonates are osteoclast inhibitors that have shown to be helpful in treating bone lesions of LCH. To date, there are no large international studies to describe their role in treating bone lesions of LCH. METHOD: We conducted a multicenter retrospective review of 13 patients with histologically proven LCH, who had received bisphosphonates either at diagnosis or at disease reactivation. RESULTS: Ten patients (77%) had a single system bone disease, and 3 (23%) had bone lesions as part of multisystem disease. Median follow-up time post-bisphosphonate therapy was 4.6 years (range, 0.8 to 8.2 years). Treatment with bisphosphonates was associated with significant pain relief in almost all patients. Twelve (92%) achieved resolution of active bone lesions, and 10 out of them had no active disease for a median of 3.5 years (range, 0.8 to 5 years). One patient did not respond. No major adverse effects were reported in this series. CONCLUSION: Bisphosphonates are well-tolerated drugs that can significantly improve bone pain and induce remission in active bone LCH. Future prospective studies evaluating the role of bisphosphonates in LCH are warranted.

12.
Liver Transpl ; 22(9): 1245-53, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27216884

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening systemic disease, characterized by overwhelming stimulation of the immune system and categorized as primary or secondary types. Occasionally, acute liver failure (ALF) may dominate the clinical presentation. Given the systemic nature of HLH and risk of recurrence, HLH is considered by many a contraindication to liver transplantation (LT). The aim of this study is to review our single-center experience with LT in children with secondary HLH and ALF (HLH-ALF). This is a cross-sectional, retrospective study of children with secondary HLH-ALF that underwent LT in 2005-2014. Of 246 LTs, 9 patients (3 males; median age, 5 years; range, 0.7-15.4 years) underwent LT for secondary HLH-ALF. Disease progression was rapid with median 14 days (range, 6-27 days) between first symptoms and LT. Low fibrinogen/high triglycerides, elevated ferritin, hemophagocytosis on liver biopsy, and soluble interleukin 2 receptor levels were the most commonly fulfilled diagnostic criteria; HLH genetic studies were negative in all patients. Immunosuppressive therapy after LT included corticosteroids adjusted to HLH treatment protocol and tacrolimus. Thymoglobulin (n = 5), etoposide (n = 4), and alemtuzumab (n = 2) were used in cases of recurrence. Five (56%) patients experienced HLH recurrence, 1 requiring repeat LT, and 3 died. Overall graft and patient survival were 60% and 67%, respectively. Six patients are alive and well at a median of 24 months (range, 15-72 months) after transplantation. In conclusion, LT can be beneficial in selected patients with secondary HLH-ALF and can restore good health in an otherwise lethal condition. Liver Transplantation 22 1245-1253 2016 AASLD.


Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Linfo-Histiocitose Hemofagocítica/diagnóstico , Doenças Raras/complicações , Adolescente , Biópsia , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Feminino , Ferritinas/sangue , Fibrinogênio/análise , Humanos , Imunossupressão/métodos , Lactente , Fígado/patologia , Falência Hepática Aguda/sangue , Falência Hepática Aguda/etiologia , Falência Hepática Aguda/mortalidade , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/mortalidade , Masculino , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Tempo para o Tratamento , Resultado do Tratamento , Triglicerídeos/sangue
13.
Am J Hematol ; 91(5): 486-91, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26872652

RESUMO

Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted.


Assuntos
Antineoplásicos/administração & dosagem , Linfoma de Células B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Rituximab/administração & dosagem , Adolescente , Antígenos CD20/imunologia , Antineoplásicos/efeitos adversos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Criança , Pré-Escolar , Terapia Combinada , Avaliação de Medicamentos , Hipersensibilidade a Drogas/etiologia , Feminino , Cefaleia/induzido quimicamente , Humanos , Lactente , Injeções Intraventriculares , Injeções Espinhais , Linfoma de Células B/mortalidade , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Indução de Remissão , Estudos Retrospectivos , Rituximab/efeitos adversos , Terapia de Salvação , Convulsões/induzido quimicamente , Transplante , Resultado do Tratamento , Adulto Jovem
14.
Pediatr Blood Cancer ; 63(5): 794-800, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26728447

RESUMO

BACKGROUND: Non-Hodgkin lymphoma (NHL) is a relatively common malignancy in pediatric patients; however, a small subgroup have unusual lymphoma subtypes for the pediatric population. PROCEDURE: The Children's Oncology Group Rare and Cutaneous NHL registry's (protocol ANHL 04B1) main objectives were to determine the pathologic, biologic, and clinical features of rare and cutaneous pediatric NHL and establish a bank of centrally reviewed tissue specimens. We report the clinical data, treatment data, and outcome for rare pediatric NHL. RESULTS: In 101 lymphomas, there is a 97.8% concordance between the reviewing study pathologists and an 87.6% concordance between the central and institutional pathology review. Samples in the specimen bank include primary tumor tissue that is snap frozen, in paraffin blocks, or H&E-stained and unstained paraffin slides as well as blood, serum, and bone marrow. This descriptive analysis shows that children with pediatric follicular lymphoma, mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, primary cutaneous, primary central nervous system lymphoma, and subcutaneous panniculitis-like T-cell lymphomas have 100% survival at a median of 2 years from enrollment. There are early deaths, mostly from progressive disease, in subjects with peripheral T-cell (not otherwise specified), NKT, and hepatosplenic T-cell lymphomas. CONCLUSIONS: This registry provides high-quality biologic specimens with clinical data to investigators working on the biology of these unusual pediatric diseases.


Assuntos
Linfoma não Hodgkin/patologia , Doenças Raras/patologia , Sistema de Registros , Neoplasias Cutâneas/patologia , Bancos de Tecidos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
15.
Pediatr Blood Cancer ; 63(2): 355-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26398727

RESUMO

Hematopoietic stem cell transplantation (HSCT) is currently the only available curative therapy for X-linked inhibitor of apoptosis (XIAP) deficiency. Myeloablative conditioning regimens are associated with high mortality rates. Reduced-intensity conditioning (RIC) is recommended in order to decrease treatment-related toxicities, but RIC regimens increase the risk for mixed donor-recipient chimerism that may progress to graft loss. We report our experience with a patient with XIAP deficiency who was successfully treated with allogeneic HSCT using a RIC protocol. Post-transplant chimerism was vigilantly monitored and maintained with donor lymphocyte infusions and a stem cell boost to a level that prevented hemophagocytic lymphohistiocytosis recurrence.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Transtornos Linfoproliferativos/cirurgia , Agonistas Mieloablativos/uso terapêutico , Condicionamento Pré-Transplante/métodos , Alemtuzumab , Anticorpos Monoclonais Humanizados/administração & dosagem , Pré-Escolar , Humanos , Masculino , Melfalan/administração & dosagem , Transplante Homólogo/métodos , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
16.
Artigo em Inglês | MEDLINE | ID: mdl-26637773

RESUMO

Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ~50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim-Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK -ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.


Assuntos
Histiocitose de Células de Langerhans/terapia , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Ensaios Clínicos como Assunto , Doença de Erdheim-Chester/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Indóis/uso terapêutico , Inflamação , MAP Quinase Quinase 1/genética , Mutação , Fosforilação , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/genética , Recidiva , Risco , Sulfonamidas/uso terapêutico , Vemurafenib
17.
Haematologica ; 100(8): 997-1004, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26314082

RESUMO

The hyperinflammatory syndrome hemophagocytic lymphohistiocytosis can occur in the context of malignancies. Malignancy-triggered hemophagocytic lymphohistiocytosis should be regarded separately from hemophagocytic lymphohistiocytosis during chemotherapeutic treatment, which is frequently associated with an infectious trigger. The substantial overlap between the features of hemophagocytic lymphohistiocytosis with features of neoplasms makes its identification difficult when it occurs in malignant conditions. To facilitate recognition and diagnostic workup, and provide guidance regarding the treatment of malignancy-associated hemophagocytic lymphohistiocytosis, consensus recommendations were developed by the Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society, an interdisciplinary group consisting of pediatric and adult hemato-oncologists and immunologists.


Assuntos
Linfo-Histiocitose Hemofagocítica/complicações , Neoplasias/diagnóstico , Neoplasias/etiologia , Neoplasias/terapia , Gerenciamento Clínico , Humanos
18.
Blood ; 126(12): 1415-23, 2015 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-26194764

RESUMO

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.


Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Histiocitose de Células de Langerhans/tratamento farmacológico , Imunossupressores/uso terapêutico , Antineoplásicos/efeitos adversos , Pré-Escolar , Cladribina/efeitos adversos , Citarabina/efeitos adversos , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Imunossupressores/efeitos adversos , Lactente , Células de Langerhans/efeitos dos fármacos , Células de Langerhans/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Recidiva , Baço/efeitos dos fármacos , Baço/patologia , Análise de Sobrevida , Taxa de Sobrevida , Vimblastina/uso terapêutico
19.
Pediatr Blood Cancer ; 62(12): 2162-6, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26179251

RESUMO

BACKGROUND: Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients. METHODS: Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients. RESULTS: The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14). CONCLUSION: Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.


Assuntos
Doenças Ósseas/mortalidade , Doenças Ósseas/terapia , Histiocitose de Células de Langerhans/mortalidade , Histiocitose de Células de Langerhans/terapia , Doenças Neurodegenerativas/mortalidade , Doenças Neurodegenerativas/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
20.
Artigo em Inglês | MEDLINE | ID: mdl-25980698

RESUMO

Over the past 50 years, survival for children in high-income countries has increased from 30% to over 80%, compared to 10-30% in low and middle income countries (LMIC). Given this gap in survival, established paediatric cancer treatment centres, such as The Hospital for Sick Children (SickKids) are well positioned to share clinical expertise. Through the SickKids Centre for Global Child Health, the SickKids-Caribbean Initiative (SCI) was launched in March 2013 to improve the outcomes and quality of life for children with cancer and blood disorders in the Caribbean. The six participating Caribbean countries are among those defined by the United Nations as Small Island Developing States, due to their small size, remote location and limited accessibility. Telemedicine presents an opportunity to increase their accessibility to health care services and has been used by SCI to facilitate two series of interprofessional rounds. Case Consultation Review Rounds are a forum for learning about diagnostic work-up, management challenges and treatment recommendations for these diseases. To date, 54 cases have been reviewed by SickKids staff, of which 35 have been presented in monthly rounds. Patient Care Education Rounds provide nurses and other staff with the knowledge base needed to safely care for children and adolescents receiving treatment. Five of these rounds have taken place to date, with over 200 attendees. Utilized by SCI for both clinical and non-clinical meetings, telemedicine has enhanced opportunities for collaboration within the Caribbean region. By building capacity and nurturing expert knowledge through education, SCI hopes to contribute to closing the gap in childhood survival between high and low-resource settings.


Assuntos
Países em Desenvolvimento , Doenças Hematológicas/terapia , Área Carente de Assistência Médica , Neoplasias/terapia , Pediatria/organização & administração , Telemedicina/organização & administração , Região do Caribe , Assistência à Saúde/organização & administração , Feminino , Promoção da Saúde/organização & administração , Acesso aos Serviços de Saúde/organização & administração , Doenças Hematológicas/diagnóstico , Hematologia/organização & administração , Humanos , Masculino , Oncologia/organização & administração , Neoplasias/diagnóstico , Índias Ocidentais
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