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Lancet Haematol ; 7(3): e238-e246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31879230


BACKGROUND: Data to inform surveillance and treatment for leukaemia predisposition syndromes are scarce and recommendations are largely based on expert opinion. This study aimed to investigate the clinical features and outcomes of patients with myelodysplastic syndrome or acute myeloid leukaemia and Shwachman-Diamond syndrome, an inherited bone marrow failure disorder with high risk of developing myeloid malignancies. METHODS: We did a multicentre, retrospective, cohort study in collaboration with the North American Shwachman-Diamond Syndrome Registry. We reviewed patient medical records from 17 centres in the USA and Canada. Patients with a genetic (biallelic mutations in the SBDS gene) or clinical diagnosis (cytopenias and pancreatic dysfunction) of Shwachman-Diamond syndrome who developed myelodysplastic syndrome or acute myeloid leukaemia were eligible without additional restriction. Medical records were reviewed between March 1, 2001, and Oct 5, 2017. Masked central review of bone marrow pathology was done if available to confirm leukaemia or myelodysplastic syndrome diagnosis. We describe the clinical features and overall survival of these patients. FINDINGS: We initially identified 37 patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia. 27 patients had samples available for central pathology review and were reclassified accordingly (central diagnosis concurred with local in 15 [56%] cases), 10 had no samples available and were classified based on the local review data, and 1 patient was excluded at this stage as not eligible. 36 patients were included in the analysis, of whom 10 (28%) initially presented with acute myeloid leukaemia and 26 (72%) initially presented with myelodysplastic syndrome. With a median follow-up of 4·9 years (IQR 3·9-8·4), median overall survival for patients with myelodysplastic syndrome was 7·7 years (95% CI 0·8-not reached) and 0·99 years (95% CI 0·2-2·4) for patients with acute myeloid leukaemia. Overall survival at 3 years was 11% (95% CI 1-39) for patients with leukaemia and 51% (29-68) for patients with myelodysplastic syndrome. Management and surveillance were variable. 18 (69%) of 26 patients with myelodysplastic syndrome received upfront therapy (14 haematopoietic stem cell transplantation and 4 chemotherapy), 4 (15%) patients received no treatment, 2 (8%) had unavailable data, and 2 (8%) progressed to acute myeloid leukaemia before receiving treatment. 12 patients received treatment for acute myeloid leukaemia-including the two patients initially diagnosed with myelodysplastic who progressed- two (16%) received HSCT as initial therapy and ten (83%) received chemotherapy with intent to proceed with HSCT. 33 (92%) of 36 patients (eight of ten with leukaemia and 25 of 26 with myelodysplastic syndrome) were known to have Shwachman-Diamond syndrome before development of a myeloid malignancy and could have been monitored with bone marrow surveillance. Bone marrow surveillance before myeloid malignancy diagnosis was done in three (33%) of nine patients with leukaemia for whom surveillance status was confirmed and 11 (46%) of 24 patients with myelodysplastic syndrome. Patients monitored had a 3-year overall survival of 62% (95% CI 32-82; n=14) compared with 28% (95% CI 10-50; n=19; p=0·13) without surveillance. Six (40%) of 15 patients with available longitudinal data developed myelodysplastic syndrome in the setting of stable blood counts. INTERPRETATION: Our results suggest that prognosis is poor for patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia owing to both therapy-resistant disease and treatment-related toxicities. Improved surveillance algorithms and risk stratification tools, studies of clonal evolution, and prospective trials are needed to inform effective prevention and treatment strategies for leukaemia predisposition in patients with Shwachman-Diamond syndrome. FUNDING: National Institute of Health.

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Síndromes Mielodisplásicas/mortalidade , /mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Retrospectivos , /terapia , Taxa de Sobrevida , Adulto Jovem
Haematologica ; 104(10): 1974-1983, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30948484


Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia.

J Surg Res ; 233: 256-261, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502256


BACKGROUND: Lymphatic malformations (LMs) are congenital and arise from errors in vascular embryogenesis. LMs are categorized by cyst size as microcystic, macrocystic, or combined. Abdominal LMs are rare. Surgical resection of abdominal LMs has been the mainstay of therapy, but recurrence and morbidity are high. We sought to determine the effectiveness of sclerotherapy treatment for abdominal LM. METHODS: A single-center, retrospective review from 2014 to 2018 was conducted evaluating pediatric patients with abdominal LM. RESULTS: Ten patients were included, n = 9 had macrocystic LM and one patient had combined disease. The average age at first treatment was 6.8 y. The most common presenting symptoms were abdominal distention, pain, infection, and anemia. Preprocedural imaging was performed for all patients; median pretreatment volume was 1572.9 cm3 (range, 67.2-13,226.4). LMs were accessed using ultrasound guidance and injected with opacified doxycycline. Patients received a mean of 7.1 sclerotherapy injections. Complications included intraperitoneal doxycycline extravasation (n = 1), managed conservatively, and LM infection (n = 1), treated with intravenous antibiotics and drainage. One patient went on to surgical resection due to inability gain stable intracystic access; follow-up ultrasonography showed no recurrence. Postprocedural imaging was available in n = 8. Volume decreased by 96.7% after sclerotherapy. The median remaining volume was 0 cm3 (range, 0-599.7) (P = 0.016). Postsclerotherapy magnetic resonance imaging was obtained in n = 6, with complete resolution in 83.3%. All patients had resolution of presenting symptoms. Follow-up duration was 12.3 mo. CONCLUSIONS: Initial results demonstrate that sclerotherapy is an effective and durable treatment for symptom resolution and volume reduction of abdominal LM.

Doxiciclina/administração & dosagem , Anormalidades Linfáticas/terapia , Escleroterapia/métodos , Prevenção Secundária/métodos , Cavidade Abdominal/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Extravasamento de Materiais Terapêuticos e Diagnósticos/epidemiologia , Extravasamento de Materiais Terapêuticos e Diagnósticos/etnologia , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Anormalidades Linfáticas/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Recidiva , Estudos Retrospectivos , Escleroterapia/efeitos adversos , Resultado do Tratamento , Ultrassonografia de Intervenção
Front Pediatr ; 5: 158, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28791278


The presence of a vascular anomaly suggests that capillaries, veins, arteries, and/or lymphatic vessels have demonstrated abnormal development and growth. Often dilated and misshaped, these vessels augment normal flow of blood and lymphatic fluids that increases the overall risk to develop intralesional thrombosis. Abnormal endothelial and lymphoendothelial cells activate hemostasis and hyperfibrinolytic pathways through poorly understood mechanisms, which contribute to the development of localized intravascular coagulopathy. Vascular malformations, tumors, and complex combined syndromes demonstrate varying degrees of prothrombotic activity and consumptive coagulopathy depending on the vessels involved and the pattern and extent of abnormal growth. The clinical impact of venous thromboembolism in pediatric vascular anomalies varies from painful syndromes that disrupt quality of life to life-threatening embolic disease. There remains little literature on the study, evaluation, and treatment of thrombosis in pediatric vascular anomalies. However, there have been great advances in our ability to image complex lesions, to surgically and interventionally augment disease, and to provide enhanced supportive care including patient education, compression therapy, and strategic use of anticoagulation.

Proc Natl Acad Sci U S A ; 113(29): 8272-7, 2016 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-27307436


Infiltration of T cells in breast tumors correlates with improved survival of patients with breast cancer, despite relatively few mutations in these tumors. To determine if T-cell specificity can be harnessed to augment immunotherapies of breast cancer, we sought to identify the alpha-beta paired T-cell receptors (TCRs) of tumor-infiltrating lymphocytes shared between multiple patients. Because TCRs function as heterodimeric proteins, we used an emulsion-based RT-PCR assay to link and amplify TCR pairs. Using this assay on engineered T-cell hybridomas, we observed ∼85% accurate pairing fidelity, although TCR recovery frequency varied. When we applied this technique to patient samples, we found that for any given TCR pair, the dominant alpha- or beta-binding partner comprised ∼90% of the total binding partners. Analysis of TCR sequences from primary tumors showed about fourfold more overlap in tumor-involved relative to tumor-free sentinel lymph nodes. Additionally, comparison of sequences from both tumors of a patient with bilateral breast cancer showed 10% overlap. Finally, we identified a panel of unique TCRs shared between patients' tumors and peripheral blood that were not found in the peripheral blood of controls. These TCRs encoded a range of V, J, and complementarity determining region 3 (CDR3) sequences on the alpha-chain, and displayed restricted V-beta use. The nucleotides encoding these shared TCR CDR3s varied, suggesting immune selection of this response. Harnessing these T cells may provide practical strategies to improve the shared antigen-specific response to breast cancer.

Neoplasias da Mama/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/metabolismo , Sequência de Bases , Linhagem Celular , Emulsões , Feminino , Humanos , Reação em Cadeia da Polimerase/métodos
J Biol Chem ; 286(46): 40343-53, 2011 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-21949236


Although sialic acids have a key role in many aspects of human biology, the expression of polysialic acid (PSA) in human tissues is thought to be relatively rare. We identified a derivative of PSA called neuraminic acid-containing PSA or NeuPSA that was highly expressed in primary human melanoma tumors and in several cancer cell lines. Moreover, anti-NeuPSA antibodies could induce apoptosis of cancer cells. However, little was known about NeuPSA expression in normal or diseased tissues. In this study we investigated the complete expression profile of NeuPSA in human tissues and a few primary tumors using the anti-NeuPSA monoclonal antibody, SEAM 3. Almost every human tissue tested spanning a representative sample of all organ types was positive for SEAM 3 binding. Specificity of SEAM 3 binding was established by inhibition with NeuPSA but not closely related meningococcal C polysaccharide and loss of SEAM 3 binding when specimens were treated with periodate at high pH, which specifically destroys NeuPSA. Only subsets of cells in each specimen stained positive, and the relative staining between tissues was variable. The distribution and amount of NeuPSA antigen in tissues was correlated with known levels of polysialyltransferase PST or STX expression. The majority of anti-NeuPSA binding occurred intracellularly in the cytoplasm of cells. Tumors generally exhibited considerably increased staining compared with corresponding normal tissues. Identifying the diverse tissue distribution and intracellular location of NeuPSA provides a foundation for investigating the functional role of NeuPSA in human health and disease.

Regulação Neoplásica da Expressão Gênica , Neoplasias/metabolismo , Ácidos Siálicos/biossíntese , Animais , Anticorpos Monoclonais Murinos/química , Humanos , Camundongos , Proteínas de Neoplasias/biossíntese , Neoplasias/patologia , Especificidade de Órgãos , Sialiltransferases/biossíntese