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1.
Leukemia ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060402

RESUMO

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (<0.01%) remission in most patients (70%). EOI MRD positivity was predictive of 5-year EFS (HR = 6.00, p < 0.001) and OS (HR = 9.57, p = 0.003). Patients who cleared MRD by EOC had worse survival compared with those EOI MRD negative. In contrast to adults with MPAL, ALL therapy without transplantation was adequate to treat most pediatric patients. Earlier MRD clearance was associated with better treatment success and survival. Prospective trials are now necessary to validate and refine MRD thresholds within the pediatric MPAL population and to identify salvage strategies for those with poor predicted survival.

2.
Blood ; 135(4): 274-286, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31738823

RESUMO

Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma-related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

3.
Leuk Lymphoma ; 61(2): 420-428, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31526067

RESUMO

Asparaginase (ASNase) is an integral part of pediatric induction chemotherapy that has also been shown to improve adult survival rates; however, pegylated (PEG)-ASNase induces severe hepatotoxicity in this population. Recent case reports describe the incorporation of levocarnitine (LC) supplementation into PEG-ASNase-containing induction regimens to prevent or treat hepatotoxicity. Because LC facilitates the metabolism of free fatty acids (FFA), a primary fuel source for ALL cells, LC could potentially interfere with ALL chemotherapy efficacy. To test this, we employed in vitro and in vivo models of ALL. We show in vitro that LC supplementation does not impact cytotoxicity from vincristine, daunorubicin, dexamethasone, or ASNase on human ALL cells nor lead to an increase in ALL cell metabolic rate. In vivo, we demonstrate LC does not impair PEG-ASNase monotherapy in mice with syngeneic ALL. Together, our findings show that LC supplementation is a safe strategy to prevent/reverse ASNase-induced toxicities in preclinical models.

4.
Lancet Haematol ; 7(3): e238-e246, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31879230

RESUMO

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.


Assuntos
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
5.
Pediatr Blood Cancer ; 65(9): e27265, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29797659

RESUMO

A pediatric patient diagnosed initially with B-lymphoblastic leukemia (B-ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T-cell (CAR-T) therapy and hematopoietic stem cell transplant. A TCF3-ZNF384 fusion was identified at diagnosis, persisted through B-ALL relapse, and was also present in the AML relapse cell population. ZNF384-rearrangements define a molecular subtype of B-ALL characterized by a pro-B-cell immunophenotype; furthermore, ZNF384-rearrangements are prevalent in mixed-phenotype acute leukemias. Lineage switch following CAR-T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia Mieloide Aguda/etiologia , Células Mieloides/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos Quiméricos/imunologia , Subpopulações de Linfócitos T/imunologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula , Terapia Combinada , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Evolução Fatal , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Leucemia Mieloide Aguda/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Terapia de Salvação , Transativadores/genética
6.
Leukemia ; 32(7): 1515-1528, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29550836

RESUMO

The rarity of mixed-phenotype acute leukemia (MPAL) has resulted in diffuse literature consisting of small case series, thus precluding a consensus treatment approach. We conducted a meta-analysis and systematic review to investigate the association of treatment type (acute lymphoblastic leukemia [ALL], acute myeloid leukemia [AML], or "hybrid" regimens), disease response, and survival. We searched seven databases from inception through June 2017 without age or language restriction. Included studies reported sufficient treatment detail for de novo MPAL classified according to the well-established European Group for Immunological Characterization of Acute Leukemias (EGIL) or World Health Organization (WHO2008) criteria. Meta-analyses and multivariable analyses of a patient-level compiled case series were performed for the endpoints of complete remission (CR) and overall survival (OS). We identified 97 reports from 33 countries meeting criteria, resulting in 1,499 unique patients with data, of whom 1,351 had sufficient detail for quantitative analysis of the study endpoints. Using either definition of MPAL, meta-analyses revealed that AML induction was less likely to achieve a CR as compared to ALL regimens, (WHO2008 odds ratio [OR] = 0.33, 95% confidence interval [95% CI] 0.18-0.58; EGIL, OR = 0.18, 95% CI 0.08-0.40). Multivariable analysis of the patient-level data supported poorer efficacy for AML induction (versus ALL: OR = 0.45 95% CI 0.27-0.77). Meta-analyses similarly found better OS for those beginning with ALL versus AML therapy (WHO2008 OR = 0.45, 95% CI 0.26-0.77; EGIL, OR = 0.43, 95% CI 0.24-0.78), but multivariable analysis of patient-level data showed only those starting with hybrid therapy fared worse (hazard ratio [HR] = 2.11, 95% CI 1.30-3.43). MPAL definition did not impact trends within each endpoint and were similarly predictive of outcome. Using either definition of MPAL, ALL-therapy is associated with higher initial remission rates for MPAL and is at least equivalent to more intensive AML therapy for long-term survival. Prospective trials are needed to establish a uniform approach to this heterogeneous disease.


Assuntos
Leucemia Aguda Bifenotípica/diagnóstico , Leucemia Aguda Bifenotípica/terapia , Adulto , Animais , Criança , Terapia Combinada , Gerenciamento Clínico , Humanos , Leucemia Aguda Bifenotípica/mortalidade , Prognóstico , Indução de Remissão , Resultado do Tratamento
7.
Pediatr Blood Cancer ; 65(2)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28876513

RESUMO

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1-21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5-94.5] versus 86.5% [95% CI, 77.7-92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Taxa de Sobrevida
8.
Pediatr Blood Cancer ; 65(3)2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29218844

RESUMO

BACKGROUND: Hepatotoxicity and pancreatitis are common treatment-related toxicities (TRTs) during contemporary treatment regimens for acute lymphoblastic leukemia (ALL). Limited detailed data from Children's Oncology Group (COG) regimens has been previously reported to enable identification of patient and treatment risk factors for these toxicities and their impact on outcomes. PROCEDURE: We analyzed a retrospective pediatric ALL cohort treated at a single institution according to COG regimens from 2008 to 2015. The primary endpoint was cumulative incidence of study-defined "severe" hepatotoxicity (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≥ 4 transaminitis or Grade ≥ 3 hyperbilirubinemia) and clinically significant pancreatitis (any grade). Pancreatitis was additionally classified using the Ponte di Legno (PdL) toxicity criteria. Secondary endpoints were chemotherapy interruptions, early disease response (end of induction [EOI] minimal residual disease [MRD]), and event-free survival (EFS). RESULTS: We identified 262 patients, of whom 71 (27%) and 28 (11%) developed hepatotoxicity and pancreatitis, respectively. Three cases of pancreatitis did not fulfill PdL criteria despite otherwise consistent presentations. Both TRTs occurred throughout therapy, but approximately 25% of hepatotoxicity (18/71) and pancreatitis (8/28) occurred during induction alone. Both obesity and age (≥10 years) were identified as predictors of hepatotoxicity (subdistribution hazard ratio [SHR] obesity = 1.75, 95% confidence interval [95% CI] 1.04-2.96; SHR age ≥10 = 1.9, 95% CI 1.19-3.10) and pancreatitis (SHR obesity = 2.18, 95% CI 1.01-4.67; SHR age ≥ 10 = 2.76, 95% CI 1.19-6.39, P = 0.018). Dose interruptions were common but neither toxicity influenced EOI MRD nor EFS. CONCLUSIONS: Obese and/or older children are particularly at risk for hepatotoxicity and pancreatitis, and may benefit from toxicity surveillance and chemoprotective strategies to prevent or mitigate associated morbidity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Pancreatite/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Fatores Etários , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Lactente , Masculino , Obesidade/epidemiologia , Pancreatite/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
9.
Mol Cancer Res ; 15(12): 1704-1713, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29117945

RESUMO

Obesity is associated with poorer outcome for many cancers. Previously, we observed that adipocytes protect acute lymphoblastic leukemia (ALL) cells from the anthracycline, daunorubicin. In this study, it is determined whether adipocytes clear daunorubicin from the tumor microenvironment (TME). Intracellular daunorubicin concentrations were evaluated using fluorescence. Daunorubicin and its largely inactive metabolite, daunorubicinol, were analytically measured in media, cells, and tissues using liquid chromatography/mass spectrometry (LC/MS). Expression of daunorubicin-metabolizing enzymes, aldo-keto reductases (AKR1A1, AKR1B1, AKR1C1, AKR1C2, AKR1C3, and AKR7A2) and carbonyl reductases (CBR1, CBR3), in human adipose tissue, were queried using public databases and directly measured by quantitative PCR (qPCR) and immunoblot. Adipose tissue AKR activity was measured by colorimetric assay. Adipocytes absorbed and efficiently metabolized daunorubicin to daunorubicinol, reducing its antileukemia effect in the local microenvironment. Murine studies confirmed adipose tissue conversion of daunorubicin to daunorubicinol in vivo Adipocytes expressed high levels of AKR and CBR isoenzymes that deactivate anthracyclines. Indeed, adipocyte protein levels of AKR1C1, AKR1C2, and AKR1C3 are higher than all other human noncancerous cell types. To our knowledge, this is the first demonstration that adipocytes metabolize and inactivate a therapeutic drug. Adipocyte-mediated daunorubicin metabolism reduces active drug concentration in the TME. These results could be clinically important for adipocyte-rich cancer microenvironments such as omentum, breast, and marrow. As AKR and CBR enzymes metabolize several drugs, and can be expressed at higher levels in obese individuals, this proof-of-principle finding has important implications across many diseases.Implications: Adipocyte absorption and metabolism of chemotherapies can reduce cytotoxicity in cancer microenvironments, potentially contributing to poorer survival outcomes. Mol Cancer Res; 15(12); 1704-13. ©2017 AACR.


Assuntos
Daunorrubicina/metabolismo , Obesidade/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Microambiente Tumoral/genética , 20-Hidroxiesteroide Desidrogenases/genética , Adipócitos/metabolismo , Adipócitos/patologia , Oxirredutases do Álcool/genética , Aldeído Redutase/genética , Membro C3 da Família 1 de alfa-Ceto Redutase/genética , Linhagem Celular Tumoral , Daunorrubicina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Leucêmica da Expressão Gênica , Humanos , Hidroxiesteroide Desidrogenases/genética , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo
10.
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
11.
Cancer Genet ; 216-217: 91-99, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29025601

RESUMO

The 2016 World Health Organization (2016 WHO) classification of hematopoietic malignancies classifies neoplasms with a fusion between the FIP1L1 and PDGFRA genes in 4q12 into a group called "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2". Neoplasms characterized by this fusion are pluripotent stem cell disorders that can show both myeloid and lymphoid differentiation. They typically occur in adult patients and most are characterized by eosinophilia. We describe identification of a FIP1L1-PDGFRA fusion in a 13-year-old boy who presented with T-lymphoblastic leukemia/lymphoma without eosinophilia. Detection of FIP1L1-PDGFRA driven neoplasms at diagnosis is usually critical for proper treatment, since almost all reported cases responded to tyrosine kinase inhibitors. However, our patient's leukemia was refractory to standard chemotherapy, and did not show a meaningful response to tyrosine kinase inhibitor therapy. Testing for a FIP1L1-PDGFRA rearrangement is at present limited to patients with idiopathic hypereosinophilia, and we hypothesize that this abnormality may be under-diagnosed in children with acute leukemias.


Assuntos
Eosinofilia/complicações , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Adolescente , Criança , Cromossomos Humanos/genética , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Cariotipagem , Linfonodos/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
12.
Am J Clin Pathol ; 147(4): 374-381, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28340210

RESUMO

Objectives: Diagnosis of B-cell acute lymphoblastic leukemia (B-ALL) requires immunophenotypic evidence of B-lineage and absence of specific myeloid or T-lineage markers. Rare cases of otherwise typical B-ALL express myeloperoxidase (MPO) detectable by flow cytometry with an absence of other myeloid markers, but the clinical significance of this finding is not well studied. Methods: A retrospective cohort analysis of flow cytometry and clinical data was performed to investigate the clinical outcome of this specific group of patients. Results: Twenty-nine cases of otherwise typical B-ALL that expressed MPO by flow cytometry (B-ALL-isoMPO) without expression of other myeloid markers were identified. The B-ALL-isoMPO group had a significantly increased incidence of relapse (univariate log rank P = .0083; multivariate hazard ratio, 2.50; 95% confidence interval, 1.07-5.85; P = .034) and significantly worse event-free survival by univariate analysis (log rank P = .0066) compared with a reference group of patients with B-ALL from the same time period (n = 264). Conclusions: To our knowledge, this is the first report to document the clinical outcomes in a group of pediatric patients with B-ALL that expresses MPO in the absence of other myeloid markers. This group had an increased rate of relapse and a worse event-free survival than the patients with B-ALL who did not express MPO.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia de Células B/diagnóstico , Peroxidase/metabolismo , Adolescente , Linfócitos B/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Leucemia de Células B/metabolismo , Masculino , Recidiva , Estudos Retrospectivos , Risco
13.
Emerg Infect Dis ; 22(11)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27767010

RESUMO

Babesia microti, an intraerythrocytic parasite, is tickborne in nature. In contrast to transmission by blood transfusion, which has been well documented, transmission associated with solid organ transplantation has not been reported. We describe parasitologically confirmed cases of babesiosis diagnosed ≈8 weeks posttransplantation in 2 recipients of renal allografts from an organ donor who was multiply transfused on the day he died from traumatic injuries. The organ donor and recipients had no identified risk factors for tickborne infection. Antibodies against B. microti parasites were not detected by serologic testing of archived pretransplant specimens. However, 1 of the organ donor's blood donors was seropositive when tested postdonation and had risk factors for tick exposure. The organ donor probably served as a conduit of Babesia parasites from the seropositive blood donor to both kidney recipients. Babesiosis should be included in the differential diagnosis of unexplained fever and hemolytic anemia after blood transfusion or organ transplantation.


Assuntos
Babesia microti , Babesiose/parasitologia , Babesiose/transmissão , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Babesia microti/genética , Babesia microti/imunologia , Babesiose/diagnóstico , Babesiose/tratamento farmacológico , Biomarcadores , Transfusão de Sangue , Eritrócitos/parasitologia , Eritrócitos/patologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Fatores de Tempo , Doadores de Tecidos , Tomografia Computadorizada por Raios X , Transplante Homólogo
15.
Am J Clin Pathol ; 142(3): 411-8, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25125633

RESUMO

OBJECTIVES: Flow cytometry is essential for the evaluation of lymphoproliferative disorders (LPDs) and their classification. Flow panels routinely incorporate a large array of antibodies, making testing complex and expensive; such panels are likely unnecessary in benign cases or those with straightforward diagnoses. Our aim was to develop a more cost-effective testing strategy based on a retrospective analysis of flow studies for possible LPDs in blood. METHODS: We identified LPD frequencies and types, as well as associated results with patient age and absolute lymphocyte count. RESULTS: We found that the likelihood of LPDs increased with patient age and absolute lymphocyte count and that CD5-positive LPD was the most common LPD diagnosed in our institution (71% of LPDs). Using these data, we devised flow-testing algorithms with a screening test for patients at low risk of disease and a focus on CD5-positive LPD detection, with reflexing as needed. CONCLUSIONS: We project this approach will result in a 40% decrease in antibody utilization.


Assuntos
Citometria de Fluxo/economia , Transtornos Linfoproliferativos/diagnóstico , Melhoria de Qualidade , Algoritmos , Análise Custo-Benefício , Humanos , Transtornos Linfoproliferativos/economia
17.
Histopathology ; 63(4): 499-508, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23926923

RESUMO

AIM: To assess the validity and potential clinical utility of evaluating MYC expression by immunohistochemistry (IHC) in mantle cell lymphoma (MCL). METHODS AND RESULTS: MYC IHC was scored on a tissue microarray containing 62 MCLs and 29 controls by two pathologists. Inter-observer correlation was high (intra-class correlation of 0.98). MYC IHC scores correlated with MYC expression (Spearman's rank correlation 0.69, P < 0.0001) and weakly with Ki67 proliferation index (Spearman's rank correlation 0.30, P = 0.03). Six blastic MCLs did not have higher mean MYC IHC scores or MYC mRNA expression than non-blastic MCLs. None of 57 cases assessed, including all of the blastic cases, showed MYC rearrangement by fluorescence in-situ hybridization. Multivariate analysis with backward selection from potential predictors including age, lactate dehydrogenase, leukocyte count, MIPI score, ECOG performance status, blastic morphology and Ki67 index showed that MYC IHC score is an independent predictor of progression-free survival (hazard ratio 2.34, 95% CI 1.42-3.88, P = 0.0009) and overall survival (hazard ratio 1.90, 95% CI 1.05-3.43, P = 0.034). CONCLUSIONS: We show that a new monoclonal anti-MYC antibody can enable accurate and reproducible visual assessment of MYC expression that is independently predictive of clinical outcomes in MCL.


Assuntos
Biomarcadores Tumorais/análise , Linfoma de Célula do Manto/metabolismo , Proteínas Proto-Oncogênicas c-myc/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas c-myc/análise , RNA Mensageiro/análise , Análise Serial de Tecidos
18.
Am J Hematol ; 88(6): 522-6, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23423840

RESUMO

Cobalamin (vitamin B12) deficiency is a common cause of megaloblastic anemia in Western populations. Laboratory evaluation of megaloblastic anemia frequently includes the assessment of patient cobalamin and folate status. Current total serum cobalamin measurements are performed in the clinical laboratory with competitive binding luminescence assays, whose results may not always accurately reflect actual cobalamin stores. Surrogate markers of cobalamin deficiency such as methylmalonic acid and homocysteine have been utilized to improve diagnostic accuracy; however, the specificity of these tests by themselves is rather low. Measurement of the biologically active fraction of cobalamin, holotranscobalamin, has been proposed as a replacement for current total cobalamin assays. Although holotranscobalamin measurements appear to have slighter better sensitivity, the specificity of this assay remains to be determined. The relative merits and demerits of commonly available methods to assess cobalamin deficiency in patients with suspected megaloblastic anemia are discussed.


Assuntos
Anemia Megaloblástica/sangue , Deficiência de Vitamina B 12/sangue , Vitamina B 12/sangue , Humanos
19.
Am J Blood Res ; 2(1): 1-8, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22432082

RESUMO

The Vav family of proteins are guanine nucleotide exchange factors which have been shown to be deregulated in several types of human cancer. There are three members of the Vav family that have been identified which are members of the Dbl domain superfamily and have specificity towards Rho/Rac GTPases. The Vav family plays an important role in normal hematologic system development and homeostasis, and Vav1 is largely restricted to the hematologic system. While Vav1 was originally identified as a proto-oncogene, several recent studies have shown that Vav family deletion leads to the development of T-cell malignancies in mice. In addition, Vav1 has been shown to play a role in the ATRA-mediated differentiation of promyelocytic leukemia cells. In this concise review, the gene structure and normal function of Vav1, as well as a possible role for Vav1 in the development of hematologic and other malignancies is reviewed.

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