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1.
Pediatr Blood Cancer ; 71(11): e31281, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39169521

RESUMO

Detailed characterization of the B-lymphoblastic leukemia (B-ALL) cells which invade the central nervous system (CNS) has been limited by practical challenges. To test whether the clonal composition of the cerebrospinal fluid (CSF) reflects the primary B-ALL tissue, we applied immunoglobulin (Ig) high-throughput sequencing (HTS) of archival CSF cytospin preparations from six patients with morphologically defined CNS involvement. We discovered that most CSF clones are detectable at some timepoint in the primary tissue, but that shifting clonal abundance is prevalent across tissue sites between diagnosis and relapse. Ig HTS of CSF cytospins may improve understanding of sanctuary site dissemination in B-ALL.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Criança , Masculino , Feminino , Pré-Escolar , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adolescente , Lactente
2.
Cytometry B Clin Cytom ; 106(5): 405-411, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38708886

RESUMO

Meningeal infiltration in children with B acute lymphoblastic leukemia is one of the most serious complications. Timely diagnosis not only significantly enhances treatment efficacy but also leads to improve patient outcome and reduce risk of relapse. This is particularly crucial in low to middle income countries facing health constraints, where optimizing resources is essential. Conventional cytology (CC) study of cerebrospinal fluid (CSF) is considered in different countries to be the Gold-standard despite its low sensitivity (< 50%). The study of CSF by multiparametric flow cytometry (MFC) appears to be an alternative. The aim of our study was to assess MFC analytical performance compared with CC. Our cross sectional study was conducted over a six-month period in the biological hematology department. CSF samples underwent analysis for the presence of blasts using both CC and MFC. Cytological slides of the CSF were prepared by cytocentrifugation in a Shandon Cytospin 4™. Flow cytometric analysis was performed on the BD FACSLyric™ flow cytometer. All statistical analyses were performed using SPSS version 21.0 (SPSS Inc.). Agreement between the two methods was made using the Kappa index and χ2 test. This study was approved by the local ethics committee. Sixty CSF samples from 39 children with B acute lymphoblastic leukemia were analyzed. Meningeal infiltration was detected respectively in 20% of cases by MFC and 5% of cases by CC, with a significant difference p = 0.006. Comparing the two methods, the Kappa coefficient was 0.35, indicating weak agreement between the two methods. Moreover, MFC positivity was higher even for hypocellular samples. Of the 51 hypocellular samples, eight were positive by MFC while they were negative by CC. MFC shows better sensitivity while retaining good specificity for the detection of meningeal involvement. MFC could therefore be a complementary method to CC for detecting blast cells in the central nervous system.


Assuntos
Citometria de Fluxo , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Citometria de Fluxo/métodos , Criança , Masculino , Feminino , Pré-Escolar , Estudos Transversais , Adolescente , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Lactente , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano
4.
Technol Cancer Res Treat ; 20: 15330338211016372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34060372

RESUMO

OBJECTIVE: To investigate the characteristics of central nervous system (CNS) involvement in children with non-Hodgkin's lymphoma (NHL) and the value of flow cytometry (FC) in the diagnosis of CNS disease in pediatric NHL. METHODS: The data of 56 newly diagnosed pediatric NHL patients with CNS involvement (CNS+/mass, CNS+/palsy, CNS+/CSF) were analyzed. The proportions and formats of CNS disease in different pathological types were compared. In addition, FC and conventional cytology (CC) of cerebrospinal fluid (CSF) were carried out in 383 newly diagnosed NHL cases. RESULTS: A total of 383 children with NHL were enrolled. Among these patients, 56 (14.6%) were diagnosed with positive CNS involvement (CNS+), 33 had bulky disease (tumor diameter >10 cm), 32 had bone marrow invasion, 32 had lactate dehydrogenase levels >1000 U/L, and 25 had invasion of more than 4 organs at the time of diagnosis. There were 14 patients with T lymphoblastic lymphoma (T-LBL), 9 with B lymphoblastic lymphoma (B-LBL), 26 with Burkitt's lymphoma (BL), and 2 with Epstein-Barr virus-positive diffuse large B cell lymphoma (EBV + DLBCL). Among the 56 CNS+ patients, 35 were CSF-positive (CSF+); there were 2 patients who were CSF+ via CC detection and 35 who were CSF+ via FC detection. The difference between CC and FC was statistically significant (P < 0.01). In the T-LBL group, 14 patients were CNS+/CSF, and in the B-LBL group, 8 were CNS+/mass. In the BL group, 22 patients were CNS+/mass and 15 were CNS+/CSF. In the anaplastic large-cell lymphoma group, 5 patients were CNS+/mass. Nine of the 56 CNS+ patients had events. The 2-year overall survival rate was 87% ± 0.046%, and the 2-year event-free survival rate was 76.2% ± 0.07%. CONCLUSION: CNS+ diagnoses were more common in pediatric NHL patients with bulky disease and/or bone marrow involvement and/or involvement of more than 4 organs at the time of diagnosis, and they were also common in the EBV + DLBCL and BL groups. FC of CSF showed important clinical significance in the diagnosis of CNS disease in pediatric NHL patients, and it can be used to significantly improve the CNS+ detection rate.


Assuntos
Doenças do Sistema Nervoso Central/líquido cefalorraquidiano , Doenças do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/patologia , Linfoma não Hodgkin/líquido cefalorraquidiano , Linfoma não Hodgkin/patologia , Adolescente , Medula Óssea/patologia , Linfoma de Burkitt/líquido cefalorraquidiano , Linfoma de Burkitt/complicações , Linfoma de Burkitt/patologia , Doenças do Sistema Nervoso Central/etiologia , Neoplasias do Sistema Nervoso Central/etiologia , Líquido Cefalorraquidiano/citologia , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/complicações , Feminino , Citometria de Fluxo , Humanos , L-Lactato Desidrogenase/sangue , Linfoma Difuso de Grandes Células B/líquido cefalorraquidiano , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/virologia , Linfoma não Hodgkin/complicações , Masculino , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Taxa de Sobrevida , Carga Tumoral
5.
Blood ; 138(4): 331-343, 2021 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-33684941

RESUMO

To identify the prognostic factors that are useful to improve central nervous system (CNS) control in children with acute lymphoblastic leukemia (ALL), we analyzed the outcome of 7640 consecutive patients treated on Chinese Children's Cancer Group ALL-2015 protocol between 2015 and 2019. This protocol featured prephase dexamethasone treatment before conventional remission induction and subsequent risk-directed therapy, including 16 to 22 triple intrathecal treatments, without prophylactic cranial irradiation. The 5-year event-free survival was 80.3% (95% confidence interval [CI], 78.9-81.7), and overall survival 91.1% (95% CI, 90.1-92.1). The cumulative risk of isolated CNS relapse was 1.9% (95% CI, 1.5-2.3), and any CNS relapse 2.7% (95% CI, 2.2-3.2). The isolated CNS relapse rate was significantly lower in patients with B-cell ALL (B-ALL) than in those with T-cell ALL (T-ALL) (1.6%; 95% CI, 1.2-2.0 vs 4.6%; 95% CI, 2.9-6.3; P < .001). Independent risk factors for isolated CNS relapse included male sex (hazard ratio [HR], 1.8; 95% CI, 1.1-3.0; P = .03), the presence of BCR-ABL1 fusion (HR, 3.8; 95% CI, 2.0-7.3; P < .001) in B-ALL, and presenting leukocyte count ≥50×109/L (HR, 4.3; 95% CI, 1.5-12.2; P = .007) in T-ALL. Significantly lower isolated CNS relapse was associated with the use of total intravenous anesthesia during intrathecal therapy (HR, 0.2; 95% CI, 0.04-0.7; P = .02) and flow cytometry examination of diagnostic cerebrospinal fluid (CSF) (HR, 0.2; 95% CI, 0.06-0.6; P = .006) among patients with B-ALL. Prephase dexamethasone treatment, delayed intrathecal therapy, use of total intravenous anesthesia during intrathecal therapy, and flow cytometry examination of diagnostic CSF may improve CNS control in childhood ALL. This trial was registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-14005706).


Assuntos
Neoplasias do Sistema Nervoso Central , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Fatores Etários , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/terapia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Fatores de Risco , Fatores Sexuais , Taxa de Sobrevida
6.
Cell Rep Med ; 2(12): 100470, 2021 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-35028611

RESUMO

Acute lymphoblastic leukemia (ALL) dissemination to the central nervous system (CNS) is a challenging clinical problem whose underlying mechanisms are poorly understood. Here, we show that primary human ALL samples injected into the femora of immunodeficient mice migrate to the skull and vertebral bone marrow and provoke bone lesions that enable passage into the subarachnoid space. Treatment of leukemia xenografted mice with a biologic antagonist of receptor activator of nuclear factor κB ligand (RANKL) blocks this entry route. In addition to erosion of cranial and vertebral bone, samples from individuals with B-ALL also penetrate the blood-cerebrospinal fluid barrier of recipient mice. Co-administration of C-X-C chemokine receptor 4 (CXCR4) and RANKL antagonists attenuate both identified routes of entry. Our findings suggest that targeted RANKL and CXCR4 pathway inhibitors could attenuate routes of leukemia blast CNS invasion and provide benefit for B-ALL-affected individuals.


Assuntos
Sistema Nervoso Central/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Animais , Crise Blástica/patologia , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/metabolismo , Rearranjo Gênico , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Camundongos Endogâmicos NOD , Modelos Biológicos , Proteína de Leucina Linfoide-Mieloide/metabolismo , Invasividade Neoplásica , Osteoprotegerina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Ligante RANK/antagonistas & inibidores , Ligante RANK/metabolismo , Receptores CXCR4/metabolismo , Coluna Vertebral/patologia , Espaço Subaracnóideo/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Pediatr Hematol Oncol ; 42(4): e202-e206, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31815886

RESUMO

BACKGROUND: Outcomes of childhood hematolymphoid malignancies have improved several fold because of immunosuppressive chemotherapy and broad-spectrum antibiotics for managing febrile neutropenia. An apparent trade-off has been an increase in invasive fungal disease (IFD), affecting multiple organs. We report the diagnostic and therapeutic challenges in 8 children with lymphoid cancers who developed intracranial (IC) fungal abscesses between 2010 and 2017. METHODS: Children below 15 years of age undergoing treatment for leukemia/lymphoma with clinicoradiologic and microbiologic evidence of IC fungal abscess were included. Demographic details, clinical profile, and management were retrospectively audited. Treatment was guided by European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions for IFD with therapeutic drug monitoring (TDM)-directed azole dosing, and surgical intervention. RESULTS: Eight patients (4 B-cell acute lymphoblastic leukemia, 2 relapsed B-cell acute lymphoblastic leukemia, and 2 non-Hodgkin lymphoma) were eligible for analysis. Proven, probable, and possible IFDs were seen in 2 (25%), 4 (50%), and 2 (25%) patients, respectively. Proven IFDs were invasive mucormycosis with remaining having mold infections. Cerebrospinal fluid galactomannan was positive in all 4 patients in whom it was tested. TDM was possible in 5/8 (63%) patients. Antifungal therapy was given for a median period of 4.2 months with 5 (63%) patients having complete resolution. Three (37%) patients expired, of which 2 were attributable to IFDs. CONCLUSIONS: IC fungal abscesses in children can cause significant morbidity and mortality in children with hematolymphoid cancers. Evaluation of cerebrospinal fluid galactomannan may help in early diagnosis and therapy. Prolonged antifungal therapy steered by TDM can help achieve resolution in some cases.


Assuntos
Antifúngicos/administração & dosagem , Infecções Fúngicas do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Mucormicose/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Adolescente , Antifúngicos/farmacocinética , Infecções Fúngicas do Sistema Nervoso Central/líquido cefalorraquidiano , Criança , Pré-Escolar , Feminino , Galactose/análogos & derivados , Humanos , Linfoma não Hodgkin/líquido cefalorraquidiano , Linfoma não Hodgkin/mortalidade , Masculino , Mananas/líquido cefalorraquidiano , Mucormicose/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Estudos Retrospectivos
8.
J Clin Oncol ; 35(22): 2527-2534, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28535084

RESUMO

Purpose To determine the prognostic significance of blasts, and of white and red blood cells, in CSF samples at diagnosis of acute lymphoblastic leukemia (ALL), a uniform CSF and risk group classification schema was incorporated into Children's Oncology Group B-cell ALL (B-ALL) clinical trials. Methods CSF status was designated as follows: CNS1, no blasts; CNS2a to 2c, < 5 WBCs/µL and blasts with/without ≥ 10 RBCs/µL or ≥ 5 WBCs/µL plus blasts, with WBCs ≥ 5 times the number of RBCs; CNS3a to 3c, ≥ 5 WBCs/µL plus blasts with/without ≥ 10 RBCs/µL or clinical signs of CNS disease. CNS2 status did not affect therapy; patients with CNS3 status received two extra intrathecal treatments during induction and augmented postinduction therapy with 18 Gy of cranial radiation. Results Among 8,379 evaluable patients enrolled from 2004 to 2010, 7,395 (88.3%) had CNS1 status; 857 (10.2%), CNS2; and 127 (1.5%), CNS3. The 5-year event-free and overall survival rates were, respectively, 85% and 92.7% for CNS1, 76% and 86.8% for CNS2, and 76% and 82.1% for CNS3 ( P < .001). In multivariable analysis that included age, race/ethnicity, initial WBC, and day-29 minimal residual disease < 0.1%, CSF blast, regardless of cell count, was an independent adverse predictor of outcome for patients with standard- or high-risk disease according to National Cancer Institute criteria. The EFS difference reflected a significant difference in the incidence of CNS, not marrow, relapse in patients with CNS1 versus CNS2 and/or CNS3 status. Conclusion Low levels of CNS leukemia, regardless of RBCs, predict inferior outcome and higher rates of CNS relapse. These data suggest that additional augmentation of CNS-directed therapy is warranted for CNS2 disease.


Assuntos
Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/administração & dosagem , Neoplasias do Sistema Nervoso Central/classificação , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/terapia , Líquido Cefalorraquidiano/citologia , Criança , Ensaios Clínicos como Assunto , Irradiação Craniana , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Contagem de Eritrócitos , Feminino , Humanos , Leucovorina/administração & dosagem , Contagem de Leucócitos , Masculino , Metotrexato/administração & dosagem , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prednisona/administração & dosagem , Fatores de Risco , Taxa de Sobrevida
9.
Pediatr Hematol Oncol ; 33(3): 151-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27110933

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although curable, approximately 20% of patients relapse. In an effort to detect relapse earlier, our institution performed surveillance bone marrow (BM) and cerebrospinal fluid (CSF) evaluations every 3 months from the end of therapy to 1 year off. This study retrospectively reviewed all patients with B-cell ALL (B-ALL) from September 2005 to September 2010 to determine the benefit and cost of these procedures. Forty-one patients completed therapy and had 190 BMs and 190 lumbar punctures (LPs) performed. Four of 41 patients (9.8%) experienced a relapse. Relapse was detected in only 1 patient by routine BM evaluation (0.5%). Zero LPs were positive. The professional fees for the procedures were $8,738/patient. Therefore, off-therapy BM and CSF evaluations are not effective at detecting relapse and are expensive. Our institution has abandoned off-therapy surveillance for ALL.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Adolescente , Exame de Medula Óssea , Criança , Pré-Escolar , Feminino , Custos de Cuidados de Saúde , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Recidiva
10.
Am J Clin Pathol ; 135(1): 22-34, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21173121

RESUMO

Flow cytometric immunophenotyping (FCI) is recommended in the evaluation of cerebrospinal fluid (CSF) specimens for hematologic neoplasms. This study reviewed FCI of CSF specimens collected for primary diagnosis (n = 77) and follow-up for known malignancy (n = 153). FCI was positive in 11 (4.8%) of 230 specimens: acute myeloid leukemia, 6; precursor B-acute lymphoblastic leukemia, 2; B-cell lymphoma, 2; and T-cell lymphoma, 1. Positive results were obtained in low-cellularity specimens, including 2 with fewer than 100 events in the population of interest. FCI was indeterminate in 19 (8.3%) of 230 specimens, including 3 with only sparse events, 8 with possible artifact (apparent lack of staining, nonspecific or background staining, and aspirated air), and 8 with phenotypic findings considered insufficient for diagnosis. Indeterminate specimens were often limited by low cellularity and lacked normal cell populations to evaluate for appropriate staining. FCI may be of value in low-cellularity CSF specimens, although the results should be interpreted with caution.


Assuntos
Líquido Cefalorraquidiano/imunologia , Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Leucemia Mieloide Aguda/diagnóstico , Linfoma de Células B/diagnóstico , Linfoma de Células T/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Doença Aguda , Humanos , Leucemia Mieloide Aguda/líquido cefalorraquidiano , Leucemia Mieloide Aguda/imunologia , Linfoma de Células B/líquido cefalorraquidiano , Linfoma de Células B/imunologia , Linfoma de Células T/líquido cefalorraquidiano , Linfoma de Células T/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia
11.
J Pediatr Hematol Oncol ; 31(5): 352-4, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19415018

RESUMO

A 10-year-old girl who presented to our hospital was diagnosed as having B-precursor cell acute lymphoblastic leukemia. St Jude's Total XIII protocol was started. In the second block of the consolidation phase, 10 hours after triple intrathecal treatment, we realized that instead of 12 mg, 120 mg of methotrexate had accidentally been given. Although the patient had no symptoms 10 hours after intrathecal treatment, to prevent the possible neurotoxic effects of methotrexate, a cerebrospinal fluid exchange was performed. Simultaneously, systemic dexamethasone and calcium folinic acid were given. At the time of this writing (2 y), the patient has had no symptoms and has continued on the chemotherapy protocol as planned. Administration of high-dose intrathecal methotrexate may not lead to symptoms, as was the case in our patient. This may be related to individual variations in cerebrospinal fluid dynamics and drug metabolism.


Assuntos
Antimetabólitos Antineoplásicos/intoxicação , Metotrexato/intoxicação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/líquido cefalorraquidiano , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Líquido Cefalorraquidiano , Criança , Citarabina/administração & dosagem , Overdose de Drogas/terapia , Feminino , Humanos , Injeções Espinhais , Metotrexato/administração & dosagem , Metotrexato/líquido cefalorraquidiano , Prednisolona/administração & dosagem
12.
Pediatr Blood Cancer ; 42(4): 350-6, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-14966832

RESUMO

BACKGROUND: The activity of lysosomal enzymes is increased in body fluids during inflammation, in which cellular malfunction and cellular death occurs. Because chemotherapy also causes cell malfunction and death, for identifying a neurologic effect, we studied the activity of beta-glucuronidase in the cerebrospinal fluid (CSF) of leukemic children during treatment. PROCEDURE: The beta-glucuronidase activity in CSF was determined in 13 patients with B-precursor acute lymphoblastic leukemia (ALL) treated with the medium risk arm of ALL Berlin-Frankfurt-Munster (BFM) 95 protocol. Plasma methotrexate (MTX) levels were determined at 24 and 48 hr after the infusion of high-dose (5 g/m(2)/24 hr) MTX (MCA phase). RESULTS: The mean (SD) beta-glucuronidase activity prior to the onset of chemotherapy was 19.9 (5.6) nmoles/4-methylumbelliferone/ml/hr. No significant changes in activity were noted during the phases of the protocol except of the MCA3. The activity was 24.4 (6.8) on MCA2, 28.4 (9.3) on MCA3, and 24.1 (9.5) on MCA4. The beta-glucuronidase activity was positively correlated with the plasma MTX levels at both 24 hr (r = 0.483, P = 0.006) and 48 hr (r = 0.676, P < 0.0001). No progressive changes were noted during the different phases of the protocol. The greatest beta-glucuronidase activity was measured in two patients with neurotoxicity. CONCLUSIONS: The beta-glucuronidase activity is increased in the CSF of leukemic children receiving high-dose MTX and particularly in neurotoxicity. It is positively correlated with plasma MTX levels. No cumulative effect of the chemotherapy was observed. The increased beta-glucuronidase activity is most likely due to enzyme leakage through the cell membranes caused mainly by a toxic effect of MTX on the cells of the central nervous system (CNS).


Assuntos
Glucuronidase/líquido cefalorraquidiano , Metotrexato/administração & dosagem , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Biomarcadores/líquido cefalorraquidiano , Criança , Pré-Escolar , Ensaios Enzimáticos Clínicos , Feminino , Humanos , Lactente , Inflamação/induzido quimicamente , Modelos Lineares , Masculino , Metotrexato/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
14.
Leukemia ; 7(8): 1294-9, 1993 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8350631

RESUMO

In B-precursor acute lymphoblastic leukemia (ALL), the nucleotide sequence of the complementarity determining region III (CDRIII) in the rearranged immunoglobulin heavy chain gene (IgH) has been used as a molecular fingerprint to identify the leukemic cells. In a child with B-precursor ALL without central nervous system (CNS) disease at diagnosis and a subsequent isolated CNS relapse, we examined the stability of the rearranged IgH by comparing the nucleotide sequences of the CDRIII in the leukemic cells from the marrow at diagnosis to the sequences in the leukemic cells from the cerebrospinal fluid at relapse. Whereas two of the three IgH sequences isolated from the leukemic cells at CNS relapse were identical to sequences originally isolated from the marrow lymphoblasts at diagnosis, the third CNS sequence was similar but not identical to the third marrow sequence. The third IgH sequence identified in the CNS differed from the marrow sequence only at the variable gene segment adjoining the CDRIII. Using a detection method based on the polymerase chain reaction, the altered IgH sequence identified in the leukemic cells from the cerebrospinal fluid was noted to be present in the CNS at a higher frequency than the related diagnostic sequence and was not detected in the marrow either at diagnosis or at CNS relapse. These findings indicate that the clonal pattern of leukemia in the CNS may differ from that in the marrow.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Sequência de Bases , Biomarcadores Tumorais/genética , Medula Óssea/metabolismo , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/imunologia , Criança , Feminino , Humanos , Região Variável de Imunoglobulina/genética , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Recidiva
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