RESUMEN
INTRODUCTION: MEFV is the gene responsible for familial Mediterranean fever. It encodes pyrin, which controls inflammation. Besides, previous studies have reported that some germline MEFV variants were associated with tumour susceptibility. MATERIALS AND METHODS: The loci of 12 germline MEFV variants were genotyped in 153 Japanese children with cancer, and the frequencies of these variants among the patient groups were compared with those in the general Japanese population. Additionally, the relationship between these variants and clinical data, including relapse and death, was investigated. RESULTS: Minor allele frequencies did not differ between patients and the general population, or between sex, age at diagnosis, and diagnosis among patients. P369S/R408Q associated with significantly lower relapse-free survival in all patient analyses and in patients with solid tumours. Additionally, although the results were not significant, E148Q/L110P was likely to associate with worse relapse-free survival in patients with solid tumours. DISCUSSION/CONCLUSION: Despite several limitations, this study provided the novel insight that the germline MEFV variants are associated with the clinical outcome of paediatric cancer.
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Proteínas del Citoesqueleto , Neoplasias , Niño , Proteínas del Citoesqueleto/genética , Predisposición Genética a la Enfermedad , Células Germinativas , Humanos , Japón/epidemiología , Mutación , Neoplasias/genética , Pronóstico , Pirina/genéticaRESUMEN
BACKGROUND: Clonal evolution of malignancy is a complex process related to intratumoral heterogeneity, as recent studies have also demonstrated in rhabdomyosarcoma. The purpose of this study is to present a distinct clonal feature of a case with anaplastic embryonal type rhabdomyosarcoma (ERMS) using molecular analysis. METHODS: A five-year-old girl developed a metastatic pelvic tumor. We cultured neoplastic cells isolated from the biopsy sample. Next, to characterize the current case, we analyzed the biopsy sample, autopsy sample, and established cell line using combined modalities, including histopathological, cytogenetic, and molecular assay. We also undertook the backtrack mutation-specific polymerase chain reaction to reveal clonal composition. RESULTS: The histology of the biopsy sample was consistent with ERMS with focal anaplasia. We established a permanently growing cell line, ICH-ERMS-1, from the biopsy sample. On molecular analysis, the biopsied tissue revealed a missense mutation at codon 245 of TP53. In contrast, the autopsy tumor tissue and the cell line established from the biopsied tissue showed a missense mutation at codon 248. A backtrack study using mutation-specific polymerase chain reaction detected a TP53 codon 248 mutation in the original biopsy sample. All the specimens examined had a missense mutation at PTPN11 codon 69. CONCLUSIONS: This study highlights intratumoral heterogeneity and distinct clonal change related to the functional context in our anaplastic ERMS case, supporting the concept of intratumoral heterogeneity and clonal evolution. It requires further case collection to reveal whether p14ARF-p53-MDM2 tumor suppressor pathway alteration, considered a late event in ERMS tumorigenesis, is responsible for anaplasia in ERMS.
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Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Preescolar , Evolución Clonal , Femenino , Humanos , Mutación , Reacción en Cadena de la Polimerasa , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma Embrionario/genéticaRESUMEN
We present two infants with KMT2A(MLL)-gene-R-associated BCP-ALL, who received HLA haploidentical PBSCT after RIC. The patients developed ALL at age 6 months and 3 months, respectively. Case 1 underwent PBSCT at the second CR with detectable KMT2A-AFF1(MLL-AF4) fusion gene transcript at 11 months of age, and Case 2 at the first CR without KMT2A-MLLT1(MLL-ENL) fusion gene transcript at 8 months of age. Both patients received G-CSF-mobilized unmanipulated peripheral blood mononuclear cells from their HLA haploidentical mothers after administration of FLU, MEL, and ATG. Tacrolimus, methotrexate, and mPSL were administered as prophylaxis against GVHD. Engraftment was rapidly obtained with complete chimerism in both patients. Acute adverse events included acute GVHD in Case 1 and bacterial sepsis in Case 2. At last clinical check at age 5 years and 4 years, respectively, both patients were recurrence-free and attained normal growth and development. We conclude that PBSCT from an HLA haploidentical mother with non-TBI and non-BU regimen seems feasible and efficacious, offering favorable life quality for infants.
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Trasplante de Células Madre de Sangre Periférica/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico , Biomarcadores de Tumor/genética , Femenino , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Lactante , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genéticaAsunto(s)
Anomalías Múltiples , Anemia Perniciosa , Enfermedades Hematológicas , Enfermedades Vestibulares , Anomalías Múltiples/diagnóstico , Anemia Perniciosa/complicaciones , Anemia Perniciosa/diagnóstico , Cara/anomalías , Enfermedades Hematológicas/complicaciones , Enfermedades Hematológicas/diagnóstico , Humanos , Mutación , Fenotipo , Enfermedades Vestibulares/complicaciones , Enfermedades Vestibulares/diagnósticoRESUMEN
The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.
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Antimetabolitos Antineoplásicos/administración & dosificación , Genotipo , Mercaptopurina/administración & dosificación , Farmacogenética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genética , Adolescente , Factores de Edad , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Niño , Preescolar , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Metiltransferasas/genética , Polimorfismo GenéticoRESUMEN
The 2008 World Health Organization classification proposed a new entity in childhood myelodysplastic syndrome, refractory cytopenia of childhood. However, it is unclear whether this morphological classification reflects clinical outcomes. We retrospectively reviewed bone marrow morphology in 186 children (median age 8 years; range 1-16 years) who were enrolled in the prospective study and received horse antithymocyte globulin and cyclosporine between July 1999 and November 2008. The median follow-up period was 87 months (range 1-146 months). Out of 186 patients, 62 (33%) were classified with aplastic anemia, 94 (49%) with refractory cytopenia of childhood, and 34 (18%) with refractory cytopenia with multilineage dysplasia. Aplastic anemia patients received granulocyte colony-stimulating factor more frequently and for longer durations than other patients (P<0.01). After six months, response rates to immunosuppressive therapy were not significantly different among the 3 groups. Acquisition of chromosomal abnormalities was observed in 5 patients with aplastic anemia, 4 patients with refractory cytopenia of childhood, and 3 patients with refractory cytopenia with multilineage dysplasia. Although the cumulative incidence of total clonal evolution at ten years was not significantly different among the 3 groups, the cumulative incidence of monosomy 7 development was significantly higher in aplastic anemia than in the other groups (P=0.02). Multivariate analysis revealed that only granulocyte colony-stimulating factor administration duration of 40 days or more was a significant risk factor for monosomy 7 development (P=0.02). These findings suggest that even the introduction of a strict morphological distinction from hypoplastic myelodysplastic syndrome cannot eradicate clonal evolution in children with aplastic anemia.
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Anemia Aplásica , Suero Antilinfocítico/administración & dosificación , Deleción Cromosómica , Trastornos de los Cromosomas , Ciclosporina/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Anemia Aplásica/sangre , Anemia Aplásica/complicaciones , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/patología , Niño , Preescolar , Trastornos de los Cromosomas/sangre , Trastornos de los Cromosomas/etiología , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 7 , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/patología , Masculino , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/patología , Estudios ProspectivosRESUMEN
Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by subepidermal blisters due to deposit of autoantibody against dermal basement membrane protein. It has been reported that BP can occur after allogeneic hematopoietic stem cell transplantation (HSCT). We describe a patient with BP having autoantibody against BP180 after unrelated-donor HSCT against T lymphoblastic leukemia. The patient was treated with steroid leading to complete resolution of BP, but T lymphoblastic leukemia progressed rapidly after steroid hormone treatment. Given that immunosuppressant may reduce graft-versus-tumor effect, immunomodulatory agents such as nicotinamide and tetracycline, erythromycin, and immunoglobulin may be appropriate as soon as typical blister lesions are seen after HSCT.
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Trasplante de Células Madre Hematopoyéticas/efectos adversos , Penfigoide Ampolloso/etiología , Piel/patología , Adolescente , Humanos , Leucemia de Células T/terapia , Masculino , Penfigoide Ampolloso/diagnósticoRESUMEN
BACKGROUND: Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment-related toxicity, and be used individually in dose modification of 6-mercaptopurine (6-MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients. METHODS: Fifty-three children who received maintenance chemotherapy were enrolled in this study. The scheduled dose of oral 6-MP was 40 mg/m(2) daily and that of oral MTX was 25 mg/m(2) weekly. The doses were adjusted according to white blood cell count (target range, 2.5-3.5 × 10(9) /L) and aspartate aminotransferase and alanine aminotransferase level (< 750 IU/L). Eight polymorphisms in six candidate genes, TPMT, ITPA, MRP4, MTHFR, RFC1, and SLCO1B1, were genotyped using the Taqman PCR method. Clinical course was reviewed retrospectively from medical records. RESULTS: The average dose of 6-MP was lower in the patients with at least one variant allele at SLCO1B1 c.521 T > C than in the patients with wild homozygous genotype. The other analyzed polymorphisms were not associated with toxicity, 6-MP, or MTX dose. CONCLUSIONS: Polymorphism of SLCO1B1 c.521 T > C could be a strong predictor of 6-MP dose reduction in maintenance chemotherapy in childhood ALL.
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Antineoplásicos/administración & dosificación , ADN de Neoplasias/genética , Leucemia/tratamiento farmacológico , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Quimioterapia de Mantención/métodos , Polimorfismo Genético , Adolescente , Alelos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Lactante , Leucemia/genética , Leucemia/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Estudios Retrospectivos , Factores de TiempoRESUMEN
Juvenile myelomonocytic leukaemia (JMML) is a rare haematopoietic stem cell disease of early childhood, which can progress to blast crisis in some children. A total of 153 children diagnosed with JMML were reported to the Myelodysplastic Syndrome Committee in Japan between 1989 and 2007; 15 of them (9·8%) had 20% or more blasts in the bone marrow (blast crisis) during the disease course. Blast crisis occurred during observation without therapy (n = 3) or with oral 6-mercaptopurine treatment (n = 9) and in relapse after haematopoietic stem cell transplantation (HSCT; n = 3). Six patients had a complex karyotype (5 including monosomy 7) and an additional three patients had isolated monosomy 7 at blast crisis. Seven patients received HSCT after blast crisis and four of them achieved remission. Eleven out of the 15 patients died; the cause of death was disease progression in 10 patients and transplant-related complication in one patient. In summary, patients with blast crisis have poor prognosis and can be cured only by HSCT. The emergence of monosomy 7 and complex karyotype may be characteristic of blast crisis in a substantial subset of children.
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Crisis Blástica/terapia , Leucemia Mielomonocítica Juvenil/patología , Crisis Blástica/genética , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 7 , Progresión de la Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Cariotipo , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/terapia , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
This study analysed 65 children who were prospectively registered between 1999 and 2008 and fulfilled the World Health Organization 2008 criteria of refractory cytopenia of childhood (RCC). First-line therapy was determined by the treating physicians: 25 patients received immunosuppressive therapy (IST), 12 patients received haematopoietic stem cell transplantation (HSCT) and one patient received intensive chemotherapy. The remaining 27 patients were followed without treatment for more than 2 years (watch and wait; WW). In the WW group, 18 patients had stable disease without further intervention. Thirteen of 29 patients (45%) who ended up receiving IST showed response. The combination of ciclosporin and antithymocyte globulin was not shown to be superior to ciclosporin alone with regard to response rate or survival. Of 28 patients who ended up undergoing HSCT, 17 patients are alive in complete remission, whereas nine patients died mostly due to transplantation-related mortality. The 5-year overall survival for all patients was 82 ± 5%. Eight patients suffered from disease progression. Patients with monosomy 7 or multilineage-dysplasia had a significantly higher incidence of disease progression. This analysis revealed heterogeneity in the clinical course of RCC, varying from those who remained stable for long periods to those who progressed to advanced disease.
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Trasplante de Células Madre Hematopoyéticas/métodos , Síndromes Mielodisplásicos/terapia , Pancitopenia/terapia , Adolescente , Suero Antilinfocítico/uso terapéutico , Niño , Preescolar , Ciclosporina/uso terapéutico , Progresión de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Resultado del Tratamiento , Organización Mundial de la SaludRESUMEN
With improvement in survival, it is important to evaluate the impact of treatment on secondary cancers in acute lymphoblastic leukaemia (ALL) survivors. A retrospective cohort study comprising 2918 children diagnosed with ALL and enrolled on Tokyo Children's Cancer Study Group (TCCSG) protocols between 1984 and 2005 was conducted to evaluate the incidence of secondary cancers and associated factors including treatment protocol, cranial irradiation and other characteristics of the primary ALL. Thirty-seven patients developed secondary cancers, including acute myeloid leukaemia (n = 11), myelodysplastic syndrome (n = 5), non-Hodgkin lymphoma (n = 2), brain tumours (n = 13) and other solid carcinomas (n = 6) within a median follow-up duration of 9·5 years. The cumulative incidence of any secondary cancers was 1·0% (95% confidence interval (CI), 0·7-1·4%) at 10 years and 2·4% (95% CI, 1·5-3·7%) at 20 years, respectively. Standardized incidence rate ratio of secondary cancers was 9·3 (95% CI, 6·5-12·8). Multivariate analyses showed an increased risk of secondary cancers associated with the recent treatment protocol and cranial irradiation. There was no evidence of a reduction in secondary cancer incidence despite marked decreases in cranial irradiation use in the recent protocols.
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Neoplasias Primarias Secundarias/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioradioterapia , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Incidencia , Lactante , Masculino , Neoplasias Primarias Secundarias/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Tokio/epidemiologíaRESUMEN
The Tokyo Children's Cancer Study Group conducted a randomized controlled study to evaluate the effect of experimental early intensification using high-dose cytarabine and L-asparaginase in paediatric intermediate-risk (IR) acute lymphoblastic leukaemia (ALL). A total of 310 IR ALL patients were randomized to receive either experimental early intensification (n = 156) or standard early intensification including standard-dose cytarabine arm (n = 154) after induction therapy. The experimental arm consisted of high-dose cytarabine and L-asparaginase, while the standard arm consisted of standard-dose cytarabine, oral 6-mercaptopurine and cyclophosphamide. The probabilities of event-free survival at 8 years in the experimental and standard arms were 72·3 ± 3·7% and 77·5 ± 3·5%, respectively (P = 0·32). The 8-year overall survival rates for these two arms were 85·0 ± 3·0% and 86·9 ± 2·8%, respectively (P = 0·72). The frequency of infectious events was significantly higher in the experimental arm (66·4%) than in the standard arm (24·6%) (P < 0·001). In conclusion, experimental early intensification including high-dose cytarabine followed by L-asparaginase had no advantage over standard early intensification in paediatric IR ALL patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Asparaginasa/administración & dosificación , Niño , Preescolar , Citarabina/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Masculino , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The aim of this study was to prospectively evaluate the PK and safety of ivBU in 25 Japanese children (median age six yr; range, five months-17 yr) as one of a combination of drugs in a pretransplant regimen. The patients had acute leukemia (n = 14), CML (2), JMML (5), solid tumors (2), chronic granulomatous disease (1), or metachromatic leukodystrophy (1). Five different dose schedules were used according to the patient's ABW: <9 kg (1.0 mg/kg), 9 to <16 (1.2 mg/kg), 16-23 (1.1 mg/kg), >23-34 (0.95 mg/kg), and >34 kg of BW (0.8 mg/kg). Each dose was given over two h, and sample blood was drawn at nine or 11 separate points for analysis by gas chromatography-mass spectrometry. The AUC varied from 796 to 1905 µmol min/L, and 19 of the 25 patients (76%) remained within the target range without dose adjustment. Two were diagnosed with engraftment failure. Hepatic VOD developed in four, and only one of these showed high AUC (>1500 µmol min/L). Toxicities did not correlate with the BU level. Our data showed very similar PK to those in previous studies, and these dose schedules are applicable to Japanese children.
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Busulfano/farmacocinética , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Adolescente , Área Bajo la Curva , Pueblo Asiatico , Busulfano/administración & dosificación , Niño , Preescolar , Femenino , Cromatografía de Gases y Espectrometría de Masas , Enfermedad Injerto contra Huésped , Humanos , Lactante , Infusiones Intravenosas , Japón , Masculino , Agonistas Mieloablativos/farmacocinética , Estudios Prospectivos , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: The pain associated with bone marrow aspiration and biopsy (BMAB) has an enormous impact on pediatric cancer patients and their families, but no specific reference standards for sedation and analgesia have been developed in Japan. To determine the problems associated with pain management during BMAB, a cross-sectional investigation was conducted. METHODS: A survey was sent in October 2011 to data managers in institutions belonging to the Tokyo Children's Cancer Study Group, addressing the non-pharmacological and pharmacological pain management for BMAB performed on pediatric cancer inpatients between January 2010 and December 2010. RESULTS: The eligible response rate was 41 of 57 institutions (71.9%). Non-pharmacological pain intervention was provided in 68% of surveyed institutions. All institutions provided pharmacological pain management. In most institutions, sedation/analgesia was performed by pediatric oncologists in a treatment room in the ward. Standards for pain management were developed and utilized in only four institutions. Other means of pain management were provided in various settings. Twelve institutions reported insufficient sedation/analgesia. In total, 80% of institutions reported some adverse events. Two serious adverse events were reported in cases of underlying or complicated conditions. No serious long-term consequences were reported. CONCLUSIONS: Significant issues were identified regarding the efficacy and safety of pain management. Adverse events can occur in any institution. Children with underlying or complicated conditions are at high risk for serious adverse events. Therefore, adequate and systematic assessment, patient monitoring, preparation and treatment for adverse events, and cooperation with skilled specialists of pediatric oncology, anesthesiology, and intensive care are essential.
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Examen de la Médula Ósea , Neoplasias/complicaciones , Manejo del Dolor/métodos , Biopsia con Aguja , Preescolar , Estudios Transversales , HumanosRESUMEN
The cryptic t(5;11)(q35;p15.5) creates a fusion gene between the NUP98 and NSD1 genes. To ascertain the significance of this gene fusion, we explored its frequency, clinical impact, and gene expression pattern using DNA microarray in pediatric acute myeloid leukemia (AML) patients. NUP98-NSD1 fusion transcripts were detected in 6 (4.8%) of 124 pediatric AML patients. Supervised hierarchical clustering analyses using probe sets that were differentially expressed in these patients detected a characteristic gene expression pattern, including 18 NUP98-NSD1-negative patients (NUP98-NSD1-like patients). In total, a NUP98-NSD1-related gene expression signature (NUP98-NSD1 signature) was found in 19% (24/124) and in 58% (15/26) of cytogenetically normal cases. Their 4-year overall survival (OS) and event-free survival (EFS) were poor (33.3% in NUP98-NSD1-positive and 38.9% in NUP98-NSD1-like patients) compared with 100 NUP98-NSD1 signature-negative patients (4-year OS: 86.0%, 4-year EFS: 72.0%). Interestingly, t(7;11)(p15;p15)/NUP98-HOXA13, t(6;11)(q27;q23)/MLL-MLLT4 and t(6;9)(p22;q34)/DEK-NUP214, which are known as poor prognostic markers, were found in NUP98-NSD1-like patients. Furthermore, another type of NUP98-NSD1 fusion transcript was identified by additional RT-PCR analyses using other primers in a NUP98-NSD1-like patient, revealing the significance of this signature to detect NUP98-NSD1 gene fusions and to identify a new poor prognostic subgroup in AML.
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Regulación Neoplásica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética/genética , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 5/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Proteínas de Homeodominio , Humanos , Leucemia Mieloide Aguda/patología , Masculino , PronósticoRESUMEN
The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF-TP53-MDM2 pathway and amplification of MDM2 and CDK4.
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Amplificación de Genes , Proteína Proto-Oncogénica N-Myc , Neuroblastoma , Proteínas Proto-Oncogénicas c-mdm2 , Humanos , Neuroblastoma/genética , Neuroblastoma/patología , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Femenino , Niño , Amplificación de Genes/genética , Línea Celular Tumoral , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Telómero/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Homeostasis del Telómero/genéticaRESUMEN
We retrospectively analyzed the effect of HLA mismatching (HLA-A, -B, -C, -DRB1, -DQB1) with molecular typing on transplantation outcome for 301 patients with acquired severe aplastic anemia (SAA) who received an unrelated BM transplant through the Japan Marrow Donor Program. Additional effect of HLA-DPB1 mismatching was analyzed for 10 of 10 or 9 of 10 HLA allele-matched pairs (n = 169). Of the 301 recipient/donor pairs, 101 (33.6%) were completely matched at 10 of 10 alleles, 69 (23%) were mismatched at 1 allele, and 131 (43.5%) were mismatched at ≥ 2 alleles. Subjects were classified into 5 subgroups: complete match group (group I); single-allele mismatch group (groups II and III); multiple alleles restricted to HLA-C, -DRB1, and -DQB1 mismatch group (group IV); and others (group V). Multivariate analysis indicated that only HLA disparity of group V was a significant risk factor for poor survival and grade II-IV acute GVHD. HLA-DPB1 mismatching was not associated with any clinical outcome. We recommend the use of an HLA 10 of 10 allele-matched unrelated donor. However, if such a donor is not available, any single-allele or multiple-allele (HLA-C, -DRB1, -DQB1) mismatched donor is acceptable as an unrelated donor for patients with severe aplastic anemia.
Asunto(s)
Anemia Aplásica/terapia , Trasplante de Médula Ósea/inmunología , Antígenos HLA/inmunología , Prueba de Histocompatibilidad , Donantes de Tejidos , Adolescente , Adulto , Anemia Aplásica/inmunología , Anemia Aplásica/mortalidad , Trasplante de Médula Ósea/mortalidad , Trasplante de Médula Ósea/normas , Niño , Preescolar , Femenino , Cadenas beta de HLA-DP/genética , Cadenas beta de HLA-DP/inmunología , Prueba de Histocompatibilidad/normas , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Tipificación Molecular , Índice de Severidad de la Enfermedad , Relaciones entre Hermanos , Adulto JovenRESUMEN
Recent advances in unrelated cord blood transplantation (UCBT) and high-resolution typing of human leukocyte antigen (HLA) from an unrelated donor have increased choices in alternative donor/stem cell source selection. We assessed HLA-mismatched locus-specific comparison of the outcomes of 351 single-unit UCB and 1,028 unrelated bone marrow (UBM) adult recipients 16 years old or older at the time of transplantation who received first stem cell transplantation with myeloablative conditioning for acute leukemia or myelodysplastic syndromes. With adjusted analyses, HLA 0 to 2 mismatched UCBT showed similar overall mortality (relative risk [RR] = 0.85, 95% confidence interval [CI], 0.68-1.06; P = .149) compared with that of single-HLA-DRB1-mismatched UBMT. UCBT showed inferior neutrophil recovery (RR = 0.50, 95% CI, 0.42-0.60; P < .001), lower risk of acute graft-versus-host disease (RR = 0.55, 95% CI, 0.42-0.72; P < .001), and lower risk of transplantation-related mortality (RR = 0.68, 95% CI, 0.50-0.92; P = .011) compared with single-HLA-DRB1-mismatched UBMT. No significant difference was observed for risk of relapse (RR = 1.28, 95% CI, 0.93-1.76; P = .125). HLA 0 to 2 antigen-mismatched UCBT is a reasonable second alternative donor/stem cell source with a survival outcome similar to that of single-HLA-DRB1-mismatched or other 7 of 8 UBMT.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Antígenos HLA/inmunología , Leucemia/terapia , Síndromes Mielodisplásicos/terapia , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Trasplante de Médula Ósea , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Prueba de Histocompatibilidad , Humanos , Leucemia/inmunología , Leucemia/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Recurrencia , Factores de Riesgo , Donante no EmparentadoRESUMEN
Early T-cell precursor acute lymphoblastic leukaemia (ETP-ALL) is a recently identified subtype of T-ALL with distinctive gene expression and cell marker profiles, poor response to chemotherapy and a very high risk of relapse. We determined the reliability of restricted panel of cell markers to identify EPT-ALL using a previously classified cohort. Then, we applied the cell marker profile that best discriminated ETP-ALL to a cohort of 91 patients with T-ALL enrolled in the Tokyo Children's Cancer Study Group L99-15 study, which included allogeneic stem cell transplantation (allo-SCT) for patients with poor prednisone response. Five of the 91 patients (5·5%) met the ETP-ALL criteria. There were no significant differences in presenting clinical features between these and the remaining 86 patients. Response to early remission induction therapy was inferior in ETP-ALL as compared with T-ALL. The ETP-ALL subgroup showed a significantly poorer event-free survival (4-year rate; 40%) than the T-ALL subgroup (70%, P=0·014). Of note, three of four relapsed ETP-ALL patients survived after allo-SCT, indicating that allo-SCT can be effective for this drug-resistant subtype of T-ALL.