RESUMEN
BACKGROUND: The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. METHODS: A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. RESULTS: One hundred and twenty-eight patients (1.3 %) developed secondary cancers within a median follow-up of 8.4 years. The cumulative incidence rate was 1.1 % (95 % confidence interval [CI] 0.9-1.4) at 10 years and 2.6 % (95 % CI 2.1-3.3) at 20 years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n = 5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95 % CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95 % CI 1.53-9.47) for retinoblastoma, 2.78 (95 % CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95 % CI 1.16-2.83) for allogeneic stem cell transplantation. CONCLUSIONS: The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers.
Asunto(s)
Neoplasias Óseas/terapia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias de la Retina/terapia , Retinoblastoma/terapia , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Sobrevivientes/estadística & datos numéricos , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Japón , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Trasplante de Células Madre/estadística & datos numéricos , Encuestas y Cuestionarios , Tasa de Supervivencia , Factores de Tiempo , Trasplante Homólogo/estadística & datos numéricos , Adulto JovenRESUMEN
Myeloid leukemia in Down syndrome (ML-DS) is associated with good response to chemotherapy and favorable prognosis. Because little research has been focused on refractory/relapsed (R/R) cases, we conducted a retrospective analysis for R/R ML-DS. Among ML-DS patients diagnosed between 2000 and 2010 in Japan, 26 relapsed (25 in the BM and 1 in the skin), and 3 refractory patients were enrolled. The male/female ratio was 18/11. The median age at initial diagnosis of ML-DS was 2 years, and the median time to relapse was 8.6 months. Each patient initially had been treated with ML-DS-specific protocols. Thirteen of the 26 patients achieved complete remission with various kinds of reinduction chemotherapies; 2 of 8 survived without further recurrence after receiving allogeneic hematopoietic stem cell transplantation, and 4 of 5 maintained complete remissions with chemotherapy alone. Treatment failures mostly were associated with disease progression rather than treatment-related toxicities. The 3-year OS rate was 25.9% ± 8.5%. A longer duration from initial diagnosis to relapse was a significant favorable prognostic factor (P < .0001). We conclude that clinical outcome for patients with R/R ML-DS generally are unfavorable, even in those receiving hematopoietic stem cell transplantation. Novel methods to identify poor prognostic factors for ML-DS are necessary.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Síndrome de Down/complicaciones , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide/terapia , Adolescente , Niño , Preescolar , Terapia Combinada , Progresión de la Enfermedad , Síndrome de Down/genética , Resistencia a Antineoplásicos , Femenino , Factor de Transcripción GATA1/genética , Humanos , Lactante , Cariotipo , Leucemia Mieloide/complicaciones , Leucemia Mieloide/genética , Masculino , Análisis Multivariante , Mutación , Pronóstico , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Allogeneic hematopoietic stem cell transplantation (HSCT) has not been widely used in patients with acute myeloid leukemia (AML) and Down syndrome (DS) due to fear of transplantation-related toxicity. A retrospective analysis of the outcome of allogeneic HSCT was conducted in 15 patients with AML and DS. The five patients transplanted with the reduced intensity conditioning (4 in complete remission (CR) and 1 in non-CR) had a significantly better survival rate than 10 patients transplanted with a conventional conditioning (4 in CR and 6 in non-CR) (3-year EFS (95% confidence interval): 80.0% (20.4-96.9%) vs. 10.0% (0.6%-35.8%), P = 0.039).
Asunto(s)
Síndrome de Down/terapia , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/terapia , Acondicionamiento Pretrasplante , Adolescente , Niño , Preescolar , Síndrome de Down/mortalidad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Lactante , Recién Nacido , Leucemia Mieloide Aguda/mortalidad , Masculino , Recurrencia Local de Neoplasia/mortalidad , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
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.
Asunto(s)
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
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.
Asunto(s)
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
BACKGROUND: Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. PROCEDURE: This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. RESULT: Neutrophil recovery was faster after PBSCT than after BMT (ALL: P < 0.0001; AML: P = 0.0002), as was platelet recovery (ALL: P = 0.0008; AML: P = 0.0848). However, the cumulative incidence of chronic graft-versus-host disease (GvHD) was higher after PBSCT than after BMT (ALL: 26.0% vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P < 0.0001). The 5-year disease-free survival (DFS) was lower after PBSCT than after BMT for ALL (40.6% vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. CONCLUSION: PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/mortalidad , Leucemia Mieloide Aguda , Donadores Vivos , Trasplante de Células Madre de Sangre Periférica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Hermanos , Adolescente , Pueblo Asiatico , Niño , Preescolar , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Prueba de Histocompatibilidad , Humanos , Lactante , Recién Nacido , Japón , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Factores de Riesgo , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
In childhood acute promyelocytic leukaemia (APL), the efficacy of therapy combining cytarabine with all-trans retinoic acid (ATRA) and anthracyclines remains unclear in terms of long-term prognosis. Between August 1997 and March 2004, 58 children with APL (median age: 11 years) were enrolled into an acute myeloid leukaemia (AML) study (AML99-M3) and followed up for a median time of 86 months. The regimen included ATRA and anthracyclines combined with cytarabine in both induction and consolidation. In induction, two patients died of haemorrhage and four patients developed retinoic acid syndrome. Of 58 patients, 56 (96·6%) achieved complete remission, two of whom relapsed in the bone marrow after 15 and 19 months respectively. Sepsis was a major complication, with an incidence of 5·6-10·9% in the consolidation blocks, from which all but one of patients recovered. Consequently, 7-year overall and event-free survival rates were 93·1% and 91·4% respectively, and cumulative incidence of relapse plateaued at 3·6% after 2 years. Follow-up survey of 54 patients revealed no patients with late cardiotoxicity or secondary malignancy, except one with asymptomatic prolongation of QTc interval. This study suggests that the combination of cytarabine with ATRA and anthracycline-based therapy may have useful implications in the perspective of long-term prognosis and late adverse effects for childhood APL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Adolescente , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Aberraciones Cromosómicas , Citarabina/administración & dosificación , Citarabina/efectos adversos , Métodos Epidemiológicos , Femenino , Humanos , Lactante , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/genética , Recuento de Leucocitos , Masculino , Neoplasia Residual , Neutropenia/inducido químicamente , Pronóstico , Recurrencia , Resultado del Tratamiento , Tretinoina/administración & dosificación , Tretinoina/efectos adversosRESUMEN
BACKGROUND: A nationwide mass screening for neuroblastoma (NBL) in 6-month-old infants (MS6M) was performed in Japan from 1985 to 2003. Favorable biological features were identified for most of the detected tumors; consequently, we began an observation program for selected screened patients in 1993. Here, we report the clinicopathological findings and present status of patients enrolled in our observation program, with the goal of evaluating its usefulness. PROCEDURE: Between 1993 and 2003, 53 of 101 patients with NBL detected by MS6M were enrolled. The patients were divided into four groups according to changes in urinary VMA and HVA levels and tumor size. RESULTS: Urinary VMA and HVA levels decreased in 39 of 53 patients. In 17 of these 39 patients, the tumor became undetectable (Group A); in 22 patients the tumor was detectable (Group B). In seven patients, tumor marker levels varied, and tumor volume gradually increased (Group C). In six patients, tumor marker levels and tumor volume increased in the short term (Group D). One patient had multiple tumors (1M according to International Neuroblastoma Staging System). All tumors in Groups C and D, four tumors in Group B, and one tumor in the 1M patient were removed. No unfavorable biologic factors were noted in any excised tumor. CONCLUSIONS: The observation program of the present study, one of the largest series for MS6M, confirmed that over 70% of patients who fulfilled the criteria could be observed without surgery.
Asunto(s)
Biomarcadores de Tumor/orina , Tamizaje Masivo , Regresión Neoplásica Espontánea , Neuroblastoma/patología , Antineoplásicos/uso terapéutico , Terapia Combinada , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Ácido Homovanílico/orina , Humanos , Lactante , Masculino , Estadificación de Neoplasias , Neuroblastoma/terapia , Neuroblastoma/orina , Procedimientos NeuroquirúrgicosRESUMEN
Tacrolimus (FK) and cyclosporine (CsA) have been shown to be effective in the prophylaxis of graft-versus-host disease (GVHD). However, no comparative studies have yet been conducted to examine the efficacy of FK/methotrexate (MTX) and CsA/MTX in patients with severe aplastic anemia (SAA) given unrelated donor bone marrow transplantation (U-BMT). We used matched-pair analysis to compare FK/MTX with CsA/MTX in patients with SAA who received U-BMT through the Japan Marrow Donor Program. Forty-seven pairs could be matched exactly for recipient age and conditioning regimens. Forty-five patients achieved engraftment in the FK group and 42 patients in the CsA group. The probability of grade II-IV acute GVHD (aGVHD) was 28.9% in the FK group and 32.6% in the CsA group (P=.558). The probability of chronic GVHD (cGVHD) was 13.3% in the FK group and 36.0% in the CsA group (P=.104). The 5-year survival rate was 82.8% in the FK group and 49.5% in the CsA group (P=.012). The study shows the superiority of FK/MTX over CsA/MTX in overall survival because of the lower incidence of transplantation-related deaths. A prospective randomized study comparing FK/MTX and CsA/MTX is warranted.
Asunto(s)
Anemia Aplásica/cirugía , Trasplante de Médula Ósea/métodos , Ciclosporina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Tacrolimus/uso terapéutico , Trasplante de Médula Ósea/inmunología , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/inmunología , Humanos , Masculino , Análisis por Apareamiento , Tasa de Supervivencia , Donantes de TejidosRESUMEN
Non-T-cell-depleted HLA-haploidentical hematopoietic stem cell transplantation (SCT) from family members has been reported, but its effectiveness and safety are not fully known. In this study, we examined the outcomes of 83 children and adolescents with nonmalignant (n = 11) or malignant (n = 72) disorders who underwent SCT mismatched at 2 or 3 HLA loci, either from the mother (n = 56), a noninherited maternal antigen (NIMA)-mismatched sibling (n = 14), or the father/a noninherited paternal antigen (NIPA)-mismatched sibling (n = 13). Engraftment was satisfactory. Severe (grade III-IV) acute graft-versushost disease (GVHD) was noted only in malignant disease, with an incidence of 21 of 64 evaluable patients. GVHD prophylaxis with a combination of tacrolimus and methotrexate was significantly associated with a lower risk of severe acute GVHD, compared with other types of prophylaxis (P = .04). Nine of 11 patients with nonmalignant disease and 29 of 72 patients with malignant disease were alive at a median follow-up of 26 months (range, 4-57 months). Outcomes were not significantly different among the 3 donor groups (mother versus NIMA-mismatched sibling versus father/NIPA-mismatched sibling) for the malignancy disorders. Our results indicate that non-T-cell-depleted HLA-haploidentical SCT may be feasible, with appropriate GVHD prophylaxis, for young recipients who lack immediate access to a conventional stem cell source.
Asunto(s)
Quimerismo , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Tacrolimus/uso terapéutico , Adolescente , Trasplante de Médula Ósea/métodos , Niño , Preescolar , Quimioterapia Combinada , Enfermedades Genéticas Congénitas/terapia , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Estimación de Kaplan-Meier , Trasplante de Células Madre de Sangre Periférica/métodos , Estudios Retrospectivos , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Neuroblastoma undergoes spontaneous regression frequently during its natural course. Although programmed cell death (PCD) has been implicated in this process, accumulating evidence suggests that apoptosis, a form of PCD that is regulated by caspases, may not play a major role. We examined the mechanism(s) of spontaneous regression of neuroblastoma, focusing on the role of Ras, a favorable prognostic marker of neuroblastoma. METHODS: Tumor tissues were analyzed by light microscopy, electron microscopy, and immunohistochemistry to examine cell degeneration and expression of Ras and several indicators of PCD. Cell degeneration was also studied in vitro in neuroblastoma cells transfected with the H-ras gene. All statistical tests were two-sided. RESULTS: Immunohistochemical analyses revealed that Ras expression was increased in areas of cellular degeneration lacking apoptotic characteristics. The degenerating cells were fragmented without nuclear condensation and, essentially, lacked caspase-3 activation and apoptotic DNA fragmentation. These cells had ultrastructural features of autophagic degeneration, another form of PCD that is distinct from apoptosis. Focal areas of degeneration associated with Ras expression were seen more frequently in tumors from patients detected in a mass-screening program (53 [60.9%] of 87) than in tumors from clinically detected, advanced-stage patients over 1 year of age (7 [29.2%] of 24) (P =.006; chi-square test), suggesting a positive relationship between Ras-associated degeneration and probability of spontaneous regression/favorable prognosis. The characteristic features of Ras-associated nonapoptotic degeneration observed in tumor samples were recapitulated in vitro by transfection-mediated Ras expression, and Ras-mediated degeneration was augmented by TrkA, another favorable prognostic marker. CONCLUSIONS: High-level expression of H-Ras in neuroblastoma cells is associated with caspase cascade-independent, nonapoptotic PCD. This Ras-mediated nonapoptotic tumor cell death may play a key role in spontaneous regression of neuroblastoma.
Asunto(s)
Apoptosis , Regulación Neoplásica de la Expresión Génica , Genes ras/genética , Regresión Neoplásica Espontánea , Neuroblastoma/metabolismo , Neuroblastoma/patología , Receptor trkA , Proteínas ras/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas Portadoras/metabolismo , Caspasas/metabolismo , Niño , Preescolar , ADN de Neoplasias/metabolismo , Humanos , Técnicas para Inmunoenzimas , Técnicas In Vitro , Lactante , Proteínas de la Membrana/metabolismo , Microscopía Electrónica , Valor Predictivo de las Pruebas , Pronóstico , Transducción de Señal , Transfección , Células Tumorales Cultivadas , Regulación hacia Arriba , Proteínas ras/biosíntesis , Proteínas ras/genéticaRESUMEN
To seek a novel therapeutic approach to neuroblastoma (NBL), we used three NBL cell lines (SK-N-DZ, NH12, and SK-N-SH) to examine the underlining molecular mechanisms of cellular reactions and sensitivity to all-trans-retinoic acid (ATRA). SK-N-DZ cells expressed relatively high levels of retinoic acid receptor alpha (RAR-alpha) and underwent ATRA-induced cell death that was blocked by an RAR-alpha antagonist. By contrast, RAR-alpha expression gradually decreased in NH12 and SK-N-SH cells, which did not experience increased cell death in response to ATRA. We report here the ubiquitin-dependent down-regulation of RAR-alpha expression during ATRA treatment. Our data suggest that SK-N-DZ cells have a defect in RAR-alpha down-regulation, resulting in sustained high expression of RAR-alpha that confers high sensitivity to ATRA. Accordingly, treatment with a proteasome inhibitor dramatically increased ATRA-induced cell death in NH12 and SK-N-SH cell lines. Our results reveal the crucial involvement of the RAR-alpha signaling pathway in NBL cell death and show that three NBL cell lines are differentially sensitive to ATRA. These data suggest a potential novel therapy for NBL involving retinoic acid treatment combined with the inhibition of RAR-alpha degradation.
Asunto(s)
Neuroblastoma/tratamiento farmacológico , Inhibidores de Proteasoma , Receptores de Ácido Retinoico/metabolismo , Tretinoina/farmacología , Benzoatos/farmacología , División Celular/efectos de los fármacos , Línea Celular Tumoral , Cromanos/farmacología , Humanos , Leupeptinas/farmacología , Neuroblastoma/patología , ARN Mensajero/análisis , Receptores de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico , Ubiquitina/metabolismoRESUMEN
The International Immune Tolerance Induction (I-ITI) Study in hemophilia A patients with inhibitors included 16 Japanese patients among a total of 115 test subjects. The results within this group of Japanese patients were 11 cases of I-ITI off-study, three cases of I-ITI on-study, and two cases of tolerance on prophylaxis. There was no significant difference in success rate between the low-dose and high-dose groups (Study I). Successively, independent follow-up survey in Japan was conducted in 14 cases, with consent (Study II). Ten cases were off-study at the end of the I-ITI Study. Of these 10 cases, seven of seven successful cases remained clinical successes at the end of the follow-up study, one partial success became a full success while a second relapsed, and one failure was subsequently evaluated as a partial success. Four cases that were on-study at the end of I-ITI Study were classified as three successes and one failure at the end of the follow-up study. As a result, the status at the end of follow-up study was: 11 ITI successes (78.6 %); one partial success; one failure; and one relapse. Thus, the ITI follow-up study was helpful in providing a long-term prognostic determination of inhibitors.
Asunto(s)
Factor VIII/inmunología , Factor VIII/uso terapéutico , Hemofilia A/inmunología , Hemofilia A/terapia , Pueblo Asiatico , Preescolar , Factor VIII/administración & dosificación , Femenino , Estudios de Seguimiento , Hemofilia A/epidemiología , Humanos , Tolerancia Inmunológica , Lactante , Japón/epidemiología , Masculino , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéuticoRESUMEN
We retrospectively analyzed the clinical results of 81 patients with congenital genetic diseases who were treated with bone marrow transplantation (BMT) from unrelated donors identified through the Japan Marrow Donor Program. The patients were aged between 1 and 38 years (median, 4 years). Thirty-five patients underwent transplantation for metabolic disease (MD), ie, mucopolysaccharidosis (n = 25), adrenoleukodystrophy (n = 7), and others (n = 3). The remaining 46 patients had Wiskott-Aldrich syndrome (n = 16), hemophagocytic syndrome including the inherited type (n = 9), severe combined immunodeficiency (n = 6), hyper-IgM syndrome (n = 4), Chédiak-Higashi syndrome (n = 3), Kostmann syndrome (n = 3), and others (n = 5). Fifty-two donor-patient pairs were fully matched at HLA-A, HLA-B, and HLA-DRB1 alleles. The remaining 24 patients received allele-mismatched grafts (20 matched at 5 of 6 loci and 4 matched at 4 of 6 loci). Engraftment occurred in 82.4% of the MD group and 90.7% of the other genetic disease (OGD) group; however, 14 patients (18.2%) experienced either early or late graft failure. The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 35.5% - 9.8% in the MD group and 47.3% - 9.5% in the OGD group, and the rate of chronic GVHD was 20% in both groups. Forty-nine patients have survived for 3 to 96 months (median, 20 months). The probabilities of 5-year overall survival and event-free survival were 72.6% - 11.5% and 65.3% - 8.6%, respectively, for MD (n = 35) and 72.5% - 7.3% and 63.6% - 7.3% for OGD (n = 46). Although patient status before BMT and the occurrence of grade III to IV acute GVHD significantly affected outcome, unrelated BMT is a curative therapeutic option for children with congenital genetic diseases who have no HLA-matched family donors.
Asunto(s)
Trasplante de Médula Ósea/fisiología , Enfermedades Genéticas Congénitas/cirugía , Síndromes de Inmunodeficiencia/cirugía , Errores Innatos del Metabolismo/cirugía , Adolescente , Adulto , Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/mortalidad , Trasplante de Médula Ósea/estadística & datos numéricos , Niño , Preescolar , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/mortalidad , Prueba de Histocompatibilidad , Humanos , Lactante , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Acondicionamiento Pretrasplante/métodos , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Pancreatoblastoma (PBL) is a rare neoplasm that generally occurs in the pediatric age group and shows unique histopathology, including squamoid corpuscles that may contain tumor cells with optically clear nuclei (OCN) rich in biotin. In the English-language literature there have been two reports on the cytology of PBL, but neither of them refers to the cytologic features of squamoid corpuscles. CASE: A 3-year-old boy with nausea and general fatigue was referred to our center. Imaging studies showed an approximately 7.5-cm, left-sided abdominal mass and multiple metastases in the lung. The abdominal mass was biopsied, and its histology showed solid cellular nests with occasional acinar differentiation and squamoid corpuscles. Imprint cytology of the biopsied sample displayed cellular epithelial nests with focal acinar structures and foci composed of larger cells with a low nuclear/cytoplasmic ratio. These foci contained a few tumor cells with biotin-rich OCN and were determined to be squamoid corpuscles. CONCLUSION: Detection of occasional squamoid corpuscles with biotin-rich OCN can be useful in making a diagnosis of PBL on cytologic samples.
Asunto(s)
Células Epiteliales/patología , Neoplasias de Células Germinales y Embrionarias/patología , Páncreas/patología , Neoplasias Pancreáticas/patología , Células Madre/patología , Biomarcadores de Tumor , Biotina/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/patología , Preescolar , Células Epiteliales/metabolismo , Humanos , Cuerpos de Inclusión/patología , Masculino , Neoplasias de Células Germinales y Embrionarias/metabolismo , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo , Células Madre/metabolismoRESUMEN
A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: (A) melphalan and busulfan for 40 patients, (B) melphalan, busulfan and TBI for 44 patients, (C) other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 micrograms/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR 1, 41% for 41 patients at CR 2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR 1 and CR 2, the 5-year DFS by conditioning regimen was 63% for regimen (A), 54% for regimen (B) and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Melfalán/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Acondicionamiento Pretrasplante/métodos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Humanos , Lactante , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidadRESUMEN
We report five consecutive patients who underwent hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma early in their lives and later manifested abnormal patterns of adipose tissue distribution. Lipoatrophy was remarkable in the gluteal regions and extremities, whereas subcutaneous fat was preserved in the cheeks, neck, and abdomen. In addition, visceral fat deposition, fatty changes in the liver, and metabolic derangements such as insulin resistance and hypertriglyceridemia were evident. These features resemble Dunnigan-type familial partial lipodystrophy, which is a rare condition caused by LMNA gene mutation. These patients shared a common medical history involving HSCT, including conditioning with total body irradiation (TBI). They also received intensive chemotherapy because of multiple metastases (n = 3), relapse (n = 3), and repetitive HSCT (n = 3). We propose HSCT as a new etiology for acquired partial lipodystrophy and recommend that patients who undergo HSCT with TBI and intensive chemotherapy early in their lives must receive careful observation for the possible development of lipodystrophy and metabolic complications.
RESUMEN
Synovial sarcoma, which is difficult to diagnose precisely, is one of the most common childhood nonrhabdomyosarcoma soft-tissue sarcomas. The purpose of this study is to develop new molecular cytogenetic assay. We used two sets of two-color break-apart FISH probes, flanking either the SSX1/SSX4 or SSX2 locus. Each set of probes is composed of differentially labeled DNA fragments complementary to sequences proximal or distal to the break point within the SSX1/SSX4 or SSX2 locus, which are applied separately to histopathological sections. Interphase nuclei containing a translocation that disrupts either SSX1, SSX2, or SSX4 locus will display two single-color signals that have "broken apart" from each other. We applied it to two synovial sarcoma cell lines and clinical samples. This assay can detect translocation at either SSX1/SSX4, or SSX2 locus on interphase spread prepared from synovial sarcoma cell line and histopathological sections, which is sufficient to diagnose as synovial sarcoma. Our new FISH assay has several advantages, including its applicability to paraffin-embedded samples, discrimination of the SS18-SSX1 and SS18-SSX2 translocations particularly in cases with aneuploidy, and potentially detecting translocations in all cases of synovial sarcoma, even with variant translocations. Our strategy will improve the accuracy of diagnoses, thereby facilitating appropriate treatment planning.