RESUMEN
BACKGROUND AIMS: This study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. METHODS: A retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0-70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. RESULTS: Among 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0-24 years, indicating that both sources are viable choices for young patients. CONCLUSIONS: This real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.
Asunto(s)
Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Trasplante de Células Madre de Sangre Periférica , Células Madre de Sangre Periférica , Humanos , Médula Ósea , Trasplante de Médula Ósea/métodos , Estudios Retrospectivos , Japón , Calidad de Vida , Recurrencia Local de Neoplasia/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Neoplasias Hematológicas/terapia , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre de Sangre Periférica/métodosRESUMEN
Pediatric myelodysplasia syndrome is often characterized by hypoplastic bone marrow morphology and predisposition to infection. Invasive aspergillosis during hematopoietic stem cell transplantation poses a significant threat and often requires voriconazole (VRCZ) therapy. However, difficulties in achieving appropriate VRCZ blood levels due to drug interactions have prompted the exploration of alternative treatments, such as isavuconazole (ISCZ). We present the case of a 4-year-old boy with myelodysplasia syndrome who developed multiple abscesses, including a brain abscess caused by Aspergillus fumigatus, and was successfully treated with ISCZ. Despite initial treatment with liposomal amphotericin B and VRCZ, the patient's condition deteriorated. Transitioning to ISCZ treatment resulted in significant clinical improvement, resolution of the abscesses, and reduced antigen levels. Although ISCZ induced hepatic enzyme elevation, supportive care improved without discontinuation of treatment. This case highlights the potential of ISCZ in cases of pediatric invasive aspergillosis where traditional therapies fail, underscoring the need for further research and formulation development to optimize its use in this population. As more cases accumulate, ISCZ may become a promising option for treating severe invasive aspergillosis in pediatric patients undergoing hematopoietic stem cell transplantation.
RESUMEN
The analysis of 165 children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia showed disease status at hematopoietic stem cell transplantation was a strong prognostic factor and clearly separated the patient outcomes.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Niño , Adolescente , Adulto Joven , Trasplante Homólogo , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapiaRESUMEN
We analyzed a Japanese registry database to elucidate the incidence, risk factors, and outcomes of adenovirus (AdV) disease after autologous and allogeneic hematopoietic cell transplantation (HCT) in contemporary real-world patients. We evaluated the cumulative incidence of AdV disease, as well as risk factors, survival, and treatment details, among 25 233 patients who underwent autologous HCT and 48 380 patients who underwent allogeneic HCT between 2005 and 2019. The 1-year cumulative incidences of AdV disease after autologous and allogeneic HCT were 0.18% and 1.52%, respectively, in children, and 0.49% and 2.99%, respectively, in adults. Among patients with AdV disease, renourinary infection was the most common manifestation, and viremia or disseminated disease occurred in 6% of those after autologous HCT and 19% of those after allogeneic HCT. In multivariate analysis, age ≥50 years and lymphoma were associated with AdV disease after autologous HCT, while patients age ≥50 years, male patients, lymphoma, HCT-specific comorbidity index ≥3, human leukocyte antigen-mismatched or haploidentical donors, cord blood, in vivo T-cell depletion, HCT from 2005 to 2009, acute graft-versus-host disease (GVHD), and chronic GVHD were associated with AdV disease after allogeneic HCT. The 1-year probabilities of survival after disease diagnosis were 65% in autologous HCT and 44% in allogeneic HCT. Regardless of the AdV disease burden, there was an increased risk of mortality after both autologous and allogeneic HCT. The most commonly used antiviral agents were cidofovir and vidarabine. The probabilities of improvement and survival with currently available agents were suboptimal. AdV disease after HCT remains a challenge. Better antiviral modalities are necessary.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfoma , Adulto , Niño , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Japón/epidemiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Linfoma/terapia , Sistema de Registros , AdenoviridaeRESUMEN
Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vß11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d.
Asunto(s)
Antígenos CD1d/metabolismo , Leucemia/inmunología , Leucemia/metabolismo , Activación de Linfocitos/inmunología , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Animales , Antígenos CD1d/genética , Biomarcadores , Degranulación de la Célula , Línea Celular Tumoral , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citocinas/metabolismo , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Femenino , Edición Génica , Xenoinjertos , Humanos , Inmunofenotipificación , Leucemia/genética , Leucemia/patología , Activación de Linfocitos/genética , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Gatillantes de la Citotoxidad Natural/metabolismoAsunto(s)
Dermatomiositis , Linfoma de Células B , Autoanticuerpos , Niño , Dermatomiositis/complicaciones , Dermatomiositis/patología , Femenino , HumanosRESUMEN
Fusion genes involving ZNF384 have recently been identified in B-cell precursor acute lymphoblastic leukemia, and 7 fusion partners have been reported. We further characterized this type of fusion gene by whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2K as a novel fusion partner for ZNF384 Including the EP300-ZNF384 that we reported recently, the total frequency of ZNF384-related fusion genes was 4.1% in 291 B-cell precursor acute lymphoblastic leukemia patients enrolled in a single clinical trial, and TCF3-ZNF384 was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotype of weak CD10 and aberrant CD13 and/or CD33 expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3-ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300-ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1-positive and ZNF384-fusion-negative patients. However, clinical features of TCF3-ZNF384-positive patients are markedly different from those of EP300-ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3-ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genes consist of a distinct subgroup of B-cell precursor acute lymphoblastic leukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.
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Inmunofenotipificación , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Transactivadores/genética , Transactivadores/metabolismo , Adolescente , Biomarcadores de Tumor , Niño , Preescolar , Análisis por Conglomerados , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Frecuencia de los Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Pronóstico , Transcriptoma , Translocación GenéticaAsunto(s)
Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Alelos , Niño , Humanos , Mercaptopurina/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genética , Estudios RetrospectivosRESUMEN
Constitutional 11q interstitial deletion syndrome presents with congenital anomalies including microcephaly with craniostenosis, minor dysmorphic features, vitreoretinopathy, and renal anomalies. This syndrome is occasionally associated with neuroblastoma (NB) as a life-threatening complication, which is important for clinical care. Although the corresponding locus to NB has been predicted to exist in 11q22-23 by previous deletion studies related to NB, the causative haploinsufficient genes have not yet been identified. We herein reported for the first time the simultaneous coexistence of adrenal NB and abdominal prevertebral ganglioneuroma in a 6-year-old girl with a constitutional hemizygous 11q14.1-23.3 deletion. Of the 11 haploinsufficient genes predicted with an in silico database, we focused on NCAM1 and CADM1 as the genes accountable for NB and ganglioneuroma. The deletion range, especially the 11q22.3 involvement, needs to be determined in 11q deletion cases in order to predict susceptibility to peripheral nerve tumors involving NB and ganglioneuroma.
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Antígeno CD56/genética , Moléculas de Adhesión Celular/genética , Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Ganglioneuroma/genética , Inmunoglobulinas/genética , Neoplasias Primarias Múltiples/genética , Neuroblastoma/genética , Molécula 1 de Adhesión Celular , Niño , Femenino , Ganglioneuroma/patología , Humanos , Cariotipificación , Neoplasias Primarias Múltiples/patología , Neuroblastoma/patología , FenotipoRESUMEN
Programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway blockade has become a promising therapeutic target in adult cancers. We evaluated PD-L1 expression and tumor-infiltrating CD8(+) T cells in formalin-fixed, paraffin-embedded tumor specimens from 53 untreated pediatric patients with eight cancer types: neuroblastoma, extracranial malignant germ cell tumor, hepatoblastoma, germinoma, medulloblastoma, renal tumor, rhabdomyosarcoma, and atypical teratoid/rhabdoid tumor. One rhabdomyosarcoma with the shortest survival exhibited membranous PD-L1 expression and germinoma contained abundant tumor-infiltrating CD8(+) T cells and PD-L1-positive macrophages. The PD-1/PD-L1 pathway tended to be inactive in pediatric cancers.
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Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Macrófagos/inmunología , Neoplasias/patología , Receptor de Muerte Celular Programada 1/metabolismo , Adolescente , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Linfocitos Infiltrantes de Tumor/inmunología , Estudios Retrospectivos , Microambiente Tumoral/inmunologíaRESUMEN
We report an 8-year-old patient with catheter-related bacteremia caused by linezolid-resistant Staphylococcus epidermidis that was isolated after the long-term, repeated use of linezolid. Three S. epidermidis strains isolated from this patient were bacteriologically analyzed. While the strain isolated prior to linezolid initiation was susceptible to linezolid, two strains after linezolid therapy displayed low-level linezolid susceptibility (MIC, 4 mg/L) and linezolid resistance (MIC, 16 mg/L). T2500A mutation in two copies and G2575T mutations in three copies of 23S rRNA were detected in the low-susceptible strain and the resistant strain, respectively. Linezolid-resistant S. epidermidis infection is rare, but may occur with the long-term administration of linezolid.
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Antibacterianos , Farmacorresistencia Bacteriana/efectos de los fármacos , Linezolid , Infecciones Estafilocócicas , Staphylococcus epidermidis/efectos de los fármacos , Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Niño , Farmacorresistencia Bacteriana/genética , Resultado Fatal , Femenino , Humanos , Leucemia Mieloide Aguda/complicaciones , Linezolid/administración & dosificación , Linezolid/farmacología , Linezolid/uso terapéutico , Pruebas de Sensibilidad Microbiana , Infecciones Estafilocócicas/complicaciones , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus epidermidis/genéticaRESUMEN
PURPOSE: In the recent years in Japan, an increasing number of patients with neuroblastoma (NB) are being treated by the "delayed local treatment (DL)" policy, undergoing surgery after the completion of high-dose chemotherapy with hematopoietic stem cell rescue (HDC). We reviewed the histopathological findings of second-look operations, including those of patients treated with DL. PATIENTS: From 1998 to 2013, 26 patients with high-risk NB underwent radical operation following chemotherapy. Surgery was performed after induction chemotherapy in 17 cases (standard; STD), whereas 9 cases completed induction chemotherapy and HDC before undergoing tumor resection (DL). The amount of necrosis and the degree of differentiation within the post-treatment tumor were assessed. RESULTS: Eighty-eight percent of the tumors showed necrosis in more than 1/3 of the specimen. Two DL cases showed complete disappearance of viable tumor cells. Amount of necrosis did not affect the prognosis of the patient. Tumors with immature, poorly differentiated phenotypes showed an extremely aggressive thereafter. Though not statistically proven, (123)I-MIBG (metaiodobenzylguanidine) uptake may be correlated with the amount of viable cells remaining within the tumor, but not with the degree of differentiation. CONCLUSIONS: Our results support the previous reports advocating that tumors that sustain unfavorable histology after chemotherapy behave aggressively thereafter.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia de Inducción/métodos , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/tratamiento farmacológico , 3-Yodobencilguanidina , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Japón , Masculino , Neuroblastoma/cirugía , Cintigrafía , Radiofármacos , Estudios Retrospectivos , Segunda Cirugía/métodos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.
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Antígenos CD34 , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia Mieloide Aguda , Receptores KIR , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Enfermedad Injerto contra Huésped/etiología , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Estudios RetrospectivosRESUMEN
BACKGROUND: Soft tissue sarcomas (STS) of pelvic origin in boys often involve the urogenital organs. The optimal extensiveness of radical surgery has long been an issue of discussion, since exenterative surgeries result in severe urogenital adverse effects. We conducted a retrospective review of patients with pelvic STS treated in two regional center hospitals and assessed the radicality of surgery and the functional outcome of the bladder. PATIENTS: Medical records and surgical reports of nine cases (embryonal rhabdomyosarcoma 6, malignant triton tumor 2, suspected rhabdomyosarcoma 1) treated within 1997-2012 were reviewed. Site of origin was prostate in seven, retroperitoneal in two. Average follow-up period was 96 months. TREATMENT AND OUTCOME: All cases were subjected to neoadjuvant chemotherapy. Response was PR in four, SD in two, and PD in two. Radical surgery resulted in gross total resection in eight, and partial resection in one. Three underwent cystoprostatectomy, two cases underwent prostatectomy, and bladder-preserving tumor resection was carried out in four cases. At the last follow-up, three retained a functional bladder. Two required augmentation cystoplasty with intestinal conduits. CONCLUSIONS: The majority of the on-going clinical trials recommend conservative surgery for bladder/prostate rhabdomyosarcoma, and to preserve the bladder function particularly in chemosensitive tumors. Some other groups, however, advocate the importance of radical surgery to prevent local relapse. These reports include heterogenous group of patients in the cohort, and therefore it is difficult to draw a conclusion of which approach truly contributes to the survival of the patients better. Future studies should evaluate bladder and sexual function objectively to establish reliable evidence regarding the benefit and adverse effects of different surgical approaches. These data would be informative to optimize the treatment balance for children with pelvic rhabdomyosarcomas.
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Neoplasias Pélvicas/cirugía , Rabdomiosarcoma/cirugía , Sarcoma/cirugía , Micción/fisiología , Neoplasias Urogenitales/cirugía , Procedimientos Quirúrgicos Urogenitales/métodos , Preescolar , Estudios de Seguimiento , Humanos , Lactante , Masculino , Neoplasias Pélvicas/diagnóstico , Neoplasias Pélvicas/fisiopatología , Estudios Retrospectivos , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/fisiopatología , Sarcoma/diagnóstico , Sarcoma/fisiopatología , Resultado del Tratamiento , Neoplasias Urogenitales/diagnóstico , Neoplasias Urogenitales/fisiopatologíaRESUMEN
Hematological malignancy and solid tumor are major risks for invasive pneumococcal disease. Thirteen-valent pneumococcal conjugate vaccine (PCV13) is recommended for immunocompromised patients aged 6 years and older and adults who had not received the vaccine previously. However, vaccination for these individuals is not publicly subsidized in Japan. We measured pneumococcal serotype-specific IgGs (Pn-IgGs) and opsonophagocytic activities (Pn-OPAs) against PCV13 serotypes (1, 3, 5, 6A, 7F, and 19A) in patients with hematological malignancies and solid tumors who were outside the recommended age range for routine vaccination at baseline and at 1 and 6 months after the first dose of PCV13. Pneumococcal serotype-specific memory B cells (Pn-MBCs) against serotype 3 were measured from a portion of the study samples. Thirty-seven patients (30 in the young patient group and 7 in the adult patient group) completed the study. Pn-IgGs were significantly elevated at 1 month post-vaccination and persisted in protection level for 6 months after the first vaccination against all six serotypes measured except serotype 3. Pn-OPAs were significantly elevated and persisted as well against all six serotypes. Pn-MBCs were measured in 10 patients, and 90% of them had at least one detectable Pn-MBC, and 70% of them showed an increased frequency of Pn-MBCs against serotype 3. No serious adverse events were observed up to 1 month after vaccination. PCV13 is thus safe and immunogenic, including against serotype 3, in patients with hematological malignancies and solid tumors outside the recommended age range for routine vaccination.
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Neoplasias Hematológicas , Neoplasias , Infecciones Neumocócicas , Anticuerpos Antibacterianos , Humanos , Lactante , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas/efectos adversos , Vacunación/efectos adversos , Vacunas Conjugadas/efectos adversosRESUMEN
The effect of genetic variation on second malignant neoplasms (SMNs) remains unclear. First, we identified the pathogenic germline variants in cancer-predisposing genes among 15 children with SMNs after childhood leukemia/lymphoma using whole-exome sequencing. Because the prevalence was low, we focused on the association between SMNs and NUDT15 in primary acute lymphoblastic leukemia (ALL) cases. NUDT15 is one of the 6-mercaptopurine (6-MP) metabolic genes, and its variants are common in East Asian individuals. The prevalence of NUDT15 hypomorphic variants was higher in patients with SMNs (n = 14; 42.9%) than in the general population in the gnomAD database (19.7%; P = .042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMNs was significantly higher among those with (3.0%; 95% confidence interval [CI], 0.6% to 9.4%) than among those without NUDT15 variants (0.3%; 95% CI, 0.0% to 1.5%; P = .045). The 6-MP dose administered to patients with ALL with a NUDT15 variant was higher than that given to those without SMNs (P = .045). The 6-MP-related mutational signature was observed in SMN specimens after 6-MP exposure. In cells exposed to 6-MP, a higher level of 6-MP induced DNA damage in NUDT15-knockdown induced pluripotent stem cells. Our study indicates that NUDT15 variants may confer a risk of SMNs after treatment with 6-MP in patients with ALL.
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Neoplasias Primarias Secundarias , Leucemia-Linfoma Linfoblástico de Células Precursoras , Antimetabolitos Antineoplásicos/uso terapéutico , Niño , Humanos , Incidencia , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatasas/genética , Pirofosfatasas/uso terapéuticoRESUMEN
Immediate allergy to l-asparaginase (ASP) is a major obstacle in treating lymphoid malignancies. ASP-specific immunoglobulin G (ASP-IgG) has been used as a surrogate marker. Recently, the CD203c-basophil activation test (BAT) was found to be useful in diagnosing IgE-mediated allergies. We compared the diagnostic utility of the CD203c-BAT to that of ASP-IgG levels in determining ASP allergies in children. Eight ASP allergic reactions occurred over 75 ASP treatment courses. The sensitivity, specificity and area under the receiver operating characteristic curve of CD203c-BAT were similar to the ASP-IgG levels (0.75 vs. 0.85, 0.82 vs. 0.78 and 0.81 vs. 0.85, respectively). Positive skin prick test results in patients with ASP allergy suggested that ASP-IgE was one of the key players in ASP allergy. A combination of the BAT with the ASP-IgG level had the highest specificity (0.95) and positive predictive value (0.62), which permitted us to identify ASP allergy more effectively.
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Asparaginasa/inmunología , Basófilos/inmunología , Basófilos/metabolismo , Hipersensibilidad Inmediata/inmunología , Hipersensibilidad Inmediata/metabolismo , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/metabolismo , Adolescente , Biomarcadores/sangre , Biomarcadores/metabolismo , Niño , Preescolar , Femenino , Humanos , Hipersensibilidad Inmediata/diagnóstico , Inmunoglobulina E/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Lactante , Linfoma/complicaciones , Linfoma/terapia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sensibilidad y EspecificidadRESUMEN
We described a 7-year-old girl with reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. She initially presented with high fever and pancytopenia, leading to a diagnosis of most severe type aplastic anemia. We treated her with cyclosporine, methylprednisolone and anti-thymocyte globulin. Thereafter she recurrently complained of a very severe headache called as thunderclap, and finally exhibited loss of consciousness. Brain imaging revealed massive parenchymal hemorrhage between the left occipital and parietal lobes on computed tomography, and diffuse cerebral vasoconstriction on magnetic resonance angiography. The cerebral vasoconstriction resolved within two months, and thus we diagnosed her as having reversible cerebral vasoconstriction syndrome associated with brain parenchymal hemorrhage. This syndrome has been frequently reported in adult females, but rarely in children. However, even in children, a so called thunderclap headache may become a clue for the diagnosis of reversible cerebral vasoconstriction syndrome, especially in cases taking immunosuppressive agents. Immediate magnetic resonance angiography is essential to diagnose this syndrome, and a prompt application of calcium channel inhibitors should be considered to resolve constriction of the vessels and to prevent subsequent brain damage.