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1.
Blood Adv ; 2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34662904

RESUMO

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. As 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 SMN (n = 14, 42.9%) than general population in gnomAD database (19.7%) (p = 0.042). In the validation study with a cohort of 438 unselected patients with ALL, the cumulative incidence of SMN was significantly higher among cases with NUDT15 variant (3.0%, 95% CI, 0.6%-9.4%) than those without (0.3%, 95% CI, 0.0-1.5%) (p = 0.045). The 6-MP dose of SMN patients with a NUDT15 variant was higher than that of those without SMN (p = 0.045). The 6-MP related mutational signature was observed in SMN specimens after 6-MP exposure. In cells under 6-MP exposure, a higher level of 6-MP-induced DNA damage in NUDT15 knockdown iPS cells. Our study indicates that NUDT15 variants may confer a risk of SMN after treatment with 6-MP among patients with ALL.

2.
Rinsho Ketsueki ; 62(8): 1275-1280, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497216

RESUMO

Allogeneic hematopoietic cell transplantation (allo-HCT) plays an important role as the most potent therapeutic option for refractory acute lymphoblastic leukemia (ALL). However, advances of supporting therapy have enabled more intensive chemotherapy, and severe late complication of allo-HCT has been recognized, thus, indication of allo-HCT is now limited to carefully selected population with highest risk for relapse, based on assessment by minimal residual disease status. Furthermore, especially for B-cell precursor ALL, we should re-establish a role of allo-HCT in the entire of therapeutic strategy, including novel options, such as small molecular agents and immunotherapy. We are now required to maximize safety and efficacy of allo-HCT for selected high-risk ALL.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recidiva , Transplante Homólogo
3.
Artigo em Inglês | MEDLINE | ID: mdl-34508178

RESUMO

Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.

5.
Cancer Rep (Hoboken) ; : e1559, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34553842

RESUMO

BACKGROUND: Lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) are categorized as the same entity under precursor lymphoid neoplasms in the World Health Organization classification. However, compared to B-cell ALL, the molecular genetic makeup of B-cell LBL remains to be understood, mainly due to its rarity. We performed whole exome sequencing (WES) on seven patients with TCF3-PBX1-positive B-cell LBL. METHODS: WES was performed using DNA extracted from tumor specimens and paired blood samples at remission for six patients, and tumor-only analysis was performed for one patient whose remission sample was not available. For one patient, a relapsed sample was also analyzed. RESULTS: KMT2D variants and 6q LOH were found as recurrent alterations. Somatic variants of KMT2D were identified in three of the seven patients. Of note, the two patients with heterozygous nonsense variant of KMT2D were at stage III, without bone marrow infiltration. 6q LOH was also identified in two others, out of the seven patients. The common 6q deleted region of the two patients ranged from 6q12 to 6q16.3. Both patients had bone marrow infiltration. Analysis of recurrent case also revealed that the relapsed clone might be derived from a minor clone of the bone marrow at diagnosis. CONCLUSION: In this study, through WES for seven patients with TCF3-PBX1-positive B-LBL, we identified KMT2D mutations and 6q LOH as recurrent alterations. In order to elucidate the relationship between these recurrent alterations and disease specificity or outcomes, further studies comparing with TCF3-PBX1-positive B-ALL are required.

6.
Cancer Rep (Hoboken) ; : e1545, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34472720

RESUMO

BACKGROUND: An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B-cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG-MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG-MYC by aberrant somatic hypermutation or class switch recombination, and BL-specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG-MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL. CASE: The patient showed BL-like morphology with IGH-MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole-exome sequencing. The breakpoint analysis revealed the IG-MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism. CONCLUSION: The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.

7.
J Neurooncol ; 154(2): 247-256, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34398431

RESUMO

PURPOSE: Primary central nervous system (CNS) rhabdomyosarcoma is a rare mesenchymal tumor predominantly seen in children and associated with a poor outcome. We report a case of primary CNS rhabdomyosarcoma with PAX3-NCOA2 fusion and present a systematic meta-review of primary CNS rhabdomyosarcoma to characterize this rare tumor. METHODS: We present the case of a 6-year-old boy with primary CNS rhabdomyosarcoma in the posterior fossa. In a systematic meta-review, we compare the demographic data of primary CNS rhabdomyosarcoma with data of rhabdomyosarcoma at all sites from the SEER database and analyze clinical factors associated with survival outcome. RESULTS: Our patient underwent gross total resection and received vincristine, actinomycin-D, cyclophosphamide with early introduction of concurrent focal radiation and remained alive with no evidence of disease for 2 years after the end of therapy. Histopathological review revealed embryonal-type rhabdomyosarcoma, and whole-transcriptome analysis revealed PAX3 (EX6)-NCOA2 (EX12) fusion. In all, 77 cases of primary CNS rhabdomyosarcoma were identified through the meta-review. The demographic data of primary CNS rhabdomyosarcoma were similar to data of rhabdomyosarcoma at all sites. Overall and event-free survival outcomes were available for 64 and 56 patients, respectively, with a 3-year OS of 29.0% and a 3-year EFS of 25.7%. The group that received trimodal treatment exhibited better survival outcomes, with a 3-year OS of 57.4% and a 3-year EFS of 46.3%. CONCLUSIONS: Primary CNS rhabdomyosarcoma shares common histological, molecular, and demographic features with non-CNS rhabdomyosarcoma. A trimodal treatment approach with early introduction of radiation therapy may result in favorable survival outcomes.

8.
J Hum Genet ; 2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34341476

RESUMO

PAX3/7-FOXO1 fusion-negative alveolar rhabdomyosarcoma (ARMS) developed in a patient presenting with intellectual disability and dysmorphic facial features. Whole exome sequencing analysis of a germline sample identified a PACS1 c.607 C>T de novo variant and the patient was diagnosed with Schuurs-Hoeijmakers syndrome (SHS). SHS is a rare disease characterized by intellectual disability and dysmorphic facial features, among various physical abnormalities, due to PACS1 c.607 C>T de novo variant. Due to the rarity of the SHS, diagnosis based on phenotypic information is difficult. To date, there have been no previous reports describing malignancy associated with SHS. Comprehensive somatic mutation analysis revealed a unique pattern of genetic alterations in the PAX3/7-FOXO1 fusion-negative ARMS tumor, including mutations in the oncogene, HRAS; MYOD1, a molecule essential for muscle differentiation; and KMT2C and TET1, genes encoding factors involved in epigenetic regulation. Although the role of PACS1 in tumorigenesis is unclear, it is reported to function in apoptosis regulation. Our case suggests that PACS1 could have a novel role in oncogenesis.

9.
J Clin Immunol ; 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34448087

RESUMO

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID patients after HCT in Japan. METHODS: A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974-2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP). RESULTS: The 10-year overall survival (OS) of the patients who received HCT in 2006-2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (n = 21) and matched sibling donors (n = 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006-2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8, P = 0.006), cytomegalovirus infection prior to HCT (HR: 9.4, P = 0.03), ≥ 4 months of age at HCT (HR: 25.5, P = 0.009), and mismatched UCB (HR: 19.8, P = 0.01). CONCLUSION: We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.

10.
J Allergy Clin Immunol Pract ; 9(10): 3767-3780, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34246792

RESUMO

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE: To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS: A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS: Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS: This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.

11.
Transplant Cell Ther ; 27(10): 872.e1-872.e8, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34298243

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many high-risk pediatric hematological malignant diseases (MD) and several nonmalignant diseases (NMD), including primary immune deficiencies. Infections must be managed to obtain better outcomes after HSCT. In this prospective observational study, viral monitoring was performed on 74 pediatric patients with MD and NMD who underwent HSCT. The incidence, risk factors, and impact of common opportunistic viral infections occurring within the first 100 days following HSCT were assessed. The viral pathogens included human herpesviruses, BK polyomavirus (BKV), adenovirus, parvovirus B19, and hepatitis B virus. In total, 52 (70%) patients had viral DNAemia, and 53% and 41% of patients developed human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV) DNAemia, respectively. The risk factors were as follows: negative CMV serology for any viral infections; age ≥ 2 years and negative CMV serology for HHV-6; age ≥5 years and female sex for BKV. The risk of viral infection did not significantly differ between MD and NMD, and no risk factor was identified for viral disease, likely because of the small sample numbers. However, despite the absence of symptoms, CMV DNAemia was found to increase the risk of mortality. The findings of the current study could improve the risk stratification and the management of pediatric HSCT recipients.

13.
Nat Commun ; 12(1): 4181, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234136

RESUMO

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.


Assuntos
Aciclovir/farmacologia , Antivirais/farmacologia , Infecções por Citomegalovirus/prevenção & controle , Ganciclovir/análogos & derivados , Pirofosfatases/genética , Aciclovir/uso terapêutico , Adolescente , Adulto , Idoso , Animais , Antibioticoprofilaxia , Antivirais/uso terapêutico , Variação Biológica da População/genética , Linhagem Celular , Criança , Pré-Escolar , Cristalografia por Raios X , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/virologia , DNA Viral/sangue , DNA Viral/isolamento & purificação , Modelos Animais de Doenças , Farmacorresistência Viral , Feminino , Ganciclovir/farmacologia , Ganciclovir/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Interações entre Hospedeiro e Microrganismos/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Muromegalovirus/isolamento & purificação , Muromegalovirus/patogenicidade , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Pirofosfatases/metabolismo , Pirofosfatases/ultraestrutura , Resultado do Tratamento , Adulto Jovem
14.
BMC Palliat Care ; 20(1): 82, 2021 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-34098925

RESUMO

BACKGROUND: Adult patients with hematologic malignancies are less likely to receive palliative care and more likely to accept intensive anti-cancer treatments until end-of-life than those with solid tumors, but limited data are available regarding the quality of end-of-life care (EOLC) for children with hematologic malignancies. To improve the quality of EOLC for children with hematologic malignancies, the aims of this study were (i) to compare intensive EOLC between children with hematologic malignancies and those with solid tumors; and (ii) to describe factors associated with intensive EOLC in children with hematologic malignancies. METHODS: We retrospectively reviewed 0- to 18-year-old patients with cancer, who died in hospital between April 2012 and March 2016 in Japan using the Diagnosis Procedure Combination per-diem payment system. Indicators of intensive inpatient EOLC were defined as intensive care unit admission, cardiopulmonary resuscitation (CPR), intubation and/or mechanical ventilation, hemodialysis, or extra-corporeal membrane oxygenation in the last 30 days of life, or intravenous chemotherapy in the last 14 days. We determined factors associated with intensive EOLC using regression models. Data regarding use of blood transfusion were also obtained from the database. RESULTS: Among 1199 patients, 433 (36%) had hematological malignancies. Children with hematologic malignancies were significantly more likely than those with solid tumors to have intubation and/or mechanical ventilation (37.9% vs. 23.5%), intensive care unit admission (21.9% vs. 7.2%), CPR (14.5% vs. 7.7%), hemodialysis (13.2% vs. 3.1%) or extra-corporeal membrane oxygenation (2.5% vs. 0.4%) in their last 30 days, or intravenous chemotherapy (47.8% vs. 18.4%; all P < .01) within their last 14 days of life. Over 90% of children with hematological malignancies received a blood transfusion within the last 7 days of life. For hematological malignancies, age under 5 years was associated with CPR and ≥ 2 intensive EOLC indicators. Longer hospital stays had decreased odds of ≥ 2 intensive EOLC indicators. CONCLUSION: Children with hematologic malignancies are more likely to receive intensive EOLC compared to those with solid tumors. A younger age and shorter hospital stay might be associated with intensive EOLC in children with hematologic malignancies.


Assuntos
Neoplasias Hematológicas , Cuidados Paliativos na Terminalidade da Vida , Assistência Terminal , Adolescente , Adulto , Criança , Pré-Escolar , Neoplasias Hematológicas/terapia , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva , Cuidados Paliativos , Estudos Retrospectivos
15.
Lancet Haematol ; 8(7): e513-e523, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34171282

RESUMO

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.


Assuntos
Antineoplásicos/efeitos adversos , Médicos/psicologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Cegueira/etiologia , Criança , Perda Auditiva/etiologia , Doenças Hematológicas/etiologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Intervalo Livre de Progressão , Insuficiência Renal/etiologia
16.
Pediatr Int ; 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33998750

RESUMO

BACKGROUND: We aimed to evaluate the utility of plain X-ray radiograph (PXR) findings in suggesting a diagnosis of acute leukemia in children presenting with bone pain in the emergency department (ED) of a children's hospital. METHODS: Using our radiology reporting system and registered data for childhood acute leukemia, we collected data regarding patients who underwent musculoskeletal PXR examinations in the ED because of bone pain in their extremities from March 1, 2002 to June 30, 2015. We retrospectively reviewed their PXR findings and clinical information from the electronic medical records. RESULTS: A total of 1331 patients underwent PXR examinations and 12 among them had suspected acute leukemia from PXR findings. From the registered data, we found 12 acute leukemia patients who underwent emergency extremity PXR. Ten patients were finally confirmed to have acute leukemia by bone marrow examinations. The most common finding was lucent metaphyseal bands demonstrated in seven cases, whereas six patients did not show any abnormalities in their peripheral blood cell counts. Sensitivity and specificity values of PXR for acute leukemia diagnosis were 90.0% and 99.8%, respectively. Positive predictive value and negative predictive values were 75.0% and 99.9%. CONCLUSIONS: PXR is a useful diagnostic tool to detect possible acute leukemia in patients presenting with bone pain earlier than abnormalities of their peripheral blood cell counts. Our results implied the possibility of having acute leukemia and re-examining PXRs more carefully, even when there are no abnormalities in blood cell counts.

17.
Int J Hematol ; 114(2): 271-279, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34008044

RESUMO

Osteonecrosis (ON), a long-term complication of acute lymphoblastic leukemia (ALL) treatment affects patients' quality of life. Although the incidence of any ON, including asymptomatic, was 21.7% among children with ALL in the U.S., the actual incidence and risk factors in Asia remain unknown. For over 11 years, we performed hip magnetic resonance imaging (MRI) screening to detect asymptomatic ON while initiating maintenance chemotherapy in newly diagnosed children with ALL. Overall, 164 of 175 patients underwent hip MRI screening. The incidence of symptomatic or any ON was 3.0% and 11.6%, respectively. Asymptomatic ON in patients < 10 and ≥ 10 years old was 4.0% and 35.9%, respectively (P < 0.001). In multivariate analysis, age ≥ 10 years was the only significant risk factor. Asymptomatic ON with necrosis of > 30% of the epiphyseal surface of the femoral head was detected in four patients (2.4%). All were ≥ 10 years. Three of them progressed to severe symptomatic ON. The incidence of any ON in Asia may be lower than that seen in the only screening study in the U.S. Future studies should clarify factors affecting such regional differences and develop an effective approach to avoid the progression of ON in children with ALL.


Assuntos
Grupo com Ancestrais do Continente Asiático , Necrose da Cabeça do Fêmur/epidemiologia , Necrose da Cabeça do Fêmur/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/epidemiologia , Adolescente , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Progressão da Doença , Suscetibilidade a Doenças , Feminino , Necrose da Cabeça do Fêmur/diagnóstico , Humanos , Incidência , Imageamento por Ressonância Magnética , Masculino , Avaliação de Resultados da Assistência ao Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Vigilância em Saúde Pública , Fatores de Risco
18.
Pediatr Blood Cancer ; 68(8): e29069, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33881202

RESUMO

BACKGROUND: Therapeutic drug monitoring for busulfan is important to prevent adverse events and improve outcomes in stem cell transplantation. We investigated intravenous busulfan pharmacokinetics and evaluated the utility of limited sampling strategy (LSS) as a simple method to estimate the area under the concentration-time curve (AUC). PROCEDURE: The study comprised 87 busulfan measurements in 54 children who received intravenous busulfan between August 2015 and May 2020. AUCs were calculated from three to five blood sampling points in each patient, and the correlation between AUC and plasma concentrations (ng/mL) at 1, 2, 3, 4, and 6 h after initiating busulfan infusion (C1 , C2 , C3 , C4 , and C6 , respectively). RESULTS: By one-point sampling strategy, the most relevant predicted AUC was based on C6 (r2  = 0.789; precision, 11.0%) in all patients. The predicted AUC based on C6 was acceptable (r2  = 0.937; precision, 5.9%) for adolescent patients weighing >23 kg, but the correlation was poor in infants and young children weighing ≤ 23 kg (r2  = 0.782; precision, 11.4%). By two-point sampling strategy, the predicted AUC based on C3 and C6 showed the most relevant concentrations (r2  = 0.943; precision, 6.4%), even in infants and young children, whereas the predicted AUC based on C3 and C6 was acceptable (r2  = 0.963; precision, 5.7%). CONCLUSIONS: The AUC of busulfan can be predicted based on C6 in adolescent patients. However, there was substantial interindividual variation in busulfan pharmacokinetics in infants and young children, in whom two-point LSS was necessary for accurate AUC prediction.

19.
Pediatr Int ; 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33884705

RESUMO

BACKGROUND: Some monogenic inflammatory bowel diseases (IBDs) are known to be refractory to conventional treatments. Although allogeneic hematopoietic stem-cell transplantation (allo-HSCT) has become a curative therapeutic option for certain monogenic IBDs, its effectiveness regarding endoscopic improvements has not been clarified. METHODS: The clinical course and endoscopic findings of patients with monogenic IBDs who were treated with allo-HSCT between December 2017 and November 2018 at the National Center for Child Health and Development, were retrospectively reviewed. The clinical disease activity was assessed using the weighted Pediatric Crohn's Disease Activity Index (wPCDAI) and the endoscopic finding was evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD). Clinical remission was defined as a wPCDAI <10 and endoscopic remission was defined as an SES-CD of 2 or less. RESULTS: Four patients with severe monogenic IBDs, including three with X-linked inhibitors of apoptosis protein (XIAP) deficiency and one with interleukin-10 signaling defect, were treated with allo-HSCT with reduced-intensity conditioning. In four patients, the maximum scores of wPCDAI and SES-CD before allo-HSCT ranged from 67.5 to 120 and 20 to 34, respectively. After allo-HSCT, all four patients showed a significant improvement in intestinal inflammation and achieved both clinical and endoscopic remission. Although patients with XIAP deficiency presented with post-transplant hemophagocytic lymphohistiocytosis and a relatively late engraftment, all patients achieved prolonged clinical remission, and IBD medications were successfully discontinued in all patients. CONCLUSION: Allo-HSCT for monogenic IBD resulted in complete clinical resolution with endoscopically confirmed mucosal healing.

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