Nationwide study of pediatric B-cell precursor acute lymphoblastic leukemia with chromosome 8q24/MYC rearrangement in Japan.

BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.

Characterization of a large UNC13D gene duplication in a patient with familial hemophagocytic lymphohistiocytosis type 3.

Familial hemophagocytic lymphohistiocytosis (FHL) type 3 is a life-threatening immune dysregulation syndrome caused by mutations in the UNC13D gene, encoding the munc13-4 protein, which is important for function of cytotoxic lymphocytes. FHL3 accounts for 30-40% of FHL cases, and more than 100 mutations in the UNC13D gene have been described to date. We describe the first case of FHL3 carrying an intragenic duplication of UNC13D, apparently mediated by recombination of Alu elements. NK cell degranulation and munc13-4 protein expression assays are useful for early identification of such mutations, which may be missed by analysis of genomic DNA alone.

Role of Second Transplantation for Children With Acute Myeloid Leukemia Following Posttransplantation Relapse.

BACKGROUND: In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) in first remission is indicated for patients with a relatively high risk of relapse. Second HSCT is a curative option; however, few reports have been published about a second HSCT in children for AML with posttransplantation relapse. PROCEDURE: Using the database provided by the Japanese Society of Hematopoietic Cell Transplantation, we analyzed 46 children with AML who underwent a second allogeneic HSCT after achieving a second remission. RESULTS: The median duration from the first to second HSCT was 20 months, and the source of the second HSCT was related bone marrow (BM) in 22, related peripheral blood in 6, unrelated BM in 14, and unrelated cord blood in 4 patients. Twenty-five children eventually died of the following causes: progressive disease in 14 and transplant-related toxicities in 9. The 5-year overall survival rate was 41.7 ± 7.7%. An interval of less than 24 months between the first and second HSCT was a significant poor prognostic factor. CONCLUSIONS: Children with AML who experience a relapse after HSCT in first remission have a good chance of survival with a second HSCT if a second remission is achieved.

TKI dasatinib monotherapy for a patient with Ph-like ALL bearing ATF7IP/PDGFRB translocation.

We report a 10-year-old male with relapsing Ph-like acute lymphoblastic leukemia (ALL) bearing ATF7IP/PDGFRB translocation. He was refractory to conventional therapy, and was finally treated with single-agent second-generation TKI dasatinib. The therapeutic response was prompt, with the disappearance of minimum residual disease (MRD) based on genomic PCR analysis within 3 months, and he has maintained complete molecular remission for 12 months. This case report describes an early-phase response to TKI monotherapy on Ph-like ALL, and technical tips for MRD monitoring on long-term follow-up.

Early onset epileptic encephalopathy caused by de novo SCN8A mutations.

OBJECTIVE: De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs). METHODS: A total of 163 patients with EOEEs without mutations in known genes, including 6 with malignant migrating partial seizures in infancy (MMPSI), and 60 with unclassified EOEEs, were analyzed by target capture (28 samples) or whole-exome sequencing (135 samples). RESULTS: We identified de novo SCN8A mutations in 7 patients: 6 of 60 unclassified EOEEs (10.0%), and one of 6 MMPSI cases (16.7%). The mutations were scattered through the entire gene: four mutations were located in linker regions, two in the fourth transmembrane segments, and one in the C-terminal domain. The type of the initial seizures was variable including generalized tonic-clonic, atypical absence, partial, apneic attack, febrile convulsion, and loss of tone and consciousness. Onset of seizures was during the neonatal period in two patients, and between 3 and 7 months of age in five patients. Brain magnetic resonance imaging (MRI) showed cerebellar and cerebral atrophy in one and six patients, respectively. All patients with SCN8A missense mutations showed initially uncontrollable seizures by any drugs, but eventually one was seizure-free and three were controlled at the last examination. All patients showed developmental delay or regression in infancy, resulting in severe intellectual disability. SIGNIFICANCE: Our data reveal that SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified EOEEs, and rarely as MMPSI. Together with previous reports, our study further indicates that genetic testing of SCN8A should be considered in children with unclassified severe epilepsy.

ATF7IP as a novel PDGFRB fusion partner in acute lymphoblastic leukaemia in children.

We identified ATF7IP as a novel PDGFRB fusion partner in B-progenitor acute lymphoblastic leukaemia (B-ALL) and showed that B-ALL with ATF7IP/PDGFRB translocation is included within the genomic lesions of a Philadelphia chromosome (Ph)-like ALL subgroup. Comprehensive analyses of previous repositories of gene expression data sets disclosed that B-ALL cases with high PDGFRB expression level in the context of the Ph-like ALL gene are likely to have a PDGFRB translocation. Thus, it is possible that measurement of the PDGFRB expression level can be utilized as a screening test for the detection of the cryptic PDGFRB translocation, especially within the Ph-like ALL subgroup.

Spread of CTX-M-15 extended-spectrum ß-lactamase-producing Escherichia coli isolates through household contact and plasmid transfer.

We document the household spread of extended-spectrum ß-lactamase-producing Escherichia coli. One isolate belonged to sequence type 1193 and caused urinary tract infection in a 4-month-old female, and the other isolate belonged to sequence type 131 and colonized three family members, including the index patient. These isolates carried similar Inc-I1-Iγ plasmids, harboring blaCTX-M-15.

Outcomes of childhood pulmonary arterial hypertension in BMPR2 and ALK1 mutation carriers.

Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and the activin receptor-like kinase 1 (ALK1) gene have been reported in heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH). However, the relation between clinical characteristics and each gene mutation in IPAH and HPAH is still unclear, especially in childhood. The aim of this study was to determine, in a retrospective study, the influence and clinical outcomes of gene mutations in childhood IPAH and HPAH. Fifty-four patients with IPAH or HPAH whose onset of disease was at <16 years of age were included. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared in BMPR2 and ALK1 mutation carriers and noncarriers. Overall 5-year survival for all patients was 76%. Eighteen BMPR2 mutation carriers and 7 ALK1 mutation carriers were detected in the 54 patients with childhood IPAH or HPAH. Five-year survival was lower in BMPR2 mutation carriers than mutation noncarriers (55% vs 90%, hazard ratio 12.54, p = 0.0003). ALK1 mutation carriers also had a tendency to have worse outcome than mutation noncarriers (5-year survival rate 64%, hazard ratio 5.14, p = 0.1205). In conclusion, patients with childhood IPAH or HPAH with BMPR2 mutation have the poorest clinical outcomes. ALK1 mutation carriers tended to have worse outcomes than mutation noncarriers. It is important to consider aggressive treatment for BMPR2 or ALK1 mutation carriers.

Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection.

We report two patients with chronic granulomatous disease (CGD). The first patient presented with granulomatous colitis and pulmonary aspergillosis, and the second patient with liver abscess and restrictive pulmonary disorder. Both patients underwent allogeneic hematopoietic stem cell transplantation, the first from an HLA-matched sibling donor, and the second from an HLA-matched unrelated donor, after preconditioning with fludarabine, anti-thymocyte globulin, cyclophosphamide, and total-body irradiation of 3 Gy. The engraftment was prompt and the regimen-related toxicity was mild. The patients are able to return to their daily lives with full donor chimerism, although the second patient underwent a living-related-donor orthotopic liver transplantation from his mother for chronic liver graft-versus-host disease. The conditioning regimen we used was feasible and applicable to patients with CGD accompanied by inflammatory disease and severe infection.

Improvement of vitamin D status in Japanese institutionalized elderly by supplementation with 800 IU of vitamin D(3).

To study the adequate intake (AI) for vitamin D in the elderly, we have performed an intervention study with 800 IU/d of vitamin D(3) in the institutionalized elderly. Sixty-two institutionalized elderly were randomly assigned to two groups; receiving either supplements of 200 mg calcium plus 800 IU vitamin D(3)/d (Ca+VD group), or supplements of 200 mg calcium/d (Ca group) for 30 d in October. Serum concentrations of 25-hydroxyvitamin D (25OH-D), parathyroid hormone (PTH), and bone turnover markers were measured before and after intervention. Average dietary vitamin D intake during the intervention period was approximately 300 IU/d in both groups, exceeding the AI in Dietary Reference Intakes for Japanese 2005 of 200 IU/d. In both groups, mean serum 25OH-D level at baseline fell into the hypovitaminosis D range (9.7 ng/mL), despite apparently adequate vitamin D intake. Serum PTH level at baseline was within the reference range. Mean serum 25OH-D concentration significantly increased to 19.3 ng/mL in the Ca+VD group and to 11.1 ng/mL in the Ca group. Post intervention serum 25OH-D level was significantly higher in the Ca+VD group than in the Ca group (p<0.001). In 53 subjects (85.5%) who took more than 80% of their supplements for 30 d, serum PTH level in the Ca+VD group was significantly lower than in the Ca groups (p=0.05). Bone turnover markers were not significantly changed after intervention in either group. Daily supplementation of 800 IU vitamin D(3) was considered effective in the institutionalized elderly with minimal chance of sun exposure, but further studies with longer duration are necessary.

IgA nephropathy associated with leukemia and lymphoma: report of two cases.

IgA nephropathy (IgAN) associated with leukemia and lymphoma has not, to our knowledge, been reported in children. Two children suffering from these diseases are described here. One patient developed IgAN at the end of 5 years' chemotherapy for acute lymphocytic leukemia. The other had microscopic hematuria 3 years before the onset of non-Hodgkin lymphoma, and hematuria continued during chemotherapy. Each disease occurred after a long interval, and the clinical courses did not run parallel. The association was thought to be incidental in our cases. Chemotherapy with adrenocorticosteroids and immunosuppressants [6-mercaptopurine (6-MP) and cyclophosphamide (CY)] for leukemia and lymphoma did not affect the clinical course of IgAN.

Dental management of pediatric patients undergoing hematopoietic stem cell transplant.

This study was conducted to evaluate the outcomes of a dental management program the authors designed for pediatric patients receiving hematopoietic stem cell transplant (HSCT) for hematological malignancy. Thirty pediatric patients with hematological malignancies received dental management before HSCT. The outcomes of the dental management and any episode of odontogenic complication were retrospectively evaluated. The pretransplant oral examination showed one or more dental pathologies in 19 children (63.3%), and the remaining 11 patients showed no dental pathologies. Fifteen of the 19 children with dental pathologies received dental treatment, which included restoration, tooth-brushing instruction, scaling, endodontic therapy for permanent teeth, and extraction of primary teeth. No odontogenic infection occurred in any patient during the immunosuppressive period.