Kensuke Kondoh

Quantification of κ-deleting recombination excision circles in Guthrie cards for the identification of early B-cell maturation defects

In conclusion, the associations among asthma, biofilmforming bacteria, and revision ESS are strong and robust after adjusting for other factors in patients with CRS from a tertiary medical center. Despite its limitations, this study may improve our understanding of refractory CRS pathogenesis, possibly leading to more effective treatment strategies, such as incorporating the treatments of asthma and biofilm infection into conventional CRS therapies. Prospective cohort studies in diverse populations are needed to assess the causality of these associations.

Susceptibility to 6‐MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia

Genotyping of TPMT prior to 6‐mercaptopurine (6‐MP) administration in acute lymphoblastic leukaemia (ALL) patients has been integrated into clinical practice in some populations of European ancestry. However, the comparable rates of 6‐MP myelotoxicity, but rarity of TPMT variants, in Asians suggest that major determinants have yet to be discovered in this population. We genotyped 92 Japanese paediatric ALL patients for NUDT15 rs116855232, a 6‐MP toxicity‐related locus discovered in Asians. Logistic regression and survival analysis were used to evaluate its association with leucopenia, hepatotoxicity, 6‐MP dose reduction, therapy interruption and event‐free survival. The allele frequency of rs116855232 was 0·16, and leucopenia was more common in carriers of the T allele (odds ratio, 7·20; 95% confidence interval, 2·49–20·80; P = 2·7 × 10−4). As leucopenia results in 6‐MP dose reduction, we observed average doses during maintenance therapy of 40·7, 29·3 and 8·8 mg/m2 for patients with CC, CT and TT genotypes, respectively (P < 0·001). Hepatotoxicity was observed only in CC genotype patients. Event‐free survival did not significantly differ by NUDT15 genotype. rs116855232 is an important determinant of 6‐MP myelotoxicity in Japanese children with ALL and may represent the most robust toxicity‐related locus in Asians to date. Considerations for clinical application may be warranted.

The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children

The association between inosine triphosphate pyrophosphatase (ITPA) activity and toxicity of 6-mercaptopurine (6-MP) was retrospectively evaluated in 65 Japanese children with acute lymphoblastic leukemia (ALL). Patients with an ITPA activity of less than 126 μmol/h/gHb presented with hepatotoxicity more frequently than those with higher ITPA activity (p<0.01). The average 6-MP dose during maintenance therapy administered to two patients with the ITPA deficiency was lower than that given to the other patients. Measuring ITPA activity is important for ensuring the safety of maintenance therapy for Asians with ALL because thiopurine S-methyl transferase mutations are rare in the Asian population.

Methylenetetrahydrofolate reductase gene haplotypes affect toxicity during maintenance therapy for childhood acute lymphoblastic leukemia in Japanese patients

Abstract The aim of this study was to investigate the influence of daily 6-mercaptopurine (6-MP) and low-dose weekly methotrexate (MTX) combination treatment and methylenetetrahydrofolate reductase (MTHFR) haplotypes on toxicity during maintenance therapy in Japanese childhood acute lymphoblastic leukemia (ALL). We retrospectively analyzed the MTHFR C677T and A1298C polymorphisms and influence of haplotypes on toxicity in 73 patients. Patients with the MTHFR 677TT and 677CT + 1298AC were associated with severe liver toxicity (p = 0.014, odds ratio [OR] = 3.82, 95% confidence interval [CI] = 1.27–11.46) and more rapid onset of liver toxicity (p = 0.010). Patients with MTHFR 677TT and 677CT + 1298AC were associated with lower frequency of 6-MP and MTX dose reduction due to leukopenia (p < 0.05). No difference was observed in average drug doses in the MTHFR genotypes. In conclusion, the MTHFR C677T and A1298C haplotypes might be useful for monitoring adverse effects in childhood ALL maintenance therapy in Japanese patients.

T-cell large granular lymphocyte leukemia in a child with anemia and Crohn's disease

T‐LGL leukemia has been rarely reported in children. We report a child with T‐LGL leukemia who presented with anemia and went on to develop Crohns disease. Although prednisolone treatment proved effective in the treatment of anemia, large granular lymphocyte counts increased as the doses were tapered. T‐cell rearrangement studies revealed a clonal rearrangement of the TCR Vβ/jβ2 gene. Concurrently, the patient developed severe diarrhea. Inflammatory changes across the upper and lower intestines led to the diagnosis of Crohns disease. This case highlights that T‐LGL leukemia could be occurred in children. Flow cytometry and/or T‐cell gene rearrangement studies are recommend in patients of anemia and various kind of autoimmune diseases including Crohns disease, even in children.

A child with myeloid/natural killer cell precursor acute leukemia treated successfully with acute myeloid leukemia-oriented chemotherapy incorporating l-asparaginase

Myeloid/natural killer (myeloid/NK) cell precursor acute eukemia was initially identified as a leukemia of natural killer (NK) ells, with co-expression of both myeloid and NK cell precursor ntigens [1]. The leukemic cells of myeloid/NK cell precursor acute eukemia are negative for myeloperoxidase staining (<3% of total ells) but positive for CD7, CD56, and myeloid antigens [1]. In comarison with other types of NK malignancy, this disease entity is onsidered to be caused by immature leukemic cells, in terms of orphology, phenotype, and genotype [1]. The prognosis of myeloid/NK cell precursor acute leukemia is eportedly poor. Although chemotherapeutic regimens designed or acute myeloid leukemia (AML) can effective induce comlete remission in patients with myeloid/NK cell precursor acute eukemia, most of them subsequently relapse, and there have been o reports of patients surviving for more than 4 years [1]. To ur knowledge, all previous reports of long-term remission have nvolved patients who underwent hematopoietic stem cell translantation (HSCT) at the time of initial complete remission [2,3]. ecently, l-asparaginase (l-asp) has been shown to induce selective poptosis of NK cell lymphoma cells in vitro [4]. Indeed, successful

Hypocellular acute myeloid leukemia treated with bone marrow transplantation

Hypocellular acute myeloid leukemia (AML) mainly occurs in elderly patients, and is extremely rare in childhood. There is still no established treatment for hypocellular AML. We report the case of an 11‐year‐old boy with hypocellular AML who was treated successfully with allogenic bone marrow transplantation (allo‐BMT). He presented with fever, pallor and pancytopenia. Bone marrow aspiration and biopsy confirmed a diagnosis of hypocellular AML. Although low‐dose cytarabine induced reduction of blasts, it did not lead to complete remission. He subsequently received myeloablative conditioning and allo‐BMT. Graft‐versus‐host disease (GVHD) prophylaxis included short‐course methotrexate and cyclosporine. Neutrophil engraftment (>5 × 108/L) and platelet recovery (>10 × 1010/L) were achieved on days 13 and 27, respectively. He developed acute GVHD of the skin (grade 2), which responded well to treatment with prednisolone. He has remained in complete remission for 5 years since allo‐BMT. We consider allo‐BMT to be feasible for children with hypocellular AML.

High-dose chemotherapy followed by autologous peripheral blood stem cell transplantation for recurrent primary mediastinal malignant germ cell tumor: A case report

A 15‐yr‐old boy presented with an anterior mediastinal mass, multiple lung metastases and obstruction of the left brachiocephalic vein, the superior vena cava and the subclavian vein. Tumor biopsy by CT guidance confirmed a diagnosis of GCT. Five courses of BEP therapy were performed, and CT of the chest revealed reduction in the anterior mediastinal mass and disappearance of the multiple lung metastases. We performed the anterior mediastinal mass extraction followed by adjuvant chemotherapy consisting of ICE and TIP. However, the AFP levels became elevated soon after. Abnormal accumulation was observed in the right upper lung by DW‐MRI. After the operation, two courses of TI chemotherapy and two courses of HDCT followed by auto‐PBSCT were performed. He was complicated with auditory disorder and renal dysfunction. Although HDCT followed by auto‐PBSCT was effective for the relapsed primary mediastinal GCT, a treatment strategy avoiding late complications is warranted.