Yuya Sato

Anti-tumor activity of antizyme which targets the ornithine decarboxylase (ODC) required for cell growth and transformation.

Cell proliferation and transformation induced by growth factor stimulation or by carcinogens, viruses, or oncogenes are characterized by an associated increase in polyamine levels, which is mediated by increased polyamine biosynthesis and enhanced uptake of polyamines. Polyamine biosynthesis is catalyzed particularly, in the level of ornithine decarboxylase (ODC). The elevation of cellular polyamine levels on the other hand accelerates the induction of ornithine decarboxylase antizyme (antizyme), which is involved not only in ODC-degradation, but in the negative regulation of polyamine transport. Taking advantage of these characteristics of antizyme, the potential of antizyme as a factor having anti-cell growth and anti-tumor activity was investigated. We show that antizyme can induce cell death associated with a rapid decline of intracellular polyamine contents. The possible anti-tumor activities of ectopically expressed antizyme were tested in p21H-ras (Val 12)-transformed NIH3T3 cells and several human malignant cell lines including a line with loss of p53 expression, and they were shown to be as sensitive as nontransformed NIH3T3 cells in vitro. The in vivo anti-tumor activity was also tested using nude mice inoculated with H-ras transformed NIH3T3 cells that had been transfected with inducible antizyme expression vector and the results showed that antizyme expression in vivo blocks tumor formation in these mice. These results suggest that ectopic antizyme expression is of possible therapeutic benefit in the treatment of cancer, which is mediated by ODC inactivation and intracellular polyamine depletion.

Chronic active Epstein–Barr virus infection with mosquito allergy successfully treated with reduced‐intensity unrelated allogeneic bone marrow transplantation in a boy

Abstract:  EBV‐infected T‐/NK cells play an important role in the pathogenesis of mosquito allergy, and the prognosis of most patients with mosquito allergy is poor without proper treatment. We describe a 13‐yr‐old boy who had CAEBV with mosquito allergy and was successfully treated with BMT from an unrelated donor after reduced‐intensity preconditioning. Because combination chemotherapy failed to achieve CR, we performed unrelated BMT to reconstitute normal immunity and eradicate any residual EBV‐infected cells. To reduce complications after BMT, we selected a reduced‐intensity preconditioning regimen consisting of fludarabine, l‐phenylalanine mustard, and antithymocyte Ig instead of a conventional myeloablative preconditioning. Although grade II acute GVHD developed, it was successfully controlled with immunosuppressive therapy. After 27 months, the patient has been well without any signs of CAEBV, and the EBV DNA has been undetectable with real‐time PCR analysis. We conclude that RIST from the bone marrow of an unrelated donor is indicated for some patients who have CAEBV that is refractory to chemotherapy and who have no HLA‐matched related donors or cord blood as a source of stem cells.

13-cis-retinoic acid-associated bone marrow edema in neuroblastoma.

To the Editor: Administration of 13-cis-retinoic acid (13-cis-RA) in patients with neuroblastoma has resulted in improved prognosis [1]. However, toxicities of 13-cis-RA have been observed [2]. Bone marrow edema represents a rare complication and is important to differentiate from neuroblastoma relapse. An 8-year-old male presented with neuroblastoma with unfavorable histology according to international neuroblastoma pathology classification, non-amplification of MYCN, and increased of vanillylmandelic acid (VMA), homovanillic acid (HVA), and neuron-specific enolase (NSE). Chemotherapy, irradiation of the abdominal cavity, surgical resection of the adrenal gland and autologous peripheral blood stem cell infusion were preformed. However, residual disease was remained. 13-cis-RA treatment (160 mg/m/day; 14 days followed by 14 days rest) was initiated as a treatment for the residual tumor. Twelve weeks after the onset of 13-cis-RA treatment, the patient presented with severe ankle pain. The magnetic resonance imaging (MRI) identified a low signal intensity lesion on T1 weighted imaging (Fig. 1A) and a high signal intensity lesion on diffusion weighted imaging (Fig. 1B) of the bilateral distal tibias. The

I-131-Metaiodobenzylguanidine therapy with allogeneic cord blood stem cell transplantation for recurrent neuroblastoma.

Iodine-131-metaiodiobenzylguanidine (131I-MIBG) therapy combined with allogeneic cord blood stem cell transplantation (SCT) was used to treat a 4-year-old girl with recurrent neuroblastoma. The patient experienced relapse 2 years after receiving first-line therapies, which included chemotherapy, surgical resection, irradiation, and autologous peripheral SCT. Although 131I-MIBG treatment did not achieve complete remission, the size of the tumor was reduced after treatment. Based on our findings, we suggest that 131I-MIBG treatment with myeloablative allogeneic SCT should be considered as first-line therapy for high-risk neuroblastoma patients when possible.

Clear cell sarcoma of the kidney with calcification and a novel chromosomal abnormality: a case report

A 9-year-old male presented with a renal tumor that showed a cystic structure with calcification on computed tomography. A pathological analysis of the resected tumor suggested clear cell sarcoma of the kidney (CCSK). Thus, this patient suffered atypical CCSK with significant calcification and gross necrosis. A novel chromosomal abnormality was also identified in the tumor.

Paternally inherited WT1 mutation plus uniparental disomy of 11p may be an essential mechanism for development of WT1-mutated familial Wilms tumor

To the Editor: Various abnormalities of theWilms tumor gene-1 (WT1) gene have been detected in 15%–25% of Wilms tumors (WTs)1; however, familial WT harboring a germline WT1 mutation is rare, and only 10 families have been reported to date (Supporting Information Table S1).2–8 Duplication of paternal insulin-like growth factor 2 (IGF2) and loss of maternal imprinting of IGF2 have been frequently detected in WT1mutant WTs,9 and simultaneous abnormalities of the WT1 and IGF2 genes have been shown to play an essential role in the development ofWTs.10 A 10-month-old female developed WT in the left kidney. Her 30-year-old father also had a WT of the same histology when he was 6 months old (Figure 1A). Neither the patient nor her father had congenitalmalformations and had normal renal function. Sequencing analyses of WT1 DNA from normal kidney, tumor tissues and peripheral bloods cells (PBCs) from the patient and her fathers preserved tumor tissues and PBCs performed. The same heterozygous nonsense mutation, p.Y227X/c.681,wasdetected in exon4ofWT1 in thepatients normal kidney tissue and her fathers PBCs. This mutation was homozygous in the tumor samples of the patient and her father (Supporting Information Figure S1). To investigate how the heterozygous mutation in normal tissue became a homozygousmutation in the tumor, a single-nucleotide polymorphism (SNP) arraywas used to evaluate chromosome11 in thenormal and tumor tissues of the patient. The results indicated the presence of uniparental disomy of 11p (11pUPD) in the tumor but not in normal tissues, and this 11pUPD region includes the WT1 and IGF2 loci (Figure 1B). The fathers tumor DNA could not be analyzed by SNP array because of partial DNA degradation. Combined bisulfite restriction analysis of the differentially methylated region of H19 detected only the methylated band, indicating paternal origin of 11pUPD (Figure 1C). Previous studies of familialWTs examinedWT1mutations in normal and tumor tissues of the probands and in the PBCs, but not tumor tissues, of their parents.2–8 This appears to be the first study reporting a WT1 mutation in tumor tissues of the proband and the parent. Parents of probands in whom germlineWT1 mutations were identified but who did not develop WTs have been reported.2,4–7 Those reports indicated that WT1 is a tumor suppressor gene, and biallelic

Necessary stem cell transplantation using myeloablative therapy for myelodysplastic syndrome with progression of genotypic abnormalities and TP53 dysfunction in a young adult.

A 14‐yr‐old male was admitted to our hospital with MDS and the chromosomal abnormality 45,XY,der(5;17)(p10;q10). He rapidly developed karyotype abnormalities, accompanied by the loss of tumor suppressor gene TP53 function. He suffered an early relapse after reduced‐intensity‐conditioning SCT and ultimately required myeloablative therapy before a second SCT. We consider that the analysis of TP53 mutations is essential when planning the treatment of patients with MDS.

Viridans Streptococcal Bacteremia–Related Encephalopathy in Childhood with Malignancy

Viridans streptococcal bacteremia is a prognostic factor in pediatric patients with malignant disease accompanied by severe neutropenia. Here the authors describe 4 patients with viridans streptococcal bacteremia–related encephalopathy who showed serious complications, which included seizures and loss of consciousness. Therapy for relief of brain edema on seizures was started quickly, and included the administration of midazolam, dexamethasone, and mannitol with antimicrobial therapy. The treatment was successfully completed without sequelae. The authors registered 28 episodes of viridans streptococcal bacteremia in their hospital. The peak of serum C-reaction protein was higher in viridans streptococcal bacteremia patients with encephalopathy than in those without encephalopathy. The authors concluded that viridans streptococcal bacteremia can induce encephalopathy in pediatric patients with malignancy and that it is crucial to establish an accurate diagnosis and initiate therapy as soon as possible.