Tomohei Nakao

The induction of tumor‐specific CD4+ T cells via major histocompatibility complex class II is required to gain optimal anti‐tumor immunity against B16 melanoma cell line in tumor immunotherapy using dendritic cells

Abstract:  We have demonstrated that dendritic cells (DCs) genetically modified to express tumor‐associated antigens (TAAs) with retroviral vectors elicit more potential anti‐tumor effect than those loaded with peptides because they can prime antigen‐specific CD4+ T cells resulting in production of tumor‐specific antibody. In this study, we showed the importance of antigen presentation via a major histocompatibility complex (MHC) class II molecule in cancer immunity against non‐membrane bound TAAs such as the melanoma antigen gp100 by using DCs derived from MHC class II‐deficient mice (C2KO). DCs were prepared by transduction of gp100 cDNA into haematopoietic progenitor cells obtained from C2KO followed by differentiation with cytokines (C2KO‐gp/DCs). When C2KO‐gp/DCs were inoculated into immunocompetent mice, the mice scarcely primed the antigen‐specific Th1 cells and developed fewer CD8 T cells than did those inoculated with transduced DCs prepared from normal mice. The attenuated anti‐tumor effect was also confirmed in a postimmunization setting where, while two of eight control mice eradicated the pre‐existing melanoma cell line B16 (25%), no mice inoculated with C2KO‐gp/DCs did. These results suggested not only the limitation of current protocols using MHC class I‐restricted tumor peptides but also the usefulness of DCs expressing gp100 in vaccine therapy against melanoma.

Genotyping NUDT15 can predict the dose reduction of 6-MP for children with acute lymphoblastic leukemia especially at a preschool age

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

Pediatric nasopharyngeal carcinoma treated with proton beam therapy. Two case reports

Pediatric nasopharyngeal carcinoma (NPC) is one of the most frequent epithelial tumors in children [1]. Combination treatment of photon radiotherapy and chemotherapy is effective for pediatric nasopharyngeal cancer and overall survival has increased to 70 – 80% with advances of chemotherapy regimens and radiotherapy techniques. However, photon radiotherapy for pediatric NPC often causes facial deformity, pituitary dysfunction, and xerostomia, especially in younger children. Here, we report two cases of pediatric NPC treated with proton therapy as an alternative to photon radiotherapy.

FATAL SIBLING CASES OF FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (FHL) WITH MUNC13–4 MUTATIONS: Case Reports

The authors report here sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) type 3 that took fatal courses despite intensive treatment. The older brother achieved remission by immunochemotherapy, but a central nervous system lesion occurred before the introduction of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patient died on day +1 of allo-HSCT due to progression of the disease. The younger brother developed symptoms of hemophagocytic lymphohistiocytosis mimicking neonatal hemochromatosis at birth. He died without a chance to receive allo-HSCT. Both siblings showed low natural killer cell (NK) activity and the compound heterozygous Munc13–4 gene mutations 1596+1 and 1723insA were identified postmortem in the younger brother. With recent progress in the molecular diagnosis of FHL, prompt and most appropriate therapeutic measures should be introduced to improve the prognosis of FHL patients.

Influence of SLCO1B1 polymorphism on maintenance therapy for childhood leukemia

Management of the adverse effects of chemotherapy is essential to improve outcome of children with leukemia. Some genetic polymorphisms can predict treatment‐related toxicity, and be used individually in dose modification of 6‐mercaptopurine (6‐MP) and methotrexate (MTX) in maintenance therapy for childhood acute lymphoblastic leukemia (ALL). We investigated associations between clinical course and candidate gene polymorphisms less evaluated in Japanese patients.

Molecular genetic and cytogenetic analysis of a primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma.

We performed cytogenetic and molecular cytogenetic analyses of a primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, a rare type of primary cutaneous T-cell lymphoma. G-banded analysis at initial diagnosis and recurrence revealed complex karyotype and clonal evolution reflecting genomic instability that parallels the aggressive clinical course observed. Spectral karyotyping revealed numerous structural abnormalities. SNP array-based analysis of an initial diagnostic sample revealed numerous gains and losses of chromosomal material, including loss of short arm of the chromosome 17, to which TP53 is mapped. The molecular cytogenetics and array data of this case suggest genomic instability, particularly chromosomal instability and haploinsufficiency for TP53, the latter possibly giving rise to alteration of p14ARF-Mdm2-p53 tumor suppressor protein pathway, likely to be associated with unfavorable clinical course.

Polymorphisms of MTHFR Associated with Higher Relapse/Death Ratio and Delayed Weekly MTX Administration in Pediatric Lymphoid Malignancies

Backgrounds. Outcome of childhood malignancy has been improved mostly due to the advances in diagnostic techniques and treatment strategies. While methotrexate (MTX) related polymorphisms have been under investigation in childhood malignancies, many controversial results have been offered. Objectives. To evaluate associations of polymorphisms related MTX metabolisms and clinical course in childhood lymphoid malignancies. Method. Eighty-two acute lymphoblastic leukemia and 21 non-Hodgkins lymphoma children were enrolled in this study. Four single nucleotide polymorphisms in 2 genes (MTHFR (rs1801133/c.677C>T/p.Ala222Val and rs1801131/c.1298A>C/p.Glu429Ala) and SLCO1B1 (rs4149056/c.521T>C/p.V174A and rs11045879/c.1865+4846T>C)) were genotyped by Taqman PCR method or direct sequencing. Clinical courses were reviewed retrospectively. Results. No patient who had the AC/CC genotype of rs1801131 (MTHFR) had relapsed or died, in which distribution was statistically different among the AA genotype of rs1801131 (P = 0.004). Polymorphisms of SLCO1B1 (rs11045879 and rs4149056) were not correlated with MTX concentrations, adverse events, or disease outcome. Conclusions. Polymorphisms of MTHFR (rs1801131) could be the plausive candidate for prognostic predictor in childhood lymphoid malignancies.

Pulmonary veno-occlusive disease associated with partial anomalous pulmonary venous connection

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension associated with fibrotic occlusion of small pulmonary veins and venules. 1 There are only few reported cases of PVOD occurring in Asians. 2 Although viral infection, genetic factors, chemical or radiation exposure, and bone marrow transplantation are suggested to be possible underlying pathomechanisms of PVOD, 1 the exact etiology of the disease remains unknown, and definitive therapy has not been established. Recently, vasodilator therapy using intravenous administration of prostacyclin (PGI 2 ) and inhalation of nitric oxide (NO) were introduced in the treatment of patients with primary pulmonary hypertension (PPH). However, while the effectiveness of such therapy has been clinically demonstrated in the literature, use of this therapy in the treatment of PVOD is still controversial. 1,3 We present an infant with PVOD complicating partial anomalous pulmonary venous connection (PAPVC), who was treated with intravenous PGI 2 and NO inhalation.

Parental Post-Traumatic Stress Symptoms as Predictors of Psychosocial Problems in Children Treated for Cancer

The purpose of this study was to explore the association between psychosocial functioning of children treated for cancer and that of their parents. Factors associated with psychosocial functioning were also examined. The present study was a cross-sectional survey of 33 mothers and one father (mean age: 37.9), each of whom had a child that had been treated for cancer. The participants answered a package of questionnaires consisting of the Impact of Event Scale-Revised (IES-R), the Parent Experience of Child Illness (PECI), and the Child Behavior Checklist (CBCL). Information about the children’s illnesses was collected from medical records. The CBCL total problems T score was correlated with the parental IES-R total scores. Intensity of treatment independently predicted the variance of parental long-term uncertainty. In conclusion, psychosocial problems of children with cancer were associated with parental post-traumatic stress symptoms (PTSS). Provision of early, adequate support to parents who are vulnerable to PTSS will help not only the parents, but also their children with cancer.

Continuous regional arterial infusion effective for children with acute necrotizing pancreatitis even under neutropenia

Severe acute pancreatitis is one of the critical conditions that may develop in children with cancer. The leading cause of death due to acute pancreatitis is infectious pancreatitis or circulation collapse. Therefore, patients who develop acute pancreatitis while undergoing chemotherapy or after hematopoietic transplantation are at risk for a life‐threatening and fatal course. We treated 140 patients with malignancy from April 2002 to March 2009 at our hospital and encountered 3 patients under neutropenia who developed severe acute pancreatitis. Two of them were successfully treated with continuous regional arterial infusion of a protease inhibitor and antibiotic even under agranulocytosis. Another patient was treated with conventional therapy with intravenous antibiotics plus a protease inhibitor and total or partial parenteral nutrition. Even though the two patients treated with continuous regional arterial infusion presented much more severe conditions, their symptoms resolved earlier. In conclusion, acute pancreatitis is one of the severe complications of childhood malignancy. Even under agranulocytosis, continuous regional arterial infusion of a protease inhibitor and antibiotic was well tolerated and effective among our cases and might reduce early death due to pancreatitis.