Biomedical subjects

Atsushi Kikuta

Publications and source records attributed to Atsushi Kikuta.

12 recordsLinked to original sources

PubMed2007

Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma.

BACKGROUND: Despite the progress of therapy, about 25% of patients with hepatoblastoma succumb to the disease. Prognostic factors, as well as improved therapies, are needed for these patients. We investigated the incidence and clinical significance of genetic and epigenetic aberrations in hepatoblastoma. PROCEDURE: beta-catenin mutation was analyzed by sequencing and promoter hypermethylation of the RASSF1A and SFRP genes by methylation-specific PCR after bisulfate treatment of DNA samples from 39 hepatoblastomas. Association of the clinical and biological features, including sex, age of patients, stage of the disease, the histological type, and the beta-catenin and RASSF1A status with overall survival was evaluated using univariate and multivariate analysis. RESULTS: beta-catenin mutation and RASSF1A methylation were found in 22 (56.4%) and 15 (38.5%) of 39 hepatoblastomas, respectively, but SFRPs methylation was not found in any of them. RASSF1A and SFRPs were unmethylated in five adjacent normal liver tissues. Patients with a RASSF1A methylated tumor were older in age (>or=2 years, P=0.036), at more advanced stages (P=0.009), and had more frequent beta-catenin mutation (P<0.001) and poorer outcome (P<0.001) than those with a RASSF1A unmethylated tumor. While univariate analysis showed the prognostic significance of age, stage, the histological type, and the beta-catenin and RASSF1A status, multivariate analysis showed only the RASSF1A methylation status as an independent factor predicting outcome (relative risk, 10.51; 95% CI, 1.21 approximately 90.97; P=0.033). CONCLUSIONS: RASSF1A methylation may be a novel molecular-genetic marker for treatment outcome in hepatoblastoma if confirmed by studies examining a larger number of hepatoblastomas.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Association of 11q loss, trisomy 12, and possible 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor.

We evaluated the WT1 and IGF2 status and performed chromosome and/or comparative genomic hybridization analysis in 43 tumor samples from patients with Wilms tumor. On this basis, we classified them into 4 groups: WT1 abnormality, loss of heterozygosity (LOH) of IGF2, loss of imprinting (LOI) of IGF2, and retention of imprinting (ROI) of IGF2, which were seen in 12%, 30%, 16%, and 42% of the tumors, respectively. Patients in the LOI group were older than those in other groups (P < 0.01), and tumors in the WT1 group had fewer cytogenetic changes than did those in the other groups (P < 0.01). It was found that 11q- and +12 were more frequent in the LOI group than in the WT1+LOH+ROI group (P < 0.01 and P < 0.01). There was no difference in the incidence of 16q- between the LOI group and the other groups; however, when we excluded 16 tumors with LOH on 11p15, 16q- tended to be more frequent in the LOI group than in the WT1+ROI group (P = 0.06). The association of 11q- or +12 with LOI of IGF2 found in the present study suggests that many tumors with no WT1 abnormalities need overexpression of IGF2 together with biallelic inactivation of the tumor-suppressor gene on 11q and/or overexpression of growth-promoting genes on chromosome 12. The 11q gene may code for one of the proteins that constitute a CTCF insulator complex, and its mutation, deletion, or haploinsufficiency may cause insulator abnormalities that might lead to LOI of IGF2.

Child↗

PubMed2006

Hemolytic disease of the newborn due to anti-Di: a case study and review of the literature.

BACKGROUND: The severity of hemolytic disease of the newborn (HDN) due to Diego(b) (Di(b)) mismatch ranges from no symptoms to severe jaundice that requires exchange transfusion (ET). The clinical significance of anti-Di(b) is incompletely recognized. CASE REPORT: A male newborn, referred with jaundice, was revealed to have HDN due to Di(b) mismatch and was treated successfully with phototherapy and high-dose intravenous gamma globulin (IVGG). STUDY DESIGN AND METHODS: The literature of HDN caused by Di(b) mismatch was reviewed. The cases were classified into three groups according to their severity: the mildest needed no therapy (NO), the moderate group received phototherapy alone (PHOTO), and the most severe was treated with ET and/or high-dose IVGG therapy plus phototherapy (ET/IVGG). RESULTS: Among 27 cases of HDN due to Di(b) reported to date, 10, 6, and 11 cases required NO, PHOTO, and ET/IVGG, respectively. A significant correlation (p < 0.01) was found between the maternal anti-Di(b) titer and the severity of the disease when the ET/IVGG group was compared with the NO group. All mothers of the group that needed ET/IVGG had an anti-Di(b) titer of 64 or greater. CONCLUSION: A maternal high titer (> or =64) of anti-Di(b) is associated with a higher risk of severe hyperbilirubinemia for mismatched newborns.

Erythroblastosis, Fetal↗

PubMed2006

Collection by a simple bag method and the function of granulocytes in granulocyte transfusion.

Granulocyte transfusion is effective for treating some intractable infections. We have recently developed a simple bag method for collecting granulocytes without using apheresis. A recombinant human granulocyte colony-stimulating factor (G-CSF) (50, 100, 200, and 400 microg nartograstim) was administered to 5 healthy male adult volunteers. The quantity and quality of the collected granulocytes were evaluated. The G-CSF dose proportionally increased the collected neutrophil count. The count of collected neutrophils correlated strongly with the count before collection (r2 = 0.684; P < .001). The neutrophil counts collected from 200 mL whole blood were 0.90 x 10(9), 1.68 x 10(9), 2.40 x 10(9), and 2.99 x 10(9) at 50, 100, 200, and 400 microg G-CSF, respectively. There was no significant difference in neutrophil counts between the 200-microg and 400-microg doses. doses. Concerning granulocyte functions, active oxygen production and phagocytic capacity were not affected by irradiation with 15 Gy. Transient arthralgia occurred in 2 subjects. A single administration of 200 microg G-CSF enabled the collection of large quantities of granulocytes by the bag method. We consider that the collection of granulocytes by the bag method from 400 mL of whole blood drawn twice can theoretically provide 3 x 10(8)/kg of granulocytes for treating children weighing less than 30 kg.

Adult↗

PubMed2003

Clinical and genetic characteristics of Japanese Burkitt lymphomas with or without leukemic presentation.

To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis using MYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream of MYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients (P = .003); however, the incidence rates of TP53 mutation, p16INK4a deletion, and p15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.

Adolescent↗

PubMed2003

Transcriptional profiling in hepatoblastomas using high-density oligonucleotide DNA array.

Hepatoblastoma is a common hepatic tumor in children. Although evidence regarding cytogenetic and molecular genetic alterations in hepatoblastomas has been reported, the molecular events affecting the biologic characteristics of this tumor, including alterations of the gene expression profile, are largely unknown. To identify genes differentially expressed between nondiseased liver (NDL) and hepatoblastoma tumor (HBT), we analyzed the gene expression profile in 14 NDL and 16 HBT samples using a high-density oligonucleotide DNA array. Using Mann-Whitney U test followed by the k-nearest neighbor algorithm, we identified 26 genes (predictor genes) that were able to assign unknown samples derived from NDL and HBT to either the NDL group or HBT group with 100% accuracy. Using a cross-validation approach, we confirmed that the k-nearest neighbor algorithm assigned the particular samples derived from NDL and HBT to either the NDL or HBT group with 93.3% (28/30 samples) accuracy. In the 26 predictor genes, we found alteration of the expression of genes regulating cell division (NAP1L1, STMN1, CCNG2, and CDC7L1) and tumor cell growth (IGF2 and IGFBP4) in HBT. Four predictor genes (ETV3, TPR, CD34, and NR1I3) were also found to be mapped to the chromosomal region 1q21 approximately q32, which has been reported to be frequently involved in the development of hepatoblastoma. The findings obtained in this study suggest that alteration of the expression of some genes regulating cell division and tumor cell growth may be characteristics of the gene expression profile in HBT, and that alteration of the expression of the four predictor genes mapped to chromosomal region 1q21 approximately q32 may also contribute to the differences in gene expression profile between NDL and HBT.

Child↗

PubMed2002

Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program.

We retrospectively analyzed results for 154 patients with acquired severe aplastic anemia who received bone marrow transplants between 1993 and 2000 from unrelated donors identified through the Japan Marrow Donor Program. Patients were aged between 1 and 46 years (median, 17 years). Seventy-nine donor-patient pairs matched at HLA-A, -B, and -DRB1 loci, as shown by DNA typing. Among the 75 mismatched pairs, DNA typing of 63 pairs showed that 51 were mismatched at 1 HLA locus (18 HLA-A, 11 HLA-B, 22 HLA-DRB1) and 12 were mismatched at 2 or more loci. Seventeen patients (11%) experienced either early or late graft rejection. The incidence of grade III/IV acute graft versus host disease and chronic graft versus host disease was 20% (range, 7%-33%) and 30% (range, 12%-48%), respectively. Currently, 99 patients are alive, having survived for 3 to 82 months (median, 29 months) after their transplantations. The probability of overall survival at 5 years was 56% (95% confidence interval, 34%-78%). Multivariate analysis revealed the following unfavorable factors: transplantation more than 3 years after diagnosis (relative risk [RR], 1.86; P =.02), patients older than 20 years (RR, 2.27; P =.03), preconditioning regimen without antithymocyte globulin (RR 2.28; P =.04), and HLA-A or -B locus mismatching as determined by DNA typing. Matching of HLA class I alleles and improvement of preparative regimens should result in improved outcomes in patients with severe aplastic anemia who receive transplants from unrelated donors.

Adolescent↗

PubMed2002

Cryptic t(12;15)(p13;q26) producing the ETV6-NTRK3 fusion gene and no loss of IGF2 imprinting in congenital mesoblastic nephroma with trisomy 11: fluorescence in situ hybridization and IGF2 allelic expression analysis.

In the present fluorescence in situ hybridization (FISH) study of six congenital mesoblastic nephromas (CMNs) using ETV6 and NTRK3 probes as well as a chromosome 15 painting probe, we identified a cryptic reciprocal translocation, t(12;15)(p13;q26), in one tumor, and an insertion, ins(12;15)(p13;q22q26), in another that were not previously identified by cytogenetic analysis. An interphase FISH study with the same probes detected the ETV6-NTRK3 fusion signal in all three cellular or mixed type tumors, but not in all three classical type tumors. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis detected the ETV6-NTRK3 fusion transcript in the three cellular or mixed type tumors, but not in the three classical type tumors. FISH analysis using a chromosome 11-centromere probe detected trisomy or tetrasomy 11 in all three tumors with the ETV6-NTRK3 fusion signal. To clarify whether IGF2, a paternally expressed gene on chromosome 11, has a certain role in the tumorigenic process of CMN through a loss of imprinting (LOI), we studied IGF2 allelic expression. We found no LOI in two cellular or mixed type tumors or in two classical type tumors, and concluded that the role of the LOI of IGF2 is not essential for the development and progression of CMN with or without trisomy 11. Furthermore, we showed no rearrangements of the MLL gene, which is frequently rearranged in acute leukemia with +11 in the three CMN tumors with +11.

Alleles↗

PubMed2002

Treatment for the decline of ionized calcium levels during peripheral blood progenitor cell harvesting.

BACKGROUND: ACD-A solution containing sodium citrate and citric acid is used as an anticoagulant agent during peripheral blood progenitor cell (PBPC) harvesting, and in rare cases can cause fatal citrate intoxication. The aim of this study was to establish effective methods for stabilizing ionized calcium (ICa) levels during PBPC harvesting. STUDY DESIGN AND METHODS: ICa was measured during 46 apheresis procedures conducted in 26 patients. Four patients in four procedures were infused with calcium gluconate solution before PBPC harvesting; three patients in six procedures were infused with calcium gluconate when symptoms of citrate intoxication appeared; and four patients in five procedures received a continuous infusion. Five patients in five procedures took an isotonic sports drink containing calcium when hypocalcemic symptoms appeared. The ICa level, blood pressure, and pulse rate were measured. RESULTS: ICa declined rapidly from the preapheresis level of 1.081(+/-0.092) mM to 0.937(+/-0.081) mM (13.3%, p < 0.0001) 10 minutes after the start of apheresis and continued to decline until the completion of the procedure. When patients received a continuous infusion of calcium during apheresis, ICa was relatively stabilized. ICa significantly rose (6.1 +/- 3.6%, p < 0.02) within 2 to 5 minutes after oral intake of an isotonic sports drink containing calcium and was maintained within normal range for 31 to 55 minutes. CONCLUSION: An isotonic sports drink containing calcium has a quick stabilizing and a longer maintenance effect on ICa. Thus, we recommend the intake of an isotonic sports drink containing calcium as the easiest and best method for preventing hypocalcemia during apheresis.

Administration, Oral↗

PubMed2002

HLA-identical sibling peripheral blood stem cell transplantation in children and adolescents.

Allogeneic peripheral blood stem cell transplantation (PBSCT) was performed in children and adolescents for the treatment of malignant (n = 49) and nonmalignant hematological disease (n = 8). Granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCs were apheresed from 57 HLA-matched siblings aged 9 months to 24 years (median, 8 years) without any serious adverse, effects. No abnormalities were found in these donors for a median follow-up of 25 months (range, 6-56 months). Patients were conditioned with a TBI-containing regimen (n = 17) or a non-TBI regimen (n = 40). GVHD prophylaxis consisted of methotrexate (MTX) plus cyclosporine A (CSP) for 23 patients, CSP plus methylprednisolone (mPDN) for 22 patients, MTX only for 7 patients, CSP only for 4 patients, and MTX plus CSP plus mPDN for 1 patient. Engraftment was prompt, with a median number of days to reach an absolute neutrophil count (ANC) above 0.5 x 10(9)/L of 13 days (range, 8-23 days), with 1 graft failure. Acute GVHD (grades II-IV) occurred in 8 (16%) of 49 evaluable patients, and chronic GVHD developed in 23 (64%) of 36 evaluable patients. Notably, two thirds of chronic GVHD was extensive. The Kaplan-Meier estimate of 3-year disease-free survival was 0% for refractory disease (n = 6), 37.2% +/- 11.8% for high-risk malignancies (n = 25), 81.4% +/- 9.7% for standard-risk malignancies (n = 18), and 100% for nonmalignant disease (n = 8). The estimated 100-day nonrelapse mortality rate was 9.9% +/- 4.2%. In conclusion, allogeneic PBSCT is feasible in a pediatric population. Although the grade of acute GVHD was set low, as in Japanese BMT studies, the incidence and severity of chronic GVHD appears to be relatively high. For nonmalignant disease, the question arises of whether the higher incidence and severity of chronic GVHD is a drawback of this procedure. For high-risk malignancies, whether or not a graft-versus-leukemia effect prevents relapse needs to be clarified in future comparative studies with BMT.

Adolescent↗

PubMed2002

Minimal residual disease in early phase of chemotherapy reflects poor outcome in children with acute lymphoblastic leukemia--a retrospective study by the Children's Cancer and Leukemia Study Group in Japan.

We analyzed the minimal residual disease (MRD) in 50 children with acute lymphoblastic leukemia (ALL) by amplifying the clonally rearranged T-cell receptor (TCR) gamma/delta chain and/or immunoglobulin (Ig) kappa chain gene using the allele-specific-PCR method. All children were treated according to the protocols of the Children's Cancer and Leukemia Study Group of Japan (CCLSG). The patients were stratified into four risk-groups according to the leukocyte count and age at diagnosis. We prospectively sampled the patients' bone marrow at 1 month (point 1) and 3 months (point 2) after the initiation of chemotherapy and quantitated the MRD retrospectively. The results of MRD were closely related with the clinical outcome. The relapse rate of the patients MRD-positive at points 1 and 2 was 46% (6/13) and 86% (6/7), respectively, whereas those MRD-negative results at point 1 and 2 were 13% (3/13) and 3% (3/30), respectively. We found significant differences in the event-free survival between MRD-positive children and MRD-negative children like the reports, which have been made by BFM and EORTC groups. We conclude that MRD in an early phase of chemotherapy can be a good predictor of the prognosis of childhood ALL regardless of the protocol of chemotherapy or race.

Adolescent↗

PubMed2002

[Successful treatment with combined anti-thymocyte globulin and methylprednisolone for bronchiolitis obliterans after allogeneic bone marrow transplantation in a child with chronic myelogenous leukemia].

A 9-year-old boy with secondary chronic myelogenous leukemia after treatment of acute lymphoblastic leukemia underwent allogeneic bone marrow transplantation (BMT) from an HLA-identical sibling in December 1998. Grade II acute GVHD developed on day 24 and chronic GVHD developed 5 months after BMT. Cough and dyspnea appeared 9 months after BMT. Despite administration of tacrolimus and methylprednisolone (m-PSL) pulse therapy, the dyspnea gradually increased in severity. Bronchiolitis obliterans was diagnosed on the basis of lung biopsy in January 1999. Because renal dysfunction made it difficult to continue the use of tacrolimus, we attempted antithymocyte globulin (ATG) + m-PSL therapy. Major BCR/ABL mRNA was transiently positive on RT-PCR after the ATG + m-PSL therapy, but no severe complications were observed. A decreasing V50/V25 level and increasing peak flow value were observed in respiratory function tests after ATG + m-PSL therapy, and the patient is currently free of dyspnea. Our findings suggest that ATG + m-PSL therapy is beneficIal for patients with drug-resistant bronchiolitis obliterans after BMT.

Anti-Inflammatory Agents↗