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Biomedical subjects

R Hanada

Publications and source records attributed to R Hanada.

At least 19 recordsLinked to original sources
PubMed2008

Neuroblastoma presenting with dilated cardiomyopathy.

We report an infant with neuroblastoma who presented with dilated cardiomyopathy. A 3-month-old girl presented with dilated cardiomyopathy diagnosed as stage III neuroblastoma. Since total resection was impossible, chemotherapy was started. Cardiomyopathy was normalized by improvement of neuroblastoma. The prompt improvement of cardiac function following treatment of neuroblastoma suggested that cardiomyopathy in this patient was caused by the increase in catecholamines secreted by neuroblastoma and that reduction in catecholamines by treatment of neuroblastoma led to improvement in the cardiomyopathy.

Cardiomyopathy, Dilated↗
PubMed2002

Chronic active Epstein-Barr virus infection (CAEBV) successfully treated with allogeneic peripheral blood stem cell transplantation.

We report a pediatric case of CAEBV and T cell-based Hodgkin's-like disease successfully treated with allo PBSCT from an HLA-matched sibling. The diagnosis of CAEBV was made from clinical signs and the presence of the EBV genome in PBMC and tumor cells. Conditioning with busulfan (BU) + etoposide (VP16) + cyclophosphamide (CY) was effective and well tolerated. EBV was totally eradicated by 3 months after allo PBSCT. Although she suffered from chronic GVHD of the liver, she has been well and free of disease for 47 months since PBSCT. We suggest allo PBSCT for CAEBV as a potent therapeutic strategy for eradication of the EBV genome and allowing immunological reconstitution.

Antineoplastic Agents↗
PubMed2001

A role for neuromedin U in stress response.

Neuromedin U (NMU) is a hypothalamic peptide that has been recently found to reduce food intake, but few is known about its other functions in the central nervous system. We here studied behavioral activities induced by an intracerebroventricular (ICV) administration of NMU in rats and mice. NMU increased gross locomotor activity, face washing behavior, and grooming. NMU-induced stress response was significantly abolished by pretreatment with an antagonist of corticotropin-releasing hormone (CRH), alpha-helical CRH (9-41) (alpha-hCRH), or anti-CRH IgG. NMU did not induce locomotor activity in CRH knockout mice. NMU that interacts anatomically and/or functionally with the CRH system is a novel physiological regulator of stress response.

Animals↗
PubMed2001

Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma.

We previously reported a high incidence of loss of heterozygosity (LOH) on chromosome 2q33 in neuroblastoma (NB), observed in various types of human cancers including lung cancer, head and neck cancer and follicular thyroid carcinoma. To better elucidate the role of chromosome 2q aberrations in NB, we examined common allelic imbalance (AI) regions on chromosome 2q in 82 NB patients using 10 polymorphic microsatellite markers. AI on 2q was detected in 26 (32%) of 82 NB cases. There was a distinct common AI region between the D2S115 and D2S307 markers on 2q33. The distance between these markers was about 2.0 cM. Recently, the caspase 8 and caspase 10 genes, both of which encode cystein protease, were mapped to chromosome 2q33. Since the common AI region on 2q33 includes the caspase 8 and caspase 10 genes, the alterations of these genes were examined further. Absent or reduced expression of caspase 8 and caspase 10 were found in 19 (70%) of 27 and two (7%) of 27 NB cell lines by reverse transcription-polymerase chain reaction, respectively. A missense mutation was detected at codon 96, GCT (Alanine) to GTT (Valine), of the caspase 8 gene in one of the NB cell lines lacking caspase 8 expression. Thirteen (68%) of 19 cell lines lacking caspase 8 expression displayed methylation of the CpG island of the caspase 8 gene, whereas only one (13%) of eight cell lines with caspase 8 expression showed caspase 8 methylation (P=0.031). Furthermore, there was a significant association between AI at 2q33 and loss of caspase 8 expression (P=0.026). These results indicated that there was a tumor suppressor gene in the common AI region on chromosome 2q33 involved in the pathogenesis of a subset of NB. It is possible that the caspase 8 gene is one of the candidate tumor suppressor genes for NB and inactivation of this gene plays an important role in the tumorigenesis of NB through mainly its methylation.

Allelic Imbalance↗
PubMed2001

Delay of the diagnostic lumbar puncture and intrathecal chemotherapy in children with acute lymphoblastic leukemia who undergo routine corticosteroid testing: Tokyo Children's Cancer Study Group study L89-12.

PURPOSE: To determine the effects of eliminating initial lumbar punctures in 418 consecutively treated children with acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Patients were enrolled onto a trial conducted in central Japan between 1989 and 1992. Treatment consisted of standard four-drug induction therapy followed by a risk-based intensification phase, reinduction therapy, late intensification, and remission maintenance therapy (total of 104 weeks). The initial lumbar puncture, with an intrathecal injection of chemotherapy, was performed after 1 week of prednisolone sensitivity testing (day 8). End points included response to prednisolone, CNS status at the time of the day 8 lumbar puncture, subsequent adverse events in CNS and bone marrow, and event-free survival (EFS). RESULTS: The remission induction rate was 93.1% with a 6-year EFS rate (+/- SE) of 68.7% +/- 2.4%, which is similar to historical results for patients who received their diagnostic lumbar puncture and first instillation of intrathecal chemotherapy on day 0. Overall, 84.5% of the patients had good responses to prednisolone, whereas 15.5% had poor responses. Clinical outcome was strikingly better for the good responders (6-year EFS, 74.1% +/- 2.5% compared with 40.1% +/- 6.4% for patients with poor responses), suggesting that omission of intrathecal chemotherapy did not alter the predictive value of drug sensitivity testing. Eighteen patients experienced CNS relapse as their first adverse event (cumulative risk, 5.1%; 95% confidence interval, 2.7% to 7.4%), coincident with reports from groups using conventional strategies of CNS clinical management. Bleeding into the CSF at the time of the day 8 lumbar puncture was apparent in 29 cases (8.1%), but leukemic blasts were identified in only two. CONCLUSION: Delay of the initial lumbar puncture and intrathecal injection of chemotherapy seems to be feasible in children with ALL. Further controlled evaluations are needed to establish the validity of this conclusion.

Adolescent↗
PubMed2001

Surgical treatment for abdominal neuroblastoma in the laparoscopic era.

BACKGROUND: The role of laparoscopy in children with cancer has not been fully defined. The aims of this study were to develop an optimal surgical procedure for the treatment of abdominal neuroblastoma in the laparoscopic era and to evaluate the advantages and disadvantages of laparoscopy in the pediatric population. METHODS: Since July 1997, 37 children were diagnosed with abdominal neuroblastoma at our center, and 44 surgical procedures were performed on them. Patients with advanced neuroblastoma underwent laparoscopic biopsy, open biopsy, and delayed primary or second-look excision, whereas early neuroblastoma cases had either laparoscopic or open excision. We compared the length of the operation, intraoperative blood loss, length of hospital stay, complications, and time to start postoperative feeding and chemotherapy for the laparoscopic and open surgery groups. RESULTS: Length of stay and time to postoperative feeding and chemotherapy were significantly lower in the laparoscopic group than the open surgery group. However, there were no significant differences between the two groups in length of operation and intraoperative blood loss. CONCLUSION: Laparoscopic biopsy and excision of abdominal neuroblastoma are effective and efficient surgical procedures in children.

Abdominal Neoplasms↗
PubMed2001

Coduplication of the MLL and FLT3 genes in patients with acute myeloid leukemia.

Tandem duplication (TD) of the MLL or FLT3 gene in acute myeloid leukemia (AML) has been reported. We examined whether TD of these two genes occurs simultaneously. We analyzed 13 AML and 2 myelodysplastic syndrome patients, including 6 adult patients with trisomy 11 and 9 pediatric patients with TD of the FLT3 gene, using RT-PCR followed by sequencing. Among these, TD of the MLL and FLT3 genes was found in 5 and 10 patients, respectively. Notably, TD of both the MLL and FLT3 genes (coduplication) was detected in two AML patients, who died 6 and 14 months after diagnosis. TD of these two genes in AML is rare; thus, coduplication of these genes in the same patient is predicted to be very rare. Although the mechanisms of TD of both genes are different, development of TD of both genes may be related to an unknown similar etiology in leukemia because the frequency of coduplication of these genes in a single patient is considered to be very low. Further studies of the coduplication of these genes in AML patients may lead to the clarification of its mechanism and clinical implications.

Acute Disease↗
PubMed2001

Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13.

BACKGROUND: The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor and reports from large studies are scarce. We evaluated the efficacy of allogeneic bone marrow transplantation (allo-BMT) for children with this type of leukemia. PROCEDURE: The chemotherapy regimens consisted of an induction phase and very intensive consolidation followed by a reinduction phase and late intensification treatment. The selection of treatment modalities such as chemotherapy, allo-BMT, or autologous transplantation was made by each institute. The principal endpoint was the outcome of children with Ph(+) ALL according to the treatment options. RESULTS: Thirty-two patients (4.3%) were diagnosed as Ph(+) ALL out of the 741 cases of ALL consecutively enrolled in two protocols of the Tokyo Children's Cancer Study Group (TCCSG) from 1989 to 1994. Thirty patients (93.8%) were induced into complete remission (CR). Of these 30 patients, eight children electively received allo-BMT in the first CR. Six of these patients are in continuous remission at a median follow-up of 58 (range 48-105) months after the diagnosis. One patient died following recurrence and another patient died of graft vs. host disease. Three patients treated with autologous BMT or peripheral blood stem cell transplantation in the first CR experienced a subsequent relapse. In the remaining 19 patients, 13 patients were treated with very high-risk chemotherapy alone and all relapsed within 28 months. One patient was excluded from the analysis because he was treated with standard-risk chemotherapy until relapse. The other five patients were also excluded from the analysis because Philadelphia chromosome was not detected until they relapsed. None of the relapsed patients survived in spite of treatment including allo-BMT. In multivariate analysis, only allo-BMT remained as an independent factor for good prognosis. CONCLUSIONS: The only way to cure children with Ph(+) ALL was allo-BMT in this study and its outcome seemed promising.

Adolescent↗
PubMed2001

Distinctive multidrug sensitivity and outcome of acute erythroblastic and megakaryoblastic leukemia in children with Down syndrome.

We assessed the in vitro chemosensitivity of acute erythroblastic and megakaryoblastic leukemia cells from children with Down syndrome (DS) compared to non-DS children. We conducted in vitro tests using the MTT assay of bone marrow samples from 12 children with DS and 16 children without DS. Patients were newly diagnosed based on the morphology and expression of platelet-specific antigens. Induction failure occurred more frequently in the non-DS group (n = 4) than in the DS group (n = 0, P = .053). Children with DS had a superior event-free survival (EFS) probability of 0.750 at 4 years, compared to an EFS probability of 0.375 for non-DS children (P = .049). Blast cells from DS patients were significantly more sensitive to daunorubicin, melphalan, mitoxantrone, 4-hydroperoxy-cyclophosphamide, vincristine, etoposide, bleomycin, and pirarubicin than those from non-DS patients. Four of the 16 non-DS patients were found to have acquired an extra chromosome 21 in their leukemia cells: blasts from these patients also tended to have greater chemosensitivity than those from patients without an extra chromosome 21. Blast cells from DS patients are markedly sensitive to various drugs. These results suggest that the fragility of blast cells derived from DS patients may be related to an increased susceptibility to apoptosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Maturation of mass-screened localized adrenal neuroblastoma.

BACKGROUND/PURPOSE: In infants, neuroblastoma has been known to spontaneously differentiate into a benign ganglioneuroma. Although several investigators have compared mass-screened with unscreened, disseminated with localized, and adrenal with retroperitoneal neuroblastoma, there are very few cross-comparisons of the above parameters. Herein, the authors report the maturation of mass-screened, localized adrenal neuroblastoma. METHODS: Fifty-one mass-screened adrenal neuroblastomas were divided into 2 groups. In infants less than 1 year of age (Group A), 45 neuroblastomas were resected, whereas 6 neuroblastomas were resected after observation in 1- to 4-year-old children (group B). Histopathology of the tumors in the 2 groups was compared. Data were analyzed by X(2) test, and P <.05 was considered significant. RESULTS: According to the International Neuroblastoma Pathological Classification, 41 of 45 tumors of group A were "differentiating neuroblastoma" and 4 of 6 tumors of group B were "maturing ganglioneuroma." Maturation toward ganglioneuroblastoma was observed in 16 neuroblastomas of group A (36%) and 6 neuroblastomas of group B (100%). In group A, 58% had low mitosis karyorrhexis index (MKI); all patients in group B had low MKI. CONCLUSIONS: If left untreated, maturation of mass-screened, localized adrenal neuroblastomas is a common phenomenon. These children do not need to undergo early operation.

Adrenal Gland Neoplasms↗
PubMed2000

Central effects of neuromedin U in the regulation of energy homeostasis.

Neuromedin U (NMU) is a brain-gut peptide whose peripheral activities are well-understood but whose central actions have yet to be clarified. The recent identification of two NMU receptors in rat brain has provided a springboard for further investigation into its role in the central nervous system. Intracerebroventricular administration of NMU to free-feeding rats decreased food intake and body weight. Conversely, NMU increased gross locomotor activity, body temperature, and heat production. NMU, a potent endogenous anorectic peptide, serves as a catabolic signaling molecule in the brain. Further investigation of the biochemical and physiological functions of NMU will help our better understanding of the mechanisms of energy homeostasis.

Animals↗
PubMed2000

Purification and identification of neuromedin U as an endogenous ligand for an orphan receptor GPR66 (FM3).

GPR66 is an orphan G-protein-coupled receptor (GPCR) whose structure is similar to the ghrelin and motilin receptors. We have tried to purify a natural ligand for GPR66 in rat tissues and identified a 23-amino-acid peptide as the endogenous ligand. Sequence analysis revealed the peptide as neuromedin U (NMU), a smooth-muscle-contracting peptide that was first purified from porcine spinal cord by our group. NMU binds to GPR66-expressing cells with high specificity to induce intracellular calcium mobilization. When NMU was injected intracerebroventricularly (ICV) into rats, it potently suppressed food intake. In contrast, ICV injection of NMU-antibody increased food intake. These results suggest that NMU is a potent endogenous anorexic peptide.

Amino Acid Sequence↗
PubMed2000

Possible involvement of orexin in the stress reaction in rats.

We examined whether corticotropin-releasing factor (CRF) was involved in orexin-induced grooming and face-washing behaviors, and whether orexin was involved in the stress reaction. Administration of alpha-helical CRF, CRF antagonist, alone had no behavioral effect, but it blocked the orexin-induced grooming and face-washing behaviors in rats. The level of corticosterone increased in a dose-dependent manner 15 min after icv injection of orexin, and it remained high for at least 60 min. In 2-month-old rats, 1 h of immobilization stress increased orexin mRNA levels, but not the melanin-concentrating hormone (MCH) mRNA, in the lateral hypothalamic area (LHA). In 6-month-old rats, 30 min of cold stress increased the expression of orexin mRNA in the LHA. Unlike in the 2-month-old rats, immobilization stress did not change orexin mRNA expression in 6-month-old rats. These results suggest that CRF is involved in orexin-induced behaviors, and that orexin may play an important role in some stress reactions.

Animals↗
PubMed2000

Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system.

Agouti protein and agouti-related protein (AGRP) antagonize alpha-melanocyte-stimulating hormone that binds to and activates the melanocortin-4 receptor (MC4-R) in the hypothalamus, thereby stimulating food intake. Melanin-concentrating hormone (MCH) and orexin are orexigenic peptides that specifically are synthesized in the lateral hypothalamus. MCH gene expression was augmented in A(y)/a (agouti) mice which overexpress agouti protein, but orexin mRNA was not. AGRP administered intracerebroventricularly into wild-type rats augmented MCH but not orexin gene expression. Also, SHU9119, a peptidergic antagonist of MC4-R, increased only MCH mRNA. These findings indicate that interruption of signaling at MC4-R activates the MCH but not the orexin gene. The biosyntheses of MCH and orexin are regulated through different pathways.

Agouti Signaling Protein↗
PubMed2000

Absent or reduced expression of the caspase 8 gene occurs frequently in neuroblastoma, but not commonly in Ewing sarcoma or rhabdomyosarcoma.

PROCEDURE: To clarify whether the caspase 8 gene is involved in the pathogenesis of neuroblastoma (NB), we examined alterations of the caspase 8 gene in 15 NB, seven Ewing sarcoma (ES), and eight rhabdomyosarcoma (RMS) cell lines, using reverse transcription-polymerase chain reaction (RT-PCR) and RT-PCR single-strand conformation polymorphism (SSCP) analyses. RESULTS: The caspase 8 gene was not expressed in 11 (73%) of 15 NB cell lines, it was absent in only one of seven ES cell lines, but was present in all eight RMS cell lines examined. No mutations were detected in any cell lines examined. CONCLUSIONS: Inactivation of the caspase 8 gene is considered to be involved in the pathogenesis of NB, but not ES or RMS.

Caspase 8↗