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Biomedical subjects

H Sakamaki

Publications and source records attributed to H Sakamaki.

At least 55 records · Page 3Linked to original sources
PubMed2000

Therapy-related leukemia and myelodysplastic syndrome: a large-scale Japanese study of clinical and cytogenetic features as well as prognostic factors.

It is known that alkylating agents and topoisomerase II inhibitors can cause distinct forms of therapy-related leukemia and myelodysplastic syndrome (TRL/MDS). Although several reports have been made on each of these agents separately, no study has yet been conducted to evaluate the effect of these two types of agents in the same population. In a nationwide, large-scale population study, the clinical and cytogenetic features as well as the prognostic factors in 256 patients with TRL/MDS were assessed. Median age was 61 years, and the median period of latency from primary malignancies was 47.9 months. The latency period was significantly shorter in patients undergoing chemotherapy, especially that of topoisomerase II inhibitors, for primary cancer. The morphological diagnosis of TRL/MDS was acute myeloid leukemia in 59% and MDS in 41% of patients. Chromosome abnormalities that frequently involved chromosomes 5, 7 or 11 were documented in 77% of the 189 patients examined. MLL gene rearrangements were detected in 11 of 58 subjects and were correlated with a borderline significance (P = 0.072) with topoisomerase II inhibitor administration. Overall median survival was only 9.7 months. Survival was similar in cases with or without MLL gene rearrangement. Multivariate analysis identified chromosome 5 abnormalities, hypoproteinemia, poor therapy outcomes for primary cancer, C-reactive protein, and thrombocytopenia as being significantly poor prognostic factors (P < 0.05). This large-population study provided a comprehensive update of TRL/MDS status in Japan, identified significant prognostic factors, and enabled the clinical significance of MLL gene rearrangement to be assessed.

Adult↗
PubMed2000

[Allogeneic bone marrow transplantation for primary myelofibrosis after splenectomy].

A 46-year-old woman was given a diagnosis of primary myelofibrosis (PMF) in 1996. Because of the progression of anemia and splenomegaly, she was scheduled for allogeneic bone marrow transplantation (BMT) from an HLA-matched sibling donor in April 1998. Cyclophosphamide and busulfan were used as the conditioning regimen. Before BMT, the patient was treated with hydroxycarbamide, which did not resolve splenomegaly. She then underwent a splenectomy, which was followed by massive portal vein thrombosis without any significant clinical outcome. After BMT, the patient obtained rapid hematologic engraftment. Moreover, the alleviation of marrow fibrosis was confirmed 4 months after BMT. We concluded that allogenic BMT can cure patients with PMF, but that the issue of splenectomy and the indications for BMT need to be evaluated further.

Bone Marrow Transplantation↗
PubMed2000

Quality of life in adult patients after stem cell transplantation.

Many articles pertaining to quality of life (QOL) following stem cell transplantation have been published in the US and western Europe. However, since the actions of health insurance systems and overall cultural aspects are strongly associated with QOL, investigations into QOL should be carried out within all countries. Therefore, we have investigated the QOL of adult patients following stem cell transplantation at 31 hospitals in Japan. The survivors, who were surveyed by mail questionnaire, were 20 years or older at the time of this study. The underlying diseases were acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, myelodysplastic syndrome, and multiple myeloma. Median age at the time of the study was 36 years, and median interval after transplantation was 35.3 months. Of 383 patients surveyed, 282 (73.6%) responded to the questionnaire. One hundred and ninety-two patients were treated with an allogeneic-related transplantation, 52 with allogeneic-unrelated, and 38 with an autologous transplantation. Our data revealed that the length of time since transplantation and the diagnosis of chronic GVHD were associated with QOL. When unrelated and related transplantation recipients were compared, ratings on relief from pain, stability in weight, and confidence in dealing with daily life were lower among unrelated transplantation patients.

Adolescent↗
PubMed1999

Augmented proliferation of human alveolar macrophages after allogeneic bone marrow transplantation.

After allogeneic bone marrow transplantation (allo-BMT), recipient alveolar macrophages (AM) are gradually replaced by AM of the donor origin. An influx of mononuclear phagocytes of donor origin to the lung is responsible for the repopulation, but the detailed kinetics remain unclear. We therefore studied 24 BMT recipients who underwent bronchoalveolar lavage (BAL) from 24 to 83 days after BMT. AM cell number, size, morphology, proliferating ability, and genotype of AM were measured. Before day 50, the number and size of AM in BAL fluid were similar to those of normal nonsmokers. However, after day 50, the mean number of AM increased threefold and the mean cell size decreased due to the increase of small AM. These small cells are presumably of donor origin based on DNA fingerprinting analysis and based on fluorescence in situ hybridization for the Y chromosome in a sex-mismatched case. Immunohistochemistry and cell cycle analysis demonstrated that the increase in AM number coincided with a remarkable increase of AM expressing proliferating cell nuclear antigen, suggesting that small AM are proliferating. This is the first report representing that augmented proliferation of donor AM in situ may contribute to the reconstitution of AM population after BMT.

Adolescent↗
PubMed1999

Granulocytic sarcoma of the thymus in a nonleukaemic patient.

We report a case of granulocytic sarcoma arising from the thymus in a 17-year-old nonleukaemic patient. The patient presented with an anterior mediastinal tumour and underwent surgical resection. Histological examination showed a diffuse infiltrate of immature round cells in the thymus. Tumour cells were diffusely peroxidase positive, but naphthol AS-D chloroacetate esterase negative. Immunohistochemical staining revealed expression of CD34 and terminal deoxynucleotidyl transferase (TdT), but not of CD13 and CD33. Ultrastructurally, electron-dense or medium-density granules were present in the cytoplasm. Four months after successful autogenic bone marrow transplantation, pleural and pericardial fluid contained tumour cells with azurophilic granules, which expressed CD13 and CD33, but not CD34 and TdT. The patient died of the disease 18 months after clinical manifestation, but still without developing leukaemia. The granulocytic sarcoma in the present case may have originated from myeloid precursors in the thymus and remained within the extramedullary site despite the differentiation into a more committed myeloid lineage at the relapse.

Adolescent↗
PubMed1999

CTLA4 gene polymorphism correlates with the mode of onset and presence of ICA512 Ab in Japanese type 1 diabetes.

Recently, the association of CTLA4 gene polymorphism with type 1 diabetes and AITD has been reported in several populations. CTLA4 was originally reported to regulate T-cell activity and T-B cognate interaction. To investigate the role of CTLA4 in autoimmune diseases, we examined the correlation between CTLA4 gene polymorphism and the clinical characteristics of Japanese patients with type 1 diabetes, including the mode of onset of diabetes and presence of islet-specific autoantibodies (GAD, ICA 512 Ab) in the serum. We studied 111 patients with type 1 diabetes and 445 normal subjects. CTLA4 exon 1 position 49 (A/G: codon 17: Thr/Ala) polymorphism was defined, employing PCR-RFLP. Sixty-three (57%) patients had AITD. The allele frequencies of G and A in both 111 patients (G: 65%; A: 35%) and 63 patients (G: 62%; A: 38%) were not significantly different from the control subjects (G: 63%; A: 37%). Serum samples of 69 patients were obtained within a year after onset and used for pancreas specific autoantibodies analysis. These samples were also used for further analysis between CTLA4 gene polymorphism and clinical characteristics. The allele frequencies of G and A in patients who presented with diabetic ketoacidosis (DK+) (G: 75%; A: 25%) were significantly different from those in DK- patients (G: 50%, A: 50%, P = 0.003). Allele and genotype analyses showed significant differences between DK+ patients and control subjects (P = 0.014, P = 0.046, respectively). Allele frequencies of G and A were not significant between patients who were positive and negative for GAD Ab, but significant for ICA 512 Ab (G: 83%, A:17% versus G: 59%, A: 41%: positive patients versus negative patients, P = 0.004). Our results showed a significant correlation between CTLA4 gene polymorphism and ICA 512 Ab. Our results also indicated that CTLA4 gene polymorphism is associated with the onset mode of Japanese type 1 diabetes and the presence of ICA512 Ab. Further analysis of this polymorphism is necessary to fully understand the pathogenesis and progression of type 1 diabetes.

Abatacept↗
PubMed1999

Molecular remission in adult T cell leukemia after autologous CD34+ peripheral blood stem cell transplantation.

This report describes a patient with acute-type adult T cell leukemia/lymphoma (ATLL) successfully treated by autologous CD34+ peripheral blood stem cell transplantation after fractionated total body irradiation and high-dose cytarabine and cyclophosphamide. A newly established inverse polymerase chain reaction method was used to demonstrate the disappearance of ATLL clonal cells. The patient achieved a sustained molecular remission after transplantation, but died from opportunistic infection 4 months after transplantation. Thus, autologous CD34+ peripheral blood stem cell transplantation is promising for this type of malignancy. However, a prudent clinical attitude toward immunological fragility after transplantation is needed for better outcome.

Antigens, CD34↗
PubMed1999

Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia.

In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60-71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented.

Acute Disease↗
PubMed1999

Peripheral blood stem cell mobilization and apheresis: analysis of adverse events in 94 normal donors.

Adverse events were analyzed in 94 normal donors who underwent PBSC harvest with G-CSF. The median dose of G-CSF was 9.7 microg/kg/day (range, 2.0-16.7), and the duration of administration was 4-6 days. Frequent symptoms were bone pain (71%), general fatigue (33%), headache (28%), insomnia (14%), anorexia (11%), nausea and/or vomiting (11%). One donor (1%) developed grade 3 toxicity bone pain (WHO criteria). WBC counts and ANC increased during G-CSF administration. After leukapheresis, three donors (3%) developed grade 3 toxicity neutropenia. Platelet counts decreased after leukapheresis. Three donors (3%) developed grade 3 thrombocytopenia. The means of both ALP and LDH increased approximately 1.9-fold compared with pretreatment levels. In one pediatric donor (1%), ALP was elevated to the grade 3 toxicity level. From multivariate analysis, the incidence of bone pain increased when G-CSF was given at a dose of 8.8 microg/kg/day or more, headaches were frequent in donors younger than 35 years, and the incidence of nausea and/or vomiting was high in female donors. The peak levels of WBC counts and ANC and post-treatment level of LDH increased in correspondence with the escalation of G-CSF dose. All adverse events normalized on follow-up evaluation. In conclusion, although PBSC harvest for normal donors is acceptable, care must be taken for all donors in terms of their sex and age as well as the G-CSF dose. We recommend less than 8.8 microg/kg/day as the G-CSF dose for PBSC mobilization in normal donors.

Adolescent↗
PubMed1999

Early diagnosis of central nervous system aspergillosis using polymerase chain reaction, latex agglutination test, and enzyme-linked immunosorbent assay.

To investigate the usefulness of examination of cerebrospinal fluids (CSF) in the diagnosis of central nervous system (CNS) aspergillosis, we examined five patients with either brain abscesses or cerebral infarctions and 11 control patients. CSF samples were subjected to enzyme-linked immunosorbent assay (EIA), latex agglutination test (LA) and polymerase chain reaction (PCR). Cultures of CSF samples were negative in all the patients, but PCR, EIA and LA were positive in five, four and four patients with CNS aspergillosis, respectively. None of these tests were positive in the control patients. CSF examination may be beneficial in the diagnosis of CNS aspergillosis.

Adult↗
PubMed1999

Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations.

Hyperglycemia-induced embryonic malformations may be due to an increase in radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. In the past, we have investigated the role of the glutathione-dependent antioxidant system and GSH on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational day 11 showed a significantly higher frequency of embryonic malformations (neural lesions 21.5 vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth retardation than those of normal mothers. The formation of intracellular reactive oxygen species (ROS), estimated by flow cytometry, was increased in isolated embryonic cells of diabetic rats on gestational day 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly lower than that of normal rats. The activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of diabetic rats was significantly low, associated with reduced expression of gamma-GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to diabetic rats during the period of maximal teratogenic susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3 vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of ROS, leading to normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs. 47.4%), and growth retardation with the restoration of GSH contents. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes.

Animals↗
PubMed1999

No beneficial effect from addition of etoposide to daunorubicin, cytarabine, and 6-mercaptopurine in individualized induction therapy of adult acute myeloid leukemia: the JALSG-AML92 study. Japan Adult Leukemia Study Group.

To assess the efficacy of etoposide added to the standard remission induction therapy for acute myeloid leukemia (AML), newly diagnosed adult AML patients were randomized to receive either daunorubicin (40 mg/m2/day x 4 or more), behenoyl cytarabine (200 mg/m2/day x 10 or more), and 6-mercaptopurine (70 mg/m2/day x 10 or more) (BHAC-DM), or the same three drugs plus etoposide (100 mg/m2/day x 5) (BHAC-EDM) for response-oriented individualized induction therapy. The patients achieving complete remission (CR) received the same 3 courses of consolidation therapy followed by 6 courses of maintenance/intensification therapy. M3 patients were excluded because all-trans retinoic acid was used. Of 667 patients registered, 655 were evaluable. The median age was 49 (range 15 to 85). CR rates were 77% in the BHAC-DM group and 75% in the BHAC-EDM group. In 173 M4 patients, CR rates were 86% and 69% (P = 0.009), and in 32 M5 patients, 80% and 77% (P = 0.810) in the BHAC-DM and the BHAC-EDM groups, respectively. The predicted 6-year overall survival rates were 30% and 38% (P = 0.925) for the BHAC-DM and BHAC-EDM groups, and the disease-free survival rates of CR patients were 25% and 35% (P = 0.352), respectively. Nonhematological toxicities after the first course of induction therapy were almost equal among the two groups, with the exception of a greater loss of hair (P = 0.024) and more frequent diarrhea (P = 0.013) in the BHAC-EDM group. We concluded that in the present study, the addition of etoposide to the standard individualized induction therapy showed no advantage in adult AML, even among M4 and M5 patients.

Acute Disease↗
PubMed1999

[Differences in therapeutic strategies for adult leukemia and lymphoma between Japan and western countries].

The purpose of this paper is to clarify the differences in therapeutic strategies for adult leukemia and lymphoma between Japan and western countries. Since in Japan, high-dose cytarabine for acute leukemia is not covered by health insurance, post-remission therapy might be less intense compared to western countries and it takes a long time to complete the therapy. The results of chemotherapy for adult acute lymphocytic leukemia (ALL) in Japan have been inferior to those in foreign reports. Accordingly, many Japanese hematologists believe that adult ALL has a worse prognosis than acute myeloid leukemia (AML), and almost all young adult patients with ALL should receive allogeneic bone marrow transplantation (BMT) from related or unrelated donors. Japanese hematologists also consider that Interferon as the first-line chemotherapy for chronic myelogenous leukemia (CML), and that BMT from a HLA matched sibling donor should be done as soon as possible. Recently, some foreign reports of BMT from unrelated donors for CML revealed results comparable to BMT from related donors showing that even transplants from unrelated donors should be done as soon as possible. Since chronic lymphocytic leukemia and Hodgkin's disease are so rare in Japan, the available drugs for these diseases are limited. The quality and quantity of Japanese clinical studies in this field are inferior to studies in western countries. This, in fact, is a more serious problem than the differences in therapeutic strategies.

Adult↗