Yoshiharu Yoshida

Risk of Myelodysplastic Syndromes in People Exposed to Ionizing Radiation: A Retrospective Cohort Study of Nagasaki Atomic Bomb Survivors

PURPOSE The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors. PATIENTS AND METHODS We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk. RESULTS There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young. CONCLUSION A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

Characterization of the human IL-5 receptors on eosinophils

Interleukin 5 (IL-5) receptors on the cell surface of human eosinophils and other hematopoietic cells were characterized using radiolabeled recombinant IL-5. The binding of 35S-labeled murine IL-5 to eosinophils from normal human peripheral blood was rapid and saturable within a 30-min incubation at both 4 and 37 degrees C. The binding of 35S-labeled murine IL-5 to eosinophils was inhibited by an excess of unlabeled murine and human IL-5 or by an anti-murine IL-5 monoclonal antibody (NC17) but not by other human cytokines. Scatchard plot analysis revealed that human eosinophils have a single class of high affinity receptor (Kd 170-330 pM; number of binding sites: 260-380/cell). IL-5 receptors on eosinophils from four patients with eosinophilia displayed similar characteristics. Affinity cross-linking experiments resulted in the identification of human IL-5 receptor on eosinophils with a molecular mass of 55-60 kDa. Among the various cells besides eosinophils and cell lines that we could test, a subline of HL-60 (YY-1 cells) was found to display a significant number of IL-5 receptor. These results suggest that IL-5 may act on limited types of cells in the human system.

Dysmegakaryocytopoiesis in acute leukaemias: its predominance in myelomonocytic (M4) leukaemia and implication for poor response to chemotherapy

Megakaryocytopoiesis was morphologically investigated in 129 adults with de novo acute leukaemia. Three types were identified: type I (84 cases), no detectable megakaryocytes; type II (32 cases), quantitatively preserved megakaryocytes with normal morphology; type III (13 cases): quantitatively preserved megakaryocytes but with distinct dysplastic changes such as micromegakaryocytes and megakaryocytes with multiple small separated nuclei. Type III was found in M1 (one out of 21 cases), M2 (one out of 20 cases), M4 (eight out of 24 cases), M6 (two out of four cases) and hypoplastic leukaemia (one out of 13 cases). M3 cases were all classified into type I. Most of acute lymphoid leukaemia cases (21 cases) belonged to type II. Among AML cases, the complete remission (CR) rate by intensive chemotherapy with daunorubicin and cytosine arabinoside was significantly lower in type III (11%) than in types I (87%) and II (71%). Among M4 cases, CR rates in type III (14%) was also significantly lower than those in type I (75%) and II (100%). Thus, the present study indicates the importance of recognizing dysmegakaryocytopoiesis in AML for clariflcation of the heterogeneous biology or pathophysiology of acute leukaemias and formulation of an appropriate therapeutic strategy.

Cytogenetic evidence for partially committed myeloid progenitor cell origin of chronic myelomonocytic leukaemia and juvenile chronic myeloid leukaemia: both granuloctye-macrophage precursors and erythroid precursors carry identical marker chromosome

Summary. We used a micromethod for cytogenetic analysis from single haematopoietic colonies to study two adults with chronic myelomonocytic leukaemia (CMML) and a boy with juvenile chronic myeloid leukaemia (JCML) carrying distinct chromosome abnormalities, 7q—, der(21), and trisomy 21. We wanted to know if both granulocyte‐macrophage (GM) and erythroid precursors are involved in the abnormal clone. In all three patients, their chromosome abnormality was seen in almost all metaphases obtained from GM‐colonies and erythroid bursts. Peripheral blood leucocytes stimulated with phytohaemagglutinin exhibited only normal karyotypes. Clones of B‐cell produced by Epstein‐Barr virus had only normal karyotypes in the CMML patients. These findings indicate that CMML and JCML are clonal haemopathies that originate in a partially committed myeloid progenitor cell.

Lymphoid crisis with T-cell phenotypes in a patient with Philadelphia chromosome negative chronic myeloid leukaemia

Summary A case of Philadelphia (Ph1) chromosome negative chronic myeloid leukaemia (CML) developed lymphoid crisis. Immunological marker studies disclosed that the lymphoid cells were sheep erythrocyte‐rosetting‐, Leu‐1+, Leu‐5+, OKT‐4+, OKT‐8+, common ALL antigen‐, HLA‐DR‐, cytoplasmic and surface immunoglobulin‐, MAS 036C(antithymocyte)+ (after in vitro culture) and terminal deoxynucleotidyl transferase‐, indicating T‐cell phenotypes, probably of common thymocytes. Cytochemical staining also demonstrated immature T‐cell characters: dot‐positivity for acid phosphatase and beta‐glucuronidase, and negative for acid alpha‐naphthyl acetate esterase. All bone marrow metaphases exhibited normal karyotypes. Our observation suggests that the neoplastic features of a common stem cell for myeloid and lymphoid cell lines are very similar in Ph1 positive and negative CMLs, and that the stem cell can differentiate towards T‐lineage.

Low-dose cytosine arabinoside regimen induced a complete remission with normal karyotypes in a case with hypoplastic acute myeloid leukaemia with no. 8-trisomy: in vitro and in vivo evidence for normal haematopoietic recovery

Complete remission was achieved in a case of hypoplastic acute myeloid leukaemia with chromosomal abberation of No. 8‐trisomy by giving very low dose of cytosine arabinoside (ara‐C), 10 mg (7.5 mg/m2)/d, by 24 h continuous intravenous infusion for 20 d. We observed a definite cytoreduction phase in the bone marrow (BM) before normal haematopoiesis resumed. The remission BM showed only normal karyotypes in all metaphases examined. Granulocyte/macrophage colonies and erythroid bursts recovered sufficiently in numbers and cytogenetic study on single colonies and bursts revealed only normal karyotypes. These observations provide evidence that a low dose ara‐C regimen can induce remission by cytoreduction which diverts the growth advantage from the leukaemic clone to the normal clones.

Remission with morphological myelodysplasia in de novo acute myeloid leukaemia: implications for early relapse

Myelodysplastic features of remission bone marrow were investigated in 46 adults with de novo acute myeloid leukaemia (AML) according to the FAB morphological criteria for myelodysplastic syndromes (MDS). Compared with a group of 18 patients with the common type of acute lymphoblastic leukaemia in remission, micromegakaryo‐cytes (30·4%v. 5·6%, P<0·05), multi‐separated nuclear megakaryocytes (45·7%v. 0%, P<0·01), degranulated neutrophils (39·1%v. 5·6%, P<0·05), and neutrophils with hyposegmented nuclei (34·8%v. 0%, P<0·01) were significantly more common in the AML patients. In contrast, dyserythropoietic changes had a similar incidence in both groups. When compared with the clinical features at initial diagnosis in AML cases, the dysmegakaryocytic changes in remission marrow were found to be significantly more frequent in patients with monocytic involvement (mainly M4) or trilineage myelodysplasia (T‐MDS AML). Disease‐free survival was significantly shorter in patients with micro‐megakaryocytes (P<0·05) or neutrophils with hyposegmented nuclei (P<0·05) than in those without these features. Overall survival was also significantly shorter in patients with micromegakaryocytes (P<0·05). These findings may help in developing new strategies for the post‐remission therapy of AML, and also suggest that myelodysplastic changes in the remission marrow of de novo AML patients may be related to haematopoietic recovery by a preleukaemic clone which eventually leads to early leukaemic relapse. Dysplastic marrow, however, was not necessarily associated with peripheral pancytopenia in the present series, warranting basic research on such putative clonal remissions.

Reduced helper (OKT4+): suppressor (OKT8+) T ratios in aplastic anaemia: relation to immunosuppressive therapy

Summary. T cell subset composition of peripheral blood and bone marrow from 22 patients with aplastic anaemia (AA) was studied by monoclonal antibodies (OKT3, OKT4 and OKT8). In the peripheral blood, OKT3 (pan‐T). OKT4 (helper/inducer‐T) and OKT8 (suppressor‐T) cells varied widely in number. The ratios of OKT4:OKT8 exhibited the same tendency. However, a subgroup of AA with a reduced ratio of lower than 1.0 was present both in cases with or without prior prednisolone therapy. Of the eight patients treated with immunosuppressants, four with reduced ratios responded, whereas the other four with normal or higher ratios did not. The ratios of two of the four responders gradually reached the normal level. These results suggest that the reduced OKT4: OKT8 ratio may be related to the cell‐mediated immunosuppressive mechanism postulated as a cause of stem cell inhibition in a subgroup of AA, and indicate prospectively the effectiveness of immunosuppressive therapy.

De novo acute myeloid leukemia in the elderly; a consistent fraction of long-term survivors by standard-dose chemotherapy

To clarify the characteristics of de novo acute myeloid leukemia (AML) among the elderly, we reviewed 112 patients over 60 years old (median age 72 years) who were treated at hospitals in Nagasaki Prefecture with a population of 1.5 million between 1987 and 1994. Reclassification of morphological diagnosis revealed that the proportion of M3 was lower but that of M6 and the incidence of cases with trilineage dysplasia (TLD), known as poor prognostic features, were higher in the elderly than in patients less than 60 years old. Similarly, chromosomal data showed a lower frequency of favorable karyotypes such as t(8;21) and t(15;17) in the elderly. The overall survival of all 112 patients was 10.3% at 5 years. Multivariate analysis indicated that good performance status (PS), low WBC at diagnosis, standard dose multi-drug chemotherapy and all-trans retinoic acid (ATRA) treatment for M3 patients, and morphological findings without TLD were significantly correlated with longer survival. Most of the long-term survivors were found among those who received standard dose therapy in this series, although no consensus has been established how to treat elderly AML patients. We propose that a prospective controlled trial is necessary to confirm the role of standard dose chemotherapy for elderly patients with de novo AML.

Minimally differentiated acute myeloid leukemia (AML-M0) with extensive erythrophagocytosis and del(20)(q11) chromosome abnormality

We describe an 84-year-old woman who presented severe pancytopenia and 36.6% of blasts accompanied with erythrophagocytosis in the bone marrow. According to cytochemical and immunological findings, a diagnosis of minimally differentiated acute myeloid leukemia (AML-M0) was established. Cytogenetic analysis revealed del(20)(q11) which were previously reported for one case each of ALL and MDS associated with cytophagocytosis by blasts, leading us to speculate a disease entity. Interestingly, a high expression of mRNA of TNF-alpha was detected by RT-PCR on the bone marrow mononuclear cells.