Atsushi Kuramoto

Cancer Incidence in Atomic Bomb Survivors. Part III: Leukemia, Lymphoma and Multiple Myeloma, 1950-1987

This paper presents an analysis of data on the incidence of leukemia, lymphoma and myeloma in the Life Span Study cohort of atomic bomb survivors during the period from late 1950 through the end of 1987 (93,696 survivors accounting for 2,778,000 person-years). These analyses add 9 additional years of follow-up for leukemia and 12 for myeloma to that in the last comprehensive reports on these diseases. This is the first analysis of the lymphoma incidence data in the cohort. Using both the Leukemia Registry and the Hiroshima and Nagasaki tumor registries, a total of 290 leukemia, 229 lymphoma and 73 myeloma cases were identified. The primary analyses were restricted to first primary tumors diagnosed among residents of the cities or surrounding areas with Dosimetry System 1986 dose estimates between 0 and 4 Gy kerma (231 leukemias, 208 lymphomas and 62 myelomas). Analyses focused on time-dependent models for the excess absolute risk. Separate analyses were carried out for acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelocytic leukemia (CML) and adult T-cell leukemia (ATL). There were few cases of chronic lymphocytic leukemia in this population. There was strong evidence of radiation-induced risks for all subtypes except ATL, and there were significant subtype differences with respect to the effects of age at exposure and sex and in the temporal pattern of risk. The AML dose-response function was nonlinear, whereas there was no evidence against linearity for the other subtypes. When averaged over the follow-up period, the excess absolute risk (EAR) estimates (in cases per 10(4) PY Sv) for the leukemia subtypes were 0.6, 1.1 and 0.9 for ALL, AML and CML, respectively. The corresponding estimated average excess relative risks at 1 Sv are 9.1, 3.3 and 6.2 respectively. There was some evidence of an increased risk of lymphoma in males (EAR = 0.6 cases per 10(4) PY Sv) but no evidence of any excess in females. There was no evidence of an excess risk for multiple myeloma in our standard analyses.

Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature POSSIBLE EXISTENCE OF A NEW CLINICAL ENTITY ORIGINATING FROM THE THIRD LINEAGE OF LYMPHOID CELLS

The morphologic, immunologic, genotypic and functional properties of peripheral blood and bone marrow cells or cultured cells from four patients with a clinically aggressive non‐T, non‐B natural killer cell leukaemia/lymphoma (ANKL/L) are described. The leukaemic cells possessed medium to large granules in the cytoplasm, antigens against CD38, CD2, OKIa1 and NKH‐1 (CD56) monoclonal antibodies on their cell‐surface, and also showed natural killer (NK) activity. In addition, these ANKL/L belonged to neither T‐ nor B‐cell lineage, proved by studying clonal gene rearrangement for the Tβ, Tγ and Tδ receptors, and immunoglobulin.

Transforming growth factor-β regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts

Summary Three growth factors present in platelets, namely platelet‐derived growth factor (PDGF), transforming growth factor‐β (TGF‐β) and epidermal growth factor (EGF), have been implicated in the pathogenesis of bone marrow fibrosis frequently associated with myeloproliferative disorders. In this study, regulation of the proliferation, as well as collagen and fibronectin synthesis from marrow fibroblasts by TGF‐β was investigated. TGF‐β alone at high plating density stimulated the proliferation of cells at low concentrations, but rather showed inhibition at high concentrations in both MPD patients and control subjects. In the presence of PDGF, which has been confirmed to be a main growth factor for marrow fibroblasts, low concentration of TGF‐β inhibited the proliferation at low cell density, but there was no inhibition at high cell density. The synthesis of both type I and type III procollagen was enhanced by high concentrations of TGF‐β in both MPD patients and control subjects, while PDGF or EGF showed no effect. The fibronectin synthesis was also enhanced by TGF‐β, but not by PDGF or EGF. These results suggest that growth and stromal protein synthesis of fibroblasts causing marrow fibrosis are regulated by TGF‐β as well as PDGF and EGF, when these factors are released or leaked from platelets or megakaryocytes into marrow environment in MPD patients.

c-kit point mutation of extracellular domain in patients with myeloproliferative disorders.

Summary. c‐kit is a tyrosine kinase receptor whose ligand is stem cell factor (SCF). Gene alteration of the c‐kit extracellular domain was analysed by polymerase chain reaction‐single strand conformation polymorphism (PCR‐SSCP) in 25 patients with myeloproliferative disorders (MPD). In the N‐terminal part of the domain, mobility shifts indicating sequence alteration were detected in three of the patients, two primary myelofibrosis (PMF) and one chronic myelogenous leukaemia (CML). The subsequent sequencing revealed the same point mutations at codon 52 causing amino acid substitution (Asp → Asn). To our knowledge this is the first report with a c‐kit point mutation found in human fresh tumour cells.

Identification of early plasma cells in peripheral blood and their clinical significance.

In the peripheral blood (PB) we detected so‐called early plasma cells that might already be committed to entering the bone marrow (BM). By two‐colour staining with FITC–anti‐CD38 antibody, their intensity (CD38++) of expression of CD38 antigen was between that of germinal centre (GC) B cells (low expression (CD38+)) and that of BM plasma cells (high expression (CD38+++)), and their phenotype was CD38++ CD19+ CD10− CD20− CD21+ CD24− CD39+ CD5− VLA‐4+ VLA‐5− MPC‐1− without expression of surface membrane IgM (SmIgM). Morphological and immunological examination of the sorted cells confirmed that they were plasmacytoid cells with expression of cytoplasmic IgG (cIgG). Variations of these early plasma cells were examined in various diseases. In active systemic lupus erythematosus, bacterial septicaemia and liver cirrhosis, early plasma cell levels were significantly increased in PB, and after subsidence of such inflammation (inactive states) these cells returned to normal levels. In contrast, normal early plasma cells were significantly suppressed in myelomas, whilst normal or slightly increased numbers of early plasma cells was found in benign monoclonal gammopathy (BMG). In addition, the number of normal early plasma cells returned to a normal level in myeloma cases with complete responses. Therefore, early plasma cells were identified phenotypically, and an increase and decrease in these cells in PB may reflect mobilization and suppression, respectively, of activated B cells into BM plasma cells.

Effects of platelet derived growth factor, epidermal growth factor and transforming growth factor-β on the growth of human marrow fibroblasts

Summary. The effects of three growth factors contained in platelets on human bone marrow fibroblasts as well as fibroblast colony‐forming cells were investigated to clarify the pathogenesis of marrow fibrosis frequently associated with myeloproliferative disorders. Two growth factors, platelet derived growth factor (PDGF) and epidermal growth factor (EGF), cooperatively stimulated the growth of passaged fibroblasts as well as fibroblast colony‐forming cells. Transforming growth factor‐β augmented the growth of fibroblasts at low concentrations in the presence of EGF and/or PDGF, but inhibited that of colony‐forming cells in the presence of PDGF or EGF. These results suggest that the growth of fibroblasts causing marrow fibrosis might be finely regulated, depending on the concentrations of growth factors released or leaked from platelets or megakaryocytes into marrow environment.

Nationwide Study of Idiopathic Thrombocytopenic Purpura in Pregnant Women and the Clinical Influence on Neonates

Idiopathic thrombocytopenic purpura (ITP) occurs more commonly in young women during the reproductive years. To obtain information for management of ITP in pregnancy, we performed a nationwide retrospective survey. Findings from a total of 284 pregnant women with ITP and their 286 newborn infants were available for analysis. The bleeding tendency at delivery was managed chiefly with corticosteroid, intravenous high-dose γulin, and platelet transfusion. Maternal complications occurred in 77 cases (27.1%) and were frequently seen in cases with poor control of ITP. Neonatal abnormalities, which were not influenced by the clinical state of the mother, occurred at a frequency of 17.8%. Thrombocytopenia in neonates occurred in 48 cases (22.4%), and bleeding tendency was found in 16 cases (6.3%) without severe bleeding. Prediction of thrombocytopenia in neonates was difficult. However, infants from splenectomized mothers with well-controlled ITP showed thrombocytopenia more frequently than those from nonsplenectomized mothers. Mothers treated with steroids at doses greater than 15 mg/day showed a high frequency of maternal complications and fetal abnormal body weight. These observations will be useful in the management of pregnant women with ITP and their infants.

Efficacy of granulocyte colony‐stimulating factor in the treatment of acute myelogenous leukaemia: a multicentre randomized study

Summary. To investigate the efficacy and safety of granulocyte colony‐stimulating factor (G‐CSF) in patients with acute myelogenous leukaemia, a multicentre randomized study was performed. From October 1993 to September 1996, 270 patients with newly diagnosed acute myelogenous leukaemia were randomized to G‐CSF or control groups after remission induction therapy. The G‐CSF group received G‐CSF (Filgrastim) from 48 h after the completing chemotherapy until the absolute neutrophil count exceeded 1·5 × 109/l. The control group did not receive G‐CSF unless severe infection occurred. There were 245 evaluable patients (120 and 125 in the G‐CSF and control groups respectively). The complete remission rate was similar in the G‐CSF and control groups (80·8% versus 76·8%), as was the 5‐year probability of disease‐free survival (34·5% versus 33·6%) and overall survival (42·7% versus 35·6%). Neutrophil recovery was significantly faster in the G‐CSF group than in the control group (12 d versus 18 d, P = 0·0001). The median duration of febrile neutropenia was significantly shorter in the G‐CSF group than in the control group (3 d versus 4 d, P = 0·0001). In conclusion, prophylactic administration of G‐CSF after remission induction therapy for acute myelogenous leukaemia is safe and useful even in patients without infection on completing chemotherapy.

Oligoclonal accumulation of T cells in peripheral blood from patients with idiopathic thrombocytopenic purpura

To determine whether clonal T cells accumulate in idiopathic thrombocytopenic purpura (ITP), we performed single‐strand conformation polymorphism (SSCP) analysis to detect T‐cell receptor (TCR) β‐chain usage of peripheral T cells. We detected significantly more oligoclonal T cells (15.5 ± 8.9 bands representative for clonal T‐cell expansions) in peripheral blood from ITP patients than from healthy donors (2.8 ± 2.6 bands). Frequently used Vβ genes in these accumulated T cells in ITP were Vβ 3, 6, 10, 13.1 and 14. To determine whether these bands were derived from clonal T cells, presumably in a preactivated state, we established some T‐cell clones (expressing CD4 and TCR Vβ 6, 13.1, or 14) by nonspecific stimulation from patients’ peripheral mononuclear cells, and examined their clonotypes. Clonal identities for three out of seven clones tested were confirmed using SSCP analyses to compare the migration of their β‐chain complementarity determining region 3 (CDR3) cDNAs, expanded by polymerase chain reaction (PCR) with those from peripheral blood. Therefore, distinctive T‐cell clones accumulated in the periphery in ITP and they may be related to the autoimmune‐mediated destruction of platelets.

Aggressive Natural Killer Cell Leukemia/Lymphoma with N901-Positive:Surface Phenotype: Evidence for the Existence of a Third Lineage in Lymphoid Cells

The morphology, immunologic and functional properties of peripheral blood and bone marrow cells or cultured cells from 2 patients with clinically aggressive non-T, non-B lymphoma/leukemia are described. The leukemic cells possessed medium to large granules in the cytoplasm, antigens against CD38, CD2, CD25, OKIa1, CD16, TA-1, CD9, CD24 and NKH-1 (N901) monoclonal antibodies on their cell surface, and also showed a high natural killer (NK) activity. Phenotypically, the cells in these disorders were quite different from T gamma leukemia cells bearing Fc receptor or the traditionally reported NK leukemia cells possessing HNK-1 (Leu 7) antigens on their surface. In addition, these leukemias/lymphomas belonged to neither T- nor B-cell lineage, proved by studying clonal gene rearrangement for the T beta and T gamma receptor, and immunoglobulin. Hence, a quite interesting and important point, as suggested by our data, is that all our cases expressed an antigen for NKH-1 (N901), which is detectable on all NK cell surfaces and they lacked the antigen for Leu 7 (HNK-1), which is usually detected on the surface of leukemic NK cells. These facts indicate that we are dealing with a leukemic NK cell subset which is quite different from cells of all other reported cases of NK cell leukemias. We therefore concluded that such disorders with an aggressive clinical nature and a poor prognosis as in our cases belong to a new clinical entity originating from a portion of the NK cell subset.(ABSTRACT TRUNCATED AT 250 WORDS)