Masuko Tagawa

Prevalence of Monoclonal Gammopathy of Undetermined Significance: Study of 52,802 Persons in Nagasaki City, Japan

OBJECTIVE To assess the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a large Japanese population. PARTICIPANTS AND METHODS From October 1, 1988, to March 31, 2004, a total of 52,802 (of 71,675) Japanese survivors of the atomic bomb explosion in Nagasaki City, Japan, were screened for M protein. The youngest participant was 42.3 years as of October 1, 1988. A 2-step screening was performed with a serum protein electrophoresis followed by immunoelectrophoresis and a quantitative determination of serum concentration of immunoglobulins. Twenty-one patients who were diagnosed for the first time at the time of screening as having multiple myeloma and Waldenström macroglobulinemia were excluded from analyses. Age- and sex-specific prevalence rates of MGUS were calculated. RESULTS Monoclonal gammopathy of undetermined significance was identified in 1088 of the 52,781 study participants. The overall prevalence of MGUS was 2.1% (95% confidence interval [CI], 1.9%-2.2%) in the total population screened and 2.4% (95% CI, 2.0%-2.6%) in those 50 years or older. The prevalence was significantly higher in men than in women (2.8% vs 1.6%; age-adjusted odds ratio, 2.0; 95% CI, 1.8-2.3; P less than .001). In both sexes, the prevalence rose with increasing age from 1.0% in participants aged 42 to 49 years, 1.9% in those 50 to 59 years, 2.6% in those 60 to 69 years, and 3.0% in those 70 to 79 years, to 4.4% in those 80 years and older. The heavy chain isotypes of immunoglobulin were IgG in 73.6% of patients, IgA in 17.7%, IgM in 7.5%, and oligoclonal gammopathies in 1.1%. CONCLUSION The prevalence of MGUS is lower in this Japanese population than that reported in Western countries among people older than 60 years, especially among women.

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.

Significance of chromosome 14 anomaly at band 14Q11 in Japanese patients with adult T-cell leukemia

The chromosomes of leukemic blood cells in eight Japanese patients with acute adult T‐cell leukemia (ATL) were examined by a direct method or short‐term culture method without any mitogens. Six patients showed a chromosome 14 anomaly with a break at band q11–13: inv(14)(q11q32) in two patients, t(11;14)(p13;q13) in one patient, t(14;14)(q11;q32) in addition to del(14)(q11q13) in another, and only del(14)(q11q13) in two patients. Thus, a proximal 14q rearrangement exists in ATL as in other types of T‐cell malignancies. Based on these facts, the pathogenesis of ATL is discussed in reference to the literature.

IL-2-Dependent ATL cell lines with phenotypes differing from the original leukemia cells

Adult T-cell leukemia (ATL) cells have been shown to express the receptor for IL-2 by studies using anti-CD25 monoclonal antibody, but these cells usually show no or only a weak proliferative response to IL-2. In the present study, we established thirteen IL-2-dependent T-cell lines from four ATL patients. Examination of the clonalities of these cell lines by the rearrangement profiles of the TCR beta-chain gene and the integration sites of the HTLV-I proviral genome, revealed that two cell lines (KK-1 and KK-5) were of real ATL cell origin. The others were of normal T-cell origin and had been established by infection with HTLV-I. The KK-1 and KK-5 cell lines were derived from a single ATL patient (KK). Interestingly, these cells showed different phenotypic features from the majority of original leukemia cells (CD3 +/- CD4+ CD8-). The KK-1 cell line acquired CD8 antigen expression and became double-positive (CD3 +/- CD4+ CD8+), while the KK-5 cell line prominently expressed CD3 antigen (CD3+ CD4+ CD8-). These results indicate that the phenotypic feature of ATL cells are not fixed, but can change in vitro as has occasionally been observed in vivo.

Prognostic significance of the proportion of Ki‐67‐positive cells in adult t‐cell leukemia

The authors examined peripheral blood samples from patients with adult T‐cell leukemia (ATL) using the monoclonal antibody Ki‐67 which detects a nuclear antigen present in actively proliferating cells. In patients with chronic ATL, the percentage of Ki‐67‐positive cells was significantly lower than in acute ATL patients (median values, 3.3% versus 18.9%, P < 0.001). Furthermore, there was a significant inverse correlation between the percentage of Ki‐67‐positive cells and the length of survival (P < 0.001). Serum lactic dehydrogenase (LDH) levels also showed a significant inverse correlation with survival, but this was less strong than that for Ki‐67 (0.01 < P < 0.02). Thus, Ki‐67 positivity appears to indicate the aggressiveness of ATL, and can possibly be used for the clinical classification of ATL patients as well as for the prediction of prognosis.

Mental health conditions among atomic bomb survivors in Nagasaki

To elucidate the effects of the bombing on the atomic bomb survivors’ mental health, a mental health survey was conducted using a 12‐item version of the General Health Questionnaire (GHQ‐12) and a mail survey on atomic bomb exposure conditions and lifestyle using a self‐administered questionnaire. A total of 3526 atomic bomb survivors in Nagasaki responded and a high GHQ‐12 score, as defined when the responses to four or more items were positive, was observed in 296 (8.4%) subjects. It was indicated that the risk of a high GHQ‐12 score will decrease 0.98‐fold with every 1‐year increase in age, and will increase 1.45‐fold and 1.70‐fold in those who lost family members due to the bombing and those who had acute symptoms, respectively, compared with those who did not. It was indicated that the atomic bomb exposure has affected survivors’ mental health and that the care of their mental health is important.

Primary biliary cirrhosis among atomic bomb survivors in Nagasaki, Japan

Despite rapid progress in methods for analyzing radiation effects, much remains to be learned about the mechanisms and processes of radiation-induced immunological dysfunction. Among 17,899 sera obtained from atomic bomb survivors in Nagasaki, Japan, sera from 484 participants who complied with a reexamination for alkaline phosphatase (ALP) were tested for antimitochondrial antibody (AMA) by indirect immunofluorescence, and autoantibodies against 2-oxo-acid dehydrogenase complex (2-OADC) by immunoblotting to investigate the prevalence of primary biliary cirrhosis (PBC). Of these 484 sera, 28 (5.8%) were seropositive for AMA. The 484 participants were divided into three groups according to distance from the hypocenter: 72 who were exposed within 1999 m (closest group), 368 from 2000 to 5999 m (intermediate distant group), and 44 outside 6000 m (distant group). The positivity rates for AMA in these three groups were 6/72 (8.3%), 22/368 (6.0%), and 0/44 (0%), respectively (P =.08). Furthermore, high titers ( > 1:320) of AMA were observed in 3/6 (50%) AMA-positive sera from the closest group, in contrast to 4/22 (18%) from the intermediate distant group, although there was no significant correlation between AMA titer and distance from the hypocenter (P =.07). Of these 28 AMA-positive sera, 11 (39%) were from participants who had already been diagnosed with PBC, and 25 (89%) contained antibodies against at least one component of 2-OADC enzymes by immunoblotting. Therefore, the prevalence of PBC was estimated to be at least 615 cases per million (792 per million women). Our results suggest that the prevalence of PBC in atomic bomb survivors in Nagasaki is higher than that reported for the general population in Japan, and a further survey of the environmental factors, including radiation exposure, that predispose to PBC would be needed for understanding this disease of unknown etiology.

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors

Radiation exposure is a possible predisposing factor for monoclonal gammopathy of undetermined significance (MGUS), but the association has been uncertain. We investigated the relationship between radiation exposure and MGUS prevalence by using data from the M-protein screening for Nagasaki atomic bomb survivors between 1988 and 2004. Radiation exposure was assessed by exposure distance from the hypocenter and exposure radiation dose. We computed prevalence ratios (PRs) and the 95% confidence intervals (CIs) adjusting for exposure age and sex. A total of 1082 cases of MGUS were identified from 52 525 participants. MGUS prevalence was significantly higher in people exposed at distance within 1.5 km than beyond 3.0 km (PR, 1.4; 95% CI, 1.1-1.9) among those exposed at age 20 years or younger, but it was not found among those exposed at age 20 years or older. MGUS prevalence was also significantly higher in people exposed to more than 0.1 Gy than those exposed to less than 0.01 Gy (PR, 1.7; 95% CI, 1.0-2.8) among those exposed at age 20 years or younger. Thus, people exposed at younger age exhibited a significantly high risk of MGUS when exposed to a high radiation dose. There was no clear association between radiation exposure and the malignant progression of MGUS. Further detailed analysis is needed.

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.

16;21 translocation in acute nonlymphocytic leukemia with abnormal eosinophils : a unique subtype

Two patients with acute nonlymphocytic leukemia (ANLL) and t(16;21)(p11;q22) were studied. The patients exhibited such clinical and hematological pictures, characterized by M2 and M4 with eosinophilia (FAB classification), as relatively matured leukemic cells, low neutrophil alkaline phosphatase activity, abnormal eosinophils and a high count of monocytic cells in the bone marrow. The prognosis was poor in both patients. From these data, the chromosomal abnormality of t(16;21)(p11;q22) seems to be specifically associated with a unique subtype of ANLL.