Hair dye use and occupational exposure to organic solvents as risk factors for myelodysplastic syndrome.

To investigate the relationships of personal hair dye use and environmental factors to myelodysplastic syndromes (MDS), we conducted a case-control study in Japan. A total of 111 MDS cases and 830 controls randomly selected from the residents in the same prefecture of cases using telephone directories responded to a health questionnaire. The odds ratio (OR) for ever having used hair dye was 1.99 (95% confidence interval (CI) 1.17-3.38) and there were statistically significant trends in risk with increasing duration and number of hair dye use. Occupational exposure to organic solvents was marginally associated with the risk of MDS (OR = 1.99; 95% CI 0.97-4.10).

Diagnostic and biological significance of sideroblastic erythropoiesis in the myelodysplastic syndromes.

We retrospectively reviewed clinical and hematologic features of nine patients with acquired idiopathic sideroblastic anemia (AISA). Seven of them had ringed sideroblasts (RS) more than 15% of marrow nucleated cells. RS persisted in the marrow even in the remaining two patients who had a relatively low marrow erythroblasts despite RS ranging from 1/4 to half of the marrow erythroid series. However, RS declined in proportion in another two patients of the nine whose disease progressed to refractory anemia with excess of blasts (RAEB), although a high proportion of RS reappeared in one patient at the time of relapse following allogeneic marrow transplantation. A similar decline of RS concomitant with disease progression was also seen in seven additional patients with RAEB or RAEB in transformation (RAEB-t) with sideroblastic erythropoiesis. Cytogenetic abnormalities, although rare initially, became detectable either at the time of disease progression or at the worsening of anemia in AISA. These observations suggest that the majority of AISA fall in the category of myelodysplasia, and that a progressive decline in RS is part of the natural history of myelodysplasia. Closer follow-up of the proportion of RS in patients with AISA is warranted to better understand its biologic significance.

Mode of disease progression in primary myelodysplastic syndromes: a Japanese co-operative study. The Refractory Anemia Study Group of The Ministry of Health and Welfare, Japan.

Chronological changes in hematological findings were analyzed in 225 patients with myelodysplastic syndromes (MDS). They were diagnosed between 1990 and 1992. Their hematological findings, i.e. hemoglobin levels, leukocyte and platelet counts, proportions of peripheral blood (PB) blasts and monocytes, and proportion of blasts in bone marrow (BM), were recorded for up to 42 months after diagnosis, when available. BM was examined regularly in only a few patients. Therefore, it was impractical to use the French-American-British Cooperative Group criteria for subtype classification during the disease course. Thus, we used the percentage of PB blasts as the only indicator of stage evolution. We classified the disease into four stages: stage 1, less than 1% PB blasts; stage 2, 1-5% PB blasts; stage 3, 5-30% PB blasts; and stage 4, 30% or more PB blasts. There were 171 patients initially in stage 1, 37 initially in stage 2, and 17 initially in stage 3. Less than half (45%) of the patients initially in stage 1 progressed to stage 2, while 91% of the patients initially in stage 2 and all of the patients initially in stage 3 showed stage evolution. Eight variables, i.e. BM blasts 5% or more, male sex, karyotypic abnormalities, micromegakaryocytes, mononuclear large megakaryocytes, platelet counts 50 x 10(9)/l or higher, abnormal nucleus of granulocytes, and abnormal granules of granulocytes, were found to be significant risk factors for evolution from stage 1 to 2. Evolution from stage 1 to a higher stage within 15 months of diagnosis was associated with impending poor prognosis in most patients. However, of the 67 patients initially in stage 1 who died, 30 did not show stage evolution. Evolution from stage 2 to a higher stage and from stage 3 to stage 4 was also associated with impending poor prognosis. Higher levels of cytopenia were not associated with poorer prognosis in the stage 1 patients. In conclusion, our grading system proved to be useful in evaluating the chronological changes in MDS patients.

Stable human T-lymphotropic virus type I carrier rates for 7 years among a teenaged blood donor cohort of 1986 in Kumamoto, Japan.

The human T-lymphotropic virus type I (HTLV-I) carrier rates for blood donors in Kumamoto, Kyushu, Japan for 8 years, 1986-1993, are currently available. The data show that 16-19-year-olds in 1986 and 20-29-year-olds in 1993 represent nearly the same cohort, because the median age in both groups is 24.5 years in 1993. Therefore, comparison of the HTLV-I positive rate for the two groups gives an estimate of the change in the rate over 7 years within the cohort. In males, 265 of 22,143 donors (1.20%) were seropositive for HTLV-I among 16-19-year-olds in 1986, and 214 were seropositive among 20,076 (1.07%) donors in 20-29-year-olds in 1993. In females, 203 were seropositive among 20,677 (0.98%) donors in 16-19-year-olds in 1986, and there 154 were seropositive among 18,660 (0.83%) donors in 20-29-year-olds in 1993. Thus, the seropositive rates declined in both sexes. However, the average annual rate of immigration to Kumamoto Prefecture was 2.37%. If seropositive rates for 20-29-year-olds in 1993 are adjusted for the dilution effect due to immigration (under the assumption that all immigrants were HTLV-I negative), the adjusted carrier rate for males is 1.26% and that for females is 0.98%. The adjusted carrier rates for both sexes are almost the same as those for 16-19-year-olds in 1986. This indicates that horizontal transmission was negligible for those in the cohort who were in their early reproductive period. Using all 8 year carrier rates for 16-19-year-olds and 20-29-year-olds, chronological changes of 20-29-year-olds, in the near future was estimated. The best goodness of fit model indicated that the HTLV-I carrier rate will decline exponentially, and that the rate will decrease by 50% approximately every 10 years for both sexes. It is probable that in recent years south-west Japan has lost the conditions that are favorable for HTLV-I endemicity and the virus will be virtually non-endemic within a few generations.

Clinical characteristics of Japanese patients with primary myelodysplastic syndromes: a co-operative study based on 838 cases. Anemia Study Group of the Ministry of Health and Welfare.

The characteristics of Japanese (JPN) patients with myelodysplastic syndromes (MDS) were investigated in 838 retrospectively collected cases. The median age of the JPN patients was 60 years, about 10 years younger than that in most of the reports based on Western patients. Median survivals were 65 months for refractory anemia (RA), 58 months for RA with ring sideroblasts (RARS), 16 months for RA with an excess of blasts (RAEB), 10 months for RAEB in transformation (RAEBT), and 20 months for chronic myelomonocytic leukemia (CMML). Cumulative leukemia-free rates at final observation were 73% for RA, 79% for RARS, 24% for RAEB, 20% for RAEBT, and 53% for CMML. When low-risk (RA and RARS) patients were divided into two groups, those 40 years of age and older, and those under 40, the cumulative leukemia-free rate was 94% for the younger patients (n = 101), compared with 66% for the older patients (n = 318). The prognostic factors for survival were different from those in Western reports, i.e., variables representing quantitative abnormalities (hemoglobin levels, granulocyte, and platelet counts) were not major prognostic factors, while variables representing qualitative abnormalities (morphological abnormalities in granulocytic and megakaryocytic series cells) were highly significant. Two scoring systems for overall survival and for leukemic transformation were developed, based on multivariate prognostic factor analysis. Neither system included variables representing the degree of cytopenia. Whatever the reason for the different prognostic factors in JPN and Western MDS patients, the use of a scoring system based on Western patients for clinical decision-making in a JPN patient could be misleading, and vice versa.

Infection in myelodysplastic syndromes before evolution into acute non-lymphoblastic leukemia.

The frequencies, kinds, pathogens, and risk factors of infections in the myelodysplastic syndromes (MDS) were analysed in 430 cases. The overall tendency was for one infectious episode per 1023.5 patient days. The frequency of infectious episodes was highest just after diagnosis of MDS when more than 4 episodes per 1000 patient days occurred. Thereafter, the rate declined rapidly to about 0.3 episodes per 1000 patient days within 4 years. The most frequent infection was that of the respiratory tract followed by sepsis and fever of unknown origin (FUO). Among the types of infection resulting in death, sepsis and FUO comprised the highest proportion (40%) followed by respiratory tract infections (39%). The most frequent pathogen observed was Staphylococcus bacteria. The significant multivariate risk factors for fatal infections were subtype, hemoglobin, dependence on red blood cell transfusion, age, and sex. A staging system was created using these five simple variables at diagnosis.

Successful bone marrow transplantation with rabbit anti-human thymocyte globulin in aplastic anemia. Report of a case previously treated with equine anti-human lymphocyte globulin.

Bone marrow transplantation is widely accepted as the first line therapy for patients with severe aplastic anemia. Patients with less severe forms of aplastic anemia are treated with immunosuppressive agents, hematopoietic growth factors or androgenic steroids. The use of rabbit anti-human thymocyte globulin allowed us to successfully transplant in a patient with a moderately severe form who once failed to respond to all conservative treatment including equine anti-human lymphocyte globulin. We propose that, given the availability of rabbit anti-human thymocyte globulin, marrow transplantation should be considered in non-severe aplastic anemia patients who are refractory to equine anti-human lymphocyte globulin.

[Relationship between aseptic necrosis of femoral head bone and immunosuppression therapy, especially CsA administration].

We reviewed 224 patients, who underwent kidney transplantation to investigate relationship between aseptic necrosis (AN) and administration of steroid, Cyclosporin A (CsA), body weight gain. We classified patients into 4 groups by the type of immunosuppressant: the AP group had received Azathioprine (AZ) + Prednisolone (Pre); the CP group, CsA + Pre; the ACP group, AZ + CsA + Pre; and others. There were total 24 AN patients (10.7%). The incidences of AN is 18% in the CP group, 9.3% in the AP group and 0% in the ACP group. In the AP group, weight gain at 1 and 2 month after transplantation and cumulative steroid dose at 3, 4, 5 and 6 month after transplantation correlated with AN. In the patients with AN of the CP and ACP groups, CsA doses per kilogram of body were higher than those in patients without AN at 5, 6 and 12 month after transplantation. In the CP group, the incidence of AN is significantly higher, and administration dose of CsA was higher than that in the ACP group. However steroid dose and body weight gain were lower in the CP group. Therefore AN was associated with CsA in the CP group. In contrast, AN correlated with weight gain and early high cumulative steroid dose administration in the AP group.

Clinical importance of CD7 expression in acute myelocytic leukemia. The Japan Cooperative Group of Leukemia/Lymphoma.

Forty patients (9 females and 31 males; mean age 41.9 years) with CD7+ acute myelocytic leukemia (AML) were investigated; they were classified into the following subgroups according to French-American-British classification: 15 M1, 18 M2, 3 M4, and 4 M5. Leukemic cells from all the patients were negative for T-cell-specific antigens, surface CD3, and T-cell-receptor molecules. The sex and age distributions were different from those of CD7- AML patients (P < .01). Hepatomegaly and central nervous system involvement were also frequent in the CD7+ AML patients. The phenotype of and responsiveness to hematopoietic growth factors by the leukemic cells showed their immaturity, as evidenced by frequent expression of CD34, HLA-DR, and TdT, and the greatest growth response to interleukin-3. No particular karyotypic abnormality was shown. One hundred eighty AML patients were treated with a therapeutic regimen routinely used for AML. The CD7+ AML patients showed a significantly lower response than CD7- AML patients (P < .01), and had a poorer prognosis (P < .01). CD7+ AML patients with M1 or M5b had unfavorable responses to the therapeutic regimen in comparison with patients with M2, M4, or M5a. In addition, 3 of 4 CD7+ CD2+ AML patients, who did not respond to the therapy, were induced into complete remission with an acute lymphoblastic leukemia therapy. The results presented here indicate the diagnostic importance of CD7 positivity in AML, suggesting that the cellular and clinical characteristics of CD7+ AML are sufficient for it to be recognized as a distinct category of AML.

Re-analysis of prognosis in refractory anemia alone, with ring sideroblasts, and with excess of blasts.

Based on 473 primary cases of refractory anemia (RA), RA with ring sideroblasts (RARS), or with an excess of blasts (RAEB), new staging systems for overall survival, leukemic transformation, and nonleukemic death were developed. The reproducibility of these new staging systems, our former staging systems for leukemic transformation and nonleukemic death, and that for overall survival provided by Sanz et al. (Blood 1989;74:395-408), were estimated using a total of 132 patients with RA, RARS, or RAEB (test sample). The correlation of risk ratios of the test sample from our system and that of Sanz et al. was poor (tau = 0.24; Kendall rank correlation). Our risk ratio was a significant (p = 0.0012) continuous covariate of the Cox model life-table analysis in the test sample but that of Sanz et al. was not. The new and previous staging systems for leukemic transformation were highly similar (tau = 0.7) and risk ratios of both systems were significant in the test sample (p = 0.00046 and 0.0017, respectively). Based upon the new system, patients at high risk for leukemic transformation RA or RARS were identified as males, with bone marrow myeloblasts higher than 2.5%, abnormal granules in the granulocytes, and circulating erythroblasts. Their cumulative leukemic transformation rate exceeded 50% within 2 years from presentation. The new and previous systems for nonleukemic death were moderately correlated (tau = 0.47). The risk ratios of both systems were significant in the test sample (p = 0.00012 and 0.000024, respectively) but failed to stratify test sample patients into three distinct risk groups. In conclusion, our new staging systems for overall survival and leukemic transformation were reproducible in RA, RARS, or RAEB patients and will be useful especially in identifying high-risk patients with RA or RARS, who are considered to be at lower risk by the FAB classification.

[Effect of intra-venous hyperalimentation on hepatic energy metabolism after hepatic resection in the cirrhotic rat].

We evaluated experimentally the effect of administration of glucose on hepatic energy metabolism, mitochondrial functions and lipid metabolism after hepatic resection. The 75% hepatic resection was performed on thioacetamide induced cirrhotic rat. Glucose solution with 30 Cal/kg/day (group I) or 200 Cal/kg/day (group II) was administrated intravenously for 48 hours after hepatic resection. Blood levels of ketone bodies and glucagon, tissue activities of ATP synthesis and tissue content of adenine nucleotides were measured in both groups. Hepatic energy charge was significantly decreased in group II, comparing with group I. When fatty acid was used as a substrate for respiratory system, the activity of ATP synthesis on mitochondria after hepatic resection rose, while in case pyruvate was used as a substrate the value was declined. On the levels of serum free fatty acids and ketone bodies, there were no remarkable changes in group I, while in group II, obvious declines were investigated. It is suggested that the overload of glucose in the early stage after hepatic resection is unfavorable to hepatic energy metabolism because of decline of serum free fatty acid by hyperinsulinemia and suppression of fatty acid oxidation by decline of blood glucagon.

A randomized study of alfacalcidol in the refractory myelodysplastic anaemias. A Japanese cooperative study.

A multi-institutional randomized trial of alfacalcidol (1 alpha hydroxyvitamin D3) was performed to determine the therapeutic effect of alfacalcidol in patients with refractory myelodysplastic anaemias. Twenty-three evaluable patients were randomized to receive either a single daily oral dose of 6 micrograms of alfacalcidol or only supportive care as a control. Treatment was continued, whenever possible, for a period of 6 months. Response was assessed by weekly blood counts, clinical course and repeated marrow examinations. No significant difference was noted between the alfacalcidol and control groups. Three of the 13 patients in the alfacalcidol group, and two of the 10 patients in the control group, suffered a progression of their disease. One patient with refractory anaemia showed a good response to alfacalcidol in all three haematopoietic cell lineages; the response, however, could not be maintained, because discontinuation of the drug resulted in a worsening of pancytopenia which was refractory to a second course of alfacalcidol therapy. Hypercalcaemia was the major toxic side-effect of alfacalcidol therapy. The results indicate that alfacalcidol therapy, when used alone, does not induce a beneficial effect in patients with refractory myelodysplastic anaemias.

Clinical features of long-term survivors of refractory myelodysplastic anemias. A Japanese cooperative study.

Eighty-one of 473 patients with refractory myelodysplastic anemias registered by the Japanese Cooperative Study Group prior to January 1987 survived more than 5 years. At presentation, most patients had mild cytopenia, a less aggressive form of the disease (48 with refractory anemia, 23 with refractory anemia with ring sideroblasts, 10 with refractory anemia with excess of blasts), less blast cells in the marrow and blood, and onset at younger ages. Their clinical profiles 5 years after presentation showed no significant improvement. The results suggest that the long-term survivors were found in a subpopulation of patients with a favorable prognosis and that it is a part of the natural course rather than the results of treatment.

Accelerated declining tendency of human T-cell leukemia virus type I carrier rates among younger blood donors in Kumamoto, Japan.

The annual age- and sex-specific human T-cell leukemia virus type I carrier rate of blood donors in Kumamoto, Kyushu, Japan from 1986 to 1990 revealed that the carrier rates of all the age groups below 50 years declined linearly in both sexes (P less than 0.005). Furthermore, the annual declining rates relative to the carrier rates of 16-19-year-old and 20-29-year-old males were higher than those of all of the older males (P less than 0.02), and all female age groups below 50 years had higher relative declining rates than 50-64-year-old females (P less than 0.05). Although several factors, such as a notification program at obstetric clinics, methodological and technical improvement of the assays, wider knowledge of human T-cell leukemia virus type I infection in the latter years, and immigration of individuals from a nonendemic area, might cause an absolute decline of the carrier rate of the blood donors, these factors could not explain the acceleration of the relative declining rate among younger donors. Therefore, this acceleration represents the tendency of the general population.

Geographical aspects of bcl-2 gene involvement in Japanese patients with non-Hodgkin's B-cell lymphomas.

Using three separate bcl-2 probes, we examined involvement of the bcl-2 gene in Japanese patients with non-Hodgkin's B-cell lymphomas. Of 52 patients with follicular lymphoma (FL), 24 had rearrangements. In a group of 50 patients with diffuse lymphoma, three of 32 patients with diffuse large cell lymphoma had rearrangements. The frequency of rearrangements in each of these groups, as detected by both major and minor breakpoint cluster region probes, was compatible with that found in other Far Eastern studies. However, the difference in frequency between the groups studied in the Far East and the West was significant, and these two geographically distinct populations also displayed a difference in the breakpoint distribution. In the immunophenotype study of 33 patients with FL, the expression of CD10 antigen correlated with bcl-2 involvement, whereas none of the other B markers emerged as parameters to distinguish between the two lymphoma groups; those with, and without, the rearrangements.