Tadashi Maekawa

Criteria for Diagnosis of DIC Based on the Analysis of Clinical and Laboratory Findings in 345 DIC Patients Collected by the Research Committee on DIC in Japan

From analysis of the clinical and laboratory findings in the DIC patients collected by JRDC, diagnostic criteria for the diagnosis of DIC are proposed. The characteristics of the criteria are as follows: (1) a scoring system is adopted; (2) as the tests for scoring, PT, plasma Fbg level, serum FDP level, and platelet count are used; (3) different scores are given according to the grade of change in the results of the tests; (4) bleeding and clinical signs indicating organ dysfunction due to DIC are included in the scoring system; and (5) recognition of the well-known etiological factors of DIC is also scored.

Tissue factor activity in leukemia cells. Special reference to disseminated intravascular coagulation

Tissue factor activity (TFA) of 108 leukemia cells was measured in 82 patients with acute nonlymphoid leukemia by the clotting method. The TFA bore a significant correlation to the development of disseminated intravascular coagulation (DIC) in these cases. Mean TFA value with standard deviation (SD) was 8.3 ± 6.3 U in 48 cases with DIC, which was significantly higher than 0.3 ± 4.2 U in 34 cases without DIC. Whereas Mean TFA in non‐M3 was 0.9 ± 6.3 U which was significantly lower than 37.2 ± 2.3 U in M3, some non‐M3 showed TFA as high as M3 and were complicated by DIC. In heparin treatment, dosage of heparin could not be controlled by either APTT or AcCT but was controlled by the extent of TFA of leukemia cells. Retrospective analysis of clinical features revealed that 9700X + 9000 units/day (X = logarithm value of TFA) of heparin is an adequate dosage for the successful treatment of DIC when TFA of leukemia cells is 0.8 U or more. Cancer 59:748‐754, 1987.

Clinical characteristics of Japanese patients with primary myelodysplastic syndromes: A co-operative study based on 838 cases

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.

Nation-wide randomized comparative study of doxorubicin, vincristine and prednisolone combination therapy with and without L-asparaginase for adult acute lymphoblastic leukemia

A randomized clinical trial of combination chemotherapy for adult acute lymphoblastic leukemia (ALL) with doxorubicin, vincristine and prednisolone with and withoutL-asparaginase (AdVP vs L-AdVP) was conducted, involving 58 institutions throughout Japan. After reaching complete remission (CR), patients were treated with the same regimen for more than 2 years. Among 166 evaluable cases of the 198 cases enrolled, CR rates were 63.1% (53/84) with AdVP and 64.6% (53/82) with L-AdVP (P=0.837). Median survival times and 7-year survival rates were 12.7 months and 21.2% with AdVP, and 16.0 months and 22.3% with L-AdVP (P=0.955 by generalized Wilcoxon test [GW],P=0.952 by log-rank test [LR]). Median diseasefree survival times and 7-year survival rates were 13.5 months and 23.8% with AdVP and 17.0 months and 30.6% with L-AdVP, showing some increments for L-AdVP but no statistical significance (P=0.141 by GW,P=0.300 by LR). Among the cases of extramurally confirmed FAB subtypes, CR rates were 75.9% (63/83) for the L1 subtype and 51.3% (39/76) for the L2 subtype (P=0.001). As to adverse effects, pancreatitis was complicated more frequently in L-AdVP than in AdVP (P=0.039). Other side effects such as hyperbilirubinemia, diabetes mellitus, diarrhea and hypofibrinogenemia were observed more frequently with L-AdVP, but with no statistical significance. Thus, addition of a single course of L-asparaginase in the induction phase of combination chemotherapy with doxorubicin, vincristine and prednisolone did not significantly enhance the effect of antileukemic treatment of adult ALL.

Treatment of acute myelogenous leukemia in adults with N4-behenoyl-1-β-D-arabinofuranosylcytosine

Forty‐five previously‐untreated adult patients with acute myelogenous leukemia (AML) were treated with N4‐behenoyl‐1‐β‐D‐arabinofuranosyl‐cytosine (BHAC) in a multi‐institutional cooperative study. Among 41 evaluable patients, 15 (36.6%) achieved complete remission (CR) and 10 (24.4%) achieved partial remission by daily administration of 3 to 8 mg/kg of BHAC. Higher daily doses (5 mg/kg or more) produced higher CR rates, and all of the CR were observed among the patients receiving a total BHAC dosage of 50 mg/kg or more in a period of 10 days or more. The side effects were mild and acceptable: nausea–anorexia was observed in 27% of the patients and vomiting in 17%. The results of this study thus indicate BHAC to be effective for remission induction of AML, and to deserve further clinical trials in combination with other anti‐leukemic drugs. Cancer 56: 1913‐1917, 1985.

Prognostic aspects of aplastic anemia in pregnancy

ZusammenfassungBerichte über Schwangerschaften bei aplastischer Anämie oder das Auftreten einer aplastischen Anämie in der Schwangerschaft sind selten. Anhand von 6 eigenen derartigen Fällen und von 43 Fällen aus der Literatur wurden die hämatologischen und klinischen Befunde in Hinsicht auf ihre prognostische Bedeutung untersucht.Bei den hämatologischen Parametern war lediglich die Hämoglobinkonzentration von prognostischer Bedeutung. Bei Auftreten der aplastischen Anämie vor der Schwangerschaft war die Prognose besser als bei Auftreten während der Schwangerschaft. Der Prozentsatz der erfolgreich ausgetragenen Schwangerschaften stieg von 21% vor 1958 auf 67% in der Zeit von 1959 bis 1969 und auf 71% nach 1970. Blutungen und Infektionen waren die beiden wichtigsten mütterlichen Todesursachen. Aus den Ergebnissen ist abzuleiten, daß bei ausgeprägtem Kinderwunsch und gutem Allgemeinzustand von einer Schwangerschaft bei bestehender aplastischer Anämie nicht immer abgeraten werden muß und daß andererseits bei einer progredienten aplastischen Anämie, die in der Schwangerschaft auftritt, möglichst früh eine Schwangerschafts-unterbrechung erfolgen muß.SummaryOur recent experience on six cases of aplastic anemia complicated with pregnancy is described. In addition, 43 similar cases were collected from the literature and reviewed to analyze some prognostic aspects of this relatively rare but potentially serious complication. Clinical and hematological data were treated to extract some clinically meaningful factors in relation to the success and failure of pregnancy.Among initial hematological parameters, no significant difference was found between successful and unsuccessful cases with an exception of hemoglobin concentration. The patients diagnosed as aplastic anemia prior to conception demonstrated an better outcome of pregnancy as well as survival rate of mother when compared with those diagnosed during pregnancy. Mortality has apparently improved after the late 1950s. Success rate of pregnancy before 1958 was 21% while it was 67% and 71% in the era of 1959–1969 and after 1970, respectively. However, hemorrhage and infection remained to be two major causes of maternal death in both eras.Based on these observations, the currently recommendable attitude to this complication is discussed.

Case Report: Familial nephrotic syndrome with focal glomerular sclerosis

Two brothers with nephrotic syndrome are reported. Their parents were first cousins. The nephrotic syndrome developed at the age of 14 and 15 years and was resistant to the treatment with corticosteroid. The elder patient fell into renal failure about 2-1/2 years after the development of nephrotic syndrome, and the younger has demonstrated a progressive decrease in renal function. The renal histopathology in one patient revealed findings typical of focal glomerular sclerosis. In light of the clinical similarities in these two patients, it is likely that they have a familial form of focal glomerular sclerosis.

Proliferative kinetics of the leukemic cells in meningeal leukemia.

The proliferative kinetics of leukemic cells was investigated in the cerebrospinal fluid (CSF) and the leptomeninges of 5 patients with meningeal leukemia (ML) and 15 selected autopsies showing meningeal involvement. The 3H‐thymidine labeling index (TLI), mitotic index (MI) and 3H‐uridine labeling index (ULI) of leukemic cells in the CSF at the time of diagnosis were 0.7 ± 0.2, less than 0.01 and 96.2 ± 0.7%, respectively. The TLI was found to be higher at the time of recurrence than at the initial diagnosis of meningeal leukemia. The grade of leukemic cell infiltration was classified according to Prices criteria. The mitotic index was also estimated on the histologic sections. An infiltration of Grade 2 or greater was observed in all 4 patients who had not received an intrathecal administration of methotrexate (MTX). The clinical course of 2 patients with a higher MI (0.88 and 0.32%) was shorter than the other 2 (0.03 and 0.01%). In the patients who did not show clinical manifestations of ML, the infiltration of leukemic cells in the leptomeninges was mild in degree, and the MI was less than 0.01%. Likewise, mild infiltration and low MI was observed in 8 cases treated with an intrathecal administration of methotrexate. These findings seem to support the general concept that the proliferation of leukemia cells infiltrating leptomeninges is remarkably slow at an incipient stage of ML; then it undergoes a gradual acceleration, possibly slowing down again at an advanced stage of the disease.

Studies on leukemic cell tissue factor

Apoprotein part of tissue factor of human placenta was purified 871 fold from the starting material with 4.2% yield by concanavalin A-Sepharose affinity chromatography and SDS-PAGE. The molecular weight of purified apoprotein was 45,000 in non-reduced condition and 49,000 in reduced condition. Tissue factor of human leukemia cells (FAB classification:M2 and M3) and cultured leukemia cell lines (HL-60 and Molt-4) was analyzed using specific rabbit anti-tissue factor IgG raised against purified material. Endotoxin stimulated HL-60 and Molt-4 also expressed procoagulant activity which was inhibited by tissue factor immune IgG. By immunostaining of the purified material, the lysate of leukemia cells (M2 and M3) and cultured leukemia cells (HL-60 and MOLT-4) revealed a major band of the same apparent molecular weight. Immuno-electron microscopic study on tissue factor of HL-60 cells produced the following findings: stimulation by endotoxin resulted in the formation of pseudopods of the cell membrane, and immunogold particles accumulated mainly on these pseudopods and cisternal spaces of rough endoplasmic reticulum, indicating exposure of the tissue factor to the surface of perturbed cell membrane with concurrent increase in tissue factor synthesis.

Hematological study on a case with cerebellar hemangioblastoma associated with erythrocytosis, with special reference to a erythropoiesis-stimulating activity present in the fluid of the cyst of tumor

SummaryA case of cerebellar hemangioblastoma associated with slight but definite erythrocytosis is reported. Operative removal of the tumor resulted in the reversion to a normal blood picture. Erythropoietin-like activity, being non-dialyzable and relatively thermolabile, was detected in the fluid aspirated from tumor. The mother of the reported patient suffered from the same disease which was also associated with a slight degree of erythrocytosis.ZusammenfassungEs wird über den Fall eines cerebellaren Hämangioblastoms begleitet von einer leichten, aber doch eindeutig diagnostizierten Erythrozytose berichtet. Die operative Entfernung des Tumors führte zu einer Renormalisierung des Blutbildes. In der aus dem Tumor aspirierten Flüssigkeit wurde eine erythropoetinähnliche Wirkung entdeckt, die relativ thermolabil und nicht dialysierbar war. Die Mutter des geschilderten Patienten litt an der gleichen Krankheit, die ebenfalls von einer Erythrozytose leichten Grades begleitet war.