Akatsuka J

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.

High frequency of etoposide (VP-16)-related secondary leukemia in children with non-Hodgkin's lymphoma.

Patients and Methods : We report patients who were treated for non-Hodgkins lymphoma (NHL) or Ki-1 antigen-positive (Ki-1) lymphoma with a T-8801 protocol that included etoposide (VP-16) and behenoylcytosine arabinoside. Results : Secondary acute myeloid leukemia (AML) developed in 5 of 38 NHL and Ki-1 lymphoma patients, and the cumulative risk at 4 years was 18.4%. The median time from the initiation of the chemotherapy to the development of AML was 21 months (range, 13–30). Four patients had a FAB M5 morphology, and one had FAB M2. In four of five examined cases, chromosomal alterations involving the long arm of chromosome 11 were demonstrated at the time of development of AML. None of the 46 NHL patients who we treated with another protocol (B-8801), using significantly higher cumulative doses of VP-16 than in the case of the patients with T-8801 and a different schedule of VP-16 administration, developed secondary AML. Conclusions : The risk of secondary AML possibly related to the use of VP-16 given twice weekly.

Consensus guideline for diagnosis and treatment of childhood idiopathic thrombocytopenic purpura.

A practice guideline aimed at standardizing the treatment for childhood idiopathic thrombocytopenic purpura (ITP) is presented. This consensus guideline is based on a survey carried out via a questionnaire prepared by the ITP Committee of the Japanese Society of Pediatric Hematology and sent to society members. The survey questionnaire included questions on the diagnosis of ITP submitted for the purpose of revising the ITP diagnostic guideline prepared in 1990 by the Research Group for Intractable Hematopoietic Disorders; a revised diagnostic guideline also is presented.

BUN/Cr ratio as an index of gastrointestinal bleeding mass in children.

Determining the site and severity of blood loss is important in the management of children with gastrointestinal (GI) bleeding. Blood urea nitrogen (BUN) and serum creatinine (Cr) were measured on the day of hospitalization and the ratio of BUN/Cr was calculated in 11 children with 16 episodes of upper GI bleeding and 49 with lower GI bleeding. There was a significant difference between the two GI bleeding groups with regard to BUN/ Cr ratio (p ≥ 0.001). When the ratio was 30 or above, the specificity of upper GI bleeding was 98% with a sensitivity of 68.8%. A linear relationship was found between the BUN/Cr ratio and AHb (AHb = 0.08 χ BUN/Cr ± 0.8 g/dl) for bleeding originating from the upper GI tract. This study confirms that measurement of the BUN/Cr ratio is useful for localizing the source of bleeding to the upper GI tract and also demonstrates its usefulness as an estimation of the severity of blood loss from the upper GI tract.

Recombinant human interferon α-2b (rh IFNα-2b) therapy for steroid resistant idiopathic thrombocytopenic purpura (ITP)

The efficacy of recombinant human interferon α‐2b (rh IFNα‐2b) in the treatment of steroid resistant idiopathic thrombocytopenic purpura (ITP) was studied in 50 cases.

Thrombocytopenia in Neonates Born to Women with Autoimmune Thrombocytopenic Purpura

We conducted a survey by questionnaire to clarify the actual conditions of neonates born to mothers with autoimmune thrombocytopenic purpura (ATP) in Japan. We investigated 93 pregnancies (1 resulting in twins) in 31 hospitals between 1985 and 1994. Forty-nine of the neonates (52%) had thrombocytopenia (below 150 x 10(9)/L). Nineteen neonates (20%) showed a bleeding tendency, but this was generally mild. In only one neonate (1%) (a case of asymptomatic intracranial hemorrhage, ICH), deep bleeding occurred due to thrombocytopenia. The lowest platelet count of neonates after birth occurred on day 4, not on day 0. There was no correlation between maternal and neonatal platelet counts. However, there was an apparent correlation between the neonatal platelet count on day 0 and the lowest platelet count after birth. Treatment of the mothers with intravenous high-dose gamma-globulin and prednisolone did not prevent risk of neonatal thrombocytopenia significantly.

TESTICULAR MORPHOLOGICAL CHANGES IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA FOLLOWING CHEMOTHERAPY

Morphological changes in the testis induced by chemotherapy given according to the Tokyo Childrens Cancer Study Group (TCCSG) regimens were studied in children with acute lymphoblastic leukemia (ALL). After informed consent, testicular biopsies were performed 14 times in 12 patients at the end of treatment. The testicular morphology in all cases had sustained a degree of damage. The tubular fertility index (TFI), calculated as the percentage of seminiferous tubules containing identifiable spermatogonia, was from 0 to 42.8% (mean 33.4%) below the normal value. Infiltration of leukemic cells was the most significant factor contributing to the decrease in TFI. There were no‐differences in the TFI among the TCCSG protocols. Formation of sperm was recognized in six cases, whose ages were 7, 8, 9, 10, 15 and 19 years. In two children, testicular biopsy was performed twice. In the second biopsy, TFI was elevated and sperm formation with the maturation of Leydig cells was observed. A number of other pathological changes were observed: modification of spermatogonia, Sertoli cells and inclusion bodies in spermatogonia, abnormal maturation of Leydig cells, evidence of interstitial fibrosis and thickening of the basement membrane. These results suggest that recent strong chemotherapy for the treatment of ALL might cause severe but not fatal damage to childrens testicular tissue. As chemotherapy escalates, more investigation of testicular function will be necessary.

Peripheral blood progenitor cell transplantation estimated by three-colour (CD34, HLA-DR, CD33) flow cytometry

The relationships between transfused cell number of CD34+ cell subpopulations divided by HLA-DR and CD33 antibodies and hematopoietic recovery patterns after peripheral blood progenitor cell transplantation (PBPCT) subsequent to myeloablative chemoradiotherapy were investigated in 14 children with cancer. Both logarithm of transfused CD34+ cell number/10(6)/kg and logarithm of transfused cell number/10(6)/kg of the CD34+HLA-DR+CD33+ subpopulation, which is supposed to be myeloid-committed cells, were correlated with myeloid recovery after PBSCT, though they were not correlated with erythroid or platelets recovery. On the other hand, logarithm of transfused cell number/10(6)/kg of CD34 + HLA-DR-CD33-subpopulation, which is supposed to be immature progenitor cells, was not correlated with myeloid recovery but correlated with erythroid recovery and platelet recovery. These results suggested that rapid myelopoiesis after PBPCT occurs following transfusion of sufficient numbers of myeloid-committed cells and complete hematopoietic reconstitution occurs after transfusion of sufficient numbers of immature hematopoietic progenitor cells.

Ex vivo expansion of umbilical cord blood hematopoietic progenitor cells by combinations of cytokines.

Ex vivo expansion of hematopoietic progenitor cells in the umbilical cord blood mononuclear cells (CB‐MNC) was investigated in liquid culture system with various combinations of cytokines (stem cell factor [SCF], interleukin [IL]‐3, IL‐6, granulocyte‐colony stimulating factor [G‐CSF], erythropoietin [EPO], and interferon [INF]‐γ). Non‐lineage‐committed hematopoietic progenitor cells and lineage committed hematopoietic progenitor cells were represented as CD34+CD38− and CD34+CD38+ subpopulations, respectively. Although absolute CD34+CD38− cell numbers decreased even in the presence of multicytokines, the combinations of SCF plus IL‐6 and SCF plus IL‐3 plus IL‐6 plus INF‐γ were significantly effective in maintaining CD34+CD38− cells than the other combinations (P < 0.05). After 4 weeks of culture, CD34+CD38− cells disappeared in all combinations of cytokines. Absolute CD34+CD38+ cell numbers increased in the presence of cytokines. Maximal expansion of CD34+CD38+ cells were observed in the combinations of SCF plus IL‐3 plus IL‐6 plus EPO (19.8 ± 3.3 ‐fold) and SCF plus IL‐3 plus IL‐6 plus G‐CSF (18.3 ± 2.6). The combination of SCF plus IL‐3 plus IL‐6 was also effective to expand CD34+CD38+ cells (15.8 ± 3.9). However, the expansion was transient and they decreased to zero within 3 weeks. In the combinations of SCF plus IL‐6 and SCF plus IL‐3 plus IL‐6 plus INF‐γ, maximal expansion was inferior to the others but CD34+CD38+ cells were maintained more than 4 weeks. These results suggested that the indication of CBT can be expanded into older children by ex vivo augmentation of CB hematopoietic progenitor cells using multi‐cytokines.

Establishment and characteristics of a T-cell acute lymphoblastic leukemia cell line, JK-T1, with a chromosomal translocation between 8q24 and 14q13

A human leukemia cell line, JK-T1, was established from the bone marrow of a 10-year-old boy with T-cell acute lymphoblastic leukemia. The origin of the leukemic cell line, JK-T1, was demonstrated by its chromosomal and immunologic similarity to the patients fresh leukemic cells. Karyotypic analysis revealed 46,XY,del(6)(q?),t(8;14)(q24;q13),der(9)t(9;?)(q34;?). In JK-T1, neither rearrangement nor amplification of the c-myc gene was observed apparently because the breakpoint of chromosome 14 was not q11 but q13. JK-T1 was independent of interleukin 2 (IL-2) because of little production of IL-2, little IL-2 receptor (CD25) on the surface, and no response to exogenous IL-2. JK-T1 had lymphocyte function associated antigen-1 (LFA-1) (CD11a, CD18) on its surface and could adhere to the hematologic stromal layer. These characteristics of JK-T1 cell line are considered to be useful not only for evaluating the role of t(8;14) but also in studying the adhesion molecules of leukemia.