Hirokazu Murakami

The Usefulness of 18 F-fluorodeoxyglucose Positron Emission Tomography ( 18 F-FDG-PET) and a Comparison of 18 F-FDG-PET With 67 Gallium Scintigraphy in the Evaluation of Lymphoma Relation to Histologic Subtypes Based on the World Health Organization Classification

Although studies comparing conventional imaging modalities with 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET) for the detection of lymphoma and although the relations between 18F‐FDG‐PET and histologic types were reported previously, most studies were not systematic and involved relatively small numbers of patients.

High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura.

Abstract:  Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by increased platelet clearance because of antiplatelet antibodies. It was recently reported that the balance of T helper 1 (Th1) and T helper 2 (Th2) subsets has been implicated in the regulation of many immune responses. In this study, the intracellular interleukin‐4 and interferon‐γ production in CD4+ T‐lymphocytes activated by phorbol 12‐myristate 13‐acetate and ionomycin was assessed via flow cytometry in order to determine the clinical significance of the Th1/Th2 ratio in 42 patients with ITP. The study cohort included 28 untreated patients, seven postprednisolone therapy patients and seven postsplenectomy patients. The mean level of the Th1/Th2 ratio in the untreated group was 36.9 (95% CI 25.8–47.9), and significantly higher than in the control group (mean 12.8, 95% CI 9.5–16.1). The mean levels of the Th1/Th2 ratio in the postprednisolone therapy and postsplenectomy groups were 20.5 (95% CI 8.4–32.6) and 16.4 (95% CI 3.1–29.7), respectively, but were no significant differences as compared with control subjects. When untreated patients were divided into two subgroups by Th1/Th2 ratio, the mean level of platelet associated IgG in the high Th1/Th2 subgroup (higher than upper limit of control group) tended to be higher than in the normal Th1/Th2 subgroup. In conclusion, the high Th1/Th2 ratio was closely related to the etiology and disease status of chronic ITP.

Immunomodulation by vitamin B12 : Augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment

It has been suggested that vitamin B12 (vit.B12) plays an important role in immune system regulation, but the details are still obscure. In order to examine the action of vit.B12 on cells of the human immune system, lymphocyte subpopulations and NK cell activity were evaluated in 11 patients with vit.B12 deficiency anaemia and in 13 control subjects. Decreases in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells, an abnormally high CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects. In all 11 patients and eight control subjects, these immune parameters were evaluated before and after methyl‐B12 injection. The lymphocyte counts and number of CD8+ cells increased both in patients and in control subjects. The high CD4/CD8 ratio and suppressed NK cell activity were improved by methyl‐B12 treatment. Augmentation of CD3−CD16+ cells occurred in patients after methyl‐B12 treatment. In contrast, antibody‐dependent cell‐mediated cytotoxicity (ADCC) activity, lectin‐stimulated lymphocyte blast formation, and serum levels of immunoglobulins were not changed by methyl‐B12 treatment. These results indicate that vit.B12 might play an important role in cellular immunity, especially relativing to CD8+ cells and the NK cell system, which suggests effects on cytotoxic cells. We conclude that vit.B12 acts as an immunomodulator for cellular immunity.

Poor response to intensive chemotherapy in de novo acute myeloid leukaemia with trilineage myelodysplasia

Summary. The findings of morphologically dysplastic features in haemopoietic cells in de novo acute myeloid leukaemia (AML) has been named AML with trilineage myelodysplasia (AML/TMDS). We analysed the clinical data, karyotypes, and treatment outcomes of 230 de novo AML patients treated with the Japan Adult Leukaemia Study Group AML‐87 protocol. 40 (17%) patients had AML/TMDS. Platelet count was significantly higher (F=0·006) and bone marrow blasts were fewer (P=0·01) in the AML/TMDS group than in the AML without TMDS. Abnormal karyotype was shown in 12/30 patients (40%) analysed.

Steroid‐refractory chronic idiopathic thrombocytopenic purpura associated with hepatitis C virus infection

Abstract: Objectives: Hepatitis C virus infection has often been suggested as a possible cause of various kinds of autoimmune diseases. The aim of this study was to determine the relationship between chronic idiopathic thrombocytopenic purpura (ITP) and hepatitis C virus infection and to characterize the clinical features of anti‐HCV antibody (HCVab) positive chronic ITP patients. Subjects and methods: We studied HCVab in 79 patients with chronic ITP (25 males, 54 females, mean age 42.3 yr, range 11–86 yr) using the third‐generation ELISA method. Results: HCVab was detected in 11 of the 79 patients (13.9%). Quantitative HCV‐RNA studies showed a high serum concentration of HCV‐RNA in these patients. The platelet counts in these 11 HCVab‐positive patients (Group 1) were lower than in the 68 HCVab‐negative patients (Group 2)[(2.6 ± 0.9) versus (4.9 ± 3.0) × 1010/L, respectively; p<0.02]. Significantly more patients in Group 1 required prednisolone therapy (10/11, 90.9%) than in Group 2 (31/68, 45.6%) (P < 0.005). The response rate to prednisolone treatment was significantly higher in Group 2 (19/31, 61.3%) than in Group 1(0/10, 0%) (P < 0.001). There was no difference in the response to splenectomy between Groups 1 (4/7, 57.1%) and 2 (3/5, 60%). Conclusion: Given these findings, we recommend that HCVab is measured upon diagnosis of chronic ITP, and that splenectomy is planned in patients with HCVab in the event that prednisolone treatment is ineffective.

Immunological abnormalities in splenic marginal zone cell lymphoma

The clinical features of patients with splenic marginal zone cell lymphoma (SMZCL) have rarely been reported. In the present study, immunological abnormalities, particularly hematological abnormalities, observed in SMZCL were described. Autoimmune hemolytic anemia, immune thrombocytopenia, and appearance of lupus anticoagulant were observed in 2 of 3 patients with SMZCL. Other abnormal data including monoclonal gammopathy and cold agglutinin were also observed in 2 of the 3 patients. Immunological abnormalities may be characteristic complications in patients with SMZCL and must be followed carefully, since they may be a reliable marker of this type of lymphoma activity. Am. J. Hematol. 56:173–178, 1997.

Prevalence and Clinical Characteristics of Acute Myeloid Leukemia Associated with Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is one of the important complications to develop in patients with acute myeloid leukemia (AML). While acute promyelocytic leukemia (APL) is a strong risk factor for DIC, other clinical features have not been fully defined. We retrospectively analyzed 161 consecutive adult patients with de novo non-APL AML. DIC was diagnosed in 52 patients (32%); 28 patients at diagnosis and 24 soon after the initiation of induction chemotherapy. Leukocyte counts, C-reactive protein, and lactate dehydrogenase were significantly higher in the DIC+ group. Negative expressions of CD13, CD19, CD34, and HLA-DR were more prevalent in the DIC+ group. On multivariate logistic-regression analysis, variables that were independently associated with the development of DIC were high C-reactive protein, high leukocyte count, negative expressions of CD13 and HLA-DR, and cytogenetics with a normal karyotype or 11q23 abnormality. Although DIC is considered to be associated with serious morbidity and occasional mortality, we did not find any significant differences in the complete remission rate, overall or disease-free survival between DIC+ and DIC- groups. This study is the first to define the clinical characteristics associated with DIC in patients with non-APL AML, but exactly how and when DIC should be treated remains to be determined.

Improvement of extrathymic T cell type of large granular lymphocyte (LGL) leukemia by cyclosporin A: the serum level of Fas ligand is a marker of LGL leukemia activity

Abstract: We report a case of γδ T‐cell‐type large granular lymphocyte (LGL) leukemia (CD3+,CD8+, CD57+,TCR γδ+), which was accompanied by pure red cell aplasia, neutropenia and thrombocytosis. Southern blotting analysis of the T‐cell receptor β gene showed the germline configuration, but clonal TCR J γ rearrangements were identified. These granular lymphocytes demonstrated non‐major histocompatibility complex‐restricted cytotoxicitity. The serum‐soluble FasL (sFasL) concentration of this patient was very high, whereas the serum levels of tumor necrosis factor alpha (TNF‐α), interferon gamma (IFN‐γ), interleukin‐1 beta (IL‐1β), interleukin‐2 (IL‐2) and thrombopoietin were normal. After treatment with cyclosporin A, anemia and thrombocytosis were improved, and LGL and the elevated sFasL concentration decreased. These observations suggested that FasL may have played a role in the establishment of the clinical symptoms of this patient and could be useful as an indicator of disease activity.

JAK2-V617F mutation analysis of granulocytes and platelets from patients with chronic myeloproliferative disorders: advantage of studying platelets

There have been conflicting reports over the JAK2‐V617F mutation status of platelets in chronic myeloproliferative diseases (CMPDs). The aim of this study was to analyse JAK2‐V617F status, not only in granulocytes but also in platelets. The JAK2‐V617F mutation was analysed in both granulocytes and platelets in 115 patients with CMPDs using direct sequencing. JAK2‐V617F was detected in granulocytes from 71 of those patients, all 71 of whom also had platelet JAK2‐V617F expression. The remaining 44 patients showed negative JAK2‐V617F expression on granulocytes, but positive JAK2‐V617F expression was detected on the platelets from nine of the 33 essential thrombocythaemia (ET) patients, one of the eight polycythaemia vera patients, and two of the three primary myelofibrosis patients. When ET patients were divided into three groups according to granulocyte and platelet JAK2‐V617F status (both‐positive, platelets‐only positive and both‐negative), the both‐positive and platelets‐only positive groups shared the clinical features of higher white blood cell count and frequent thrombosis. These results suggest that analysis of platelets is a more sensitive approach for detecting JAK2‐V617F in CMPD patients than analysis of granulocytes. They also suggest that previous reports of the incidence of JAK2‐V617F in CMPD patients, obtained using only analysis of granulocytes, could be underestimations.

Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma

We report the results of a non‐randomized phase II study of low‐dose thalidomide plus low‐dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression‐free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low‐dose thalidomide plus low‐dose dexamethasone therapy was as effective as high‐dose thalidomide plus high‐dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.