Takashi Kageyama

Increased frequency of somatic mutations at glycophorin A loci in patients with aplastic anaemia, myelodysplastic syndrome and paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH), aplastic anaemia (AA) and myelodysplastic syndrome (MDS) are haemopoietic stem cell disorders. These disorders have some features in common, and a percentage of cases progress to acute leukaemia. We speculated that changes in gene stability are involved in the pathogenesis of these haemopoietic stem cell disorders. Therefore we investigated in vivo mutation frequencies in these disorders by erythrocyte glycophorin A (GPA) mutation assay. The assay enumerates NO or NN variant cells in 106 erythrocytes of the MN type using a flowcytometric technique. Patients undergoing chemotherapy known to be at risk of hypermutageneity were also studied. Events exceeding the 95th percentile of healthy donors (≧ 32 and 34 events, respectively for NO and NN variants) were defined as abnormal. Abnormal events in the NO variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, two out of seven patients with MDS, and four out of nine patients with PNH. Abnormal events in the NN variants were found in three out of seven patients undergoing chemotherapy, two out of nine patients with AA, one out of seven patients with MDS, and two out of nine patients with PNH. These results suggest that not only PIG‐A, but also other genes including the GPA gene, are hypermutable in haemopoietic stem cell disorders, and that mutagenic pressure and/or gene instability can contribute to the pathogenesis of these disorders.

Efficacy of sulbactam/cefoperazone for the treatment of infections in patients with hematologic diseases

The efficacy and safety of sulbactam/cefoperazone (SBT/CPZ) was studied in 94 patients with severe infections and concomitant hematologic diseases. All of the study patients were included in the evaluation for safety, and 76 cases were evaluable for efficacy. Clinical efficacy was excellent in 13 cases (17.1%), good in 27 cases (35.5%), fair in seven cases (9.2%), and poor in 29 cases (38.2%). The bacteriologic eradication was 66.7% for Gram-negative bacilli and 50.0% for Gram-positive bacteria. The efficacy rate for neutropenic patients with counts less than 50 mm3 and 100 mm3 were 47.5 and 42.9%, respectively. Efficacy in patients for whom other antibiotic therapy before treatment with SBT/CPZ had been ineffective was 46.2%. Side effects were reported in one case (1.1%), and abnormal serum liver tests in five cases (5.3%); both returned to normal after discontinuation of the study medication. SBT/CPZ was an effective antibiotic for the treatment of severe infections in the presence of concurrent hematologic diseases.

Autopsy case of lymphoplasmacytic lymphoma with a large submucosal tumor in the stomach

An autopsy case of lymphoplasmacytic lymphoma with a large submucosal tumor in the stomach is presented. The patient was a 77‐year‐old woman with gastric lymphoma associated with Waldenström’s macroglobulinemia of IgM‐λ type. Diagnosis was initially mucosa‐associated lymphoid tissue (MALT) lymphoma of the stomach, because gastric biopsy specimens showed epitheliotropic proliferation (lymphoepithelial lesion) of the lymphoma cells. Post‐mortem examination revealed a large gastric lymphoma with metastatic foci in the esophagus, larynx, trachea, lungs, spleen and lymph nodes. The bone marrow was also involved. Lymphoma cells consisted of small lymphocytoid cells occasionally admixed with blast‐like large cells and a large number of plasmacytoid or plasma cells. Centrocyte‐like cells were not found. Lymphoepithelial lesions were not conspicuous in autopsy specimens. Immunohistochemically, lymphoma cells reacted with CD20, CD45, CD79a, anti‐IgM, anti‐λ protein and anti‐BCL‐2, but not with CD5, CD10, CD23 or CD38. Based on these findings, the revised diagnosis of the present case was lymphoplasmacytic lymphoma, and it highlighted the differential diagnostic problem from marginal zone B‐cell lymphoma of MALT type.

My4+/LeuM3- Molecule and CD19 Antigen Are Down-Modulate by Low Affinity Fc Gamma Receptor II (CD32) Stimulation on CD56-Positive B - Lymphoma Cells

My4+/LeuM3- molecule is recognized by My4, but not by LeuM3, both well known mAbs to CD14. In a previous study we showed that the My4+/LeuM3- molecule on a human mono-blastic cell line, U937, is not CD14, but another cell surface antigen. The roles and functions of the My4+/LeuM3- molecule remained unknown. We now report that specific stimulation of FcyR with aggregated IgG or anti-FcγRII antibody down-modulated the My4+/LeuM3- molecules, as well as CD 19, in a case of CD56-positive B cell lymphoma. Stimulation of FcγR with anti-μ antibody, which induced concomitant stimulation of slg, did not induce down-modulation of either molecule. Stimulation of CR2 (CD21), a protein which is functionally or physically associated with CD 19, with anti-CR2 (CD21) mAbs also had no effect. The modulation occurred specifically on CD56-positive B-lymphoma cells, since My4+/LeuM3- -positive, CD56-negative B-lymphoma cells did not respond to the stimulation. These results suggest that CD 19 and My4+/LeuM3- molecules are functionally or physically associated with FcyR II on CD56 positive B-lymphoma cells defined as being at a terminal B cell differentiation stage.

Myelodysplastic Symdrome Complicated by Malignant Lymphoma : Report of an Autopsy Case.

A case of myelodysplastic syndrome (MDS) complicated by malignant lymphoma is reported. The patient was a 68-year-old male who was admitted to hospital with severe anemia and was diagnosed as having MDS on the basis of hematological examinations and the findings of bone marrow biopsy. Treatment with steroid hormones, anabolic hormone preparations, and blood transfusion proved unsuccessful and he died of infection six months later.At autopsy, the bone marrow was hypoplastic and blast cells showed very poor differentiation, the megakaryocytes were decreased in number, and the erythroblasts had abnormal nuclei. Systemic lymphadenopathy (paratracheal, mesenteric, parapancreatic and paraaortic) was found. Histological examination of the lymph-nodes revealed diffuse proliferation of medium sized lymphocytes which had B cell markers and showed plasmacytoid differentiation.The starry sky constellation of large mononuclear phagocytes in the lymphoma tissue was quite similar to the histology of Burkitts lymphoma. There was evidence of generalized cryptococcosis and candidiasis. Malignant lymphoma complicating MDS is very rare, but the exsistence of this case suggests that a clonal abnormality of the pluripotent hematopoietic stem cells occurs in MDS.