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A 47-year-old man was diagnosed with acute promyelocytic leukemia (APL) accompanied by pancytopenia and left forearm swelling. Complete remission was achieved with remission induction therapy using all-trans retinoic acid (ATRA), and consolidation therapy was completed. Three months after the treatment, left ear closure was observed, and a mass lesion was found in the left external auditory canal. An initial tumor biopsy only revealed inflammatory cell infiltration. Moreover, the tumor's rebiopsy performed 3 months later revealed MPO-positive and CD68-positive granulocyte infiltration. Furthermore, the rebiopsy revealed 4.9×10 5 copies/µgRNA of PML/RARα, the patient was diagnosed with locally recurrent APL. A bone marrow examination 2 weeks later confirmed an increase in myeloblasts and promyelocytes for the first time since the confirmation of remission. Therefore, it was diagnosed as bone marrow recurrence. Reinduction therapy using ATRA and arsenic trioxide again led to complete remission, after which autologous peripheral blood stem cell transplantation was performed. Currently, complete remission is being maintained. In this case, the recurrence of the external auditory canal lesion preceded the bone marrow recurrence. Therefore, it is important to note the nonspecific leukemia recurrence patterns of the external auditory canal.

We report a patient with refractory idiopathic thrombotic thrombocytopenic purpura (TTP) who was successfully treated with rituximab. A 50-year-old woman was referred to our hospital with progressive psychoneurotic symptoms, hemolytic anemia and thrombocytopenia. The diagnosis of TTP was confirmed by the absence of ADAMTS13 activity with the presence of circulating ADAMTS13 inhibitor. High-dose steroid therapy and plasma exchange were performed. Despite 21 sessions of plasma exchange, however, there was no remarkable improvement. We then administered rituximab. Fifteen days after the first infusion of rituximab, she achieved complete remission and ADAMTS13 activity increased up to 14%. The patient has remained in remission for more than 9 months.

A 58-year-old man was referred to our hospital because of painful swelling in the left lower leg and leukocytosis in January 1999. Moderate hepatosplenomegaly but no lymph node swelling was observed. Marked leukocytosis (leukocytes 44.9 x 10(4)/microliter with 95% morphologically prolymphocytes) and thrombocytopenia were detected. The surface phenotype of the leukemia cells was CD1-2+3+5+7+4+8+25+. Magnetic resonance imaging revealed dilated veins in the left lower leg. An abnormal 47XY, +22 karyotype was detected in 1/20 cells. Tests for HTLV-I antibody were negative. A diagnosis of T-cell prolymphocytic leukemia (T-PLL) was made on the basis of data including cytochemical and electron microscopic findings. Although 2 courses of chemotherapy comprising vincristine, cyclophosphamide, and prednisolone improved the venous thrombosis in the leg, the leukemia cells were refractory to chemotherapy. To prevent the recurrence of venous thrombosis due to leukostasis, the patient underwent repeated leukapheresis. The leukocyte count was maintained at around 20.0 x 10(4)/microliter after total 7 courses of leukapheresis, one course of which comprised 7l of extracorporeal circulation. In addition to the rare presentation of venous thrombosis, the CD4+8+25+ phenotype observed in this case is rare in patients with T-PLL.

We reported a rare case of pancytopenia caused by allopurinol. A 61-year-old man was first admitted in May 1993, because of thrombocytosis. He had suffered from chronic glomerulonephritis. He was administered allopurinol for hyperuricemia from March 1993. On first admission the laboratory findings revealed leukocytosis (10,100/microliter) and thrombocytosis (971 x 10(3)/microliter) in the peripheral blood. Myelofibrosis was strongly suspected due to increased number of MgK and reticular fiber in the bone marrow. Two months later, he readmitted due to pancytopenia (WBC 1,300/microliter, Hb 6.2g/dl, Plt 10 x 10(3)/microliter). His bone marrow showed markedly hypocellular. Because we suspected that pancytopenia was induced by allopurinol, we discontinued allopurinol and administered oxymetholone, G-CSF, and EPO, WBC, RBC, and platelet count had been recovered about one and half months later. In vitro co-culture indicated that CFU-G, E, and Meg in the bone marrow cells after recovery from pancytopenia were markedly suppressed in the presence of patient's serum and oxipurinol. Pancytopenia due to allopurinol was reported to be rare, and some authors showed that it will sometimes be fatal. Because pancytopenia of this case had been recovered in a relatively short time with cytokine therapy, it was thought to be effective for pancytopenia due to drug like this case.

Many cytoplasmic processes of megakaryocytes were seen in a 45-year-old male patient of Munchausen syndrome with sustained severe anemia due to repeated self-blood drawing. He had a past history of repeated infection and removal of skin-graft transplanted for giant congenital melanocytic nevus due to self-infliction (later confessed by the patient). On the admission, he presented with high fever (39 approximately 40 degrees C) and severe sustained anemia refractory to repeated blood transfusions. Any specific clinical data indicating bleeding or hemolysis were not found. Self-blood drawing was discovered by a nurse on his 27th hospital day. Syringes and needles for blooddrawing were also found. He recovered from anemia under intensive watching without any specific treatment. He confessed that the high fever was artificial. It was of interest that cytoplasmic processes of megakaryocytes were seen in the peripheral blood film until he recovered from anemia for one month. The serum level of erythropoietin was elevated (1540 mU/ml), but not significantly was that of thrombopoietin (1.54 fmol/ml). This case was considered to be valuable to understand the mechanism of platelet-production by megakaryocytes at persistent bleeding.

A 20-year-old Japanese woman was admitted to our hospital with anemia and mild splenomegaly. Peripheral blood examination revealed Hb 9.4 g/dl, Ht 29.3%, RBC 4.74 x 10(6)/microliters, reticulocytes 2.4%, WBC 5,200/microliters, platelets 24.9 x 10(4)/microliters, MCV 61.7 fl, and MCH 19.9 pg. Poikilocytosis with target cells was recognized on the peripheral blood smear. A bone marrow aspirate revealed erythroid hyperplasia. Serum iron and ferritin were in the normal range. beta-thalassemia was suggested by the increase in HbA2 (6.5%) and HbF (7.5%). Analysis of beta globin DNA by single strand conformation polymorphism (SSCP) and amplification refractory mutation system (ARMS) confirmed a diagnosis of homozygous beta(+)-thalassemia due to -31 A to G mutation. A familial study revealed that her parents were heterozygous for this allele. This is the 8th case of homozygous beta(+)-thalassemia due to -31 A to G mutation in Japan.

Sixty-seven years-old female, who was an atomic bomb survivor in Hiroshima, was pointed out as having leukopenia and anemia in 1991. She was referred to Tsukuba University Hospital in June 1992. Her peripheral blood count showed pancytopenia- 2,600/microliters WBC, 10.5 g/dl hemoglobin, and 80,000/microliters platelets- at that time. BM biopsy revealed hypoplastic marrow and increased peroxidase-negative blasts (32.8%). Surface marker analysis of the blasts showed a feature of CD2+ CD33+ CD34+ CD13+ CD3-. Electronmicroscopically, myeloperoxidase was positive. She was diagnosed as having hypoplastic leukemia of which the blasts had a feature of AML-M0 by FAB-group. After 6 months' silent period, her pancytopenia became profound. We successfully reduced the blasts by BAM therapy. However, she died of bacterial pneumonia during the myelosuppressive state. This is a case of minimally differentiated hypoplastic AML.

We reported a case of von Recklinghausen's disease complicated by macroglobulinemia, malignant Schwannoma and pheochromocytoma. A 43-year-old male patient who was diagnosed as von Recklinghausen's disease developed abdominal masses at 5 years after the adrenalectomy for pheochromocytoma. Computed tomography showed multiple heterogeneous tumors in abdominal cavity. Histological examination of resected tumor was compatible with malignant Schwannoma. At the same time, peripheral blood and bone marrow smears showed a large number of plasmacytoid lymphocytes. Immunoelectrophoresis revealed M-protein of IgM, kappa type. He was also diagnosed of coexistence with macroglobulinemia. The chemotherapeutic protocols used were not effective against both malignant Schwannoma and macroglobulinemia. The present case is a rare case of von Recklinghausen's disease associated with triple neoplasms.

Between April 1990 and June 1992, a multicenter clinical trial of chemotherapy regimens was performed with patients, aged 65 years or more, suffering from malignant lymphoma. The total number of patients was 38 included 30 initial cases (median age: 72) and 8 relapsed cases (79). The chemotherapy regimen, administered every 3 weeks, included pirarubicin (30 mg/m2; day 1), cyclophosphamide (500 mg/m2; day 1), vindesine (1.5 mg/m2; day 1), and prednisolone (40 mg/m2; days 1-5) for the initial cases, and etoposide (100 mg/m2; days 1-5) in addition for relapse cases. The complete response and partial response rates were 50.0% and 40.0% in initial cases, respectively, and 50.0% and 0% in relapsed cases, respectively. The 50% survival period was 25.9 months in initial cases and 18.0 months in relapse cases. There were no serious side effects related to the regimens. Performance status deteriorated in only one case after chemotherapy. We concluded that the chemotherapy regimens were useful and safe for elderly patients with malignant lymphoma.

To distinguish hypoplastic myelodysplastic syndrome (MDS) from aplastic anemia (AA), morphological abnormalities of bone marrow hematopoietic cells in 8 patients with MDS and 39 patients with AA were studied. All the patients with MDS and AA showed prolonged plasma iron disappearance time, (PIDT1/2) > 120 min. Five hundred erythroid and myeloid cells, as well as 20 megakaryocytes were counted. Dysplastic changes were defined if morphological changes were present in more than 1.0% cells with only one lineage, or in more than 0.6% cells with more than two lineages. Twenty six of 39 patients with AA showed morphological abnormalities. In MDS cases, morphological abnormalities were prominent in trilineage cells in some cases, in bilineage (erythroid and megakaryocytic or myeloid and megakaryocytic cells), in others, or solely in myeloid cells or in megakaryocytic cells in other cases. Morphological abnormalities seen solely in erythroid cells, especially those with segmented nuclei were considered to be less significant for the diagnosis of MDS. The findings were considered to be useful to distinguish hypoplastic MDS from AA.

Chronic myeloproliferative disorders (CMPD) consisted of the disease with chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF) and other proliferative diseases have commonly developed increased megakaryocytes. Recently, clonal assay for megakaryocytic progenitors, identification of young megakaryocytes and isolation of megakaryocytes have been greatly facilitated an analysis of megakaryopoeisis. It is still difficult quantitatively and serially to estimate megakaryopoiesis in CMPD. However, number of CFU-Meg, number of megakaryocytes (PGPIIb/IIIb) in the clot section, cytoplasmic area and DNA content of megakaryocytes were measurable in the clinical materials. The present lecture has been focused to following points; 1) megakaryopoiesis in CML, 2) differences of megakaryopoiesis between ET and PV, 3) megakaryopoiesis in Ph1 positive ET, and 4) megakaryopoiesis in rective thrombocytosis by our data and previous studies.

An elderly man with an intestinal hemorrhage from bowel diverticulosis developed human parvovirus B19-induced aplastic crisis. A 71-year-old man noticed occasional tarry stools and at the same time showed fever, arthralgia and severe anemia. Blood counts revealed Hgb 5.3g/dl, reticulocytes 0%, and WBC 1,900/microliters. Bone marrow examination showed hypocellular marrow with rare erythroid precursors (4.8%). A few giant proerythroblasts were found in the bone marrow smears. A diagnosis of parvovirus B19 infection was made because of detection of B19-specific IgM and IgG antibodies. Parvovirus B19 infection should be carefully checked for in patients with hemorrhage as well as those with hemolysis.

We report a therapeutic protocol for elderly patients with chronic idiopathic thrombocytopenic purpura (ITP) and related conditions. Twelve chronic ITP patients over 60 years of age (elderly group), and 40, 59 years old or less (young group) were evaluated in this study. The therapeutic protocol for ITP, proposed by the Japanese Idiopathic Disease of Hematopoietic Organ Research Committee, was modified for the elderly (group) as follows: the initial dosage of prednisolone was reduced by half and danazol therapy was selected in cases in which splenectomy was impossible. Platelet counts and PAIgG showed no significant difference between the two groups. All 12 elderly patients were initially treated with prednisolone, and five patients responded to it. Among the seven non-responders, four patients underwent splenectomy, and the three three others (non splenectomized patients) were treated with danazol. Platelet counts were maintained over 150 x 10(3)/microliters in eleven patients except one splenectomized patient. The outcome in the elderly ITP group was better than in the young group.

We investigated 9 cases of Ki-1 lymphomas morphologically and immunohistochemically. The lymphoma cells infiltrated in the lymph nodes in 7 cases, in the skin in 6 cases, in both in 4 cases and in the bone marrow in 2 cases. In lymph nodes, the giant tumor cells infiltrated paracortical areas, showing a sheet-like appearance or free cell growth pattern and in the marginal and medullary sinuses as well. In the skin, they formed subcutaneous tumor and infiltrated diffusely also in dermis. All cases were positive for Ber-H2, Ki-1 and HLA-DR and 8 cases revealed some of the T cell phenotypes. But Leu-4 and beta F1 for which all 11 peripheral T cell lymphomas were positive, were only positive in 2 cases, respectively. In the present study, the tumor cells were positive for a few antibodies for T lymphocytes and there were few cases showed positivity for Leu-4 and beta F1. The results suggest that it was questionable whether the tumor cells were derived from T lymphocytes. There may be few cases of Ki-1 lymphomas of distinct T cell lineage.

Clinicopathological analyses of 6 cases of mantle zone lymphoma (MZL) were carried out. The median age of the patients was 62 years with a range of 41 to 71 years and the male-to-female ratio was 1:1. Superficial lymph node (LN) swelling was present only in 2 patients. Giant LN swellings of the mesenteric or inguinal regions were present in 4, and bone marrow involvement by lymphoma cells in 5. Serum protein electrophoresis revealed a monoclonal protein of IgM kappa type in 2 patients. One of these also had polyclonal hypergammaglobulinemia. An immunohistochemical study of 6 patients revealed LN-1-(-)+, LN-2+(-)++, sIgM+, sIgD+, CALLA +/-(-)+, DRC-1+(-)++. The immunohistochemical features of the cases were similar to those of small lymphocytic lymphoma or follicular lymphoma. Only 1 patients out of 6 achieved complete remission. Two patients died, one of pneumonia after chemotherapy and the other of cancer. The others were alive 4 to 100 months after the diagnoses. Although giant LN swelling and bone marrow involvement of lymphoma cells which were refractory to treatments were frequently observed, we consider MZL to be a slowly progressive and low-grade type of non-Hodgkin's lymphoma.

A 50-year-old woman with anorexia nervosa was admitted for evaluation of neutropenia (WBC 1,600/microliters). Her bone marrow was gelatinous, and myeloid cells had decreased. Homogeneous substance deposited in the marrow, stained by alcian blue (pH 2.5), indicative of acid mucopolysaccharides. CFU-G and CFU-GM were decreased in number and myeloid pool in the bone marrow also decreased. Anti-neutrophilic antibody was negative. Neutropenia may be related to myeloid hypoplasia, due to increase of acid mucopolysaccharides replacing adipose cells in the bone marrow under long-term mal-nutritional state. Neutrophils markedly increased by administration of rhG-CSF 5.0 micrograms/kg/day for 14 days without the first peak. Serum G-CSF level did not increase (less than 60 pg/ml). It is effective to administer G-CSF to anorexia nervosa with neutropenia.

We reported rare manifestations of adult T cell lymphoma/leukemia. Patient was 41 year-old woman who has had progressive alopecia from childhood and developed multiple huge tumors (largest 10 x 15 cm) of scalp and wide destruction of cerebral bone at age of 39. A few abnormal lymphocytes (10%) appeared in the peripheral smear. Surface markers of peripheral lymphocytes showed two populations of CD4+/CD8- and CD4+/CD8+. HTLV-1 proviral DNA was demonstrated in the peripheral lymphocytes. Serum anti-ATLA antibodies was positive (X80). Biopsy of tumor revealed diffuse and large cell type of malignant lymphoma. Magnetic resonance imaging of head showed that tumors lysed the bone and invaded into cerebral regions. She was treated with CHOP regimen and irradiation, resulting of decreased tumor size and population of CD4+/CD8+.

Fifty-four ITP patients were treated by the protocol proposed by Japanese Idiopathic Disease of Hematopoietic Organ Research Committee. Forty-eight patients were treated with corticosteroid (CS). Twenty-eight patients out of 30 patients who were refractory to CS were splenectomized. To study natural courses of splenectomized patients, 25 patients were splenectomized without elevation of platelet counts at the operation and were followed up their platelet counts and PAIgG for one month without treatment. Clinical courses after splenectomy were classified into four types by the platelet increment followed by splenectomy and the platelet counts at one month after splenectomy; type I (markedly over-shooted platelet peak and normalized platelet counts), type II (moderate platelet peak and 50 approximately 100 x 10(3)/microliters platelets), type III (minimal platelet peak and less than 50 x 10(3)/microliters platelets), and type IV (elevation of platelet counts at day 7 or later of splenectomy and normalized platelet counts). The results of analyses from 25 patients indicated that the numbers of type I, II, III and IV were 10, 5, 6 and 4, respectively. The clinical course of type IV suggests that platelet production may be impaired by anti-platelet antibodies.

A case of chronic myelogenous leukemia (CML) with marked thrombocytosis and its megakaryokinetics were reported. Patient was 57-year old woman who had a marked thrombocytosis (1,413 x 10(3)/microliters) and a bone marrow megakaryocytosis. Bone marrow karyotype demonstrated Ph1 chromosome in all cells examined. However, on physical examination, there was no splenomegaly. CBC showed no immature myeloid cells, and neutrophil alkaline phosphatase was elevated. These manifestations were consistent with so called essential thrombocythemia (ET) with Ph1 chromosome reported by Nissenblatt. To know the megakaryokinetics of this case, we examined the number of colony forming unit-megakaryocyte (CFU-M), platelet glycoprotein (PGP) IIb/IIIa positive cells, cytoplasmic area, and DNA content, comparing with those of normal subjects, CML, and ET. We found a marked increase of CFU-M and PGP IIb/IIIa positive cells, but in contrast, decreased DNA content and cytoplasmic area. This pattern of megakaryokinetics was consistent with that of CML. We conclude that ET with Ph1 chromosome may be a variant of CML rather than ET itself.

A defective cell-mediated immunity was seen in a 62-year-old female with paroxysmal nocturnal hemoglobinuria (PNH). We studied the functional defect of the patient's lymphocytes and its relation to the deficiency of decay-accelerating factor (DAF) on the lymphocytes. T cells (CD 5+) and B cells (CD 20+) were obtained by cell-sorting using fluorescence-activated cell sorter (FACS-IV). These two types of cells from the patient were demonstrated to be deficient in DAF by the fluorometric measurement of DAF content using monoclonal anti-DAF antibodies. These cells were shown to be more susceptible to complement-mediated lysis than normal human lymphocytes by a complement-mediated lysis study. It was carried out by treatment of the lymphocytes with either anti-CD 5 or anti-CD 20 antibody plus rabbit complement. The lymphocytes became more susceptible to complement-mediated lysis by an additional treatment with an anti-DAF antibody both in PNH and in normal controls. From these results, we suggest that DAF plays an inhibitory role against complement activation on human lymphocytes. The mononuclear cells of the patient responded poorly to phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). Skin tests both for PPD and for DNCB showed negative. From these findings, we suggest T cell function in the patient is impaired. Causative relations of the deficiency of DAF to the poor responses of the lymphocytes to lectins and to negative skin tests were discussed.

A 32-year-old man with an 18-year history of protein losing enteropathy (PLE) was admitted to hospital for abdominal distention. On physical examination, he had massive pleural effusion, ascites and edema of the right leg, but no superficial lymphadenopathy or organomegaly. Laboratory studies revealed mild microcytic anemia and hypoproteinemia. alpha 1-antitrypsin clearance was elevated (316 ml/day). Examination of ascites disclosed numerous lymphoblastoid cells of B cell phenotype with mu chain and lambda light chain of immunoglobulin (Ig) in the cytoplasm. Southern blot analysis showed monoclonal rearrangement of mu chain and lambda chain genes. No evidence of lymphomatous involvement of lymph nodes and non-lymphoid organs was found by CT scan, ultrasound echography and gallium scan of the chest and abdomen. Bone marrow biopsy was negative. Thus, a diagnosis of non-Hodgkin lymphoma (NHL) stage IVB limited in the pleural and peritoneal cavities was made. He was treated with the combination chemotherapy of BACOD with high dose ara-C or methotrexate followed by 4 doses of autologous LAK cell infusion resulting in no significant response. The massive pleural effusion, ascites and edema of the leg have not been improved. We consider this to be a rare case of NHL associated with PLE which is extremely resistant to chemotherapy or LAK therapy.