[Successful treatment with immunosuppressive therapy for aplastic anemia developed after resection of thymoma].

We report here a very severe case of thymoma-related aplastic anemia that developed after thymectomy. The patient was a 50-year-old man diagnosed with myasthenia gravis. Chest CT showed thymoma measuring 7.5 cm in diameter, and extended thymectomy was performed. Irradiation to the anterior mediastinum was added postoperatively. Thirteen months after surgery, hemogram showed severe neutropenia: leukocyte count 0.32×10(9)/l with 11% neutrophils; Hb 10.7 g/dl; and platelet count 100×10(9)/l. Although cyclosporine (CSP, 5 mg/kg/day) was administered, dose reduction was necessary because of renal damage. Cytopenia deteriorated to a leukocyte count of 0.71×10(9)/l with 21% neutrophils; Hb 5.9 g/dl; and platelet count 24×10(9)/l. However, addition of antithymocyte globulin (ATG, 15 mg/kg) led to hematopoietic recovery of all three lineages within one month. He is clinically stable with no transfusion requirement after 22 months with CSP maintenance therapy. Although thymoma-related aplastic anemia has been reported to have an extremely poor prognosis, high efficacy of CSP has been reported recently. In our case, ATG in combination with CSP was efficient. Adequate immunosuppressive therapy seems to be important for the clinical management of these patients.

Vitamin K2 modulates differentiation and apoptosis of both myeloid and erythroid lineages.

Vitamin K2 (VK2) can improve cytopenia in some patients with myelodysplastic syndrome (MDS). Although it is well known that VK2 induces differentiation and apoptosis in acute myeloid leukemia (AML) cell lines, little is known about its effect on normal hematopoietic progenitors. The effects of VK2 on primary myeloid and erythroid progenitors were examined. Mobilized CD34-positive cells from peripheral blood were used for the examination of myeloid lineage cells, and erythroid progenitors purified from peripheral blood were used for erythroid lineage cells. VK2 upregulated the expressions of myeloid markers CD11b and CD14, and increased the mRNA expression levels of CCAAT/enhancer binding protein-α (C/EBPα) and PU.1 in myeloid progenitors. In erythroid progenitors, VK2 did not show a significant effect on differentiation. However, VK2 exhibited an anti-apoptotic effect on erythroid progenitors under erythropoietin depletion. This anti-apoptotic effect was restricted to normal erythroid progenitors and was not shown in erythroleukemic cell line AS-E2. Steroid and xenobiotic receptor (SXR), which was recently identified as a receptor of VK2, was expressed on myeloid progenitors, and the SXR agonist rifampicin (RIF) also upregulated CD11b and CD14 expressions on myeloid progenitors. These results indicate that SXR is involved in the effect of VK2 on myeloid progenitors. The major effect of VK2 on myeloid progenitors was promoting differentiation, whereas its anti-apoptotic effect seemed to be dominant in erythroid progenitors. Although the detailed mechanism of VK2's effect on differentiation or apoptosis of hematopoietic progenitors remains unknown, the effect of VK2 therapy in patients with MDS could be partly explained by these mechanisms.

[Five adult cases of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis].

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is more common in children, and is characterized by pancytopenia, liver dysfunction and coagulopathy caused by interactions between EBV-infected T cells and activated macrophages. We describe here five adults with EBV-HLH. The median age was 17 years (range 16 approximately 40). HLH developed in 4 patients within 2 months after the primary infection, and in the other one during the reactivation. All patients had a high EBV viral load in peripheral blood (2 x 10(2)-3 x 10(6) copies/ml) and monoclonal proliferation of EBV-infected T cells. All patients received immunosuppressive therapy with or without etoposide, and two patients required plasmapheresis due to the severity. Three patients are alive in complete remission (follow up periods; 13, 19, 30 months), while two patients became refractory to chemo-immunotherapy and died despite multidrug chemotherapy. EBV-HLH should be more widely recognized in adults in order to achieve early diagnosis and appropriate treatment.

Primary mediastinal non-seminomatous germ cell tumor associated with hemophagocytic syndrome.

A 20-year-old man with a primary non-seminomatous mediastinal germ cell tumor (yolk sac tumor and immature teratoma) developed hemophagocytic syndrome (HPS) three months after surgical resection. Around the same time, the patient was found to have bone metastases of the germ cell tumor. No other hereditary or acquired diseases related to HPS were found. The thrombocytopenia was refractory to corticosteroid therapy but improved after chemotherapy performed for germ cell tumor progression. Only three cases of germ cell tumor associated with reactive hemophagocytosis have been previously reported. Successful treatment of the present case by chemotherapy for HPS suggests a close relationship between this rare complication and germ cell tumor.

Pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in regulation of erythroid progenitor cell proliferation and differentiation.

OBJECTIVE: The aim of this study was to reveal the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in erythropoiesis. METHODS: The effects of PPARgamma ligands on cellular proliferation and differentiation were investigated in erythroid colony-forming cells (ECFCs) purified from human peripheral blood. RESULTS: RT-PCR analysis revealed that PPARgamma mRNA is expressed in ECFCs. Synthetic PPARgamma ligands, troglitazone or pioglitazone, suppressed cellular proliferation without inducing apoptosis and delayed maturation of ECFCs, as determined by flow cytometry. The delay in erythroid maturation by troglitazone was confirmed by the down-regulation of gamma-globin, beta-globin and GATA-1 mRNA, and the maintenance of GATA-2 mRNA. CONCLUSIONS: Our results suggest that PPARgamma modulates the differentiation process of erythroid progenitor cells, and plays a crucial role in regulating the balance of hematopoiesis.

[Second nonmyeloablative allogeneic peripheral blood stem cell transplantation with more immunosuppressive conditioning regimen for the late graft failure of the patient with acute myeloid leukemia].

A 53-year-old woman with acute myeloid leukemia (M2; normal karyotype) in first remission underwent the nonmyeloablative allogeneic peripheral blood stem cell transplantation from her HLA-identical brother, with conditioning consisting of fludarabine and low dose total body irradiation (2Gy). Karyotype analysis of bone marrow on day 28 after the recovery of the hematopoiesis showed 46 XY (20/20). However, pancytopenia progressed from day 130 and the patient became transfusion dependent. Because of the hypoplastic bone marrow and the high ratio (81%) of recipient cells among the peripheral T-cells, she was diagnosed as the late graft failure. Cyclophosphamide was added to the conditioning and the second transplant was performed using the same donor's cryopreserved stem cells. Hematopoiesis recovered and the complete chimerism in T-cells was confirmed on day 28. Although the transplant dose of the CD34 and CD3 positive cells was the same between the two transplantation, the patient suffering from the late graft failure obtained the stable engraftment after the second transplant with more immunosuppressive conditioning regimen.

[Follicular lymphoma complicated with autoimmune hemolytic anemia and pure red cell aplasia].

Malignant lymphomas are often associated with immunological disorders. We describe here a 54-year-old woman with follicular lymphoma, simultaneously complicated with autoimmune hemolytic anemia and pure red cell aplasia. The patient had bilateral cervical, axillar and inguinal lymph node swellings. Peripheral blood analysis revealed severe anemia (Hb 3.4g/dl) and reticulocytopenia (2260/ml), and then the bone marrow showed erythroid hypoplasia. Furthermore, a direct Coombs test was positive and the serum haptoglobin level was undetectable. After treatment with CHOP followed by 1 mg/kg of prednisolone daily, the patient obtained complete remission and her anemia improved to the normal level.

[Nonmyeloablative allogeneic stem cell transplantation for a 70-year-old woman with relapsed acute myelogenous leukemia].

We describe a 70-year-old woman with acute myelogenous leukemia with t(8;21) in the first relapse who underwent nonmyeloablative transplantation with conditioning of fludarabine and low-dose total body irradiation (2Gy). Myelosuppression was very mild, and the patient developed transient grade I renal and hepatic toxicities. Complete chimerism was achieved on day 120. The level of the AML1/MTG8 fusion gene in bone marrow decreased to an undetectable level on day 56 and the patient is alive and in complete remission with a follow-up at day 450. This transplant regimen might be well tolerated even by the elderly patients and bring a durable remission.

Successful treatment with nonmyeloablative allogeneic hematopoietic stem cell transplantation in a patient with acute myeloid leukemia complicated with pulmonary infection.

We describe the case of a 48-year-old man with acute myeloid leukemia complicated with pulmonary infection that was successfully treated by nonmyeloablative allogeneic peripheral blood stem cell transplantation with conditioning by low-dose total body irradiation and fludarabine. The disease was diagnosed immunophenotypically as myeloid/natural killer cell precursor acute leukemia. After two courses of induction therapy, complete remission was achieved. However, the patient developed pneumonia from prolonged severe neutropenia. Nonmyeloablative allogeneic transplantation was performed because of the active pulmonary infection and the patient's poor performance status. Myelosuppression after transplantation was mild, and the pulmonary infiltration was well controlled during the course of treatment. At the time of this report the patient was an outpatient in our clinic, and on day 500, his disease was in remission with well-controlled chronic graft-versus-host disease. Nonmyeloablative transplantation may provide a new therapeutic strategy for treating patients with active infection who cannot tolerate conventional transplantation with high-dose chemoradiotherapy.

[Persistent T-cell mixed chimerism in a case of malignant lymphoma after nonmyeloablative allogeneic peripheral blood stem cell transplantation].

We describe a 51-year-old woman with recurrent follicular lymphoma from the age of 47 despite chemo-radio therapy, who subsequently underwent nonmyeloablative stem cell transplantation with conditioning consisting of fludarabine and low-dose total body irradiation (2 Gy). Myelosuppression was very mild, so the patient required no transfusions. Chimerism analysis from peripheral blood showed that T-cell mixed chimerism continued over 12 months after stem cell transplantation (the percentage of recipient T-cells was approximately 20%). Despite this, the lymphadenopathy disappeared, and the patient developed grade II acute GVHD (graft versus host disease). It has been considered that the establishment of full donor chimerism is required to induce GVHD and GVM (graft versus malignancy) effects. In this case, however, an allo-response was observed despite the persistence of T-cell mixed chimerism.