Nobuyasu Toyoshima

Progressive disappearance of anti-hepatitis B surface antigen antibody and reverse seroconversion after allogeneic hematopoietic stem cell transplantation in patients with previous hepatitis B virus infection

Reactivation of resolved hepatitis B virus (HBV) infection, which is known as reverse seroconversion (RS), has been reported as a rare complication of allogeneic hematopoietic stem cell transplantation. We retrospectively studied HBV serologic markers in 14 recipients with pretransplant anti-hepatitis B surface antigen antibody (anti-HBs). Progressive decreases in anti-HBs titer were observed in all cases. In 12 cases, anti-HBs titer had decreased to under the protective value. RS occurred in seven cases after disappearance of anti-HBs. Although reseroconversion occurred in five cases, two cases remained in an HBV-carrier status after resolution of hepatitis. In the other five cases, RS did not occur even after disappearance of anti-HBs. The actual risks of anti-HBs disappearance and RS were estimated to be 75.0% and 39.8% at 2 years and 100.0% and 70.0% at 5 years, respectively. In conclusion, RS is a late-onset complication with high frequency that can be predicted by careful monitoring of progressive decrease in anti-HBs titer.

Successful treatment of immunoblastic lymphadenopathy-like T-cell lymphoma with cyclosporin A.

Immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma is considered to belong to peripheral T-cell lymphoma. Its prognosis is grave and effective treatments have not been established. Recently, we gave oral cyclosporin A (CsA) to a patient with IBL-like T-cell lymphoma, and succeeded in achieving dramatic remission. In this case, serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF alpha) were elevated and decreased or returned to normal after achieving remission. Since CsA is a potent suppressor of the immune system and most notably T-cells, the immunosuppression of T-cell function might have played an important role in achieving remission in this case, although the precise mechanism still remains to be elucidated. The present case indicates that administration of CsA may be a very effective and safe selection of therapy for IBL-like T-cell lymphoma, as well as analogous disorders such as IBL and angioimmunoblastic lymphadenopathy with dysproteinemia (AILD), thereby will contribute to improving the prognosis of patients with these diseases.

Molecular Analysis of T-Cell Repertoire in Patients with Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Complementarity-determining region (CDR3) size spectratyping has often been used to analyze the clonal expansion of T-cells. CDR3 size spectratyping has been useful in the analysis of the oligoclonal expansion of T-cells in virus infection, graft-versus-leukemia effect (GVL), graft-versus-host disease (GVHD), and immune reconstitution of T-cells after allogeneic stem cell transplantation (allo-SCT). We analyzed 26 T cell receptor (TCR)-β-chain subfamilies (VB) in 25 patients who underwent allo-SCT. Fifteen of these patients developed acute GVHD (aGVHD). Many TCR-VB were skewed in the early stage. In these TCR-VB subfamilies, VB6 was most often skewed at the time of skin aGVHD. We then analyzed the average score of the complexity of 26 TCR-VB spectratypings in patients with or without cGVHD. The patients who developed chronic GVHD (cGVHD) had a lower average score of TCR-VB complexity than that of patients without cGVHD (P = 0.010). In particular, the patients who developed the quiescent type and de novo type of cGVHD from 4 months after allo- SCT had a lower average score of TCR-VB complexity at 3 months than that of the patients who had no cGVHD (P = 0.0055). These results suggest that we might be able to consider a possible development of cGVHD by analyzing TCR-VB spectratyping after allo-SCT.

Successful micafungin (FK463) treatment of invasive pulmonary aspergillosis in a patient with acute lymphoblastic leukemia in a phase II study.

We treated a 52-year-old woman with acute lymphoblastic leukemia (ALL) who developed invasive pulmonary aspergillosis (IPA) as a result of neutropenia following remission-induction chemotherapy. Although serological test results, such as those for platelia and pastrex, were all negative and the serum level of β-D—glucan was low,Aspergillus DNA was detected in blood by the polymerase chain reaction method. A clinically documented diagnosis of IPA was made on the basis of chest x-rays, computed tomography scan findings, and the detection ofAspergillus DNA. Micafungin (FK463), a candin class anti-fungal agent, was administered at a dose of 75 to 150 mg/day, because other antifungal agents were not effective. The increase in serum concentration of micafungin was dose-dependent and was accompanied by improvement of symptoms and objective findings. Micafungin was effective for the treatment of IPA in this patient with ALL.

Efficacy of etoposide, cyclophosphamide, and total body irradiation in allogeneic bone marrow transplantation for adult patients with hematological malignancies

Abstract:  Introduction:  A combination of fractionated total body irradiation (TBI) with etoposide (VP‐16) and cyclophosphamide (CY) as a preconditioning regimen (VP/CY/TBI) has been reported to be safe and effective for both adults and children undergoing allogeneic bone marrow transplantation (allo‐BMT). However, the reported doses of VP‐16 were different. We evaluated the efficacy and safety of a VP‐16 (at less than the usual dose)/CY/TBI regimen for adults with hematological malignancies who are required to receive allo‐BMT.

Increased Proportion of HLA-Class-I-Specific Natural Killer Cell Receptors (CD94) on Peripheral Blood Mononuclear Cells after Allogeneic Bone Marrow Transplantation

In the present study, we investigated the inhibitory natural killer cell receptor (NKR) expression of CD94/NKG2A on PBMC after allogeneic bone marrow transplantation (BMT). The proportion of CD94 expression on PBMC was higher in patients without chronic graft-versus-host disease (cGVHD) and also in cGVHD patients with good response to conventional immunosuppressive therapy than in cGVHD patients with poor response. Also, the proportions of CD94+/CD3+ cells and CD94+/CD8+ cells were higher in cGVHD patients showing good response. In addition, the proportion of NKG2A-expressing cells was higher in patients without cGVHD than in patients with cGVHD. Therefore, chronic allostimulation after allo-BMT may augment the proportion of CD94/NKG2A-positive cells, and these cells may play some role in the regulation of alloresponse in some patients.

Chronic eosinophilic leukemia with t(6;11)(q27;q23) translocation

Abstract We report a rare case of chronic eosinophilic leukemia (CEL) with a chromosomal abnormality of t(6;11)(q27;q23). The patient was diagnosed as having thyroid cancer with metastases to the lung and cervical lymph nodes in 1993. Percutaneous ethanol injection therapy (PEIT), total thyroidectomy, and radiotherapy were performed . The patient was also diagnosed as having prostatic cancer with bone metastasis in July 1999, and hormonal therapy was performed. At the time of the diagnosis of prostatic cancer, leukocytosis with eosinophilia was also revealed. Thereafter, cytogenetical analysis and reverse transcriptase polymerase chain reaction (RT-PCR) analysis of bone marrow showed t(6;11)(q27;q23) translocation and MLL/AF6 fusion products, respectively. No transcripts of the BCR/ABL chimeric gene were found by RT-PCR in bone marrow. Analysis of serum cytokines revealed a slight elevation of GM-CSF but no elevation of IL-3 or IL-5. Tissue damage due to infiltration of eosinophils was not observed throughout the clinical course. On the basis of the cytogenetic and molecular abnormality, the patient was diagnosed as having CEL, rather than reactive eosinophilia due to thyroid or prostatic cancer or other reactive inflammation. This is the first case report of CEL with t(6;11)(q27;q23) translocation.

Multiple osteolytic bone lesions with high serum levels of interleukin‐6 and CCL chemokines in a patient with adult T cell leukemia

A 37‐year‐old woman was diagnosed as having chronic adult T‐cell leukemia (ATL) of the skin by a skin biopsy and human T‐cell leukemia virus type‐1 serology at our hospital in August 1992. The skin lesions of ATL were improved by treatment with psoralen ultraviolet ray A. She complained of severe pain in her bilateral forearms, hands and ankles, and X‐ray examination in July 1999 revealed multiple punched‐out lesions of the extremities. Serum levels of parathyroid hormone‐related peptide, interleukin‐1β (IL‐1β), tumor necrosis factor‐α and total serum receptor activator of nuclear factor κB ligand were not elevated. However, serum levels of IL‐6, CCL2 monocyte chemoattractant protein‐1 (MCP‐1), CCL3 [macrophage inflammatory protein‐1α (MIP‐1α)] and CCL4 (MIP‐1β) were markedly elevated. Here, we have discussed the possible mechanism underlying the onset of the osteolytic lesions.

Primary Gastric Hodgkin’s Lymphoma Expressing a B-Cell Profile Including Oct-2 and Bob-1 Proteins

Classic Hodgkin’s lymphoma (cHL) most often involves lymph nodes, and gastric involvement is rare. Hodgkin’s and Reed-Sternberg (H-RS) cells in cHL are known to often lack expression of several B-lineage markers, such as CD20, CD79a, Oct-2, and Bob-1. We present an extremely rare case of mixed-cellularity cHL in the stomach in which expression of these B-cells was detected immunohistochemically. The patient was an 83-year-old Japanese woman who developed a sensation of abdominal fullness and appetite loss. Endoscopic and abdominal computed tomography examinations revealed a gastric ulcer lesion and swelling of para-aortic lymph nodes, respectively. A subtotal gastrectomy was performed, and the histopathologic diagnosis was established as a typical cHL compatible with stomach origin. The patient underwent postoperative chemotherapy of 3 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and has since been in complete remission. Immunohistochemically, the H-RS cells in the cHL were positive not only for CD30 but also for CD20, CD79a, Oct-2, and Bob-1, whereas they were negative for CD3, CD15, CD45, EMA, and ALK1. Our patient may have had an intermediate cHL disease overlapping that of non-Hodgkin’s peripheral B-cell lymphoma, possibly reflecting derivation from germinal-center B-cells.

Allogeneic bone marrow transplantation from an unrelated donor for the treatment of chronic myelogenous leukemia in blast crisis in a patient with Kleinfelter's syndrome

We describe the first reported Klinefelters syndrome (KS) in which allogeneic bone marrow transplantation from an unrelated donor (UR-BMT) was performed for treatment of chronic myelogenous leukemia in blast crisis (CML-BC). A 31-year-old male patient was diagnosed as having CML-BC with KS in April 2001. The result of a bone marrow chromosomal examination were 47, XXY, t(9;22)(q34;q11). After he had been treated with chemotherapy and imatinib mesylate, he underwent UR-BMT in February 2002. After the UR-BMT, his bone marrow chromosome changed from 47, XXY, t(9;22)(q34;q11) to 46,XY and 100% donor-type chimerism was obtained. However, he relapsed on day 83 after UR-BMT. After treatment with imatinib mesylate and tapering of immunosuppressive agents, skin and liver GVHD developed and then donor-type chimerism was increased with decreased blast cells. However, the patient died due to progression of disease in October 2002.