Two cases of mycosis fungoides treated by reduced-intensity cord blood transplantation.

Mycosis fungoides is a cutaneous T-cell lymphoma, which is clinically divided into three stages: patch, plaque and tumor. Despite a variety of treatments the prognosis is poor in advanced mycosis fungoides. Recently, allogeneic hematopoietic stem cell transplantation has been successfully applied for such cases. We performed reduced-intensity umbilical cord blood transplantation for two advanced mycosis fungoides patients. Case 1 was a 56-year-old man and case 2 was a 30-year-old woman. Tumors of each case were refractory to conventional chemotherapy. Although radiation therapy was considerably effective, tumors relapsed after several months. Reduced-intensity umbilical cord blood transplantation was performed because case 1 had no human leukocyte antigen-identical siblings and the sibling of case 2 did not agree to be the donor. The male patient died of pulmonary failure 23 days after reduced-intensity umbilical cord blood transplantation. The case 2 patient succeeded in reduced-intensity umbilical cord blood transplantation and remained in complete/partial remission for 13 months. However, chemotherapy-resistant tumors relapsed, and allogeneic hematopoietic stem cell transplantation was performed at 17 months. She died of cerebral hemorrhage 23 days after the procedure. Reduced-intensity umbilical cord blood transplantation may be included in the treatments for advanced mycosis fungoides, where graft-versus-lymphoma effect seems to be a significant factor for the success of the treatment.

A novel five-way chromosomal translocation observed in chronic myelogenous leukemia.

Most patients with chronic myelogenous leukemia (CML) show a Philadelphia (Ph) chromosome with a characteristic translocation between chromosomes 9 and 22. However, there are variant complex translocations involving other chromosomes in addition to the standard translocation. We describe a case of CML showing a complex and novel chromosomal translocation involving five chromosomes, t(4;12;7;9;22).

Induction of leukemia-specific antibodies by immunotherapy with leukemia-cell-derived heat shock protein 70.

Cancer immunotherapy using heat shock protein (HSP) derived from autologous tumor requires cluster of differentiation (CD)4(+) as well as CD8(+) T-cells for the prolongation of patient survival, suggesting that a humoral immune response through CD4(+) T-cells is important in addition to cellular immunity. However, the role of humoral responses in HSP-based autologous tumor immunotherapy remains unclear. In the present study, we investigated whether leukemia-specific antibodies and antibody-mediated cytotoxicity against autologous leukemia cells have a crucial role in a mouse A20 leukemia model by immunizing A20-derived HSP70. Immunization with A20-derived HSP70 induced the production of anti-A20-antibodies and the antibodies recognized HSP70-binding peptides derived from A20. One of those was a major histocompatibility complex (MHC) class-I binding peptide, which has been clarified as the target peptide of CD8+ cytotoxic T-cells (CTL) against A20. The anti-A20-antibodies produced by immunization with A20-derived HSP70 induced complement-dependent cytotoxicity (CDC) against A20 in vitro. In addition, immunization with A20-derived HSP70 increased intracellular interleukin-4 (IL4)-production of CD4(+) T-cells, confirming the activation of type-2 helper T-cells. Taken together, immunization with leukemia-cell-derived HSP70 induces antibodies against leukemia-cell-specific peptides and might play a crucial role in the eradication of leukemia cells by CDC in mice. These findings will enable future establishment of a novel therapeutic strategy using antileukemia antibodies in HSP-based autologous tumor immunotherapy.

[Breakthrough pulmonary mucormycosis during voriconazole treatment after reduced-intensity cord blood transplantation for a patient with acute myeloid leukemia].

A 59-year-old man was admitted to our hospital with a diagnosis of acute myeloid leukemia in September 2004. He developed invasive pulmonary aspergillosis (IPA) and candidiasis, which were improved by administration of micafungin and amphotericin B (AMPH-B). He received reduced-intensity unrelated cord-blood transplantation without induction chemotherapy. He developed grade IV graft-versus-host disease (GVHD) and the administration of steroids against GVHD was prolonged. Voriconazole (VRCZ) was used for a long period to prevent recurrence of the IPA. Afterwards, infiltrates in the bilateral upper lung fields were detected on a chest CT scan, and a diagnosis of pulmonary mucormycosis was made following detection of Mucor circinelloides from the patient's sputum culture. He then began receiving AMPH-B but died of massive hemoptysis. Mucormycosis usually occurs in immunocompromised hosts such as neutropenic patients with hematologic diseases and is a fatal fungal infection characterized by a rapid and progressive clinical course. Some overseas investigators have recently reported that VRCZ prophylaxis may result in breakthrough mucormycosis in hematopoietic stem cell transplant recipients. These findings suggest that it is very important to pay attention to mucormycosis in hematopoietic stem cell transplant recipients in this country.

Combined use of dendritic cells enhances specific antileukemia immunity by leukemia cell-derived heat shock protein 70 in a mouse model with minimal residual leukemia cells.

We have reported that immunotherapy using leukemia cell-derived heat shock proteins (HSPs) is effective against minimal residual disease (MRD) after syngeneic stem cell transplantation (SCT) in mice. However, leukemia patients after SCT are usually immunocompromised and immunologically tolerant to leukemia cells. We investigated whether the use of dendritic cells (DCs) in combination with HSP70 enhances cytotoxicity against B-cell leukemia cell line A20 in mice after syngeneic SCT. All unimmunized mice died of leukemia early after A20 cell inoculation, whereas mice immunized with HSP70 or HSP70-pulsed DCs survived significantly longer. Although only 60% of the HSP70-immunized mice survived, all mice immunized with HSP70-pulsed DCs survived without MRD. In addition, the cytotoxicities against A20 cells for splenocytes from mice immunized with HSP70-pulsed DCs were significantly higher than those of HSP70-immunized mice, and the cytotoxicities against A20 cells were significantly blocked by anti-CD8 antibody and by major histocompatibility complex class I antibody, but not by anti-CD4 antibody. Moreover, abnormalities were detected in neither the biochemical data nor the histopathologic findings. These findings indicate that the combined use of DCs and leukemia cell-derived HSP70 enhances the antileukemia effect by inducing the specific cytotoxicities of CD8+ cytotoxic T-cells, thereby eradicating MRD effectively and safely, even in an immunocompromised state after syngeneic SCT. This approach may thus be useful for further application of HSP in leukemia patients after autologous SCT.

[A neuron specific enolase-producing multiple myeloma].

A 53-year-old woman was admitted to our hospital with left chest-wall pain. Computed tomography scans showed a homogenous mass on the left chest-wall with pleural effusion. Laboratory data showed anemia, hypercalcemia, and high levels of serum IgG. An IgG-lambda monoclonal protein was detected with serum immunoelectrophoresis. In addition, the serum level of neuron specific enolase (NSE) was elevated. A chest-wall tumor biopsy and a bone marrow aspiration revealed diffuse proliferation of atypical plasma cells, which were positive for cytoplasmic CD38 and IgG-lambda. The patient was diagnosed as having IgG-lambda type multiple myeloma with a chest-wall plasmacytoma. Immunostaining revealed diffuse NSE staining in the cytoplasm of the atypical plasma cells. These findings suggested that the myeloma cells produced NSE. The left chest-wall tumor and bone marrow myeloma cells disappeared following several courses of chemotherapy and radiotherapy and the serum levels of IgG and NSE also normalized. No recurrence of the multiple myeloma was seen after an autologous peripheral blood stem cell transplantation. This is the second report of an NSE-producing multiple myeloma. Interestingly, our case has similar clinical phenotypes with the previously reported case, such as chest-wall plasmacytoma, pleural effusion and hypercalcemia.

Severe hepatic injury caused by imatinib mesylate administered for the treatment of chronic myeloid leukemia and the efficacy of prednisolone for its management.

Imatinib mesylate is a specific inhibitor of BCR-ABL tyrosine kinase, which is now widely used for the treatment of chronic myeloid leukemia (CML) with a high efficacy. Although severe hepatic injury caused by imatinib mesylate is rare, such a side effect may force patients to discontinue taking imatinib mesylate. In the present paper, we report on the case of a 51-year-old woman with CML who experienced hepatic injury with severe hyperbilirubinemia caused by imatinib mesylate. The findings from a liver biopsy specimen and her clinical course suggested the hepatic injury to presumably have been caused by an allergic mechanism. The co-administration of prednisolone was thus tried, and she has been able to continue imatinib mesylate administration without any liver dysfunction and finally was able to obtain a complete cytogenetic response.We therefore recommend that prednisolone should be tried when severe hepatic injury caused by imatinib mesylate is observed, since it might enable such patients to continue imatinib mesylate treatment and thereby improve the prognosis in such cases.

Upregulation of hepcidin by interleukin-1beta in human hepatoma cell lines.

Anemia of chronic disease (ACD) is commonly observed in chronic inflammation, although its pathogenesis is poorly understood. Hepcidin is thought to be a key regulator in iron metabolism and has been implicated in ACD. Although the induction of hepcidin by an inflammatory cytokine interleukin-6 (IL-6) seems to have been confirmed, it is still controversial whether interleukin-1beta (IL-1beta), also known as an inflammatory cytokine, regulates hepcidin expression. We demonstrated that hepcidin mRNA was upregulated by IL-1beta in human hepatoma-derived HuH-7 cells, particularly at low concentrations of IL-1beta, while high concentrations of IL-6 were needed for the upregulation of hepcidin mRNA. Therefore, IL-1beta might be more important for the upregulation of hepcidin in physiological conditions than IL-6. Although IL-1beta induces IL-6 production in hepatocytes, our data indicate that the effect of IL-1beta on hepcidin expression is independent from that of IL-6. In conclusion, IL-1beta might have an important role in ACD.

[Acute lymphoblastic leukemia with t(4;11)(q21;q23) after iodine-131 treatment for thyroid cancer].

A 49-year-old Japanese woman was diagnosed on March 1996 as having thyroid cancer with lung metastasis. Following a total thyroidectomy, she was treated with a total dose of 350 mCi iodine-131 (131I) for metastatic thyroid cancer. Four years later she returned to our hospital under the chief complaint of subcutaneous bleeding. Hematological examinations revealed marked leukocytosis associated with anemia and thrombocytopenia. A bone marrow aspiration showed a hypercellular marrow consisting of 90% blasts negatively stained by myeloperoxidase. Immunophenotyping of the blasts indicated they were CD19, 34, HLA-DR positive but CD3, 10, 13 negative. She was given the diagnosis of pro-B acute lymphoblastic leukemia (pro-B ALL). Cytogenetic analysis showed a chromosomal aberration t(4; 11)(q21; q23) and MLL-AF4 chimeric gene mRNA was detected by RT-PCR analysis. She had never been exposed to any kind of chemoradiotherapy other than 131I therapy and her leukemia showed a t(4; 11) chromosomal aberration and no expression of CD10 on the blasts, which are the characteristics frequently found in therapy-related pro-B ALL patients, suggesting a relationship between the development of pro-B ALL with t(4; 11) and 131I therapy. Although leukemia has been recognized as a late uncommon complication after 131I therapy for thyroid cancer, to the best of our knowledge this is the first patient who developed ALL with t(4 ;11) after 131I therapy among patients with thyroid cancer.