We describe a rare case of primary mediastinal large cell neuroendocrine carcinoma (LCNEC) with brain metastases. A 65-year-old man presented with a mediastinal abnormal shadow on chest radiography. A computed tomography-guided needle biopsy of the mediastinal tumor revealed malignant cells. After biopsy, dyspnea, leg weakness and a waddling gait rapidly developed. Magnetic resonance imaging of the brain revealed three masses with ring enhancements. His pro-GRP value was 95.5 pg/ml. Since the cerebellar tumor extended to the brain stem, it was removed surgically. The brain tumor demonstrated LCNEC. He received systemic chemotherapy of cisplatin and irinotecan, because his leg weakness and waddling gait had improved markedly after surgery followed by whole brain irradiation.

In 2006, Takahashi and Yamanaka reported a groundbreaking study showing mouse and human somatic cells that can be reprogrammed to the pluripotent state by expression of only a few transcription factors (Oct4, Sox2, Klf4, and c-Myc). This novel strategy can be used for transplantation therapies without immune rejection providing additional advantages regarding ethic issues of oocyte donation. For neurological diseases, disease-specific induced pluripotent stem (iPS) cells may serve as an invaluable model for clarifying pathogenesis and for screening new drug therapies. In particular, differentiated neurons derived from patient iPS cells could infinitely provide an alternative cellular-biochemical material for research instead of biopsy and autopsy. This review summarizes the current studies applying iPS cells in the field of neurology and discusses their potential and limitations for therapy against neurological diseases.

Mesenchymal stem cells (MSCs) can show osteogenic differentiation capability when implanted in vivo , as well as cultured in vitro; therefore we attempted to use allogeneic MSCs for a patient with hypophosphatasia, which is caused by mutations in tissue non-specific alkaline phosphatase (TNSALP) gene. Donor MSCs were obtained by culture expansion of fresh marrow from the patient's father. Some of the MSCs were further cultured under osteogenic conditions on a culture dish or porous hydroxyapatite ceramics, resulting in cultured osteoblasts and osteogenic constructs, respectively. After traditional bone marrow transplantation, The donor MSCs and osteoblasts were injected into the patient and the constructs were implanted subcutaneously or intraosseous lesions. The patient's respiratory condition improved and donor cells were detected in newly formed bone tissue. These findings showed the importance of allogeneic MSC transplantation for the hypophosphatasia patient.

Hypophosphatsia is caused by the defect of tissue-nonspecific alkaline phosphatase (ALP), and exhibits hypomineralization of skeleton and rachitic change of bone. The most severe form of hypophosphatasia is a perinatal form, which is also called a lethal form. However, some patients of this form can survive due to advances in neonatology. Other forms consist of infantile, childhood, adult and odonto types. Conventional therapies for hypophosphatasia are administration of vitamin B6 for convulsion and low calcium-containing milk for hypercalcemia. Bone marrow transplantation has been reported to treat several patients with hypophosphatasia. However, the method must be developed which improves the survival of donor mesenchymal cells in patients. Recombinant bone-targeted ALP therapy is now on clinical trial in Canada and U.S.A and expected to be available in near future.

The brain is an organ that is extremely rich in lipid and fatty acid binding proteins, and among fatty molecules, polyunsaturated fatty acids (PUFAs), especially docosahexanoic acid (DHA) and arachidonic acid (ARA), are the major components. However, the precise role of PUFAs and their signals for brain formation and maintenance and mental functions remain largely unknown. Neurogenesis is one of the key events in brain development and maintenance. An intriguing association of decreased hippocampal neurogenesis and deficits in prepulse inhibition (PPI), one of the compelling endophenotypes of mental disorders including schizophrenia, has been reported in several animal models. Currently, we are proposing a "neurogenesis theory" that connects the integrity of neurogenesis and PPI based on animal models and exploring the possibility that even postnatal manipulation of neurogenesis could affect PPI. In parallel, we have tested the potential of dietary PUFAs, ARA and/or DHA, to promote neurogenesis and concomitantly improve PPI, given that PUFAs are ligands for Fabp members and they are abundantly expressed in neural stem/progenitor cells in the hippocampus. Our results suggest a potential benefit of PUFA in ameliorating the PPI relevant to psychiatric disorders through an augmented postnatal neurogenesis.

Recent studies clearly showed that neurogenesis continues to occur in the certain brain regions including the hippocampus. The stem or progenitor cells are divided equally (proliferation) or unequally, survive apoptosis and differentiate to mature neuron and glia. Such newborn cells integrate into existing neuronal networks, make synaptic contacts and finally change the plasticity. The proliferation is decreased by stress, but chronic treatment with antidepressants increases it. We have shown the involvement of the cAMP-CREB cascade in mature granule cells of the dentate gyrus (DG) around stem/progenitor cells in the drug action. To see the direct effect of some psychotropic drugs, we established a culture system of adult rat DG-derived neural precursor cells (ADP). Several antidepressants did not affect the proliferation. Moreover 5-HT did not promote the proliferation of ADPs. The findings suggested SSRI might affect neurogenesis through an indirect pathway.

A 19-year-old girl with T-lymphoblastic lymphoma (T-LBL) was referred to our hospital because of refractory disease. After complete remission was achieved by the JALSG ALL-97 protocol, she received a bone marrow transplantation (BMT) from an unrelated, HLA-matched donor with myeloablative conditioning. Four months after BMT, T-LBL relapsed and donor lymphocyte infusion was ineffective. After partial remission was achieved with l-asparaginase therapy, she received 2 antigen-mismatched cord blood transplantation with non-myeloablative conditioning; however, sustained engraftment of cord blood stem cells has failed. This was associated with the reappearance of the blood cells from the first donor and the disappearance of leukemic cells from both the peripheral blood and bone marrow. Computed tomography showed no enlarged lymph nodes. The patient and the cord blood donor shared two minor histocompatibility antigens (mHAgs), while these mHAgs were not detected in the blood cells of the first donor. TCR analysis disclosed expanded oligoclonal Vbeta2T cells in the peripheral blood at relapse, and these cells secreted IFN-gamma in response to stimulation by the patient's leukemic cells. Moreover, these cells exhibited cytotoxicity against both leukemic cells and cord blood mononuclear cells. These results strongly suggest that Vbeta2T cells, derived from the first donor, may have been cytotoxic lymphocytes against both leukemic cells and cord blood stem cells.

We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.

Anti-tumor effects of current cancer vaccines are limited. However, detailed analyses of clinical trials revealed several important points to be improved towards immunological tumor rejection. These are, (1) identification of tumor antigens involved in tumor cell proliferation/survival and expressed in cancer stem cells, (2) development of in situ tumor destruction methods which release tumor antigens in an immunogenic manner to induce immune responses to multiple endogenous tumor antigens, (3) development of methods to augment antigen processing and presentation by dendritic cells, including effective adjuvants, (4) development of methods to expand CTL and helper T cells in vivo, (5) understanding of mechanisms underlying cancer induced immunosuppression and development of methods to overcome them. Comprehensive interventions on these points in the antitumor immune network will lead to effective cancer immunotherapy.

The prognosis of angioimmunoblastic T cell lymphoma (AITL) is poor because of chemotherapy-resistance and the short duration of remission. In recent years, cyclosporin A (CyA) has been employed as a alternative treatment for AITL in some patients with the rationale that CyA inhibits the activity and proliferation of neoplastic T cells. We herein report 4 chemotherapy-resistant AITL patients who were treated with oral CyA. The dosage of CyA was individually determined in each patient in order to achieve a blood CyA concentration of around 200 ng/ml at the trough level. A patient in whom AITL had relapsed 3 months after high dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) achieved a sustained complete remission (CR) with CyA and underwent allogeneic HSCT. In 2 patients who had failed to respond to conventional chemotherapies, the circulating lymphoma cells rapidly disappeared after the initiation of CyA, and one of these patients demonstrated a durable CR. The other patient showed a good response to CyA, but the agent was discontinued because of infection. The remaining one patient with advanced AITL did not respond to CyA and died of disease progression. To our knowledge, the efficacy of CyA for chemotherapy-resistant AITL, even in a leukemic state, has not previously been reported.