CD34 positive cells were first defined as endothelial progenitor cells(EPCs) from circulating mononuclear cells in peripheral blood. EPCs have shown to be mobilized from bone marrow by the various factors, incorporate into sites of physiological and pathological neovascularization and differentiate into mature endothelial cells (ECs). Post-natal vasculogenesis has been considered to be involved in neovascularization of adult tissues. Recently, freshly isolated CD34 positive cells transplantation has started as clinical trial for ischemic diseases. In the clinical situation, we should consider the cell number and cell quality derived from the patients who have atherosclerosis background, especially diabetes. Ex vivo expansion or gene modification of EPCs could be the strategies for the next generation cell therapy to overcome these issues.

Tissue kallikrein is expressed in many species and is widely distributed throughout the body, including the brain. In general, this protease is well known to release the vasoactive peptide, kinin, from kininogen. We report here that kallikrein has a prominent growth-stimulating effect on neural stem cells prepared from the brains of prenatal rats. This growth-stimulating effect was suppressed by antiserum against rat tissue kallikrein. Since bradykinin B2-receptor antagonist, Hoe140, did not suppress the growth-stimulating effect, kallikrein-mediated kinin release does not appear to be involved in this effect. Thus, our data suggest a new physiological function of kallikrein, the growth of neural stem cells. Such involvement would suggest that kallikrein is not only potentially involved in an important function of brain development, but also available for studies on regenerative medicine for neurons.

A priming X-ray exposure to 0.05-0.10 Gy or 0.3-0.5 Gy imparts radioresistance (decrease in bone marrow death rate after high-dose X-rays) in mice 2-2.5 months or 9-17 days postexposure, respectively. This radiation-adaptive response in whole animals differs from that in cells observed several hours to several days (at most) later. An adaptive response was observed in ICR and C57BL/6 strains of mice, but not in BALB/c and C3H strains. The biological mechanisms of an acquired radioresistance induced by a priming exposure to 0.45 Gy in C57BL/6 mice have been studied. The recovery of blood-forming stem cells, determined as endogenous spleen colonies, was markedly stimulated by priming irradiation. The reduction in bone marrow death seems chiefly due to the stimulated recovery of blood-forming stem cells. But mice pretreated at this priming dose did not show a marked recovery of peripheral blood cell counts after challenging irradiation with mid- or sublethal X-ray doses (a significant, albeit slight, increase in the blood cell counts in the preirradiated group was observed after a lower challenging exposure to 5.0 Gy). The adaptive response depends on p53, as observed in cell experiments. The stem cells might produce an unknown factor(s) that contributes to acquired radioresistance. In a preliminary experiment, the life span of C57BL/6 mice after ascertaining their 30-day survival rates was not shortened by preirradiation.

A 60-year-old female patient with a therapy-resistant Bence-Jones (BJ) lambda-type multiple myeloma was treated with bortezomib. She had been treated with tandem autologous stem cell transplantations and achieved complete remission before her disease relapsed. Sixteen hours after the first administration of bortezomib, an episode of fever, slight consciousness disturbance and vomiting occurred, which was accompanied by a remarkable elevation of LDH (3608 IU/l). Serum levels of creatinine, uric acid, and AST were also transiently elevated. Serum interleukin-6 level was also increased after the administration of bortezomib. The symptoms disappeared rapidly within 48 hours. Bortezomib at a 25%-reduced dose was administered again along with dexamethasone 26 days later, which caused a moderate increase in LDH levels, but no other symptoms. Further treatment caused no increase in LDH. The treatment was very effective and eradicated both urinary BJ protein and bone marrow myeloma cells after 8 sessions of bortezomib administration. These findings suggest that a bortezomib-induced rapid reduction in tumor burden led to tumor lysis syndrome, for which caution is needed when treating myeloma patients with this very effective agent.

Tetrasomy 8 is a rare chromosomal abnormality in acute leukemia, and it has recently been considered as a poor prognostic factor. A 20-year-old woman was admitted because of purpura on the upper and lower limbs in February 2002. On admission, her leukocyte count was 6.5 x 10(9)/l with 66% of blasts, the hemoglobin level was 11.2 g/dl, and the platelet count was 101 x 10(9)/l. The bone marrow aspirate contained 85.6% of peroxidase-negative, alpha-naphthyl-butyrate esterase-positive, and CD4+ CD56+ blast cells. Karyotypic analysis of the bone marrow cells showed 48, XY, + 8, + 8[17]/47, XY, +8[3]. The patient was diagnosed as having AML (M5a), and treatment with daunorubicin (70 mg x 5 days) and cytosine arabinoside (150 mg x 7 days) resulted in a complete remission. She relapsed four months later, however, with an extramedullary tumor in T12. Remission could not be achieved, and the patient underwent allogeneic peripheral blood stem cell transplantation from her HLA-identical mother. Her clinical course was almost uneventful except for a phlegmon in the right leg, but on day 49 a relapse occurred, and she died of acute renal failure on day 73. This case strongly illustrates the characteristic of tetrasomy 8 as a poor prognostic factor in acute leukemia.

We report the clinical courses of two cases with relapsed acute lymphoblastic leukemia (ALL) after allogeneic bone marrow transplantation (BMT). After reinduction chemotherapy, the patients received reduced-intensity stem cell transplantation using allogeneic peripheral blood stem cells harvested from their previous BMT donors. The conditioning regimen used consisted of fludarabine and melphalan. Graft-versus-host disease (GVHD) prophylaxis was performed with low dose cyclosporin A (CsA, 1 mg/kg/day d.i.v.) on its own. The regimen related toxicity was minimal, and stable engraftment was achieved. Since acute GVHD had not developed by day 30, CsA was stopped abruptly in both cases. After CsA withdrawal, acute GVHD developed, and subsequent chronic GVHD. One of two cases is alive without any relapse of the leukemia 40 months after the peripheral blood stem cell transplantation (PBSCT). In the other case, ALL relapsed 15 months after the PBSCT, however, complete remission was again induced concomitantly with reactivated GVHD. In both these cases, the results suggest that using PBSC as a stem cell source and abrupt cessation of GVHD prophylaxis provided a potent graft-versus-leukemia effect.