[Reinduction therapy with gemtuzumab ozogamicin for relapsed or refractory CD33-positive acute myelogeneous leukemia].

The efficacy and safety of reinduction therapy with gemtuzumab ozogamicin (GO)were investigated in 7 patients with relapsed or refractory CD33-positive acute myelogeneous leukemia. As the administration method, intravenous drip infusion of 9 mg/m(2) was conducted on day 1 and 15. Though CR was attained in 3 patients, the remaining 4 patients were assessed as PD. Grade 3-4 neutropenia and thrombopenia occurred in all patients, 4 of whom were complicated with febrile neutropenia and 1 with new pneumonia. On the other hand, except for grade 1 digestive symptoms and grade 1 GPT increase, none of the patients had serious complications. Though the treatment with GO is considered comparatively safe, sufficient supportive therapy as in the case of conventional chemotherapy is necessary against hematological toxicity. The effect of monotherapy with GO in reinduction is limited. It is necessary to appropriately select the cases and to investigate an effective administration method including the concomitant use of antitumor agent.

[Gemtuzumab ozogamicin successfully induced molecular remission in relapsed therapy-related acute promyelocytic leukemia].

A 37-year-old woman was diagnosed with therapy-related acute promyelocytic leukemia (t-APL) in May 2006 after chemotherapy that included etoposide for ovarian cancer in November 2003. After treatment with all-trans retinoic acid in combination with chemotherapy, complete remission was attained. The patient was admitted on March 19, 2007 due to cerebral infarction and it was found that t-APL had recurred. Induction therapy with gemtuzumab ozogamicin (GO) was attempted. Molecular remission was attained without serious complication. GO is considered a promising agent to achieve molecular remission in patients with relapsed t-APL.

[Treatment results of acute leukemia in elderly patients: analysis of 61 consecutive patients in a single institution].

In order to investigate the clinical characteristics and management of elderly patients with acute leukemia, we retrospectively analyzed treatment results for 61 acute leukemia patients aged 65 years or more (median age 72) admitted to our department between October 1995 and September 2006. There were 6 elderly patients with ALL (acute lymphocytic leukemia) and 55 patients with AML (acute myelogenous leukemia). Among them, 51 patients could receive chemotherapy, but 10 patients received symptomatic therapy only. Complete remission was achieved in 50% of 46 patients who received chemotherapy, and median overall survival was 237 days. We analyzed treatment results for AML patients who underwent chemotherapy as follows. The intensive chemotherapy group and the de novo leukemia group showed a significantly higher CR rate and longer survival. No differences were found in karyotype, performance status or complications. Intensive chemotherapy was effective for 65-74-year-old patients with de novo AML. In future, we consider that the prognosis for elderly patients with acute leukemia will improve, if made-to-order treatment is given, depending on evidence-based stratification of patients with organs having low reserve capacity.

Acute myelogeneous leukemia (M5a) that demonstrated chromosomal abnormality of robertsonian 13;21 translocation at onset.

A 27-year-old woman had congenital lissencephaly syndrome and mental retardation. She had a fever of unknown origin and visited her local physician. Blood test indicated leukocytosis, so she was referred to our hospital for detailed examination. She was diagnosed to have acute myelogeneous leukemia (M5a). The chromosome analysis in blast cells revealed Robertsonian 13;21 translocation. Complete remission was obtained by induction chemotherapy. As normal karyotype (46, XX) was observed in the chromosome analysis of bone marrow cells after remission, it was considered that the patient had acquired Robertsonian 13;21 translocation complicated by acute myelogeneous leukemia.

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation for the treatment of multiple myeloma refractory to conventional chemotherapy].

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to five patients with refractory myeloma. To collect peripheral blood stem cells, apheresis was done by administering doxorubicin 40 mg/m2 on the first day, and etoposide 60 mg/m2 on the first, second, and third days, followed by G-CSF administration to harvest cells. The high-dose chemotherapy consisted of melphalan 60 mg/m2 administered for 4 days and infusion of mononuclear cells. No serious side effects were observed during the clinical course. After transplantation, complete or partial responses were achieved. APBSCT is considered to be a useful method because it had an antitumor effect against multiple myeloma that is refractory to conventional chemotherapy, as well as against multiple myeloma that is sensitive to chemotherapy, and it can be safely performed.

Aging accelerates endotoxin-induced thrombosis : increased responses of plasminogen activator inhibitor-1 and lipopolysaccharide signaling with aging.

Although older subjects are susceptible to thrombosis under septic conditions, the underlying molecular mechanisms have not been fully elucidated. Since elevated plasminogen activator inhibitor-1 (PAI-1) primarily contributes to endotoxin-induced thrombosis, we first compared the induction of PAI-1 by lipopolysaccharide (LPS) between young and aged mice. The higher induction of PAI-1 antigen and mRNA with increased renal glomerular fibrin deposition was observed in LPS-treated aged mice compared to young mice. In situ hybridization analysis showed that the aging-associated induction of PAI-1 mRNA by LPS was pronounced in hepatocytes and in renal glomerular cells. The increased magnitude of the response of aged mice to lower doses of LPS was observed in terms of renal glomerular fibrin deposition and PAI-1 mRNA induction in the tissues. Furthermore, older PAI-1 deficient mice treated with LPS developed much less fibrin deposition in kidneys. Importantly, a larger induction of receptor molecules for LPS (eg, CD14 and Toll-like receptor 4) was demonstrated in LPS-treated aged mice as compared with young mice. The enhanced LPS signaling in aged mice was also demonstrated by the marked induction of nuclear factor-kappaB in the tissues after endotoxin treatment. As a consequence, increases in an inflammatory cytokine, tumor necrosis factor-alpha, were pronounced in plasma and tissues of LPS-treated aged mice. These results emphasize the key role played by PAI-1 in aging-associated deterioration in this thrombosis model, and suggest that the hyperresponse of PAI-1 gene to LPS results from the enhanced LPS signaling and the subsequent inflammatory response in aged mice.

Aging and obesity augment the stress-induced expression of tissue factor gene in the mouse.

Hypercoagulability and thrombotic tendency are frequently induced by a variety of stressors. Clinically, aged subjects and obese patients are more susceptible to thrombotic diseases associated with stress, but the underlying mechanisms are unknown. We investigated the expression of a procoagulant gene, tissue factor (TF), in a mouse model of restraint stress. Twenty hours of restraint stress to mice caused a substantial induction of TF mRNA in several tissues. Importantly, the magnitude of induction of TF mRNA by restraint stress was larger in aged mice compared with young mice. In situ hybridization analysis of the stressed aged mice revealed that strong signals for TF mRNA were localized to renal epithelial cells, smooth muscle cells, adventitial cells, and adipocytes but not to vascular endothelial cells. These observations suggest that restraint stress induces the TF expression in a tissue-specific and cell type-specific manner. Genetically obese mice were also hyperresponsive to restraint stress in the induction of TF gene, especially in their livers and adipose tissues. Stress-induced microthrombi formation was pronounced in renal glomeruli and within the vasculature in adipose tissues of aged mice. Tumor necrosis factor-alpha (TNF-alpha) antigen in plasma was elevated by stress in aged mice and obese mice, and pretreatment of mice with anti-TNF-alpha antibody partially attenuated the stress-mediated induction of TF gene in adipose tissues in these mice. These results suggest that the induction of TF gene may increase the risk of stress-associated thrombosis in older and obese subjects and that TNF-alpha may be involved.

[Successful treatment of myeloid/natural killer cell precursor acute leukemia with allogeneic peripheral blood stem cell transplantation].

We report a case of myeloid/NK cell precursor acute leukemia, which was successfully treated with allogeneic peripheral blood stem cell transplantation (allo PBSCT). A 31-year-old woman was admitted to our hospital with general fatigue, anorexia and leukocytosis. Bone marrow aspiration showed infiltration of many atypical blasts. She was diagnosed as having myeloid/NK cell precursor acute leukemia by morphological and immunohistochemical analysis. Complete remission was achieved by induction chemotherapy, but as myeloid/NK cell precursor acute leukemia is reported to have an extremely poor prognosis due to frequent relapse, the patient underwent allo PBSCT from her HLA-identical father, together with a myeloablative conditioning regimen. She suffered several transplantation-related complications including acute graft versus host disease (grade II) and ischemic enterocolitis associated with thrombotic microangiopathy, but these were overcome by supportive therapy. She was discharged on day 168 after allo PBSCT, and so far there has been no evidence of relapse during a follow-up period of 15 months.

Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals.

Plasminogen activator inhibitor-1 (PAI-1) is one of the primary inhibitors of the fibrinolytic system and has been implicated in a variety of thrombotic disorders. In this report, stress-induced changes in murine PAI-1 gene expression were investigated to study the role of this inhibitor in the development of stress-induced hypercoagulability. Restraint stress led to a dramatic induction of plasma PAI-1 antigen and of tissue PAI-1 mRNA with maximum induction in adipose tissues. In situ hybridization analysis of the stressed mice revealed that strong signals for PAI-1 mRNA were localized to hepatocytes, renal tubular epithelial cells, adrenomedullar chromaffin cells, neural cells in the paraaortic sympathetic ganglion, vascular smooth muscle cells, and adipocytes, but not to endothelial cells. These observations indicate that the stress induces the PAI-1 gene expression in a tissue-specific and cell type-specific manner. The induction of PAI-1 mRNA by restraint stress was greater than that observed for heat shock protein, a typical stress protein, suggesting that PAI-1 is one of the most highly induced stress proteins. Importantly, the magnitude of induction of PAI-1 mRNA by stress increased markedly with age, and this increase in PAI-1 correlated with tissue thrombosis in the older stressed mice. Moreover, much less tissue thrombosis was induced by restraint stress in young and aged PAI-1-deficient mice compared with age-matched wild-type mice. These results suggest that the large induction of PAI-1 by stress increases the risk for thrombosis in the older populations, and that the adipose tissue may be involved.