Five-day regimen of azacitidine for lower-risk myelodysplastic syndromes (refractory anemia or refractory anemia with ringed sideroblasts): A prospective single-arm phase 2 trial.

Although azacitidine is the first-line drug for higher-risk myelodysplastic syndrome (MDS) patients, its efficacy for lower-risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5-day regimen of azacitidine (AZA-5) for lower-risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower-risk MDS based on the French-American-British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51-88). These patients received AZA-5 (75 mg/m2 ; once daily for 5 sequential days). The median number of AZA-5 courses was 8 (range: 1-57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA-5 is feasible and effective for lower-risk MDS patients as well as for higher-risk MDS patients.

Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan.

An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-ß-D-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31% achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7% of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as "not classified" compared with "possible invasive fungal disease" according to the EORTC/MSG criteria. Moreover, six "not classified" patients were positive for either plasma (1-3)-ß-D-glucan (n = 5) or Aspergillus PCR in blood (n = 2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-ß-D-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections.

Correlation and association between plasma platelet-, monocyte- and endothelial cell-derived microparticles in hypertensive patients with type 2 diabetes mellitus.

Elevated platelet-derived mircoparticles (MP) (PDMP), endothelial cell-derived MP (EDMP), and monocyte-derived MP (MDMP) concentrations are documented in almost all thrombotic diseases. However, the intricate interactions between PDMP, MDMP and EDMP in hypertensive patients with or without type 2 diabetes remains poorly understood. Therefore, to clarify the correlation and association of MPs, we measured and analysed the levels of MPs in 359 hypertensive patients. We compared the results of chemokines, cell adhesion molecules, platelet activation markers and microparticles in hypertensive patients with and without type 2 diabetes mellitus. The levels of all markers were significantly higher in the hypertensive patients with diabetes than in the non-diabetic patients. For hypertensive patients with diabetes, univariate analysis showed that age, body mass index, systolic blood pressure, high density lipoprotein cholesterol (HDL-CHO), creatinine (CRTN), soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble CD40 ligand (sCD40L), regulated on activation normally T-cell expressed and secreted (RANTES), monocyte chemotactic peptide-1 (MCP-1), MDMP and EDMP were significantly associated with PDMP. In addition, systolic blood pressure, HDL cholesterol, sP-selectin, sE-selectin, sVCAM-1, sCD40L, RANTES, MDMP and EDMP were significant factors in the multivariate model with PDMP. Furthermore, a correlation between plasma PDMP and MDMP or EDMP in hypertensive patients were observed both with and without diabetes. These results suggest that the existence of diabetes mellitus affects PDMP generation in hypertensive patients and that enhanced plasma levels of PDMP and an association between the plasma levels of PDMP, MDMP and EDMP may result in the development of atherothrombotic complications in hypertensive patients.

The effects of pitavastatin, eicosapentaenoic acid and combined therapy on platelet-derived microparticles and adiponectin in hyperlipidemic, diabetic patients.

Platelet-derived microparticles (PDMP) play an important role in the pathogenesis of diabetic vasculopathy, and statins or eicosapentaenoic acid (EPA) have been shown to have a beneficial effect on atherosclerosis in hyperlipidemic patients. However, the influence of EPA and statins on PDMP and adiponectin in atherosclerosis is poorly understood. We investigated the effect of pitavastatin and EPA on circulating levels of PDMP and adiponectin in hyperlipidemic patients with type II diabetes. A total of 191 hyperlipidemic patients with type II diabetes were divided into three groups: group A received pitavastatin 2 mg once daily (n = 64), group B received EPA 1800 mg daily (n = 55) and group C received both drugs (n = 72). PDMP and adiponectin were measured by ELISA at baseline and after 3 and 6 months of drug treatment. Thirty normolipidemic patients were recruited as healthy controls. PDMP levels prior to treatment in hyperlipidemic patients with diabetes were higher than levels in healthy controls (10.4 +/- 1.9 vs. 3.1 +/- 0.4 U/ml, p < 0.0001), and adiponectin levels were lower than controls (3.20 +/- 0.49 vs. 5.98 +/- 0.42 microg/ml, p < 0.0001). PDMP decreased significantly in group B (before vs. 6M, 10.6 +/- 2.0 vs. 8.0 +/- 1.7 U/ml, p < 0.01), but not in group A (before vs. 6M, 9.4 +/- 1.9 vs. 9.6 +/- 1.7 U/ml, not significant). In contrast, group A exhibited a significant increase in adiponectin levels after treatment (before vs. 6M, 3.29 +/- 0.51 vs. 4.16 +/- 0.60 microg/ml, p < 0.001). Furthermore, group C exhibited significant improvement in both PDMP and adiponectin levels after treatment (PDMP, before vs. 6M, 11.2 +/- 2.0 vs. 4.5 +/- 2.7 U/ml, p < 0.001; adiponectin, before vs. 6M, 3.24 +/- 0.41 vs. 4.02 +/- 0.70 microg/ml, p < 0.001). Reductions of PDMP in combined therapy were significantly greater than those observed with EPA alone (p < 0.05 by ANOVA). In addition, soluble CD40 ligand exhibited almost the same change as PDMP in all therapy groups. These results suggest that pitavastatin possesses an adiponectin-dependent antiatherosclerotic effect, and this drug is able to enhance the anti-platelet effect of EPA. The combination therapy of pitavastatin and EPA may be beneficial for the prevention of vascular complication in hyperlipidemic patients with type II diabetes.

Evaluation of angiopoietins and cell-derived microparticles after stem cell transplantation.

Although stem cell transplantation (SCT) is being used for hematopoietic reconstitution following high-dose chemotherapy for malignancy, it involves certain serious transplant-related complications such as graft-versus-host disease (GVHD). Angiopoietins play important roles in angiogenesis. However, the role of angiopoietins after SCT is poorly understood. In this study, 52 patients underwent SCT; 26 patients received allogeneic SCT, while the remaining 26 received autologous SCT. In 48 of 52 patients, levels of angiopoietins, cytokines, and soluble factors were measured by enzyme-linked immunosorbent assay. Soluble Fas ligand (sFasL) and endothelial cell-derived microparticle (EDMP) exhibited significant elevation in the early phase (2-3 weeks) after SCT. In addition, the elevation of interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and sIL-2 receptor (sIL-2R), which are GVHD markers after allogeneic SCT was observed. The level of angiopoietin (Ang)-2 in allogeneic SCT continued to increase for up to 4 weeks, although the level of Ang-1 did not show significant changes. The patients with high Ang-2 exhibited significant increase of sFasL and EDMP compared with those with low Ang-2. In addition, the patients with high-grade GVHD exhibited a significant increase in Ang-2 compared to patients with low-grade GVHD. In the in vitro experiment using endothelial cells, the suppressive effect of Ang-1 on EDMP generation by TNF-alpha was partially inhibited by the addition of Ang-2. Furthermore, multivariate regression analysis showed that EDMP and sFasL were significant factors in Ang-2 elevation. Our results suggest that Ang-2 generation after allogeneic SCT relates to GVHD.

A case of Behcet's disease in a patient with albinism.

A 22-year old female suffering from recurrent oral ulcers, genital ulcers, erythema nodosum, and folliculitis, was diagnosed as having Behcet's disease (BD). She has also hypopigmentation of skin and hair, and optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, and reduced visual acuity. In this report, we discuss the possibility of precipitating factor in BD that the hypersensitivity, mental stress, and drug resistance which is caused by albinism.

Retrospective analysis of primary plasma cell leukemia in Kansai Myeloma Forum registry.

We retrospectively analyzed twenty-six patients with primary plasma cell leukemia (pPCL) registered from May 2005 until April 2015 by the Kansai Myeloma Forum. Twenty patients received novel agents (bortezomib or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent autologous stem cell transplantation (SCT) was 40 months, those undergoing allogeneic SCT 55 months, and those undergoing both types of SCT (auto-allo) 61 months; whereas for those who did not undergo SCT it was 28 months (p = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia.

[VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, predonisolone, bleomycin) therapy in elderly patients with aggressive non-Hodgkin lymphoma--a study of efficacy and safety, final report].

We experienced the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, predonisolone, bleomycin) combination regimen for the treatment of elderly patients with aggressive non-Hodgkin lymphoma (NHL) in a multicenter study by 6 collaborative institutions. Patients were previously untreated > or = 60 years of age and received prophylactic G-CSF. Twenty patients entered this trial, and all of them were evaluated for feasibility, toxicity, and efficacy. The complete remission rate was 75.0%, with a 100% overall response rate; overall survival (OS) rate at 3 years was 79.1% (median follow up 761.5 days), with a 60.7% progression-free 3-year survival (PFS) rate (median follow-up 600.0 days). Our trial was promising and well-tolerated. According to IPI, high/high-intermediate risk was associated with significantly worse OS and PFS than low/low-intermediate risk (2-year OS: 51.8% versus 100.0%, p=0.0118; 2-year PFS: 33.3% versus 80.0%, p=0.0125). Grade 3/4 infections occurred in 3 patients, but no patients experienced it with predonisolone reduced.

VNCOP-B plus rituximab therapy in elderly patients with aggressive B-cell non-Hodgkin lymphoma: a multicenter experience.

CHOP (cyclophosphamide, adriamycin, vincristine, and prednisolone) plus rituximab is a standard chemotherapy used to treat patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, among elderly patients, this regimen has not been completely satisfactory in its efficacy and safety. We report our clinical experience in 8 collaborative institutions to determine if the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, prednisolone, and bleomycin) combination therapy plus rituximab was effective and safe to treat elderly patients with aggressive B-NHL. Between September 2004 and December 2007, 23 previously untreated patients, median age 73 years, 50.0% classified as high-intermediate/high-risk on the standard International Prognostic Index (IPI) entered this trial. Complete remission rate was 90.5%, with a 100% overall response rate (RR) at the end of induction therapy; overall survival (OS) rate at 3 years was 76.4% (median follow-up 744 days), with an 82.6% 3-year progression-free survival (PFS) rate (median follow-up 744 days). The most common grade 3/4 toxicities were hematologic, including neutropenia in 75.0% of the patients despite prophylactic administration of granulocyte colony-stimulating factor (G-CSF), febrile neutropenia in 30.0%, respectively. There was no treatment-related mortality (TRM). Rituximab not only combined with chemotherapy but also given sequentially improved survival. R-VNCOP-B could be another option for elderly patients who are not considered to tolerate in receiving R-CHOP.

Significance of soluble CD40 ligand, adiponectin and reactive oxygen metabolites in aging.

We analyzed the association between platelet activation, adiponectin, insulin resistance and oxidative stress in aging. In addition, we included American football (AB) players to investigate whether this association is modulated by exercise. Eighty-six old age patients (> or = 65 years old) hospitalized at the nursing institution and 62 AB players were recruited as study subjects. Reactive oxygen metabolites (ROM), soluble CD40 ligand (sCD40L) and adiponectin were estimated with these patients. In comparison to old age, plasma adiponectin levels in AB players were significantly low. In addition, the adiponectin values of elder group (> 80 years) in old age were significantly increased higher than those for younger group (< or = 80 years). There were no differences of sCD40L in two groups. Levels of ROM in AB players were also significantly lower than that in old age. However, the ROM values of younger group in old age were significantly increased higher than those for elder group. The sCD40L also exhibited the same results. There were no significant differences in ROM and adiponectin levels between the high homeostasis model assessment-insulin resistance (HOMA-IR) (> 2.0) and the low HOMA-IR (< or = 2.0). In contrast, in the old age, the sCD40L and ROM levels in the high HOMA-IR group were significantly higher than those in the low HOMA-IR group. In addition, the adiponectin level in the high HOMA-IR group was significantly lower than that in the low HOMA-IR group. Our results suggest that platelet activation, adiponectin and oxidative stress are the very important factors for aging, and the maintenance of exercise could prevent the occurrence of metabolic syndrome or insulin resistance.

Effects of eicosapentaenoic acid on endothelial cell-derived microparticles, angiopoietins and adiponectin in patients with type 2 diabetes.

AIM: The aim of this study was to evaluate the significance of endothelial cell-derived microparticles (EDMP), angiopoietin-2 (Ang-2) and adiponectin in hyperlipidemic patients with and without type 2 diabetes mellitus, and to compare the two for the effects of eicosapentaenoic acid (EPA) on these markers. METHODS: One hundred and twenty-six hyperlipidemic patients with and without type 2 diabetes mellitus received EPA 1,800 mg daily, and 50 of the patients were non-diabetic. RESULTS: EDMP and Ang-2 levels prior to treatment were higher in diabetic patients than in non-diabetic patients, whereas adiponectin levels were lower in diabetics. When diabetic patients were classified into two groups on the basis of Ang-2 levels, the levels of all markers remained unchanged in those without a high Ang-2 level after EPA treatment. In contrast, all markers except for adiponectin were decreased significantly in diabetic patients with high Ang-2 levels after 6 months of EPA treatment. These diabetic patients with high Ang-2 levels displayed a more significant increase in adiponectin levels after EPA treatment than those who did not. CONCLUSION: These results suggest that EPA possesses an adiponectin-dependent anti-atherosclerotic effect and may be beneficial for the prevention of vascular complications in diabetic patients with high Ang-2 levels.

The significance of EMAP-II after allogeneic stem cell transplantation.

Endothelial monocyte-activating polypeptide-II (EMAP-II) appears to play an important role in neovascularization and endothelial abnormalities. However, the role of EMAP-II in development of graft-versus-host disease (GVHD) after allogeneic SCT is poorly understood. We measured and compared the levels of EMAP-II, cytokines, and soluble factors in patients undergoing allogeneic SCT. The subjects were 23 patients who underwent allogeneic SCT. Most of the cytokines/soluble factors exhibited a significant elevation after allogeneic SCT, although Angiopoietin-1 did not change. On the other hand, the levels of these factors did not change significantly in the recipients of autologous SCT. When the relationship between EMAP-II and cytokines/soluble factors was analyzed, EMAP-II levels correlated positively with sIL-2R, sVCAM-1, sE-selectin, sFasL and EDMP. However, IL-6, Angiopoietin-1, Angiopoietin-2 and VEGF were not correlated with EMAP-II. Our results suggest that EMAP-II plays an important role in endothelial cell dysfunction related to GVHD after allogeneic SCT.

Effects of pitavastatin on monocyte chemoattractant protein-1 in hyperlipidemic patients.

The effects of statins on platelet activation markers, chemokines and adiponectin, were investigated in 135 patients with hyperlipidemia. Of the 135 hyperlipidemic patients, 63 were allocated to the simvastatin group, treated with simvastatin at the dose of 10 mg daily, and the remaining 72 were allocated to the pitavastatin group, treated with pitavastatin at the dose of 2 mg daily. Plasma levels of platelet-derived microparticles (PDMP), cell adhesion molecules (sCD40L and sP-selectin), chemokines [monocyte chemoattractant protein-1 (MCP-1) and regulated on activation normally T-cell expressed and secreted] and adiponectin were measured at the baseline and after 6 months of treatment in both the groups. In addition, we carried out a basic study to investigate the MCP-1-dependent induction of tissue factor expression on a histiocytic cell line (U937 cells). The plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 were higher, whereas those of adiponectin were lower, in the hyperlipidemic patients than in the normolipidemic controls. Plasma PDMP and sCD40L were positively correlated, whereas plasma adiponectin was negatively correlated, with the plasma levels of MCP-1. No significant differences in the plasma levels of PDMP, sCD40L, sP-selectin, regulated on activation normally T-cell expressed and secreted and MCP-1 measured before and after treatment were observed in either the simvastatin or pitavastatin group. A significant increase of the plasma adiponectin levels was observed after 6 months of treatment with pitavastatin but not after an equal duration of treatment with simvastatin. When pitavastatin-treated patients were divided into two groups according to the adiponectin response to pitavastatin treatment, significant decreases of the plasma MCP-1, PDMP and sCD40L levels were observed after pitavastatin treatment in the responder group. In the aforementioned basic study, MCP-1 by itself did not induce the expression of tissue factor on the U937 cells. However, the recombinant sCD40L-induced expression of tissue factor on U937 was enhanced by the addition of MCP-1. These findings suggest that PDMP, sCD40L and MCP-1 may participate in the development of atherothrombosis in patients with hyperlipidemia and that pitavastatin may exert an adiponectin-dependent antiatherothrombotic effect in hyperlipidemic patients.

Successful treatment using tacrolimus plus corticosteroid in a patient with RA associated with MDS.

We report a case of rheumatoid arthritis (RA) complicated by myelodysplastic syndrome (MDS) successfully treated by tacrolimus. A 57-year-old woman had persistent pain and swelling in bilateral wrist and knee joints, in addition to severe anemia and leukopenia. She was diagnosed with MDS and RA based on the results of bone marrow aspiration and the criteria of RA. Combination therapy with tacrolimus (1.5 mg day(-1)) and prednisolone (10 mg day(-1)) improved her bicytopenia and polyarthralgia.