Association between Rapid Dementia Screening Test score and clinical events in elderly patients with cardiovascular disease: a retrospective cohort study.

AIMS: Cognitive decline is prevalent among patients with cardiovascular disease (CVD). Cognitive measurement has been considered as a standard assessment for secondary prevention; however, standard cognitive tests are sometimes infeasible due to time constraints. This study aimed to examine the association between the Rapid Dementia Screening Test (RDST), a brief screening tool for cognitive function, and clinical events in elderly patients with CVD. METHODS AND RESULTS: This retrospective cohort study included 140 hospitalized patients with CVD who participated in inpatient cardiac rehabilitation (median age, 75 years; male, 67%). Cognitive function for each patient was assessed using the RDST and Montreal Cognitive Assessment (MoCA), a standard test of mild cognitive impairment. The clinical events assessed as outcomes included all-cause mortality and unplanned rehospitalization. Receiver-operating characteristic (ROC) curve analysis showed similar predictive accuracy for the study outcome (P = 0.337) between the RDST [area under the curve, 0.651; 95% confidence interval (CI), 0.559-0.743] and MoCA (0.625; 0.530-0.720). The ROC analysis identified a cut-off value of 9 points for the RDST (sensitivity, 77.8%; specificity, 50.5%). Patients with RDST ≤9 showed a poor survival rate compared with those with ≥10 points (log-rank test, P = 0.002; hazard ratio, 2.94, 95% CI, 1.46-5.94). This result was consistent even after adjusting for potential confounders. CONCLUSION: The RDST was associated with clinical events in elderly patients with CVD and its predictive capability was comparable with that of MoCA, a standard cognitive test. The RDST may be useful in CVD as an alternative screening tool for cognitive decline.

Erythroblast predominance without CD41/cyCD41-positive blasts predicts favorable prognosis in patients with myelodysplastic syndromes and acute myeloid leukemias treated with azacitidine.

This study examined the prognostic impact of erythroblast predominance (EP) in 61 patients with myelodysplastic syndromes (MDS) (n = 51) or acute myeloid leukemia (n = 10) treated with azacitidine. Median age was 78 years. EP, defined as > 40% erythroblasts and M/E < 1.0, was found in 21 patients, including 9 complex karyotypes (CK). In the 24 CK of the entire cohort, 5 were hyperdiploid and 15 were monosomal karyotype with -5/5q-, and 10 had immunophenotypically CD41/cyCD41 positive blasts (cyCD41+). The complete response (CR) rate was 32.8%. Median follow-up was 14 months, and median overall survival (OS) was 17 months. Although all patients with EP achieved high CR rates (61.9%) and extended OS (28 M, P = 0.056), patients with EP and cyCD41+ blasts had shorter OS (8 M, P = 0.002). EP (HR 0.39, P = 0.009) and cyCD41+ (HR 3.49, P = 0.018) were identified as prognostic factors in multivariate analysis. All patients with cyCD41+ had hyperdiploid or CK with -5/5q-. In conclusion, we divided patients into three risk categories: high (cyCD41+), low (EP without cyCD41+), and intermediate (non-CD41+ and non-EP), and median OS in these categories was 34, 17 and 8 months, respectively (P < 0.001).

[Venetoclax and azacitidine induced cytogenetic response in an elderly patient with IDH2- and DNMT3A-mutated refractory acute myeloid leukemia].

The optimal regimen for refractory acute myeloid leukemia (AML) in the elderly with good performance status has not been established. A 71-year-old man was admitted to our hospital with pancytopenia and 1.0% blasts in the peripheral blood. The patient was diagnosed with AML with DNMT3A (R882H)- and IDH2 (R172K)-positive myeloblasts. He received a reduced dose of idarubicin and cytarabine therapy. However, induction failure with 20% bone marrow blasts and DNMT3A mutations were observed. A reinduction therapy with venetoclax and azacitidine (VEN+AZA) was administered and led to a sustained complete response with significantly reduced DNMT3A-mutated blasts. Even 9 months after starting VEN+AZA, the patient is still alive and healthy without AML recurrence. Thus, VEN+AZA therapy may be highly effective for treating IDH2- and DNMT3A-mutated AML in elderly patients.

Association between Big Five Personality Traits and Participation in Cardiac Rehabilitation in Japanese Patients with Cardiovascular Disease: A Retrospective Cohort Study.

Cardiac rehabilitation (CR) remains underutilised, despite its established clinical benefit. A personality traits assessment may help promote CR implementation, as they are determinants of health-related behaviour. This study aimed to examine the association between the Big Five personality traits and outpatient CR participation in patients with cardiovascular disease (CVD) after discharge. This retrospective cohort study included 163 patients aged <80 years, who underwent inpatient CR when hospitalised for CVD. The Big Five personality traits (conscientiousness, neuroticism, openness, extraversion, and agreeableness) of each patient were evaluated at discharge, using the Japanese version of the Ten-Item Personality Inventory. We examined the relationship of each personality trait with non-participation in outpatient CR and dropout within three months, using logistic regression analysis. Out of 61 patients who initiated the outpatient CR, 29 patients dropped out, leaving us with 32 subjects. The logistic regression analysis results showed that high conscientiousness was associated with non-participation in CR. The primary reason for this was a lack of motivation. Conversely, low conscientiousness and high openness were predictors of dropout. This study suggests that the assessment of the Big Five personality traits, especially conscientiousness and openness, can help improve health communication with patients to promote outpatient CR participation after discharge.

Usefulness of the Japanese version of Rapid Dementia Screening Test for mild cognitive impairment in older patients with cardiovascular disease: a cross-sectional study.

BACKGROUND: Cognitive decline is common among older patients with cardiovascular disease (CVD) and can decrease their self-management abilities. However, the instruments for identifying mild cognitive impairment (MCI) are not always feasible in clinical practice. Therefore, this study evaluated whether MCI could be detected using the Japanese version of the Rapid Dementia Screening Test (RDST-J), which is a simple screening tool for identifying cognitive decline. METHODS: This retrospective single-center study included patients who were ≥ 65 years old and hospitalized because of CVD. Patients with a pre-hospitalization diagnosis of dementia were excluded. Each patient's cognitive function had been measured at discharge using the RDST-J and the Japanese version of the Montreal Cognitive Assessment (MoCA-J), which is a standard tool for MCI screening. The correlation between the two scores was evaluated using Spearman's rank correlation coefficient. Receiver operating characteristic (ROC) analysis was also to evaluate whether the RDST-J could identify MCI, which was defined as a MoCA-J score of ≤ 25 points. RESULTS: The study included 78 patients (mean age: 77.2 ± 8.9 years). The RDST-J and MoCA-J scores were strongly correlated (r = 0.835, P < 0.001). The ROC analysis revealed that an RDST-J score of ≤ 9 points provided 75.4% sensitivity and 95.2% specificity for identifying MCI, with an area under the curve of 0.899 (95% CI: 0.835-0.964). The same cut-off value was identified when excluding patients with a high probability of dementia (RDST-J score of ≤ 4 points). CONCLUSIONS: The RDST-J may be a simple and effective tool for identifying MCI in older patients with CVD.

Oncolytic Virus Therapy with HSV-1 for Hematological Malignancies.

Oncolytic herpes simplex virus type 1 (HSV-1) has been investigated to expand its application to various malignancies. Because hematopoietic cells are resistant to HSV-1, its application to hematological malignancies has been rare. Here, we show that the third generation oncolytic HSV-1, T-01, infected and killed 18 of 26 human cell lines and 8 of 15 primary cells derived from various lineages of hematological malignancies. T-01 replicated at low levels in the cell lines. Viral entry and the oncolytic effect were positively correlated with the expression level of nectin-1 and to a lesser extent 3-O-sulfated heparan sulfate, receptors for glycoprotein D of HSV-1, on tumor cells. Transfection of nectin-1 into nectin-1-negative tumor cells made them susceptible to T-01. The oncolytic effects did not appear to correlate with the expression or phosphorylation of antiviral molecules in the cyclic GMP-AMP (cGAS)-stimulator of interferon genes (STING) and PKR-eIF2α pathways. In an immunocompetent mouse model, intratumoral injection of T-01 into lymphoma induced regression of injected, as well as non-injected, contralateral tumors accompanied by abundant infiltration of antigen-specific CD8+ T cells. These data suggest that intratumoral injection of oncolytic HSV-1 may be applicable to systemic hematological malignancies. Nectin-1 expression may be the most useful biomarker for optimal efficacy.

KIF20A, highly expressed in immature hematopoietic cells, supports the growth of HL60 cell line.

A microtubule-associated motor protein, kinesin-like family member 20A (KIF20A; also called MKlp2) is required for cytokinesis and contributes to intracellular vesicular trafficking. KIF20A plays a critical role in the development of several cancers, but its role in blood cells and hematological malignancies have not been studied. In the present study, we focused on the role of KIF20A in hematopoietic cells and possible involvement in myeloid neoplasms. We found that human leukemia cell lines and normal bone marrow CD34-positive cells stimulated by growth factors, but not mature peripheral blood cells, exhibit high KIF20A expression. We further found that HL60 cells, which originally express a large amount of KIF20A, showed decreased KIF20A expression in parallel with both neutrophil-like and macrophage-like differentiation-induction. KIF20A-knockdown using a lentivirus shRNA transfection system led to partial cell cycle arrest at the G2/M phase and frequent appearance of multinucleated cells. Treatment with a KIF20A-selective inhibitor, paprotrain enhanced the multinuclearity of KIF20A-knockdown cell clones and suppressed growth. The present study contributes to our understanding of the role of KIF20A in blood cells and leukemia cells in particular.

Charlson comorbidity index predicts poor outcome in CML patients treated with tyrosine kinase inhibitor.

Although the Sokal and Hasford scoring systems are well-known prognostic models specific to chronic myeloid leukemia (CML), whether they can effectively predict outcomes in elderly CML patients with comorbidities has not been fully elucidated. We evaluated the association between comorbidity at diagnosis with treatment outcome and survival in chronic phase CML patients. A questionnaire was administered to patients diagnosed with CML between 2001 and 2012 and treated with tyrosine kinase inhibitors (TKIs). The Charlson comorbidity index (CCI) was used to determine concomitant diseases. In total, 79 patients (33 females; median age, 57 years) were enrolled. CCI scores at diagnosis were between 2 and 11. At the last follow-up, 46 patients showed a major molecular response. Complete cytogenetic response was achieved in 73.4 % of the cases 12 months after TKI administration. We observed only five deaths during the 55.5-month median follow-up period. The risk categories (low/intermediate/high) associated with Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The 27 cases with a CCI score >3 had significantly poorer survival after diagnosis (52 cases had a CCI score <2). CCI scores were inversely associated to overall survival. Concomitant comorbidity at diagnosis is associated with poor outcome in CML patients treated with TKIs.

Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma.

BACKGROUND: Human multiple myeloma (MM) is an incurable hematological malignancy for which novel therapeutic agents are needed. Calmodulin (CaM) antagonists have been reported to induce apoptosis and inhibit tumor cell invasion and metastasis in various tumor models. However, the antitumor effects of CaM antagonists on MM are poorly understood. In this study, we investigated the antitumor effects of naphthalenesulfonamide derivative selective CaM antagonists W-7 and W-13 on MM cell lines both in vitro and in vivo. METHODS: The proliferative ability was analyzed by the WST-8 assay. Cell cycle was evaluated by flow cytometry after staining of cells with PI. Apoptosis was quantified by flow cytometry after double-staining of cells by Annexin-V/PI. Molecular changes of cell cycle and apoptosis were determined by Western blot. Intracellular calcium levels and mitochondrial membrane potentials were determined using Fluo-4/AM dye and JC-10 dye, respectively. Moreover, we examined the in vivo anti-MM effects of CaM antagonists using a murine xenograft model of the human MM cell line. RESULTS: Treatment with W-7 and W-13 resulted in the dose-dependent inhibition of cell proliferation in various MM cell lines. W-7 and W-13 induced G1 phase cell cycle arrest by downregulating cyclins and upregulating p21cip1. In addition, W-7 and W-13 induced apoptosis via caspase activation; this occurred partly through the elevation of intracellular calcium levels and mitochondrial membrane potential depolarization and through inhibition of the STAT3 phosphorylation and subsequent downregulation of Mcl-1 protein. In tumor xenograft mouse models, tumor growth rates in CaM antagonist-treated groups were significantly reduced compared with those in the vehicle-treated groups. CONCLUSIONS: Our results demonstrate that CaM antagonists induce cell cycle arrest, induce apoptosis via caspase activation, and inhibit tumor growth in a murine MM model and raise the possibility that inhibition of CaM might be a useful therapeutic strategy for the treatment of MM.

[Composite lymphoma cosisting of mantle cell lymphoma and follicular lymphoma].

Herein, we report the case of a 56-year-old man with composite lymphoma (CL) comprised of mantle cell lymphoma (MCL) and follicular lymphoma (FL). Six months after developing a right brachial tumor, he was diagnosed as having grade 3 FL with normal-size mantle zone. Simultaneously, advanced stage MCL with a diffuse growth pattern in a sigmoid colon tumor and abnormal lymphoid cells in bone marrow were observed. Thereafter, the right brachial tumor was re-examined and its mantle zone cells were immunophenotypically positive for cyclin D1 (CCND1) and cytogenetically positive for the IgH-CCND1 fusion gene. Consequently, he was diagnosed with composite lymphoma (CL) comprised of FL and MCL. As MCL and FL may form CL, the possible complication of MCL should be considered and steps taken to detect MCL.

H2-receptor antagonist influences dasatinib pharmacokinetics in a patient with Philadelphia-positive acute lymphoblastic leukemia.

We recently reported in this journal that administration of acid suppressant such as an H2-receptor antagonist (H2RA) and a proton pump inhibitor can decrease the absorption of dasatinib from the gastrointestinal tract, thereby resulting in a significant decrease in its plasma concentration. Here, we report a patient treated with dasatinib and H2RA famotidine for whom the total area under the total plasma concentration-time curve (AUC(0-12)) of dasatinib dramatically increased after cessation of famotidine from 505.7 to 1,816.3 ng·h/mL. This is the first report to confirm the drug interaction between dasatinib and H2RA by using sequential pharmacokinetic profiling.

Approach to new therapeutics: investigation by the use of MDS-derived cell lines.

Myelodysplastic syndromes (MDS) are a group of aquired hematopoietic disorders characterized by ineffective hematopoiesis, and increased risk of progression of acute myeloid leukemia. For a long period of time, the standard therapy for MDS was hematopoietic stem cell transplantation, however DNA methyltransferase inhibitors (DNMT inhibitors) including decitabine (DAC) and azacitidine (AZA), and lenalidomide, a derivative of thalidomide have been highlighted as new chemotherapeutic agents for MDS. However, the underlying mechanisms of action of these drugs have not been fully defined yet. Therefore, we investigated the in vitro effects of DNMT inhibitors and lenalidomide on an MDS-derived cell line, MDS92 and its blastic subline MDS-L, both of which carry del(5q). MDS-L cells were found to be quite sensitive to DAC, which induced to cell death through DNA damage-mediated G2 arrest via p53- independent pathways. Gene expression profiling suggested that DAC affects biogroups representing hematological systems, cellular development, cell death and apoptosis. Next, we examined the effects of lenalidomide on MDS-L. Cell growth was inhibited and multinucleated cells were frequently formed prior to cell death by lenalidomide treatment. Time-lapse microscopic observation and DNA ploidy analysis revealed that lenalidomide does not affect DNA synthesis itself but inhibits cytokinesis of MDS-L cells. The gene expression profiling showed decreased expression of M phase-related genes. These data contribute to the understanding of action mechanisms of lenalidomide on MDS with del(5q).

Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation.

Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-ß1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce ß1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.

[Effective treatment with rituximab for primary thrombotic thrombocytopenic purpura complicated with multiple cerebral infarctions].

A 22-year-old woman was diagnosed with thrombotic thrombocytopenic purpura (TTP). She had a high fever and disorientation without renal dysfunction. She immediately underwent plasma exchange and prednisolone treatment, but they proved ineffective. She subsequently suffered from left major cerebral infarction with right-side hemiplegia. Therefore, 375 mg/m(2) of rituximab was administered weekly from day 14 with informed consent. Immediate improvements were noted in not only the hematological and biochemical parameters such as platelet count, hemoglobin level, rate of fragmented red cells, and serum LDH level but also the neurological symptoms and MRI findings. The universal histopathologic findings of TTP are characterized by hyaline thrombi formed by the aggregation of platelets, mostly in small arterioles and capillaries. Therefore, abnormal findings are rarely detected by imaging modalities such as CT and MRI. Moreover, TTP with major stroke is an extremely rare occurrence. In conclusion, we present a patient with refractory TTP with major cerebral infarction, who was effectively treated with rituximab.

[Multiple autologous transplantations with intermediate-dose melphalan for two elderly patients with relapsed or refractory diffuse large B-cell lymphoma].

High-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (PBSCT) is beneficial for patients with relapsed or refractory but chemosensitive diffuse large B-cell lymphoma (DLBCL). However, most elderly patients are not indicated for that therapy and receive supportive treatment only. We describe here two elderly patients with relapsed or refractory DLBCL who achieved prolonged disease-free survival after undergoing intermediate-dose melphalan therapy supported by PBSCT (MEL100) three times. Case 1 was an early relapse (within one year) after the first remission and case 2 was a second relapse. Both cases are currently alive without relapse and have maintained a good performance status for 41 months and 32 months, respectively, after MEL100. Febrile neutropenia and herpes zoster as non-hematological toxicities (grade > or = 3) occurred only in case 1. Considering the benefits vs. toxic effects, this regimen may improve the prognosis of elderly patients with relapsed or refractory DLBCL by MEL100.

Validation of the revised 2008 WHO diagnostic criteria in 75 suspected cases of myeloproliferative neoplasm.

The objective of this study was to validate the recently revised 2008 WHO diagnostic criteria of myeloproliferative neoplasms (MPN) together with the analysis of correlation of JAK2 (Janus kinase 2)-V617F mutant allele burden with clinical/laboratory findings on each patient. We made a diagnosis of 75 suspected MPN patients based on both diagnostic criteria of the 2001 WHO classification and the revised 2008 WHO classification, and found that both criteria show a quite similar diagnostic power except for two patients (idiopathic erythrocytosis (IE) and thrombocytosis) who were diagnosed as essential thrombocythemia by the 2008 WHO criteria. From JAK2-V617F analysis, hemoglobin and hematocrit values were significantly higher and platelet count was lower in JAK2-V617F high allele burden group than JAK2-V617F middle allele burden group. Mutant allele burden of polycythemia vera (PV) group was higher than that of essential thrombocythemia group. Therefore, the amount of mutant allele seemed to define the disease phenotypes. We further found a PV case presenting a rare type of JAK2-exon12 mutation. In contrast, IE presented a good prognosis unlike MPN. Hereafter, the 2008 WHO criteria with JAK2 gene analysis are useful for precise diagnosis of MPN and the patients with erythrocytosis.