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.

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.

[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.

[Disseminated carcinomatosis of the bone marrow in two patients with prostate cancer].

Disseminated carcinomatosis of the bone marrow is caused by metastasis to the bone marrow and can cause disseminated intravascular coagulation (DIC), leucoerythroblastosis, and microangiopathic hemolytic anemia (MHA). The prognosis of this syndrome is poor. We report herein two rare cases of disseminated carcinomatosis of the bone marrow in association with prostate cancer. Case 1 involved a 61-year-old man admitted to our department with elevated prostate-specific antigen (PSA) levels. Prostate biopsy revealed prostate cancer, and imaging studies were performed. Under a diagnosis of prostate cancer (T3N1Mx), the patient was treated using hormonotherapy, but died 2 months after admission due to gastrointestinal bleeding of unknown cause, refractory DIC, and cachexia. Bone marrow biopsy after his death revealed metastasis of the prostate cancer to the bone marrow. Case 2 involved a 68-year-old man admitted to our department with gross hematuria. Cystoscopy revealed non-papillary tumor in the prostatic urethra. Transurethral biopsy was performed and histology identified prostate cancer. Treatment was initiated with hormonotherapy and zoledronate. After 8 months, he complained of general fatigue and blood testing identified anemia and thrombocytopenia. Bone marrow biopsy revealed adenocarcinoma in the bone marrow. Alternative androgen therapy and chemotherapy with docetaxel was started, and the patient recovered from pancytopenia and general fatigue.

Left ventricular diastolic dysfunction in normotensive diabetic patients in various age strata.

Although patients with type 2 diabetes demonstrate cardiac diastolic dysfunction, it is well known that cardiac diastolic dysfunction is produced by hypertension and aging. The purpose of the present study was to elucidate the cardiac structure and function in normotensive patients with type 2 diabetes in various age strata in order to assess the effect of diabetes mellitus itself on cardiac function. Echocardiographic examination was performed in 77 normotensive patients with type 2 diabetes (age: 63+/-11 years) and 76 healthy control subjects (age: 60+/-11 years) who were in their forties, fifties, sixties, and seventies. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) using the transmitral flow velocity, which were obtained by Doppler echocardiography. No difference was observed in the relative wall thickness, LV mass index, or LVEF between the diabetic patients and control subjects in any of the age strata. The E/A ratio in the patients with type 2 diabetes was not different from that in the control subjects in their 40s (1.17+/-0.35 versus 1.20+/-0.36). However, E/A was significantly lower in the diabetic patients than in the control subjects in their 50s (0.87+/-0.28 versus 1.14+/-0.24), 60s (0.78+/-0.22 versus 0.97+/-0.27), and 70s (0.66+/-0.19 versus 0.84+/-0.21) (p<0.05). The duration of type 2 diabetes was significantly longer in patients in their 50s (7.0+/-2.5 years), 60s (8.0+/-3.2 years), and 70s (10.4+/-3.2 years) than in patients in their 40s (3.3+/-1.9 years) (p<0.001). The value of E/A in the diabetic patients correlated with the duration of type 2 diabetes (r=-0.62, p<0.001). These results indicate that cardiac diastolic dysfunction without LV systolic dysfunction in patients with well-controlled type 2 diabetes is related neither to hypertension nor LV hypertrophy, but rather to aging and the duration of type 2 diabetes.

Cardiac function as assessed by echocardiography in the oldest old > or = 90 years of age.

Although several studies have demonstrated that cardiac diastolic function is impaired but cardiac systolic function is preserved with aging, no large-scale analysis of cardiac function by echocardiography in subjects aged > or = 90 years exists. The purpose of the present study was to elucidate the cardiac structure and function in the oldest old in order to assess the effect of aging on cardiac function. Echocardiographic examination was performed in 1793 subjects who were in their fifties, sixties, seventies, eighties, and nineties. Left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. LV ejection fraction (LVEF) was calculated and used as the parameter representing LV systolic function. LV diastolic function was assessed using the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial contraction (A velocity), and the ratio of E to A (E/A) by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. The E/A decreased progressively with aging, and demonstrated the closest correlation with age among all the indexes of cardiac function (r = -0.44, P < 0.001). In contrast, LVEF and the Tei index demonstrated a very weak correlation with age (r = -0.13, P < 0.001 and r = 0.16, P < 0.001, respectively). The mean value for LVEF remained normal with aging in all age strata (50s: 71 +/- 8%, 60s: 71 +/- 8%, 70s: 70 +/- 9%, and 80s: 71 +/- 10%), but decreased significantly in subjects in their 90s (66 +/- 10%, P < 0.001). In addition, the mean value for the Tei index also remained normal with aging in subjects in their 50s (0.35 +/- 0.10), 60s (0.38 +/- 0.14), 70s (0.38 +/- 0.12), and 80s (0.39 +/- 0.15), but showed an abnormal value in subjects in their 90s (0.45 +/- 0.12, P < 0.001). In conclusion, both diastolic dysfunction and systolic dysfunction with advancing age were observed in the oldest old aged > or = 90 years. The age-related impairment of systolic function as well as diastolic function should be considered when echocardiography is used to evaluate the causes of heart failure in the oldest old.

Latent cardiac dysfunction as assessed by echocardiography in bed-bound patients following cerebrovascular accidents: comparison with nutritional status.

The aim of this study was to elucidate the cardiac function in bed-bound patients following cerebrovascular accidents. In accord with the criteria for activities of daily living (ADL) of the Japanese Ministry of Health, Labour and Welfare, 51 age-matched poststroke patients without heart disease were classified into 3 groups: rank A (house-bound) (n = 16, age, 85 +/- 6 years), rank B (chair-bound) (n = 16, age, 84 +/- 8 years), and rank C (bed-bound) (n = 19, age, 85 +/- 9 years). Using echocardiography, the left ventricular (LV) diastolic function was assessed by the ratio of early filling (E) and atrial contraction (A) transmitral flow velocities (E/A) of LV inflow. LV systolic function was assessed by LV ejection fraction (LVEF), and the Tei index was also measured to assess both LV systolic and diastolic function. No difference was observed in the E/A and LVEF among the 3 groups. The Tei index was higher in rank C (0.56 +/- 0.17) than in rank A (0.39 +/- 0.06) and rank B (0.48 +/- 0.17), and a statistically significant difference was observed between rank A and rank C (P < 0.05). Serum albumin and blood hemoglobin were significantly lower in rank C (3.1 +/- 0.4 and 10.6 +/- 1.8 g/dL) than in rank A (4.1 +/- 0.3 and 12.4 +/- 1.2 g/dL) (P < 0.001 and P < 0.05, respectively). These results indicate that latent cardiac dysfunction and poor nutritional status may exist in bed-bound patients (rank C) following cerebrovascular accidents. The Tei index may be a useful index of cardiac dysfunction in bed-bound patients because it is independent of the cardiac loading condition.

Left ventricular diastolic dysfunction as assessed by echocardiography in metabolic syndrome.

The purpose of the present study was to elucidate the cardiac structure and function in patients who have metabolic syndrome but no history of cardiovascular disease by analyzing echocardiographic findings. Echocardiographic examination was performed to screen for cardiovascular disease in 135 patients who were in their sixties. Patients were divided into metabolic syndrome (n=65, age: 65+/-2.7 years) and non-metabolic syndrome (n=70, age: 66+/-2.5 years) groups based on the criteria for metabolic syndrome proposed by the Japanese Society of Hypertension and seven other societies in 2005. The left ventricular (LV) wall thickness and dimension were measured by M-mode echocardiography. The relative wall thickness, LV mass index, and LV ejection fraction (LVEF) were calculated. LV diastolic function was assessed by the peak velocity of early rapid filling (E velocity) and the peak velocity of atrial filling (A velocity), and the ratio of E to A (E/A) was assessed by the transmitral flow. The Tei index, which reflects both LV diastolic and systolic function, was also calculated. There were no differences in relative wall thickness, LV mass index, or LVEF between the two groups. However, both the EIA and Tei index were significantly different between the metabolic syndrome (0.66+/-0.14 and 0.36+/-0.07, respectively) and non-metabolic syndrome (0.88+/-0.25 and 0.29+/-0.09) groups (p<0.001). These results indicate that patients with metabolic syndrome can have cardiac diastolic dysfunction even if they have neither LV hypertrophy nor systolic dysfunction.

Relationships between echocardiographic findings, pulse wave velocity, and carotid atherosclerosis in type 2 diabetic patients.

The purpose of the present study was to analyze the relationships between echocardiographic findings, brachial-ankle pulse wave velocity, and carotid atherosclerosis in type 2 diabetic patients. In 70 type 2 diabetic patients without cardiovascular disease, pulse wave velocity was measured using an automatic waveform analyzer, and the carotid plaque score was obtained by carotid ultrasonography. The left ventricular wall thickness and the indexes of left ventricular diastolic function (the peak velocity of early rapid filling [E velocity], the peak velocity of atrial filling [A velocity], and the E/A ratio) were obtained by echocardiography. Brachial-ankle pulse wave velocity correlated significantly with the carotid plaque score, but the correlation was weak (r=0.37, p=0.001). The brachial-ankle pulse wave velocity demonstrated a strong correlation with the A velocity (r=0.73, p<0.001), the ratio of E to A (E/A) (r=-0.63, p<0.001), and the deceleration time of the E velocity (r=0.48, p<0.001). Stepwise regression analysis showed that the A velocity (beta coefficient=0.42, p<0.001) and ventricular septal thickness at the left ventricular outflow tract (beta coefficient=0.27, p=0.001) were independently associated with brachial-ankle pulse wave velocity. Stepwise regression analysis indicated that ventricular septal thickness at the left ventricular outflow tract (beta coefficient=0.38, p=0.001) was independently associated with the plaque score. These results indicate that left ventricular diastolic dysfunction as revealed by increased peak velocity of atrial filling reflects arterial stiffening in type 2 diabetic patients. In addition, myocardial wall thickening at the left ventricular outflow tract reflects not only arterial stiffening but also carotid atherosclerosis. Therefore, these abnormal echocardiographic findings of left ventricular diastolic dysfunction and myocardial wall thickening may be useful markers of the presence of progressive arteriosclerosis in type 2 diabetic patients.