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Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings., Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy., Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups., Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected., (© 2015 by The American Society of Hematology.)

Angioimmunoblastic T-cell lymphoma (AITL) is a major type of peripheral T-cell lymphoma (PTCL). To elucidate the clinicopathologic characteristics and prognosis of AITL in Japan, we retrospectively analyzed 207 patients with AITL. The median patient age was 67 years (range, 34-91 years), with 73% of patients older than 60 years. With a median follow-up of 42 months in surviving patients, 3-year overall survival (OS) was 54% and progression-free survival (PFS) was 38%. The International Prognostic Index (IPI) and the prognostic index for PTCL, not otherwise specified (PIT) were predictive for OS in this analysis. Multivariate analysis found that age older than 60 years, elevated white blood cell (WBC) and IgA levels, the presence of anemia and thrombocytopenia, and extranodal involvement at > 1 site were significant prognostic factors for OS, and IgA, anemia, and mediastinal lymphadenopathy were significant prognostic factors for PFS. A novel prognostic model consisting of the prognostic factors for OS was successfully constructed. In conclusion, IPI and PIT were still useful for prognostication of AITL, and other factors, including those not used in IPI, such as IgA, anemia, WBC count, thrombocytopenia, and mediastinal lymphadenopathy, also significantly affected prognosis. Future investigations for IgA as a unique prognostic factor are warranted.

Definitive risk factors for the development of adult T-cell leukemia (ATL) among asymptomatic human T-cell leukemia virus type I (HTLV-1) carriers remain unclear. Recently, HTLV-1 proviral loads have been evaluated as important predictors of ATL, but a few small prospective studies have been conducted. We prospectively evaluated 1218 asymptomatic HTLV-1 carriers (426 males and 792 females) who were enrolled during 2002 to 2008. The proviral load at enrollment was significantly higher in males than females (median, 2.10 vs 1.39 copies/100 peripheral blood mononuclear cells [PBMCs]; P < .001), in those 40 to 49 and 50 to 59 years of age than that of those 40 years of age and younger (P = .02 and .007, respectively), and in those with a family history of ATL than those without the history (median, 2.32 vs 1.33 copies/100 PBMCs; P = .005). During follow-up, 14 participants progressed to overt ATL. Their baseline proviral load was high (range, 4.17-28.58 copies/100 PBMCs). None developed ATL among those with a baseline proviral load lower than approximately 4 copies. Multivariate Cox analyses indicated that not only a higher proviral load, advanced age, family history of ATL, and first opportunity for HTLV-1 testing during treatment for other diseases were independent risk factors for progression of ATL.

Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure.

This study was performed to determine the relationship between the two common polymorphisms of cholesteryl ester transfer protein (CETP) gene and LDL size in Japanese individuals. The LDL size was determined by gradient gel electrophoresis in 136 patients undergoing routine check-ups. The presence of two polymorphisms (I405V and Taq1B) was determined using PCR-based methods. The VV genotype for the I405V polymorphism was associated with both a lower plasma CETP concentration and a higher plasma HDL-C concentration. Further, the LDL size in patients with the VV genotype was significantly smaller than that in patients with the II+IV genotype (26.0 +/- 0.8 vs. 26.3 +/- 0.7 nm, P<0.05). Although the B2B2 genotype for the Taq1B polymorphism was also associated with both a lower plasma CETP concentration and a higher plasma HDL-C concentration, it had no effect on the LDL size (26.2 +/- 0.7 vs. 26.3 +/- 0.8 nm, P=0.73). Stepwise multiple regression analysis revealed that the VV genotype, as well as plasma TG concentration, age, HbA1c concentration, and BMI, were determinants of LDL size, while no significant relationships were seen between any of the Taq1B polymorphisms and LDL size. These data suggest that the I405V polymorphism but not the Taq1B polymorphism may be responsible for the distribution of LDL size. This may explain the differential effects of these two polymorphisms on the risk of CHD.

Background: Dietary fish oil potentiates the susceptibility of cellular membranes to lipid peroxidation, although it is also known to have beneficial effects on the development of cardiovascular diseases., Objective: The effects of dietary fish oil against doxorubicin-induced cardiomyopathy, in which free radicals and lipid peroxidation are involved, were investigated in rats., Animals and Methods: Sprague-Dawley rats (100 g) were fed a standard diet or a high fish oil diet (containing 10% fish oil) throughout the experimental period. Four weeks after starting each diet, experimental rats were treated with doxorubicin (cumulative dose 15 mg/kg) or vehicle (0.28 M dextrose solution). After three weeks of doxorubicin treatment, the cardiac performance, myocardial lipid peroxidation and myocardial vitamin E level were assessed., Results: Compared with control rats, doxorubicin-treated rats showed a significantly increased mortality rate (P<0.05), and significantly decreased systolic blood pressure and left ventricular fractional shortening (P<0.01). The myocardial thiobarbituric acid-reactive substance level was significantly higher in doxorubicin-treated rats than in control rats (P<0.01), while the myocardial vitamin E level was significantly lower (P<0.05). Dietary fish oil enhanced the myocardial lipid peroxidation caused by doxorubicin, which was associated with a further decrease in myocardial vitamin E level. As a result, the rats treated with both doxorubicin and the high fish oil diet showed the highest mortality rate and the lowest cardiac performance of all the experimental groups., Conclusions: Dietary fish oil may reduce antioxidant defences and accelerate susceptibility of the myocardium to lipid peroxidation in rats under doxorubicin treatment. This may partly explain why dietary fish oil does not prevent doxorubicin-induced cardiomyopathy.

Background: Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models., Objective: To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency., Methods and Results: Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment., Conclusions: The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Background: Blood flow is calculated from mean velocity across the vessel and its cross-sectional area and is related to the fetal growth., Aim: To investigate the relationship between diameter pulse waveform (DPW) and flow velocity waveform (FVW) in the fetal descending aorta during fetal development., Study Design: Doppler ultrasound and a phase-locked loop echo tracking system were used to measure the FVW and DPW in the fetal descending aorta, respectively., Subjects: We studied 137 normal-growth fetuses (normal group, 20-40 weeks) and 51 fetuses with high umbilical artery pulsatility index (umbilical placental insufficiency, UPI group, 26-40 weeks)., Outcome Measures: We measured the systolic (Sd), diastolic (Dd) diameters, time diameter integral (TDI) and time velocity integral (TVI) and then calculated the TVI x TDI and TVI to TDI ratio., Results: Normal fetal growth was associated with an increase in Sd, Dd, pulse amplitude, TVI, TDI and TVI x TDI. The FVW began to resemble the DPW with decreasing downstream resistance produced by growth of the placenta. The TVI was increased relative to the TDI. The differences in Sd, Dd, TDI and TVI x TDI between the normal and UPI groups were not significant. The TVI was decreased relative to the TDI. There was a decrease in the TVI as a ratio of the TDI. The Dd per unit fetal weight was high in the compromised fetuses. Fetal outcome was examined in relation to the TVI to TDI ratio. Those with a low ratio (below 10th centile) exhibited significantly more adverse indices of fetal outcome., Conclusions: In fetal compromise there is an increase in diastolic pressure in association with high placental resistance, which causes a major increase in afterload. The efficient circulation associated with fetal growth might be represented by an increase in the ratio of the TVI to the TDI (an index of efficient circulation) when these waveform shapes resemble each other.

Abnormal lipid metabolism has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. In this study, we measured myocardial lipid levels, including 1,2-diacylglycerol (1,2-DAG) and ceramide (CM), and myocardial function in diabetic rats. We also evaluated the effects of etomoxir (ETM), a carnitine palmitoyl transferase I inhibitor, on diabetic rat hearts from the viewpoints of alterations in lipid second messengers and myocardial function. Rats were injected with streptozotocin (60 mg/kg) to induce diabetes and were treated 5 weeks later with ETM (18 mg/kg) for 8 days. In diabetic rats, heart rate, systolic blood pressure, and fractional shortening were significantly reduced compared with those in controls. Treatment of diabetic rats with ETM ameliorated myocardial dysfunction other than heart rate. Myocardial 1,2-DAG levels in diabetic rats were significantly elevated compared with those in controls, while myocardial CM levels were not. ETM treatment caused an additional increase in myocardial 1,2-DAG levels in diabetic rats, but the CM levels did not change. There was a marked difference in fatty acid pattern of 1,2-DAG between diabetic and ETM-treated diabetic rat hearts. The fatty acids 18:1 and 18:2 were significantly increased and the fatty acids 16:0, 18:0, 20:4, and 22:6 were significantly reduced in ETM-treated diabetic rat hearts. These data suggest 1,2-DAG is involved in ameliorating myocardial dysfunction in diabetic rats and that its source is different between diabetic and ETM-treated diabetic rats. CM is unlikely to be involved in the pathogenesis of diabetic cardiomyopathy or the improvement of cardiac contractility in diabetic rats by ETM.

Establishment of Chinese hamster ovary (CHO) cell lines expressing human glutathione S-transferase-pi (GST-pi) was performed after cotransfection of pSV2-neo and human GST-pi cDNA-carrying plasmid p beta actGPi-2. About 30 G418-resistant clones were tested for their expression of GST-pi by Northern blot analysis. Two clones, beta 2-3 and beta 2-5, expressed a significant amount of GST-pi mRNA; and one clone, beta 1-1, that did not was also used for further study. Western blot analysis with anti-GST-pi antibody showed significant increases of GST-pi in beta 2-3 and beta 2-5, but not in beta 1-1. Northern blot analysis with the human GST-pi cDNA probe showed that the increase in the expression of GST-pi-mRNA in beta 2-3 and beta 2-5 was respectively 2- and 4-fold higher than that in beta 1-1. Southern blotting analysis showed that beta 1-1, beta 2-3 and beta 2-5 contained about one copy of the human GST-pi cDNA sequence. beta 2-3 and beta 2-5 were resistant to 1.4- and 3.0-fold higher doses of CDDP than CHO, respectively, but beta 1-1 was not. Increased expression of GST-pi might be associated with CDDP-resistance in CHO cells.

A reciprocal translocation involving the short arms of chromosomes 7 and 11, t(7;11)(p15;p15), was found in nine patients including eight with acute myelogenous leukemia (AML) and one with Philadelphia (Ph1) chromosome-positive chronic myelogenous leukemia (CML) in blastic crisis. Although a similar chromosome rearrangement has previously been reported in five patients, including three with AML and two with CML, the 7p breakpoint in some of these cases was slightly different from that detected in our patients. Notable cytogenetic and clinicohematologic findings in our patients and those reported in the literature were as follows: (a) t(7;11) occurred in myeloid leukemia, predominantly AML with subtype M2, and occasionally in other AML subtypes and in CML with or without Ph1 chromosome; (b) t(7;11) frequently occurred as the sole chromosome abnormality; (c) most patients showed a low neutrophil alkaline phosphatase score; and (d) Auer rods were present in leukemic cells of most cases including Ph1-positive CML. Our findings suggest that a t(7;11)-associated leukemia constitutes a subgroup of myeloid malignancy involving maturing leukemic cells.