Treatment strategy at the decision for allogeneic transplantation in patients with myelodysplastic syndrome in the era of azacitidine: A KSGCT prospective study.

The optimal bridge strategy at the decision for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelodysplastic syndrome (MDS) is unclear. We performed a prospective observational study in which 110 patients with MDS who were decided to undergo HSCT were enrolled. Among these 110 patients, 77 patients were enrolled in this study within 1 month from the decision for HSCT. Among these 77 patients, 13 patients had a human leukocyte antigen (HLA)-matched sibling, 54 patients started an unrelated donor search, and the other 10 patients directly selected cord blood (CB) at the decision for HSCT, and 13 (100%), 38 (70.4%), and 9 (90%) patients actually underwent HSCT within 1 year, respectively. The overall survival (OS) at 1 year from their enrollment was 70.9%, and the selection of azacitidine use at the decision for HSCT was not associated with OS. Among 60 of the 77 patients who actually underwent HSCT within a year from their enrollment, a lower relapse rate after HSCT was observed in those who selected CB at the decision to undergo HSCT. However, this preferable effect of CB selection disappeared when patients who were enrolled in this study in > 1 month from the decision for HSCT were additionally included in the analyses. In conclusion, the selection of bridge strategy at the decision for HSCT did not affect outcomes in patients with MDS. The immediate performance of HSCT may be associated with better outcomes.

Dietary olive oil intake induces female-specific hepatic lipid accumulation without metabolic impairment in mice.

Olive oil is one of the most widely researched Mediterranean diet components in both experimental models and clinical studies. However, the relationship between dietary olive oil intake and liver function in a healthy state of the body remains unclear. Because men are at a greater risk of developing hepatic diseases than women, and because hepatic metabolism is regulated by sex hormones, we hypothesized that olive oil-induced changes in hepatic metabolism would differ by sex. To test our hypothesis, 12-week-old C57BL/6JJcl male and female mice were fed an olive oil diet for 4 weeks. Blood was collected and serum biochemical components were analyzed. Hepatic lipid accumulation was determined via histological analysis using Sudan III staining. Finally, transcript expression levels of hepatic metabolism-related genes were analyzed using quantitative polymerase chain reaction. We observed significant increased hepatic lipid droplet accumulation in olive oil-fed female mice. Serum biochemical and liver messenger RNA expression analyses revealed that the hepatic lipid accumulation was nonpathological and did not involve inflammation. Moreover, the expression of genes related to triacylglycerol and fatty acid synthesis (Dgat1, Dgat2, Agpat3, and Fasn) was significantly upregulated in the liver of olive oil-fed female mice compared with control female mice. Our study demonstrates female-specific hepatic lipid accumulation without liver impairment in a dietary olive oil-fed mouse model. These findings provide a deeper mechanistic understanding of sex-dependent hepatic lipid metabolism of dietary oils.

Comparison of the impact of two post-remission therapy regimens on cardiac events in acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation.

High-dose cytarabine (HD-AraC) or anthracycline-containing chemotherapies are used as post-remission therapy for acute myeloid leukemia (AML) patients. However, it remains unclear which regimen would be better as post-remission therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, we compared the incidence of cardiac events and event-free survival (EFS) after allo-HSCT at two Japanese hospitals between HD-AraC and anthracycline-containing post-remission therapy to clarify the safety of post-remission therapy. Of a total of 132 patients, 68 received HD-AraC (HD-AraC group) and 64 received anthracycline-containing chemotherapy (ANT group). HD-AraC was preferentially selected for core-binding factor AML patients (p = 0.008). The median cumulative anthracycline dose was 115.2 mg/m2 in the HD-AraC group and 318.7 mg/m2 in the ANT group (p < 0.0001). Cardiac events were observed in 18 (13.6%) patients during the follow-up period. The 3-year cumulative incidence of cardiac events was 9.1% in the HD-AraC group and 11.0% in the ANT group (p = 0.70). EFS at 3 years after allo-HSCT was 40.9% in the HD-AraC group and 39.6% in the ANT group (p = 0.51). In conclusion, incidence of cardiac events did not differ significantly between post-remission therapy regimens in AML patients who underwent allo-HSCT.

[Low psoas muscle index as independent poor prognostic factor for diffuse large B-cell lymphoma in elderly patients].

Sarcopenia is associated with poor clinical outcomes in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, the clinical significance and optimal assessment of sarcopenia remain unclear. We retrospectively evaluated the prognostic value of low skeletal muscle mass based on the psoas muscle index (PMI) in patients with DLBCL aged 70 years and older treated with R-CHOP therapy. We included 71 patients, including 27 classified under low PMI. There were no differences in baseline characteristics (body mass index, lactate dehydrogenase, performance status [PS], stage, revised-IPI, relative dose intensity) and overall response rate between the low and high PMI groups. The low PMI group had a significantly worse overall survival (OS, p=0.015), but not progression-free survival (PFS, p=0.252), compared with the high PMI group. On multivariate analysis, low PMI and PS were independent negative prognostic factors for OS. Subgroup analysis revealed that the low PS groups had significantly worse PFS regardless of the PMI status. The low PMI and low PS group had markedly poorer OS than all the other groups. However, the poor prognosis associated with low PS was overcome by a high PMI.

Dietary Olive Oil Intake Improves Running Endurance with Intramuscular Triacylglycerol Accumulation in Mice.

Olive oil is a functional food shown to have a variety of bioactive effects. Therefore, we expect it to be a novel functional food with an exercise-mimetic effect on skeletal muscles. This study aimed to investigate the effect of olive oil on the endurance capacity and muscle metabolism in mice. Mice fed a 7% (w/w) olive oil diet for eight weeks showed improved treadmill running endurance and increased intramuscular triacylglycerol (IMTG) accumulation in the gastrocnemius muscle compared to soybean oil diet-fed controls. The increase in running endurance with olive oil intake was independent of the muscle fiber type. To elucidate underlying the mechanism of elevated IMTG levels, we examined the expression levels of the genes related to lipid metabolism. We found that the expression of diacylglycerol O-acyltransferase1 (DGAT1) was significantly upregulated in the muscle of olive oil diet-fed mice. In addition, the olive oil diet-fed mice showed no metabolic impairment or differences in growth profiles compared to the controls. These results suggest that dietary olive oil intake affects muscle metabolism and muscle endurance by increasing energy accumulation.

Effect of dietary fish oil intake on ubiquitin ligase expression during muscle atrophy induced by sciatic nerve denervation in mice.

Dietary fish oil intake improves muscle atrophy in several atrophy models however the effect on denervation-induced muscle atrophy is not clear. Thus, the aim of this study was to investigate the effects of dietary fish oil intake on muscle atrophy and the expression of muscle atrophy markers induced by sciatic nerve denervation in mice. We performed histological and quantitative mRNA expression analysis of muscle atrophy markers in mice fed with fish oil with sciatic nerve denervation. Histological analysis indicated that dietary fish oil intake slightly prevented the decrease of muscle fiber diameter induced by denervation treatment. In addition, dietary fish oil intake suppressed the MuRF1 (tripartite motif-containing 63) expression up-regulated by denervation treatment, and this was due to decreased tumor necrosis factor-alpha (TNF-α) production in skeletal muscle. We concluded that dietary fish oil intake suppressed MuRF1 expression by decreasing TNF-α production during muscle atrophy induced by sciatic nerve denervation in mice.

Safety of avoiding systemic corticosteroid administration for grade II acute graft-versus-host disease limited to the skin.

We hypothesized that systemic corticosteroid administration would be safely avoided not only in grade I acute graft-versus-host disease (GVHD) but also in selected patients with grade II acute GVHD limited to the skin (grade IIs GVHD). We retrospectively evaluated risk factors for subsequent GVHD progression, defined as the involvement of other organs or progression to grade III to IV GVHD, in 50 patients with acute GVHD of grade IIs at its onset. Sixteen patients received systemic corticosteroid administration before GVHD progression. The cumulative incidence of GVHD progression at 28 days from the onset of grade IIs GVHD was 24%. Twenty-five patients did not require systemic corticosteroid administration throughout the entire episode of acute GVHD. Systemic corticosteroid administration before GVHD progression did not affect GVHD progression, chronic GVHD, or non-relapse mortality. Early onset (less than 26 days from transplantation) of grade IIs GVHD was identified as the only statistically significant risk factor for GVHD progression (hazard ratio 6.73, 95% confidence interval 1.5-31.1, P = 0.01). In conclusion, avoiding systemic corticosteroid administration for selected patients with grade IIs GVHD before GVHD progression did not compromise the transplantation outcomes. Patients with early-onset grade IIs GVHD were at high risk for GVHD progression.

Positive Cytotoxic Crossmatch Predicts Delayed Neutrophil Engraftment in Allogeneic Hematopoietic Cell Transplantation from HLA-Mismatched Related Donors.

Although a positive cytotoxic crossmatch (XM) has been reported to predict graft failure, mainly in solid organ transplantations, its significance in allogeneic hematopoietic cell transplantation (HCT) remains to be elucidated. We retrospectively assessed the impact of positive XM on neutrophil engraftment in 41 patients who underwent HCT with an HLA-mismatched related donor. XM was positive in 22 patients. Six of these 22 patients were also positive for anti-HLA antibody, whereas only 1 was positive for donor-specific anti-HLA antibody. The cumulative incidence of engraftment at day +28 was 89.5% in patients with negative XM versus 59.1% in those with positive XM (P = .08). In particular, positive B cell warm XM was significantly associated with a lower probability of engraftment at day +28 (46.7% versus 88.5%; P = .04). In a multivariate analysis, both positive XM and positive B cell warm XM were significantly associated with delayed engraftment (hazard ratio [HR], .46; P = .02 and HR, .41; P = .01, respectively). There was no significant difference in the achievement of engraftment between those with and without detection of anti-HLA antibodies. In conclusion, positive XM might be associated with a delayed neutrophil engraftment after HCT from HLA-mismatched related donors.

Acyclovir-resistant herpes simplex virus 1 infection early after allogeneic hematopoietic stem cell transplantation with T-cell depletion.

We previously reported that oral low-dose acyclovir (200 mg/day) for the prevention of herpes simplex virus (HSV) infections after allogenic hematopoietic stem cell transplantation (HSCT) is effective without the emergence of acyclovir-resistant HSV infections. However, HSV infections are of significant concern because the number of allogeneic HSCT with T-cell depletion, which is a risk factor of the emergence of drug-resistant HSV infections, has been increasing. We experienced a 25-year-old female who received allogenic HSCT from an unrelated donor with 1-antigen mismatch using anti-thymocyte globulin. Despite acyclovir prophylaxis (200 mg/day), she developed the right palatal ulcer that was positive for HSV-1 specific antigen by fluorescent antibody on day 20 and developed new hypoglossal and tongue ulcers on day 33. Replacement of acyclovir with foscarnet improved her ulcers. We isolated 2 acyclovir-resistant and foscarnet-sensitive strains from the right palatal and hypoglossal ulcers, which had the same frame shift mutation in the thymidine kinase genes. The rate of proliferation of the isolate from the hypoglossal ulcer was faster than that from the right palatal ulcer in the plaque reduction assay. HSV strains that acquired acyclovir-resistant mutations at the right palatal ulcer with larger plaque might spread to the hypoglossal ulcer as the secondary site of infection because of better growth property. Second-line antiviral agents should be considered when we suspect treatment failure of HSV infection, especially in HSCT with T-cell depletion. Further studies are required whether low-dose acyclovir prophylaxis leads to the emergence of virological resistance.

Fast-to-slow shift of muscle fiber-type composition by dietary apple polyphenols in rats: Impact of the low-dose supplementation.

Our previous studies demonstrated that an 8-week intake of 5% (w/w) apple polyphenol (APP) in the diet improves muscle endurance of young-adult rats. In order to identify a lower limit of the dietary contribution of APP to the effect, the experiments were designed for lower-dose supplementation (8-week feeding of 0.5% APP in AIN-93G diet) to 12-week-old male Sprague-Dawley rats. Results clearly showed that the 0.5% APP diet significantly up-regulates slower myosin-heavy-chain (MyHC) isoform ratios (IIx and IIa relative to total MyHC) and myoglobin expression in lower hind-limb muscles examined (P < 0.05). There was a trend to increased fatigue resistance detected from measurements of relative isometric plantar-flexion force torque generated by a stimulus train delivered to the tibial nerve (F(98, 1372) = 1.246, P = 0.0574). Importantly, there was no significant difference in the animal body-phenotypes or locomotor activity shown as total moving distance in light and dark periods. Therefore, the present study encourages the notion that even low APP-intake may increase the proportions of fatigue-resistant myofibers, and has promise as a strategy for modifying performance in human sports and improving function in age-related muscle atrophy.

Clinical characteristics and predictive factors for mortality in coryneform bacteria bloodstream infection in hematological patients.

BACKGROUND: We examined the clinical characteristics and predictive factors for mortality in coryneform bacteria bloodstream infection in hematological patients. METHODS: We searched for hematological patients who had positive blood cultures for coryneform bacteria at our center between April 2007 and January 2016. Patients with definite bloodstream infections were included. We started species identification in April 2014. RESULTS: Twenty of twenty-eight cases with a positive blood culture for coryneform bacteria were regarded as definite infections. Sixteen and two patients were allogeneic and autologous hematopoietic stem cell transplantation (HSCT) recipients, respectively. Corynebacterium striatum was identified in all nine of the cases tested and one patient was co-infected with Corynebacterium amycolatum. None of the patients died directly due to coryneform bacteria infection. The survival rates at 30, 60 and 180 days were 100%, 73.7% and 51.3%, respectively. Causes of mortality included progression of the underlying disease (n = 6), other infections (n = 4) and HSCT complications (n = 2). Mixed infection (hazard ratio (HR) 5.47, 95% confidence interval (CI) 1.30-23.0), renal impairment (HR 6.31, 95% CI 1.06-37.4) and absence of a central venous (CV) catheter at the onset (HR 6.39, 95% CI 1.04-39.45) were identified as predictive factors for mortality. CONCLUSION: Most of the coryneform bacteria bloodstream infections occurred in HSCT recipients. Contamination seemed to be less common when coryneform bacteria were detected in blood in hematological patients. Although coryneform bacteria bloodstream infection seemed to mostly be manageable, the prognosis was not desirable, particularly in patients with mixed infection, renal impairment and absence of a CV catheter.

Development tuberculous meningitis during chemotherapy for CD5-positive diffuse large B-cell lymphoma.

The patient was a 62-year-old woman with CD5(+) diffuse large B-cell lymphoma. Treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) was started. On the eleventh day of the third cycle, headache and low grade fever developed. Her consciousness gradually deteriorated. Seven days after symptom onset, she was brought to the emergency department of our hospital. Cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 25/µl, and a protein level of 188 mg/dl. Antibacterial and antiviral agents were administered based on a diagnosis of acute meningitis. She showed no improvement. We performed another lumbar puncture and intrathecal chemotherapy, a combination of methotrexate and dexamethasone, was administered because we suspected central nervous system involvement of lymphoma. She showed transient improvement. On day 12, we started the R-MPV regimen (rituximab, methotrexate, procarbazine, and vincristine). However, fever and disturbance of consciousness persisted. On day 20, we empirically started anti-tuberculosis treatment. Four days later, tubercle bacilli were confirmed by CSF culture after a 23-day incubation. We ultimately confirmed a diagnosis of tuberculous meningitis. Impaired cellular immunity in lymphoma patients increases the risk of tuberculosis. It is important to consider tuberculous meningitis in the differential diagnosis of a lymphoma patient presenting with meningitis.

Risk Factors and Impact of Secondary Failure of Platelet Recovery After Allogeneic Stem Cell Transplantation.

Secondary failure of platelet recovery (SFPR), a late decrease in the platelet count after primary platelet recovery that is not due to relapse or graft rejection, occasionally occurs after allogeneic hematopoietic stem cell transplantation (HSCT). The risk factors and impact of SFPR on transplantation outcomes are not well known in the clinical setting. Therefore, we retrospectively evaluated 184 adult patients who underwent their first allogeneic HSCT and achieved primary platelet recovery. The cumulative incidence of SFPR, defined as a decrease in the platelet count to below 20,000/µL for more than 7 days, was 12.2% at 3 years, with a median onset of 81 days (range, 39 to 729) after HSCT. Among patients who developed SFPR (n = 23), 19 (82.6%) showed recovery to a sustained platelet count of more than 20,000/µL without transfusion support, and the median duration of SFPR was 23 days (range, 7 to 1048 days). A multivariate analysis showed that in vivo T cell depletion (hazard ratio [HR], 6.92; 95% confidence interval [CI], 2.31 to 20.7; P < .001), grades II to IV acute graft-versus-host disease (HR, 3.99; 95% CI, 1.52 to 10.5; P = .005), and the use of ganciclovir or valganciclovir (HR, 2.86; 95% CI, 1.05 to 7.77; P = .039) were associated with an increased risk for SFPR. The occurrence of SFPR as a time-dependent covariate was significantly associated with inferior overall survival (HR, 2.29; 95% CI, 1.18 to 4.46; P = .015) in a multivariate analysis. These findings may help to improve the management and treatment strategy for SFPR.

Improvement of Endurance Based on Muscle Fiber-Type Composition by Treatment with Dietary Apple Polyphenols in Rats.

A recent study demonstrated a positive effect of apple polyphenol (APP) intake on muscle endurance of young-adult animals. While an enhancement of lipid metabolism may be responsible, in part, for the improvement, the contributing mechanisms still need clarification. Here we show that an 8-week intake of 5% (w/w) APP in the diet, up-regulates two features related to fiber type: the ratio of myosin heavy chain (MyHC) type IIx/IIb and myoglobin protein expression in plantaris muscle of 9-week-old male Fischer F344 rats compared to pair-fed controls (P < 0.05). Results were demonstrated by our SDS-PAGE system specialized for MyHC isoform separation and western blotting of whole muscles. Animal-growth profiles (food intake, body-weight gain, and internal-organ weights) did not differ between the control and 5% APP-fed animals (n = 9/group). Findings may account for the increase in fatigue resistance of lower hind limb muscles, as evidenced by a slower decline in the maximum isometric planter-flexion torque generated by a 100-s train of electrical stimulation of the tibial nerve. Additionally, the fatigue resistance was lower after 8 weeks of a 0.5% APP diet than after 5% APP, supporting an APP-dose dependency of the shift in fiber-type composition. Therefore, the present study highlights a promising contribution of dietary APP intake to increasing endurance based on fiber-type composition in rat muscle. Results may help in developing a novel strategy for application in animal sciences, and human sports and age-related health sciences.

Bortezomib plus melphalan and prednisone (VMP regimen) as the initial treatment for IgE multiple myeloma: a case study.

Patients with IgE multiple myeloma have poor prognosis. Due to the rarity of this condition, no standard treatment has been developed. As the VMP regimen (bortezomib plus melphalan and prednisone) has been reported to be highly effective in the treatment of other types of myeloma, we treated a patient with newly diagnosed IgE myeloma using the VMP regimen. Her myeloma responded well to VMP regimen. The results of this case report thus suggest that physicians may consider VMP regimen for use as the initial treatment for IgE myeloma.