Differences in serum and plasma levels of microRNAs and their time-course changes after blood collection.

Background: Serum and plasma are used for measurements of microRNAs (miRNAs) as biomarkers of various diseases. However, no consistent findings have been obtained regarding differences in serum and plasma levels of miRNAs. The purpose of this study was to clarify differences in serum and plasma levels of total miRNAs and their time-course changes after blood collection. Methods: Venous blood was collected from healthy men, and samples were prepared at the time points of 0, 15, 30, 60 and 180 min after blood collection for plasma and after clot formation for serum. Levels of total miRNAs were analyzed by the hybridization method using the 3D-Gene miRNA Oligo chip. Results: About one third of 2632 miRNAs tested showed levels high enough for comparison of serum and plasma levels and for investigation of their time-course changes. Levels of 299 miRNAs at time 0 were significantly different in serum and plasma. Levels of representative platelet-derived miRNAs including miR-185-5p, -22-3p and -320b were significantly higher in plasma than in serum, while levels of representative erythrocyte-derived miRNAs including miR-451a, -486-5p and -92a-3p were not significantly different in serum and plasma. Plasma levels of 173 miRNAs and 6 miRNAs showed significant decreasing and increasing tendencies, respectively, while there were no miRNAs in serum that showed significant time-course changes. Conclusion: The results suggest that careful attention should be paid when comparing serum and plasma levels of miRNAs and that plasma samples should be prepared early after blood collection.

Short- versus long-term Dual AntiPlatelet Therapy for Stent-Assisted treatment of CErebral aneurysm (DAPTS ACE): a multicenter, open-label, randomized clinical trial.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after stent-assisted coil embolization (SACE) for cerebral aneurysm remains uncertain. This randomized trial of short- versus long-term Dual AntiPlatelet Therapy for Stent-Assisted treatment of CErebral aneurysm (DAPTS ACE) aimed to clarify whether long-term DAPT can reduce the occurrence of ischemic stroke in patients with cerebral aneurysms treated by SACE compared with short-term DAPT. METHODS: Patients treated for cerebral aneurysm with SACE were enrolled from 17 hospitals in Japan. Patients were enrolled within 30 days after SACE and assigned in a 1:1 ratio to receive long-term (12 months) or short-term (3 months) DAPT with aspirin and clopidogrel. Randomization was performed centrally through a web-based system. The primary outcome was the time to ischemic stroke event during 3 to 12 months after SACE. This trial was registered with the Japan Registry of Clinical Trials (jRCTs051180141). RESULTS: A total of 142 patients were recruited from November 4, 2016 to January 7, 2019. Among them, 65 and 68 patients assigned to the long- and short-term DAPT groups, respectively, were included in the full analysis set. Ischemic stroke occurred in no patients in the long-term DAPT group and in one patient in the short-term DAPT group. The incidence rate did not differ between the groups (0.0 vs 2.1/100 person-years; log rank test, P=0.33). CONCLUSIONS: In this multicenter randomized controlled trial, there was not a statistically significant difference in the rate of ischemic strokes between long- and short-term DAPT.

Nocturnal Hypertension and Left Ventricular Diastolic Dysfunction in Patients With Diabetes With the Absence of Heart Failure: Prospective Cohort HSCAA Study.

BACKGROUND: Diabetes is an important risk factor for heart failure (HF) and is associated with left ventricular (LV) diastolic dysfunction. However, diabetic comorbid conditions, such as nocturnal hypertension, as predictors of diastolic dysfunction are not known in the absence of an HF period. The present study was conducted as the longitudinal examination of the predictive value of nocturnal hypertension profiles on the progression of LV diastolic dysfunction in patients with and without diabetes without HF. METHODS: The subjects (154 diabetes and 268 nondiabetes) in the absence of HF were followed for 36.8±18.2 months. The relationships among the patterns of nocturnal hypertension and the outcome of LV diastolic dysfunction, defined as an increase in E/e'>14, were investigated in the patients with and without diabetes. RESULTS: The interaction effect of the diabetes status and the patterns of nocturnal hypertension on the hazard rate of the occurrence of E/e'>14 was statistically significant (P=0.017). Kaplan-Meier analysis results revealed that patients with diabetes with nondipper (P=0.021 versus dipper) and riser (P=0.006 versus dipper) had a greater risk for a diastolic dysfunction event. Furthermore, multivariable Cox proportional hazards analysis revealed that nondipper (hazard ratio, 4.56 [95% CI, 1.49-13.96]; P=0.007) and riser (hazard ratio, 3.89 [95% CI, 1.31-11.57]; P=0.014) patterns were associated with elevated risk of the outcome of LV diastolic dysfunction. In contrast, no similar significant associations were found in patients without diabetes. CONCLUSIONS: During the absence of HF periods, nocturnal hypertension is an important predictor for the progression of LV diastolic dysfunction in patients with diabetes.

Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa.

Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.

Resection of positive tissue on methionine-PET is associated with improved survival in glioblastomas.

BACKGROUND AND PURPOSE: The volume of excised tumor in contrast-enhanced areas evaluated via magnetic resonance imaging is known to have a strong influence on the survival of patients with glioblastoma (GBM). In this study, we investigated the effect of tumor resection on the survival of patients with GBM in the 11 C-methionine (MET) accumulation area using MET-positron emission tomography (MET-PET). METHODS: A total of 26 patients (median age, 69 years; 15 males) who had undergone tumor resection and MET-PET before and after surgery, after being newly diagnosed with GBM, were included in the study. MET-PET before and after tumor resection were compared. The association between the decrease in the maximum standardized uptake value (SUV) of the tumor divided by the normal cortical mean SUV (%; ΔT/N), the MET extent of resection (MET-EOR) from the % reduction in the MET accumulation area (%), and residual MET accumulation area (in cm3 ; MET-residual tumor volume [RTV]), as well as the survival time of patients with GBM, were evaluated via univariate analysis. RESULTS: ΔT/N were positively associated with survival (hazard ratio [HR], 0.98 [95% confidence interval (CI), 0.97-0.99], p = .02). MET-RTV revealed a negative association with survival (HR, 1.02 [95% CI, 1.01-1.04], p = .04). Additionally, MET-EOR showed a strong trend with survival (HR, 0.99 [95% CI, 0.97-1.01], p = .06). CONCLUSIONS: Surgical resection of MET-accumulated areas in GBM significantly prolongs the survival of patients with GBM. However, a prospective large-scale multicenter study is needed to confirm our findings.

A randomized phase III study of docetaxel alone versus docetaxel plus S-1 in patients with previously treated non-small cell lung cancer: JMTO LC09-01.

BACKGROUND: This study evaluated the efficacy and safety of the combination chemotherapy of docetaxel plus S-1 in patients with previously treated non-small cell lung cancer (NSCLC) compared to docetaxel alone. METHODS: Patients with previously treated NSCLC were randomly assigned to docetaxel alone (arm A) or a combination of docetaxel and S-1 (arm B) for a maximum of four cycles. The primary endpoint was overall survival (OS). RESULTS: The study was terminated early because of poor accrual. The number of patients evaluated were 74 and 77 in arm A and arm B, respectively. The median OS was 9.8 months (95% confidence interval [CI]: 6.8-15.2) and 12.3 months (95% CI: 9.2-14.5) in arms A and B, respectively. In arms A and B, the median progression-free survival was 3.5 months (95% CI: 2.7-4.0) and 4.1 months (95% CI: 3.2-4.7), respectively. No statistically significant difference was observed in OS (hazard ratio [HR]: 0.984, 95% CI: 0.682-1.419, p = 0.4569) or progression-free survival (HR: 0.823, 95% CI: 0.528-1.282, p = 0.0953). The major toxicity was myelosuppression. The incidence of grade 3 or more neutropenia was higher in arm A than in arm B (44.6% vs. 35.1%). However, the incidence of grade 3 or more febrile neutropenia and infection with neutropenia (12.2% vs. 22.1%) was more frequently observed in arm B. CONCLUSIONS: The prematurely terminated study did not show the benefit of two cytotoxic agents over single-agent therapy for previously treated NSCLC patients.

Hematometabolic Index as a New Discriminator of Cardiometabolic Risk in Middle-Aged Men with Polycythemia and High Leukocyte Count in Peripheral Blood.

Background: Both polycythemia and high leukocyte count are associated with the risk of cardiovascular disease. However, it remains to be determined whether polycythemia and high leukocyte count show synergistic increasing effects on cardiometabolic risk. Methods: Cardiometabolic risk was evaluated by cardiometabolic index (CMI) and metabolic syndrome in a cohort of middle-aged men (n = 11,140) who underwent annual health check-up examinations. The subjects were divided into three tertile groups by hemoglobin concentration or leukocyte count in peripheral blood, and their relations with CMI and metabolic syndrome were investigated. A new index, named hematometabolic index (HMI), was defined as the product of hemoglobin concentration (g/dL)-minus-13.0 and leukocyte count (/µL)-minus-3000. Results: When the subjects were further classified by tertiles for hemoglobin concentration and leukocyte count into nine groups, the odds ratios for high CMI and metabolic syndrome of the group categorized in the highest (third) tertiles for both hemoglobin concentration and leukocyte count versus the group of the lowest (first) tertiles for both of them were highest among the nine groups. In receiver-operating characteristic (ROC) analysis for relationships of HMI with high CMI and metabolic syndrome, areas under the ROC curves (AUCs) were significantly larger than the reference level and tended to be smaller with an increase in age. In subjects from 30 to 39 years of age, the AUC for the relationship between HMI and metabolic syndrome was 0.707 (0.663-0.751) and the cutoff of HMI was 9850. Conclusions: HMI, reflecting hemoglobin concentration and leukocyte count, is thought to be a possible marker for discriminating cardiometabolic risk.

Usefulness of the placebo lead-in design for clinical trials with binary outcomes.

BACKGROUND: In placebo-controlled clinical trials to develop new drugs for the treatment of psychiatric or neurological disorders, a high and sometimes greater-than-expected placebo response makes it difficult to show the superiority of an investigational drug over a corresponding placebo. To avoid such difficulty, a placebo lead-in design has been presented, but its usefulness has been open to discussion. Although the statistical properties of the placebo lead-in design are investigated in the context of continuous outcomes, whether these properties can be generalized for binary or ordinal cases remains unclear. METHODS: We investigate whether the placebo lead-in design is useful in clinical trials with binary outcomes through mathematical formulae and a numerical investigation. Specifically, we compare the proportion of placebo responders, the drug-placebo difference, and the effect size between two populations: one enriched for placebo nonresponders and the other comprising the all-comers. RESULTS: Under positive correlation of the data between the lead-in stage and the randomized stage for both treatment groups, we mathematically show that the proportion of responders in the population enriched for placebo nonresponders is less than that in the all-comers population, and whether the placebo lead-in design increases the drug-placebo difference depends on the variances of outcomes in both treatment groups as well as the correlations of the outcomes between two stages. Further, through a numerical investigation, we show that whether the placebo lead-in design increases the effect size strongly depends on the magnitude of the correlations and their difference. CONCLUSION: If the correlation of the placebo-placebo group is much higher than that of the placebo-drug group, the placebo lead-in design is advantageous in most cases but has an impact on an estimand in placebo nonresponders. Therefore, we do not recommend using the placebo lead-in design for clinical trials with binary outcomes.

Peritransplantation Glucocorticoid Haploidentical Stem Cell Transplantation Is a Promising Strategy for AML Patients With High Leukemic Burden: Comparison With Transplantations Using Other Donor Types.

Using a murine haploidentical bone marrow transplantation (BMT) model, we recently showed that peritransplantation administration of glucocorticoid (GC) redistributed donor T cells from the gastrointestinal tract to bone marrow, which resulted in a significant reduction of graft-versus-host disease (GVHD) while promoting graft-versus-leukemia effects. Furthermore, in a retrospective clinical study of patients with acute myelogenous leukemia (AML) undergoing transplantation in non-remission, we also showed that haploidentical stem cell transplantation (haplo-SCT) using peritransplantation GC administration led to a significantly lower relapse rate and better overall survival rate compared with haplo-SCT using post-transplantation cyclophosphamide. In the present study, using the same dataset of patients undergoing GC haplo-SCT, we retrospectively compared with patients with AML undergoing transplantation in non-remission using 3 other donor types: matched sibling donor (MSD), matched unrelated donor (MUD), and umbilical cord blood (UCB). For GC haplo-SCT, 44 patients underwent peripheral blood stem cell transplantation in a single center (Hyogo College of Medicine), with the conditioning treatment consisting of fludarabine, melphalan, anti-thymocyte globulin (2.5 mg/kg), and TBI 3 Gy. Methylprednisolone was given from the start of conditioning treatment, and the GVHD prophylaxis consisted of tacrolimus and methylprednisolone (1 mg/kg). The transplantation outcomes were compared with data of 1889 patients undergoing MSD-SCT (n = 449), MUD-BMT (n = 493), or UCB transplantation (UCBT) (n = 947) in non-CR, which were extracted from the Transplant Registry Unified Management Program data, the largest data registry in Japan. For donor engraftment, significantly faster neutrophil and platelet engraftment was achieved with GC haplo-SCT compared with allo-SCT using the 3 other donor types. Neutrophil engraftment was achieved at a median of 10 days for GC haplo-SCT, and 20 days for MSD-, MUD-, and UCB-transplants. Platelet engraftment was achieved at a median of 19.5 days for GC haplo-SCT, 42 days for MSD-SCT and MUD-BMT, and 43 days for UCBT, respectively. The incidence of grade II-IV acute GVHD was lower after allo-SCTs using MSD (hazard ratio [HR] = 0.465, P = .003), MUD (HR = 0.524, P = .010), and UCB (HR = 0.647, P = .067) compared with GC haplo-SCT. There was no significant difference in the incidence of chronic GVHD between GC haplo-SCT and allo-SCT using the other 3 donor types. Regarding relapse, GC haplo-SCT was associated with a significantly lower risk compared with MSD-SCT (P < .001) or MUD-BMT (P = .004). GC haplo-SCT tended to have a lower risk compared with UCBT (P = .063). Especially, all the 43 evaluable GC haplo-SCT recipients achieved CR after transplantation, whereas 23.9%, 22.8%, and 27.0% of patients who underwent MSD-SCT, MUD-BMT, and UCBT could not achieve CR after transplantation, respectively. Regarding non-relapse mortality, GC haplo-SCT was associated with a significantly higher risk compared with MUD-BMT (P = .014), and tended to have a higher risk compared with MSD-SCT (P = .061). There was no significant difference between GC haplo-SCT and UCBT (P = .600). Allo-SCTs using MSD (HR = 2.548, P < .001), MUD (HR = 2.134, P = .005), and UCB (HR = 2.376, P = .001) lead to significantly higher overall mortality compared with GC haplo-SCT; the adjusted overall survival at 3 years was 19.8% for MSD, 26.1% for MUD, 28.0% for UCB, and 65.1% for GC haplo. Thus GC haplo-SCT is a promising treatment option for patients with AML with a high leukemic burden.

Novel nomogram developed for determining suitability of metastatic castration-resistant prostate cancer patients to receive maximum benefit from radium-223 dichloride treatment-Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial.

PURPOSE: To develop a novel nomogram for determining radium-223 dichloride (Ra-223) treatment suitability for metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: This Japanese Ra-223 Therapy in Prostate Cancer using Bone Scan Index (J-RAP-BSI) Trial was a retrospective multicenter investigation enrolled 258 mCRPC patients in Japan with Ra-223 treatment between June 2016 and August 2020, with bone scintigraphy findings before treatment, clinical data, and survival outcome available. A nomogram was constructed using prognostic factors for overall survival (OS) based on a least absolute shrinkage and selection operator Cox regression model. A sub-analysis was also conducted for patients meeting European Medicines Agency (EMA) guidelines. RESULTS: Within a median of 17.4 months after initial Ra-223 treatment, 124 patients (48.1%) died from prostate cancer. Predictive factors included (1) sum of prior treatment history (score 0, never prior novel androgen receptor-targeted agents (ARTA) therapy, never prior taxane-based chemotherapy, and ever prior bisphosphonate/denosumab treatment), (2) Eastern Cooperative Oncology Group (ECOG) performance status, (3) prostate-specific antigen doubling time (PSADT), (4) hemoglobin, (5) lactate dehydrogenase (LDH), and (6) alkaline phosphatase (ALP) levels, and (7) automated bone scan index (aBSI) value based on bone scintigraphy. The nomogram using those factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.748 and 0.734, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.771, 0.818, and 0.771, respectively. In 227 patients meeting EMA recommendation, the nomogram with seven factors showed good discrimination, with apparent and optimism-corrected Harrell's concordance index values of 0.722 and 0.704, respectively. Time-dependent area under the curve values at 1, 2, and 3 years were 0.747, 0.790, and 0.759, respectively. CONCLUSION: This novel nomogram including aBSI to select mCRPC patients to receive Ra-223 with significantly prolonged OS possibility was found suitable for assisting therapeutic decision-making, regardless of EMA recommendation.

Clinical Efficacy and Safety of Nivolumab in Malignant Non-Pleural Mesothelioma: A Multicenter, Open-Label, Single-Arm, Japanese Phase II Trial (Viola) Protocol.

BACKGROUND: There is no authorized treatment for malignant non-pleural mesothelioma (MNPM) worldwide. In contrast to malignant pleural mesothelioma, MNPM has not been investigated, and no treatment has been established due to its rarity. OBJECTIVES: This multicenter, open-label, single-arm, Japanese phase II trial aims at evaluating the efficacy and safety of nivolumab, an immune checkpoint inhibitor, in advanced or metastatic MNPM treatment. METHODS: This phase II trial commenced in October 2020. Twenty-three patients with advanced or metastatic MNPM who meet the inclusion and exclusion criteria were enrolled from five institutions within 2 years. Regardless of prior therapy, 240 mg of nivolumab will be administered intravenously to MNPM patients every 2 weeks to investigate its efficacy and safety until disease progression or unacceptable toxicities are detected, or the patient's condition meets the withdrawal criteria. RESULTS: The primary endpoint is the objective response rate by central assessment following the Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints include disease control rate, overall survival, progression-free survival, adverse events, and treatment-related adverse events. CONCLUSIONS: This is the first prospective investigator-initiated trial to evaluate the effect of nivolumab monotherapy for MNPM.

Attenuation by habitual alcohol drinking of the associations of obesity with blood pressure and pulse pressure.

BACKGROUND: Obesity and alcohol drinking are known to be risk factors for hypertension. However, it remains to be determined whether alcohol affects the relationships of obesity with blood pressure and pulse pressure. METHODS: The participants in this study were 29 171 men who had received annual health checkups. Relationships of BMI with blood pressure and pulse pressure were investigated in four subject groups divided by average daily alcohol consumption (grams of ethanol/day), non-, light (<22), moderate (≥22 and <44) and heavy (≥44) drinkers. RESULTS: BMI was significantly correlated with SBP and DBP levels both in nondrinkers and drinkers. The strength of the correlations was significantly weaker in drinkers than in nondrinkers. Odds ratios for hypertension in subjects with vs. subjects without obesity tended to be lower with an increase in alcohol intake (odds ratios with 95% confidence intervals: 4.09 (3.69-4.52) in nondrinkers; 3.11 (2.62-3.68) in light drinkers; 2.87 (2.61-3.16) in moderate drinkers; 2.81 (2.49-3.18) in heavy drinkers). Pulse pressure was weakly but significantly associated with BMI and obesity, and these associations were significantly weaker in heavy drinkers than in nondrinkers. There were significant odds ratios for hypertension and high pulse pressure of the interaction term between obesity and alcohol drinking. CONCLUSION: The associations of BMI with blood pressure and pulse pressure and the associations of obesity with hypertension and high pulse pressure were weaker in drinkers than in nondrinkers. Thus, alcohol drinking attenuates the associations of obesity with hypertension and high pulse pressure.

Sleep Apnea and Physical Movement During Sleep, But Not Sleep Duration, Are Independently Associated With Progression of Left Ventricular Diastolic Dysfunction: Prospective Hyogo Sleep Cardio-Autonomic Atherosclerosis Cohort Study.

Background Although co-occurrence of sleep disorder with heart failure is known, it is not clear whether that condition is a cause or consequence of heart failure. The present study was conducted as a longitudinal examination of the predictive value of sleep parameters on progression of left ventricular diastolic dysfunction. Methods and Results Four-hundred fifty-two subjects were followed for a mean of 34.7 months. An outcome of diastolic dysfunction was defined as increase in early inflow velocity/early diastolic tissue velocity >14. Sleep apnea-hypopnea index, minimal oxygen saturation, sleep duration, and activity index (physical movement during sleep time, a potential parameter of poor sleep quality) were determined using apnomonitor and actigraphy findings, while heart rate variability was measured with a 24-hour active tracer device. Sixty-six of the patients developed diastolic dysfunction during the follow-up period, with a median time of 25 months. Kaplan-Meier analysis results revealed that those with sleep apnea classified as moderate (apnea-hypopnea index 15 to <30, P<0.01 versus none) or severe (apnea-hypopnea index ≥30, P<0.01 versus none), and with a high activity index (Q3 or Q4, P<0.01 versus Q1), but not short sleep duration (P=0.27) had a significantly greater risk for a diastolic dysfunction event. Results of multivariable Cox proportional hazards regression analysis indicated that moderate to severe sleep apnea after a follow-up period of 3 years (hazard ratio [HR], 9.26 [95% CI, 1.89-45.26], P<0.01) and high activity index (HR, 1.85 [95% CI, 1.01-3.39], P=0.04) were significantly and independently associated with future diastolic dysfunction. Moreover, significant association of high activity index with the outcome was not confounded by either minimal oxygen saturation or heart rate variability. Conclusions Sleep apnea and physical movement during sleep, but not sleep duration and autonomic nervous dysfunction, are independent important predictors for progression of left ventricular diastolic dysfunction.

Regulatory issues and the potential use of Bayesian approaches for early drug approval systems in Japan.

Bayesian methods quantify and interpret the therapeutic effects of investigational drugs based on probability statements of the posterior distribution. However, the basic principle underlying the use of Bayesian methods in registration trials for new drug applications in Japan has not been adequately discussed. Motivated by the two drug approval systems for early approval recently enacted in Japan, we present our perspectives on the application of the Bayesian approach in registration trials in Japan. These are based on discussions among academic, industry, and regulatory experts at invited workshops. Based on the aforementioned early approval systems, we discuss putative common regulatory issues related to the use of the Bayesian approach and introduce instances of clinical trials in which the Bayesian approach is expected to be used. This article provides a well-defined premise for the discussion between industry and regulatory agencies on the use of Bayesian approaches for early drug approval in Japan.

Intratumor hemodynamics using contrast-enhanced MRI in intra-arterial chemotherapy for head and neck cancer.

OBJECTIVE: The objectives of the study were to estimate the perfusion of tumors by drugs used in intra-arterial chemotherapy for head and neck cancer with magnetic resonance imaging and to establish the factors involved in determining the optimal dose. STUDY DESIGN: Contrast agent was administered intra-arterially into either the lingual or maxillary artery in 43 patients. Triple-phase continuous fast spin echo magnetic resonance imaging was performed. Changes in blood water longitudinal relaxation rate (⊿R1) were measured in relation to imaging phase, type of artery, measurement site, and tumor size. RESULTS: ⊿R1 was significantly higher at the tumor margin than at the center for both arteries, except in the first phase for the lingual artery. ⊿R1 was greatest in the third phase for the lingual artery and in the second phase for the maxillary artery. For both arteries, as the tumor size increased, there was a significant decrease in ⊿R1 at the center of the tumor compared with the margin. CONCLUSIONS: The factors associated with ⊿R1 were imaging phase, type of artery, measurement site, and tumor size. When determining a drug's optimal dose, the type of artery and tumor size must be taken into consideration.

Heterogeneous reduction in regional wall stress after aortic valve replacement for aortic regurgitation: a distinct feature from aortic stenosis.

Geometric changes caused by volume reduction early after aortic valve replacement (AVR) for aortic regurgitation (AR) may not be uniform, resulting in varying regional end-systolic wall stress (ESS). This study compared changes in regional ESS between AR and aortic stenosis (AS) patients in the early phase following AVR. Computer-tomographic left ventricular (LV) angiography was performed for 10 patients with AR and 13 with AS before and three months after AVR. Regional ESS at the base, middle, and apex levels, each subdivided into four segments, was calculated based on the Janz equation: ESS = end-systolic LV pressure × local cross-sectional area of LV cavity/that of LV wall. Following AVR, median LV end-diastolic volume index fell from 106 to 69 ml/m2 (P = 0.001) in AR and 60 to 46 ml/m2 (P = 0.01) in AS patients. Global ESS also declined in both (AR, 186 to 124 kdyne/cm2, P = 0.02; AS, 187 to 108 kdyne/cm2, P < 0.001, respectively). Regional ESS was reduced in all segments in AS patients, accompanied by left ventricular ejection fraction (LVEF) improvement (71-80%, P = 0.02). In contrast, regional ESS in AR patients was heterogeneously reduced, as regional ESS fell significantly in the antero-septal wall but was unchanged in the infero-lateral wall, and LVEF remained unchanged (65 to 62%, P = 0.42). In the early postoperative phase after AVR, the loading condition of the regional LV wall in AR patients was characterized by a heterogeneous reduction in regional ESS in contrast to a uniform decline in AS patients.

Neoadjuvant pemetrexed plus cisplatin followed by pleurectomy for malignant pleural mesothelioma.

PURPOSE: Despite becoming the preferred surgical technique for malignant pleural mesothelioma, pleurectomy/decortication has received few prospective clinical trials. Therefore, the Japan Mesothelioma Interest Group conducted a prospective multi-institutional study to evaluate the feasibility of neoadjuvant chemotherapy followed by pleurectomy/decortication. METHODS: Patients with histologically confirmed, resectable malignant pleural mesothelioma underwent neoadjuvant chemotherapy comprising pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 for 3 cycles, followed by pleurectomy/decortication. The primary end point was macroscopic complete resection rate regardless of the surgical technique used. RESULTS: Among the 24 patients enrolled, 20 received neoadjuvant chemotherapy and 18 proceeded to surgery, all of whom achieved macroscopic complete resection. Pleurectomy/decortication was performed in 15 patients. The trial satisfied the primary end point, with a macroscopic complete resection rate of 90% (18/20, 95% confidence interval, 68.3-98.8). No treatment-related 30- and 90-day mortality occurred. The overall survival after 1 and 2 years and median overall survival after registration were 95.0% (95% confidence interval, 69.5-99.3), 70.0% (95% confidence interval, 45.1-85.3), and 3.45 years (95% confidence interval, 1.64 to not available), respectively. The cumulative incidence of progression after 1 and 2 years and median time to progression were 33.3% (95% confidence interval, 17.3-64.1), 61.1% (95% confidence interval, 42.3-88.3), and 1.71 years (95% confidence interval, 1.00-2.99), respectively. The best postoperative value for forced expiratory volume was 78.0% of preoperative values. CONCLUSIONS: Neoadjuvant chemotherapy followed by pleurectomy/decortication was feasible with acceptable survival and mortality/morbidity. Postoperative pulmonary function was approximately 80% of the preoperative pulmonary function.

Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT.

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that glucocorticoid administration from days -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%-47%) with high overall survival at 3 years (58%; 95% CI, 38%-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

Associations of Blood Urate Level with Glycemic Status and Other Cardiometabolic Risk Factors in Middle-Aged Women.

Background: Hyperuricemia is a risk factor of cardiovascular disease. It remains to be elucidated how blood urate level is associated with hyperglycemia in women. Methods: The participants were 4612 middle-aged Japanese female workers. They were divided into four quartile groups by serum urate level, and cardiovascular risk factors were compared in the quartile groups. Results: With an increase of the quartile for urate, the means of waist-to-height ratio, systolic and diastolic blood pressure, log-transformed triglycerides, low-density lipoprotein (LDL) cholesterol, and cardiometabolic index (CMI) tended to be higher and high-density lipoprotein (HDL) cholesterol tended to be lower. Hemoglobin A1c was significantly higher in the 4th quartile for urate than in the 1st quartile, but this difference was not found when body mass index (BMI) was adjusted. The odds ratios versus the 1st quartile for high waist-to-height ratio, hypertension, hypertriglyceridemia, hypo-HDL cholesterolemia, hyper-LDL cholesterolemia, high CMI, and diabetes tended to be higher with an increase of the quartile. The odds ratios of the 4th versus 1st quartiles for these abnormalities except for high waist-to-height ratio and diabetes were significantly higher than the reference level even with adjustment for BMI. Hemoglobin A1c showed a weak but significant positive correlation with urate in analysis with adjustment for BMI. Conclusion: Blood urate was positively associated with adiposity, blood pressure, triglycerides, LDL cholesterol, and glycemic status and was inversely associated with HDL cholesterol in middle-aged women. The associations of urate with blood pressure, blood lipids, and glycemic status remained independent of adiposity, although being confounded by adiposity.

Ethnic Differences in Serum Levels of microRNAs Potentially Regulating Alcohol Dehydrogenase 1B and Aldehyde Dehydrogenase 2.

Ethnic difference is known in genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B), which cause Asian flushing by blood vessel dilation due to accumulation of acetaldehyde. We investigated ethnic differences in microRNAs (miRNAs) related to ALDH2 and ADH1B. miRNA levels in serum were totally analyzed by using miRNA oligo chip arrays and compared in Austrian and Japanese middle-aged men. There were no ALDH2- and ADH1B-related miRNAs that had previously been reported in humans and that showed significantly different serum levels between Austrian and Japanese men. With the use of miRNA prediction tools, we identified four and five miRNAs that were predicted to target ALDH2 and ADH1B, respectively, and they had expression levels high enough for comparison. Among the ADH1B-related miRNAs, miR-150-3p, -3127-5p and -4314 were significantly higher and miR-3151-5p was significantly lower in Austrian compared with Japanese men, while no significant difference was found for miR-449b-3p. miR-150-3p and miR-4314 showed relatively high fold changes (1.5 or higher). The levels of ALDH2-related miRNAs (miR-30d-5p, -6127, -6130 and -6133) were not significantly different between the countries. miR-150-3p and miR-4314 are candidates of miRNAs that may be involved in the ethnic difference in sensitivity to alcohol through modifying the expression of ADH1B.