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.

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.

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.

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.

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.

Bilateral Internal Thoracic Artery Grafting Improves Survival for Severe Left Ventricular Dysfunction and Diabetes.

BACKGROUND: In patients with severe left ventricular (LV) dysfunction requiring coronary artery bypass grafting (CABG), the association between diabetic status and outcomes after surgery, as well as with survival benefit following bilateral internal thoracic artery (ITA) grafting, remain largely unknown.Methods and Results:Patients (n=188; mean [±SD] age 67±9 years) with LV ejection fraction ≤40% who underwent isolated initial CABG were classified into non-diabetic (n=64), non-insulin-dependent diabetic (NIDM; n=74), and insulin-dependent diabetic (IDM; n=50) groups. During follow-up (mean [±SD] 68±47 months), the 5-year survival rate was 84% and 65% among non-diabetic and diabetic patients, respectively (P=0.034). After adjusting for all covariates, both NIDM and IDM were associated with increased mortality, with hazard ratios (HRs) of 1.9 (95% confidence interval [CI] 1.0-3.7; P=0.049) and 2.4 (95% CI 1.2-4.8; P=0.016), respectively. Among non-diabetic patients, there was no difference in the 5-year survival rate between single and bilateral ITA grafting (86% vs. 80%, respectively; P=0.95), whereas bilateral ITA grafting increased survival among diabetic patients (57% vs. 81%; P=0.004). Multivariate analysis revealed that bilateral ITA was significantly associated with a decreased risk of mortality (HR 0.3; 95% CI 0.1-0.8; P=0.024). CONCLUSIONS: NIDM and IDM were significantly associated with worse long-term clinical outcome after CABG for severe LV dysfunction. Bilateral ITA grafting has the potential to improve survival in diabetic patients with severe LV dysfunction.

Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration.

We assessed the feasibility of transplanting a sheet of retinal pigment epithelial (RPE) cells differentiated from induced pluripotent stem cells (iPSCs) in a patient with neovascular age-related macular degeneration. The iPSCs were generated from skin fibroblasts obtained from two patients with advanced neovascular age-related macular degeneration and were differentiated into RPE cells. The RPE cells and the iPSCs from which they were derived were subject to extensive testing. A surgery that included the removal of the neovascular membrane and transplantation of the autologous iPSC-derived RPE cell sheet under the retina was performed in one of the patients. At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present. (Funded by Highway Program for Realization of Regenerative Medicine and others; University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number, UMIN000011929 .).

Recovery From Exhaustion of the Frank-Starling Mechanism by Mechanical Unloading With a Continuous-Flow Ventricular Assist Device.

BACKGROUND: We describe our original left ventricular assist device (LVAD) speed ramp and volume loading test designed to evaluate native heart function under continuous-flow LVAD support.Methods and Results:LVAD speed was decreased in 4 stages from the patient's optimal speed to the minimum setting for each device. Under minimal LVAD support, patients were subjected to saline loading (body weight [kg]×10 mL in 15 min). Echocardiographic and hemodynamic data were obtained at each stage of the LVAD speed ramp and every 3 min during saline loading. Patients were divided into Recovery (with successful LVAD removal; n=8) and Non-recovery (others; n=31) groups. During testing, increased pulmonary capillary wedge pressure caused by volume loading was milder in the Recovery than Non-recovery group (repeated measures analysis of variance; group effect, P=0.0069; time effect, P<0.0001; interaction effect, P=0.0173). Increased cardiac output from volume loading was significantly higher in the Recovery than Non-recovery group (group effect, P=0.0124; time effect, P<0.0001; interaction effect, P=0.0091). Therefore, the Frank-Starling curve of the Recovery group was located upward and to the left of that of the Non-recovery group. CONCLUSIONS: The LVAD speed ramp and volume loading test facilitates the precise evaluation of native heart function during continuous-flow LVAD support.

Sequential parallel comparison design with two coprimary endpoints.

A placebo-controlled randomized clinical trial is required to demonstrate that an experimental treatment is superior to its corresponding placebo on multiple coprimary endpoints. This is particularly true in the field of neurology. In fact, clinical trials for neurological disorders need to show the superiority of an experimental treatment over a placebo in two coprimary endpoints. Unfortunately, these trials often fail to detect a true treatment effect for the experimental treatment versus the placebo owing to an unexpectedly high placebo response rate. Sequential parallel comparison design (SPCD) can be used to address this problem. However, the SPCD has not yet been discussed in relation to clinical trials with coprimary endpoints. In this article, our aim was to develop a hypothesis-testing method and a method for calculating the corresponding sample size for the SPCD with two coprimary endpoints. In a simulation, we show that the proposed hypothesis-testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy. In addition, the usefulness of our methods is confirmed by returning to an SPCD trial with a single primary endpoint of Alzheimer disease-related agitation.

Bayesian sample-size determination methods considering both worthwhileness and unpromisingness for exploratory two-arm randomized clinical trials with binary endpoints.

A randomized exploratory clinical trial comparing an experimental treatment with a control treatment on a binary endpoint is often conducted to make a go or no-go decision. Such an exploratory trial needs to have an adequate sample size such that it will provide convincing evidence that the experimental treatment is either worthwhile or unpromising relative to the control treatment. In this paper, we propose three new sample-size determination methods for an exploratory trial, which utilize the posterior probabilities calculated from predefined efficacy and inefficacy criteria leading to a declaration of the worthwhileness or unpromisingness of the experimental treatment. Simulation studies, including numerical investigation, showed that all three methods could declare the experimental treatment as worthwhile or unpromising with a high probability when the true response probability of the experimental treatment group is higher or lower, respectively, than that of the control treatment group.

A Bayesian basket trial design that borrows information across strata based on the similarity between the posterior distributions of the response probability.

Basket trials simultaneously evaluate the effect of one or more drugs on a defined biomarker, genetic alteration, or molecular target in a variety of disease subtypes, often called strata. A conventional approach for analyzing such trials is an independent analysis of each of the strata. This analysis is inefficient as it lacks the power to detect the effect of drugs in each stratum. To address these issues, various designs for basket trials have been proposed, centering on designs using Bayesian hierarchical models. In this article, we propose a novel Bayesian basket trial design that incorporates predictive sample size determination, early termination for inefficacy and efficacy, and the borrowing of information across strata. The borrowing of information is based on the similarity between the posterior distributions of the response probability. In general, Bayesian hierarchical models have many distributional assumptions along with multiple parameters. By contrast, our method has prior distributions for response probability and two parameters for similarity of distributions. The proposed design is easier to implement and less computationally demanding than other Bayesian basket designs. Through a simulation with various scenarios, our proposed design is compared with other designs including one that does not borrow information and one that uses a Bayesian hierarchical model.

Efficacy and Safety of the Ultra-Short-Acting ß1-Selective Blocker Landiolol in Patients With Recurrent Hemodynamically Unstable Ventricular Tachyarrhymias　- Outcomes of J-Land II Study.

BACKGROUND: We aimed to investigate the efficacy and safety of landiolol in Japanese patients with recurrent hemodynamically unstable ventricular tachycardia or recurrent ventricular fibrillation (recurrent VT/VF).Methods and Results:This was an open-label, uncontrolled, multicenter study. Patients with hemodynamically unstable VT or VF 24 h prior to providing informed consent, and who were refractory to class III antiarrhythmic drugs, were enrolled. Landiolol was started at a dose of 1 µg/kg/min, after VT/VF was suppressed with electrical defibrillation. Landiolol was titrated up to 10 µg/kg/min in 1 h and adjusted between 1 and 40 µg/kg/min for the efficacy assessment (1-49 h). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF. Secondary efficacy endpoints included the number of recurrent VT/VF events and the survival rate 30 days after the start of landiolol treatment. Adverse events (AEs) were assessed for safety; 27 and 29 patients were analyzed for efficacy and safety, respectively. The proportion of patients free from recurrent VT/VF was 77.8% (95% CI 57.1-89.3). The mean (±standard deviation) number of recurrent VT/VF events was 9.3±7.9. The survival rate was 96.3%. The overall incidence of AEs and of serious AEs was 72.4% and 6.9%, respectively. CONCLUSIONS: Landiolol may be useful for Japanese patients with recurrent VT/VF who do not respond to class III antiarrhythmic drugs.

Effect of Continuous-Flow Mechanical Circulatory Support on Microvasculature Remodeling in the Failing Heart.

Left ventricle (LV) unloading caused by a left ventricular assist device (LVAD) has been shown to enhance reverse LV remodeling in end-stage cardiomyopathy. Several reports consistently suggest that a pulsatile-flow LVAD has more profound effects compared to continuous-flow LVAD, though the responsible mechanisms are not fully understood. We hypothesized that arterial pulsatility, being affected by the type of LVAD, may affect microvasculature and functional/pathological LV remodeling in end-stage cardiomyopathy. The study included 18 patients with chronic heart failure who underwent LVAD implantation. Eight patients were implanted with pulsatile-flow LVAD, and 10 patients were implanted with continuous-flow LVAD. The results of serial echocardiograms and histopathological assessment of transmural LV tissues, which were collected during the implantation and removal of LVADs, were compared between the groups. The results of echocardiography showed that LV systolic dimension and LV ejection fraction improved greatly in the pulsatile-flow LVAD group compared to the continuous-flow LVAD group. Histological analysis showed that in both groups, increased microvasculature density and decreased cardiomyocyte size during LVAD support had no significant difference. In contrast, only the patients with continuous-flow LVADs had presented with significant increase in α-smooth muscle actin (α-SMA)-positive layer thickness and the number of proliferating cell nuclear antigen (PCNA)-positive cells of myocardial arterioles. We concluded that the use of long-term continuous-flow LVAD support, having less pulsatility, had induced more thickening to the medial layer of myocardial arterioles compared to the use of pulsatile-flow LVADs. Our findings suggest that the pathological impairment of myocardial microvascular structure during continuous-flow LVAD support may be a novel mechanism which accounts for the difference in LV remodeling depending on the type of LVAD.

Comparison of discrimination for cardio-metabolic risk by different cut-off values of the ratio of triglycerides to HDL cholesterol.

BACKGROUND: The ratio of triglycerides to HDL cholesterol (TG/HDL-C ratio) is known as a good predictor for cardiovascular disease. The purpose of this study was to compare discrimination for cardiovascular risk by different cut-off values of the TG/HDL-C ratio. METHODS: Receiver operating characteristic (ROC) analysis was performed for the relationship between TG/HDL-C ratio and accumulation of cardio-metabolic risk factors including visceral obesity, hypertension and diabetes. Logistic regression analysis was performed for the relationships of TG/HDL-C ratio with cardio-metabolic risk factors using the cut-off values obtained by ROC analysis and conventional cut-off values (men, 3.75; women, 3.00). RESULTS: In ROC analysis, the optimal cut-off values for TG/HDL-C ratio were 2.967 in men and 2.237 in women, which were much smaller than the conventional cut-of values. Odds ratios for multiple cardio-metabolic risk factors of subjects with vs. subjects without a high TG/HDL-C ratio in men and women were 5.75 (4.43-7.46) and 18.76 (10.32-34.13), respectively, by using the new cut-off values and they were 5.03 (3.96-6.39) and 16.11 (9.20-28.20), respectively, by using the conventional cut-off values. The odds ratios for visceral obesity, hypertension and diabetes were comparable when using these two different cut-off values. CONCLUSION: Cut-off values should be ideally calculated by ROC analysis. However, the discrimination power of cut-off values for the TG/HDL-C ratio calculated by ROC analysis for cardio-metabolic risk was similar to those by using the conventional cut-off values. Further studies using cardiovascular events as outcomes in the analysis may be needed to determine more suitable cut-off values of the TG/HDL-C ratio.

Proneness to high blood lipid-related indices in female smokers.

BACKGROUND: Smoking is a major risk factor for dyslipidemia. However, it remains to be clarified whether light smoking in Asian women affects lipid profiles and lipid-related indices. The aim of this study was to determine the relationships between lipid-related indices and smoking in Japanese women. Alcohol drinking influences blood lipid levels and is a potent confounder for the relationship between smoking and blood lipids. Thus, analysis for the relationships between smoking and blood lipid-related indices was also performed after stratification of drinking status. METHODS: The participants were 18,793 Japanese women aged 35-70 years. A cross-sectional study was performed using a local population-based database. The relationships of smoking with each index were investigated by using analysis of covariance and logistic regression analysis with adjustment for age and other lifestyle factors such as alcohol drinking and regular exercise. RESULTS: In multivariate logistic regression analysis, odds ratios of smokers vs. nonsmokers for high ratio of LDL cholesterol to HDL cholesterol (LDL-C/HDL-C), high ratio of triglycerides to HDL cholesterol (TG/HDL-C), high lipid accumulation product (LAP) and high cardio metabolic index (CMI) were significantly higher than the reference level of 1.00 in overall participants (2.17 [1.78-2.66], 1.70 [1.47-1.97], 1.17 [1.08-1.27] and 1.41 [1.30-1.53], respectively), nondrinking participants (2.29 [1.80-2.91], 1.68 [1.39-2.02], 1.21 [1.08-1.36] and 1.46 [1.30-1.63], respectively), and drinking participants (1.96 [1.35-2.85], 1.76 [1.39-2.21], 1.13 [1.01-1.27] and 1.38 [1.22-1.55], respectively). In overall participants, nondrinking participants, and drinking participants, LDL-C/HDL-C, TG/HDL-C, LAP and CMI were significantly higher in smokers than in nonsmokers. In nondrinking participants, triglycerides and LDL cholesterol were significantly higher in smokers than in nonsmokers, while the ratio of waist circumference to height and HDL cholesterol were significantly lower in smokers than in nonsmokers. CONCLUSION: In women, all of the four lipid-related indices tested were higher in smokers than in nonsmokers, and these associations were independent of alcohol drinking. The high levels of the lipid-related indices in smokers result from the detrimental effects of smoking on levels of blood lipids such as triglycerides, HDL cholesterol and LDL cholesterol.

A simple test for the treatment effect in clinical trials with a sequential parallel comparison design and negative binomial outcomes.

In placebo-controlled, double-blinded, randomized clinical trials, the presence of placebo responders reduces the effect size for comparison of the active drug group with the placebo group. An attempt to resolve this problem is to use the sequential parallel comparison design (SPCD). Although there are SPCDs with dichotomous or continuous outcomes, an SPCD with negative binomial outcomes-with which investigators deal eg, in clinical trials involving multiple sclerosis, where the investigators are still concerned about the presence of placebo responders-has not yet been discussed. In this article, we propose a simple test for the treatment effect in clinical trials with an SPCD and negative binomial outcomes. Through simulations, we show that the analysis method achieves the nominal type I error rate and power, whereas the sample size calculation provides the sample size with adequate power accuracy.

Sequential parallel comparison design for "gold standard" noninferiority trials with a prespecified margin.

Three-arm noninferiority trials (involving an experimental treatment, a reference treatment, and a placebo)-called the "gold standard" noninferiority trials-are conducted in patients with mental disorders whenever feasible, but often fail to show superiority of the experimental treatment and/or the reference treatment over the placebo. One possible reason is that some of the patients receiving the placebo show apparent improvement in the clinical condition. An approach to addressing this problem is the use of the sequential parallel comparison design (SPCD). Nonetheless, the SPCD has not yet been discussed in relation to gold standard noninferiority trials. In this article, our aim was to develop a hypothesis-testing method and its corresponding sample size calculation method for gold standard noninferiority trials with the SPCD. In a simulation, we show that the proposed hypothesis-testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy.

A prospective multicenter phase II study of intrabone marrow transplantation of unwashed cord blood using reduced-intensity conditioning.

Cord blood transplantation (CBT) is associated with delayed hematopoietic recovery and graft failure. To overcome these problems, we conducted a prospective, multicenter phase II study of intrabone marrow transplantation in which patients received reduced-intensity conditioning without anti-thymocyte globulin (ATG). The primary endpoint was the probability of full donor engraftment. Forty patients with hematologic malignancies were enrolled. Cord blood (CB) cells were injected without washing into 4 iliac bone sites (2 at each hemipelvis), at which approximately 6 mL of CB was administered at one site with local anesthesia. Full donor engraftment rate was 86.8%. The cumulative incidence of neutrophil and platelet engraftment was 86.4% and 85.5%, respectively. The median time to neutrophil (>0.5 × 109 /L) and platelet (2.0 × 109 /L) recovery was 17.5 and 44 days, respectively. The probability of severe acute graft-vs-host disease (GVHD) was 47.5%. The cumulative incidence of extensive chronic GVHD was 3.0%. The probability of relapse and non-relapse mortality was 30.4% and 28.0%, respectively. The survival rate at 3 years was 45.6%, although most patients were at an advanced stage. These results suggest that our intrabone marrow-CBT procedure without using ATG improves hematopoietic recovery and decreases the incidence of chronic GVHD, but does not decrease the incidence of acute GVHD.

Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke: ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient).

BACKGROUND AND PURPOSE: Several studies suggested that statins during hospitalization were associated with better disability outcomes in patients with acute ischemic stroke, but only 1 small randomized trial is available. METHODS: We conducted a multicenter, open-label, randomized controlled trial in patients with acute ischemic strokes in 11 hospitals in Japan. Patients with acute ischemic stroke and dyslipidemia randomly received statins within 24 hours after admission in the early group or on the seventh day in the delayed group, in a 1:1 ratio. Statins were administered for 12 weeks. The primary outcome was patient disability assessed by modified Rankin Scale at 90 days. RESULTS: A total of 257 patients were randomized and analyzed (early 131, delayed 126). At 90 days, modified Rankin Scale score distribution did not differ between groups (P=0.68), and the adjusted common odds ratio of the early statin group was 0.84 (95% confidence interval, 0.53-1.3; P=0.46) compared with the delayed statin group. There were 3 deaths at 90 days (2 in the early group, 1 in the delayed group) because of malignancy. Ischemic stroke recurred in 9 patients (6.9%) in the early group and 5 patients (4.0%) in the delayed group. The safety profile was similar between groups. CONCLUSIONS: Our randomized trial involving patients with acute ischemic stroke and dyslipidemia did not show any superiority of early statin therapy within 24 hours of admission compared with delayed statin therapy 7 days after admission to alleviate the degree of disability at 90 days after onset. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02549846.

Proton beam therapy for bone sarcomas of the skull base and spine: A retrospective nationwide multicenter study in Japan.

We conducted a retrospective, nationwide multicenter study to evaluate the clinical outcomes of proton beam therapy for bone sarcomas of the skull base and spine in Japan. Eligibility criteria included: (i) histologically proven bone sarcomas of the skull base or spine; (ii) no metastases; (iii) ≥20 years of age; and (iv) no prior treatment with radiotherapy. Of the 103 patients treated between January 2004 and January 2012, we retrospectively analyzed data from 96 patients who were followed-up for >6 months or had died within 6 months. Seventy-two patients (75.0%) had chordoma, 20 patients (20.8%) had chondrosarcoma, and four patients (7.2%) had osteosarcoma. The most frequent tumor locations included the skull base in 68 patients (70.8%) and the sacral spine in 13 patients (13.5%). Patients received a median total dose of 70.0 Gy (relative biological effectiveness). The median follow-up was 52.6 (range, 6.3-131.9) months. The 5-year overall survival, progression-free survival, and local control rates were 75.3%, 49.6%, and 71.1%, respectively. Performance status was a significant factor for overall survival and progression-free survival, whilst sex was a significant factor for local control. Acute Grade 3 and late toxicities of ≥Grade 3 were observed in nine patients (9.4%) each (late Grade 4 toxicities [n = 3 patients; 3.1%]). No treatment-related deaths occurred. Proton beam therapy is safe and effective for the treatment of bone sarcomas of the skull base and spine in Japan. However, larger prospective studies with a longer follow-up are warranted.