Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised,Multicentre, Open-label,Phase 3 Trial (JCOG0401)2

BackgroundNo standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP).ObjectiveTo determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients.Design, setting, and participantsThis study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) ± SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr.Outcome measurements and statistical analysisThe primary endpoint was time to treatment failure (TTF) of BCL.Results and limitationsTTF of BCL was significantly longer in the SRT ± SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40–0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT ± SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT ± SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions.ConclusionsInitial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT ± SHT is more beneficial than SHT alone.Patient summaryPatients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy.     

Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs

We previously showed a beneficial effect of hemofiltration on hemodynamics of endotoxic shock pigs. To test the hypothesis that this effect of hemofiltration is caused by convective removal of factors that adversely effect hemodynamics during endotoxemia, we infused ultrafiltrate from endotoxic shock pigs into healthy pigs. Their hemodynamics were compared with those of pigs who were infused with ultrafiltrate from healthy pigs. Twelve anesthetized and ventilated pigs were hemodynamically monitored for 150 minutes following the infusion of 2 L of ultrafiltrate from 12 donor pigs. The acceptor pigs were randomly divided into two groups; group 1 received ultrafiltrate from pigs who were hemofiltered after the infusion of 0.5 mg/kg endotoxin over 30 minutes; group 2 served as a control group, receiving ultrafiltrate from healthy donor pigs. Group 1 showed a decrease in mean arterial pressure of 28 ± 7 mm Hg (mean ± SEM) versus an increase of 17 ± 3 mm Hg in group 2 (P < .04). Mean pulmonary artery pressure increased more in group 1 than in group 2 (9 ± 2 mm Hg versus 1 ± 1 mm Hg, P < .04). The decrease in cardiac output in group 1 was greater than in group 2 (3.3 ± 0.2 L/ min v 0.3 ± 0.3 L /min, P < .02) and was due to a decrease in stroke volume. The decrease in right ventricular ejection fraction was also greater (0.15 ± 0.02 v 0.01 ± 0.00, P < .01). Systemic vascular resistance, right atrial pressure, right ventricular end-diastolic volume, pulmonary wedge pressure and heart rate did not differ between groups. In contrast to ultrafiltrate from healthy pigs, ultrafiltrate from endotoxic shock pigs contains soluble, filtrable factors that increase pulmonary artery pressure and depress cardiac performance.     

健康医疗大数据驱动下的疾病防控新模式

随着互联网技术的快速发展和医疗信息化的不断推进，健康医疗大数据已逐渐成为创新健康管理、满足人民群众日益增长的健康需求的重要资源，成为国家全面实施大数据战略的重要组成部分。宁波市鄞州区通过构建健康大数据平台及大数据技术的应用，积极探索健康医疗大数据在传染病、预防接种、慢性病等疾病防控领域的防控模式创新，期望通过"互联网+健康医疗"提高区域疾病防控和健康管理水平，培育发展新业态，成为健康中国的有力支撑。本文对鄞州区的这一防控新模式的实践探索进行介绍，并对模式的初步成效进行讨论。     

Development of Quality Indicators for the Management of Acute Type A Aortic Dissection

In an effort to further improve surgical outcomes in patients with acute type A aortic dissection (ATAD), the Canadian Thoracic Aortic Collaborative (CTAC), with the support of the Canadian Society of Cardiac Surgeons (CSCS), endeavoured to develop quality indicators (QIs) for the management of patients with ATAD. After 2 successive consultations with the CTAC membership, 11 QIs were selected and separated into 5 broad categories: preoperative (time from presentation to diagnosis, time from presentation to the operating room), intraoperative (use of hypothermic circulatory arrest and antegrade cerebral perfusion), 30-day outcomes (30-day rates of all-cause mortality, 30-day rates of new postoperative stroke), 1-year outcomes (1-year rates of follow-up imaging, 1-year rates of all-cause mortality, and 1-year rates of surgical reintervention), and institutional (institutional surgical volumes, individual surgical volumes, and presence of institutional aortic disease teams). The purpose of this article is to describe the process by which QIs for the management of ATAD were developed and the feasibility by which they may be collected using existing clinical and administrative data sources. Furthermore, we demonstrate how they may be used to evaluate success following surgery for repair of ATAD and ultimately improve clinical outcomes.     

Pathogenic variants in arteriopathy genes detected in a targeted sequencing study: Penetrance and 1-year outcomes after return of results

PurposeWe estimated the penetrance of pathogenic/likely pathogenic (P/LP) variants in arteriopathy-related genes and assessed near-term outcomes following return of results.MethodsParticipants (N = 24,520) in phase III of the Electronic Medical Records and Genomics network underwent targeted sequencing of 68 actionable genes, including 9 genes associated with arterial aneurysmal diseases. Penetrance was estimated on the basis of the presence of relevant clinical traits. Outcomes occurring within 1 year of return of results included new diagnoses, referral to a specialist, new tests ordered, surveillance initiated, and new medications started.ResultsP/LP variants were present in 34 participants. The average penetrance across genes was 59%, ranging from 86% for FBN1 variants to 25% for SMAD3. Of 16 participants in whom results were returned, 1-year outcomes occurred in 63%. A new diagnosis was made in 44% of the participants, 56% were referred to a specialist, a new test was ordered in 44%, surveillance was initiated in 31%, and a new medication was started in 31%.ConclusionPenetrance of P/LP variants in arteriopathy-related genes, identified in a large, targeted sequencing study, was variable and overall lower than that reported in clinical cohorts. Meaningful outcomes within the first year were noted in 63% of participants who received results.     

Heterozygous UCHL1 loss-of-function variants cause a neurodegenerative disorder with spasticity,ataxia, neuropathy,and optic atrophy

PurposeBiallelic variants in UCHL1 have been associated with a progressive early-onset neurodegenerative disorder, autosomal recessive spastic paraplegia type 79. In this study, we investigated heterozygous UCHL1 variants on the basis of results from cohort-based burden analyses.MethodsGene-burden analyses were performed on exome and genome data of independent cohorts of patients with hereditary ataxia and spastic paraplegia from Germany and the United Kingdom in a total of 3169 patients and 33,141 controls. Clinical data of affected individuals and additional independent families were collected and evaluated. Patients’ fibroblasts were used to perform mass spectrometry-based proteomics.ResultsUCHL1 was prioritized in both independent cohorts as a candidate gene for an autosomal dominant disorder. We identified a total of 34 cases from 18 unrelated families, carrying 13 heterozygous loss-of-function variants (15 families) and an inframe insertion (3 families). Affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17). The mass spectrometry-based proteomics showed approximately 50% reduction of UCHL1 expression in patients’ fibroblasts.ConclusionOur bioinformatic analysis, in-depth clinical and genetic workup, and functional studies established haploinsufficiency of UCHL1 as a novel disease mechanism in spastic ataxia.