Multicenter Recruitment Research Articles

Germline genetic mutations in a multi-center cohort of 248 phyllodes tumors.

Germline genetic mutations in women with phyllodes tumors (PT) are understudied, although some describe associations of PT with various mutations. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in women with PT. A 6-site multi-center study of women with a PT was initiated, then expanded nationally through an online "Phyllodes Support Group." All women underwent 84-gene panel testing. We defined eligibility for testing based on select NCCN (National Comprehensive Cancer Network) criteria (v1.2022). Logistic regression was used to estimate the association of covariates with the likelihood of a P/LP variant. 274 women were enrolled: 164 (59.9%) through multi-center recruitment and 110 (40.1%) via online recruitment. 248 women completed testing; overall 14.1% (N = 35) had a P/LP variant, and over half (N = 19) of these individuals had a mutation in genes associated with autosomal dominant (AD) cancer conditions. The most common AD genes with a P/LP variant included CHEK2, ATM, and RAD51D. A quarter of participants (23.8%) met NCCN criteria for testing, but we found no difference in prevalence of a P/LP variant based on eligibility (p = 0.54). After adjustment, the presence of P/LP variants was not associated with age, NCCN testing eligibility, or PT type (all p > 0.05). Our study demonstrates that 7.7% of women with PT harbor germline P/LP variants in genes associated with AD cancer conditions. Early identification of these variants has implications for screening, risk reduction, and/or treatment. National guidelines for women with PT do not currently address germline genetic testing, which could be considered.

Comparison of Obstetrical Randomized Controlled Trials in the United States and Abroad [ID 2683467

INTRODUCTION: Research priorities and governing regulations differ between the United States and other nations (non-United States). This study compared the characteristics of U.S. and non-U.S. obstetric randomized controlled trials (RCTs). METHODS: Original research articles published in seven journals (NEJM, JAMA, The Lancet, AJOG, AJOG-MFM, BJOG, and Obstetrics & Gynecology) from 2017 to 2022 were examined, and all RCTs with an obstetric focus were analyzed. Studies were categorized based on whether they were conducted in the United States. RESULTS: Of 238 RCTs in this study, 110 (46.2%) occurred in the United States. Compared to non-U.S. studies, U.S. RCTs were more likely to be published in obstetrics and gynecology journals (90.9% versus 73.4%; P=.001) and to be multicenter studies (59.4% versus 29.9%; P<.001). U.S. RCTs had a smaller median sample size (172 versus 335; P<.001) and a shorter median study length (19.9 versus 28.9 months; P=.026). U.S. RCTs were less likely to study the antepartum period (P<.001), to have a primary outcome examining the fetus/neonate (11.8% versus 37.8%; P<.001), and to study preventative interventions (51.6% versus 68.9%; P=.011). There was no difference in intervention type (drug, behavior, procedure, or device; P=.96) or whether the trial had a positive result (6.0% versus 3.7%; P=.52) between U.S. and non-U.S. studies. CONCLUSION: U.S. RCTs had smaller sample sizes and shorter study lengths, perhaps because of multicenter recruitment. Despite being potentially more generalizable, U.S. studies are less likely to be published in general medical journals. Further research is warranted to pursue this discrepancy as broad dissemination of information is important for improving maternal and fetal outcomes.

Questioning the Utility of Temporal Artery Biopsy in Giant Cell Arteritis: A Negative Biopsy May Facilitate Decision-making.

We undertook a prospective study of adult patients undergoing TAB for GCA in Calgary. Consecutive, multicenter recruitment was performed over 2 years. Primary outcomes included initiation or discontinuation and duration of corticosteroids. Twenty-one TABs were performed in 20 patients. Nineteen percent of TABs were positive, and 71.4%, negative. In 9.5% of patients, accidental sampling of a vessel other than the superficial temporal artery occurred. Fifty-two percent of patients received steroids before TAB, of which the mean duration was 8.0 days for TAB+ (postive temporal artery biopsy result) patients and 8.4 days for TAB- (negative temporal artery biopsy result; P = 0.22) patients. Before TAB, the American College of Rheumatology score was 2.5 for TAB+ patients and 2.4 for TAB- (P = 0.74). Postbiopsy, the American College of Rheumatology score was 3.5 for TAB+ patients (therefore reaching diagnostic threshold of 3) but remained 2.4 for TAB- (P = 0.02). TAB+ patients were treated for 352.3 days, whereas TAB- patients for 16.7 days (P = 0.29). Complications were more likely with long-term (>6 weeks) steroids (P = 0.17). In patients with a low suspicion of GCA, a negative TAB helps bolster physician confidence and leads to a shorter steroid duration.

A survey of registered pharmacological clinical trials on rare neurological diseases in children in 2010-2020.

To clarify the current state of methodology of clinical trials for rare neurological diseases in children, and to provide a basis for the further optimization of the trial design. Data of clinical trials for the rare neurological diseases with childhood onset (searched through https://rarediseases.info.nih.gov/diseases and www.Orpha.net) registered on the Clinicaltrils.gov from January 2010 to June 2020 was collected. Analysis on the methodology of the clinical trials were performed, focusing on initiator of the studies, multi or single research center, study design, sample size, and the endpoint using in the trial. A total of 162 clinical trials were included, covering only 7.3% (61/835) of rare neurological diseases in children. 101 (62.3%) were initiated by pharmaceutical companies, and 61 (37.7%) by investigators. Most (95.4%) of global multicenter studies were initiated by pharmaceutical companies, whereas most (70.0%) of single-center studies were initiated by investigators (χ 2 = 61.635, P < 0.001). Of the 162 trials, 74 (45.7%) were open-label single-arm trials, 68 (42.0%) were randomized double-blind parallel controlled trials (RCT), 12 (7.4%) were randomized crossover trials. Most of RCTs (73.5%) and 54.1% of open-label single-arm trials were initiated by pharmaceutical companies. The proportion of RCTs in clinical trials for diseases with a prevalence of ≥1/10,000 (62.5%) was higher than that in diseases with prevalence ≤1/1,000,000 (12.0%) or 1/1,000,000~1/10,000 (43.1%) (χ 2 = 14.790, P = 0.001). The median expected sample size of the studies was 34 (4-500). 132 (132/162, 81.5%) studies enrolled fewer than 100 cases. Diseases with a prevalence of ≥1/10,000 had significantly larger sample sizes than other prevalence classes (P < 0.001, P = 0.003). There were few clinical trials targeting on treatment of rare neurological diseases in children. Trials on rare diseases used fewer participants, and high-quality randomized controlled trials were less common. It is necessary to conduct global multicenter recruitment and choose optimal study designs to improve the level of evidence in clinical trials on rare diseases.

Independent Association Between Occupational Exposure and Decline of FVC in Systemic Sclerosis: A Multicenter Recruitment Retrospective Cohort Study

Although male sex is associated with poor prognosis in systemic sclerosis (SSc), it is unclear whether this association is independent of confounding factors such as occupational exposure to toxicants. What is the respective impact of sex and occupational exposure on characteristics of patients with SSc with a focus on lung function decline? Patients with SSc (n= 210; 55 men) underwent standardized quantitative assessment of occupational exposure through a cumulative exposure score (CES) in a multicenter recruitment retrospective cohort. Association of the CES with patients' characteristics was assessed. Mixed linear, logistic, and Cox regression models were used to identify predictors of time variation of FVC and the diffusing capacity of the lungs for CO2 corrected for hemoglobin (Dlcoc). Male sex was associated strongly with occupational exposure (OR, 10.3; P< .0001). The CES was correlated inversely (r= -0.20) and associated independently with decline in FVC over time and with occurrence of FVC decline of≥ 10%from baseline (P< .05). By contrast, the CES was not associated with decline in Dlcoc or Dlcoc decline of≥ 15%. No independent association was found between sex and decline in FVC or Dlcoc. The prevalence of interstitial lung disease was similar across sex or occupational exposure. Occupational exposure to toxicants seems to predict decline of FVC in patients with SSc independently, regardless of sex. Assessment of occupational exposure may be useful for SSc prognostication.

Preferences for Accessing Patient Reported Outcomes and Health Information Among Thrombotic Thrombocytopenic Purpura Survivors

Introduction: Our previous qualitative studies of immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors revealed that patients did not communicate to their hematologists about residual cognitive and fatigue issues. A way to overcome this communication barrier is implementation of patient-reported outcomes (PROs) in routine care. Integration of PROs into the clinical care of other diseases has resulted in improved patient-provider communication, symptom management, quality of life and overall patient satisfaction. However, decisions about the mode of administration are challenging. Although 92% of the United States population has access to the internet, studies have shown minorities prefer alternative modes of administration. Given that iTTP disproportionately affects Black women, understanding patient preference is critical for integrating PRO instruments into routine care. The primary study goal was to determine the preferred mode of administration of PRO instruments in iTTP. Furthermore, many individuals use the internet as a source of medical information/advice. A study of iTTP literacy reported that only 34% of survivors correctly identified disease relapse risk factors suggesting a critical knowledge gap. A secondary goal was to describe iTTP survivors' behaviors regarding using the internet for medical information or support.Methods: We utilized a cross-sectional study design. iTTP survivors were recruited from August 2019 until present. Eligibility included: 1) age >18 years, 2) documented ADAMTS13 deficiency (< 10% activity) at diagnosis or during a relapse and 3) > 1-year clinical remission. Multi-center recruitment of survivors included: Oklahoma University, Ohio State University, University of Minnesota, Johns Hopkins University, University of Rochester, University of Pennsylvania, University of Alabama at Birmingham, University of Utah and the University of Vermont. Following informed consent, survivors were administered the PROMIS ® cognitive function ability, anxiety and fatigue instruments via their preferred mode (online, telephone, or self-administered). Typical internet usage, behaviors regarding searching for health information online and demographics were also obtained.Results: To date, 94 survivors have completed the study (83% female; 54% White; 34% Black; median age 49 years [range 26-85 years]). A majority (54%) preferred completing PROMIS ® surveys online vs. self-administered or telephone administered. However, among Black survivors, only 38% preferred online administration and among survivors aged ≥65 years only 22% preferred online administration. Interestingly, there was an overall shift in a preference toward online administration following the onset of the COVID-19 pandemic (45% (21/47) preferred online pre vs 66% (31/47) preferred online post).Ninety-one percent (86/94) of survivors reported at least occasional internet use vs 8 (9%) reported none. Similarly, 82% (70/85) had searched the internet for health/medical information for themselves in the past year. Also 62% (53/86) of the survivors selected ‘strongly agree’ or ‘agree’ to the statement that the internet helps them determine if symptoms are important enough to see a doctor. Likewise, 62% used the internet to interpret doctor's recommendations. Additionally, 47% (40/86) ‘strongly agree/agree’ the internet helped determine if they would take a medication/seek alternative treatment.Moreover, 64% (55/86) agreed the internet was a good way to find others experiencing similar health problems. However, when asked about behaviors over the past year, only 42% (36/85) used online social networking sites like Facebook to look for health information or find others with iTTP and only 36% (31/85) had actually participated in online iTTP support groups.Conclusions: Overall iTTP survivors preferred online PRO administration; however, Black and older survivors preferred other methods. Recognizing these preferences is a vital step toward integrating PROs into routine care. Furthermore, iTTP survivors are using the internet as a source of medical support and information. Therefore, it is critical to not only educate iTTP survivors about credible online resources but also to create additional content. Also, future studies are needed to further explore the impact of the COVID-19 pandemic on online health behaviors. DisclosuresTerrell: Sanofi: Consultancy; Takeda: Consultancy. Journeycake: HEMA Biologics: Honoraria; LFB: Honoraria. Mazepa: Answering TTP Foundation: Research Funding; Sanofi Aventis: Other. Cuker: Spark Therapeutics: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Bayer: Research Funding; Alexion: Research Funding; UpToDate: Patents & Royalties; Synergy: Consultancy. Chaturvedi: Dova: Other: Advisory board member; UCB: Other: Advisory board participation; Argenx: Other: Advisory board member; Alexion: Other: Advisory board member; Sanofi Genzyme: Other: Advisory board member. Lim: Hema Biologics: Honoraria; Sanofi Genzyme: Honoraria; Dova Pharmaceuticals: Honoraria. Gangaraju: Alexion: Consultancy; Sanofi Genzyme: Consultancy. Cataland: Alexion: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Ablynx/Sanofi: Consultancy, Research Funding; Takeda: Consultancy.

A feasibility study to assess the design of a multicentre randomized controlled trial of the clinical and cost-effectiveness of a caregiving intervention for people following hip fracture surgery.

AimsThis study aims to assess the feasibility of conducting a pragmatic, multicentre randomized controlled trial (RCT) to test the clinical and cost-effectiveness of an informal caregiver training programme to support the recovery of people following hip fracture surgery.MethodsThis will be a mixed-methods feasibility RCT, recruiting 60 patients following hip fracture surgery and their informal caregivers. Patients will be randomized to usual NHS care, versus usual NHS care plus a caregiver-patient dyad training programme (HIP HELPER). This programme will comprise of three, one-hour, one-to-one training sessions for the patient and caregiver, delivered by a nurse, physiotherapist, or occupational therapist. Training will be delivered in the hospital setting pre-patient discharge. It will include practical skills for rehabilitation such as: transfers and walking; recovery goal setting and expectations; pacing and stress management techniques; and introduction to the HIP HELPER Caregiver Workbook, which provides information on recovery, exercises, worksheets, and goal-setting plans to facilitate a ‘good’ recovery. After discharge, patients and caregivers will be supported in delivering rehabilitation through three telephone coaching sessions. Data, collected at baseline and four months post-randomization, will include: screening logs, intervention logs, fidelity checklists, quality assurance monitoring visit data, and clinical outcomes assessing quality of life, physical, emotional, adverse events, and resource use outcomes. The acceptability of the study intervention and RCT design will be explored through qualitative methods with 20 participants (patients and informal caregivers) and 12 health professionals.DiscussionA multicentre recruitment approach will provide greater external validity across population characteristics in England. The mixed-methods approach will permit in-depth examination of the intervention and trial design parameters. The findings will inform whether and how a definitive trial may be undertaken to test the effectiveness of this caregiver intervention for patients after hip fracture surgery.Cite this article: Bone Jt Open 2021;2(11):909–920.

Artificial intelligence: Deep learning in oncological radiomics and challenges of interpretability and data harmonization.

Over the last decade there has been an extensive evolution in the Artificial Intelligence (AI) field. Modern radiation oncology is based on the exploitation of advanced computational methods aiming to personalization and high diagnostic and therapeutic precision. The quantity of the available imaging data and the increased developments of Machine Learning (ML), particularly Deep Learning (DL), triggered the research on uncovering "hidden" biomarkers and quantitative features from anatomical and functional medical images. Deep Neural Networks (DNN) have achieved outstanding performance and broad implementation in image processing tasks. Lately, DNNs have been considered for radiomics and their potentials for explainable AI (XAI) may help classification and prediction in clinical practice. However, most of them are using limited datasets and lack generalized applicability. In this study we review the basics of radiomics feature extraction, DNNs in image analysis, and major interpretability methods that help enable explainable AI. Furthermore, we discuss the crucial requirement of multicenter recruitment of large datasets, increasing the biomarkers variability, so as to establish the potential clinical value of radiomics and the development of robust explainable AI models.

Interim recruitment prediction for multi-center clinical trials.

SummaryWe introduce a general framework for monitoring, modeling, and predicting the recruitment to multi-center clinical trials. The work is motivated by overly optimistic and narrow prediction intervals produced by existing time-homogeneous recruitment models for multi-center recruitment. We first present two tests for detection of decay in recruitment rates, together with a power study. We then introduce a model based on the inhomogeneous Poisson process with monotonically decaying intensity, motivated by recruitment trends observed in oncology trials. The general form of the model permits adaptation to any parametric curve-shape. A general method for constructing sensible parameter priors is provided and Bayesian model averaging is used for making predictions which account for the uncertainty in both the parameters and the model. The validity of the method and its robustness to misspecification are tested using simulated datasets. The new methodology is then applied to oncology trial data, where we make interim accrual predictions, comparing them to those obtained by existing methods, and indicate where unexpected changes in the accrual pattern occur.

Single-site 123I-FP-CIT reference values from individuals with non-degenerative parkinsonism\u2014comparison with values from healthy volunteers

PurposeIodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) SPECT can be performed to distinguish degenerative forms of movement disorders/parkinsonism/tremor from other entities such as idiopathic tremor or drug-induced parkinsonism. For equivocal cases, semi-quantification and comparison to reference values are a necessary addition to visual interpretation of 123I-FP-CIT scans. To overcome the challenges of multi-center recruitment and scanning of healthy volunteers, we generated 123I-FP-CIT reference values from individuals with various neurological conditions but without dopaminergic degeneration, scanned at a single center on the same SPECT-CT system following the same protocol, and compared them to references from a multi-center database built using healthy volunteers’ data.MethodsFrom a cohort of 1884 patients, we identified 237 subjects (120 men, 117 women, age range 16–88 years) through a two-stage selection process. Every patient had a final clinical diagnosis after a mean follow-up of 4.8 ± 1.3 years. Images were reconstructed using (1) Flash3D with scatter and CT-based attenuation corrections (AC) and (2) filtered back projection with Chang AC. Volume-of-interest analysis was performed using a commercial software to calculate specific binding ratios (SBRs), caudate-to-putamen ratios, and asymmetry values on different striatal regions. Generated reference values were assessed according to age and gender and compared with those from the ENC-DAT study, and their robustness was tested against a cohort of patients with different diagnoses.ResultsAge had a significant negative linear effect on all SBRs. Overall, the reduction rate per decade in SBR was between 3.80 and 5.70%. Women had greater SBRs than men, but this gender difference was only statistically significant for the Flash3D database. Linear regression was used to correct for age-dependency of SBRs and to allow comparisons to age-matched reference values and “normality” limits. Generated regression parameters and their 95% confidence intervals (CIs) were comparable to corresponding European Normal Control Database of DaTscan (ENC-DAT) results. For example, 95% CI mean slope for the striatum in women is − 0.015 ([− 0.019, − 0.011]) for the Flash3D database versus − 0.015 ([− 0.021, − 0.009]) for ENC-DAT. Caudate-to-putamen ratios and asymmetries were not influenced by age or gender.ConclusionThe generated 123I-FP-CIT references values have similar age-related distribution, with no increase in variance due to comorbidities when compared to values from a multi-center study with healthy volunteers. This makes it possible for sites to build their 123I-FP-CIT references from scans acquired during routine clinical practice.

Analysis of 30 clinical trials on rare neurological diseases in children

Objective To explore the methods for generating evidence on health outcomes in children with rare diseases. Methods The data from 30 clinical trials on rare neurological diseases in children from January 2008 to December 2018 were collected and analyzed.Statistical analysis was conducted on the relationship between the study sponsor and the study center, the number of participants and the prevalence rate. Results Thirty studies involved 6 types of diseases, including 14 kinds of diseases.(1) All global multicenter studies (14 items) were initiated by pharmaceutical companies, whereas most of single-center studies (6/7 kinds, 86%) and multiple centers within one country(7/9 kinds, 78%) were initiated by investigators.There was a significant correlation between the research center and the research sponsor(P<0.001). (2) Most of the drugs studied were selected based on previous clinical trials (9/30 items) and animal experiments (9/30 items). (3) The median number of participants included 39 cases (10-215 cases), and 60%(18/30 items) of the studies was fewer than 50 cases.(4) Study design: 53%(16/30 items) of studies were randomized controlled studies, 33%(10/30 items) studies were open-label single-arm studies, and 14% (4/30 items) were randomized cross-over trials.Seventy-five percent(12/16 items)of randomized controlled studies were initiated by pharmaceutical companies, 50%(5/10 items) open-label single-arm studies and all randomized cross-over trials were initiated by investigators.There was a statistical correlation between the study sponsors and the study design method (χ2=7.602, P=0.022). (5) Outcome index: Scale score was used as the primary outcome in half of studies.Other studies used symptom improvement or pathological changes. Conclusions Clinical trials in rare diseases enrolled fewer participants than that in non-rare diseases, and the study design method was relatively simple.Therefore, it is necessary to further improve the level of evidence of clinical research of rare diseases through global and multi-center recruitment, initiation of pharmaceutical companies and improving the study design method. Key words: Child; Rare diseases; Drug intervention study; Research design method

1411The effect of eplerenone on fibrosis in hypertrophic cardiomyopathy. A randomised controlled trial assessed using cardiopulmonary exercise testing and cardiovascular magnetic resonance

Abstract Background Recent studies have implicated aldosterone, a hormone of the renin-angiotensin-aldosterone system to cardiac hypertrophy, and cardiac and vascular fibrosis in cardiomyopathy. High levels of circulating aldosterone have been shown to cause myocardial and aortic fibrosis in animal models. In humans, high aldosterone concentrations have been associated with endothelial dysfunction, myocardial infarction, left ventricular hypertrophy and death. Aldosterone antagonism with spironolactone or eplerenone reverses the process of fibrosis in animal models. Purpose Left ventricular dysfunction due to hypertrophic cardiomyopathy (HCM) is a disorder associated with an increased risk of morbidity and premature mortality. An important pathological feature seen in cardiomyopathy is the development of fibrosis and its association with functional impairment and arrhythmia, including predisposition to sudden cardiac death. This trial observes the effect of eplerenone on myocardial fibrosis and exercise tolerance in patients with HCM. Methods 42 patients were recruited into a double-blinded, placebo-controlled randomised study. Each patient had an established diagnosis of HCM without exclusion criteria (figure 1). 2 patients withdrew before enrolment. Enrolled patients were established on maximally tolerated doses of standard drugs used in the treatment of HCM and the doses of these drugs remained unchanged in the 2 months preceding enrolment to the trial. Patients were randomised to receive a maximal dose of 50mg eplerenone (n=21) or placebo (n=19). The patients underwent cardiopulmonary exercise testing and cardiovascular magnetic resonance (CMR) scan at baseline and 52 week follow up. Results At 52 weeks follow up there was no difference between placebo and treatment groups in peak oxygen consumption (−1.05 vs 0.63, p=0.32), anaerobic threshold (0.4 vs 1.45, p=0.31) or ventilatory efficiency slope (−0.77 vs 1.76, p=0.065). In addition, there was no significant difference observed in LV mass or fibrosis as assessed by CMR. Inclusion and Exclusion Criteria Conclusion In the first randomised controlled trial using eplerenone in humans with HCM, we report no effect of treatment after 52 weeks on exercise capacity compared with placebo. In addition, we report no effect of treatment on the presence of fibrosis detected by CMR. Interpretation of these results are limited by small sample size and further studies will require a multi-centre recruitment process. The data presented here support the feasibility of eplerenone treatment in patients with HCM and provide statistical power calculation for future trials.

A Pilot Randomized Controlled Trial Comparing Levothyroxine to Placebo in Neurologically Deceased Donors.

Although commonly prescribed, the efficacy of levothyroxine to improve heart function in neurologically deceased donors is unclear. We evaluated the feasibility of a randomized controlled trial to compare levothyroxine to placebo on the variation of left ventricular ejection fraction, in hemodynamically unstable donors. We conducted a pilot, double-blinded, randomized controlled trial. Deceased donors with reduced left ventricular ejection fraction or needing vasopressors were included. We randomized participants to a 20 μg bolus followed by a 20 μg/h infusion of levothyroxine or an identically appearing placebo. We report the proportion of recruited participants, the time to the administration of the study drug, and protocol violations. Twenty-four participants (N = 24/104; 23.1%) were eligible. Five of them (N = 5/24; 20.8%) were excluded by the attending physician. Four others were not included, due to family refusal for research (n = 2/24;8.3%) and unavailability of research staff (n = 2/24; 8.3%). Fifteen participants were randomized (N = 15/104; 14.4%). Mean time between the echocardiography and the initiation of the drug was 1.73 hours, and14 (93.3%) of 15 of the participants received the drug within 2 hours after the echocardiography. We report no study violation. The study was stopped prematurely because of low recruitment. This pilot trial suggests that the success of a definitive randomized control trial to assess the efficacy of levothyroxine in deceased donors could benefit from a multicenter recruitment and education on the evidence surrounding the pharmacological management of organ donors. The need for consent to research interventions in deceased donors should also be clarified.

Dex-CSDH randomised, placebo-controlled trial of dexamethasone for chronic subdural haematoma: report of the internal pilot phase

The Dex-CSDH trial is a randomised, double-blind, placebo-controlled trial of dexamethasone for patients with a symptomatic chronic subdural haematoma. The trial commenced with an internal pilot, whose primary objective was to assess the feasibility of multi-centre recruitment. Primary outcome data collection and safety were also assessed, whilst maintaining blinding. We aimed to recruit 100 patients from United Kingdom Neurosurgical Units within 12 months. Trial participants were randomised to a 2-week course of dexamethasone or placebo in addition to receiving standard care (which could include surgery). The primary outcome measure of the trial is the modified Rankin Scale at 6 months. This pilot recruited ahead of target; 100 patients were recruited within nine months of commencement. 47% of screened patients consented to recruitment. The primary outcome measure was collected in 98% of patients. No safety concerns were raised by the independent data monitoring and ethics committee and only five patients were withdrawn from drug treatment. Pilot trial data can inform on the design and resource provision for substantive trials. This internal pilot was successful in determining recruitment feasibility. Excellent follow-up rates were achieved and exploratory outcome measures were added to increase the scientific value of the trial.

External Validation of the MEESSI Acute Heart Failure Risk Score: A Cohort Study.

The MEESSI-AHF (Multiple Estimation of risk based on the Emergency department Spanish Score In patients with AHF) score was developed to predict 30-day mortality in patients presenting with acute heart failure (AHF) to emergency departments (EDs) in Spain. Whether it performs well in other countries is unknown. To externally validate the MEESSI-AHF score in another country. Prospective cohort study. (ClinicalTrials.gov: NCT01831115). Multicenter recruitment of dyspneic patients presenting to the ED. The external validation cohort included 1572 patients with AHF. Calculation of the MEESSI-AHF score using an established model containing 12 independent risk factors. Among 1572 patients with adjudicated AHF, 1247 had complete data that allowed calculation of the MEESSI-AHF score. Of these, 102 (8.2%) died within 30 days. The score predicted 30-day mortality with excellent discrimination (c-statistic, 0.80). Assessment of cumulative mortality showed a steep gradient in 30-day mortality over 6 predefined risk groups (0 patients in the lowest-risk group vs. 35 [28.5%] in the highest-risk group). Risk was overestimated in the high-risk groups, resulting in a Hosmer-Lemeshow P value of 0.022. However, after adjustment of the intercept, the model showed good concordance between predicted risks and observed outcomes (P= 0.23). Findings were confirmed in sensitivity analyses that used multiple imputation for missing values in the overall cohort of 1572 patients. External validation was done using a reduced model. Findings are specific to patients with AHF who present to the ED and are clinically stable enough to provide informed consent. Performance in patients with terminal kidney failure who are receiving long-term dialysis cannot be commented on. External validation of the MEESSI-AHF risk score showed excellent discrimination. Recalibration may be needed when the score is introduced to new populations. The European Union, the Swiss National Science Foundation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, and University Hospital Basel.

A Cost-Effectiveness Analysis Comparing Clinical Decision Rules PECARN, CATCH, and CHALICE With Usual Care for the Management of Pediatric Head Injury

To determine the cost-effectiveness of 3 clinical decision rules in comparison to Australian and New Zealand usual care: the Children's Head Injury Algorithm for the Prediction of Important Clinical Events (CHALICE), the Pediatric Emergency Care Applied Research Network (PECARN), and the Canadian Assessment of Tomography for Childhood Head Injury (CATCH). A decision analytic model was constructed from the Australian health care system perspective to compare costs and outcomesof the 3 clinical decision rules compared with Australian and New Zealand usual care. The study involved multicenter recruitment from 10 Australian and New Zealand hospitals; recruitment was based on the Australian Pediatric Head Injury Rules Study involving 18,913 children younger than 18 years and with a head injury, and with Glasgow Coma Scale score 13 to 15 on presentation toemergency departments (EDs). We determined the cost-effectiveness of the 3 clinical decision rules compared with usual care. Usual care, CHALICE, PECARN, and CATCH strategies cost on average AUD $6,390, $6,423, $6,433, and $6,457 per patient, respectively. Usual care was more effective and less costly than all other strategies and is therefore the dominant strategy. Probabilistic sensitivity analyses showed that when simulated 1,000 times, usual care dominated all clinical decision rules in 61%, 62%, and 60% of simulations (CHALICE, PECARN, and CATCH, respectively). The difference in cost between all rules was less than $36 (95% confidence interval -$7 to $77) and the difference in quality-adjusted life-years was less than 0.00097 (95% confidence interval 0.0015 to 0.00044). Results remained robust under sensitivity analyses. This evaluation demonstrated that the 3 published international pediatric head injury clinical decision rules were not more cost-effective than usual care in Australian and New Zealand tertiary EDs. Understanding the usual care context and the likely cost-effectiveness is useful before investing in implementation of clinical decision rules or incorporation into a guideline.

Characteristics of Randomized Trials Focusing on Stroke due to Intracerebral Hemorrhage: Systematic Review.

The absence of treatments for intracerebral hemorrhage with significant consistent benefit in randomized controlled trials (RCTs) could be because of lack of treatment efficacy or the design of RCTs. We searched the Cochrane Stroke Group Trials Register in December 2015 for completed and published RCTs reporting clinical outcome in adults with intracerebral hemorrhage. We collected data on publication year and language, study characteristics, and effect size. We regarded RCTs to be at lower risk of bias if they performed ≥2 of describing randomization, using blinding, or specifying the primary outcome. We registered this systematic review (PROSPERO, international prospective register of systematic reviews CRD42016051103). We found 136 eligible RCTs: 57% were phase II, 76% were single center, 98% studied acute treatments, 49% involved drug interventions, 24% were placebo-controlled, the primary outcome was death or disability in 30%, and median sample size was 77 (interquartile range, 47-160). Forty-six percent explained randomization, 24% blinded treatment allocation, and 24% specified the primary outcome such that 38 (28%) were at lower risk of bias. RCTs at lower risk of bias were more likely to use multicenter recruitment (adjusted odds ratio, 6.95; 95% confidence interval, 2.2-21.5) and be published in English (adjusted odds ratio, 12.9, 95% confidence interval, 2.7-62.5). RCTs with larger sample sizes were independently more likely to be phase III/IV (P<0.01) and use multicenter recruitment (P<0.01). RCTs at lower risk of bias had smaller pooled treatment effects on death/disability (P=0.02). Intracerebral hemorrhage RCTs have often been at high risk of bias, and these RCTs have been characterized by small sample sizes and larger effect sizes.

The effects of glycine on auditory mismatch negativity in schizophrenia

Glycine increases N-methyl-d-aspartate receptor (NMDAR) mediated glutamatergic function. Mismatch negativity (MMN) is a proposed biomarker of glutamate-induced improvements in clinical symptoms, however, the effect of glycine-mediated NMDAR activation on MMN in schizophrenia is not well understood. This study aimed to determine the effects of acute and 6-week chronic glycine administration on MMN in schizophrenia patients. MMN amplitude was compared at baseline between 22 patients (schizophrenia or schizoaffective disorder; receiving stable antipsychotic medication; multi-centre recruitment) and 21 age- and gender-matched controls. Patients underwent a randomised, double-blind, placebo-controlled clinical trial with glycine added to their regular antipsychotic medication (placebo, n=10; glycine, n=12). MMN was reassessed post-45-minutes of first dose (0.2g/kg) and post-6-weeks treatment (incremented to 0.6g/kg/day). Clinical symptoms were assessed at baseline and post-6-weeks treatment. At baseline, duration MMN was smaller in schizophrenia compared to controls. Acute glycine increased duration MMN (compared to placebo), whilst this difference was absent post-6-weeks treatment. Six weeks of chronic glycine administration improved PANSS-Total, PANSS-Negative and PANSS-General symptoms compared to placebo. Smaller baseline duration MMN was associated with greater PANSS-Negative symptoms and predicted (at trend level) PANSS-Negative symptom improvement post-6-weeks glycine treatment (not placebo). These findings support the benefits of chronic glycine administration and demonstrate, for the first time, that acute glycine improves duration MMN in schizophrenia. This result, together with smaller baseline duration MMN predicting greater clinical treatment response, suggests the potential for duration MMN as a biomarker of glycine-induced improvements in negative symptoms in schizophrenia.

Abstract OT1-04-03: Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS)

Abstract Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m2/day, Day 2 to Day 4) and cisplatin (70 mg/m2, Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM. Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-03.

The assessment of fetal brain growth in diabetic pregnancy using in utero magnetic resonance imaging

To assess fetal brain growth over the third trimester in pregnant women with diabetes using in utero magnetic resonance imaging (iuMRI) to determine if greater brain growth occurs in type 1 (T1DM) when compared to gestational (GDM) diabetes mellitus. Each consented participant was scanned at three fixed times during the third trimester using iuMRI. One hundred and fifty-seven patients were approached, 48 participants were recruited, and 36 complete data sets were analysed. Three-dimensional (3D) iuMRI volume data sets were manually segmented using software to construct models of the fetal brain from which brain volumes could be calculated. Inter-rater analysis was performed, and volume differences and growth rates were compared between T1DM and GDM. Recruitment proved difficult with low uptake and high attrition rates (77.1%). Inter-rater analysis revealed excellent correlation (intraclass correlation coefficient=0.93, p<0.001) and agreement with no significant difference between operators (p=0.194). There was no evidence of increased brain volume in the T1DM group. Growth rates between visit 1 and 3 for T1DM and GDM were not significantly different (p=0.095). T1DM brain volumes were not significantly larger than GDM volumes and there was no significant divergence of brain growth over the third trimester. Constructing volume models from 3D iuMRI acquisitions is a novel technique that can be used to assess fetal brain growth. No specialist software or knowledge is required. Larger studies attempting to recruit pregnant women in the later stages of pregnancy should employ multicentre recruitment to overcome recruitment difficulties and high attrition rates.