Planning Of Future Clinical Trials Research Articles

Roadmap for the next generation of Children's Oncology Group rhabdomyosarcoma trials.

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

Genetic Background Strongly Influences the Impact of Carrying the Thr92Ala-DIO2 Polymorphism in the Male Mouse.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.

Treatment Effect Modifiers for Return-to-Work in Patients With Musculoskeletal Disorders

Investigating how individual characteristics modify treatment effects can improve understanding, interpretation, and translation of trial findings. The purpose of this secondary analysis was to identify treatment effect modifiers of the MI-NAV trial, a 3 arm, parallel randomized controlled trial which compared motivational interviewing and stratified vocational advice intervention in addition to usual case management (UC), to UC alone. This study included (n = 514) participants with musculoskeletal disorders on sick leave for at least 50% of their contracted work hours for at least 7 consecutive weeks with the Norwegian Labour and Welfare Administration. Sickness absence days was the primary outcome, measured from baseline assessment date until the 6-month follow-up. Potential treatment effect modifiers, identified a priori and informed by expert consultation and literature, were evaluated using linear regression models and statistical interaction tests. For motivational interviewing versus UC, age (mean difference [MD] −.7, 95% confidence interval [CI] −1.5 to .2; P = .13) and self-perceived health status (MD −.3, 95% CI −.7 to .1; P = .19) were identified as potential effect modifiers (P ≤ .2). For stratified vocational advice intervention versus UC, analgesic medication use (MD −26.2, 95% CI −45.7 to −6.7; P = .009) was identified as a treatment effect modifier (P ≤ .05). These findings may assist in more targeted treatment adaptation and translation as well as the planning of future clinical trials. PerspectiveThis secondary analysis of the MI-NAV trial found that analgesic medication use, age, and self-perceived health may modify the effect of 2 vocational interventions on reducing sickness absence in people with musculoskeletal disorders.

Dietary prevention strategies for childhood asthma.

Asthma is the most common chronic disease in childhood and a rise in prevalence has been observed concomitantly with changing dietary habits in the Western world. This change has favored a more Westernized diet characterized by high intake of processed food and fat in contrast to a Mediterranean diet high in fruit, vegetable and fish intake. This has resulted in a decreased intake of several antioxidants and micronutrients including n-3 long-chained polyunsaturated fatty acids and vitamin D that are speculated to have anti-inflammatory effects and hold immunoregulatory properties. Several observational studies have investigated associations between dietary intake and wheeze and asthma but only few large well-conducted randomized controlled trials (RCTs) have been performed investigating the primary preventive effect of micronutrient supplementations. Currently, the recommendations from the Global Initiative for Asthma (GINA) for primary prevention of asthma in children do not include maternal dietary changes or supplementations during pregnancy, although the most recent report mentions both specific dietary patterns and micronutrients as potential protective supplementation regimes. This review will present the current literature and future research needs focusing on primary and secondary prevention of both early and late childhood asthma from dietary intake during pregnancy and early childhood to highlight potential preventive effects of specific dietary patterns and micronutrient supplements, which may facilitate the planning of future clinical trials in search of a preemptive strategy.

Phenotypic analysis of HIV-1 resistance to CD4 binding site broadly-neutralizing antibodies

Abstract Broadly neutralizing antibodies (bNAbs) show strong immunotherapy potential by targeting conserved regions of the HIV-1 envelope. Single bNAb use in viremic individuals quickly results in the emergence of escape variants, likely originating from existing quasispecies. An ex vivo assay was developed to predict bNAb efficacy in viremic individuals. The development of a predictive bNAb efficacy model may assist with the planning of future clinical trials. The ex vivoassay used pre-infusion CD4 +T cells from participants enrolled in the VRC 607/ACTG A5378 phase I study of the CD4 binding site (CD4bs) bNAbs’ VRC01LS (n=7) or VRC07-523LS (n=9). From these assays, the escape variant signatures of outgrowth viruses that replicated in presence of CD4bs bNAbs, were identified. We found that these escape variants contained key changes to the ß23-V5 region of the gp120 envelope, including charge changes, glycan loss, and/or glycan shifts. Outgrowth viruses from each participant had similar escape mutation patterns. Resistance mutations of the viral env sequences were confirmed in pseudovirus-based neutralization assays. We found complementary escape profiles from 3 CD4bs bNAbs (1–18LS, N6LS, and VRC01v23) with ex vivoand neutralization assays showing suppression by 1 or 2 but not all 3 bNAbs, supporting the potential for combination bNAb therapy. Our data suggest that the simultaneous use of multiple CD4 binding site bNAbs together could aid in limiting viral escape. Supported by intramural funds from NIH.

A Proposal for Post Hoc Subgroup Analysis in Support of Regulatory Submission.

In clinical trials, it is not uncommon that the primary analysis fails to achieve the study objective for demonstrating the safety and efficacy of a test treatment under investigation, while a specific sub-population analysis shows a significant positive result. In this case, whether the observed positive sub-population analysis results can be used in support of regulatory submission of the test treatment under investigation is an interesting question to both the investigator(s) and the regulatory medical/statistical reviewers. In this article, several statistical evaluations for confirming the integrity and validity of the observed sub-population analysis results were proposed in support of the regulatory submission. Selection bias caused by looking at one subgroup is adjusted before all statistical evaluations, including reproducibility, consistency between sub-population and the entire population, generalizability between the promising sub-population and other sub-populations, and sensitivity index when there are shifts in mean and/or variability between sub-populations. The multiplicity issue is also addressed in measuring generalizability. A numerical example of a global (multi-regional) clinical trial was presented for illustration purposes. The choice of applying which estimation approach relies on the scale of test statistics. Recommendations for incorporating statistical evaluations in measuring sub-population analysis are provided. Finally, we proposed possible solutions such as real-world data and real-world evidence for regulatory concerns, which may increase the insufficient power. Sub-population analysis can contribute to regulatory submission if it passes the evaluation. This analysis can also support hypothesis generation and the planning of future clinical trials, though it fails to pass the measurement process.

GCT-04. Pattern of Treatment Failures in Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT): A Pooled Analysis of Clinical Trials

Abstract BACKGROUND: Central Nervous System- Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, treatment failures remain a poorly characterized disease with unfavorable outcomes. In this study, we sought to characterize the treatment failures in a large cohort of prospectively treated patients. METHODS: European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol-guidelines were included as an independent, non-overlapping cohort. RESULTS: A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy and additional eleven patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients’ metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; p=0.026). In our analysis, focal or whole ventricular (WVI) radiation therapy was not associated with an increased risk of metastatic relapses. CONCLUSIONS: Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses, are associated with elevated tumor markers, and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Pattern of treatment failures in patients with central nervous system non-germinomatous germ cell tumors (CNS-NGGCT): A pooled analysis of clinical trials.

Central Nervous System Non-Germinomatous Germ Cell Tumors (CNS-NGGCT) are rare but curable tumors. Due to their rarity, patients with treatment failures remain a poorly characterized group with unfavorable outcomes. In this study, we sought to characterize patients with treatment failures in a large, prospectively treated cohort. European and North American clinical trials for patients with CNS-NGGCT (SIOP-GCT-96, SFOP-TGM-TC 90/92, COG-ACNS0122, and COG-ACNS1123) were pooled for analysis. Additionally, patients included and treated in the UK and France national registries under strict protocol guidelines were included as an independent, non-overlapping cohort. A total of 118 patients experienced a treatment failure. Twenty-four patients had progressive disease during therapy, and additional 11 patients were diagnosed with growing teratoma syndrome (GTS). Patients with GTS are significantly younger and present with local failures and negative tumor markers. Eighty-three individuals experienced disease relapses after treatment ended. Patients' metastatic relapses presented significantly earlier than local relapses and were associated with tumor marker elevation (OR: 4.39; P = .026). In our analysis, focal or whole-ventricular radiation therapy was not associated with an increased risk of metastatic relapses. Herein, we present the largest pooled dataset of prospectively treated patients with relapsed CNS-NGGCT. Our study identified younger age and negative tumor markers to be characteristic of GTS. Additionally, we elucidated that metastatic relapses occur earlier than local relapses are associated with elevated tumor markers and are not associated with the field of radiation therapy. These findings are of utmost importance for the planning of future clinical trials and the implementation of surveillance strategies in these patients.

Neuroblastoma signalling models unveil combination therapies targeting feedback-mediated resistance

Very high risk neuroblastoma is characterised by increased MAPK signalling, and targeting MAPK signalling is a promising therapeutic strategy. We used a deeply characterised panel of neuroblastoma cell lines and found that the sensitivity to MEK inhibitors varied drastically between these cell lines. By generating quantitative perturbation data and mathematical modelling, we determined potential resistance mechanisms. We found that negative feedbacks within MAPK signalling and via the IGF receptor mediate re-activation of MAPK signalling upon treatment in resistant cell lines. By using cell-line specific models, we predict that combinations of MEK inhibitors with RAF or IGFR inhibitors can overcome resistance, and tested these predictions experimentally. In addition, phospho-proteomic profiling confirmed the cell-specific feedback effects and synergy of MEK and IGFR targeted treatment. Our study shows that a quantitative understanding of signalling and feedback mechanisms facilitated by models can help to develop and optimise therapeutic strategies. Our findings should be considered for the planning of future clinical trials introducing MEKi in the treatment of neuroblastoma.

Cardioprotective mechanisms of mitochondria-targeted S-nitrosating agent and adenosine triphosphate-sensitive potassium channel opener are mutually exclusive

BackgroundMyocytes exposed to stress exhibit significant swelling and reduced contractility. These consequences are ameliorated by adenosine triphosphate–sensitive potassium (KATP) channel opener diazoxide (DZX) via an unknown mechanism. KATP channel openers also provide cardioprotection in multiple animal models. Nitric oxide donors are similarly cardioprotective, and their combination with KATP activation may provide synergistic benefit. We hypothesized that mitochondria-targeted S-nitrosating agent (MitoSNO) would provide synergistic cardioprotection with DZX. MethodsMyocyte volume and contractility were compared following Tyrode's physiologic solution (20 minutes) and stress (hyperkalemic cardioplegia [CPG] ± DZX; n = 5-20 each; 20 minutes) with or without MitoSNO (n = 5-11 each) at the end of stress, followed by Tyrode's solution (20 minutes). Isolated mouse hearts received CPG ± DZX (n = 8-10 each) before global ischemia (90 minutes) with or without MitoSNO (n = 8 each) at the end of ischemia, followed by reperfusion (30 minutes). Left ventricular (LV) pressures were compared using a linear mixed model to assess the impact of treatment on the outcome, adjusting for baseline and balloon volume. ResultsStress (CPG) was associated with reduced myocyte contractility that was prevented by DZX and MitoSNO individually; however, their combination was associated with loss of cardioprotection. Similarly, DZX and MitoSNO improved LV function after prolonged ischemia compared with CPG alone, and cardioprotection was lost with their combination. ConclusionsMitoSNO and DZX provide cardioprotection that is lost with their combination, suggesting mutually exclusive mechanisms of action. The lack of a synergistic beneficial effect informs the current knowledge of the cardioprotective mechanisms of DZX and will aid planning of future clinical trials.

Proposed guidance on cost-avoidance studies in pharmacy practice.

Cost-avoidance studies of pharmacist interventions are common and often the first type of study conducted by investigators to quantify the economic impact of clinical pharmacy services. The purpose of this primer is to provide guidance for conducting cost-avoidance studies pertaining to clinical pharmacy practice. Cost-avoidance studies represent a paradigm conceptually different from traditional pharmacoeconomic analysis. A cost-avoidance study reports on cost savings from a given intervention, where the savings is estimated based on a counterfactual scenario. Investigators need to determine what specifically would have happened to the patient if the intervention did not occur. This assessment can be fundamentally flawed, depending on underlying assumptions regarding the pharmacists' action and the patient trajectory. It requires careful identification of the potential consequence of nonaction, as well as probability and cost assessment. Given the uncertainty of assumptions, sensitivity analyses should be performed. A step-by-step methodology, formula for calculations, and best practice guidance is provided. Cost-avoidance studies focused on pharmacist interventions should be considered low-level evidence. These studies are acceptable to provide pilot data for the planning of future clinical trials. The guidance provided in this article should be followed to improve the quality and validity of such investigations.

P176 Self-management of depression in axial spondyloarthritis using internet-delivered cognitive behavioural therapy: a feasibility study

Abstract Background/Aims Depression is common among axial spondyloarthritis (axSpA) patients and is associated with greater axSpA disease severity. Cognitive behavioural therapy (CBT) is recommended by NICE, but access is often limited. Internet-delivered CBT (iCBT) is efficacious for treating depression in other healthcare settings. The aims of this study were to: 1) test the acceptability of iCBT for axSpA patients with depressive symptoms; and 2) evaluate whether it changes symptoms of anxiety/depression, well-being, quality of life, or axSpA disease activity. Methods Adults with a rheumatologist diagnosis of axSpA with at least mild depression on screening (Patient Health Questionnaire-4 (PHQ4) score ≥3) were enrolled onto the “Space in Chronic Pain from Depression and Anxiety” programme, comprising 10 modules covering the core CBT concepts. It could be completed at the participants’ own pace over 8 weeks, with commitment of 30-45 minutes/week. Each week, a trained supporter reviewed each participant’s progress and promoted continued engagement. Participants completed BASDAI, spinal pain, BASFI, the Hospital Anxiety and Depression Scale (HADS), Warwick-Edinburgh Wellbeing Scale (WBS) and EQ5D-5L at baseline and week 8. Results Between June 2019 and March 2020, 35 axSpA patients were recruited. The mean age was 50 years (SD 12) and 54% were males. The mean PHQ4 was 8.6 (SD 2.5). All participants were sent email invitations and reminders; 18 (51%) signed up. Six (17%) remained active for the full 8 weeks. The median time actively enrolled in the program was 6.3 weeks (IQR 0, 8.0), and the total time spent was a median of 2.1 hrs (IQR 2.0, 11.0); 5 did not return after the first day. There were no meaningful changes in any of the secondary outcomes between baseline and week 8. P176 Table 1:Did not sign upSigned upp-valueN1718Age, mean (SD)47.4 (11.6)52.9 (11.5)0.16Male, n (%)11 (65%)8 (44%)0.23PHQ4, mean (SD)8.4 (2.6)8.8 (2.5)0.67BASDAI baseline, mean (SD)6.1 (1.6)5.0 (2.3)0.26Spinal pain baseline, mean (SD)5.4 (2.1)5.3 (2.7)0.88BASFI baseline, mean (SD)6.1 (2.5)4.5 (2.6)0.19Delay from invitation to start, days, median (IQR)na1.0 (0.0, 14.0)naTotal weeks active in the programme, median (IQR)na6.3 (0, 8.0)naNumber of log-ins, median (IQR)na8.0 (2.0, 11.0)naTotal time spent, Hours, median (IQR)na2.1 (0.7, 3.4)naNumber of progress checks, median (IQR)na5.0 (4.0, 7.0)na Conclusion iCBT may be a useful intervention for axSpA patients with depression. However, low levels of engagement and high attrition rates (common in intervention studies of depression) resulted in only 17% completing the full programme. These figures will be essential for planning of future clinical trials in this area. Future work could also consider strategies to promote engagement and use and potential adaptation of interventional content for iCBT delivery in this population. Disclosure S.S. Zhao: None. D. Richards: Other; DR is the Chief Science Officer for SilverCloud Health. N. Goodson: None.

Cholinergic nucleus 4 atrophy and gait impairment in Parkinson's disease.

There is evidence that cortical cholinergic denervation contributes to gait and balance impairment in Parkinson's Disease (PD), especially reduced gait speed. The objective of this study was to determine the relationship between cholinergic basal forebrain gray matter density (GMD) and gait in PD patients. We investigated 66 PD patients who underwent a pre-surgical evaluation for a neurosurgical procedure to treat motor symptoms of PD. As part of this evaluation patients had a brain MRI and formal gait assessments. By applying probabilistic maps of the cholinergic basal forebrain to voxel-based morphometry of brain MRI, we calculated gray matter density (GMD) for cholinergic nucleus 4 (Ch4), cholinergic nucleus 1, 2, and 3 (Ch123), and the entire cortex. Reduced Ch4 GMD was associated with reduced Fast Walking Speed in the "on" medication state (FWSON, p = 0.004). Bilateral cortical GMD was also associated with FWSON (p = 0.009), but Ch123 GMD was not (p = 0.1). Bilateral cortical GMD was not associated with FWSON after adjusting for Ch4 GMD (p = 0.44). While Ch4 GMD was not associated with improvement in Timed Up and Go (TUG) or Cognitive TUG in the "on" medication state, reduced Ch4 GMD was associated with greater percent worsening based on dual tasks (p = 0.021). Reduced Ch4 GMD is associated with slower gait speed in PD and greater percent worsening in TUG during dual tasks in patients with PD. These findings have implications for planning of future clinical trials investigating cholinergic therapies to improve gait impairment in PD.

Clinically advanced renal cell carcinoma (RCC) and renal sarcoma (RSC) in young patients: A comprehensive genomic profiling (CGP) study.

5066 Background: We queried whether the landscape of genomic alterations (GA) would differ in patients with metastatic RCC under 40 years of age (under40) and patients 40 years of age or older (over40). Methods: FFPE tissues from 2,128 clinically advanced RCC and 25 RSC underwent hybrid-capture based CGP to evaluate all classes of GA. Samples were classified at time of sequencing as the following RCC subtypes: clear cell (ccRCC), papillary (papRCC), chromophobe (chrRCC), medullary (medRCC), collecting duct (cdRC), sarcomatoid (sarcRCC) and NOS (nosRCC). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA. Tumor cell PD-L1 expression was determined by IHC (Dako 22C3). Results: The male preponderance increased in the over40 patients. The GA/tumor increased in the over40 cohorts except for medRCC. Similarly, TMB was consistently higher in over40 groups. MSI high status was virtually absent. PD-L1 expression, available only in small subsets, was generally absent although 44% high positive staining in sarcRCC was noteworthy. Differences in GA in under40 vs over40 RCC were seen and included increased PBRM1 and SETD2 GA in over40 vs under40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in over40 vs under40 papRCC; increased TP53 and decreased VHL, BAP1, SETD2 and PTEN in over40 vs under40 chrRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in over40 vs under 40 sarcRCC; and increased TP53, VHL and TERT in over40 vs under40 nosRCC. Changes in GA in under40 vs over40 medRCC, cdRCC and RSC were noted but insufficient cases prevented further evaluation. Conclusions: When separately evaluated by under/over 40 years of age, CGP of clinically advanced RCC demonstrates differences in genomic landscapes with over40 cases featuring increasing male preponderance, higher GA/tumor, higher TMB and increases in a variety of GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of metastatic RCC. [Table: see text]

Metastatic renal cell carcinoma (mRCC) in young patients: A comprehensive genomic profiling (CGP) study.

727 Background: We studied the genomic alterations (GA) in patients with mRCC under 40 years of age (<40) and patients 40 years of age or older (>40). Methods: 2,128 mRCC underwent hybrid-capture based CGP. Clear cell (ccRCC), papillary (pRCC), sarcomatoid (sRCC), NOS (nosRCC), chromophobe (chrRCC), medullary (medRCC) and collecting duct (cdRCC) were separately evaluated. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Male preponderance in all subsets increased in the >40 patients. The GA/tumor increased significantly in the >40 cohorts except for in medRCC. The relatively low TMB was higher in all >40 and MSI high status was infrequent in all groups. PD-L1 expression was generally low, the 44% high positive PD-L1 in sRCC was noteworthy. Significant differences in GA in <40 vs >40 RCC included increased PBRM1 and SETD2 GA in >40 vs <40 ccRCC; increased C DKN2A/B and TERT and decreased FH GA in >40 vs <40 pRCC; increased TP53, PTEN and TERT GA with decreased NF2 GA in >40 vs <40 sRCC; increased TP53, VHL and TERT in >40 vs <40 nosRCC. Changes in GA in <40 vs >40 chrRCC, medRCC and cdRCC were noted but insufficient cases prevented statistical evaluation. Conclusions: When evaluated by age, CGP of mRCC demonstrates significant differences in the genomic landscapes with >40 cases featuring increasing male preponderance and higher GA/tumor, TMB and increases in TP53, CDKN2A/B and TERT GA. These findings may play important roles in the planning of future clinical trials designed to personalize the treatment of mRCC.[Table: see text]

Protocol for a systematic review of reporting standards of anaesthetic interventions in randomised controlled trials

IntroductionThere is significant variation in how anaesthesia is defined and reported in clinical research. This lack of standardisation complicates the interpretation of published evidence and planning of future clinical trials....

Editors' note: Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment

In their prospective observational study of 166 survivors of cardiac arrest with anoxic brain injury, Beretta and colleagues categorized patients according to 1 of 4 mutually exclusive EEG patterns: (1) benign, (2) refractory status epilepticus (RSE), (3) generalized periodic discharges (GPDs), or (4) discontinuous/unreactive. The investigators assessed long-term survival and functional outcome based on a minimum of 5 days of EEG monitoring and other clinical and serologic biomarkers. In response, Dr. Nitin Sethi stresses how EEG patterns may vary with time following anoxic brain injury. Dr. Beretta agrees that EEG patterns are likely to fluctuate with time (and treatment) and, for this reason, classified patients according to the most severe pattern observed. Interrater agreement for each of these EEG categories was high (κ = 0.92). Importantly, patients with discontinuous or unreactive background activity or GPDs had extremely poor outcomes (mortality rates of 85% and 98%, respectively), whereas those with RSE had a 53% chance of long-term survival and 44% chance of a good functional outcome. Dr. Sethi also raises several concerns as to when one should initiate EEG monitoring and at what point one should use this electrophysiological data for neuroprognostication. In this investigation, Dr. Beretta and colleagues found a mean duration of RSE to be 4.7 days and therefore suggested 5 days as a reasonable initial assessment point for prognostication. This information may be helpful in the planning of future clinical trials, especially because a pattern of RSE may be associated with a better prognosis than GPD or discontinuous activity. In their prospective observational study of 166 survivors of cardiac arrest with anoxic brain injury, Beretta and colleagues categorized patients according to 1 of 4 mutually exclusive EEG patterns: (1) benign, (2) refractory status epilepticus (RSE), (3) generalized periodic discharges (GPDs), or (4) discontinuous/unreactive. The investigators assessed long-term survival and functional outcome based on a minimum of 5 days of EEG monitoring and other clinical and serologic biomarkers. In response, Dr. Nitin Sethi stresses how EEG patterns may vary with time following anoxic brain injury. Dr. Beretta agrees that EEG patterns are likely to fluctuate with time (and treatment) and, for this reason, classified patients according to the most severe pattern observed. Interrater agreement for each of these EEG categories was high (κ = 0.92). Importantly, patients with discontinuous or unreactive background activity or GPDs had extremely poor outcomes (mortality rates of 85% and 98%, respectively), whereas those with RSE had a 53% chance of long-term survival and 44% chance of a good functional outcome. Dr. Sethi also raises several concerns as to when one should initiate EEG monitoring and at what point one should use this electrophysiological data for neuroprognostication. In this investigation, Dr. Beretta and colleagues found a mean duration of RSE to be 4.7 days and therefore suggested 5 days as a reasonable initial assessment point for prognostication. This information may be helpful in the planning of future clinical trials, especially because a pattern of RSE may be associated with a better prognosis than GPD or discontinuous activity.

Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials

BackgroundFunding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we...

WMH and long-term outcomes in ischemic stroke: A systematic review and meta-analysis.

To investigate the relationship between baseline white matter hyperintensities (WMH) in patients with ischemic stroke and long-term risk of dementia, functional impairment, recurrent stroke, and mortality. Following the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO protocol: CRD42018092857), we systematically searched Medline and Scopus for cohort studies of ischemic stroke patients examining whether MRI- or CT-assessed WMH at baseline are associated with dementia, functional impairment, recurrent stroke, and mortality at 3 months or later poststroke. We extracted data and evaluated study quality with the Newcastle-Ottawa scale. We pooled relative risks (RR) for the presence and severity of WMH using random-effects models. We included 104 studies with 71,298 ischemic stroke patients. Moderate/severe WMH at baseline were associated with increased risk of dementia (RR 2.17, 95% confidence interval [CI] 1.72-2.73), cognitive impairment (RR 2.29, 95% CI 1.48-3.54), functional impairment (RR 2.21, 95% CI 1.83-2.67), any recurrent stroke (RR 1.65, 95% CI 1.36-2.01), recurrent ischemic stroke (RR 1.90, 95% CI 1.26-2.88), all-cause mortality (RR 1.72, 95% CI 1.47-2.01), and cardiovascular mortality (RR 2.02, 95% CI 1.44-2.83). The associations followed dose-response patterns for WMH severity and were consistent for both MRI- and CT-defined WMH. The results remained stable in sensitivity analyses adjusting for age, stroke severity, and cardiovascular risk factors, in analyses of studies scoring high in quality, and in analyses adjusted for publication bias. Presence and severity of WMH are associated with substantially increased risk of dementia, functional impairment, stroke recurrence, and mortality after ischemic stroke. WMH may aid clinical prognostication and the planning of future clinical trials.

Abstract B128: Timing and sequence of CpG and anti-OX40 is critical for in situ vaccination

Abstract Immunotherapy seeks to enhance or manipulate host antitumor immunity by various approaches, among them, in situ vaccination. In situ vaccination is a local intervention in which immune enhancing agents are injected locally into one site of tumor, triggering a T-cell immune response locally that then travels to attack cancer throughout the body. We have employed a preclinical strategy whereby the same syngeneic tumor is implanted at two separate sites in the body. One tumor is then injected with the test agents and the resulting systemic immune response, if any, is detected by the regression of the distant, untreated tumor. In this test for abscopal therapeutic effects, the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG)—a TLR9 ligand—and agonist anti-OX40 antibody has provided the most impressive results. This combination lead to durable disease control and long-term treatment-free survival in multiple mouse models of cancer. CpG induced myeloid cells to secrete cytokines, which subsequently induced OX40 expression on T-cells. Thus, we hypothesized that administration sequence and timing may affect the antitumor responses of in situ vaccination. In order to screen for the best sequence and timing we implanted A20 lymphoma tumors bilaterally in opposite sides of the abdomen of Balb/C mice. After tumors were established, one tumor was injected at the selected sequence and timing with the test agents and the resulting immune response was monitored by the measuring growth of the distant, untreated tumor. The systemic antitumor response required the presence of both CD4+ and CD8+ T-cells, as mice treated with the corresponding depleting antibodies were unable to control tumor growth. Even a single injection of low-dose CpG (50µg) and anti-OX40 (8µg) resulted in a fully protective systemic immune response. In addition, the cured animals were protected from rechallenge with the same A20 tumor but not unrelated tumors. Decreasing the dose even further to 10µg CpG and 1µg anti-OX40 partially preserved the therapeutic response with a long-term survival of 60%. Concurrent administration of CpG and anti-OX40 resulted in eradication of both local and distant disease. Sequential administration of CpG followed by anti-OX40 preserved the therapeutic efficacy. However, sequential administration of anti-OX40 followed by CpG significantly attenuated the therapeutic effect. While CpG followed by a 24- or 48-hour-delayed anti-OX40 treatment preserved the therapeutic efficacy of concurrent therapy, 72h delay in anti-OX40 administration resulted in reduced therapeutic effect. These data demonstrate the importance of the administration sequence for fully protective and curative antitumor immune responses. Our data suggest that the anti-OX40 antibody should be administered at the same time as CpG or somewhat delayed but not the other way around. The combination of anti-OX40 and CpG is currently studied in a phase I trial. Our results here impact the planning of future clinical trials of in situ vaccination with these two agents. Citation Format: Idit Sagiv-Barfi, Debra K. Czerwinski, Ronald Levy. Timing and sequence of CpG and anti-OX40 is critical for in situ vaccination [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B128.