Future Trials Research Articles

Design and methodology for a proof of mechanism study of individualized neuronavigated continuous Theta burst stimulation for auditory processing in adolescents with autism spectrum disorder.

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.

Validation of a modified version of the gross motor function measure in PPPR5D related neurodevelopmental disorder

BackgroundProtein phosphatase 2 regulatory subunit B’ Delta (PPP2R5D)-related neurodevelopmental disorder is a rare genetic condition caused by pathogenic variants in the PPP2R5D gene. Clinical signs include hypotonia, gross motor delay, intellectual disability (ID), epilepsy, speech delays, and abnormal gait among other impairments. As this disorder was recognized within the last decade, there are only 103 people published diagnoses to date. A thorough understanding of the motor manifestations of this disorder has not yet been established. Knowledge of the natural history of PPP2R5D related neurodevelopmental disorder will lead to improved standard of care treatments as well as serve as a baseline foundation for future clinical trials. Appropriate outcome measures are necessary for use in clinical trials to uniformly measure function and monitor potential for change. The aim of this study was to validate the gross motor function measure (GMFM) in children and adults with PPP2R5D-related neurodevelopmental disorder in order to better characterize the disorder.ResultsThirty-eight individuals with PPP2R5D pathogenic variants, median age 8.0 years (range 1–27) were evaluated. Gross motor, upper limb and ambulatory function were assessed using the GMFM-66, six-minute walk test (6MWT), 10-meter walk run (10MWR), timed up and go (TUG), and revised upper limb module (RULM). The pediatric disability inventory computer adapted test (PEDI-CAT) captured caregiver reported assessment. Median GMFM-66 score was 60.6 (SD = 17.3, range 21.1–96.0). There were strong associations between the GMFM-66 and related mobility measures, 10MWR (rs = −0.733; p < 0.001), TUG (rs= −0.747; p = 0.003), 6MWT (r = 0.633; p = 0.006), RULM (r = 0.763; p < 0.001), PEDICAT-mobility (r = 0.855; p < 0.001), and daily activities (r = 0.822; p < 0.001) domains.ConclusionsThe GMFM is a valid measure for characterizing motor function in individuals with PPP2R5D related neurodevelopmental disorder. The GMFM-66 had strong associations with the RULM and timed function tests which characterized gross motor, upper limb and ambulatory function demonstrating concurrent validity. The GMFM-66 was also able to differentiate between functional levels in PPP2R5D related neurodevelopmental disorder demonstrating discriminant validity. Future studies should examine its sensitivity to change over time, ability to identify sub-phenotypes, and suitability as an outcome measure in future clinical trials in individuals with PPP2R5D variants.

Predicting subgroup treatment effects for a new study: Motivations, results and learnings from running a data challenge in a pharmaceutical corporation.

We present the motivation, experience, and learnings from a data challenge conducted at a large pharmaceutical corporation on the topic of subgroup identification. The data challenge aimed at exploring approaches to subgroup identification for future clinical trials. To mimic a realistic setting, participants had access to 4 Phase III clinical trials to derive a subgroup and predict its treatment effect on a future study not accessible to challenge participants. A total of 30 teams registered for the challenge with around 100 participants, primarily from Biostatistics organization. We outline the motivation for running the challenge, the challenge rules, and logistics. Finally, we present the results of the challenge, the participant feedback as well as the learnings. We also present our view on the implications of the results on exploratory analyses related to treatment effect heterogeneity.

An online clinical decision tool to screen for vertebral fragility fractures (Vfrac) in older women presenting with back pain in general practice: protocol for a feasibility study in preparation for a future cluster randomised controlled trial

SummaryThis feasibility study for a future definitive randomized trial assesses the use and acceptability of a new clinical decision tool to identify risk of a vertebral fracture and those who should be referred for spinal radiography in women aged 65 or over presenting to primary care with back pain.PurposeApproximately 12% of older adults have vertebral fragility fractures, but currently fewer than one-third are diagnosed, potentially limiting access to bone protection treatment. Vfrac is a vertebral fracture screening tool which classifies individuals into high or low risk of having a vertebral fracture, allowing targeting of spinal radiographs to high-risk individuals. The objective of this study was to investigate the feasibility of conducting a cluster randomized controlled trial to evaluate the use of an online version of Vfrac in primary care.MethodsThe study will run in six general practices, with three given the Vfrac tool for use on older women (> 65 years) consulting with back pain and three using standard clinical processes for managing such back pain. Anonymised data covering a 12-month period will be collected from all sites on consultations by older women with back pain. Focus groups will be undertaken with healthcare professionals and patients on whom the tool was used to understand the acceptability of Vfrac and identify factors that impact its use. These patients will be sent a paper version of the Vfrac questionnaire to self-complete at home. Outputs of the self-completion Vfrac (high versus low risk) will be compared with the face-to-face Vfrac (high versus low risk), and agreement assessed using Cohen’s kappa.ResultsThis study will evaluate the use and acceptability of Vfrac within primary care and determine if data on resource use can be collected accurately and comprehensively.ConclusionsThis article describes the protocol of the Vfrac feasibility study.Trial registrationISRCTN18000119 (registered 01/03/2022) and ISRCTN12150779 (registered 10/01/2022).

Prognostic impact of HER2 biomarker levels in trastuzumab-treated early HER2-positive breast cancer

BackgroundOverexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab.MethodsThis retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS).ResultsThe analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4–5.3, p = 0.003 and HR = 2.1, CI 1.1–3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4–5.1, p = 0.003 and HR = 2.8, CI 1.4–5.5, p = 0.004, respectively) compared to those with intermediate levels.ConclusionsOur findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.

Early Detection of Disease Progression in Metastatic Cancers: Could CTCs Improve RECIST Criteria?

Early detection of disease progression is a crucial issue in the management of cancer patients, especially in metastatic settings. Currently, treatment selection mostly relies on criteria based on radiologic evaluations (RECIST). The aim of the present retrospective study is to evaluate the potential inclusion of circulating tumor cells (CTCs) in hybrid criteria. CTC counts from a total of 160 patients with different metastatic tumors were analyzed for this purpose. In our cohort, 73 patients were affected by breast cancer, 69 by colorectal cancer and 18 by prostate cancer. PFS and OS were evaluated according to the corresponding prediction of disease progression by CTCs and RECIST criteria. In breast cancer, CTC-I has an important impact on the progression-free survival (PFS) and overall survival (OS) values. When CTC-I predicted earlier than RECIST-I, the disease progression, the PFS and OS were shorter with respect to the opposite case. In particular, PFS was 11 (5-16) vs. 34 (23-45)-with p < 0.001-and OS was 80 (22-138) vs. 116 (43-189), p = 0.33. The results suggest a promising role of CTCs as complementary information which could significantly improve the clinical outcomes, and they encourage consideration of future trials to evaluate new hybrid criteria, particularly for patients with breast cancer.

Feasibility, Acceptability, and Preliminary Effectiveness of a Combined Digital Platform and Community Health Worker Intervention for Patients With Heart Failure: Protocol for a Randomized Controlled Trial.

Interventions focused on remote monitoring and social needs care have shown promise in improving clinical outcomes for patients with heart failure (HF). However, patient willingness to use technology as well as concerns about access in underresourced settings have limited digital platform implementation and adoption. There is little research in HF populations examining the effect of a combined digital and social needs care intervention that could enhance patient engagement in digital platform use while closing gaps in care related to social determinants of health. Here, we describe the protocol for a clinical trial of a digitally enabled community health worker intervention designed for patients with HF. This study aims to describe the protocol for a randomized controlled trial assessing the acceptability, feasibility, and preliminary effectiveness of an intervention that combines remote monitoring with a digital platform and community health worker (CHW) social needs care for patients with HF who are transitioning from hospital to home. Given the elevated morbidity and mortality, identifying comprehensive and patient-centered interventions at the time of hospital care transitions that can improve clinical outcomes, impact cost, and augment the quality of care for this cohort is a priority. This trial randomized adult inpatient participants (n=50) with a diagnosis of HF receiving care at a single academic health care institution to the 30-day intervention (digital platform+CHW pairing+usual care) or the 30-day control (CHW pairing+usual care) arms. All study participants completed baseline questionnaires and 30-day exit interviews and questionnaires. The primary outcomes will be acceptability, feasibility, and preliminary effectiveness. This clinical trial opened for enrollment in September 2022 and was completed in June 2023. Initial results are expected to be published in the spring of 2024, and analysis is currently underway. Feasibility outcome measures will include the use rates of the biometric sensor (average hours per day), the digital blood pressure monitor (average times per day), the weight scale (average times per day), and the completion of the symptoms questionnaire (average times per day). The acceptability outcome will be measured by the patients' response to the truthfulness of the statement that they would be willing to use the digital platform in the future (response options: very true, somewhat true, or not true). Preliminary effectiveness will be measured by tracking 30-day clinical outcomes (hospital readmissions, emergency room visits, and missed primary care and cardiology appointments). The results of this investigation are expected to contribute to our understanding of the use of digital interventions and the implementation of supportive home-based social needs care to enhance engagement and the potential effectiveness of clinically focused digital platforms. These results may inform the construction of a future multi-institutional trial designed to test the true effectiveness of this intervention in HF. ClinicalTrials.gov NCT05130008; https://clinicaltrials.gov/study/NCT05130008. DERR1-10.2196/55687.

A Pilot Randomized Controlled Trial Evaluating Peer Recovery Coaches for Addiction Recovery among Indigenous Americans

Addiction is a common and devastating problem among many Indigenous American (IA) groups around the United States. Too few IA health care providers are available to deliver care in a way that leverages IA values and traditions to support addiction recovery. Peer Recovery Coaches (PRCs) are individuals who have lived experience of addiction and have received specialized training in helping others in recovery. IA PRCs hold significant potential in helping to fill the gap of culturally-specific support in addiction. In this feasibility trial, we recruited a total of 120 adult (≥19 years) IAs with a substance use disorder through Facebook advertisements. Ninety participants were randomized to the PRC (experimental) group which received support from PRC and 30 to the Attention-Control (AC) group which received support from research nurse. Both groups received weekly support for 12 weeks. Participants completed weekly surveys during the 12-week intervention and monthly surveys during a three-month follow-up phase. The two groups had similar quantities of alcohol consumed, days of alcohol use, and days of drug use except that the PRC group had fewer days of alcohol use in the first three weeks of the intervention phase (2.05 days v. 3.5 days, p=0.04). We found that “support and advocacy” was the most common intervention provided by the PRC. The PRC intervention was widely accepted and appreciated by individuals who completed the program with 79% of individuals giving positive feedback regarding the PRCs and the remaining 21% giving neutral feedback. This trial provides some insights upon which future trials can draw to further evaluate the potential of PRCs in this hard-to-reach population with a high level of need. Trials or programs that rely on national recruitment may be successful in reaching a sufficient number of individuals but they may lack the more intensive in-person capacity that will likely help with retention. Despite this limitation, the current pilot demonstrated that racially-concordant PRC services likely have a high degree of acceptability among IA populations. Future studies may draw on these findings by having trained IA coaches recruit and work with individuals in-person to assist with higher levels of retention.

Priorities for efficacy trials of gender-affirming hormone therapy with estrogen: collaborative design and results of a community survey.

Treatment guidelines for gender-affirming hormone therapy with estrogen (GAHT-E) recommend specific dosing regimens based on limited data. Well-controlled efficacy trials are essential to tailoring treatment to patient goals as the guidelines recommend. The goal of this study was to take a foundational step toward designing community-centered effectiveness trials for gender-diverse individuals seeking GAHT-E. Our team developed a cross-sectional survey based on broad clinical experience and consultation with our community advisory board. The survey included 60 items covering demographics, transition history, goals and priorities for treatment, indicators of treatment success, sexual function goals, and future research priorities. The survey was distributed during the summer of 2021, primarily through social networks designed for gender-expansive individuals seeking treatment with estrogen. A total of 1270 individuals completed the survey. Overall treatment goals most frequently rated "extremely important" or "very important" were the following: (1) improved satisfaction with life (81%), (2) appearing more feminine (80%), (3) appearing less masculine (77%), (4) improved mental health (76%), and (5) being seen as your true gender by others (75%). The three body characteristics most frequently rated "highest priority" or "high priority" among changes were the following: (1) facial hair (85%), (2) breast shape or size (84%), and (3) body shape (80%). The highest-rated research priority was comparing feminization with different routes of estrogen administration. The goals and experiences of individuals seeking GAHT-E are diverse. Future clinical trials of GAHT-E should be grounded in the needs and priorities of community stakeholders.

The effective combination therapies with irinotecan for colorectal cancer.

Colorectal cancer is the third most common type of cancer worldwide and has become one of the major human disease burdens. In clinical practice, the treatment of colorectal cancer has been closely related to the use of irinotecan. Irinotecan combines with many other anticancer drugs and has a broader range of drug combinations. Combination therapy is one of the most important means of improving anti-tumor efficacy and overcoming drug resistance. Reasonable combination therapy can lead to better patient treatment options, and inappropriate combination therapy will increase patient risk. For the colorectal therapeutic field, the significance of combination therapy is to improve the efficacy, reduce the adverse effects, and improve the ease of treatment. Therefore, we explored the clinical advantages of its combination therapy based on mechanism or metabolism and reviewed the rationale basis and its limitations in conducting exploratory clinical trials on irinotecan combination therapy, including the results of clinical trials on the combination potentiation of cytotoxic drugs, targeted agents, and herbal medicine. We hope that these can evoke more efforts to conduct irinotecan in the laboratory for further studies and evaluations, as well as the possibility of more in-depth development in future clinical trials.

Treatment of chronic symptoms following mild traumatic brain injury with transcranial LED: a sham run-in pilot study of photobiomodulation therapy

ABSTRACT Primary Objective We evaluated whether photobiomodulation with red/near infrared light applied transcranially via light emitting diodes (LED) was associated with reduced symptoms and improved cognitive functioning in patients with chronic symptoms following mild traumatic brain injury. Research Design Participants (3 men, 6 women; 22–61 years-old) underwent a 6-week intervention involving 18 40-minute transcranial LED treatment sessions. Methods and Procedures Reliable change indices were calculated for 10 neuropsychological test scores and 3 self-report questionnaires of subjective cognition, post-concussion symptoms, and depression at baseline and following treatment. Questionnaires were also administered after 2-week sham and at 1-month and 2-month follow-ups. Main Outcome and Results Only 2 participants improved on neuropsychological testing. On questionnaires, 4 reported improved cognition, 5 reported improved post-concussion symptoms, and 3 reported improved depression. Significant improvement in 2 or more domains was reported by 4 participants and mostly maintained at both follow-ups. Conclusions Most participants did not improve on neuropsychological testing. A minority self-reported improvement in symptoms, potentially explained by the intervention, psychiatric medication changes, placebo effects, or other factors. Selecting participants with different clinical characteristics, and dosing and delivery system changes, may produce different results. A study design accounting for placebo effects appears warranted in future trials.

Mechanism matters: mortality and endothelial cell damage marker differences between blunt and penetrating traumatic injuries across three prehospital clinical trials.

Injury mechanism is an important consideration when conducting clinical trials in trauma. Mechanisms of injury may be associated with differences in mortality risk and immune response to injury, impacting the potential success of the trial. We sought to characterize clinical and endothelial cell damage marker differences across blunt and penetrating injured patients enrolled in three large, prehospital randomized trials which focused on hemorrhagic shock. In this secondary analysis, patients with systolic blood pressure < 70 or systolic blood pressure < 90 and heart rate > 108 were included. In addition, patients with both blunt and penetrating injuries were excluded. The primary outcome was 30-day mortality. Mortality was characterized using Kaplan-Meier and Cox proportional-hazards models. Generalized linear models were used to compare biomarkers. Chi squared tests and Wilcoxon rank-sum were used to compare secondary outcomes. We characterized data of 696 enrolled patients that met all secondary analysis inclusion criteria. Blunt injured patients had significantly greater 24-h (18.6% vs. 10.7%, log rank p = 0.048) and 30-day mortality rates (29.7% vs. 14.0%, log rank p = 0.001) relative to penetrating injured patients with a different time course. After adjusting for confounders, blunt mechanism of injury was independently predictive of mortality at 30-days (HR 1.84, 95% CI 1.06-3.20, p = 0.029), but not 24-h (HR 1.65, 95% CI 0.86-3.18, p = 0.133). Elevated admission levels of endothelial cell damage markers, VEGF, syndecan-1, TM, S100A10, suPAR and HcDNA were associated with blunt mechanism of injury. Although there was no difference in multiple organ failure (MOF) rates across injury mechanism (48.4% vs. 42.98%, p = 0.275), blunt injured patients had higher Denver MOF score (p < 0.01). The significant increase in 30-day mortality and endothelial cell damage markers in blunt injury relative to penetrating injured patients highlights the importance of considering mechanism of injury within the inclusion and exclusion criteria of future clinical trials.

Impact of postoperative cardiovascular complications on 30-day mortality after major abdominal surgery: an international prospective cohort study.

Cardiovascular complications after major surgery are associated with increases in morbidity and mortality. There is confusion over definitions of cardiac injury or complications, and variability in the assessment and management of patients. This international prospective cohort study aimed to define the incidence and timing of these complications and to investigate their impact on 30-day all-cause mortality. We performed a prospective, international cohort study between January 2022 and May 2022. Data were collected on consecutive patients undergoing major abdominal surgery in 446 hospitals from 28 countries across Europe. The primary outcome measure was cardiovascular complications as defined by the Standardised Endpoints for Perioperative Medicine-Core Outcome Measures for Perioperative and Anaesthetic Care initiative up to 30 days after surgery. The secondary outcome was 30-day postoperative mortality. This study included 24,203 patients, of whom 611 (2.5%) developed cardiovascular complications. In total, 458 (1.9%) patients died within 30 days of surgery, of which 123 (26.9%) deaths were judged to be cardiac-related. Mortality rates were higher in patients who developed postoperative cardiovascular complications than in those who did not (19.8% vs. 1.4%), which persisted after risk adjustment (hazard ratio (95%CI) 4.15 (3.14-5.48)). We estimated an absolute risk reduction (95%CI) of 0.4 (0.3-0.5) in mortality in the absence of all cardiovascular complications. This would confer a relative risk reduction in mortality of 21.1% if all cardiovascular complications were prevented. Postoperative cardiovascular complications are relatively common and occur early after major abdominal surgery. However, over 1 in 5 postoperative deaths were attributable to these complications, highlighting an important area for future randomised trials.

Optic nerve sheath diameter measurements to predict delayed neurological sequelae after carbon monoxide poisoning

Objectives Delayed neurological sequelae are a major complication of carbon monoxide poisoning. However, today there is still no objective screening tool for predicting delayed neurological sequelae in patients with carbon monoxide poisoning. The present study aimed to assess the usefulness of optic nerve sheath diameter measurements in predicting delayed neurological sequelae after carbon monoxide poisoning. Methods In this retrospective study, patients with a diagnosis of carbon monoxide poisoning in the emergency department from 2010 to 2021 were included in the study. Right and left optic nerve sheath diameters were calculated based on cranial computed tomography scans, and the presence of delayed neurological sequelae was evaluated. Results The mean (± standard deviation) optic nerve sheath diameter in patients who developed delayed neurological sequelae was statistically significantly greater on both the right and left compared to patients who did not develop delayed neurological sequelae (right; 5.02 ± 0.06 mm versus 4.89 ± 0.07 mm, P < 0.001; left; 5.03 ± 0.09 mm versus 4.85 ± 0.10 mm, P < 0.001). A multivariate linear regression analysis revealed that carboxyhemoglobin and both right and left optic nerve sheath diameter were the factors associated with the delayed neurological sequelae. Discussion The present study revealed that optic nerve sheath diameter measurements may be a useful screening tool to predict delayed neurological sequelae after carbon monoxide poisoning. The ability to predict a poor neurological prognosis in carbon monoxide poisoning is important for initiating early rehabilitation interventions and make help future trials. Limitations of this study include that normal optic nerve sheath diameters are not well established, and that not every patient underwent computed tomography. Conclusions Optic nerve sheath diameters measurements may be a helpful screening tool for predicting delayed neurological sequelae after carbon monoxide poisoning.

Abstract WP128: Using Clinical Data to Reclassify ESUS Patients to Either Large Artery Atherosclerotic or Cardioembolic Stroke Mechanisms

Introduction: Defining the specific underlying pathophysiology of ischemic stroke is critical for minimizing the risk of recurrent events with personalized secondary prevention treatments. A notable portion of ischemic strokes are classified as embolic stroke of undetermined source (ESUS), leaving these patients without optimal treatment tailored to their pathophysiology. Hypothesis: Standard clinically collected data can reliably reclassify a substantial portion of ESUS patients into either a large artery atherosclerotic (LAA) or cardioembolic (CE) cause. Methods: A statistical model was developed to discriminate LAA from CE using a retrospective cohort of ischemic stroke patients treated at the University of Washington. A total of 189 patients were included (79 CE and 61 LAA to train the model, 49 ESUS patients to assess reclassification). Sixteen candidate predictors were collected across several sources: clinical risk factors, blood tests, echocardiography, ECG, and neurovascular imaging (Table 1). The LASSO (least absolute shrinkage and selection operator) was used to select important predictors in a penalized logistic regression model with stroke etiology (LAA vs. CE) as the outcome. ESUS patients were considered reclassified if the model-based probability of CE or LAA was at least 75%. Results: Of 189 patients, the mean (SD) age was 68 (14) years and 40% were women. The LASSO selected 12 predictors to discriminate CE vs. LAA (Table 1), with a corresponding cross-validated C-statistic = 0.87 (95% CI: 0.82-0.94). When the model was applied to the 49 ESUS patients, 23 (47%) were reclassified to LAA and 6 (12%) to CE. Conclusions: A multivariate model based on standard clinical data can separate LAA from CE with a high degree of discrimination. Applying this model led to reclassification to either LAA or CE in 59% of ESUS patients. Such approaches may enable more personalized secondary prevention strategies, but need to be tested in future trials.

Collaborative care model versus usual care for the management of musculoskeletal and co-existing mental health conditions: a randomised feasibility mixed-methods study

ObjectiveThis study aimed to assess the feasibility of a future trial comparing the collaborative care model with usual care for patients with musculoskeletal conditions and co-existing symptoms of anxiety and...

Whole-school interventions promoting student commitment to school to prevent substance use and violence, and improve educational attainment: a systematic review.

Whole-school interventions modify the school environment to promote health. A subset of these interventions promotes student commitment to school to prevent substance (tobacco, alcohol, other drugs) use and/or violence. A previous review identified the theory of human functioning and school organisation as a comprehensive theory of such interventions, and found evidence that these interventions reduce substance use and/or violence. The objectives were to search for, appraise and synthesise evidence to address the following questions: (1) What whole-school interventions promoting student commitment to school to prevent substance use and/or violence have been evaluated, what intervention subtypes are apparent and how closely do these align with the theory of human functioning and school organisation? (2) What factors relating to setting, population and intervention affect implementation? (3) What are the effects on student substance use, violence and educational attainment? (4) What is the cost-effectiveness of such interventions? (5) Are intervention effects mediated by student commitment to school or moderated by setting or population? A total of 56 information sources were searched (in January 2020), then an updated search of 48 of these was carried out (in May 2021). Reference lists were also searched and experts were contacted. Eligible studies were process/outcome evaluations of whole-school interventions to reduce student violence or substance use among students aged 5-18 years attending schools, via actions aligning with the theory of human functioning and school organisation: modifying teaching to increase engagement, enhancing student-staff relationships, revising school policies, encouraging volunteering or increasing parental involvement. Data extraction and quality assessments used existing tools. Theory and process reports were synthesised qualitatively. Outcome and economic data were synthesised narratively; outcome data were meta-analysed. Searches retrieved 63 eligible reports on 27 studies of 22 interventions. We identified four intervention subtypes focused on student participation in school-wide decisions, improving staff-student relationships, increasing engagement in learning and involving parents. The theories of change of most intervention subtypes aligned closely with the theory of human functioning and school organisation, and informed refinement of an intervention theory of change. Theories of change for interventions increasing learning engagement did not align with this theory, aiming instead to increase school commitment primarily via social skills curricula. Factors influencing the implementation included whether or not interventions were tailorable, workable and well explained. Interventions with action groups comprising staff/students, etc. and providing local data were well implemented. Implementation was also affected by whether or not schools accepted the need for change and staff had the resources for delivery. Meta-analyses suggest small, but significant, intervention effects in preventing violence victimisation and perpetration, and substance use. There was sparse and inconsistent evidence of moderation and some evidence of mediation by student commitment to school. Two economic evaluations suggested that there is the potential for the interventions to be cost-effective. The quality of the studies was variable and the economic synthesis was limited to two studies. Whole-school interventions aiming to promote student commitment to school share similar theories of change and factors affecting implementation. They have the potential to contribute to preventing violence and substance use among young people. Future trials should aim to optimise intervention effectiveness by better theorisation, and assess implementation and effect moderators and mediators. This study is registered as PROSPERO CRD42019154334. This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 17/151/05) and is published in full in Public Health Research; Vol. 12, No. 2. See the NIHR Funding and Awards website for further award information.

A meta-analysis of overall survival and response in metastatic adrenocortical carcinoma: A review of 23 prospective trials of 880 patients.

4 Background: Metastatic adrenocortical carcinoma (mACC) is a rare, aggressive tumour of the adrenal gland, with historically poor survival and limited established treatment modalities. The aim of this study was to systematically search for and analyse all prospective trials for mACC to establish benchmark response and survival outcomes. The study was registered on PROSPERO CRD42023430557. Methods: A systematic review and meta-analysis of five databases was performed between June 2023- July 2023. Key outcomes extracted included patient demographics, overall survival (OS), progression-free survival (PFS) and objective response rates (ORR). ORR was calculated using a random effects model and inverse variance methods. Time-to-event outcomes including PFS and OS, were extracted digitally from available Kaplan- Meier curves using the IPDfromKM tool and individual patient data (IPD) was generated as per Guyot et al. The PFS and OS data from individual studies were then pooled using a multivariate extension of the DerSimonian–Laird method to generate summary survival curves. Results: The final 23 trials (5 Phase 1b, 16 Phase II and 3 Phase 3) encompassed 880 patients were retrieved. Pooled ORR was 9.0% overall (2.9% for targeted therapy, 12.3% for chemotherapy and 15.3% for immunotherapy). Median OS was 9.9 months (7.4 months for targeted therapy, 11.2 months for chemotherapy and 10.6 months for immunotherapy). Median PFS was 2.6 months (2.7 months for targeted therapy, 3.0 months for chemotherapy and 2.1 months for immunotherapy). Kaplan-Meier curves for OS were available for 10 treatment lines (n = 605), with a pooled median OS of 9.9 months (95% CI 7.7-11.9) and 12-month OS of 41.6% (95CI 33.1-51.2). Median OS was 7.4 months for patients receiving targeted therapy (95% CI 4.7–12.0), 11.2 months for patients receiving chemotherapy (95% CI 6.9–14.7) and 10.6 months for patients receiving immunotherapy (95% CI 4.4–13.2]. 12-month OS was 30.4% (95% CI 15.9-58.3) for patients receiving targeted therapy, 45.4% (95% CI 33.7-61.2) for patients receiving chemotherapy and 45.3% (95% CI 36.2-56.6) for patients receiving immunotherapy. Conclusions: This study found that current treatments strategies confer limited survival and response benefit in mACC and highlight the need for research into the pathogenesis and novel strategies in the disease. Immunotherapy and chemotherapy demonstrate modest benefits for patients and future trials should attempt to surpass the survival benchmarks set in this study.

Abstract B025: MHC class II and CD1d expressing conventional dendritic cells with immunoglobulin therapy drives anti-tumor abscopal effect by recruiting Natural Killer T cells to the tumor microenvironment

Abstract Background Dendritic cells (DC) are the primary antigen presenting cells in the body responsible for processing and presenting MHC Class I and II antigens to initiate adaptive T cell response against cancer. In addition to MHC, DC also express non-classical receptors such as CD1d to activate invariant TCR α chain natural killer T (iNKT) cells. The conventional type-I dendritic cells (cDC1) presenting MHC class-II tumor associated antigens within tumor microenvironment (TME) have shown robust efficacy in mouse models of breast cancer (BC). Here, we have extended prior knowledge to deliver DC-based therapeutics, co-presenting class II antigens and CD1d directly to TME to show the potential of co-stimulation of multiple effector T cells in combination of tumor specific antibody (IgG1) mediating antibody dependent cellular cytotoxicity (ADCC). We hypothesize that merger of adaptive and innate responses will attain greater pathologic response in pre-clinical and clinical settings to design futuristic therapeutics against BC. Methods Present study uses variety of pre-clinical mouse models of BC and other types of cancer to test the therapeutic efficacy of intratumoral delivery of mouse bone marrow-derived conventional type I (CD103+ CD1d+) polarized DC pulsed with MHC class II HER2-derived peptides (HER2-DC1) in combination with systemic delivery of tumor specific IgG1 (aSEMA4D) to evoke ADCC. Cellular mechanism of response was evaluated using downstream methods including multiplex immunofluorescence, flow cytometry, and transcriptomics assays. Results We exhibit that specifically intratumoral combination therapy of HER2-DC1 expressing CD1d and aSEMA4D primes both innate and adaptive immune responses to completely regress tumor in 75-80% of mice with significant survival advantage in comparison to mice that received no therapy or monotherapies. The early CD4 Th1 response through interferon gamma combined with ADCC played a critical role in the decrease of pro-tumorigenic myeloid cells and increase in anti-tumor effector cells with a major contribution from classical CD4+ NKT cells within the TME. Interestingly, intratumoral combination therapy intensified DC1 migration from primary tumor to secondary tumor sites along with dynamic changes in subpopulations of DC with an associated increase in NKT cells at untreated tumor sites to display abscopal effect. Likewise, early data from phase I/II clinical trial illustrated great potential of cDC1 and IgG1 combination therapy to recruit anti-tumor effector cells such CD8 and NKT cells to mediate cancer eradication in HER2+ BC setting. Conclusions Specifically, intratumoral delivery of HER2-DC1 in combination with anti-tumor antibody mediating ADCC shows great promise for future BC clinical trials and improved patient outcomes. Furthermore, present study highlighted the role of NKT cells in favorable anti-tumor response. Our future studies are focused on understanding the crosstalk between DC and NKT to modulate the function of various cell types in TME to design improved cancer immunotherapies. Citation Format: Saurabh K Garg, Colin Snyder, Ganesan Ramamoorthi, Elizabeth E Evans, Amy L Aldrich, Namrata Gautam, Doris Wiener, Marie C Lee, Hyo S Han, Koski K Gary, Brian J Czerniecki. MHC class II and CD1d expressing conventional dendritic cells with immunoglobulin therapy drives anti-tumor abscopal effect by recruiting Natural Killer T cells to the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B025.

Early recurrence, time-to-recurrence, and recurrence patterns: Assessing their impact on survival outcomes in head and neck squamous cell carcinoma (R/M-HNSCC) patients treated with first line platinum-based chemotherapy.

R/M-HNSCC patients typically receive 1L platinum-based chemotherapy with pembrolizumab or cetuximab. However, the outcomes for patients with early recurrence (<6 months) remain unclear due to their exclusion from most 1L studies. This study aimed to assess the impact of time-to-recurrence intervals (TTRI) and recurrence patterns on the survival of R/M-HNSCC patients. We identified non-curable R/M-HNSCC patients at our institution from 1/2008 through 6/2020. We analyzed the outcomes of early recurrent patients who received 1L systemic treatment, with different TTRIs and recurrence patterns. Our study included 234 eligible patients. The majority (47%) experienced early recurrence (<6 months), while 22%, 20%, and 11% had recurrences at 6-12 months, >12 months, and de novo metastasis, respectively. The platinum-based regimen was the most commonly used chemotherapy (86%), with cetuximab and immunotherapy utilized in 3% and 5% of cases, respectively. Significant differences in PFS and OS were observed among TTRI groups. For patients with early recurrence, both platinum-doublet and monotherapy treatments significantly improved OS. Locoregional recurrence (47%) was the most common, followed by distant metastasis (22%) and both (20%). Recurrence patterns were significantly associated with OS but not with PFS. In multivariate analysis, TTRI ≥12 months significantly correlated with improved PFS (HR 0.51; p = 0.004) and OS (HR 0.58; p = 0.009), whereas recurrent pattern did not. TTRI significantly influenced the survival, while recurrence patterns did not. In our study, the retrospective design limited our ability to definitively establish whether early recurrent R/M-HNSCC patients would benefit more from platinum-doublet. Despite poor prognosis, early recurrent patients benefited from 1L systemic treatments. Given the variation in prognoses, TTRI should be considered a stratification factor in future clinical trials.