Pre-specified Interval Research Articles

Short-Term and Long-Term Mortality Risk After Preterm Birth

Preterm birth (PTB) is a leading cause of neonatal mortality. However, evidence on mortality beyond the neonatal period is limited, especially in North America. To examine associations of PTB with all-cause and cause-specific mortality from birth through 23 to 36 years of age. This population-based matched cohort study of live births in Canada included individuals born between January 1, 1983, and December 31, 1996, and followed up until December 31, 2019. Data were analyzed from June 1, 2023, to April 30, 2024. PTBs, between 24 and 37 weeks' gestation (with gestational age [GA]-specific subcategories of 24 to 27 weeks, 28 to 31 weeks, 32 to 33 weeks, and 34 to 36 weeks) compared with term births (37-41 weeks' gestation). All-cause mortality and cause-specific mortality were the main outcomes. Risk differences (RDs) and risk ratios (RRs) were estimated for all-cause mortality using log-binomial regressions and hazard ratios were estimated for cause-specific mortality using Cox proportional hazards regression models (censoring individuals who died from other causes) within prespecified age intervals (ages 0-11 months and ages 1-5, 6-12, 13-17, 18-28, and 29-36 years). Observed confounding was accounted for using coarsened exact matching on baseline characteristics. Of 4 998 560 births (54.2% male), 6.9% were born preterm (with GA-specific subcategories of 0.3% born at 24-27 weeks, 0.6% at 28-31 weeks, 0.8% at 32-33 weeks, and 5.1% at 34-36 weeks). During a median of 29 years of follow-up, 72 662 individuals died (14 312 born preterm and 58 350 at term). PTB was associated with an increased risk of death in all age intervals, with the highest RDs and RRs from birth through infancy (ages 0-11 months) (RD, 2.29% [95% CI, 2.23%-2.35%]; RR, 11.61 [95% CI, 11.09-12.15]) and in early childhood (ages 1-5 years) (RD, 0.34% [95% CI, 0.31%-0.36%]; RR, 2.79 [95% CI, 2.61-2.98]) and the lowest RDs and RRs among those between ages 18 and 28 years (RD, 0.07% [95% CI, 0.04%-0.10%]; RR, 1.13 [95% CI, 1.07-1.19]). We identified increased risks of mortality associated with several causes, including respiratory, circulatory, and digestive system disorders; nervous system, endocrine, and infectious diseases; cancers; congenital malformations; and conditions originating in the perinatal period. No associations were found for external causes of deaths. Associations by GA categories suggested lower risks with higher GA. The findings of this population-based matched cohort study suggest that individuals born preterm were at an increased risk of death from birth until their third and fourth decades of life, with higher risks as GA decreased. Some of these associations may have been partly due to underlying health determinants that affected PTB and mortality. These findings suggest that PTB should be recognized as a risk factor for mortality and could inform preventive strategies.

Comparative bioavailability of single-dose zavegepant during and between migraine attacks: A phase 1, randomized, open-label, fixed-sequence, two-period study.

To compare the rate and extent of absorption of zavegepant 10 mg (therapeutic dose) or 20 mg (supratherapeutic dose) nasal spray during a migraine attack versus non-migraine period, assess safety, and explore efficacy and the relationship between zavegepant concentration and therapeutic response. Physiologic changes occurring during a migraine attack could affect the pharmacokinetics of treatments for migraine. This was a Phase 1, multicenter, open-label, randomized, single-dose, two-period, fixed-sequence, comparative bioavailability study. Participants with a history of 2-8 migraine attacks per month of moderate or severe pain intensity were randomized to a single dose of zavegepant 10 or 20 mg, administered intranasally during a migraine attack (Period 1) and in a non-migraine period (Period 2). Blood samples were collected pre-dose and at pre-specified intervals up to 24 h post-dose for plasma zavegepant concentration measurement. Safety was monitored throughout, and efficacy (migraine pain intensity score, nausea, photophobia, phonophobia, aura, and functional disability) assessed during Period 1. Plasma zavegepant pharmacokinetic parameters were calculated by standard noncompartmental methods, including maximum plasma concentration (Cmax), area under plasma concentration-time curve from time zero to infinity (AUC0-inf), and time of Cmax (Tmax). A total of 37 participants were evaluable for pharmacokinetics. Following administration of zavegepant 10 mg, geometric mean ratios for Period 1/Period 2 were 82.8% (90% confidence interval [CI] 60.5-113.2) for Cmax and 90.1% (90% CI 70.2-115.5) for AUC0-inf. Following administration of zavegepant 20 mg, geometric mean ratios for Period 1/Period 2 were 72.5% (90% CI 57.9-90.8) for Cmax and 73.4% (90% CI 58.8-91.7) for AUC0-inf. Averaging over the study period, geometric mean ratios for zavegepant 20 mg/10 mg were 142.5% (90% CI 118.6-171.4) for Cmax and 157.0% (90% CI 133.6-184.5) for AUC0-inf. Median Tmax was 0.5 h for both doses regardless of Period. Zavegepant was well tolerated in both study periods and effective during Period 1 at both dose levels. There was no apparent correlation between concentration at 0.5 h or 2 h post-dose and efficacy outcomes. Zavegepant exposure was comparable during a migraine attack and a non-migraine period, particularly at the therapeutic dose of 10 mg. When averaging over migraine and non-migraine periods, there was a less-than-dose proportional increase in zavegepant exposure when the dose was doubled from 10 to 20 mg. The median Tmax was 0.5 h regardless of migraine attack or dose. Zavegepant 10 and 20 mg exhibited favorable safety profiles during migraine attacks and non-migraine periods, and were effective to relieve pain, associated symptoms, and functional disability during migraine attacks, with no apparent correlation between zavegepant concentration and efficacy outcomes.

Leveraging pharmacokinetic parameters as covariate in Bayesian logistic regression model to optimize dose selection in early phase oncology trial

ABSTRACT Dose selection and optimization in early phase of oncology drug development serves as the foundation for the success of late phases drug development. Bivariate Bayesian logistic regression model (BLRM) is a widely utilized model-based algorithm that has been shown to improve the accuracy for identifying recommended phase 2 dose (RP2D) based on dose-limiting-toxicity (DLT) over traditional method such as 3 + 3. However, it remains a challenge to optimize dose selection that strikes a proper balance between safety and efficacy in escalation and expansion phase of phase I trials. In this paper, we first use a phase I clinical trial to demonstrate how the variability of drug exposure related to pharmacokinetic (PK) parameters among trial participants may add to the difficulties of identifying optimal dose. We use simulation to show that concurrently or retrospectively fitting BLRM model for dose/toxicity data from escalation phase with dose-independent PK parameters as covariate lead to improved accuracy of identifying dose level at which DLT rate is within a prespecified toxicity interval. Furthermore, we proposed both model- and rule-based methods to modify dose at patient level in expansion cohorts based on their PK/exposure parameters. Simulation studies show this approach leads to higher likelihood for a dose level with a manageable toxicity and desirable efficacy margin to be advanced to late phase pipeline after being screened at expansion phase of phase I trial.

Adaptive Steroid Tapering Impedes Corticosteroid-free Remissions Compared with Forced Tapering in Clinical Trials of Ulcerative Colitis.

It is unclear if steroid tapering protocols can affect clinical trial outcomes in ulcerative colitis [UC], particularly fixed versus adaptive steroid tapering. Fixed steroid tapering involves incremental dose decreases at prespecified intervals, and adaptive steroid tapering uses investigator discretion as determined by the patient's response. In this post-hoc analysis from six clinical trials of UC [VARSITY, ACT 1, PURSUIT, GEMINI1, OCTAVE, and ULTRA2], responders to induction therapy with baseline corticosteroid use were considered as the primary population of interest. Adjustments were made to account for treat-through versus re-randomisation designs, and multivariate regression was performed to account for other potential confounding variables. The primary outcome was corticosteroid-free clinical remission [CR] at 1 year, and secondary outcomes were CR and endoscopic improvement. There was a total of 861 patients who had achieved clinical response after induction and were using corticosteroids. Within multivariate analysis, patients using adaptive steroid tapering regimens were less likely to achieve corticosteroid-free CR at 1 year (odds ratio [OR] 0.66 [95% confidence interval, CI, 0.48-0.92], p = 0.015) but had increased odds for achieving CR at 1 year (OR 1.9 [95% CI 1.43-2.52], p < 0.001). The steroid tapering regimen was not associated with achievement of endoscopic improvement at 1 year. Among patients with UC on corticosteroids in clinical trials, patients using adaptive steroid weaning regimens were less likely to achieve corticosteroid-free CR at 1 year but more likely to achieve CR at 1 year. Consideration should be given to implementing mandatory fixed steroid weaning protocols in future clinical trials of UC.

Addition of Mask to High-flow Nasal Oxygen: A Strategy to Improve Oxygenation in Hypoxemic Respiratory Failure Secondary to COVID-19.

High-flow nasal cannula (HFNO) reduces the need for invasive mechanical ventilation in COVID-19 patients with hypoxemic-respiratory failure. During HFNO entrainment of room air dilutes the delivered fractional inspiratory oxygen (FiO2), thereby preventing improvement in oxygenation. The placement of a mask over HFNO to improve oxygenation has provided conflicting results. We aimed to determine and compare the effect of placing various mask types over HFNO on oxygen saturation (SPO2). In this prospective physiological study 40 patients with COVID-19-associated hypoxemic respiratory failure on HFNO with O2 concentration <92% were included. The effect of placing different masks over HFNO on oxygenation, respiratory rate, heart rate, blood pressure, patient comfort, and partial pressure of carbon dioxide level (pCO2) was recorded after a prespecified time interval. We observed a significantly higher mean SPO2 and lower mean respiratory rate on using various study masks over HFNO compared to HFNO alone. On comparing various mask types, the use of N95 masks and nonrebreather (NRB) masks with O2 showed a significant increase in O2 concentration and reduction in respiratory rate compared to surgical mask (SM) and NRB without O2. The proportion of patients who achieved SPO2 of >92% was higher with the use of N95 masks (47.5%) or NRB with O2 (45%) over HFNO compared to SM (35%) and NRB without O2 (35%). No significant change was observed in heart rate, blood pressure, and CO2 level with the use of any mask over HFNO. This study demonstrates improvement in oxygenation and reduction in respiratory rate with the use of various masks over HFNO in patients of COVID-19-related hypoxemic-respiratory-failure. Significantly greater benefit was achieved with the use of N95 or NRB with O2 compared to SM or NRB without O2.

Spaced Digital Education for Health Professionals: Systematic Review and Meta-Analysis.

Spaced digital education applies digital tools to deliver educational content via multiple, repeated learning sessions separated by prespecified time intervals. Spaced digital education appears to promote acquisition and long-term retention of knowledge, skills, and change in clinical behavior. The aim of this review was to assess the effectiveness of spaced digital education in improving pre- and postregistration health care professionals' knowledge, skills, attitudes, satisfaction, and change in clinical behavior. This review followed Cochrane's methodology and PRISMA (Preferred Reporting Items of Systematic Reviews and Meta-Analyses) reporting guidelines. We searched MEDLINE, Embase, Web of Science, ERIC, PsycINFO, CINAHL, CENTRAL, and ProQuest Dissertation and Theses databases from January 1990 to February 2023. We included randomized controlled trials (RCTs), cluster RCTs, and quasi-RCTs comparing spaced digital education with nonspaced education, spaced nondigital education, traditional learning, or no intervention for pre- or postregistration health care professionals. Study selection, data extraction, study quality, and certainty of evidence were assessed by 2 independent reviewers. Meta-analyses were conducted using random effect models. We included 23 studies evaluating spaced online education (n=17, 74%) or spaced digital simulation (n=6, 26%) interventions. Most studies assessed 1 or 2 outcomes, including knowledge (n=15, 65%), skills (n=9, 39%), attitudes (n=8, 35%), clinical behavior change (n=8, 35%), and satisfaction (n=7, 30%). Most studies had an unclear or a high risk of bias (n=19, 83%). Spaced online education was superior to massed online education for postintervention knowledge (n=9, 39%; standardized mean difference [SMD] 0.32, 95% CI 0.13-0.51, I2=66%, moderate certainty of evidence). Spaced online education (n=3, 13%) was superior to massed online education (n=2, 9%) and no intervention (n=1, 4%; SMD 0.67, 95% CI 0.43-0.91, I2=5%, moderate certainty of evidence) for postintervention clinical behavior change. Spaced digital simulation was superior to massed simulation for postintervention surgical skills (n=2, 9%; SMD 1.15, 95% CI 0.34-1.96, I2=74%, low certainty of evidence). Spaced digital education positively impacted confidence and satisfaction with the intervention. Spaced digital education is effective in improving knowledge, particularly in substantially improving surgical skills and promoting clinical behavior change in pre- and postregistration health care professionals. Our findings support the use of spaced digital education interventions in undergraduate and postgraduate health profession education. Trial Registration: PROSPERO CRD42021241969. PROSPERO CRD42021241969; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=241969.

Efficacy and Safety of Umbilical Cord-Derived Mesenchymal Stromal Cell Therapy in Preclinical Models of Sepsis: A Systematic Review and Meta-analysis.

In preclinical studies, mesenchymal stromal cells (MSCs), including umbilical cord-derived MSCs (UC-MSCs), demonstrate the ability to modulate numerous pathophysiological processes related to sepsis; however, a systematic synthesis of the literature is needed to assess the efficacy of UC-MSCs for treating sepsis. To examine the effects of UC-MSCs on overall mortality (primary outcome) as well as on organ dysfunction, coagulopathy, endothelial permeability, pathogen clearance, and systemic inflammation (secondary outcomes) at prespecified time intervals in preclinical models of sepsis. A systematic search was conducted on Embase, Ovid MEDLINE, and Web of Science up to June 20, 2023. Preclinical controlled studies using in vivo sepsis models with systemic UC-MSC administration were included. Meta-analyses were conducted and expressed as odds ratios (OR) and ratios of the weighted means with 95% CI for categorical and continuous data, respectively. Risk of bias was assessed with the SYRCLE tool. Twenty-six studies (34 experiments, n = 1258 animals) were included in this review. Overall mortality was significantly reduced with UC-MSC treatment as compared to controls (OR: 0.26, 95% CI: 0.18-0.36). At various prespecified time intervals, UC-MSCs reduced surrogate measures of organ dysfunction related to the kidney, liver, and lung; reduced coagulopathy and endothelial permeability; and enhanced pathogen clearance from multiple sites. UC-MSCs also modulated systemic inflammatory mediators. No studies were rated as low risk across all SYCLE domains. These results demonstrate the efficacy of UC-MSC treatment in preclinical sepsis models and highlight their potential as a therapeutic intervention for septic shock.

Comparison of the efficacy and safety of a proposed biosimilar MSB11456 with tocilizumab reference product in subjects with moderate-to-severe rheumatoid arthritis: results of a randomised double-blind study

ObjectiveTo evaluate the efficacy, immunogenicity and safety of the proposed biosimilar MSB11456 versus European Union (EU)-approved tocilizumab reference product in patients with rheumatoid arthritis (RA) in a multicentre, randomised, double-blind,...

Surgical Resection Alone is Associated With Higher Long-Term Survival Than Multiagent Chemotherapy Alone for Patients With Localized Biliary Tract Cancers

IntroductionWe compared long-term survival of patients with localized biliary tract cancers (BTCs) treated with either surgical resection or multiagent chemotherapy. MethodsPatients with localized BTC [gallbladder adenocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma] were identified within the National Cancer Database (2010-2017). Piecewise-constant hazard modeling was used to estimate hazard ratios (HRs) at prespecified intervals: 0-30 d, 31-60 d, 61-90 d, and >90 d post-treatment. ResultsA total of 5988 patients with localized BTC were identified: 2697 (45.0%) received multiagent chemotherapy and 3291 (55.0%) underwent surgical resection. Patients with gallbladder adenocarcinoma or extrahepatic cholangiocarcinoma who were treated with surgical resection had an associated decline in overall survival (OS) as compared to those treated with multiagent chemotherapy within 0-30 d of treatment initiation (gallbladder adenocarcinoma [adjusted HR = 3.94, 95% confidence interval [CI]: 1.77-8.80]; extrahepatic cholangiocarcinoma [adjusted HR = 4.88, 95% CI: 2.76-8.61]). However, there was an associated improvement in OS for patients treated with surgical resection after 90 d from treatment initiation (gallbladder adenocarcinoma [adjusted HR = 0.36, 95% CI: 0.28-0.46]; extrahepatic cholangiocarcinoma [adjusted HR = 0.27, 95% CI: 0.24-0.32]). Among patients with intrahepatic cholangiocarcinoma, those who underwent surgical resection had an associated improvement in OS at 31-60 d (adjusted HR = 0.63, 95% CI: 0.40-0.99) and a further associated increase in OS at 61-90 d (adjusted HR = 0.34, 95% CI: 0.21-0.54) and after 90 d (HR = 0.23, 95% CI: 0.21-0.27) of treatment initiation. ConclusionsFor patients with localized BTC, surgical resection alone is associated with improved long-term survival outcomes compared to multiagent chemotherapy alone.

Indoor particulate matter concentrations and air cleaner intervention association with biomarkers in former smokers with COPD

BackgroundIndoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear. MethodsFormer smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM2.5, PM10, and ultrafine particles [UFP; PM<0.1]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM10-2.5) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1β, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally. ResultsFifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM2.5 6.8% [p = 0.002], PM10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1β with PM10-2.5. UFP and PM2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers. DiscussionAmong former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM<0.1), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels.

Experience with Accelerometer Physical Activity Tracking in Adults and Adolescents with Hemophilia A: Tool Validation Using Results from the XTEND-1 Efanesoctocog Alfa Phase 3 Trial

Introduction Wearable physical activity trackers have become increasingly common within clinical studies, patient monitoring, and health assessments. Physical activity is a key endpoint of interest when evaluating treatments for hemophilia. The objective of this analysis was to describe the psychometric properties of five outcome measures of physical activity from the accelerometer activity monitor used in the XTEND-1 study. Methods XTEND-1 (NCT04161495) was a Phase 3, open-label, multicenter study of the efficacy, safety, and pharmacokinetics of efanesoctocog alfa in previously treated adults and adolescents aged ≥12 years with severe hemophilia A. Patients receiving prior standard-of-care prophylaxis factor VIII (FVIII) received once-weekly (qw) prophylactic efanesoctocog alfa for 52 weeks (Arm A); patients on prior on-demand FVIII treatment received efanesoctocog alfa on-demand for 26 weeks, then prophylactic efanesoctocog alfa qw for 26 weeks (Arm B). Patients wore a triaxial medical grade accelerometer activity monitor device for continuous monitoring during pre-specified intervals 8 consecutive days after (or before) scheduled visits (to collect data for a full 7-day week + 1 additional day): after the screening, baseline, Week 4, 13, 26, 39 visits, and before the Week 52 visit. Compliance was assessed based on number of monitoring intervals and number of days wearing the device, and number of minutes spent wearing the device within those days. Five outcomes were assessed: light physical activity (LPA), moderate-to-vigorous activity, sedentary behavior (minutes/day spent in these individual outcomes out of total number minutes wearing device while awake), steps (number of steps taken per day), and metabolic equivalent of a task (MET; total estimated metabolic rate per day). Psychometric analyses of these outcomes using data from Arm A were conducted to evaluate test-retest reliability (TRTR), concurrent validity, known-groups validity, ability to detect change, and meaningful within-patient change (MWPC) of physical activity measurements ( Table 1). An analysis to detect potential influential outlier patients for each outcome that could potentially bias results, was conducted. Results In total, 132 out of 133 patients in Arm A and 26 out of 26 patients in Arm B, distributed in 19 countries, had accelerometer data. Compliance was defined post-hoc as ≥12 consecutive wear hours/day and results are presented for days achieving this threshold; no meaningful differences in results were found when incorporating number of monitoring intervals or number of days within the interval in the compliance definition. Most patients maintained or improved physical activity as measured by the activity monitors, with an overall increase in mean (SD) minutes during each monitoring period for LPA (baseline: 636 [234]; Week 52: 653 [237]), though there were variable changes throughout the study period. Measurements of LPA demonstrated acceptable TRTR, concurrent validity with three validation criteria, and ability to detect change with all or most of the anchor variables, while demonstrating good separation for improvement and deterioration thresholds to provide for MWPC ( Table 1). Two patients were identified as influential outliers for LPA. For moderate-to-vigorous activity, the concurrent validity showed that two validators met the criteria, and for steps, four validators met the criteria. Sedentary behavior and MET did not meet criterion with any of the validators ( Table 1). Out of the outcomes assessed, LPA showed the best psychometric properties within the study. Conclusion These analyses show how physical activity tracking through wearables was used to assess outcomes in patients with severe hemophilia A, who switched to a FVIII replacement therapy that provided normal to near-normal FVIII activity for most of the weekly dosing interval, resulting in reduced pain and improved physical functioning as assessed by patient-reported outcome measures. Analyses of these results revealed limitations in the psychometric properties of the assessed outcomes. To further understand the personal motivation and barriers for improving physical activity, addition of goal-setting could be considered in future clinical studies.

EPCORE FL-1: Phase 3 Trial of Subcutaneous Epcoritamab with Rituximab and Lenalidomide (R 2) Vs R 2 Alone in Patients with Relapsed or Refractory Follicular Lymphoma

Background: Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma (NHL). Several treatment options are approved by the US Food and Drug Administration for second- or later-line FL therapy, including rituximab + lenalidomide (R 2). However, advanced-stage FL remains incurable and new treatment options for relapsed or refractory (R/R) disease are needed. Epcoritamab, a subcutaneously administered, bispecific antibody that binds CD3 on T lymphocytes and CD20 on B cells, induces potent and selective T-cell-mediated killing of malignant CD20 + B cells (van der Horst et al, Blood Cancer J 2021). In the first-in-human, phase 1/2 EPCORE NHL-1 trial (NCT03625037) in heavily pretreated patients with B-cell NHL (N=68), epcoritamab showed manageable safety and promising single-agent anti-tumor activity (Hutchings et al, Lancet 2021). Among 10 patients with R/R FL, objective response rate (ORR) was 90% (95% CI: 55-100) and complete response (CR) rate was 50%. In the ongoing phase 1b/2 trial evaluating epcoritamab + R 2 for R/R FL (EPCORE NHL-2 arms 2a and 2b; NCT04663347), ORR was 98% among 104 efficacy-evaluable patients, with a complete metabolic response in 87%. Most cytokine release syndrome (CRS) events were low grade (n=111; grade 1-2, 46%; grade 3, 2%) and occurred in cycle 1; all CRS events resolved with routine management. These encouraging data, and the distinct mechanisms of action of epcoritamab and R 2, support ongoing evaluation of this combination for its potential to improve clinical outcomes in patients with R/R FL. The phase 3 EPCORE FL-1 trial was designed to evaluate epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL with ≥1 prior line of anti-lymphoma therapy. We present an updated protocol, reflecting recent developments and revisions implemented in this study. Study Design and Methods: EPCORE FL-1 (NCT05409066) is a global, randomized, open-label, multicenter phase 3 trial designed to evaluate efficacy and safety of epcoritamab in combination with R 2 vs R 2 alone in patients with R/R FL. Adult patients must have histologically confirmed classic FL (previously grades 1 to 3a FL) stage II, III, or IV with a CD20 + tumor on a representative biopsy based on local pathology report and no evidence of histologic transformation. Patients must have R/R disease after ≥1 prior anti-lymphoma regimen that contained an anti-CD20 monoclonal antibody in combination with chemotherapy; patients receiving only prior anti-CD20 monoclonal antibody monotherapy and/or radiation are not eligible. Other key eligibility criteria include Eastern Cooperative Oncology Group performance status 0 to 2, fluorodeoxyglucose positron emission tomography-avid disease, and ≥1 measurable disease site per Lugano 2014 criteria. Lenalidomide-refractory FL (best response to lenalidomide of stable or progressive disease or progressive disease within 6 months of completion of lenalidomide) is excluded. Approximately 520 patients will be enrolled and randomized 1:1 to receive a full dose of epcoritamab in combination with R 2 or R 2 alone ( Figure); the trial is currently enrolling in 2 arms, Arms A &amp; C. Based on emerging safety and efficacy data, Arm B has been closed to enrollment and the recommended dose of epcoritamab in combination with R 2 is 48 mg. Epcoritamab will be subcutaneously administered using a step-up dosing regimen to full dose in cycle 1 (28 days/cycle). Full dose of epcoritamab will be administered weekly in cycles 2-3 and monthly from cycle 4 onward for up to 12 cycles of treatment. Patients will be serially assessed for disease progression at prespecified intervals. The primary endpoint is progression-free survival assessed by independent review committee (IRC) per Lugano criteria. Key secondary efficacy endpoints include CR rate (by IRC per Lugano criteria), overall survival, and minimal residual disease negativity. Other efficacy endpoints include best overall response, duration of response, duration of complete response, time to progression, event-free survival, time to next anti-lymphoma treatment, and patient-reported outcomes. Safety endpoints include incidence and severity of treatment-emergent adverse events and adverse events of special interest. Exploratory endpoints include assessments of pharmacodynamic and pharmacokinetic data. The study opened for enrollment in 2022 in North America, South America, Europe, Africa, Asia, and Australia.

Association of p16, a Biomarker of Cellular Senescence, with Receipt of Therapy for Plasma Cell Disorders

Introduction Multiple myeloma (MM) and immunoglobulin light chain (AL) amyloidosis are clonal plasma cell disorders (PCDs) of aging, with median ages at diagnosis of 69 and 76 years, respectively. The care of adults with these disorders is often challenging due to the higher prevalence of vulnerabilities with advancing age. We examined patterns of senescence biomarkers and associations with therapy receipt among adults treated for plasma cell disorders. Methods Adults undergoing treatment for PCDs were recruited to a longitudinal observational study (NCT03717844) from 2018 to 2020. Study participants provided blood samples and completed study assessments at pre-specified intervals. Cellular senescence was quantified by measuring mRNA expression of p16 in peripheral blood T lymphocytes. Expression of p16 is reported as log2 arbitrary units. A linear regression formula previously derived from p16 expression in 633 subjects was utilized to translate p16 expression levels into an age equivalent. These values were used to calculate the p16AgeGap, a difference between an individual's p16 expression and their chronological age. Subjects with p16 levels below the age-appropriate population mean have a negative p16AgeGap, and those with p16 above the population mean have a positive p16AgeGap. Exposures included both treatment receipt and duration of therapy. Treatment was assessed via categorical classification of treatment intensity, and treatment duration was quantified from diagnosis to time of p16 blood draw. Descriptive statistics were calculated for baseline demographic and disease characteristic variables. The p16 and p16AgeGap variables were summarized in terms of means and 95% confidence intervals (CI). The significance of associations between p16/p16AgeGap and categorical variables was assessed via Kruskal-Wallis or Wilcoxon rank-sum tests. Associations between continuous variables were assessed via calculation of Pearson correlation coefficients. Results The cohort consisted of 109 individuals (88 with multiple myeloma and 21 with other plasma cell disorders). Mean age was 68 years (range 39-91). The sample was predominantly male (56.9%) and White (70.6%). Samples for p16 were drawn prior to any treatment in 20 subjects. The remainder had received prior therapy and 36 had relapsed/refractory disease. There was a significant association between the treatment receipt and p16 as well as between the treatment receipt and p16AgeGap (Figure 1). We observed a significant modest positive correlation between the duration of treatment and p16 (correlation coefficient 0.27, p=0.007) and p16AgeGap (0.22, p=0.03). Among those who had undergone transplant, we observed higher mean p16 (mean 12.84 [95% CI 12.46-13.23] vs 11.81 [11.51-12.11] for non-recipients, p=0.0001) and p16AgeGap (mean 50.6 [39.6-61.6] vs 16.9 [8.4-25.4], p &amp;lt;0.0001). There was a significant association between receipt of bortezomib-containing regimens with both p16 levels p16AgeGap, with higher mean p16 &amp; mean p16AgeGap for those who did not receive bortezomib. For the subset of patients with transplant date before the p16 collection date (N=38), there was no significant association between time since transplant and either p16 level or p16AgeGap. Conclusion This study elucidates the relationship between markers of cellular senescence, specifically p16 levels and the p16AgeGap, and the impact of treatment receipt and duration in a cohort of patients undergoing treatment for plasma cell disorders. There was a clear significant association between the receipt of treatment and both markers of senescence, along with a modest positive correlation between the duration of treatment and these markers. Further analyses involving this cohort will evaluate the relationship between these biomarkers and patient-centered endpoints, including disease-related symptoms and functional outcomes.

Interference Avoidance through Periodic UAV Scheduling in RIS-Aided UAV Cluster Communications

This article investigates the transmission of downlink control signals for multiple unmanned aerial vehicle (UAV) clusters in collaborative search and rescue operations in mountainous environments. In this scenario, a reconfigurable intelligent surface (RIS) mounted on the UAV is utilized to overcome obstacles between the ground base station (BS) and UAVs. By leveraging the fixed channel of the RIS to the BS, the line-of-sight (LoS) path characteristics of the air-to-air channel, and the position information of the UAV, the RIS forms a directional beam by adjusting the RIS coefficient, which points towards UAVs in the cluster. To ensure low delay in control signaling and UAV state transmission, we adopt semi-persistent scheduling (SPS), which allocates pre-specified periodic intervals to each UAV for the formation of corresponding RIS coefficients. The allocation of time slots is constrained by the transmission intervals required by different UAVs and the number of RISs available. We propose a time slot scheduling scheme for UAVs to reduce inter-cluster interference caused by RIS beams. The time slot allocation problem is formulated as a combinatorial optimization problem. To solve this problem, we first propose an intuitive greedy scheme called local interference minimization (LIM). Building upon the LIM scheme, we propose a rollout-based algorithm called rollout interference minimization (RIM). Through simulation, we compare the LIM and RIM schemes with the benchmark scheduling scheme. The results demonstrate that our proposed scheme significantly reduces interference between UAV clusters while satisfying the conditions of periodic transmission and RIS quantity constraints.

Does Head Positioning After Percutaneous Glycerol Rhizotomy for Trigeminal Neuralgia Matter?

Percutaneous glycerol rhizotomy (PGR) is a minimally invasive procedure for patients with trigeminal neuralgia who are not candidates for microvascular decompression. PGR has widely varying success rates. It has been postulated that differences in post-injection head positioning might account for the various success rates. By comparing glycerol dispersion after injection at various head positions, we provide the first evidence supporting post-injection head flexion positioning. Furthermore, we study the clival-Meckel cave (CMC) angle as a predictor of beneficial glycerol flow, measured on computed tomography images. Twenty-two dissected cadaveric specimens were injected with dyed glycerol through the Hartel approach. The glycerol dispersion was measured at prespecified intervals for 1 hour. The Mann-Whitney U and χ2 tests were used to determine the most ideal angle of head flexion to avoid posterior glycerol dispersion and ensure V1-V3 branch glycerol submersion. We found that 30° of anterior head flexion provided optimal trigeminal nerve glycerol submersion (81.82%) in comparison to neutral (27.27%) and 15° (68.18%), P < 0.001. There was minimal unfavorable dispersion beyond 30 minutes at all angles. More obtuse CMC angles were associated with higher rates of unfavorable BC dispersion (U= 6.0; P= 0.001). For specimens with CMC angles >75°, unfavorable BC dispersion was prevented by head flexion (U= 4.5; P= 0.021). We show that 30° of lateral head tilt achieves V1 submersion in all specimens by 30 minutes [X2(1,N= 44)= 22.759; P < 0.001]. We found that 30° anterior head flexion for >30 minutes provides ideal conditions for PGR to avoid BC dispersion and ensure V1-V3 branches achieve glycerol submersion. For patients with V1 symptoms, contralateral head flexion might help optimize treatment effects.

A - 189 Subjective Response to a Social Stressor in Individuals with Mild Cognitive Impairment.

Because stress is a risk factor for Alzheimer's disease (ad), characterizing individual differences in the stress response could help identify those who might be targeted in risk-prevention efforts. Studies measuring the stress response in individuals with mild cognitive impairment (MCI), however, are lacking, in part due to concerns that doing so would be too distressing to these individuals. In this study, we aimed to characterize the subjective response to an acute stressor in individuals with mild cognitive impairment (MCI). This study consisted of 20 community-dwelling individuals (9 with MCI and 11 cognitively normal individuals; 11 women) 60years and older (Mean = 70.1, SD = 5.6) who underwent the Trier Social Stress Test (TSST). Subjects rated their subjective distress using a standardized visual analog scale at prespecified intervals 3 points prior to, and 6 points following, the TSST. Data were subjected to repeated measures analysis with sex as a covariate. Subjects with MCI rated the TSST as less stressful than their cognitively normal peers (p = 0.04), due to group differences in both post-TSST ratings of subjective distress (p = 0.013) and an increase from pre-TSST to post-TSST ratings of subjective distress (p = 0.04). No individuals withdrew from the study while participating in the TSST. Our finding that individuals with MCI reported experiencing lower distress than their cognitively normal peers in response to a laboratory-based stressor may help alleviate concerns regarding the risks of studying stress in this population. Future research with larger samples will be valuable in studying other determinants of the stress response in these individuals.

Incident Learning in an Academic Radiation Oncology Practice during the COVID Era.

Incident learning is key to developing and maintaining quality and safety in healthcare. We aimed to characterize acute and sustained changes in incident submissions, point of incident origin/detection, severity and associated contributing factors during the COVID-19 pandemic. The frequency and pattern of incident origin/detection were changed by altered workflows in response to COVID-19. Events from our experienced incident learning system were analyzed between three 12-month intervals: pre-COVID (March 1, 2019 - February 29, 2020), early-COVID (March 1, 2020 - February 28, 2021), and late-COVID (March 1, 2021 - February 28, 2022). In addition to review by the department quality and safety committee, at least two physicians reviewed all incidents. Using descriptive statistics and chi-square test as applicable, we compared the reporting rates, incident severity, contributing factors, points of origin/ detection according to time the pre-specified time intervals prior to and during COVID. See Table. During COVID the number of reported incidents, particularly incidents reaching the patient, markedly declined. The number of incidents per patient increased with early-COVID altered workflows. This suggests that existing quality and safety checks were effective during early-COVID. The point of incident origin was similar across time periods. During early-COVID, the point of incident detection shifted to earlier points in the care pathway (e.g., pre-RT chart checks vs chart checks during RT), p<0.001. During late-COVID, as clinical workflows adapted, the point of detection shifted to later in the care pathway consistent with pre-COVID patterns. During COVID, workload was implicated in fewer incidents (in the setting of reduced treatment volumes), while communication and hand-offs were more frequently cited as contributing factors (in the setting of remote work). Our data supports the utility of consistent standards, minimizing inter-provider variations and maintaining robust quality and safety checks to optimize communication and safe patient care in radiation oncology.

Clival-Meckel's Cave Angle: A Predictor of Glycerol Displacement in Percutaneous Glycerol Rhizotomy for Trigeminal Neuralgia.

Percutaneous glycerol rhizotomy successfully treats trigeminal neuralgia although failure rates and durability of the procedure are variable. Some of this variability in clinical outcome might be due to egress of glycerol from Meckel's cave (MC) because of surgical positioning and individual patient anatomy. In this article, we quantitatively analyzed the anatomic variances that affect glycerol fluid dynamics to better predict patients more amenable for percutaneous glycerol injections. Computed tomography imaging of 11 cadaveric heads was used to calculate bilateral Clival-Meckel's cave (CMC) and sella-temporal (ST) angles. Twenty-two cadaveric percutaneous injections of dyed glycerol into the Meckel's cave were performed using Härtel's approach, and the fluid movement was documented at prespecified intervals over 1 hour. The relationship between the angles and glycerol migration was studied. Specimens with basal cistern involvement by 60 minutes had significantly greater CMC angles (median [IQR]: basal cistern involvement = 74.5° [59.5°-89.5°] vs no basal cistern involvement = 58.0° [49.0°-67.0°]), U = 6.0, P < .001. This model may predict which patients will experience glycerol migration away from the Gasserian ganglion (area under the curve: 0.950, SE: 0.046, CI: 0.859-1.041, P < .001). Increased ST angle was associated with lateral flow of glycerol (r s = 0.639, P = .001), and CMC angle was associated with total area of dispersion (r s = -0.474, P = .026). Anatomic variation in skull base angles affects glycerol migration. Specifically, a more obtuse CMC angle was associated with a higher risk of posterior migration away from the Gasserian ganglion. This may be a reason for differing rates of surgical success. These results suggest that anterior head flexion for 60 minutes may prevent percutaneous glycerol rhizotomy failures and some patients with large CMC angles are more likely to benefit from postinjection head positioning. However, this clinical effect needs validation in vivo.

Temporal change in repolarization parameters after surgical correction of valvular heart diseases.

Ventricular tachyarrhythmia is a potentially fatal outcome of cardiac surgery. Abrupt changes in the hemodynamics after surgical correction of valvular heart disease (VHD) can lead to alterations in ventricular repolarization. We compared the difference between temporal changes in repolarization parameters after correction of left-sided VHD. We retrospectively analyzed the electrograms of patients who underwent surgical correction of isolated VHD between 2006 and 2015 at Asan Medical Center, including mitral stenosis (MS), mitral regurgitation (MR), aortic stenosis (AS), and aortic regurgitation (AR). Ventricular repolarization parameters were measured at pre-specified time intervals after index surgery using a custom-made ECG analysis program. We compared repolarization parameters, including QT and corrected QT intervals, T peak-to-end interval, and corrected T peak-to-end interval. Analysis of 8265 ECGs from 2110 patients (266 MS, 1059 MR, 421 AS, and 364 AR) was performed. Patients with AS were characterized by older age and more comorbidities than other VHDs. The corrected QT interval showed a peak value immediately after surgery and decreased thereafter in the AS groups. However, a gradual increase over 1month after surgery in AR, MS, and MR groups was observed. The corrected T peak-to-end interval increased in the MS and MR groups and was unchanged in the AS and AR groups. The repolarization parameters of surgery changed dynamically after left-sided valvular surgery. Understanding differential temporal change of repolarization parameters according to the type of VHD would help clinicians avoid fatal arrhythmias related to the repolarization changes.

Alternating short-course oxaliplatin-based chemotherapy and nivolumab as first-line treatment of patients with abdominal metastases from microsatellite-stable (MSS) colorectal cancer (CRC): A randomized phase 2 trial.

3552 Background: The CRC incidence increases sharply from the age of 60. Most patients harbor primarily non-immunogenic MSS disease and abdominal metastases are in particular considered unresponsive to immune checkpoint blockade (ICB). The METIMMOX trial explored if MSS-CRC can be transformed into an immunogenic malignancy by short-course oxaliplatin-based therapy and if followed by ICB (without concomitant chemotherapy that might compromise an invoked tumor-defeating immunity) may result in durable clinical response for patients with abdominal metastases. Methods: Patients had MSS-CRC with infradiaphragmatic metastases deemed unresectable, ECOG performance status 0-1, and were eligible for first-line oxaliplatin-based therapy. They were randomly assigned to FLOX (oxaliplatin 85 mg/m2 day 1, bolus 5-fluorouracil 500 mg/m2 and folinic acid 100 mg days 1-2) Q2W (control arm) or alternating cycles of 2 FLOX Q2W and 2 nivolumab (240 mg) Q2W (experimental (exp) arm) with break periods at prespecified intervals. Response assessment per i/RECIST by blinded central review was done every 8 weeks with progression-free survival (PFS) as primary endpoint. Sample size of 40 in each arm with 1:1 randomization would detect exp arm doubling of median PFS. Associations between PFS and relevant patient and disease variables were estimated by Cox proportional-hazards regression models. Prespecified correlative analyses included circulating tumor DNA (ctDNA) by droplet digital PCR and circulating immune cell composition by high-dimensional single-cell mass cytometry. Results: Of 80 enrolled subjects (05/2018-10/2021), 76 intention-to-treat (ITT) cases were equally allocated to the study arms and followed to censoring at 10/2022 with identical median PFS of 9.3 months (95% CI, 6.4-12.9 (control arm) and 4.6-15.2 (exp arm)). The adjusted Cox model revealed interaction between age and study arm, as patients ≥60 years had significantly lowered risk of progression when receiving exp therapy (median PFS 13.6 months (95% CI, 8.5-18.8); p = 0.022). No unexpected adverse events were recorded; specifically, no grade ≥4 immune-mediated adverse event occurred. Of note, 17% of exp arm patients had durable complete response, among whom all BRAF-mutant cases ( n = 3) with PFS 21-35 months and rapid clearance of baseline BRAF-mutant ctDNA (control arm BRAF-mutant cases ( n = 10), median PFS 3.6 months). Responding exp arm patients showed distinct subsets of circulating immune cells with more homogenous profiles than ICB-unresponsive subjects. Conclusions: With equal primary endpoint for the ITT cases, alternating short-course oxaliplatin-based therapy and nivolumab significantly improved PFS compared to standard first-line chemotherapy in MSS-CRC patients ≥60 years with abdominal metastases. Clinical trial information: NCT03388190 .