Enrollment Criteria Research Articles

Effect of immunotherapy combined with chemotherapy with or without thoracic radiotherapy on markers of myocardial injury in patients with thoracic tumors.

e14624 Background: Thoracic radiotherapy (TRT) is widely used in the treatment of thoracic tumors (TTs) including esophageal and lung cancers. Previous studies suggest that it may increase the risk of myocardial injury. The use of immune checkpoint inhibitors combined with chemotherapy (ICC) in TTs is becoming prevalent, and immune myocarditis is of interest to clinicians. Markers of myocardial injury (MMIs) (e.g., cTnT, CK-MB) have been used with high sensitivity and specificity for the diagnosis of immune myocarditis. Previous studies have focused on severe immune myocarditis due to its high lethality, and less attention has been paid to myocarditis with mildly elevated MMIs. However, ICC are increasingly being used in the treatment of earlier-stage TTs (e.g., neoadjuvant treatment of NSCLC), so the safety of treatment is particularly crucial. The main objective of this study was to analyze the effect of ICC with or without TRT on the MMIs in patients with TTs. Methods: This is a single-center retrospective study with the following main inclusion criteria: 1, pathologically confirmed esophageal and lung cancers only; 2, treated with ICC; 3, presence of comparable serial MMIs results from 1 week prior to the start of treatment to 12 weeks after the end of treatment; 4, TRT allowed in the same period. Primary exclusion criteria: 1，Elevation of MMIs occurs before ICC. 2，For patients who have received TRT, MMIs elevated before radiotherapy. As Chinese Society of Clinical Oncology PD-1 treatment-related myocarditis diagnostic criteria, cTnT was defined as elevated when it was significantly higher than baseline (20 μg/mL) and CK-MB was defined as elevated when it was 2.5 times higher than the upper limit of normal (≥62.5 U/L); Elevation of cTnT and CK-MB after treatment was used as the primary observation and a chi-square test was performed using the SPSS version 25. Results: This study investigated patient data from Jan 1st,2019 to Sep 20th,2022 for a total of 196 patients with esophageal squamous cancer and 298 patients with lung cancer (SCLC vs NSCLC = 13:285) who met the enrollment criteria. The median age was 64 years (29-89 years), male vs female = 406:88. 256 patients received ICC plus radiotherapy (Group A) and 238 patients without radiotherapy (Group B). The median dose of TRT was 50.4 Gy (12 - 60 Gy). The median cycles of use of Immune checkpoint inhibitors (including PD-1 and PD-L1 inhibitors) was 5 (1- 43). The proportion of all patients with post-treatment elevations of cTnT was 12.2% (29/238), including 11.9% (13/109) and 12.4% (16/129) in group A and B, p > 0.05. The whole proportion of patients with elevated CK-MB was 2.7% (13/473), including 3.2% (8/251) and 2.3% (5/222) in group A and B, p > 0.05. Conclusions: Elevated MMIs were common after the use of ICC in patients with TTs with or without radiotherapy, and TRT did not increase the risk of elevation of MMIs.

Characterization of Severe Uncontrolled Asthma in Japan: Analysis of Baseline Data from the PROSPECT Study.

Treatment patterns and patient characteristics are not well elucidated among Japanese patients with severe uncontrolled asthma who currently have various treatment options, including biologics. We analyzed baseline characteristics of patients who did/did not initiate biologic treatment in PROSPECT, a 24-month observational study. Patients with severe uncontrolled asthma were prospectively enrolled at 34 sites in Japan from December 2019 to September 2021. The enrolled population was divided based on initiation/non-initiation of biologic treatment within 12 weeks after enrollment. Patient demographics, clinical characteristics, biomarker levels, and asthma-related treatment were assessed at enrollment. Of 289 patients meeting the enrollment criteria, 127 patients initiated biologic treatment (BIO group: omalizumab, n = 16; mepolizumab, n = 10; benralizumab, n = 41; and dupilumab, n = 60) and 162 patients did not (non-BIO group). The proportion of patients with ≥2 asthma exacerbations was higher in the BIO group than the non-BIO group (65.0% vs 47.5%). Patients receiving omalizumab had the highest frequency of allergic rhinitis (87.5% vs other BIOs: 40.0%-53.3%). Patients receiving benralizumab and dupilumab had the highest incidence of nasal polyps (benralizumab: 19.5%, dupilumab: 23.3%, other BIOs: 0.0%). The proportion of patients with blood eosinophils ≥300 cells/μL was higher with benralizumab (75.6%) than other BIOs (26.7%-42.9%). This analysis of baseline data from the PROSPECT study is the first to clarify the characteristics of Japanese patients with severe uncontrolled asthma. BIOs were not necessarily prescribed to patients in whom they were indicated; however, for patients who received them, selection appeared to be made appropriately based on asthma phenotypes.

Molecular profiling of ctDNA from NCI-MATCH patients enrolled for treatment with mTOR1/2 inhibitor sapanisertib (arm M) and the Hedgehog pathway inhibitor vismodegib (arm T).

3047 Background: The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) multi-arm phase II clinical trial tested biopsies from patients with advanced refractory cancer to assign treatment based on tumor molecular profile. Enrollment criteria for treatment with the mTOR1/2 inhibitor sapanisertib in Arm M, or the Hedgehog pathway inhibitor vismodegib in Arm T, included detection of mutations in TSC1/TSC2 or PTCH1/SMO in tissue, respectively. For a subset of patients enrolled on these two arms, matched plasma was also collected at time of enrollment or on treatment to evaluate ctDNA. Methods: Screening for NCI-MATCH was based on tissue sequencing that was initially performed centrally using the 143-gene Oncomine Comprehensive Assay version 2 (OCAv2) and later referred to NCI-MATCH Designated Laboratory (DL) Network to perform sequencing for patient referral. Cell-free DNA (cfDNA) extracted from plasma collected in Streck tubes was input at 10 – 30 ng into a modified version of the Illumina TruSight Oncology 500 assay (TSO 500). Following error correction and read collapsing post-sequencing, variant calls were made and concordance between cfDNA libraries meeting prespecified QC criteria and tissue was evaluated. Results: Plasma, representing multiple collection timepoints, was available for 30/49 Arm M and 21/34 Arm T enrolled patients. A total of 95 cfDNA libraries, including replicates, were constructed and sequenced. Unique patient samples were tested across various timepoints (n = 35 pretreatment; n = 35 Cycle 2 Day 1; n = 8 at progression) plus replicates, with 90 (94.7%) libraries passing all prespecified QC criteria. Among Arm M patients there were 3 patients whose enrollment variant did not overlap with the TSO 500 gene panel. In total, 14 of 27 (51.8%) patients in Arm M and 18 of 21 (85.7%) patients in Arm T were concordant for enrollment mutation for at least one collection timepoint. In Arm T, 85.7% (n=38) of patient samples had at least one oncogenic or likely oncogenic (O/LO) mutation in the tumor sample at enrollment, with 73.6% (n = 28) of those also being detected by cfDNA. Interestingly, within Arm M and Arm T, a total of 7 patient samples were detected as MSI-H, with corresponding bTMB scores ranging from ~6 to > 100 Mut/Mb (median = 86.7). Conclusions: Detection of the enrollment mutations in treatment arms was observed in 51.8% - 85.7% of patients tested by ctDNA with overall variant concordance between tissue and ctDNA of at least 73.6%. These findings support the use of liquid biopsy as a tool for understanding genomic profiles of cancer patients both at diagnosis and progression, less invasively than standard tissue biopsies. In addition, 7 patients were identified as MSI-H, suggesting that blood-based testing could complement tissue testing for identifying patients who may benefit from targeted therapy.

Clinical spectrum and genetic causes of mitochondrial hepatopathy phenotype in children.

Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH. We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes. Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported. Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

0810 Effect of supraglottoplasty on respiratory parameters in infants and children with laryngomalacia and oxygen dependence

Abstract Introduction Supraglottoplasty (SGP) is the surgical treatment of choice for laryngomalacia and obstructive sleep apnea (OSA). Several recent studies have shown that oxygen can act to stabilize ventilatory control in infants with OSA and high loop gain. However, there is very limited information on the effect of SGP on OSA in infants with laryngomalacia and evidence of high loop gain. Methods A retrospective chart review was performed in infants with laryngomalacia and OSA at Cincinnati Children’s Hospital Medical Center from January 2008 to June 2022. Only patients treated with oxygen prior to SGP were included in the analysis. The pre-surgical polysomnograms (PSGs) were classified by responsiveness to oxygen into 2 groups; oxygen responders ([R]; &amp;gt;50% decrease in apnea-hypopnea index (AHI) with oxygen, indirect evidence of high loop gain) and non-responders ([NR]; &amp;lt; 50% decrease in AHI). Data were reported as mean±SD. The comparison of AHI and obstructive AHI (OAHI) between pre-surgical and post-surgical PSGs were performed in each group using paired t-test or Wilcoxon signed rank test. The differences of percentage decreases in AHI and OAHI after surgery between R and NR were calculated using Wilcoxon Rank Sum test. Results Forty-nine infants (with 52 SGPs) met the study enrollment criteria, with 33 (67.3%) male and 16 (32.7%) female patients. There were no statistically significant differences in age or sex between oxygen responders and non-responders. AHI after SGP in both oxygen responders (50.1±59.2/hr [pre] vs 17.6±21.1/hr [post]; P&amp;lt; 0.0001) and oxygen non-responders (25.2±13.3/hr [pre] vs 12.4±9.4/hr [post] vs; P=0.0006] decreased significantly. Similarly, there were significant decreases in OAHI after SGP in both groups. Additionally, there were no significant differences in the percentage decreases of AHI (57.3±26.1% [R] vs 41.4±48.8%[NR]; P=0.6410) and OAHI (64.0±21.9% [R] vs 50.3±41.4% [NR]; P=0.5260) between the 2 groups. Conclusion Both oxygen responders and non-responders had significant decreases in AHI and OAHI after surgery with similar magnitude of improvement. Supraglottoplasty is an effective treatment in infants with larygnomalacia and OSA, even in those with evidence of high loop gain. We speculate that non-anatomic traits such as high loop gain would only manifest in the context of significant respiratory disturbances from anatomic traits. Support (if any)

0375 Increased Engagement with a Tailored Sleep Guide is Associated with Reduced Variability in Sleep Efficiency in Chronic Insomnia

Abstract Introduction Insomnia is highly prevalent, but difficult to diagnose due to night-to-night sleep variability, and difficult to treat in part due to the lack of trained providers. Consumer sleep technology (CST) allows for longitudinal sleep monitoring in a natural environment. One such device, the Sleep Score Max (SleepScore Labs) combines longitudinal non-contact sleep tracking via radio-frequency biomotion sensor technology with an individualized sleep guide function, which provides tailored recommendations to improve sleep based on the user’s objectively measured sleep, bedroom environment, and self-reported daily activity. Focusing on sleep efficiency, we examined if level of engagement with the sleep guide is related to sleep improvement in chronic insomnia. Methods As part of a larger study, N=30 individuals with chronic insomnia (ages 38.7±14.9; 8 male) participated in an 8-week at-home sleep monitoring study. Enrollment criteria included being 18-65y old and meeting ICSD-3 criteria for chronic insomnia with no other clinically relevant condition contributing to sleep disturbance. Participants were instructed to track their sleep with the aforementioned device and engage with the sleep guide daily for 8 consecutive weeks. For observed sleep efficiency, means (characterizing sleep overall) and within-subject standard deviations (characterizing ­night-to-night variability) were assessed by week, and change scores from week 1 to week 8 were correlated with level of engagement with the sleep guide function (defined as percentage of days interacted with the guide within the 8-week period). Results From week 1 to week 8, mean sleep efficiency increased non-significantly (t[23]=0.83, p=0.42), but night-to-night variability decreased significantly (t[23]=-2.16, p=0.041). There was no significant relationship between change in mean sleep efficiency and level of engagement with the sleep guide (r=0.005, p=0.980), but there was a significant relationship between change in night-to-night variability and level of engagement (r=-0.48, p=0.018), such that night-to-night ­variability decreased more in those with greater engagement. Conclusion Night-to-night sleep variability is a chief complaint of people with chronic insomnia, and reduced night-to-night variability in sleep efficiency may indicate improvement. As such, engagement with an individualized sleep guide incorporated in a CST device may help individuals with chronic insomnia improve their sleep. Support (if any) NIH grant KL2TR002317; research devices provided by SleepScore Labs.

The Role of Family Members in Psychiatric Deep Brain Stimulation Trials: More Than Psychosocial Support

Family members can provide crucial support to individuals participating in clinical trials. In research on the “newest frontier” of Deep Brain Stimulation (DBS)—the use of DBS for psychiatric conditions—family member support is frequently listed as a criterion for trial enrollment. Despite the significance of family members, qualitative ethics research on DBS for psychiatric conditions has focused almost exclusively on the perspectives and experiences of DBS recipients. This qualitative study is one of the first to include both DBS recipients and their family members as interview participants. Using dyadic thematic analysis—an approach that takes both the individuals and the relationship as units of analyses—this study analyzes the complex ways in which family relationships can affect DBS trial participation, and how DBS trial participation in turn influences family relationships. Based on these findings, we propose ways to improve study designs to better take family relationships into account, and better support family members in taking on the complex, essential roles that they play in DBS trials for psychiatric conditions.

Development and Validation of a Joint Attention–Based Deep Learning System for Detection and Symptom Severity Assessment of Autism Spectrum Disorder

Joint attention, composed of complex behaviors, is an early-emerging social function that is deficient in children with autism spectrum disorder (ASD). Currently, no methods are available for objectively quantifying joint attention. To train deep learning (DL) models to distinguish ASD from typical development (TD) and to differentiate ASD symptom severities using video data of joint attention behaviors. In this diagnostic study, joint attention tasks were administered to children with and without ASD, and video data were collected from multiple institutions from August 5, 2021, to July 18, 2022. Of 110 children, 95 (86.4%) completed study measures. Enrollment criteria were 24 to 72 months of age and ability to sit with no history of visual or auditory deficits. Children were screened using the Childhood Autism Rating Scale. Forty-five children were diagnosed with ASD. Three types of joint attention were assessed using a specific protocol. Correctly distinguishing ASD from TD and different levels of ASD symptom severity using the DL model area under the receiver operating characteristic curve (AUROC), accuracy, precision, and recall. The analytical population consisted of 45 children with ASD (mean [SD] age, 48.0 [13.4] months; 24 [53.3%] boys) vs 50 with TD (mean [SD] age, 47.9 [12.5] months; 27 [54.0%] boys). The DL ASD vs TD models showed good predictive performance for initiation of joint attention (IJA) (AUROC, 99.6% [95% CI, 99.4%-99.7%]; accuracy, 97.6% [95% CI, 97.1%-98.1%]; precision, 95.5% [95% CI, 94.4%-96.5%]; and recall, 99.2% [95% CI, 98.7%-99.6%]), low-level response to joint attention (RJA) (AUROC, 99.8% [95% CI, 99.6%-99.9%]; accuracy, 98.8% [95% CI, 98.4%-99.2%]; precision, 98.9% [95% CI, 98.3%-99.4%]; and recall, 99.1% [95% CI, 98.6%-99.5%]), and high-level RJA (AUROC, 99.5% [95% CI, 99.2%-99.8%]; accuracy, 98.4% [95% CI, 97.9%-98.9%]; precision, 98.8% [95% CI, 98.2%-99.4%]; and recall, 98.6% [95% CI, 97.9%-99.2%]). The DL-based ASD symptom severity models showed reasonable predictive performance for IJA (AUROC, 90.3% [95% CI, 88.8%-91.8%]; accuracy, 84.8% [95% CI, 82.3%-87.2%]; precision, 76.2% [95% CI, 72.9%-79.6%]; and recall, 84.8% [95% CI, 82.3%-87.2%]), low-level RJA (AUROC, 84.4% [95% CI, 82.0%-86.7%]; accuracy, 78.4% [95% CI, 75.0%-81.7%]; precision, 74.7% [95% CI, 70.4%-78.8%]; and recall, 78.4% [95% CI, 75.0%-81.7%]), and high-level RJA (AUROC, 84.2% [95% CI, 81.8%-86.6%]; accuracy, 81.0% [95% CI, 77.3%-84.4%]; precision, 68.6% [95% CI, 63.8%-73.6%]; and recall, 81.0% [95% CI, 77.3%-84.4%]). In this diagnostic study, DL models for identifying ASD and differentiating levels of ASD symptom severity were developed and the premises for DL-based predictions were visualized. The findings suggest that this method may allow digital measurement of joint attention; however, follow-up studies are necessary for further validation.

Outcomes of catheter ablation vs.medical treatment for atrial fibrillation and heart failure: a meta-analysis.

The benefit of catheter ablation vs. medical treatment has been reported to be inconsistent in randomized controlled trials (RCTs) for patients with atrial fibrillation (AF) and heart failure (HF) due to different enrollment criteria. This meta-analysis aimed to decipher the differential outcomes stratified by different left ventricular ejection fractions (LVEFs) and AF types. We searched PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and ClinicalTrials.gov databases for RCTs comparing medical treatment and catheter ablation in patients with AF and HF published before March 31, 2023. Nine studies were included. When patients were stratified by LVEF, improved LVEF and 6-min walk distance, less AF recurrence, and lower all-cause mortality in favor of catheter ablation were observed in patients with LVEF ≤50% but not in patients with LVEF ≤35%, and short HF hospitalization was observed in patients with LVEF ≤50% and LVEF ≤35%. When patients were stratified by AF types, improved LVEF and 6-min walk distance, better HF questionnaire score, and short HF hospitalization in favor of catheter ablation were observed both in patients with nonparoxysmal AF and mixed AF (paroxysmal and persistent) and less AF recurrence and lower all-cause mortality in favor of catheter ablation were observed in only patients with mixed AF. This meta-analysis showed improved LVEF and 6-min walk distance, less AF recurrence, and lower all-cause mortality in favor of catheter ablation vs. medical treatment in AF patients with HF and LVEF of 36%-50%. Compared with medical treatment, catheter ablation improved LVEF and had better HF status in patients with nonparoxysmal AF and mixed AF; however, AF recurrence and all-cause mortality in favor of catheter ablation were observed in only HF patients with mixed AF.

An Evaluation of an Advanced Practice Provider Led Weight Intervention in Liver Disease (WILD) Pathway.

Within the scope of their practice, advanced practice providers provide similar patient care as physicians, but in some cases have outperformed physicians in terms of health outcomes, satisfaction, and cost-effectiveness. At an academic medical center, hepatology trained advanced practice providers, who were also certified in obesity management, led an interprofessional team to develop the Weight Intervention in Liver Disease pathway. In September 2018, patients who were seen in the hepatology practice and met criteria for enrollment were referred to the Weight Intervention in Liver Disease program for comprehensive care of obesity and related metabolic disorders. A program evaluation was conducted in 2021 to identify whether the effectiveness of the advanced practice provider-led structure and process, and the Weight Intervention in Liver Disease pathway, supported weight loss goals as well as improvement in alanine aminotransferase levels, patient satisfaction, and provider satisfaction. Results found that the structure of the pathway and the implementation are resulting in positive outcomes of 100% patient satisfaction, 80% provider satisfaction, and a total average sustained weight loss of 5.05% ( SD = 7.98, p < .01). A weight loss pathway led by trained advanced practice providers proves successful in long-term weight loss goals.

Management of depression in patients with coronary artery disease: A systematic review.

Depression is an independent risk factor for coronary artery disease (CAD). Both illnesses contribute significantly to the global burden of disease. This systematic literature review examines treatment interventions for CAD patients with comorbid depression. We systematically reviewed The Cochrane Library, MEDLINE, EMBASE, PsycINFO, PUBMED, CINAHL and the ISRCTN Registry for English language randomised control trials investigating treatment interventions for depression in adults with CAD and comorbid depression. Data extracted included author name(s), year published, number of participants, enrolment criteria, depression definition/measures (standardised interviews, rating scales), description of control arms and interventions (psychotherapy and/or medications), randomisation, blinding, follow-up duration, follow-up loss, depression scores and medical outcome. The database search revealed 4464 articles. The review yielded 19 trials. Antidepressant and/or psychotherapy did not significantly influence CAD outcomes in the overall population. There was no difference between antidepressant use and aerobic exercises. Psychological interventions and pharmacological interventions provide small effect on depression outcomes in CAD patients. Patient autonomy in choice of treatment is associated with greater depression treatment satisfaction, but the majority of studies are underpowered. More research is required to explore the role of neurostimulation treatment, complementary and alternative treatments.

Total Transit Time and Probiotic Persistence in Healthy Adults: A Pilot Study

Motility, stool characteristics, and microbiota composition are expected to modulate probiotics' passage through the gut but their effects on persistence after intake cessation remain uncharacterized. This pilot, open-label study aims at characterizing probiotic fecal detection parameters (onset, persistence, and duration) and their relationship with whole gut transit time (WGTT). Correlations with fecal microbiota composition are also explored. Thirty healthy adults (30.4 ± 13.3 years) received a probiotic (30 × 109 CFU/capsule/day, 2 weeks; containing Lactobacillus helveticus R0052, Lacticaseibacillus paracasei HA-108, Bifidobacterium breve HA-129, Bifidobacterium longum R0175, and Streptococcus thermophilus HA-110). Probiotic intake was flanked by 4-week washout periods, with 18 stool collections throughout the study. WGTT was measured using 80% recovery of radio-opaque markers. Tested strains were detected in feces ~1-2 days after first intake and persistence after intake cessation was not significantly different for R0052, HA-108, and HA-129 (~3-6 days). We identified 3 WGTT subgroups within this population (named Fast, Intermediate, and Slow), which could be classified by machine learning with high accuracy based on differentially abundant taxa. On average, R0175 persisted significantly longer in the intermediate WGTT subgroup (~8.5 days), which was mainly due to 6 of the 13 Intermediate participants for whom R0175 persisted ≥ 15 days. Machine learning classified these 13 participants according to their WGTT cluster (≥ 15 days or < 5 days) with high accuracy, highlighting differentially abundant taxa potentially associated with R0175 persistence. These results support the notion that host-specific parameters such as WGTT and microbiota composition should be considered when designing studies involving probiotics, especially for the optimization of washout duration in crossover studies but also for the definition of enrollment criteria or supplementation regimen in specific populations.

Effect of endocrine disrupting chemicals on early disease course in Multiple sclerosis (P5-3.004)

<h3>Objective:</h3> Analyze whether endocrine disrupting chemicals (EDCs) correlate with initiation of Multiple sclerosis (MS) in females <h3>Background:</h3> MS is the most common neuroinflammatory disease with a female predominant ratio of 3:1. Sex hormones are implicated, as most pediatric MS cases occur after puberty, and pregnancy is protective against disease activity. EDCs including phenols, parabens, and phthalates are found ubiquitously in the modern lifestyle. They interfere with natural hormone homeostasis in the body via estrogen receptor signaling. This study focuses on whether exposure to EDCs affect MS initiation. <h3>Design/Methods:</h3> 30 female patients were recruited from the Brigham MS Center. Enrollment criteria included diagnosis with MS within the past 5 years, and consent to provide a blood and urine sample and completed a questionnaire about potential EDC exposures. Exclusion criteria were intravenous steroids in the past 30 days. Samples were analyzed by NSF International (Ann Arbor, Michigan) by LC-MS for phenols, parabens, and phthalates. Statistical results were obtained using R. <h3>Results:</h3> We find that females with higher levels of the phthalates mECPP and mEOHP had higher annualized relapse rates (ARR) from onset of disease (Spearman coefficient, R=0.55, p=0.0014; R=0.65, p=7.8e-05). mECPP and mEOHP levels also correlated with increased number of T2 lesions on MRI (R=0.51, p=0.0033; R=0.57, p=8e-04). mECPP levels were inversely correlated with fish intake (R=−0.38, p=0.02. mEOHP was non-significantly inversely correlated with fish intake (R=−0.30, p=0.06). None of the EDCs analyzed were correlated with use of dishwashers, personal care products, or exposure to microplastics. <h3>Conclusions:</h3> Higher serum levels of phthalates mECPP and mEOHP are correlated with increased lesion burden and disease activity in female MS patients within the first five years of disease onset. Fish intake was inversely correlated with serum levels of these phthalates. This study highlights how diet and exposures to environmental EDCs might partly explain sex differences in disease course in MS. <b>Disclosure:</b> Dr. Chuang has nothing to disclose. Ms. Feldman has nothing to disclose. The institution of Mr. Healy has received research support from Analysis Group. The institution of Mr. Healy has received research support from Bristol-Myers Squibb. The institution of Mr. Healy has received research support from Verily Life Sciences. The institution of Mr. Healy has received research support from Novartis. The institution of Mr. Healy has received research support from Merck Serono. The institution of Mr. Healy has received research support from Genzyme. Shrishti Saxena has nothing to disclose. Ms. Sanon has received personal compensation for serving as an employee of Brigham and Women’s Hospital . Ms. Saraceno has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cumming Foundation. The institution of Ms. Saraceno has received research support from I-Mab Biopharma. Dr. Chitnis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Chitnis has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche-Genentech. Dr. Chitnis has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Academic CME. The institution of Dr. Chitnis has received research support from Novartis. The institution of Dr. Chitnis has received research support from Sanofi. The institution of Dr. Chitnis has received research support from Octave.

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients. This review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC. We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories. Our search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials. We found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.

Impaired pulmonary function and associated factors in the elderly with tuberculosis on admission: a preliminary report

BackgroundPulmonary tuberculosis (TB) can impair pulmonary function (PF), especially in the elderly. The risk factors associated with the severity of PF impairment in the elderly with pulmonary TB remain unclear. Hence, this retrospective study aimed to address this issue to help improve the management of TB in the elderly population.MethodsFrom January 2019 to February 2022, the elderly who were admitted to our hospital for pulmonary TB and underwent PF testing were included in this analysis. The forced expiratory volume in one second percent of predicted (FEV1% predicted) and clinical characteristics were collected and analyzed retrospectively. The extent of impaired PF was then categorized based on the FEV1% predicted and classified as grade 1–5. Logistic regression analysis was used to analyze the risk factors for impaired PF.ResultsA total of 249 patients who met the enrollment criteria were included in this analysis. According to the results of FEV1% predicted, all patients were classified as grade 1 (n = 37), grade 2 (n = 46), grade 3 (n = 55), grade 4 (n = 56), or grade 5 (n = 55). Statistical analysis showed that albumin (adjusted odds ratio (aOR) = 0.928, P = 0.013), body mass index (BMI) < 18.5 kg/m2 (aOR = 4.968, P = 0.046), lesion number ≥ 3 (aOR = 4.229, P < 0.001), male (aOR = 2.252, P = 0.009), respiratory disease (aOR = 1.669, P = 0.046), and cardiovascular disease (aOR = 2.489, P = 0.027) were related to the impairment of PF.ConclusionsPF impairment is common in the elderly with pulmonary TB. The male sex, BMI < 18.5 kg/m2, lesion number ≥ 3, hypoproteinemia, and respiratory and cardiovascular comorbidities were identified as risk factors for significant PF impairment. Our findings highlight the risk factors associated with PF impairment, which may be helpful to improve the current management of pulmonary TB in the elderly to save their lung function.

Abstract CT158: BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Molecular alterations in genes regulating homologous recombination (HR) confer sensitivity of mCRPC to poly ADP-ribose polymerase inhibitors (PARPi). Increased activation of thePI3K-AKT-mTOR pathway in mCRPC contributes to tumor progression and represents an important therapeutic target. Preclinical studies have shown that PI3K inhibitors (PI3Ki) impair HR and sensitize cancer cells to PARPi even in the absence of HR gene mutations. We hypothesize that dual PI3K and PARP inhibition may improve clinical outcomes of mCRPC. We describe preliminary results of a phase Ib/II study investigating safety of the combination of copanlisib (pan-class I PI3Ki) and rucaparib (PARP-1, -2 and -3 inhibitor). Methods: Enrollment criteria included progressive mCRPC, prior androgen inhibitors (abiraterone, enzalutamide, and/or apalutamide); prior taxane chemotherapy was allowed. HR defects (HRD) was not required for the phase Ib but was an inclusion criterion for the Phase II component of the trial. The phase I followed a standard 3+3 escalation design. Dose level (DL) 1 consisted of rucaparib 400 mg PO BID continuously and copanlisib 45 mg IV days 1, 8 and 15 every 28 days; in DL -1 the copanlisib was reduced to 45 mg days 1 and 15 only. Adverse events (AE) were graded by CTCAE v5.0. The primary aim of the phase I was to establish the MTD and the recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Results: Thirteen patients were enrolled with a median age of 64 (55-78) and a median baseline PSA of 11.7 ng/mL (0.015-1939.2). Nine patients (69%) received prior chemotherapy (docetaxel [6], cabazitaxel [3]). Seven patients had HRD (54%) BRCA1 (1), BRCA2 (4), CDK12 (1), and FANCA (1). Treatment-related AEs included grade 2 (G2) leukopenia (46%), G2/G3 anemia (31%), G2/G3 rash (31%). Two dose-limiting toxicities (DLTs) were observed in 5 patients treated in DL 1: G3 rash and G3 AST/ALT elevation attributed to both drugs. Six patients were treated at DL -1 without DLTs; this was identified as the RP2D. Two additional patients have been treated at this dose in Phase II of the study. By RECIST 1.1 criteria, one patient (8%) achieved a partial response (BRCA1 mutation) and three (23%) achieved stable disease resulting in a clinical benefit rate of 30.7%. Median duration of treatment was 12 weeks. One patient harboring a PALB2 VUS mutation remained on treatment for 21.7 months. Of 13 evaluable patients, there were 2 confirmed PSA responses (15%) (one patient without an HRD and one with a BRCA1 mutation). Conclusions: The combination of rucaparib and copanlisib is well tolerated. The RP2D was rucaparib 400mg BID with copanlisib 45mg (D1, D15; 28-day cycle) with signal of efficacy in patients with and without HRD. Clinical trial information: NCT04253262. Citation Format: Matthew J. Hadfield, Andre De Souza, Dragan Golijanin, Roxanne Wood, Adam Olszewski, Sheldon L. Holder, Wafik S. El-Deiry, Rahul Aggarwal, Anthony Mega, Benedito A. Carneiro. BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT158.

Examining Recruitment Strategies in the Enrollment Cascade of Youth Living With HIV: Descriptive Findings From a Nationwide Web-Based Adherence Protocol.

Digital strategies and broadened eligibility criteria may optimize the enrollment of youth living with HIV in mobile health adaptive interventions. Prior research suggests that digital recruitment strategies are more efficient than traditional methods for overcoming enrollment challenges of youth living with HIV in the United States. This study highlights the challenges and strategies that explain screening and enrollment milestones in a national web-based adherence protocol for youth living with HIV. Baseline data from a national web-based HIV adherence protocol for youth living with HIV, collected from July 2018 to February 2021, were analyzed. A centralized recruitment procedure was developed, which used web-based recruitment via Online Master Screener; paid targeted advertisements on social media platforms (eg, Facebook and Reddit) and geosocial networking dating apps (eg, Grindr and Jack'd); and site and provider referrals from Subject Recruitment Venues and other AIDS service organizations, website referrals, and text-in recruitment. A total of 3 distinct cohorts of youth living with HIV were identified, marked by changes in recruitment strategies. Overall, 3270 individuals consented to screening, 2721 completed screening, 581 were eligible, and 83 completed enrollment. We examined sociodemographic and behavioral differences in completing milestones from eligibility to full enrollment (ie, submitting antiretroviral therapy and viral load data and completing the baseline web-based survey). Those with the most recent viral load tests >6 months ago were half as likely to enroll (odds ratio 0.45, 95% CI 0.21-0.94). Moreover, eligible participants with self-reported antiretroviral therapy adherence (SRA) between 50% and 80% were statistically significant (P<.001 to P=.03) and more likely to enroll than those with SRA >80%. The findings add to our knowledge on the use of digital technologies for youth living with HIV before and during the COVID-19 pandemic and provide insight into the impact of expanding eligibility criteria on enrollment. As the COVID-19 pandemic continues and the use of and engagement with social media and dating apps among youth living with HIV changes, these platforms should continue to be investigated as potential recruitment tools. Using a wide variety of recruitment strategies such as using social media and dating apps as well as provider referral mechanisms, increasing compensation amounts, and including SRA in enrollment criteria should continue to be studied with respect to their ability to successfully recruit and enroll eligible participants. RR2-10.2196/11183.

Comparison of the long-term outcomes of EUS-guided gallbladder drainage and endoscopic transpapillary gallbladder drainage for calculous cholecystitis in poor surgical candidates: a multicenter propensity score–matched analysis

Although long-term stent placement using endoscopic transpapillary gallbladder drainage (ETGBD) and EUS-guided gallbladder drainage (EUS-GBD) reportedly reduces cholecystitis recurrence, comparative evidence of their safety and efficacy is scarce. This study aimed to examine and compare the long-term utility of EUS-GBD versus that of ETGBD in poor surgical candidates. A total of 379 high-risk surgical patients with acute calculous cholecystitis met the eligibility criteria for enrollment in this study. The technical success and adverse events (AEs) were compared between the EUS-GBD and ETGBD groups, and propensity score matching was performed to adjust for differences between the groups. Both groups underwent plastic stent placement, and scheduled stent exchange and removal were not performed in either group. The technical success rate of EUS-GBD was significantly higher than that of ETGBD (96.7% vs 78.9%, P< .001), whereas the early AE rate did not differ significantly between the 2 methods (7.8% vs 8.9%, P= 1.000). The rate of recurrent cholecystitis did not differ significantly (3.8% vs 3.0%, P= 1.000), but the rate of symptomatic late AEs, in addition to cholecystitis, was significantly lower with EUS-GBD than with ETGBD (1.3% vs 13.4%, P= .006). Consequently, the overall late AE rate was significantly lower with EUS-GBD (5.0% vs 16.4%, P= .029). Multivariate analysis revealed that EUS-GBD was associated with a significantly longer time to late AE (hazard ratio, .26; 95% confidence interval, .10-.67; P= .005). Long-term stent placement via EUS-GBD is a promising potential option for limiting late AEs, including recurrence, in poor surgical candidates with calculous cholecystitis.

Preoperative Corticosteroid Injections Are Not Associated with Deep Infection after Unicompartmental Knee Arthroplasty.

Prior to unicompartmental knee arthroplasty (UKA), corticosteroid injections (CSI) are a common nonoperative treatment for arthritis. It is unclear whether CSI prior to UKA impacts the likelihood of postoperative infection. This study sought to determine if there is a time- and/or dose-dependent relationship between preoperative CSI and postoperative infection. An administrative claims database was queried for patients undergoing UKA with more than 1 year of pre-enrollment and follow-up. Of 31,676 patients with a UKA who met enrollment criteria, 8,628 patients had a CSI 0 to 3 months prior to surgery, 111 had a CSI 3 to 12 months prior to surgery, and 22,937 never received an injection. Overall, 246 postoperative deep infections were reported (0.8%). Time-dependent and dose-dependent relationships were modeled using multivariable logistic regressions. Postoperative deep infections occurred in 64 patients with CSI 0 to 3 months prior to surgery (0.7%), compared with 0 patients with CSI 3 to 12 months before surgery (0.0%) and 182 controls (0.8%, p = 0.58). CSI within 1 month prior to UKA was not statistically associated with postoperative infection (p = 0.66). Two or more CSI within 3 months prior to UKA were associated with a twofold elevated odds of infection, compared with receiving a single injection (odds ratio [OR]: 2.08, p = 0.03). Univariable predictors of infection included younger age, increasing Charlson Comorbidity Index, smoking, asthma, chronic obstructive pulmonary disease, chronic kidney disease, diabetes, liver disease, and obesity. Multivariable analysis controlling for these characteristics elicited no relationship between recent CSI administration and postoperative infection. CSI within 3 months of surgery (1.5%) or 3 to 12 months (1.8%) were associated with increased conversion to total knee arthroplasty (TKA) compared with those who did not receive an injection (1.1%, p = 0.01), although TKA for indication of periprosthetic joint infection was not statistically different (p = 0.72). Preoperative CSI within 3 months of UKA is not associated with postoperative infection, although significant medical comorbidity does show an association. Preoperative CSI is associated with increased conversion from UKA to TKA for noninfectious indications.