Median Percentage Research Articles

Gastrointestinal Myoelectrical Activity (GIMA) Biomarker for Noninvasive Diagnosis of Endometriosis.

Background/Objectives: Endometriosis represents substantial direct and indirect healthcare costs impacted by an absence of uniformly accurate, non-invasive diagnostic tools. We endeavored to demonstrate gastrointestinal myoelectrical activity (GIMA) biomarkers, unique to endometriosis, will allow non-invasive, uniformly accurate diagnosis or exclusion of endometriosis. Methods: Prospective open-label comparative study of 154 patients, age ≥ 18, with or without diagnosed endometriosis. Population included 62 non-endometriosis controls (Cohort 1), 43 subjects with surgically/histologically confirmed endometriosis (Cohort 2), and 49 subjects with abdominal pain and negative imaging (Cohort 3). Non-invasive electroviscerography (EVG) recorded GIMA biomarkers from three abdominal electrodes before and 30 min post water load protocol. Cohort 2 had postoperative EVG and Cohort 3 had preoperative EVG. Calculated specificity, sensitivity, negative predictive value (NPV), positive predictive value (PPV), and predictive probability or C-statistic used univariate, multivariate, linear, and logistical regression analyses of the area under the curve (AUC) at all frequency and time points, including age and pain covariants. Results: The non-endometriosis cohort differed significantly from the endometriosis cohorts (p < 0.001) for median (IQR) and AUC percent frequency distribution of power at baseline, 10 min, 20 min, and 30 min post water load at all frequency ranges: 15-20 cpm, 30-40 cpm, and 40-50 cpm. The endometriosis cohorts were statistically similar (p > 0.05). GIMA biomarker threshold scoring demonstrated 95%/91% sensitivity and PPV, 96%/95% specificity and NPV, and a C-statistic of >99%/98%, respectively, for age subsets. GIMA biomarkers in Cohort 3 predicted 47/49 subjects positive and 2/49 negative for endometriosis, confirmed surgically. Hormonal therapy, surgical stage, nor pain score affected diagnostic accuracy. Conclusions: EVG with GIMA biomarker detection distinguished participants with and without endometriosis based upon endometriosis-specific GIMA biomarkers threshold scoring.

Continuous Glucose Monitoring Profiles in Pregnancies With and Without Gestational Diabetes Mellitus.

To determine whether continuous glucose monitoring (CGM)-derived glycemic patterns can characterize pregnancies with gestational diabetes mellitus (GDM) as diagnosed by standard oral glucose tolerance test at 24-28 weeks' gestation compared with those without GDM. The analysis includes 768 individuals enrolled from two sites prior to 17 weeks' gestation between June 2020 and December 2021 in a prospective observational study. Participants wore blinded Dexcom G6 CGMs throughout gestation. Main outcome of interest was a diagnosis of GDM by oral glucose tolerance test (OGTT). Glycemic levels in participants with GDM versus without GDM were characterized using CGM-measured glycemic metrics. Participants with GDM (n = 58 [8%]) had higher mean glucose (109 ± 13 vs. 100 ± 8 mg/dL [6.0 ± 0.7 vs. 5.6 ± 0.4 mmol/L], P < 0.001), greater glucose SD (23 ± 4 vs. 19 ± 3 mg/dL [1.3 ± 0.2 vs. 1.1 ± 0.2 mmol/L], P < 0.001), less time in range 63-120 mg/dL (3.5-6.7 mmol/L) (70% ± 17% vs. 84% ± 8%, P < 0.001), greater percent time >120 mg/dL (>6.7 mmol/L) (median 23% vs. 12%, P < 0.001), and greater percent time >140 mg/dL (>7.8 mmol/L) (median 7.4% vs. 2.7%, P < 0.001) than those without GDM throughout gestation prior to OGTT. Median percent time >120 mg/dL (>6.7 mmol/L) and time >140 mg/dL (>7.8 mmol/L) were higher as early as 13-14 weeks of gestation (32% vs. 14%, P < 0.001, and 5.2% vs. 2.0%, P < 0.001, respectively) and persisted during the entire study period prior to OGTT. Prior to OGTT at 24-34 weeks' gestation, pregnant individuals who develop GDM have higher CGM-measured glucose levels and more hyperglycemia compared with those who do not develop GDM.

Transforming the oncology data paradigm by creating, capturing, and retrieving structured cancer data at the point of care: A Mayo Clinic pilot.

Structured data capture requires defined languages such as minimal Common Oncology Data Elements (mCODE). This pilot assessed the feasibility of capturing 5 mCODE categories (stage, disease status, performance status (PS), intent of therapy and intent to change therapy). A tool (SmartPhrase) using existing and custom structured data elements was Built to capture 4 data categories (disease status, PS, intent of therapy and intent to change therapy) typically documented as free-text within notes. Existing functionality for stage was supported by the Build. Participant survey data, presence of data (per encounter), and time in chart were collected prior to go-live and repeat timepoints. The anticipated outcome was capture of >50% sustained over time without undue burden. Pre-intervention (5-weeks before go-live), participants had 1390 encounters (1207 patients). The median percent capture across all participants was 32% for stage; no structured data was available for other categories pre-intervention. During a 6-month pilot with 14 participants across three sites, 4995 encounters (3071 patients) occurred. The median percent capture across all participants and all post-intervention months increased to 64% for stage and 81%-82% for the other data categories post-intervention. No increase in participant time in chart was noted. Participants reported that data were meaningful to capture. Structured data can be captured (1) in real-time, (2) sustained over time without (3) undue provider burden using note-based tools. Our system is expanding the pilot, with integration of these data into clinical decision support, practice dashboards and potential for clinical trial matching.

Prospective pilot study utilizing changes in quantitative values obtained on serial fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) in dogs with appendicular osteosarcoma before and after stereotactic body radiation therapy (SBRT) and carboplatin chemotherapy to assess for prediction of survival and therapeutic effectiveness.

Serial fluorine 18 fluorodeoxyglucose (18F-FDG) positron emission tomography-CT (PET/CT) is commonly used in human oncology to prognosticate and evaluate for therapeutic effectiveness. In this pilot study, dogs with naturally occurring appendicular osteosarcoma were evaluated with serial 18F-FDG PET/CT in an attempt to assess for response to therapy, prognostic factors, and appropriateness of imaging intervals. Fourteen dogs were enrolled in the trial. All dogs had the initial 18F-FDG PET/CT (PET1), with nine dogs having their end-of-therapy 18F-FDG PET/CT (EoT PET) 3 months after stereotactic body radiation therapy (SBRT) to the primary tumor. The median percent change from the PET1 to the EoT PET for the standard uptake value maximum (SUVmax%) was -58% (range: -17 to -88%), metabolic tumor volume (MTV%) was -99.8% (range: -65 to -100%), and total lesion glycolysis (TLG%) was -99.8% (range: -75 to -100%), all of which were significant (P<.05, <.05, and <.05, respectively). On evaluation, it was found that volumes of GTV and CTV were significant for survival (P<.05 and <.05), MTV1, TLG1, and SUVmax on the EoT PET (SUVmaxEoT) were predictive of metastasis (P<.05), and the SUVmax% was significantly correlated to the time to first event (P<.05). Based on this data, serial 18F-FDG PET/CT performed 3 months after SBRT can show a significant reduction in avidity, and the quantitative data collected may help predict metastatic disease in canine appendicular osteosarcoma.

Efficacy, safety, and tolerability of adjunctive brivaracetam in adult Asian patients with uncontrolled focal-onset seizures: A phase III randomized, double-blind, placebo-controlled trial.

Evaluate efficacy, safety, and tolerability of adjunctive brivaracetam (BRV) in adult Asian patients with focal-onset seizures (FOS). Phase III, randomized, double-blind, placebo-controlled study (EP0083; NCT03083665) evaluating BRV 50 mg/day and 200 mg/day in patients (≥16-80 years) with FOS with/without secondary generalization (focal to bilateral tonic-clonic seizures) despite current treatment with 1 or 2 concomitant antiseizure medications. Following an 8-week baseline, patients were randomized 1:1:1 to placebo, BRV 50 mg/day, or BRV 200 mg/day, and entered a 12-week treatment period. Efficacy outcomes: percent reduction over placebo in 28-day FOS frequency (primary); 50% responder rate in FOS frequency; median percent reduction in FOS frequency from baseline; seizure freedom during treatment period (secondary). Primary safety endpoints: incidences of treatment-emergent adverse events (TEAEs); TEAEs leading to discontinuation; serious TEAEs. In this study, 448/449 randomized patients (mean age, 34.5 years; 53.8% female) received ≥1 dose of study medication (placebo/BRV 50 mg/BRV 200 mg/day: n = 149/151/148). Percent reduction over placebo in 28-day adjusted FOS frequency was 24.5% (p = 0.0005) and 33.4% (p < 0.0001) with BRV 50 mg/day and 200 mg/day, respectively, 50% responder rate was 19.0%, 41.1%, and 49.3% with placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p < 0.0001 for both BRV groups vs. placebo). Median percent reduction in FOS frequency from baseline was 21.3%/38.9%/46.7% in patients on placebo/BRV 50 mg/BRV 200 mg/day, respectively. Overall, 0, 7 (4.6%), and 10 (6.8%) patients were classified as seizure-free during the treatment period on placebo, BRV 50 mg/day, and BRV 200 mg/day, respectively (p = 0.0146/p = 0.0017 for BRV 50 mg/200 mg/day vs. placebo, respectively). TEAE incidences were similar between patients on placebo (58.4%) and all patients receiving BRV (58.5%); TEAE incidences for BRV 50 mg/day and BRV 200 mg/day were 57.0% and 60.1%, respectively. Overall, 0.7% of patients on placebo and 2.0% of all patients on BRV reported serious TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 1.3% and 2.7%, respectively), 20.1% of patients on placebo and 33.1% of all patients on BRV reported drug-related TEAEs (incidences for BRV 50 mg/day and BRV 200 mg/day were 26.5% and 39.9%, respectively), and 4.7% of patients on placebo and 3.0% of all patients on BRV discontinued due to TEAEs (discontinuation incidences for BRV 50 mg/day and BRV 200 mg/day were 2.6% and 3.4%, respectively). Adjunctive BRV was efficacious and well tolerated in adult Asian patients with FOS. Efficacy and safety profiles were consistent with BRV studies in predominantly non-Asian populations. Brivaracetam is used to treat partial or focal seizures in people with epilepsy. Most studies with brivaracetam tablets have involved people from non-Asian racial backgrounds. In this study, 449 Asian adults with epilepsy took part. One third took 50 mg of brivaracetam, one third took 200 mg of brivaracetam, and one third took a placebo each day for 12 weeks. On average, those who took brivaracetam had fewer seizures than those given the placebo. Most of the side effects were mild and the number and type of side effects seen were as expected for this medication.

271 A Retrospective, Chart Review Study of the Efficacy and Safety of the RNS System in Pediatric Populations for Medically Refractory Focal Epilepsy

INTRODUCTION: The Responsive Neurostimulation System (RNS) (NeuroPace, Mountain View) is a direct intracranial neurostimulator that is FDA-approved for adults with medically refractory focal epilepsy. There currently exists limited data regarding its efficacy and safety in pediatric populations. METHODS: A retrospective chart review was conducted of pediatric patients treated with the RNS System between January 1, 2019 and December 31, 2021 at Rady Children’s Hospital for at least one year. Data collected included percent change in median disabling seizure frequency from baseline at years 1, 2, and 3, as well as device-related serious adverse events. RESULTS: Twenty patients with medically refractory focal epilepsy were identified who had been treated with the RNS System for at least one year. Median duration of follow-up was 24 months (interquartile range [IQR]: 15-35 months) The median percent reduction in disabling seizures was 29% (N = 20, IQR = 0-84%) at 1 year, 53% (N = 12, IQR = -5-81%) at 2 years, and 67% (N = 4, IQR = 25-100%) at 3 years. 40% of patients reported a &gt;90% reduction in median disabling seizure frequency, and 25% were seizure-free at last follow-up. Reductions in median seizure frequency were comparable based on patient age, age at seizure onset, neuroimaging findings, and prior intracranial monitoring. Zero patients experienced implant site infections. One patient (5%) required lead revision, and another patient (5%) had a spontaneous intraparenchymal hemorrhage at the generator site 2 years after implantation that resolved with expectant management. Neither of these events were associated with long-lasting neurological complications. CONCLUSIONS: The RNS System is a safe and efficacious treatment for pediatric patients with medically refractory focal epilepsy.

Intake of free sugars by 11–13-year-old schoolchildren living in Delhi, India

Intake of free sugars is associated with a risk of non-communicable diseases including dental caries, and authoritative organisations recommend limiting intake to &lt;5% energy intake (E) or lower (1, 2). National surveys of schoolchildren in India indicate the prevalence of obesity is rising &gt;10%/year(3) and that 52.5% of young adolescents are affected with dental caries(4), yet, there is a dearth of data on dietary intake of sugars by this population. The objective of this research was to assess the intake of total and free sugars, and the contribution of food sources to free sugars intake, in a random sample of 11–13-year-old schoolchildren in Delhi, India. The study was approved by The University of Adelaide Human Research Ethics Committee and the Independent Ethics Committee of the Centre for Chronic Disease Control, New Delhi. The target sample size of 360 was based on a ± 5% margin of error in estimated sugars intake. A statistician external to the research team generated a random sample of 150 schools stratified by district (n = 11). Schools were recruited in turn from the list until 10 schools had consented. Teachers shared study information with parents who were invited to complete an online consent form. Child assent was obtained before data collection. Participants recorded all food and drink consumed over three consecutive days, including one weekend day, in a food diary. The information recorded was entered into an online dietary assessment tool, Intake24 (Southeast Asia version), during an interview with each participant during which portion size was ascertained with reference to the database of over 2400 food photographs of more than 100 foods. The Intake24 database converted food and drink reported into the intake of total and free sugars through integrated food compositional tables. Of 514 pupils providing consent, 393 participants (76.5%) (169 girls, 224 boys) completed the study. In girls, the median (IQR) daily intakes of total and free sugars were 95.0 (70.1-120.2) g/day and 43.0 (28.1-68.5) g/day respectively. The corresponding values in boys were significantly higher at 104.0 (80.2-138.7) g/day and 53.1 (34.1-76.5) g/day (p = 0.004). No between-gender difference was observed in the median percent contribution of sugars to E: total and free sugars contributed 14.9% (IQR 11.4-18.1%) and 7.1% (IQR 4.8-10.1%) respectively. The percent contribution of the main sources of sugars to free sugars intake were: (i) Sugars Preserves and Syrups (31.2% (IQR. 9.6-51.7%)); (ii) Cakes and Biscuits (13.7% (IQR 0-26.4%)); (iii) Desserts (5.4% (0-17.5%)) and (iv) Sugar-Sweetened Beverages and Juices (2.1% (IQR 0-15.7%)). In conclusion, in this sample of 11-13-year-old schoolchildren from Delhi, free sugars intake was above the WHO &lt;5% E threshold. Forms of sugars that are added to foods by the consumer made the largest contribution to intake.

Implementation of a pharmacist-led weight loss service to improve medication access and weight loss

BackgroundObesity is a prevalent medical condition that can contribute to an increased risk of developing serious comorbidities, leading to an increase in hospitalizations, morbidity, and mortality. Many of these medical conditions can be improved with weight loss. ObjectivesThis project was designed to improve weight loss outcomes and assess the utilization of services provided by clinical pharmacists for collaborative weight loss management. MethodsThe study design was a single-center, retrospective, and quality improvement study within 3 outpatient clinics at Tufts Medical Center. Patients referred to the pharmacist-led weight loss service from September 1 to October 31, 2022, and continued care for up to 6 months were included. Pharmacist services included selection of weight loss medication, assistance with medication access, device teaching and dose titration, lifestyle counseling, and follow-up. The primary outcome was percent weight loss from baseline. ResultsSeventy-nine patients were referred to the pharmacist-led weight loss service. Mean age of patients was 51 years (SD ±13). Sixty-one patients were female (77.2%). Median baseline weight was 105.5 kg (IQR 93.1 to 120.5 kg) and body mass index 38.1 kg/m2 (IQR 33.9 to 43.5 kg/m2). The median percent weight loss from baseline through the end of the study duration was −8.0% (IQR -3.1 to −12.1%). ConclusionPharmacists were able to effectively provide weight loss care through a pharmacist-led weight loss service by aiding in medication access, providing education on devices and lifestyle management, and engaging in frequent follow-up. Future directions of this study include expansion of the pharmacist-led weight loss service to other ambulatory care clinics within TMC.

Efficacy and Feasibility of Short-Stretch Compression Therapy for Filarial Lymphedema in Sri Lanka.

The WHO-recommended essential package of care (EPC) for filarial limb lymphedema consists of daily limb washing, entry lesion management, limb protection, exercises, and elevation. Decongestive therapy (DT) with compression bandaging by trained lymphedema therapists adds additional benefit but is unavailable for most in low- and middle-income countries (LMICs). To determine whether DT using self-adjustable, short-stretch compression garments (SSCG), prefitted using portable, three-dimensional infrared imaging (3DII), would be effective and feasible in LMIC settings, we conducted a pilot 6-week, interventional, single-group, open-label pilot study in Galle, Sri Lanka. Ten participants with Dreyer stage 3 lymphedema used SSCG for 2 weeks after a 4-week lead-in EPC period. Effect of EPC and compression on quality of life was assessed using the 12-item WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Median participant age was 73 years (range: 32-85 years). Median percent limb volume reduction due to compression was 11.3% (range: 1.1-27.2%). WHODAS 2.0 scores did not change significantly between enrollment and study end. Garment acceptability was high throughout the study. These results provide proof of concept for 3DII-enabled SSCG in LMICs where trained therapists for filarial lymphedema may not be available.

Abstract 6221: First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin

Abstract Background: Suboptimal delivery of anti-cancer agents to cancer tissue compromises the effectiveness of therapeutics. PS101 consists of microclusters of perfluorobutane microbubbles and perfluoromethylcyclopentane (PFMCP) microdroplets. Acoustic cluster therapy (ACT) consists of PS101 administered intravenously and insonated over a tumour with diagnostic ultrasound (2 MHz or above), which fuses the components of PS101 to form larger ACT bubbles that are temporarily trapped in capillaries, followed by low frequency (0.5 MHz) insonation, which induces oscillation of the ACT bubbles, stretching capillaries. Given concurrently with chemotherapy, this enhances delivery of chemotherapy to target tissues. Methods: We describe a first-in-human phase1 study to evaluate the safety and tolerability, pharmacokinetics, and preliminary anti-cancer activity of ACT treatment and the chemotherapy regimens FOLFOX or FOLFIRI in patients with liver metastases of colorectal origin (NCT04021277). The dose escalation cohorts evaluated safety of 20 µL/kg and 40 µL/kg dose levels of PS101 combined with chemotherapy. The primary assessment of anti-tumor activity consisted of within-patient comparison of radiographic responses between ACT-treated lesions (insonated) and control lesions (non-insonated). Results: We had previously treated mice bearing SW620 xenografts treated with a control arm of Irinotecan at 60 mg/kg IP or Irinotecan plus PS101 at 2ml/kg and insonation in the experimental arm and showed a difference in survival in the experimental arm 34 days Vs 54 days p &amp;lt;0.01 (1). In the first in human clinical trial 8 patients were enrolled into the dose escalation part of the study, of which 2 subjects were not evaluable for dose escalation decision. There were no CTCAE grade 3, or above AEs or SAEs related to PS101 or the ultrasound. 4/8 patients discontinued treatment due to AEs - all related to chemotherapy. Median plasma concentration of PFMPC 5 minutes after the injection was 117 ng/ml (n=3, range 82 to 158) in the 20 µl/kg cohort and 233 ng/ml (n=4, range 217 to 275) in the 40 µl/kg cohort. 5 out of 6 patients had greater shrinkage of the insonated lesion compared with control lesions. The median percentage difference in maximum diameter of lesions between baseline and week 8 assessments, for insonated and non-insonated lesions, was -16% (range 25 to -42) and -3% (range 12 to -19), respectively. The dose expansion part of the study is ongoing, randomizing patients receiving FOLFIRI chemotherapy up to 10 patients each between 20 µl/kg and 40 µl/kg dose levels. Conclusions: Following preclinical activity in xenograft models, the ongoing first in human study of ACT in patients with colorectal cancer has shown clinical translation of differential activity in insonated metastasis. Reference: Reference: 1.Bush N et al Front Pharmacol 2019, 10:1299 Citation Format: Udai Banerji, Wing Yau, Mark T. O'Leary, Nigel Bush, Sumita Gurung, Amir Snapir, Jeff C. Bamber, Nina Tunariu. First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6221.

Abstract 578: Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with deficient DNA mismatch repair (d-MMR) cancers, yet less than half of patients with metastatic colorectal cancer (mCRC) receive clinical benefit. We analyzed heterogeneity within d-MMR tumors using a multi-omics approach inclusive of percent unstable microsatellite loci (MS). Methods: We studied consecutive patients with d-MMR mCRC with available primary tumors (N=32) that were treated with an anti-PD-1 antibody at Mayo Clinic (2015-2022). Tumors were profiled using a whole exome and transcriptome platform (ImmunoID NeXT®). MSIsensor was used to calculate percent unstable microsatellite loci from whole exome sequencing data. CIBERSORT and ssGSEA were used to analyze immune gene expression in relationship to percent unstable microsatellite loci. An immune checkpoint gene expression signature was calculated as the mean expression of CD274, CTLA-4, HAVCR2, LAG-3, PDCD1, PDCD1LG2, TIGIT. Aforementioned variables were analyzed in relationship to objective tumor response (RECIST version 1.1). A Cox proportional hazards model was fit to predict progression-free survival (PFS). Results: Among 32 patients with d-MMR mCRC treated with PD-1 blockade, 16 (50%) received first-line anti-PD-1 therapy; others had &amp;gt; 1 prior chemotherapy regimen. Eighteen (56.3%) tumors harbored BRAFV600E, 4 (12.5%) had mutant KRAS, and median PFS was 24.6 months (95% CI: 8.4, NR) with 18 events. Neither tumor mutation burden (TMB) nor PD-L1 mRNA expression predicted PFS. Median percent unstable MS loci was 14.38 (IQR: 2.6-23.2). Patients whose tumors had higher percent unstable MS loci had significantly better PFS (Q2-4 vs Q1; HR: 0.22, 95%CI: 0.06, 0.62; P=0.003), and were associated with increased objective response (P=0.049). Tumors with higher unstable loci also had higher neoantigen clonality (R= 0.64; P= 0.0003) and increased M0 (resting) macrophages (P=0.02). Nonresponders (vs responders) to PD-1 blockade had an increased immune checkpoint expression signature (P= 0.005). Conclusion: A higher percentage of unstable microsatellite loci, associated with higher neoantigen clonality and resting macrophages, was predictive of anti-PD-1 efficacy. Furthermore, an immune checkpoint gene expression signature was associated with objective response. Citation Format: Bahar Saberzadeh-Ardestani, Oluwadunni E. Emiloju, Rondell P. Graham, Jason T. Lewis, Charles W. Abbott, Sean M. Boyle, Frank A. Sinicrope. Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 578.

Abstract 848: Influence of young age at diagnosis on the clinical presentation of disease and survival among patients with multiple myeloma

Abstract Background: Age is an important prognostic factor for multiple myeloma (MM). We evaluated the influence of age on the clinical presentation and outcomes among newly diagnosed patients with MM to optimize risk stratification. Methods: In 850 patients with first primary confirmed MM prospectively enrolled in the Integrative Molecular And Genetic Epidemiology (IMAGE) study (2009-2020), we evaluated the presence of diagnostic myeloma-defining events (MDE), progression free survival (PFS) and overall survival (OS) by young age at diagnosis (≤50 years). We evaluated the association of young age with the prevalence of diagnostic MDE, clinical features and chromosomal abnormalities using the prevalence odds ratio (OR) and corresponding 95% confidence interval (CI) calculated from multivariable logistic regression. Median PFS and OS were graphically examined using Kaplan-Meier survival curves with log-rank tests used to compare survival by diagnostic age group. Risks of disease progression and all-cause mortality were estimated using hazard ratios (HR) and corresponding 95% CI calculated from multivariable Cox proportional hazard models. Results.: Of the 850 patients, 15.4% were diagnosed at ≤50 years of age, 54% were male and 40% self-identified as Black. Compared to patients diagnosed with MM over the age of 50, young patients were more likely to self-identify as Black (59.5% vs 40.5%; P&amp;lt;0.0001) and to report a negative smoking history (66.2% v 56.4%; P=0.01), and less likely to present with age-dependent comorbidities including hypertension, hyperlipidemia and diabetes mellitus type II (P≤0.0001). In multivariable analyses, young patients, compared to older patients, were more likely to present at diagnosis with higher median percent bone marrow plasma cells (70% v 55%; P=0.02) and to undergo autologous stem cell transplant (ASCT) as part of their first-line treatment (82.0% v 67.6%; P=0.01) after controlling for sex, race, body mass index, smoking status and comorbidities. We did not observe significant associations of young age with the prevalence of any other MDE, clinical feature or chromosomal abnormality evaluated. The median OS was 106.9 months (range, 0.23-356.1). OS was significantly longer in young patients with MM compared to patients aged greater than 50 years (159 v 99 months, respectively; P&amp;lt;0.001) leading to a suggestive 1.5-fold decreased risk of mortality among younger newly diagnosed patients (HR=0.67, 95% CI 0.39-1.14; P=0.14) after adjusting for sex, International Staging System-stage, adverse cytogenetic abnormalities, and ASCT. We did not observe associations with age and PFS (P=0.81). Conclusions: Findings suggest that newly diagnosed younger patients with MM are more likely to self-identify as Black, present with more bone marrow plasma cells, have less age-dependent comorbidities, and undergo ASCT leading to a suggestive survival advantage. Citation Format: Krystle L. Ong, Kevin D. Arnold, Gayathri Ravi, Luciano J. Costa, Elizabeth E. Brown. Influence of young age at diagnosis on the clinical presentation of disease and survival among patients with multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 848.

Abstract 355: BCLxL inhibition enhances copanlisib response in colorectal cancer

Abstract Background: Anti-apoptotic signaling, including through BCLxL, is a potential mechanism of resistance to PI3K inhibition in PIK3CA mutant cancers. We have previously demonstrated enhanced activity of PI3K inhibition in combination with BCLxL inhibition in PIK3CA mutated colorectal cancer (CRC) models. Here we examine the potential impact of BCLxL expression in PIK3CA mutant CRCs and the mechanism of treatment response with the combination of copanlisib and navitoclax. Methods: PIK3CA mutant CRCs were identified within TCGA colorectal adenocarcinoma data set and two cohorts were generated based on BCL2L1 (gene that encodes protein BCLxL) expression. Differentially expressed genes and gene set enrichment analysis were performed. CRC cell lines SW48 and SW48PK (Horizon Discovery, SW48 with a PIK3CAH1047R/+ mutation) were treated with copanlisib (copan) (1-100 nM) and navitoclax (250 nM). Immunoblotting was performed quantified using ImageJ to evaluate PI3K and apoptotic signaling. Flow cytometry using annexin V and propidium iodide (PI) was performed as a measure of apoptosis. Immunohistochemistry (IHC) using Ki67 was performed as a measure of cell proliferation on SW48PK xenografts and quantified as percent positive nuclei at 40x field of view (FOV). Results: Two datasets comprised of PIK3CA mutant CRC patients with either high or low BCL2L1 expression containing 39 and 47 patients, respectively, were used in the TGCA analysis. There was no difference in age, gender, or staging between these two datasets. An increase in DNA repair (false discovery rate q-value= 0.034) and interferon alpha signaling pathways (q= 0.022) was seen in PIK3CA mutant and high BCL2L1 expression compared to PIK3CA mutant and low BCL2L1 expression patients. PIK3CA mutant patients with low expression of BCL2L1 had a greater disease-free and overall survival (p= 0.037 and p= 0.042, respectively). Combination of copan and navitoclax treatment of the SW48 and SW48PK cell lines resulted in a reduction in activated ribosomal protein S6 (pRPS6) as compared with control or navitoclax alone at both 6 and 24. Cleaved PARP increased in SW48PK cells treated with 100 nM copan plus navitoclax versus control at both 6 and 24 hour timepoints (p= 0.03, p= 0.049). SW48 and SW48PK cells that were treated with copan and navitoclax for 24 hours had an increase in annexin v, a marker for apoptosis, compared to cells treated with control or single agents. In SW48PK xenografts, a significant reduction in Ki67 percent positive nuclei was seen in combination compared to control (median percent positive nuclei: 20.5, control: 33.2, p&amp;lt;0.001). Conclusions: High BCLxL expression is a sign of poor prognosis for PIK3CA mutant CRC. Inhibiting BCLxL can enhance the sensitivity of PI3K inhibition in PIK3CA mutant cancers and deserves further investigation clinically. Citation Format: Alexa E. Schmitz, Rebecca A. DeStefanis, Alyssa K. DeZeeuw, Autumn M. Olson, Anna L. Lippert, Kennedy J. Maduscha, Katherine A. Johnson, Sean Kraus, Cheri A. Pasch, Dustin A. Deming. BCLxL inhibition enhances copanlisib response in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 355.

Temporal effects of caffeine on intrapulmonary shunt in preterm ventilated infants.

We hypothesized that caffeine would be associated with a transient reduction in the right-to-left shunt and VA/Q. We aimed to explore the temporal effects of caffeine on right-to-left shunt, ventilation perfusion ratio (VA/Q) and shift of the oxyhaemoglobin dissociation curve (ODC) in premature ventilated infants. Retrospective cohort study at a tertiary neonatal unit of infants born at less than 31weeks of gestation that were mechanically ventilated on day three of life. The non-invasive method of the ODC was used to determine the right-to-left shunt, VA/Q and shift before and at 1, 4 and 20 h after a maintenance dose of caffeine citrate. A total of 21 infants were included with a median (range) gestational age of 27 (23.7-30.7) weeks. The median shunt percentage was significantly reduced, compared to baseline at 1 h (8 (range: 7-9) % vs. 4 (range: 0-6) %, p=0.042) and 4 h post caffeine administration (8 (range: 7-9) % vs. 0 (range: 0-3) %, p=0.042), but the VA/Q and the right shift of the ODC did not differ significantly between these time points. At 20 h, there were no significant differences between these indices compared to baseline values. Caffeine led to a transient decrease in intrapulmonary shunt from one to 4 h after administration and this may be due to its diuretic action.

Bimekizumab Efficacy through Year 1 in Patients with Moderate to Severe Plaque Psoriasis Who Had Not Achieved a PASI 90 Response by Week 16: A Pooled Analysis from Four Phase 3/3B Trials

Introduction: Psoriasis Area and Severity Index (PASI) is a commonly used tool for evaluating skin clearance; patients with ≥90% reduction from baseline PASI (PASI 90) have a level of skin clearance that has been associated with improved quality of life.1 Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A.2 High PASI 90 response rates have been observed with BKZ, maintained through three years, across four phase 3/3b trials and an open-label extension (OLE).3–7 Here, we evaluate PASI response through Year 1 in patients who had not had a PASI 90 response during at least one visit up to and including Week 16, in four phase 3/3b trials of BKZ in moderate to severe plaque psoriasis. &#x0D; Methods: Data were pooled from the double-blinded 52-week BE VIVID,3 56-week BE READY,4 56-week BE SURE,5 phase 3 trials, and the 48-week double-blind period of the BE RADIANT6 phase 3b trial. Included patients were randomized to BKZ 320 mg every 4 weeks (Q4W) to Week 16 and then received either BKZ 320 mg Q4W or Q8W maintenance dosing until end of Year 1 (Week 52 for BE VIVID; Week 48 for other trials). Results are reported as observed case (OC).&#x0D; Results: Of the 1,362 patients randomized to BKZ across four phase 3/3b trials, 92.6% (n=1,261) had a PASI 90 response during at least one visit up to and including Week 16 while 7.1% (n=97) had not. PASI response was unavailable for 4 patients. The median (minimum, maximum) percent change from baseline PASI among the 97 patients without a PASI 90 response by Week 16 was −77.3 (−89.7, +20.0) at Week 16 (n=78) and −92.9 (−100, +90.7) at Year 1 (n=51).&#x0D; Overall, 61.9% (60/97) of patients without a PASI 90 response by Week 16 completed their respective phase 3/3b trials and entered an OLE. By Year 1, 55.0% (33/60) achieved PASI 90 during at least one visit.&#x0D; Conclusion: While the vast majority (92.6%) of patients treated with BKZ had a PASI 90 response during at least one visit up to Week 16, a large proportion of patients without a PASI 90 response by Week 16 who completed the phase 3/3b trials and entered an OLE had a PASI 90 response during at least one visit up to Year 1 (55.0%).

Deriving life-course residential histories in brain bank cohorts: A feasibility study.

The exposome is theorized to interact with biological mechanisms to influence risk for Alzheimer's disease but is not well-integrated into existing Alzheimer's Disease Research Center (ADRC) brain bank data collection. We apply public data tracing, an iterative, dual abstraction and validation process rooted in rigorous historic archival methods, to develop life-course residential histories for 1254 ADRC decedents. The median percentage of the life course with an address is 78.1% (IQR 24.9); 56.5% of the sample has an address for at least 75% of their life course. Archivists had 89.7% agreement at the address level. This method matched current residential survey methodology 97.4% on average. This novel method demonstrates feasibility, reproducibility, and rigor for historic data collection. To our knowledge, this is the first study to show that public data tracing methods for brain bank decedent residential history development can be used to better integrate the social exposome with biobank specimens. Public data tracing compares favorably to survey-based residential history. Public data tracing is feasible and reproducible between archivists. Archivists achieved 89.7% agreement at the address level. This method identifies residences for nearly 80% of life-years, on average. This novel method enables brain banks to add social characterizations.

Efficacy and Safety of adjunctive Perampanel in a prospective, real-world, Phase IV study in Indian patients aged ≥12 years for Treatment of focal-onset Epilepsy: Study 508.

ESPRITE (Study 508; NCT03836924) evaluated the real-world safety, tolerability, and efficacy of adjunctive perampanel in patients aged ≥12 years with focal-onset seizures (FOS), with or without focal to bilateral tonic-clonic seizures (FBTCS), in India. ESPRITE was a prospective, multicenter, single-arm, observational, Phase IV study with a 6-month Treatment Period. Patients were aged ≥12 years and had been prescribed perampanel for adjunctive treatment of FOS, with or without FBTCS. Assessments included incidence of treatment-emergent adverse events (TEAEs; primary endpoint), median percent reduction in seizure frequency per 28 days from baseline, 50% responder rates, and seizure-freedom rates. Overall, 200 patients were enrolled (199 patients in the Safety Analysis Set and 174 patients who completed all visits in the main efficacy analyses). TEAEs (all mild or moderate in severity) were reported in 18.1% (n = 36/199) of patients (the most common were dizziness [3.0%] and irritability [2.0%]). TEAEs leading to discontinuation of perampanel were reported in 2.0% of patients; no deaths or serious TEAEs occurred. At 6 months, median percent reduction in seizure frequency was 100.0%, 50% responder rate was 83.3%, and seizure-freedom rate was 49.4%. Adjunctive perampanel (at a mean daily dose of 4 mg/day) was shown to be well tolerated and effective in patients aged ≥12 years with FOS, with or without FBTCS, from India. Many patients do not receive adequate treatment for epilepsy and need effective seizure control medications. In this 6-month clinical study, 199 patients from India, aged 12 years or older, added perampanel to the anti-seizure medications they were already taking. At 6 months, 49% of patients experienced no seizures since starting perampanel and seizure frequency was reduced by half in 83% of patients. Side effects occurred in 18% of patients (most commonly dizziness and irritability) and caused 2% to stop perampanel; no deaths were reported. Perampanel was an effective and generally safe added medication for patients with epilepsy from India.

Association of EEG Background With Diffusion-Weighted Magnetic Resonance Neuroimaging and Short-Term Outcomes After Pediatric Cardiac Arrest.

EEG and MRI features are independently associated with pediatric cardiac arrest (CA) outcomes, but it is unclear whether their combination improves outcome prediction. We aimed to assess the association of early EEG background category with MRI ischemia after pediatric CA and determine whether addition of MRI ischemia to EEG background features and clinical variables improves short-term outcome prediction. This was a single-center retrospective cohort study of pediatric CA with EEG initiated ≤24 hours and MRI obtained ≤7 days of return of spontaneous circulation. Initial EEG background was categorized as normal, slow/disorganized, discontinuous/burst-suppression, or attenuated-featureless. MRI ischemia was defined as percentage of brain tissue with apparent diffusion coefficient (ADC) <650 × 10-6 mm2/s and categorized as high (≥10%) or low (<10%). Outcomes were mortality and unfavorable neurologic outcome (Pediatric Cerebral Performance Category increase ≥1 from baseline resulting in ICU discharge score ≥3). The Kruskal-Wallis test evaluated the association of EEG with MRI. Area under the receiver operating characteristic (AUROC) curve evaluated predictive accuracy. Logistic regression and likelihood ratio tests assessed multivariable outcome prediction. We evaluated 90 individuals. EEG background was normal in 16 (18%), slow/disorganized in 42 (47%), discontinuous/burst-suppressed in 12 (13%), and attenuated-featureless in 20 (22%) individuals. The median percentage of MRI ischemia was 5% (interquartile range 1-18); 32 (36%) individuals had high MRI ischemia burden. Twenty-eight (31%) individuals died, and 58 (64%) had unfavorable neurologic outcome. Worse EEG background category was associated with more MRI ischemia (p < 0.001). The combination of EEG background and MRI ischemia burden had higher predictive accuracy than EEG alone (AUROC: mortality: 0.92 vs 0.87, p = 0.03) or MRI alone (AUROC: mortality: 0.92 vs 0.84, p = 0.02; unfavorable: 0.83 vs 0.73, p < 0.01). Addition of percentage of MRI ischemia to clinical variables and EEG background category improved prediction for mortality (χ2 = 19.1, p < 0.001) and unfavorable neurologic outcome (χ2 = 4.8, p = 0.03) and achieved high predictive accuracy (AUROC: mortality: 0.97; unfavorable: 0.92). Early EEG background category was associated with MRI ischemia after pediatric CA. Combining EEG and MRI data yielded higher outcome predictive accuracy than either modality alone. The addition of MRI ischemia to clinical variables and EEG background improved short-term outcome prediction.

Graduate medical education well-being directors in the United States: who are they, and what does the role entail?

BackgroundInstitutional Graduate Medical Education (GME) Well-being Director (WBD) roles have recently emerged in the United States to support resident and fellow well-being. However, with a standard position description lacking, the current scope and responsibilities of such roles is unknown. This study describes the scope of work, salary support, and opportunities for role definition for those holding institutional leadership positions for GME well-being.MethodsIn November 2021, 43 members of a national network of GME WBDs in the United States were invited to complete a cross-sectional survey that included questions about job responsibilities, percent effort, and dedicated budget, and a free text response question about unique leadership challenges for GME WBDs. The survey was analyzed using descriptive statistics for quantitative data and thematic analysis for qualitative data.Results26 members (60%) responded. Most were physicians, and the majority identified as female and White. Median percent effort salary support was 40%. A small minority reported overseeing an allocated budget. Most respondents worked to improve access to mental health services, oversaw institution-wide well-being programs, designed or delivered well-being content, provided consultations to individual programs, met with trainees, and partnered with diversity, equity, and inclusion (DEI) efforts. GME WBDs described unique challenges that had implications for perceived effectiveness related to resources, culture, institutional structure, and regulatory requirements in GME.DiscussionThere was high concordance for several key responsibilities, which may represent a set of core priorities for this role. Other reported responsibilities may reflect institution-specific needs or opportunities for role definition. A wide scope of responsibilities, coupled with limited defined budgetary support described by many GME Well-being Directors, could limit effective role execution. Future efforts to better define the role, optimize organizational reporting structures and provide funding commensurate with the scope of work may allow the GME Well-being Director to more effectively develop and execute strategic interventions.

Abstract A017: An analysis of 13 independently performed assays to measure homologous recombination deficiency using 90 freshly extracted high grade serous ovarian tumors: findings from the friends of cancer research hrd harmonization project

Abstract A017: An analysis of 13 independently performed assays to measure homologous recombination deficiency using 90 freshly extracted high grade serous ovarian tumors: findings from the friends of cancer research hrd harmonization project