Central Institutional Review Board Research Articles

Abstract 1134: Dissecting pancreatic cancer tumor-immune microenvironment crosstalk using spatial transcriptomics

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) often fails to respond to immune therapies due to various factors, including the role of Epithelial to Mesenchymal Transition (EMT) plasticity in conferring broad resistance to diverse therapies. However, the relationship between cancer cell heterogeneity and the tumor immune microenvironment remains unclear. To address this, we utilized single cell RNA-seq and spatial transcriptomics to uncover the landscape of these cell-cell interactions in human PDAC. Here, we applied to specimens from a clinical trial testing Losartan, an indirect TGF-beta inhibitor with FOLFIRINOX chemotherapy and nivolumab (anti-PD1) in a randomized multi-institutional clinical trial for PDAC (NCT03563248). Methods: Using the NanoString GeoMx Digital Spatial Profiler, we selected multiple regions of interest in formalin-fixed paraffin-embedded (FFPE) human PDAC specimens. Immunofluorescent antibody-guided isolation of RNA and protein from cancer cells (pan-cytokeratin), cancer-associated fibroblasts (alpha-SMA), and immune cells (CD45) were performed. Utilizing the whole transcriptome assay (WTA; 18,000+ protein-coding genes) and a new IO Proteome Atlas (IPA; 500+ plex proteins), we ventured to understand the relationship between tumor cells and the surrounding microenvironment. Results: PDAC cells, CAFs, and immune cells were successfully characterized using NanoString GeoMx in clinical trial specimens. Analysis revealed associations between cancer cell plasticity, TGF-beta signaling mesenchymal subtypes in PDAC cells. These TGF-beta enriched mesenchymal PDAC cells were enriched in Arm 1 (FOLFIRINOX) compared to Arm 2 (FOLFIRINOX+losartan). Immune deconvolution analysis identified variations in immune infiltrates, showing an anti-correlation between macrophages and T-cells. The IPA analysis revealed lower MHC I protein levels in short compared to long term survivors in Arm 3. Conclusions: Spatial transcriptomics and proteomics reveal insights into the spatial relationship between PDAC tumor cell EMT plasticity, CAFs, and immune infiltrates. This enables the discovery of novel immune response biomarkers and potential therapeutic avenues to target tumor and microenvironment interactions. Trial Registration: DF/HCC protocol 18-179: Losartan and Nivolumab in Combination With FOLFIRINOX and SBRT in Localized Pancreatic Cancer. NCT03563248 Ethics Approval: All studies presented were approved by the Dana-Farber/Harvard Cancer Center IRB protocols 18-179. Citation Format: Amaya Pankaj, Michael J. Raabe, Bidish K. Patel, Evan R. Lang, Joshua R. Kocher, Katherine H. Xu, Linda T. Nieman, William L. Hwang, Alec C. Kimmelman, David P. Ryan, Theodore S. Hong, Martin J. Aryee, David T. Ting. Dissecting pancreatic cancer tumor-immune microenvironment crosstalk using spatial transcriptomics [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 1134.

Improving safety and preventing falls using an evidence-based, front-line staff huddling practice: protocol for a pragmatic trial to increase quality of care in State Veterans Homes

IntroductionFalls in nursing homes are a major cause for decreases in residents’ quality of life and overall health. This study aims to reduce resident falls by implementing the LOCK Falls...

The Military Health History: An Educational Initiative to Improve Veteran Healthcare.

As a result of the nature of military service, veterans are a unique patient population with many special health considerations. For various reasons, measures are often not taken by clinicians to address such special considerations. This results in a healthcare disparity for veterans first described by Dr. Jeffrey Brown in 2012. To address this disparity, we introduced "the military health history" to third-year medical students at a large medical school in the southeastern United States. Our objective was to assess the effectiveness of this educational intervention and determine its potential role in creating a future in which veteran healthcare is of the highest quality. This study was approved as a quality assurance/quality improvement project by both Louisiana State University Health Science Center and Southeast Louisiana Veteran Healthcare System IRB offices. A short lecture outlining the components of the military health history was presented to 186 third-year medical students. The students were given the opportunity to answer five survey questions before and after the lecture. These questions assessed the students' current confidence performing a military health history, perceived importance of doing so, and likelihood of future implementation. To determine useful retention of the lecture material, the post-lecture survey was readministered to the same population sample 6 months after the lecture. A series of repeated measures analyses of variance were conducted to examine changes in mean levels of confidence, importance, and likelihood of ascertaining military history during a patient encounter at pre- and post-presentation as well as at the 6 month follow-up. Results revealed a significant effect of time on importance, Wilks' Lambda = 0.74, F (2, 87) = 15.41, P < 0.001; confidence, Wilks' Lambda = 0.61, F (2, 87) = 27.58, P < 0.001; and likelihood of ascertaining a military history during a future patient encounter, Wilks' Lambda = 0.46, F (2, 88) = 50.58, P < 0.001. Results are demonstrated in detail in Table I of the manuscript. The lecture resulted in a statistically significant increase over 6 months in both the likelihood and confidence parameters. The team believes that this result indicates that the students demonstrated useful retention of the lecture material. Our hope is that these students continue to employ the military health history throughout their years of clinical work. In the future, we plan to survey veterans immediately following Veterans Health Administration clinic visits with members of our study population to assess the patient's perceived benefit of the military health history. The team will continue to investigate ways in which military health curricula can be implemented in undergraduate medical education.

Fibroids and unexplained infertility treatment with epigallocatechin gallate: a natural compound in green tea (FRIEND) – protocol for a randomised placebo-controlled US multicentre clinical trial of EGCG to improve fertility in women with uterine fibroids

IntroductionUterine fibroids affect 30%–77% of reproductive-age women and are a significant cause of infertility. Surgical myomectomies can restore fertility, but they often have limited and temporary benefits, with postoperative complications...

Government Initiatives for Research Ethics During COVID-19 Pandemic in Korea.

Despite the growing necessity for government-led policy changes on clinical research ethics during pandemic, the scope of previous literature is limited to Korean government's pandemic response strategies or reflections of research ethics at the level of institutions and academic societies. This paper examines the proactive policy changes and responses by the South Korean government in addressing the challenges and issues of research ethics against the backdrop of the urgency of rapid development and emergency supply of medical products during the coronavirus disease 2019 (COVID-19) pandemic. We conducted searches of various government documents, using predetermined keywords related to research ethics and integrity during the COVID-19 pandemic. Only documents issued by governments or public institutions were included. A total of 24 documents were selected for analysis. They were divided into two phases: the first phase for urgent response (January 2020-February 2021) and the second phase (March 2021-February 2023) for long-term preparedness. The Korean government recommended several measures of research governance to accelerate the ethical review of COVID-related research to be shortened less than one week: the joint operation of Institutional Review Boards (IRBs), exempted or expedited review by a special review committee, guidelines for urgent reviews, and designation of the Korean Academy of Medical Sciences as the supervising agency for the Clinical Trial Safety Support Institution as well as the Central IRB. It allowed temporary non-face-to-face methods for informed consent process (telephone explanations and a photo of the original signed consent) and clinical trials (telephone counselling and prescription, proxy prescription, and drug delivery and supply to clinical trial participants, and online ethics training). As a result of South Korea's commitment to ethical principles in their pandemic response, the medical system did not experience collapses due to the pandemic, and pandemic research was conducted with careful ethical considerations. The pandemic ethics immunization during the Middle East respiratory syndrome epidemic in 2015 laid the foundation for prompt government initiatives that ensured both pandemic research ethics and pandemic response ethics.

Protocol for an evaluation of the initiation of an integrated longitudinal outpatient care model for severe chronic non-communicable diseases (PEN-Plus) at secondary care facilities (district hospitals) in 10 lower-income countries

IntroductionThe Package of Essential Noncommunicable Disease Interventions—Plus (PEN-Plus) is a strategy decentralising care for severe non-communicable diseases (NCDs) including type 1 diabetes, rheumatic heart disease and sickle cell disease, to...

Maintenance of the synergistic effects of cord blood cells and erythropoietin combination therapy after additional cord blood infusion in children with cerebral palsy: 1-year open-label extension study of randomized placebo-controlled trial

BackgroundThis 1-year open-label extension study aimed to identify the persistent synergistic effects of allogeneic umbilical cord blood (UCB) cells and erythropoietin (EPO) in children with cerebral palsy (CP) for up to 2 years.MethodsThis open-label extension study followed children with CP who were enrolled in the previous randomized, double blind, placebo-controlled trial. The following groups from the first trial were maintained: (A) UCB + EPO, (B) UCB, (C) EPO, and (D) only placebo, and all the participants had continued active rehabilitation. This extended study started 3 months after termination of the first trial, which had a 1-year follow-up duration. All subjects received single additional UCB intravenous infusion at the extension baseline regardless of their initial allocation. Outcome measures were the gross motor performance measure (GMPM), gross motor function measure-66 (GMFM-66), and Bayley scales of infant development-II (BSID-II), which were followed at 3, 6, and 12 months after the extension baseline. Changes in the outcome scores from the baseline values of the previous trial and this study were analysed.ResultsSixty-nine children (4.29 ± 1.28 years, M:F = 34:35) were included in this study. Each group showed improvements in the outcome measures at 12 months after additional UCB infusion compared to the baseline scores, except for GMFM and GMPM in Group C which were elevated at 3 and 6 months post-therapy. Total subject analyses did not show significant differences in the outcome measures between the four different groups at 3, 6 and 12 months after additional UCB therapy. However, patients with severe dysfunction, whose GMFCS levels were IV and V, revealed a larger improvement of the GMPM score in Group A than in Group D (Ps < 0.05) from the baseline value of the previous trial. The changes in BSID-II mental scale scores were positively correlated with the number of administered total nucleated cells per unit body weight during this one-year extension study period (r = 0.536, P = 0.001).ConclusionsThese results suggest that when administering UCB to treat patients with CP, combination therapy with EPO is more effective, and the effect might last as long as 2 years, especially in patients with severe impairments.Trial registration: CHA Bundang Medical Center IRB, No. 2015–06-093, approved on July 29, 2015, (https://www.e-irb.com:3443/devlpg/nlpgS200.jsp), ClinicalTrials.gov, NCT03130816, retrospectively registered on April 27, 2017 (https://clinicaltrials.gov/ct2/show/NCT03130816?term=NCT03130816&draw=2&rank=1).

Grassroots Approaches to Community‐Based Representative Recruitment in a Large Multidomain Lifestyle Intervention Trial

AbstractBackgroundU.S. POINTER is a randomized, controlled, multi‐domain 2‐year clinical trial in 2000 older Americans to slow cognitive decline via culturally‐appropriate healthy lifestyle interventions. Participant diversity is essential, with targeted enrollment of 50% women and 23% enrollees from communities of color (reflecting the U.S. population in the 2016 Census). Other recruitment priorities include individuals with lower traditional educational attainment, older age within our eligibility range (75‐79 years old), and rural residence. This diversification aims to (1) better represent our communities particularly affected by ADRD, and (2) help ensure that this intervention can be successful across broad cultural differences for long‐term implementation.MethodU.S. POINTER developed and deployed a community‐based recruitment strategy via a centrally‐coordinated grassroots outreach team at each site. The strategy includes evidence‐based and innovative community engagement tactics and is a multi‐faceted, agile approach that accounts for variations in: demographics across sites’ respective communities; levels of home institution‐community connectedness/integration; and outreach experience across team members. Tactics include: employing a multi‐tiered outreach framework that leverages existing community networks in order to augment team outreach capacity and ensure continuous community engagement; innovating approval procedures with central IRB to reduce barriers to producing timely outreach materials as needed; and standardizing onboarding for new team members across experience levels.ResultThe POINTER grassroots recruitment strategy has accounted for 22% of the trial’s overall enrollment. As of Jan 18, 2023, POINTER has enrolled 1879 participants, 29% of whom are from communities of color, 30% are men, 30% do not hold college degrees, and 13% are over 75 years old. Lessons learned include navigating local institutional reputations, retaining consistent team personnel for long‐term relationship building, setting trajectories for mutually‐beneficial long‐term community investment, and employing a formidable equity lens at all levels of staffing, outreach, and intervention design to better identify and eliminate barriers to participation, amongst others.ConclusionKey recommendations emerging from recruitment success in enrolling a diverse cohort include: approaching recruitment with long‐term vision and commitment toward community investment; leveraging existing community assets and working in partnership with respected community voices; and employing consistent, diverse, multimodal community outreach touchpoints for traction.

Impact of Acute Exercise Challenge on Airway Dynamics in Children and Young Adults with Sickle Cell Anemia

Background Sickle cell anemia (SCA) complications such as frequent pain, chronic anemia, and acute and chronic organ damage lead to reduced physical functioning and cardiopulmonary fitness in affected individuals. Limited data support the safety of maximal cardiopulmonary exercise testing (CPET) in SCA, yet the safety of submaximal, longer-duration exercise at moderate to high intensity in SCA is unclear. The Sickle Cell Pro-Inflammatory Response to Interval Testing Study (SPRINTS) was a multicenter, prospective study that evaluated the impact of longer, submaximal exercise, which mimics the physical activity patterns of children better than CPET, on the acute inflammatory response and airway dynamics in children and young adults with SCA. In this analysis, we defined the effect of moderate to vigorous exercise on forced expiratory volume in 1 second (FEV1) and acute bronchoconstriction. We hypothesized the risk of exercise-induced bronchoconstriction (EIB) in children with SCA is greater than in controls. Methods SPRINTS was approved by the Lurie Children's central Institutional Review Board. Subjects 10-21 years old with hemoglobin (Hb) SS or S/β0 thalassemia and race-matched controls without SCA or sickle cell trait were enrolled across 4 institutions. Subjects were excluded for 1) inability to perform exercise, 2) receiving chronic transfusions, 3) history of exercise-related arrhythmia/syncope, 4) physician-diagnosed asthma, 5) history of EIB, or 6) history of cardiac disease precluding exercise testing. Participants performed maximal CPET on a cycle ergometer using a standardized Godfrey protocol. At least 2 weeks later, participants performed a controlled intensity interval test (CIIT) consisting of 8 bouts of constant workload cycling randomized to either 50% (moderate intensity) or 70% (vigorous intensity) of peak workload achieved during CPET. Exercise bouts were 2 min each with 1-min rest intervals between bouts. Spirometry was performed pre/post (5, 10, 15, and 30 min) CPET and CIIT. EIB was defined as a drop in FEV1 ≥10% from baseline to the lowest FEV1 recorded. Bivariable comparisons were performed, and logistic regression models analyzed the association between EIB and covariables (age, sex, SCA status, max workload, exercise intensity (CIIT only), baseline FEV1 % predicted, FEV1/FVC % predicted) using IBM ® SPSS ® Statistics. Results Available data from 64 subjects (48% F, 73% on hydroxyurea, mean 13.8±2.8 years) and 40 controls (45% F, mean 15.4±2.9 years) were analyzed. Baseline Hb (8.5±1.2 vs. 13±1.4 g/dL, p &amp;lt; 0.001) and maximal workload achieved during CPET (85±26 vs. 135±45 watts, p &amp;lt; 0.001) were lower in subjects vs. controls. The percentage of participants who completed CIIT did not differ between subjects and controls, and no respiratory-related adverse events, including need for bronchodilator therapy, occurred. At baseline, FEV1 and FEV1 % predicted and other parameters (FVC and FVC % predicted, MMEF and MMEF % predicted) were significantly lower in subjects vs. controls (Table 1). However, there was no between-group difference in baseline FEV1/FVC % predicted. Post-exercise, the percentage of participants who met criteria for EIB did not differ between subjects and controls after CPET (21 vs. 26%, p = 0.537) or CIIT (32 vs. 17%, p = 0.126). There was also no significant between-group difference in the greatest drop in FEV1 from baseline to any post-exercise timepoint (mean value or as % of baseline) after CPET or CIIT. In logistic regression models, SCA status, age, sex, maximal workload during CPET, exercise intensity (CIIT only), baseline FEV1 % predicted and FEV1/FVC % predicted were not associated with EIB after CPET or CIIT (Table 2). Conclusion Compared to controls, children and young adults with SCA and no history of asthma or EIB had lower baseline values on all spirometry parameters except FEV1/FVC % predicted. EIB was not more common in subjects with SCA vs. controls after maximal CPET or a submaximal exercise challenge of longer duration at moderate or vigorous intensity. No independent factors were associated with development of EIB after acute exercise. Despite concerns that undiagnosed lower airways disease in children with SCA is common, our results suggest the risk of EIB in SCA is low and underscore the safety of moderate to vigorous exercise toward developing evidence-based exercise guidelines in non-asthmatic children and young adults with SCA.

High Hydroxyurea Usage in Sickle Cell Anemia Regardless of Patient Demographic

Introduction/Background: Hydroxyurea is highly effective in sickle cell disease, yet it is still underutilized. The Pediatric Sickle Cell Program of Northern Virginia recently published a 10-year analysis of uniform hydroxyurea (HU) implementation starting in infancy for all patients with sickle cell disease of severe genotype (SCA), demonstrating rise in HU usage from 32.5% baseline rate to 79.6% after two years, and to &amp;gt; 90% after 8 years. 1 Other HU utilization studies reporting lower rates largely use Medicaid data, and lower socioeconomics is often cited as a barrier to HU utilization. The Northern Virginia study reported on all patients with SCA regardless of insurance coverage, thus raising the question whether the high HU usage rate achieved in this program was influenced by a high proportion of non-Medicaid patients or other unusual demographic features. Therefore, we analyzed 10 years of HU usage data by insurance, ethnicity, and age. Methods: HUdata extracted from a longitudinal REDCap database and electronic medical records (EMR) with IRB approval (Children's National Medical Center IRB, Pro00002745, Pro00013374) previously reported 1 for five 2-year intervals are additionally analyzed for insurance, ethnicity, and age, with new data for 2019-2021. HU-eligibility includes SCA patients age ≥ 9 months and not chronically transfused. HU users (on HU) are patients demonstrating Hgb F rise and expected hemogram changes in response to HU, monitored every 2-3 months; HU non-users (not on HU) are patients who refuse HU or are grossly non-adherent as evidenced by lack of changes in Hgb F and hemogram. Pharmacy dispense records available in Epic EMR are used as corroborative information. Results: 1. Medicaid patients comprised 39 - 46% and non-Medicaid patients comprised 54 - 61% of all patients over the five 2-year periods. African-American (AA) and African patients comprised 85% of all patients. Medicaid coverage ranged from 24 - 39% for AA patients and 38 - 48% for African patients. (African is defined as born in Africa or having parents born in Africa who immigrated to the US.) 2. Comparing HU usage by insurance over the five 2-year periods, HU users increased from 72% to 91% for Medicaid patients and from 83% to 95% for non-Medicaid patients. Conversely, HU non-users decreased from 28% to 9% for Medicaid patients and from 17% to 5% for non-Medicaid patients. No statistical difference was detected in HU usage by Medicaid versus non-Medicaid insurance in any interval (p = 0.13 to 0.91) (Table 1). 3. HU usage rates in AA and African patients were not statistically different (p = 0.07 to 0.32), except in one interval (2013-15) (p = 0.006) (Table 1). 4. Comparison of HU usage in two age groups, 9 months-12 years and ≥ 13 years, showed that while HU non-acceptance/non-adherence tended to be higher in the age ≥ 13 group, no statistical significance was reached in any interval (p = 0.13 to 0.97) (Table 1). 5. The uniform HU implementation program targeted for fetal hemoglobin (Hgb F) 30% or higher by frequent HU dose optimization and close adherence monitoring. Hgb F &amp;gt; 20% was considered good adherence, and Hgb F 10-20% reflected partial adherence. Partially adherent patients did not distribute differently between Medicaid and non-Medicaid insurance (p = 0.07 to 0.86) but were predominantly age &amp;gt; 13 (p = 0.0005 to 0.001) (Table 2). Conclusion: 1. HU users and HU non-users did not disproportionately distribute to any demographic group. 2. Uniform HU implementation was effective in both Medicaid and non-Medicaid populations. 3. Ethnicity and age were not significant factors in HU uptake or acceptance, but decreased HU adherence is more frequent in teenagers. 4. HU can be effectively implemented for all SCA patients across demographic groups. Medicaid insurance, as a proxy for socioeconomic level, is not a barrier to high HU usage. Reference: 1. Phan V, Park JA, Dulman R, Lewis A, Briere N, Notarangelo B, Yang E. Ten-year longitudinal analysis of hydroxyurea implementation in a pediatric sickle cell program. Eur J Haematol. 2022 Nov;109(5):465-473. doi: 10.1111/ejh.13827. Epub 2022 Sep 2. PMID: 35811388.

Athn Transcends Natural History Cohort Study of Bleeding Symptoms and Treatment Outcomes in Patients with Glanzmann Thrombasthenia

Background Glanzmann thrombasthenia (GT) is a rare, inherited, qualitative platelet disorder caused by a deficiency of one or both platelet surface proteins alpha IIb beta 3. This protein on the platelet functions as the fibrinogen receptor and is essential for hemostasis. Individuals with GT have lifelong bleeding episodes that can be frequent and severe often involving the muco-cutaneous membranes. GT is an autosomal recessive disorder with variations of the ITGA2B or ITGB3 genes. The prevalence of GT is estimated to be 1:1,000,000 in the general population. In populations with high consanguinity, the prevalence is higher. Reports of the impact of living with GT are lacking. Platelets have previously been the mainstay of treatment for severe bleeding and to manage surgical bleeding in people with GT. However, platelet transfusions carry a number of risks including allergic reactions (anaphylaxis, acute lung injury), pathogen transmission, and the formation of allo-antibodies. Primary bleeding prophylaxis is currently not available and all treatment for bleeding is reactive and on-demand. As potential new therapies emerge, clinicians require unbiased, long-term data on the safety and effectiveness of both current and new therapies. Therefore, we designed a registry of people with GT with the aims of assessing the bleeding rate and phenotype for people with this condition, as well as describing their lived experience. Rationale Due to the rare nature of GT, data within individual center registries are naturally limited. There is variation in the data held and method of collection. The aim of the study is to collect biospecimens, phenotypic characteristics, bleeding patterns, and treatment utilization, from people who have been diagnosed with GT. To achieve this, a comprehensive, multi-institutional, observational cohort study will be conducted to: Allow collection of longitudinal safety and clinical practice data for treatments in patients with GT, allowing monitoring of recently approved and well-established therapies; Aid new discovery, through the collection of biospecimens and phenotype data; Provide sufficient, unified data capture in participants with this rare disorder across the United States. Objectives To describe the bleeding phenotype in GT, including the frequency of bleeds, the Site of bleeds, and to describe real-world effectiveness of therapies used in GT, by evaluating; the frequency of bleeds, Patient reported outcomes, Healthcare and treatment utilization, To create a database for future research. Methods ATHN Transcends (NCT04398628) assesses the safety and effectiveness of contemporary therapies for people with inherited bleeding and clotting disorders. The primary aim of ATHN Transcends is to collect specific adverse events harmonized with the European Haemophilia Safety Surveillance (EUHASS). The study is constructed to allow the addition of specific modules. We have designed the GT module in ATHN Transcends to assess the safety and effectiveness of current therapy for GT. In addition, we will be collecting data around the actual bleeding rate in those who live with GT as well as more fully describing the lived experience of being impacted by GT. The study will be conducted through ATHN-affiliated centers who care for those impacted by GT. Study Design This study is a longitudinal, natural history, observational cohort study of approximately 50 participants with GT at 16 ATHN-affiliated treatment centers across the United States and a sub-cohort from one international ATHN Affiliate. The minimum planned duration of study participation for participants is approximately 18 months. Up to 10 pediatric subjects aged 2 years to &amp;lt;10 years, up to 10 aged 10 to &amp;lt;18 years, and a minimum of 30 adults &amp;gt;18 years with GT are expected to be enrolled. Each subject will complete a daily record for three months of bleeding event details, and any treatments. Summary ATHN Transcends has received central IRB approval and is currently being rolled out across participating American Thrombosis and Hemostasis Network (ATHN) Affiliates in the United States. Enrollment in the GT Module can begin as soon as a site opens ATHN Transcends to enrollment. Conclusion ATHN Transcends provides a real-world mechanism in which to collect safety and effectiveness data of contemporary therapies for people with GT. The GT Module of ATHN Transcends will allow collection of Good Clinical Practice-grade data.

Women with limb loss: rationale, design and protocol for a national, exploratory needs assessment to evaluate the unique physical and psychosocial needs of women with limb loss

IntroductionThere is a growing population of women with limb loss, yet limited research is available to provide evidentiary support for clinical decision-making in this demographic. As such, there is a...

Identification of potential biomarkers related to mesenchymal stem cell response in patients with Alzheimer’s disease

BackgroundPreclinical studies showed that mesenchymal stem cells (MSCs) ameliorate tau phosphorylation, amyloid-beta accumulation, and inflammation in Alzheimer’s disease (AD) mouse models via secretion of neurotrophic factors and cytokines. We aimed to identify CSF biomarkers that can be used to predict or monitor the response to MSCs in patients with AD.MethodsAD patients were injected with human umbilical cord blood-MSCs (n = 22) or placebo (n = 12). The cerebrospinal fluid (CSF) samples were collected at baseline, one day after the first injection, and one day after the third injection. The patients injected with MSCs were classified into good responder (GR) or poor responder (PR) groups based on the rate of changes in the ratio of total-tau and phosphorylated-tau in the CSF. We selected three typical participants in each group, and their CSF protein levels were analyzed using liquid chromatography/tandem mass spectrometry (LC–MS/MS).ResultsIn the LC–MS/MS analysis, 1,667 proteins were identified. Eleven proteins showed significant differences between the typical GR and PR at baseline. Based on their significance level and known functions, two proteins, reticulocalbin-3 (RCN3) and follistatin-related protein 3 (FSTL3), were selected as potential biomarkers to predict MSC response. A total of 173 proteins showed significant change one day after the third injection compared to the baseline in typical GR. We excluded 45 proteins that showed significant change after the third injection compared to the baseline in the typical PR. Based on their significance level and known function, four proteins, scrapie-responsive protein 1 (SCRG1), neural proliferation differentiation and control protein (NPDC1), apolipoprotein E (ApoE), and cystatin C (CysC), were selected as potential biomarker to monitor MSC response. Additionally, functional analysis revealed that the increased CSF proteins after the third injection compared to the baseline in the typical GR were associated with synaptogenesis.ConclusionsThis study identified two proteins (RCN3 and FSTL3) that may be potential biomarkers for predicting MSC response and four proteins (SCRG1, NPDC1, ApoE, CysC) that may be potential biomarkers for monitoring MSC response in patients with AD. Further studies are needed to validate our results.Trial registration Clinical Trials.gov, NCT02054208. Registered on 4 February 2014. Samsung Medical Center IRB File No.2017-04-025. Registered on 20 June 2017.

Patiromer utility as an adjunct treatment in patients needing urgent hyperkalaemia management (PLATINUM): design of a multicentre, randomised, double-blind, placebo-controlled, parallel-group study

IntroductionHyperkalaemia is common, life-threatening and often requires emergency department (ED) management; however, no standardised ED treatment protocol exists. Common treatments transiently reducing serum potassium (K+) (including albuterol, glucose and insulin)...

Streamlining regulatory review in a multicenter platform trial: Opportunity to enhance patient centered care and drive innovation and efficiency.

1572 Background: In addition to being required by the Federal Policy for the Protection of Human Subjects for United States-based institutions that receive federal funding and are engaged in cooperative research projects, the use of a central Institutional Review Board (cIRB) has multiple benefits. Yet more advanced trial designs have unique needs and challenges that may hinder adoption of an efficient cIRB. Platform trials, which require both a master protocol and successive individual protocol amendments for each new agent, are prone to high regulatory burden that can slow trial recruitment, representing a significant workload for study personnel. Specific challenges for platform trials include high burden of new amendments and IRB review schedules staggered across sites, making it challenging to have all sites operating under the same amendment concurrently. Methods: Administrative assessments were collected over the course of the I-SPY2 trial. The primary outcome of interest was time from amendment submission to approval (calculated as the number of days from submission to the local IRB by the site investigators to approval by the local IRB). Quantitative data in terms of hours spent on regulatory tasks pre- and post-cIRB implementation was estimated. Site investigators were asked in December 2022 to complete a brief questionnaire to investigate perceptions on changes to workload and level of comfort using a cIRB. Results: Amendments were activated when 50% of high accruing sites had IRB approval. The number of sites with approval for an amendment to go live was &lt; 25% prior to cIRB adoption, and 83% after. Following transition to the cIRB in February 2021, the mean time from amendment submission to approval decreased from 54.4 to 20.7 days by Jan 2023. Changes to the informed consent were possible once the cIRB was adopted, including: standardizing site-specific IRB language in a section of the consent, so it need not be adjusted with every new agent amendment; standardizing site-specific workflows; shortening consent and making it more patient friendly. The average time that CRCs spent on regulatory work at each site decreased by an average of 160 minutes, but was variable, revealing continued use of local IRB, other committees at some sites. A total of 14 respondents completed the survey; most respondents indicated that keeping up with the amendment approval process was easier post-cIRB and 94% were comfortable relying on a cIRB. The short time for cIRB approval revealed the inefficiency of other processes, including coverage analysis and building of drug order sets. Conclusions: Active engagement of cIRB leadership and IRB working group has enabled regulatory review that now takes less than 30 days. The cIRB is now the standard for the I-SPY family of trials. Other services can also be shared and will continue to drive efficiency and reduce the regulatory burden for sites.

Training oncologists (Oncs) to conduct better informed discussions with African American (AA) cancer (CA) patients (pts) about tumor genomic profiling (TGP): Results of a randomized pilot trial of gene pilot pro (GPP).

10552 Background: Molecular characterization of tumors to guide therapy choices using next-generation sequencing-based TGP has become standard practice for pts w/multiple CA types. AAs are more likely to have negative attitudes towards genetics, rooted in concerns about privacy, cost and discrimination, and higher mistrust of medical institutions. Oncs are poorly prepared for informed discussions w/CA pts about secondary hereditary risks of TGP and often fail to have these conversations despite 2015 ASCO guidelines benchmarking this standard, and further are poorly informed of the potential challenges of discussing TGP and germline risk w/their AA CA pts. Methods: Formative work included 1-on-1 interviews (n = 10) to assess oncs’ perceptions of TGP use and discussions w/AA CA pts, and a national survey (n = 50) to assess TGP practice patterns, communication of hereditary risk, and challenges encountered in AAs. Interviews/survey data and advisory board input informed development of GPP, a 12 min online training video to improve Oncs’ awareness of ASCO guidelines, confidence and preparation to have TGP discussions w/pts, and improve awareness of barriers to TGP unique to AA CA pts. The control consisted of 10 slides with information about TGP drawn from industry/academic websites and the 2015 ASCO guidelines. Participants (n = 63) completed baseline (100%), post-intervention (100%), and 1-month (95%) follow-up surveys. The study was approved by the Fox Chase Cancer Center IRB 18-8006. Results: Oncs were recruited by email and randomized to view GPP or control material. The majority were age 40-49 (38%), 71% male, 44% White, w/mean 15 yrs in practice; 85% reported none or only informal training to communicate TGP risks/results to pts. GPP produced a durable increase in recognition of 4 core ASCO guideline elements (20% baseline, 67% post, 63% 1 month). At 1-month follow-up, GPP significantly improved recognition of barriers specific to AA CA pts related to TGP and hereditary risk (p = 0.001) and promoted greater preparedness to support TGP discussions w/AA pts including preparedness to identify (p &lt; 0.01) and understand (p &lt; 0.01) issues that matter most to their AA pts. 1-month confidence to conduct difficult discussions related to genetic mistrust (p = 0.004) and TGP cost (p = 0.003) was better preserved after viewing GPP compared to control. Among Oncs viewing GPP, 90% agreed/strongly agreed that GPP helped them “better understand how to address concerns my AA pts may have about TGP” and 97% definitely/probably would recommend GPP to other Oncs. Conclusions: GPP significantly improved Oncs’ awareness of barriers related to TGP communication in AA CA pts, improved preparedness to facilitate informed decision-making, and supported sustained confidence to lead difficult discussions.

Phase 2 randomized trial of neoadjuvant or palliative chemotherapy with or without immunotherapy for peritoneal mesothelioma (Alliance A092001).

TPS8603 Background: Peritoneal mesothelioma is a rare and poorly studied disease with few treatment options. For patients (pts) who are not surgical candidates, treatment recommendations for systemic therapy have been extrapolated from clinical trials for pleural mesothelioma that commonly exclude pts with peritoneal mesothelioma. Recently, the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab received FDA-approval for the frontline treatment of non-resectable pleural mesothelioma. Additionally, a prospective, non-randomized phase 2 trial demonstrated activity with combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade in peritoneal mesothelioma. In parallel, encouraging activity with combined chemo-immunotherapy has been reported in pleural mesothelioma. Given the benefits observed with immunotherapy, and the potential to improve upon those with chemotherapy and VEGF inhibition, we seek to determine whether the addition of the PD-L1 inhibitor atezolizumab improves outcomes with chemotherapy and bevacizumab in pts with newly diagnosed peritoneal mesothelioma. Methods: Alliance for Clinical Trials in Oncology A092001 is a prospective, randomized phase 2 clinical trial. All pts with newly diagnosed peritoneal mesothelioma will be randomized 1:1 using a dynamic allocation Pocock-Simon procedure to receive carboplatin, pemetrexed and bevacizumab, with or without atezolizumab, every 21 days for four cycles. Patients who are eligible to proceed with surgery after four cycles of therapy will then do so. Pts who are not eligible to proceed with surgery may receive maintenance bevacizumab and atezolizumab, or second-line atezolizumab with bevacizumab until progression of disease or toxicity. The primary objective is to determine if frontline treatment with carboplatin, pemetrexed, bevacizumab and atezolizumab results in a superior best response rate (RR) to carboplatin, pemetrexed and bevacizumab as determined by RECIST. With 31 eligible pts per arm (62 eligible total), this randomized design has 80% power to detect an improvement in the RR from 20% to 45%, with a 1-sided significance level of 0.10 where an interim futility analysis will be conducted after 32 pts are enrolled. Stratification factors include eligibility for cytoreductive surgery at diagnosis and histologic subtype. Secondary endpoints include progression-free survival, overall survival and adverse events. As integrated biomarkers, we will determine if soluble mesothelin-related peptides and megakaryocyte potentiating factor correlate with responses. This trial was recently approved by the National Cancer Institute Central IRB and is activating at sites across the country. Clinical trial information: NCT05001880 .

770 Outcome Results of the Prospective CEA Registry

Abstract Introduction Cultured epidermal autograft (CEA) is a permanent skin replacement indicated for use in adult and pediatric patients with deep dermal or full thickness burns comprising a total body surface area (TBSA) ≥ 30%. CEA may be used in conjunction with split-thickness autografts or alone, in patients for whom split-thickness autografts may not be an option due to the severity and extent of their burns. CEA was approved for use in adults in the United States in 2007 as a Humanitarian Use Device (HUD) under a Humanitarian Device Exemption (HDE) and was approved for pediatric use in 2016. Methods The objective of the CEA Registry is to allow prospective collection and analysis of demographic, treatment, and outcome data for the real-world use of CEA. Prior to initiation of the Registry, a central Institutional Review Board reviewed and approved written procedures and informed consent from each participating burn center. As of the date of this analysis, 5 centers were enrolling patients in the Registry. The data are collected and stored in a 21 Code of Federal Regulations (CFR) Part 11 and Health Insurance Portability and Accountability Act (HIPAA) compliant environment. First patient enrollment in the Registry was 13 June 2019 and data cutoff for this analysis was 28 July 2022. Results Sixtyeight patients (50 adults and 18 children) had completed data in the registry, up through hospital discharge, for this analysis. Except for age and revised Baux score, demographics and burn characteristics were similar between the adult and pediatric populations. The majority of patients were male in both the adult (76%) and pediatric (67%) groups, with burn caused by flame the most common etiology (86% and 78%, respectively). The total body surface area (TBSA) of burn was 58% in adults and 56% in pediatric patients (range 30% to 96%), and almost half had inhalation injury in each group. Approximately 74% of adults and 67% of pediatric patients had TBSA ≥50%. Median age in the adult group was 42 years, and in the pediatric group was 15 years. Since age is a component of the calculation of Baux score, pediatric patients had lower mean revised Baux scores (75) compared to adults (107.5). Overall, 59 of the 68 patients (87%) survived until hospital discharge. The mean % graft take (engraftment) in both adult (81%) and pediatric (84%) groups is notable when compared to mean final graft take in 453 Epiceltreated patients reported in the HDE database (67% in adults and 70% in pediatric). By age group, adults had 84% survival rate and pediatric patients had 94% survival. Conclusions Outcomes from this prospective collection of data in severely burned patients treated with CEA demonstrate favorable engraftment and survival rates and are in general agreement with recent literature. Applicability of Research to Practice Reported outcomes from the CEA Registry can be used as a benchmark by centers using CEA for treatment of burns.

Abortion on TikTok Versus YouTube: An Analysis of Abortion Stance and Purpose [ID: 1365895

INTRODUCTION: Social media platforms are an accessible way for individuals to consume medical information. The topic of abortion is undergoing extensive discussion, and there is increasing need to understand the information available to the public. We aimed to assess whether the social media video platform affected abortion content stance and purpose. METHODS: We performed a cross-sectional study of abortion content on TikTok and YouTube. We searched the term “abortion” on each platform and reviewed the first 155 videos. Videos were categorized by purpose, abortion stance, and medical misinformation. We calculated descriptive statistics and used χ2 testing to compare between groups. The Albany Medical Center IRB determined this study was exempt. RESULTS: Of 310 videos, 280 were included for analysis with 137 YouTube videos and 143 TikTok videos. YouTube is more likely than TikTok to have anti-abortion content (19.71% versus 7.69%, P=.003) and strongly anti-abortion content (15.33% versus 4.20%, P=.002). YouTube is more likely than TikTok to have content categorized as news (33.58% versus 0.70%, P&lt;.001) and less likely to have personal experience content (14.6% versus 41.26%, P&lt;.001). The platforms were similar in their content containing medical misinformation (10.14% on YouTube versus 5.44% on TikTok, P=.137). CONCLUSION: There are significant differences in abortion content available for public consumption on popular social media video platforms. Understanding these differences can help us recognize content biases outside the clinical setting, facilitate creation of medically accurate and patient friendly content, and spur future work on medical misinformation and changes in social media over time.

Effect of Race on Obstetric Ultrasound Keepsakes [ID: 1376924

INTRODUCTION: Differences in treatment and health outcomes by race are well-documented. Ultrasound photos represent important keepsakes and may affect patient experience and care. We examined whether race and other factors affected the number of keepsakes given during obstetric ultrasound. A secondary outcome was patient satisfaction. METHODS: From October 2021 to September 2022, we distributed a survey after outpatient obstetric ultrasounds at a tertiary care hospital, including questions on demographics, number of photos received, and overall satisfaction. Exclusion criteria included inability to complete the survey in one of four available languages or carrying a multifetal gestation. Ultrasound staff and faculty were blinded to the research question. This study was approved by the Beth Israel Deaconess Medical Center IRB. RESULTS: Of 405 individuals approached, 251 completed the survey (response rate of 62.0%). Of these, 53.4% identified as White, 16.3% Asian, 10.4% Black, 7.2% as multiple races, 6.8% other race, and 6.0% preferred not to say. In total, 81.3% of patients received photos (median, 4; interquartile range [IQR], 3–6), with no difference in number by race, ethnicity, primary language, or body mass index. Most patients expected to receive photos, with no appreciable differences by race. Ratings for visits were high (IQR, 8–10/10) with no difference between patients who did or did not receive photos or by number of photos. CONCLUSION: We found no difference in number of photos patients received by race. Overall ratings of ultrasound visits were high and not associated with number of keepsakes received. While reassuring, further research is needed into equitable treatment in obstetric ultrasound.