Oregon Health And Science University Research Articles

Abstract 6341: Targeting myeloid epithelial tyrosine kinase (MERTK) receptor in acute myeloid leukemia using a novel antibody-drug conjugate, RGX-019-MMAE

Abstract Background: Myeloid epithelial reproductive tyrosine kinase (MERTK), a transmembrane protein receptor from the TAM (Tyro3, Axl, Mertk) family, is overexpressed in cancer and associated with reduced apoptosis and chemoresistance, making it an attractive therapeutic target. RGX-019-MMAE, a novel humanized IgG1-MMAE antibody-drug conjugate (ADC) (Inspirna, Inc), selectively binds to MERTK with high affinity on tumor cells, resulting in internalization and degradation of the receptor. It then induces cytotoxicity through the release of the payload, MMAE (monomethyl auristatin E), which disrupts mitosis. We hypothesize that targeting MERTK via RGX-019-MMAE exerts an antileukemic effect. Methods: First, to determine the clinical relevance of MERTK, using the Oregon Health and Science University (OHSU) acute myeloid leukemia (AML) dataset, we divided patients into low and high MERTK mRNA expression based on mean expression and compared their overall survival. To identify the AML subtypes with the highest MERTK expression, we analyzed samples from 810 AML patients at MD Anderson using reverse phase protein arrays (RPPA), as well as 8 AML cell lines and the peripheral blood of 9 AML patients using flow cytometry. Then, the cell lines with the highest MERTK expression were treated with varying doses of RGX-019-MMAE or isotype control for 120 hours and assessed for viability with CellTiter-Glo 2.0. Likewise, we administered RGX-019-MMAE to primary cells from AML patients and determined the anti-leukemic effect. Finally, we investigated the synergistic effect of RGX-019-MMAE with venetoclax, a BCL2 inhibitor, or cytarabine, a chemotherapy agent, in vitro. Results: In the AML OHSU dataset, patients with high MERTK mRNA expression had significantly worse overall survival (p=0.02). RPPA revealed that patients with PTPN11 mutation, t (9;11), and monocytic AML subtypes had significantly higher MERTK protein expression. MERTK protein expression varied in AML cell lines and was highest in Kasumi-1 and OCI-AML3. Treatment of these two cell lines with RGX-019-MMAE resulted in significantly more killing of leukemic cells than the isotype control ADC in a dose-dependent manner (p<0.01). Similarly, in primary AML cells with high MERTK expression, RGX-019-MMAE treatment induced significant cell death compared to the control ADC. In addition, Kasumi-1 and OCl-AML3 cells treated with RGX-019-MMAE combined with venetoclax or cytarabine showed a synergistic cytotoxic effect in a dose-dependent manner. Conclusion: High MERTK expression in monocytic AML suggested that MERTK is a promising therapeutic target in this subtype. RGX-019-MMAE significantly induced AML cell death and produced a synergistic anti-leukemic effect in combination with chemotherapeutic agents and targeted therapy in vitro, suggesting its potential for targeting patients with high-risk AML. Citation Format: Anudishi Tyagi, Maryam Siddiqui, Isabel Kurth, Shugaku Takeda, Amanda Eckstrom, Jenny Borgman, Abhishek Maiti, Venkata Lokesh Battula. Targeting myeloid epithelial tyrosine kinase (MERTK) receptor in acute myeloid leukemia using a novel antibody-drug conjugate, RGX-019-MMAE [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 6341.

Holistic Care of the Immunocompromised Rheumatologic Patient – Case Analysis

Patients with rheumatologic conditions, such as eosinophilic granulomatosis with polyangiitis (EGPA), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), often face being immunocompromised due to their disease state, or the immunosuppressive effect of their treatments. Managing immunocompromised rheumatologic patients can be challenging and complex. This article reviews a GSK-sponsored Innovation Theatre session that took place during the American College of Rheumatology (ACR) Convergence 2023 Annual Meeting in San Diego, California, USA, on 14th November 2023. Kevin Winthrop, Professor of Infectious Diseases at the School of Medicine at Oregon Health and Science University (OHSU); and Professor of Public Health at OHSU-Portland State University (PSU) School of Public Health, Portland, Oregon, USA, provided insights into the immunocompromised patient within rheumatology. He considered the challenges of associated comorbidities, diagnosis, and implementing preventative measures. Leonard Calabrese, Professor of Medicine at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University; Director of Clinical Immunology of the R.J. Fasenmyer Center; and Vice Chairman at the Department of Rheumatic & Immunologic Disease, Cleveland Clinic, Ohio, USA, presented an interactive patient case overview of EGPA. He identified the need for practitioners to take ownership of patients with serious and opportunistic infections. The session provided awareness of the origins of immunocompromised states, including disease pathophysiology and treatments. It also explained the increased risks of opportunistic infections among patients with rheumatological conditions, due to their disease and treatment. Additionally, it identified the need for holistic approaches in the management of those patients living with immunocompromising conditions.

Delayed Management of Sickle Cell Disease Vaso-Occlusive Episodes and the Impact on Prolonged Hospitalizations at a Single Academic Center

Introduction: Sickle Cell Disease (SCD) affects nearly 100,000 people in the United States (Centers for Disease Control and Prevention, 2023). Vaso-occlusive episode (VOE) is the most common reason for hospitalization in SCD. Many providers are unfamiliar with the pain management timing and dosages required to adequately treat these episodes (Jang et al., J Transl Med 2021). Nationally, areas with comprehensive sickle cell centers have shown decreased hospital utilization, fewer VOEs, and improved quality of life (Oyedeji et al. JAMA 2020). Even in areas without a comprehensive center, implementing individualized pain care plans for SCD has reduced admission rates of high-utilizing patients while not impacting their pain rating scores (Welch-Coltrane et al. Pain Medicine 2021). Our academic hospital, Oregon Health and Science University (OHSU), lacks a comprehensive SCD center and VOE treatment plans are not easily accessible for these patients. We conducted a retrospective analysis on a cohort of patients with SCD to investigate the factors influencing the length of emergency department (ED) and hospital stays for VOE. We aim to identify if implementing individualized pain plans via a standardized template within the electronic health record (EHR) for these patients will decrease hospital admission, length of stay and time to ED discharge. We also aim to integrate individualized pain plans into the EHR that would allow for direct exposure to the care team by creating plans that are easily accessible, reviewed, and routinely utilized for clinical decision-making. Methods: We performed a preliminary retrospective analysis of encounters (n=107) from 2008-2023 at OHSU, where the primary diagnosis was either a VOE or an equivalent diagnosis. Based on data demonstrating earlier maximum opioid doses leading to shortened hospital stays in frequent pain patients, we recorded the timing of the first opioid and morphine milliequivalents per hour in the first 24 hours (Payne et al. Pediatr Blood Cancer 2018). Additionally, we recorded the length of stay, admission rates, time to first IV fluid, and the type of IV fluid used. We performed a linear regression analysis on the collected data with the dependent variable as the length of stay across the independent variables of time to first opioid, time to first intravenous fluid, and morphine milliequivalents per hour during the first 24 hours after presentation. Results: Eighteen patients accounted for the 107 analyzed encounters. Thirteen patients (72%) had Hgb-SS disease, 2 (11%) had Hgb-SC disease, and 3 (17%) had Hgb-S-beta thalassemia. Sixty-two admissions (58%) were ED discharges, and 45 (42%) were ED to hospital admissions. The length of stay and time to the first opioid positively correlated with p=0.005 (Figure 1a). The length of stay and time to first intravenous fluid administration was also positively correlated with p=0.01. The length of stay and morphine milliequivalents per hour in the first 24 hours were negatively correlated with p<0.0001 (Figure 1b). Conclusions: Longer time to administration of opioids and intravenous fluids correlated with a longer length of stay in both the ED and the hospital. Additionally, lower morphine milliequivalents in the first 24 hours of presentation were associated with a prolonged hospital stay at our institution. We hypothesize that these three factors are secondary to delays in care and inappropriate initial treatment of VOE. To address these factors, we aim to implement standardized pain plans in the EHR of our institution. Implementation of individualized pain plans, particularly in the ED, has led to the earlier initiation of opioids (Della-Moretta et al. Ann Emerg Med 2020). We anticipate similar effectiveness for timely and appropriate fluid administration and adequate opioid dosing. We plan to continue retrospective analysis and compare this data to VOE encounters post-implementation. By implementing individualized plans that are integrated within the EHR and efficiently utilized by the care team, we hope to improve VOE management at our institution with decreased length of stay, less ED to hospital admissions, and improved patient satisfaction.

CAPABLE: A Scoring System Utilizing Patient-Reported Measures to Evaluate Patient Experience After Mohs Surgery.

Patient experience metrics are gaining prominence in health care. We introduce the CAPABLE survey to assess postoperative experiences of Mohs surgery patients. We sought to determine whether CAPABLE scores aligned with overall patient satisfaction in Mohs surgery. This was a cross-sectional, survey-based study of patients presenting for their first postoperative visit after Mohs surgery. The CAPABLE survey included questions on postoperative instructions, activity limitations, pain control, provider accessibility, and bleeding, followed by 2 overall satisfaction questions taken from the Outpatient and Ambulatory Surgery Consumer Assessment of Healthcare Providers and Systems survey. The pilot study took place at the University of Texas Dell Medical School (DMS), followed by a validation study ( n = 206) at DMS and Oregon Health and Science University (OHSU). We assessed for correlations between CAPABLE scores and overall satisfaction. In the pilot study ( n = 137), overall CAPABLE scores and scores of individual CAPABLE components correlated positively with overall satisfaction.In the multisite validation study ( n = 206) spanning DMS and OHSU, CAPABLE scores correlated positively with overall satisfaction. The CAPABLE survey is a concise tool for assessing specific, actionable components of the postoperative patient experience in Mohs surgery, while correlating with overall patient satisfaction.

Influence of Neighborhood Socioeconomic Status on Adverse Outcomes in Pregnancy.

To evaluate whether ZIP-code level neighborhood socioeconomic status (SES) is associated with adverse pregnancy outcomes. A retrospective study of 2009-2014 Oregon Health and Science University (OHSU) births with maternal ZIP codes in one of 89 Portland metropolitan area ZIP codes. Deliveries with ZIP codes outside of the Portland metro area were excluded. Deliveries were stratified by SES based on ZIP code median household income: low (below 10th percentile), medium (11th-89th percentile), and high (above 90th percentile). Univariate analysis and multivariable logistic regression with medium SES as the reference group evaluated perinatal outcomes and strength of association between SES and adverse events. This study included 8118 deliveries with 1654 (20%) classified as low SES, 5856 (72%) medium SES, and 608 (8%) high SES. The low SES group was more likely to be younger, have a higher maternal BMI, have increased tobacco use, identify as Hispanic or Black, and less likely to have private insurance. Low SES was associated with a significantly increased risk of preeclampsia (RR 1.23 95% CI 1.01-1.49), but this was no longer significant after adjusting for confounders (aRR 1.23 95% CI .971-1.55). High SES was negatively associated with gestational diabetes mellitus (GDM), even after adjusting for confounders (aRR 0.710, 95% CI 0.507-0.995). In the Portland metropolitan area, high SES was associated with a lower risk of GDM. Low SES was associated with a higher risk of preeclampsia before accounting for covariates. ZIP code-based risk assessment may be a useful indicator in detecting healthcare disparities.

A Comparison between Efficacy of Tele-Simulation-Based and Traditional Simulation-Based Training of Private Hospitals Network in Thailand

OBJECTIVES: To compare efficacy of tele-Simulation-based (online) and traditional Simulation-based (onsite) training on theoretical knowledge, practical skills and satisfied domains during the COVID-19 pandemic for The Center of Excellence (COE) of a private hospital network in Thailand. MATERIALS AND METHODS: 951 participants completed four courses in 2020 either through traditional (694 participants) or tele-based trainings (257 participants) with complete data were included, theoretical knowledge before and after training was assessed by a standard multiplechoice questionnaire while skills were assessed once using tools developed by an expert and specialist facilitator in a private hospital network to fit COE specific learners’ performance checklist.Satisfaction was assessed by using a Likert scale questionnaire modified from the Simulation Effectiveness Tool-Modified (SET-M) of Oregon Health and Science University (OHSU). RESULTS: The study showed most participants were female, working as nurses. 34.1% had worked for more than 7 years, and 25.5% had attended Simulation training more than 5 times. The average theoretical knowledge pre-tests and post-test scores of online training was 62.1 ± 18.9 and 82.5 ± 14.3. While the theoretical knowledge score of pre-tests and post-test of onsite training was 65.6 ± 19.0 and 79.6 ± 15.6, both were statistically significant (p < 0.0001). An evaluation of efficacies in practical skills and satistified domain in all training courses for COE either via the tele-Simulation-based training or the traditional Simulation-based training found that both methods were significantly increased. Also, the participants’ satisfied outcome towards the training course was ‘good’ to ‘very good’ in every area. CONCLUSION: The outcome of the study showed that the efficacy of online based training was not lower than onsite training.

Increased Number and Severity of Open Globe Injuries during COVID-19 Stay-at-home Orders

ABSTRACT Purpose To evaluate the occurrence and outcome of open globe injury during state-mandated COVID-19 stay-at-home orders compared to historical averages at a tertiary medical center in Portland, Oregon. Methods Open globe injury between January 1, 2015 and December 31, 2020 was identified using relevant procedure codes. The number of injuries, mechanism of trauma, and short-term outcomes of globes repaired during the study period of March 23, 2020 to July 6, 2020 when stay-at-home orders were in effect were compared to a cohort from the same 15-week time frame in 2015–2019. We also evaluated injuries occurring throughout 2020 as compared to the prior 5 years. Results 263 consecutive open globe injuries were identified between January 2015 and December 2020. While Oregon’s stay-at-home orders were in effect, we observed a significant increase in the number of open globe injuries treated compared to the prior 5 years (p = .004). Twenty-four cases identified during the study period represent a 2-fold increase over the 2015–2019 average of 11.8 globe repairs during the same 15-week time period. Visual acuity < 20/200 at 6 months (p = .008) and secondary enucleation (p < .001) were more frequent during stay-at-home orders, and severity of injury as calculated by the Ocular Trauma Scores (OTS) was higher. Time-to-repair was similar between the two cohorts. Conclusion At our center, there was an increased number and severity of open globe injury during the period of mandatory COVID-19 stay-at-home orders. Visual acuity outcomes and risk for secondary enucleation were poorer compared to the reference cohort. Abbreviations: Ocular Trauma Score (OTS), Open globe injury (OGI), Emergency department (ED), Oregon Health and Science University (OHSU)

Correlation of Narrative Evaluations to Clerkship Grades Using Statistical Sentiment Analysis.

Narrative evaluations are essential components of medical student assessment. This study evaluated how well narrative clerkship evaluation word choice correlated with an assigned letter grade. One hundred clerkship evaluations, 50 from family medicine (FM) and 50 from internal medicine (IM), with even distribution of "Honors" and "Near-Honors" among medical students that graduated in 2020 from the Oregon Health and Science University (OHSU) were examined. A textual sentiment analysis, which evaluates positive and negative word choice, was used to determine each evaluation's collective sentiment. An average sentiment score and character count were calculated for Honors and Near-Honors evaluations from both clerkship disciplines. Sentiment word totals were used to form "word clouds" that highlight the most frequent word selections. While sentiment scores positively correlated with the assigned grade, there was no statistically significant difference between the average sentiment scores among Honors and Near Honors graded evaluations within the FM or IM clerkship evaluation sets. There was no significant difference in evaluation character length among the assigned grades. Among FM evaluations, "outstanding" and "excellent" were the two most common sentiment words used in both Honors and Near-Honors. Among IM evaluations, outstanding and excellent were most commonly used in Honors evaluations, while "excellent" and "good" were most common in Near-Honors. This study outlines a novel text analysis method for analyzing narrative evaluation association with assigned grade that other institutions can utilize. Sentiment word choices are not significantly different among Honors and Near Honors clerkship narrative evaluations. The online version contains supplementary material available at 10.1007/s40670-022-01654-2.

α-Synuclein Seed Amplification in CSF and Brain from Patients with Different Brain Distributions of Pathological α-Synuclein in the Context of Co-Pathology and Non-LBD Diagnoses.

The purpose of this study was to determine the sensitivity and specificity of α-synuclein seed amplification assay (αSyn-SAA) in antemortem and postmortem cerebrospinal fluid (CSF) of autopsy-confirmed patients with different distributions of pathological αSyn, co-pathologies, and clinical diagnoses. The αSyn-SAA was used to test antemortem CSF samples from 119 subjects with a variety of clinical syndromes and standardized neuropathological examinations from Oregon Health and Science University (OHSU) and University of California San Diego (UCSD; 56 additional postmortem CSF samples available). The αSyn-SAA was also applied to frontal cortex and amygdala homogenates. Sensitivity and specificity were compared across distributions of αSyn pathology. Clinical data and co-pathologies were compared across αSyn-SAA positive and negative groups. Fifty-three individuals without and 66 with αSyn-pathology (neocortical [n=38], limbic [n=7], and amygdala-predominant [n=21]) were included. There was a sensitivity of 97.8% and specificity of 98.1% of the αSyn-SAA to identify patients with limbic/neocortical pathology from antemortem CSF. Sensitivity to detect amygdala-predominant pathology was only 14.3%. Postmortem CSF and brain tissue αSyn-SAA analyses also showed higher assay positivity in samples from limbic/neocortical cases. CSF αSyn-SAA reliably identifies αSyn seeds in patients with diffuse αSyn pathology in the context of co-pathology and non-Lewy body disease (LBD) diagnoses. The analysis of brain homogenates suggests that pathological αSyn in the amygdala might differ from pathological αSyn in the frontal cortex. The αSyn-SAA might facilitate the differential diagnosis of dementias with mixed pathologies. ANN NEUROL 2022;92:650-662.

The Prevalence of Retinal Disease and Associated CNS Disease in Young Patients with Incontinentia Pigmenti

To evaluate the prevalence of retinal disease on fluorescein angiography (FA) in patients with incontinentia pigmenti (IP) and to compare the severity of retinal disease in those with and without known central nervous system (CNS) disease. Multi-institutional consecutive retrospective case series. New patients with a diagnosis of IP were seen at the Casey Eye Institute at the Oregon Health and Science University (OHSU), Moran Eye Center, University of Utah, or Bascom Palmer Eye Institute, University of Miami from December 2011 to September2018. Detailed ophthalmoscopic examination and FA were recommended for all new patients and performed on every patient who had parental consent. Ophthalmoscopic findings and FA images were graded for severity by 2 masked graders on a 3-point scale: 0= no disease, 1= vascular abnormalities without leakage, 2= leakage or neovascularization, and 3= retinal detachment. The presence of known CNS disease was documented. Additional cases were obtained from a pediatric retina listserv for examples of phenotypic variation. The proportion of eyes noted to have disease on ophthalmoscopy compared with FA and the severity of retinal disease in those with and without known CNS disease. Retinal pathology was detected in 18 of 35 patients (51%) by indirect ophthalmoscopy and 26 of 35 patients (74%) by FA (P= 0.048) in a predominantly pediatric population (median age, 9 months). Ten patients (29%) had known CNS disease at the time of the eye examination. A Wilcoxon rank-sum test indicated that the retinal severity scores for patients with CNS disease (median, 2) were significantly higher than the retinal severity scores for patients without CNS disease (median, 1), z= -2.12, P= 0.034. Retinal disease is present in the majority of patients with IP, and ophthalmoscopic examination is less sensitive than FA for detection of disease. There may be a correlation between the severity of retinal and CNS disease.

Wy'east: An Innovative, Culturally Responsive Postbaccalaureate Pathway for American Indians and Alaska Natives.

American Indians and Alaska Natives (AIANs) face significant health disparities that are exacerbated by limited access to high-quality, culturally congruent health care providers. There are no premedical postbaccalaureate programs focused on AIAN students. The Northwest Native American Center of Excellence designed the Wy'east Pathway in 2018 to increase the number of AIANs matriculating to U.S. medical schools by supporting those on the cusp of matriculation. Wy'east scholars undertake 10 months of structured programming to augment their academic preparation, improve their Medical College Admission Test (MCAT) scores, and enhance their confidence and cultural identity. Cultural events and mentorship opportunities with AIAN faculty, staff, and cultural liaisons are threaded throughout the pathway curriculum to foster cultural resilience, mentorship, and community. Scholars earn conditional acceptance to Oregon Health and Science University (OHSU) School of Medicine if they complete Wy'east and meet the following criteria: pass all examinations in the primary curricular threads, obtain a qualifying MCAT score, and meet professionalism standards. All 14 scholars who successfully completed Wy'east and met criteria in the first 2 cohorts (academic years 2018-2019 and 2019-2020) earned conditional acceptance to OHSU School of Medicine. Ten of the 14 scholars (71.4%) matriculated to OHSU School of Medicine, 2 (14.3%) matriculated to other medical schools, and 2 (14.3%) chose to pursue other health care fields. Wy'east scholars rated the foundational science of medicine and population health and epidemiology threads higher in terms of making them feel better prepared for medical school (mean = 4.71 and 4.83, respectively) than the academic skills and wellness thread (mean = 3.43). Over the next 5 years, Wy'east will grow incrementally to offer a total of 18 conditional acceptance spots per cohort across 3 medical schools. Longitudinal tracking of Wy'east scholars' medical training and career outcomes will be conducted.

Stability of Free Available Chlorine Levels in Dilute Sodium Hypochlorite Solutions over a 6-Week Period.

Animal care and use programs commonly use chlorine and chlorine-based disinfectants to help prevent facility acquired infections in animals. The Department of Comparative Medicine (DCM) at Oregon Health and Science University (OHSU) follows the Centers for Disease Control and Prevention (CDC) disinfection guidelines for preparing and storing these disinfectants. DCM prepares bottles of dilute solutions of sodium hypochlorite (that is, commercial bleach) daily. In this study, we tested whether dilute bleach solutions, as prepared following the DCM protocol, remained stable under real-world practice conditions for up to 6 wk. We tested 4 groups of spray bottles filled with 0.5% bleach solutions in these experiments. Specifically, we sprayed 2 groups of bottles daily to mimic use while 2 other groups of bottles were not sprayed. We then measured free available chlorine (FAC) using 2 methods, spectrophotometry and colorimetric strips. All 4 test groups showed stable maintenance of FAC concentration for the length of the experiment. Mean FAC loss from baseline levels was not significantly different in the group of bottles not sprayed daily (6% for group 2 at week 5 compared with 7% for Group 4 at week 6). All bottles in Groups 1 and 3 measured by colorimetric strips showed concentrations at or near 5000 mg/L at all weekly time points throughout the experiment. This study shows that 0.5% sodium hypochlorite solutions stored and used in a standard rodent housing room and sprayed daily will maintain acceptable FAC concentrations for at least 5 to 6 wk, perhaps longer. In addition, we report that colorimetric strips may be a useful and accessible quality control tool for testing freshly prepared solutions at regular intervals. We conclude that sodium hypochlorite solutions can be prepared on a weekly, biweekly, or monthly basis with no loss in disinfection effectiveness.

Safety of intra-arterial chemotherapy with or without osmotic blood-brain barrier disruption for the treatment of patients with brain tumors.

BackgroundIntra-arterial administration of chemotherapy with or without osmotic blood–brain barrier disruption enhances delivery of therapeutic agents to brain tumors. The aim of this study is to evaluate the safety of these procedures.MethodsRetrospectively collected data from a prospective database of consecutive patients with primary and metastatic brain tumors who received intra-arterial chemotherapy without osmotic blood–brain barrier disruption (IA) or intra-arterial chemotherapy with osmotic blood–brain barrier disruption (IA/OBBBD) at Oregon Health and Science University (OHSU) between December 1997 and November 2018 is reported. Chemotherapy-related complications are detailed per Common Terminology Criteria for Adverse Events (CTCAE) guidelines. Procedure-related complications are grouped as major and minor.Results4939 procedures (1102 IA; 3837 IA/OBBBD) were performed on 436 patients with various pathologies (primary central nervous system lymphoma [26.4%], glioblastoma [18.1%], and oligodendroglioma [14.7%]). Major procedure-related complications (IA: 12, 1%; IA/OBBBD: 27, 0.7%; P = .292) occurred in 39 procedures including 3 arterial dissections requiring intervention, 21 symptomatic strokes, 3 myocardial infarctions, 6 cervical cord injuries, and 6 deaths within 3 days. Minor procedure-related complications occurred in 330 procedures (IA: 41, 3.7%; IA/OBBBD: 289, 7.5%; P = .001). Chemotherapy-related complications with a CTCAE attribution and grade higher than 3 was seen in 359 (82.3%) patients.ConclusionsWe provide safety and tolerability data from the largest cohort of consecutive patients who received IA or IA/OBBBD. Our data demonstrate that IA or IA/OBBBD safely enhance drug delivery to brain tumors and brain around the tumor.

84. A Survey Based Assessment of Provider Practice Around Obtaining Repeat Blood Cultures

Abstract Background Apart from Staphylococcus aureus and Candida species, there is little guidance on whether to obtain repeat blood cultures after an initial positive set. We have noted heterogeneity in practice amongst our Infectious Disease (ID) group at Oregon Health and Science University (OHSU) and suspect there is heterogeneity amongst adult hospitalist providers as well. Methods We created a survey using clinical vignettes encompassing commonly encountered scenarios among hospitalized patients on medical wards to assess provider practices in obtaining repeat blood cultures. The survey was sent to adult ID providers and adult hospitalist providers at OHSU. These vignettes represented 9 of the most common bacteria seen in positive blood cultures and asked the question of whether providers would obtain repeat blood cultures after an initial positive set. The organisms included beta hemolytic streptococcus, Enterococcus faecalis, Streptococcus gallolyticus, coagulase-negative staphylococci, alpha hemolytic strep, E coli, Proteus mirabilis, Pseudomonas aeruginosa, and Bacteroides fragilis. We then asked questions around repeat blood culture practices for Staphylococcus aureus and Candida species, understanding that while repeat blood cultures for these organisms is recommended, the manner in which individual providers implement this may vary. Results The survey response rate was ~45%. Results were heterogenous with only 3 questions having inter- and intra- group agreement. Those 3 questions represented a case of E faecalis bacteremia without known source, a case of asymptomatic Staphylococcus epidermidis blood culture positivity, and a case of E. coli bacteremia from a pyelonephritis. All other vignettes had inter- and intra- group differences signifying clinical uncertainty around the practice of obtaining repeat blood cultures. There was similar heterogeneity among the responses asking how providers obtain repeat blood cultures around S. aureus and Candida bloodstream infections. Clinical vignette survey answers Answers from 10 clinical vignettes on obtaining repeat blood cultures after an initial positive set for stable patients on medical wards. Staphylococcus aureus Candida sp Conclusion There is significant heterogeneity amongst adult ID and hospitalist providers on what organisms and situations should prompt repeat blood cultures. There are differences around how repeat blood cultures should be obtained, including for Staphylococcus aureus and Candida sp. Disclosures All Authors: No reported disclosures

Ethics and Responsibility of Scientific Researchers in a Pandemic Era.

The purpose of this paper is to critique the links between science and scientific researchers, politics and capital surrounding vaccines and vaccination in a pandemic era. It also introduces standards for adapting ethical guidelines for research under public health emergencies to specific circumstances and contexts. It also introduces ethical standards to be applied to scientific research. that is, scientific relevance, social value, cooperative partnerships, reasonable risk-benefit costs, fair and voluntary participation, independent review, and equal moral respect for participants and affected communities. It also outlines the COVID-19 (coronavirus disease 2019) pandemic-consent and other research procedure modifications proposed by Oregon Health and Science University (OHSU). We are on the lookout for powerful capital and hegemonic groups inseparable from politics and important decision makers in the pandemic era - that is, scientists, supporters, and scientific civic groups. It underscores the need for an independent and formal scientific advisory body with the right balance between science and politics.

Performance Evaluation Study of a Novel Digital Microscopy System for the Quantitative Analysis of Bone Marrow Aspirates

Background. We report here a trial in progress for the evaluation of a novel system aimed to provide an all-digital standardized bone marrow aspirate (BMA) analysis, Scopio Labs X100, empowered by artificial intelligence (AI) based cell pre-classification. Current methods for the analysis and reporting of BMA specimens are based on analog microscopy, as whole slide imaging at x100 magnification is not practically available. The lack of uniformity between experts in the field, originating from a subjective manual review, can lead to inconsistencies in disease diagnosis and classification, and thereby affect treatment and clinical outcomes. For example, ICSH and WHO guidelines require that at least 500 cells should be counted in at least two smears when a precise percentage of an abnormal cell type is required for diagnosis and classification. It is also recommended that in order reduce imprecision from sampling error, the total number of cells counted in the differential should be increased, specifically if the abnormal cell count is very close to a critical threshold for disease stratification or response assessment. For the general evaluation of hematopoiesis, Myeloid to Erythroid (M:E) ratio is reported. Considering the complexity of the manual BMA analysis, even more so in routine laboratory settings with competitive turnaround times, a digital transformation can sustain the desired standardization, and increase sensitivity and efficiency in routine workflow.Study Design and Methods. This multisite study is taking place at: Hospital of the University of Pennsylvania (HUP), Oregon Health and Science University (OHSU), and Tel Aviv Sourasky Medical Center (TASMC). BMA analysis is performed with a manual microscope as the reference arm and in Scopio Labs X100 Full Field BMA application as the test arm (Figure 1A). Two hematopathologists at each site independently review 265 BMA specimens, including 205 with a Romanowsky stain and 60 with a Prussian Blue stain, in both the test and the reference arms. There is a 3 week washout period between arms (Figure 1B, right). ICSH guidelines were rigorously translated into a comprehensive report format used in both study arms. The report presents 27 primary and 13 secondary characteristics for the morphological assessment of BMA (Figure 1C). These include evaluation of specimen quality, evaluation of count, maturation and morphology of trilineage hematopoietic elements (myeloid, erythroid and megakaryocytic), as well as lymphocytes and plasma cells. For a repeatability study, 8 representative samples are analyzed through 20 days, 2 daily runs and 2 replicas in one site. For reproducibility study, 8 representative samples are analyzed in all sites for 5 days with 5 replicas (Figure 1B, left).The collected BMA samples hold a distribution of 55.61% males, with 2.02%, 9.46%, 16.39%, 54.73% and 17.40% of ages 13-21, 22-39, 40-55, 56-75 and >75 respectively. All samples were diagnosed by WHO criteria. Diagnoses include AML, ALL, MPN, MDS, PCN, lymphoid neoplasms, aplastic anemia, ITP and normal morphology marrow and hemodiluted samples. All samples were retrieved from the sites' bone marrow sample storage.For the method comparison study, the primary and secondary characteristics are aggregated into three primary and secondary evaluation categories of specimen quality, count, and morphology and maturation assessments (Figure 1B, left, 1C). For the primary groups, confusion matrix will be produced. For the secondary groups, contingency tables will be generated (Figure 1B, left). For the repeatability and reproducibility (R&R) studies, two-way nested ANOVA tables will be created (Figure 1, right). Primary groups will be measured for accuracy in the form of efficiency, sensitivity and specificity. Secondary groups will be measured for overall agreement. R&R will be measured for SD and CV.The introduction of Scopio's full field morphological evaluation of BMA smears, promotes an accurate diagnosis of hematological disorders including hematological malignancies, and enables a remote evaluation of BMA smears. By reviewing the entire BMA smear, and by counting a very large number of cells, this novel approach provides a new and highly accurate tool for early detection of pathological conditions, including residual disease following therapy. [Display omitted] DisclosuresBagg: Scopio Labs: Research Funding. Raess: Scopio Labs: Research Funding. Jengehino: Scorpio Labs: Other: Partial Salary Support. Wiszniewska: Scopio Labs: Research Funding. Huynh: Scorpio Labs: Other: Salary Support. Fan: Scopio Labs: Research Funding. Bhattacharyya: Scorpio Labs: Other: Partial Salary Support. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Katz: Scopio Labs: Consultancy.

Addressing a rapidly changing service landscape during the COVID-19 pandemic: Creation of the Oregon substance use disorder resource collaborative

Following the rising crisis of COVID-19 and the Oregon governor's stay-at-home orders, members of the Oregon Health and Science University (OHSU) inpatient addiction consult service recognized that local addiction treatment and recovery organizations were operating at limited capacity. As a result, discharge planning, patient access to local community-based treatment, and safety-net programming were affected. Given structural and intersectional risk vulnerabilities of people with substance use disorders (SUDs), the OHSU members felt that COVID-19 would disproportionately impact chronically marginalized members of our community. These inequities inspired the formation of the Oregon substance use disorder resources collaborative (ORSUD) led by four medical students. ORSUD's mission is to support the efforts of local safety-net organizations that and front-line providers who serve chronically marginalized community members in the midst of the global pandemic. We operationalized our mission through: 1) collecting and disseminating operational and capacity changes in local addiction and harm reduction services to the broader treatment community, and 2) identifying and addressing immediate resource needs for local safety-net programs. Our program uses a real-time public-facing document to collate local programmatic updates and general community resources. COVID-19 disproportionately burdens people with SUDs; thus, ORSUD exists to support programs serving people with SUDs and will continue to evolve to meet their needs and the needs of those who serve them.

Polysubstance Use Common in SUD Patients

Polysubstance Use Common in SUD Patients

Molecular Modeling of the FOXO4-TP53 Interaction to Design Senolytic Peptides for the Elimination of Senescent Cancer Cells

Background: Senescent cells accumulate in tissues over time as part of the natural aging process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to eliminate senescent cancer cells to prevent cancer recurrence or progression. Methods: We used molecular modeling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cancer cells both in cell culture and in vivo. Findings: Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it co-localizes with FOXO4 foci and binds FOXO4 to a greater extent compared to TP53. Finally, we show that concomitant intra-tumoral injection of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis in a transgenic mouse model of melanoma. Interpretation: Taken together, our results reveal that peptides can be generated to specifically eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding Statement: This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health & Science University. Declaration of Interests: S.S. Cinaroglu, Y. Ahiska, U. Sezerman, G.B. Akcapinar, E. Timucin have a patent for the ES2 structure and are members of a company, Eternans Ltd. that is working on ES2 for therapeutic use. No potential conflicts of interest were disclosed by the other authors. Ethics Approval Statement: All experiments were approved by Oregon Health and Science University (OHSU) Institutional Animal Care and Use Committee (IACUC) (TR01_I0674) and conformed to the guidelines set by United States Animal Welfare Act and the National Institutes of Health.

Early Outcomes in an Emerging Facial Nerve Center: The Oregon Health and Science University (OHSU) Experience.

Nerve transfer (NT) and free gracilis muscle transfer (FGMT) are procedures for reanimation of the paralyzed face. Assessing the surgical outcomes of these procedures is imperative when evaluating the effectiveness of these interventions, especially when establishing a new center focused on the treatment of patients with facial paralysis. We desired to discuss the factors to consider when implementing a facial nerve center and the means by which the specialist can assess and analyze outcomes. Patients with facial palsy secondary to multiple etiologies, including cerebellopontine angle tumors, head and neck carcinoma, and trauma, who underwent NT or FGMT between 2014 and 2019 were included. Primary outcomes were facial symmetry and smile excursion, calculated using FACE-gram and Emotrics software. Subjective quality of life outcomes, including the Facial Clinimetric Evaluation (FaCE) Scale and Synkinesis Assessment Questionnaire (SAQ), were also assessed. 14/22 NT and 6/6 FGMT patients met inclusion criteria having both pre-and postoperative photo documentation. NT increased oral commissure excursion from 0.4 mm (SD 5.3) to 2.9 mm (SD 6.8) (P = 0.05), and improved symmetry of excursion (P < 0.001) and angle (P < 0.001). FGMT increased oral commissure excursion from -1.4 mm (SD 3.9) to 2.1 mm (SD 3.7), (P = 0.02), and improved symmetry of excursion (P < 0.001). FaCE scores improved in NT patients postoperatively (P < 0.001). Measuring outcomes, critical analyses, and a multidisciplinary approach are necessary components when building a facial nerve center. At our emerging facial nerve center, we found NT and FGMT procedures improved smile excursion and symmetry, and improved QOL following NT in patients with facial palsy secondary to multiple etiologies.