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Abstract BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive pulmonary disease characterized by aberrant tissue remodeling, formation of scar tissue within the lungs and continuous loss of lung function. The areas of fibrosis seen in lungs of IPF patients share many features with normal aging lung with cellular senescence being one. The contribution of the immune system to the etiology of IPF remains poorly understood. Evidence obtained from animal models and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. Currently, there is only modestly effective pharmacotherapy for IPF. Mesenchymal stem cells (MSCs)-based therapies have emerged as a potential option treatment of IPF. This study explores the possibility of using autologous MSCs as an IPF therapy and present an attempt to determine if the disease occurring in the lungs can be reflected on peripheral blood immune status. MethodsComprehensive characterization of autologous adipose derived MSCs (aMSCs) from five IPF patients and five age and gender matched Healthy Controls (HC) was done using flow cytometry, Droplet Digital PCR (ddPCR), Multiplex Luminex xMAP technology and confocal microscopy. For assessing the self renewal capacity and osteogenic differentiation IncuCyte Live Cell Imaging technology was used. Multi-parameter quantitative flow cytometry of un-manipulated whole blood of another group of 15 IPF patients and 87 (30 age and gender matched) HC was used to analyze 110 peripheral phenotypes.ResultsThere are no differences between autologous aMSCs from IPF patients and HC in their stem cell properties, self renewal capacity, plasticity for osteogenic differentiation, secretome content, cell cycle inhibitor marker levels and mitochondrial health. IPF patients had altered peripheral blood immunophenotype including reduced B cells subsets, increased T cell subsets, and increased granulocytes among others demonstrating clear and significant differences.ConclusionsOur results indicate that there is no difference in aMSCs properties from IPF patients and HC, suggesting that autologous aMSCs may be an acceptable option for IPF therapy.Characterization of peripheral immune phenotype may be a valuable indicator for successful therapy, and for potentially staging the disease.

OBJECTIVES: Investigate the challenges experienced by survivors of critical illness and their caregivers across the transitions of care from intensive care to community, and the potential problem-solving strategies used to navigate these challenges. DESIGN: Qualitative design—data generation via interviews and data analysis via the framework analysis method. SETTING: Patients and caregivers from three continents, identified through the Society of Critical Care Medicine’s THRIVE international collaborative sites (follow-up clinics and peer support groups). SUBJECTS: Patients and caregivers following critical illness. INTERVENTIONS: Nil MEASUREMENTS AND MAIN RESULTS: From 86 interviews (66 patients, 20 caregivers), we identified the following major themes: 1) Challenges for patients—interacting with the health system and gaps in care; managing others’ expectations of illness and recovery. 2) Challenges for caregivers—health system shortfalls and inadequate communication; lack of support for caregivers. 3) Patient and caregiver-driven problem solving across the transitions of care—personal attributes, resources, and initiative; receiving support and helping others; and acceptance. CONCLUSIONS: Survivors and caregivers experienced a range of challenges across the transitions of care. There were distinct and contrasting themes related to the caregiver experience. Survivors and caregivers used comparable problem-solving strategies to navigate the challenges encountered across the transitions of care.

11009 Background: Gender & racial/ethnic leadership disparities have been independently identified in academic hematology/oncology (HO) and radiation oncology (RO). Here, we evaluate gender and racial/ethnic intersectionality from the trainee to the leadership level. Methods: All ACGME accredited HO and RO training program websites were queried to identify constituent trainees, academic faculty, program directors (PD) and department chairs (DC), with a leadership position defined as PD or DC. Individual gender & race/ethnicity was determined using externally validated software tools (Gender-API, NamSor, & Onolytics), publicly available descriptors, and image review. We grouped individuals into 6 categories: White Male (WM), White Female (WF), Asian Male (AM), Asian Female (AF), Underrepresented Groups in Medicine (as defined by AAMC) Male (URMM) and Female (URMF). The chi-squared goodness-of-fit test was applied to examine if deviations exist between the observed vs. expected proportions of gender/race dyads in trainees, PD, and DC compared to academic faculty. Results: We identified 7,722 individuals from 2019-2020: 1,759 trainees (HO=1525; RO=234), 5,726 faculty (HO=4834; RO=892), 242 PD (HO=149; RO=93) and 237 DC (HO=144; RO=93). Leadership positions were most often comprised by WM (52.6%), and least often comprised by URMF (2.9%). Combined HO/RO analysis revealed significant differences in the observed representation of trainees & DC vs expected levels based on total faculty, respectively: WM (33.7% & 60.3% vs. 42.3%), WF (19.2% & 13.9% vs. 22.3%), AM (20.75% & 16.9% vs. 16.4%), AF (17.9% & 2.5% vs. 12.7%), URMM (4.09% & 5.5% vs. 3.5%) and URMF (4.3% & 0.8% vs. 2.8%), p<0.01. No differences were seen between PD vs total faculty. On subset analysis, there were significant differences observed in HO programs at the trainee, PD and DC levels compared to total faculty, whereas significant differences in RO programs were seen only at the DC level [Table]. Conclusions: Gender & racial/ethnic disparity is present in academic oncology. Specifically, women of all races/ethnicities are proportionally underrepresented in DC positions in HO and RO programs. These data can serve as a benchmark to raise awareness and monitor progress towards a more balanced workforce in oncology.[Table: see text]

10541 Background: Biomechanical tissue properties may vary in the breasts of patients at elevated risk for breast cancer. We aim to quantify in vivo biomechanical tissue properties in various breast densities and in both normal risk and high risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association of biomechanical properties of the breast with cancer risk. Methods: In this IRB–approved prospective single-institution study, we recruited two groups of women differing by breast cancer risk to undergo a 3.0 T dynamic contrast enhanced MRI/MRE of the breast. Low-average risk women were defined as having no personal or significant family history of breast cancer, no prior high risk breast biopsies and a negative mammography within 12 months. High-risk breast cancer patients were recruited from those patients who underwent standard of care breast MR. Within each breast density group (non-dense versus dense), two-sample t-tests were used to compare breast stiffness, elasticity, and viscosity across risk groups (low-average vs high). Results: There were 50 low-average risk and 86 high-risk patients recruited to the study. The risk groups were similar on age (mean age = 55.6 and 53.6 years), density (68% vs. 64% dense breasts) and menopausal status (66.0% vs. 69.8%). Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high risk patients ( N = 55) compared to low-average risk patients ( N = 34; all p < 0.001). In the multivariate logistic regression model, breast stiffness remained a significant predictor of risk status (OR=4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, MRI BPE, age, and menopausal status. Similar results were seen for breast elasticity (OR=4.88, 95% CI [2.08, 11.43]) and viscosity (OR=11.49, 95% CI [1.15, 114.89]). Conclusions: Structurally-based, quantitative biomarker of tissue stiffness obtained from global 3D breast MRE is associated with differences in breast cancer risk in dense breasts. As such, tissue stiffness could provide a novel prognostic marker to help identify the subset of high-risk women with dense breasts who would benefit from increased surveillance.[Table: see text]

e18561 Background: Young women with breast cancer (BC) have unique issues, including fertility, genetic, and emotional health concerns; these may sometimes be inadequately addressed by providers. Given documented disparities in BC care and outcomes, we sought to explore whether provider attention to these issues differs by race, as well as to examine racial differences in satisfaction with care among young patients with BC. Methods: The Young & Strong Study was a cluster randomized trial of an educational and supportive care intervention at 14 academic + 40 community oncology practices across the US enrolling women with newly diagnosed BC at age ≤45 and their providers. Patients completed surveys at baseline, 3, 6, and 12 months after enrollment. Race was self-reported at baseline. Provider attention to fertility, genetics, and emotional health was evaluated by medical record review. The proportions of patients with attention to these concerns by 3 months was compared by race (white, Black, Asian, multi-racial/other/unknown) using Fisher’s exact tests. Satisfaction with care was assessed with the Patient Satisfaction Questionnaire-18 (PSQ-18) at 3 months. Median scores for each of 7 PSQ-18 subscales (1-5 scale, higher scores=more satisfaction) were compared by race with the Kruskal-Wallis test. Results: 465/467 (99.6%) of enrolled patients had evaluable data. 77% were white, 12% Black, 4% Asian, and 7% multiracial/other/unk. Median age at diagnosis was 40 (range: 22-45) years. Provider attention to genetics (≥85%) and emotional health (≥90%) was high across groups, and there were no differences by race in attention to fertility, genetics, or emotional health (Table). Among 359/465 women (77%) who completed the PSQ-18, median subscale scores ranged from 3.5-4.5, indicating high levels of satisfaction with care. For the PSQ-18 technical quality domain, median scores were lower (p=.03), indicating less satisfaction, in Black and Asian women (4.0) and higher in white women (4.5). Median scores for other PSQ-18 domains (general satisfaction, interpersonal manner, communication, financial, time spent with doctor, accessibility) did not differ by race. Conclusions: Satisfaction with care was high and issues related to fertility, genetics and emotional health were addressed by providers in the majority of young women in our study, with minimal differences by race. These patients were all enrolled in a clinical trial and had access to high-quality care, limiting the generalizability of our findings. Larger, population-based studies in more diverse settings are warranted. Clinical trial information: NCT01647607. Attention to psychosocial concerns by race. [Table: see text]

7050 Background: Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm manifesting as unifocal, multifocal, multisystem (MS) or pulmonary LCH (smoking-related). In pediatric LCH, somatic BRAFV600E prevalence is reported at 55-70%, and associated with increased risk of multisystem disease and early treatment failure. Our aim was to describe the prevalence of BRAFV600E mutation and evaluate its association with clinical manifestations and outcomes in adults with LCH. Methods: A retrospective review of adult patients diagnosed with LCH consecutively seen at Mayo Clinic from 2011 to 2020 was performed.Evaluation of association of BRAFV600E mutational status and clinical factors was conducted by the Chi-square test for independence. Progression-free survival (PFS) and overall survival (OS) were analyzed via the Kaplan Meier method and compared with the log-rank test to assess the effect of BRAFV600E. Results: Of the total LCH cohort ( n= 128), 88 patients with available BRAFV600E results were included in the study. Median age at diagnosis was 41y (range 19 - 88); 52.3% were male. 40 (45.5%) patients had a BRAFV600E mutation. Increasing age was associated with BRAFV600E (10-year increase OR 1.42, 95%CI 1.07-1.89; p= 0.017). No correlation was observed between BRAFV600E status and site of disease, risk organ (RO: liver, spleen, marrow) involvement, or MS disease. Patients with BRAFV600E were 4 times more likely to receive targeted therapy ( BRAF inhibitor) than non- BRAFV600E patients ( p= 0.018). After a median follow up of 46 mo (95% CI 30.8-61.2), PFS was similar between BRAFV600E and non- BRAFV600E patients ( p= 0.167). However, patients with BRAFV600E had a worse 3-year OS compared with non- BRAFV600E patients (84% vs. 97.1%, p= 0.027). Patients who died had a significantly higher age at LCH diagnosis (median 62 vs. 38 years; p= 0.0002). Conclusions: In our cohort of adults with LCH, BRAFV600E was less frequent than reported in pediatric literature and was associated with worse OS. The frequency of BRAFV600E was positively correlated with increasing age. Contrary to reports in pediatric LCH, there were no significant associations between BRAFV600E and high-risk or multisystem disease.[Table: see text]

5526 Background: HR-HPV DNA testing, with or without cervical cytology, provides excellent sensitivity for detection of cervical cancer (CC) and its precursors; negative test results indicate that risk of disease is extremely low and enable women to undergo reduced screening with safety. However, management of women who screen positive remains challenging as many will prove to have self-limited HR-HPV infections. DNA methylation is an early event in carcinogenesis that could enhance CC screening specificity. Methods: For discovery, DNA from 70 FFPE CC (36 squamous, 34 adenocarcinoma) tissues that were reviewed microscopically, 18 fresh frozen benign cervicovaginal (BCV) tissues collected at the time of benign hysterectomy, and 18 buffy coats from cancer-free women underwent reduced representation bisulfite sequencing (RRBS) to identify MDMs associated with CC. Candidate MDM selection was based on area under the receiver operating characteristic curve (AUC) discrimination, methylation fold change, and low background methylation among benign controls. Candidate MDMs were re-tested using methylation-specific PCR (MSP) to confirm performance. Blinded biological validation was performed using MSP on DNA extracted from independent FFPE CC (38 squamous, 43 adenocarcinoma) and BCV (40) tissues. The performance of CC MDMs was also tested in DNA extracted from cervical dysplasia (36 adenocarcinoma in situ (AIS), 32 cervical intraepithelial neoplasia (CIN) 2/3, 11 CIN 1) FFPE tissues. Results: From RRBS discovery and technical validation via MSP, 30 candidate MDMs showed marked methylation fold changes (10 to >1000) across both CC histologies compared to BCV tissue from cancer-free women. Each of the 30 MDMs highly discriminated CC from BCV tissue with 9 MDMs having an AUC >0.90 (Table). CC MDMs also highly discriminated AIS from BCV but did not perform well in CIN 2/3 and CIN 1 (Table). Conclusions: Whole methylome sequencing, stringent filtering criteria, and biological validation have yielded outstanding candidate MDMs for CC that highly discriminate CC from BCV, notably with high specificity. Performance in cervical dysplasias varied with higher positivity rates in AIS than in CIN 2/3 and CIN 1. Translation to testing these novel MDMs in lower genital tract biospecimens and the addition of HR-HPV to the CC panel are warranted.[Table: see text]

e15511 Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]

3070 Background: A multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA technology to detect cancer and predict cancer signal origin (CSO) has potential to efficiently identify malignancies for which effective screening modalities do not exist. A previous version of a blood-based MCED test demonstrated favorable classification and test characteristics. Samples from the ongoing PATHFINDER study were reanalyzed in a prespecified interim analysis to evaluate performance of a more recent version of the test with an updated classifier (eg, updated CSO localization, hematological signal threshold) that is planned for clinical implementation as a general multi-cancer screening tool. Methods: PATHFINDER (NCT04241796) is an interventional, prospective study in which results (cancer signal detected/not detected and predicted CSO) using a previous version of the MCED test are returned to investigators, and those with a signal detected undergo further diagnostic testing. In this prespecified interim analysis, samples from those enrolled as of October 6, 2020 were reanalyzed with the more recent version of the MCED test (these results were not returned to investigators). The positive predictive value (PPV) for cancer detection, overall CSO accuracy, and concordance between the two test versions were assessed. Results: A total of 4011/4047 (99%) participants (pts) were analyzable (mean [SD] age 63.9 [8.7] years, 62% female, 92% white, 24% with prior cancer history, 39% ever smoker [4% current], 6% with genetic cancer predisposition). Cancer signal was detected in 0.95% (38/4011). A total of 27/38 also had signal detected by the previous version of the MCED test, including 19 who reached diagnostic resolution (13 with cancer diagnosis and 6 without); 11/38 were discordant positives. Nine different cancer types were detected in the 13 pts (2 stage I, 3 stage II, 2 stage III, and 3 stage IV); 1 had no AJCC stage expected, 1 metastatic recurrence and 1 stage evaluation underway. A conservative minimal PPV assuming all discordant positives are false positives, was 43.3% (13/30, 95% CI 27.4-60.8%) based on 19 pts with diagnostic resolution and 11 discordant positives. High negative percent agreement (PA) 99.7% (99.5-99.8%) between the two test versions was observed. Positive PA of 43.5% (95% CI, 31.9-55.9%) was consistent with the more stringent threshold for hematologic signal in the recent MCED version, as most discrepant cases had hematologic CSO with the previous MCED test. Among 13 detected cancers, accuracy of the top CSO prediction was 92.3% (12/13, 95% CI 66.7-99.6%). Conclusions: In this prespecified interim analysis, the more recent version of the MCED test detected cancers with high PPV and high accuracy of CSO prediction, supporting readiness for use in clinical practice. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.

3010 Background: PATHFINDER (NCT04241796) is an interventional, prospective study evaluating implementation of a blood-based multi-cancer early detection (MCED) test that uses targeted methylation-based cfDNA analysis to detect multiple cancer types and simultaneously predict cancer signal origin (CSO). We present a prespecified interim analysis of PATHFINDER evaluating an MCED test in a clinical setting. Methods: Participants (pts; ≥50y) were enrolled into 2 risk cohorts: non-elevated and elevated (smoking history, prior cancer [ > 3y post treatment], or genetic predisposition). MCED test results (cancer signal detected/not detected) were returned to investigators; pts with a signal detected also received a CSO prediction and underwent further diagnostic testing by their medical team. The primary objective was to assess the extent of diagnostic testing needed to achieve diagnostic resolution (eg, time to resolution, number/type of tests). Secondary endpoints included positive predictive value (PPV) and a measure of test satisfaction (following diagnostic resolution [signal detected] and post test [signal not detected]). Results: PATHFINDER consented 6796 pts before closing accrual on 12/4/20; as of October 6, 2020, 4086 consented, 4047 enrolled, and 4033 analyzable pts were included in the interim analysis (62.4% female, 92.1% white). Two study-related adverse events (anxiety of mild severity) were reported. Cancer signal was detected in 1.5% (62/4033) of pts; 40/62 reached diagnostic resolution to date. Kaplan-Meier estimate of median time to resolution was 78 (95% CI, 54-151) days. Among 40 pts that reached diagnostic resolution, ≥1 imaging test was performed in 93% (37/40); ≥1 invasive procedure was performed in 72% (13/18) versus 18% (4/22) of pts with diagnostic resolution of cancer versus no cancer, respectively. Based on results to date, PPV was 45% (95% CI, 30.7-60.2%; 18/40). Of 18 cancer diagnoses, 11 were solid tumors (3 stage IV, 6 stages I-III, 1 metastatic recurrence, 1 missing stage), and 7 were hematologic malignancies (1 stage IV, 4 stages I-III, 2 without AJCC stage). Accuracy of the top CSO prediction in true positives was 82.4% (95% CI, 59.0-93.8%; 14/17). Most pts were satisfied with the test (43.7% extremely satisfied, 30.7% very satisfied, 14.6% satisfied). Signal detection rate and test satisfaction were similar in the 2 risk cohorts; PPV tended to be higher in the elevated risk cohort, as expected. Conclusions: An interim analysis of this return of results study demonstrated promising MCED test results. Of 40 pts achieving diagnostic resolution, nearly half had a diagnostic workup confirming cancer; CSO was predicted with high accuracy for detected cancers. Taken together with the rarity of adverse events and high test satisfaction, these results support the feasibility of clinical implementation. Full enrollment cohort data will be available at the meeting. Clinical trial information: NCT04241796.