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Abstract Objective We examined the long-term effects of premenopausal bilateral oophorectomy (PBO) with or without concurrent or preceding hysterectomy on physical and cognitive function and on odds of chronic conditions. Methods We enrolled 274 women with PBO with or without concurrent or preceding hysterectomy and 240 referents aged 55 years and older who were residents of Olmsted County, MN as of the PBO or index date. Chronic conditions were assessed via medical record abstraction. Cognitive diagnoses were based on neurocognitive testing. A physical function assessment included measures of strength and mobility. Multivariable regression models compared characteristics for women with PBO <46 years, PBO 46–49 years, and referent women with adjustments for age and other confounders. Results The clinical visits (median age, 67 years) were a median of 22 years after the PBO or index date. Of 274 women with PBO, 161 (59%) were <46 years at PBO and 113 (41%) were 46–49 years. Compared with referents, women with a history of PBO <46 years had increased odds of arthritis (odds ratio [OR], 1.64; 95% confidence interval [CI], 1.06–2.55), asthma (OR, 1.74; 95% CI, 1.03–2.93), obstructive sleep apnea (OR, 2.00; 95% CI, 1.23–3.26), and bone fractures (OR, 2.86; 95% CI, 1.17–6.98), and walked a shorter mean distance on a 6-minute walk test ( b = −18.43; P = 0.034). Compared with referents, women with a history of PBO at age 46–49 years had increased odds of arthritis (OR, 1.92; 95% CI, 1.16–3.18) and obstructive sleep apnea (OR, 2.21; 95% CI, 1.33–3.66). There were no significant differences in cognitive status in women with PBO compared with referents. Conclusions Women with a history of PBO with or without concurrent or preceding hysterectomy, especially at age <46 years, have more chronic conditions in late mid-life compared with referents.

In response to the social inequities that exist in health care, the NIH-funded Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) recently formed a diversity committee to examine systemic racism and implicit bias in the care and research of eosinophilic gastrointestinal diseases (EGIDs). Herein, we describe our process, highlighting milestones and issues addressed since the committee’s inception, which we hope will inspire other researchers to enhance diversity, equity, inclusion, and accessibility (DEIA) in their fields. Our journey began by establishing mission and vision statements to define the purpose of the committee. Regular discussion of diversity-related topics was incorporated into existing meetings and web-based materials were shared. This was followed by educational initiatives, including establishing a library of relevant publications and a speaker series to address DEIA topics. We then established a research agenda focused on the following actionable items: (1) to define what is known about the demographics of EGIDs by systematic review of population-based studies; (2) to develop a practical tool for reporting participant demographics to reduce bias in EGID literature; (3) to examine health disparities in the care of individuals with eosinophilic esophagitis who present to the emergency department with an esophageal food impaction; (4) to examine how access to a gastroenterologist affects the conclusions of published research examining the prevalence of pediatric eosinophilic esophagitis; and (5) to develop a model for examining the dimensions of diversity, and provide a framework for CEGIR’s ongoing projects and data capture. In addition to promoting consciousness of DEIA, this initiative has fostered inclusivity among CEGIR members and will continue to inspire positive changes in EGID care and research.

Males are characterized by lower ANP and BNP with greater prevalence of cardiometabolic disease. The ANP genetic variant rs5068 was associated with less metabolic dysfunction in males, whereas no metabolic profile was related to the BNP genetic variant rs198389 in the general population. ANP may play a more biological role in metabolic homeostasis compared with BNP in the general population with greater physiological metabolic actions in males compared with females.

TB remains a leading cause of morbidity and mortality worldwide. However, most infected immunocompetent individuals are asymptomatic and only 5–10% of these will eventually develop active TB during their lifetime (typically within 2 years after exposure). Therefore, rapid diagnosis and efficient management of asymptomatic infected individuals who are at the highest risk of progression and transmission remain major clinical and public health challenges. In recent years, there has been important scientific progress in our understanding of the spectrum of asymptomatic Mycobacterium tuberculosis (Mtb) infections that not only includes the dynamic state of latent TB infection (LTBI), but also the preclinical state of incipient and subclinical TB. The latter is possibly as prevalent as symptomatically active TB and potentially contributes to global Mtb transmission in various settings. We summarize the latest developments and current challenges of the existing testing tools for LTBI and describe promising biomarkers and diagnostics for the spectrum of asymptomatic TB. Following the negative results of a recent clinical trial for a biomarker-guided preventive therapy approach, we also suggest some treatment options for incipient TB.

AbstractBackgroundWomen have higher rates of hypertension at the time of menopausal transition than men. Although elevated systolic and diastolic blood pressures (SBP and DBP) are risk factors for white matter (WM) injury both in women and men, WM hyperintensities (WMH), a marker of WM injury, are more common in women than in men after the age of 60. Thus, women may be vulnerable to the effects of elevated BP on WM integrity during menopausal transition. We investigated the association of BP in recently postmenopausal women with good cardiovascular health with WMH volume assessed 13 years later.MethodWomen (n = 212; median age = 67; range 58‐72), who were previously enrolled in a multi‐site randomized menopausal hormone therapy trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP and DBP were measured at KEEPS baseline (median age = 54 years; range 44‐59). Participants who were on antihypertensive medications at KEEPS baseline were excluded from the analysis (n = 34). Approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions, WM integrity was assessed with automated WMH volume measurements from 3D‐FLAIR MRI. Associations of baseline SBP and DBP with logWMH volume measured 13 years later were tested by linear regression analyses. Model 1 was adjusted for age, study site, and total intracranial volume. Model 2 was adjusted for covariates of model 1, triglycerides, low density lipoproteins, and waist/hip ratio.ResultThe median SBP was 116 (range 83‐158) and DBP was 74 (range 56‐98). Higher SBP was associated with greater WMH volume (model 1:p = 0.005; model 2:p = 0.005). Similarly, higher DBP was associated with greater WMH volume (model 1:p = 0.008; model 2:p = 0.006) (Figure 1). Neither menopausal hormone therapies versus placebo, nor having high/low SBP (≥120/<120) modified these associations. Voxel‐based analyses demonstrate the association of BPs with the spatial distribution of WMHs (Figure 2).ConclusionHigher BPs in recently menopausal women were associated with greater WM injury more than a decade later after adjusting for CVD risk factors. Early postmenopausal stage is a critical time for BP control in women, which may reduce the risk of WM injury later in life.

This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on β-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the β-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the β-cell.

9569 Background: Immune-checkpoint inhibitor (ICI) immunotherapy increases survival in patients with melanoma. Yet only half of the patients respond, and 10-40% of patients experience immune-related adverse events (irAEs). Previous studies have found a correlation between the development of an irAE and treatment response. Modifying the gut microbiome could positively affect response to ICIs and reduce toxicities. We sought to determine if the microbiome at the onset of treatment, during an irAE, and at 12 weeks, can predict the response or toxicity during ICI treatment for metastatic melanoma. Methods: Melanoma patients (pts) > 18 yo treated with ICI enrolled in a prospective observational cohort study at The Ohio State University Comprehensive Cancer Center Skin Cancer Clinic. Excluded were patients on corticosteroids at the start of ICI cycle 1, except for adrenal physiologic replacement. Stools were collected at baseline, within 2 days of an adverse event assessed by physician chart review using CTCAE (Common Terminology Criteria for Adverse Events) v5.0, and at 12 weeks. Response (ORR) to ICIs was assessed by Response Evaluation Criteria in Solid Tumors (RECIST v1.1) q12 weeks and progression-free survival recorded. Metagenomic whole-genome shotgun sequencing was performed on an Illumina NovaSeq 6000 and classified using HUMAnN3. The effect of microbe relative abundances on irAEs was modeled by logistic regression with the R package glmm. Results: Of the 88 patients enrolled, 48 had metastatic disease with 32 assessable for response. ORR at 12 weeks was 28% (1 CR, 8 PR, 17 SD, and 6 PD) and 24 patients showed PFS at 12 months. Grade > 2 irAEs were observed in 11/48 pts. Abundance of Bacteroides dorei (False Discovery Rate Corrected p-value = 9.5E-07) and Blautia species CAG:257 (padj = 0.001) were enriched in responders, Prevotella Stercorea (padj = 1.1E-07) and a phage with a predicted target of Salmonella (padj = 8.3E-09) in non-responders. Responders with an irAE had enrichment of Bacteroides plebeius (padj = 4.2E-13) and Bacteroides coprophilus (padj = 0.0002) whereas responders without irAE had enrichment of Eubacterium siraeum (padj = 7.2E-05). Conclusions: Longitudinal and event-driven biospecimen collection in patients treated with ICIs showed several bacteria and viruses but no fungi associated with response, with and without the development of an irAE. The abundance of the two high-taxonomic rank microbe groups is significantly associated with irAEs. The association with the Bacteroides Genus is consistent with previous studies and is associated with response to ICIs. A microbiome abundant in Bacteroides and lacking Prevotella is associated with response to ICI. An abundance of Bacteroides could be a biomarker for irAEs, and an abundance of Eubacterium, a biomarker for response without irAEs. Future analyses are necessary to assign causal roles for microbe biomarkers with specific irAEs. Clinical trial information: NCT05102773 .

8567 Background: Adjuvant osimertinib (osi) improves disease-free survival (DFS) in patients (pts) with resected, early-stage, EGFR-mutant (EGFRmut) NSCLC, yet the benefit of osi after CRT in pts with unresectable locally advanced NSCLC is unknown. Post-hoc analysis of the PACIFIC trial showed a lack of survival benefit with consolidation durva versus placebo in pts with EGFRmut NSCLC. Comparisons between consolidation durva and EGFR TKIs in unresectable EGFRmut NSCLC following CRT are lacking. Methods: We conducted a multi-institutional retrospective analysis of pts with stage III unresectable EGFRmut NSCLC (exon19 deletion, exon21 L858R), who received EGFR TKI or durva after ≥ 2 cycles of platinum-based chemotherapy plus definitive radiation therapy between 2015-2022. Baseline characteristics including age, sex, smoking history, PD-L1 status, and outcomes on DFS, overall survival (OS), and safety were collected. Multivariable (MVA) cox regression analysis was used for statistical analysis. Treatment-related adverse events (trAE) were defined using CTCAE 5.0. Results: Seventeen pts from 12 institutions received an EGFR TKI (osi, n=15; erlotinib, n=2), and 13 pts received consolidation durva. Median follow-up was 23 months. Median age of all pts was 61 years (IQR:52-72) and 76.7% were female. Most pts in both groups had never-smoked and had adenocarcinoma. All pts received ≥ 60 Gy of radiation with concurrent chemotherapy. PD-L1 expression was ≥ 50% in 1/10 (10%) pts treated with durva vs 6/13 (46.2%) treated with TKI, p=0.09. Median duration on treatment for EGFR TKI and durva was 12.2 months and 4.8 months, respectively. Pts treated with EGFR TKI had significantly longer 24-month DFS versus pts treated with durva after adjusting for stage (3A vs 3B vs 3C) (Table). Any grade tRAE occurred in 58.8% (10/17) of pts treated with EGFR TKI vs 38.5% (5/13) with durva. Grade > 3 tRAE occurred in 15.4% (1 pneumonitis and 1 AST/ALT elevation) of pts treated with durva but in none of pts treated with EGFR TKI. Three pts within each arm came off treatment due to toxicity (EGFR TKI: 1 pneumonitis and 2 dermatitis; durva: 1 of each pneumonitis, Type 1 diabetes, AST/ALT elevation). Conclusions: EGFR TKI therapy after definitive CRT was associated with significantly longer DFS compared to durva in this retrospective study of pts with stage III unresectable EGFRmut NSCLC, without unanticipated safety signals. Follow-up is ongoing and OS outcomes will be evaluated subsequently. Further investigation is warranted to define the optimal therapy for locally advanced EGFRmut NSCLC. [Table: see text]

6520 Background: Increased patient engagement in decision making may mitigate disparities in breast cancer surgical care. Socioeconomically disadvantaged patients disproportionately experience barriers to engagement. Decision aids (DA) increase engagement by providing information, establishing role expectations during the consult, and increasing confidence in surgeon interactions. The objective was to test the effectiveness of a surgical web-based DA in increasing engagement among breast cancer patients in clinics that care for a high proportion of socioeconomically disadvantaged patients. Methods: A stepped wedge trial was conducted with 10 NCI Community Oncology Research Program clinics (Alliance for Clinical Trials in Oncology Research Base, 6/19-12/21). Clinics were randomized to time of transition from usual care (UC) to delivery of a web-based DA. Patients with stage 0-3 breast cancer eligible for surgery provided consent prior to a surgical consult. Socioeconomic disadvantage was assessed with the Area Deprivation Index measured at the zip+4 level and dichotomized. Patient engagement was measured by Patient’s Self-Efficacy in Patient-Physician Interactions (PEPPI-5, follow-up survey) and count of Active Patient Behaviors (Street protocol, audio recorded consult). Intervention effects were tested with linear mixed-effects models, accounting for surgeon and clinic-level clustering, time, and enrollment post-COVID. Heterogeneity of treatment effect by socioeconomic disadvantage was assessed with an interaction term. Results: 573 patients enrolled. 44% (136/309) reviewed the DA. No significant difference in engagement was observed comparing DA and UC for PEPPI-5 (-0.80 [95% CI -2.13, 0.54], p = 0.24) or Active Patient Behaviors (2.52 [CI -4.11, 9.15], p = 0.46). Enrollment post-COVID was associated with increased Active Patient Behaviors (9.59 [CI 1.76, 17.43], p = 0.02) but no change in PEPPI-5 (-1.31 [CI -2.88, 0.26], p = 0.10). No heterogeneity of treatment effect was observed. Conclusions: In this trial conducted in clinics that serve diverse populations, no significant relationship was observed between a web-based DA and patient engagement. Conducting this stepped wedge trial during the pandemic was challenging. Future analyses will explore the impact of COVID on outcomes and effect of the decision aid for patients who reviewed it. UG1 CA189823; AHRQ R01HS025194; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03766009 . [Table: see text]