Citations

Abstract Introduction The aim of this study was to develop a conditional normative model for Rey's Auditory Verbal Learning Test (AVLT) that accounts for practice effects. Methods In our normative sample, robust conditional norms were derived from 1001 cognitively unimpaired (CU) adults ages 50 to 89 who completed the AVLT up to eight times. Linear mixed‐effects models adjusted for baseline performance, prior test exposures, time, demographics, and interaction terms. In our preliminary validation, mean performance on conditional and typical normative scores across two to four completed follow‐up tests in preclinical Alzheimer's disease participants at baseline with positive amyloid and tau positron emission ( n = 27 CU amyloid [A]+tau[T]+) was compared to biomarker negative individuals ( n = 269 CU A–T–). Results AVLT performance using typical norms did not differ across A+T+ and A–T– groups. Conditional norms z‐scores were lower in the A+T+ relative to the A–T– group for 30‐minute recall ( P = .033) and sum of trials ( P = .030). Discussion Conditional normative methods that account for practice effects show promise for identifying longitudinal cognitive decline.

Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.

ABSTRACT Medical evacuation (MEDEVAC) from a combat zone requires complex decision-making and coordination of assets. A MEDEVAC helicopter team transports not only battle-injured patients but also patients with urgent non-battle-related medical diagnoses from extremely remote locations and are at the mercy of terrain, weather, and enemy contact. The military represents a young population particularly susceptible to venous thoracic outlet syndrome (vTOS) given the rigorous physical activity demands. Current literature supports immediate anticoagulation and surgical decompression within 14 days of diagnosis of vTOS to prevent long-term morbidity. Presented is a case of service member with vTOS presenting at an extremely remote military clinic who underwent a prompt evacuation ∼7,000 miles utilizing rotary-wing transport, followed by three to four more fixed-wing flights to a military treatment facility in the United States. Immediate recognition and ultrasound of this patient to confirm vTOS upon presentation and effective communication to non-medical military commanders and the receiving medical personnel at each Echelon was necessary to ensure an expedited evacuation. The surgeons treating this patient recommend prompt evacuation of deployed service members with suspected vTOS, venogram at the Role 3 if ultrasound is inconclusive, anticoagulation, and return to a Role 4 CONUS facility for definitive surgical management within 14 days. This case is an example of the efficiency of the military MEDEVAC system on a global scale, ensuring optimum medical care for all service members deployed.

Background Accumulating evidence suggests that primary aldosteronism (PA) is associated with several features of the metabolic syndrome, in particular with obesity, type 2 diabetes mellitus, and dyslipidemia. Whether these manifestations are primarily linked to aldosterone-producing adenoma (APA) or bilateral idiopathic hyperaldosteronism (IHA) remains unclear. The aim of the present study was to investigate differences in metabolic parameters between APA and IHA patients and to assess the impact of treatment on these clinical characteristics. Methods We conducted a retrospective multicenter study including 3566 patients with APA or IHA of Caucasian and Asian origin. We compared the prevalence of metabolic disorders between APA and IHA patients at the time of diagnosis and 1-year post-intervention, with special references to sex differences. Furthermore, correlations between metabolic parameters and plasma aldosterone, renin, or plasma cortisol levels after 1 mg dexamethasone (DST) were performed. Results As expected, APA patients were characterized by higher plasma aldosterone and lower serum potassium levels. Only female IHA patients demonstrated significantly worse metabolic parameters than age-matched female APA patients, which were associated with lower cortisol levels upon DST. One-year post-intervention, female adrenalectomized patients showed deterioration of their lipid profile, when compared to patients treated with mineralocorticoid receptor antagonists. Plasma aldosterone levels negatively correlated with the BMI only in APA patients. Conclusions Metabolic alterations appear more prominent in women with IHA. Although IHA patients have worse metabolic profiles, a correlation with cortisol autonomy is documented only in APAs, suggesting an uncoupling of cortisol action from metabolic traits in IHA patients.

6080 Background: Alterations in RET are targetable oncogenic drivers in TC. Pralsetinib is a highly potent, selective RET inhibitor, with demonstrated efficacy in pts with RET-altered TC. In a previous analysis of the Phase I/II ARROW trial (NCT03037385; data cutoff: 22 May 2020), overall response rates [ORR; measurable-disease population] with pralsetinib at 400 mg once daily (QD) were 60% (33/55) and 71% (15/21) in pts with RET-mutant medullary TC ( RET-mutant MTC) who had received prior multikinase inhibitors cabozantinib and/or vandetanib (C/V), and those who were treatment naïve, respectively, and 89% (8/9) in pts with previously treated RET fusion-positive TC ( RET-fp TC). Here we report an updated analysis of these cohorts in the intention-to-treat (ITT) population. Methods: Adult pts with RET-altered locally advanced/metastatic TC who had enrolled in ARROW and initiated pralsetinib at 400 mg QD, were included. Phase II primary endpoints: ORR (by blinded independent central review, per RECIST v1.1) and safety. Efficacy endpoints for this analysis were assessed in the ITT population. Safety was assessed in all pts with RET-altered TC who initiated pralsetinib at 400 mg QD. Enrolment cutoff: 23 August 2020 for the ITT population; data cutoff: 12 April 2021. Results: The ITT population comprised 145 pts with RET-mutant MTC (with or without prior systemic therapy, including C/V) and 22 pts with RET-fp TC, 21 of whom had received prior systemic therapy (including multikinase inhibitor[s] and/or radioactive iodine). In pts with RET-mutant MTC who had received prior C/V (n = 67), ORR was 51% (34/67; 95% CI 38–63; 2 complete responses [CR]; 32 partial responses [PR]), median duration of response (DoR) was 25.8 months (95% CI 18.0–not reached [NR]) and median progression-free survival (PFS) was 24.9 months (95% CI 19.7–31.2). In treatment-naïve pts with RET-mutant MTC, ORR was 72% (48/67; 95% CI 59–82; 4 CR; 44 PR), and median DoR and median PFS were not reached. In pts with previously treated RET-fp TC, ORR was 86% (18/21; 95% CI 64–97; 3 CR; 15 PR), median DoR was 17.5 months (95% CI 16.0–NR) and median PFS was 19.4 months (95% CI 13.0–NR). Median overall survival (OS) was not reached in any of the cohorts. The safety population comprised 172 pts with RET-altered TC treated at 400 mg QD. The most common treatment-related adverse events (TRAEs) were increased aspartate aminotransferase (n = 67; 39%), anemia (n = 60; 35%), hypertension (n = 57; 33%) and decreased white blood cell count (n = 52; 30%). Serious TRAEs were reported in 27 pts (16%); the most frequent was pneumonitis (n = 5; 3%). Nine pts (5%) discontinued pralsetinib due to a TRAE and one patient ( < 1%) died due to a TRAE ( pneumocystis jirovecii pneumonia) following 44 days ( < 3 cycles) on pralsetinib. Conclusions: In this updated analysis including more pts, pralsetinib continues to be efficacious with a manageable safety profile in pts with RET-altered TC. Clinical trial information: NCT03037385.

Abstract Introduction: The immune microenvironment of the breast is critical in the development and progression of breast cancer. By analyzing the immune components of breast tissues from patients at varying degrees of breast cancer risk, we may gain enhanced understanding of breast cancer risk and mechanisms of carcinogenesis. Methods: We compared the immune cell composition in breast lobules of age-matched patients with normal and benign breast disease (BBD) at progressively lower breast cancer risk: 1) 18 women with germline mutations in (BRCA1/2); 2) women at intermediate risk (BBD), and 3) women at normal risk (Komen Tissue Bank- (KTB)). We performed immunohistochemical stains for T lymphocytes (CD4, CD8); dendritic cells (CD11c); B lymphocytes (CD20) and macrophages (CD68) and quantitated immune cell densities in up to 10 representative lobules per sample. Results: The median age of all groups was 43.8 years (range: 34-67). BRCA carriers and BBD patients had a higher percentage of fibrocystic lobules (50% fibrocystic) compared to KTB samples (15% fibrocystic), p&lt;0.001. BRCA carriers had significantly higher densities of CD4, CD8, CD11c, and CD68 positive immune cells compared to KTB donor breast tissues, see Table. Compared with BBD patients, mutation carriers had higher densities of CD8+ cells and suggestively higher CD4+ cells, with similar results for other markers assessed. Conclusions: Preliminarily, these data showed that benign prophylactic breast tissues from BRCA mutation carriers contain increased numbers of several immune cell types versus tissues from patients at lower breast cancer risk, including BBD patients and research tissue donors. Further investigation is needed to confirm and expand these findings in relation to breast cancer risk. Table: Pairwise Wilcoxon rank-sum p-values comparing immune cell densities in breast lobules from women with BRCA germline mutations, vs BBD and KTB groups. All Lobules BRCA BBD KTB BRCA vs BBD BRCA vs KTB Median Median Median p-value p-value (IQR) (IQR) (IQR) CD4+, cells/mm2 116.3 63.8 17.7 0.08 &lt;0.001 (46.4-183.6) (25.0-121.1) (13.3-40.6) CD8+, cells/mm2 354.4 200 150.9 0.01 &lt;0.001 (285.5-473.2) (118.9-385) (110.1-225.0) CD11c+, % pp 3.5 3.4 0.4 0.66 &lt;0.001 (1.9-6.8) (1.6-4.7) (0-0.6) CD20+, cells/mm2 6.2 16.7 0 0.16 0.65 (0-25.4) (0-58.3) (0-20.8) CD68, cells/mm2 237.5 219 57.8 0.99 &lt;0.001 (122.9-281.8) (75.0-459.4) (29.2-100.0) IQR - Interquartile Range pp - pixel positive Citation Format: Joshua W. Ogony, Tanya L. Hoskin, Melody L. Stallings Mann, Stacey J. Winham, Rushin Brahmbhatt, Muhammad Asad Arshad, Alvaro Pena Jimenez, Teresa M. Allers, Mark E. Sherrman, Daniel W. Visscher, Derek C. Radisky, Amy C. Degnim. Immune biomarkers in breast tissues of patients with BRCA1/2 mutations, benign breast disease, and normal tissue donors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5947.

Abstract Funding Acknowledgements Type of funding sources: None. Immunomodulatory effect of different statin regimens on regulatory T-cells among patients with acute coronary syndrome: a systematic review and network meta-analysis of randomized clinical trials Introduction In patients with acute coronary syndrome (ACS), studies suggest that statin therapy, besides its role in reducing the progression of atherosclerosis through its pharmacological effect, plays a pivotal role in controlling the pathogenesis of ACS through the anti-inflammatory effects of suppressor regulatory T cells (Tregs). Purpose We conducted a network meta-analysis (NMA) to determine the effects of low-dose conventional statin therapy (CST) (20 mg/day or less) and high-dose intensive statin therapy (IST) (40 mg/day or more) on the frequency of Tregs and their associated cytokines (IFN-γ, IL-10, TGF-β), compared to placebo. Methods The PubMed, Cochrane Library, and EMBASE databases were searched for randomized clinical trials (RCTs) to identify relevant articles published until June 2021. We pooled data extracted from the included studies using the standardized mean difference (SMD). A random-effects model was used to conduct this NMA. Heterogeneity was evaluated using Cochran's Q- and the I2-test. GRADE(Grading of Recommendations, Assessment, Development and Evaluations) was used to assess the study's quality. Data analysis was conducted using R software. Results A total of 505 patients were enrolled in the 5 RCTs. The NMA indicated a significant increase in Treg frequency in the CST group compared with the control group (SMD 1.77; 95% CI: 0.77 – 2.76; P-value = 0.0005) and a larger increase in the Treg frequency associated with the IST group compared with the control group (SMD 2.12; 95% CI: 1.15 – 3.10; P-value &lt; 0.0001). However, there was significant heterogeneity and inconsistency among the included studies (τ2 = 0.6096; τ = 0.7808; I2 = 91.2% [80.5%; 96.0%]). When compared to the placebo, both CST and IST increased levels of secreted IL-10 (SMD 2.69; 95% CI: 2.07 – 3.31; P-value &lt; 0.0001 and (SMD 2.14; 95% CI: 1.76 – 2.52; P-value &lt; 0.0001), respectively. In comparison to the control group, CST was associated with increased levels of TGF-β (SMD 3.83; 95% CI: 0.63 – 7.0; P-value = 0.0189). This association was not seen in the IST group. IFN-γ levels decreased significantly in both the IST and CST groups (SMD -1.52; 95% CI: -1.94 – -1.10; P-value &lt; 0.0001) and (SMD -2.34; 95% CI: -2.73 – -1.95; P-value &lt; 0.0001) respectively. Conclusions Our study suggests that both high and low dose statin groups showed increased Treg frequency compared to the placebo group. IST showed larger benefits. Statin therapy also increased IL-10 and TGF-β cytokine levels and decreased IFN-γ levels. Therefore, statins have the potential to be the main treatment to reduce the incidence of cardiovascular events and improve cardiac function in patients with ACS through immunomodulatory effect on Treg.

e24087 Background: Patients with advanced cancer and their caregivers experience a substantial amount of distress. Limited research suggests that mindfulness-based interventions may improve quality of life and reduce anxiety. The virtually delivered Resilient Living program consisted of online modules, a print journal, and a total of 4 virtual training sessions focused on techniques for managing stress and building resilience (mindful presence, uplifting emotions, reframing experiences through principles of gratitude, compassion, acceptance, meaning, and forgiveness). The current pilot study was performed to assess the feasibility of the virtual Resilient Living Program for patients with advanced cancer and their caregivers, as well as preliminary effects on anxiety and related outcomes. Methods: Eligible patients included those age ≥18 years with a diagnosis of advanced cancer with expected prognosis > 6 months. Feasibility was defined as consent of at least 25% of eligible patients and their caregivers. Adherence was defined as 75% of the enrolled participants completing at least 3 of the 4 Resilient Living sessions. The primary outcome measure was anxiety as measured by the GAD-7; others included stress (PSS), quality of life (LASA), sleep (ISI), resiliency (Resiliency Scale), and fatigue (PROMIS-Fatigue SF). Results: Seventy-two eligible patients were referred to the study, of these 33 patients enrolled (46% enrollment), 15 also had a caregiver enroll. Thirty participants completed at least 3 virtual sessions (63% adherence). Data was collected at baseline, week 5 (after 2 session), week 9 (after 4 sessions), and week 12 (1 month after completion) for patients and caregivers. There were statistically significant improvements in anxiety at weeks 5, 9 and 12 (i.e., p < 0.05). Other results are outlined in the table. Conclusions: Virtual participation in the Resilient Living Program is feasible and acceptable for patients with advanced cancer and their caregivers. Data from this pilot study suggest that the program may positivity impact anxiety, stress, sleep, quality of life and resiliency. A larger randomized prospective clinical trial is warranted to confirm these preliminary findings. Clinical trial information: NCT04480008. [Table: see text]