Citations

e13893 Background: For individuals with CNS tumors who have experience difficulties with in-person (IP) evaluations due to disease-related neurologic disability or the costs associated with travel, telehealth (TH) offers a convenient and timely alternative for accessing specialized neuro-oncology care. We report our institution’s experience with telehealth utilization in neuro-oncology. Methods: We conducted a retrospective review of patients who had at least one neuro-oncology telehealth visit between August 2021 and May 2024 at Mayo Clinic in Rochester, Minnesota. Reasons for visits, outcomes of appointments, acute care utilization following visits was reviewed. Results: A total of 660 patients who had at least one TH visit between August 2021 and May 2024 were included in the analysis. Median age was 56 (range 20-98), 49% were female, and 92% were white. Most patients resided in the US Midwest (84%), followed by the South (8%), West (5%), Northeast (1%), and US Territories (< 1%). Less than two percent were international patients. The most common primary visit diagnosis was glioblastoma (GBM, 26%), followed by astrocytoma, IDH-mutant (17%), meningioma (17%), oligodendroglioma, IDH-mutant, 1p/19q codeleted (7%). Of 6657 visits reviewed, 2745 (41%) were conducted via TH. Telehealth visits served various purposes, including consultation for newly diagnosed tumors or abnormal MRIs (n = 26), second opinion for an established tumor diagnosis (n = 119), discussion about clinical trial participation (n = 108), tumor-related treatment discussions (n = 719), chemotherapy education (n = 161), new symptom assessment (n = 117), symptom management (n = 366), and tumor surveillance (n = 1694). Outcomes from telehealth visits included enrollment in clinical trials (n = 28), proceeding with tumor-directed surgery (n = 46), initiation of radiation therapy (n = 88), starting or changing systemic therapy (n = 377), continuing existing systemic therapy (n = 932), transition to supportive care (n = 45), tumor diagnostic workup (n = 28), continuation of tumor surveillance (n = 1254). Acute care utilization, defined as an emergency department visit or hospitalization within one month of an appointment, was the same following telehealth visits compared to in-person visits (6.9% for IP vs 5% for TH, p = 0.507). Conclusions: Our findings demonstrate that telehealth can effectively support all aspects of neuro-oncology care, ranging from initial diagnosis discussions to systemic therapy management and transitions to supportive care. Telehealth offers a convenient and accessible method of care delivery option for patients faced with neurologic illness. Additionally, THs do not lead to increased acute care utilization compared to IP evaluations.

5041 Background: Prior studies suggest that chemotherapy-naïve pts with mCRPC treated with AA have a higher CV event-related hospitalization risk than those treated with ENZA. To further explore this association, this real-world, comparative causal inference study used a large US dataset to assess CV event risk in chemotherapy-naïve pts with mCRPC who initiated treatment (Tx) with ENZA or AA and provide outcome data based on history of (h/o) CV disease (CVD). Methods: Using US Medicare fee-for-service claims (Jan 2010–Dec 2022), we identified chemotherapy-naïve pts aged ≥65 years with mCRPC who initiated ENZA or AA between Sep 2014 and May 2017. The primary endpoint was a 4-point major adverse CV event (MACE-4; composite of acute myocardial infarction [AMI], stroke, unstable angina/revascularization [UA/R], and heart failure). Atrial fibrillation (AFib), venous thromboembolism (VTE), and all-cause death were also analyzed. Groups were propensity score matched (PSM) to adjust for differences in pt characteristics, assessed using standardized mean difference (SMD). Cause-specific Cox proportional hazards models were used to comparethe risk of CV outcomes between intention-to-treat cohorts, with death as a competing event. Subgroup analyses were conducted based on h/o CVD. Sensitivity analysis was performed with a MACE-5 endpoint, defined as MACE-4 or CV-related death. Results: Of 6319 pts in the total study population (ENZA: 2934; AA: 3385), 2913 PSM pts were included from each group. The ENZA and AA cohorts had similar baseline characteristics even before PSM (SMD<0.1), with a mean (standard deviation) age of 78.8 (7.3) years; 76% of pts had prior CVD. Compared with pts on ENZA, pts on AA had a significantly higher risk of experiencing MACE-4—particularly UA/R—as well as a higher risk of AFib and VTE (Table). Similar results were found in the subgroup of pts with a h/o CVD and the sensitivity analyses. Additionally, pts on AA had a higher risk of all-cause death than pts on ENZA, regardless of CVD history (h/o CVD hazard ratio [HR]: 1.14, 95% confidence interval [CI]: 1.07–1.21, P =0.0001; no h/o CVD HR: 1.12, 95% CI: 1.01–1.26, P =0.036). Conclusions: This matched analysis of US Medicare beneficiaries showed an increased risk for MACE-4, AFib, and VTE in pts with mCRPC treated with AA compared to ENZA, in the overall pt population and pts with a h/o CVD. The risk of all-cause death was higher with AA in all pts. These findings provide insights into Tx decision-making for pts with mCRPC, especially those at high risk of CV events. Outcomes HR* (95% CI) P -value MACE-4 1.12 (1.02–1.24) 0.028 AMI 1.01 (0.76–1.32) 0.987 Stroke 0.92 (0.70–1.20) 0.505 UA/R 1.13 (1.01–1.26) 0.041 Heart failure 1.19 (0.90–1.58) 0.237 AFib 1.73 (1.31–2.29) 0.0001 VTE 1.37 (1.02–1.85) 0.037 All-cause death 1.13 (1.07–1.19) 0.0001 *ENZA = reference group.

Abstract Introduction Solid organ transplant recipients experience high rates of cognitive impairment; however, little is known about what modifiable factors contribute to cognitive impairment after transplantation, limiting evidence-based treatment options. Insomnia is a sleep disorder that is associated with poor cognitive functioning in healthy adults and is amenable to interventions, but the relationship between insomnia and cognitive impairment after organ transplantation has not been explored. The purpose of this study was to identify relationships between insomnia, sleep characteristics, and perceived cognitive function after organ transplantation. Methods We conducted a descriptive, cross-sectional study of adult (&gt;18 years) transplant recipients. We used the Insomnia Severity Index to measure insomnia, 10 days of continuous wrist actigraphy (Ambulatory Monitoring Inc. MicroMotionlogger) to measure sleep characteristics, and the PROMIS Cognitive Function to elicit perceived cognitive function. Descriptive statistics, Spearman’s Rho correlations, and Pearson’s correlations were used to describe relationships. Results We enrolled 34 participants [Mean age 62.5 years (SD 10.7), 64.7% (n=22) female, 85.3% (n=29) white, 17 liver/9 heart/8 kidney, average time since transplant 4.8 years (SD 4.2)]. 73.3% had clinically significant insomnia [mean ISI: 12.9 (SD 6.9)]. Sleep characteristics were obtained using actigraphy (mean duration: 7.03 hours [SD 1.28], onset latency: 9.16 min [SD 4.90], efficiency: 89.49% [SD 8.96], wake after sleep onset: 49.61 [SD 37.37]). Perceived cognitive function for the sample was worse than that of the general population, with a mean T-score of 45.21 (SD 11.44). Lower perceived cognitive function scores were significantly associated with younger age (rs = -.416, p=.016) and shorter time since transplant (rs =-.386, p=.024). Longer wake after sleep onset (rs =.347, p=.048) and lower sleep efficiency (rs=-.358, p=.041) were associated with lower perceived cognitive function. Lower perceived cognitive function was strongly associated with higher insomnia severity scores (r=.817, p=&lt;.001). Conclusion Insomnia was common in our sample of transplant recipients and was strongly correlated with worse perceived cognitive function. Future research should incorporate objective measures of cognitive functioning and should consider insomnia treatment as a potential intervention to promote optimal cognitive functioning after organ transplantation. Support (if any) Mayo Clinic Center for Clinical and Translational Science.

Abstract Introduction The majority of adults with inflammatory bowel disease (IBD) experience disability which is not fully explained by disease activity. Up to 80% of adults with IBD experience poor sleep health, which is associated with disability in other populations; however, the relationship between disability and sleep health among patients with IBD is largely unexamined. The purpose of this study was to compare the sleep health characteristics of those with and without IBD-related disability. Methods We recruited adults (18 to 59 years old) with IBD from a single academic medical center from 2022 to 2024. We measured disease activity using the Manitoba IBD Index and sleep using the PROMIS Sleep Disturbance and PROMIS Sleep-Related Impairment scales, the Insomnia Severity Index, and 14 days of wrist-worn actigraphy (Phillips Spectrum Plus, Phillips Respironics). We asked participants how many days they missed or had at least 50% reduced productivity in paid work or household work or missed leisure activities in the last 3 months related to their IBD. Disability was defined as missing six or more day over three months. We conducted bivariate analyses and logistic regressions to study associations. Results Among 83 adults with IBD [mean age = 40.4 years (SD 10.7), 59 (71.1%) were female, 56 (71.1%) had Crohn’s disease], and 49 (62.0%) had IBD-related disability. Patients with disability had more severe sleep disturbance (56.4 vs. 51.0, p &lt;.001), sleep-related impairment (58.3 vs 50.3, p &lt;.001), more severe insomnia (12.7 vs. 9.4, p =.029), and actigraph-measured higher wake after sleep onset (41.6 minutes vs. 34.0 minutes, p = 0.012) and lower sleep efficiency (85.1% vs. 87.9%, p = 0.032) compared to those without disability. After controlling for age and disease activity, sleep-related impairment (OR = 1.1, 95% CI 1.03, 1.15) was independently associated with disability. Conclusion Patients with IBD-related disability experience poor sleep health. Sleep related daytime impairment uniquely contributed to disability when controlling for disease activity. Sleep interventions need to be tested in adults with IBD to determine if they are effective at addressing disability in this population. Support (if any) Mayo Clinic Bonner Fund

Introduction: Although primarily supplied by the vertebrobasilar system, the hippocampus is partially supplied by ipsilateral carotid artery branches through the anterior choroidal artery or a prominent posterior communicating artery. We report a patient with acute hippocampus infarction likely due to symptomatic ipsilateral tandem carotid stenosis and discuss acute vascular-mediated hippocampal injury. Case Report: An 80-year-old female with obesity, dyslipidemia, hypertension, alcohol use disorder, history of breast cancer on letrozole, and traumatic brain injury was brought into our emergency department for 24 hours of confusion. On examination, she exhibited limited registration, recall, and executive dysfunction with otherwise normal language, visuo-spatial orientation, and praxis. Brain MRI showed a small area of diffusion restriction in the anterior right hippocampus with matched FLAIR hyperintensity, consistent with acute infarction. Computed tomography angiogram head and neck showed 90% stenosis of the proximal right internal carotid artery (ICA), <50% narrowing of the proximal left ICA, and moderate bilateral narrowing of the paraclinoid ICAs, all due to calcific atheromatous plaques. The etiology of the hippocampal infarction was suspected embolism from the ipsilateral severe carotid stenosis. Planning for right cervical carotid revascularization ensued. Conclusion: This case highlights the dual hippocampal vascular supply and that hippocampal embolic infarcts could be a sign of a symptomatic severe carotid artery stenosis that may require urgent revascularization for stroke secondary prevention.

Abstract Rationale: Asthma involves airway inflammation, hyperresponsiveness (AHR), and remodeling (cell proliferation and fibrosis), with both aspects not fully alleviated by current therapies. GPCR-based drugs represent a major aspect of current asthma therapy. Asthmatic airways express several orphan receptors with unknown physiological roles, highlighting a potentially novel and significant area for therapeutic exploration. Herein, we focus on orphan retinoic acid (RA)-induced Class C GPCR members GPRC5A (RAIG1; 5A) and GPRC5B (RAIG2; 5B). We leveraged recently identified 5A agonists to test the hypothesis that these GPCRs have alleviating effects in airways. Methods: Primary human airway smooth muscle cells (ASM) originating from non-asthmatic (NA) and asthmatic (Asth) individuals were obtained post-surgery from lung tissues after approval by the Mayo Clinic Institutional Review Board. PRESTO-Tango assay was used to determine 5A and 5B activity. cADDis assay was used to assess cAMP levels. Fluorescence imaging was used to determine calcium regulation. Recently identified 5A agonists [tryptamine, 7 fluoro-tryptamine (7FT), L-tryptophan, N-methyltryptamine, and indole-3-acetic acid] were used in assays, along with RA and 5A vs. 5B siRNAs. Results: PRESTO-Tango assay showed that tryptamine (10/100 µM) and 7FT (1/10/100 µM) increased 5A activity while high concentrations of 7FT (100 µM) increased 5B activity as well. cADDis assay showed 100 µM tryptamine increased cAMP more than 1/10 µM tryptamine and that 10 µM 7FT increased cAMP more than 1/100 µM 7FT in NA ASM.Calcium imaging showed that 5A agonist blunts responses to histamine, especially in Asth ASM. Calcium responses were higher in Asth ASM and 5A siRNA-treated ASM while 5B siRNA had an alleviating effect. Conclusions: Class C GPCRs 5A and 5B interestingly have opposing effects in human ASM towards blunting calcium responses to bronchoconstrictor agonists in the context of asthma. Thus, 5A agonists and 5B antagonists may represent novel GPCR-based approaches in airway diseases.

Abstract Rationale: Moderate hyperoxia (&lt;60% O2) in premature infants promotes bronchial airway hyperresponsiveness (AHR) and impaired bronchodilation involving airway smooth muscle (ASM). Understanding mechanisms by which hyperoxia initiates long-term bronchial airway changes in prematurity is critical for novel therapies for wheezing disorders and asthma in children. Underdeveloped lungs in prematurity have immature antioxidant systems, which may be due to disrupted dynamics that promote susceptibility to oxidative stress from O2. Cytoplasmic and mitochondrial calcium signaling mechanisms and O2 metabolism are pathways highly relevant to ASM and airway disease. We propose that the novel gasotransmitter hydrogen sulfide (H2S) attenuates effects of O2 in developing ASM and hypothesize that hyperoxia in prematurity promotes cellular and mitochondrial calcium signaling dysfunction, effects which are counteracted by H2S.Methods: Human fetal (fASM) cells isolated from tracheobronchial samples of de-identified 18-22 week fetuses following fetal demise (Mayo IRB approved as exempt) were exposed to 21% vs 40% O2. fASM were treated 24-72 hours with H2S donor GYY4137, mitochondrial-specific H2S donor AP39, cystathione-β-synthase (CBS) stabilizer AdoMet, cAMP inhibitors SQ22536 or KT5720, or vehicle control (DMSO). CBS shRNA lentiviral particles were used to generate stable knockdown cell lines. Protein markers were measured by Western blot. Intracellular calcium ([Ca2+]i) was measured using 5μM Fura-2/AM and mitochondrial calcium ([Ca2+]m) with 1μM Rhod-2 AM using fluorescence microscopy. Results: CBS expression was lower in fASM exposed to 40% O2 compared to 21% O2. Lentivirus induced CBS KD was exacerbated by 40% O2. Hyperoxia increased [Ca2+]i and [Ca2+]m response to histamine (10μM) in vehicle and Scr controls compared to normoxia. CBS KD increased [Ca2+]i and [Ca2+]m responses to histamine compared to Scr fASM in 21% O2. CBS KD fASM exposed to hyperoxia showed increased [Ca2+]i and [Ca2+]m responses to histamine, but the effect was not amplified by CBS KD. [Ca2+]i and [Ca2+]m responses to histamine were decreased in normoxia by H2S donors GYY4137 (50μM) and AP39 (100nM) and CBS stabilizer AdoMet (100nM); effects which also blunted hyperoxia induced increases. SQ22536 and KT5720 inhibited effects of AP39 and GYY4137 in hyperoxia. Conclusions:Our findings suggest hyperoxia leads to [Ca2+]i and [Ca2+]m dysfunction in developing airway cells, which can be alleviated through modulation of H2S pathways, offering potential targets for future therapies to blunt hyperoxia effects on bronchoconstriction and bronchodilation. Acknowledgment: Supported by AHA Postdoctoral Fellowship 20POST35210002 (Bartman), NIH R01 HL-056470 (Prakash), and HL-160570 (Pabelick).

Abstract Rationale: Asthma in the elderly (AIE) presents a unique challenge characterized by hyperreactive and thickened, fibrotic airways (remodeling) that is not adequately addressed by current therapies. Thus, understanding mechanisms that drive AIE become important. Here, airway smooth muscle (ASM) cells play important roles in normal airway physiology and asthma pathophysiology. Recent discoveries have highlighted the significance of mechanosensitive Piezo (Pz) in health and disease. The lung generates mechanical forces of normal breathing and other maneuvers that are transmitted to bronchial airways via tethering parenchyma. While Pz channels are highly expressed in the lung, their specific role in ASM function remains largely unexplored. In this study, we used human ASM cells to test the hypothesis that increased airway stiffness associated with normal aging blunts Pz expression and mechanosensitive functionality, whereas asthmatic triggers (e.g. inflammation) enhance Pz expression and downstream signaling. Methods: Primary human ASM cells isolated from lungs of young (&lt;45y) vs. aged (&gt;65y) non-asthmatic vs. asthmatic individuals were obtained post-surgery (Mayo Clinic IRB approved). Cells were exposed to mechanical stretch (mimicking breathing) and mediators relevant to asthma (TNFα, IL-13) or fibrosis (TGFβ) to determine expression of Pz1/2 across the age spectrum. Separately, intracellular Ca2+ and contractility responses, proliferation and extracellular matrix (ECM) deposition across age/asthma groups were assessed in response to mechanical stretch and Pz1/2 modulation (inhibitors/activators, genetic approaches). Manipulation of Pz1/2 expression or function in ASM accompanied by mechanical stretch was used to assess impact on canonical Wnt/β-catenin signaling. Results: We observed increased Pz1/2 expression with age and asthma as well as with inflammation and mitogenic stimuli. Functionally, Pz1 agonist, Yoda1 induced increase in intracellular Ca2+, ASM proliferation and ECM deposition with greater effects observed in aging asthmatic ASM. Towards linking mechanosensation (via Pz) to remodeling via Wnt signaling, we find that Wnt3a is upregulated by Yoda1 but suppressed by Pz1 shRNA. Yoda1 stimulates TGFβ-induced Wnt3a and β-catenin, an effect further enhanced under mechanical stretch. Conclusions: By elucidating the role of Pz channels in ASM, we aimed to identify novel therapeutic targets for airway diseases. Understanding how mechanical forces and inflammatory stimuli influence Pz-mediated signaling pathways will lead to the development of innovative strategies to prevent or reverse airway remodeling in elderly asthmatic patients. Acknowledgement: Supported by 24POST1241979 (NAB) and NIH grants R01-HL142061 (CMP and YSP), R01- HL088029 (YSP).

Abstract Rationale: With an increasing elderly population, understanding mechanisms that contribute to structural and functional changes in aging lung is important in the context of healthy aging and diseases such as asthma and pulmonary fibrosis that disproportionately affect the elderly. Asthma in the elderly (AIE) is a particular challenge, with thickened fibrotic bronchial airways (remodeling) and inflammation compared to non-asthmatic elderly: issues not addressed by current therapies. Factors such as iron regulation that are critical for normal physiology can become dysregulated in disease. Iron overload can catalyze a Fenton reaction that increases ROS which oxidizes lipids and proteins, i.e. iron-mediated lipid peroxidation cell death (ferroptosis).The goal of this study was to determine iron regulation in aging- and AIE-associated in human ASM (hASM), a cell type important in airway contractility and remodeling. Methods: hASM cells and lung tissues from young (&lt;45y), and aged (&gt;65y) male/female patients with/without asthma were used (approved by Mayo IRB #16-009655). Cells were treated with ferroptosis inhibitor deferoxamine (DFO) [100µM], inducer RSL3 [125 nM] or vehicle (DMSO) for 24 hrs. Levels of intracellular iron (Fe2+) were determined using FerroOrange. Cell lysates were examined for iron accumulation and ferroptosis markers (4-HNE, FTH1, TfR1, SLC7A11, and KEAP1), cell proliferation, and ECM production (COL1A1 and FN1), and supernatants analyzed for proinflammatory mediators IL-6 and IL-8. Results: Non-asthmatic and asthmatic elderly hASM cells showed a higher cytosolic Fe2+ and lower end-product of lipid peroxidation (4-HNE), higher level of SLC7A11 and KEAP1 (regulators of redox systems) compared to cells from young individuals. High level of iron storage (FTH1) was observed in asthmatics compared to non-asthmatic elderly, but no difference was observed for iron transporters (TfR1). Furthermore, COL1A1 and FN1 were higher in AIE hASM, compared to young hASM. COL1A1 was higher in aging hASM compared to young. DFO reduced COL1A1 in elderly, but upregulated in AIE. Cell proliferation was inhibited by DFO in aging hASM but not in young and AIE. The ferroptosis inducer RLS3 impaired antioxidant system and increased lipid peroxidation and IL-8 levels. Conclusions: Our findings suggest that iron regulation is impaired in aging and AIE hASM, resulting in iron accumulation which modulates airway remodeling via cell proliferation and ECM production. While ferroptosis per se can be targeted, it will be important to explore modulation of specific iron regulatory pathways in alleviating the impact of aging and asthma.