Gilman, Elizabeth A.

Objectives Long-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms. Methods Participants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks. Results All randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant. Conclusions tcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.

10578 Background: Multicancer detection (MCD) testing using cell-free DNA methylation patterns is a novel blood-based approach to cancer screening. In 2022, Mayo Clinic implemented offering MCD testing into routine clinical practice. Prior real-world reports have been limited to single-site experiences. We evaluated enterprise-wide implementation of MCD testing across all three Mayo Clinic sites using the Mayo Clinic Platform. Methods: We performed a retrospective analysis of de-identified clinical data from Mayo Clinic Platform Discover, including GRAIL Galleri tests performed at Mayo Clinic sites in Rochester, MN; Scottsdale, AZ; and Jacksonville, FL. This activity did not require IRB review per 45 CFR 46.102. Demographics, test results, cancer diagnoses, and prior cancer history were extracted using a privacy-preserving protocol, with data de-identified by expert determination. ICD-10 diagnostic codes were used to identify subsequent cancer diagnoses. Results: A total of 8,201 Galleri tests were performed in 7,300 patients; some patients underwent repeat testing. Fifty-seven tests (0.7%) were positive. Among MCD-positive patients, cancer diagnostic codes were identified in 32 patients, yielding a positive predictive value (PPV) of 58.7%. The most common cancers identified were oropharyngeal (34.4%), lymphoid and hematopoietic (34.4%), and gastrointestinal malignancies (18.8%).Among 8,144 MCD-negative tests (99.3% of all testing performed), 423 patients (5.2%) subsequently received a cancer diagnostic code, yielding a negative predictive value of 92.5%. The most commonly identified cancers in this group were male genital organs (36.6%), urinary tract (10.6%), and thyroid or other endocrine glands (7.3%). Overall, 10.1% of patients had a prior cancer history, which was more common in MCD-positive than MCD-negative patients (22.6% vs 10.0%). Patients with positive tests were older (mean age 68.4 vs 61.5 years) and more often male (67% vs 62%). Race distribution was similar. Conclusions: Enterprise-wide implementation of MCD testing across diverse clinical settings is feasible within routine workflows. Over half of positive tests were associated with cancer diagnostic codes, supporting the clinical promise of MCD testing. Limitations include incomplete capture of externally diagnosed cancers and lack of cancer signal-of-origin data. The Mayo Clinic Platform enables scalable, secure analytics to support future cancer interception strategies.

Background: Artificial intelligence (AI) platforms can potentially enhance clinical decision-making (CDM) in primary care settings. OpenEvidence (OE), an AI tool, draws from trusted sources to generate evidence-based medicine (EBM) recommendations to address clinical questions. However, its effectiveness in real-world primary care cases remains unknown. Objective: To evaluate the performance of OE in providing EBM recommendations for five common chronic conditions in primary care: hypertension, hyperlipidemia, diabetes mellitus type 2, depression, and obesity. Methods: Five patient cases were retrospectively analyzed. Physicians posed specific clinical questions, and OE responses were evaluated on clarity, relevance, evidence support, impact on CDM, and overall satisfaction. Four independent physicians provided ratings using a 0 to 4 scale. Results: OE provided accurate, evidence-based recommendations in all cases, aligning with physician plans. OE was scored on a scale of zero to four, where zero was very unclear, and four was very clear. Mean scores across cases were clarity (3.55 ± 0.60), relevance (3.75 ± 0.44), support (3.35 ± 0.49), and satisfaction (3.60 ± 0.60). However, the impact on CDM was limited (1.95 ± 1.05), as OE primarily reinforced rather than modified plans. Conclusion: OE was rated high in clarity, relevance, and evidence-based support, reinforcing physician decisions in common chronic conditions. While the impact on CDM was minimal due to the study’s retrospective nature, OE shows promise in augmenting the primary care physician. Prospective trials are needed to evaluate its utility in complex cases and multidisciplinary settings.

Objective: Multicancer Detection (MCD) tests, such as the GRAIL Galleri, offer a novel approach to cancer screening by detecting cancer-specific methylation patterns in cell-free DNA through a single blood sample. This study evaluated an 18-month implementation of MCD testing in a tertiary ambulatory internal medicine clinic. Patients and Methods: Between June 2022 and November 2023, 2244 asymptomatic (without symptoms attributed to cancer) patients underwent MCD testing. The study focused on operational workflows, patient and physician education, and diagnostic follow-up of positive results. Standardized materials, including electronic health record (EHR) workflows, FAQs, and diagnostic pathways, were developed to facilitate implementation. Challenges included managing false positives, patient anxiety, costs, and ethical considerations. Results: Of the 2244 patients tested, 17 (0.76%) had positive results, and 15 underwent further diagnostic evaluation. Cancer was confirmed in 11 (73.3%) patients, including cases of breast, colon, esophageal, lymphoma, ovarian, and pancreatic cancers. Four patients had no identifiable malignancy despite comprehensive work-up. Conclusions: MCD testing is feasible in routine clinical workflows, with 73% of positive cases yielding cancer diagnoses. While promising, further research is required to assess long-term outcomes, cost-effectiveness, and optimal implementation strategies of cancer interception in broader healthcare settings.

Introduction: The Undiagnosed Mass Clinic (UMC) at our institution is a clinical and research program created to address gaps in the early diagnostic phase of the cancer care continuum for patients with potential malignant neoplasms. All patients referred to the UMC are invited to participate in the UMC registry, which tracks operational and clinical metrics while maintaining a repository of blood and tissue specimens for future research. Methods: We conducted a retrospective cohort study of the first 100 patients enrolled in the UMC registry. We analyzed patient demographics, final diagnoses, and the time from initial consultation to final diagnosis. Results: Most participants were White (86%), non-Hispanic (93%), and married (72%). The mean (SD) age was 64 (13.9) years. The final diagnoses of the masses were categorized as malignant/neoplastic with malignant potential (n = 53), benign (n = 36), or requiring diagnostic surveillance (n = 10). The mean (SD) time from initial consultation to final diagnosis of malignant/neoplastic with malignant potential masses significantly improved from 37.4 (36.6) days for the first 50 participants to 17.3 (19.7) days for the next 50 participants ( P = .006). Conclusions: These initial insights from the UMC registry will help direct future efforts to improve the care of patients with potential malignant neoplasms.

A 67-year-old male with positive signals for neuroendocrine and head/neck cancer on a commercially available multicancer detection test underwent an extensive negative diagnostic workup at a local hospital. Referred to our medical center for advanced imaging and endoscopic procedures ultimately led to the diagnosis of an early-stage seminoma with eventual orchiectomy. This case highlights challenges in evaluating positive multicancer detection results, emphasizing the need for a broader understanding of how to interpret these testing results to fully evaluate complex cases, as well as the need for protocolized follow-up approaches to a positive multicancer detection test.

Background: Angiosarcomas are rare tumors that can be difficult to diagnose due to subtle changes in the vascular endothelium. When there is evidence to suggest malignancy, such as a pathologic fracture, further investigation is needed, and a high suspicion for angiosarcoma needs to be present so that appropriate immunohistochemical stains are utilized on biopsied tissue. In situations where such suspicion is high and prior biopsies have been negative, performance of splenectomy, can be both diagnostic and therapeutic when splenomegaly is present. Case Report: This is a case of a 52-year-old woman with splenomegaly, initially attributed to infection, in the setting of upper respiratory symptoms and thrombocytopenia. Three months later, however, she presented with back pain. Imaging showed lytic bone lesions with pathologic vertebral fracture and numerous liver lesions that were too small to characterize further. Initial biopsies of the liver and bone did not reveal a pathologic process. Several months later, still without a unifying diagnosis, she presented to our institution. MRI of the brain was done for neurologic concerns and showed pathologic enhancement in the calvarium. A PET scan showed diffuse avidity of the skeleton and spleen. After discussing the case with a hematologist, splenectomy was performed for both diagnostic and therapeutic purposes. Angiosarcoma was identified in the spleen and in a PET-directed bone biopsy. With a definitive diagnosis, she returned home and subsequently elected to pursue hospice care. Conclusion: When there is a high clinical suspicion for malignant angiosarcoma, a multidisciplinary approach is necessary to direct both tissue acquisition and necessary histochemical staining.

Background: In addition to the morbidity and mortality associated with acute infection, COVID-19 has been associated with persistent symptoms (>30 days), often referred to as Long COVID (LC). LC symptoms often cluster into phenotypes, resembling conditions such as fibromyalgia, postural orthostatic tachycardiac syndrome (POTS), and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). LC clinics have been established to best address the needs of LC patients and continuity of care. We developed a cross-sectional survey to assess treatment response through our LC Clinic (LCC). Methods: A 25-question survey (1-10 Likert scale) was expert- and content-validated by LCC clinicians, patients, and patient advocates. The survey assessed LC symptoms and the helpfulness of different interventions, including medications and supplements. A total of 852 LCC patients were asked to complete the survey, with 536 (62.9%) responding. Results: The mean time from associated COVID-19 infection to survey completion was 23.2 ± 6.4 months. The mean age of responders was 52.3 ± 14.1 (63% females). Self-reported symptoms were all significantly improved ( P < .001) from the initial visit to the LCC (baseline) to the time of the follow-up survey. However, only 4.5% (24/536) of patients rated all symptoms low (1-2) at the time of the survey, indicating low levels of full recovery in our cohort. The patients rated numerous interventions as being helpful, including low-dose naltrexone (45/77; 58%), vagal nerve stimulation (18/34; 53%), and fisetin (28/44; 64%). Conclusions: Patients report general improvements in symptoms following the initial LCC visit, but complete recovery rates remain low at 23.2 ± 6.4 months.

Background: Over 30% of patients with COVID-19 have persistent symptoms that last beyond 30 days and referred to as Long COVID. Long COVID has been associated with a persistent elevation in peripheral cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α. This study reports cytokine profiles of patients in our clinic across SARS-COV-2 variant epochs. Methods: The clinical cytokine panel was analyzed in patients with Long COVID during periods that were stratified according to variant epoch. The 4 variant epochs were defined as: (1) wild-type through alpha, (2) alpha/beta/gamma, (3) delta, and (4) omicron variants. Results: A total of 390 patients had the clinical cytokine panel performed; the median age was 48 years (IQR 38-59) and 62% were female. Distribution by variant was wild-type and alpha, 50% (n = 196); alpha/beta/gamma, 7.9% (n = 31); delta, 18% (n = 72); and omicron, 23% (n = 91). Time to cytokine panel testing was significantly longer for the earlier epochs. Tumor necrosis factor-α ( P < .001) and interleukin 1β ( P < .001) were significantly more elevated in the earlier epochs (median of 558 days in wild-type through Alpha epoch vs 263 days in omicron epoch, P < .001)). Nucleocapsid antibodies were consistently detected across epochs. Discussion: When stratified by variant epoch, patients with early epoch Long COVID had persistently elevated peripheral pro-inflammatory cytokine levels when compared to later epoch Long COVID. Patients with Long COVID have similar clusters of symptoms across epochs, suggesting that the underlying pathology is independent of the peripheral cytokine signature.