Citations

Abstract Background: Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated significant clinical efficacy in hematologic malignancies, but have proven challenging in solid tumors, in part owing to a lack of tumor-specific targets and unmanageable toxicity. Mesothelin (MSLN) expression normally is limited to the mesothelium of major body cavities but can be upregulated in diverse solid tumor types (cancer.gov/tcga), making it a potential target for cancer therapy. MSLN-targeted cell therapy approaches, including CAR T and T-cell receptor fusion therapies, have shown promising clinical activity; however, on-target, off-tumor toxicity including fatal events have occurred (Beatty, et al. Gastroenterology. 2018.; Haas, et al. Mol Ther. 2023.; Hong, et al. ESMO 2021. Abstract 9590.). A2B694 is an autologous logic-gated, MSLN-targeted Tmod CAR T therapy that addresses the challenges of on-target, off-tumor toxicity by combining 2 CARs: an activating and blocking receptor. The activator recognizes MSLN present on the surface of both tumor and normal cells; the blocker inhibits the CAR T activator when it binds human leukocyte antigen (HLA)-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 loss of heterozygosity (LOH), the blocker prevents on-target, off-tumor toxicity on normal cells owing to retained HLA-A*02 expression (Hamburger, et al. Mol Immunol. 2020). Through this unique selective mechanism, A2B694 may provide a therapeutic window to treat patients with MSLN-expressing solid tumors exhibiting HLA-A*02 LOH. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 in adults with recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including non-small cell lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, mesothelioma, or other solid tumors with MSLN expression. Eligible patients must have progressed following standard of care therapy. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), which identifies patients with tumor-associated HLA-A*02 LOH via next-generation sequencing (Tempus AI, Inc). Eligible patients enroll in the BASECAMP-1 study and undergo leukapheresis. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess overall response rate per RECIST v1.1. The first patient was enrolled on EVEREST-2 in April 2024. Dose escalation is ongoing. Citation Format: Julian R. Molina, Antonious Hazim, Oliver Dorigo, Salman R. Punekar, Monica Avila, Diane M. Simeone, Kedar Kirtane, Gottfried E. Konecny, Jeffrey Ward, Matthew Block, Jennifer Specht, Leslie Boyd, Yanyan Lou, Jong Chul Park, Jacqueline D. Xuan, Ramez N. Eskander, Gayanie Ong, Marco Davila, Wendy Langeberg, Marcela Maus, Armen Mardiros, Frederick L. Locke, Andrea Wise, David G. Maloney, John Welch, J. Randolph Hecht. EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod CAR T-cell therapy, in patients with mesothelin-expressing solid tumors with human leukocyte antigen-A*02 loss of heterozygosity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT186.

Abstract Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by the presence of left ventricular dilatation and systolic dysfunction unexplained by abnormal loading conditions or coronary artery disease. However, a broad range of phenotypic manifestations, encompassing isolated scar, DCM with preserved ejection fraction, and overt DCM, should be regarded as a diagnostic classification representing a broad spectrum of underlying aetiologies, including both inherited and acquired heart muscle disorders. A multimodal non-invasive imaging approach is essential for accurate morpho-functional assessment of cardiac chambers and is key to establish the cardiac phenotype and to rule out an underlying ischaemic aetiology. Furthermore, advanced imaging techniques enable deep cardiovascular phenotyping and non-invasive tissue characterization. The aim of this review is to propose a systematic approach to the diagnosis of DCM, emphasizing the importance of genetics and clinical findings for a precise and practical clinical approach. Also, we strive to qualify the role of cardiac imaging in the diagnosis of DCM, particularly on the relevance of novel techniques and clinical utility of actionable parameters to improve current diagnostic schemes and risk stratification algorithms. We further elaborate on the role of cardiac imaging to deliver optimal guidance to aetiology-based therapeutic approaches, verification of treatment response and disease progression monitoring.

Abstract Context Pituitary adenomas and cysts are rare in pediatric patients and improved understanding can guide management recommendations. Objective To report incidence, presentation, management, and outcomes in a pediatric population-based cohort with pituitary adenomas and cysts, and to explore the relationship between these lesions and brain magnetic resonance imaging (MRI) rates, as well as lesion size and headaches with disease progression. Methods In this retrospective cohort study of pediatric patients (≤18 years) with incident pituitary adenomas and cysts in Olmsted County, MN, from 1976 to 2021, 234 unique patients were identified using diagnostic codes through the Rochester Epidemiology Project, with 37 confirmed cases of pituitary adenoma or cyst included. Incidence rates were calculated using census data. Descriptive statistics were used for extracted clinical data. Results Incidence of pediatric adenomas and cysts was 2.29 cases per 100 000 person-years. Of the 37 cases, 68% were nonfunctioning adenomas or cysts, 27% were prolactinomas, and there was 1 each of growth hormone (GH)– and thyrotropin (TSH)-secreting adenomas. Median lesion diameter was 5.5 mm (IQR, 4.0-8.0). Median follow-up was 7.4 years (IQR, 4.5-15.4). Four patients had disease progression which stabilized with second-line therapy. Brain MRI rates did not correlate with lesion incidence. No clinically meaningful relationship was found between lesion size or headache and disease progression. Conclusion Pituitary adenomas and cysts are rare in pediatric patients. Most are small, nonfunctioning, and stable on long-term follow-up. Larger studies on small nonfunctioning pituitary lesions are needed to enhance understanding of their natural history and develop long-term management recommendations.

Abstract Reconstruction of clival defects may be challenging in expanded endonasal skull base surgery. We conducted a systematic review to evaluate the outcomes of vascularized flaps used for clival reconstruction. The following databases were searched using a combination of Medical Subject Headings (MeSH) and keywords related to clival reconstruction in July 2024: Ovid Medline, Ovid Embase, Scopus, and Web of Science. Studies reporting outcomes of clival reconstruction with vascularized free and pedicled flaps in patients were selected for complete review. Twenty-three studies were included for detailed study. Clival reconstruction with free flaps was done in 18 patients; 17 had a successful repair, outcome was not reported for 1. Facial vessels were preferred for microvascular anastomosis. Radial artery forearm flap and anterolateral thigh flap were most utilized. Pedicled flaps were used in 68 patients, with reported success in 85.3%. Nasoseptal flap was the most common intranasal flap, used in 34 patients with successful reconstruction in 85.3%. Temporoparietal fascia flap was the most common extranasal flap, successfully used in 13 patients. Intranasal pedicled flaps, wherever available, were preferably used for primary reconstruction; extranasal flaps were the next choice. Free flaps were reserved for salvage reconstruction due to prior failed or unavailable local pedicled flaps. Satisfactory reconstructive outcomes are reported using pedicled and free flaps. The flap of choice is determined by the previous surgical history, radiotherapy, wound vascularity, defect size, overall health of the surrounding nasal mucosa, simultaneous clival surgery, and the preferred pedicle transposition route (free flaps).

ImportanceUnderstanding the global barriers to otolaryngology–head and neck surgery (OHNS) care is crucial in addressing disparities in access to care, particularly in low-income and middle-income countries (LMICs).ObjectiveTo characterize barriers to comprehensive otolaryngology care across World Bank income groups.Design, Setting, and ParticipantsUsing an online cross-sectional survey that was administered by the Global OHNS Initiative via international and national professional societies, personal contacts, and social media, this study captured the perceptions of otolaryngologists regarding barriers to OHNS care at the levels of the country, health sector, clinician, and patient. Participants included otolaryngologists from the 194 World Health Organization member states and Taiwan. Eligibility criteria included a medical degree and specialized training in managing conditions of the ear, nose, and throat. The nonresponse rate was not recorded. The data collection period spanned from October 2022 to June 2023.ExposuresExposures included World Bank income group classification.Main Outcomes and MeasuresThe primary outcomes were Likert scale responses regarding frequency of barriers to OHNS care. The a priori hypothesis was that LMICs would report more frequent barriers to OHNS care.ResultsThe study involved 146 otolaryngologists (47 female individuals [32%]), with 69 (47%) from high-income countries and 77 (53%) from LMICs. Male individuals represented 45 high-income country respondents (65%) and 54 LMIC respondents (70%). Barriers were reported across income groups at all levels of the health system, with a higher frequency in LMICs. Several barriers were reported to be more substantial in LMICs, such as the national volume and distribution of otolaryngologists, financial compensation for clinicians, and patient stigma, and others were common across income settings, such as the availability of operating rooms and inflexible working hours. Common concerns included national and health sector barriers: OHNS workforce, referral networks, government support; clinician barriers: excessive clinician workloads, understaffing, poor administration support; patient barriers: distance to health care facilities, financial burdens such as medical costs and foregone wages, stigma, and health literacy.Conclusions and RelevanceThe results of this cross-sectional study suggest that there are barriers to otolaryngology care globally that affected all levels of the health care system. This work may inform prioritization of otolaryngology within research and policy, and it emphasizes the need for effective strategies to expand access to otolaryngology care, particularly in lower-income settings.

Abstract Brain responses to sensory stimuli depend on the specific task performed by the observer. Previously, fMRI measurements in ventral temporal cortex (VTC) showed that BOLD responses to visual input scale with task demands. This scaling of BOLD responses is thought to be driven by the engagement of cognitive functions required for the task. To better understand how these cognitive task demands influence neural activity in VTC, we measured electrocorticography (ECoG) responses to images of varying contrast in two human participants during either a fixation or image categorization task. ECoG high frequency broadband activity (>70 Hz) showed that local neuronal responses increased with image contrast as expected for sensory encoding, and were scaled by task demands approximately 200 ms after stimulus onset. In contrast, ECoG low frequency activity in the alpha/beta range (8-28 Hz) was insensitive to image contrast and showed larger decreases with increasing task demands. These results indicate that high frequencies in VTC reflect both the encoding of sensory inputs and task demands, similar to prior BOLD response measurements, whereas low frequency oscillations represent task demands, not sensory inputs per se. In line with the interpretation that low frequency oscillations reflect pulsed inhibition, we speculate that a power decrease in low frequency oscillations amplifies neural activity in VTC in support of visual task demands.

Background: Although it is well established that the type of organism can be a risk factor for failure in patients with periprosthetic joint infection (PJI), no study to date has examined the impact of the number of positive cultures on treatment outcomes in patients undergoing 2-stage exchange. The purpose of this multicenter study was to determine the prognostic utility of multiple positive cultures at resection as a predictor of failure following reimplantation. Methods: This retrospective multicenter study identified 437 patients with chronic knee PJI who had undergone 2-stage exchange arthroplasty with a minimum of 1 year of follow-up following reimplantation. PJI was defined with use of the 2013 Musculoskeletal Infection Society (MSIS) criteria. Patients with culture-negative PJI were excluded (n = 138). Treatment failure was defined as either any reoperation for infection or PJI-related mortality. Multivariable regression controlling for risk factors for failure after a 2-stage arthroplasty was performed to determine whether ≥2 positive intraoperative cultures at resection can predict outcomes following reimplantation when compared with a single positive culture. Results: Two hundred and ninety-nine patients were included. At a mean follow-up of 6.2 ± 2.6 years, 48 patients (16.1%) experienced failure. Patients who had a failure were more likely to have had a longer interstage interval (p = 0.038) and were also more likely to have had ≥2 positive cultures at the time of resection arthroplasty (95.8% versus 75.3%; p = 0.001). On regression analysis, ≥2 positive cultures at resection was the only variable that was identified as a risk factor for failure following reimplantation in both the univariate (odds ratio [OR], 7.55 [95% CI, 2.24 to 47.0]; p = 0.006) and multivariable models (OR, 8.12 [95% CI, 2.31 to 51.9]; p = 0.005). Conclusions: This is the first study to examine the impact of the number of positive cultures on outcomes in patients with PJI. We found that the presence of ≥2 positive cultures at resection was an indicator of a poor prognosis and resulted in a greater than eightfold increase in the risk of treatment failure in patients undergoing a 2-stage exchange. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Bicuspid aortic valve (BAV) and thoracic aortic aneurysms and dissections (TAAD) are recognized in syndromic connective tissue diseases (CTD), but most cases occur sporadically. The extent to which non-syndromic BAV or TAAD predisposes to additional arteriopathies, particularly in younger individuals, remains unclear. We retrospectively analyzed 1438 patients (mean age = 48.0, 67.7% female), excluding those with CTDs. Participants were ≤60 years old and categorized by the presence of BAV and/or TAAD. We examined co-existing arterial pathologies, including fibromuscular dysplasia, spontaneous coronary artery dissection, abdominal aortic aneurysms (AAA), mesenteric, peripheral extremity, and carotid/cerebral arteriopathies. Overall, 44.6% had either BAV or TAAD, and 27.2% had multiple arteriopathies. While vascular diseases were frequently noted, odds ratios demonstrated no significantly increased risk of extra-aortic arteriopathies in the BAV or TAAD cohorts. AAA exhibited a non-significant trend toward higher prevalence in TAAD patients. These findings support current guidelines recommending targeted imaging (transthoracic echocardiography of the aortic root and ascending aorta) over comprehensive “head-to-pelvis” screening for non-syndromic BAV or TAAD patients without additional risk factors. Ongoing genetic analyses may elucidate whether particular variants predispose to multi-site aneurysms or dissections. Consequently, targeted surveillance remains appropriate, with broader imaging reserved for patients with genetic or clinical indicators of higher risk.

Abstract Death from myocarditis due to Lyme disease is uncommon but may be under-recognized. Myocarditis can lead to sudden and/or unexpected death due to fatal cardiac arrhythmias, which may be misattributed to more common causes, such as coronary artery disease. We report an unexpected death in a 69-year-old man from a Lyme-endemic area who had multiple cardiovascular risk factors. His death was initially attributed to coronary artery disease by the local coroner's office but was later confirmed to be due to Lyme disease, based on positive serological testing, characteristic cardiac histopathology findings, and the detection of Borrelia burgdorferi spirochetes, antigens, and DNA in the heart using various methods. Forensic pathologists should maintain a high suspicion of Lyme carditis, particularly in cases of sudden/unexpected death in Lyme-endemic areas. A history of rash or recent insect bites should prompt serologic testing for Lyme disease.

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=−10.76: −26.51; 5.00 vs. SOC=−4.99: −21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (−27.94±41.80) versus SOC (−16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.