Citations

TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. 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 the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .

Abstract Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer’s disease (AD), particularly in individuals carrying the APOE-ε4 allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (Aβ42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in APOE-ε4 carriers. Furthermore, we found a loss-of-function variant in the fibronectin 1 ( FN1 ) gene significantly reduces aggregated fibronectin levels and decreases AD risk among APOE-ε4 carriers. Yet, the molecular mechanisms downstream of fibronectin at the BBB remain unclear. The extracellular matrix (ECM) plays a crucial role in maintaining BBB homeostasis and orchestrating the interactions between BBB cell types, including endothelia and astrocytes. Understanding the mechanisms affecting the ECM and BBB cell types will be critical for developing effective therapies against AD, especially among APOE-ε4 carriers. Here, we demonstrate that APOE-ε4 , Aβ42, and inflammation drive the induction of FN1 expression in several models including zebrafish, mice, iPSC-derived human 3D astrocyte and 3D cerebrovascular cell cultures, and in human brains. Fibronectin accumulation disrupts astroglial-endothelial interactions and the signalling cascade between vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor (HBEGF) and Insulin-like growth factor 1 (IGF1). This accumulation of fibronectin in APOE-ε4- associated AD potentiates BBB dysfunction, which strongly implicates reducing fibronectin deposition as a potential therapeutic target for AD. Graphical abstract Accessibility text This image illustrates the effects of different APOE isoforms (ApoE-ε3 and ApoE-ε4) on blood-brain barrier (BBB) integrity, focusing on the molecular interactions between astrocytes and endothelial cells. This figure emphasizes the detrimental effects of ApoE-ε4 on BBB integrity via fibronectin accumulation and altered signaling pathways. The top section provides a schematic overview of the blood-brain barrier, highlighting astrocytes, endothelial cells, and their interface. The left panel represents the ApoE-ε3 condition: Normal fibronectin (FN1) levels support healthy interactions between astrocytes and endothelial cells. Growth factors, including VEGFA, HBEGF, and IGF1, maintain BBB integrity through their respective receptors (VEGFR and EGFR). Green arrows indicate activation of these signaling pathways. The right panel depicts the ApoE-ε4 condition: Elevated fibronectin (FN1) disrupts astrocyte-endothelium interactions. FN1 binds integrins and activates focal adhesion kinase (FAK), inhibiting VEGFA, which is required for endothelial HBEGF that in turn activates IGF1 signaling. Red symbols indicate inhibition of HBEGF, VEGFA, and IGF1 pathways, leading to BBB dysfunction. Highlights APOE-ε4 drives fibronectin deposition in Alzheimer’s, disrupting astrocyte-endothelia interactions. APOE-ε4 and fibronectin co-localize, forming aggregates at blood-brain barrier (BBB). Fibronectin alters the signaling between VEGF, IGF1, and HBEGF impairing BBB function. Reducing fibronectin restores BBB integrity and offsets APOE-ε4 pathology.

Abstract Background We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn’s disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content. Methods Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested. Results Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = −0.39 [95% confidence interval {CI}: −0.61, −0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P < .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = −.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = −.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13). Conclusions Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.

Background Current randomized controlled trials are investigating the efficacy and safety of mechanical thrombectomy (MT) in patients with medium vessel occlusion (MeVO) stroke. Whether best medical management (MM) is more efficient than unsuccessful vessel recanalization during MT remains unknown. Methods This was a retrospective cohort study using data from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. Only patients with occlusion of the distal branches (M2 and M3) of the middle cerebral artery territory were included. Unsuccessful MT was defined as a modified Thrombolysis in Cerebral Infarction score of 0–2a. Propensity score matching was used to control for confounders. The primary outcome was functional independence, defined as a modified Rankin Scale (mRS) score of 0–2 at 90 days after treatment. Multivariable regression analysis was used to assess factors associated with the primary outcome. Results Of 2903 patients screened for eligibility, 532 patients were analyzed (266 per group) after propensity score matching. The MM group had superior functional outcomes, with 32% achieving mRS 0–1 at 90 days compared with 21% in the MT group (P=0.011). Patients in the MM group also had significantly lower rates of symptomatic intracranial hemorrhage (sICH) (3.4% vs 16%, P<0.001) and any hemorrhage (18% vs 48%, P<0.001). On multivariable regression, unsuccessful MT was associated with reduced odds of functional independence (OR 0.50, 95% CI 0.29 to 0.85, P=0.011) and increased odds of sICH (OR 4.32, 95% CI 1.84 to 10.10, P<0.001). Mortality rates were similar between groups (27% in MM vs 29% in MT, P=0.73). Conclusion Unsuccessful MT for MeVO was linked to worse outcomes than best MM. These findings highlight the risks of prolonged attempts and emphasize the importance of efficient procedural decision-making to reduce complications and improve patient outcomes.

Background: Historically, the standard of care for advanced biliary tract cancers (aBTCs) was gemcitabine plus cisplatin (GemCis). Immunotherapy plus GemCis is now recommended as a first-line treatment for aBTCs. Whether patients can tolerate eight cycles of GemCis in clinical practice, as per the Advanced Biliary Cancer (ABC)-02 study, remains to be assessed. We performed a retrospective observational cohort study to assess real-world treatment patterns and overall survival (OS) in patients with de novo or recurrent aBTCs treated with first-line gemcitabine-based chemotherapy in the United States. Methods: This retrospective observational cohort study used Optum’s de-identified Market Clarity Data (Market Clarity). Adults diagnosed with de novo or recurrent aBTCs in the United States who began first-line gemcitabine-based chemotherapy from January 2016–March 2022 were identified and followed from index until death, the end of continuous enrolment, or the end of study period. Treatment patterns and OS were assessed. Results: Overall, 559 patients were included (de novo, n = 462; recurrent, n = 97). GemCis was the most common first-line therapy received (de novo: 73.8%; recurrent: 57.7%). Most patients received approximately five cycles of GemCis; median (95% CI) time to discontinuation was 4.6 (4.3–5.1) months. Most patients died over the follow-up period (de novo: 70.3%; recurrent: 62.9%). Median OS (95% CI) was 14.2 (12.1–16.1) months (de novo) and 18.5 (15.6–26.9) months (recurrent). Conclusions: GemCis was the most common first-line therapy received during the study period; most patients were unable to receive eight cycles of GemCis. Survival was limited over the follow-up period, highlighting the need for new treatments for aBTCs. Future studies are warranted to understand the real-world impact of first-line immunotherapy plus GemCis for patients with aBTCs.

Cases: Two patients with spontaneous loss of thumb interphalangeal joint extension were referred after history, electrodiagnostic, and/or magnetic resonance imaging (MRI) findings were felt to demonstrate a posterior interosseous nerve (PIN) palsy. Subsequent physical examination and additional directed studies suggested an alternative explanation: rupture of the extensor pollicis longus (EPL) tendon, subsequently confirmed at surgery. An extensor indicis proprius to EPL transfer restored thumb function. Conclusion: Electrodiagnostic and MRI changes consistent with diffuse PIN palsy may occur in the setting of EPL rupture. An accurate diagnosis of EPL dysfunction requires careful physical examination and confirmatory imaging. Further study of this previously unreported phenomenon is required.

Modulating immune function is a critical strategy in cancer and atherosclerosis treatments. For cancer, boosting or maintaining the immune system is crucial to prevent tumor growth. However, in vascular disease, mitigating immune responses can decrease inflammation and slow atherosclerosis progression. Anti-inflammatory therapy, therefore, presents a unique dilemma for cancer survivors: while it may decrease cardiovascular risk, it might also promote cancer growth and metastasis by suppressing the immune response. Senescence presents a potentially targetable solution to this challenge; senescence increases the risk of both cancer therapy resistance and vascular disease. Exercise, notably, shows promise in delaying this premature senescence, potentially improving cancer outcomes and lowering vascular disease risk post-treatment. This review focuses on the long-term impact of cancer therapies on vascular health. We underscore the importance of modulating senescence to balance cancer treatment’s effectiveness and its vascular impact, and we emphasize investigating the role of exercise-mediated suppression of senescence in improving cancer survivorship.

Importance The emergency department (ED) offers an opportunity to initiate palliative care for older adults with serious, life-limiting illness. Objective To assess the effect of a multicomponent intervention to initiate palliative care in the ED on hospital admission, subsequent health care use, and survival in older adults with serious, life-limiting illness. Design, Setting, and Participants Cluster randomized, stepped-wedge, clinical trial including patients aged 66 years or older who visited 1 of 29 EDs across the US between May 1, 2018, and December 31, 2022, had 12 months of prior Medicare enrollment, and a Gagne comorbidity score greater than 6, representing a risk of short-term mortality greater than 30%. Nursing home patients were excluded. Intervention A multicomponent intervention (the Primary Palliative Care for Emergency Medicine intervention) included (1) evidence-based multidisciplinary education; (2) simulation-based workshops on serious illness communication; (3) clinical decision support; and (4) audit and feedback for ED clinical staff. Main Outcome and Measures The primary outcome was hospital admission. The secondary outcomes included subsequent health care use and survival at 6 months. Results There were 98 922 initial ED visits during the study period (median age, 77 years [IQR, 71-84 years]; 50% were female; 13% were Black and 78% were White; and the median Gagne comorbidity score was 8 [IQR, 7-10]). The rate of hospital admission was 64.4% during the preintervention period vs 61.3% during the postintervention period (absolute difference, −3.1% [95% CI, −3.7% to −2.5%]; adjusted odds ratio [OR], 1.03 [95% CI, 0.93 to 1.14]). There was no difference in the secondary outcomes before vs after the intervention. The rate of admission to an intensive care unit was 7.8% during the preintervention period vs 6.7% during the postintervention period (adjusted OR, 0.98 [95% CI, 0.83 to 1.15]). The rate of at least 1 revisit to the ED was 34.2% during the preintervention period vs 32.2% during the postintervention period (adjusted OR, 1.00 [95% CI, 0.91 to 1.09]). The rate of hospice use was 17.7% during the preintervention period vs 17.2% during the postintervention period (adjusted OR, 1.04 [95% CI, 0.93 to 1.16]). The rate of home health use was 42.0% during the preintervention period vs 38.1% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of at least 1 hospital readmission was 41.0% during the preintervention period vs 36.6% during the postintervention period (adjusted OR, 1.01 [95% CI, 0.92 to 1.10]). The rate of death was 28.1% during the preintervention period vs 28.7% during the postintervention period (adjusted OR, 1.07 [95% CI, 0.98 to 1.18]). Conclusions and Relevance This multicomponent intervention to initiate palliative care in the ED did not have an effect on hospital admission, subsequent health care use, or short-term mortality in older adults with serious, life-limiting illness. Trial Registration ClinicalTrials.gov Identifier: NCT03424109