Citations

Abstract Rationale Amikacin liposome inhalation suspension (ALIS), as part of a combination antibacterial regimen, is currently the only FDA-approved treatment for patients with refractory Mycobacterium avium complex lung disease (rMACLD). MAC is the most common cause of nontuberculous mycobacterial lung disease (NTMLD). A real-world evidence study demonstrated significant decreases in hospitalizations from baseline over a 12-month follow-up period following ALIS initiation; however, study conclusions were limited by the absence of a comparator arm. In this study, we compared healthcare resource utilization in US patients who initiated ALIS versus non-ALIS antibiotic treatment for possible rMACLD. Methods This was a retrospective claims analysis using the Merative™ MarketScan® databases between 2016 and 2021. As no diagnosis codes for MACLD exist in claims, we defined 2 cohorts of patients receiving treatment for possible rMACLD as follows: 1) patients who initiated ≥28 days of continuous treatment with ALIS; and 2) patients who initiated ≥28 days of continuous treatment with ≥1 non-ALIS antibiotic used to treat rMACLD (i.e., parenteral aminoglycoside, clofazimine, fluoroquinolones, linezolid, tedizolid, or bedaquiline) ≥6 months after initiating treatment used for MACLD (i.e., with a combination of ≥2 antibiotics from a macrolide, ethambutol, and a rifamycin). The date of initiating treatment with ALIS or non-ALIS antibiotic for rMACLD was referred to as the index date. Other inclusion criteria: ≥1 diagnosis code for NTMLD anytime pre-index, ≥6 months continuous eligibility pre-index, and ≥12 months continuous eligibility post-index. Hospitalizations (all-cause, respiratory-related, NTMLD-related) and emergency room (ER) visits at 0-6 and 7-12 month post-index periods were compared with baseline (6 month pre-index period) per treatment arm. Results A total of 116 patients comprised the ALIS cohort and 63 patients the non-ALIS cohort. In the ALIS cohort, statistically significant reductions from baseline in all-cause, respiratory-related, and NTMLD-related hospitalizations were observed during the 7-12 month post-index period (Table). In contrast, the non-ALIS cohort did not show significant reductions from baseline in hospitalizations at follow-up. No statistically significant changes from baseline in ER visits were observed in either group. Conclusions Patients treated with ALIS for rMACLD had statistically significant reductions in hospitalizations from baseline during the 7-12 month post-index period, whereas no statistically significant improvements in hospitalizations were observed in the non-ALIS antibiotics group.

Importance Many older adults with advanced cancer never communicate goals of care or treatment preferences to their clinicians, raising the risk that care received will not match their values. Scalable models of care may help surmount this barrier. Objective To test whether a combined patient and clinician intervention increased the rate of advance care planning (ACP) documentation in large health care systems. Design, Setting, and Participants This stepped-wedge cluster randomized clinical trial using an open cohort design included patients aged 65 years or older with advanced cancer seen at oncology clinics in 3 health care systems located in the US South, Midwest, and Mid-Atlantic regions from April 1, 2020, to November 30, 2022. Data collection ended in 2024. Intervention The intervention involved delivering brief evidence-based patient-facing video decision aids available in 25 languages as well as goals-of-care communication training to oncology clinicians. Patients in the control period received usual care. Main Outcomes and Measures The primary outcome was ACP documentation, which included any electronic health record documentation of a goals-of-care conversation, palliative care, hospice, or limitation of life-sustaining treatments, identified via a validated natural language processing program. Analysis was performed on an intention-to-treat basis. Results Twenty-nine practices, comprising 13 800 unique eligible patients with a total of 29 357 repeated measurements, were included (mean [SD] age, 74.5 [6.6] years; 52.3% men [15 344 of 29 357 measurements]). The proportion of patients with ACP documentation was greater in the intervention phase compared with the usual care phase (adjusted rate difference, 6.8% [95% CI, 2.8%-10.8%]; P < .001). ACP documentation in the intervention phase occurred among 3980 of 15 754 patients (25.3%) (goals-of-care conversation, 21.4% [3377 of 15 754]; palliative care, 9.6% [1517 of 15 754]; hospice, 5.4% [847 of 15 754]; and limitation of life-sustaining treatments, 7.2% [1128 of 15 754]). In comparison, ACP documentation in the usual care phase occurred among 2834 of 13 603 patients (20.8%) (goals-of-care conversation, 16.8% [2281 of 13 603]; palliative care, 9.5% [1287 of 13 603]; hospice, 5.3% [724 of 13 603]; and limitation of life-sustaining treatments, 8.4% [1149 of 13 603]). Conclusions and Relevance In this stepped-wedge cluster randomized clinical trial for older adults with advanced cancer, a bundled evidence-based decision aid and communication training intervention increased the proportion of older patients with ACP documentation. This approach offers an innovative paradigm with a clinically meaningful increase in ACP documentation, a widely used quality metric that reflects high-quality patient-centered care delivery. Trial Registration ClinicalTrials.gov Identifier: NCT03609177

Abstract Background Percutaneous ablation of parathyroid adenomas provides a minimally invasive treatment option for primary hyperparathyroidism. However, the overall performance of this technique remains underexplored. This meta-analysis evaluates the effectiveness and safety of various ablation techniques for parathyroid adenomas. Methods Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, multiple databases, including Ovid MEDLINE and Cochrane, were systematically searched. Studies that provided separate data for radiofrequency (RF), microwave ablation (MWA), and ethanol ablation technique were included. Outcomes of interest were changes in serum calcium, PTH, and phosphorus levels, along with normocalcemia rates at 6 to 12 months after ablation. Safety outcomes included transient hoarseness, permanent hoarseness, severe hemorrhage, major complications, and severe hypocalcemia. Data were pooled using a random-effects model, with pooled prevalence and 95% CIs calculated. Also, the publication bias was assessed with Egger's test for each outcome measure. Results Twenty studies (815 patients) were included. The posttreatment normocalcemia rate at 6 to 12 months was 85.6% (95% CI, 80.48-90.72). Serum PTH and calcium levels significantly decreased, with mean differences of 101.49 pg/mL (95% CI, 73.50-129.48) and 0.39 mmol/L (95% CI, 0.34-.45), respectively. Permanent hoarseness and major complications were rare, with incidences of 0.28% (95% CI, 0.00-1.05) and 0.31% (95% CI, 0.00-1.09). The safety and efficacy outcomes of RF, MWA, and ethanol ablation were comparable. Conclusion Our findings indicate that percutaneous ablation of parathyroid adenomas is safe and effective within the first year of the treatment. Additionally, they suggest that RF, MWA, and ethanol ablation techniques can each be employed depending on patients' needs without particular limitations.

Engaging employees in providing exemplary patient experience has been challenging for healthcare leaders in recent years given the pressures of the regulatory environment, increases in staff burnout and rising patient expectations. Amid these challenges, addressing patient experience remains a top priority for healthcare organizations. A novel intervention has been applied at Mayo Clinic with the goal of improving both employee engagement and patient experience. Previous efforts to teach service excellence involved customer service trainings, sometimes purchased through outside vendors. This new initiative is based on our organizational culture and values, input from our employees and patients, and considers the changing needs of a contemporary healthcare workforce. It leverages management practices shown to boost an employee's sense of equity, achievement, and camaraderie. It also highlights staff motivation to do their best work by involving them in conversations about the essential ingredients that make up both exceptional employee and patient experiences.

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 Breast cancer (BC) is the most common cancer diagnosed in American women. The majority of breast cancers express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2). However, 15-20% lack expression of all three and are called triple-negative breast cancer (TNBC). TNBC accounts for a disproportionately large amount of morbidity and mortality due to its aggressive nature and the paucity of effective adjuvant maintenance therapy, driving an urgent need for novel therapeutics. Z-endoxifen (ENDX) is a potent tamoxifen metabolite that dually targets ERα and protein kinase C beta I (PKCβI). We recently described next-generation molecules, the first-in-class endoxifen-PROTAC (ENDX-PROTAC) compounds which incorporate ENDX as the warhead and cereblon (CRBN) as the E3 ubiquitin ligase recruitment moiety (Jayaraman 2024, SABCS). We used the PRISM screen of over 900 cancer cell lines to determine that ENDX-PROTACs have broad antitumor activity in both TNBC and ER+ breast cancer in addition to, leukemia, pancreatic, lymphoma, lung, melanoma, and ovarian cancer cells, among others. ENDX-PROTACs primarily target a key translation termination factor, G to S phase transition 1 (GSPT1). Here, we demonstrate for the first time that these compounds also cause marked DNA damage. The lead compounds of this series, EPrC-007 and EPrC-009 demonstrated potent anti-proliferative effects in MDA-MB-231, BT549, and MDA-MB-436 TNBC cell lines. EPrC-007 induced substantial DNA double strand breaks in MDA-MB-231 cells as assessed by γ-H2AX Western blotting. Interrogation of DNA repair pathways revealed activation of ATM/CHK2 and downregulation of ATR/CHK1, suggesting inhibition of DNA repair as a potential mechanism. Additionally, EPrC-007 also induced γ-H2AX foci in MDA-MB-231 and BT549 cells, but not in the MCF10A normal breast tissue cell line, suggesting selective anti-tumor activity. Since we suspect that EPrC-007 blocks DNA repair machinery, we next sought to determine if these molecules would synergize with DNA damaging agents or other DNA repair inhibitors. Promisingly, EPrC-007 demonstrated remarkable synergy with olaparib (poly-(ADP-ribose) polymerase (PARP) inhibitor), hydroxyurea (ribonucleotide reductase inhibitor), and cisplatin (direct DNA damaging agent), but not camptothecin (topoisomerase I inhibitor). Importantly, only olaparib co-treatment demonstrated synergy in the PARP- and PROTAC-resistant HCC1143 TNBC cell line. Furthermore, the combination of EPrC-007 with olaparib induced markedly more γ-H2AX foci than either agent alone, confirming synergy at the DNA damage level. Taken together, our studies demonstrate the remarkable potential of ENDX-PROTACs in the single-agent setting as well as in combination with PARP inhibitors. Citation Format: Aamod S. Dekhne, Swaathi Jayaraman, Lucy Rai Thulung, Becky Bruinsma, Baustin M. Welch, Samuel Wyatt, Esther P. Rodman, Sayantani Bhattacharya, Thomas R. Caulfield, John R. Hawse, Matthew J. Schellenberg, Matthew P. Goetz. Novel endoxifen-based proteolysis targeting chimera (PROTAC) small molecules synergize with olaparib and exhibit potent antitumor activity in triple negative breast cancer through induction of DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1666.

In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.

Abstract Background The COVID-19 pandemic has underscored challenges with patient adherence to medical directives, particularly vaccine acceptance. While sociodemographic factors have been linked to non-COVID-19 vaccine hesitancy, the relationships between patient experience, the COVID-19 pandemic, and adherence to routine vaccinations are uncertain.Figure 1:Yearly influenza vaccine refusal, influenza vaccine administrations, and overall patient satisfaction since establishing care with a primary care provider from 2017-2023.Panel A (Influenza Refusals): the number of vaccine refusals among individuals who are Intermittently Vaccinated and Never Vaccinated for seasonal influenza since establishing care with a primary care provider over time.Panel B (Influenza Vaccinations): the number of vaccines administered over time since establishing care with a primary care provider among those who are Always Vaccinated and Intermittently Vaccinated for seasonal influenza.Panel C (Overall Satisfaction): the number of patients who indicated that they were maximally satisfied with their overall care following any interaction with the healthcare system over time. Methods We retrospectively analyzed influenza vaccination records of adult primary care patients in Olmsted County, Minnesota. Vaccination history was examined during two phases: Pre-Pandemic (1/1/2017—2/28/2020) and Pandemic-Plus (3/1/2020—12/31/2023). Vaccination status was defined as “always vaccinated” (AV), “never vaccinated” (NV), or “intermittently missed years of vaccinations” (IV) for seasonal influenza. Patient dissatisfaction was determined if patients negatively ranked their overall quality of care on standard patient experience surveys. We explored the relationship between influenza vaccination rates, healthcare engagement, and patient satisfaction.Figure 2:Multinomial logistic regression of patient satisfaction on vaccination status across the phases of the COVID-19 Pandemic, adjusted for engagement in the health care system, participation, and area of deprivation index (ADI) for patients that were (A) intermittently vaccinated compared to always vaccinated and (B) never vaccinated comparted to always vaccinated. The “Pre-pandemic phase” refers to influenza immunization data and patient satisfaction data prior to March 2020. The “Pandemic-plus phase” refers to immunization data and patient satisfaction data from March 2020 to January 2024. Low ADI ranking refers to areas with a low level of deprivation, whereas high ADI ranking refers to areas with a high level of deprivation. Individuals were considered low if they came from an area with a state ADI ranking from 1 to 5 and were considered high if they came from an area with a state ADI ranking from 6 to 10. Results From 1/1/2017 to 12/31/2023, 21% of individuals were AV (n=36,632), 52% were IV (n=90,776), and 27% were NV (n=46,418) for seasonal influenza. Post-pandemic onset, 7% (n=3,556) of the Pre-Pandemic AV and 32% (n=16,710) of the Pre-Pandemic IV never received another influenza vaccine. In the Pandemic-Plus phase, the IV and NV had a higher likelihood of disengagement with the healthcare system [odds ratio (OR) (95% CI): 1.59 (1.55, 1.64); 4.21 (4.09, 4.33)], residing in areas of greater deprivation [1.58 (1.53, 1.62); 1.99 (1.94, 2.05)], and self-identifying their race as Black [2.29 (2.09, 2.51); 3.29 (3.01, 3.60)] compared to the AV. After adjusting for healthcare engagement and area of deprivation, dissatisfaction OR increased from 1.03 (0.99,1.07) Pre-Pandemic to 1.07 (1.03,1.12) in the Pandemic-Plus phase among IV compared to AV. Similarly, the OR of dissatisfaction rose from 1.11 (1.05, 1.18) Pre-Pandemic to 1.16 (1.09, 1.24) in the Pandemic-Plus phase among those who were NV compared to those AV. Conclusion Higher healthcare dissatisfaction was observed among those inconsistently adherent to vaccination recommendations. Targeted efforts to enhance patient satisfaction may boost vaccination rates. Disclosures All Authors: No reported disclosures

766 Background: BASECAMP-1 (NCT04981119) is a pre-screening study to identify patients with tumor-associated human leukocyte antigen (HLA)-A*02 loss of heterozygosity (LOH) for interventional studies, such as EVEREST-2 (NCT06051695), a phase 1/2 study of logic-gated chimeric antigen receptor T-cell (CAR T) therapy for MSLN-expressing cancers. MSLN is a cell surface protein expressed in several cancer types, including mesothelioma (MESO), colorectal (CRC), non-small cell lung (NSCLC), ovarian (OVCA), and pancreatic (PANC) cancer, which can be associated with poor prognosis (1). Longitudinal clinical, genomic, and biomarker data were collected from patients enrolled in BASECAMP-1, providing a large dataset for translational discovery and propensity scoring. The aim of this analysis was to determine whether MSLN expression measured by RNAseq and IHC are correlated among patients with solid tumors. Methods: In BASECAMP-1, tumor tissue from patients with germline heterozygous HLA-A*02 is tested for HLA-A*02 LOH using an investigational next generation sequencing device codeveloped with Tempus Labs (Lozac'hmeur, et al. NPJ Precis Oncol. 2024) that detects somatic alterations, including HLA LOH, and generates RNAseq data (eg, MSLN expression). Gene-level transcripts per million read (TPM) values were determined and the log2 TPM +1 was displayed in a scatter plot (the mean and standard deviation [SD] are provided in the Table). Patients with HLA-A*02 LOH also submit tissue for IHC testing for exploratory biomarkers (eg, MSLN expression using anti-MSLN clone 5B2). Statistical significance was determined with ANOVA or t-tests. Results: As of June 1, 2024, 314 patients had been screened for BASECAMP-1 and had RNAseq results; 34 patients also had MSLN IHC results. MSLN expression by RNAseq was consistently higher in patients with PANC or OVCA vs CRC or NSCLC ( P <0.001). MSLN expression by RNAseq and IHC were correlated overall ( P <0.001), particularly among patients with PANC and OVCA. Among the 8 patients with OVCA or PANC who were IHC+ for MSLN, only 1 had an RNAseq value below 6 log2 TPM+1; this patient had mesonephric-like ovarian adenocarcinoma, which may account for the low value. The one MESO sample with both RNAseq and IHC available was IHC+ and had a high RNAseq value. Conclusions: This analysis demonstrated high correlation between RNAseq and IHC MSLN expression in tumor tissue. 1. Faust, et al. Cancers. 2022. Clinical trial information: NCT04981119 . MSLN expression by RNASeq by tumor type and IHC status. Tumor Overall (N=314) IHC data available (n=34) MSLN Positive MSLN Negative n Mean TPM a (SD) n Mean TPM a (SD) n Mean TPM a (SD) All 314 5.1 (2.3) 20 6.0 (2.1) 14 2.3 (1.7) adNSCLC 33 3.8 (2.4) 2 4.7 (1.7) 7 1.5 (1.3) sqNSCLC 4 3.1 (1.8) 0 0 MESO 4 4.5 (4.2) 1 5.7 0 CRC 148 4.4 (2.0) 8 5.1 (2.1) 7 3.1 (1.6) PANC 100 6.1 (1.8) 3 7.8 (0.6) 0 OVCA 25 7.2 (2.1) 5 6.6 (2.8) 0 a MSLN log2 transcripts per million+1. ad, adenocarcinoma; sq, squamous.

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 .