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ABSTRACT Background and Objectives Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm 3 , SE=317.0, p= 0.0046, f 2 =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm 3 , SE=29.9, p= 0.035, f 2 =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

2646 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of many advanced cancers but identifying patients who are likely or unlikely to benefit from ICI treatment remains a critical challenge. Biomarkers, such as PD-L1, mismatch repair deficiency, and tumor mutational burden, capture only static, unidimensional features of the complex tumor microenvironment, and therefore inadequately predict response to immunotherapy in patients. In contrast, live tumor fragments (LTFs) preserve the full complexity of the tumor microenvironment and enable functional ex vivo assessments of ICI activity. Previous efforts have had limited clinical applicability because they required larger resection specimens often collected at a single academic center. Here, the predictive capability of an ex vivo platform using core needle and forceps biopsies from multiple clinical sites was assessed and compared to approved biomarkers. Methods: Patients with eligible solid tumors (where ICI has an indication, including renal, non-small cell lung, bladder, colorectal, and triple-negative breast cancer, and others) were enrolled in ongoing, prospective observational trials (NCT05478538, NCT05520099, NCT06349642). Biopsies were cut into LTFs, encapsulated in hydrogel, and treated sequentially with IgG antibody followed by ICI (αPD-[L]1 with or without αCTLA-4). Cytokine production was assessed by a multiplexed bead-based immunoassay at multiple time points during ex vivo treatment. Using receiver operating characteristic and precision recall analyses, we identified 9 predictive cytokines (including IFN-γ, granzyme B, and CXCL9/10), which were used to develop the Elephas score (ELP-score) to assess cytokine response to ex vivo ICI treatment. Results: Of 167 eligible patient specimens, 85% (n = 142) passed quality control metrics and 130 were used for model development. Hierarchical clustering of cytokine production revealed that 27% (n = 35) of patient specimens exhibited a cytokine response to ICI. In a validation set of 20 tumors, collected from patients who were subsequently treated with ICI, ELP-score positivity correctly identified 9 of 11 patients (82%) who had an objective response (PR/CR) to ICI, including 2 patients who were negative for FDA-approved standard-of-care ICI biomarkers. Furthermore, 5 of 5 patients (100%) with clinical progressive disease were correctly characterized as ELP-score negative. Conclusions: Using routine biopsy specimens, the ex vivo live tumor platform accurately identifies patients with clinical response to ICI therapy, including those incorrectly identified by conventional biomarkers. Ongoing efforts will test these findings in an additional validation set. If confirmed, the ex vivo LTF platform could enable the identification of patients likely to benefit from ICI therapy. Clinical trial information: NCT05478538 , NCT05520099 , NCT06349642 .

ABSTRACT Pulmonary arterial hypertension (PAH) is associated with significant symptoms and impaired health‐related quality of life (HRQOL) and survival. Specialty palliative care (SPC), an intervention delivered by a multidisciplinary team, is focused on improving HRQOL. We performed a randomized controlled trial (RCT) of SPC among adults with PAH and impaired HRQOL to determine the impact of SPC on HRQOL as assessed by PAH‐SYMPACT. PAH‐SYMPACT is a validated PAH disease‐specific patient‐reported outcome measure that assesses HRQOL across four domains: cardiopulmonary symptoms, cardiovascular symptoms, physical impact, and cognitive/emotional impact. Sixty‐two patients were included (36 usual care, 26 SPC plus usual care), but only 58% of patients randomized to SPC completed their SPC visits. In the intention‐to‐treat analysis, SPC was associated with similar changes in total, symptom, and physical impact domain scores and increased cognitive/emotional impact scores, indicative of worse HRQOL. In the per‐protocol analysis, SPC was not associated with significant changes in total or individual domain scores. According to a survey of patients who completed SPC visits, most were satisfied with their visit and were likely to recommend SPC for other patients with PAH. In conclusion, limited SPC visits in this single‐center RCT were not associated with significant improvements in HRQOL among patients with PAH and impaired HRQOL, but the majority of patients who participated in a SPC intervention were satisfied and would recommend SPC to other PAH patients. Future studies of SPC in PAH are needed to determine the appropriate patient selection and timing for SPC. www.clinicaltrials.gov (NCT03905421).

Abstract Rationale Portopulmonary hypertension (POPH) and hepatopulmonary syndrome (HPS) are two distinct pulmonary vascular complications of liver disease. POPH is characterized by pulmonary hypertension and elevated pulmonary vascular resistance while HPS is characterized by intrapulmonary vasodilation and hypoxemia. POPH and HPS reflect opposing pulmonary vascular responses with markedly different therapeutic and transplant implications. Accurate distinction on imaging may aid clinical decision-making and risk stratification. We aimed to quantitatively characterize and compare chest CT imaging features of POPH and HPS compared to controls with isolated portal hypertension (PoH). Methods Three cohorts of HPS, POPH, and PoH were included (n = 5 per cohort). POPH patients with intrapulmonary vasodilation on contrast echocardiography were excluded. Contrast-enhanced chest CTs with slice thickness ≤ 1.5mm obtained closest to the time of diagnosis were selected (mean 2.7 years following diagnosis). CT images were analyzed using a deep learning algorithm developed in-house that segmented and computed volumes of central, interlobar, peripheral, upper peripheral, and lower peripheral pulmonary arteries (PAs); total, upper, and lower pulmonary veins (PVs); and the four cardiac chambers. Resulting volumes were indexed by body-surface area. One-way analysis of variance (ANOVA) was performed with a post-hoc pairwise Mann-Whitney U test for comparison. Results Patients with HPS were 80% male, had a mean age of 48.6±17.4, and mean MELD-Na of 15.4±3.4. The POPH cohort was 20% male, had a mean age of 56.8±11.9, and mean MELD-Na of 13.4±4.0. The PoH cohort was 100% male, had a mean age of 62.8±4.8, and mean MELD-Na of 12.8±8.8. HPS patients had smaller central PA volumes (mean 26.4±1.8 mm2/m2) compared to both PoH (mean 38.6±9.8 mm2/m2, p = 0.03) and POPH patients (44.8±10.8 mm2/m2, p = 0.008). HPS patients, however, had larger lower peripheral PA (mean 30.7±1.9 mm2/m2) and PV (mean 28.3±6.7 mm2/m2) volumes compared to PoH (PAs mean 20.1±4.8 mm2/m2, p = 0.008; PVs mean 18.2±2.8 mm2/m2, p = 0.02) and larger lower peripheral PA volumes compared to POPH patients (PAs mean 22.1±5.1 mm2/m2, p = 0.03). There was no significant difference in volumes between POPH and PoH for all segments. Conclusion Compared to PoH and POPH, HPS is associated with lower central PA volume and higher peripheral PA volume in the lower lungs. Volumes were similar between POPH and PoH; however, this may reflect limited statistical power given the small sample size. Larger studies are needed to further delineate imaging distinctions between POPH, HPS, and PoH. This abstract is funded by: NHLBI

Abstract Rationale The pathophysiology and clinical impact of liver injury in pulmonary hypertension (PH) is poorly understood. Liver injury in PH is often attributed to hepatic congestion, but some studies have failed to find strong associations with hemodynamics, suggesting alternative mechanisms. We sought to define the prevalence of liver injury and patterns of liver injury across the spectrum of PH and to determine whether patterns of liver injury were associated with clinical characteristics, hemodynamics and outcomes. Methods We performed an analysis of the PVDOMICS study, a multicenter, prospective, longitudinal cohort study that enrolled incident and prevalent patients with PH and disease comparators. The prevalence of liver injury, defined as aspartate or alanine aminotransferase (AST or ALT) or total bilirubin above the upper limit of normal, and different patterns of liver injury [hepatocellular (elevated AST or ALT with normal bilirubin), cholestatic (elevated bilirubin) and no liver injury] was defined among participants with known or suspected PH. Associations between patterns of liver injury with demographics, hemodynamics, right ventricular function, exercise capacity and quality of life (QoL) were assessed. We used Cox proportional hazards models adjusted for age and sex to assess the association of liver injury patterns with transplant-free survival. Results Liver injury was present in 27.8% (288/1036) of participants (19.0% cholestatic and 8.8% hepatocellular). Patients with liver injury were less likely to be female and have prevalent disease with differences in PH classification (Table 1). Patients with hepatocellular liver injury had a higher body mass index. A cholestatic liver injury pattern was most consistently associated with worse functional class, biventricular filling pressures, pulmonary vascular resistance, right ventricular function, natriuretic peptide elevation, exercise capacity, and REVEAL risk scores. Total bilirubin levels and right atrial pressure as a marker of systemic congestion were weakly correlated (r2=0.02, p < 0.0001). Compared to no liver injury, cholestatic liver injury was associated with an increased risk of death in age and sex adjusted models (HR 1.6, 95% CI 1.3-2.1, p < 0.001) but hepatocellular liver injury was not (p > 0.05). Conclusions Liver injury is common among patients with known or suspected PH. In contrast to a hepatocellular injury pattern, a cholestatic liver injury pattern was most consistently associated with worse hemodynamics, exercise capacity, QoL and survival. However, the weak relationship between right atrial pressure and bilirubin suggests that systemic congestion alone is unlikely to completely explain cholestatic liver injury. Further study is needed to uncouple the pathophysiological basis of cholestasis in PH. This abstract is funded by: NHLBI

Abstract Rationale Sotatercept is a novel activin signaling inhibitor approved for the treatment of pulmonary arterial hypertension (PAH). Sotatercept has been studied in randomized clinical trials, but little is known regarding the real-world use of sotatercept. We sought to describe the safety, tolerability and efficacy of sotatercept in our clinical practice. Methods We performed a combined prospective and retrospective cohort study of all patients treated with sotatercept at Mayo Clinic Rochester since its approval in March 2024. Patients enrolled in a separate clinical trial of sotatercept were excluded from this analysis as their data will be reported separately. Clinical data was abstracted from the electronic health record. Follow-up data was collected at 6 ± 3 months after initiation of sotatercept. Data is summarized as n (%) and mean ± SD. We used paired t-tests to compare baseline and follow-up characteristics within individuals. Results Fifty-eight PAH patients treated with sotatercept were included. Patients were 48.4 ± 37.6 years old at treatment initiation and were predominantly female with a mean duration of PAH of 6.7 years and a range of PAH etiologies including portopulmonary hypertension, congenital heart disease, and pulmonary veno-occlusive disease (Table 1). Twenty-one (36%) of patients had mixed etiologies of PH. Six months after initiation of sotatercept, patients had a significant improvement in NTproBNP (1922 ± 4464 to 363 ± 596 pg/ml, p = 0.04), 6 minute walk distance (378.8 ±144.6 to 395.7±129.5 meters, p = 0.02) and right ventricular systolic pressure (74.6 ± 20.5 to 60.6 ± 20.3 mm Hg, p < 0.001). No patients permanently discontinued due to abnormal laboratory values. Mean highest hemoglobin achieved over the initial 6 months of treatment was 15.5 ± 2.1 g/dL and mean lowest platelet count was 181 ± 74K. Seven patients discontinued sotatercept at a range of 170-275 days after starting. Four patients discontinued due to possible treatment-related adverse effects: 1 each of gastrointestinal hemorrhage, retinal hemorrhage, hypoxia/intrapulmonary vasodilatation and spontaneous bilateral subdural hematomas. Three patients discontinued due to other reasons: newly diagnosed metastatic cancer leading to transition to hospice and two due to lack of improvement. Conclusions In this real-world registry of sotatercept in PAH, sotatercept was well-tolerated among patients with PAH and associated with improvements in exercise capacity, echocardiographic parameters, and NTproBNP. Overall discontinuation due to possible treatment-related adverse effects was low and reasons for discontinuation included bleeding and hypoxia attributed to intrapulmonary vasodilatation. This abstract is funded by: None

Abstract Introduction Sotatercept was FDA-approved for Group 1 pulmonary arterial hypertension (PAH) in spring 2024, but patients with portopulmonary hypertension (POPH) were not included in major clinical trials that led to its approval. Therefore, safety and efficacy of sotatercept is not well-understood among patients with POPH. We present a case of severe POPH treated with sotatercept. Case Report A 61 year-old female presented to pulmonary hypertension (PH) clinic for follow-up of POPH. History notable for cirrhosis in setting of Hepatis C virus and portosystemic shunts status post embolization. She was on triple PAH therapy with sildenafil, macitentan, and IV epoprostenol. She had functional class 2 dyspnea on exertion, and transthoracic echocardiogram (TTE) demonstrated mild-moderate RV enlargement and mild dysfunction, with estimated right ventricular systolic pressure (RVSP) 76 mmHg. Right heart catheterization (RHC) revealed mean pulmonary arterial pressure (MPAP) 46 mmHg, pulmonary vascular resistance (PVR) 7.9 wood units (WU), cardiac output (CO) 4.9 L/minute, and low biventricular filling pressures. She was started on sotatercept, with goal of improving hemodynamics, RV function, and ultimately qualifying for POPH Model for End-Stage Liver Disease (MELD) exception. She returned for assessment several months later and reported progressive dyspnea with decreasing oxygen saturations. Arterial blood gas (ABG) revealed decreased PaO2 (56 mmHg, compared with 64 mmHg approximately 3 months prior before sotatercept initiation). She was noted to have cutaneous telangiectasias on face, chest, upper extremities, and back (Figure 1). TTE showed decreased RV size and improved function and RVSP (62 mmHg) but large intrapulmonary shunt per agitated saline (“bubble”) study. RHC demonstrated improvement in hemodynamics but remained inadequate to meet POPH MELD exception criteria (MPAP 36 mmHg, PVR 4.6 WU). Sotatercept was discontinued. Follow-up ABG demonstrated increase in PaO2 (63 mmHg), similar to prior baseline, and TTE approximately 6 weeks after stopping sotatercept demonstrated notable decrease in intrapulmonary shunting, now described as small. Telangiectasias improved as well. Discussion The use of sotatercept in patient with POPH and/or liver disease remains an exciting area of investigation, and additional clinical studies are warranted. Potential sequelae such as increased intrapulmonary shunting may particularly affect this patient population, given their unique and complex multiorgan pathology. In current clinical practice, close monitoring is essential when using sotatercept among patients with POPH. This abstract is funded by: n/a

Abstract Rationale Pulmonary hypertension (PH) is classified into five groups. Diagnosis requires multiple tests delaying treatment. This study compared patient and diagnostic characteristics for pulmonary arterial hypertension (PAH; Group 1 PH), Group 2-5 PH, and non-PH using machine-learning in an Electronic Health Record (EHR) dataset. This is novel as prior studies use claims data which may lack hemodynamic parameters. Methods This study analyzed adult patient records from a HIPPA-complaint EHR dataset from Mayo Clinic (2015-2024). Cohort definitions: PAH: right heart catheterization (RHC) data [mPAP>20 mmHg, PVR>2 WU, PCWP≤15 mmHg]; ≥2 PAH ICD diagnosis codes or positive natural language processing (NLP) sentiments separated by ≥ 30 days; and use of at least one PAH medication within six months after index date. Group 2-5 PH: RHC (mPAP>20mmHg) and ICD codes or positive NLP sentiment separated by ≥ 30 days for corresponding PH subtype. Non-PH: mPAP ≤ 20 mmHg and/or TRV ≤ 2.8 m/s. Index was the earliest NLP or ICD for PAH, earliest RHC for group 2-5 PH and most recent TRV/ mPAP for the non-PH cohort. Clinical variables were analyzed one-year before study index acknowledging data missingness as a limitation of retrospective dataset studies. Results 593 PAH, 817 Group 2-5 PH (67% with group 2 PH), and 11,600 non-PH patients (1:10 propensity-matched) were identified. Age, race, and symptoms were similar across cohorts. PAH had the highest proportion of females (60%) [Group 2-5 PH (50%) and non-PH cohort (53%)]. Clinical characteristic comparison is presented in Table 1. Comorbidities differed across cohorts. RHC: As expected, compared to Group 2-5, the PAH cohort had higher mPAP and PVR and lower PCWP. confirming a distinctly pre-capillary profile. ECHO: Compared to Group 2-5 PH, the PAH cohort had more pronounced right ventricular (RV) pressure overload and dysfunction and more impaired RV longitudinal strain, while TAPSE was similar. At the same time, left heart structure was less affected in PAH compared to Group 2-5. Among laboratory tests, serum creatinine was higher in Group 2-5 and ANA was higher in PAH cohort. Compared to the no-PH cohort, PAH and Group 2-5 cohorts exhibited clinically non-normal RHC and ECHO findings. Conclusion Although symptoms and demographic characteristics were similar among patients with and without PAH, unique RHC, ECHO, laboratory profiles and comorbidities differentiated PAH patients. Screening techniques using these distinct profiles could be considered to facilitate earlier diagnosis and treatment of PAH in clinical settings. This abstract is funded by: Merck & Co., Inc., Rahway, NJ, USA

Abstract Rationale Pulmonary arterial hypertension (PAH) is a rare and progressive disease, where the guideline-recommended diagnostic confirmation is via right heart catheterization (RHC). However, due to non-specific symptomology, patients often experience delays in diagnosis that potentially impact disease outcomes. We sought to develop a machine learning (ML) based approach for early and appropriate detection of PAH. Methods Three cohorts were derived from Mayo Clinic electronic health record (EHR): confirmed PAH (N = 1,169), No PH (N = 11,600) and Other PH (Group 2-5 PH, N = 817), based on 2022 ESC/ERS guidelines. The study index was defined as the earliest diagnosis dates for PH cohorts (PAH & Other PH) or the latest PH negative echocardiogram (ECHO) or RHC for the No-PH cohort. Patients included in the study had at least one symptom (dyspnea, fatigue, syncope, chest pain, or lower extremity swelling) within one year prior to the study index. A two-step sequential ML modelling strategy was applied: Step 1 differentiated PH (PAH + Other PH) from No PH and step 2 differentiated PAH from Other PH. Models were trained using a combination of structured data, unstructured clinical notes to detect symptoms using natural language processing and ECG waveforms captured one year prior to study index. Models were tested both with and without ECHO parameters. SHAP (SHapley Additive explanations) values were used to determine important features contributing to models (without ECG waveforms). Results Models including ECHO parameters performed better compared to those without (Figure 1). The top feature impacting model without ECHO parameters was dyspnea in the preceding three months followed by heart failure and systolic blood pressure for the PH vs no PH; and T wave peak in V1 and ANA level in PAH vs other PH cohort. The top feature impacting model with ECHO was tricuspid regurgitation velocity followed by heart failure and right atrial pressure for the PH vs no PH; and mean blood pressure and left ventricular diameter in the PAH vs other PH cohort. Figure 1: Model performance in the two-step sequential approach PR-AUC=Precision Recall-Area Under Curve Conclusion This study demonstrates that ML models can aid in the identification of PAH in symptomatic patient populations. While ECG can identify patients for further testing, ECHO can further increase the accuracy and the need to refer patients to RHC for confirming diagnosis of PAH. This abstract is funded by: Merck & Co., Inc., Rahway, NJ, USA