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Background: Hyperkinetic biliary dyskinesia, defined as a gallbladder ejection fraction (EF) ≥80% on cholecystokinin (CCK)-stimulated hepatobiliary iminodiacetic acid scans in the setting of biliary-type pain, has been increasingly recognized as a potential functional gallbladder disorder. The clinical significance of this entity and the role of cholecystectomy remain uncertain. Patients and Methods: We conducted a systematic review and meta-analysis of studies reporting outcomes in patients with CCK-hepatobiliary iminodiacetic acid EF ≥80% who underwent cholecystectomy due to non-acute biliary-type pain. Primary outcomes included mean EF, rates of symptom resolution and improvement following cholecystectomy, and prevalence of chronic cholecystitis on pathology. Secondary outcomes included normal histology rates and symptom reproduction with CCK stimulation. All statistical analyses were conducted in R (version 4.5.0) using a random-effects model to obtain pooled estimates. Results: A total of 14 retrospective studies, including 686 patients, were analyzed. The pooled mean gallbladder EF was 90.27% (95% CI: 88.73–91.80, I 2 = 86.6%). Symptom resolution occurred in 83.1% (95% CI: 76.7–89.4, I 2 = 76.8%), and symptom improvement in 91.6% (95% CI: 89.0–94.2, I 2 = 29.7%) of patients following cholecystectomy. Histopathologic analysis revealed chronic cholecystitis in 85.1% (95% CI: 76.9–93.4, I 2 = 90.6%) of surgical specimens, while normal gallbladder histology was rare, observed in only 9.9% (95% CI: 4.6–15.2, I 2 = 83.7%). The pooled risk ratio indicated a 6.70-fold higher likelihood of chronic cholecystitis compared with normal histology (95% CI: 3.69–12.17, I 2 = 65.2%, P = 0.0022). Functional reproduction of symptoms during CCK stimulation was frequent, with a pooled rate of 78.3% (95% CI: 70.4–86.3, I 2 = 35.6%). Egger regression test suggested potential publication bias for the normal histology outcome ( P = 0.0223), but not for symptom resolution ( P = 0.1589). Conclusions: This meta-analysis suggests that a high gallbladder EF in the setting of biliary-type pain could represent clinically relevant hyperkinetic biliary dyskinesia rather than normal physiology. Cholecystectomy appears to provide meaningful symptom relief in appropriately selected patients, and pathologic findings frequently indicate underlying chronic inflammation. Further studies are needed to establish clear diagnostic cutoffs and guide management.

Purpose Radioligand therapy (RLT) with [ 177 Lu] Lu-PSMA-617 has shown significant benefits in metastatic castration-resistant prostate cancer (mCRPC), including prolonged overall survival (OS) and progression-free survival (PFS), as well as improved quality of life. For patients previously treated with [ 177 Lu]Lu-PSMA-617 who subsequently experience disease progression, retreatment with [ 177 Lu] Lu-PSMA-617 has emerged as a potential approach, yet data on the outcomes of RLT retreatment remains limited. This study aimed to assess the efficacy and safety of retreatment RLT in mCRPC. Methods Clinical and imaging data of patients who underwent at least two cycles of [ 177 Lu] Lu-PSMA-617, followed by a second course of treatment with [ 177 Lu] Lu-PSMA-617 between March 2018 and December 2024, were retrospectively reviewed. Endpoints included biochemical response, imaging response, toxicity, PSA-PFS, rPFS, and OS. Radiologic and biochemical responses were evaluated using RECIST 1.1 criteria and PSA levels, respectively. Results A total of 589 patients underwent [ 177 Lu] Lu-PSMA-617 RLT, of whom 20 (3.4%, 20/589) received RLT retreatment. The median age was 71.3 years (range: 63.7–95.2), and the median follow-up was 73.3 months (95% CI, 35.7–77.2 months) after the initial treatment and 21.7 months (95% CI, 16.9–26.0 months) after retreatment. The initial treatment involved a median of 4.5 cycles (range: 2–6). Following the first course of RLT, 15 patients (75%, 15/20) had exhibited a >50% decline in PSA levels, including 9 who achieved a >90% decrease. Additionally, 12 patients (60%, 12/20) had demonstrated a complete or partial imaging response, while 3 (15%, 3/20) patients had stable disease, and 5 (25%, 5/20) patients had progressive radiologic disease. Patients received a median of 4 retreatment cycles (range, 1–6), and the median interval between initial RLT and retreatment RLT was 33.1 months (IQR, 16.2–48.9 months; range, 10.7–58.8 months). A PSA decline of ≥50% was observed in 9 out of 20 patients (45%, 9/20). An imaging response was observed in 10 patients (50%, 10/20), with 4 achieving a complete response and 6 achieving a partial response, whereas 10 patients (50%, 10/20) showed progression. The median PSA-PFS was 9.8 months (95% CI, 4.1–17.9 months), and the median rPFS was 8.2 months (95% CI, 3.3–17.9 months). Eight deaths occurred during follow-up. The estimated Kaplan Meier OS rates were 83.6% at 12 months (95% CI, 57.3%–94.4%) and 53.7% at 24 months (95% CI, 28.3%–73.7%). Grade 2 renal toxicity was observed in one patient (5%, 1/20). Three patients (15%, 3/20) developed Grade 2 anemia. Notably, no grade 3 or grade 4 adverse events were observed during either treatment period. Conclusion In our cohort, retreatment with [¹ 77 Lu]Lu-PSMA-617 RLT was associated with biochemical and imaging responses in some patients, with observed survival outcomes that support further investigation. However, given the retrospective single-arm design and small sample size, large prospective studies are needed to more rigorously evaluate the safety, efficacy, and optimal patient selection for retreatment RLT.

Abstract Background Diabetes mellitus elevates Parkinson’s disease (PD) risk, via hypothesized cerebrovascular mediation. Whether the diabetes/prediabetes vascular-risk phenotype concentrates in cardiometabolic risk or macrovascular events across prodromal and clinically diagnosed PD remains unresolved. Objectives To quantify the vascular-risk burden associated with diabetes/prediabetes across the PPMI diagnostic cohorts to test whether this association differs by cohort. Methods Cross-sectional analysis of 413 PPMI participants (76 healthy controls, 145 prodromal PD, 192 clinically diagnosed PD) examined diabetes/prediabetes (n = 73) and seven vascular risk factors. The Vascular Burden Score (0 to 7) was a priori partitioned into microvascular and macrovascular sub-scores. Modified Poisson regression estimated adjusted prevalence ratios (aPR), adjusted for age, sex, and body mass index. A cohort-by-diabetes interaction tested cross-cohort consistency. Sensitivity analyses incorporated nigral diffusion tensor imaging (PD-risk biomarker) and FreeSurfer white matter hypointensity volume (cerebrovascular marker). Results Diabetes/prediabetes elevated Vascular Burden Score (β = 0.53, 95% CI 0.29 to 0.77, p < 0.001) versus non-diabetic participants, with a non-significant cohort-by-diabetes interaction (F = 0.29, p = 0.747). Three microvascular factors survived false discovery rate correction: obesity (aPR 2.28), hypertension (aPR 1.60), and hyperlipidemia (aPR 1.45). Macrovascular events showed no diabetic amplification (β = −0.06, p = 0.25). In the imaging-phenotyped subset, Vascular Burden Score components contributed classifier variance distinct from nigral microstructure. Conclusions Diabetes/prediabetes operationalize a microvascular cluster stable across prodromal and idiopathic PD. Cardiometabolic phenotyping may complement established PD-risk biomarkers (dopamine transporter SPECT, nigral diffusion), pending longitudinal validation linking vascular phenotype to dopaminergic markers.

5068 Background: 177 Lu-PSMA-617 (LuPSMA) is a groundbreaking therapy for mPC, but biomarkers are urgently needed to improve patient selection. Plasma-derived EVs are emerging blood-based markers of tumor burden. Here, we analyzed levels of EVs of 123 patients (pts) from 4 cohorts: a pre- and during LuPSMA treatment for a contemporary prospective Mayo Clinic cohort, pre-treatment plasma levels of EVs for a historical Tulane cohort, localized prostate cancer (LPC) after radical prostatectomy (RP), and male healthy donors (HD). Methods: Blood samples were collected from 51 pts pre-cycles (pre-C) 1-3 of LuPSMA at Mayo Clinic from 12/2024-12/2025 and 26 pts pre-C1 at Tulane Cancer Center between 12/2018-1/2025. Small and large EVs were incubated with fluorescently conjugated antibodies (PSMA, STEAP1, CEACAM5, and TROP2) and enumerated using nanoscale flow cytometry. EVs from blood samples of 10 HD and 36 LPC post-RP from 6/2020-8/2024 at Mayo Clinic as controls. AUC-ROC and logistic regression analyses were performed to identify marker signatures associated with PSA50 response. Results: Baseline demographics are shown in the table. Median levels of PSMA, STEAP1, CEACAM5, and TROP2 EV/milliliter (mL) were all significantly higher for pts with mPC (pooled Tulane and Mayo cohorts) compared to LPC post-RP (p<0.001) and HD (p<0.001). In the Mayo cohort, 10 of 51 pts (20%) had undetectable PSA pre-C1. There were no significant differences in median pre-C1 plasma EV levels for these 4 different types of EVs comparing pts with undetectable vs detectable PSA. For 41 Mayo pts with detectable PSA pre-C1, 20 achieved PSA50 response at time of data cutoff (49%), while 7 pts (17%) had persistent PSA rise on LuPSMA. For pts who achieved PSA50, there was a significant decline in both CEACAM5 and TROP2 EVs/mL pre-C1 compared to pre-C3 (19 x 10 6 vs 5.8 x 10 6 , p=0.003 and 16 x 10 6 vs 5.5 x 10 6 , p<0.001, respectively), while no significant changes occurred for the 7 pts with no PSA response. A composite score of pre-C1 CEACAM5 and TROP2 EVs (large- and small-sized EVs) demonstrated the strongest association with PSA50 response (OR=2.96, 95% CI: 1.27-6.44, p=0.038), achieving AUC of 0.73. PSMA and STEAP1 EVs did not show any significant changes from pre-C1 to pre-C3. Conclusions: Plasma-derived EVs are a promising biomarker to identify patients who will benefit from LuPSMA. Longer follow-up and enrolling a larger cohort are underway. Clinical trial information: NCT06200103 . Median values for pre-LuPSMA (Mayo and Tulane), post-RP for LPC, and HD. Mayo mPC (n=51) Tulane mPC (n=26) LPC (n=36) HD (n=10) Age (range) 73 (57-87) 71 (54-83) 66 (56-77) 55 (50-57) Prior lines (range) 1 (1-3) 4 (1-11) - - Gleason score 9 8 7 - PSA (range) 1.0 (0-182) 75 (0.8-503) - - PSMA EV/mL 3.7 x 10 6 14 x 10 6 2.0 x 10 6 1.4 x 10 6 STEAP1 EV/mL 30 x 10 6 45 x 10 6 12 x 10 6 12 x 10 6 CEACAM5 EV/mL 17 x 10 6 5.1 x 10 6 3.7 x 10 6 3.9 x 10 6 TROP2 EV/mL 13 x 10 6 5.2 x 10 6 4.5 x 10 6 3.6 x 10 6

Abstract Introduction: Suboptimal response to therapy, early disease relapse, and limited long-term survival remain critical challenges in a substantial number of patients with multiple myeloma (MM). While cross-sectional imaging studies are commonly obtained in clinical practice, only limited information is currently incorporated into risk stratification efforts and clinical decision making. Here, we investigate the use of novel image-based biomarkers to identify patients at high risk for adverse outcomes. Methods: We obtained the pretreatment 18F-FDG PET/CT scans of patients with newly diagnosed MM with available clinical and laboratory data seen at Mayo Clinic between 2006 and 2022. In this analysis, we included 637 patients with detectable metabolic tumor volume on their pretreatment scan. The native DICOM images were pre-processed and subjected to automated image segmentation using nnU-Net (nnU-Net v1.0, inference using a pre-trained hematologic malignancies model). Limitations of this automated segmentation approach include heterogeneity introduced by varying image quality, technical variability in PET reconstruction, and potential inclusion of non-neoplastic FDG-avid lesions in segmented regions. PyRadiomics was used to extract quantitative radiomics features for clinical prediction modeling. We evaluated the predictive power of tumor size-, shape-, and texture-related radiomics features for identifying high-risk disease (advanced ISS stage at diagnosis, the presence of high-risk FISH abnormalities, failure to achieve a stringent complete response [sCR] to first-line therapy by IWMG criteria, and early mortality). All radiomics features were quantile-normalized for downstream modeling. Forward and backward feature selection as well as testing for multicollinearity were used to remove redundant features. Results: Median age at diagnosis of the 637 myeloma patients was 64 years (range 22–90), and 387 patients (61%) were male. After a median follow-up of 4.4 years (95% CI 0.2–11.7), median overall survival (OS) was 7.3 years (95% CI 6.3–8.3). Increased total tumor volume (upper tertile vs lower tertiles), measured by the total tumor surface area, was associated with advanced ISS stage (III vs I+II; OR 1.73, 95% CI 1.24–2.42, p=0.001, n=637). Increased tumor density (dichotomized at the median), measured by the median gray level intensity (OR 1.93, 95% CI 1.94–3.12, p=0.007, n=303), and decreased tumor heterogeneity (lower tertile vs upper tertiles), measured by the variability of gray-level intensities (OR 1.88, 95% CI 1.49–3.12, p=0.012, n=303), were associated with the presence of high-risk cytogenetics. Both increased total tumor volume (4.9% increase per tertile, 95% CI 2.2–7.6, p&lt;0.001, n=600) and tumor density (8.9% increase per tertile, 95% CI 4.5–13.3, p&lt;0.001, n=600) were independently associated with more extensive bone marrow involvement at diagnosis. Increased tumor heterogeneity (upper tertiles vs lower tertile), as measured by rapid changes of gray level intensities, was associated with failure to achieve a stringent complete response to first-line therapy (OR 0.50, 95% CI 0.30–0.82, p=0.006, n=351). Increased tumor volume was associated with shorter OS (HR 1.35 per tertile, 95% CI 1.11–1.63, p=0.002, n=301), independent of age, sex, ISS stage, and the presence of high-risk cytogenetics. A simple additive score consisting of tertiles of total tumor volume, ISS stage, and plasma cell labeling index ≥2% identified patients at risk of mortality within 3 years of diagnosis (OR 2.00, 95% CI 1.40–2.85, p&lt;0.001, n=126), with moderate discrimination (AUC=0.71). Sensitivity analysis demonstrated total tumor volume and texture as most predictive of overall survival in a random forest survival model (C-index 0.712, 95% CI 0.649–0.775) and tumor texture as most predictive of response to therapy in a random forest classification model (C-index 0.693, 95% CI 0.607–0.779). Conclusions: Automated image segmentation and radiomics feature extraction from 18F-FDG PET/CT scans produces biomarkers that capture disease stage, burden, and risk in newly diagnosed MM. Total tumor volume and heterogeneity are strongly associated with important disease characteristics and can be used to identify patients at high risk for therapeutic resistance, early mortality, and inferior long-term outcomes.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (&lt;30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.