Citations

Abstract Background Young age is a known risk factor for breast cancer recurrence and mortality, particularly in hormone receptor-positive disease. However, no specific evidence exists on whether age at diagnosis influences clinical behavior and outcomes among carriers of germline BRCA pathogenic or likely pathogenic variants (PVs). Methods The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study including women with germline BRCA1 and/or BRCA2 PVs and diagnosed with stage I-III breast cancer at the age of 40 years or younger between January 2000 and December 2020. The present analysis aimed to evaluate clinical features and outcomes of breast cancer in young BRCA carriers according to age at diagnosis, by comparing patients aged ≤30 years with those aged 31-35 and 36-40 years at breast cancer diagnosis. The primary endpoint was disease-free survival (DFS). Overall survival (OS) was a secondary endpoint. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs), adjusting for risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) (time-dependent), and stratifying by country, year of diagnosis, tumor size, nodal involvement, tumor grade and hormone receptor status. Results From 109 centers in 5 continents, 5350 young BRCA carriers were included, of whom 1106 (20.7%) were ≤30 years of age, 1945 (36.4%) were 31-35 years and 2299 (43.0%) were 36-40 years at the time of breast cancer diagnosis. Compared to patients aged 31-35 and 36-40 years, those aged ≤30 years were more likely to harbor BRCA1 PVs (71.3%, 62.4%, 61.1%, respectively), to present with high-grade (G3 in 71.3%, 66.6%, 65.0%, respectively), triple-negative breast cancer (56.3%, 48.1%, 46.6%, respectively), and less frequently smaller tumor size (T1: 31.7%, 36.6% and 39.5%, respectively). Consequently, chemotherapy was administered more frequently among patients aged ≤30 years (94.4%, 92.6%, 89.7%, respectively). At a median follow-up of 8.2 years (IQR, 4.7-12.8), 8-year DFS rate was 65.0% among patients aged ≤30 years, 64.7% in the 31-35 years group, and 65.8% in the 36-40 years group. No significant association between age at diagnosis and DFS outcome was observed (31-35 vs. ≤30 years: aHR 1.03, 95% CI 0.89-1.19; 36-40 vs. ≤30 years aHR 1.00, 95% CI 0.87-1.16). Similarly, no significant association between age at diagnosis and OS was observed (31-35 vs. ≤30 years: aHR 1.10, 95% CI 0.86-1.41; 36-40 vs. ≤30 years: aHR 1.11, 95% CI 0.87-1.43). Subgroup analyses by specific BRCA gene, tumor subtype, tumor size, nodal status, and chemotherapy use revealed no statistically significant interaction with age at diagnosis in terms of DFS or OS (all p for interaction > 0.05). Specifically, no significant differences between age groups were observed among patients with luminal-like tumors for both DFS and OS. Conclusions In this unique international cohort of BRCA carriers diagnosed with breast cancer at a young age (≤40 years), we found no significant differences in DFS nor OS across different age groups. Notably, very young age (≤30 years) at diagnosis was not associated with worse outcomes compared to 31-35 years or 36-40 years. Age per se should not be considered a negative prognostic factor in BRCA carriers when appropriate treatment is provided. Citation Format: E. Blondeaux, A. Meacci, M. Fragío Gil, E. Klocker, F. Coussy, H. Kim, R. Bernstein Molho, F. Hilbers, A. Di Meglio, A. Kwong, K. Pogoda, J. Bajpai, H. Wildiers, E. Agostinetto, J. Balmana, H. C. Moore, K. Phillips, A. H. Partridge, C. Rousset-Jablonski, F. A. Peccatori, A. Toss, T. Renaud, C. Anghelone, A. Benitez Cruz, S. Paluch-Shimon, J. Lee, R. Fruscio, W. Cui, S. M. Wong, M. Lee, M. Rozenblit, C. Vernieri, C. Villarreal-Garza, A. Matikas, M. Dieci, L. De Marchis, J. K. Plichta, K. J. Ruddy, D. Can Guven, F. Puglisi, Z. Kemp, P. A. Meireles, L. Del Mastro, V. Delucchi, M. Lambertini. Association between age at diagnosis and survival among young BRCA carriers with breast cancer: results from an international multicenter hospital-based cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-07.

ABSTRACT This international, multidisciplinary consensus report represents the first effort to systematically define and characterize fatty pancreas. A key outcome of this endeavor was the recommendation to adopt “fatty pancreas” as the standardized and inclusive term to describe all forms of fat accumulation in the pancreas. This terminological consensus provides a critical foundation for unified reporting and clinical communication. Another major contribution of the report is the consensus on diagnostic imaging findings, which was based on radiological and endoscopic modalities. The proposed criteria aim to enhance consistency in clinical assessment and support the development of standardized research protocols. In addition to establishing terminology and diagnostic frameworks, the report also synthesizes current knowledge across a wide range of relevant domains. These include the etiology and epidemiology of fatty pancreas, as well as its associations with alcohol consumption, smoking, acute and chronic pancreatitis, pancreatic exocrine insufficiency, type 2 diabetes mellitus, and surgical outcomes. The potential links between fatty pancreas and neoplastic conditions such as intraductal papillary mucinous neoplasms and pancreatic cancer are also addressed, alongside the current understanding of its metabolic implications (beta‐cell function and glucose homeostasis) and treatment strategies. Throughout the consensus process, a consistent theme emerged: the limited availability of high‐quality, prospective clinical data. Therefore, many of the recommendations in this report are based on expert consensus rather than strong empirical evidence. As such, the statements require rigorous prospective validation before they can be adopted into routine clinical practice. This underscores a critical need for further research, particularly studies aimed at clarifying causal relationships, validating diagnostic tools, and determining the clinical relevance of fatty pancreas across diverse patient populations. This report serves as both a summary of our current understanding and a roadmap for future investigations, aiming to close existing knowledge gaps and guide evidence‐based clinical practice in this emerging field.

Background Bacterial infections remain a major global health burden, causing significant morbidity and mortality. Despite ongoing advances, prompt diagnosis is still hampered by nonspecific host biomarkers and the inherently slow turnaround of traditional microbiological cultures. These limitations often delay the initiation of appropriate treatments. In recent years, affinity-based proteomic approaches have been explored to address this gap. Among them, the Proximity Extension Assay (PEA) has emerged as a promising multiplexed protein quantification tool, capable of simultaneously measuring hundreds of immune and inflammatory proteins with high sensitivity from minimal sample volumes. Such technologies hold the potential to identify novel biomarkers, thereby improving both diagnosis and patient management in bacterial infections. Main body In this systematic scoping review, we examined studies applying PEA-based proteomics to adult bacterial infections. Out of the records screened, ten studies met inclusion criteria. Most were conducted in Europe and North America, relied primarily on plasma samples, and employed commercially available panels enriched for immune and inflammatory mediators. Study quality varied, with some evidence of variability and potential risk of bias. Across the 379 proteins investigated, a subset of proteins were consistently associated with bacterial infections across multiple clinical contexts, whereas others showed limited or no associations. Conclusions Current applications of PEA-based proteomics in adult bacterial infections is limited and largely exploratory. Rather than supporting immediate clinical translation, the available evidence suggests the value of PEA-based approaches for informing biomarker discovery. Future research should prioritize well-designed, longitudinal, and pathogen-stratified studies in clinically relevant settings to strengthen evidence robustness and support the rational development of proteomics-informed diagnostic and translational strategies.

BACKGROUND: No large registries of patients with acute eosinophilic myocarditis (EM) are available. However, EM is perceived as a cardiac disease with high mortality, affecting mainly young and middle-aged adults according to small series and case reports. Awareness of the clinical presentation, associated systemic conditions, treatments, and outcomes of this uncommon condition is an unmet need. METHODS: In this international, multicenter, retrospective cohort study, 53 centers screened 193 patients with histologically proven acute EM between 1992 and 2023. After the exclusion of patients with insufficient data (n=10), symptoms lasting >30 days (n=19), or histological diagnosis not confirmed after review (n=8), 156 patients were included. RESULTS: Median age at presentation was 48 years (first to third quartile, 34–59 years) with male predominance (67.3%), and only 2 were pediatric cases (≤16 years of age; 1.3%). The main signs and symptoms at presentation were dyspnea (75.6%), fever (61.3%), and chest pain (53.2%). Unexpectedly, peripheral eosinophilia was reported in only 57.4% of cases, with a median cell count of 630 eosinophils/μL. The median left ventricular ejection fraction at presentation was 32% (first to third quartile, 25%–48%). The disorders most frequently associated with EM were eosinophilic granulomatosis with polyangiitis (22.4% of cases) and hypersensitivity forms (14.1%). Idiopathic/undefined forms accounted for 44.9% of cases, and miscellaneous causes accounted for 18.6%. In-hospital death or need for heart transplantation (HTx) occurred in 23 patients (14.7%; 22 deaths and 1 HTx), despite 43.6% being treated with temporary mechanical circulatory support and 92.9% being treated with immunosuppressive agents. Estimated rates of death or HTx at 1 and 3 years were 19.0% and 23.8%. Increased age, decreased left ventricular ejection fraction on admission, and no immunosuppressive therapy during hospitalization were independent predictors of death or HTx. A nonsignificant higher occurrence of deaths or HTx was observed in the hypersensitivity form (46.1%) compared with the eosinophilic granulomatosis with polyangiitis–associated form (13.1%) at 3 years ( P =0.15). CONCLUSIONS: Acute EM can often present without peripheral eosinophilia, and rates of in-hospital and midterm mortality or HTx are high. Endomyocardial biopsy is required to reach the final diagnosis of EM because relying on peripheral eosinophilia can lead to missing diagnosis. In-hospital immunosuppression is associated with HTx-free survival, although tailored immunosuppressive therapies are needed to improve outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06447935.

Abstract Background Loss-of-function variants in TTN-encoded titin are the most common genetic cause of dilated cardiomyopathy (DCM). In addition, titin truncating variants (TTNtvs) are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD) suggesting that in rare circumstances TTNtvs may cause arrhythmias in a pre-cardiomyopathic electrical phase. Purpose To compare the prevalence of AF, sustained ventricular arrhythmias (VAs) and SCA/SCD between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, non-dilated left ventricular cardiomyopathy (NDLVC) and DCM. Methods Retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with TTNtvs in high proportion spliced-in (>90%) exons classified as pathogenic or likely pathogenic according to current American College of Medical Genetics and Genomics variant classification guidelines. Demographic, electrocardiographic, imaging and outcome data were extracted from the electronic record. After exclusion of those without satisfactory imaging data, each TTNtv-positive patient was classified as having G+/P- disease, NDLVC, or DCM according to the 2023 European Society of Cardiology Guidelines for the management of cardiomyopathies. The prevalence of AF, non-SCA major VA events (sustained VT and appropriate VT/VF-terminating ICD therapies), and SCA/SCD was then compared between the three left ventricular morphofunctional subgroups. Results Overall, 232 TTNtv-positive patients (mean age of 44 ± 17 years; 57% male) were included (average LVEF of 39 ± 17%; 32% with a history of AF; 23% with a history of non-SCA VA event and 6% with a history of SCA). Forty-nine (21%) were G+/P-, 45 (19%) had NDLVC, and 138 (59%) had DCM at the time of their most recent clinical evaluation. As expected, the prevalence of AF was higher in TTNtv-DCM patients when compared to both TTNtv-NDLVC [56/138 (41%) vs. 11/45 (24%); p=0.04] and G+/P- disease [56/138 (41%) vs. 5/49 (10%); p<0.001]. Similarly, the number of patients who experienced a non-SCA major VA event was higher in TTNtv-DCM than either TTNtv-NDLVC [44/138 (32%) vs. 6/45 (9%); p=0.01] or G+/P- disease [44/138 (31%) vs. 4/49 (8%); p<0.001]. Interestingly, no difference in the number of TTNtv-positive patients who experienced a SCA/SCD was observed across subgroups [2/49 (4%) for G+/P-; 2/45 (4%) for NDLVC; and 8/138 (6%) for DCM; p=ns for all comparisons]. Conclusion In patients with TTNtv substrates who were evaluated at a quaternary medical center, the prevalence of AF and major VA events correlates with left ventricular morphology/function with the greatest risk observed in those with DCM. However, the prevalence of AF and major VA events, including SCA, in TTNtv-positive patients with G+/P- and NDLVC disease is not trivial and highlights the ability of TTNtvs to present in a pre-cardiomyopathic electrical phase.

Abstract Background The extravascular implantable cardioverter defibrillator (EV-ICD) was designed to avoid lead-related complications associated with transvenous systems and deliver features such as anti-tachycardia pacing (ATP) and reduced generator size that provide an advantage over a subcutaneous ICD (S-ICD). As such, the EV-ICD is an attractive alternative for younger patients with genetic heart diseases (GHDs) who are not in need of permanent pacing. Objective To examine the indications, complications, and the clinical outcomes of patients with GHDs who received an EV-ICD. Methods A retrospective review of the electronic record was done for all GHD patients evaluated in genetic heart rhythm and/or cardiomyopathy clinics who had an EV-ICD implanted between 1/2021 and 2/2025. Basic demographic, ICD indications, complications, and therapy data were then extracted for all study patients. Results Overall, 23 patients (35% female; mean age 39 ± 16 years; 61% with a disease-causative genetic variant; mean LVEF 57%) with an underlying GHD (hypertrophic cardiomyopathy in 9, arrhythmogenic cardiomyopathy in 8, idiopathic ventricular fibrillation in 3, dilated cardiomyopathy in 2, and long QT syndrome in 1) had an EV-ICD implanted. For the majority, an EV-ICD was implanted for primary prevention (15/23; 65%) and represented their first ICD system (21/23; 91%). The success rate of the procedure was 96% with only one abandoned procedure because of poor R-wave sensing. Inadvertent intraprocedural lead placement in the pericardial space occurred in 1 patient with previous thoracotomy and surgically placed epicardial lead without sequelae or need for revision. Over a mean follow-up of 8±9 months, the rate of complications was low (1/23; 4%) with one electrode displacement and this patient underwent defibrillation threshold testing (DFT), the device properly detected VF and emitted a successful shock 30 J. Thus far, 2 patients have received appropriate VT/VF-terminating therapies (3 ICD shocks, 0 ATP) with successful conversion to sinus rhythm. One patient died following an electrical storm. One patient had 3 inappropriate ICD shock for sinus tachycardia while exercising followed by 1 successful shock for VF. Conclusion In this early experience, EV-ICDs appear to be safe and effective in younger patients with genetic arrhythmogenic and hypertrophic cardiomyopathies. Future studies are needed to better understand the utility of EV-ICDs in patients with cardiac channelopathies and advantages of EV-ICDs over transvenous and S-ICD systems in patients with an array of sudden death-predisposing GHDs.

The purpose of this study was to examine the validity of a Garmin device for estimating heart rate, energy expenditure, and step count during incremental treadmill exercise. Eighteen physically active males (n = 12; mean ± SD age = 22.8 ± 4.7 years; body mass = 83.8 ± 13.4 kg) and females (n = 6; 24.2 ± 5.6 years; 65.2 ± 9.6 kg) completed an incremental treadmill test with the Garmin Vivoactive 4 and criterion methods measuring heart rate, energy expenditure, and step count. Mean absolute percent error (MAPE) and Bland–Altman plots were used to assess accuracy. Acceptable accuracy was defined as MAPE < 5% for heart rate and <10% for energy expenditure and step count. MAPE (±SD) values were 13.0 (±10.1), 19.1 (±15.0), and 4.6 (±5.3)% for heart rate, energy expenditure, and step count, respectively. The Bland–Altman regression analyses illustrated proportional bias was present for heart rate (r = 0.591, p < 0.001) and step count (r = 0.516, p = 0.028), but not energy expenditure (r = 0.351, p = 0.153). These findings indicated that the Garmin Vivoactive 4 provided acceptable accuracy for step count but unacceptable accuracy for heart rate and energy expenditure during incremental treadmill exercise.

Abstract Background A unified definition of prosthetic joint infection outcomes (PJI) is crucial for consistent data, study comparisons, and better care. This study systematically reviews how PJIs outcomes are defined, building on our prior research on native vertebral osteomyelitis and postoperative spinal infection.Figure 1Network plot illustrating the co-occurrence of outcome criteria in prosthetic joint infection studies. Edge thickness reflects the frequency of the co-occurrence of each criterion. Each plot highlights one criterion, namely (1) clinical signs, (2) imaging, (3) microbiology, (4) histopathology, (5) antibiotics-related, (6) surgical-related, (7) mortality. Methods We conducted a comprehensive search of the Cochrane, Embase, Medline, and Scopus databases for studies published after 2005 that clearly defined outcomes for PJI. Eligible studies included randomized controlled trials and cohort studies with a minimum of 10 patients diagnosed with PJI. Our methodology adhered closely to the PRISMA guidelines. Using a saturation approach, we extracted and grouped explicit definitions of PJI outcomes into thematic criteria. A network plot (Figure 1) was used to visualize how frequently these criteria appeared and how they co-occurred across the included studies. Results Out of 7,584 screened studies, 552 (7.3%) met the inclusion criteria. This pilot analysis included 49 randomly selected studies (8,162 patients), mostly retrospective (48/49, 98%), focusing on mixed joint replacements (25/49, 51%), two-stage exchanges (15/49, 31%), or mixed surgeries (24/49, 49%). Only 6/49 (12.2%) applied a society-endorsed definition, and 13/49 (26.5%) cited a reference for their outcome definitions. Overall, 32/49 (65.3%) explicitly defined "success," 35/49 (71.4%) defined "failure," and 16/49 (32.7%) defined both. Most studies (25/49, 51%) had follow-up periods over two years, and 14/49 (28.6%) included patient-reported outcomes, identifying 14 unique PROMs (most commonly UCLA, HHS, and KSS scores). Functional outcomes were assessed in 13/49 (26.5%) studies. We identified 16 distinct outcome criteria across seven categories: clinical signs, microbiology, imaging, histopathology, antibiotics-related, surgical-related, and mortality. Network analysis revealed strong links among clinical signs, microbiology, surgical factors, mortality, and imaging. Conclusion Our pilot study found major variation in PJI outcome definitions, with few standardized criteria. A consensus-driven approach is needed to strengthen evidence synthesis and advance patient care in PJI. Disclosures All Authors: No reported disclosures

Abstract Background The Joint Propagation Model (JPM)‐based CenTauR scale was recently introduced to harmonize tau‐PET quantification across different radiotracers. This study examined how CenTauR harmonization enhances the comparability of tau‐PET quantification across matched cohorts using different tracers. The evaluation focused on three key aspects: (1) comparing tau‐PET positivity rates as defined by CenTauR, (2) evaluating its diagnostic accuracy for symptomatic AD, and (3) analyzing longitudinal changes in tau‐PET rates over time. Method The JPM, developed by the CPAD‐led Tau PET Harmonization Working Group (Leuzy et al., Alzheimers Dement. 2024; Figure 1A), models relationships between anchor point subjects and head‐to‐head tau‐PET SUVR data onto the CenTauR scale, providing conversion equations for multiple tracers. JPM equations were applied to [ 18 F]flortaucipir SUVR (Meta‐temporal ROI) data from 561 cognitively impaired participants in the ADNI and OASIS‐3 studies. Using ROC analysis, we determined the CenTauR cut‐off for positivity (T+) that maximized the Youden index for discriminating between FDA‐approved positive/negative visual reads. Three separate cohorts, scanned using [ 18 F]flortaucipir (ADNI), [ 18 F]MK‐6240 (CPAS), and [ 18 F]RO‐948 (BioFINDER‐2), were matched 1:1 by age, MMSE, amyloid‐β, and clinical diagnosis. CenTauR‐based metrics were compared across these cohorts. Result A cut‐off of 18 CenTauRs was found to optimally classify [ 18 F]flortaucipir PET visual reads (Figure 1B). The matching procedure identified 1089 participants (363 per cohort). The frequency of T+ using the 18 CenTauRs cut‐off for the Meta‐Temporal ROI was highly comparable across tracers across groups, except for the Aβ‐positive cognitively unimpaired group, where variability was more pronounced due to a smaller sample size (Figure 2A). Similarly, tau‐PET discriminative accuracy for symptomatic AD vs controls remained similar across [ 18 F]flortaucipir and [ 18 F]MK‐6240 (Figure 2B). In a separate sample of 212 matched participants from ADNI ([ 18 F]flortaucipir) and AIBL ([ 18 F]MK‐6240) with baseline and 1‐year follow‐up tau‐PET scans, 1‐year change in CenTauRs was comparable (Figure 2C). An exploratory voxelwise transformation, utilizing the Meta‐Temporal conversion equation in a representative case scanned with both [ 18 F]flortaucipir and [ 18 F]MK‐6240, demonstrates the potential for voxelwise CenTauR harmonization (Figure 3). Conclusion These analyses suggest that CenTauR harmonization increases the comparability of tau‐PET data acquired with different tracers. Additional validation analyses with larger cohorts including other radiotracers ([ 18 F]PI‐2620) are underway.