Citations

Abstract INTRODUCTION Neurofilament light chain (NfL) quantification aids in diagnosing and predicting neurological disorders, but clinical and laboratory practices vary across centers. Differences in result interpretation and reporting further challenge test commutability. This study aimed to review the global analytical and post‐analytical methods used for NfL measurement in routine clinical practice across different contexts. METHODS We established an international working group (WG) and distributed a survey to its members to gather information on context of use (COU), (pre) analytical methods, cutoff usage, as well as the interpretation and reporting of NfL measurements. RESULTS Among the centers, 63% measured NfL in cerebrospinal fluid (CSF), 87% in blood, and 53% in both. COU was widespread, with 50% defining pathological cutoffs based on publications and 42% considering age. Reporting was primarily done through numeric results (95%). DISCUSSION Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice. Highlights Unique international overview of current analytical and post‐analytical methods for neurofilament light chain (NfL) measurement in routine clinical practice. Tailored sheets for each neurological application. Strategies to harmonize cutoffs, reporting, and interpretation of NfL's measurement.

Abstract Atrial fibrillation (AF) is increasingly diagnosed early, close to its first occurrence due to: (i) increased public awareness with self-screening; (ii) health care initiatives including population screening and opportunistic case finding; and (iii) increased use and surveillance of implantable cardiac devices. At its onset, AF is often low burden, and cardiovascular co-morbidities may be absent or at an early stage. Thus, the management of recent-onset AF has become an issue of growing importance. Professional guidelines have traditionally focused on anticoagulant thromboprophylaxis, generally recommending a cautious approach to rhythm control, and priority has been given to rate control to alleviate symptoms. In recent guidelines, the importance of managing lifestyle and co-morbidities has increased. The AF-SCREEN collaboration proposes that a vigorous approach to active management of recent-onset AF may be warranted. This includes addressing co-morbidities and promoting healthy lifestyles to prevent the emergence or progression of AF and associated cardiovascular disease, as well as the initiation of active rhythm control ± anticoagulation to prevent AF-related morbidity and mortality, including stroke and heart failure (HF). Intuitively, intervention early after AF onset would be beneficial since lifestyle and co-morbidity management, plus rhythm control and anticoagulation, are important contributors to improved outcomes in patients with established AF, but robust evidence is lacking for recent-onset AF. There is a delicate balance between achieving favourable outcomes such as preventing strokes, HF and AF progression vs the complications and potential adverse effects of interventions. Given the serious long-term consequences, innovative approaches are necessary to determine the value and risks of initiating active therapy very early in the course of AF. More data are needed to guide the best management of recent-onset AF, bearing AF burden in mind. Long-term studies using large national databases linked to electronic medical records and rhythm monitoring devices offer excellent opportunities. Shorter-term studies focusing on reducing AF burden to slow AF progression and studies focusing on outcomes such as HF could be used in both randomized clinical trials and observational cohort studies.

Abstract Background Jamestown Canyon virus (JCV) is an emerging arboviral pathogen transmitted by mosquitoes in the United States and Canada. It is associated with neuroinvasive diseases and a wide spectrum of clinical presentations. Methods A retrospective chart review was conducted at the Mayo Clinic Health System in Northwest Wisconsin from January 2018 to December 2024, analyzing data from 12 hospitalized patients diagnosed with JCV infection. This study aimed to characterize the clinical, laboratory, imaging, and outcome profiles of the disease. The cohort included individuals aged 19 to 75 years, predominantly male (75%), with all patients reporting outdoor activity and 75% being pet owners. Results Only 27% of the patients recalled a mosquito bite. Among the cohort, 2 patients acquired an infection during the first trimester of pregnancy and subsequently delivered healthy infants. Coinfections with Borrelia burgdorferi were found in 33% of cases, while 16.7% of cases were seropositive to La Crosse virus. Magnetic resonance imaging of the brain was obtained in 5 patients and was nonspecific. Cerebrospinal fluid analysis demonstrated lymphocytic or monocytic pleocytosis in all cases where the test was performed. Conclusions All patients experienced clinical improvement, with only 1 developing lingering neurological symptoms in the form of brain fog. This study highlights the clinical heterogeneity of JCV infections and underscores the importance of including JCV in the differential diagnosis for patients residing in or traveling from endemic areas.

Abstract This review explores the pivotal role of preanalytical variables in bringing liquid biopsy approaches into the clinic for brain tumors. Preanalytical variables encompass a range of critical issues, from blood sample collection and handling to the impact of tumor heterogeneity and patient-specific factors. These variables introduce challenges such as false positives, false negatives, and variability in the analysis of tumor signals, which can hinder the diagnostic and prognostic utility of liquid biopsies. Understanding the nuances of preanalytical variables is essential for the successful implementation of liquid biopsy in clinical settings. This paper delves into strategies aimed at mitigating the influence of preanalytical variables by emphasizing the importance of standardized sample collection protocols, optimized sample processing and storage, quality control measures, and the integration of multiple liquid biopsy modalities.

Abstract Background and Objectives Radiomics extracts imaging features that may not be detectable through conventional volumetric analyses. Given their role in multiple sclerosis (MS), we applied radiomics to thalamic nuclei and examined their associations with cognitive performance. Methods A total of 601 individuals were included (342 people with MS-PwMS from two cohorts, and 259 healthy controls-HC). Radiomic features (RF) and volumes were extracted from the whole thalamus, five thalamic nuclei, and the putamen segmented on 3D T1-weighted images. Cognitive performance was assessed using the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in PwMS, and the Digit Symbol Substitution Test (DSST) in HC. In the first MS cohort, multivariate linear regression in a discovery set (N=103) identified thalamus-derived RF associated with SDMT, which were retested in a replication set (N=63). Their associations with PASAT in a second MS cohort (N=176) and DSST in HC were also evaluated. We then tested whether the same RF, when extracted from the putamen, were associated with SDMT. LASSO models assessed the combined predictive value of RF and volumes. Figure 2 presents an overview of the involvement of different cohorts in the study, outlining the specific study objectives and the statistical analysis approaches employed. Results Twenty-eight RF–ROI pairs were associated with SDMT in the replication set (FDR<0.05). Of these, 24 were also associated with PASAT (FDR≤0.03), and 2 with DSST. Only ventral nuclei volume showed replicated associations among volumetrics. Only 4 putamen-derived pairs were associated with SDMT (FDR=0.04). LASSO results confirmed RF outperformed volumes. Discussion RF extracted from the thalamus are strongly associated with cognitive performance in PwMS, outperforming volumetric measures and supporting their potential as sensitive imaging biomarkers.

ABSTRACT Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

Abstract Most myelofibrosis (MF) drug approvals by Health Authorities are based on 1 or 2 outcome measures such as spleen volume reduction and/or improved quality-of-life. This 1–2 dimensional approach fails to capture the clinical complexity of MF. A European LeukemiaNet (ELN) taskforce developed a composite endpoint which allows multiple outcomes to be simultaneously measured. The panel used the Desirability-Of-Outcome-Ranking (DOOR) method to assign 25 outcomes into 4 quartiles based on a multi-dimensional desirability score and build a 5-layer composite outcome named Desirability-of-Myelofibrosis-Outcomes (DEMYO). Outcome operational definitions were tested by Delphi consensus and correlations with survival validated by a literature review. The outcomes assigned to the first two quartiles were negatively correlated with leukemia-free survival and survival. DEMYO comprehensively captures relevant MF clinical features and meaningful endpoints. Despite DEMYO requires validation based on available trial data, it is expected to improve the quality of Health Authority approvals for new drugs for MF.

1089 Background: T-DXd has become an important treatment option in mBC and other malignancies. Interstitial lung disease/pneumonitis (ILD) occurred in 10-14% of pts in the DESTINY-Breast trials (0-2% G5 ILD), and with potential lower incidence/severity in earlier line settings (Krop et al, ASCO 2023). We previously reported the Mayo Clinic Rochester, MN experience with T-DXd related ILD in mBC (Hoppenworth et al, ASCO 2024). Here, we expand the data to include patients treated at all locations of the Mayo Clinic Enterprise. Methods: We retrospectively identified pts with mBC who received ≥1 dose of T-DXd across the Mayo Clinic enterprise (Rochester, MN; Mayo Clinic Health System locations in MN/WI; Scottsdale, AZ; and Jacksonville, FL) between July 2022-December 2023. Demographic, mBC characteristics, and pulmonary clinical variables were abstracted from the clinical records. Data were summarized using descriptive statistics. Diagnosis of ILD was determined by treating clinicians, and severity was approximated to CTCAE V5 based on clinical documentation. Results: 252 pts with mBC received T-DXd during the study period. The majority were Caucasian (86%) and female (99%) with a median age of 63. 91 pts (36%) were current/formers smokers and 97 (39%) had prior pulmonary comorbidities. The majority had HER2 low (155, 62%) and HR positive (164, 65%) mBC. 35 (14%) developed any grade ILD [G1: 6 (17%), G2: 13 (37%), G3: 3 (8.6%), G4: 3 (8.6%), G5: 10 (29%)], with 15 (43%) presenting with ≥G3. 29 (83%) presented with at least 1 symptom (cough or SOB). Among those with previous pulmonary toxicity, 4 (33%) had previous pneumonitis in the ILD cohort. The median prior lines of all therapies (including endocrine therapy) were 5, with a median of 3 prior lines of chemotherapy in both the ILD (range 1-13) and non-ILD cohorts (range 1-13). Median onset to any grade ILD was 7 cycles. 20 pts (57%) received steroids for ILD. 14 (40%) had a bronchoscopy, all had a CT chest, 16 (46%) were hospitalized, 7 (20%) were intubated and 1 (3%) had a lung biopsy. Pts with G5 ILD had a median of 3 lines of chemo and a median of 8 cycles prior to onset of ILD, compared to 3 lines of chemo and a median of 7 cycles for those with G1-4 ILD. G5 pts were all Caucasian females, 5 were former smokers, 5 were non-smokers, 1 had a history of pneumonitis. T-DXd was rechallenged in 4 pts (G1-2 ILD) without ILD recurrence. Conclusions: In this retrospective case series,14% of pts treated with T-DXd experienced any grade ILD (4% G5) which is in alignment with the rate observed in the pivotal DESTINY-Breast trials, though with higher rates of G5 toxicity. Among those with ILD, increased lines of therapy were not associated with increased risk. Further research is needed to correlate risk.