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Human Epilepsy Project (1) Investigators. Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy Barnard SN, Chen Z, Holmes M, Kanner AM, Hegde M, Kuzniecky R, Lowenstein D, French JA. JAMA Neurol . 2025 Aug 25:e252949. doi: 10.1001/jamaneurol.2025.2949. Epub ahead of print. PMID: 40853673 Importance: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. Objective: To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. Design, setting, and participants: The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. Exposure: ASM (variable). Main outcomes and measures: The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). Results: Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21–44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33–3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7–16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8–3.2) than those who did (median, 7.4 months; 95% CI, 4.0–10.7). Those with infrequent pretreatment seizures were 0.30-fold less likely to be treatment resistant than those with very frequent seizures (hazard ratio, 0.30; 95% CI, 0.14–0.64; P = .002; Holm–Bonferroni-corrected P = .006). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (relative risk, 1.78; 95% CI, 1.26–2.52; P = .001). Conclusions and relevance: In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor.

Carotid blowout is the rupture of a carotid artery or branch vessel, a dangerous complication in post-treatment head and neck cancer patients. The purpose of this retrospective case review is to identify imaging features suggestive of eminent carotid blowout on routine surveillance post-treatment neck imaging, so that a prompt neuroendovascular consult is obtained and the patient is preemptively treated, thus improving patient outcomes. It is important to carefully interrogate the carotid vessels with appropriate window/leveling for irregularity, adjacent tissue ulceration, exposed vessel to either air or fluid, surrounding tumor, and pseudoaneurysm.

ABSTRACT Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, accounting for 90%–95% of all thyroid cancers worldwide. For many years, treatment options for patients with locally advanced or metastatic radioiodine refractory disease were limited. Advances in understanding oncogenic and angiogenic signaling pathways, such as vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet derived growth factor receptor, rearranged during transfection ( RET) , and BRAF have led to the development of targeted therapies that have transformed management over the past two decades. Multikinase inhibitors such as lenvatinib, sorafenib, vandetanib, and cabozantinib have demonstrated clinical efficacy in randomized clinical trials. Most recently, mutation-specific kinase inhibitors such as selpercatinib for RET -fusion positive cancers, and the combination of dabrafenib with trametinib for BRAF V600E -mutant disease, have been approved and further expanded treatment options for these patients. In this review, we summarize the current evidence on Food and Drug Administration-approved targeted therapies for metastatic thyroid cancer and discuss their clinical impact.

Background: Carriers of a pathogenic variant (PV) in BRCA1 face a high risk of breast cancer. This study estimated the risk of developing breast cancer according to mutation type and location. Methods: BRCA1 carriers with no personal history of breast cancer or bilateral mastectomy were included. Detailed information on clinical and family history was collected by questionnaire. Survival analysis was used to estimate 15-year cumulative risk according to PV type and location. Results: A total of 3677 BRCA1 carriers were followed for a mean of 7.2 years (range 0.1–15.0 years); 481 incident breast cancers were documented. Overall, the 15-year cumulative incidence was 25%. Risk estimates varied by exon, ranging from 9% (exon 21) to 19% (exon 12) to 36% (exon 15); however, strata were small. Carriers of four founder mutations common in Eastern Europe (c.5263_5264insC, c.181T > G, c.66_67delAG and c.4034delA) experienced a lower-than-expected cancer risk (15.9–24.4%) compared to other PVs (28.8%) (p = 0.02). Conclusions: Although our data suggests some variability in penetrance based on specific BRCA1 PV, this was based on a large number of founder mutations. Breast cancer management strategies should continue to be based on comprehensive risk assessment.

ABSTRACT Background This post hoc analysis examined the reduction in monthly headache days ( MHDs ) by frequency category shifts and associated improvements following eptinezumab treatment. Methods The DELIVER trial evaluated eptinezumab in adults with migraine for whom 2–4 previous preventive treatments failed. During a 24‐week, double‐blind, placebo‐controlled period followed by a 48‐week extension period, participants received IV eptinezumab 100 mg, 300 mg, or placebo every 12 weeks, with all receiving eptinezumab beginning Week 25 (dose‐blinded). Participants were categorized by MHD frequency: > 14, 8–14, 4 to < 8, 1 to < 4, 0. MHD category shifts were evaluated in the total population and several subgroups (including participants with > 14 baseline MHDs and early ≥ 50% responders). In participants reporting < 8 MHDs after all doses, the associated changes in headache intensity and disease status were evaluated. Results Of randomized participants, 88% (782/890) completed the trial. The percentage of participants randomized initially to eptinezumab who reported < 4 MHDs was 23% (138/592) over Weeks 1–12 and 47% (236/498) over Weeks 61–72; 9% reported 0 MHDs after the final dose. Of participants randomized initially to eptinezumab who shifted from ≥ 8 MHDs at baseline to < 8 over Weeks 1–12, 71% (170/241) reported < 8 MHDs for the rest of the trial; of those who shifted from > 14 to < 8 MHDs, 66% (49/74) reported < 8 MHDs for the rest of the trial. Reduction to < 8 MHDs was associated with robust improvements in headache intensity and disease burden. Conclusions Eptinezumab was associated with sustained reduction in MHD category, with some achieving headache/migraine freedom in patients with a history of preventive treatments that failed. Trial Registration ClinicalTrials.gov (identifier: NCT04418765; https://www.clinicaltrials.gov/ct2/show/NCT04418765 ) and EudraCT (identifier: 2019‐004497‐25; https://www.clinicaltrialsregister.eu/ctr‐search/search?query=2019‐004497‐25 )

ABSTRACT Background IDH mutations are found in 15%–20% of acute myeloid leukemia (AML). Recent evidence suggests that IDH mutation subtypes may respond differently to intensive chemotherapy. We evaluated blast clearance patterns, remission outcomes, and overall survival (OS) in AML patients with IDH2 R140, IDH2 R172, and IDH1 R132 mutations to assess differences in treatment response. Methods We retrospectively reviewed AML patients diagnosed at Mayo Clinic, Rochester (2016–2023) with NGS data and treated with intensive chemotherapy (7+3 or CPX‐351). Bone marrow blasts were assessed at diagnosis, mid‐induction, and end‐of‐cycle; blast clearance was defined as < 5%. Composite remission (CRc) included CR/CRi per ELN 2022. IDH2 responders were classified as early (after Cycle 1) or late (≥ 2 cycles). Blast reduction was calculated as log 10 (diagnosis blasts/end‐induction blasts) and normalized per day. OS was measured from diagnosis. Results Among 381 patients, 31 had IDH2 mutations (23 R140, 8 R172) and eight had IDH1 R132. Baseline blasts were similar. Mid‐cycle blasts were lower in R140 versus R172 (4% vs. 10%), with higher clearance (68% vs. 38%). End‐induction blasts were lower in R140 versus R172 (2% vs. 4%) with higher clearance (100% vs. 75%). IDH1 and IDH2 showed similar clearance patterns. Log 10 analyses showed deeper and faster blast reduction in R140 versus R172, with comparable kinetics between IDH1 and IDH2 . OS did not differ across subtypes. Early CRc in IDH2 ‐mutated patients was associated with numerically longer OS. Conclusion IDH2 R140 demonstrated faster blast clearance than R172, while remission and survival were similar across IDH subtypes. Trial Registration : The authors have confirmed clinical trial registration is not needed for this submission.

Abstract INTRODUCTION Brief digital cognitive measures may be a valuable and scalable alternative to traditional tests for improving early detection and disease monitoring in patients with early‐onset Alzheimer's disease (EOAD). METHODS We examined the convergent, diagnostic, and neuroanatomical validity of Tablet‐based Cognitive Assessment Tool (TabCAT) tests in the multisite Longitudinal Early‐Onset Alzheimer's Disease Study. Four hundred seventy‐five participants from 16 sites (83 cognitively unimpaired participants, 146 individuals diagnosed with mild cognitive impairment [MCI], and 246 with mild dementia) underwent TabCAT testing, including two executive/attentional tasks (Match and Flanker) and two visuospatial tasks (Line Length and Line Orientation). RESULTS TabCAT tests showed good convergent validity with traditional pen‐and‐paper tests. Match was the most accurate TabCAT test in differentiating among clinical groups (controls vs. MCI vs. dementia) and predicting amyloid positron emission tomography (PET) positivity in clinically impaired participants. TabCAT tests were associated with regional tau PET patterns. DISCUSSION TabCAT digital measures have promise for frontline identification of patients with EOAD. Highlights Four hundred seventy‐five participants from 16 US sites underwent tablet‐based cognitive assessment. Digital tests assessed executive function and visuospatial abilities. Digital tests correlated with traditional pen‐and‐paper cognitive tests. Match (test of executive function) differentiated clinical groups. Digital tests were associated with amyloid positron emission tomography (PET) status and regional tau PET patterns.

Multimodal imaging plays a central role in optimizing the evaluation and management of myocardial ischemia by leveraging the complementary strengths of echocardiography, cardiac magnetic resonance imaging (CMR), single photon emission computed tomography (SPECT), positron emission tomography (PET), and invasive coronary angiography (ICA). Noninvasive functional imaging is typically recommended for patients with intermediate to high pre-test probability of coronary artery disease, while coronary computed tomography angiography (CCTA) is preferred for low to intermediate risk. Stress echocardiography is valuable for detecting wall motion abnormalities and is particularly effective in multivessel or left main disease, where perfusion techniques may miss balanced ischemia. CMR offers high spatial resolution and quantitative assessment of myocardial blood flow (MBF), while SPECT and PET quantify ischemic burden, with PET providing superior accuracy for MBF and microvascular disease. ICA remains the gold standard for defining the presence, location, and severity of epicardial coronary stenosis. It is indicated when noninvasive imaging reveals high-risk features, when symptoms are refractory to medical therapy, or when noninvasive results are inconclusive. While ICA offers high spatial resolution, it alone cannot assess the hemodynamic significance of intermediate lesions, nor the coronary microvasculature. Adjunctive invasive hemodynamic and provocative coronary testing (e.g., Fractional Flow Reserve—FFR, invasive Coronary Flow Reserve—CFR, Index of Microcirculatory Resistance—IMR, acetylcholine test) provide essential insights, especially in ischemia with nonobstructive coronary arteries. Given its procedural risks, ICA should be reserved for cases where it will impact management. Intravascular imaging may be used to further characterize lesions. In summary, modality selection should be individualized based on patient characteristics, comorbidities, contraindications, and the need for anatomical versus physiological data. Integrating noninvasive and invasive modalities provides a comprehensive, patient-centered approach to ischemia evaluation.