Citations

Importance Tau positron emission tomography (PET) allows in vivo detection of neurofibrillary tangles, a core neuropathologic feature of Alzheimer disease (AD). Objective To provide estimates of the frequency of tau PET positivity and its associated risk of clinical outcomes. Design, Setting, and Participants Longitudinal study using data pooled from 21 cohorts, comprising a convenience sample of 6514 participants from 13 countries, collected between January 2013 and June 2024. Cognitively unimpaired individuals and patients with a clinical diagnosis of mild cognitive impairment (MCI), AD dementia, or other neurodegenerative disorders were included. Exposures Tau PET with flortaucipir F 18, amyloid-β (Aβ) PET, and clinical examinations. Tau PET scans were visually rated as positive according to a US Food and Drug Administration– and European Medicines Agency–approved method, designed to indicate the presence of advanced neurofibrillary tangle pathology (Braak stages V-VI). Main Outcomes and Measures Frequency of tau PET positivity and absolute risk of clinical progression (eg, progression to MCI or dementia). Results Among the 6514 participants (mean age, 69.5 years; 50.5% female), median follow-up time ranged from 1.5 to 4.0 years. Of 3487 cognitively unimpaired participants, 349 (9.8%) were tau PET positive; the estimated frequency of tau PET positivity was less than 1% in those aged younger than 50 years, and increased from 3% (95% CI, 2%-4%) at 60 years to 19% (95% CI, 16%-24%) at 90 years. Tau PET positivity frequency estimates increased across MCI and AD dementia clinical diagnoses (43% [95% CI, 41%-46%] and 79% [95% CI, 77%-82%] at 75 years, respectively). Most tau PET–positive individuals (92%) were also Aβ PET positive. Cognitively unimpaired participants who were positive for both Aβ PET and tau PET had a higher absolute risk of progression to MCI or dementia over the following 5 years (57% [95% CI, 45%-71%]) compared with both Aβ PET–positive/tau PET–negative (17% [95% CI, 13%-22%]) and Aβ PET–negative/tau PET–negative (6% [95% CI, 5%-8%]) individuals. Among participants with MCI at the time of the tau PET scan, an Aβ PET–positive/tau PET–positive profile was associated with a 5-year absolute risk of progression to dementia of 70% (95% CI, 59%-81%). Conclusions and Relevance In a large convenience sample, a positive tau PET scan occurred at a nonnegligible rate among cognitively unimpaired individuals, and the combination of Aβ PET positivity and tau PET positivity was associated with a high risk of clinical progression in both preclinical and symptomatic stages of AD. These findings underscore the potential of tau PET as a biomarker for staging AD pathology.

Abstract Medical devices that use electromagnetic fields for diagnostic and therapeutic purposes are rapidly evolving. Understanding the interactions between electromagnetic signals and biological tissue is fundamental to developing safe, novel diagnostic and therapy treatments. This study characterizes the dielectric properties of porcine hearts from 10 male and 10 female animals. Dielectric properties are measured using an open-ended coaxial probe dielectric spectroscopy method over a frequency range of 0.5 to 20 GHz. Scatter parameters (S11) collected from various anatomical cardiac locations (LA, RA, LV, RV, SA, IAS, IVS) are converted into frequency-dependent complex permittivity. The calculated dielectric properties vary regionally within the heart, indicating heterogeneity in tissue properties observed at microwave frequencies.

LBA3500 Background: BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC). The study previously met one of its dual primary endpoints (EPs) demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) by blinded independent central review (BICR) in the ORR subset. These results were the basis for the FDA accelerated approval of EC+mFOLFOX6 for BRAF V600E-mutant mCRC, including in the 1L, under Project Frontrunner. Here, we report the primary analysis of progression-free survival (PFS) by BICR, updated interim analysis of OS, updated safety, and other analyses. Methods: Eligible patients (pts) with untreated BRAF V600E-mutant mCRC were randomized 1:1:1 to receive EC, EC+mFOLFOX6, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs: ORR and PFS by BICR (EC+mFOLFOX6 vs SOC); key secondary EP: OS (EC+mFOLFOX6 vs SOC). Results: 637 pts were randomized to EC, EC+mFOLFOX6, or SOC. Baseline demographics and disease characteristics were generally balanced between arms. EC+mFOLFOX6 (data cutoff: Jan 6, 2025) demonstrated a clinically meaningful and statistically significant PFS improvement vs SOC, meeting the other dual primary EP; HR=0.53 (95% CI 0.407, 0.677; P<0.0001); median PFS 12.8 vs 7.1 mo. OS was clinically meaningful and statistically significant vs SOC; HR=0.49 (95% CI 0.375, 0.632; P<0.0001); median OS 30.3 vs 15.1 mo. Median PFS and OS in the EC arm were 6.8 and 19.5 mo. These data and response data for all randomized pts are shown in the table. Serious treatment-emergent adverse events occurred in 30%, 46%, and 39% of pts in the safety analysis set. Safety was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC. Clinical trial information: NCT04607421 . ECn=158 EC+mFOLFOX6n=236 SOCn=243 EC+mFOLFOX6vs SOCHR (95% CI)P-value a Median PFS b , mo (95% CI) 6.8(5.7, 8.3) 12.8(11.2, 15.9) 7.1(6.8, 8.5) 0.53 (0.407, 0.677) <0.0001 Median OS, mo (95% CI) 19.5(17.6, 22.5) 30.3(21.7, NE) 15.1(13.7, 17.7) 0.49 (0.375, 0.632)<0.0001 ORR, b % (95% CI) 45.6(38.0, 53.3) 65.7(59.4, 71.4) 37.4(31.6, 43.7) Median DOR b , mo (95% CI) c 7.0 (4.2, 11.6) 13.9 (10.9, 18.5) 10.8 (7.6, 13.4) DOR b ≥6 mo, n (%) c 29 (40.3) 110 (71.0) 38 (41.8) DOR b ≥12 mo, n (%) c 15 (20.8) 54 (34.8) 16 (17.6) Median time to response, b wk (range) c 6.6(4.3-86.4) 7.0(5.1-103.6) 7.3 (5.4-48.0) a 1-sided stratified log rank test. b By BICR. c Responders: n=72, n=155, and n=91. DOR, duration of response.

SUMMARY Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in developing severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in TB progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We proposed that by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis. GRAPHICAL ABSTRACT Brief In tuberculosis, necrotic granuloma-like structures release extracellular ATP (eATP), which triggers P2RX7-mediated immune cell death. CD39 degrades eATP, preventing P2RX7 activation and promoting macrophage survival, thereby limiting inflammation, tissue damage, and bacterial dissemination.

ABSTRACT An increasing number of cancer patients are benefiting from long term cancer-directed therapy with an ever-expanding arsenal of novel agents from monoclonal antibodies to small molecules and cellular therapies in addition to the mainstay cytotoxic chemotherapy. All these therapies are accompanied by a unique array of adverse events, which include kidney toxicity. In this context, the need for onco-nephrology expertise continues to grow. Oncologists and hematologists collaborate closely with onco-nephrologists to determine: (i) treatment options for special populations based on accurate assessment of patients’ glomerular filtration rate, (ii) supportive therapies for those whose treatment course is complicated by acute kidney injury, and (iii) pharmacologic strategies to continue or restart cancer therapy during kidney dysfunction. Here we outline 10 tips for common clinical scenarios in an outpatient onco-nephrology clinic.

e13701 Background: The optimal therapeutic strategy for advanced epithelial ovarian cancer (EOC) — primary debulking surgery (PDS) followed by adjuvant chemotherapy vs. neoadjuvant chemotherapy (NACT) followed by interval debulking surgery — remains debated. NACT is often chosen for unresectable disease, typically identified only during surgery. This study aims to develop a deep learning (DL) model to predict tumor resectability from pre-operative computed tomography (CT) scans. Methods: We retrospectively included EOC patients, FIGO stage III-IV, who underwent PDS between 01/ 2016 and 12/2023 at the European Institute of Oncology, Milan, Italy. The dataset included anonymized portal venous phase contrast-enhanced CT scans. Residual tumor (RT) annotations were extracted from operative reports and categorized as optimal RT (< 1cm) and suboptimal RT (≥1cm). A DL segmentation model (based on open-source TotalSegmentator) was used to identify pelvic/abdominal organ volumes and to remove couch artifacts. The dataset was split into training/validation (80%) and testing (20%) sets. A pre-trained Vision Transformer (ViT) encoder was adapted for 3D imaging, converting CT volumes into features refined by an attention mechanism and classified as optimal RT or suboptimal RT . We trained two ViT configurations (vit-base-patch16-224 and dinov2-small-imagenet1k-1-layer) and compared them with DenseNet121, a widely used Convolutional Neural Network (CNN) for image classification. Performance metrics included accuracy and F1 score. Results: Out of 521 patients, 416 (80%) had optimal RT and 105 (20%) suboptimal RT , the proportion being respected througouth the training/validation and testing groups. The median age at diagnosis was 60.0 years (IQR, 53.0-67.0). ViT models showed better performance compared to CNN in terms of accuracy (0.80 and 0.77 vs. 0.62) and F1 score (0.43 and 0.33 vs. 0.12). Conclusions: A pioneering ViT-based model was capable to predict tumor resectability from pre-operative CT scans in patients with advanced EOC. This improvement in performance, compared to CNN, might be due to the ViTs' ability to capture long-range dependencies and global context, which are crucial for predicting tumor resectability. In contrast, CNNs are limited by localized feature extraction and inductive bias, hindering their ability to capture the complex spatial relationships. By addressing the limitations of current radiological assessments, the model has the potential to serve as a clinical decision-support tool, enabling personalized management strategies for patients. Future work will focus on further improving the model performance.