Cancer-associated thrombosis (CAT) is a frequent and severe complication of malignancy. While patients are anticoagulated, risks of recurrent venous thromboembolism (VTE) and major bleeding (MB) remain substantial, but data are limited according to specific tumor sites and in patients with frailty. Our objective was to evaluate 6-month incidences of recurrent VTE, MB, and death in patients with CAT treated with tinzaparin, and to assess the influence of tumor site and frailty on these risks. Individual patient-level data from 1,413 patients were pooled from three prospective cohort studies and the tinzaparin arm of a randomized controlled trial. Frailty was defined as age ≥75 years, creatinine clearance <50 mL/min, body weight ≤50 kg, or ECOG ≥2. Cumulative incidences were estimated using Kalbfleisch and Prentice method and plotted to illustrate the benefit-risk balance by tumor site and frailty. At 6 months, cumulative incidences of recurrent VTE and MB were 6.2% and 3.4%, respectively. Recurrent VTE incidence surpassed MB incidence in gastrointestinal, lung, genitourinary, and gynecological cancers, whereas MB risk exceeded VTE risk in breast cancer. Among patients with frailty criteria, recurrent VTE risk increased with the number of frailty factors, while MB remained relatively stable. In patients with CAT receiving tinzaparin, VTE recurrence, unlike bleeding risk, varies according to tumor site and patient frailty.. In CAT patients with frailty treated with standard full-dose tinzaparin, these findings do not support routine dose modification.
Objective. Joint assessment of tissue oxygenation and microvascular perfusion could offer valuable insights into vascular function across a wide range of biomedical applications. Multispectral photoacoustic imaging enables the evaluation of blood oxygenation, while ultrasound localization microscopy provides sub-diffraction visualization of the microvasculature and blood perfusion. Here, we combine these two complementary modalities to simultaneously generate co-registered, volumetric maps of blood oxygenation and perfusion. Approach. Photoacoustic imaging and ultrasound localization microscopy are both ultrasound-based techniques. We developed an imaging platform that integrates the two modalities using a single planar ultrasonic matrix array, a state-of-the-art array for 3D ultrasound localization microscopy. The bimodal platform was validated in vitro using vessel-mimicking phantoms, then in vivo in mice. Main results. In vitro bimodal images of tubes injected with contrast agents demonstrated a coregistration accuracy of 20 μm and revealed complementary structural and functional information. Multispectral photoacoustic imaging achieved oxygen saturation measurements spanning the physiological range (60-95
BACKGROUND:Activating mutations in the RAS-MAPK pathway account for ~20% of cases of pediatric hypertrophic cardiomyopathy (HCM) and are associated with poor outcomes. Mavacamten is approved for obstructive HCM; however, patients with RAS-associated HCM have not been included in the clinical trials so far. We aimed to characterize the functional and energetic disturbances in an in vitro RAS-HCM model and evaluate the therapeutic effects of mavacamten. METHODS:Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying a CRISPR-induced BRAF (p.Thr599Arg) mutation and their isogenic control were studied. Cell size, contractility, and transcriptomics were assessed, while energetics were determined using MitoStress assays, live ATP imaging, and NAD(P)H/FAD autofluorescence. RESULTS:BRAF-mutant hiPSC-CMs showed hypertrophy, hypercontractility, increased mitochondrial cofactor pools, and enhanced maximal respiratory capacity. Despite this, they developed ATP deficiency in response to rapid pacing, suggesting mitochondrial inefficiencies or an overwhelming ATP demand. Mavacamten normalized mitochondrial respiration and excessive ATP consumption, partially restoring energetic balance and highlighting hypercontractility as a major burden in RAS-HCM. CONCLUSIONS:BRAF-mutant cardiomyocytes recapitulate the characteristics of HCM in vitro. Mavacamten mitigates dysfunctions and restores energetic balance under stress conditions, indicating it holds potential as a therapeutic option for RASopathy-associated HCM. IMPACT:BRAF-mutant hiPSC-CMs exhibit hypertrophy, hypercontractility, and energetic imbalance under stress, reproducing pathological characteristics of RAS-HCM. Mitochondrial stress tests showed a higher basal respiration and maximal respiratory capacity, indicating that mitochondrial dysfunction is not the main cause of this imbalance. Mavacamten normalized basal mitochondrial respiration and ATP utilization under stress, indicating that hypercontractility represents a major energetic burden. The beneficial effects of mavacamten on BRAF-mutant hiPSC-CMs suggest therapeutic potential for treating RASopathy-associated HCM.
