Citations

Purpose: Fenestrated stent-grafts with proximal bare-metal fixation stent (BMFS) may provide better rotational movement to facilitate vessel catheterization, but novel designs with covered fixation stents (CFSs) have been increasingly utilized with lower profile fabric. This study aimed to evaluate procedural metrics and outcomes of fenestrated endovascular repair (FEVAR) using BMFS and CFS devices. Methods: Clinical data of 502 consecutive patients enrolled in a prospective, non-randomized investigational device exemption (IDE) study were reviewed. Patients with 4-vessel fenestrated stent-grafts with BMFS or CFS for treatment of complex abdominal aortic aneurysms (CAAAs) and Extent IV thoracoabdominal aortic aneurysms (TAAAs) were included. Patients with Extent I-III TAAAs and stent-grafts designed with <4 fenestrations or scallops were excluded. Endpoints were technical success, radiation exposure, major adverse events (MAEs), patient survival, freedom from secondary interventions, and target artery instability (TAI). Results: There were 147 patients (29%; 85% male, median 75 years old) treated by FEVAR using 4-vessel fenestrated stent-grafts with BMFS in 79 patients or CFS in 68 patients. Patients treated with BMFS designs had significantly (p<0.05) higher prevalence of cigarette smoking and peripheral artery disease and less often had Extent IV TAAAs. Use of BMFS designs decreased from 88% (64/73) to 20% (15/74) after 2018 (p<0.001). Technical success was similar in patients treated with or without BMFS designs (99% vs 100%, p=0.47), but total operating time and cumulative air karma were significantly lower (p<0.05) in patients with CFS designs. Overall 30-day mortality was 1%, with no difference in mortality and MAEs among patients treated with or without BMFS (1% vs 1%, p=1.0 and 15% vs 12%, p=0.59), respectively. Patient survival at 1 and 3 years was 95%±2%, and 85%±4% for all patients with no difference between groups (p=0.51). Freedom from secondary interventions was 88%±3.6% for patients with BMFS and 86%±4.6% for those with CFS at 1 year (p=0.71), with also no difference at 3 years (p=0.55). Conclusion: FEVAR for CAAAs and Extent IV TAAAs was performed with high technical success, low mortality, and MAEs, independent of the use of BMFS. There is no difference in patient survival and freedom from secondary interventions in patients treated with or without BMFS. Clinical Impact One hundred forty-seven patients were treated with bare-metal fixation-stent (79) or covered fixation stents (68). Technical success was similar (p=.47). Overall 30-day mortality was 1%, with no difference in major adverse events (MAEs; p=.59). At 1- and 3-year, there was no difference in patient survival (p=.51), freedom from secondary intervention (p=.71). In conclusion, FEVAR for CAAAs and Extent IV TAAAs was performed with high technical success, low mortality and MAEs, independent of the use of bare-metal fixation stent.

Objective: Target vessel stenosis or occlusion is a common indication for secondary intervention after fenestrated-branched endovascular aortic repair requiring long-term imaging surveillance including duplex ultrasound (DUS). This study aimed to describe and compare longitudinal changes in peak systolic velocity (PSV) measurements for renal and mesenteric arteries targeted by directional branches (DBs) or reinforced fenestrations (RFs). Methods: Patients enrolled in a prospective, nonrandomized study (2013-2020) had DUS of celiac axis, superior mesenteric artery, and renal arteries (RAs) obtained preoperatively, at 6 to 8 weeks, 6 months, and annually. Vessels with preprocedural stenosis were excluded. Outcomes were variations in PSV over time for target vessels incorporated by DBs or RFs, differences in balloon-expandable stent-grafts (BESGs) and self-expandable stent-grafts (SESGs), PSV measurements prior to secondary interventions related to vessel stenosis, and a predictive value of PSV for stenosis requiring secondary intervention. Results: A total of 419 patients (292 male, mean age 74 ± 8 years old) were enrolled, with 1,311 target vessels analyzed preoperatively, including 607 mesenteric and 704 RAs. Over a median follow-up of 23 months (interquartile range [IQR], 7-36), PSV measurements decreased in the first 6 to 8 weeks after DB incorporation, remained stable, followed by a nonsignificant increase at 5 years. PSV increased in the first 6 months using RFs with postoperative velocities significantly higher ( P < .05) for RFs compared to DBs. Branched mesenteric vessels stented with BESGs had higher velocities than SESGs ( P < .05). Of the 23 target vessels treated by secondary intervention for stenosis, 19 (83%) had velocities above the thresholds for native, nonstented vessels. Furthermore, in RAs (n = 20) PSV effectively predicted clinically relevant stenosis, AUC was 0.98, with a 231 cm/s threshold offering 84% sensitivity with 100% specificity. Conclusion: Longitudinal follow-up shows that velocity changes vary depending on the type of incorporation, vessel, and bridging stent. For DBs, PSV decreased initially, stabilized, and showed a nonsignificant increase at 5 years. In contrast, PSV increased with RFs and remained higher than DBs. Despite these variations, velocities remained below established thresholds for clinically significant stenosis in nonstented vessels. Criteria for in-stent stenosis may differ, and PSV alone should not be the sole indicator for reintervention. Clinical Impact This study provides new insight into duplex ultrasound (DUS) surveillance after fenestrated and branched endovascular aneurysm repair (FB-EVAR). Peak systolic velocity (PSV) trends differed between fenestrations and branches, and stent type influenced flow dynamics. Importantly, most vessels with secondary interventions had elevated PSVs, but many others exceeded native stenosis thresholds without clinical consequence. Despite these variations, velocities remained below established thresholds for clinically significant stenosis in non-stented vessels. Criteria for in-stent stenosis may differ, and PSV alone should not be the sole indicator for reintervention.The reported PSV measurements served as a benchmark for DUS surveillance following FB-EVAR.

Abstract Traumatic brain injury (TBI) can lead to chronic complications, including headache and facial hypersensitivity. Second-impact syndrome (SIS), occurring when a second TBI precedes recovery from an initial injury, often causes severe long-term symptoms. Neuroinflammation is implicated, but the comprehensive pathophysiology of SIS remains unclear. This study characterized neurological/behavioral outcomes, facial nociception, plasma inflammatory markers, and central nervous system (CNS) histopathology in rat models of SIS and single mild TBI. Female Wistar rats (n = 6/group) were assigned to naïve control, sham surgery, single impact (TBI), or double impact (SIS; intervals: 1h, 24h, 3d, 7d, 14d). Mild TBI was induced using a modified Marmarou weight-drop model. Assessments (facial mechanical sensitivity via von Frey, Neurological Severity Scale (NSS), Neurobehavioral Scale (NBS)) were performed pre-injury and on days 1,3,5,7 post-injury. Plasma IL-6 and TNF-α were measured by ELISA. Histopathology (H&E) assessed CNS inflammation. All impact groups developed transient facial mechanical allodynia and acute neurobehavioral deficits (impaired NSS/NBS at day 1). SIS groups, particularly with longer intervals (≥ 24h), exhibited more prolonged facial allodynia and significant neurological deficits compared to single TBI at specific timepoints. Plasma cytokines showed minimal changes. Histopathology revealed significantly elevated CNS inflammation in both TBI and SIS groups versus controls, with SIS groups (intervals 24h-14d) showing robust responses. Repeated TBI, especially with longer recovery intervals between injuries, results in more severe and prolonged facial allodynia, neurological deficits, and CNS neuroinflammation than a single mild TBI. These findings illuminate SIS pathophysiology and underscore the critical need for protection post-concussion.

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 Patients undergoing transcatheter aortic valve implantation (TAVI) often require long‐term oral anticoagulation (OAC), but it is unclear whether to continue or interrupt OAC during the procedure. This meta‐analysis compares clinical outcomes of continuing versus interrupting OAC during TAVI. PubMed, Embase, and Cochrane Central databases were searched from inception to September 2024 for studies comparing continuation versus interruption of OAC in patients undergoing TAVI with an indication for OAC, including vitamin K antagonists and direct oral anticoagulants. Risk ratios (RR) with 95% confidence intervals (CI) were pooled using a random‐effects model. Sensitivity analysis was performed using the Hartung‐Knapp‐Sidik‐Jonkman method. Three studies were included, one randomized controlled trial and two cohort studies, with 2773 patients, of whom 1314 (47.4%) continued OAC during TAVI. At a 30‐day follow‐up after TAVI, there were no significant differences between groups in all‐cause mortality (RR 0.74; 95% CI 0.45–1.20; p = 0.22), any bleeding (RR 1.08; 95% CI 0.81–1.43; p = 0.60), and major bleeding (RR 0.90; 95% CI 0.67–1.21; p = 0.48). However, the continued OAC group was associated with a lower stroke rate (RR 0.65; 95% CI 0.42–1.01; p = 0.053), also attested after a sensitivity analysis (RR 0.65; 95% CI 0.47–0.90; p < 0.03). In patients with an indication for OAC undergoing TAVI, uninterrupted anticoagulation is associated with similar thrombotic and hemorrhagic outcomes compared to interrupted OAC. Stroke risk was lower in the continued OAC group, with a significant reduction, as demonstrated in sensitivity analysis.

ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide and, despite treatment advances, immune suppression remains an obstacle to effective therapy. Effector CD4 + T cells (CD4 + Teffs) are critical for antitumor immunity, but their function is often inhibited by regulatory T cells (Tregs), which accumulate in lung tumors and perform suppressive functions through multiple mechanisms. This suppression leads to tumor progression and poor patient outcomes. However, the mechanisms underlying Treg-mediated suppression are not fully understood. Here, we identify the extracellular ATP receptor P2RX7 as a key regulator of Treg function in lung tumors. Using a murine lung cancer model induced by Lewis lung carcinoma cells, we demonstrate that P2RX7 enhances the suppressive capacity of tumor-infiltrating Tregs, promoting tumor growth. In T cell-specific P2RX7-KO mice, reduced Treg infiltration was accompanied by increased CD4 + Teff accumulation and improved tumor control. Treg-specific P2RX7-KO mice exhibit reduced tumor growth, confirming a cell-intrinsic role of P2RX7 in Tregs. Suppression assays revealed that tumor-infiltrating WT Tregs have greater suppressive activity compared to P2RX7-KO Tregs, which failed to inhibit type 1 and Tfh-like responses. This was associated with increased tumor-specific IgG production by lung B cells in P2RX7-KO mice. We also observed that WT Tregs express higher levels of the immunosuppressive surface molecule CTLA-4 when compared to P2RX7-KO Tregs. In summary, we show that P2RX7 expression on Tregs is essential for their suppressive function in lung cancer, and targeting of P2RX7 may constitute a novel strategy to improve lung cancer treatment by alleviating Treg-mediated immune suppression.

AbstractBackgroundTau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.MethodWe assessed 51 cognitively unimpaired (CU) and 49 cognitively impaired participants (mean [SD] age 69.4 [7.5] years) with at least two tau‐PET ligands ([18F]MK6240, [18F]AV1451, and/or [18F]RO948) at McGill University, as part of the HEAD study. We calculated standardized uptake value ratios (SUVR) in Braak‐like regions of interest (ROI) for each ligand and investigated their association using Spearman’s correlation. Thresholds defined the presence of tauopathy in each Braak ROI, which was used to assign a Braak stage to each participant. Finally, we assessed the agreement between the Braak staging provided by each tracer, both for the traditional (using separate Braak stages – 0, I, II, III, IV, V, and VI) and simplified (using joint Braak stages – 0, I‐II, III‐IV, and V‐VI) frameworks.ResultIn all Braak ROIs, we found positive correlations between the SUVR values of the three tracers (Figure 1). The strongest correlation was between [18F]MK6240 and [18F]RO948 in Braak II (r=0.94), and the weakest between [18F]AV1451 and [18F]RO948 in VI (r=0.51). Inter‐tracer agreement regarding the latest stage of abnormality was substantial or nearly perfect between pairs of tracers but moderate between the three tracers (Figure 2A). The simplified framework presented greater agreement compared to traditional Braak staging, except between [18F]MK6240 and [18F]RO948. At the ROI level, the lowest agreements were observed for Braak II and I‐II, when [18F]MK6240 and [18F]RO948 were compared to [18F]AV1451 (Figure 2B‐C). [18F]AV1451 had the highest probability of overestimating the Braak stage assigned by [18F]MK6240 and by [18F]RO948, especially at earlier stages (Figure 3).ConclusionThe ligands presented moderate to nearly perfect agreement for in vivo staging of AD severity. Off‐target binding of [18F]AV1451 to the choroid plexus might explain disagreements at early stages. Overall, slight improvements in agreements were achieved with the simplified framework, as observed in histopathological staging.

AbstractBackgroundTau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.MethodWe assessed 51 cognitively unimpaired (CU) and 49 cognitively impaired participants (mean [SD] age 69.4 [7.5] years) with at least two tau‐PET ligands ([18F]MK6240, [18F]AV1451, and/or [18F]RO948) at McGill University, as part of the HEAD study. We calculated standardized uptake value ratios (SUVR) in Braak‐like regions of interest (ROI) for each ligand and investigated their association using Spearman’s correlation. Thresholds defined the presence of tauopathy in each Braak ROI, which was used to assign a Braak stage to each participant. Finally, we assessed the agreement between the Braak staging provided by each tracer, both for the traditional (using separate Braak stages – 0, I, II, III, IV, V, and VI) and simplified (using joint Braak stages – 0, I‐II, III‐IV, and V‐VI) frameworks.ResultIn all Braak ROIs, we found positive correlations between the SUVR values of the three tracers (Fig. 1). The strongest correlation was between [18F]MK6240 and [18F]RO948 in Braak II (r=0.94), and the weakest between [18F]AV1451 and [18F]RO948 in VI (r=0.51). Inter‐tracer agreement regarding the latest stage of abnormality was substantial or nearly perfect between pairs of tracers but moderate between the three tracers (Fig. 2A). The simplified framework presented greater agreement compared to traditional Braak staging, except between [18F]MK6240 and [18F]RO948. At the ROI level, the lowest agreements were observed for Braak II and I‐II, when [18F]MK6240 and [18F]RO948 were compared to [18F]AV1451 (Fig. 2B‐C). [18F]AV1451 had the highest probability of overestimating the Braak stage assigned by [18F]MK6240 and by [18F]RO948, especially at earlier stages (Fig. 3).ConclusionThe ligands presented moderate to nearly perfect agreement for in vivo staging of AD severity. Off‐target binding of [18F]AV1451 to the choroid plexus might explain disagreements at early stages. Overall, slight improvements in agreements were achieved with the simplified framework, as observed in histopathological staging.

ABSTRACT Background Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC. Methods We performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold treatment-naïve TNBCs. Functional analyses, including loss-of-function and reconstitution experiments, were conducted to investigate the role of Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of anti-cancer Antibody Drug Conjugates (ADCs), in promoting TNBC progression. A humanized TROP2 syngeneic TNBC model was used to assess the effects of TROP2-targeting in combination with anti-PD1 therapy. Additionally, data from patients treated with immune checkpoint blockade were used to test hypotheses from the preclinical findings. Results We reveal that TROP2 controls barrier-mediated immune exclusion in TNBC through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and predicts poor outcomes in TNBC. We demonstrate that TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. We show that TROP2 targeting via hRS7, the antibody component of the ADC Sacituzumab govitecan (SG), enhances the anti-PD1 response and improves T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Conclusions This study defines a new mechanism of barrier-mediated immune exclusion in cancer controlled by TROP2-dependent tight junctions. This mechanism drives tumor progression but can be targeted via TROP2-directed therapy to activate anti-tumor immunity and enhance immunotherapy response. What is already known on this topic Barrier-mediated immune exclusion is emerging as a mechanism of immune evasion in cancer such as triple-negative breast cancer (TNBC), but its molecular underpinnings remain poorly understood. TROP2 is a surface glycoprotein targeted by antibody-drug conjugates such as Sacituzumab govitecan, yet its functional role beyond drug delivery has been unclear. What this study adds This study identifies TROP2 as a key regulator of tight junction-mediated immune exclusion in TNBC, independent of its intracellular signaling function. TROP2 promotes an immune-cold tumor microenvironment by enforcing mechanical barriers that limit T cell infiltration. How this study might affect research, practice or policy These findings establish TROP2 as a functional driver of immune evasion and provide a mechanistic rationale for combining TROP2-targeting therapies with immune checkpoint inhibitors to overcome resistance in immune-excluded tumors.

Background: Autologous arteriovenous fistulas (AVF) are the preferred choice for hemodialysis access due to their longevity, lower complication rates, and mortality benefit. Their use is limited by vein size and necessary maturation period, excluding up to a third of patients. A novel solution to this problem is pump-assisted vein dilation (PAVD), where the vein is “pre-matured” using a miniatured centrifugal pump that draws blood from a central vein, delivering it into the recipient vein (e.g., cephalic) under pressure. The aim of this study is to report the initial safety studies in sheep and a first-in-human (FIH) pilot study as a prelude to a phase 2 clinical study. Methods: Preclinical Study: Three anesthetized male sheep (50-70 kg) underwent cephalic PAVD using the Amplifi Vein Dilation System for 7 days (mean). These subjects and two control animals (no-PAVD) underwent brachiocephalic AVF creation and observation for 6 weeks, with weekly surveillance fistulagrams and duplex ultrasound (U/S). AVFs were then explanted for histological analysis. Clinical Study: Ten patients were recruited for a phase 1 study. They underwent cephalic PAVD for 7 days (mean), followed by brachiocephalic AVF creation and surveillance at 2 and 6 wks. Data on vein diameter and flow rates of the AVF were collected, as well as safety data on complications such as bleeding, infection, and embolism. Results: Preclinical Study: PAVD increased mean±SD vein diameter (mm) from 4.5±1.0 to 8.4±1.0 (p=0.005); leading to greater cephalic vein diameter at the time of AVF creation in the PAVD group vs no-PAVD (8.2±1.3 vs. 3.3±0.7; p<0.05). After 6 wks of maturation, mean vein diameter was still greater in the PAVD group compared to no-PAVD (12.8±2.8 vs. 8.4±0.7; p<0.05). Mean flow increased at 41 mL/min/day versus control animals at 5.2 mL/min/day. Clinical Study: All subjects saw an increase in vein diameter with PAVD at baseline vs. at 6 wks (2.3±0.5 vs. 5.2±0.7; p<0.05), as well as mean flows (mL/min) (285±30 vs. 724±149). There were no Amplifi-related or procedure-related serious adverse events. Conclusion: The translation of PAVD for AVF creation from bench-to-bedside provides safety and efficacy data on a novel solution that can increase the availability of autologous AVFs in patients excluded due to size criteria. The Amplifi vein dilation system can effectively and rapidly dilate peripheral veins without stimulating neointimal hyperplasia. PAVD should be explored in a phase 2 clinical study.