Faculty Bibliography

INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICI) have transformed the treatment landscape for triple-negative breast cancer (TNBC), but their efficacy in older adults remains unclear. The objective of this systematic review is to evaluate the efficacy of ICI in patients with TNBC aged ≥65 years. MATERIALS AND METHODS/METHODS:We conducted a systematic review of randomized controlled trials (RCTs) between January 2013 and September 2023 using searches of Medline, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. RESULTS:Eighteen full-text articles representing 11 unique RCTs were identified. Only four RCTs reported efficacy outcomes for patients ≥65 years: KEYNOTE 355, KEYNOTE 522, IMpassion130, and IMpassion131. Across these trials, 602 of 3215 patients (18.7%) were 65 and older. The overall risk of bias was low to intermediate, but heterogeneity in trial design and endpoints precluded meta-analysis. Pembrolizumab, the only FDA-approved ICI in TNBC, showed a nonsignificant trend toward improved pathological complete response and event-free survival among older adults with early-stage TNBC (KEYNOTE-522). In the metastatic setting, pembrolizumab may improve overall survival in older patients with PD-L1 combined positive score ≥ 10 (KEYNOTE-355). All studies enrolled few older patients, and none prespecified age-stratified analyses. DISCUSSION/CONCLUSIONS:These findings highlight a major evidence gap and underscore the need for further research evaluating ICI outcomes in older adults with TNBC.

INTRODUCTION/BACKGROUND:Chronic traumatic encephalopathy (CTE) is a tauopathy linked to repetitive head impacts. Factors influencing brain regional susceptibility to tau deposition and spreading remain unclear. METHODS:We used three datasets: [18F]flortaucipir positron emission tomography (PET) in 157 former professional American football players and 53 controls (DIAGNOSE CTE); cortical myelin water fractions (MWF) in 50 healthy individuals (Myelin Water Atlas); and white matter (WM) tract MWF and functional connectivity (FC) in 100 healthy individuals (Human Connectome Project). We tested associations between tau-PET uptake and covariance in football players and typical cortical gray matter (GM) MWF, WM tract MWF, and FC. RESULTS:Cortical regions with lower typical GM MWF showed higher tau-PET uptake (β = -0.399, p = 0.001). WM tracts with lower typical MWF were associated with higher tau-PET covariance (β = -0.238, p < 0.001). Higher typical FC was associated with higher tau-PET covariance (β = 0.447, p < 0.001). DISCUSSION/CONCLUSIONS:In former football players at risk for CTE, regional susceptibility to tau deposition may be driven by low myelin and high FC.

PURPOSE/OBJECTIVE:This study evaluates radiographic outcomes and reoperations in patients undergoing anterior vertebral body tethering (VBT) of the lumbar spine. METHODS:A retrospective review of an EOS database identified pediatric patients who underwent lumbar VBT. Demographic and surgical data were collected, as well as radiographic and clinical outcomes including complications, reoperations, and conversion to posterior spinal fusion (PSIF). Analyses included paired t-tests, Wilcoxon signed-rank tests and chi-square. RESULTS:Thirty-two patients with idiopathic scoliosis who underwent thoracolumbar VBT with 2-year follow-up were included. Mean age at surgery was 13.7 ± 1.8 years (mean follow-up 2.0 ± 0.2 years); median Sanders score was 3 (50% ≤ 3). Lumbar Cobb decreased from 48° ± 12 to 20° ± 10 postoperatively (p < 0.001) with correction loss to 29° ± 12 at 2 years (p < 0.001). Tethered Cobb decreased from 46° ± 8 to 13° ± 9 postoperatively (p < 0.001), with correction loss to 17° ± 12 at 2 years (p = 0.284). At 2 years, 31% had > 5° of correction loss and 84% had a tethered Cobb < 30°. Correction loss did not differ by Sanders stage (p = 0.92). Seven patients (23.3%) demonstrated > 5° of additional curve correction postoperatively. Four patients (12.5%) had unplanned reoperation and five others (15.6%) required PSIF: 28.1% total reoperation rate. CONCLUSIONS:Lumbar VBT provided substantial initial correction with maintenance of correction across the tethered levels at 2-year follow-up. While most patients maintained a tethered Cobb angle < 30° at 2 years, 28.1% of patients underwent reoperation (12.5% UPROR; 15.6% PSIF conversion). Longer follow-up in larger multicenter cohorts is required to more accurately define lumbar VBT durability and conversion-to-fusion risk. LEVEL OF EVIDENCE/METHODS:IV.

BACKGROUND/UNASSIGNED:Recent observational studies have suggested that early treatment (<12 hours from diagnosis) of intermediate risk pulmonary embolism (PE) with catheter-based therapies may reduce morbidity and mortality. However, the effect of early versus late mechanical thrombectomy on acute pulmonary hemodynamics and right ventricular mechanics is less well defined. METHODS/UNASSIGNED:Patients enrolled in SYMPHONY-PE were divided into one of 2 groups based on the time from baseline CT pulmonary angiography to mechanical thrombectomy: Early <12 hours versus late ≥12 hours. The primary safety end point was the rate of major adverse events within 48 hours, as adjudicated by an academic independent safety board. The primary efficacy end point was the core-lab assessed mean change in right ventricle-to-left ventricle ratio from baseline to 48 hours. RESULTS/UNASSIGNED:=0.431) between groups, and there were no mortalities. The differences in efficacy outcomes were greatest in higher-risk patients per the Composite Pulmonary Embolism Shock score. CONCLUSIONS/UNASSIGNED:Early mechanical thrombectomy was associated with larger reductions in right ventricle-to-left ventricle ratio and mean pulmonary artery pressure, with no significant differences in safety event rates compared with patients who underwent late thrombectomy. Randomized trials are needed to test these associations. REGISTRATION/UNASSIGNED:URL: https://www.clinicaltrials.gov; Unique identifier: NCT06062329.

We assess the combined effect of sustained mucosal delivery of the anti-HIV small molecule S-acyl-2-mercaptobenzamide thioester 247 (SAMT-247) via an intravaginal ring (IVR) and ΔV1DNA/ALVAC-SIV/ΔV1gp120/alum (ΔV1-SIV) immunization in female macaques. The combined approach reduces the risk of vaginal SIV_mac251 infection by 82.8%, with 58% of animals remaining uninfected following 14 weekly low-dose challenges; about half of the initially protected animals also remain uninfected during a second challenge phase. Compared with a historical vaccine-only cohort, continued IVR use shows a trend toward improved protection. Protection correlates with the expansion of tolerogenic CD73⁺ dendritic cells, IL-10⁺ macrophages, IL-17-producing NKp44⁺ innate lymphoid cells (ILCs), and antibody-mediated natural killer (NK) cytotoxic activity targeting the V2 helical conformation. In vitro studies support ex vivo observations that SAMT-247 enhances gp120-reactive anti-inflammatory mucosal immunity and NK activity. These findings support sustained IVR-based delivery of SAMT-247 combined with V1-deleted immunogens as a promising strategy to prevent vaginal HIV transmission.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS:A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm3. Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS:A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION/CONCLUSIONS:VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

Cannabis policies vary from strict prohibition to commercialised legalisation and are rapidly evolving worldwide. Here, we reviewed evidence for associations between international cannabis policy changes from 2000-25 and cannabis use, cannabis use disorder, and other psychiatric disorders. Commercialised legal markets for non-medical use in Canada and the USA were associated with increased prevalence of cannabis use and cannabis use disorder in adults and increases in cannabis potency since legalisation. There was no consistent evidence for associations between policy change and the prevalence or incidence of psychotic disorders. Commercialised legalisation was associated with an increase in hospital admissions for psychosis, and for psychotic disorders comorbid with cannabis use disorder. Poorly regulated legal access to medical cannabis, in the absence of efficacy and safety data, could increase risk of harm. Policies that limit commercialisation, such as strictly regulated legalisation of medical or non-medical supply, were not as strongly associated with cannabis use or psychiatric disorders, but long-term evaluation is needed. There was little evidence that decriminalisation of non-medical cannabis in Europe, Africa, Oceania, and Asia was associated with cannabis use or psychiatric disorders.