Citations

OBJECTIVE Open resective surgery (ORS) has become the standard of care for focal drug-resistant epilepsy (DRE). However, minimally invasive surgical alternatives, such as laser interstitial thermal therapy (LITT), have also been shown to be safe and effective. A meta-analysis comparing both treatments is warranted to assess the benefits of each modality for focal DRE. METHODS A literature search was conducted until March 14, 2024, to identify studies comparing LITT and ORS in patients with DRE. The primary outcomes included seizure freedom (SF), length of hospital stay (LHS), and complication rate (CR). Subgroup analyses were performed based on age, epilepsy etiology, and propensity score–matched (PSM) studies. RESULTS Of 558 articles, 15 cohort studies met the authors’ inclusion criteria, encompassing 3873 patients for analysis. The rate of SF in the LITT group was 52.5% (95% CI 0.453–0.597, I 2 = 47.4%) and 67.1% (95% CI 0.602–0.739, I 2 = 57.4%) for the ORS group. LITT showed a significantly lower rate of SF compared to ORS (risk ratio [RR] 0.78, 95% CI 0.70–0.88, p ≤ 0.0001). However, when PSM studies (RR 0.85, 95% CI 0.63–1.15, p = 0.30) and studies on patients with temporal lobe epilepsy (TLE) (RR 0.88, 95% CI 0.67–1.14, p = 0.34) were analyzed, the SF rates were similar. Patients who underwent LITT had a significantly shorter LHS (mean difference 2.95 days, 95% CI 1.12–4.78, p < 0.00001), lower CR (RR 0.54, 95% CI 0.37–0.79, p < 0.002, I 2 = 32%), lower rate of ischemic stroke (RR 0.15, 95% CI 0.04–0.65, p = 0.01), and lower rate of permanent neurological deficits (RR 0.13, 95% CI 0.05–0.36, p < 0.0001). CONCLUSIONS Across unmatched studies evaluating focal DRE, ORS showed a higher rate of SF. However, pooled matched-cohort analyses showed no difference between interventions in achieving SF, a trend also noted in the authors’ PSM TLE sample. LITT, however, offered significantly shorter LHS and lower CRs. Future prospective studies should match patient populations to control for confounding factors and assess key outcomes, such as postoperative neurocognitive follow-up and quality of life measurements, in order to fully evaluate the risks and benefits of each approach.

Abstract Active learning strategies enhance medical education by fostering self‐directed learning, communication, and problem‐solving skills. The paper puzzle, a game‐based learning approach, provides an engaging way to reinforce anatomical knowledge and promote collaboration. This study assessed its impact on student performance and perceptions in clinical anatomy, comparing it to PowerPoint‐based imaging reviews and evaluating the role of Near Peer Teachers (NPTs). A prospective, longitudinal, quasi‐experimental study with a mixed‐methods approach was conducted on first‐year medical students enrolled in the Human Anatomy course. Surveys using a Likert scale assessed student and NPT perceptions, while focus groups and interviews provided qualitative insights. Thematic analysis identified key themes related to engagement, knowledge reinforcement, and effectiveness. A total of 907 medical students and 30 NPTs completed a survey, while 75 students and 10 NPTs participated in the qualitative phase. Students perceived the paper puzzle as an engaging and interactive review tool that reduced stress, increased involvement, and enhanced knowledge retrieval through collaboration and a structured gameplay loop. They also valued the emotional impact on learning. NPTs reported benefits for student motivation and teamwork but noted that time constraints limited content coverage. The activity's effectiveness was highly dependent on the NPT's facilitation, emphasizing the need for structured implementation. Findings suggested that game‐based learning strategies like the paper puzzle can improve motivation, teamwork, and content retrieving in anatomy education when carefully designed and effectively executed by NPTs.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

BACKGROUND: Whereas antiphospholipid syndrome (APS) is best known for increasing the risk of macrovascular thrombosis, APS vasculopathy is characterized by the abnormal proliferation of endothelial and smooth muscle cells, leading to occlusion of small blood vessels in the skin, kidneys, and heart, among other organs. The underlying mechanisms remain unclear, and targeted treatment options for patients with APS are lacking. METHODS: To identify and analyze APS microvascular endothelial cells (MVECs), skin biopsies of patients with APS complicated by livedo racemosa were characterized using single-cell RNA sequencing. CCN1 (cellular communication network factor 1) and CCN2 were identified in skin and kidney biopsies by immunofluorescence microscopy and in plasma by ELISA. Healthy dermal MVECs were cultured with APS patient–derived serum or immunoglobulin G (IgG), and relevant signaling pathways were characterized using quantitative PCR, immunoblotting, and immunofluorescence microscopy. The proliferation and migration of vascular smooth muscle cells were determined after exposure to conditioned medium from APS IgG–stimulated MVECs. A mouse model of APS IgG–accelerated neointima formation was developed. Anti-CCN2 monoclonal antibodies were tested in vascular smooth muscle cell functional assays and the mouse model. RESULTS: Increased endothelial cell expression of CCN1 and CCN2 was identified by single-cell RNA sequencing and further confirmed in APS skin by microscopy as well as in APS plasma by ELISA. Exposure of healthy MVECs to patient IgG triggered the upregulation of CCN1 and CCN2 via Toll-like receptor 4– and YAP1 (yes-associated protein 1)–mediated signaling. CCN2, originating from APS IgG–stimulated MVECs led to the proliferation and migration of vascular smooth muscle cells, phenotypes that were inhibited by an anti-CCN2 antibody or depletion of EGFR (epidermal growth factor receptor). We further observed increased expression of CCN2, along with evidence of YAP1 nuclear translocation, in kidney vessels of APS nephropathy biopsies. Finally, CCN2 inhibition with an anti-CCN2 monoclonal antibody significantly reduced neointima thickening and cell proliferation in a mouse model of APS IgG–accelerated neointima formation. CONCLUSIONS: This study revealed activation of YAP1-mediated signaling in APS dermal microvessels and demonstrated that the YAP1 target CCN2 plays a role in facilitating pro-proliferative communication between MVECs and vascular smooth muscle cells. These findings offer insights into the cellular and molecular mechanisms underlying APS vasculopathy, providing potential therapeutic targets for patients.

BACKGROUND AND OBJECTIVES: Embolization is part of multidisciplinary brain arteriovenous malformations (AVMs) treatment, yet safety data for novel liquid embolization agents (LEAs) such as Squid and PHIL remain limited. This study reports complications and outcomes from curative embolization using Onyx, Squid, PHIL, and Glue. METHODS: Adult patients with brain AVMs treated with LEAs from July 2015 to December 2022 were reviewed for intraprocedural technical issues, postoperative hemorrhagic, and ischemic complications. Minor (modified Rankin Scale ≤2) and major complication rate (morbidity/modified Rankin Scale >2), mortality, and 6-month angiographic cure rate were evaluated. RESULTS: In total, 135 patients (62.2% male, mean age 41.7 ± 15.1 years) with 206 embolizations (34% Onyx, 18.9% Squid, 17.5% PHIL, 28.2% Glue) were included. Overall, 87.4% procedures were in ruptured AVMs and 84% treated by the transarterial technique (84%). The 6-month angiographic cure rate was 53.3%, higher when nonadhesive LEAs were used than Glue (65.3% vs 17.6%, P < .001). In adjusted analysis, only eloquent location (odds ratio [OR] = 4.4; P = .007) and Glue (OR = 9.1; 95% CI 2.9-28.9, P < .001) were predictors of lower angiographic occlusion rate, whereas size had an inverse correlation (OR = 0.67; P = .019). Technical procedural complications, hemorrhagic, and ischemic rates were 10.2% (2.2% morbidity), 13.1% (3.7% morbidity and 2.2% mortality), and 9.2% (2.2% morbidity, 0% mortality), respectively, regardless of the preferred LEA. Minor, major complications, and mortality rates were 3.7%, 4.4%, and 2.2%, respectively. Hemorrhage was the major contributor to morbidity and mortality, whereas deep venous drainage was an independent predictor of hemorrhage and mortality. CONCLUSION: PHIL and Squid demonstrated complication and angiographic cure rates comparable with Onyx. However, curative embolization of brain AVMs resulted in only moderate angiographic occlusion. Larger multicenter studies with standardized operator protocols, cost-effectiveness assessments, and extended follow-up are warranted to validate these findings.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

Abstract Background: Responsiveness to mood-stabilizing pharmacotherapy varies in bipolar disorder (BD). We investigated clinical correlates of second-generation antipsychotic (SGA) treatment response and conducted the first genome-wide association study (GWAS), including exploratory polygenic scores (PGS), of SGA pharmacogenomic treatment response in BD. Methods: Treatment response was quantified using the Alda scale, and GWAS was performed using Alda-A score, controlling for sex, genotyping batch, and the genomic principal components. Results: The cohort included 2,159 adults with BD (1,416 BD-I, 691 BD-II, 51 schizoaffective BD), mean age 41.8 years, 62% female, 84% white, and 14% Hispanic. Nearly half (48%) were treated with SGAs. Current SGA users were younger (41.2±14.7 vs. 42.5±15.3 years, p =0.040), more likely to be Hispanic (14% vs. 11%, p =0.047), had a higher body mass index (BMI; 30.4±7.6 vs. 29.5±7.1 kg/m 2 , p =0.005). Lifetime comorbidity patterns for current SGA users include higher rates of manic psychosis (29% vs. 17%, p <0.001) and eating disorders — Anorexia Nervosa (7% vs. 4%, p =0.003), Bulimia Nervosa (7% vs. 4%, p =0.003), and Binge Eating Disorder (14% vs. 11%, p =0.030). We detected a genome-wide significant association between SGA Alda-A scores and GAS7 variants (top variant: rs202127418, β =-2.998, p =4.96E-08). However, SGA response was not significantly associated with PGS for schizophrenia, BD, and major depression (FDR>0.05). Conclusions: SGAs are frequently utilized as mood stabilizers in patients with BD and are associated with manic psychosis and eating disorders. GAS7 variants may predict SGA response, but larger, more diverse cohorts are needed for validation.

Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, with a higher risk of recurrence in the early-stage setting compared to other subtypes. While TNBC is defined as breast cancer that lacks estrogen receptor and progesterone receptor expression and is without human epidermal growth factor receptor 2 (HER2) overexpression, it is increasingly recognized as a very heterogeneous disease. Utilization of neoadjuvant chemotherapy (NAC), with or without immunotherapy (depending on the clinical stage), has significantly improved clinical outcomes in early-stage TNBC (particularly in Stage II and III disease). Use of NAC offers the opportunity to de-escalate surgical treatment and evaluate treatment response, allowing for improved prognostication and further tailoring of post-operative systemic therapy. However, there continues to be a need for the personalization of systemic therapy strategies according to recurrence risk. More effective systemic therapies are still needed for patients who have poor response to NAC. Conversely, there remains a need for the identification of appropriate candidates for systemic therapy de-escalation, particularly given the potentially life-altering toxicities of current chemo-immunotherapy strategies. In this review the authors outline the current neoadjuvant paradigm for early-stage TNBC and emerging therapeutic strategies in this challenging disease state, along with questions that remain unanswered in the field.

THE theme of this year’s American Society of Clinical Oncology (ASCO) Annual Meeting was ‘Driving Knowledge to Action: Building a Better Future’. This year’s annual meeting delivered on this theme with instant practice changing and practice informing presentations. Several highly anticipated breast cancer randomized clinical trials that could result in new indications were reported.