Citations

OBJECTIVE Communicating hydrocephalus may occur following stereotactic radiosurgery (SRS) for vestibular schwannomas (VSs), yet identifying individual patient risk factors associated with this post-SRS complication remains a challenge. This study examined predictors of nonobstructive ventricular enlargement and symptomatic communicating hydrocephalus following primary SRS treatment for VS via a single-center institutional cohort review and meta-analysis of the literature. METHODS A retrospective single-institution cohort study and systematic literature review and meta-analysis examining post-SRS communicating hydrocephalus in VS was performed. RESULTS The institutional cohort consisted of 634 patients who received primary SRS as treatment for VS. The cohort was 51.6% female, with a median age of 64 (range 18–89) years. Following SRS treatment, 364 patients (57.4%) experienced tumor shrinkage, 218 (34.4%) had no change in the size of their lesion, and 52 (8.2%) experienced tumor growth. Nonobstructive ventricular enlargement was observed in 23 patients (3.6%) following SRS treatment, of whom 9 (39.1%) remained asymptomatic and 14 (60.9%) required placement of a ventriculoperitoneal (VP) shunt, with a median time to shunt placement of 8 months. In the multivariate analysis, patients ≥ 65 years old (p = 0.038), SRS target volume ≥ 5 cm 3 (p < 0.001), maximum SRS dose ≥ 26 Gy (p = 0.015), and tumor growth at the most recent follow-up (p = 0.002) were associated with an increased risk of post-SRS ventricular enlargement. Similarly, patients with older age (p = 0.049), increased SRS target volume (p = 0.002), and tumor growth (p = 0.016) were at an increased risk of symptomatic communicating hydrocephalus requiring VP shunt placement. Twenty-nine studies, including the cohort in this study, met inclusion criteria in the meta-analysis. Of the pooled 7825 patients, the overall incidence of hydrocephalus following SRS was 5%, and a subanalysis of 7081 patients demonstrated the incidence of symptomatic hydrocephalus requiring a VP shunt to be 4%. In this subanalysis, the overall shunting rate in patients who experienced post-SRS ventriculomegaly was 92%. Among individual studies in the literature, increased tumor size was most commonly found to be a statistically significant risk factor for post-SRS hydrocephalus. CONCLUSIONS Approximately 5% of patients may experience nonobstructive ventricular enlargement following primary SRS treatment for VS. However, not all patients may be symptomatic and require shunting. Patients who are older (≥ 65 years), those with larger tumor volumes, and those with post-SRS tumor growth may be at increased risk of communicating hydrocephalus and may benefit from closer clinical monitoring.

ABSTRACT Aims Exercise capacity is a powerful predictor of cardiovascular risk. In patients unable to exercise, body composition analysis can potentially be used to estimate cardiorespiratory fitness. We developed a body composition “fitness” score, then validated its utility in two external populations. Methods and Results We included patients from four sites undergoing single photon emission computed tomography (SPECT) and twelve sites undergoing positron emission tomography (PET). We quantified body composition using deep learning. We evaluated associations between body composition and good exercise capacity (defined as completing ≥7 minutes on a Bruce protocol) then developed a body composition “fitness” score. We then assessed the associations of “fitness” score with exercise capacity and all-cause mortality in external populations. In total, 36471 patients were included with median age 67 (interquartile range 58 – 74). Median skeletal muscle density was higher among patients with good exercise capacity. In the external SPECT population, the body composition “fitness” score had higher prediction performance for good exercise capacity (AUC 0.771, 95% CI 0.752 – 0.789) than age (AUC 0.717, p<0.01). In the external PET population, high body composition “fitness” score was associated with lower cardiovascular death (adjusted hazard ratio 0.70, 95% CI 0.62 – 0.79, p<0.001). Conclusions We demonstrated that a comprehensive body composition “fitness” score could identify patients with good cardiorespiratory fitness. This approach transforms routinely acquired CT data into a surrogate marker of fitness which can be applied in patients undergoing PET, or other CT imaging, where exercise testing is not performed. Graphical Abstract Overview of study design. The overall population (n=36471) was split as outlined above. Body composition was analyzed from available computed tomography imaging. The distribution of body composition measures were analyzed in the combined single photon emission computed tomography (SPECT) populations. A body composition “fitness” score was derived to predict good exercise capacity in the internal population, with associations assessed in the two external testing populations.

Abstract Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it’s in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1 -knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload–expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1 -KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

Background: Objective performance assessment is essential in surgical skill training, yet current methods are labor-intensive and focus on observing the trainee rather than the end-product of the procedure. Machine learning (ML) methods offer reproducible feedback but have mainly relied on kinematic or video data, often reducing assessment to binary or ternary classification. Our objective was to compare ML regression models predicting expert-assigned scores of vascular anastomoses from computational fluid dynamics (CFD) features of the final product. Additionally, we aimed to assess biomechanical plausibility of predictions. Methods: A total of 146 participants performed 419 end-to-side anastomoses on case-specific three-dimensional (3D) printed simulators. Anastomoses were digitized via 3D scanning, ranked by experts, and characterized using CFD-derived hemodynamic features. These served as input for linear models (Ridge, Partial Least Squares), support vector machines, and tree-based ensembles (Random Forest, Extremely Randomized Trees, and Extreme Gradient Boosting [XGBoost]), evaluated using 10-fold nested cross-validation with genetic hyperparameter optimization. Results: Inter-rater reliability of expert indicated strong agreement (intraclass correlation coefficient ICC3k = 0.846). XGBoost achieved the lowest mean root mean squared error of 0.758 (95% bootstrap CI: 0.722–0.799) and a coefficient of determination (R2) of 0.673 (0.617–0.725), with the most stable performance across folds. Shapley additive explanations (SHAP) identified the wall shear stress gradient, transverse wall shear stress, and maximum pressure as the most influential features—variables associated with intimal hyperplasia and atherosclerotic remodeling. Conclusions: Tree-based ensemble methods, particularly XGBoost, effectively modeled biomechanical properties against expert scores. Combining CFD and ML can provide reproducible, mechanistically relevant feedback in vascular surgical skill training.

Background: Premedications used to prevent paclitaxel-associated infusion hypersensitivity reactions (iHSRs) can cause undesirable toxicities, such as sleep disturbance and weight gain. Although phase II data suggest that discontinuing premedications after paclitaxel-associated iHSRs may be safe and feasible in select patients without prior iHSRs, no prospective randomized trials have evaluated this approach. Patients and Methods: This randomized clinical trial enrolled patients with breast cancer receiving paclitaxel chemotherapy. Those who experienced no iHSRs with the first 2 doses of paclitaxel were randomized to either continue standard premedications (control arm) or to discontinue all premedications (investigational arm). Both arms were followed longitudinally for any subsequent iHSRs requiring parenteral rescue medications. Additionally, changes in weight, drug-related side effects, and quality of life were assessed. Results: A total of 98 patients were randomized; 89 were evaluable (46 in the control arm and 43 in the investigational arm). Only 1 (2.3%) patient in the investigational arm experienced an iHSR, which resolved with rescue medications. No iHSRs occurred in the control arm. The estimated proportion of subjects who experienced a hypersensitivity reaction (exact binomial 95% CI) was 2.3% (95% CI, 0.1%–12.3%) in the investigational arm and 0.0% (95% CI, 0.0%–7.7%) in the control arm. Patients in the investigational arm reported significantly less sleep disruption (0.5 vs 1.7; P =.002) and unwanted appetite increases (1.0 vs 2.5; P =.0018). Conclusions: Discontinuation of premedications after 2 uneventful paclitaxel doses was not associated with a high rate of subsequent iHSRs and resulted in fewer steroid-related side effects. This strategy may reduce unnecessary medication exposure, improve patient experience, and streamline clinical workflows. For patients who do not experience iHSRs during the first 2 paclitaxel treatments, discontinuing premedications appears safe and may improve tolerability.

ABSTRACT Supplemental oxygen (hyperoxia), often provided to premature infants, can disrupt lung growth and contribute to development of neonatal and pediatric lung diseases, necessitating understanding of underlying mechanisms. We previously showed that even moderate hyperoxia (< 60% O 2 ) induces detrimental cellular senescence in 18–22 weeks human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling. In this study, we examined the ability of senotherapeutics Fucoidan and Dasatinib (D) + Quercetin (Q) (D + Q) to mitigate adverse effects of hyperoxia and assessed the preventive effect of mitochondrial antioxidants (MitoQ). fASM cells exposed to normoxia (21% O 2 ) or hyperoxia (50% O 2 ) were treated with Fucoidan [100 μg/mL], D + Q [250 nM + 375 nM] or MitoQ [100 nM] and assessed for senescence markers, senescence‐associated secretory profile (SASP), extracellular matrix (ECM) deposition, and cell viability. Our results showed that moderate hyperoxia increases senescence markers and SASP. Fucoidan decreased p21 expression and inhibited SASP release without inducing cell death, while D + Q decreased β‐galactosidase (β‐Gal) activity, p21 and plasminogen activator inhibitor‐1 (PAI‐1) expression, and caused cell death without affecting SASP in hyperoxia‐induced senescent fASM. MitoQ prevented increases in senescence markers and SASP in hyperoxia‐exposed fASM. These findings demonstrate distinct and viable strategies to counter hyperoxia‐induced fASM senescence. Fucoidan (senomorphic), D + Q (senolytic), and MitoQ (prophylactic antioxidant) represent promising, mechanistically different approaches to alleviate detrimental effects of moderate hyperoxia in developing airways towards limiting perinatal lung disease.

Abstract Prostate adenocarcinomas (PRAD) can acquire resistance to androgen receptor signaling inhibitors through lineage transition to a cell state known as neuroendocrine prostate cancer (NEPC). Using a panel of isogenic PRAD and NEPC mouse tumoroids, we show that NEPC cells acquire new transcription factor (TF) dependencies that function in a previously undefined network. Through selective perturbation of each TF, we identify ASCL1 as a key regulator of NE lineage fate whereas MYCL functions downstream to drive NEPC growth/survival by recruitment of the TIP60/KAT5 acetyltransferase. Interestingly, while dependencies on specific TF family paralogs can vary across NEPC models, all show markedly enhanced dependency on TIP60. Moreover, the H2A.Z-acetyltransferase activity of the TIP60 complex (TIP60-C) is required for NEPC as well as the acetyl-reader BRD8, which is newly incorporated as a TIP60-C subunit with the NEPC transition. Targeted degradation studies in isogenic tumoroids reveal increased dependence on MYCL in NEPC relative to its paralog MYC in PRAD. In addition to a paralog switch (MYC to MYCL), the MYC pathway-addicted NE state is accompanied by a chaperone switch (from TIP60-C to SRCAP) for H2A.Z histone exchange and a coactivator switch (to TIP60) for MYC target gene expression. The NE-specific coupling of MYCL with TIP60 reveals a previously unappreciated opportunity to target MYC-driven NE diseases through pharmacological inhibition of TIP60.

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of &lt;30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.