Citations

Abstract Glioblastoma is the most common type of malignant primary brain tumor and a major cause of morbidity and mortality. In 2021, the World Health Organization updated the classification of Central Nervous System (CNS) tumors to restrict glioblastomas to isocitrate dehydrogenase-wildtype (IDHwt) tumors, improving understanding of the prognosis and optimal therapy for these tumors. This revision also enables more homogeneous populations of patients to be enrolled in clinical trials, facilitating the evaluation of novel therapies. In this updated consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of patients with glioblastoma is discussed. In addition, novel therapies such as immunotherapies, viral therapies, targeted molecular therapies, theranostics, and antibody–drug conjugates will be reviewed, as well as the current challenges and future directions for research.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Purpose: To describe an improved snare technique for the removal of an intraocular foreign body (IOFB) from the posterior segment. Methods: The snare is fashioned from a 23 or 25-gauge blunt-tipped cannula, a 5-0 or 6-0 nylon suture, and a cotton-tipped applicator. The snare is introduced through a 23 or 25-gauge vitrectomy port and tightened around the IOFB, maintaining a closed system. The IOFB can be extracted from the eye by pulling the cannula and extending the circumferential sclerotomy. Results: Four cases of IOFBs were treated using the improved nylon suture snare technique. Three of the four were traumatic open-globe injuries with retained IOFB, for which the snare technique was suitable for removal of the object. In the fourth case, the snare technique was used to remove a posteriorly dislocated silicone intraocular lens optic. No cases of postoperative retinal detachments or endophthalmitis were observed. Conclusion: This snare is fashioned from readily available, inexpensive materials and provides a safe and reliable method for IOFB removal through the vitrectomy port. By maintaining a closed system during IOFB mobilization and removal, the view through the cornea remains stable and intraocular pressure remains constant. Moreover, the snare can grasp irregularly shaped or large IOFBs.

Abstract Introduction While randomized clinical trials (RCT) confirmed superiority of Mepitel film (MF) in reducing acute radiation dermatitis (ARD) compared to standard-of-care (SoC), the incremental cost difference has limited its use. A cost-effectiveness analysis (CEA) was conducted from a Canadian healthcare payer’s perspective to guide policy decisions. Methods: A decision model was constructed to perform a CEA for MF compared to SoC (moisturisers) for prevention of grade 2 or higher ARD following adjuvant hypo-fractionated whole-breast radiotherapy (RT) based on a Canadian multicentre RCT. Direct and indirect cost data were collected from two oncology centres in Canada. Quality-of-life (QoL) utility values were derived from mapping Dermatology Life Quality Index (DLQI) scores for patients with grade 2 or higher ARD at week 6 of RT to EQ-5D. A willingness-to-pay (WTF) threshold of CAD 50,000 per quality-adjusted life years (QALY) gained was used. One-way sensitivity analysis was performed to account for uncertainty in decision model assumptions. Results: Base case analysis demonstrated that MF is cost-effective in preventing grade 2 or higher ARD as compared with SoC with an incremental cost-effectiveness ratio (ICER) of CAD 3,366 per QALY gained. When nursing costs were included, MF resulted in an ICER of CAD 2,823 per QALY gained. One-way sensitivity analysis showed that the results were most sensitive to the QoL utility value for ARD. All sensitivity variations remained well below the WTP threshold. Conclusions: MF is a cost-effective intervention for preventing high-grade ARD and should be recommended for patients with breast cancer undergoing adjuvant RT.

ABSTRACT Objectives Multicenter research of geriatric emergency department (GED) care remains limited. Our objectives were to: 1. Prospectively collect data prioritized by the Geriatric Emergency care Applied Research (GEAR) network, a transdisciplinary taskforce for GED care, and create a multicenter GED research repository of prospective and electronic health record (EHR) data, 2. Assess concordance between prospective and EHR data. Methods The GEAR Standardization Study (GEARSS) is a multicenter, prospective study of older emergency department (ED) patients (65+) focusing on the 4Ms of age‐friendly care (mobility, medication safety, mentation, what matters) and elder mistreatment. Demographic and clinical data were collected via interviews by trained research assistants (RA) on Days 0, 4, 30, and 90 and linked to EHR. Prevalence of chronic comorbidities and incident delirium were measured and reported using descriptive statistics. Prospective and EHR data concordance was assessed with Cohen's Kappa. Results 999 participants were recruited from 5 EDs (3/25/2021–6/30/2022) across 3 institutions: Grady Health System, Northwestern Memorial Hospital, and Yale New Haven Health. The cohort was 57.0% female, 55.2% White, 39.1% Black, and 3.4% Hispanic, and the mean age was 75.1 years. For rheumatologic disease, peptic ulcer disease, diabetes, renal disease, and cancer, prevalence differed between prospective and EHR data by > 10%. About two‐thirds of participants were at risk for falls. Concordance between prospective and EHR data was good for ethnicity ( K = 0.73); excellent for sex ( K = 1.00), age ( K = 1.00), and race ( K = 0.98); fair for disposition ( K = 0.53); slight for ED observation status ( K = 0.33) and dementia diagnosis ( K = 0.24); poor for delirium presence ( K = 0.07). Conclusion In GEARSS, demographic variables aligned strongly between prospective and EHR data, while diagnosis, disposition, and mentation factors did not. This multicenter data source provides preliminary findings for common geriatric syndromes and conditions. Choice of measures using these data should be driven by GED research questions.

ABSTRACT Purpose Optical coherence tomography (OCT) is a widely used imaging modality in ophthalmology. Accurate semantic segmentation of these images is critical for both clinical and research applications, yet existing convolutional neural network (CNN)-based methods face challenges in generalizability and robustness. This study introduces MAYOCTransformer, the first transformer-based deep learning model for comprehensive semantic segmentation of OCT images, and evaluates its performance against CNN-based models. Methods A large dataset of 3,500 OCT images was manually segmented using an iterative deep learning-assisted workflow. The MAYOCTransformer model, based on the Mask2Former architecture, was trained and compared against CNN-based segmentation models, including U-Net, U-Net++, FPN, and DeepLabV3+. Comprehensive segmentation tasks included 10 retinal layer segmentation, choroid stroma and vessel segmentation, and the identification of 9 types of discrete pathological findings including intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), intraretinal hyper-reflective foci, and reticular pseudodrusen. Model performance was evaluated using the Dice similarity coefficient (DSC) on a hold-out test set with five-fold cross-validation. Additional validation was performed using external datasets, open-source segmentation models, and a randomized blinded expert evaluation. Results MAYOCTransformer outperformed CNN-based models in most segmentation tasks. Choroid segmentation performance was comparable between MAYOCTransformer and CNN models. External validation demonstrated the model’s generalizability, achieving higher DSC scores than publicly available segmentation models. A blinded expert evaluation showed that MAYOCTransformer’s segmentation was non-inferior to manual annotations. Conclusion MAYOCTransformer provides improved segmentation performance over CNN-based models. Its ability to generalize to external datasets suggests potential applicability in clinical and research settings.

PURPOSE Stereotactic radiation (SRS/SRT) as opposed to whole-brain radiation (WBRT) represents the standard of care for patients with a limited number of brain metastases given the relatively favorable toxicity profile associated with stereotactic treatment. However, in patients with small cell lung cancer (SCLC), WBRT remains standard because of a lack of prospective data supporting SRS/SRT and concerns related to intracranial progression and neurologic death when WBRT is omitted. We conducted a single-arm, multicenter, phase II trial of SRS/SRT in patients with SCLC and 1-10 brain metastases to assess neurologic death rates relative to historical controls managed with WBRT (ClinicalTrials.gov identifier: NCT03391362 ). METHODS Patients were eligible if they had SCLC or an extrathoracic small cell primary and 1-10 brain metastases. Previous brain-directed radiation including prophylactic cranial irradiation was not permitted. Neurologic death was defined as marked, progressive, radiographic brain progression accompanied by corresponding neurologic symptomatology without systemic disease progression or systemic symptoms of a life-threatening nature. Close imaging-based surveillance of the brain post-SRS/SRT was used. RESULTS Between February 2018 and April 2023, 100 patients were enrolled. The median number of brain metastases was 2 (IQR, 1-4; range, 1-10). The median overall survival was 10.2 months; only 22% of patients required salvage WBRT. In total, 20 neurologic deaths were observed, relative to 64 non-neurologic deaths. The neurologic death rate at 1 year was 11.0% (95% CI, 5.8 to 18.1); the historical rate in patients managed with WBRT was 17.5%. CONCLUSION Our prospective, multi-institutional study demonstrated low rates of neurologic death when SRS/SRT as opposed to WBRT is used in patients with SCLC and 1-10 brain metastases who are surveilled closely post-treatment, supporting the utility of stereotactic approaches in this population.

Background Excellence in healthcare delivery is dependent on individuals working together on a team. Objective We sought to enhance team performance by partnering with human resources (HR) to identify opportunities unrecognised by unit leadership. Methods 100 individuals representing a cross-section of the multidisciplinary team participated in an interview focused on teamwork conducted by an HR representative. Action plans were then developed and implemented. Press Ganey Survey results for the question, “Staff worked together to care for you/your baby?” were tracked to assess patient perception of teamwork. Results Between 2022 and 2024, we observed improvement in the per cent of patients who assigned the highest rating of teamwork, culminating in 100% of patients reporting the highest score in the final quarter. Conclusion The model of HR facilitated discussions with work unit team members identified barriers to optimal teamwork, led to the implementation of action plans and resulted in an improvement in our teamwork rating by patients.

Three-dimensional radiomic analysis of digital breast tomosynthesis outperformed two-dimensional measures in breast cancer risk assessment.

Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC90 of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells.