Citations

Abstract Objective This study aimed to understand the factors limiting access to medications for the preventive treatment of migraine and to improve access to evidence‐based preventive care. Background For decades, the effective use of medication for the preventive treatment of migraine was limited by slow onset, slow and complex dose titration schedules, modest benefits, drug interactions, frequent side effects, and very low long‐term adherence. The calcitonin gene‐related peptide (CGRP) targeted preventive medications mitigate some of these limitations and demonstrated substantial therapeutic benefits in a significant proportion of adults with migraine. The American Headache Society considers these medications among the first‐line options for migraine prevention, although access to them remains limited. The American Migraine Foundation hosted a single‐day, multidisciplinary expert panel discussion to identify barriers to optimal preventive care and developed recommendations to address them. Methods Participants identified and prioritized barriers and used a modified nominal group technique to achieve consensus on them. A series of moderated discussions in plenary and breakout sessions was used to create possible solutions. Modified nominal group technique was also employed to achieve consensus on the priorities among these barriers and to achieve whole‐group consensus on the recommendations. Ethical issues that inform access were discussed. Results Participants included eight neurologists and board‐certified headache specialists, six representatives of reimbursement decision‐makers, six employees of life sciences companies, four patient advocates with lived experience with migraine, and a medical ethicist. Among those who have consulted healthcare professionals and received a diagnosis of migraine, we identified four main barriers to accessing preventive treatment: restrictive prior authorization requirements, the perceived lack of real‐world evidence and treatment guidelines, the need for clinician education, and the need for patient education. Consensus recommendations for eliminating barriers centered on using new evidence to evaluate policies that restrict the selection of first‐line therapies, initiating/improving collaboration among stakeholders, sharing of data and best practices, and increased training. Participants agreed to explore novel definitions of the value of preventive treatment and to establish the Migraine Prevention Network to facilitate ongoing cooperation and collective action. However, due to financial limitations, staffing changes, and time constraints, post‐meeting discussions led to a shift from establishing a broad Migraine Prevention Network to forming smaller task forces focused on the top‐priority barriers (real‐world evidence and The Patient Playbook ) identified through collaborative voting among American Headache Society, American Migraine Foundation, and industry stakeholders. Conclusions Adults with migraine face multiple barriers in accessing novel migraine‐specific, CGRP‐targeted preventive treatment. Stakeholders in the delivery of care, including clinicians, reimbursement decision‐makers, life sciences companies, and patient and clinician advocates, may be able to overcome many of these barriers and improve access by working with and on behalf of patients.

OBJECTIVE Resection of common peroneal nerve (CPN) schwannomas is generally believed to be associated with a high risk of postoperative deficit, especially the chance for development of a foot drop. The goal of this study was to investigate the surgical results for resection of schwannomas from the CPN around the knee and specifically the chance of developing a postoperative motor deficit. METHODS Data from 36 patients with sporadic schwannomas and 8 patients with schwannomatosis (12 schwannomas total) treated at two centers were retrospectively analyzed. For sporadic cases, different locations around the knee were compared (i.e., proximal to the fibular head [FH], at the FH, and distal to the FH), taking into account the preoperative duration of symptoms, size at presentation, and surgical results of resection. The literature was systematically reviewed for reported cases by searching the PubMed and Embase databases. RESULTS A total of 24 schwannomas proximal to the FH were surgically treated: 11 at the FH, and 13 distal to the FH. For the entire cohort, the mean size of CPN schwannomas distal to the FH at presentation was smaller (1.4 × 1.8 cm) compared with those proximal to (2.0 × 2.2 cm) and at (2.2 × 2.3 cm) the FH, although these differences were not statistically significant. The mean preoperative duration of symptoms was slightly longer for schwannomas distal to the FH (35 months) than for those proximal to the FH (21 months) and at the FH (27 months); however, this difference was not significant. Postoperative deficits occurred in 3 sporadic cases: 2 patients with temporary weakness (Medical Research Council grade 4) that completely resolved within several months and 1 patient who had previously undergone surgery elsewhere and presented with deficits and in whom weakness increased after resection. Improvement in preoperative deficits was observed in 1 patient with extensor hallucis longus muscle paralysis that completely recovered. One patient with schwannomatosis developed muscle weakness after resection of a plexiform schwannoma. A systematic review of 21 previously reported cases in the literature showed that larger CPN schwannomas (> 5 cm) were more likely to result in permanent motor deficits. CONCLUSIONS This retrospective study of 44 patients shows that peroneal nerve schwannomas around the knee can be safely removed with a low risk of deficits. The systematic review of the literature suggests that larger schwannomas are more likely to result in permanent deficit. In the authors’ opinion, CPN schwannomas can best be resected, preferably when the lesion is relatively small.

Objective Prior work has identified numerous barriers to standardized outcome measurement in cleft care. The objective of this study was to evaluate a multifaceted implementation strategy to collect standardized outcomes for children with cleft lip and/or palate (CL/P). Design A one-armed, single-site pilot study of a multifaceted implementation strategy. Setting A metropolitan children's hospital. Patients Five-year-old children with CL/P. Interventions A multifaceted implementation strategy for standardized outcome measurement. Main Outcomes Measures The primary outcome measure was penetration of the intervention, defined as the proportion of children for whom the standardized measures of aesthetic, dental, and speech outcomes were collected. Penetration pre-implementation and 12 months post-implementation were compared. The secondary outcome was acceptability of standardized outcome measurement among providers and staff, evaluated with the Acceptability of Intervention Measure. Results The implementation strategy resulted in high penetration of standardized outcome measurement: measurement of aesthetic outcomes increased from 7% to 82% ( p < .0001); measurement of dental outcomes increased from 0% to 56% ( p < .0001); measurement of speech outcomes increased from 29% to 77% ( p = .0001). Acceptability of standardized outcome measurement was high, with 93% of cleft team providers and staff (n = 14/15) reporting that they somewhat or completely agreed that standardized outcome measurement met their approval, was appealing, was welcomed, and was liked. Penetration continued to improve after the implementation period, with high rates of outcome measure collection sustained for four years following implementation. Conclusions Deployment of a multifaceted implementation strategy led to substantial increases in the collection of aesthetic, dental, and speech outcomes among children with CL/P.

Respiratory muscle fatigue could occur following involuntary breathing movements during maximal breath-holds. We measured respiratory muscle strength pre and post three preparatory and maximal breath-holds. We found significant reductions in diaphragm strength and total inspiratory and expiratory strength in some, but not all, divers. Divers that had respiratory muscle fatigue had a lower pseudo O 2 delivery (HR × [Formula: see text]) during the struggle phase. This suggests that reduced oxygen delivery may contribute to respiratory muscle fatigue during a breath-hold.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Article Title: Colorectal Cancer Screening Based on Predicted Risk: A Randomized Controlled Trial.

Abstract BACKGROUND IDH-mutant gliomas are diffusely infiltrating, slow-growing brain tumors that inevitably undergo malignant progression to grade IV astrocytoma - a highly aggressive and uniformly fatal disease with dismal prognosis. Despite extensive research, the molecular mechanisms underlying this transformation remain poorly understood. While alterations in canonical driver genes such as CDKN2A, PTEN, and PDGFRA have been implicated, the broader landscape of genetic drivers involved in IDH-mutant glioma progression is largely uncharacterized. In contrast to many other malignancies, IDH-mutant gliomas acquire relatively few somatic point mutations during progression - typically in the range of 30 to 40 - suggesting that alternative mechanisms may be driving tumor evolution. Notably, these tumors exhibit widespread chromosomal instability, resulting in a heterogeneous and highly prevalent pattern of copy number alterations (CNAs). This observation raises the possibility that gene dosage changes due to CNAs play a critical role in tumor progression. MATERIAL AND METHODS To investigate this hypothesis, we performed integrative analysis of IDH-mutant glioma cohorts from the Mayo Clinic and TCGA datasets (~1,500 patients), identifying twelve highly recurrent CNAs significantly associated with patient outcomes. We refer to these as malignant IDH-associated CNAs (mIDH CNAs). We hypothesized that these recurrent CNAs harbor driver genes that confer selective growth advantages, thereby contributing to their recurrence and prognostic relevance. To systematically assess the functional impact of genes within these regions, we developed a novel in vivo CRISPR-based screening platform, termed CRISPR-Knock Out and Activation Linked Assay (CRISPR-KOALA). This approach utilizes stereotaxic delivery of lentiviral gRNA libraries - targeting mouse orthologs of ~1,800 genes within recurrently deleted regions and ~1,200 genes within amplified regions - into the brains of a genetically engineered mouse model of IDH-mutant glioma (rs557mut;IDHmut;P53KO;AtrxKO;Cas9GFP: Yanchus et. al Science 2022). RESULTS Mice injected with mIDH CNA-targeting libraries developed tumors significantly more rapidly than control cohorts. Deconvolution of the CRISPR-KOALA screen identified several putative driver genes, including regulators of the NOTCH signaling pathway, lipid metabolism modulators such as THEM6, and the NMDA receptor modulator GRINA - implicating dysregulation of metabolism, immune response, and glutamatergic signaling in the malignant transformation of IDH-mutant gliomas. CONCLUSION Together, these findings provide critical insights into the genetic mechanisms driving the progression of IDH-mutant gliomas and identify new candidate genes and pathways for potential therapeutic targeting.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (&gt;124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.