Citations

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Abstract Introduction The impact of multiple feeding arteries on clinical outcomes of cerebral arteriovenous malformations (AVMs) is not well understood. This study aims to compare outcomes between AVMs with multiple versus single feeding arteries. Patients and Methods Data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium were analyzed. Propensity score matching (PSM) was used to balance cohorts. Subgroup analysis was conducted for ruptured and unruptured AVMs and different treatment options, and multivariable logistic regression was applied to assess the impact of feeding artery origin. Results Among 953 patients, 661(69.4%) had multiple feeding arteries, and 292 (30.6%) had a single feeding artery. After PSM, which included 422 matched patients (211 in each group), the differences in obliteration rates (68.7% vs 74.8%, OR 0.73, 95% CI: 0.48–1.12, p = 0.16) and symptomatic complications (15.6% vs 11.8%, OR 1.37, 95% CI: 0.78–2.41, p = 0.25) were not significant. Subgroup analysis comparing ruptured and unruptured AVMs and different treatment options showed no significant differences across all subgroups. Multivariable analysis identified PICA feeders as significantly associated with increased odds of all complications (OR 7.33, 95% CI: 2.14–25.1, p = 0.002). Discussion and Conclusion AVMs with a single feeding artery were more likely to present with rupture, but no significant differences in obliteration rates or complications were observed between the groups after PSM. These findings suggest that while the number of feeding arteries may influence the initial presentation, it does not appear to impact overall treatment success or patient prognosis. Further prospective studies are needed to confirm these findings.

Background: The incidence of pediatric thyroid cancer has been increasing, and care varies due to socioeconomic disparities or differing practice patterns. Clinical guidelines call for care in multidisciplinary teams to minimize variance and provide protocols. Based on expert opinion, we hope to describe the form and function of such multidisciplinary teams for pediatric thyroid programs. Methods: A modified Delphi method to reach consensus statements over two rounds. Twenty-one experts with varying backgrounds responded to each statement on a 9-point Likert scale. Upon completion of the survey, the panel reviewed and shared the results and comments from participants and modified the statements accordingly. This process was repeated such that statements reached consensus, were deemed no consensus, or had no change in the mean. Results: There was an 88% and 83% completion rate for Rounds 1 and 2, respectively. A consensus was observed that there is a distinct definable model of care for pediatric thyroid patients. No consensus was reached for the age range of patients, but programs should care for children with medullary thyroid cancer, differentiated thyroid cancer, and patients with genetic predisposition syndromes. A comprehensive team includes, but is not limited to, a thyroid surgeon, a pediatric endocrinologist, a high-volume fine-needle aspiration (FNA) proceduralist, an oncologist, a nuclear medicine physician, a pediatric pathologist, a pediatric radiologist, and a nurse coordinator. Necessary support services involve care coordination, access to a multidisciplinary tumor board, ability to perform ultrasound-guided FNA, and access to molecular testing. The panel emphasized cross-institutional collaborative research prioritizing guidelines development, disease-specific outcomes, treatment toxicity, and the molecular landscape of thyroid cancer. Conclusions: These consensus statements can be beneficial in improving multidisciplinary care, by describing which elements of pediatric thyroid programs should be consistent across institutions. Overall, the panel agreed that pediatric thyroid centers should provide integrated care with defined team members, services, resources, and research priorities. This model has the potential to standardize various aspects of clinical care and enhance our ability to study patient outcomes, improve health care delivery, and increase scholarly collaboration.

Background: Arteriovenous malformations (AVMs) are complex vascular anomalies with a high risk of hemorrhage and neurological deficits, especially when located in eloquent brain regions. The eloquence of an AVM location is a critical factor in the treatment planning, influencing both the risk of complications and long-term functional outcomes. This study aims to compare outcomes between eloquent and non-eloquent AVMs. Methods: This multicenter, retrospective study utilized data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium. Patients with eloquent and non-eloquent AVMs were compared on baseline characteristics, angiographic outcomes, and functional outcomes using the modified Rankin Scale (mRS). Propensity score weighting (IPTW) was applied to adjust for confounding variables. Results: The study included 1013 patients, with 498 (49.2%) AVMs located in eloquent regions and 515 (50.8%) in non-eloquent regions. In unadjusted analysis, eloquent AVMs had lower complete obliteration rates (67.6% vs 79.5%, OR: 0.53, 95% CI: 0.39–0.72, p < 0.001) and higher complication rates (24.5% vs 19.0%, OR: 1.38, 95% CI: 1.02–1.86, p = 0.03) compared to non-eloquent AVMs. After IPTW adjustment, eloquent AVMs continued to show significantly higher odds of overall complications (OR: 1.68, 95% CI: 1.12–2.52, p = 0.01) and symptomatic complications (OR: 1.77, 95% CI: 1.12–2.80, p = 0.01). Secondary analysis within the eloquent group indicated that embolization was linked to an elevated risk of complications. Surgery and radiosurgery showed comparable functional outcomes at last follow-up and complications rates with higher complete obliteration rates in surgery. Conclusion: AVMs in eloquent brain areas present higher risks of complications and lower obliteration rates, emphasizing the need for cautious, individualized treatment planning. Within the eloquent group, embolization increased the risk of complications, while surgery and radiosurgery showed comparable functional outcomes at last follow-up and complication rates with higher complete obliteration rates in surgery. These findings highlight the importance of location in AVM management and support further research focusing on comparing treatment strategies for AVMs in eloquent brain areas.

Backgrounds and Aims: HBV-related liver disease ranks as the seventh leading cause of mortality. Despite advances in prevention and treatment, global disparities in the burden of primary liver cancer (PLC) persist. We evaluate global trends in the prevalence, incidence, and death of HBV-related liver disease. Approach and Results: Data from the Global Burden of Disease Study 2021 evaluated acute HBV infection, HBV-related cirrhosis, and HBV-related liver cancer prevalence, incidence, and death. In 2021, there were 7.30 million cases of acute HBV, 283.64 million cases of HBV-related cirrhosis, and 288,110 cases of HBV-related PLC. HBV-related PLC accounted for 39% of the global incidence of PLC; Western Pacific had the highest rates for HBV-related PLC, with an incidence of 5.24 and a death rate of 4.38 per 100,000 population. Between 2000 and 2021, age-standardized incidence, prevalence, and death rates from HBV-related liver disease decreased; however, the incidence of HBV-related PLC rose in 65 countries from 2000 to 2021. In parallel, age-standardized prevalent rates from HBV-related PLC increased in Europe (annual percent change: 0.77%, 95% CI: 0.72%–0.81%) and the Americas (annual percent change: 1.05%, 95% CI: 1.00%–1.10%). Conclusions: From 2000 to 2021, decreases in HBV-related liver disease incidence and prevalence were observed; however, more than one-third of countries showed an increase in the incidence of HBV-related PLC. These findings highlight the need for strengthened HBV treatment efforts to reduce the risk of liver cancer.

Objectives To evaluate the feasibility for use of electronic health record (EHR) data in conducting adverse event surveillance among women who received mid-urethral slings (MUS) to treat stress urinary incontinence (SUI) in five health systems. Design Retrospective observational study using EHR data from 2010 through 2021. Women with a history of MUS were identified using common data models; a common analytic code was executed at each site. A manual chart review was conducted in a per-site random patient subset to establish a reference standard. Automated text processing (Text Processed Integrated (TPI)) was developed and evaluated at each site to determine the surgical approach and synthetic mesh implantation. Patients were characterized and surgical outcomes were ascertained over 730 subsequent days. Setting Five large tertiary care academic medical centers. Participants Across five health systems, 9,906 eligible patients (mean age 57–60 per site) were identified. Main outcome measures Determination of surgical approach, synthetic mesh implantation, and assessment of the duration of surveillance for mortality and reoperation rates following MUS implantation. Results In the TPI cohort analysis, 3,331 patients were identified. Surgical approach per site was retropubic (42% to 77%), transobturator (6% to 44%), single incision (0% to 24%), and adjustable sling (0% to <4%). Concordance rates for TPI using chart review were 71%–90% at each site for the surgical approach and 28%–85% for synthetic mesh implantation. Patient follow-up observation rates for mortality and reoperation ranged from 22% to 36% at 90 days, 15% to 30% at 365 days, and 8% to 19% at 730 days. Conclusion Using EHR data alone, identification of medical devices and surgical approaches was feasible among women with MUS surgery for SUI, but long-term follow-up ascertainment rates were low. Medical device surveillance using EHR data should be evaluated in the context of the clinical use case, as applicability may vary.

The peritoneum is the second most common site of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). Up to half of all patients that undergo curative-intent resection eventually develop peritoneal metastasis (PM), which accounts for significant morbidity and drives mortality. Despite recent advances in management, PM is associated with very poor prognosis, which is often measured in weeks to months. Clinical manifestations including bowel obstruction, ascites, and urinary obstruction have profound impact on quality of life. Even with relatively advanced disease, PM often remains occult on imaging and thus tend to be underdiagnosed and understudied. Many patients with peritoneal-only PM are excluded from clinical trials because response cannot be measured by standard radiographic criteria. Furthermore, as patients with PM are not eligible for surgical resection and low-volume peritoneal disease is often not amenable to percutaneous biopsy, tissue samples for peritoneal-specific translational studies are limited. Intraperitoneal therapeutics have been proposed as an attractive option for PM, as better penetration of tumor tissue can be achieved with less systemic toxicity compared with intravenous chemotherapy. Heated intraperitoneal chemotherapy (HIPEC), typically combined with cytoreductive surgery (CRS), is an option for select patients with PM from gynecologic or gastrointestinal primary, and for patients with primary peritoneal mesothelioma. However, the incorporation of locoregional therapy for PM in patients with PDAC has been poorly studied given the aggressive nature of pancreatic cancer and overall poor prognosis. With recent advances in existing treatment options, there may be a subset of patients who may derive benefits from locoregional control with cytoreduction and/or intraperitoneal chemotherapy. Critically, additional work is needed to determine PM-favorable clinical and tumoral predictive biomarkers to identify patients who may benefit from a more aggressive approach. We describe the current state of management of patients with peritoneal metastasis from PDAC and review the available data exploring peritoneal-directed therapy with cytoreductive surgery and/or intraperitoneal chemotherapy.

INTRODUCTION: Barrett esophagus (BE) is the strongest known risk factor for developing esophageal adenocarcinoma (EAC), the second-most lethal cancer in the United States. Esopredict is a novel validated methylation-based biomarker assay that provides precise quantification of neoplastic progression risk in BE patients. Inherit challenges, including tissue heterogeneity, sampling error, interobserver variability, and inconsistent adherence to surveillance biopsy guidelines, may affect the predictive value results of Esopredict obtained at different anatomic locations or different sampling time points. METHODS: To investigate the spatiotemporal performance of Esopredict across multiple spatiotemporal sampling points, we profiled 220 biopsies obtained from 58 BE patients, including 11 patients with overlapping spatial and temporal biopsies. We focused on spatial profiling (i.e., multiple biopsies obtained at several anatomic locations during a single endoscopy) and temporal profiling (i.e., biopsies obtained from multiple endoscopies performed at different time points). Each patient had an initial histologic diagnosis of nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia. Final follow-up (endpoint) biopsies showed either high-grade dysplasia or EAC (progressors), or nondysplastic Barrett esophagus, indefinite for dysplasia, or low-grade dysplasia (nonprogressors). Biopsies were analyzed with Esopredict to compute a progression risk score, which quantified the likelihood of future progression to high-grade dysplasia or EAC within 5 years. RESULTS: In 52 spatially profiled patients, Esopredict demonstrated a sensitivity of 81% (17/21 progressor patients), based on the highest-scoring biopsy from each patient; sensitivity increased to 100% (12/12) when end point biopsies occurred within 5 years of the index (initial) biopsy. In 28 temporally profiled patients, sensitivity was 100% (8/8 patients), based on the biopsy performed at the time point closest to the end point biopsy. DISCUSSION: Esopredict showed high predictive performance in multiple spatiotemporal samples in BE patients. These data further support the use of Esopredict as a robust test to distinguish high-risk BE patients, who may benefit from endoscopic eradication therapy or increased surveillance frequency, from low-risk patients, who may be candidates for less frequent surveillance and noninterventional observation.

In a retrospective study of patients with Lynch syndrome vs non‐Lynch syndrome and microsatellite instability high colorectal cancer, there were no observed differences with immune checkpoint inhibitors toward progression‐free survival or overall survival. Univariate analysis of Stage IV patients showed BRAF V600E mutations were associated with decreased survival.

Objectives Evaluate the training background of surgeons performing high volumes of cochlear implants (CIs) and estimate the ratio of providers trained in otology/neurotology (O&N) to the number of traditional CI candidates and audiologists. Methods A retrospective review of US surgeon registration data from a single CI manufacturer was performed to determine CI volume based on surgeon training. The prevalence of traditional candidates for CIs was estimated from US census population data and compared with the number of O&N providers. The ratio of audiologists to O&N providers was estimated from the Bureau of Labor and Statistics and American Speech‐Language‐Hearing Association databases. Results From 2021 to 2023, a mean of 88% of providers performing ≥25 CIs per year and 90% performing ≥40 per year had training in O&N. All surgeons registering ≥100 implants per year were O&N providers. The mean percentage of O&N providers performing ≥25 CIs per year and ≥ 40 per year was higher than the percentage of General and Pediatric Otolaryngology providers performing the same volume: mean difference = 76%, p < 0.001 and mean difference = 79%, p < 0.001, respectively. The mean estimated prevalence of traditional CI candidates per O&N provider is 3,354 with an estimated mean of 32 audiologists (3.5 trained in CIs) per O&N provider. Conclusion 88% of high‐volume CI surgeons have fellowship training in O&N. To meet the current state of CI underutilization and anticipated growing population of CI candidates, we propose increasing the surgical capacity of O&N providers and the number of surgeons proficient in CIs. Level of Evidence NA Laryngoscope , 135:2146–2153, 2025