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Background: Bilateral cardiac sympathetic denervation (BCSD) has shown promise in treating patients with nonischemic cardiomyopathy (NICM) suffering from refractory multifocal premature ventricular contractions (PVCs) and ventricular tachycardia (VT). Despite its growing use, the effectiveness of BCSD across different NICM etiologies has not been extensively studied. Research Question: How effective is BCSD across a variety of NICM etiologies? Goals: To evaluate the effectiveness of BCSD on left ventricular ejection fraction (LVEF) and PVC burden in patients with NICM. Methods: We conducted a subset analysis on a previous retrospective, observational study of NICM patients who underwent BCSD. Eight NICM etiologies were assessed. Results: 43 NICM patients underwent BCSD (mean age 52.3±14.7 years; 30% females). Overall, LVEF significantly improved (38.7±7.9% to 46.2±9.6%, p <0.001), and PVC burden (PVCb) significantly decreased (23.7±9.9% to 1.3±1%, p <0.001). A similar phenomenon was seen in idiopathic/dilated cardiomyopathy (CM) (LVEF: +8.7%, p <0.001; PVCb: -20.6%, p <0.001), post-viral CM (LVEF: +4.8%, p =0.2; PVCb: -24.2%, p <0.001), familial CM (LVEF: +10%; PVCb: +23.3%), giant cell CM (LVEF: +10%; PVCb: + 30.5%), and arrhythmogenic right ventricular CM (LVEF: +12.5%, p=0.09; PVCb -30.6%, p =0.001). Catecholaminergic polymorphic VT had a non-significant increase in LVEF (+5%, p=0.5) but a significant decrease in PVCb (-21.8%, p=0.02), whereas sarcoidosis had the opposite effect with significant increase in LVEF (LVEF: +13.4%, p=0.3) but non-significant decrease in PVCb (-16.1%, p=0.02). Lastly, hypertrophic CM remained unchanged in LVEF (30%) but PVCb decreased (-8%). Conclusion: BCSD demonstrates efficacy in improving LVEF and reducing PVCb across almost all NICM with refractory VT. However, a case-by-case evaluation is still needed for its use.

Background: Autologous arteriovenous fistulas (AVF) are the preferred choice for hemodialysis access due to their longevity, lower complication rates, and mortality benefit. Their use is limited by vein size and necessary maturation period, excluding up to a third of patients. A novel solution to this problem is pump-assisted vein dilation (PAVD), where the vein is “pre-matured” using a miniatured centrifugal pump that draws blood from a central vein, delivering it into the recipient vein (e.g., cephalic) under pressure. The aim of this study is to report the initial safety studies in sheep and a first-in-human (FIH) pilot study as a prelude to a phase 2 clinical study. Methods: Preclinical Study: Three anesthetized male sheep (50-70 kg) underwent cephalic PAVD using the Amplifi Vein Dilation System for 7 days (mean). These subjects and two control animals (no-PAVD) underwent brachiocephalic AVF creation and observation for 6 weeks, with weekly surveillance fistulagrams and duplex ultrasound (U/S). AVFs were then explanted for histological analysis. Clinical Study: Ten patients were recruited for a phase 1 study. They underwent cephalic PAVD for 7 days (mean), followed by brachiocephalic AVF creation and surveillance at 2 and 6 wks. Data on vein diameter and flow rates of the AVF were collected, as well as safety data on complications such as bleeding, infection, and embolism. Results: Preclinical Study: PAVD increased mean±SD vein diameter (mm) from 4.5±1.0 to 8.4±1.0 (p=0.005); leading to greater cephalic vein diameter at the time of AVF creation in the PAVD group vs no-PAVD (8.2±1.3 vs. 3.3±0.7; p<0.05). After 6 wks of maturation, mean vein diameter was still greater in the PAVD group compared to no-PAVD (12.8±2.8 vs. 8.4±0.7; p<0.05). Mean flow increased at 41 mL/min/day versus control animals at 5.2 mL/min/day. Clinical Study: All subjects saw an increase in vein diameter with PAVD at baseline vs. at 6 wks (2.3±0.5 vs. 5.2±0.7; p<0.05), as well as mean flows (mL/min) (285±30 vs. 724±149). There were no Amplifi-related or procedure-related serious adverse events. Conclusion: The translation of PAVD for AVF creation from bench-to-bedside provides safety and efficacy data on a novel solution that can increase the availability of autologous AVFs in patients excluded due to size criteria. The Amplifi vein dilation system can effectively and rapidly dilate peripheral veins without stimulating neointimal hyperplasia. PAVD should be explored in a phase 2 clinical study.

Abstract BACKGROUND Selinexor (SEL) is a first-in-class XPO1 inhibitor with potent antitumor activity through the nuclear retention and reactivation of tumor suppressor proteins, reduced translation of oncogenes, and decreased expression of anti-apoptotic proteins. As a single agent, SEL has demonstrated brain penetration and clinically relevant responses in glioblastoma. We seek to enhance the effect and benefit of SEL by priming with temozolomide (TMZ). METHODS Through an NCI Project Team, we developed a multi-institutional phase I/II clinical trial which opened across the NCI Experimental Therapeutics Clinical Trial Network. Eligibility included histologically confirmed 1st recurrent MGMT promoter methylated glioblastoma. We evaluated safety, tolerability, and dose finding with an IQ 3 + 3 design of TMZ 150mg/m2 on days 1-5 of a 28-day cycle plus SEL on days 8 and 15. RESULTS From October 2022 to March 2024, we enrolled 12 patients (n=11 evaluable) into phase I of the study. Patient characteristics included 82% male, median age 62 (range 50-77), 64% white. The median number of cycles administered was 6 (range 1-12). Two dose levels (SEL 60mg and SEL 80mg) were evaluated. No dose-limiting toxicities (DLTs) were observed. The most common treatment related adverse events were nausea (58%), decreased platelet count (50%), fatigue (50%), constipation (42%), vomiting (25%), decreased lymphocyte count (25%), and decreased neutrophil count (25%). Grade 3+ treatment related adverse events included nausea, grade 3 (n=1); decreased lymphocyte count, grades 3-4 (n=2); and anorexia, grade 3 (n=1). Phase I has completed enrollment and the recommended phase II dose will be SEL 80mg. Additional results will be presented. CONCLUSION Results suggest that a sequential dosing regimen of SEL+TMZ is feasible, well-tolerated, and may minimize the cumulative toxicity of SEL. The phase II randomized portion of this trial is enrolling nationwide and will investigate efficacy and candidate molecular signatures of vulnerability (NCI #10505, NCT05432804).

BACKGROUND AND OBJECTIVE: This investigation evaluates the safety and efficacy of stereotactic radiosurgery (SRS) vs observation for Koos grade I vestibular schwannomas (VS). METHODS: In a multicenter study, we retrospectively analyzed data of patients with Koos grade I VS who underwent SRS (SRS group) or were observed (observation group). Propensity score matching was used to equilibrate demographics, tumor size, and audiometric data across groups. The outcome analyzed included tumor control, preservation of serviceable hearing, and neurological function. RESULTS: The study matched 142 patients, providing a median follow-up period of 36 months. SRS significantly enhanced tumor control compared with observation, with a 100% control rate at both 5- and 8-year marks in the SRS group vs 48.6% and 29.5% in the observation group at the same time intervals, respectively ( P < .001). Preservation of serviceable hearing outcomes between groups showed no significant difference at 5 and 8 years, ensuring a comparable quality of auditory function (SRS 70.1% vs observation 53.4% at 5 years; P = .33). Furthermore, SRS was associated with a reduced likelihood of tinnitus (odds ratio [OR] = 0.46, P = .04), vestibular dysfunction (OR = 0.17, P = .002), and overall cranial nerve dysfunction (OR = 0.49, P = .03) at last follow-up. CONCLUSION: SRS management of patients with Koos grade I VS was associated with superior tumor control and reduced odds for cranial nerve dysfunction, while not compromising hearing preservation compared with observation. These findings support the safety and efficacy of SRS as a primary care approach for this patient population.

BACKGROUND AND OBJECTIVES: This study assessed the efficacy and safety of stereotactic radiosurgery (SRS) in comparison with watchful waiting for managing Koos grade II vestibular schwannomas (VS). METHODS: A retrospective, multicentric analysis was conducted, focusing on patients with Koos grade II VS who either received SRS (SRS group) or were observed (observation group). To ensure comparability between groups, propensity score matching was used, including factors such as demographic characteristics, tumor dimensions, and hearing assessments. The primary end points examined were tumor control, maintenance of serviceable hearing, and neurological outcomes. RESULTS: A total of 92 patients were equally matched across both cohorts, with a median follow-up of 37 months for the SRS group and 27.5 months for those observed. The SRS cohort exhibited superior tumor control over observation across 3, 5, and 8 years, achieving a 100% control rate vs 47.9%, 40.1%, and 34.3% for the observation group at these time intervals, respectively ( P < .001). Serviceable hearing preservation rates were comparable between the 2 groups throughout 3, 5, and 7 years (72.9% for SRS vs 65.4% for observation at 3 years; P = .86). Moreover, SRS management correlated with a lower incidence of vestibular symptoms (odds ratio = 0.11, P = .002), with no significant disparity in the deterioration of cranial nerve (CN) V or CN VII functions. Notably, the likelihood of experiencing any CN impairment was significantly diminished in the SRS cohort (odds ratio = 0.47, P = .04). CONCLUSION: For patients with Koos grade II VS, SRS offers superior tumor control rate and a lower risk of CN dysfunction without sacrificing hearing preservation.

Background Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors. Methods Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high. Results The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control. Conclusions Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors. Trial registration number NCT04510129.

Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. Evidence Review PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched. Findings In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. Conclusions and Relevance The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.