Citations

Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized MRI examinations, which, in the absence of new symptoms or signs, are usually scheduled every 2–3 months. Here, we hypothesized that changes in daily activity are associated with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of 6 patients with GBM wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with 1-minute resolution. After tumor resection and radiation, daily activity declined in 2 patients 19 and 55 days before detection of progression by MRI but did not change for the 4 patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Abstract Description PBC is an archetypal autoimmune disease where the dominant autoantigen is mitochondrial PDC-E2. Hitherto, PBC treatment has been neither specific nor directed toward restoration of tolerance. CNP-104, a tolerogenic nanoparticle encapsulating PDC-E2, is hypothesized to restore tolerance to pathogenic T cells. We conducted a Phase 2a First-in-Human randomized controlled trial of CNP-104 in PBC patients unresponsive/intolerant to ursodeoxycholic acid. The 42 enrolled subjects were randomized 2:1 to receive two doses of CNP-104 or placebo (PBO) one week apart and were followed for 120 days to assess safety and treatment durability. CNP-104 was safe and well-tolerated. Compared to PBO, the CNP-104 group had a reduced percentage of antigen-specific Th17 T cells and increased antigen-specific tolerogenic CD8+ T cell counts (TIGIT, GARP). ALP, ALT, and total bilirubin were similar between groups. Clinically relevant effects on albumin levels, liver stiffness, and the rate of change in 5-year UK-PBC risk for liver outcomes were improved in the CNP-104 group compared to PBO. This trial is limited by small size and data variability. Induction of antigen-specific T cell tolerance, shown by reduced Th17 cells and increased TIGIT and GARP cells correlates with improved liver stiffness, albumin, and UK-PBC. These findings suggest the CNP-104 tolerogenic mechanism of action translates to clinical benefits. These data support future studies with this unique therapeutic platform to treat PBC. Topic Categories Therapeutic Approaches to Autoimmunity (THER)

Abstract Description Cellular immune responses are critical for protection from environmental and genetic insults, including pathogens and cancer. However, immunity can also drive pathogenic responses that damage organs and drive pathogenesis. Immune response quality is influenced by several factors including genetics, age, sex and the environment. Environmental influences including everyday activities and lifestyle have been shown to modulate the immune system but are often difficult to monitor. We have developed a system of serial monitoring of peripheral blood mononuclear cells that coincided with wearable device activity monitoring to further understand how biometric data correlates with the composition of blood derived immune cells. Using a 31-marker CyTOF phenotyping panel we monitored blood derived immune cell composition over a 14-week period in an individual volunteer while biometric data was collected via wearable technology. To determine whether interventions can be introduced that change peripheral blood immune cell phenotypes our volunteer introduced lifestyle changes at specific intervals in this period of monitoring. These included intermittent fasting and the introduction of regular exercise. In addition, the individual was immunized against COVID-19 during this time to provide an immune challenge that would perturb immune homeostasis. In this study, we find that lifestyle changes can promote alterations in immune cell phenotypes identified using high parameter mass cytometry. Topic Categories Translational and Interventional Immunology (TI)

ABSTRACT We present the case of a 28‐year‐old right‐handed woman with medically refractory focal epilepsy. Her seizure semiology and electroencephalography (EEG) indicated a seizure onset zone in the right central‐parietal area. However, both MRI and PET scans were unremarkable, showing no focal lesions or areas of altered metabolism. Intracranial monitoring, with extensive evaluation of both hemispheres, confirmed the seizure onset zone in the right central‐parietal region. This area not only served as the site of seizure onset but also encompassed the primary sensory cortex.

Background Preclinical studies demonstrate the benefits of ultra‐high dose‐rate (FLASH) radiation, reducing normal tissue toxicity while maintaining tumoricidal effects. Proton FLASH (pFLASH) studies typically use transmission beams, missing the normal tissue‐sparing advantage of the spread‐out Bragg peak (SOBP). Purpose This study aims to propose and implement a series of modifications to enable a clinical Mevion S250i gantry‐mounted synchrocyclotron to deliver pFLASH within the SOBP of the proton beam. Methods A clinical synchrocyclotron was modified to enable FLASH proton beam delivery using the Mevion FLASH accessory kit, a commercially available tool that allows for the delivery of a single spot SOBP at FLASH dose rates. To ensure accurate beam monitoring, a Faraday cup was utilized to measure the integral charge per delivery at different dose rates and calibrate the FLASH transmission ion chamber (FLASHTic), which is integrated in the FLASH accessory mount attached to the nozzle of the gantry. The FLASHTic was specifically designed to prevent saturation at the dose rates associated with FLASH. To generate the desired single spot SOBP, boron carbide absorbers, a range modulating hole filter, and an 11‐mm‐diameter circle brass aperture were employed on the FLASH nozzle mount. Results The results indicate that the FLASHTic measurements demonstrated a strong correlation with the Faraday cup post calibration, suggesting that the FLASHTic can be effectively utilized for both monitoring and terminating the proton beam. The 80%–80% width of the SOBP was 2.01 cm. The peak dose rate at the SOBP proximal peak reached 105.03 Gy/s, with an average of 96.18 Gy/s over five days. Transitioning between FLASH and clinical mode required less than one hour without affecting the clinical beam. Conclusions The commissioning of a 230 MeV proton synchrocyclotron for SOBP FLASH delivery was achieved, providing a platform for preclinical small animal studies on pFLASH effects.

Abstract Objectives Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)‐guided depth leads to provide responsive stimulation to neocortical gray matter. Methods Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti‐responders (≤0%) based on percent seizure reduction at 1 year post‐implant (1‐Y). Pre‐operative T1‐weighted magnetic resonance imaging and post‐operative computed tomography images were merged, and the Euclidean distance between the sEEG epileptic focus (sEEG‐EF) and the nearest RNS System depth lead contacts was calculated. Results A total of 87 depth leads were implanted in 55 patients across neocortical brain regions. The median reduction in clinical seizures improved from 66.7% at 1‐Y to 77.5% at long‐term follow‐up (LTFU: 2.35 ± 0.95 years), with 10 patients (18.2%) achieving complete seizure freedom. Seven patients (12.7%) experienced six serious adverse events. At 1‐Y, shorter Euclidean distance between the sEEG‐EF and RNS System depth leads predicted improved seizure outcome in strong responders ( β = −0.84, p = 0.008) but not in weak responders ( β = 0.21, p = 0.9) or anti‐responders ( β = −20.34, p = 0.11). At LTFU, there was no significant relationship between Euclidean distance and seizure reduction in strong responders ( β = 0.77, p = 0.18), weak responders ( β = 2.05, p = 0.54), or anti‐responders ( β = 0.24, p = 0.99). Exploratory analyses at 1‐Y showed nominal associations between older age ( ρ = 0.32), longer epilepsy duration ( ρ = 0.27), and non‐mesial temporal sEEG‐EFs and greater seizure reduction; however, none survived Bonferroni correction (adjusted α = 0.0027; all post‐correction p > 0.0027), and no associations were observed at LTFU. Significance In this series, neocortical depth leads for RNS therapy had favorable safety and efficacy and proximity to the sEEG‐EF drove initial outcomes for strong responders to RNS therapy. Plain Language Summary In this multi‐center study, patients with difficult‐to‐treat seizures received brain‐responsive stimulation using a device called responsive neurostimulation (RNS), which delivers small electrical pulses to reduce seizures. We focused on patients treated with electrodes placed in the brain's outer regions (the neocortex) and guided by a mapping procedure called sEEG. On average, patients had their seizures cut by two‐thirds after one year and by more than three‐quarters with longer follow‐up, with about one in five becoming seizure‐free. The treatment was safe, and closer electrode placement to the seizure source helped explain early—but not long‐term—improvements.

Background: Injury to the medial ulnar collateral ligament (MUCL) is a common setback for throwing athletes, often requiring reconstruction with 12 to 18 months of rehabilitation. The authors previously described a more anatomic technique with improved mechanical strength as compared with the docking technique, which may allow for an accelerated return to sport. Purpose: To evaluate return-to-sport rates, time to return to sport, and the effect on the functional performance of amateur and professional throwing athletes who underwent anatomic MUCL reconstruction with suture tape augmentation. Study Design: Case series; Level of evidence, 4. Methods: A retrospective case series was performed including baseball players who underwent anatomic MUCL reconstruction with suture tape augmentation by a single surgeon from 2018 to 2022. Inclusion criteria consisted of a minimum 2-year follow-up, participation in baseball, and utilization of autograft (palmaris longus or gracilis). Patients who underwent previous MUCL reconstruction were excluded from the study. All patients initially followed an accelerated rehabilitation protocol. Outcome measures were collected, including Kerlan-Jobe Orthopaedic Clinic (KJOC), Single Assessment Numeric Evaluation (SANE), and Conway-Jobe scores, as well as throwing metrics such as ball velocity and spin rate. Results: Thirty-four baseball players (mean ± SD age, 21 ± 3 years) underwent primary MUCL reconstruction. Time of final follow-up was 36.1 ± 10.3 months. Of these, 16 were professional athletes and 18 were amateur. All throwers returned to live gameplay at a mean 10.1 ± 2.0 months after reconstruction (professional, 10.6 ± 2.3; amateur, 9.7 ± 1.8). Furthermore, 97% (94% professional, 100% amateur) advanced through the accelerated postoperative protocol without issues, and 91% (88% professional, 94% amateur) returned to the same role and 85% (75% professional, 94% amateur) to the same level of play. Professional postinjury KJOC scores improved from 42.6 ± 16 to 87.5 ± 8.3 and SANE scores from 25.0 ± 11.2 to 95.6 ± 4.2. Amateur postinjury KJOC scores improved from 35.6 ± 10.7 to 90.9 ± 8.6 and SANE scores from 57.5 ± 16.9 to 95.2 ± 7.2. No significant difference was identified in preinjury versus postreconstruction throwing velocity, ball spin rate, or horizontal/vertical ball movement. The overall failure rate was 2.9%, with 1 professional pitcher requiring revision for graft rupture at 3 years postoperatively. Conclusion: Anatomic reconstruction of the MUCL with suture tape is a viable option for MUCL injuries, allowing an expedited return to sport at 10.1 ± 2.0 months (professional, 10.6 ± 2.3; amateur, 9.7 ± 1.8) in baseball players, with a low failure rate.

Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.