Citations

ABSTRACT Objective To evaluate the long‐term safety and clinical effect of INO‐3107 immunotherapy in adults with recurrent respiratory papillomatosis (RRP). Methods RRP‐002 was a retrospective, observational extension study that followed patients enrolled in the 52‐week RRP‐001 study. Patients with moderate to severe juvenile or adult‐onset RRP who had undergone ≥ 2 surgical interventions in the year preceding dosing were eligible for enrollment in RRP‐001. Participants underwent surgical debulking within 14 days prior to initial dosing and then received INO‐3107 on Day 0, Weeks 3, 6, and 9. Efficacy assessments during RRP‐002 follow‐up were the frequency of surgical interventions and alternative medication use. The safety evaluation included reported serious adverse events (SAEs). Results Twenty‐eight (28) of 32 participants from the 52‐week RRP‐001 study were enrolled in RRP‐002. The median follow‐up time for RRP‐002 was 1.8 years (range: 1.2–2.4 years) for a total median assessment time of 2.8 years (range: 1.0–3.5 years). There were no SAEs or long‐term safety concerns identified. The mean number of surgeries was reduced from 4.1 in the pre‐treatment period to 1.7 in the first year post‐INO‐3107 treatment (Year 1) to 0.9 in the second year (Year 2). The complete response rate (0 surgeries per year) increased from 28% (9/32) in Year 1 to 50% (14/28) in Year 2. Conclusion INO‐3107 is well tolerated and provides a continued clinical effect against HPV‐6 and 11 RRP that results in further reduction of the surgical burden observed in Year 1. These data support the role of INO‐3107 immunotherapy for adult patients with RRP. Level of Evidence: III.

ABSTRACT The International Consensus Conference “Optimising Performance of the Elite Athlete,” held in November 2024, brought together 29 scientists, some coaches, and athletes to establish evidence‐based consensus statements aimed at enhancing elite athletic performance and health. The conference addressed critical themes including training strategies, nutrition, female athlete considerations, injury management, and emerging technologies. Key conclusions emphasize individualized, sport‐specific approaches to training and nutrition, integrating concurrent training modalities to improve endurance, resilience, and efficiency. Nutrition strategies highlight the importance of tailored energy and macronutrient periodization, recognition of low energy availability risks, and cautious use of dietary supplements. Special attention was directed to female athletes, advocating for improved monitoring of menstrual cycles and hormonal status, while acknowledging current knowledge gaps in hormonal influences on performance and injury risk. Injury prevention remains a challenge, with tendon overuse and Achilles tendon ruptures significantly impacting athlete careers; rehabilitation should rely on criteria‐based progression and multidisciplinary input. Emerging technologies, including wearable sensors and multi‐omics analyses, hold promise for personalized training and nutrition but require further validation in elite contexts. Despite robust consensus, the panel identified substantial research gaps, particularly regarding female athletes, longitudinal training effects, and efficacy of novel interventions. This consensus provides a practical, scientifically grounded framework to optimize elite athlete performance and health, while underscoring the need for continued research to address outstanding questions and promote inclusive evidence‐based practices.

Abstract The link between regional tau load and clinical manifestation of Alzheimer’s disease (AD) highlights the importance of characterizing spatial tau distribution across disease variants. In typical (memory-predominant) AD, the spatial progression of tau pathology mirrors the functional connections from temporal lobe epicentres. However, given the limited spatial heterogeneity of tau in typical AD, atypical (non-amnestic-predominant) AD variants with distinct tau patterns provide a key opportunity to investigate the universality of connectivity as a scaffold for tau progression. In this large-scale, multicentre study across 14 international sites, we included cross-sectional tau-PET data from 320 individuals with atypical AD (n = 139 posterior cortical atrophy/PCA-AD; n = 103 logopenic variant primary progressive aphasia/lvPPA-AD; n = 35 behavioural variant AD/bvAD; n = 43 corticobasal syndrome/CBS-AD), with a subset of individuals (n = 78) having longitudinal tau-PET data. Additionally, as an independent sample, we included regional post-mortem tau stainings from 93 atypical AD patients from two sites (n = 19 PCA-AD, n = 32 lvPPA-AD, n = 23 bvAD, n = 19 CBS-AD). Gaussian mixture modelling was used to harmonize different tau-PET tracers by transforming tau-PET standardized uptake value ratios to tau positivity probabilities (a uniform scale ranging from 0% to 100%). Using linear regression, we assessed whether brain regions with stronger resting-state functional MRI-based functional connectivity, derived from healthy elderly controls in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), showed greater covariance in cross-sectional and longitudinal tau-PET and post-mortem tau pathology. Furthermore, we examined whether functional connectivity of tau-PET epicentres (i.e. the top 5% of regions with the highest baseline tau load) and tau-PET accumulation epicentres (i.e. the top 5% of regions with the highest tau accumulation rates) was associated with cross-sectional and longitudinal tau patterns. Our findings show that tau-PET epicentres aligned with clinical variants, e.g. a visual network predominant pattern in PCA-AD (‘visual AD’) and left-hemispheric temporal predominance, particularly within the language network, in lvPPA-AD (‘language AD’). Moreover, more strongly functionally connected regions showed correlated concurrent tau-PET levels (confirmed with post-mortem data) and tau-PET accumulation rates. The functional connectivity profile of tau-PET epicentres and accumulation epicentres corresponded to tau-PET progression patterns, with higher tau-PET levels and accumulation rates in functionally close regions, and lower tau-PET levels and accumulation rates in functionally distant regions. Our data are consistent with the hypothesis that tau propagation occurs along functional connections originating from local epicentres, across all AD clinical variants. Since tau proteinopathy is a major driver of neurodegeneration and cognitive decline, this finding may advance personalized medicine and participant-specific end points in clinical trials.

Background: The radiolunate joint is conventionally thought to be spared from radiocarpal osteoarthritis, but proximal lunate degenerative changes have been noted. An investigation of radiolunate arthrokinematics in ostensibly healthy wrists may improve understanding of posttraumatic and postoperative outcomes. We hypothesize that four-dimensional computed tomography (4DCT)-derived radiolunate arthrokinematics during motion will differ between wrists with type 1 and type 2 lunates. The clinical-translational relevance of this analysis is highlighted using a 4DCT case study of scaphoid excision with 4-corner arthrodesis (SEFCA). Methods: Four-dimensional computed tomography data were collected during flexion-extension and radioulnar deviation in 19 healthy wrists (mean [SD] age: 43.6 [11.7] years, 21.1% female) and 1 wrist 3 years after SEFCA (male, 52 years). Carpal osteokinematics and joint arthrokinematics were calculated to derive median radiolunate interosseous proximities at each 4DCT-captured timepoint. Results: Median radiolunate interosseous proximities during motion are well approximated by second-order regressions in uninjured wrists. In the arthrodesed wrist, closest proximities occurred at the extremes of motion except maximum radial deviation. Conclusions: This study quantifies a normative range of median radiolunate interosseous proximities during wrist motion. The normative 4DCT datasets provide a reference range for evaluating postoperative arthrokinematics, suggesting the clinical-translational potential of dynamic imaging. The case study highlights applications for patient-level postoperative evaluation, which can be expanded to other pathologies, surgeries, or conditions in the future.

Abstract Background: With over 1 billion individuals affected globally, obesity and obesity related diseases is now a leading cause of death. Metabolic and bariatric surgery (MBS) has emerged as a cornerstone intervention for severe obesity and its associated comorbidities. Despite its efficacy, postoperative care and follow-up after MBS remains highly variable worldwide. Objective: The PARTNER study aimed to evaluate global clinical practices in the postoperative management following MBS by surveying multidisciplinary healthcare professionals . Methods: This study was an international online survey conducted between October 2024 and January 2025. A multidisciplinary team developed the questionnaire based on existing literature and international guidelines. The survey assessed five domains: follow-up care, postoperative treatment, dietary management, patient support, and measurement of surgical outcomes. Responses were analysed descriptively. Results: A total of 262 responses were received from 62 countries. Most respondents were bariatric surgeons (72.1%) working in public healthcare systems (73.3%). While 78.7% reported conducting three-month postoperative reviews, only 23.7% offered indefinite follow-up. Hybrid models of care (virtual and in-person) were common (56.9%). VTE prophylaxis and postoperative PPI use were recommended by 64.1% and 84.3% respectively. Nearly all respondents (98.1%) provided dietary advice, with protein and micronutrient supplementation widely endorsed. Only 56.1% routinely referred patients for psychological follow-up. Definitions of surgical success and failure varied widely, with inconsistent objective outcome measures. Conclusion: The PARTNER study reveals significant international variation in postoperative management practices following MBS. These findings underscore the need for more standardized, evidence-based guidelines to improve long-term outcomes and equity of care worldwide.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

The NCCN Guidelines for Uterine Neoplasms provide recommendations for diagnostic workup, clinical staging, and treatment options for patients with endometrial cancer and uterine sarcoma. The NCCN Cervical Uterine Panel meets at least annually to review comments from reviewers within their institutions; examine relevant new data from publications, abstracts, and recent FDA approvals; and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s deliberations on the new FIGO 2023 staging system and updates on the new systemic therapy recommendations for the management of endometrial cancer.

Intronic GGGGCC hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Despite its intronic location, this repeat avidly supports synthesis of pathogenic dipeptide repeat (DPR) proteins via repeat-associated non-AUG (RAN) translation. However, the template RNA species that undergoes RAN translation endogenously remains unclear. Using long-read based 5′ RNA ligase-mediated rapid amplification of cDNA ends (5′ Repeat-RLM-RACE), we identified C9orf72 transcripts initiating within intron 1 in a C9BAC mouse model, patient-derived iNeurons, and iNeuron-derived polysomes. These cryptic m 7 G-capped mRNAs are at least partially polyadenylated and are more abundant than transcripts derived from intron retention or circular intron lariats. In RAN translation reporter assays, intronic template transcripts–even those with short (32 nucleotide) leaders–exhibited robust expression compared to exon–intron and repeat-containing lariat reporters. To assess endogenous repeat-containing lariat RNA contributions to RAN translation, we enhanced endogenous lariat stability by knocking down the lariat debranching enzyme Dbr1. However, this modulation did not impact DPR production in patient-derived iNeurons. These findings identify cryptic, linear, m 7 G-capped intron-initiating C9orf72 mRNAs as an endogenous template for RAN translation and DPR production, with implications for disease pathogenesis and therapeutic development.