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With their unique therapeutic properties and amenability to engineering modifications, exosomes are considered a promising tool for treating peripheral nerve injuries. Through genetic engineering or physicochemical modifications, the targeting ability and functionality of exosomes can be further enhanced, enabling efficient delivery of therapeutic molecules and significantly boosting their therapeutic potential. This review aims to explore exosome-based therapies in peripheral nerve repair and their mechanisms and summarizes recent advances in the roles of exosomes in neuroprotection, axonal regeneration, vascular regeneration, and inflammatory modulation. Exosomes act as natural messengers between cells, carrying genetic materials, cytokines, and growth factors that can modulate the local microenvironment and foster peripheral nerve regeneration. Studies have shown that exosomes derived from Schwann cells, macrophages, neurons, and mesenchymal stem cells can all promote axonal regeneration and modulate inflammatory responses through various mechanisms. Compared with cell therapy, exosome therapy offers greater stability and safety, with the ability to traverse biological barriers, presenting new possibilities for regenerative medicine and precision therapy. However, challenges such as the heterogeneity and complexity of exosomes, uncertainty of in vivo distribution and metabolic pathways, and the limitations of targeting remain to be addressed. Future research will focus on the engineering modifications of exosomes to enhance their therapeutic efficiency and targeting precision.

Background: Skin cancer patients who undergo Mohs surgery may require subsequent reconstructive rhinoplasty for large nasal defects. Autologous cartilage is the primary source of supporting cartilage grafts, but carries the risk of potential donor-site complications. In this study, we demonstrate the safety and efficacy of nonterminally irradiated fresh frozen human costal cartilage allografts (CCAs) in reconstructive rhinoplasty after skin cancer removal. Methods: A retrospective chart review of 25 patients who underwent reconstructive rhinoplasties using human CCA after basal cell carcinoma resection was conducted. Human CCA undergoes a process of sterilization without terminal irradiation and is stored frozen (−40°C to −80°C). Anthropometric measurements were taken on pre- and postoperative photographs to evaluate nasal tip projection. Adverse events were evaluated. Results: There were 25 participants, with an average age of 71 years at the time of surgery (range: 42–90). The average follow-up duration was 12 months (range: 3–66 mo). Types of grafts used included alar batten graft (n = 17, 68%), nasal tip graft (n = 7, 28%), and alar batten graft with nasal tip graft (n = 1, 4%). Measurements on the 2-dimensional photographs of the patients showed no significant resorption or deviation at the 6- or 12-month follow-up. No significant complications related to the use of the cartilage were noted. Conclusions: Our data highlight the low complication rate and aesthetically positive outcomes from using nonterminally irradiated human CCA for reconstructive rhinoplasties in post-Mohs surgery for older patients. This approach offers a reliable source of high-quality cartilage for reconstruction.

The Society of Thoracic Radiology (STR) membership enthusiastically embraced the launch of its mentorship program, with peaks in participation and engagement after annual meetings and during the COVID pandemic. The program provides a valuable resource for early to mid-career thoracic radiologists, especially those lacking local resources. This report describes the program’s inception and design, and summarizes the program’s successes and challenges at 5 years, based on a 2023 mentorship survey. STR mentees, spanning early to mid-career stages, most frequently sought mentorship in career development, graduate medical education, research portfolio development, publishing, cardiac imaging, grant funding, and artificial intelligence. Mentors offered expertise in these areas, plus lung cancer screening, career development, and workplace navigation. The committee prioritized creating dyads based on mutual interest and expertise, achieving mutual top-choice match rates of 70% to 97%. Enduring dyads flourished as the program matured. At 5 years, a survey of participants was fielded. Mentees reported moderate to high program impact on scholarly activities, leadership, networking, clinical service, education, and career satisfaction. Mentors described satisfaction in their roles, highlighting networking, career satisfaction, and the opportunity to influence upcoming generations of cardiothoracic radiologists, thereby impacting the field’s future. Most participants expressed high career satisfaction. Descriptive comments further enriched findings. Survey results confirmed that strengthening dyad formation and enhancing mentoring outcomes remain pivotal. Remote mentorship, while valuable, presents challenges—personal connections and contextual familiarity, considered essential to successful mentorship relationships, are typically absent in these settings. Activities to potentially enhance the STR mentorship program are offered.

Abstract Introduction / Rationale Mucus plugs (MPs) on chest computed tomography (CT) are associated with increased respiratory symptoms, worse lung function, and elevated mortality and acute exacerbations among individuals with GOLD2-4 COPD. Whether mucus plug distribution in the upper versus lower lobes differentially impacts future acute exacerbations (AEs) has been incompletely explored. Methods Data from current and former tobacco users, ages 40-80, with ≥10 pack-years, at the enrollment visit in COPDGene were analyzed. MPs were visually-assessed on chest CTs using a sequential reading system; the MP score was calculated as the number of bronchopulmonary segments with plugs (range 0-18). Among subjects with MPs, the percent of lower lobe MPs (%LLMPs) was calculated as the number of bronchopulmonary segments in the right and left lower lobes divided by the total number of bronchopulmonary segments (range 0-100%). Moderate-to-severe AEs were assessed prospectively biannually for up to 15.5 years. Zero-inflated Poisson regression, adjusting for age, sex, BMI, race, smoking status, pack-years, FEV1% predicted, history of AEs (year prior to enrollment), and clinical center assessed the relationship between %LLMPs, total MPs, and prospective AEs; duration of follow-up was included as the offset. Subgroup analyses by lung function category (GOLD0, GOLD 1-4 COPD, and Preserved Ratio Impaired Spirometry, PRISm) were also performed using the same model. Results Among 10,198 tobacco-exposed individuals, 9,406 subjects (mean age 59.7±9.0, 53.4% male, 68% non-Hispanic white) had chest CT scans scored for MPs. The overall prevalence of MP>0 was 30.4%, with an average MP score of 0.78±1.88 and average %LLMP of 48%±39%. The prevalence of MPs varied by lung function category (20.1% GOLD0, 26.2% PRISm, 40.8% COPD) as did the mean MP score (0.28±0.93 GOLD0, 0.49±1.38 PRISm, 1.30±2.42 COPD) (Figure 1). The %LLMP also varied by lung function category (33%±39% GOLD0, 38%±37% PRISm, 57%±37% COPD). Among subjects with MPs>0 (n=2,857), higher %LLMP was associated with a significantly increased risk for future AEs (adjusted rate ratio (aRR) [95%CI]= 1.11[1.05-1.17]; Figure 1). Subgroup analyses by lung function category supported a significant association between increased %LLMP and future AEs in GOLD0 (aRR 1.45 [1.25-1.69]), but not in the COPD or PRISm subgroups (Figure 1). Conclusions A higher proportion of lower lobe mucus plugs is significantly associated with increased risk for future AEs among tobacco-exposed persons. Despite having the lowest burden of MPs, the highest risk for prospective AEs with increasing %LLMP was observed in the subgroup with normal spirometry (GOLD0).

ABSTRACT Long segment losses exceeding 10 cm in the sciatic nerve are challenging in both the reconstructive techniques and optimizing sensory and motor function recovery. This case report and literature review describes our experience of using a pedicled vascularized common peroneal nerve graft to repair a 14‐cm sciatic nerve defect, involving L4 , L5 , and S1 nerve roots. Additionally, we conducted a literature review of various types of nerve autografts for large sciatic nerve defects, summarizing their characteristics and outcomes to aid clinicians in decision‐making and expected results in different scenarios. The patient, a 23‐year‐old female diagnosed with neurofibromatosis type I, underwent R0 tumor resection of the proximal left sciatic nerve due to a malignant peripheral nerve sheath tumor. She received an ipsilateral pedicled vascularized common peroneal nerve graft. The reconstruction included the L4 , L5 , and S1 nerve roots beyond the greater sciatic foramen into the inner pelvis. The patient's postoperative course was uneventful. At the 26‐month follow‐up, she showed MRC grade 4/5 strength in hamstrings with 90°knee flexion and a steady gait pattern. At the 32‐month follow‐up, she could ambulate very well with an ankle‐foot orthosis. The outcomes support the use of a pedicled vascularized common peroneal nerve graft in a single‐staged surgery to restore motor function for large sciatic nerve defects. Our literature review revealed that in cases where sural nerves are insufficient or injured for sciatic nerve reconstruction, the common peroneal nerve is a viable alternative to help patients regain functional independence.

Abstract Background: Ivosidenib (IVO) is a first-in-class oral inhibitor of the IDH1 mutant (mIDH) enzyme. In the ClarIDHy phase 3 study of previously treated patients with mIDH cholangiocarcinoma (CCA), IVO treatment led to improved progression-free survival (PFS) and overall survival (OS) vs placebo (median PFS: 2.7 vs. 1.4 months and OS 10.3 vs. 5.1 months, when adjusted for the 70% crossover rate; HR, 0.49 [95% CI, 0.34-0.70]; 1-sided P<0.001. Here, we studied the dynamics of mutations emerging after 6 months of IVO treatment using ctDNA analyses. Methods: Prior to enrollment, all subjects in ClarIDHy had IDH1 R132 mutations confirmed by a central NGS panel utilizing tumor biopsy tissue. Since post-progression tissue samples were unavailable, discovery of emerging mutations was limited to plasma ctDNA assessments. To explore molecular changes associated with acquired resistance, an analysis was performed on 18 subjects treated with IVO for ≥6 months (4 partial response; 12 stable disease, 2 NA) using matched baseline and end of treatment (EOT) samples (PGDx elioTM plasma complete, 521 gene panel). A subset of the oncogenic alterations identified were selected for confirmation by ddPCR analysis in ctDNA samples collected longitudinally. Longitudinal plasma 2HG levels were also evaluated. Results: This analysis identified several EOT mutations not present at baseline. The most common mutations were in the MAPK pathway, including activating KRAS, NRAS, and MAP2K1 mutations and loss-of-function NF1 mutations (6/18 patients, 33%). In 2/6 patients, multiple MAPK pathway mutations were detected. There was a range of variant allele frequencies (VAFs) of RAS alterations, including some that had comparable levels to the truncal mIDH, suggesting that MAPK activation may have made a major contribution to the burden of resistant disease. ddPCR analyses from longitudinal plasma samples from selected cases confirmed these findings. In addition, 2 patients had mutations affecting transcription/epigenetics (WT1 and KMT2C). Finally, only 1 patient had acquired mutations in IDH genes (IDH2-R172K and IDH1-G131V). The WT1, KMT2C, and IDH variants had a low VAF. Accordingly, EOT plasma 2HG levels were reduced vs pre-treatment levels in the patient with secondary mIDH, indicating a limited role in the overall emergence of resistance. Conclusion: Analyses of paired baseline/EOT samples suggest that multiple acquired mutations could contribute to IVO resistance, with oncogenic MAPK pathway alterations being the most common. Consistent with previous clinical studies conducted in AML, IDH1 second site mutations and isotype switching to IDH2, rarely emerge during IVO treatment. The lack of detectable mutations in the majority of patients could reflect the sensitivity of the NGS assay or a role for non-genetic mechanisms of resistance. Citation Format: Hatice Duygu Saatcioglu, Haley Ellis, Jinkai Wan, Sam Lubner, Milind Javle, Ghassan K. Abou-Alfa, James M. Cleary, Robin Kate Kelley, Mitesh J. Borad, Teresa Macarulla, Do Youn Oh, Camelia Gliser, Susan Pandya, Sung Chloe, Nabeel Bardeesy, Adriana Tron. Circulating tumor DNA analysis demonstrates newly emerging alterations in previously treated IDH1 mutated cholangiocarcinoma patients enrolled in the ClarIDHy study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4648.

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

Despite ongoing efforts to employ structure-based methods to discover targeted protein degraders (TPD), the prevailing strategy remains synthesizing a focused set of heterobifunctional compounds and screening them for target protein degradation.

Abstract Background Conventional proton dose calculation methods are either time‐ and resource‐intensive, like Monte Carlo (MC) simulations, or they sacrifice accuracy, as seen with analytical methods. This trade‐off between computational efficiency and accuracy highlights the need for improved dose calculation approaches in clinical settings. Purpose This study aims to develop a deep‐learning‐based model that calculates dose‐to‐water ( D W ) and dose‐to‐medium ( D M ) using patient anatomy and proton spot map (PSM), achieving approaching MC‐level accuracy with significantly reduced computation time. Additionally, the study seeks to generalize the model to different treatment sites using transfer learning. Methods A SwinUNetr model was developed using 259 four‐field prostate proton stereotactic body radiation therapy (SBRT) plans to calculate patient‐specific D W and D M distributions from CT and projected PSM (PPSM). The PPSM was created by projecting PSM into the CT scans using spot coordinates, stopping power ratio, beam divergence, and water‐equivalent thickness. Fine‐tuning was then performed for the central nervous system (CNS) site using 84 CNS plans. The model's accuracy was evaluated against MC simulation benchmarks using mean absolute error (MAE), gamma analysis (2% local dose difference, 2‐mm distance‐to‐agreement, 10% low dose threshold), and relevant clinical indices on the test dataset. Results The trained model achieved a single‐field dose calculation time of 0.07 s on a Nvidia‐A100 GPU, over 100 times faster than MC simulators. For the prostate site, the best‐performing model showed an average MAE of 0.26 ± 0.17 Gy and a gamma index of 92.2% ± 3.1% in dose regions above 10% of the maximum dose for D W calculations, and an MAE of 0.30 ± 0.19 Gy with a gamma index of 89.7% ± 3.9% for D M calculations. After transfer learning for CNS plans, the model achieved an MAE of 0.49 ± 0.24 Gy and a gamma index of 90.1% ± 2.7% for D W computations, and an MAE of 0.47 ± 0.25 Gy with a gamma index of 85.4% ± 7.1% for D M computations. Conclusions The SwinUNetr model provides an efficient and accurate method for computing dose distributions in proton therapy. It also opens the possibility of reverse‐engineering PSM from D W , potentially speeding up treatment planning while maintaining accuracy.

AbstractBackgroundThe 17q21.31 region with various structural forms characterized by the H1/H2 haplotypes and three large copy number variations (CNVs) represents the strongest risk locus in progressive supranuclear palsy (PSP).ObjectiveTo investigate the association between CNVs and structural forms on 17q.21.31 with the risk of PSP.MethodsUtilizing whole genome sequencing data from 1684 PSP cases and 2392 controls, the three large CNVs (α, β, and γ) and structural forms within 17q21.31 were identified and analyzed for their association with PSP.ResultsWe found that the copy number of γ was associated with increased PSP risk (odds ratio [OR] = 1.10, P = 0.0018). From H1β1γ1 (OR = 1.21) and H1β2γ1 (OR = 1.24) to H1β1γ4 (OR = 1.57), structural forms of H1 with additional copies of γ displayed a higher risk for PSP. The frequency of the risk sub‐haplotype H1c rises from 1% in individuals with two γ copies to 88% in those with eight copies. Additionally, γ duplication up‐regulates expression of ARL17B, LRRC37A/LRRC37A2, and NSFP1, while down‐regulating KANSL1. Single‐nucleus RNA‐seq of the dorsolateral prefrontal cortex analysis reveals γ duplication primarily up‐regulates LRRC37A/LRRC37A2 in neuronal cells.ConclusionsThe copy number of γ is associated with the risk of PSP after adjusting for H1/H2, indicating that the complex structure at 17q21.31 is an important consideration when evaluating the genetic risk of PSP. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.