Citations

Abstract Background DNA methylation profiling can be used to robustly predict postsurgical outcomes and response to radiotherapy (RT) for meningioma patients. To allow for seamless integration of these complementary models into clinical practice, a practical framework is needed. Methods We leveraged a cohort of nearly 2000 surgically-treated meningiomas with DNA methylation profiling and clinical outcomes data. Existing methylation-based prediction models were dichotomized to yield four risk groups: low and high recurrent risk, each with RT sensitive and resistant subgroups. Risk groups were correlated with progression-free survival in the context of existing biomarkers including extent of resection and WHO grade. Results We first demonstrated that all risk groups benefit from gross total resection. All “high-risk, RT sensitive” tumors (n = 306, 15.7%) also benefited from adjuvant RT: after GTR, median PFS increased from 4.68 (4.13-9.48) years to not reached (P = .003); after subtotal resection (STR), from 2.12 (1.59-3.02) to 4.09 (3.41-not reached) years (P = .004). “Low-risk, RT sensitive cases” (n = 1207, 61.8%) also benefited from RT after STR (median PFS 7.39 (6.66-12.8) vs. 16.53 (10.35-not reached) years, P = .03), suggesting that RT be considered in these patients. Neither “low-risk RT resistant” (n = 84, 4.3%) nor “high-risk RT resistant” (n = 356, 18.2%) cases benefited from RT, and the latter group was associated with universally poor outcomes. Conclusions We identify methylation-defined risk groups of meningioma for which additional benefit is gained from adjuvant RT, leading to a clinical decision-making framework for straightforward integration of molecular models into clinical practice.

Background: Meniscal preservation has been demonstrated to contribute to long-term knee health and has been a successful intervention in isolation and in patients with anterior cruciate ligament reconstruction (ACLR). The long-term results of meniscal repair in the setting of revision ACLR have yet to be documented. Purpose: To report the incidence of meniscal repair failures at the 6-year follow-up in a cohort of patients who underwent concurrent revision ACLR and primary meniscal repair. Study Design: Prospective cohort study; Level of evidence, 2. Methods: All revision ACLRs with concomitant primary meniscal repair cases from a multicenter group between 2006 and 2011 were selected. Six-year follow-up was obtained to determine whether any subsequent surgery had occurred since their initial revision ACLR. If so, operative reports were obtained, whenever possible, to verify pathological condition and treatment. Results: In total, 221 patients from 1234 revision ACLRs underwent concurrent primary meniscal repairs (18% of the cohort). There were 238 repairs performed: 173 medial and 65 lateral. The majority of these repairs (n = 181; 76%) were performed with an all-inside technique. Six-year surgical follow-up was obtained in 77% (171/221) of the cohort, or 189 of 238 (79%) of the repairs (136 medial, 53 lateral). The meniscal repair failure rate, defined as reoperation, was 16% (31/189) at 6 years. Of the 31 failures, 28 were medial (24 all-inside, 4 inside-out; 28/136 = 20.6% failure rate) and 3 were lateral (2 all-inside, 1 inside-out; 3/53 = 5.7% failure rate). Three medial failures were treated in conjunction with a subsequent repeat revision ACLR. Medial tears underwent reoperation for failure at a significantly higher rate than lateral tears (20.6% vs 5.7%; P = .01) and had a significantly shorter survival time compared with lateral tears ( P = .02). No difference was found between the failure and nonfailure groups when it came to tear type, tear length, repair technique utilized, suture/implant type, or number of sutures used between the 2 groups. Conclusion: Meniscal repair in the revision ACLR setting has a 16% failure rate at 6 years. Failure rates for medial tears (20.6%) were found to be higher than that for lateral tears (5.7%), which aligns with previous studies in both the revision and primary ACLR setting.

Malignant glioma is considered invariably recalcitrant, thus necessitating development of new therapeutic approaches. Spontaneously arising canine glioma exhibits important molecular and pathological similarities to malignant pediatric glioma, making it an invaluable model for testing novel therapies. We evaluated safety and activity of RNA lipid particle aggregates (LPAs) designed to provoke cancer immunogenicity in 10 dogs with histologically confirmed glioma. Vaccine manufacturing was feasible in all subjects and generally well tolerated. Median survival time was 123 and 155 days in dogs receiving three (Group A) or four (Group B) vaccines, respectively; this was increased from historical reporting of subjects receiving palliative care. Responding animals had a robust cytokine response following infusions. In animals receiving non-specific RNA-LPAs, there was localization of messenger RNA (mRNA) payloads to the brain tumor microenvironment and a rapid shift in immunologic gene signatures consistent with a viral response. These data demonstrate the ability to induce rapid viremic response in the tumor microenvironment following a single peripherally administered mRNA vaccine. Since RNA-LPAs are amenable to repeat boosts, these formulations may overcome challenges of tumor immunosuppression and therapeutic access and are currently under evaluation in first-in-human trials ( NCT04573140 , NCT06389591 ).

Abstract INTRODUCTION Glioblastoma (GBM) contains metabolically distinct cell lineages: treatment-sensitive cells (TSCs) dependent on glycolysis and treatment-resistant persister cells (TRPCs) reliant on lipid metabolism. Our integrative systems biology approach, combining spatial multi-omics and targeted analyses, uncovers lipid acquisition in TRPCs as a pivotal driver of GBM progression which is supported by a retrospective study of statin-treated patients, providing clinical evidence for the therapeutic potential of targeting lipid metabolism in GBM patients stratified based on high TRPC signatures. METHODS We applied spatial transcriptomics and proteomics combined with 3D reconstruction of the tumor microenvironment to map TRPC- and TSC-enriched regions. Immunohistochemically stained tissues were analyzed using CellProfiler and our custom SNAQ algorithm for single-cell neighborhood analysis. Lipid transfer from Tumor-Associated Myeloid Cells (TAMCs) to TRPCs was tracked via flow cytometry, holotomography, and time-lapse imaging. Genetic and pharmacological targeting of CCR2, CSF1R, and FABP3 was performed in vitro and in vivo. Finally, a retrospective analysis of 4,085 GBM patients assessed the impact of statin treatment in relation to TRPC signatures. RESULTS TRPCs exploit recruited TAMCs to acquire lipids, supporting their survival and immune evasion. These interactions are mediated by CCL2/7–CCR2 and CSF1–CSF1R signaling. Disruption of TRPC-TAM lipid homeostasis significantly remodeled the immune microenvironment, reduced tumor growth, and extended survival in preclinical models. Patients with high TRPC signatures typically had poor outcomes; however, retrospective analysis revealed that statin treatment was associated with improved survival in this subgroup. These findings position lipid trafficking as a metabolic vulnerability in GBM and highlight the therapeutic relevance of targeting TRPC–TAMC interactions. CONCLUSION Our study reveals lipid trafficking to TRPCs as a key mechanism driving GBM progression. Targeting TAMC-mediated lipid transfer disrupts immune suppression and tumor growth. Transcriptomic profiling may guide patient stratification, identifying those likely to benefit from lipid metabolism-targeted therapies such as statins.

Abstract The 5-year survival rate for metastatic melanoma (MM) is 35% with rates increasing to ~50% with immune checkpoint blockade (ICB) treatment. Unfortunately, melanoma brain metastases (MBM) develop in nearly half of MM patients and often relapse rapidly following ICB treatment. MBM resistance to ICB can be attributed to tumor-associated macrophages (TAM). Transcriptional profiling of MM revealed that TAMs possess a lipidated phenotype suggesting that aberrant lipogenic processes confer ICB resistance. Stearoyl-CoA desaturase (SCD) is a lipogenic enzyme that is overexpressed in MM and may cause TAM lipidation. SCD serves as an attractive target for inhibition and combination with ICB for treating MBM. We hypothesize that SCD overexpression produces lipid-rich tumor cells that trigger a phenotypic switch towards immunosuppressive lipid-laden macrophages (LL-Mø). Clinical correlation analysis was conducted to assess SCD expression with ICB response. scRNA-seq data of MBM were analyzed to assess TAMs exhibiting lipidated phenotype. Phagocytosis and lipid transfer was assessed via macrophage and melanoma co-culture using time-lapse microscopy. In-silico modeling and LC-MS/MS was performed to assess blood brain barrier (BBB) penetrance of two small molecule inhibitors of SCD (SCDi): MTI-301 and MF-438. Clinical correlation analysis of MM patients revealed high SCD expression associated with decreased survival of patients treated with ICB. scRNA-seq analysis of MBM revealed upregulation of de novo lipogenesis and cholesterol uptake transcripts within TAM populations. Time-lapse co-culture studies reveal rapid lipid accumulation in macrophages. In-silico modeling predicted SCDi BBB penetration and was corroborated by LC-MS/MS. MBM are notoriously difficult to treat due to poor drug penetrance into CNS and unique microenvironment. We demonstrate that macrophages reprogram towards immunosuppressive LL-Mø, which can be exploited for anti-tumor targeting. The potential for SCDi to synergize with ICB in MBM may improve patient outcomes. MTI-301 is approved for first-in-human clinical trial starting end of 2025.

Abstract Zanubrutinib is a second-generation Bruton Tyrosine Kinase (BTK) inhibitor, FDA-approved for Mantle Cell Lymphoma (MCL), designed to be more selective and potentially better tolerated than first-generation agents like Ibrutinib. Progressive multifocal leukoencephalopathy (PML), a rare but severe complication, has not previously been reported with Zanubrutinib. We report a 74-year-old woman with a germline CHEK2 mutation and asymptomatic MCL (CD5+, cyclin D1+, Ki67 10–20%) diagnosed in 2016, managed with surveillance. In 2023, she was also diagnosed with localized breast cancer treated with lumpectomy and exemestane. Later that year, she developed new headaches. Brain MRI revealed diffuse bilateral pachymeningeal enhancement, suspicious for lymphomatous spread, without parenchymal involvement. By early 2024, follow-up imaging showed stable pachymeningeal enhancement with new scattered punctate right frontal subcortical lesions, coinciding with systemic MCL progression. Spinal imaging revealed epidural and bone marrow involvement; CSF was negative for malignancy. Zanubrutinib was initiated in March 2024. By August 2024, new bilateral frontal and parietal fuzzy hyperintense and faintly enhancing white matter lesions emerged, while prior punctate lesions regressed. Biopsy confirmed PML with JC virus DNA by in situ hybridization and absence of B-cell clonality. Zanubrutinib was discontinued. Follow-up imaging showed regression of lesions without new enhancement, consistent with immune reconstitution. The initial subcortical punctate lesions remained stable. In 2025, she was diagnosed with localized pancreatic adenocarcinoma, precluding cytotoxic therapy initially due to concern for PML reactivation. However, as of May 2025, neuroimaging remains stable, and patient was started on palliative gemcitabine/paclitaxel. This is the first reported case of PML associated with Zanubrutinib. It underscores the importance of vigilance for PML even in patients without overt immunosuppression, especially those with overlapping malignancies and treatment exposures in the correct clinical context.

Background. Assessment tools in surgical education help identify improvement areas for trainees. We developed and present validity evidence for a novel Transplant Operative Assessment Tool to optimize technical feedback for surgical trainees in transplantation. Methods. The Transplant Operative Assessment Tool assesses learners on anatomy, technical skills, judgment, and communication. Performance is rated across 5 competency levels. Content validity evidence included a construct map using existing literature and expert cognitive interviews. Ratings were used to develop an item response theory calibration, which was then used to evaluate the tool and provide validity evidence. Results. Eighty-two assessments for 28 trainees (16 residents, 12 fellows) were completed by 25 faculty surgeons across 4 programs. Fifty-six kidney transplants, 13 liver transplants, and 13 donor nephrectomies were assessed. The mean assessment completion time was 4.1 ± 4.3 min. Internal structure validity was evaluated by calculating item infit (range, 0.86–1.15), indicating a strong model fit and confirming a high quality of items. Internal consistency was also high (Cronbach’s alpha = 0.94). There was a positive correlation between ratings and training level ( P < 0.01), indicating strong discriminatory power. Warm ischemia time for transplant operations did not correlate with performance ( P = 0.16). Conclusions. These data provide validity evidence for a novel operative assessment tool. This instrument can measure performance, monitor progress, document competency, and has the potential to provide valuable feedback.

Motility disorders, particularly gastroparesis, are prevalent complications following solid organ transplantation, significantly impacting quality of life, nutritional status, graft survival, and mortality. This comprehensive review synthesises evidence from PubMed, Scopus, and Embase databases on pathophysiology, clinical manifestations, diagnosis, management, and prognostic factors across transplant types. Mechanisms include vagal nerve injury (highest in lung transplants, prevalence 40–91%), immunosuppressive effects (e.g., tacrolimus accelerates motility; mycophenolate impairs it), surgical trauma, microbiome dysbiosis (reduced Firmicutes/Bacteroidetes ratio), and metabolic factors like post-transplant diabetes (OR 5.17 in kidney recipients). Pediatric and thoracic recipients face the highest risks, with lung transplant gastroparesis conferring a 2.7-fold increased mortality/retransplantation hazard (p < 0.05). Diagnosis relies on gastric emptying scintigraphy (gold standard, sensitivity 85–95%) and wireless motility capsules (100% sensitivity for delay), while management encompasses prokinetics (60–80% response), endoscopic G-POEM (85% success), gastric electrical stimulation (100% quality-of-life improvement in series), and nutritional support. Prognostic factors include younger age (better intervention response), aetiology (anatomical worse than metabolic), and early therapy success. Outcomes vary: lung recipients experience severe impacts on chronic allograft dysfunction (83% oesophageal motility abnormalities correlate with 66–67% rejection). Future directions emphasise microbiome therapies, AI predictive models (AUC 0.85), and wearables for continuous monitoring. Multidisciplinary approaches are essential to balance immunosuppression with GI management, addressing ethical dilemmas like drug interactions and access disparities. Ultimately, early screening and personalised interventions can mitigate complications, enhancing long-term transplant success.