Citations

Abstract INTRODUCTION Glioblastoma (GBM) is a brain cancer known for its complex tumor microenvironment and ability to reprogram glucose metabolism and evade host immune responses. CAR-T cell therapy has attracted considerable attention due to its potential for high specificity and efficacy across various cancer types. However, its success in GBM has been limited due to the unique and hostile metabolic landscape of the tumor microenvironment. GBM tumor cells exhibit enhanced aerobic glycolysis, resulting in elevated glucose consumption. This restricts glucose availability for T cells, impairing activation and anti-tumor response. In our study, we enhanced the tumoricidal activity of CD70 CAR T-cells by overexpressing the glucose transporters GLUT1 and GLUT3, thereby improving their metabolic fitness and enabling them to overcome tumor-induced glucose deprivation. METHODS The CD70 CAR T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The efficacy and safety of metabolically modified CD70 CAR T-cells was investigated in in vitro and in vivo platforms. RESULTS GLUTs overexpression does not negatively affect T-cell differentiation and function but improves glucose consumption and intra-tumoral T-cell trafficking. We then used CD70 CAR-T platform and overexpress GLUT1 and GLUT3 to engineer T-cells. GLUT overexpression provided metabolic advantage to CD70CAR T-cells, which showed enhanced activation and cell avidity when co-cultured with GBM cells in both glucose enriched and restricted conditions. The metabolic modifications regulate CAR T-cell efficacy by enhancing intra-tumoral trafficking and persistence, followed by improved anti-tumor response and survival in mice. The lack of significant alterations in body weight and organ morphology in mice receiving GLUT-overexpressing CD70 CAR T-cells suggests that the adoptive transfer of these metabolically enhanced T cells does not elicit toxicity, thereby demonstrating a favorable safety profile during treatment. CONCLUSION Our study demonstrates development of immunotherapeutic strategies by incorporating core principles of tumor and immune cell metabolism, thus providing evidence that targeting immune-metabolic pathways is a potential approach to treat brain tumor.

Introduction Many clinical practice guidelines (CPGs) claim to use Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, but its implementation varies. This suggests that CPG developers, methodologists and users would benefit from an instrument to evaluate the extent to which CPGs adhere to GRADE approach. Such a structured instrument is currently unavailable. Accordingly, this study will develop an evaluation instrument for assessing guideline adherence to the GRADE approach, which we have named ‘GRADE-Check’. The goal is to target items to which CPGs fail to adhere and that potentially have serious consequences resulting in inaccuracies in certainty of evidence and inappropriate direction or strength of recommendations, thereby discriminating across CPGs in issues of importance. Methods and analysis The panel will include up to 25 individuals with specific knowledge and expertise, including experienced authors, educators and methodologists on CPGs methodology and GRADE approach from relevant organisations. The instrument will focus on the key elements of GRADE, aiming for clarity for GRADE experts and non-GRADE experts to apply. The development process for GRADE-Check will consist of the following five phases: (1) recruitment of a panel of GRADE experts; (2) development of objectives and scope for the development of GRADE-Check and criteria for item selection; (3) generation of candidate items through a literature review and panel consultation; (4) panellist discussion to construct the initial draft and extended explanation manual and (5) user testing. Ethics and dissemination This study has been approved by the Medical Ethics Committee of Zhongnan Hospital of Wuhan University (no. (2025047K)). Our research findings will be published in peer-reviewed journal articles and presented at academic conferences. Additionally, the dissemination plan will include considerations for the development of implementation manuals, a dedicated project website and training tools.

ABSTRACT Objective Fetal surgery (FS) for spina bifida (SB) repair improves infant outcomes; however, spontaneous preterm birth (sPTB) is common. We aimed to evaluate maternal and fetal immune responses following FS for SB repair. Method Pregnant participants undergoing fetoscopic SB repair at 24–26 weeks of gestational age (GA) were prospectively recruited and compared to GA matched low‐risk controls. Blood samples were collected at baseline, 2‐week post‐surgery (POD14), and delivery. Cytokine analysis, flow cytometry, and T cell receptor (TCR) sequencing were performed. Results sPTB occurred in 5/6 of the FS group (0/6 of controls). Maternal blood in the FS group demonstrated increased alpha‐fetoprotein (AFP) and anti‐inflammatory IL‐1RA at baseline and POD14, increased pro‐inflammatory IL‐8 only post‐operatively, and elevated growth factors throughout. T cell phenotypes following FS revealed reduced TH17 frequency but increased activation receptors on cytotoxic T cells. At delivery, the FS cohort had reduced Th2 and Th17 helper T cells and CD4+ memory T cells, but CD8 T cells still showed increased activation. No TCR expansion was detected post‐surgery, suggesting antigen‐independent activation. Cord blood in FS repaired neonates had increased AFP, IL‐8, IL‐1RA. Conclusion Systemic immune changes following FS, particularly T cell maturation and activation, were observed. Further characterization of these mechanisms may help predict and prevent surgery‐induced PTB, improving outcomes.

PURPOSE Immunotherapy has demonstrated limited efficacy in the treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) to date. We evaluated whether an off-the-shelf, multipeptide vaccine, PolyPEPI1018, in conjunction with standard chemotherapy can induce broad antitumor immune responses, potentially improving disease control in refractory mCRC. PATIENTS AND METHODS This single-arm, open-label study enrolled adults with MSS mCRC who had progressed after ≤2 previous lines of therapy for metastatic disease. PolyPEPI1018 was administered subcutaneously to four anatomical sites on days 1 and 15 and TAS-102 orally twice a day on days 1-5 and 8-12 of a 28-day cycle. Patients were treated for seven cycles or until disease progression. The primary end point was safety. Secondary end points were overall response rate, progression-free survival (PFS), overall survival (OS), and immune and genetic correlates. RESULTS Fifteen patients were enrolled; 80% had liver metastases and 67% had KRAS mutations. Adverse events (AEs) related to PolyPEPI1018 were grade 1 and 2 local skin reactions (n = 14). Grade 3 AEs (n = 15) at least possibly related to treatment were fatigue, decreased lymphocyte and neutrophil counts, and diarrhea. None had objective tumor response; the disease control rate was 53.3%. The median PFS (mPFS) was 4.0 (95% CI, 2.2 to 6.1) months and the median OS (mOS) was 8.7 (95% CI, 6.4 to 15.2) months. In post hoc subgroup analyses, patients without active liver metastasis had improved mPFS of 9.7 months and mOS of 14.8 months. In addition, patients who were predicted to have broader immune responses to vaccine based on human leukocyte antigen genotype had longer mOS (10.3 v 4.6 months, hazard ratio, 0.29 [95% CI, 0.07 to 1.17]). CONCLUSION The addition of PolyPEPI1018 to TAS-102 was safe and induced immunological responses that were associated with improved clinical outcomes. Further investigation of this chemo-immunotherapeutic is warranted.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

ABSTRACT Objectives Xylitol, a low‐permeability sugar alcohol, is recommended for treating chronic rhinosinusitis (CRS) due to its ability to decrease liquid salt concentration at the airway surface. This study investigated the efficacy of xylitol nasal irrigation for the management of CRS and its postoperative care. Methods We analysed 7 studies with 263 participants after reviewing the studies that were retrieved from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases up to December 2024. Those comparing changes in endoscopic score, Sinonasal Outcome Test (SNOT), Nasal Obstruction Symptom Evaluation (NOSE), olfactory dysfunction, and CRS‐related visual analogue scale from baseline to post‐treatment between xylitol and normal saline nasal irrigation groups were analysed. Results Nasal irrigation with xylitol significantly improved sinonasal well‐being in CRS patients compared to irrigation with saline (SMD 0.6253, 95% CI [0.0067; 1.2438]; I 2 = 0.0%). Patients who underwent endoscopic sinus surgery showed substantial SNOT improvement (SMD 3.1284, 95% CI [0.5229; 5.7338]; I 2 = 86.1%), while no significant changes were observed in non‐ESS patients (SMD 0.2571, 95% CI [−0.4872; 1.0014]). The xylitol group also showed significant improvements in NOSE (SMD 0.5976, 95% CI [0.2297; 0.9656]; I 2 = 49.3%) and SNOT scores (SMD 0.3608, 95% CI [0.0724; 0.6493]; I 2 = 49.1%). However, there were no significant changes in endoscopic scoring (SMD 0.1309, 95% CI [−0.1777; 0.4396]; I 2 = 0.0%), olfaction (SMD −0.0292, 95% CI [−0.3633; 0.3050]; I 2 = 0.0%), or saccharine clearance time (SMD 0.3816, 95% CI [−0.3816; 1.1449]; I 2 = 61.6%). Xylitol irrigation was well tolerated, with minimal, transient side effects and no significant adverse events. Conclusion Nasal irrigation with xylitol significantly improves the subjective management of CRS and postoperative care compared to saline irrigation but does not alter objective outcomes.

Importance Primary brain and central nervous system cancer (collectively referred to as CNS cancer) comprises 2% of all human cancers and poses significant health and economic challenges in the United States. Objective To analyze CNS cancer burden in the US, stratified by time, location (state and division), sex, age group, and Sociodemographic Index (SDI). Design, Setting, and Participants This cross-sectional study involved a repeated analysis of Global Burden of Disease Study (GBD) 2021 data in 2024. Using data from 183 sources, CNS cancer metrics in the US were estimated across states and years. US CNS cancer metrics across all sexes and age groups were included in the GBD. Exposure CNS cancer diagnosis. Main Outcomes and Measures Overall and age-standardized estimates of the incidence, prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost, and years lived with disability per 100 000 population, including 95% uncertainty intervals (UIs), and time trends. Results In 2021, for all age groups and sexes across the US, there were 31 780 incident cases (95% UI, 29971.1 to 32843.9). Age-standardized incidence, DALYs, and mortality rates per 100 000 population were 6.91 (95% UI, 6.58 to 7.12), 134.38 (95% UI, 129.83 to 137.95), and 4.1 (95% UI, 3.87 to 4.22), respectively. Despite no significant change observed in the overall incidence between 1990 and 2021, DALY and mortality rates decreased by 15.77% (95% UI, −17.75% to −13.68%) and 8.41% (95% UI, −11.09% to −6.22%), respectively. Substantial geographic variability was noted. Mississippi, Alabama, Kentucky, and Kansas (West North Central and East South Central divisions) and West Virginia faced persistently high burdens over the past 30 years. Sex differences were evident; disease burden was consistently higher in males compared with females. Age-specific estimates showed a bimodal distribution: the youngest group (<5 years) showed a significant decrease in incidence rate (−34.42% to −11.56%), whereas older age groups (>70 years) experienced increasing trends. DALYs and mortality rates were negatively correlated with SDI (ρ = −0.6860 and ρ = −0.6391; P < .001). Conclusions and Relevance These findings provide valuable insights into the CNS cancer burden across the US by age, sex, location, and SDI, enabling better public health status assessments, health care policy restructuring, and resource redistribution for improved care.

Importance Contemporary guidelines recommend sentinel lymph node biopsy (SLNB) for patients with melanoma with predicted risk of SLN metastasis greater than 10% and consideration of SLNB when the risk is 5% to 10%. A gene expression profile (GEP)–based test that can accurately identify patients with a low risk of SLN metastasis would refine selection for SLNB. Objective To establish the predictive capability of the combined clinicopathological factors and GEP (CP-GEP) test to identify patients with primary cutaneous melanoma who can safely forgo SLNB and to investigate the prognostic value of CP-GEP regarding the outcome in patients with cutaneous melanoma after a negative SLNB (not reported herein). Design, Setting, and Participants This prognostic study was conducted from September 2021 to June 2024 at 9 academic medical centers with experienced melanoma surgeons. Included were patients with biopsy-proven invasive cutaneous melanoma with T1 to T3 tumors and clinically negative regional LNs. All patients were deemed candidates for SLNB using standard clinical criteria. GEP was performed on formalin-fixed, paraffin-embedded tissue from the primary melanoma biopsy. Analyses were performed from December 2024 to August 2025. Intervention CP-GEP testing to determine risk of having a positive SLNB in patients with T1 to T3 cutaneous melanoma who were considered appropriate candidates for the procedure based on standard clinical parameters. Main Outcomes and Measures CP-GEP results were reported as low risk or high risk; the primary outcome measure was negative predictive value (NPV) in low-risk cases. Analyses included NPV assessment by tumor (T) subcategory, primary site, and age. Results A total of 1761 patients (median [IQR] age, 64 [53-72] years; 997 male [56.6%]) underwent SLNB (310 [17.6%] SLN positive) and had a successful CP-GEP test; GEP was successful in 97.7% of samples. A total of 651 patients (37.0%) were considered low risk by CP-GEP. Among low-risk cases, 46 (7.1%) were SLN positive, and NPV was 92.9% (95% CI, 90.7%-94.8%). High-risk cases had a 23.8% (264 of 1110) SLN-positive rate. The percentage of cases with low-risk CP-GEP declined with increasing T category (T1 = 346 of 507 [68.2%]; T2 = 295 of 897 [32.9%]; T3 = 10 of 357 [2.8%]). CP-GEP results were consistent in discriminating SLN-positive rates across primary sites, histologic subtypes, and mitotic count categories. In 2 large subsets, clinical stage IB (n = 1187) and patients 65 years and older (n = 832), 6.5% (95% CI, 4.6%-8.8%) of low-risk clinical stage IB cases and 6.6% (95% CI, 4.2%-9.7%) of all low-risk cases in patients 65 years and older were SLN positive vs 18.3% (95% CI, 15.3%-21.6%) and 20.3% (95% CI, 16.8%-24.2%) for high-risk cases, respectively. Conclusions and Relevance In this multicenter, prospective, blinded, prognostic study, the CP-GEP test reliably identified patients with melanoma with less than 10% SLN metastasis risk. SLN metastasis rates were approximately 3-fold greater for high-risk vs low-risk CP-GEP cases. In appropriately selected patients, the CP-GEP test may add value for shared patient-surgeon decision-making.

ABSTRACT At the 42nd Annual Meeting of the American Association of Clinical Anatomists (AACA) in Bellevue, Washington, June 2025, two inaugural events—the Clinical Anatomy Fireside Chat (CAFC) and the Clinical Anatomy Symposium: Head and Neck 2025 (CAS)—fostered rich dialogue on the evolving role and operational definition of clinical anatomy. Experts from various clinical and anatomical disciplines explored the meaning of clinical anatomy, highlighting the absence of a universal definition despite its frequent use in education and research. Through these interdisciplinary discussions, a consensus emerged: clinical anatomy is not defined solely by the possession of clinical credentials but by the integration of anatomical knowledge and clinical relevance, achieved most effectively through collaboration. Clinical anatomy education and research require different depths of clinical knowledge depending on the audience and objective, and meaningful collaboration can bridge gaps in expertise. The symposium further illustrated that high‐quality clinical anatomy emerges from mutual respect and reciprocal insight between clinicians and anatomists. This article presents a consensus statement developed by AACA representatives and invited speakers, affirming that collaboration is not only foundational to the practice of clinical anatomy but also fundamental to its definition. These conclusions aim to guide future educational models, research strategies, and interdisciplinary partnerships in the field of clinical anatomy.