Citations

Radiation therapy is central to the management of gynecological cancers, including endometrial, cervical, ovarian, and vaginal malignancies. Despite advances in photon-based techniques, treatment-related toxicity remains significant owing to the anatomical proximity of pelvic targets to critical organs at risk (OARs), including the bowel, bladder, and bone marrow. Proton beam therapy exploits the Bragg peak to deliver a precise dose at depth with minimal exit dose, potentially reducing OAR exposure. This review develops the physical principles, dosimetric evidence, and early clinical data for proton therapy in gynecological malignancies, including cervical, endometrial, ovarian, vaginal, and vulvar cancers. Major focus is given to clinical conditions where conventional brachytherapy is not practical, and proton therapy may offer the greatest advantages, such as reirradiation for recurrent disease, post-operative pelvic irradiation, and extended field nodal treatment. This review also emphasizes current constraints that have slowed down wide clinical implementation, such as the lack of mature prospective data, cost, and accessibility. Finally, we emphasize future directions, including well-designed comparative trials, integration with systemic and immunotherapies, and adaptive treatment strategies. As the body of accumulated evidence evolves, the proton beam therapy potential for the treatment of gynecological malignancies has tremendously increased due to its role in safety and personalization of radiation treatment.

ABSTRACT Background & Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is highly prevalent and increasingly recognized as a multisystem cardiometabolic disorder. The global burden, incidence and prognostic implications of coexisting chronic kidney disease (CKD) in MASLD remain uncertain. Methods In this meta‐analysis, we searched MEDLINE and EMBASE from inception through September 25, 2025, for observational studies reporting CKD prevalence and/or incidence among adults (≥ 18 years) with MASLD. The primary outcomes were pooled CKD prevalence, estimated using random‐effects models on the logit scale with the Hartung–Knapp adjustment, and pooled CKD incidence (per 1000 person‐years), estimated using random‐effects models with exact Poisson confidence intervals. Secondary outcomes included all‐cause mortality and cardiovascular, renal and cancer outcomes. Results From 2811 records, 36 observational studies met the inclusion criteria. Twenty‐three studies contributed prevalence estimates (575 615 participants; 56 248 CKD cases) and thirteen studies contributed incidence estimates (27 996 new events). The pooled global CKD prevalence among individuals with MASLD was 15.22% (95% CI 9.69–23.12). The pooled CKD incidence was 22.17 per 1000 person‐years (95% CI 11.44–32.89) in the MASLD population. Hypertension (OR 1.49, 95% CI 1.29–1.72), dyslipidaemia (OR 1.22, 95% CI 1.20–1.24) and diabetes (OR 1.94, 95% CI 1.69–2.22) were associated with higher odds of CKD in the MASLD population. All‐cause mortality rates were 18.28 per 1000 person‐years (95% CI 3.45–33.11) in coexistent MASLD and CKD, more than double those in the MASLD‐only population (7.26 per 1000 person‐years (95% CI 2.97–11.56)). Conclusions Coexistent CKD affects one in seven individuals with MASLD worldwide, conferring a more than two‐fold increased risk of all‐cause mortality compared with individuals with MASLD alone.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)–related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24–0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19–0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20–0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.

Abstract Histopathological assessment has served as the gold standard for diagnosing Alzheimer’s disease (AD). Emerging technological advancements, including the development of amyloid positron emission tomography (PET), have enabled early detection of amyloid pathology, one of the neuropathological hallmarks of AD. Genome-wide association study (GWAS) across cohorts of aging and AD, leveraging different measurements of amyloid burden, may facilitate the identification of novel genetic variants that drive the earliest neuropathological changes in AD. This study presents the largest GWAS of brain amyloidosis to date, leveraging amyloid β (Aβ) measured by in vivo amyloid PET and postmortem histopathology from 13,555 individuals of European ancestry. Amyloid positivity was defined as moderate or frequent neuritic plaques according to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) staging scores for each postmortem cohort. A Gaussian mixture model (GMM) was applied to each amyloid PET cohort to identify the cohort and tracer-specific cut-offs that differentiate amyloid positive and negative populations. In silico and ex vivo analyses further characterized implicated loci, including interrogating the association between bulk and single-nucleus gene expression profiles and AD-related traits. Genetic covariance analysis assessed the extent amyloid PET and postmortem measures reflect the shared genetic architecture of brain amyloidosis. Our combined amyloidosis GWAS identified three established AD risk loci: BIN1 (rs6733839, OR = 1.20, 95% CI 1.14-1.26, P = 1.32 × 10−11), CR1 (rs4844610, OR = 1.24, 95% CI = 1.16-1.32, P = 4.21 × 10−10), APOE (rs429358, OR = 4.01, 95% CI = 3.66-4.38, P = 4.54 × 10−201), and a newly identified brain amyloidosis-associated variant on chromosome 17 (rs35635959, OR = 1.18, 95% CI = 1.12-1.25, P = 1.47 × 10−8). SuSiE fine-mapping identified a single credible set of 15 putative causal variants with rs35635959 as the lead variant. Subsequent eQTL and SuSiE-based colocalization analyses prioritized rs35635959 as a strong eQTL for TUBG2, encoding tubulin gamma 2, which is involved in microtubule organization and synaptic plasticity. Further cell-type-specific characterization of this gene in neurons from dorsolateral prefrontal cortex tissue indicated that decreased TUBG2 expression was associated with increased Aβ burden and AD case status (PFDR < 0.045). Furthermore, our study is the first to report a modest genetic covariance (covariance=0.17, P < 6.54 × 10−8) between the genetic architecture of amyloid burden captured by different modalities. While APOE showed a strong association with both amyloid endophenotypes, the observed genetic covariance was not substantially attenuated after excluding variants within the APOE region (covariance=0.16, P < 1.32 × 10−7). Our results highlight the benefits of leveraging compatible, harmonized AD endophenotypes to increase power to uncover new molecular insights into the etiology of AD neuropathology. Wang et al. present the largest GWAS of brain amyloidosis to date, analysing 13,555 individuals using amyloid PET and postmortem Aβ measures. They identify a novel amyloidosis-associated variant on chromosome 17, demonstrate genetic covariance between modalities, and highlight complex traits sharing genetic architecture with Aβ burden.

Abstract The trabecular meshwork (TM) and ciliary body (CB) regulate aqueous humor dynamics and intraocular pressure (IOP), and TM/Schlemm’s canal (SC) dysfunction underlies glaucoma. Here, we present a spatially resolved multi-omics atlas of human TM and CB, integrating snRNA-seq, scRNA-seq, and snATAC-seq from over one million cells and nuclei across 112 donors with Xenium spatial transcriptomics. We identified 9 major cell classes and 21 cell types, revealing heterogeneity, including undercharacterized fibroblast and epithelial subpopulations. Spatial mapping supported TM fibroblast zonation and CB epithelial organization. Regulatory analyses identified cell type–specific programs, including OTX/PAX networks in CB epithelium and SMAD3/TGF-β signaling in fibroblasts. Integration with glaucoma loci showed enrichment of non-coding variants in regulatory elements associated with POAG and PACG. Age- and ancestry-associated remodeling revealed divergent fibroblast aging with increased PIEZO1 , suggesting impaired outflow and elevated IOP. Together, this high-resolution atlas links cellular, regulatory, and genetic variation to anterior segment function and glaucoma susceptibility.

Abstract Autoinflammatory syndromes are increasingly recognized as heterogeneous disorders of innate immune dysregulation, often overlapping in clinical and genetic features. Although pulmonary manifestations are uncommon, several autoinflammatory conditions such as VEXAS syndrome, juvenile rheumatoid arthritis, adult-onset Still’s disease, and Familial Mediterranean Fever can produce inflammatory pulmonary nodules that mimic metastatic malignancy. Recognition of these presentations is critical, as they can respond dramatically to immunosuppressive therapy once the correct diagnosis is established. We describe a diagnostically challenging case of a young adult male initially suspected to have metastatic lung cancer, whose evaluation ultimately suggested a previously uncharacterized autoinflammatory process. We present a 26-year-old previously healthy male with progressive dry cough, exertional dyspnea, diffuse myalgias, small joint arthritis involving the fingers, wrists, and ankles, tendonitis, a Gottron-like rash on the hands and lower extremities, low-grade fevers, and occasional bloody stools. Initial external workup revealed a right infrahilar mass, right lower lobe pleural thickening, small pleural effusion, and mediastinal and hilar lymphadenopathy on CT chest, with corresponding PET activity. Initially suspected to have metastatic lung cancer, he was informed his prognosis was poor. However, transbronchial, EBUS, and mediastinal lymph node biopsies showed only active inflammation without malignancy. On presentation to our facility, a broad differential was pursued, with suspicion for an autoinflammatory or autoimmune etiology. Pulmonary function testing was normal. Laboratory evaluation revealed ESR >100, elevated CRP, positive ANA (1:160), negative HLA-B27, normal ferritin, and negative S100 staining. Cytokine analysis showed elevated TNF, IL-6, MCP-1, IL-2, and IL-18. Targeted variant testing identified a UBA1 gene variant, c.123G>T p.(M41L), with low-level mosaicism (0.004%), and a heterozygous MEFV mutation. Although his ethnicity made Familial Mediterranean Fever unlikely, these findings raised the possibility of overlapping somatic and germline contributions to innate immune activation. He was treated empirically with immunosuppression for a presumed multisystem inflammatory disorder, resulting in resolution of symptoms and marked radiologic improvement. This case highlights the expanding spectrum of adult-onset autoinflammatory diseases that may present with pulmonary findings mimicking malignancy. The coexistence of low-level UBA1 mosaicism and MEFV mutation suggests a potential interaction between somatic and inherited variants in triggering inflammation. Similar to the recent discovery of VEXAS syndrome, this case may represent a novel subtype of autoinflammatory disease. Continued genomic and immunologic investigation is warranted, as timely recognition and immunosuppressive therapy can lead to dramatic recovery. This abstract is funded by: None