Background: Meningiomas are the most common intracranial tumors. Radiotherapy (RT) serves as an adjunct following surgical resection; however, response varies. RTOG-0539 is a prospective, phase 2, trial that stratified patients risk groups based on clinical and pathological criteria, providing key benchmarks for RT outcomes. This is the first study that aims to characterize the molecular landscape of an RT clinical trial in meningiomas. Methods: Tissue from 100 patients was analyzed using DNA methylation, RNA sequencing, and whole-exome sequencing. Copy number variations and mutational profiles were assessed to determine associations with meningioma aggressiveness. Tumors were molecularly classified and pathway analyses were conducted to identify biological processes associated with RT response. Results: High-risk meningiomas exhibited cell cycle dysregulation and hypermetabolic pathway upregulation. 1p loss and 1q gain were more frequent in aggressive meningiomas, and NF2 and non-NF2 mutations co-occurred in some high-risk tumors. Molecular findings led to the reclassification of several cases, highlighting the limitations of histopathologic grading alone. Conclusions: This is the first study to comprehensively characterize the molecular landscape of any RT trial in meningioma, integrating multi-omic data to refine treatment stratification. Findings align with ongoing genomically driven meningioma clinical trials and underscore the need for prospective tissue banking to enhance biomarker-driven treatment strategies.

Background: The WHO grade of meningioma was updated in 2021 to include homozygous deletions of CDKN2A/B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations to help refine the current grading system. Methods: Chromosomal copy number profiles were inferred from from 1964 meningiomas using DNA methylation. Regularized Cox regresssion was used to identify CNAs independenly associated with post-surgical and post-RT PFS. Outcomes were stratified by WHO grade and novel CNAs to assess their potential value in WHO critiera. Results: Patients with WHO grade 1 tumours and chromosome 1p loss had similar outcomes to those with WHO grade 2 tumours (median PFS 5.83 [95% CI 4.36-Inf] vs 4.48 [4.09-5.18] years). Those with chromosome 1p loss and 1q gain had similar outcomes to those with WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years WHO grade 1, 1.90 [1.23-2.25] years WHO grade 2, compared to 2.27 [1.68-3.05] years in WHO grade 3 cases overall). Conclusions: We advocate for chromosome 1p loss being added as a criterion for a CNS WHO grade of 2 meningioma and addition of 1q gain as a criterion for a CNS WHO grade of 3.

Background: We previously developed a DNA methylation-based risk predictor for meningioma, which has been used locally in a prospective fashion. As a follow-up, we validate this model using a large prospective cohort and introduce a streamlined next-generation model compatible with newer methylation arrays. Methods: The performance of our next-generation predictor was compared with our original model and standard-of-care 2021 WHO grade using time-dependent receiver operating characteristic curves. A nomogram was generated by incorporating our methylation predictor with WHO grade and extent of resection. Results: A total of 1347 meningioma cases were utilized in the study, including 469 prospective cases from 3 institutions and a retrospective cohort of 100 WHO grade 2 cases for model validation. Both the original and next-generation models significantly outperformed 2021 WHO grade in predicting postoperative recurrence. Dichotomizing into grade-specific risk subgroups was predictive of outcome within both WHO grades 1 and 2 tumours (log-rank p<0.05). Multivariable Cox regression demonstrated benefit of adjuvant radiotherapy in high-risk cases specifically, reinforcing its informative role in clinical decision making. Conclusions: This next-generation DNA methylation-based meningioma outcome predictor significantly outperforms 2021 WHO grading in predicting time to recurrence. This will help improve prognostication and inform patient selection for RT.

Background: Meningiomas exhibit considerable heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) which address much of this heterogeneity. Despite their utility, the stochasticity of clustering methods and the requirement of multi-omics data limits the potential for classifying cases in the clinical setting. Methods: Using an international cohort of 1698 meningiomas, we constructed and validated a machine learning-based molecular classifier using DNA methylation alone. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, whole exome sequencing, and clinical outcomes. Results: Group-specific outcomes in the validation cohort were nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Predicted NF2-wildtype cases had no NF2 mutations, and 51.4% had others mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic/proliferative tumours. Conclusions: Our DNA methylation-based classifier faithfully recapitulates the biology and outcomes of the original molecular groups allowing for their widespread clinical implementation.

Background: The combination of PARP inhibitor and immune checkpoint inhibitors have been proposed as a potentially synergistic combinatorial treatment in IDH mutant glioma, targeting dysregulated homologous recombination repair pathways. This study analyzed the cell-free DNA methylome of patients in a phase 2 trial using the PARP inhibitor Olaparib and the PD-1 inhibitor Durvalumab. Methods: Patients with recurrent high-grade IDH-mutant gliomas were enrolled in a phase II open-label study (NCT03991832). Serum was collected at baseline and monthly and cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed. Binomial GLMnet models were developed and model performance was assessed using validation set data. Results: 29 patients were enrolled between 2020–2023. Patients received olaparib 300mg twice daily and durvalumab 1500mg IV every 4 weeks. The overall response rate was 10% via RANO criteria. 144 plasma samples were profiled with cfMeDIP-seq along with 30 healthy controls. The enriched circulating tumour DNA methylome during response periods exhibited a highly specific signature, accurately discriminating response versus failure (AUC 0.98 ± 0.03). Additionally, samples that were taken while on treatment were able to be discriminated from samples off therapy (AUC 0.74 ± 0.11). Conclusions: The cell-free plasma DNA methylome exhibits highly specific signatures that enable accurate prediction of response to therapy.

Discretionary foods that are energy-dense and nutrient-poor contribute to over one third of total energy intake in Australian children and adults, and the typical portion sizes of many discretionary foods have increased significantly in the last two decades(1). The portion size norms (described as a typical perception of how much of a given food people choose to eat at a single eating occasion) are likely to have increased concurrently, with larger sizes now being considered the new normal(2). Public health interventions are urgently needed to reduce the portion size norms and consumption of discretionary foods(3), but the acceptability of such interventions remains unknown. Therefore, this qualitative study aimed to gain insights into consumers’ attitudes towards potential interventions targeted at promoting portion control of discretionary foods. Four online focus group sessions were conducted via Zoom with healthy Australian adults who regularly consume discretionary foods. A question guide was developed to gather participants’ perspectives around four potential public health interventions; reduction of the default serving sizes, increasing serving size options, changes to package sizes, and improving serving size labelling. A female facilitator moderated all focus groups, with a second moderator present to capture other relevant details. Collected data were analysed using a hybrid approach combining deductive and inductive thematic analyses. A total of 35 participants completed the study (19 females, mean age 38 ± 14 years). Participants identified the current food environment as promoting overconsumption; larger serving sizes were reported to be more ubiquitous and better value for money than smaller size options. An overall positive attitude towards the proposed interventions was noted. Out of the four proposed interventions, participants considered the most acceptable intervention to be providing a wider range of serving size options while maintaining a consistent unit price. Other acceptable interventions included reducing the default serving sizes with concurrent price reduction; education and clear guidance around portion size selection (for example, the involvement of health professionals to promote portion control, along with relevant recommendations of appropriate portion sizes from health authorities); more practical on-pack serving size suggestions; and innovative package designs that enable better portion control without contributing to food and plastic waste. In conclusion, participants identified a need for and were in support of interventions aimed at the portion control of discretionary foods. Further research should focus on examining the feasibility and effectiveness of the potential interventions to reduce the purchasing and consumption of large serving sizes. More efforts from public health authorities are required to develop practical and tailored recommendations for consumers around appropriate portion sizes for discretionary foods. Collaboration with the food industry and policy makers is also necessary for implementing public health interventions to reduce the excessive intake of discretionary foods.

Ecological momentary assessment (EMA) may be a valid and acceptable method of assessing dietary intake in young adults(1). EMA may overcome some of the limitations associated with traditional dietary assessment methods such as high respondent burden and memory biases(2) by capturing time-sensitive data via concise dietary surveys. However, most dietary EMA studies either deliver signal-contingent EMAs at fixed intervals or rely on the user’s memory to self-initiate event-contingent EMAs whenever they ate. This may be inappropriate for young adults due to their highly variable eating patterns(1). Young adults are particularly vulnerable to weight gain due to major life transitions and, for this population, dietary information may need to be collected near real-time to improve recall accuracy(3). Therefore, the aim of this study was to examine the feasibility (response rate) and acceptability of an EMA protocol that delivered dietary surveys at times personalised to young adults’ (18–30 years) eating patterns and to compare this to the feasibility and acceptability of EMAs delivered at fixed intervals. A randomised, double-blinded crossover design with two four-day treatment arms was used. In one arm, participants received six EMAs per day at fixed intervals. In the other arm, EMAs were delivered at times tailored to participants’ usual eating schedules (ranged between two to six EMAs per day). Usual eating schedules were determined using time-stamped food and beverage images captured by participants over the four days immediately prior to treatments. EMA questions included, but were not limited to, time of consumption and type of food or beverage group consumed. Response rates were calculated as the percentage of EMAs responded to out of the EMAs delivered. At the end of each arm, participants completed an acceptability survey assessing their opinion of the number of EMAs per day, length of the EMAs, and number of recording days. Twenty-three subjects were included (13 female; mean age 26, SD 2.1 years). Mean response rates of the fixed interval and personalised schedule treatments were 65.1% (SE 3.7%) and 66.3% (SE 3.7%), respectively. Compared to the fixed interval treatment, EMAs delivered during the personalised schedule treatment did not align closer with participants’ eating times; the average time difference between EMA delivery and reported eating time was 1.7 hours for both treatments. Participants from both treatments reported receiving too many EMAs per day but found the length of the EMA and number of days of recording to be ‘just right’. In conclusion, EMAs delivered on a personalised schedule may not improve participant adherence. Due to the irregular nature of young adults’ eating patterns, timing of EMA delivery is difficult to tailor. Future definitive trials should use more sophisticated methods of personalisation such as wearable sensors to trigger event-contingent EMAs.

Ice shelves affect the stability of ice sheets by supporting the mass balance of ice upstream of the grounding line. Marine ice, formed from supercooled water freezing at the base of ice shelves, contributes to mass gain and affects ice dynamics. Direct measurements of marine ice thickness are rare due to the challenges of borehole drilling. Here we assume hydrostatic equilibrium to estimate marine ice distribution beneath the Amery Ice Shelf (AIS) using meteoric ice-thickness data obtained from radio-echo sounding collected during the Chinese National Antarctic Research Expedition between 2015 and 2019. This is the first mapping of marine ice beneath the AIS in nearly 20 years. Our new estimates of marine ice along two longitudinal bands beneath the northwest AIS are spatially consistent with earlier work but thicker. We also find a marine ice layer exceeding 30 m of thickness in the central ice shelf and patchy refreezing downstream of the grounding line. Thickness differences from prior results may indicate time-variation in basal melting and freezing patterns driven by polynya activity and coastal water intrusions masses under the ice shelf, highlighting that those changes in ice–ocean interaction are impacting ice-shelf stability.