Background:The Notch signalling pathway regulates cell fate, proliferation, and differentiation and consists of receptors (Notch1-4), ligands (JAG1-2, DLL1, DLL3-4), and downstream targets. Altered expression of Notch pathway-linked genes has been reported in multiple cancers, although their associations with survival may vary according to tumour type. Their relationship with biological sex and radiotherapy (RT) has been less extensively explored. Purpose:To explore associations between Notch pathway-linked gene expression and overall survival (OS) across multiple cancer types, and to examine whether these associations differ by biological sex or in an RT-treated lung cancer subgroup. Methodology:Gene expression and clinical data from patients across nine cancer types were analysed using publicly available datasets derived from The Cancer Genome Atlas (TCGA) and the Kaplan-Meier Plotter platform. Associations between the expression of 14 Notch pathway-linked genes and OS were evaluated using Kaplan-Meier survival analyses. Representative findings were further evaluated using multivariable Cox proportional hazards models incorporating clinical covariates and gene expression × sex interaction terms. Main findings:Across nine cancer types, 13 of the 14 Notch pathway-linked genes were significantly associated with OS in at least one tumour type. DLL3 and JAG1 demonstrated recurrent associations across multiple cancers, with higher DLL3 expression more frequently associated with poorer OS. Sex-stratified analyses identified additional prognostic associations; however, multivariable interaction analyses did not consistently support biological sex as an effect modifier. In the RT-treated lung adenocarcinoma subgroup, higher JAG1 expression was associated with poorer OS, although this association was not confirmed in an adjusted pan-cancer RT validation cohort. Conclusion:This exploratory pan-cancer analysis identified associations between the expression of several Notch pathway-linked genes and OS, including recurrent associations involving DLL3 and JAG1. Differences observed in sex-stratified analyses and the RT-treated lung adenocarcinoma subgroup warrant further investigation in independent cohorts.

Purpose The Proliferation Saturation Index (PSI) model is a patient-specific mathematical model designed to simulate and predict tumor volume regression (TVR) during radiation therapy (RT) using early treatment response dynamics. This study validates the PSI model in an independent external cohort of patients with non-small cell lung cancer using previously derived model parameters. Methods and Materials In a cohort of 71 patients, treated with definitive RT alone (55 Gy/20#) tumor volume measurements were extracted from 6 cone beam computed tomography (CBCT) scans acquired on days 1, 2, and 3 and weekly thereafter. Model predictions of TVR at final CBCT (CBCT6) were made using tumor volume dynamics recorded from CBCT 1-3, CBCT 1-4, and CBCT 1-5. Agreement between predicted and actual volumes were assessed using the coefficient of determination (R2) and Pearson correlation coefficient (PCC). Results Model predictions showed strong agreement with measured volumes, improving with additional input data: R2 increased from 0.81 (3 inputs) to 0.94 (5 inputs), and PCC rose from 0.90 to 0.97. Prediction using data from approximately day 10 of RT (CBCT4) yielded R2 = 0.91 and PCC = 0.95. The model demonstrated strong performance in identifying poor responders (TVR ≤10%) with sensitivity of 77.7%, specificity of 73.6%, and a negative predictive value of 90.7%. Sensitivity analysis confirmed model stability with under ±20% parameter variation. Conclusions This external validation confirms the PSI model’s reproducibility and robustness in predicting TVR in patients with non-small cell lung cancer treated with definitive RT, supporting its integration into personalized RT planning strategies.

Despite positive outcomes for novel targeted therapy screens in preclinical studies, the majority of follow on GBM clinical trials fail to meet their primary endpoints. This translational gap is partly due to models that do not accurately recapitulate the human GBM-TME and therefore fail to accurately predict patient treatment response. Here, we investigated the NFPp10a/NF5310 syngeneic mouse model of mesenchymal GBM, to assess its translational relevance for evaluating TME-targeting agents. Young and aging C57BL/6 mice bearing orthotopic NFPp10a/NF5310-Luc2 tumours underwent treatment with temozolomide (TMZ), tumour resection, anti-PD1 checkpoint blockade, and/or regorafenib (REGO). TME composition was evaluated using the murine microenvironment cell population (mMCP) counter method and multiplexed immunohistochemistry (multiple iterative labelling by antibody neodeposition). To assess translational relevance and conserved human response patterns, immune cell composition and gene expression changes were directly compared to primary human mesenchymal GBM tumours via further hypothesis generating MILAN analysis and by studying publically available ICI clinical trial data. NFPp10a/NF5310-Luc2 tumour-bearing mice showed resistance to monotherapy and neoadjuvant anti-PD1, with limited response also observed to REGO treatment. mMCP analysis revealed modest increases in CD8+ T-cells, B cells, and monocytes following anti-PD1 and REGO treatment. MILAN analysis further indicated increased cytotoxic T-cells following anti-PD1 therapy. Comparison to untreated-primary GBM and ICI-treated human GBM suggested similar exhausted CD8+ T-cell phenotypes, suggesting the NFPp10a/NF5310 TME reflects the mesenchymal GBM T-cell compartment. Overall, the NFPp10a/NF5310 model recapitulates the GBM-TME architecture and therapeutic resistance patterns observed in human GBM, supporting its use in evaluating select TME-targeting therapies. The NFPp10a/NF5310 glioblastoma model demonstrates clinically relevant response patterns and key tumour microenvironment features of mesenchymal glioblastoma, supporting its utility as a translational platform for therapeutic development.

Aims:To evaluate the association of ferroptosis-related gene expression with overall survival (OS) across multiple cancer types and explore their relationship to biological sex and radiation therapy (RT) outcomes. Methods:Ferroptosis regulators were identified through a literature review and cross-referenced with the FerrDb database, yielding 55 candidate genes. Five cancers commonly treated with RT were selected. Kaplan-Meier analyses were performed to assess OS associations for each gene, with hazard ratios (HR) and p-values recorded. Segregated analysis according to biological sex were conducted on candidate genes. The analysis was repeated in a cohort of RT treated lung cancer patients. Results:Across five cancers commonly treated with radiation therapy (RT), 18-35 of 55 ferroptosis-related genes were significantly associated with overall survival (OS). GLS2 and BECN1 were significantly associated with improved OS in all five cancers. SLC7A11 was significant in four cancers and generally associated with poorer OS. Sex differences in the association between these three genes and OS were detected. In RT-treated lung cancer patients (n = 65), HSPB1, GLS2 and GPX4 were associated with improved OS, SLC7A11 with worse OS. Conclusions:This study provides first evidence of sex-differences in ferroptosis-related gene expression with potential clinical relevance. This pan-cancer resource links ferroptosis-related genes to survival outcomes and highlights SLC7A11, BECN1, and GLS2 as high-priority candidates for future mechanistic and clinical studies. Integrating sex as a biological variable into study design and interpretation will enhance clinical relevance.

There is a substantial body of literature addressing the prevention, acute management, and follow-up care of radiation induced dermatitis (RID). The quality and application of this evidence, however, is inconsistent and its interpretation varies widely. While several national guidelines have been developed to standardise practices locally, many of these resources are not publicly available. On behalf of the European Society for Radiotherapy and Oncology (ESTRO) Radiation Therapist (RTT) Committee, an international writing group consisting of 12 experts from radiotherapy and two patient representatives composed a recommendation document for the management of RID. The consensus for these recommendations was generated based on available international guidelines, and supplemented with evidence-based review articles on the topic. These recommendations focus on the prevention and practical management of early stage RID by avoiding skin trauma and maintaining hygiene. Addressing pain and inflammation in higher grades is also covered. The current literature refutes some of the traditional recommendations, especially restricting washing as well as the use of deodorant or the potential dose build-up of lotions which has been included and rectified in recent guidelines. In addition, the importance of grading the severity, including a baseline assessment is presented. The benefit of clear, and non-contradictory communication within the multidisciplinary team as well as patient involvement (e.g. PROMs or similar) is highlighted. Furthermore, the importance of recognising different skin types and skin tones, and the impact on how RID changes these in their appearance is stressed. This document provides practical, actionable recommendations for the clinical management of RID, referencing the supporting literature. These recommendations have, however, identified a lack of high-level evidence, especially for agent-specific recommendations.

BACKGROUND:Microbeam radiation therapy (MRT) seeks to improve the therapeutic ratio of conventional radiation therapy though the delivery of high doses in micrometre-scale beamlets of synchrotron-generated X-rays. PURPOSE:To assess the MRT experimental setups and biological endpoints used in preclinical studies investigating its therapeutic potential in lung cancer models. METHODOLOGY:PubMed, Embase, Science Direct, and Web of Science were searched using the following keywords, 'microbeam', 'micro beam', 'synchrotron' and 'lung'. The reported physical parameters of the MRT set up and biological endpoints chosen to test efficacy were examined. MAIN FINDINGS:Fourteen studies were assessed. The microbeam widths ranged from 25 µm to 630 µm, and the microbeam spacing ranged from 0 µm to 4000 µm. The peak doses ranged up to 1000 Gy and dose rates ranged from 4 Gy/s to 1.4x104 Gy/s. Fibrosis was the most commonly assessed radiation-induced toxicity. CONCLUSION:MRT experimental set ups and biological endpoints are heterogeneous. Standardization could strengthen future evidence supporting its use for the management of patients with lung cancer.

Delineating the gross tumour volume (GTV) in non-small cell lung cancer (NSCLC) can be challenging due to anatomical complexities and imaging artefacts. This study evaluates a semi-automated workflow using commercial software for target volume (TV) delineation on cone-beam CT (CBCT) in patients undergoing radical radiotherapy. Seventy-six patients with 553 scans (n = 76 planning CT, n = 477 CBCT) were included. Auto-contours were adjusted by a senior Radiation Therapist and reviewed for accuracy. The majority (59.1 %) required only minor revisions, with median adjustment time of CBCT auto-contours of 83 (range 0-460) seconds. The findings support the feasibility of this approach, offering a pragmatic solution for adaptive radiotherapy workflows in NSCLC.

Background The efficacy of Stereotactic Body Radiation Therapy (SBRT) is contingent upon accurately accounting for respiratory motion. Although several methods have been developed, the extent of volumetric and dosimetric benefit, as well as the criteria for selecting appropriate methods for individual patients remain unclear. Purpose To assess the extent of target volume reduction and lung dose reduction in lung cancer patients treated with SBRT, comparing active versus non-active respiratory motion management approaches. Materials and Methods A comprehensive search was conducted across multiple databases, including MEDLINE Ovid (PubMed), EMBASE, and the Web of Science Core Collection, covering the period from 2019 to 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed to identify studies relevant to respiratory motion management in lung SBRT. Data extracted included target volume delineation, target volume sizes, and lung doses reported. Results The review included 14 studies involving 273 patients, which examined both active and non-active respiratory motion management approaches. Active respiratory motion management approaches were associated with significant reduced target volume sizes and lung doses compared to non-active approaches. Tracking and deep inspiration breath-hold demonstrated superiority in reduction in target volume and lung protection, with tracking showing the greatest reduction in target volume. Conclusion Patient selection is crucial when determining the most appropriate respiratory motion management approach. Establishing a consensus on planning objective is necessary for accurate data evaluation. Further research is required to refine these techniques and explore innovative technologies that could enhance the effectiveness and safety of respiratory motion management in lung SBRT.

Background:Stereotactic body radiotherapy (SBRT) is evolving as treatment modality for kidney cancer alongside increased recognition of the importance of sex as a biological variable (SABV) policy in generating deeper insights. Purpose:This review aimed to assess the representation of male and female patients and the reporting of sex-specific outcomes in SBRT clinical studies for primary localised kidney cancer. Methodology:A database search with appropriate search terms was carried out on EMBASE, CINAHL, and Web of Science. Consideration of biological sex was assessed with the male: female ratio, reporting of sex-specific treatment outcomes, and inclusion of sex as a variable in univariate and/or multivariate analysis. Main findings :Twenty-two studies were included. Of 961 patients (with sex stated), 29.24 % were females, with a mean male to female ratio of 2.57 and standard deviation of 1.22 across the studies. There was no relationship between the year, region and study type, and the male to female ratio recorded (Chi-squared test, p = 0.099, 0.29, and 0.719 respectively). Only six studies were sex inclusive, with three reporting sex-based outcomes, and three including sex-specific analysis. Of these, only one study reported significant difference in survival. Conclusion:Supporting the integration of SABV will promote more equitable and biologically informed evidence for the use of SBRT in the management of kidney cancer.

Purpose Evolution-informed therapies exploit evolutionary consequences of drug resistance to inhibit treatment resistance and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive response by cancer cells, which is then selectively targeted by a follow-on therapy. Although the concept of an evolutionary double-bind has long been hypothesized in cancer, it has not been measured. Here, to our knowledge, we present the first example of a quantifiable double-bind: radiation therapy (RT) with natural killer (NK) cells. RT induces lethal double-strand DNA breaks, but cancer cells adapt. Although this increases resistance to DNA-damaging agents, it also enhances expression of NK cell ligands creating an obvious choice for a double-bind strategy. Methods and Materials We investigated this potential evolutionary double-bind through in vitro studies and evolution-based mathematical models. Using multiple prostate cancer cell lines, we evaluated surface and soluble NK ligand expression following RT. In vitro competition experiments were performed with an isogenic radiation-resistant cell line model. We introduced a two-population Lotka-Volterra competition model, consisting of radiation-sensitive and radiation-resistant populations modeling intrinsic growth rates with fixed carrying capacity and inter-specific competition terms. Results Alterations in NK cell ligands resulted in a twofold increase in sensitivity to NK cell-mediated killing with selective targeting of RT-resistant cells. These dynamics were framed mathematically to quantify the double bind. RT alone slowed overall growth but strongly selected for RT-resistant cells. NK cell therapy alone suppressed the RT-resistant population, but with a surviving population of radiation-sensitive cells. Model simulation predicted that optimal tumor control would be achieved through initial RT followed by NK cells. Subsequent experiments confirmed the model prediction. Conclusions We conclude that RT and NK cell-based immunotherapy produce an evolutionary double-bind. This multidimensional approach addresses the immediate challenge of treatment resistance and lays the groundwork for the development of personalized treatment regimens tailored to the evolving dynamics of individual tumors. Significance Clinical experience demonstrates that prostate cancer has a remarkable capacity to evolve resistance to all currently available treatments resulting in progression and, ultimately, patient death. Resistance mechanisms often come at a fitness cost placing cells in a bind when competing with surrounding cells. A carefully chosen secondary drug can introduce a double-bind targeting the adaptive resistance mechanism. This manuscript provides the first direct experimental evidence quantifying an “evolutionary double-bind’ in prostate cancer supporting the combination of DNA-damaging agents and NK cell-based immunotherapy in evolutionarily guided treatment designs. Our work is mathematically novel in that it extends Evolutionary Game Theory models and establishes an experimental-mathematical framework to quantify genuine evolutionary double binds applicable across cancer types and treatment modalities.

AIMS:Prehabilitation is a process of identifying and assessing factors that could compromise the physical and psychological health of patients undergoing cancer treatment and implementing an intervention to combat such concerns. The use of prehabilitation in cancer surgery has yielded positive outcomes in rectal, lung and abdominal cancers. Prehabilitation strategies have potential to improve the management of patients receiving radiation therapy or chemoradiation. The aim of the present study was to map the evidence of the assessment and evaluation of prehabilitation for radiation therapy patients.MATERIALS AND METHODS:A database search using EMBASE and PubMed was conducted. The PRISMA guidelines were adhered to. Keywords included prehabilitation, radiation therapy/radiotherapy, chemoradiotherapy/chemoradiation, intervention and exercise. Types of prehabilitation strategy, their purposes and impact, according to cancer site, were analysed.RESULTS:Prehabilitation is most commonly evaluated in head and neck cancer, whereby unimodal, physical interventions manage dysphagia. Prehabilitation for lung cancer demonstrated its ability to widen treatment options for patients. Physical prehabilitation is administered to combat adverse effects of neoadjuvant chemoradiation therapy in patients with rectal cancer.CONCLUSION:Prehabilitation is adaptive and tailored to specific patient and site needs; thus it is applied across a wide range of cancer sites. More interventions by which radiation therapy is the definitive treatment modality and larger sample sizes within these studies are warranted to increase prehabilitation utilisation for patients undergoing radiation therapy.

Multiple lines of evidence confirm the strong association between the presence of hypoxia in solid tumours and poorer outcomes in patients with cancer resulting from both more aggressive tumour cell behaviour and impaired responses to therapy.[1 2][1] With well over 12 000 articles published in

The needs and concerns of lesbian, gay, bisexual, transgender, queer, or questioning (LGBTQ+) patients with cancer remain poorly understood. This is important as LGBTQ+ patients have an elevated risk of developing certain cancers and have poorer oncologic outcomes compared to non-LGBTQ+ patients. The lack of research may be linked to the complexity of studying the needs and concerns of this patient population. This review aimed to describe the evidence that sought to identify the needs and concerns of LGBTQ+ cancer patients. Studies were extracted using keywords such as "LGBTQ" and "Oncology." Patient participants were excluded if they did not identify as LGBTQ+ and if they did not have cancer or were not cancer survivors. Healthcare professionals were excluded if they were not oncology specific. A total of 22 studies met our inclusion criteria. LGBTQ+ cancer patients expressed concerns surrounding heteronormative assumptions made by healthcare professionals, a lack of LGBTQ±specific cancer support groups, and psychosexual concerns such as erectile dysfunction following cancer treatment. Oncology healthcare professionals lacked the knowledge and education that are required to manage this patient cohort. Further research is required to investigate the needs and concerns of LGBTQ+ cancer patients specifically in the radiation oncology setting.