Differential reinforcement of cGAS-STING pathway-involved immunotherapy by biomineralized bacterial outer membrane-sensitized EBRT and RNT.

Radiotherapy (RT), including external beam radiation therapy (EBRT) and radionuclide therapy (RNT), realizes physical killing of local tumors and activates systemic anti-tumor immunity. However, these effects need to be further strengthened and the difference between EBRT and RNT should be discovered. Herein, bacterial outer membrane (OM) was biomineralized with manganese oxide (MnO2) to obtain OM@MnO2-PEG nanoparticles for enhanced radio-immunotherapy via amplifying EBRT/RNT-induced immunogenic cell death (ICD) and cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) activation. OM@MnO2-PEG can react with H2O2 and then gradually produce O2, Mn2+ and OM fragments in the tumor microenvironment. The relieved tumor hypoxia improves the radio-sensitivity of tumor cells, resulting in enhanced ICD and DNA damage. Mn2+ together with the DNA fragments in the cytoplasm activate the cGAS-STING pathway, further exhibiting a positive role in various aspects of innate immunity and adaptive immunity. Besides, OM fragments promote tumor antigen presentation and anti-tumor macrophages polarization. More importantly, our study reveals that OM@MnO2-PEG-mediated RNT triggers much stronger cGAS-STING pathway-involved immunotherapy than that of EBRT, owing to the duration difference of RT. Therefore, this study develops a powerful sensitizer of radio-immunotherapy and uncovers some differences between EBRT and RNT in the activation of cGAS-STING pathway-related anti-tumor immunity.

Advances in personalized radiotherapy.

Radiotherapy is a mainstay of cancer treatment. The clinical response to radiotherapy is heterogeneous, from a complete response to early progression. Recent studies have explored the importance of patient characteristics in response to radiotherapy. In this editorial, we invite contributions for a BMC Cancer collection of articles titled 'Advances in personalized radiotherapy' towards the improvement of treatment response.

Low-Dose Radiation Therapy for Neurological Disorders: A Double-Edged Sword.

Radiation therapy targeting the central nervous system is widely utilized for the management of various brain tumors, significantly prolonging patient survival. Presently, investigations are assessing both clinical and preclinical applications of low-dose radiation (LDR) for the treatment of neuropathological conditions beyond tumor therapy. Special focus is given to refractory neurodegenerative diseases linked to neuroinflammation, such as Alzheimer's and Parkinson's diseases, where LDR has shown promising results. This comprehensive review examines the existing experimental data regarding the utilization of LDR in neurological disorders. It covers potential advantages in reducing neurodegenerative alterations and inflammation, as well as possible adverse effects, including neurological impairments. The review underscores the importance of the exposure protocol and the age at which LDR is administered in the context of the nervous system's pathological and physiological states, as these elements are crucial in determining LDR's therapeutic and toxic outcomes. The article concludes with a discussion on the future directions and challenges in optimizing LDR use, aiming to reduce toxicity while effectively managing neurological disorders.

"Current", "heated rods", and "hot vapour": why patients refuse radiotherapy as a treatment modality for cancer in northern Sri Lanka.

PURPOSE: Significant proportions of patients either refuse or discontinue radiotherapy, even in the curative setting, leading to poor clinical outcomes. This study explores patient perceptions that underlie decisions to refuse/discontinue radiotherapy at a cancer care facility in northern Sri Lanka. METHODS: An exploratory descriptive qualitative study was carried out among 14 purposively selected patients with cancer who refused/discontinued radiotherapy. In-depth semi-structured interviews were transcribed in Tamil, translated into English, coded, and thematically analyzed. RESULTS: All participants referred to radiotherapy as "current" with several understanding the procedure to involve electricity, heat, or hot vapour. Many pointed to gaps in information provided by healthcare providers, who were perceived to focus on side effects without explaining the procedure. In the absence of these crucial details, patients relied on family members and acquaintances for information, often based on second or third-hand accounts of experiences with radiotherapy. Many felt pressured by family to refuse radiation, feared radiation, or felt ashamed to ask questions, while for others COVID-19 was an impediment. All but three participants regretted their decision, claiming they would recommend radiation to patients with cancer, especially when it is offered with curative intent. CONCLUSION: Patients with cancer who refused/discontinued radiation therapy have significant information needs. While human resource deficits need to be addressed in low-resource settings like northern Sri Lanka, providing better supportive cancer care could improve clinical outcomes and save healthcare resources that would otherwise be wasted on patient preparation for radiotherapy.

CERN-based experiments and Monte-Carlo studies on focused dose delivery with very high energy electron (VHEE) beams for radiotherapy applications.

Very High Energy Electron (VHEE) beams are a promising alternative to conventional radiotherapy due to their highly penetrating nature and their applicability as a modality for FLASH (ultra-high dose-rate) radiotherapy. The dose distributions due to VHEE need to be optimised; one option is through the use of quadrupole magnets to focus the beam, reducing the dose to healthy tissue and allowing for targeted dose delivery at conventional or FLASH dose-rates. This paper presents an in depth exploration of the focusing achievable at the current CLEAR (CERN Linear Electron Accelerator for Research) facility, for beam energies >200 MeV. A shorter, more optimal quadrupole setup was also investigated using the TOPAS code in Monte Carlo simulations, with dimensions and beam parameters more appropriate to a clinical situation. This work provides insight into how a focused VHEE radiotherapy beam delivery system might be achieved.

Mathematical modeling of the synergistic interplay of radiotherapy and immunotherapy in anti-cancer treatments.

Introduction: While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. Methods: We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. Results: Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. Discussion: Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapy-immunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy.

[The quality and safety approach in radiotherapy : an added value for the patient]. / La démarche qualité et sécurité en radiothérapie : une plus-value pour le patient.

Radiation therapy is the use of radiation to treat cancer cells while preserving healthy tissue. More than half of cancer patients will receive radiation therapy at some point during their treatment. The implementation of a Quality Management System (QMS) in radiotherapy departments guarantees high quality care and optimal safety for patients. The QMS is a set of policies, procedures and processes aimed at ensuring effective management of the quality of treatments. It is crucial for planning, implementing, monitoring and continuously improving the care of radiotherapy patients. The benefits of the QMS for patients are multiple. It provides high quality support through specific protocols and deadlines. The security of processing is reinforced by the continuous training of personnel, the monitoring of incidents and the analysis of errors. Developing a culture of safety and continuous improvement also helps to minimize risk. In conclusion, the implementation of a QMS in radiotherapy departments guarantees quality care, secure and adapted to the individual needs of patients. This improves patient satisfaction while reducing the risk of errors.

La radiothérapie consiste à utiliser des radiations pour traiter les cellules cancéreuses, tout en préservant les tissus sains. Plus de la moitié des patients atteints de cancer recevront une radiothérapie à un moment donné de leur traitement. La mise en place d'un Système de Management Qualité (SMQ) dans les services de radiothérapie garantit des soins de haute qualité et une sécurité optimale pour les patients. Le SMQ est un ensemble de politiques, procédures et processus visant à assurer la gestion efficace de la qualité des traitements. Il est crucial pour planifier, implémenter, contrôler et améliorer continuellement la prise en charge des patients en radiothérapie. Les avantages du SMQ sont multiples. Il assure une prise en charge de haute qualité grâce à des protocoles et des délais spécifiques. La sécurité des traitements est renforcée par la formation continue du personnel, la surveillance des incidents et l'analyse des erreurs. Le développement d'une culture de sécurité et d'amélioration continue contribue également à minimiser les risques. En conclusion, la mise en place d'un SMQ dans les services de radiothérapie garantit des traitements de qualité, sécurisés et adaptés aux besoins individuels des patients. Cette approche améliore la satisfaction des patients, tout en réduisant les risques d'erreurs.

[Radiation therapy in veterinary medicine at the University of Liège]. / Radiothérapie en médecine vétérinaire à l'Université de Liège.

Radiation therapy has many indications in veterinary oncology and allows a multidisciplinary approach for the treatment of canine and feline patients. Radiation therapy can be recommended as a sole therapy in case of radiosensitive tumors or can be associated to surgery and/or chemotherapy after marginal excision for example. It can also be recommended as a palliative treatment for patients with an inoperable or painful tumor or disseminated disease. Radiation therapy significantly improves the quality of life and survival time of treated animals and should be part of the therapeutic modalities in veterinary medicine. The University of Liège developed the first veterinary center of radiation therapy in Belgium and can therefore participate in improving therapeutic management of cancerous animal patients.

La radiothérapie présente de nombreuses indications en oncologie vétérinaire et permet une approche multidisciplinaire pour le traitement de nos patients cancéreux canins et félins.La radiothérapie peut être recommandée seule pour le traitement de tumeurs radiosensibles, ou associée à la chirurgie et/ou la chimiothérapie notamment lors d'exérèse marginale. Elle a également sa place dans une prise en charge palliative de certains patients présentant une tumeur inopérable ou douloureuse, ou encore une maladie disséminée. La radiothérapie permet d'améliorer significativement la qualité et l'espérance de vie des animaux traités et à ce titre, doit faire partie de l'arsenal thérapeutique vétérinaire. L'Université de Liège possède, depuis peu, l'unique centre de radiothérapie vétérinaire en Belgique et peut ainsi participer à l'amélioration de la prise en charge des animaux cancéreux.

[The use of medical imaging as a therapeutic patient education tool in radiotherapy : a feasibility study]. / L'utilisation de l'imagerie médicale en tant qu'outil d'éducation thérapeutique du patient en radiothérapie : étude de faisabilité.

Because of its prevalence and high mortality rate, cancer is a major public health challenge. Radiotherapy is an important treatment option, and makes extensive use of medical imaging. Until now, this type of tool has been reserved to professionals, but it is now opening up to wider use, including by patients themselves for educational purposes. However, this type of usage has been little explored so far. An experimental feasibility study was carried out in the radiotherapy department of the University Hospital of Liège on adult patients with cancer or pulmonary metastases, assigned to two randomized groups. In addition to the usual information given by the radiotherapist, the patients of the experimental group benefited from an intervention consisting in the 3D visualization of their own medical images via the free and open-source computer software «Stone of Orthanc¼. The study results show a low refuse rate (8.2 %) for the 15 patients recruited. Although non-significant, the experimental group showed a median gain in global perception of knowledge, a decrease in anxiety scores and emotional distress. A significant reduction (p = 0.043) was observed for the depression score. The positive results of the feasibility study encourage further work and reinforce the positioning of medical imaging as a tool for therapeutic patient education.

De par sa fréquence et son taux de mortalité élevé, le cancer représente un problème de santé publique majeur. Parmi les traitements possibles, la radiothérapie tient une place importante et fait appel massivement à l'imagerie médicale. Jusqu'ici réservé aux professionnels, ce type d'outil s'ouvre à un usage plus large, y compris par le patient lui-même dans une perspective éducative. Mais cette utilisation est restée peu explorée jusqu'à présent. Une étude expérimentale de faisabilité a ainsi été menée au sein du service de Radiothérapie du CHU de Liège sur des patients adultes avec cancer ou métastases pulmonaires, répartis en deux groupes randomisés. En plus des informations habituellement données par le radiothérapeute, le groupe expérimental a bénéficié d'une intervention consistant en la visualisation en 3D de ses propres images médicales via le logiciel libre et open-source «Stone of Orthanc¼. Les résultats de l'étude indiquent un taux de refus faible (8,2 %) pour les 15 patients recrutés. Bien que non significatif, le groupe expérimental a montré, par rapport au groupe contrôle, un gain médian dans la perception globale de connaissances ainsi qu'une diminution des scores liés à l'anxiété et à la détresse émotionnelle. Une réduction significative (p = 0,043) est observée pour le score de dépression. Les résultats positifs de l'étude de faisabilité encouragent la poursuite des travaux et renforcent le positionnement de l'usage de l'imagerie médicale en tant qu'outil d'éducation thérapeutique du patient.

[Network science. Part 2 : in radiotherapy]. / La science des réseaux. Partie 2 : en radiothérapie.

In a former publication, we summarized basic principles of network science in order to understand its potential, especially within the field of oncology. This rather young science offers, for example, the opportunity to identify new systemic treatment options. However, these are not the only therapeutic options within the arsenal devoted to the battle against cancer. The two other main pillars of treatment are surgery and radiotherapy. It is our purpose to highlight some applications - rather limited nowadays - of network science in radiotherapy. Data are not so abundant compared to the field of systemic treatments.

Dans un article précédent, les préceptes de base de la science des réseaux ont été sommairement abordés, afin d'en illustrer l'intérêt en cancérologie, en général. Nous avons pu faire le point - de façon non exhaustive - sur l'utilité de cette science assez jeune, en montrant, par exemple, son apport en matière d'identification de moyens systémiques de traitement. Les traitements systémiques font partie de l'arsenal thérapeutique, tout comme d'ailleurs la chirurgie et la radiothérapie. Nous voulons décrire brièvement certaines applications de la science des réseaux quand il s'agit du domaine particulier des radiations ionisantes, même si leur nombre est somme toute plus limité par rapport à ce qui est publié dans le domaine des traitements systémiques.

Mechanisms of Action in FLASH Radiotherapy: A Comprehensive Review of Physicochemical and Biological Processes on Cancerous and Normal Cells.

The advent of FLASH radiotherapy (FLASH-RT) has brought forth a paradigm shift in cancer treatment, showcasing remarkable normal cell sparing effects with ultra-high dose rates (>40 Gy/s). This review delves into the multifaceted mechanisms underpinning the efficacy of FLASH effect, examining both physicochemical and biological hypotheses in cell biophysics. The physicochemical process encompasses oxygen depletion, reactive oxygen species, and free radical recombination. In parallel, the biological process explores the FLASH effect on the immune system and on blood vessels in treatment sites such as the brain, lung, gastrointestinal tract, skin, and subcutaneous tissue. This review investigated the selective targeting of cancer cells and the modulation of the tumor microenvironment through FLASH-RT. Examining these mechanisms, we explore the implications and challenges of integrating FLASH-RT into cancer treatment. The potential to spare normal cells, boost the immune response, and modify the tumor vasculature offers new therapeutic strategies. Despite progress in understanding FLASH-RT, this review highlights knowledge gaps, emphasizing the need for further research to optimize its clinical applications. The synthesis of physicochemical and biological insights serves as a comprehensive resource for cell biology, molecular biology, and biophysics researchers and clinicians navigating the evolution of FLASH-RT in cancer therapy.

Radiotherapy and immunology.

The majority of cancer patients receive radiotherapy during the course of treatment, delivered with curative intent for local tumor control or as part of a multimodality regimen aimed at eliminating distant metastasis. A major focus of research has been DNA damage; however, in the past two decades, emphasis has shifted to the important role the immune system plays in radiotherapy-induced anti-tumor effects. Radiotherapy reprograms the tumor microenvironment, triggering DNA and RNA sensing cascades that activate innate immunity and ultimately enhance adaptive immunity. In opposition, radiotherapy also induces suppression of anti-tumor immunity, including recruitment of regulatory T cells, myeloid-derived suppressor cells, and suppressive macrophages. The balance of pro- and anti-tumor immunity is regulated in part by radiotherapy-induced chemokines and cytokines. Microbiota can also influence radiotherapy outcomes and is under clinical investigation. Blockade of the PD-1/PD-L1 axis and CTLA-4 has been extensively investigated in combination with radiotherapy; we include a review of clinical trials involving inhibition of these immune checkpoints and radiotherapy.

Ionization Detail Parameters for DNA Damage Evaluation in Charged Particle Radiotherapy: Simulation Study Based on Cell Survival Database.

Details of excitation and ionization acts hide a description of the biological effects of charged particle traversal through living tissue. Nanodosimetry enables the introduction of novel quantities that characterize and quantify the particle track structure while also serving as a foundation for assessing biological effects based on this quantification. This presents an opportunity to enhance the planning of charged particle radiotherapy by taking into account the ionization detail. This work uses Monte Carlo simulations with Geant4-DNA code for a wide variety of charged particles and their radiation qualities to analyze the distribution of ionization cluster sizes within nanometer-scale volumes, similar to DNA diameter. By correlating these results with biological parameters extracted from the PIDE database for the V79 cell line, a novel parameter R2 based on ionization details is proposed for the evaluation of radiation quality in terms of biological consequences, i.e., radiobiological cross section for inactivation. By incorporating the probability p of sub-lethal damage caused by a single ionization, we address limitations associated with the usually proposed nanodosimetric parameter Fk for characterizing the biological effects of radiation. We show that the new parameter R2 correlates well with radiobiological data and can be used to predict biological outcomes.

A high-resolution large-area detector for quality assurance in radiotherapy.

Hadron therapy is an advanced radiation modality for treating cancer, which currently uses protons and carbon ions. Hadrons allow for a highly conformal dose distribution to the tumour, minimising the detrimental side-effects due to radiation received by healthy tissues. Treatment with hadrons requires sub-millimetre spatial resolution and high dosimetric accuracy. This paper discusses the design, fabrication and performance tests of a detector based on Gas Electron Multipliers (GEM) coupled to a matrix of thin-film transistors (TFT), with an active area of 60 × 80 mm2 and 200 ppi resolution. The experimental results show that this novel detector is able to detect low-energy (40 kVp X-rays), high-energy (6 MeV) photons used in conventional radiation therapy and protons and carbon ions of clinical energies used in hadron therapy. The GEM-TFT is a compact, fully scalable, radiation-hard detector that measures secondary electrons produced by the GEMs with sub-millimetre spatial resolution and a linear response for proton currents from 18 pA to 0.7 nA. Correcting known detector defects may aid in future studies on dose uniformity, LET dependence, and different gas mixture evaluation, improving the accuracy of QA in radiotherapy.

Characterization of selected additive manufacturing materials for synchrotron monochromatic imaging and broad-beam radiotherapy at the Australian synchrotron-imaging and medical beamline.

Objective.This study aims to characterize radiological properties of selected additive manufacturing (AM) materials utilizing both material extrusion and vat photopolymerization technologies. Monochromatic synchrotron x-ray images and synchrotron treatment beam dosimetry were acquired at the hutch 3B and 2B of the Australian Synchrotron-Imaging and Medical Beamline.Approach.Eight energies from 30 keV up to 65 keV were used to acquire the attenuation coefficients of the AM materials. Comparison of theoretical, and experimental attenuation data of AM materials and standard solid water for MV linac was performed. Broad-beam dosimetry experiment through attenuated dose measurement and a Geant4 Monte Carlo simulation were done for the studied materials to investigate its attenuation properties specific for a 4 tesla wiggler field with varying synchrotron radiation beam qualities.Main results.Polylactic acid (PLA) plus matches attenuation coefficients of both soft tissue and brain tissue, while acrylonitrile butadiene styrene, Acrylonitrile styrene acrylate, and Draft resin have close equivalence to adipose tissue. Lastly, PLA, co-polyester plus, thermoplastic polyurethane, and White resins are promising substitute materials for breast tissue. For broad-beam experiment and simulation, many of the studied materials were able to simulate RMI457 Solid Water and bolus within ±10% for the three synchrotron beam qualities. These results are useful in fabricating phantoms for synchrotron and other related medical radiation applications such as orthovoltage treatments.Significance and conclusion.These 3D printing materials were studied as potential substitutes for selected tissues such as breast tissue, adipose tissue, soft-tissue, and brain tissue useful in fabricating 3D printed phantoms for synchrotron imaging, therapy, and orthovoltage applications. Fabricating customizable heterogeneous anthropomorphic phantoms (e.g. breast, head, thorax) and pre-clinical animal phantoms (e.g. rodents, canine) for synchrotron imaging and radiotherapy using AM can be done based on the results of this study.

Pulsed RF knock-out extraction: a potential enabler for FLASH hadrontherapy in the Bragg peak.

One challenge on the path to delivering FLASH-compatible beams with a synchrotron is facilitating an accurate dose control for the required ultra-high dose rates. We propose the use of pulsed RFKO extraction instead of continuous beam delivery as a way to control the dose delivered per Voxel. In a first feasibility test, dose rates in pulses of up to 600 Gy s-1were observed, while the granularity at which the dose was delivered is expected to be well below 0.5 Gy.

The Assessment of the Long-Term Impact of Radiotherapy on Biophysical Skin Properties in Patients after Head and Neck Cancer.

Background and Objectives: Chronic radiotherapy-induced skin injury (cRISI) is an irreversible and progressive condition that can significantly impact a patient's quality of life. Despite the limited literature available on the assessment of the epidermal barrier in cRISI, there is a consensus that appropriate skincare, including the use of emollients, is the primary therapeutic approach for this group of patients. The aim of this study was to evaluate the biophysical properties of the skin during the late period (at least 90 days) following radiation therapy (RT) for head and neck cancer. Materials and Methods: This was a single-center prospective non-randomized study. It involved the analysis of 16 adult patients with head and neck cancer who underwent RT at the Greater Poland Cancer Center, along with 15 healthy volunteers. The study and control groups were matched for gender and age (p = 0.51). Clinical assessment, based on the LENT-SOMA scale, was conducted for all patients. Evaluation of the skin's biophysical properties included: an analysis of transepidermal water loss (TEWL), stratum corneum hydration (SCH), and skin visualization using high-frequency ultrasonography (HF-USG). Results: A significantly higher TEWL was observed in the irradiated area compared to the control area in the study group (p = 0.004). However, there was no statistically significant difference in SCH (p = 0.073). Additionally, no significant difference was observed in the values of TEWL and SCH in the irradiated area between the group of patients with and without clinically obvious RISI (p = 0.192 and p = 0.415, respectively). The skin thickness of the irradiated area, assessed by HF-USG, did not differ significantly from the skin thickness of the control area (p = 0.638). Furthermore, no difference in skin thickness was observed in patients with clinical features of cRISI in the irradiated and control areas (p = 0.345). The mean time after RT was 6.1 years. Conclusions: This study marks the first demonstration of epidermal barrier damage in patients in the long term following RT for head and neck cancer. The impairment of the epidermal barrier was observed independently of evident cRISI features. This observation underscores the necessity to recommend appropriate skin care, including the use of emollients, for all patients following RT. We also suggest that HF-USG examination is generally inconclusive in determining the degree of skin damage in the late period after RT.

The clinical manifestations and molecular pathogenesis of radiation fibrosis.

Advances in radiation techniques have enabled the precise delivery of higher doses of radiotherapy to tumours, while sparing surrounding healthy tissues. Consequently, the incidence of radiation toxicities has declined, and will likely continue to improve as radiotherapy further evolves. Nonetheless, ionizing radiation elicits tissue-specific toxicities that gradually develop into radiation-induced fibrosis, a common long-term side-effect of radiotherapy. Radiation fibrosis is characterized by an aberrant wound repair process, which promotes the deposition of extensive scar tissue, clinically manifesting as a loss of elasticity, tissue thickening, and organ-specific functional consequences. In addition to improving the existing technologies and guidelines directing the administration of radiotherapy, understanding the pathogenesis underlying radiation fibrosis is essential for the success of cancer treatments. This review integrates the principles for radiotherapy dosimetry to minimize off-target effects, the tissue-specific clinical manifestations, the key cellular and molecular drivers of radiation fibrosis, and emerging therapeutic opportunities for both prevention and treatment.