Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses.

This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment.

In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed.

In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC.

This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.

BackgroundRadiation-based therapies are a progressive modality for managing life-threatening diseases such as cancer. However, these treatments often inflict damage on non-target tissues, necessitating the development of effective radioprotective agents. Zinc, known for its diversified role under various pathological conditions, has emerged as a potential protective agent against radiation-induced injuries due to its antioxidant, anti-inflammatory and immune-regulating properties.AimThis review aims to evaluate the potential of zinc in mitigating the adverse effects associated with radiation-based therapies, focusing on its protective role in normal tissue injury.MethodsA comprehensive literature review was conducted using multiple databases, including PubMed, NCBI, SciFinder, Google Scholar and Science Direct. Relevant studies assessing the radioprotective effects of zinc were identified and analysed to summarise its efficacy and potential benefits in radiation therapy.ResultsThe review highlights the beneficial effects of zinc in managing radiation-induced adverse effects, such as oral mucositis, skin injury, dermatitis, xerostomia, dysgeusia, dysosmia, bone marrow regeneration and oxidative stress reduction. Zinc's role as an antioxidant and anti-inflammatory agent, along with its ability to regulate immune system homeostasis, underpins these protective effects.ConclusionsZinc shows promising potential as a radioprotective agent in mitigating the adverse effects of radiation-based therapies. Despite the positive preclinical and clinical findings, further randomised trials with larger sample sizes and rigorous methodologies are needed to confirm zinc's efficacy. Additionally, further research is warranted to explore zinc's potential in addressing other radiation-induced events, ultimately contributing to improved patient care during radiation therapy.

Although radiation-induced skin injuries are a concern in patients receiving radiation therapy, there are few effective treatments. The aim of this study was to evaluate the protective effects of extracorporeal shock wave therapy (ESWT) on irradiated fibroblasts and mouse skin.

In this in vitro study of human dermal fibroblasts, the experimental group was subjected to ESWT after irradiation (20 Gy). The control groups were only irradiated or only subjected to ESWT. At 24 or 48 hours after ESWT, cell viability, cell migration, and mRNA and protein expression were measured. In the in vivo study, the experimental group (7 mice) was treated with ESWT after irradiation (45 Gy). The control group (7 mice) was only irradiated. At 8 weeks after irradiation, dorsal skin was harvested for histopathologic examination and protein isolation.

In dermal fibroblasts, treatment with ESWT increased viability of irradiated cells compared with irradiated-only and untreated cells ( P = 0.005). ESWT increased cell migration 24 hours after irradiation ( P = 0.002) and decreased transforming growth factor-β (TGF-β) protein expression 48 hours after irradiation ( P = 0.024). In mice, ESWT decreased the level of radiation-related skin injury ( P = 0.006). Treatment of irradiated skin with ESWT decreased TGF-β1 ( P = 0.009) and phospho-Smad3 ( P = 0.009) protein expression, decreased myofibroblasts ( P = 0.047), and increased vessel density ( P < 0.001).

This study demonstrated that ESWT alleviated radiation-induced fibrosis by downregulating TGF-β1 expression, suggesting the potential of ESWT for the treatment of radiation-induced fibrosis.

FLASH radiotherapy is garnering attention for its capacity to diminish skin toxicity without compromising tumoricidal efficacy, presenting a stark contrast to conventional (CONV) radiotherapy. Despite its promise, the underlying molecular mechanisms of FLASH irradiation (FLASH-IR) on skin are not yet fully elucidated.

This study investigated the transcriptomic responses of human foreskin fibroblast cells (HFF-1) via the FLASH-IR or CONV irradiation (CONV-IR), employing the next-generation RNA sequencing (RNA-seq) to capture the gene expression profiles. Our comparative analysis aimed to dissect the cellular and molecular pathways influenced by these two irradiation methods.

We identified a spectrum of differentially expressed genes (DEGs), signaling pathways, and transcriptional networks that were either shared or divergent between FLASH-IR and CONV-IR. Particularly, transcription factor NR4A1 showed significant upregulation in response to FLASH-IR, while chromatin stability factor ELF3 was markedly downregulated following CONV-IR. The top 10 up-regulated DEGs were subjected to qPCR validation, confirming their differential expression in response to FLASH-IR and CONV-IR.

Collectively, our findings delineate unique regulatory landscapes of FLASH-IR and CONV-IR on skin cells, corroborating established effects and shedding new light on the molecular interplay within the context of ultra-high dose radiation.

To investigate the incidence of dysphagia among head and neck cancer (HNC) patients and assess disparities in utilization of speech-language pathology (SLP) services across different demographic groups.

Retrospective cohort study.

Analysis of data from the TriNetX global health network, comprising over 125 million deidentified electronic health records worldwide.

HNC patients diagnosed with oral, oropharyngeal, laryngeal, or nasopharyngeal cancer with and without dysphagia between January 1, 2004 and October 30, 2024 were identified. Patients were divided into two cohorts for comparison: those who received SLP services after dysphagia diagnosis and those who did not. The association of demographic characteristics (sex, ethnicity, and race) with SLP services were analyzed.

Of 269,629 HNC patients, 28.8% (n = 77,562) were diagnosed with dysphagia. Significant disparities were found: female and non-White patients were less likely to be diagnosed with dysphagia. Once diagnosed, female, Hispanic/Latino, and non-White patients were also significantly less likely to receive SLP services compared to female, Hispanic/Latino, and non-White patients. Overall, only 38.8% of patients with dysphagia received SLP services.

This study highlights significant sex, ethnic, and racial disparities in dysphagia diagnosis and SLP service utilization among HNC patients. Furthermore, SLP services are underutilized. There is a need for targeted interventions to increase dysphagia prevention and surveillance and ensure equitable access to dysphagia care, improving outcomes for all HNC survivors.

Fibrosis is a common late complication of radiation therapy. Molecular dysregulations leading to fibrosis have been characterized for the coding part of the genome, notably those involving the TGFB1 gene network. However, because a large part of the human genome encodes RNA transcripts that are not translated into proteins, exploring the involvement of the noncoding part of the genome in fibrosis susceptibility and development was the aim of this work.

Breast cancer patients having or not having developed severe breast fibrosis after radiation therapy were retrospectively selected from the COPERNIC collection. Exome sequencing and RNA-seq transcriptomic profiling were performed on 19 primary dermal fibroblast strains isolated from the patients' nonirradiated skin. Functional experiments were based on fibrogenic induction by transforming growth factor-Beta1 (TGFB1) and gene knockdown in healthy donor fibroblasts.

Coding and noncoding transcriptomes discriminated fibrosis from nonfibrosis conditions, and a signature of breast fibrosis susceptibility comprising 15 long noncoding RNAs (lncRNAs) was identified. A hazard ratio validation showed that the lncRNA vimentin antisense long noncoding RNA 1 (VIM-AS1) was the best biomarker associated with fibrosis risk. This lncRNA has not been previously associated with any fibrotic disorder, but we found it upregulated in data sets from cardiac fibrosis and scleroderma, suggesting a general role in tissue fibrosis. Functional experiments demonstrated a profibrotic action of VIM-AS1 because its knockdown reduced myofibroblast activation, collagen matrix production, and dermal organoid contraction. RNA-seq data analysis after VIM-AS1 silencing also pointed out the regulation of replication, cell cycle, and DNA repair. Mechanistically, because VIM-AS1 was found coregulated with the vimentin gene, these data support a profibrotic function of the TGFB1/VIM-AS1/vimentin axis, targeting the dynamics of fibroblast-myofibroblast transition.

Noncoding RNA analysis can provide specific biomarkers relevant to the prediction of normal tissue responses after radiation therapy, which opens perspectives of next-generation approaches for treatment, in the frame of the recent developments of RNA-based technologies.

For over a century, radiotherapy has revolutionised cancer treatment. Technological advancements aim to deliver high doses to tumours with increased precision while minimising off-target effects to organs at risk. Despite advancements such as image-guided, high-precision radiotherapy delivery, long-term toxic effects on healthy tissues remain a great clinical challenge. In this Review, we summarise common mechanisms driving acute and long-term side-effects and discuss monitoring strategies for radiotherapy survivors. We explore ways to mitigate toxic effects through novel technologies and proper patient selection and counselling. Additionally, we address policies and management strategies to minimise the severity and impact of toxicity during and after treatment. Finally, we examine the potential advantages of emerging technologies and innovative approaches to improve conformity, accuracy, and minimise off-target effects.

Radiotherapy is a critical treatment for cancer but poses significant risks to ovarian tissue, particularly in young females, leading to premature ovarian failure (POF). This study examines the therapeutic potential of etoricoxib nanostructured lipid carriers (ETO-NLC) in mitigating radiation-induced ovarian damage in female Wistar rats. Twenty-four female rats were randomly assigned to four groups: a control group receiving normal saline, a group exposed to a single dose of whole-body gamma radiation (6 Gy), a group treated with etoricoxib (10 mg/kg) post-radiation, and a group treated with ETO-NLC for 14 days following radiation. Histopathological evaluations and oxidative stress biomarker assessments were conducted, including ELISAs for reactive oxygen species (ROS), pro-inflammatory cytokines (IL-1β, TNF-α), and signaling molecules (PI3K, AKT, P38MAPK, AMH). Serum levels of estrogen, FSH, and LH were measured, and gene expression analysis for TGF-β and Nrf2 was performed using qRT-PCR. The findings indicate that ETO-NLC has the potential to ameliorate the harmful effects of ovarian damage induced by γ-radiation. These therapeutic effects were achieved through the modulation of oxidative stress, inflammation, augmentation of antioxidant defenses (including Nrf2 activation), support for cell survival pathways (via PI3K/Akt signaling), regulation of MAPK, mitigation of fibrosis (TGF-β), and preservation of ovarian reserve (as evidenced by AMH, FSH/LH, and estrogen levels). ETO-NLC shows promise as an effective strategy for attenuating radiation-induced ovarian damage, highlighting the need for further research to enhance therapeutic interventions aimed at preserving ovarian function during cancer treatment.

Premature ovarian failure (POF)is defined as the loss of normal ovarian function before the age of 40 and is characterized by increased gonadotropin levels and decreased estradiol levels and ovarian reserve, often leading to infertility. The incomplete understanding of the pathogenesis of POF is a major impediment to the development of effective treatments for this disease, so the use of animal models is a promising option for investigating and identifying the molecular mechanisms involved in POF patients and developing therapeutic agents. As mice and rats are the most commonly used models in animal research, this review article considers studies that used murine POF models. In this review based on the most recent studies, first, we introduce 10 different methods for inducing murine POF models, then we demonstrate the advantages and disadvantages of each one, and finally, we suggest the most practical method for inducing a POF model in these animals. This may help researchers find the method of creating a POF model that is most appropriate for their type of study and suits the purpose of their research.

As science and technology continue to evolve, the potential harm of radiation to the human body cannot be overlooked. Radiation has the capacity to inflict cellular and body-wide damage. Polyphenols are a group of naturally occurring compounds that are found in an array of plant foods. Scientific studies have demonstrated that these compounds possess noteworthy anti-radiation efficacy. Furthermore, they have been observed to be less toxic at higher doses. In the present review, we discussed the mechanisms of ionizing radiation damage and the progress in the research on the radiation resistance mechanism of polyphenol compounds, to provide guidance for the prevention and treatment of radiation related diseases.

Food polyphenols can reduce the oxidative damage caused by ionizing radiation, clear free radicals, reduce DNA damage, regulate NF-KB, MAPK, JAK/STAT, Wnt and other signaling pathways, improve immune function, and have significant protective effects on radiation-induced inflammation, fibrosis, cancer and other aspects. In addition, it also has significant dual effects on radiation sensitization and radiation protection. Food polyphenols come from a wide range of sources, are abundant in daily food, and have no toxic side effects, demonstrating that food polyphenols have great advantages in preventing and treating radiation-related diseases.

TGF-β is a crucial regulator in tumor microenvironment (TME), especially for myofibroblastic cancer-associated fibroblasts (myCAFs). The myCAFs can be motivated by TGF-β signaling to erect pro-tumor TME, meanwhile, myCAFs overexpress TGF-β to mediate the crosstalk between tumor and stromal cells. The blockade of TGF-β can break cancer-associated fibroblasts barrier, consequently opening the access for drugs into tumor. The TGF-β is a promising target in anti-tumor therapy. Herein, we introduced a two-stage combination therapy (TC-Therapy), including TGF-β receptor I inhibitor SB525334 (SB) and cytotoxicity agent docetaxel micelle (DTX-M). We found that SB and DTX-M synergistically inhibited myCAFs proliferation and elevated p53 protein expression in BxPC-3/3T3 mixed cells. Gene and protein tests demonstrated that SB cut off TGF-β signaling via receptor blockade and it did not arouse TGF-β legend compensated internal autocrine. On the contrary, two agents combined decreased TGF-β secretion and inhibited myCAFs viability marked by α-SMA and FAPα. TC-Therapy was applied in BxPc-3/3T3 mixed tumor-bearing mice model. After TC-Therapy, the α-SMA+/ FAPα+ myCAFs faded increasingly and collagenous fibers mainly secreted by myCAFs decreased dramatically as well. More than that, the myCAFs barrier breaking helped to normalize micro-vessels and paved way for micelle penetration. The TGF-β protein level of TC-Therapy in TME was much lower than that of simplex DTX-M, which might account for TME restoration. In conclusion, TGF-β inhibitor acted as the pioneer before nano chemotherapeutic agents. The TC-Therapy of TGF-β signaling inhibition and anti-tumor agent DTX-M is a promising regimen without arising metastasis risk to treat pancreatic cancer. The therapeutic regimen focused on TGF-β related myCAFs reminds clinicians to have a comprehensive understanding of pancreatic cancer.

A toddler presented with significant weight loss and lethargy. His CT scan chest revealed a sizeable anterior mediastinal mass of 14.5×12.0×7.0 cm, resulting in compression of the airway. The patient underwent a successful tumour resection but postoperatively experienced left diaphragmatic paralysis, which was effectively managed through conservative measures. Histopathology was consistent with thymoma (type B2, Masaoka stage I). This case emphasises the critical role of collaborative efforts among oncology, surgery and anaesthesiology teams in achieving positive outcomes for rare paediatric mediastinal tumours. It underscores the importance of comprehensive preoperative anaesthetic assessments, careful planning for potential complications and vigilant postoperative monitoring. Healthcare professionals, particularly anaesthesiologists, can find valuable insights in this case report for navigating the complexities associated with managing giant mediastinal masses in the paediatric population.

Background  Capsular contracture of breast implants is a major complication in breast surgery. Clinically, covering a breast implant with acellular dermal matrix (ADM) or autologous tissue is considered to be the most effective technique to prevent capsular contracture. This study was designed to compare the protective effects of ADM and latissimus dorsi (LD) muscle flap placement on capsular contracture by increasing the rate of capsular contracture through controlled radiation exposure in a rabbit model. Methods  Twenty New Zealand white rabbits were divided into three groups. After the implant was placed beneath the pectoralis major muscle, the lateral third of the implant was left exposed in the control group ( n  = 6). In the ADM group ( n  = 7), the exposed implant was covered with AlloDerm. In the LD flap group ( n  = 7), the exposed implant was covered with a pedicled LD muscle flap. All groups were irradiated 3 weeks after implant insertion. After 6 months, peri-implant tissues were harvested and analyzed. Results  ADM showed markedly lower myofibroblast activity than the LD flap. However, transforming growth factor-β1 levels and the activity of collagen types I and III produced in fibroblasts were significantly lower in the ADM group than in the LD flap group. Conclusion  Based on the findings of our rabbit experiments, ADM is expected to have a comparative advantage in reducing the risk of capsular contracture compared to the LD flap.

Tissue expansion (TE) is the primary method for breast reconstruction after mastectomy. In many cases, mastectomy patients undergo radiation treatment (XR). Radiation is known to induce skin fibrosis and is one of the main causes for complications during post-mastectomy breast reconstruction. TE, on the other hand, induces a pro-regenerative response that culminates in growth of new skin. However, the combined effect of XR and TE on skin mechanics is unknown. Here we used the porcine model of TE to study the effect of radiation on skin fibrosis through biaxial testing, histological analysis, and kinematic analysis of skin deformation over time. We found that XR leads to stiffening of skin compared to control based on a shift in the transition stretch (transition between a low stiffness and an exponential stress-strain region characteristic of collagenous tissue) and an increase in the high modulus (modulus computed with stress-stretch data past the transition point). The change in transition stretch can be explained by thicker, more aligned collagen fiber bundles measured in histology images. Skin subjected to both XR+TE showed similar microstructure to controls as well as similar biaxial response, suggesting that physiological remodeling of collagen induced by TE partially counteracts pro-fibrotic XR effects. Skin growth was indirectly assessed with a kinematic approach that quantified increase in permanent area changes without reduction in thickness, suggesting production of new tissue driven by TE even in the presence of radiation treatment. Future work will focus on the detailed biological mechanisms by which TE counteracts radiation induced fibrosis. STATEMENT OF SIGNIFICANCE: Breast cancer is the most prevalent in women and its treatment often results in total breast removal (mastectomy), followed by reconstruction using tissue expanders. Radiation, which is used in about a third of breast reconstruction cases, can lead to significant complications. The timing of radiation treatment remains controversial. Radiation is known to cause immediate skin damage and long-term fibrosis. Tissue expansion leads to a pro-regenerative response involving collagen remodeling. Here we show that tissue expansion immediately prior to radiation can reduce the level of radiation-induced fibrosis. Thus, we anticipate that this new evidence will open up new avenues of investigation into how the collagen remodeling and pro-regenerative effects of tissue expansion can be leverage to prevent radiation-induced fibrosis.

Radiotherapy-Induced Skin Injury (RISI) is radiation damage to normal skin tissue that primarily occurs during tumor Radiotherapy and occupational exposure. The risk of RISI is high due to the fact that the skin is not only the first body organ that ionizing radiation comes into contact with, but it is also highly sensitive to it, especially the basal cell layer and capillaries. Typical clinical manifestations of RISI include erythema, dry desquamation, moist desquamation, and ulcers, which have been established to significantly impact patient care and cancer treatment. Notably, our current understanding of RISI's pathological mechanisms and signaling pathways is inadequate, and no standard treatments have been established. Radiation-induced oxidative stress, inflammatory responses, fibrosis, apoptosis, and cellular senescence are among the known mechanisms that interact and promote disease progression. Additionally, radiation can damage all cellular components and induce genetic and epigenetic changes, which play a crucial role in the occurrence and progression of skin injury. A deeper understanding of these mechanisms and pathways is crucial for exploring the potential therapeutic targets for RISI. Therefore, in this review, we summarize the key mechanisms and potential treatment methods for RISI, offering a reference for future research and development of treatment strategies.

Intestinal fibrosis, a prominent consequence of inflammatory bowel disease (IBD), presents considerable difficulty owing to the absence of licensed antifibrotic therapies. This review assesses the therapeutic potential of phytochemicals as alternate methods for controlling intestinal fibrosis. Phytochemicals, bioactive molecules originating from plants, exhibit potential antifibrotic, anti-inflammatory, and antioxidant activities, targeting pathways associated with inflammation and fibrosis. Compounds such as Asperuloside, Berberine, and olive phenols have demonstrated potential in preclinical models by regulating critical signaling pathways, including TGF-β/Smad and NFκB, which are integral to advancing fibrosis.

The main findings suggest that these phytochemicals significantly reduce fibrotic markers, collagen deposition, and inflammation in various experimental models of IBD. These phytochemicals may function as supplementary medicines to standard treatments, perhaps enhancing patient outcomes while mitigating the adverse effects of prolonged immunosuppressive usage. Nonetheless, additional clinical trials are necessary to validate their safety, effectiveness, and bioavailability in human subjects.

Therefore, investigating phytochemicals may lead to crucial advances in the formulation of innovative treatment approaches for fibrosis associated with IBD, offering a promising avenue for future therapeutic development.

Over half of all people diagnosed with cancer receive radiation therapy. Moderate to severe radiation dermatitis occurs in most human radiation patients, causing pain, aesthetic distress, and a negative impact on tumor control. No effective prevention or treatment for radiation dermatitis exists. The lack of well-characterized, clinically relevant animal models of human radiation dermatitis contributes to the absence of strategies to mitigate radiation dermatitis. Here, we establish and characterize a hairless SKH-1 mouse model of human radiation dermatitis by correlating temporal stages of clinical and pathological skin injury. We demonstrate that a single ionizing radiation treatment of 30 Gy using 6 MeV electrons induces severe clinical grade 3 peak toxicity at 12 days, defined by marked erythema, desquamation and partial ulceration, with resolution occurring by 25 days. Histopathology reveals that radiation-induced skin injury features temporally unique inflammatory changes. Upregulation of epidermal and dermal TGF-ß1 and COX-2 protein expression occurs at peak dermatitis, with sustained epidermal TGF-ß1 expression beyond resolution. Specific histopathological variables that remain substantially high at peak toxicity and early clinical resolution, including epidermal thickening, hyperkeratosis and dermal fibroplasia/fibrosis, serve as specific measurable parameters for in vivo interventional preclinical studies that seek to mitigate radiation-induced skin injury.

Salivary gland damage and hypofunction result from various disorders, including autoimmune Sjögren's disease (SjD) and IgG4-related disease (IgG4-RD), as well as a side effect of radiotherapy for treating head and neck cancers. There are no therapeutic strategies to prevent the loss of salivary gland function in these disorders nor facilitate functional salivary gland regeneration. However, ongoing aquaporin-1 gene therapy trials to restore saliva flow show promise. To identify and develop novel therapeutic targets, we must better understand the cell-specific signaling processes involved in salivary gland regeneration. Transforming growth factor-β (TGF-β) signaling is essential to tissue fibrosis, a major endpoint in salivary gland degeneration, which develops in the salivary glands of patients with SjD, IgG4-RD, and radiation-induced damage. Though the deposition and remodeling of extracellular matrix proteins are essential to repair salivary gland damage, pathological fibrosis results in tissue hardening and chronic salivary gland dysfunction orchestrated by multiple cell types, including fibroblasts, myofibroblasts, endothelial cells, stromal cells, and lymphocytes, macrophages, and other immune cell populations. This review is focused on the role of TGF-β signaling in the development of salivary gland fibrosis and the potential for targeting TGF-β as a novel therapeutic approach to regenerate functional salivary glands. The studies presented highlight the divergent roles of TGF-β signaling in salivary gland development and dysfunction and illuminate specific cell populations in damaged or diseased salivary glands that mediate the effects of TGF-β. Overall, these studies strongly support the premise that blocking TGF-β signaling holds promise for the regeneration of functional salivary glands.

Radiation therapy (RT) has been a primary treatment modality in cancer for decades. Increasing evidence suggests that RT can induce an immunosuppressive shift via upregulation of cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). MDSCs inhibit antitumor immunity through potent immunosuppressive mechanisms and have the potential to be crucial tools for cancer prognosis and treatment. MDSCs interact with many different pathways, desensitizing tumor tissue and interacting with tumor cells to promote therapeutic resistance. Vascular damage induced by RT triggers an inflammatory signaling cascade and potentiates hypoxia in the tumor microenvironment (TME). RT can also drastically modify cytokine and chemokine signaling in the TME to promote the accumulation of MDSCs. RT activation of the cGAS-STING cytosolic DNA sensing pathway recruits MDSCs through a CCR2-mediated mechanism, inhibiting the production of type 1 interferons and hampering antitumor activity and immune surveillance in the TME. The upregulation of hypoxia-inducible factor-1 and vascular endothelial growth factor mobilizes MDSCs to the TME. After recruitment, MDSCs promote immunosuppression by releasing reactive oxygen species and upregulating nitric oxide production through inducible nitric oxide synthase expression to inhibit cytotoxic activity. Overexpression of arginase-1 on subsets of MDSCs degrades L-arginine and downregulates CD3ζ, inhibiting T-cell receptor reactivity. This review explains how radiation promotes tumor resistance through activation of immunosuppressive MDSCs in the TME and discusses current research targeting MDSCs, which could serve as a promising clinical treatment strategy in the future.

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.

Radiotherapy (RT) is an integral part of many cancer treatment protocols. Chronic radiation-induced dermatitis (CRD) is a cutaneous toxicity that occurs in one-third of all patients treated with this method. CRD is usually observed several months after completion of treatment. Typical symptoms of CRD are telangiectasia, skin discoloration, atrophy, thickening, and cutaneous fibrosis. There are currently no data in the literature on the evaluation of the dermoscopic features of CRD. The aim of this prospective study was the identification of clinical and dermoscopic features in a group of 32 patients with head and neck cancer (HNC) in whom CRD developed after RT. CRD was assessed at 3, 6, and 12 months after RT in 16, 10, and 10 patients, respectively. CRD was assessed at one time point and two time points in 28 and 4 patients, respectively. The control included skin areas of the same patient not exposed to RT. The dataset consisted of 36 clinical and 216 dermoscopic photos. Clinical evaluation was performed according to the RTOG/EORTC radiation-induced dermatitis scale. The highest score was grade 2 observed in 21 patients. Clinical observations revealed the presence of slight and patchy atrophy, pigmentation change, moderate telangiectasias, and some and total hair loss. Dotted vessels, clustered vessel distribution, white patchy scale, perifollicular white color, white structureless areas, brown dots and globules, and white lines were the most frequently noted features in dermoscopy. Three independent risk factors for chronic toxicity, such as age, gender, and surgery before RT, were identified. The dermoscopic features that had been shown in our study reflect the biological reaction of the skin towards radiation and may be used for the parametrization of CRD regarding its intensity and any other clinical consequences in the future.

Dysphagia and chronic aspiration are common post-irradiation complications in nasopharyngeal carcinoma (NPC) survivors. Expiratory Muscle Strength Training (EMST) is a simple device-driven exercise therapy for swallowing training. This study investigates the effectiveness of EMST in a group of post-irradiated NPC patients. This prospective cohort, including twelve patients with previous irradiation for NPC and with swallowing disturbance, was performed between 2019 and 2021 in a single institution. Patients were trained with EMST for 8 weeks. Non-parametric analyses examined effects of EMST on primary outcome, maximum expiratory pressure. Secondary outcomes were measured with Penetration-aspiration scale, Yale pharyngeal residue severity rating scale (YPRSRS) by flexible endoscopic evaluation of swallowing, and Eating Assessment Tool (EAT-10) and M.D. Anderson Dysphagia Inventory questionnaire. Twelve patients, with a mean (SD) age of 64.3 (8.2) were recruited. There was no patient dropout with 88.9% overall compliance of training. Maximum expiratory pressure improved by 41% (median 94.5 to 133.5 cmH2O, p = 0.003). There was reduction in Penetration-aspiration scale with thin liquid (median 4 to 3, p = 0.026), and in YPRSRS at pyriform fossa with mildly thick liquid (p = 0.021) and at vallecula with thin liquid (p = 0.034), mildly thick liquid (p = 0.014) and pureed meat congee (p = 0.016). Questionnaire scores did not significantly change statistically. EMST is an easy-to-use and effective exercise therapy to improve airway safety and swallowing function in post-irradiated NPC survivors.

Radiation-induced fibrosis is a recognised consequence of radiotherapy, especially after multiple and prolonged dosing regimens. There is no definitive treatment for late-stage radiation-induced fibrosis, although the use of autologous fat transfer has shown promise. However, the exact mechanisms by which this improves radiation-induced fibrosis remain poorly understood. We aim to explore existing literature on the effects of autologous fat transfer on both in-vitro and in-vivo radiation-induced fibrosis models, and to collate potential mechanisms of action.

PubMed, Cochrane reviews and Scopus electronic databases from inception to May 2023 were searched. Our search strategy combined both free-text terms with Boolean operators, derived from synonyms of adipose tissue and radiation-induced fibrosis.

The search strategy produced 2909 articles. Of these, 90 underwent full-text review for eligibility, yielding 31 for final analysis. Nine conducted in-vitro experiments utilising a co-culture model, whilst 25 conducted in-vivo experiments. Interventions under autologous fat transfer included adipose-derived stem cells, stromal vascular function, whole fat and microfat. Notable findings include downregulation of fibroblast proliferation, collagen deposition, epithelial cell apoptosis, and proinflammatory processes. Autologous fat transfer suppressed hypoxia and pro-inflammatory interferon-γ signalling pathways, and tissue treated with adipose-derived stem cells stained strongly for anti-inflammatory M2 macrophages. Although largely proangiogenic initially, studies show varying effects on vascularisation. There is early evidence that adipose-derived stem cell subgroups may have different functional properties.

Autologous fat transfer functions through pro-angiogenic, anti-fibrotic, immunomodulatory, and extracellular matrix remodelling properties. By characterising these mechanisms, relevant drug targets can be identified and used to further improve clinical outcomes in radiation-induced fibrosis. Further research should focus on adipose-derived stem cell sub-populations and augmentation techniques such as cell-assisted lipotransfer.

Radiation therapy often leads to late radiation-induced skin fibrosis (RISF), causing movement impairment and discomfort. We conducted a comprehensive study to assess the effectiveness of metformin and adipose-derived stem cells (ASCs), whether autologous or allogeneic, individually or in combination therapy, in mitigating RISF.

Using a female C57BL/6J mouse model subjected to hind limb irradiation as a representative RISF model, we evaluated metformin, ASCs, or their combination in two contexts: prophylactic (started on day 1 post-irradiation) and therapeutic (initiated on day 14 post-irradiation, coinciding with fibrosis symptoms). We measured limb movement, examined skin histology, and analyzed gene expression to assess treatment efficacy.

Prophylactic metformin and ASCs, whether autologous or allogeneic, effectively prevented late fibrosis, with metformin showing promising results. However, combination therapy did not provide additional benefits when used prophylactically. Autologous ASCs, alone or with metformin, proved most effective against late-stage RISF. Prophylactic intervention outperformed late therapy for mitigating radiation skin damage. Co-culture studies revealed that ASCs and metformin downregulated inflammation and fibrotic gene expression in both mouse and human fibroblasts.

Our study suggests metformin's potential as a prophylactic measure to prevent RISF, and the combination of ASCs and metformin holds promise for late-stage RISF treatment. These findings have clinical implications for improving the quality of life for those affected by radiation-induced skin fibrosis.

Radiation therapy (RT) remains one of the most effective and utilized oncologic treatments available. While it can directly yield tumor cell death, its impact on the immune microenvironment is more complex, promoting either an antitumor response or, conversely, a tumor-promoting state. TGF-β, induced by RT, yields a more immunosuppressive environment, including potentially blunting response to immune-checkpoint blockade. In this issue of the JCI, Wang and colleagues demonstrate that RT reduced expression of bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI), a TGF-β pseudoreceptor. Limiting this effect, or increasing BAMBI, improved RT-induced tumor cell killing, tumor response, and antitumor immune effects. This realization points to a pathway of potential clinical translation.

Radiation therapy is an established and effective anti-cancer treatment modality. Extensive pre-clinical experimentation has demonstrated that the pro-inflammatory properties of irradiation may be synergistic with checkpoint immunotherapy. Radiation induces double-stranded DNA breaks (dsDNA). Sensing of the dsDNA activates the cGAS/STING pathway, producing Type 1 interferons essential to recruiting antigen-presenting cells (APCs). Radiation promotes cytotoxic CD8 T-cell recruitment by releasing tumour-associated antigens captured and cross-presented by surveying antigen-presenting cells. Radiation-induced vascular normalisation may further promote T-cell trafficking and drug delivery. Radiation is also immunosuppressive. Recruitment of regulatory T cells (Tregs) and innate cells such as myeloid-derived suppressive cells (m-MDSCs) all counteract the immunostimulatory properties of radiation. Many innate immune cell types operate at the interface of the adaptive immune response. Innate immune cells, such as m-MDSCs, can exert their immunosuppressive effects by expressing immune checkpoints such as PD-L1, further highlighting the potential of combined radiation and checkpoint immunotherapy. Several early-phase clinical studies investigating the combination of radiation and immunotherapy have been disappointing. A greater appreciation of radiotherapy's impact on the innate immune system is essential to optimise radioimmunotherapy combinations. This review will summarise the impact of radiotherapy on crucial cells of the innate immune system and vital immunosuppressive cytokines.

Radiation is commonly used as a treatment intended to cure or palliate cancer patients. Despite remarkable advances in the precision of radiotherapy delivery, even the most advanced forms inevitably expose some healthy tissues surrounding the target site to radiation. On rare occasions, this results in the development of radiation-associated secondary malignancies (RASM). RASM are typically high-grade and carry a poorer prognosis than their non-radiated counterparts. RASM are characterized by a high mutation burden, increased T cell infiltration, and a microenvironment that bears unique inflammatory signatures of prior radiation, including increased expression of various cytokines (e.g., TGF-β, TNF-α, IL4, and IL10). Interestingly, these cytokines have been shown to up-regulate the expression of PD-1 and/or PD-L1-an immune checkpoint receptor/ligand pair that is commonly targeted by immune checkpoint blocking immunotherapies. Here, we review the current understanding of the tumor-immune interactions in RASM, highlight the distinct clinical and molecular characteristics of RASM that may render them immunologically "hot," and propose a rationale for the formal testing of immune checkpoint blockade as a treatment approach for patients with RASM.

This study aimed to investigate the involvement of mitochondrial biogenesis, and determine the extent of fibroblast proliferation and cellular apoptosis, in the gingiva of patients who had undergone head and neck radiation, after receiving hyperbaric oxygen therapy (HBOT), in comparison with normal gingiva.

A total of 16 patients who had undergone head and neck radiation with HBOT and six healthy subjects were included in the study. After the completion of radiation therapy, patients received HBOT at 2 ATA for 90 minutes per session, and for 20 sessions per patient. Samples of gingival tissues were then taken. The levels of: transforming growth factor beta (TGF-β); phospho-nuclear factor kappa-light-chain-enhancer of activated B cells (p-NFϰB); nuclear factor kappa-light-chain-enhancer of activated B cells (NFϰB); proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α); phospho-dynamin-related protein 1 at ser616 (p-Drp1ser616); dynamin-related protein 1 (Drp1); Bcl-2-associated X-protein (Bax); and B-cell lymphoma 2 (Bcl-2) were determined using a Western blot. Independent t-test and Chi-squared tests were used in the study.

There were no differences in the levels of TGF-β, p-NFϰB, NFϰB, p-Drp1ser616, Drp1, Bax and Bcl-2 between the two groups. However, the level of PGC-1α was greater in irradiated gingival tissues with HBOT than in the healthy gingiva.

Radiation-induced impaired wound healing can be improved by HBOT as indicated by levels of apoptosis, mitochondrial dynamics, cell proliferation and inflammation in irradiated gingiva with HBOT to a similar level to normal healthy gingiva. These findings may occur through an increase in mitochondrial biogenesis following HBOT.

Acute radiotherapy (RT)-induced external ear soft tissue changes start with erythema and dry desquamation and may progress to moist desquamation and epidermal ulceration. Chronic RT-induced changes include epithelial atrophy and subcutaneous fibrosis. Although RT-induced radiation dermatitis has been well studied, interventions for soft tissue disease involving the external auditory canal (EAC) warrant investigation. Medical management includes topical steroid treatment for EAC radiation dermatitis and topical antibiotic therapy for suppurative otitis externa. Hyperbaric oxygen and pentoxifylline-vitamin E therapy have shown promise for other applications, but their clinical effect on soft tissue EAC disease is currently undefined.

Radiation therapy can lead to late radiation-induced skin fibrosis (RISF), causing movement restriction, pain, and organ dysfunction. This study evaluated adipose-derived extracellular matrix (Ad-ECM) as a mitigator of RISF. Female C57BL/6J mice that were irradiated developed fibrosis, which was mitigated by a single local Ad-ECM injection, improving limb movement and reducing epithelium thickness and collagen deposition. Ad-ECM treatment resulted in decreased expression of pro-inflammatory and fibrotic genes, and upregulation of anti-inflammatory cytokines, promoting M2 macrophage polarization. Co-culture of irradiated human fibroblasts with Ad-ECM down-modulated fibrotic gene expression and enhanced bone marrow cell migration. Ad-ECM treatment also increased interleukin (IL)-4, IL-5, and IL-15 expression in endothelial cells, stimulating M2 macrophage polarization and alleviating RISF. Prophylactic use of Ad-ECM showed effectiveness in mitigation. This study suggests Ad-ECM's potential in treating chronic-stage fibrosis.

Swallowing impairment is a major complication of radiation treatment for oropharyngeal cancers. Developing targeted therapies that improve swallowing outcomes relies on an understanding of the mechanisms that influence motor function after radiation treatment. The purpose of this study was to determine whether there is a correlation between radiation induced changes in tongue movement and structural changes in irradiated submental muscles, as well as assess other possible causes for dysfunction. We hypothesized that a clinically relevant total radiation dose to the submental muscles would result in: a) quantifiable changes in tongue strength and displacement during drinking two months post treatment; and b) a profibrotic response and/or fiber type transition in the irradiated tissue. Sprague-Dawley adult male rats received radiation to the submental muscles at total dose-volumes known to provoke dysphagia in humans. A clinical linear accelerator administered 8 fractions of 8Gy for a total of 64Gy. Comparisons were made to sham-treated rats that received anesthesia only. Swallowing function was assessed using videofluoroscopy and tongue strength was analyzed via force lickometer. TGFβ1 expression was analyzed via ELISA. The amount of total collagen was analyzed by picrosirius red staining. Immunofluorescence was used to assess fiber type composition and size. Significant changes in licking function during drinking were observed at two months post treatment, including a slower lick rate and reduced tongue protrusion during licking. In the mylohyoid muscle, significant increases in TGFβ1 protein expression were found post radiation. Significant increases in the percentage of collagen content were observed in the irradiated geniohyoid muscle. No changes in fiber type expression were observed. Results indicate a profibrotic transition within the irradiated swallowing muscles that contributes to tongue dysfunction post-radiation treatment.

Adipose tissue is composed of a collection of cells with valuable structural and regenerative function. Taken as an autologous graft, these cells can be used to address soft tissue defects and irregularities, while also providing a reparative effect on the surrounding tissues. Adipose-derived stem or stromal cells are primarily responsible for this regenerative effect through direct differentiation into native cells and via secretion of numerous growth factors and cytokines that stimulate angiogenesis and disrupt pro-inflammatory pathways. Separating adipose tissue into its component parts, i.e., cells, scaffolds and proteins, has provided new regenerative therapies for skin and soft tissue pathology, including that resulting from radiation. Recent studies in both animal models and clinical trials have demonstrated the ability of autologous fat grafting to reverse radiation induced skin fibrosis. An improved understanding of the complex pathologic mechanism of RIF has allowed researchers to harness the specific function of the ASCs to engineer enriched fat graft constructs to improve the therapeutic effect of AFG.

Radiation therapy (RT) in the management of pelvic cancers remains a clinical challenge to urologists given the sequelae of urethral stricture disease secondary to fibrosis and vascular insults. The objective of this review is to understand the physiology of radiation-induced stricture disease and to educate urologists in clinical practice regarding future prospective options clinicians have to deal with this condition. The management of post-radiation urethral stricture consists of conservative, endoscopic, and primary reconstructive options. Endoscopic approaches remain an option, but with limited long-term success. Despite concerns with graft take, reconstructive options such as urethroplasties in this population with buccal grafts have shown long-term success rates ranging from 70 to 100%. Robotic reconstruction is augmenting previous options with faster recovery times. Radiation-induced stricture disease is challenging with multiple interventions available, but with successful outcomes demonstrated in various cohorts including urethroplasties with buccal grafts and robotic reconstruction.

To explore and analyse the perspective of patients undergoing and recovering from nasopharyngeal carcinoma (NPC) therapy.

Thirty-three NPC patients at different stages of treatment were enrolled. Seven were actively undergoing treatment, 13 were immediately post-treatment, and 13 were long-term. Patients were interviewed using a structured questionnaire based on a review of the literature that covered different phases of their treatment journey. The interview was recorded and transcribed for qualitative data analysis using a thematic inductive-deductive approach.

Three main domains embracing aspects of NPC patients' experiences were identified; side effects, psychosocial well-being, and the role and support of healthcare workers. Side effects were experienced orally, locally, and systemically. Oral side effects (oral mucositis, xerostomia, altered taste, dysphagia) were the most significant challenge experienced by NPC patients. Locally, skin injury (desquamation, fibrosis, darkening of the skin, erythema, pruritus, and swelling around the neck region) and hair loss, resolved after cessation of therapy. Systemic side effects from the treatment were related to general weakness, weight loss and nausea. The psychosocial well-being of NPC patients was influenced by a range of issues including support (healthcare workers and family), pain management, functional limitations, nutritional needs, perceived level of information, emotion, and finances.

NPC patients were significantly impacted based on the diagnosis, treatment and recovery phase affecting them locally, systemically, and psychologically. The role of family and healthcare staff was also influential in the overall treatment experience, and they have key roles to play in facilitating patients along their treatment journey.

Oral and general side effects from NPC treatment have significant impact on patients physical and emotional well-being. It is important for healthcare providers to have insights of these so as to understand and support patients during their treatment journey and recovery and be able to empathetically facilitate their clinical management.

Radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) is the cornerstone of organ-sparing or adjuvant therapy for nearly all head and neck cancers. Unfortunately, aggressive RT or CCRT can result in severe late toxicities, such as osteoradionecrosis of the jaws (ORNJ). The incidence of ORNJ is currently less than 5-6% due to advances in dental preventive care programs, RT planning systems, and RT techniques. Although numerous patient-, tumor-, and treatment-related factors may influence the incidence rates of ORNJ, RT modality (equipment), technique, and dose-volume-related factors are three of the most influential factors. This is mainly because different RT equipment and techniques have different levels of success at delivering the prescribed dose to the focal volume of the treatment while keeping the "organ at risk" safe. ORNJ risk is ultimately determined by mandibular dose, despite the RT technique and method being known predictors. Regardless of the photon delivery method, the radiobiological effects will be identical if the total dose, dose per fraction, and dose distribution within the tissue remain constant. Therefore, contemporary RT procedures mitigate this risk by reducing mandibular dosages rather than altering the ionizing radiation behavior in irradiated tissues. In light of the paucity of studies that have examined the impact of RT modality, technique, and dose-volume-related parameters, as well as their radiobiological bases, the present review aims to provide a comprehensive overview of the published literature on these specific issues to establish a common language among related disciplines and provide a more reliable comparison of research results.

Transforming growth factor-beta 3 (TGF-β3) is a ubiquitously expressed multifunctional cytokine involved in a range of physiological and pathological conditions, including embryogenesis, cell cycle regulation, immunoregulation, and fibrogenesis. The cytotoxic effects of ionizing radiation are employed in cancer radiotherapy, but its actions also influence cellular signaling pathways, including that of TGF-β3. Furthermore, the cell cycle regulating and anti-fibrotic effects of TGF-β3 have identified it as a potential mitigator of radiation- and chemotherapy-induced toxicity in healthy tissue. This review discusses the radiobiology of TGF-β3, its induction in tissue by ionizing radiation, and its potential radioprotective and anti-fibrotic effects.

Head and neck cancer (HNC) survivorship is increasing, and with it, a shift in treatment practices has occurred. Radical surgical resections for the treatment of HNC have decreased, and organ preservation treatments have increased. Although effective in treating HNC, chemoradiation therapy toxicities can be detrimental to a patient's overall health, nutrition status, and quality of life (QOL). Considering that dysphagia is typically a driving element of dysfunction, speech-language pathologists are vital to the prehabilitation phase. Prehabilitation programs include a variety of components, with the primary goal being to improve functional and QOL outcomes posttreatment.

Ataxia telangiectasia mutated kinase (ATM) inhibitors are potent radiosensitizers that regulate DNA damage responses and redox metabolism, but they have not been translated clinically because of the potential for excess normal tissue toxicity. Pharmacologic ascorbate (P-AscH-; intravenous administration achieving mM plasma concentrations) selectively enhances H2O2-induced oxidative stress and radiosensitization in tumors while acting as an antioxidant and mitigating radiation damage in normal tissues including the bowel. We hypothesized that P-AscH- could enhance the therapeutic index of ATM inhibitor-based chemoradiation by simultaneously enhancing the intended effects of ATM inhibitors in tumors and mitigating off-target effects in adjacent normal tissues.

Clonogenic survival was assessed in human (human colon tumor [HCT]116, SW480, HT29) and murine (CT26, MC38) colorectal tumor lines and normal cells (human umbilical vein endothelial cell, FHs74) after radiation ± DNA repair inhibitors ± P-AscH-. Tumor growth delay was assessed in mice with HCT116 or MC38 tumors after fractionated radiation (5 Gy × 3) ± the ATM inhibitor KU60019 ± P-AscH-. Intestinal injury, oxidative damage, and transforming growth factor β immunoreactivity were quantified using immunohistochemistry after whole abdominal radiation (10 Gy) ± KU60019 ± P-AscH-. Cell cycle distribution and ATM subcellular localization were assessed using flow cytometry and immunohistochemistry. The role of intracellular H2O2 fluxes was assessed using a stably expressed doxycycline-inducible catalase transgene.

KU60019 with P-AscH- enhanced radiosensitization in colorectal cancer models in vitro and in vivo by H2O2-dependent oxidative damage to proteins and enhanced DNA damage, abrogation of the postradiation G2 cell cycle checkpoint, and inhibition of ATM nuclear localization. In contrast, concurrent P-AscH- markedly reduced intestinal toxicity and oxidative damage with KU60019.

We provide evidence that redox modulating drugs, such as P-AscH-, may facilitate the clinical translation of ATM inhibitors by enhancing tumor radiosensitization while simultaneously protecting normal tissues.

Surgical techniques for breast cancer have been refined over the past decades to deliver an aesthetic outcome as close as possible to the contralateral intact breast. Current surgery further allows excellent aesthetic outcome even in case of mastectomy, by performing skin sparing or nipple sparing mastectomy in combination with breast reconstruction. In this review we discuss how to optimise post-operative radiation therapy after oncoplastic and breast reconstructive procedures, including dose, fractionation, volumes, surgical margins, and boost application.

The prominence of photodynamic therapy (PDT) in treating superficial skin cancer inspires innovative solutions for its congenitally deficient shadow penetration of the visible-light excitation. X-ray-induced photodynamic therapy (X-PDT) has been proven to be a successful technique in reforming the conventional PDT for deep-seated tumors by creatively utilizing penetrating X-rays as external excitation sources and has witnessed rapid developments over the past several years. Beyond the proof-of-concept demonstration, recent advances in X-PDT have exhibited a trend of minimizing X-ray radiation doses to quite low values. As such, scintillating materials used to bridge X-rays and photosensitizers play a significant role, as do diverse well-designed irradiation modes and smart strategies for improving the tumor microenvironment. Here in this review, we provide a comprehensive summary of recent achievements in X-PDT and highlight trending efforts using low doses of X-ray radiation. We first describe the concept of X-PDT and its relationships with radiodynamic therapy and radiotherapy and then dissect the mechanism of X-ray absorption and conversion by scintillating materials, reactive oxygen species evaluation for X-PDT, and radiation side effects and clinical concerns on X-ray radiation. Finally, we discuss a detailed overview of recent progress regarding low-dose X-PDT and present perspectives on possible clinical translation. It is expected that the pursuit of low-dose X-PDT will facilitate significant breakthroughs, both fundamentally and clinically, for effective deep-seated cancer treatment in the near future.

(1) Background: radiotherapy is a cornerstone of cancer treatment. When delivering a tumoricidal dose, the risk of severe late toxicities is usually kept below 5% using dose-volume constraints. However, individual radiation sensitivity (iRS) is responsible (with other technical factors) for unexpected toxicities after exposure to a dose that induces no toxicity in the general population. Diagnosing iRS before radiotherapy could avoid unnecessary toxicities in patients with a grossly normal phenotype. Thus, we reviewed iRS diagnostic data and their impact on decision-making processes and the RT workflow; (2) Methods: following a description of radiation toxicities, we conducted a critical review of the current state of the knowledge on individual determinants of cellular/tissue radiation; (3) Results: tremendous advances in technology now allow minimally-invasive genomic, epigenetic and functional testing and a better understanding of iRS. Ongoing large translational studies implement various tests and enriched NTCP models designed to improve the prediction of toxicities. iRS testing could better support informed radiotherapy decisions for individuals with a normal phenotype who experience unusual toxicities. Ethics of medical decisions with an accurate prediction of personalized radiotherapy's risk/benefits and its health economics impact are at stake; (4) Conclusions: iRS testing represents a critical unmet need to design personalized radiotherapy protocols relying on extended NTCP models integrating iRS.

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

 Radiation-associated soft tissue injury is a potentially devastating complication for head and neck cancer patients. The damage can range from minor sequelae such as xerostomia, which requires frequent daily maintenance, to destructive degenerative processes such as osteoradionecrosis, which can contribute to flap failure and delay or reverse oral rehabilitation. Despite the need for effective radioprotectants, the literature remains sparse, primarily focused on interventions beyond the surgeon's control, such as maintenance of good oral hygiene or modulation of radiation dose.

 This narrative review aggregates and explores noninvasive, systemic treatment modalities for prevention or amelioration of radiation-associated soft tissue injury.

 We highlighted nine modalities with the most clinical potential, which include amifostine, melatonin, palifermin, hyperbaric oxygen therapy, photobiomodulation, pentoxifylline-tocopherol-clodronate, pravastatin, transforming growth factor-β modulators, and deferoxamine, and reviewed the benefits and limitations of each modality. Unfortunately, none of these modalities are supported by strong evidence for prophylaxis against radiation-associated soft tissue injury.

 While we cannot endorse any of these nine modalities for immediate clinical use, they may prove fruitful areas for further investigation.