Search

The aim of this work was to investigate whether reirradiation of recurrent glioblastoma with hypofractionated stereotactic radiation therapy (HSRT) consisting of 35 Gy in 5 fractions (35 Gy/5 fx) compared with 25 Gy in 5 fractions (25 Gy/5 fx) improves outcomes while maintaining acceptable toxicity. We conducted a prospective randomized phase 2 trial involving patients with recurrent glioblastoma (per the 2007 and 2016 World Health Organization classification). A minimum interval from first radiation therapy of 5 months and gross tumor volume of 150 cc were required. Patients were randomized 1:1 to receive HSRT alone in 25 Gy/5 fx or 35 Gy/5 fx. The primary endpoint was progression-free survival (PFS). We used a randomized phase 2 screening design with a 2-sided α of 0.15 for the primary endpoint. From 2011 to 2019, 40 patients were randomized and received HSRT, with 20 patients in each group. The median age was 50 years (range, 27-71); a new resection before HSRT was performed in 75% of patients. The median PFS was 4.9 months in the 25 Gy/5 fx group and 5.2 months in the 35 Gy/5 fx group (P =.23). Six-month PFS was similar at 40% (85% CI, 24%-55%) for both groups. The median overall survival (OS) was 9.2 months in the 25 Gy/5 fx group and 10 months in the 35 Gy/5 fx group (P =.201). Grade ≥3 necrosis was numerically higher in the 35 Gy/5 fx group (3 [16%] vs 1 [5%]), but the difference was not statistically significant (P =.267). In an exploratory analysis, median OS of patients who developed treatment-related necrosis was 14.1 months, and that of patients who did not was 8.7 months (P =.003). HSRT alone with 35 Gy/5 fx was not superior to 25 Gy/5 fx in terms of PFS or OS. Due to a potential increase in the rate of clinically meaningful treatment-related necrosis, we suggest 25 Gy/5 fx as the standard dose in HSRT alone. During follow-up, attention should be given to differentiating tumor progression from potentially manageable complications. [ABSTRACT FROM AUTHOR]

In this paper, we present a review of several selected talks presented at the CTTACC conference (Cellular Therapies in Trauma and Critical Care) held in Scottsdale, AZ in May 2023. This conference review highlights the potential for cellular therapies to "reset" the dysregulated immune response and restore physiologic functions to normal. Improvements in medical care systems and technology have increasingly saved lives after major traumatic events. However, many of these patients have complicated post-traumatic sequelae, ranging from short-term multi-organ failure to chronic critical illness. Patients with chronic critical illness have been found to have dysregulated immune responses. These abnormal and harmful immune responses persist for years after the initial insult and can potentially be mitigated by treatment with cellular therapies. The sessions emphasized the need for more research and clinical trials with cellular therapies for the treatment of a multitude of chronic illnesses: post-trauma, radiation injury, COVID-19, burns, traumatic brain injury (TBI) and other chronic infections. [ABSTRACT FROM AUTHOR]

Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBE ENT/BP) were performed. Single-fraction RBE ENT/BP for 50% effect probability (tolerance dose (TD 50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBE ENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects. [ABSTRACT FROM AUTHOR]

The optimal dose and range of radiation therapy for central nervous system nongerminomatous germ cell tumors (NGGCTs) have not been uniformly established. Therefore, this study aimed to investigate the effect of individualized radiation therapy, based on the response to induction chemotherapy combined with surgery, on the prognosis of patients with NGGCTs. Based on the imaging examination and tumor markers after induction chemotherapy and pathologic results of second-look surgery, patients with NGGCT received different radiation therapy strategies, including 30.6 Gy whole ventricular irradiation + tumor-bed boost to 54 Gy, 30.6 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, 36 Gy craniospinal irradiation + tumor-bed boost to 54 Gy, and 36 Gy craniospinal irradiation + 54 Gy tumor-bed boost with 45 Gy to metastatic spinal lesions. A total of 51 patients were enrolled between January 2015 and March 2021, with a median age of 10.3 years. The 3-year event-free survival and overall survival (OS) of the entire cohort were 70.2% ± 6.9% and 77.5% ± 6.0%, respectively. The 3-year OS of patients achieving partial response after induction chemotherapy was higher than that of patients with stable disease (P =.03) or progressive disease (P =.002). The 3-year event-free survival and OS of the 18 patients receiving 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed boost were 88.9% ± 7.4% and 94.4% ± 5.4%, respectively. The results suggest that an individualized radiation therapy strategy based on response to induction chemotherapy and surgery is a feasible and promising means of achieving reduction in dose and extent of radiation in patients while still providing good response. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to investigate whether patient, tumour and radiation therapy factors are associated with development of middle ear effusion (MEE) in nasopharyngeal carcinoma (NPC) patients. Deign, Settings, and Participants: A retrospective review of NPC patients treated between January 2000 and June 2018 at Rabin Medical Center. Patient factors, tumour factors, radiation doses, and radiation fields were collected and outlined if needed (middle ear, eustachian tube [ET], tensor veli palatini [TVP], and levator palatini [LVP] muscles), then analysed and compared between patients with MEE and those without and between sides in patients with unilateral MEE. Main Outcome Measures and Results: Seventy‐three patients were enrolled. Most were males (71.2%) with advanced‐stage diseases (78%). At the time of diagnosis 14 patients (19.2%) presented with MEE. Following radiation, 18 patients, with no evidence of MEE at presentation, developed MEE. Tumour stage, histology, and laterality were not associated with development of MEE. Comparison of mean radiation field dosages including—gross target volume, clinical target volume, and patient target volume showed no association with post‐radiation MEE. In addition, no difference was found in the radiation doses to the middle ear, ET or the LVP nor the TVP between ears with and without MEE. Conclusions: Post‐irradiation MEE remains a common adverse effect in NPC patients. Surprisingly, tumour stage, tumour laterality, and histology were not associated with MEE. Similar findings were observed for total radiation doses and specific doses to the middle ear, ET, and ET muscles. [ABSTRACT FROM AUTHOR]

Background: We used transcatheter aortic valve implantation (TAVI) procedure time to investigate the association between surgical team maturity and outcome. Methods: Among patients who underwent TAVI between October 2015 and November 2019, those who had Sapien™ implanted with the transfemoral artery approach were included in the analysis. We used TAVI procedure time and surgery number to draw a learning curve. Then, we divided the patients into two groups before and after the number of cases where the sigmoid curve reaches a plateau. We compared the two groups regarding the surveyed factors and investigated the correlation between the TAVI procedure time and survey factors. Results: Ninety-nine of 149 patients were analysed. The sigmoid curve had an inflection point in 23.2 cases and reached a plateau in 43.0 cases. Patients in the Late group had a shorter operating time, less contrast media, less radiation exposure, and less myocardial escape enzymes than the Early group. Surgical procedure time showed the strongest correlation with the surgical case number. Conclusion: The number of cases required for surgeon proficiency for isolated Sapien™ valve implantation was 43. This number may serve as a guideline for switching the anesthesia management of TAVI from general to local anesthesia. [ABSTRACT FROM AUTHOR]

Background and purpose: Rare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities. Materials and methods: Radiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated. Results: For the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases. Conclusions: Our observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury. [ABSTRACT FROM AUTHOR]

Cancer-related cognitive impairment (CRCI) is a consequence of chemotherapy and extracranial radiation therapy (ECRT). Our prior work demonstrated gliosis in the brain following ECRT in SKH1 mice. The signals that induce gliosis were unclear. Right hindlimb skin from SKH1 mice was treated with 20 Gy or 30 Gy to induce subclinical or clinical dermatitis, respectively. Mice were euthanized at 6 h, 24 h, 5 days, 12 days, and 25 days post irradiation, and the brain, thoracic spinal cord, and skin were collected. The brains were harvested for spatial proteomics, immunohistochemistry, Nanostring nCounter® glial profiling, and neuroinflammation gene panels. The thoracic spinal cords were evaluated by immunohistochemistry. Radiation injury to the skin was evaluated by histology. The genes associated with neurotransmission, glial cell activation, innate immune signaling, cell signal transduction, and cancer were differentially expressed in the brains from mice treated with ECRT compared to the controls. Dose-dependent increases in neuroinflammatory-associated and neurodegenerative-disease-associated proteins were measured in the brains from ECRT-treated mice. Histologic changes in the ECRT-treated mice included acute dermatitis within the irradiated skin of the hindlimb and astrocyte activation within the thoracic spinal cord. Collectively, these findings highlight indirect neuronal transmission and glial cell activation in the pathogenesis of ECRT-related CRCI, providing possible signaling pathways for mitigation strategies. [ABSTRACT FROM AUTHOR]

Aims and Objectives: To assess the effectiveness of different nonpharmacological treatments for severe radiation‐induced oral mucositis in patients with head and neck cancer. Background: Radiation‐induced oral mucositis is highly prevalent in patients with head and neck cancer. Current medications for radiation‐induced oral mucositis are limited in effectiveness and susceptible to side effects, and while there is an increasing adoption of nonpharmacological interventions, the optimal one remains unclear. Design: Systematic review and network meta‐analysis based on the PRISMA‐NMA guidelines. Methods: Six databases were searched. Two authors independently performed the literature screening, data extraction and methodological quality assessment of the included studies. Traditional pairwise meta‐analysis was performed by R Studio. A network meta‐analysis was then conducted to assess the effects of nonpharmacological interventions for severe radiation‐induced oral mucositis in patients with head and neck cancer. Results: Fifty‐two studies involving seven types of nonpharmacological interventions were enrolled. The network meta‐analysis indicated that natural plant‐based therapies might be the most effective, health education interventions might be the second most effective, and honey might be the third most effective interventions for reducing the incidence of severe radiation‐induced oral mucositis. For reducing the incidence of severe oral mucositis‐related pain, the pairwise meta‐analysis showed that only natural plant‐based therapies and health education interventions were effective. Conclusions: Nonpharmacological interventions are effective in the management of severe radiation‐induced oral mucositis among patients with head and neck cancer. Relevance to clinical practice: Nonpharmacological interventions are a category of safe and effective adjunctive therapies that should be encouraged in clinical practice. Trial registration details: CRD42023400745. [ABSTRACT FROM AUTHOR]

The utility of Adaptive Radiotherapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, adequate randomized evidence is lacking. ReSTART (Reducing Salivary Toxicity with Adaptive Radiotherapy) is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiotherapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. Adaptive Radiotherapy arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10th and 20th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over six weeks, along with concurrent chemotherapy. The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months' post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms. The ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint. • The ReSTART, trial, evaluates the efficacy of adaptive radiotherapy in reducing xerostomia for HNSCC. • In the adaptive RT arm, two pre-planned adaptive planning are done at 10 and 20 fractions. • The CTV to PTV margin in the adaptive RT arm is 3 mm. • Primary hypothesis is a 25% benefit of 1-year salivary function, which is assessed by salivary scintigraphy. [ABSTRACT FROM AUTHOR]

For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0–36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7–35.9 Gy). IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial. • The standard tumour bed radiotherapy dose used for neuroblastoma is 21 Gy. • The optimal dose is uncertain, and a higher dose may lead to better local control. • Organ-at-risk tolerance may limit the desired dose to the target volume. • Intensity-modulated arc therapy facilitates better delivery of higher doses. [ABSTRACT FROM AUTHOR]

Key points: Disease severity in acute radiation rhinosinusitis (ARRS) peaks after radiation therapy.ARRS is mainly local inflammation, manifested by increased pro‐inflammatory cytokines.Intranasal corticosteroids are effective anti‐inflammatory drugs in the treatment of ARRS. [ABSTRACT FROM AUTHOR]

In recent years, the intersection of the academic and medical domains has increasingly spotlighted the utilization of biomaterials in radioactive disease treatment and radiation protection. Biomaterials, distinguished from conventional molecular pharmaceuticals, offer a suite of advantages in addressing radiological conditions. These include their superior biological activity, chemical stability, exceptional histocompatibility, and targeted delivery capabilities. This review comprehensively delineates the therapeutic mechanisms employed by various biomaterials in treating radiological afflictions impacting the skin, lungs, gastrointestinal tract, and hematopoietic systems. Significantly, these nanomaterials function not only as efficient drug delivery vehicles but also as protective agents against radiation, mitigating its detrimental effects on the human body. Notably, the strategic amalgamation of specific biomaterials with particular pharmacological agents can lead to a synergistic therapeutic outcome, opening new avenues in the treatment of radiation- induced diseases. However, despite their broad potential applications, the biosafety and clinical efficacy of these biomaterials still require in-depth research and investigation. Ultimately, this review aims to not only bridge the current knowledge gaps in the application of biomaterials for radiation-induced diseases but also to inspire future innovations and research directions in this rapidly evolving field. [Display omitted] [ABSTRACT FROM AUTHOR]

BACKGROUND: The clinical manifestation of acute radiation skin injury is recurrent necrotic ulcers, and its pathogenesis is still not fully understood. The establishment of a suitable animal model will have important clinical implications for the study of its pathogenesis, prevention and treatment. OBJECTIVE: To establish a model of acute β-ray radiation skin injury and to investigate the mechanism of injury. METHODS: Sixty-nine Sprague-Dawley rats were randomly divided into 30, 45, 60 Gy 32P-β-ray groups (n=21 per group) and control group (n=6). A single local irradiation of the back of the rats was performed using 32P radionuclide. The control group was operated in the same way as the irradiated groups except that it was not irradiated. The body mass and skin appearance of the rats were measured at 7, 15, 30, 45, and 60 days after irradiation. Three rats from each group were selected at each observation time point. The skin injury was observed by hematoxylin-eosin staining, Masson staining, transmission electron microscopy, and TUNEL assay. P53, Bcl-2 and Bax protein levels in the skin were measured by immunohistochemistry and western blot assay. RESULTS AND CONCLUSION: There was no accidental death after irradiation, and the body mass of rats showed a gradual increase. The rats showed different degrees of epidermal necrosis, inflammatory cell infiltration, reduction of hair follicles and appendages, and collagen fibrillation, which were evident at 60 and 45 Gy. The levels of serum inflammatory factors, interleukin-6 and tumor necrosis factor-α, were significantly increased in a dose-dependent manner. Under the electron microscope, there are varying degrees of mitochondrial reduction, vacuolization and nuclear pyknosis in the cells. The degree of cell apoptosis showed a certain dose-dependence. Immunohistochemistry and western blot results showed an increase in the expression of P53 and Bax proteins and a decrease in the expression of Bcl-2 protein in the skin after irradiation. There were significant differences between the 60 Gy group and the 45 Gy and 30 Gy groups (P < 0.05). To conclude, irradiation with 60 Gy and 45 Gy 32P radionuclide on the back of rats could successfully establish a practically pre-clinical animal model, and the mechanism is related to the up-regulation of P53 and Bax and the down-regulation of Bcl-2. This model can provide a reference for the establishment of animal models for the study of the mechanism of radiation skin injury and its prevention and treatment. [ABSTRACT FROM AUTHOR]

This document summarizes a study on the role of γδ17 T cells in radiation pneumonitis (RP), a side effect of radiation therapy. The study found that a specific subset of γδ17 T cells interact with neutrophils through the IL17A axis in the late phase of RP. These γδ17 T cells showed a terminally exhausted phenotype and likely expand from tissue-resident memory cells. The study also identified the IL17 response signature as a downstream target of γδ17 T cells and found that neutrophils exhibited the highest IL17 response signature activity. The findings suggest that targeting the γδ17 T/neutrophil axis may be a potential therapeutic approach for RP. The document also provides a summary of the biological process of RP in the early and late phases, highlighting the role of cell death, DAMPs release, neutrophil recruitment, and the activation of γδ17 T cells and mature neutrophils. The study provides insights into RP pathogenesis and suggests new therapeutic avenues. [Extracted from the article]

This research endeavor was undertaken to elucidate the impact of an innovative ascorbate formulation on the regeneration process of full-thickness excision wounds in a rat model exposed to whole-body gamma irradiation, replicating conditions akin to combat or radiation emergency scenarios. We established a comprehensive rat model by optimizing whole body γ-radiation doses (5–9 Gy) and full-thickness excision wound sizes (1–3 cm2) to mimic radiation combined injury (RCI). The developed RCI model was used to explore the healing potential of ascorbate formulation. The study includes various treatment groups (i.e., sham control, radiation alone, wound alone, radiation + wound, and radiation + wound + formulation). The ascorbate formulation was applied twice daily, with a 12-hour gap between each application, starting 1 hour after the initiation of the wound. The healing potential of the formulation in the RCI context was evaluated over 14 days through hematological, molecular, and histological parameters. The combination of a 5 Gy radiation dose and a 1 cm2 wound was identified as the optimal setting to develop the RCI model for subsequent studies. The formulation was used topically immediately following RCI, and then twice daily until complete healing. Treatment with the ascorbate formulation yielded noteworthy outcomes and led to a substantial reduction (p <.05) in the wound area, accelerated epithelialization periods, and an increased wound contraction rate. The formulation's localized healing response improved organ weights, normalized blood parameters, and enhanced hematopoietic and immune systems. A gene expression study revealed the treatment up-regulated TGF-β and FGF, and down-regulated PDGF-α, TNF-α, IL-1β, IL-6, MIP-1α, and MCP-1 (p <.05). Histopathological assessments supported the formulation's effectiveness in restoring cellular architecture and promoting tissue regeneration. Topical application of the ascorbate formulation in RCI resulted in a significant improvement in delayed wound healing, leading to accelerated wound closure by mitigating the expression of inflammatory responses. [ABSTRACT FROM AUTHOR]

Both cutaneous radiation injury and radiation combined injury (RCI) could have serious skin traumas, which are collectively referred to as radiation‐associated skin injuries in this paper. These two types of skin injuries require special managements of wounds, and the therapeutic effects still need to be further improved. Cutaneous radiation injuries are common in both radiotherapy patients and victims of radioactive source accidents, which could lead to skin necrosis and ulcers in serious conditions. At present, there are still many challenges in management of cutaneous radiation injuries including early diagnosis, lesion assessment, and treatment prognosis. Radiation combined injuries are special and important issues in severe nuclear accidents, which often accompanied by serious skin traumas. Mass victims of RCI would be the focus of public health concern. Three‐dimensional (3D) bioprinting, as a versatile and favourable technique, offers effective approaches to fabricate biomimetic architectures with bioactivity, which provides potentials for resolve the challenges in treating radiation‐associated skin injuries. Combining with the cutting‐edge advances in 3D skin bioprinting, the authors analyse the damage characteristics of skin wounds in both cutaneous radiation injury and RCI and look forward to the potential value of 3D skin bioprinting for the treatments of radiation‐associated skin injuries. [ABSTRACT FROM AUTHOR]

Background: Recurrence in glioblastoma lacks a standardized treatment, prompting an exploration of re-irradiation's efficacy. Methods: A comprehensive systematic review from January 2005 to May 2023 assessed the role of MRI sequences in recurrent glioblastoma re-irradiation. The search criteria, employing MeSH terms, targeted English-language, peer-reviewed articles. The inclusion criteria comprised both retrospective and prospective studies, excluding certain types and populations for specificity. The PICO methodology guided data extraction, and the statistical analysis employed Chi-squared tests via MedCalc v22.009. Results: Out of the 355 identified studies, 81 met the criteria, involving 3280 patients across 65 retrospective and 16 prospective studies. The key findings indicate diverse treatment modalities, with linac-based photons predominating. The median age at re-irradiation was 54 years, and the median time interval between radiation courses was 15.5 months. Contrast-enhanced T1-weighted sequences were favored for target delineation, with PET-imaging used in fewer studies. Re-irradiation was generally well tolerated (median G3 adverse events: 3.5%). The clinical outcomes varied, with a median 1-year local control rate of 61% and a median overall survival of 11 months. No significant differences were noted in the G3 toxicity and clinical outcomes based on the MRI sequence preference or PET-based delineation. Conclusions: In the setting of recurrent glioblastoma, contrast-enhanced T1-weighted sequences were preferred for target delineation, allowing clinicians to deliver a safe and effective therapeutic option; amino acid PET imaging may represent a useful device to discriminate radionecrosis from recurrent disease. Future investigations, including the ongoing GLIAA, NOA-10, ARO 2013/1 trial, will aim to refine approaches and standardize methodologies for improved outcomes in recurrent glioblastoma re-irradiation. [ABSTRACT FROM AUTHOR]

Background: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. Methods: C57BL/6J mice (9–14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45−, TER-119−, CD31−) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. Results: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. Conclusions: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS. [ABSTRACT FROM AUTHOR]

Hematopoietic acute radiation syndrome (H-ARS) involves injury to multiple organ systems following total body irradiation (TBI). Our laboratory demonstrated that captopril, an angiotensin-converting enzyme inhibitor, mitigates H-ARS in Göttingen minipigs, with improved survival and hematopoietic recovery, as well as the suppression of acute inflammation. However, the effects of captopril on the gastrointestinal (GI) system after TBI are not well known. We used a Göttingen minipig H-ARS model to investigate captopril's effects on the GI following TBI (60Co 1.79 or 1.80 Gy, 0.42–0.48 Gy/min), with endpoints at 6 or 35 days. The vehicle or captopril (0.96 mg/kg) was administered orally twice daily for 12 days, starting 4 h post-irradiation. Ilea were harvested for histological, protein, and RNA analyses. TBI increased congestion and mucosa erosion and hemorrhage, which were modulated by captopril. GPX-4 and SLC7A11 were downregulated post-irradiation, consistent with ferroptosis at 6 and 35 days post-irradiation in all groups. Interestingly, p21/waf1 increased at 6 days in vehicle-treated but not captopril-treated animals. An RT-qPCR analysis showed that radiation increased the gene expression of inflammatory cytokines IL1B, TNFA, CCL2, IL18, and CXCL8, and the inflammasome component NLRP3. Captopril suppressed radiation-induced IL1B and TNFA. Rectal microbiome analysis showed that 1 day of captopril treatment with radiation decreased overall diversity, with increased Proteobacteria phyla and Escherichia genera. By 6 days, captopril increased the relative abundance of Enterococcus, previously associated with improved H-ARS survival in mice. Our data suggest that captopril mitigates senescence, some inflammation, and microbiome alterations, but not ferroptosis markers in the intestine following TBI. [ABSTRACT FROM AUTHOR]

Objective: This research focuses on the interaction between the circadian clock and the damage caused to testicular tissue by x-ray ionizing radiation. By examining the links between circadian rhythms and radiation-induced testicular damage, a deeper understanding of the underlying mechanisms may emerge, potentially leading to new strategies to mitigate or prevent such damage and its subsequent consequences. Methods: Twenty-four Sprague-Dawley rats were divided into 3 groups. Rats in group 1 (control group) did not undergo any procedures. Rats in group 2 (day) received 6 Gy total body external x-ray radiation in a single fraction between the hours 05:00 and 06:00. Rats in group 3 (night) received 6 Gy total body external x-ray radiation in a single fraction between the hours 19:00 and 20:00. Results: The day group was compared with the control group, and a decrease in spermatogenetic cells and edematous areas was observed. In addition, there was vacuolar accumulation in the cytoplasm of spermatids in the germinal epithelium and necrotic Leydig cells in the intertubular spaces. In the night group, we observed that the changes observed in group 2 were significantly restored. In terminal deoxynucleotide transferase dUTP nick end labeling and 8-hyd roxy- 2’-de oxygu anosi ne immunohistochemical analyses, we observed significantly increased immunopositivity in group 2 compared to the control group and group 3. Conclusion: In conclusion, it reveals that the circadian clock protects against testicular damage caused by x-ray ionizing radiation. By regulating DNA repair processes, antioxidant defense mechanisms, and other important pathways, the circadian clock appears to increase the resistance of testicular tissues to radiation stress. [ABSTRACT FROM AUTHOR]

Introduction: Minimally invasive lumbar decompression (mild®) is becoming a popular procedure for treating lumbar spinal stenosis (LSS) secondary to hypertrophic ligamentum flavum (LF). The mild® procedure is commonly performed under live fluoroscopic guidance and carries a risk of radiation exposure to the patient and healthcare. Methods: One physician performed mild® on 41 patients at the Cleveland Clinic Department of Pain Management from October 2019 to December 2021, while wearing a radiation exposure monitor (Mirion Technologies). Mean fluoroscopy time, mean exposure per case, and mean exposure per unilateral level decompressed were the primary outcomes measured. The secondary outcome was to provide a comparison of radiation exposure during similar fluoroscopically guided procedures. Results: Mean patient fluoroscopy exposure time was 2.1 min ±0.9 (range: 1.1–5.6) fluoroscopy time per unilateral level decompressed. The mean patient radiation skin exposure from mild® was 1.1 ± 0.9 mGym2, and the mean total dose was 142.3 ± 108.6 mGy per procedure. On average, the physician was exposed to an average deep tissue exposure of 4.1 ± 3.2 mRem, 2.9 ± 2.2 mRem estimated eye exposure, and 14.7 ± 11.0 mRem shallow tissue exposure per unilateral level decompressed. An individual physician would exceed the annual exposure limit of 5 Rem after approximately 610 mild® procedures per year. Conclusions: This study is an attempt to quantify the radiation exposure to the physician and patient during the mild® procedure. Compared with other fluoroscopically guided pain management procedures, patient and physician radiation exposure during mild® was low. [ABSTRACT FROM AUTHOR]

Ginseng is an ancient medicinal and edible plant with many health benefits, and can serve as a drug and dietary supplement, but there are few relevant studies on its use to ease ultraviolet (UV) irradiation damage. After 0.8 mg/mL ginseng extract (GE) was added to the medium of female Drosophila melanogaster subjected to UV irradiation, the lifespan, climbing ability, sex ratio, developmental cycle, and antioxidant capacity of flies were examined to evaluate the GE function. In addition, the underlying mechanism by which GE enhances the irradiation tolerance of D. melanogaster was explored. With GE supplementation, female flies subjected to UV irradiation exhibited an extension in their lifespan, enhancement in their climbing ability, improvement in their offspring sex ratio, and restoration of the normal development cycle by increasing their antioxidant activity. Finally, further experiments indicated that GE could enhance the irradiation tolerance of female D. melanogaster by upregulating the gene expressions of SOD, GCL, and components of the autophagy signaling pathway. Finally, the performance of r4-Gal4;UAS-AMPKRNAi flies confirmed the regulatory role of the autophagy signaling pathway in mitigating UV irradiation injury. [ABSTRACT FROM AUTHOR]

Nephrogenic adenoma (NA) is an epithelial lesion that usually occurs in the mucosa of the urinary tract. Rare cases of deep infiltrative or perinephric lesions have also been reported. Recently, NA with characteristic fibromyxoid stroma (fibromyxoid NA) has been proposed as a distinct variant. Although shedding of distal renal tubular cells due to urinary tract rupture has been postulated as the cause of NA in general, the mechanism underlying extraurinary presentation of NA and fibromyxoid stromal change in fibromyxoid NA remains unknown. In this study, we performed mass spectrometry (MS) analysis in a case of perinephric fibromyxoid NA of an 82‐year‐old man who underwent right nephroureterectomy for distal ureteral cancer. The patient had no prior history of urinary tract injury or radiation. Periodic acid‐Schiff staining‐positive eosinophilic structureless deposits in the stroma of fibromyxoid NA were microdissected and subjected to liquid chromatography/MS. The analysis revealed the presence of a substantial amount of uromodulin (Tamm−Horsfall protein). The presence of urinary content in the stroma of perinephric fibromyxoid NA suggests that urinary tract rupture and engraftment of renal tubular epithelial cells directly cause the lesion. [ABSTRACT FROM AUTHOR]

Perioperative high dose rate brachytherapy involves insertion of brachytherapy catheter over the tumor bed during surgical removal of disease followed by radiation in the postoperative period. It has applications in radiotherapy dose escalation or reirradiation and for extending the surgical margins. We report here initial results of treatment in five cases of locally advanced head and neck cancers. [ABSTRACT FROM AUTHOR]

Background: The role of neoadjuvant chemotherapy (NAC) in advanced sigmoid colon carcinoma remains to be further characterized. Rationale for NAC includes downstaging on final pathology and optimization of microscopically negative margins (R0 resection). We investigated rates of neoadjuvant chemotherapy use in advanced sigmoid colon cancer at academic cancer centers and assessed factors associated with likelihood of NAC administration. Methods: The National Cancer Database was queried from 2004 to 2017 for patients with clinical T3 or T4, N0-2, M0 sigmoid colon cancer who underwent surgical resection. Those with neoadjuvant radiation or metastatic disease were excluded. The outcomes of patients who did and did not receive neoadjuvant chemotherapy were evaluated for this retrospective cohort study. Results: There were 23,597 patients of whom 364 (1.5%) received NAC. More patients received NAC at academic (41%, P <.001) and high-volume centers (27%, P <.001). Patients with Medicare/Medicaid (39%) and private insurance (52%) were more likely to receive NAC (P <.001). There was a significantly higher rate of N2 to N1 downstaging in the NAC group. Propensity-score matching demonstrated comprehensive community cancer programs (CCCP) were less likely to provide NAC (OR 0.4; 95% CI 0.23, 0.70, P <.001). There was no difference in survival (P =.20), R0 resection (P =.090), or 30-day readmission rates (P =.30) in the NAC cohort compared to the non-NAC cohort. Conclusions: Access to centers offering multi-disciplinary care with NAC prior to surgical resection is important. This care was associated with academic and high-volume centers and private or government-sponsored insurance. There was no difference in survival between NAC and non-NAC cohort. [ABSTRACT FROM AUTHOR]

Objective: Primary hyperparathyroidism (PHPT) affects approximately 0.86% of the population, with surgical resection as the treatment of choice. A 4D computed tomography (CT) is a highly effective tool in localizing parathyroid adenomas; however, there is currently no defined role for 4D CT when stratified against ultrasonography (USG) and nuclear medicine Technetium Sestamibi SPECT/CT (SES) imaging. Study Design: Retrospective Study. Setting: University Hospital. Methods: All patients who underwent parathyroidectomy for PHPT between 2014 and 2019 at a single institution were reviewed. Patients who had a 4D CT were included. We compared outcomes of 4D CT as a second line imaging modality to those of USG and SES as first line modalities. An imaging algorithm was proposed based on these findings. Results: There were 84 patients identified who had a 4D CT after unsuccessful first line imaging. A 4D CT localized parathyroid adenoma to the correct quadrant in 64% of cases, and to the correct laterality in 75% of cases. Obese patients had significantly lower rates of adenoma localization with USG (33.4%), compared to non-obese patients (67.5%; P =.006). In determining multigland disease the sensitivity of 4D CT was 86%, while the specificity was 87%. Conclusions: A 4D CT has impressive rates of accurate localization of parathyroid adenomas; however due to the radiation exposure involved, it should remain a second line imaging modality. PHPT patients should first be evaluated with USG, with 4D CT used if this is unsuccessful and patients are greater than 40 years old, have a high BMI, or are having revision surgery. [ABSTRACT FROM AUTHOR]

Objective: To explore the protective effect of human urine‐derived stem cell exosomes (hUSC‐Exos) on radiation‐induced salivary gland (SG) injuries in Sprague Dawley rats. Methods: Fresh adult urine was collected, and primary hUSCs were isolated and identified. The hUSCs were hypoxia‐pretreated with 1% oxygen for 24 h and then transferred to a normoxic culture environment for 24 h. The hUSC‐Exos were collected and identified for exosomes. A radiation‐induced injury model was established in the rats, and exosomes were introduced by local injection in the SG and tail vein. The submandibular gland was excised for morphological observation 1 week later. Immunohistochemical detection of the glandular tissue was conducted by α‐smooth muscle actin (a‐SMA), stem cell growth factor receptor (c‐Kit) staining, and periodic acid–Schiff staining. Qualitative polymerase chain reaction and western blot analysis were adopted to detect the gene and protein expression of Wnt3a, GSK3β, and Axin. Results: In both the normoxic and hypoxic hUSC‐Exo groups, microvesicular structures with bilayer membranes of approximately 80 nm in diameter were detected, and the expressions of CD9 and CD63 were detected by nanoflow cytometry. Compared with the control group, in the radiation‐induced injury model group, the expression of a‐SMA was significantly higher, the expression of c‐Kit was significantly lower, and the expressions of Wnt3a, GSK3β, and Axin were significantly upregulated; the differences were statistically significant (p < 0.05). Compared with the model group, in the normoxic and hypoxic hUSC‐Exo groups, the expression of a‐SMA was significantly decreased, the expression of c‐Kit was significantly increased, and the expressions of Wnt3a, GSK3β, and Axin were significantly upregulated; the differences were statistically significant (p < 0.05). Conclusion: Hypoxia‐pretreated hUSC‐Exos could repair radiation‐induced SG injuries by activating the Wnt3a/GSK3β pathway to suppress the expressions of a‐SMA and c‐Kit. [ABSTRACT FROM AUTHOR]

Background: Radiation-induced hyposalivation is a common complication of radiotherapy for head and neck cancers. The most commonly prescribed medication for hyposalivation is pilocarpine. However, due to the numerous systemic side-effects associated with pilocarpine, there has been a proposal to use it as a mouthwash. This study aimed to evaluate the impact of 1% pilocarpine mouthwash on salivary flow in patients with radiation-induced xerostomia. Method: This double-blind, randomized clinical trial involved 63 patients with radiation-induced xerostomia. The patients were randomly allocated into the pilocarpine hydrochloride 1% mouthwash group and the placebo one. Patients were instructed to use these mouthwashes four times a day, with 30 drops each time, for two minutes. Unstimulated saliva production in patients was measured using the spitting method at three stages: two weeks before the commencement of radiotherapy, two weeks after, and four weeks after the completion of radiotherapy. These measurements were then compared between the two groups. Statistical analysis included chi-square, independent t-test, and Analysis of Variance (ANOVA) with repeated measures and the Sidak post hoc test. Statistical analysis was conducted using SPSS 17, and a significance level of P < 0.05 was applied. Results: A comparison of saliva secretion between the pilocarpine mouthwash group and the control group at various time points after radiotherapy revealed that saliva secretion in the control group significantly decreased compared with the pilocarpine mouthwash group (P < 0.001). Conclusion: 1% pilocarpine mouthwash is recommended for managing radiation-induced xerostomia. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic acute radiation syndrome (H-ARS) occurring after exposure to ionizing radiation damages bone marrow causing cytopenias, increasing susceptibility to infections and death. We and others have shown that cellular therapies like human mesenchymal stromal cells (MSCs), or monocytes/macrophages educated ex-vivo with extracellular vesicles (EVs) from MSCs were effective in a lethal H-ARS mouse model. However, given the complexity of generating cellular therapies and the potential risks of using allogeneic products, development of an "off-the-shelf" cell-free alternative like EVs may have utility in conditions like H-ARS that require rapid deployment of available therapeutics. The purpose of this study was to determine the feasibility of producing MSC-derived EVs at large scale using a bioreactor and assess critical quality control attributes like identity, sterility, and potency in educating monocytes and promoting survival in a lethal H-ARS mouse model. Methods: EVs were isolated by ultracentrifugation from unprimed and lipopolysaccharide (LPS)-primed MSCs grown at large scale using a hollow fiber bioreactor and compared to a small scale system using flasks. The physical identity of EVs included a time course assessment of particle diameter, yield, protein content and surface marker profile by flow-cytometry. Comparison of the RNA cargo in EVs was determined by RNA-seq. Capacity of EVs to generate exosome educated monocytes (EEMos) was determined by qPCR and flow cytometry, and potency was assessed in vivo using a lethal ARS model with NSG mice. Results: Physical identity of EVs at both scales were similar but yields by volume were up to 38-fold more using a large-scale bioreactor system. RNA-seq indicated that flask EVs showed upregulated let-7 family and miR-143 micro-RNAs. EEMos educated with LPS-EVs at each scale were similar, showing increased gene expression of IL-6, IDO, FGF-2, IL-7, IL-10, and IL-15 and immunophenotyping consistent with a PD-L1 high, CD16 low, and CD86 low cell surface expression. Treatment with LPS-EVs manufactured at both scales were effective in the ARS model, improving survival and clinical scores through improved hematopoietic recovery. EVs from unprimed MSCs were less effective than LPS-EVs, with flask EVs providing some improved survival while bioreactor EVs provide no survival benefit. Conclusions: LPS-EVs as an effective treatment for H-ARS can be produced using a scale-up development manufacturing process, representing an attractive off-the-shelf, cell-free therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases are common in lung cancer and increasingly treated using targeted stereotactic radiosurgery (SRS). Post-SRS changes (including radionecrosis) may be difficult to distinguish from progressive brain metastasis on MRI. This can have important implications for guiding the most appropriate further management. Contrast clearance analysis (CCA) presents an alternative imaging technique to aid differentiation of progressive tumour from post-treatment changes. In this study, we evaluate the role of CCA, assessing its utility in a real-world setting of patients with NSCLC treated for brain metastases. In particular, we assess the impact of CCA interpretations on treatment decisions and the effects of using this imaging technique with suggestions for best practices. Our experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. Recommendations include the appreciation of a thin rim of rapid contrast clearance, which can be seen in responding tumours, and the importance of the timing of CCA prior to surgery for suspected brain metastasis progression. Background and Objective: Brain metastases are common in lung cancer and increasingly treated using targeted radiotherapy techniques such as stereotactic radiosurgery (SRS). Using MRI, post-SRS changes may be difficult to distinguish from progressive brain metastasis. Contrast clearance analysis (CCA) uses T1-weighted MRI images to assess the clearance of gadolinium and can be thus used to assess vascularity and active tumours. Design and Methods: We retrospectively assessed CCAs in 62 patients with non-small cell lung cancer (NSCLC) undergoing 104 CCA scans in a single centre. Results: The initial CCA suggested the aetiology of equivocal changes on standard MRI in 80.6% of patients. In all patients whose initial CCA showed post-SRS changes and who underwent serial CCAs, the initial diagnosis was upheld with the serial imaging. In only two cases of a presumed progressive tumour on the initial CCA, subsequent treatment for radionecrosis was instigated; a retrospective review and re-evaluation of the CCAs show that progression was reported where a thin rim of rapid contrast clearance was seen, and this finding has been subsequently recognised as a feature of post-treatment change on CCAs. The lack of concordance with CCA findings in those who underwent surgical resection was also found to be due to the over-reporting of the thin blue rim as disease in the early cases of CCA use and, in three cases, potentially related to timelines longer than 7 days prior to surgery, both factors being unknown during the early implementation phase of CCA at our centre but subsequently learned. Conclusions: Our single-centre experience shows CCA to be feasible and useful in patients with NSCLC in cases of diagnostic uncertainty in MRI. It has helped guide treatment in the majority of patients, with subsequent outcomes following the implementation of the treatment based on the results, suggesting correct classification. Recommendations from our experience of the implementation include the careful consideration of the thin rim of the rapid contrast clearance and the timing of the CCA prior to surgery for suspected brain metastasis progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Moderate hypofractionated radiotherapy (MHRT) has emerged as the preferred treatment modality for localized prostate cancer. The aim of this prospective study was to evaluate late rectal toxicity while performing a comprehensive dosimetric analysis in conjunction with rectoscopy results in the setting of MHRT. We confirmed in an homogeneous population (20 patients) that when 3DCRT is employed, delineation of rectal wall and its subsegments can provide a more in depth accurate dosimetric analysis. Furthermore, we identified that dose endpoints V52.17Gy and V56.52Gy, when hypofractionated schedule (2.75 Gy per fraction) is used, may have a significant impact on rectal mucosal injury. Implementing these variables in clinical practice may result in a decrease rate of late rectal toxicity; more data is needed to assist in further validation of this conclusion. Background: Moderate hypofractionated radiotherapy (MHRT) has emerged as the preferred treatment modality for localized prostate cancer based on randomized controlled studies regarding efficacy and toxicity using contemporary radiotherapy techniques. In the setting of MHRT, available data on dosimetric parameters and late rectal toxicity are limited. Aim: To present the effects of MHRT on late rectal toxicity while conducting an extensive dosimetric analysis in conjunction with rectoscopy results. Methods: This is a prospective study including patients with intermediate-risk prostate adenocarcinoma. All patients were treated with MHRT 44 Gy in 16 fractions to the seminal vesicles and to the prostate, followed by a sequential boost to the prostate alone of 16.5 Gy in 6 fractions delivered with three-dimensional conformal radiation therapy (3DCRT). Acute and late toxicity were assessed. Endoscopy was performed at baseline, every 3 months post-therapy for the first year, and every 6 months for the year after. The Vienna Rectoscopy Score (VRS) was used to assess rectal mucosal injury related to radiotherapy. Dosimetric analysis for the rectum, rectal wall, and its subsegments (upper, mid, and low 1/3) was performed. Results: Between September 2015 and December 2019, 20 patients enrolled. Grade 1 late gastrointestinal toxicity occurred in 10% of the patients, whereas 5% had a grade ≥2. Twelve months post radiotherapy: 4 (20%) patients had VRS 1; 2 (10%) patients had VRS 2; 1(5%) patient had VRS 3. 24 months post radiotherapy, VRS 1 was observed in 4 patients (20%) and VRS 2 in 3 (15%) patients. The dosimetric analysis demonstrated noticeable variations between the rectum, rectal wall, and rectal wall subsegments. The dosimetric analysis of the rectum, rectal wall, and its mid and low segments with respect to rectoscopy findings showed that the higher dose endpoints V52.17Gy and V56.52Gy are associated with rectal mucosal injury. Conclusions: A thorough delineation of the rectal wall and its subsegments, together with the dosimetric analysis of these structures, may reduce late rectal toxicity. Dosimetric parameters such as V52.17Gy and V56.52Gy were identified to have a significant impact on rectal mucosal injury; additional dose endpoint validation and its relation to late GI toxicity is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with Hodgkin lymphoma show excellent survival rates, emphasizing the importance of the long-term side effects of the treatment itself. This analysis aims at a cardiopulmonary risk evaluation in the context of radiation treatment for early-stage Hodgkin lymphoma using normal tissue complication probability calculations. Overall, a low cardiopulmonary risk was estimated, not exceeding 2%. Concerning radiation dose, 30 Gy is associated with consistently higher risks as compared to 20 Gy. Further individualization of treatment will be attempted in the future. Purpose: Hodgkin lymphoma is a hematologic malignancy with excellent outcomes even in advanced stages. Consequently, the importance of treatment-associated toxicity increases. However, the exact estimation of individualized rates is difficult due to different disease extents, treatment strategies and techniques. The following analysis aims at a pre-treatment estimation of relevant mediastinal toxicities. Methods: Normal tissue complication probability calculations were used to evaluate the toxicity rates for the heart, lungs and female breast of patients undergoing radiotherapy for early-stage Hodgkin lymphoma. Overall, 45 Patients of the HD16 and HD17 trials by the German Hodgkin study group were included and risks were calculated using the Lyman–Kutcher–Burman model. Results: The median values for pericarditis, pneumonitis and fibrosis of the left or right breast were 0.0%, 0.0%, 0.7% and 0.6% in the HD16 cohort, and 0.0%, 0.1%, 1.1% and 1.0% in the HD17 cohort, respectively. Correspondingly, none of the included patients displayed any of the evaluated toxicities during clinical follow-up. The use of higher doses (30 Gy) in the HD17 cohort led to an increase in toxicity compared to the HD16 cohort (20 Gy). No significant influence of the planning target volume size or the radiation technique could be found in this study. Conclusion: Both the clinically observed and calculated toxicity rates corroborate the overall low-risk profile of radiotherapy for Hodgkin lymphoma. Further treatment individualization will be attempted in the future. [ABSTRACT FROM AUTHOR]

On the one hand, ionizing radiation has been used to treat not only cancer, but also non-cancer diseases. On the other hand, associations with radiation exposure have increasingly been reported not only for cancer, but also non-cancer diseases, both at doses or dose rates much lower than previously suggested or considered. This underscores the need for considering both cancer and non-cancer effects of medical (diagnostic or therapeutic), occupational or environmental exposure to radiation. As such, this Special Issue aims to serve as a forum to gather the latest developments and discuss future prospects in the field of normal tissue responses to radiation exposure. The Special Issue is composed of 18 articles outlining the radiation effects arising in various tissues (e.g., those in the circulatory, sensory, nervous, respiratory, and reproductive systems). [ABSTRACT FROM AUTHOR]

DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure. [ABSTRACT FROM AUTHOR]

Established in 2004, the Radiation and Nuclear Countermeasures Program (RNCP), within the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health has the central mission to advance medical countermeasure mitigators/therapeutics, and biomarkers and technologies to assess, triage, and inform medical management of patients experiencing acute radiation syndrome and/or the delayed effects of acute radiation exposure. The RNCP biodosimetry mission space encompasses: (1) basic research to elucidate novel approaches for rapid and accurate assessment of radiation exposure, (2) studies to support advanced development for US Food and Drug Administration (FDA) clearance of promising triage or treatment devices/approaches, (3) characterization of biomarkers and/or assays to determine degree of tissue or organ dose that can predict outcome of radiation injuries (i.e., organ failure, morbidity, and/or mortality), and (4) outreach efforts to facilitate interactions with researchers developing cutting edge biodosimetry approaches. Thus far, no biodosimetry device has been FDA cleared for use during a radiological/nuclear incident. At NIAID, advancement of radiation biomarkers and biodosimetry approaches is facilitated by a variety of funding mechanisms (grants, contracts, cooperative and interagency agreements, and Small Business Innovation Research awards), with the objective of advancing devices and assays toward clearance, as outlined in the FDA's Radiation Biodosimetry Medical Countermeasure Devices Guidance. The ultimate goal of the RNCP biodosimetry program is to develop and establish accurate and reliable biodosimetry tools that will improve radiation preparedness and ultimately save lives during a radiological or nuclear incident. [ABSTRACT FROM AUTHOR]

As the war in Ukraine progresses, the radiological and nuclear threat has never been as real as now. The formation of life-threatening acute radiation syndrome (ARS), in particular after the deployment of a nuclear weapon or an attack on a nuclear power station, must be considered realistic. ARS is caused by massive cell death, leading to functional organ deficits and, via systemic inflammatory responses, finally aggravates into multiple organ failure. As a deterministic effect, the severity of the disease dictates the clinical outcome. Hence, predicting ARS severity via biodosimetry or alternative approaches appears straightforward. Because the disease occurs delayed, therapy starting as early as possible has the most significant benefit. A clinically relevant diagnosis should be carried out within the diagnostic time window of about 3 days after exposure. Biodosimetry assays providing retrospective dose estimations within this time frame will support medical management decision-making. However, how closely can dose estimates be associated with the later developing ARS severity degrees when considering dose as one among other determinants of radiation exposure and cell death? From a clinical/triage point of view, ARS severity degrees can be further aggregated into unexposed, weakly diseased (no acute health effects expected), and strongly diseased patient groups, with the latter requiring hospitalization as well as an early and intensive treatment. Radiation-induced gene expression (GE) changes occur early after exposure and can be quickly quantified. GE can be used for biodosimetry purposes. Can GE be used to predict later developing ARS severity degrees and allocate individuals to the three clinically relevant groups as well? [ABSTRACT FROM AUTHOR]

Radiation-related normal tissue injury sustained during cancer radiotherapy or in a radiological or mass casualty nuclear incident is a major health concern. Reducing the risk and mitigating consequences of radiation injury could have a broad impact on cancer patients and citizens. Efforts to discover biomarkers that can determine radiation dose, predict tissue damage, and aid medical triage are underway. Exposure to ionizing radiation causes changes in gene, protein, and metabolite expression that needs to be understood to provide a holistic picture for treating acute and chronic radiation-induced toxicities. We present evidence that both RNA (mRNA, microRNA, long noncoding RNA) and metabolomic assays may provide useful biomarkers of radiation injury. RNA markers may provide information on early pathway alterations after radiation injury that can predict damage and implicate downstream targets for mitigation. In contrast, metabolomics is impacted by changes in epigenetics, genetics, and proteomics and can be considered a downstream marker that incorporates all these changes to provide an assessment of what is currently happening within an organ. We highlight research from the past 10 years to understand how biomarkers may be used to improve personalized medicine in cancer therapy and medical decision-making in mass casualty scenarios. [ABSTRACT FROM AUTHOR]

Combined radiation with hemorrhage (combined injury, CI) exacerbates hematopoietic acute radiation syndrome and mortality compared to radiation alone (RI). We evaluated the effects of RI or CI on blood cell depletion as a biomarker to differentiate the two. Male CD2F1 mice were exposed to 8.75 Gy γ-radiation (60Co). Within 2 h of RI, animals were bled under anesthesia 0% (RI) or 20% (CI) of total blood volume. Blood samples were collected at 4–5 h and days 1, 2, 3, 7, and 15 after RI. CI decreased WBC at 4–5 h and continued to decrease it until day 3; counts then stayed at the nadir up to day 15. CI decreased neutrophils, lymphocytes, monocytes, eosinophils, and basophils more than RI on day 1 or day 2. CI decreased RBCs, hemoglobin, and hematocrit on days 7 and 15 more than RI, whereas hemorrhage alone returned to the baseline on days 7 and 15. RBCs depleted after CI faster than post-RI. Hemorrhage alone increased platelet counts on days 2, 3, and 7, which returned to the baseline on day 15. Our data suggest that WBC depletion may be a potential biomarker within 2 days post-RI and post-CI and RBC depletion after 3 days post-RI and post-CI. For hemorrhage alone, neutrophil counts at 4–5 h and platelets for day 2 through day 7 can be used as a tool for confirmation. [ABSTRACT FROM AUTHOR]

Background: Burns are wounds caused by thermal, chemical, electrical, or radiation injuries. They are complex wounds that are difficult to heal and are associated with thousands of deaths each year. Cinnamic acid (CA) is a natural organic compound found in plants, fruits, vegetables, and honey. CA possesses antimicrobial, anti-inflammatory, antioxidant, and wound healing properties. Objectives: The aim of this study was to compare the healing effects of CA with silver sulfadiazine (SSD), a standard topical agent for burn treatment, on deep second-degree burns. Methods: This experimental study compared the healing effects of CA and SSD on second-degree burns. Fifteen New Zealand white rabbits weighing 2 to 2.3 kg were divided into 5 equal groups. Deep second-degree burn wounds were created on the backs of the rabbits by contacting a heated circular metal plate. The first group was treated with SSD 1% cream, the second, third, and fourth groups were treated with prepared ointments containing 0.1%, 0.5%, and 1% w/w of CA in Eucerin, respectively. The fifth group was treated with Eucerin alone. Wound healing effects were assessed by measuring the rate of wound contraction and the amount of collagen in tissue specimens obtained from different groups. Additionally, histopathological studies were performed on tissue samples. Results: The results showed that CA was significantly more effective than SSD in burn wound healing. Cinnamic acid ointments significantly increased the rate of wound contraction (P < 0.05) and tissue collagen content (P < 0.001) compared to SSD and Eucerin. Conclusions: Our findings suggest that topical CA possesses burn wound healing properties and could be used as an effective topical agent for the treatment of burns. [ABSTRACT FROM AUTHOR]

Natural history studies have been informative in dissecting radiation injury, isolating its effects, and compartmentalizing injury based on the extent of exposure and the elapsed time post-irradiation. Although radiation injury models are useful for investigating the mechanism of action in isolated subsyndromes and development of medical countermeasures (MCMs), it is clear that ionizing radiation exposure leads to multi-organ injury (MOI). The Radiation and Nuclear Countermeasures Program within the National Institute of Allergy and Infectious Diseases partnered with the Biomedical Advanced Research and Development Authority to convene a virtual two-day meeting titled 'Radiation-Induced Multi-Organ Injury' on June 7-8, 2022. Invited subject matter experts presented their research findings in MOI, including study of mechanisms and possible MCMs to address complex radiation-induced injuries. This workshop report summarizes key information from each presentation and discussion by the speakers and audience participants. Understanding the mechanisms that lead to radiation-induced MOI is critical to advancing candidate MCMs that could mitigate the injury and reduce associated morbidity and mortality. The observation that some of these mechanisms associated with MOI include systemic injuries, such as inflammation and vascular damage, suggests that MCMs that address systemic pathways could be effective against multiple organ systems. [ABSTRACT FROM AUTHOR]

The growing concern over potential unintended nuclear accidents or malicious activities involving nuclear/radiological devices cannot be overstated. Exposure to whole-body doses of radiation can result in acute radiation syndrome (ARS), colloquially known as "radiation sickness," which can severely damage various organ systems. Long-term health consequences, such as cancer and cardiovascular disease, can develop many years post-exposure. Identifying effective medical countermeasures and devising a strategic medical plan represents an urgent, unmet need. Various clinical studies have investigated the therapeutic use of umbilical cord blood (UCB) for a range of illnesses, including ARS. The objective of this review is to thoroughly discuss ARS and its sub-syndromes, and to highlight recent findings regarding the use of UCB for radiation injury. UCB, a rich source of stem cells, boasts numerous advantages over other stem cell sources, like bone marrow, owing to its ease of collection and relatively low risk of severe graft-versus-host disease. Preclinical studies suggest that treatment with UCB, and often UCB-derived mesenchymal stromal cells (MSCs), results in improved survival, accelerated hematopoietic recovery, reduced gastrointestinal tract damage, and mitigation of radiation-induced pneumonitis and pulmonary fibrosis. Interestingly, recent evidence suggests that UCB-derived exosomes and their microRNAs (miRNAs) might assist in treating radiation-induced damage, largely by inhibiting fibrotic pathways. UCB holds substantial potential as a radiation countermeasure, and future research should focus on establishing treatment parameters for ARS victims. [ABSTRACT FROM AUTHOR]

The Sex Differences in Radiation Research workshop addressed the role of sex as a confounder in radiation research and its implication in real-world radiological and nuclear applications. In April 2022, HHS-wide partners from the Radiation and Nuclear Countermeasures Program, the Office of Research on Women's Health National Institutes of Health Office of Women's Health, U.S. Food and Drug Administration, and the Radiological and Nuclear Countermeasures Branch at the Biomedical Advanced Research and Development Authority conducted a workshop to address the scientific implication and knowledge gaps in understanding sex in basic and translational research. The goals of this workshop were to examine sex differences in 1. Radiation animal models and understand how these may affect radiation medical countermeasure development; 2. Biodosimetry and/or biomarkers used to assess acute radiation syndrome, delayed effects of acute radiation exposure, and/or predict major organ morbidities; 3. medical research that lacks representation from both sexes. In addition, regulatory policies that influence inclusion of women in research, and the gaps that exist in drug development and device clearance were discussed. Finally, real-world sex differences in human health scenarios were also considered. This report provides an overview of the two-day workshop, and open discussion among academic investigators, industry researchers, and U.S. government representatives. This meeting highlighted that current study designs lack the power to determine statistical significance based on sex, and much is unknown about the underlying factors that contribute to these differences. Investigators should accommodate both sexes in all stages of research to ensure that the outcome is robust, reproducible, and accurate, and will benefit public health. [ABSTRACT FROM AUTHOR]

The risk of brain exposure to ionizing radiation increases gradually due to the extensive application of nuclear technology in medical, industrial, and aerospace fields. Radiation-induced brain injury (RBI) is highly likely to cause a wide range of neurological complications, including schizophrenia, Alzheimer's disease (AD), depression. Ginkgolide B (GB) is one of the effective active components extracted from ginkgo biloba leaves, exerts protective effects on CNS, which is involved in the regulation of the Hippo signaling pathway. MST1, as one of the core kinases of the Hippo pathway, participated in regulating cell proliferation, differentiation, and apoptosis. However, it remains unclear whether GB attenuates radiation brain injury (RBI) and whether the radioprotective effect of GB refers to MST1 signaling. Hence, our study aimed to explore the radiation protection effect and the potential mechanism of GB. C57BL/6 mice were stimulated with an X-ray (20 Gy) to establish an RBI model. Then, morris water maze test (MWM) and step-down passive avoidance test (SDPAT) were used to assess the learning and memory function of mice. The open field test (OFT), tail suspension test (TST), and forced swimming test (FST) were used to assess changes in locomotor activity and hopelessness. Besides, X-ray-stimulated SH-SY5Y cells were used to verify the radioprotective effect of GB. Immunofluorescence double staining, Dihydroethidium (DHE), western blot, and flow cytometry were used to explore the role of DCC/MST1 signaling in RBI. In this study, X-ray-treated mice exhibited cognitive impairment and depression-like behavior, which was ameliorated by GB treatment. GB also reduced the ROS production and the number of TUNEL-positive cells in the hippocampus. Moreover, GB increased the protein levels of p-AKT and Bcl2, while decreased the protein levels of MST1, p-p38, p-JNK, cleaved-caspase-3 and Bax both in vivo and in vitro. Additionally, exogenous Netrin-1 alleviated X-ray-induced ROS production and apoptosis, whereas knockout of Netrin-1 receptor DCC abolished the protective effect of GB. Oxidative stress and MST1-mediated neuronal apoptosis participated in radiation-induced cognitive impairment and depression-like behaviors, and modulation of DCC by GB was an effective intervention against RBI. [ABSTRACT FROM AUTHOR]

Objectives: To explore the potential of dynamic contrast-enhanced MRI (DCE-MRI) quantitative parameters in predicting severe acute radiation-induced rectal injury (RRI) in rectal cancer. Methods: This retrospective study enrolled 49 patients with rectal cancer who underwent neoadjuvant chemoradiotherapy and rectal MRI including a DCE-MRI sequence from November 2014 to March 2021. Two radiologists independently measured DCE-MRI quantitative parameters, including the forward volume transfer constant (Ktrans), rate constant (kep), fractional extravascular extracellular space volume (ve), and the thickness of the rectal wall farthest away from the tumor. These parameters were compared between mild and severe acute RRI groups based on histopathological assessment. Receiver operating characteristic curve analysis was performed to analyze statistically significant parameters. Results: Forty-nine patients (mean age, 54 years ± 12 [standard deviation]; 37 men) were enrolled, including 25 patients with severe acute RRI. Ktrans was lower in severe acute RRI group than mild acute RRI group (0.032 min−1 vs 0.054 min−1; p = 0.008), but difference of other parameters (kep, ve and rectal wall thickness) was not significant between these two groups (all p > 0.05). The area under the receiver operating characteristic curve of Ktrans was 0.72 (95% confidence interval: 0.57, 0.84). With a Ktrans cutoff value of 0.047 min−1, the sensitivity and specificity for severe acute RRI prediction were 80% and 54%, respectively. Conclusion: Ktrans demonstrated moderate diagnostic performance in predicting severe acute RRI. Clinical relevance statement: Dynamic contrast-enhanced MRI can provide non-invasive and objective evidence for perioperative management and treatment strategies in rectal cancer patients with acute radiation-induced rectal injury. Key Points: • To our knowledge, this study is the first to evaluate the predictive value of contrast-enhanced MRI (DCE-MRI) quantitative parameters for severe acute radiation-induced rectal injury (RRI) in patients with rectal cancer. • Forward volume transfer constant (Ktrans), derived from DCE-MRI, exhibited moderate diagnostic performance (AUC = 0.72) in predicting severe acute RRI of rectal cancer, with a sensitivity of 80% and specificity of 54%. • DCE-MRI is a promising imaging marker for distinguishing the severity of acute RRI in patients with rectal cancer. [ABSTRACT FROM AUTHOR]

A survey of modern-era field Egyptologists reveals a very high incidence of unusual deaths consistent with symptoms of haematopoietic cancer, a scenario that parallels radiation sickness caused by exposure to abnormally high radiation previously reported in ancient tombs. However, the high radiation in tombs is not explained by the 'natural' background, which is rare in limestone bedrock. Here, re-examination of Egyptian funerary literature reveals reference to saffron cake in portions of 2-3-5 (yellowcake U-235), giving power by means of an invisible 'efflux', and leaving a legacy of hazardous 'excrements' (wastes) which were buried in an underground 'tomb' called the per D'jet (house of millions of years). The ancient curse warned that those who break this tomb shall meet death by a disease that no doctor can diagnose. [ABSTRACT FROM AUTHOR]

Simple Summary: FDG PET-CT scans are critical in detecting metastases during neoadjuvant chemoradiotherapy for esophageal cancer, particularly for potential liver involvement. The liver's proximity to the radiation field in distal esophageal cancer therapies raises the risk of radiation-induced liver damage. Therefore, greater FDG absorption in the liver does not always imply metastases; it could also signal radiation-induced damage, which is a concern for distal esophageal carcinoma therapies in the left hepatic lobe, potentially leading to overstaging. Accordingly, thorough monitoring of FDG activity in the liver is required to reliably distinguish between radiation effects and genuine distant metastases. If FDG activity is seen in the left or caudate liver lobes following CRT, additional diagnostic procedures are demanded to confirm or rule out distant metastases. Surgery, usually scheduled 6–8 weeks after CRT, should be followed by an FDG PET-CT scan to look for new interval metastases, as their existence may prohibit surgical intervention. In patients with esophageal cancer undergoing neoadjuvant chemoradiotherapy (nCRT), subsequent restaging with F-18-fluorodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET-CT) can reveal the presence of interval metastases, such as liver metastases, in approximately 10% of cases. Nevertheless, it is not uncommon in clinical practice to observe focal FDG uptake in the liver that is not associated with liver metastases but rather with radiation-induced liver injury (RILI), which can result in the overstaging of the disease. Liver radiation damage is also a concern during distal esophageal cancer radiotherapy due to its proximity to the left liver lobe, typically included in the radiation field. Post-CRT, if FDG activity appears in the left or caudate liver lobes, a thorough investigation is needed to confirm or rule out distant metastases. The increased FDG uptake in liver lobes post-CRT often presents a diagnostic dilemma. Distinguishing between radiation-induced liver disease and metastasis is vital for appropriate patient management, necessitating a combination of imaging techniques and an understanding of the factors influencing the radiation response. Diagnosis involves identifying new foci of hepatic FDG avidity on PET/CT scans. Geographic regions of hypoattenuation on CT and well-demarcated regions with specific enhancement patterns on contrast-enhanced CT scans and MRI are characteristic of radiation-induced liver disease (RILD). Lack of mass effect on all three modalities (CT, MRI, PET) indicates RILD. Resolution of abnormalities on subsequent examinations also helps in diagnosing RILD. Moreover, it can also help to rule out occult metastases, thereby excluding those patients from further surgery who will not benefit from esophagectomy with curative intent. [ABSTRACT FROM AUTHOR]

Simple Summary: Studies comparing performances of machine learning (ML) methods in building predictive models of toxicity in RT are rare. Thanks to the availability of a large cohort (n = 1314) of breast cancer patients homogeneously treated with tangential fields, different ML approaches could be compared. This work shows how more complex models typically achieve higher performances. At the same time, for this test case, the importance is given mainly by a few variables, and toxicity can be predicted by simpler models with similar performances. The availability of more individually characterizing features (here partially missing) is expected to have a likely much higher impact than the choice of the best-performing ML/DL approach. Purpose. Different ML models were compared to predict toxicity in RT on a large cohort (n = 1314). Methods. The endpoint was RTOG G2/G3 acute toxicity, resulting in 204/1314 patients with the event. The dataset, including 25 clinical, anatomical, and dosimetric features, was split into 984 for training and 330 for internal tests. The dataset was standardized; features with a high p-value at univariate LR and with Spearman ρ > 0.8 were excluded; synthesized data of the minority were generated to compensate for class imbalance. Twelve ML methods were considered. Model optimization and sequential backward selection were run to choose the best models with a parsimonious feature number. Finally, feature importance was derived for every model. Results. The model's performance was compared on a training–test dataset over different metrics: the best performance model was LightGBM. Logistic regression with three variables (LR3) selected via bootstrapping showed performances similar to the best-performing models. The AUC of test data is slightly above 0.65 for the best models (highest value: 0.662 with LightGBM). Conclusions. No model performed the best for all metrics: more complex ML models had better performances; however, models with just three features showed performances comparable to the best models using many (n = 13–19) features. [ABSTRACT FROM AUTHOR]

Simple Summary: Although Warthin's tumor is a well-known and frequent tumor in the salivary gland, its pathogenesis is not fully understood. Warthin's tumor is composed of oncocytic epithelial cells lining papillary and cystic structures in a lymphoid stroma. Previously several hypotheses have been postulated. The risk factors for its development are known and they include aging, smoking, and radiation exposure. Recent findings have suggested that chronic inflammation and aging cells promote the growth of Warthin's tumor. In this short review, we propose that DNA dame, metabolic dysfunction of mitochondria, senescence-associated secretory phenotype, human papillomavirus, and IgG-4 may be involved in the development of Warthin's tumor. Warthin's tumor is the second most frequent neoplasm next to pleomorphic adenoma in the salivary gland, mostly in the parotid gland. The epithelial cells constituting a tumor are characterized by the presence of mitochondria that undergo structural and functional changes, resulting in the development of oncocytes. In addition to containing epithelial cells, Warthin's tumors contain abundant lymphocytes with lymph follicles (germinal centers) that are surrounded by epithelial cells. The pathogenesis of Warthin's tumor is not fully understood, and several hypotheses have been proposed. The risk factors for the development of Warthin's tumor, which predominantly occurs in males, include aging, smoking, and radiation exposure. Recently, it has been reported that chronic inflammation and aging cells promote the growth of Warthin's tumor. Several reports regarding the origin of the tumor have suggested that (1) Warthin's tumor is an IgG4-related disease, (2) epithelial cells that compose Warthin's tumor accumulate mitochondria, and (3) Warthin's tumor is a metaplastic lesion in the lymph nodes. It is possible that the pathogenesis of Warthin's tumor includes mitochondrial metabolic abnormalities, accumulation of aged cells, chronic inflammation, and senescence-associated secretory phenotype (SASP). In this short review, we propose that DNA damage, metabolic dysfunction of mitochondria, senescent cells, SASP, human papillomavirus, and IgG4 may be involved in the development of Warthin's tumor. [ABSTRACT FROM AUTHOR]

Although Fanconi anemia patients accompany a high risk of multiple cancers, radiation therapy on these patients has been carried out only in limited cases due to the concern for radiation toxicity that stems from their susceptibility to radiation. We report a case of a 28-year-old female patient diagnosed as synchronous esophageal and tongue cancer, and underwent two cycles of radiation therapy, inevitably in the condition of coronavirus disease 2019 infection. She received radiation therapy of 30 Gy to esophageal mass with neoadjuvant aim in her first-round radiation therapy, and later received 27 Gy to tongue cancer surgical bed with adjuvant aim in her second-round radiation therapy. With no further treatment, she has been maintaining no evidence of disease state for 7 months. Managing Fanconi anemia patients with multiple cancers using radiation therapy is feasible, in which cases a dose de-escalation may be important considering the radiation toxicity and possible future re-treatment. [ABSTRACT FROM AUTHOR]