Radiation Toxicity Research Articles

Customised weight-based volume contrast media protocol for multiphase abdominal computed tomography.

Multiphase computed tomography (CT) using fixed volume contrast media may lead to high radiation exposure and toxicity in patients with low body weight. We evaluated a customised weight-based protocol for multiphase CT in terms of radiation exposure, image quality and cost savings. A total of 224 patients were recruited. An optimised CT protocol was applied using 100 kV and 1 mL/kg of contrast media dosing. The image quality and radiation dose exposure of this CT protocol were compared to those of a standard 120 kV, 80 mL fixed volume protocol. The radiation dose information and CT Hounsfield units were recorded. The signal-to-noise ratio, contrast-to-noise ratio (CNR) and figure of merit (FOM) were used as comparison metrics. The images were assessed for contrast opacification and visual quality by two radiologists. The renal function, contrast media volume and cost were also evaluated. The median effective dose was lowered by 16% in the optimised protocol, while the arterial phase images achieved significantly higher CNR and FOM. The radiologists' evaluation showed more than 97% absolute agreement with no significant differences in image quality. No significant differences were found in the pre- and post-CT estimated glomerular filtration rate. However, contrast media usage was significantly reduced by 1,680 mL, with an overall cost savings of USD 421 in the optimised protocol. The optimised weight-based protocol is cost-efficient and lowers radiation dose while maintaining overall contrast enhancement and image quality.

Fecal bacteria-free filtrate transplantation is proved as an effective way for the recovery of radiation-induced individuals in mice.

Ionizing radiation can cause intestinal microecological dysbiosis, resulting in changes in the composition and function of gut microbiota. Altered gut microbiota is closely related to the development and progression of radiation-induced intestinal damage. Although microbiota-oriented therapeutic options such as fecal microbiota transplantation (FMT) have shown some efficacy in treating radiation toxicity, safety concerns endure. Therefore, fecal bacteria-free filtrate transplantation (FFT), which has the potential to become a possible alternative therapy, is well worth investigating. Herein, we performed FFT in a mouse model of radiation exposure and monitored its effects on radiation damage phenotypes, gut microbiota, and metabolomic profiles to assess the effectiveness of FFT as an alternative therapy to FMT safety concerns. FFT treatment conferred radioprotection against radiation-induced toxicity, representing as better intestinal integrity, robust proinflammatory and anti-inflammatory cytokines homeostasis, and accompanied by significant shifts in gut microbiome. The bacterial compartment of recipients following FFT was characterized by an enrichment of radioprotective microorganisms (members of family Lachnospiraceae). Furthermore, metabolome data revealed increased levels of microbially generated short-chain fatty acids (SCFAs) in the feces of FFT mice. FFT improves radiation-induced intestinal microecological dysbiosis by reshaping intestinal mucosal barrier function, gut microbiota configurations, and host metabolic profiles, highlighting FFT regimen as a promising safe alternative therapy for FMT is effective in the treatment of radiation intestinal injury.

Metabolomic Profiles in Tissues of Nonhuman Primates Exposed to Either Total- or Partial-Body Radiation.

A complex cascade of systemic and tissue-specific responses induced by exposure to ionizing radiation can lead to functional impairment over time in the surviving population. Current methods for management of survivors of unintentional radiation exposure episodes rely on monitoring individuals over time for the development of adverse clinical symptoms due to the lack of predictive biomarkers for tissue injury. In this study, we report on changes in metabolomic and lipidomic profiles in multiple tissues of nonhuman primates (NHPs) that received either 4.0 Gy or 5.8 Gy total-body irradiation (TBI) of 60Co gamma rays, and 4.0 or 5.8 Gy partial-body irradiation (PBI) from LINAC-derived photons and were treated with a promising radiation countermeasure, gamma-tocotrienol (GT3). These include small molecule alterations that correlate with radiation effects in the jejunum, lung, kidney, and spleen of animals that either survived or succumbed to radiation toxicities over a 30-day period. Radiation-induced metabolic changes in tissues were observed in animals exposed to both doses and types of radiation, but were partially alleviated in GT3-treated and irradiated animals, with lung and spleen being most responsive. The majority of the pathways protected by GT3 treatment in these tissues were related to glucose metabolism, inflammation, and aldarate metabolism, suggesting GT3 may exert radioprotective effects in part by sparing these pathways from radiation-induced dysregulation. Taken together, the results of our study demonstrate that the prophylactic administration of GT3 results in metabolic and lipidomic shifts that likely provide an overall advantage against radiation injury. This investigation is among the first to highlight the use of a molecular phenotyping approach in a highly translatable NHP model of partial- and total-body irradiation to determine the underlying physiological mechanisms involved in the radioprotective efficacy of GT3.

More than one way to skin a dose volume: the impact of dose-surface map calculation approach on study reproducibility

Objective. Dose-surface maps (DSMs) provide spatial representations of the radiation dose to organ surfaces during radiotherapy and are a valuable tool for identifying dose deposition patterns that are predictive of radiation toxicities. Over the years, many different DSM calculation approaches have been introduced and used in dose-outcome studies. However, little consideration has been given to how these calculation approaches may be impacting the reproducibility of studies in the field. Therefore, we conducted an investigation to determine the level of equivalence of DSMs calculated with different approaches and their subsequent impact on study results. Approach. Rectum and bladder DSMs were calculated for 20 prostate radiotherapy patients using combinations of the most common slice orientation and spacing styles in the literature. Equivalence of differently calculated DSMs was evaluated using pixel-wise comparisons and DSM features (rectum only). Finally, mock cohort comparison studies were conducted with DSMs calculated using each approach to determine the level of dosimetric study reproducibility between calculation approaches. Main results. We found that rectum DSMs calculated using the planar and non-coplanar orientation styles were non-equivalent in the posterior rectal region and that equivalence of DSMs calculated with different slice spacing styles was conditional on the choice of inter-slice distance used. DSM features were highly sensitive to choice of slice orientation style and DSM sampling resolution. Finally, while general result trends were consistent between the comparison studies performed using different DSMs, statisitically significant subregions and features could vary greatly in position and magnitude. Significance. We have determined that DSMs calculated with different calculation approaches are frequently non-equivalent and can lead to differing conclusions between studies performed using the same dataset. We recommend that the DSM research community work to establish consensus calculation approaches to ensure reproducibility within the field.

Consolidative thoracic radiation therapy for extensive-stage small cell lung cancer in the era of first-line chemoimmunotherapy: preclinical data and a retrospective study in Southern Italy.

Consolidative thoracic radiotherapy (TRT) has been commonly used in the management of extensive-stage small cell lung cancer (ES-SCLC). Nevertheless, phase III trials exploring first-line chemoimmunotherapy have excluded this treatment approach. However, there is a strong biological rationale to support the use of radiotherapy (RT) as a boost to sustain anti-tumor immune responses. Currently, the benefit of TRT after chemoimmunotherapy remains unclear. The present report describes the real-world experiences of 120 patients with ES-SCLC treated with different chemoimmunotherapy combinations. Preclinical data supporting the hypothesis of anti-tumor immune responses induced by RT are also presented. A total of 120 ES-SCLC patients treated with chemoimmunotherapy since 2019 in the South of Italy were retrospectively analyzed. None of the patients included in the analysis experienced disease progression after undergoing first-line chemoimmunotherapy. Of these, 59 patients underwent TRT after a multidisciplinary decision by the treatment team. Patient characteristics, chemoimmunotherapy schedule, and timing of TRT onset were assessed. Safety served as the primary endpoint, while efficacy measured in terms of overall survival (OS) and progression-free survival (PFS) was used as the secondary endpoint. Immune pathway activation induced by RT in SCLC cells was explored to investigate the biological rationale for combining RT and immunotherapy. Preclinical data supported the activation of innate immune pathways, including the STimulator of INterferon pathway (STING), gamma-interferon-inducible protein (IFI-16), and mitochondrial antiviral-signaling protein (MAVS) related to DNA and RNA release. Clinical data showed that TRT was associated with a good safety profile. Of the 59 patients treated with TRT, only 10% experienced radiation toxicity, while no ≥ G3 radiation-induced adverse events occurred. The median time for TRT onset after cycles of chemoimmunotherapy was 62 days. Total radiation dose and fraction dose of TRT include from 30 Gy in 10 fractions, up to definitive dose in selected patients. Consolidative TRT was associated with a significantly longer PFS than systemic therapy alone (one-year PFS of 61% vs. 31%, p<0.001), with a trend toward improved OS (one-year OS of 80% vs. 61%, p=0.027). Multi-center data from establishments in the South of Italy provide a general confidence in using TRT as a consolidative strategy after chemoimmunotherapy. Considering the limits of a restrospective analysis, these preliminary results support the feasibility of the approach and encourage a prospective evaluation.

Lead-Free Double Perovskites: A Review of the Structural, Optoelectronic, Mechanical, and Thermoelectric Properties Derived from First-Principles Calculations, and Materials Design Applicable for Pedagogical Purposes

Metal halide perovskite materials have shown significant advancements in their application as light absorbers in perovskite solar cells, with power conversion efficiencies reaching 27%. However, lead-based perovskites pose a concern due to their toxicity and stability issues in moisture, UV radiation, and heat. This has led to a pressing need to explore substitute materials that do not contain lead but maintain the remarkable characteristics of lead-based perovskites. This review article focuses on halide double perovskites characterised by the A2B’B”X6 composition, highlighting their structural, optical, thermoelectric, and mechanical capabilities. Additionally, the review evaluates several materials databases to investigate materials suitable for high-throughput first-principles calculations integrated inside density functional theory. The review aims to identify novel perovskite materials, offer a thorough evaluation of the potential benefits and drawbacks associated with this class of materials, and, from the pedagogical standpoint, discover effective instructional frameworks.

Transcriptional Inflammatory Signature in Healthy Donors and Different Radiotherapy Cancer Patients.

Cancer and ionizing radiation exposure are associated with inflammation. To identify a set of radiation-specific signatures of inflammation-associated genes in the blood of partially exposed radiotherapy patients, differential expression of 249 inflammatory genes was analyzed in blood samples from cancer patients and healthy individuals. The gene expression analysis on a cohort of 63 cancer patients (endometrial, head and neck, and prostate cancer) before and during radiotherapy (24 h, 48 h, ~1 week, ~4-8 weeks, and 1 month after the last fraction) identified 31 genes and 15 up- and 16 down-regulated genes. Transcription variability under normal conditions was determined using blood drawn on three separate occasions from four healthy donors. No difference in inflammatory expression between healthy donors and cancer patients could be detected prior to radiotherapy. Remarkably, repeated sampling of healthy donors revealed an individual endogenous inflammatory signature. Next, the potential confounding effect of concomitant inflammation was studied in the blood of seven healthy donors taken before and 24 h after a flu vaccine or ex vivo LPS (lipopolysaccharide) treatment; flu vaccination was not detected at the transcriptional level and LPS did not have any effect on the radiation-induced signature identified. Finally, we identified a radiation-specific signature of 31 genes in the blood of radiotherapy patients that were common for all cancers, regardless of the immune status of patients. Confirmation via MQRT-PCR was obtained for BCL6, MYD88, MYC, IL7, CCR4 and CCR7. This study offers the foundation for future research on biomarkers of radiation exposure, radiation sensitivity, and radiation toxicity for personalized radiotherapy treatment.

The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.

AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.

Concurrent Olaparib and Radiation Therapy in Older Patients With Newly Diagnosed Glioblastoma: The Phase 1 Dose-Escalation PARADIGM Trial

Background: Patients with glioblastoma who are elderly or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiotherapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. Methods: Phase I of the PARADIGM trial was a 3+3 dose escalation study testing olaparib in combination with radiotherapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 or over (WHO PS 0-1) or aged 18-69 with PS 2. The primary outcome was the recommended phase 2 dose (RP2D) of olaparib. Secondary endpoints included safety and tolerability, overall survival (OS) and progression free survival (PFS). Effects on cognitive function were assessed by mini-mental state examination (MMSE). Results: Of 16 eligible patients (56.25% male, median age 71.5 [range 44-78 years], 75% PS 0-1), one dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the RP2D was determined as 200 mg twice daily. Median OS and PFS were 10.8 months (80% CI: 7.3-11.4) and 5.5 months (80% CI: 3.9-5.9) respectively. MMSE plots indicated that cognitive function was not adversely affected by the olaparib-radiotherapy combination. Conclusions: Olaparib can be safely combined with hypofractionated brain radiotherapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomised phase II study and support future trials of PARP inhibitors in combination with radiotherapy for patients with brain tumors.

Abstract IA006: Multifaceted effects of DNA damage response inhibitors on radiation responses of glioblastoma and the normal brain

Abstract PARP inhibitors (PARPi) and ATM inhibitors (ATMi) enhance radiation sensitivity in multiple cancer models, both in vitro and in vivo. Our observation that the radiosensitizing properties of PARPi are most pronounced in rapidly proliferating cells is reflected in early phase clinical trial data showing exacerbation of acute radiation toxicity in rapidly proliferating tissues such as oropharyngeal and esophageal mucosa. Lack of radiosensitization in late responding, slowly proliferating normal tissues indicates that PARPi may be more effectively combined with radiation therapy (RT) in patients with brain tumors. ATMi are much more potent radiosensitizers than PARPi but less is known about their impact on normal tissue toxicity since they have only recently progressed to the clinic, although preclinical in vivo data are encouraging. We are evaluating the oral PARPi olaparib and the oral ATMi AZD1390 in combination with RT +/- temozolomide (TMZ) in the treatment of glioblastoma (GBM), the most prevalent and most aggressive primary brain tumor. Patients with GBM experience very poor outcomes in terms of both median survival (c.1 year) and neurocognitive decline, which is caused primarily by RT. Early phase testing of the olaparib-RT combination is underway in three populations of patients with newly diagnosed GBM. Patients aged &amp;gt;65 with MGMT unmethylated GBM are being recruited to a randomized, placebo-controlled phase II study (PARADIGM, ISRCTN52658296) after a phase I dose escalation study showed that olaparib (200 mg twice daily) was extremely well tolerated when combined with brain irradiation (40 Gray in 15#). Good performance status patients aged under 70 are being recruited to PARADIGM-2 (ISRCTN51253312) which comprises two parallel phase I dose escalation studies: patients with MGMT unmethylated tumors are receiving daily olaparib with RT (60 Gy in 30#) without TMZ, while patients with MGMT methylated tumors are receiving intermittent olaparib with standard chemoradiation. AZD1390 is being evaluated in a first-in-human phase I dose escalation study (NCT03423628) in combination with re-irradiation (35 Gy in 10#) in patients with recurrent GBM, and with first-line radical radiotherapy (60 Gy in 30#) in patients with newly diagnosed, MGMT unmethylated GBM. In parallel, we are undertaking preclinical studies to investigate the impact of PARPi and ATMi on RT induced neurotoxicity. In vivo imaging studies support the emerging concept that RT induced neuroinflammation is important in the pathogenesis of neurotoxicity, and we have generated preliminary behavioral data indicating that both PARPi and ATMi can alleviate the neurotoxic effects of RT. Ongoing experiments are defining the roles of microglia, astrocytes and neurogenesis in this phenomenon. We will present these diverse datasets in the context of our hypothesis that combining PARPi or ATMi with RT has potential to improve outcomes for GBM patients by enhancing tumor control while simultaneously suppressing neuroinflammation and alleviating RT related neurocognitive decline. Citation Format: Anthony J. Chalmers. Multifaceted effects of DNA damage response inhibitors on radiation responses of glioblastoma and the normal brain [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA006.

Bis(1-methylimidazol-2-yl) diselenide and its evaluation as a chemical radio-protector: role of kinetic rate constants for ROS scavenging and glutathione peroxidase like activity

Bis(1-methylimidazol-2-yl) diselenide (MeImSe), a derivative of selenoneine, has been examined for bimolecular rate constants for scavenging of various radiolytically and non-radiolytically generated reactive oxygen species (ROS). Further, its potential to show glutathione peroxidase (GPx)-like activity and to protect in vitro models of DNA and lipid against radiation induced strand breakage and lipid peroxidation, respectively were studied. The results confirmed that MeImSe scavenged all major short-lived (hydroxyl radical) and long-lived (peroxyl radical, carbonate radical, nitrogen dioxide radical, hypochlorite and hydrogen peroxide) oxidants involved in the radiation toxicity either directly or through GPx-like catalytic mechanism. The rate constants of MeImSe for these oxidants were found to be comparable to analogous sulfur and selenium-based compounds. The enzyme kinetics study established that MeImSe took part in the GPx cycle through the reductive pathway. Further, MeImSe inhibited the radiation induced DNA strand cleavage and lipid peroxidation with half maximal inhibitory concentration (IC50) of ∼ 60 μM and ∼100 μM, respectively. Interestingly, MeImSe treatment in the above concentration range (>100 μM) did not show any significant toxicity in normal human lung fibroblast (WI26) cells. The balance between efficacy and toxicity of MeImSe as a chemical radioprotector was attributed to the formation of less reactive intermediates during its oxidation/reduction reactions as evidenced from NMR studies. Highlights MeImSe, a derivative of selenoneine protects DNA and lipid from radiation damage MeImSe scavenges all major short- and long-lived oxidants involved in radiation toxicity Rate constants of MeImSe for ROS scavenging determined by pulse radiolysis technique First organoselenium compound reported to scavenge nitrogen dioxide radical MeImSe exhibits GPx-like activity through reductive pathway

Veza između nivoa citokina u serumu i razvoja akutne radijacione toksičnosti kod pacijenata sa karcinomom prostate

Radiotherapy plays a significant role in the multidisciplinary approach to treating prostate cancer patients. However, some of these patients may develop severe adverse effects after receiving radiotherapy that negatively affect their quality of life. Radiotoxicity may manifest in the lower gastrointestinal (GI) tract by damaging the rectum or bowel, or genitourinary (GU) tract, causing symptoms due to urethral, bladder or prostate damage. The probability of complications in normal tissue increases as the delivered radiation dose increases. However, there are patients with satisfactory dosimetric parameters who develop radiation toxicity and vice versa. Prediction models that take into account additional parameters to identify patients most susceptible to developing toxicity may serve as essential factors toward personalized radiotherapy. The main objectives are morbidity reduction and life-quality improvement. Changes in the cytokine levels could also be connected with the occurrence of acute gastrointestinal and genitourinary toxicity. Literature data indicate the association of numerous cytokines with the appearance of GI and GU toxicity. There is proof that TGF-b1 stimulates fibroblasts to generate extracellular matrix. According to the literature, IL-6 is regarded as one of the most important immune markers for predicting the radiotherapy-induced toxicity of normal tissues. Increased IL-6 concentrations in the serum during radiotherapy are significantly linked to a higher degree of acute genitourinary toxicity. The goal of this work is to summarize the results of contemporary research in which the connection between the occurrence of acute radiation toxicity and changes in the cytokines levels in the serum during radiotherapy were examined, considering the great future potential of the use of toxicity prediction factors in clinical practice. It can be concluded that radiation therapy, the development of an inflammatory process, and the occurrence of radiation toxicity are all related. However, further research with the aim of adequate stratification of patients for the development of an individualized approach to radiotherapy is required.

Genetic profiling in radiotherapy: a comprehensive review.

This comprehensive review explores the pivotal role of radiotherapy in cancer treatment, emphasizing the diverse applications of genetic profiling. The review highlights genetic markers for predicting radiation toxicity, enabling personalized treatment planning. It delves into the impact of genetic profiling on radiotherapy strategies across various cancer types, discussing research findings related to treatment response, prognosis, and therapeutic resistance. The integration of genetic profiling is shown to transform cancer treatment paradigms, offering insights into personalized radiotherapy regimens and guiding decisions in cases where standard protocols may fall short. Ultimately, the review underscores the potential of genetic profiling to enhance patient outcomes and advance precision medicine in oncology.

Examining patient-reported late toxicity and its association with quality of life and unmet need for symptom management among nasopharyngeal cancer survivors: a cross-sectional survey.

Alongside the improved survival of nasopharyngeal cancer (NPC), late radiation toxicities are alarmingly hampering survivors' quality of life. A patient-reported symptom burden survey is lacking to address the unmet need for symptom management among local NPC survivors. A single-center cross-sectional survey was conducted on 211 NPC survivors who had completed radiation therapy for three to 120 months. We employed the Chinese version M. D. Anderson Symptom Inventory - Head & Neck Module (MDASI-HN-C), Functional Assessment of Cancer Therapy - Head & Neck (FACT-HN-C), and a question extracted from the Cancer Survivors' Unmet Needs Measure (CaSUN). Two hundred valid responses were collected. Participants suffered from at least four moderate to severe symptoms (mean = 4.84, SD = 4.99). The top five severe symptoms were dry mouth, mucus problems, difficulty swallowing or chewing, teeth or gum problems, and memory problems. MDASI-HN-C subscales were negatively correlated with the physical, emotional, functional, and HN-specific domains of the FACT-HN-C. The unmet need for symptom management was positively associated with symptom burden, either general symptoms (Adjusted odds ratio [ORadj] = 1.566, 95% CI = 1.282 - 1.914, p < 0.001) or top-5 symptoms (ORadj = 1.379, 95% CI = 1.185 - 1.604, p < 0.001), while negatively associated with post-RT time (ORadj = 0.981, 95% CI [0.972, 0.991], p < 0.001). Virtually all NPC survivors suffer from late toxicities, which interplay with survivors' perceptions intricately to affect their unmet needs for symptom management. Personalized supportive care strategies with regular assessments and stratifications are warranted.

Features of using CT and MRI in planning radiation therapy in patients with squamous cell carcinoma of the head and neck

Background. Squamous cell carcinoma of the head and neck (SCCHN) holds a significant position in global oncology. The quality of radiotherapy greatly depends on the accuracy of diagnostic procedures and radiation dosing, as even a minor increase in radiation volume can significantly raise the risk of radiation toxicity. Modern visualization methods and dose calculation algorithms are key in ensuring treatment effectiveness and reducing side effects, thereby improving patients’ quality of life. Purpose. To enhance the effectiveness of radiotherapy for SCCHN through the optimization of topometric preparation using modern visualization methods. Materials and Methods. The study was conducted at the State of Organization «Grigoriev Institute for Medical Radiology and Oncology of the National Academy of Medical Sciences of Ukraine», from January 2020 to October 2022. The study group comprised 41 cases where radiotherapy planning was performed using both CT and MRI. The comparison group included 64 cases using only CT. Radiation planning was carried out on TPS Eclipse, and irradiation was performed on a Clinac 600C linear accelerator in a classical fractionation mode with a daily dose of 2 Gy to a total dose of 66–70 Gy. Results. The clinical effectiveness of radiotherapy was not dependent on the method of planning, and a reduction in radiation volume by 11% using MRI did not affect the outcomes. It was noted that the development of grade III radiation dermatitis in patients with stage III–IV SCCHN was 2.4 times higher when using only CT compared to using both CT and MRI, which is thought to be due to a larger radiation volume. Grade III radiation mucositis was observed 2.25 times more frequently in the comparison group than in the study group. In patients with stage I–II SCCHN, there was no significant difference in effectiveness and toxicity, hence the use of MRI at these stages is not justified. Conclusions. It is necessary to use MRI with CT for planning radiotherapy in patients with stage III–IV SCCHN. This reduces the risk of grade III radiation dermatitis and mucositis compared to using only CT. For planning radiotherapy in patients with stage I–II disease, the use of CT alone is sufficient.

LGR5+ Intestinal Stem Cells Display Sex-Dependent Radiosensitivity.

Tissue radiosensitivity plays a critical role in the overall outcome of radiation therapy. Identifying characteristics that predict how a patient may respond to radiotherapy enables clinicians to maximize the therapeutic window. Limited clinical data have suggested a difference in male and female radiotherapy outcomes. Radiotherapy for gastrointestinal malignancy is still a challenge due to intestinal sensitivity to radiation toxicity. In this manuscript, we demonstrated sex-specific differences in intestinal epithelial radiosensitivity. In a mouse model of abdominal irradiation, we observed a significant increase in oxidative stress and injury in males compared to females. Lgr5+ve intestinal stem cells from male mice showed higher sensitivity to radiation-induced toxicity. However, sex-specific differences in intestinal radiosensitivity were not dependent on sex hormones, as we demonstrated similar sex-specific radiosensitivity differences in pre-pubescent mice. In an ex vivo study, we found that patient-derived intestinal organoid (PID) from males showed higher sensitivity to radiation compared to females as evident from loss of budding crypts, organoid size, and membrane integrity. Transcriptomic analysis of human Lgr5+ intestinal stem cells suggested radiation-induced upregulation of mitochondrial oxidative metabolism in males compared to females, a possible mechanism for radiosensitivity differences.

Repurposing of FDA approved kinase inhibitor bosutinib for mitigation of radiation induced damage via inhibition of JNK pathway

Radiotherapy is a common modality for cancer treatment. However, it is often associated with normal tissue toxicity in 20–80% of the patients. Radioprotectors can improve the outcome of radiotherapy by selectively protecting normal cells against radiation toxicity. In the present study, compound libraries containing 54 kinase inhibitors and 80 FDA-approved drugs were screened for radioprotection of lymphocytes using high throughput cell analysis. A second-generation FDA-approved kinase inhibitor, bosutinib, was identified as a potential radioprotector for normal cells. The radioprotective efficacy of bosutinib was evinced from a reduction in radiation induced DNA damage, caspase-3 activation, DNA fragmentation and apoptosis. Oral administration of bosutinib protected mice against whole body irradiation (WBI) induced morbidity and mortality. Bosutinib also reduced radiation induced bone-marrow aplasia and hematopoietic damage in mice exposed to 4 Gy and 6 Gy dose of WBI. Mechanistic studies revealed that the radioprotective action of bosutinib involved interaction with cellular thiols and modulation of JNK pathway. The addition of glutathione and N-acetyl cysteine significantly reduced the radioprotective efficacy of bosutinib. Moreover, bosutinib did not protect cancer cells against radiation induced toxicity. On the contrary, bosutinib per se exhibited anticancer activity against human cancer cell lines. The results highlight possible use of bosutinib as a repurposable radioprotective agent for mitigation of radiation toxicity in cancer patients undergoing radiotherapy.

Deep Learning Based on EfficientNet for Multiorgan Segmentation of Thoracic Structures on a 0.35 T MR-Linac Radiation Therapy System

The advent of the 0.35 T MR-Linac (MRIdian, ViewRay) system in radiation therapy allows precise tumor targeting for moving lesions. However, the lack of an automatic volume segmentation function in the MR-Linac’s treatment planning system poses a challenge. In this paper, we propose a deep-learning-based multiorgan segmentation approach for the thoracic region, using EfficientNet as the backbone for the network architecture. The objectives of this approach include accurate segmentation of critical organs, such as the left and right lungs, the heart, the spinal cord, and the esophagus, essential for minimizing radiation toxicity during external radiation therapy. Our proposed approach, when evaluated on an internal dataset comprising 81 patients, demonstrated superior performance compared to other state-of-the-art methods. Specifically, the results for our approach with a 2.5D strategy were as follows: a dice similarity coefficient (DSC) of 0.820 ± 0.041, an intersection over union (IoU) of 0.725 ± 0.052, and a 3D Hausdorff distance (HD) of 10.353 ± 4.974 mm. Notably, the 2.5D strategy surpassed the 2D strategy in all three metrics, exhibiting higher DSC and IoU values, as well as lower HD values. This improvement strongly suggests that our proposed approach with the 2.5D strategy may hold promise in achieving more precise and accurate segmentations when compared to the conventional 2D strategy. Our work has practical implications in the improvement of treatment planning precision, aligning with the evolution of medical imaging and innovative strategies for multiorgan segmentation tasks.

Predictive atmospheric dispersion and deposition characteristics of activated tungsten dust

Tungsten is considered to be the most promising material for plasma-facing components of fusion reactors in addition to other industrial and military uses. Activated tungsten dust produced by plasma-wall interaction and released under accidental conditions would be the emerging environmental pollutant with both chemical and radiation toxicity. For the first time, atmospheric dispersion and deposition characteristics were investigated for tungsten dust with various particle size spectrum similar as generated in fusion reactors. Euler-Lagrange approach was adopted to describe parcels motion and deposition behaviors. Proper numbers of parcels were determined for the atmospheric dispersion and various parcel diameters scale. Near-surface concentration distribution and dry deposition velocity were predicted for tungsten dust with both single size dust and realistic particle size spectrum dust. Influences of chemical forms and release factors on atmospheric dispersion and deposition of tungsten dust were preliminary identified at last. It is indicated that 150 million parcels are needed for 10 μm dust under 5 km scale. Dry deposition velocity of tungsten dust is up to 11.3 cm s−1 and increase along with particle diameter because of its high density and gravitational deposition effect. The critical diameter judging whether gravitational deposition could appear for tungsten dust is 1 µm. Deposited particle size spectrum would be completely different along the downwind distance which would result in differences in subsequent behaviors in other environmental compartments.

Temporary Knockdown of p53 During Focal Limb Irradiation Increases the Development of Sarcomas.

Strategies to prevent or mitigate acute radiation toxicities include pharmacologic inhibition of p53 and other cell death pathways. Our data show that temporarily reducing p53 during irradiation increases late effects including sarcomagenesis.