Prognostic analysis of radiation-induced liver damage following carbon-ion radiotherapy for hepatocellular carcinoma.

BACKGROUND: Radiation-induced liver damage (RILD) occasionally occurs following carbon-ion radiotherapy (CIRT) for liver tumors, such as hepatocellular carcinoma (HCC), in patients with impaired liver function disease. However, the associated risk factors remain unknown. The present study aimed to determine the risk factors of RILD after CIRT. METHODS: We retrospectively analyzed 108 patients with HCC treated with CIRT at the Osaka Heavy Ion Therapy Center between December 2018 and December 2022. RILD was defined as a worsening of two or more points in the Child-Pugh score within 12 months following CIRT. The median age of the patients was 76 years (range 47-95 years), and the median tumor diameter was 41 mm (range 5-160 mm). Based on the pretreatment liver function, 98 and 10 patients were categorized as Child-Pugh class A and B, respectively. We analyzed patients who received a radiation dose of 60 Gy (relative biological effectiveness [RBE]) in four fractions. The median follow-up period was 9.7 months (range 2.3-41.1 months), and RILD was observed in 11 patients (10.1%). RESULTS: Multivariate analysis showed that pretreatment Child-Pugh score B (p = 0.003, hazard ratio [HR] = 6.90) and normal liver volume spared from < 30 Gy RBE (VS30 < 739 cm3) (p = 0.009, HR = 5.22) were significant risk factors for RILD. The one-year cumulative incidences of RILD stratified by Child-Pugh class A or B and VS30 < 739 cm3 or ≥ 739 cm3 were 10.3% or 51.8% and 39.6% or 9.2%, respectively. CONCLUSION: In conclusion, the pretreatment Child-Pugh score and VS30 of the liver are significant risk factors for RILD following CIRT for HCC.

Radiation effects on retinal layers revealed by OCT, OCT-A, and perimetry as a function of dose and time from treatment.

Optical coherence tomography (OCT) has become a key method for diagnosing and staging radiation retinopathy, based mainly on the presence of fluid in the central macula. A robust retinal layer segmentation method is required for identification of the specific layers involved in radiation-induced pathology in individual eyes over time, in order to determine damage driven by radiation injury to the microvessels and to the inner retinal neurons. Here, we utilized OCT, OCT-angiography, visual field testing, and patient-specific dosimetry models to analyze abnormal retinal layer thickening and thinning relative to microvessel density, visual function, radiation dose, and time from radiotherapy in a cross-sectional cohort of uveal melanoma patients treated with 125I-plaque brachytherapy. Within the first 24 months of radiotherapy, we show differential thickening and thinning of the two inner retinal layers, suggestive of microvessel leakage and neurodegeneration, mostly favoring thickening. Four out of 13 eyes showed decreased inner retinal capillary density associated with a corresponding normal inner retinal thickness, indicating early microvascular pathology. Two eyes showed the opposite: significant inner retinal layer thinning and normal capillary density, indicating early neuronal damage preceding a decrease in capillary density. At later time points, inner retinal thinning becomes the dominant pathology and correlates significantly with decreased vascularity, vision loss, and dose to the optic nerve. Stable multiple retinal layer segmentation provided by 3D graph-based methods aids in assessing the microvascular and neuronal response to radiation, information needed to target therapeutics for radiation retinopathy and vision loss.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

Targeting interleukin-17 in radiation-induced toxicity and cancer progression.

Recent strategies to combine chemoradiation with immunotherapy to treat locally advanced lung cancer have improved five-year survival outcomes. However, collateral toxicity to healthy lungs, esophagus, cardiac, and vascular tissue continues to limit the effectiveness of curative-intent thoracic radiation (tRT). It is necessary to gain a deeper comprehension of the fundamental mechanisms underlying inflammation-mediated radiation-induced damage to normal cells. Several cells have been linked in published studies to the release of cytokines and chemokines after radiation therapy. Several inflammatory mediators, such as IL-1, IL-6, TNF-α, and TGF-ß, also cause the production of Interleukin-17 (IL-17), a cytokine that is essential for maintaining immunological homeostasis and plays a role in the toxicity caused by radiation therapy. However, currently, the role of IL-17 in RT-induced toxicity in conjunction with cancer progression remains poorly understood. This review provides an overview of the most recent data from the literature implicating IL-17 in radiation-mediated tissue injuries and the efficacy of tRT in lung cancer, as well as its potential as a therapeutic target for interventions to reduce the side effects of tRT with curative intent and to boost an anti-tumor immune response to improve treatment outcomes. IL-17 may also act as a biomarker for predicting the effectiveness of a given treatment as well as the toxicity caused by tRT.

Radiation necrosis after radiation therapy treatment of brain metastases: A computational approach.

Metastasis is the process through which cancer cells break away from a primary tumor, travel through the blood or lymph system, and form new tumors in distant tissues. One of the preferred sites for metastatic dissemination is the brain, affecting more than 20% of all cancer patients. This figure is increasing steadily due to improvements in treatments of primary tumors. Stereotactic radiosurgery (SRS) is one of the main treatment options for patients with a small or moderate number of brain metastases (BMs). A frequent adverse event of SRS is radiation necrosis (RN), an inflammatory condition caused by late normal tissue cell death. A major diagnostic problem is that RNs are difficult to distinguish from BM recurrences, due to their similarities on standard magnetic resonance images (MRIs). However, this distinction is key to choosing the best therapeutic approach since RNs resolve often without further interventions, while relapsing BMs may require open brain surgery. Recent research has shown that RNs have a faster growth dynamics than recurrent BMs, providing a way to differentiate the two entities, but no mechanistic explanation has been provided for those observations. In this study, computational frameworks were developed based on mathematical models of increasing complexity, providing mechanistic explanations for the differential growth dynamics of BMs relapse versus RN events and explaining the observed clinical phenomenology. Simulated tumor relapses were found to have growth exponents substantially smaller than the group in which there was inflammation due to damage induced by SRS to normal brain tissue adjacent to the BMs, thus leading to RN. ROC curves with the synthetic data had an optimal threshold that maximized the sensitivity and specificity values for a growth exponent ß* = 1.05, very close to that observed in patient datasets.

Evolution of radiation-induced temporal lobe injury after intensity-modulated radiation therapy in nasopharyngeal carcinoma: a large cohort retrospective study.

BACKGROUND: Previous studies have demonstrated conflicting findings regarding the initial MRI patterns of radiotherapy-induced temporal lobe injury (RTLI) and the evolution of different RTLI patterns. The aim of this study was to evaluate the initial MRI pattern and evolution of RTLI in patients with nasopharyngeal carcinoma (NPC) by means of a large cohort study. METHODS: Data of patients with RTLI were retrospectively collected from two hospitals between January 2011 and December 2021. The injured lobes were categorized into three patterns based on initial MRI patterns: isolated white matter lesions (WMLs), isolated contrast-enhanced lesions (CELs), and combined WMLs and CELs. The latency period, MRI appearances, and temporal changes in WMLs and CELs were evaluated. RESULTS: A total of 913 RTLI patients with 1092 injured lobes were included in this study. The numbers of isolated WMLs, isolated CELs, and combined WMLs and CELs identified at the first MRI detection were 7 (0.6%), 172 (15.8%), and 913 (83.6%), respectively. The evolution of bilateral RTLI was different in the same patient, and that of unilateral RTLI combined with WMLs and CELs also may occur asynchronously. The time intervals from the initial MRI detection of isolated WMLs, isolated CELs, combined WMLs and CELs to the last negative MRI scan were 8.6, 8.9 and 11.0 months, respectively. A significant difference was observed in the time intervals between the three patterns (H = 14.287, P = 0.001). And the time interval was identified as an independent factor influencing the initial MRI pattern of RTLI after Poisson regression (P = 0.002). CONCLUSION: Both WMLs and CELs could be the initial and only MRI abnormalities in patients with RTLI. This study is of great significance in accurately diagnosing RTLI early and providing timely treatment options. Additionally, it provides clinical evidence for guidelines on NPC, emphasizing the importance of regular follow-up of NPC patients.

Umbrella review and network meta-analysis of diagnostic imaging test accuracy studies in Differentiating between brain tumor progression versus pseudoprogression and radionecrosis.

PURPOSE: In this study we gathered and analyzed the available evidence regarding 17 different imaging modalities and performed network meta-analysis to find the most effective modality for the differentiation between brain tumor recurrence and post-treatment radiation effects. METHODS: We conducted a comprehensive systematic search on PubMed and Embase. The quality of eligible studies was assessed using the Assessment of Multiple Systematic Reviews-2 (AMSTAR-2) instrument. For each meta-analysis, we recalculated the effect size, sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio from the individual study data provided in the original meta-analysis using a random-effects model. Imaging technique comparisons were then assessed using NMA. Ranking was assessed using the multidimensional scaling approach and by visually assessing surface under the cumulative ranking curves. RESULTS: We identified 32 eligible studies. High confidence in the results was found in only one of them, with a substantial heterogeneity and small study effect in 21% and 9% of included meta-analysis respectively. Comparisons between MRS Cho/NAA, Cho/Cr, DWI, and DSC were most studied. Our analysis showed MRS (Cho/NAA) and 18F-DOPA PET displayed the highest sensitivity and negative likelihood ratios. 18-FET PET was ranked highest among the 17 studied techniques with statistical significance. APT MRI was the only non-nuclear imaging modality to rank higher than DSC, with statistical insignificance, however. CONCLUSION: The evidence regarding which imaging modality is best for the differentiation between radiation necrosis and post-treatment radiation effects is still inconclusive. Using NMA, our analysis ranked FET PET to be the best for such a task based on the available evidence. APT MRI showed promising results as a non-nuclear alternative.

Characterisation of quantitative imaging biomarkers for inflammatory and fibrotic radiation-induced lung injuries using preclinical radiomics.

BACKGROUND AND PURPOSE: Radiomics is a rapidly evolving area of research that uses medical images to develop prognostic and predictive imaging biomarkers. In this study, we aimed to identify radiomics features correlated with longitudinal biomarkers in preclinical models of acute inflammatory and late fibrotic phenotypes following irradiation. MATERIALS AND METHODS: Female C3H/HeN and C57BL6 mice were irradiated with 20 Gy targeting the upper lobe of the right lung under cone-beam computed tomography (CBCT) image-guidance. Blood samples and lung tissue were collected at baseline, weeks 1, 10 & 30 to assess changes in serum cytokines and histological biomarkers. The right lung was segmented on longitudinal CBCT scans using ITK-SNAP. Unfiltered and filtered (wavelet) radiomics features (n = 842) were extracted using PyRadiomics. Longitudinal changes were assessed by delta analysis and principal component analysis (PCA) was used to remove redundancy and identify clustering. Prediction of acute (week 1) and late responses (weeks 20 & 30) was performed through deep learning using the Random Forest Classifier (RFC) model. RESULTS: Radiomics features were identified that correlated with inflammatory and fibrotic phenotypes. Predictive features for fibrosis were detected from PCA at 10 weeks yet overt tissue density was not detectable until 30 weeks. RFC prediction models trained on 5 features were created for inflammation (AUC 0.88), early-detection of fibrosis (AUC 0.79) and established fibrosis (AUC 0.96). CONCLUSIONS: This study demonstrates the application of deep learning radiomics to establish predictive models of acute and late lung injury. This approach supports the wider application of radiomics as a non-invasive tool for detection of radiation-induced lung complications.

Mouse model of radiation retinopathy reveals vascular and neuronal injury.

PURPOSE: To characterize the neuronal and vascular pathology in vivo and in vitro in a mouse model of radiation retinopathy. METHODS: C57Bl/6J mice underwent cranial irradiation with 12 Gy and in vivo imaging by optical coherence tomography and of relative blood flow velocity by laser speckle flowgraphy for up to 3-6 months after irradiation. Retinal architecture, vascular density and leakage and apoptosis were analyzed by histology and immunohistochemistry before irradiation or at 10, 30, 240, and 365 days after treatment. RESULTS: The vascular density decreased in the plexiform layers starting at 30 days after irradiation. No impairment in retinal flow velocity was seen. Subtle perivascular leakage was present at 10 days, in particular in the outer plexiform layer. This corresponded to increased width of this layer. However, no significant change in the retinal thickness was detected by OCT-B scans. At 365 days after irradiation, the nuclear density was significantly reduced compared to baseline. Apoptosis was detected at 30 days and less prominent at 365 days. CONCLUSIONS: By histology, vascular leakage at 10 days was followed by increased neuronal apoptosis and loss of neuronal and vascular density. However, in vivo imaging approaches that are commonly used in human patients did not detect pathology in mice.

Breast Irradiation Is Well Tolerated in Carriers of a Pathogenic ATM Variant.

PURPOSE: There are mixed and limited data regarding radiation therapy (RT) tolerance in carriers of a germline pathogenic or likely pathogenic (P/LP) ATM variant. We investigated RT-related toxic effects in carriers of an ATM variant who received treatment for breast cancer. METHODS AND MATERIALS: We identified 71 patients treated with adjuvant RT for breast cancer who were carriers of a variant in ATM: 15 were classified as P/LP and 56 classified as variants of unknown significance (VUS). We additionally identified 205 consecutively treated patients during a similar timeframe who were either confirmed ATM wild type or had no prior genetic testing. RT plans were reviewed. Acute and chronic toxic effects were evaluated using Common Terminology Criteria for Adverse Events version 4.0 criteria. Fisher's exact tests for count data were performed to compare toxic effects between the cohorts (P/LP vs VUS vs control). Wilcoxon rank-sum testing was performed to assess for differences in patient characteristics. RESULTS: The median toxicity follow-up was 19.4 months; median follow-up for the subcohorts was 13.3 months (P/LP), 12.6 months (VUS), and 23.3 months (control). There were no significant differences in radiation plan heterogeneity, receipt of a boost, or size of breast/chest wall planning target volume. There was greater use of hypofractionated RT in the control cohort (P = .023). After accounting for patient- and treatment-related factors that may affect toxic effects, we found no significant differences with respect to acute dermatitis, hyperpigmentation, moist desquamation, breast/chest wall pain, or breast edema. Additionally, we found no significant differences with respect to chronic breast/chest wall pain, induration, telangiectasia, or cosmetic outcome. CONCLUSIONS: RT as part of the management of breast cancer was well tolerated in carriers of a P/LP ATM variant, with toxic effect profiles that were similar to those seen in patients without known ATM mutations. High rates of excellent or good cosmesis were observed in carriers of a P/LP ATM variant who underwent breast conservation.

Glycyrrhetinic Acid Mitigates Radiation-Induced Pulmonary Fibrosis via Inhibiting the Secretion of TGF-ß1 by Treg Cells.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a common side effect of radiation therapy for thoracic tumors without effective prevention and treatment methods at present. The aim of this study was to explore whether glycyrrhetinic acid (GA) has a protective effect on RIPF and the underlying mechanism. METHODS AND MATERIALS: A RIPF mouse model administered GA was used to determine the effect of GA on RIPF. The cocultivation of regulatory T (Treg) cells with mouse lung epithelial-12 cells or mouse embryonic fibroblasts and intervention with GA or transforming growth factor-ß1 (TGF-ß1) inhibitor to block TGF-ß1 was conducted to study the mechanism by which GA alleviates RIPF. Furthermore, injection of Treg cells into GA-treated RIPF mice to upregulate TGF-ß1 levels was performed to verify the roles of TGF-ß1 and Treg cells. RESULTS: GA intervention improved the damage to lung tissue structure and collagen deposition and inhibited Treg cell infiltration, TGF-ß1 levels, epithelial mesenchymal transition (EMT), and myofibroblast (MFB) transformation in mice after irradiation. Treg cell-induced EMT and MFB transformation in vitro were prevented by GA, as well as a TGF-ß1 inhibitor, by decreasing TGF-ß1. Furthermore, reinfusion of Treg cells upregulated TGF-ß1 levels and exacerbated RIPF in GA-treated RIPF mice. CONCLUSIONS: GA can improve RIPF in mice, and the corresponding mechanisms may be related to the inhibition of TGF-ß1 secreted by Treg cells to induce EMT and MFB transformation. Therefore, GA may be a promising therapeutic candidate for the clinical treatment of RIPF.

Treatment of pediatric cerebral radiation necrosis using hyperbaric oxygenation.

Introduction: Cerebral radiation necrosis is rarely encountered in pediatric patients. This case report describes a child with cerebral radiation necrosis who was successfully treated using corticosteroids, bevacizumab, and hyperbaric oxygenation. Case report: A 3-year-old boy developed progressive extremity weakness six months after the completion of radiation therapy for the treatment of a neuroepithelial malignancy. Treatment with corticosteroids and bevacizumab was initiated, but his symptoms did not improve, and he was then referred for hyperbaric oxygen therapy. After completing 60 hyperbaric treatments, he experienced significant improvements in mobility, which remained stable over the next year. Discussion: Cerebral radiation necrosis typically presents in children with symptoms of ataxia or headache. Corticosteroids and bevacizumab are common treatments, but hyperbaric oxygen therapy has also been studied as a therapeutic modality for this condition. When considering the use of hyperbaric oxygenation in pediatric patients, careful attention to treatment planning and patient safety can reduce the risks of adverse events such as middle ear barotrauma and confinement anxiety. Conclusion: In addition to other available pharmacologic therapies, hyperbaric oxygenation should be considered for the treatment of pediatric patients with cerebral radiation necrosis.

Reprimo (RPRM) as a Potential Preventive and Therapeutic Target for Radiation-Induced Brain Injury via Multiple Mechanisms.

Patients receiving cranial radiotherapy for primary and metastatic brain tumors may experience radiation-induced brain injury (RIBI). Thus far, there has been a lack of effective preventive and therapeutic strategies for RIBI. Due to its complicated underlying pathogenic mechanisms, it is rather difficult to develop a single approach to target them simultaneously. We have recently reported that Reprimo (RPRM), a tumor suppressor gene, is a critical player in DNA damage repair, and RPRM deletion significantly confers radioresistance to mice. Herein, by using an RPRM knockout (KO) mouse model established in our laboratory, we found that RPRM deletion alleviated RIBI in mice via targeting its multiple underlying mechanisms. Specifically, RPRM knockout significantly reduced hippocampal DNA damage and apoptosis shortly after mice were exposed to whole-brain irradiation (WBI). For the late-delayed effect of WBI, RPRM knockout obviously ameliorated a radiation-induced decline in neurocognitive function and dramatically diminished WBI-induced neurogenesis inhibition. Moreover, RPRM KO mice exhibited a significantly lower level of acute and chronic inflammation response and microglial activation than wild-type (WT) mice post-WBI. Finally, we uncovered that RPRM knockout not only protected microglia against radiation-induced damage, thus preventing microglial activation, but also protected neurons and decreased the induction of CCL2 in neurons after irradiation, in turn attenuating the activation of microglial cells nearby through paracrine CCL2. Taken together, our results indicate that RPRM plays a crucial role in the occurrence of RIBI, suggesting that RPRM may serve as a novel potential target for the prevention and treatment of RIBI.

BRAIN AND EYE AS POTENTIAL TARGETS FOR IONIZING RADIATION IMPACT. PART V - ORGANIC AND FUNCTIONAL CHANGES CORRELATION ON THE EXAMPLE OF CERTAIN DISEASES. / ГОЛОВНИЙ МОЗОК ТА ОРГАН ЗОРУ ЯК ПОТЕНЦІЙНІ МІШЕНІ ДЛЯ ВПЛИВУ ІОНІЗУЮЧОГО ВИПРОМІНЮВАННЯ: ЧАСТИНА V ­ СПІВВІДНОШЕННЯ ОРГАНІЧНИХ І ФУНКЦІОНАЛЬНИХ ЗМІН НА ПРИКЛАДІ ОКРЕМИХ ЗАХВОРЮВАНЬ.

The question about correlation between organic and functional changes in persons, exposed to radiation is still insufficiently studied. Dynamics of morbidity for different forms and classes of non-tumour diseases periodisation, proposed by epidemiologists, suggests the identification of three main periods: «early¼ (the first 6 post-Chornobyl accident years); «distant¼ (12-21 years) and «late¼ (22-30 years). However, the correspondence this periodisation to the results of epidemiological data, without taking into account the clinical features of the diseases, may contribute to the impression, that in the first period after a radiation disaster functional disorders (or autonomic regulation disorders, etc.) prevail in all cases. Meanwhile, the data from ophthalmological and neurological studies, which we aim to demonstrate in this paper, rather indicate the presence of a significant morphological basis for the development of functional disorders in early period after a radiation disaster. The objective of this work is analyse modern experimental, epidemiological and clinical data on the correlation between organic and functional changes, characteristic of radiation cerebro-ophthalmological effects - radiation cataracts, age-related macular degeneration, cerebral small vessel disease, and neurocognitive deficits. Materials and methods. The criteria for inclusion in the analytical review were peer-reviewed publications in PubMed/MEDLINE, Scopus, Web of Science, and manually selected papers; the results of our own research were also used. An additional analysis of the results of examinations conducted in 1991-2004 was performed, which included a total of 11 123 persons irradiated as the result of catastrophy at the Chornobyl NPP. Results. In the first period of radiation cataract development, which is a specific consequence of radiation exposure, morphological changes (lens opacities) are observed, which lead to a decrease in visual function only later. Analysing the correlation between organic and functional changes in the development of diseases, for which ionising radiation exposure is a significant risk factor, we observe a similar picture. For example, CSVD associated with arterial hypertension may be a manifestation of accelerated aging associated with exposure to ionising radiation.Similarly, the initial signs of age-related macular degeneration in radiation-exposed individuals are usually manifested by changes in the morphology of the retina, choroid, and pigment epithelium in the macular area, while functional disorders in the form of decreased central vision and metamorphopsia, etc., occur later.

Vitamin E ameliorates oral mucositis in gamma-irradiated rats (an in vivo study).

BACKGROUND: Radiation therapy is the primary treatment for neck and head cancer patients; however, it causes the development of oral mucositis accompanied by tissue structure destruction and functional alteration. This study was conducted to evaluate the effect of different doses of vitamin E as a treatment for radiationinduced oral mucositis in rat model. METHODS: 35 male albino rats were randomly divided into five groups: control, untreated radiation mucositis (single dose of 20 Gy), treated radiation mucositis; radiation (single dose of 20 Gy) then vitamin E at doses of 300, 360 and 500 mg/Kg for seven days started 24 h after irradiation. Body weight and food intake were evaluated for each rat. The mucositis score was assessed every day. Rats were sacrificed once at the end of the experiment, and tongue specimens were stained with hematoxylin and eosin, anti P53 and anti Ki67 antibodies. RESULTS: Results indicated more food intake and less weight reduction in vitamin E treated groups and the contrary for gamma-irradiated group. Additionally, vitamin E delayed the onset and decreased the severity and duration of mucositis. It also restored the histological structure of lingual tongue papillae. Vitamin E treated groups showed a significant higher Ki67 and lower P53 expression as compared to untreated radiation group. The overall improvement increased as vitamin E dose increased. Finally, the amelioration can be attributed to the decreased apoptosis and increased proliferation of cells. CONCLUSIONS: Vitamin E especially at dose of 500 mg/Kg could be an effective treatment for radiation-induced oral mucositis.

Dosimetric investigation of radiation-induced trigeminal nerve toxicity in parotid tumor patients.

PURPOSE: We aimed to describe the association between trigeminal nerve (TN) dose and toxicity and determine a threshold value that leads to TN toxicity in patients with parotid tumors treated with adjuvant conventional fractionated radiation therapy. METHODS AND MATERIALS: Eighteen patients who underwent adjuvant radiotherapy (RT) between 2013 and 2018 were included in this retrospective study. TN and its branches were outlined subsequently on the planning CT scans. The doses received by TN were obtained based on the dose-volume histogram. The dose and toxicity relationship was investigated over the total prescribed dose. RT-related toxicity was graded according to Common Terminology Criteria for Adverse Events V4.0 (CTCAEv4.0). RESULTS: The median follow-up was 29.5 months. After RT, 61% of patients had Grade I-II late TN toxicity divided into Grade I in 4 (22%) and Grade II in 7 (39%) patients. TN injury symptoms were as follows: loss of sensation in the chin area in 3, difficulty in jaw movements in 3, and paresthesia in 5 patients. The total RT dose (p = 0.001), Dmax (p = 0.001), PTV-TN Dmax (p = 0.001), D1cc (p = 0.004), D0.5cc (p = 0.001), and D0.1cc (p = 0.01) had a significant effect on TN toxicity. Cut-off values leading to toxicity were determined as 66, 65.5, 65.25, 63.6, and 62.7 Gy for Dmax, PTV-TN Dmax, D0.1cc, D 0.5cc, and D1cc, respectively. CONCLUSIONS: Radiation-induced TN injury in head and neck cancer patients may further be investigated in clinically prospective trials by virtue of high toxicity rates with current RT doses in our retrospectively designed dosimetric study in parotid tumors.

Comparison of Tumor Control and Skin Damage in a Mouse Model after Ultra-High Dose Rate Irradiation and Conventional Irradiation.

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose.

Radiation nephropathy: Mechanisms of injury and recovery in a murine model.

BACKGROUND: Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function. AIM: To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM). METHODS: C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy. RESULTS: RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis. CONCLUSION: For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.

[Interactions between vascular endothelium and immune cells: A key control point of radiation-induced digestive lesions]. / Interactions endothélium vasculaire ­ cellules immunitaires : un point de contrôle clef des lésions digestives radio-induites.

Radiation-induced toxicity of the digestive tract is a major clinical concern as many cancer survivors have received radiotherapy for tumours of the abdominopelvic area. The coordination and orchestration of a tissue's response to stress depend not only on the phenotype of the cells that make up the tissue but also on cell-cell interactions. The digestive system, i.e., the intestine/colon/rectum, is made up of a range of different cell populations: epithelial cells, stromal cells, i.e. endothelial cells and mesenchymal lineages, immune cells and nerve cells. Moreover, each of these populations is heterogeneous and presents very significant plasticity and differentiation states. The pathogenesis of radiation-induced digestive lesions is an integrated process that involves multiple cellular compartments interacting in a complex sequence of events. Understanding all the cellular events and communication networks that contribute to the tissue's response to stress is therefore a major conceptual and methodological scientific challenge. The study of heterogeneous populations of cells in a tissue is now possible thanks to "single cell' RNA sequencing and spatial transcriptomics techniques, which enable a comprehensive study of the transcriptomic profiles of individual cells in an integrated system. In addition, the mathematical and bioinformatics tools that are now available for the large-scale analysis of data allow the inference of cell-cell communication networks. Such approaches have become possible through advances in bioinformatics algorithms for the analysis and deciphering of interaction networks. Interactions influence the tissue regeneration process through expression of various molecules, including metabolites, integrins, junction proteins, ligands, receptors and proteins secreted into the extracellular space. The vascular network is viewed as a key player in the progression of digestive lesions, which are characterised by infiltration of a range of immune cells. A better characterisation of endothelium/immune cell interactions in suitable preclinical models, as well as in humans, may help to identify some promising therapeutic targets for the prediction, prevention or treatment of digestive toxicity after radiotherapy.

Mid-treatment 18F-FDG PET imaging changes in parotid gland correlates to radiation-induced xerostomia.

BACKGROUND: The aim of this study was to measure functional changes in parotid glands using mid-treatment FDG-PET/CT and correlate early imaging changes to subsequent xerostomia in mucosal head and neck squamous cell carcinoma patients undergoing radiotherapy. MATERIALS AND METHODS: 56 patients from two prospective imaging biomarker studies underwent FDG-PET/CT at baseline and during radiotherapy (week 3). Both parotid glands were volumetrically delineated at each time point. PET parameter SUVmedian were calculated for ipsilateral and contralateral parotid glands. Absolute and relative change (Δ) in SUVmedian were correlated to moderate-severe xerostomia (CTCAE grade ≥ 2) at 6 months. Four predictive models were subsequently created using multivariate logistic regression using clinical and radiotherapy planning parameters. Model performance was calculated using ROC analysis and compared using Akaike information criterion (AIC) RESULTS: 29 patients (51.8%) developed grade ≥ 2 xerostomia. Compared to baseline, there was an increase in SUVmedian at week 3 in ipsilateral (8.4%) and contralateral (5.5%) parotid glands. Increase in ipsilateral parotid Δ SUVmedian (p = 0.04) and contralateral mean parotid dose (p = 0.04) were correlated to xerostomia. The reference 'clinical' model correlated to xerostomia (AUC 0.667, AIC 70.9). Addition of ipsilateral parotid Δ SUVmedian to the clinical model resulted in the highest correlation to xerostomia (AUC 0.777, AIC 65.4). CONCLUSION: Our study shows functional changes occurring in the parotid gland early during radiotherapy. We demonstrate that integration of baseline and mid-treatment FDG-PET/CT changes in the parotid gland with clinical factors has the potential to improve xerostomia risk prediction which could be utilised for personalised head and neck radiotherapy.