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Objective: This study aims to examine whether radiation therapy doses are related to incidences of carotid artery stenosis and brain necrosis in a large-scale real-world database. Methods: We identified a cohort of HNC patients from the catastrophic illness patient dataset using ICD-9 or ICD-10 to compare the incidence and risks of carotid artery stenosis (CAS) and brain necrosis (RIBN) in patients who received a radiation therapy dose of ≥5400 cGy/30 fractions (group A) with those who received a radiation therapy dose of <5400 cGy/30 fractions (group B). The incidence and hazard ratios were quantified using Cox proportional hazards models. Results: A total of 19,964 patients were identified in group A and group B. Among them, 965 and 863 cases of CAS and 435 and 359 cases of RIBN were identified in group A and group B, respectively. There was no statistically significant association between the two groups for CAS risk, whereas there was a statistically significant association between the two groups for RIBN risk. The most common primary site of head and neck cancers was the nasopharynx (1144 of 19,964, 5.73%). Conclusions: Our study suggests that RT may increase the risk of carotid stenosis and brain necrosis in patients with NPC. To ensure patient safety during treatment, the optimal balance between tumor control and toxicity prevention in individual patients through minimization of the radiation dose to all relevant OARs must be properly understood.

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BACKGROUND AND PURPOSE: The evidence of longitudinal changes in cognition in nasopharyngeal carcinoma (NPC) survivors with radiation-induced brain necrosis (RIBN) after radiotherapy (RT) remained insufficient. We aimed to estimate the clinical progression rate of cognitive decline and identify patients with differential decline rates. MATERIALS AND METHODS: Based on an ongoing prospective cohort study, NPC patients aged ≥18 years old and diagnosed with RIBN were included in this current analysis if they finished the time frame of 3-year follow-up and had at least twice cognition assessments. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess the cognitive state. Linear mixed-effect models were used to analyze the annual progression rates of MoCA total and seven sub-items scores. RESULTS: Among 134 patients in this study, the transition probability from normal to mild/moderate cognitive dysfunction were 14.2 % (19/134) and 1.49 % (2/134) respectively during the median follow-up time of 2.35 years. The total MoCA score declined by -0.569 (SE 0.208) points annually (p = 0.008). Patients with ≤6 years of duration from RT to RIBN have higher annual progression rate of total scores [-0.851 (SE 0.321), p = 0.013; p for interaction = 0.041]. CONCLUSION: Our findings of the annual decline rate of cognition in NPC patients with RIBN from a 3-year longitudinal data, particularly for those who developed RIBN rapidly after RT, have important implications for the upcoming clinical trials designed to prevent or decrease cognitive decline in NPC patients with RIBN, regarding the selection of study patients and the calculation of sample size.

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[Proposal] Here, we retrospectively evaluate risk factors for radiation necrosis and local recurrence after PBT for skull base chordoma or chondrosarcoma. [Patients and Methods] We analyzed 101 patients who received PBT for skull base chordomas and chondrosarcomas from January 1989 to February 2021. Multivariable logistic regression models were applied for local recurrence, temporal lobe radiation necrosis rates, and temporal lobe radiation necrosis. [Results] In multivariate analysis, chordoma and large tumor size were independent significant factors for local recurrence. The 1-, 2-, 3-, 4- and 5-year local recurrence rates were 3.9%, 16.9%, 20.3%, 28.5% and 44.0% for chordoma and 0%, 0%, 0%, 0% and 7.1% for chondrosarcoma, respectively. The local recurrence rates of small tumors (<30 mm) were 4.3%, 14.7%, 17.7%, 17.7% and 25.9%, and those for large tumors were 3.6%, 15.1%, 19.2%, 32.7% and 59.6%, respectively. In multivariate analysis, BED Gy10 and total dose were risk factors for radiation necrosis. [Conclusions] For skull base chordoma and chondrosarcoma, the risk factors of local recurrence were chordoma and large tumor size, and those of radiation necrosis were BED Gy10 and total dose, respectively. DVH analysis is needed to investigate the risk factors for brain necrosis in more detail.

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Malnutrition is related to worsened prognosis, but the association between nutritional risk status and overall survival in radiation-induced brain necrosis (RN) has never been studied. We included consecutive patients who had received radiotherapy for head and neck cancer (HNC) and subsequently developed RN from 8 January 2005 through to 19 January 2020. The primary outcome was overall survival. We utilized three commonly-used nutritional assessments: the Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and the COntrolling NUTritional Status (CONUT) measure, to quantify the baseline nutritional risk. A total of 398 eligible patients were included. During a median follow-up of 2.3 years, 42 (10.6%) patients died of any cause. Malnutrition at admission was associated with an increased risk of future death, as assessed by the GNRI (per 1-point decreased, HR 1.05, 95%CI 1.02-1.09, p = 0.001), the PNI (per 1-point decreased, HR 1.07, 95%CI 1.03-1.12, p = 0.002), and the CONUT (per 1-point increased, HR 1.22, 95%CI 1.08-1.37, p = 0.001). There were no nonlinear correlations between all three indices and post-RN survival. Among HNC survivors with RN, the assessment of nutritional risk by composite indices upon admission could help identify patients who might be at high risk of future death and deliver better nutritional management.

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BACKGROUND: Methylprednisolone is recommended as the front-line therapy for radiation-induced brain necrosis (RN) after radiotherapy for nasopharyngeal carcinoma. However, some patients fail to benefit from methylprednisolone or even progress. This study aimed to develop and validate a radiomic model to predict the response to methylprednisolone in RN. METHODS: Sixty-six patients receiving methylprednisolone were enrolled. In total, 961 radiomic features were extracted from the pre-treatment magnetic resonance imagings of the brain. Least absolute shrinkage and selection operator regression was then applied to construct the radiomics signature. Combined with independent clinical predictors, a radiomics model was built with multivariate logistic regression analysis. Discrimination, calibration and clinical usefulness of the model were assessed. The model was internally validated using 10-fold cross-validation. RESULTS: The radiomics signature consisted of 16 selected features and achieved favorable discrimination performance. The radiomics model incorporating the radiomics signature and the duration between radiotherapy and RN diagnosis, yielded an AUC of 0.966 and an optimism-corrected AUC of 0.967 via 10-fold cross-validation, which also revealed good discrimination. Calibration curves showed good agreement. Decision curve analysis confirmed the clinical utility of the model. CONCLUSIONS: The presented radiomics model can be conveniently used to facilitate individualized prediction of the response to methylprednisolone in patients with RN.

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BACKGROUND: Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. METHODS: Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15-24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. DISCUSSION: Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. TRIAL REGISTRATION: ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

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The emergence of immune checkpoint inhibitors (ICIs) has reshaped the landscape of advanced lung cancer treatment. The brain is the most common metastatic site for lung cancer. Whether conventional criteria can evaluate the intracranial response of ICIs remains unclear. Here, we report a well-documented case of intracranial necrosis confirmed by post-operative pathology after only one cycle of chemo-immunotherapy without any radiation therapy, which suggests that immunotherapy elicits strong anti-tumor responses for intracranial metastasis and promotes intracranial necrosis, resulting in a temporary increase in size of the target lesions. Still, the specific mechanisms and management strategies need to be further explored.

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Introduction Radiation necrosis in the brain is a frequent complication of brain radiation therapy (RT) and is characterized by various neurological symptoms including cognitive dysfunction, headaches, weakness, apraxia, aphasia, and numbness. These symptoms may be progressive and treatment-resistant. Currently, risk factors for radiation necrosis are not well characterized. The goal of this study is to identify risk factors for cerebral radiation necrosis in order to improve clinicians' ability to appropriately weigh the risks and benefits of brain RT. Methods A retrospective chart review was performed on patients who were diagnosed with brain tumors and received RT (3D conformal therapy, volumetric modulated arc therapy, stereotactic radiosurgery, or stereotactic radiotherapy) at the University of Arkansas for Medical Sciences from July 1, 2017, to July 1, 2019. Data regarding demographics, characteristics of cancer, chemotherapy status and class, comorbidities, and additional medications of patients were collected via EPIC. Total RT dose, fraction size, volume of brain receiving 12 Gy (V12), and retreatment of locally recurrent tumors were recorded from Eclipse. The diagnosis of radiation necrosis was based on MRI reports that were examined for a time period of 24 months following the completion of radiation treatment and confirmed, when possible, by biopsy. Cases that did not have an MRI available at least two months after the completion of RT were excluded. Statistical association analyses were used to identify candidate risk factors to radiation necrosis. These candidate risk factors were further used to assess their associations to demographics and other characteristics of cancer and treatments. Finally, adjusted and unadjusted logistic regression models were used to predict radiation necrosis using a single risk factor or multiple risk factors. ROC curves were used to evaluate the performance of prediction or discrimination of the logistic regression models. Results A total of 139 patients were studied. The mean ± standard deviation (SD) for age was 60.4 ± 13.6 years, female:male ratio was 71:68, and White:African American:other race ratio was 112:24:3. A total of 43 (30.9%) patients were diagnosed with radiation necrosis. Radiation adjuvant to surgery, concurrent systemic therapy status, total dose, and V12 were found to be significantly associated with radiation necrosis and considered candidate risk factors of radiation necrosis in the study. Predictive models showed adjusted odds ratios ([aORs] 95% confidence intervals or CIs) of 3.70 (1.01-13.56) and 8.19 (1.78-37.78) with radiation adjuvant to surgery and concurrent systemic therapy, respectively. For every one unit (log-transformed) increase of total dose and V12, the aORs (95% CI's) were 27.35 (3.74-200.16) and 1.63 (1.15-2.32), respectively. Conclusion Our study suggested a positive correlation of concurrent systemic therapy status and post-surgical adjuvant RT with the incidence of radiation necrosis. It further demonstrated that greater total RT dose and V12 were related to the risk of developing radiation necrosis following brain RT. Given the findings of this study, the aforementioned factors should be considered when weighing the risk of radiation necrosis with the benefits of treatment.

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Background: The evidence of early treatment for radiation-induced brain necrosis (RN) in head and neck cancer survivors remains insufficient. This study aimed to determine whether early anti-RN treatment was associated with lower mortality. Methods: In this cohort study, we utilized data from the Study in Radiotherapy-related Nervous System Complications (NCT03908502) and Hong Kong Cancer Registry. We included consecutive patients who had received radiotherapy (RT) for head and neck cancers and had subsequently developed RN between Jan 8, 2005 and Jan 19, 2020. Patients who had tumor progression before the diagnosis of RN, underwent surgical brain necrosis lesions resection before corticosteroids and/or bevacizumab treatment, had intracranial metastases before the diagnosis of RN, lacked follow-up data, or had a follow-up period of less than three months were excluded. Individual-level data were extracted from electronic medical records of the above-mentioned registries. The primary outcome was all-cause death. The vital status of each patient was confirmed through a standardized telephone interview. We compared patients who received early treatment (initiating bevacizumab or corticosteroids treatment within three months after RN diagnosis) with patients who did not (following a "watch-and-wait" policy). Findings: Of 641 eligible patients, 451 patients (70·4%) received early treatment after RN diagnosis and 190 patients (29·6%) did not. Overall, 112 patients (17·5%) died, of whom 73 (16·2%) in the early treatment group and 39 (20·5%) in the watch-and-wait group, during a median follow-up of 3·87 years. The early treatment group showed a lower risk of all-cause death compared with the watch-and-wait group after adjusting for age, sex, absence or presence of neurological symptoms at baseline, RN lesion features on brain magnetic resonance imaging, history of stroke, prior tumor-related characteristics (TNM stage, RT dose and techniques, and chemotherapy), and the time interval from RT to RN (HR 0·48, 95%CI 0·30 to 0·77; p = 0·0027), and extensive sensitivity analyses yielded similar results. There was no significant difference in the effect of early treatment on post-RN survival among subgroups stratified by presence or absence of neurological symptoms at diagnosis (p for interaction=0·41). Interpretation: Among head and neck cancer survivors with RN, initiating treatment early after RN diagnosis is associated with a lower risk of all-cause mortality as compared with following the watch-and-wait policy, irrespective of whether patients exhibit symptoms or not. Further prospective randomised studies would be needed to validate our findings since the observational study design might lead to some potential confounding. In the absence of data from randomised trials, our study will have an important implication for clinicians regarding the optimal timing of treatment for RN, and provides the foundation and supporting data for future trials on this topic. Funding: National Natural Science Foundation of China (81925031, 81820108026, 81872549, 81801229, 82003389), the Science and Technology Program of Guangzhou (202007030001), Young Teacher Training Program of Sun Yat-sen University (20ykpy106), Key-Area Research and Development Program of Guangdong Province (2018B030340001), the National Medical Research Council Singapore Clinician Scientist Award (NMRC/CSA-INV/0027/2018, CSAINV20nov-0021), the Duke-NUS Oncology Academic Program Goh Foundation Proton Research Programme, NCCS Cancer Fund, the Kua Hong Pak Head and Neck Cancer Research Programme, and the National Research Foundation Clinical Research Programme Grant (NRF-CRP17-2017-05).

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Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism for cerebral radiation necrosis (CRN) development. Antiangiogenic agents (Bevacizumab) alleviates brain edema symptoms caused by CRN through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that Bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' performance status and brain necrosis imaging. Considering that the efficacy of antiangiogenic therapy is mainly related to the duration of drug action, low-dose antiangiogenic agents can achieve favorable efficacy. Prevention is the best treatment. The occurrence of CRN is associated with tumor-related factors and treatment-related factors. By controlling these factors, CRN can be effectively prevented.
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BACKGROUND AND PURPOSE: The study aimed to develop and validate a novel nomogram to predict overall survival in head and neck cancer survivors following the diagnosis of radiation-induced brain necrosis (RN). MATERIALS AND METHODS: We included head and neck cancer survivors with RN from a radiation complications registry study. A total of 495 eligible patients were 7:3 randomly allocated to a training cohort and an internal validation cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) regression was applied to select significant predictors of post-RN survival in the training cohort, and a multivariable Cox model was used to develop the nomogram. The performance of the nomogram was assessed using the internal validation cohort and externally validated using additional 88 RN patients. RESULTS: We identified five predictors of post-RN survival using the training data: age, tumor progression before RN, lower cranial nerves injury, bilateral necrosis, and history of stroke. The nomogram showed favorable performance in the internal validation cohort (C-index 0.761, 95% CI 0.676 to 0.847) and in the external validation cohort (C-index 0.795, 95% CI 0.717 to 0.874). The decision curve analysis indicated that the nomogram was clinically useful when the probabilities of death ranging from 1% to 48% at 1 year, from 3% to 50% at 3 years, and exceeding 2% at 5 years after being diagnosed with RN. CONCLUSION: In this LASSO-Cox model-based nomogram study, we developed and validated an easily applied model to predict overall survival in head and neck cancer survivors following an RN diagnosis.

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Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism for cerebral radiation necrosis (CRN) development. Antiangiogenic agents (Bevacizumab) alleviates brain edema symptoms caused by CRN through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that Bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' performance status and brain necrosis imaging. Considering that the efficacy of antiangiogenic therapy is mainly related to the duration of drug action, low-dose antiangiogenic agents can achieve favorable efficacy. Prevention is the best treatment. The occurrence of CRN is associated with tumor-related factors and treatment-related factors. By controlling these factors, CRN can be effectively prevented.
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Radiation-induced brain necrosis (RIBN) is a serious late and irreversible complication after radiation therapy for primary or secondary brain tumors as well as head and neck tumors, and there is no effective treatment. In recent years, bevacizumab has been increasingly applied in the treatment of RIBN, which has been proven to yield certain efficacy and improve patient survival. However, the optimal treatment timing and regimen have been controversial and lack of basic consensus. In this article, research progress on these issues was briefly reviewed.

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PURPOSE: Due to the employment of quadratic programming using soft constraints to implement dose volume constraints and the "trial-and-error" procedure needed to achieve a clinically acceptable plan, conventional dose volume constraints (upper limit) are not adequately effective in controlling small and isolated hot spots in the dose/linear energy transfer (LET) distribution. Such hot spots can lead to adverse events. In order to mitigate the risk of brain necrosis, one of the most clinically significant adverse events in patients receiving intensity-modulated proton therapy (IMPT) for base of skull (BOS) cancer, we propose per-voxel constraints to minimize hot spots in LET-guided robust optimization. METHODS AND MATERIALS: Ten BOS cancer patients treated with IMPT were carefully selected by meeting one of the following conditions: (1) diagnosis of brain necrosis during follow-up; and (2) considered high risk for brain necrosis by not meeting dose constraints to the brain. An optimizing structure (BrainOPT) and an evaluating structure (BrainROI) that both contained the aforementioned hot dose regions in the brain were generated for optimization and evaluation, respectively. Two plans were generated for every patient: one using conventional dose-only robust optimization, the other using LET-guided robust optimization. The impact of LET was integrated into the optimization via a term of extra biological dose (xBD). A novel optimization tool of per-voxel constraints to control small and isolated hot spots in either the dose, LET, or combined (dose/LET) distribution was developed and used to minimize dose/LET hot spots of the selected structures. Indices from dose-volume histogram (DVH) and xBD dose-volume histogram (xBDVH) were used in the plan evaluation. A newly developed tool of the dose-LET-volume histogram (DLVH) was also adopted to illustrate the underlying mechanism. Wilcoxon signed-rank test was used for statistical comparison of the DVH and xBDVH indices between the conventional dose-only and the LET-guided robustly optimized plans. RESULTS: Per-voxel constraints effectively and efficiently minimized dose hot spots in both dose-only and LET-guided robust optimization and LET hot spots in LET-guided robust optimization. Compared to the conventional dose-only robust optimization, the LET-guided robust optimization could generate plans with statistically lower xBD hot spots in BrainROI (VxBD,50 Gy[RBE], p = 0.009; VxBD,60 Gy[RBE], p = 0.025; xBD1cc, p = 0.017; xBD2cc, p = 0.022) with comparable dose coverage, dose hot spots in the target, and dose hot spots in BrainROI. DLVH analysis indicated that LET-guided robust optimization could either reduce LET at the same dose level or redistribute high LET from high dose regions to low dose regions. CONCLUSION: Per-voxel constraint is a powerful tool to minimize dose/LET hot spots in IMPT. The LET-guided robustly optimized plans outperformed the conventional dose-only robustly optimized plans in terms of xBD hot spots control.

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BACKGROUND: Blood-brain barrier (BBB) disruption after endothelial damage is a crucial part of radiation-induced brain necrosis (RN), but little is known of BBB disruption quantification and its role in the evaluation of therapeutic effect and prognosis for drug treatment. In this retrospective study, BBB repair by bevacizumab and corticosteroid and the correlation between BBB permeability and treatment response and relapse were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). METHODS: Forty-one patients with RN after radiotherapy for nasopharyngeal carcinoma (NPC) (28 treated with bevacizumab and 13 with corticosteroid), 12 patients with no RN after NPC radiotherapy, and 12 patients with no radiotherapy history were included as RN, non-RN, and normal groups, respectively. DCE-MRI assessed BBB permeability in white matter of bilateral temporal lobe. DCE parameters were compared at baseline among the three groups. DCE parameters after treatment were compared and correlated with RN volume decrease, neurological improvement, and relapse. RESULTS: The extent of BBB leakage at baseline increased from the normal group and non-RN group and to RN necrosis lesions, especially K trans (Kruskal-Wallis test, P < 0.001). In the RN group, bevacizumab-induced K trans and v e decrease in radiation necrosis lesions (both P < 0.001), while corticosteroid showed no obvious effect on BBB. The treatment response rate of bevacizumab was significantly higher than that of corticosteroid [30/34 (88.2%) vs. 10/22 (45.4%), P < 0.001]. Spearman analysis showed baseline K trans, K ep, and v p positively correlated with RN volume decrease and improvement of cognition and quality of life in bevacizumab treatment. After a 6-month follow-up for treatment response cases, the relapse rate of bevacizumab and corticosteroid was 10/30 (33.3%) and 2/9 (22.2%), respectively, with no statistical difference. Post-bevacizumab K trans level predicted relapse in 6 months with AUC 0.745 (P < 0.05, 95% CI 0.546-0.943, sensitivity = 0.800, specificity = 0.631). CONCLUSIONS: Bevacizumab improved BBB leakage in RN necrosis. DCE parameters may be useful to predict therapeutic effect and relapse after bevacizumab.

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OBJECTIVE: Our aim was to compare the clinical outcomes of patients treated with bevacizumab combined with corticosteroids and those with bevacizumab monotherapy from a radiation-induced brain necrosis (RN) registry cohort (NCT03908502). METHODS: We utilized clinical data from a prospective RN registry cohort (NCT03908502) from July 2017 to June 2020. Patients were considered eligible if they had symptomatic RN after radiotherapy for nasopharyngeal carcinoma (NPC) and received bevacizumab (5 mg/kg, two to four cycles) with a minimum follow-up time of 3 months. The primary outcome was a 2-month response rate determined by MRI and clinical symptoms. Secondary outcomes included quality of life [evaluated by the abbreviated World Health Organization Quality of Life (WHOQOL-BREF) questionnaire] and cognitive function (evaluated by the Montreal Cognitive Assessment scale) at 2 months, RN recurrence during follow-up, and adverse events. RESULTS: A total of 123 patients (34 in the combined therapy group and 89 in the monotherapy group) were enrolled in our study with a median follow-up time of 0.97 year [interquartile range (IQR) = 0.35-2.60 years]. The clinical efficacy of RN did not differ significantly between patients in these two groups [odds ratio (OR) = 1.642, 95%CI = 0.584-4.614, p = 0.347]. Furthermore, bevacizumab combined with corticosteroids did not reduce recurrence compared with bevacizumab monotherapy [hazard ratio (HR) = 1.329, 95%CI = 0.849-2.079, p = 0.213]. The most common adverse events of bevacizumab were hypertension (17.89%), followed by nosebleed (8.13%) and fatigue (8.13%). There was no difference in grade 2 or more severe adverse events between the two groups (p = 0.811). INTERPRETATION: Our results showed that the treatment strategy of combining bevacizumab with corticosteroids did not lead to better clinical outcomes for RN patients with a background of radiotherapy for nasopharyngeal carcinoma.

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PURPOSE: We investigated the relationship between RBE-weighted dose (DRBE) calculated with constant (cRBE) and variable RBE (vRBE), dose-averaged linear energy transfer (LETd) and the risk of radiographic changes in skull base patients treated with protons. METHODS: Clinical treatment plans of 45 patients were recalculated with Monte Carlo tool FRED. Radiographic changes (i.e. edema and/or necrosis) were identified by MRI. Dosimetric parameters for cRBE and vRBE were computed. Biological margin extension and voxel-based analysis were employed looking for association of DRBE(vRBE) and LETd with brain edema and/or necrosis. RESULTS: When using vRBE, Dmax in the brain was above the highest dose limits for 38% of patients, while such limit was never exceeded assuming cRBE. Similar values of Dmax were observed in necrotic regions, brain and temporal lobes. Most of the brain necrosis was in proximity to the PTV. The voxel-based analysis did not show evidence of an association with high LETd values. CONCLUSIONS: When looking at standard dosimetric parameters, the higher dose associated with vRBE seems to be responsible for an enhanced risk of radiographic changes. However, as revealed by a voxel-based analysis, the large inter-patient variability hinders the identification of a clear effect for high LETd.

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BACKGROUND: Radiation brain necrosis (RBN) is a serious complication in patients receiving radiotherapy for intracranial disease. Many studies have investigated the efficacy and safety of bevacizumab in patients with RBN. In the present study, we systematically reviewed the medical literature for studies reporting the efficacy and safety of bevacizumab, as well as for studies comparing bevacizumab with corticosteroids. MATERIALS AND METHODS: We searched PubMed, Cochrane library, EMBASE, and ClinicalTrials.gov from their inception through 1 March, 2020 for studies that evaluated the efficacy and safety of bevacizumab in patients with RBN. Two investigators independently performed the study selection, data extraction, and data synthesis. RESULTS: Overall, the present systematic review included 12 studies (eight retrospective, two prospective, and two randomized control trials [RCTs]) involving 236 patients with RBN treated who were treated with bevacizumab. The two RCTs also had control arms comprising patients with RBN who were treated with corticosteroids/placebo (n=57). Radiographic responses were recorded in 84.7% (200/236) of patients, and radiographic progression was observed in 15.3% (36/236). Clinical improvement was observed in 91% (n=127) of responding patients among seven studies (n=113). All 12 studies reported volume reduction on T1 gadolinium enhancement MRI (median: 50%, range: 26%-80%) and/or T2 FLAIR MRI images (median: 59%, range: 48%-74%). In total, 46 responding patients (34%) had recurrence. The two RCTs revealed significantly improved radiographic response in patients treated with bevacizumab (Levin et al.: p = 0.0013; Xu et al.: p < 0.001). Both also showed clinical improvement (Levin et al.: NA; Xu et al.: p = 0.039) and significant reduction in edema volume on both T1 gadolinium enhancement MRI (Levin et al.: p=0.0058; Xu et al.: p=0.027) and T2 FLAIR MRI (Levin et al.: p=0.0149; Xu et al.: p < 0.001). Neurocognitive improvement was significantly better after 2 months of treatment in patients receiving bevacizumab than in those given corticosteroids, as assessed by the MoCA scale (p = 0.028). The recurrence rate and side effects of the treatments showed no significant differences. CONCLUSIONS: Patients with RBN respond to bevacizumab, which can improve clinical outcomes and cognitive function. Bevacizumab appears to be more efficacious than corticosteroid-based treatment. The safety profile was comparable to that of the corticosteroids.

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BACKGROUND: Brain necrosis (RN) is a common radiotherapy sequela for brain metastases. Bevacizumab is identified as a therapeutic strategy for RN. This study aimed to study the clinical and radiobiological impacts on the efficacy of Bevacizumab in treating RN following stereotactic radiosurgery (SRS) for brain metastases. METHODS: From April 2011 to November 2019, 40 patients diagnosed with RN after SRS for brain metastases were retrospectively analyzed. Patients were treated with Bevacizumab for RN and follow-up for 6 months using MR imaging at different timepoints. Linear regression was performed to evaluate the relationship between these variables. RESULTS: The median time course from the end of radiotherapy to the onset of RN was 11 months (range, 7-35 months). No significant difference was found in the edema volume between the chemotherapy group and non-chemotherapy group (P>0.05). Patients received with SRS + WBRT exhibited relatively larger edema volumes post radiotherapy than those without WBRT (P<0.05). Interestingly, the ratio of BED/GTV (Gy/cm3 ) correlated positively with the severity (time for half-reduction dose of corticosteroids) (r2 =0.13, P<0.05), and negatively with the latency period (time course for development of radiation-induced brain necrosis) (r2 =0.21, P<0.01). A new radiation doses volume index, BED × GTV (Gy·cm3 ), was proposed to facilitate the risk stratifications of patients for radiation-induced brain necrosis. Furthermore, no significant difference was found in alleviating brain edema between different regimens of Bevacizumab, i.e., 5 vs. 10 mg/kg, 2 vs. >2 cycles (both P>0.05). CONCLUSIONS: Bevacizumab is a feasible and favorable salvage treatment of BN after SRS for patients with BM. The efficacy is mainly manifested in radiological improvement and symptoms alleviation. The development of RN was found to be largely associated with radiation dose and gross tumor volume, and thus we proposed two new indexes, i.e., BED/GTV (Gy/cm3 ) for quantitative assessment of the severity and latency time, and BED × GTV (Gy·cm3 ) for risk stratifications for BN. A low dose with two cycles of Bevacizumab is recommended.

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Radiotherapy is one of the most effective treatments for head and neck tumors. However, delayed radiation-induced brain necrosis (RN) remains a serious issue due to the lack of satisfying prevention and effective treatment. The pathological role of radiation in the delayed onset of brain necrosis is still largely unknown, and the traditional animal model of whole brain irradiation, although being widely used, does not produce reliable and localized brain necrosis mimicking clinical features of RN. In this study, we demonstrated a successful RN mouse model using optimized gamma knife irradiation in male C57BL/6 mice. On the premise that brain necrosis started to appear at 6 weeks postirradiation in our RN model, as confirmed by both MRI and histopathological examinations, we systematically examined different time points before the onset of RN for the histopathological changes and biochemical indicators. Our initial results demonstrated that in the ipsilateral hemisphere of the irradiated brains, a significant decrease in neuronal numbers that occurred at 4 weeks and a sustained increase in TNF-α, iNOS, and other inflammatory cytokines beginning at 1-week postirradiation. Changes of cell morphology and cell numbers of both microglia and astrocytes occurred as early as 1-week postirradiation, and intervention by bevacizumab administration resulted in reduced microglia activation and reduction of radiation-induced lesion volume, indicating that chronic glial activation may result in subsequent elevation of inflammatory factors, which led to the delayed onset of neuronal loss and brain necrosis. Since C57BL/6 is the most widely used strain of genetic engineered mouse model, our data provide an invaluable platform for the mechanistic study of RN pathogenesis, identification of potential imaging and biological biomarkers, and the development of therapeutic treatment for the disease.

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