FLASH Radiotherapy: Mechanisms of Biological Effects and the Therapeutic Potential in Cancer.

Radiotherapy is an important treatment for many unresectable advanced malignant tumors, and radiotherapy-associated inflammatory reactions to radiation and other toxic side effects are significant reasons which reduce the quality of life and survival of patients. FLASH-radiotherapy (FLASH-RT), a prominent topic in recent radiation therapy research, is an ultra-high dose rate treatment known for significantly reducing therapy time while effectively targeting tumors. This approach minimizes radiation side effects on at-risk organs and maximally protects surrounding healthy tissues. Despite decades of preclinical exploration and some notable achievements, the mechanisms behind FLASH effects remain debated. Standardization is still required for the type of FLASH-RT rays and dose patterns. This review addresses the current state of FLASH-RT research, summarizing the biological mechanisms behind the FLASH effect. Additionally, it examines the impact of FLASH-RT on immune cells, cytokines, and the tumor immune microenvironment. Lastly, this review will discuss beam characteristics, potential clinical applications, and the relevance and applicability of FLASH-RT in treating advanced cancers.

An immune-related gene prognostic prediction risk model for neoadjuvant chemoradiotherapy in rectal cancer using artificial intelligence.

Background: This study aimed to establish and validate a prognostic model based on immune-related genes (IRGPM) for predicting disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC) undergoing neoadjuvant chemoradiotherapy, and to elucidate the immune profiles associated with different prognostic outcomes. Methods: Transcriptomic and clinical data were sourced from the Gene Expression Omnibus (GEO) database and the West China Hospital database. We focused on genes from the RNA immune-oncology panel. The elastic net approach was employed to pinpoint immune-related genes significantly impacting DFS. We developed the IRGPM for rectal cancer using the random forest technique. Based on the IRGPM, we calculated prognostic risk scores to categorize patients into high-risk and low-risk groups. Comparative analysis of immune characteristics between these groups was conducted. Results: In this study, 407 LARC samples were analyzed. The elastic net identified a signature of 20 immune-related genes, forming the basis of the IRGPM. Kaplan-Meier survival analysis revealed a lower 5-year DFS in the high-risk group compared to the low-risk group. The receiver operating characteristic (ROC) curve affirmed the model's robust predictive capability. Validation of the model was performed in the GSE190826 cohort and our institution's cohort. Gene expression differences between high-risk and low-risk groups predominantly related to cytokine-cytokine receptor interactions. Notably, the low-risk group exhibited higher immune scores. Further analysis indicated a greater presence of activated B cells, activated CD8 T cells, central memory CD8 T cells, macrophages, T follicular helper cells, and type 2 helper cells in the low-risk group. Additionally, immune checkpoint analysis revealed elevated PDCD1 expression in the low-risk group. Conclusions: The IRGPM, developed through random forest and elastic net methodologies, demonstrates potential in distinguishing DFS among LARC patients receiving standard treatment. Notably, the low-risk group, as defined by the IRGPM, showed enhanced activation of adaptive immune responses within the tumor microenvironment.

Comparative dosimetric study of radiotherapy in high-grade gliomas based on the guidelines of EORTC and NRG-2019 target delineation.

Purpose: Radiotherapy is one of the most important treatments for high-grade glioma (HGG), but the best way to delineate the target areas for radiotherapy remains controversial, so our aim was to compare the dosimetric differences in radiation treatment plans generated based on the European Organization for Research and Treatment of Cancer (EORTC) and National Research Group (NRG) consensus to provide evidence for optimal target delineation for HGG. Methods: We prospectively enrolled 13 patients with a confirmed HGG from our hospital and assessed dosimetric differences in radiotherapy treatment plans generated according to the EORTC and NRG-2019 guidelines. For each patient, two treatment plans were generated. Dosimetric parameters were compared by dose-volume histograms for each plan. Results: The median volume for planning target volume (PTV) of EORTC plans, PTV1 of NRG-2019 plans, and PTV2 of NRG-2019 plans were 336.6 cm3 (range, 161.1-511.5 cm3), 365.3 cm3 (range, 123.4-535.0 cm3), and 263.2 cm3 (range, 116.8-497.7 cm3), respectively. Both treatment plans were found to have similar efficiency and evaluated as acceptable for patient treatment. Both treatment plans showed well conformal index and homogeneity index and were not statistically significantly different (P = 0.397 and P = 0.427, respectively). There was no significant difference in the volume percent of brain irradiated to 30, 46, and 60 Gy according to different target delineations (P = 0.397, P = 0.590, and P = 0.739, respectively). These two plans also showed no significant differences in the doses to the brain stem, optic chiasm, left and right optic nerves, left and right lens, left and right eyes, pituitary, and left and right temporal lobes (P = 0.858, P = 0.858, P = 0.701 and P = 0.794, P = 0.701 and P = 0.427, P = 0.489 and P = 0.898, P = 0.626, and P = 0.942 and P = 0.161, respectively). Conclusion: The NRG-2019 project did not increase the dose of organs at risk (OARs) radiation. This is a significant finding that further lays the groundwork for the application of the NRG-2019 consensus in the treatment of patients with HGGs. Clinical trial registration: The effect of radiotherapy target area and glial fibrillary acidic protein (GFAP) on the prognosis of high-grade glioma and its mechanism, number ChiCTR2100046667. Registered 26 May 2021.

The Performance of Different Machine Learning Algorithm and Regression Models in Predicting High-Grade Intracranial Meningioma.

Meningioma is the most common primary tumor of the central nervous system (CNS). Individualized treatment strategies should be formulated for the patients according to the WHO (World Health Organization) grade. Our aim was to investigate the effectiveness of various machine learning and traditional statistical models in predicting the WHO grade of preoperative patients with meningioma. Patients diagnosed with meningioma after surgery in West China Hospital and Shangjin Hospital of Sichuan University from 2009 to 2016 were included in the study cohort. As the training cohort (n = 1975), independent risk factors associated with high-grade meningioma were used to establish the Nomogram model. which was validated in a subsequent cohort (n = 1048) from 2017 to 2019 in our hospital. Logistic regression (LR), XGboost, Adaboost, Support Vector Machine (SVM), K-Nearest Neighbor (KNN), and Random Forest (RF) models were determined using F1 score, recall, accuracy, the area under the curve (ROC), calibration plot and decision curve analysis (DCA) were used to evaluate the different models. Logistic regression showed better predictive performance and interpretability than machine learning. Gender, recurrence history, T1 signal intensity, enhanced signal degree, peritumoral edema, tumor diameter, cystic, location, and NLR index were identified as independent risk factors and added to the nomogram. The AUC (Area Under Curve) value of RF was 0.812 in the training set, 0.807 in the internal validation set, and 0.842 in the external validation set. The calibration curve and DCA (Decision Curve Analysis) indicated that it had better prediction efficiency of LR than others. The Nomogram preoperative prediction model of meningioma of WHO II and III grades showed effective prediction ability. While machine learning exhibits strong fitting ability, it performs poorly in the validation set.

Diffusion-Weighted Magnetic Resonance Imaging-Guided Dose Painting in Patients With Locoregionally Advanced Nasopharyngeal Carcinoma Treated With Induction Chemotherapy Plus Concurrent Chemoradiotherapy: A Randomized, Controlled Clinical Trial.

PURPOSE: We hypothesized that diffusion-weighted magnetic resonance imaging (DWI)-guided dose-painting intensity modulated radiation therapy (DP-IMRT) is associated with improved local tumor control and survival in locoregionally advanced nasopharyngeal carcinoma (NPC). The purpose of this randomized study was to compare the efficacy and toxicity of DWI-guided DP-IMRT to conventional magnetic resonance imaging (MRI)-based IMRT in locoregional advanced NPC. METHODS AND MATERIALS: A total of 260 patients with stage III-IVa NPC disease were randomly assigned in a 1:1 ratio to receive induction chemotherapy followed by chemoradiotherapy by DWI-guided DP-IMRT (group A, n = 130) or conventional MRI-based IMRT (group B, n = 130) in this prospective clinical trial. In group A, subvolume GTVnx-DWI (gross tumor volume of nasopharynx in DWI) was defined as the areas within the GTVnx (gross tumor volume of nasopharynx) with an apparent diffusion coefficient (ADC) below the mean ADC (ADC < mean) according to MRI before induction chemotherapy. The dose to GTVnx-DWI was escalated to 75.2 Gy/32 fx in patients with T1-2 disease and to 77.55 Gy/33 fx in those with T3-4 disease in 2.35 Gy per fraction. In group B, planning gross tumor volume of nasopharynx was irradiated at 70.4 to 72.6 Gy/32 to 33 fx in 2.2 Gy per fraction. This trial is registered with chictr.org.cn (ChiCTR1800015779). RESULTS: A total of 260 patients were included in the trial (130 patients in group A and 130 in group B). Complete response rates after chemoradiotherapy were 99.2% (129 of 130) and 93.8% (122 of 130) in groups A and B, respectively (P = .042). At a median follow-up of 25 months, DWI-guided DP-IMRT was associated with improved 2-year disease-free survival (DFS; 93.6% [95% confidence interval {CI}, 88.1%-99.1%] vs 87.5% [95% CI, 81.4%-93.6%], P = .015), local recurrence-free survival (100% [95% CI, not applicable {NA}] vs 91.3% [95% CI, 85.4%-97.2%]), locoregional recurrence-free survival (LRRFS; 95.8% [95% CI, NA] vs 91.3% [95% CI, 85.4%-97.2%]), distant metastasis-free survival (DMFS; 97.8% [95% CI, NA] vs 90.9% [95% CI, 85.8%-96.0%]), and overall survival (100% [95% CI, NA] vs 94.5% [95% CI, 89.2%-99.8%]). Zero and 3 patients had local-only recurrences in group A and B, respectively. The most common site of first failure in each arm was distant organ failure. No statistically significant differences in acute and late toxic effects were observed. Multivariate analyses showed that DP (DWI-guided DP-IMRT vs conventional MRI-based IMRT without DP) was associated with DFS, local recurrence-free survival, LRRFS, and distant metastasis-free survival. Epstein-Barr virus DNA level was associated with DFS and LRRFS. CONCLUSIONS: DWI-guided DP-IMRT plus chemotherapy is associated with a disease-free survival benefit compared with conventional MRI-based IMRT among patients with locoregionally advanced NPC without increasing acute toxic effects.

Prognostic Relevance of 18F-FDG-PET/CT-Guided Target Volume Delineation in Loco-Regionally Advanced Nasopharyngeal Carcinomas: A Comparative Study.

INTRODUCTION: An optimal approach to define tumor volume in locoregionally advanced nasopharyngeal carcinoma (NPC) using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) remains unclear. This retrospective study aimed at comparing the outcomes and toxicities of different FDG-PET/CT-guided techniques for primary tumor volume delineation in locoregionally advanced NPC. METHODS: From August 2015 to February 2018, 292 patients with stage III-IVB NPC received FDG-PET/CT-guided IMRT. Three PET/CT-based techniques were used to determine the gross tumor volume (GTV) as follows: visual criteria (group A; n = 98), a standard uptake value (SUV) threshold of 2.5 (group B; n = 95), and a threshold of 50% maximal intensity (group C, n = 99) combined with a dose-painting technique. RESULTS: In groups A, B, and C, the 5-year LRFS rates were 89.4%, 90.0%, and 97.8%, respectively (p = 0.043). The 5-year DMFS rates were 75.1%, 76.0%, and 87.7%, respectively (p = 0.043). The 5-year DFS rates were 70.9%, 70.3%, and 82.2%, respectively (p = 0.048). The 5-year OS rates were 73.5%, 73.9%, and 84.9%, respectively (p = 0.038). Group C showed significantly higher 5-year LRFS, LRRFS, DMFS, DFS, and OS than those in groups A and B (p < 0.05). No statistically significant differences were observed between the three study groups in the cumulative incidences of grade 3-4 acute and late toxicities. Multivariate analyses showed that the PET/CT-guided technique for target volume delineation was an independent prognostic factor for 5-year LRFS, DFS, DMFS, and OS (p = 0.039, p = 0.030, p = 0.035 and p = 0.028, respectively), and was marginally significant in predicting LRRFS (p = 0.080). CONCLUSIONS: The 50% SUVmax threshold regimen for GTV delineation with dose-painting appeared to be superior to the visual criteria or SUV2.5 threshold in locoregionally advanced NPC, and there was no increased toxicity.

Lateral Ventricular Meningiomas: Clinical Features, Radiological Findings and Long-Term Outcomes.

PURPOSE: Lateral ventricle meningioma (LVM) is a rare type of intracranial meningioma, which has been rarely studied. It has different clinical features, imaging features, and long-term results from other locations. This study investigated the epidemiology, clinical characteristics and prognosis of LVM and comprehensively describes its characteristics. METHODS: This article analyzes the LVMs that were diagnosed pathologically in West China hospital between January 1, 2009 and July 1 2020. Demographic information, imaging characteristics and prognostic factors are discussed. Data analysis was performed using SPSS 23.0 and R version 3.5.3. RESULTS: We collected 7202 meningiomas and 195 LVMs (136 females; median age, 46 years; range, 5-81 years) were included in this study. Gross total resection was completed in 189 patients. The OS rate was 93.8%, and the recurrence rate was 5.2%. Multivariate regression analysis showed that sex (P = 0.01) and tumor size (P = 0.018) were related to WHO grade. Postoperative KPS (P = 0.003) was associated with OS. WHO grade (P = 0.025), extent of tumor resection (P < 0.001), and hospital day (P=0.028) were associated with recurrence. CONCLUSION: LVMs require long-term follow-up, individualized treatment, and follow-up strategies to be formulated according to the relevant risk factors.

Nomograms for Predicting Overall Survival Among Patients with Craniopharyngiomas at Initial Diagnosis: A SEER Population-Based Analysis.

BACKGROUND: Craniopharyngiomas (CPs) are relatively rare benign tumor located in the central nervous system (CNS). This study investigates the related risk factors of survival of craniopharyngiomas and develops a simple but detailed method predicting prognosis based on the Surveillance, Epidemiology, and End Results (SEER) database in order to improve the clinic management of CPs. METHODS: Between 2004 and 2017, 1213 patients diagnosed with craniopharyngiomas registered at the program and were included in the SEER-21 registry database. Overall survival (OS) curves were plotted with the Kaplan-Meier method and significance was determined by Log rank test. Single- and multiple-factor regression analyses were made using Cox proportional hazards model to identify independent predictors related to OS. Subsequently, we developed a nomogram with those factors to predict 3-, 5- and 10-year OS of craniopharyngiomas patients. RESULTS: We identified 1213 patients with craniopharyngioma. The OS rates at 3, 5, and 10 years after diagnosis were 89.1%, 86.2%, and 83%. Age, ethnicity, tumor size and radiation therapy were confirmed to be predictors correlating with OS at initial diagnosis. In multivariate analysis, we found that younger age (P<0.001), smaller tumor size (P<0.001), white ethnicity (P<0.001) and radiation therapy (P=0.004) were the factors that remained significantly associated with better survival. A nomogram was successfully constructed and validated by ROC, calibration plots and C-index of 0.773 (95% CI, 0.708-0.838). CONCLUSION: The well-calibrated nomogram is the first clinical prediction model for predicting the prognosis for patients with craniopharyngiomas at initial diagnosis. Our study indicates that the surgical effect is not clear. Younger white patients with radiotherapy have a better prognosis, and the gross total resection (GTR) was not effective in prolonging the OS of a patient compared to no surgery and subtotal resection (STR).

Prognostic Value of Survivin in Nasopharyngeal Carcinoma: A Systematic Review and Meta-analysis.

Background: Previous studies have shown that survivin has potential prognostic value in nasopharyngeal carcinoma. However, the results remained controversial until now. Thus, to investigate the influence of survivin expression on prognosis and clinical characteristics in nasopharyngeal carcinoma, we performed this meta-analysis. Methods: We searched PubMed, PMC, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure electronic databases from their establishment to 1 March 2021. The pooled hazard ratio (HR) and the pooled odds ratio (OR) were used to evaluate the prognostic and clinicopathological values of survivin in nasopharyngeal carcinoma. We used the I2 statistic and the Q test to evaluate heterogeneity. Meta-regression, publication bias, and sensitivity analyses were also conducted. Results: A total of 26 eligible studies with 2278 patients were included in our meta-analysis. We found that the expression of survivin is connected with poor overall survival (HR=1.94; 95% confidence interval (CI)=1.52-2.48; P<0.001), lymph node metastasis (OR=3.01; 95% CI=2.31- 3.91; P<0.001), local recurrence (OR=2.40; 95% CI=1.60-3.61, P<0.001), distant metastasis (OR=2.58; 95% CI=1.74-3.84, P<0.001), and a higher clinical stage (OR=4.58; 95% CI=2.81-7.47, P<0.001). However, no significant correlations were found between survivin expression and radio-sensitivity (OR=1.33; 95% CI=0.25-7.17, P=0.737) or gender (OR=1.02; 95% CI=0.75-1.39, P=0.887). Conclusions: This meta-analysis indicates that survivin could be used as a biomarker for predicting prognosis in nasopharyngeal carcinoma.

Effects of Cognitive Behavioral Therapy for Depression and Anxiety, Response Rates and Adverse Events in Patients with Locoregional Advanced Nasopharyngeal Carcinoma.

PURPOSE: This retrospective study investigated the effects of cognitive behavioral therapy (CBT) on depression, anxiety, response rates, and adverse events in patients with locoregional advanced nasopharyngeal carcinoma (NPC). METHODS: A total of 269 patients with diagnosis of stage III-IVA NPC received either CBT plus chemoradiotherapy (CBT group, n = 136) or treatment as usual (TAU) plus chemoradiotherapy (TAU group, n = 133). Patients in the CBT group received a series of 6 CBT sessions for 6 weeks during concurrent chemoradiotherapy. Depression and anxiety were assessed using the Hospital Anxiety and Depression Scale (HADS) score at baseline, the completion of radiotherapy, and 6, 12, and 24 months after radiotherapy. Response rates and adverse events were also evaluated. RESULTS: Patients in the CBT group showed significantly less depression and anxiety than patients in the TAU group after the completion of radiotherapy (P < .05). Complete response rates were 99.3% (135/136) and 92.5% (123/133) in the CBT group and TAU group with a small effect size (Phi coefficient = .171), respectively (P = .005). Compared with the TAU group, the CBT group showed a significantly lower incidence of acute adverse events and late toxic effects. CONCLUSIONS: The addition of CBT to chemoradiotherapy significantly reduced depressive and anxiety symptoms. CBT combined with chemoradiotherapy is associated with improved response rates, with reduced incidence of toxic effects in patients with locoregional advanced NPC. Based on this study, we registered a randomized controlled clinical trials to better define the role of CBT in patients with locoregional advanced NPC (Registration number: ChiCTR2000034701).

Nomograms Forecasting Long-Term Overall and Cancer Specific Survival of Patients With Head and Neck Neuroendocrine Carcinoma.

BACKGROUND: The purpose of this retrospective analysis was to build and validate nomograms to predict the cancer-specific survival (CSS) and overall survival (OS) of head and neck neuroendocrine carcinoma (HNNEC) patients. METHODS: A total of 493 HNNEC patients were selected from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015, and 74 HNNEC patients were collected from the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital (HCH) between 2008 and 2020. Patients from SEER were randomly assigned into training (N=345) and internal validation (N=148) groups, and the independent data group (N=74) from HCH was used for external validation. Independent prognostic factors were collected using an input method in a Cox regression model, and they were then included in nomograms to predict 3-, 5-, and 10-year CSS and OS rates of HNNEC patients. Finally, we evaluated the internal and external validity of the nomograms using the consistency index, while assessing their prediction accuracy using calibration curves. A receiver operating curve (ROC) was also used to measure the performance of the survival models. RESULTS: The 3-, 5-, and 10-year nomograms of this analysis demonstrated that M classification had the largest influence on CSS and OS of HNNEC, followed by the AJCC stage, N stage, age at diagnosis, sex/gender, radiation therapy, and marital status. The training validation C-indexes for the CSS and OS models were 0.739 and 0.713, respectively. Those for the internal validation group were 0.726 and 0.703, respectively, and for the external validation group were 0.765 and 0.709, respectively. The area under the ROC curve (AUC) of 3-, 5-, and 10-year CSS and OS models were 0.81, 0.82, 0.82, and 0.78, 0.81, and 0.82, respectively. The C-indexes were all higher than 0.7, indicating the high accuracy ability of our model's survival prediction. CONCLUSIONS: In this study, prognosis nomograms in HNNEC patients were constructed to predict CSS and OS for the first time. Clinicians can identify patients' survival risk better and help patients understand their survival prognosis for the next 3, 5, and 10 years more clearly by using these nomograms.