Radiotherapy in Preclinical Models of Brain Metastases: A Review and Recommendations for Future Studies.

Brain metastases (BMs) frequently occur in primary tumors such as lung cancer, breast cancer, and melanoma, and are associated with notably short natural survival. In addition to surgical interventions, chemotherapy, targeted therapy, and immunotherapy, radiotherapy (RT) is a crucial treatment for BM and encompasses whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS). Validating the efficacy and safety of treatment regimens through preclinical models is imperative for successful translation to clinical application. This not only advances fundamental research but also forms the theoretical foundation for clinical study. This review, grounded in animal models of brain metastases (AM-BM), explores the theoretical underpinnings and practical applications of radiotherapy in combination with chemotherapy, targeted therapy, immunotherapy, and emerging technologies such as nanomaterials and oxygen-containing microbubbles. Initially, we provided a concise overview of the establishment of AM-BMs. Subsequently, we summarize key RT parameters (RT mode, dose, fraction, dose rate) and their corresponding effects in AM-BMs. Finally, we present a comprehensive analysis of the current research status and future directions for combination therapy based on RT. In summary, there is presently no standardized regimen for AM-BM treatment involving RT. Further research is essential to deepen our understanding of the relationships between various parameters and their respective effects.

The value of postoperative radiotherapy in thymoma patients with myasthenia gravis.

INTRODUCTION: Surgery is the first-line treatment for patients with thymoma associated with myasthenia gravis (MG); however, the value of radiotherapy among these patients remains debatable. Herein, we examined the impact of postoperative radiotherapy (PORT) on the efficacy and prognosis of patients with thymoma and MG. METHODS: This retrospective cohort study included 126 patients with thymoma and MG who were enrolled in the Xiangya Hospital clinical database between 2011 and 2021. Demographic and clinical data were collected including sex, age, histologic subtype, Masaoka-Koga staging, primary tumor, lymph node, metastasis (TNM) staging, and therapeutic modalities. To evaluate short-term MG symptom improvement following PORT, we examined changes in the quantitative myasthenia gravis (QMG) scores within 3 months post-treatment. Minimal manifestation status (MMS) was the main endpoint for assessing long-term improvement in MG symptoms. Overall survival (OS) and disease-free survival (DFS) were primary endpoints to determine the impact of PORT on prognosis. RESULTS: Effects of PORT on MG symptoms: QMG scores significantly differed between the non-PORT and PORT groups (χ2 = 6.300, p = 0.012). The median time to achieve MMS was significantly shorter in the PORT group than that in the non-PORT group (2.0 years vs. 4.4 years; p = 0.031). Multivariate analysis revealed that radiotherapy was associated with a reduced time to achieve MMS (hazard ratio [HR] 1.971, 95% confidence interval [CI]:1.102-3.525, p = 0.022). Effects of PORT on DFS and OS: The 10-year OS rate of the entire cohort was 90.5%, whereas OS rates for the PORT and non-PORT groups were 94.4 and 85.1%, respectively. The 5-year DFS rates for the whole cohort, PORT group, and non-PORT group were 89.7, 95.8, and 81.5%, respectively. PORT was associated with improved DFS (HR 0.139, 95% CI: 0.037-0.533, p = 0.004). In the high-risk histologic subgroup (type B2, B3), patients who received PORT had better OS (p = 0.015) and DFS (p = 0.0053) than those who did not receive PORT. PORT was associated with improved DFS (HR 0.232, 95% CI: 0.069-0.782, p = 0.018) in Masaoka-Koga stages II, III, and IV disease. CONCLUSIONS: Overall, our findings indicate that PORT positively impacts thymoma patients with MG, particularly those with a higher histologic subtype and Masaoka-Koga staging.

The schemes, mechanisms and molecular pathway changes of Tumor Treating Fields (TTFields) alone or in combination with radiotherapy and chemotherapy.

Tumor Treating Fields (TTFields) is a physical therapy that uses moderate frequency (100-300 kHz) and low-intensity (1-3 V/cm) alternating electric fields to inhibit tumors. Currently, the Food and Drug Administration approves TTFields for treating recurrent or newly diagnosed glioblastoma (GBM) and malignant pleural mesothelioma (MPM). The classical mechanism of TTFields is mitotic inhibition by hindering the formation of tubulin and spindle. In addition, TTFields inhibits cell proliferation, invasion, migration and induces cell death, such as apoptosis, autophagy, pyroptosis, and cell cycle arrest. Meanwhile, it regulates immune function and changes the permeability of the nuclear membrane, cell membrane, and blood-brain barrier. Based on the current researches on TTFields in various tumors, this review comprehensively summarizes the in-vitro effects, changes in pathways and molecules corresponding to relevant parameters of TTFields (frequency, intensity, and duration). In addition, radiotherapy and chemotherapy are common tumor treatments. Thus, we also pay attention to the sequence and dose when TTFields combined with radiotherapy or chemotherapy. TTFields has inhibitory effects in a variety of tumors. The study of TTFields mechanism is conducive to subsequent research. How to combine common tumor therapy such as radiotherapy and chemotherapy to obtain the maximum benefit is also a problem that's worthy of our attention.

The Long-Term and Short-Term Efficacy of Immunotherapy in Non-Small Cell Lung Cancer Patients With Brain Metastases: A Systematic Review and Meta-Analysis.

Background: Although immunotherapy has been widely used, there is currently no research comparing immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). This meta-analysis addresses a gap in the comparison of immunotherapy efficacy, including immune checkpoint inhibitors (ICIs), chemotherapy (CT), radiotherapy (RT), and ICI combined CT or RT. Methods: A search of Pubmed, Cochrane, EMBASE, and ClinicalTrial.gov was conducted to identify studies which enrolled NSCLC patients with BM treated with ICIs. The outcomes consisted of intracerebral overall response rate (iORR), intracerebral disease control rate (iDCR), extracranial overall response rate (EORR), distant brain failure (DBF), local control (LC), progression-free survival (PFS), and overall survival (OS). Results: A total of 3160 participants from 46 trials were included in the final analysis. Patients treated with immunotherapy were associated with a longer PFS (0.48, 95%CI: 0.41-0.56), and a longer OS (0.64, 95%CI: 0.60-0.69) compared with immunotherapy-naive patients. In prospective studies, dual ICI combined CT and ICI combined CT achieved a better OS. The hazard ratio (HR) of dual ICI combined CT versus dual ICI was 0.61, and the HR of ICI combined CT versus ICI monotherapy was 0.58. Moreover, no statistical difference in PFS, OS, EORR, iORR, iDCR, and EDCR was found between patients with ICI monotherapy and ICI combined cranial radiotherapy. Concurrent ICI combined RT was shown to decrease the rate of DBF (OR = 0.15, 95% CI: 0.03-0.73) compared with RT after ICI. Patients treated with WBRT might have an inferior efficacy than those with SRS because the iORR of SRS was 0.75 (0.70, 0.80) and WBRT was 0. Furthermore, no obvious difference in PFS and OS was observed among the three different types of ICI, which targets PD-1, PD-L1, and CTLA-4, respectively. Conclusions: Patients treated with ICI got superior efficacy to those without ICI. Furthermore, dual ICI combined CT and ICI combined CT seemed to be optimal for NSCLC patients with BM. In terms of response and survival, concurrent administration of SRS and ICI led to better outcomes for patients with BMs than non-concurrent or non-SRS. Importance of the Study: In the new era of immunotherapy, our meta-analysis validated the importance of immunotherapy for non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). By comparing the long-term and short-term impacts of various regimens, all immunotherapy treatments had superior efficacy to immunotherapy-naive. At the same time, through pairwise comparison in immunotherapy, our findings can help clinicians to make treatment decisions for NSCLC patients with BMs. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=269621, identifier CRD42021269621.

An Immune-Related Prognostic Signature for Predicting Clinical Outcomes and Immune Landscape in IDH-Mutant Lower-Grade Gliomas.

BACKGROUND: IDH mutation is the most common in diffuse LGGs, correlated with a favorable prognosis. However, the IDH-mutant LGGs patients with poor prognoses need to be identified, and the potential mechanism leading to a worse outcome and treatment options needs to be investigated. METHODS: A six-gene immune-related prognostic signature in IDH-mutant LGGs was constructed based on two public datasets and univariate, multivariate, and LASSO Cox regression analysis. Patients were divided into low- and high-risk groups based on the median risk score in the training and validation sets. We analyzed enriched pathways and immune cell infiltration, applying the GSEA and the immune evaluation algorithms. RESULTS: Stratification and multivariate Cox analysis unveiled that the six-gene signature was an independent prognostic factor. The signature (0.806/0.795/0.822) showed a remarkable prognostic performance, with 1-, 3-, and 5-year time-dependent AUC, higher than for grade (0.612/0.638/0.649) and 1p19q codeletion status (0.606/0.658/0.676). High-risk patients had higher infiltrating immune cells. However, the specific immune escape was observed in the high-risk group after immune activation, owing to increasing immunosuppressive cells, inhibitory cytokines, and immune checkpoint molecules. Moreover, a novel nomogram model was developed to evaluate the survival in IDH-mutant LGGs patients. CONCLUSION: The six-gene signature could be a promising prognostic biomarker, which is promising to promote individual therapy and improve the clinical outcomes of IDH-mutant gliomas. The study also refined the current classification system of IDH-mutant gliomas, classifying patients into two subtypes with distinct immunophenotypes and overall survival.

Immune checkpoint inhibitors for brain metastases in non-small-cell lung cancer: from rationale to clinical application.

Brain metastases (BM) is common in non-small-cell lung cancer (NSCLC) patients. Immune checkpoint inhibitors (ICIs) have gradually become a routine treatment for NSCLC BM patients. Currently, three PD-1 inhibitors (pembrolizumab, nivolumab and cemiplimab), one PD-L1 inhibitor (atezolizumab) and one CTLA-4 inhibitor (ipilimumab) have been approved for the first-line treatment of metastatic NSCLC. It is still controversial whether PD-L1, tumor infiltrating lymphocytes, and tumor mutation burden can be used as predictive biomarkers for immune checkpoint inhibitors in NSCLC patients with BM. In addition, clinical data on NSCLC BM were inadequate. Here, we review the theoretical basis and clinical data for the application of ICIs in the therapy of NSCLC BM.

Handcrafted and Deep Learning-Based Radiomic Models Can Distinguish GBM from Brain Metastasis.

OBJECTIVE: The purpose of this study was to investigate the feasibility of applying handcrafted radiomics (HCR) and deep learning-based radiomics (DLR) for the accurate preoperative classification of glioblastoma (GBM) and solitary brain metastasis (BM). METHODS: A retrospective analysis of the magnetic resonance imaging (MRI) data of 140 patients (110 in the training dataset and 30 in the test dataset) with GBM and 128 patients (98 in the training dataset and 30 in the test dataset) with BM confirmed by surgical pathology was performed. The regions of interest (ROIs) on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and contrast-enhanced T1WI (T1CE) were drawn manually, and then, HCR and DLR analyses were performed. On this basis, different machine learning algorithms were implemented and compared to find the optimal modeling method. The final classifiers were identified and validated for different MRI modalities using HCR features and HCR + DLR features. By analyzing the receiver operating characteristic (ROC) curve, the area under the curve (AUC), accuracy, sensitivity, and specificity were calculated to evaluate the predictive efficacy of different methods. RESULTS: In multiclassifier modeling, random forest modeling showed the best distinguishing performance among all MRI modalities. HCR models already showed good results for distinguishing between the two types of brain tumors in the test dataset (T1WI, AUC = 0.86; T2WI, AUC = 0.76; T1CE, AUC = 0.93). By adding DLR features, all AUCs showed significant improvement (T1WI, AUC = 0.87; T2WI, AUC = 0.80; T1CE, AUC = 0.97; p < 0.05). The T1CE-based radiomic model showed the best classification performance (AUC = 0.99 in the training dataset and AUC = 0.97 in the test dataset), surpassing the other MRI modalities (p < 0.05). The multimodality radiomic model also showed robust performance (AUC = 1 in the training dataset and AUC = 0.84 in the test dataset). CONCLUSION: Machine learning models using MRI radiomic features can help distinguish GBM from BM effectively, especially the combination of HCR and DLR features.

Cdk5-mediated Drp1 phosphorylation drives mitochondrial defects and neuronal apoptosis in radiation-induced optic neuropathy.

Radiation-induced optic neuropathy (RION) is a devastating complication following external beam radiation therapy (EBRT) that leads to acute vision loss. To date, no efficient, available treatment for this complication, due partly to the lack of understanding regarding the developmental processes behind RION. Here, we report radiation caused changes in mitochondrial dynamics by regulating the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission-1 (Fis1). Concurrent with an excessive production of reactive oxygen species (ROS), both neuronal injury and visual dysfunction resulted. Further, our findings delineate an important mechanism by which cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation of Drp1 (Ser616) regulates defects in mitochondrial dynamics associated with neuronal injury in the development of RION. Both the pharmacological inhibition of Cdk5 by roscovitine and the inhibition of Drp1 by mdivi-1 inhibited mitochondrial fission and the production of ROS associated with radiation-induced neuronal loss. Taken together, these findings may have clinical significance in preventing the development of RION.

Clinical value of a plasma Epstein-Barr virus DNA assay in the diagnosis of recurrent or metastatic nasopharyngeal carcinoma: a meta-analysis.

BACKGROUND: To evaluate the diagnostic value of Epstein-Barr virus (EBV) DNA in nasopharyngeal carcinoma (NPC) patients with locoregional or distant recurrence. METHODS: Articles related to the diagnosis of recurrent or metastatic NPC by the detection of EBV DNA in plasma or serum were retrieved from different databases. Sensitivity, specificity, summary receiver operating characteristic (SROC) curves, and likelihood ratios were pooled to assess the diagnostic value of individual diagnostic tests. RESULTS: This meta-analysis pooled 25 eligible studies including 2496 patients with NPC. The sensitivity, specificity, positive likelihood ratio (+LR), and negative likelihood ratio (-LR) of EBV DNA in the diagnosis of NPC were 0.858 (95% confidence interval (CI): 0.801-0.901), 0.890 (95% CI: 0.866-0.909), 7.782 (95% CI: 6.423-9.429) and 0.159 (95% CI: 0.112-0.226), respectively. The diagnostic odds ratio (DOR) was 48.865 (95% CI: 31.903-74.845). The SROC for EBV DNA detection was 0.93 (95% CI: 0.90-0.95). CONCLUSION: The detection of EBV DNA for the diagnosis of recurrent or metastatic NPC has good sensitivity and specificity and might be helpful in monitoring recurrent or metastatic NPC.

Growth and differentiation factor 15 regulates PD-L1 expression in glioblastoma.

Background: Gliomablastoma multiforme (GBM) is the most fatal form of all brain cancers in human with no successful treatment available. Programmed death-ligand 1 (PD-L1) is a coinhibitory ligand predominantly expressed by tumor cells. Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in tissue development and cancer. Purpose: To investigat the expression of GDFs in GBMs, and explored the potential regulatory role of GDFs on PD-L1 expression in GBMs. Methods: GEO2R program were analyzed for the mRNA expression data of GDFs in GSE4290 dataset. Analysis of TCGA GBM datasets were further determined the relationship between GDFs and PD-L1. Western blot Western blot was used to detect the expression of PD-L1 in GBM cell lines. Results: GDFs displayed differential patterns of expression with GDF15 and myostatin (MSTN) highly enriched in GBM tissues. We also identified GDF15 as a novel regulator that induces PD-L1 expression in GBM cells. Consistently, GDF15 expression correlated with PD-L1 in TCGA GBM dataset. Further, GDF15 enhanced PD-L1 expression via Smad2/3 pathway in GBM cell line U87, U251 and SHG44, which was inhibited by Smad2/3 inhibitor SIS3. Knockdown of GDF15 attenuated Smad2/3 signaling and reduced PD-L1 expression in A172 and GIC6 glioma cells. Conclusion: GDF15 might be a novel regulator of PD-L1 expression in GBMs; targeting GDF15/PD-L1 pathway might be a promising therapeutic approach for GBM patients.

Calculation of intercepted runoff depth based on stormwater quality and environmental capacity of receiving waters for initial stormwater pollution management.

While point source pollutions have gradually been controlled in recent years, the non-point source pollution problem has become increasingly prominent. The receiving waters are frequently polluted by the initial stormwater from the separate stormwater system and the wastewater from sewage pipes through stormwater pipes. Consequently, calculating the intercepted runoff depth has become a problem that must be resolved immediately for initial stormwater pollution management. The accurate calculation of intercepted runoff depth provides a solid foundation for selecting the appropriate size of intercepting facilities in drainage and interception projects. This study establishes a separate stormwater system for the Yishan Building watershed of Fuzhou City using the InfoWorks Integrated Catchment Management (InfoWorks ICM), which can predict the stormwater flow velocity and the flow of discharge outlet after each rainfall. The intercepted runoff depth is calculated from the stormwater quality and environmental capacity of the receiving waters. The average intercepted runoff depth from six rainfall events is calculated as 4.1 mm based on stormwater quality. The average intercepted runoff depth from six rainfall events is calculated as 4.4 mm based on the environmental capacity of the receiving waters. The intercepted runoff depth differs when calculated from various aspects. The selection of the intercepted runoff depth depends on the goal of water quality control, the self-purification capacity of the water bodies, and other factors of the region.

Event mean concentration and first flush effect from different drainage systems and functional areas during storms.

This study aimed to investigate the characteristics of the event mean concentration (EMC) and first flush effect (FFE) during typical rainfall events in outfalls from different drainage systems and functional areas. Stormwater outfall quality data were collected from five outfalls throughout Fuzhou City (China) during 2011-2012. Samples were analyzed for water quality parameters, such as COD, NH3-N, TP, and SS. Analysis of values indicated that the order of the event mean concentrations (EMCs) in outfalls was intercepting combined system > direct emission combined system > separated system. Most of the rainfall events showed the FFE in all outfalls. The order of strength of the FFE was residential area of direct emission combined system > commercial area of separated system > residential area of intercepting combined system > office area of separated system > residential area of separated system. Results will serve as guide in managing water quality to reduce pollution from drainage systems.

Assessment of the service performance of drainage system and transformation of pipeline network based on urban combined sewer system model.

In recent years, due to global climate change and rapid urbanization, extreme weather events occur to the city at an increasing frequency. Waterlogging is common because of heavy rains. In this case, the urban drainage system can no longer meet the original design requirements, resulting in traffic jams and even paralysis and post a threat to urban safety. Therefore, it provides a necessary foundation for urban drainage planning and design to accurately assess the capacity of the drainage system and correctly simulate the transport effect of drainage network and the carrying capacity of drainage facilities. This study adopts InfoWorks Integrated Catchment Management (ICM) to present the two combined sewer drainage systems in Yangpu District, Shanghai (China). The model can assist the design of the drainage system. Model calibration is performed based on the historical rainfall events. The calibrated model is used for the assessment of the outlet drainage and pipe loads for the storm scenario currently existing or possibly occurring in the future. The study found that the simulation and analysis results of the drainage system model were reliable. They could fully reflect the service performance of the drainage system in the study area and provide decision-making support for regional flood control and transformation of pipeline network.