The scheme, and regulative mechanism of pyroptosis, ferroptosis, and necroptosis in radiation injury.

Radiotherapy (RT) stands as the primary treatment for tumors, but it inevitably causes damage to normal cells. Consequently, radiation injury is a crucial consideration for radiation oncologists during therapy planning. Cell death including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis play significant roles in tumor treatment. While previous studies elucidated the induction of apoptosis and autophagy by ionizing radiation (IR), recent attention has shifted to pyroptosis, ferroptosis, and necroptosis, revealing their effects induced by IR. This review aims to summarize the strategies employed by IR, either alone or in combination therapy, to induce pyroptosis, ferroptosis, and necroptosis in radiation injury. Furthermore, we explore their effects and molecular pathways, shedding light on their roles in radiation injury. Finally, we summarize the regulative agents for these three types of cell death and their mechanisms. In summary, optimizing radiation dose, dose rate, and combined treatment plans to minimize radiation damage and enhance the killing effect of RT is a key focus.

Cost-effectiveness of tumor-treating fields plus standard therapy for advanced non-small cell lung cancer progressed after platinum-based therapy in the United States.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers' perspective. Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel. Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone. Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

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.

Cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy with adjuvant pembrolizumab for early-stage non-small cell lung cancer in the United States.

Introduction: Perioperative (neoadjuvant and adjuvant) pembrolizumab has shown favorable efficacy in patients with early-stage non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of this treatment from the perspective of the United States healthcare payers. Methods: We established a Markov model to compare the cost-effectiveness of perioperative pembrolizumab with that of neoadjuvant chemotherapy in 21-day cycles, utilizing data from the phase 3 KEYNOTE-671 trial. Additional data were extracted from other publications or online sources. Sensitivity analyses were conducted to evaluate the robustness of the findings. A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained was established. The main outcomes of this study were the measurement of QALYs, overall costs, incremental cost-effectiveness ratio (ICER), and net monetary benefit (NMB). Results: During a 10-year time horizon, the total costs of perioperative pembrolizumab and the control treatment were $224,779.1 and $110,026.3, respectively. The QALYs were 4.19 and 2.97 for the two treatments, respectively, which led to an ICER of $94,222.29 per QALY gained. The NMB at the WTP threshold at $150,000 per QALY gained was $67,931.3. One-way sensitivity analysis identified the cost of pembrolizumab as the primary factor influencing cost-effectiveness. Probabilistic sensitivity analysis indicated a 97.7% probability of perioperative pembrolizumab being cost-effective at the WTP threshold. Conclusions: From the perspective of the United States healthcare payers, perioperative pembrolizumab is a cost-effective treatment for patients with early-stage NSCLC.

The protein arginine methyltransferase family (PRMTs) regulates metastases in various tumors: From experimental study to clinical application.

Tumor metastasis is the leading cause of mortality among advanced cancer patients. Understanding its mechanisms and treatment strategies is vital for clinical application. Arginine methylation, a post-translational modification catalyzed by protein arginine methyltransferases (PRMTs), is implicated in diverse physiological processes and disease progressions. Previous research has demonstrated PRMTs' involvement in tumor occurrence, progression, and metastasis. This review offers a comprehensive summary of the relationship between PRMTs, prognosis, and metastasis in various cancers. Our focus centers on elucidating the molecular mechanisms through which PRMTs regulate tumor metastasis. We also discuss relevant clinical trials and effective PRMT inhibitors, including chemical compounds, long non-coding RNA (lncRNA), micro-RNA (miRNA), and nanomaterials, for treating tumor metastasis. While a few studies present conflicting results, the overall trajectory suggests that inhibiting arginine methylation exhibits promise in curtailing tumor metastasis across various cancers. Nonetheless, the underlying mechanisms and molecular interactions are diverse. The development of inhibitors targeting arginine methylation, along with the progression of clinical trials, holds substantial potential in the field of tumor metastasis, meriting sustained attention.

CircRNAs and lung cancer: Insight into their roles in metastasis.

Lung cancer is the leading cause of cancer-related mortality worldwide. A major contributing factor to the poor survival rates in lung cancer is the high prevalence of metastasis at the time of diagnosis. To address this critical issue, it is imperative to investigate the mechanisms underlying lung cancer metastasis. Circular RNAs (circRNAs), a distinct type of ribonucleic acid characterized by their unique circular structure, have been implicated in the progression of various diseases. Recent studies have highlighted the close association between circRNAs and the occurrence and development of lung cancer, particularly in relation to metastasis. In this review, we provide a concise overview of the expression patterns and prognostic significance of circRNAs in lung cancer. Additionally, we summarized the current understanding of the clinical relevance of circRNAs in lung cancer metastasis. Furthermore, we systematically focused on the roles of circRNAs in each step of lung cancer metastasis, reflecting the sequential progression of this process. Notably, circRNAs exhibit dual functionality in lung cancer metastasis, acting both as facilitators and inhibitors of metastatic processes. Given their potential, circRNAs hold promise as novel biomarkers and therapeutic targets for lung cancer metastasis, warranting further investigation.

Optimal timing and sequence of combining stereotactic radiosurgery with immune checkpoint inhibitors in treating brain metastases: clinical evidence and mechanistic basis.

Recent evidence has shown that immune checkpoint inhibitors (ICIs) are efficacious for treating brain metastases of various primary tumors. However, the immunosuppressive tumor microenvironment and the blood-brain barrier (BBB) or blood-tumor barrier (BTB) essentially restrict the efficacy of ICIs. Stereotactic radiosurgery (SRS) can be a powerful ally to ICIs due to its trait of disrupting the BBB/BTB and increasing the immunogenicity of brain metastases. The combination of SRS + ICI has shown synergy in brain metastases in several retrospective studies. Nevertheless, the optimal schedule for the combination of SRS and ICI in brain metastases is yet to be determined. In this review, we summarized the current clinical and preclinical evidence on the timing and sequence of SRS + ICI to provide insight into the current state of knowledge about this important area in patient care.

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.

Heterogeneity of tumor immune microenvironment of EGFR/ALK-positive tumors versus EGFR/ALK-negative tumors in resected brain metastases from lung adenocarcinoma.

BACKGROUND: Previous studies found that lung adenocarcinomas (LUAD) with EGFR-positive and ALK-positive were less responsive to immunotherapy, which may be associated with a suppressive tumor immune microenvironment (TIME). Given the discordance in the TIME between primary lung cancer and brain metastasis, it is urgent to explore the TIME in patients with EGFR/ALK-positive LUAD with brain metastases (BMs). METHODS: The transcriptome feature of formalin-fixed and paraffin-embedded samples of BMs and paired primary LUAD from 70 patients with LUAD BMs was illustrated by RNA-sequencing. Six of them were available for paired sample analysis. Then, after excluding 3 co-occurring patients, we divided 67 BMs patients into 41 EGFR/ALK-positive and 26 EGFR/ALK-negative patients. The differences in immune profiling between the two groups were analyzed from three dimensions: TIME, T-cell receptor repertoire, and immunohistochemistry. Finally, the survival data of 55 patients were collected. RESULTS: Compared with primary LUAD, BMs present an immunosuppressed TIME, manifested as: inhibition of immune-related pathways; low expression of immune checkpoint; decreased infiltration of CD8+T cells and cytotoxic lymphocyte; increased proportion of suppressive M2 macrophages. In different subgroups based on EGFR/ALK gene variation status, both EGFR-positive and ALK-positive tumors present a relatively immunosuppressive microenvironment, but the heterogeneity of tumor microenvironment may undergo different mechanisms. EGFR-positive BMs showed decreased CD8+T cells and increased regulatory T cells (Treg) cells, while ALK-positive BMs showed decreased CD8+T cells and increased M2 macrophages. Moreover, in the TCGA-LUAD cohort, EGFR-positive tumors showed reduced CD8+T cell infiltrations (p<0.001) and borderline significantly higher Tregs than EGFR/ALK-negative (p=0.072). In parallel, ALK-positive tumors had higher median M2 macrophages infiltrations than EGFR/ALK-negative (p=0.175), although there was no statistical significance. Collectively, there was a similar immunosuppressive milieu between EGFR/ALK-positive primary LUAD and BMs. Moreover, survival analysis uncovered higher CD8A expression, cytotoxic lymphocyte infiltration, and immune scores were significantly associated with better prognosis in both EGFR/ALK-positive and EGFR/ALK-negative groups. CONCLUSION: This study found that LUAD-derived BMs exhibited an immunosuppressive TIME and revealed that EGFR-positive and ALK-positive BMs exhibited different immunosuppressive characteristics. Meanwhile, EGFR-negative BMs showed a potential benefit to immunotherapy. These findings boost molecular and clinical understanding of LUAD BMs.

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.

Molecular Subtypes and Prognostic Signature of Pyroptosis-Related lncRNAs in Glioma Patients.

The relationship between pyroptosis-related long non-coding RNAs (pyroptosis-related lncRNAs) and glioma prognosis have not been studied clearly. Basing on The Cancer Genome Atlas and The Chinese Glioma Genome Atlas datasets, we firstly identified 23 pyroptosis-related lncRNAs with Pearson coefficient |r| > 0.5 and p < 0.001. The survival probability was lower in cluster 1. 13 lncRNAs was included into signature and divided all the glioma patients into two groups, among which survival probability of the high-risk group was lower than that in low-risk group (P<0.001). The risk score was higher in the age>60, dead grade 3, cluster 1 and immune score high groups. Furthermore, subgroup analysis showed patients with different grades, IDH and 1p19ql state distinguished by the median of risk score had different survival probability. Risk score was one of independent factors for glioma prognosis, and 1-, 3-, 5-years survival were calculated in nomogram. Meanwhile, the same as the median risk score in TCGA cohort, the glioma patients from CGGA were categorized into two groups and validated the outcome mentioned above(P<0.01). GO and KEGG analysis revealed the immunity process of the targeted genes. Thus, the immune filtration we compared showed naive B cell, resting dendritic cells, activated NK cells, activated Mast cells, monocytes are higher in low-risk group. Moreover, level of the activated NK cells, M0-and M1 Macrophages was in positive relationship with the risk score. Besides, competing endogenous RNA (ceRNA) network display interaction among microRNA, lncRNAs and their targeted genes. Pyroptosis-related lncRNAs could be a dependent prognosis factor and maybe linked to the immune response in glioma. This prognosis signature had potential value in estimate the survival of the patients with glioma.