Background DNA damage-based radiotherapy (RT) is a conventional and effective local treatment for lung adenocarcinoma (LUAD). However, residual or recurrent tumors often occur due to radio-resistance. The underlying mechanisms by which radio-resistance occurs are still not fully understood. Novel predictive markers and potential therapeutic targets for LUAD radio-resistance need to be investigated. Methods Bioinformatic tools were used to evaluate the biological functions of MTHFD2 in LUAD patients. The association of MTHFD2 with radiotherapy efficacy in LUAD patients was confirmed by immunohistochemistry. The baseline radioresponsiveness of different LUAD cells was identified and cells with acquired radio-resistance were generated. MTHFD2 in malignant phenotype and DNA damage after irradiation (IR) in LUAD cells were investigated by Western blotting, colony formation and neutral comet assays, etc. LC-MS and co-immunoprecipitation analyses were used to determine the interaction between MTHFD2 and XRCC6. Mouse models were used to verify these effects in vivo. Results In this study, we showed that methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) plays an important role in intrinsic and acquired radio-resistance in LUAD. High MTHFD2 expression correlates with poor RT response and reduced radiation-induced DNA damage. Mechanistically, MTHFD2 directly interacts with XRCC6 to facilitate XRCC6/XRCC5 complex formation, promoting non-homologous end joining (NHEJ)-mediated repair of DNA double-strand breaks, as evidenced by LC-MS and co-immunoprecipitation (Co-IP). Conclusions This study establishes MTHFD2 as a master regulator of NHEJ-mediated radio-resistance through direct interaction with XRCC6. Our findings propose MTHFD2 expression as both a predictive biomarker for radiotherapy stratification and a therapeutic target for radiosensitization in LUAD.

Coal and gas outburst represents a highly destructive dynamic phenomenon inherent in deep coal mining operations. Currently, outburst prediction frameworks rely heavily on a uniform critical threshold system recommended by national regulations. However, within heterogeneous coal seams characterized by complex geological conditions, this universal approach frequently leads to "low-index outburst" incidents or excessive engineering redundancy, significantly undermining the intrinsic safety of mine operations. To address this core scientific bottleneck, the present study establishes a theoretical methodology for the quantitative determination of sensitive prediction indicators and proposes a hierarchical optimization framework for both regional and local critical thresholds. By integrating long-term historical statistics, laboratory kinetic tests of gas desorption, and in-situ multi-point tracking and verification, the critical thresholds undergo scientific calibration and site-specific alignment. Empirical research conducted on the No. 1 coal seam of the Miluo Coal Mine in Guizhou demonstrates that, at the regional prediction level, gas content and gas pressure exhibit equivalent sensitivity, with established critical values of 8.0 m3/t and 0.74 MPa, respectively. Furthermore, the sensitivity hierarchy for local prediction indicators was determined as [Formula: see text]. Significantly, the finalized local thresholds ([Formula: see text]= 0.47 mL/(g·min0.5), [Formula: see text]= 184 Pa, and S= 6.0 kg/m) are more stringent than the recommendations set forth in the Detailed Rules for Prevention and Control of Coal and Gas Outburst. The proposed prediction system effectively standardizes disaster characterization in complex coal seams and provides strategic guidance for coal mining enterprises to establish precision-based, site-specific outburst prevention standards. Coal and gas outbursts constitute a highly destructive dynamic phenomenon inherent in deep coal mining operations. Current outburst prediction frameworks largely depend on a uniform critical threshold system mandated by national regulations. However, in heterogeneous coal seams characterized by complex geological conditions, this universal approach frequently leads to "low-index outburst" incidents or excessive engineering redundancy, significantly undermining the intrinsic safety of mining operations. To resolve this fundamental scientific bottleneck, the present study establishes a theoretical methodology for the quantitative determination of sensitive prediction indicators and proposes a hierarchical optimization framework for both regional and local critical thresholds. By integrating long-term historical statistics, laboratory kinetic tests of gas desorption, and in-situ multi-point tracking and verification, the critical thresholds undergo rigorous scientific calibration and site-specific alignment. Empirical research conducted on the No. 1 coal seam of the Miluo Coal Mine in Guizhou demonstrates that, at the regional prediction level, gas content (w) and gas pressure (p) exhibit equivalent sensitivity, with established critical values of 8.0 m3/t and 0.74 MPa, respectively. Furthermore, the sensitivity hierarchy for local prediction indicators was established as [Formula: see text]. Significantly, the finalized local thresholds ([Formula: see text]= 0.47 mL/(g·min0.5), [Formula: see text]= 184 Pa, and S= 6.0 kg/m) are more stringent than the standards set forth in the Detailed Rules for Prevention and Control of Coal and Gas Outburst. The proposed prediction system effectively standardizes hazard characterization in complex coal seams and provides strategic guidance for coal mining enterprises to establish precision-based, site-specific outburst prevention standards.

The most appropriate time of primary tumor radiotherapy in non-small cell lung cancer(NSCLC) with EGFR-TKIs remains unclear. The aim of this study was to investigate the effect of the time factor of primary tumor radiotherapy on long-term overall survival(OS)and provide a theoretical basis for further clinical research. In total, 238 patients with EGFR-TKIs and OS ≥ 12 months were statistically analysed. Patients were grouped: the D group without primary tumor radiotherapy and the R group with it.The R group were divided into three groups according to the interval between the start of EGFR-TKIs and the start of primary tumor radiotherapy: R0 − 30(<30 days), R30 − PD(≥ 30 days and disease stable), and RPD(radiotherapy after disease progression). The Kaplan-Meier method and log-rank test were used for survival analyses. Exploratory landmark analyses were investigated. The OS rates at 1, 2, 3, 5 years for the R group and D group were 96.8

Purpose.- This study aimed to assess the shifting patterns of the mediastinum, including the target volume and the isocenter point during the postoperative radiotherapy (PORT) process of non-small cell lung cancer (NSCLC), and to observe the occurrence of radiation injury. Additionally, we investigated the significance of mid-term assessment during the implementation of the PORT process. Material and methods.- We established coordinate axes based on bone anatomy and measured the mediastinum's three-dimensional direction and the shift of the isocenter point's shift in the PORT process. Statistical analysis was performed using Wilcoxon, Kruskal-Wallis, and the Chi-square test. P < 0.05 was considered statistically significant. Results.- In this study, the analysis of patients revealed that the shift of anterior and posterior mediastinum (X), left and right mediastinum (Y), upper and lower mediastinum (Z), anterior and posterior isocenter point (X-i), and the left and right isocenter points (Y-i) in the PORT process were 0.04-0.53, 0.00-0.84, 0.00-1.27, 0.01-0.86, and 0.00-0.66 cm, respectively. The shift distance of the mediastinum was Z > Y > X, and the shift distance of the isocenter point was X-i > Y-i. According to the ROC curve, the cut-off values were 0.263, 0.352, 0.405, 0.238, and 0.258, respectively, which were more significant than the cut-off values in 25 cases (25%), 30 cases (30%), 30 cases (30%), 17 cases (17%), and 15 cases (15%). In addition, there was a significant difference in the shift of the mediastinum and the isocenter point (all P = 0.00). Kruskal-Wallis test showed no statistically significant difference between mediastinal shift and resection site in X, Y, and Z directions (P = 0.355, P = 0.239, P = 0.256), surgical method (P = 0.241, P = 0.110, P = 0.064). There was no significant difference in the incidence of RE and RP in PORT patients (P > 0.05). No III-IV RP occurred. However, the incidence of >= grade III RE in the modified plan cases after M-S was significantly lower than in the original PORT patients, 0% and 7%, respectively (P = 0.000). Conclusion.- In conclusion, this study provides evidence that mediastinal shift is a potential complication during the PORT process for patients with N2 stage or R1-2 resection following radical resection of NSCLC. This shift affects about 20-30% of patients, manifesting as actual radiation damage to normal tissue and reducing the local control rate. Therefore, mid-term repositioning of the PORT and revision of the target volume and radiation therapy plan can aid in maintaining QA and QC during the treatment of NSCLC patients and may result in improved patient outcomes. (c) 2023 Published by Elsevier Masson SAS on behalf of Societe francaise de radiotherapie oncologique (SFRO).

e20004 Background: To investigate the efficacy and safety of folic acid intervention in lung cancer patients with radiation esophagitis caused by concurrent chemoradiotherapy. Methods: It was a randomized, controlled, single-center clinical trial of 82 patients with stage N2~N3 lung cancer including SCLC and NSCLC were prospectively included. All patients were randomly divided into experimental and control group according to 1:1, and patients were required to receive radiation therapy for lung lesions and mediastinal metastatic lymph nodes (More than 2 cycles of chemotherapy were completed during the same period of radiotherapy or take targeted drugs at the same time, the cumulative radiation dose of chest lesions should exceed 40Gy). The experimental group took folic acid tablets 30mg/day orally at the beginning of radiotherapy until the end of radiotherapy, while the control group did not receive any drug intervention.When two groups appeared radiation esophagitis, the grading criteria for RTOG should be evaluated first, then according to the guidelines of symptomatic treatment.Esophageal toxicity was evaluated during radiotherapy, and improved RTOG and NCI-CTC ratings were performed weekly at the onset of radiation esophagitis and thereafter until 1 week after the end of radiotherapy. Results: The incidence of radiation esophagitis in the experimental group was low during the observation period, and the occurrence time of radiation esophagitis could be delayed in the experimental group, but there was no statistical significance between the two groups ( P=0.456). After folic acid intervention, the symptoms of pain and dysphagia of radiation esophagitis in the experimental group were significantly decreased, especially the RTOG grade and NCI-CTC improvement grade decreased significantly 2 weeks after the occurrence of radiation esophagitis( P=0.007, P=0.009). In the experimental group, it was found that the greater the change of hemoglobin before and after radiotherapy, the occurrence time of radiation esophagitis was about delayed, which was statistically significant(r=0.348, P=0.040).The correlation analysis of the control group showed that the change of body mass index was positively correlated with the onset time of radiation esophagitis(r=0.372, P=0.020);The lower the hemoglobin content after radiotherapy and the larger the hemoglobin difference before and after radiotherapy, the higher the highest incidence of radiation esophagitis(r= -0.454, P=0.004;r= -0.343, P=0.032). Conclusions: Oral folic acid can delay the onset of radiation esophagitis due to concurrent chemoradiotherapy and promote the recovery of radiation esophagitis to a certain extent,but can not interfere with the occurrence of radiation esophagitis.This trial is registered in Clinical Trials(NCT0529636). Clinical trial information: NCT0529636 .

The traditional Chinese medicine (TCM) bupleurum-ginger-licorice formula presents significant anti-cancer effects, but its active ingredients and inhibitory mechanism remain unclear. In this work, the core effective ingredient quercetin and its signal transducer and activator of transcription 3 (Stat3) receptor both were identified by network pharmacology. Quercetin is a low-toxicity, non-carcinogenic flavonoid with antioxidant, anti-inflammatory and anticancer activities, which is widely distributed in edible plants. Stat3 can bind to specific DNA response elements and serves as a transcription factor to promote the translation of some invasion/migration-related target genes, considered as a potential anticancer target. Here, molecular docking and molecular dynamics (MD) simulation both were used to explore molecular recognition of quercetin with Stat3. The results show that quercetin impairs DNA transcription efficiency by hindering Stat3 dimerization, partially destroying DNA conformation. Specifically, when the ligand occupies the SH2 cavity of the enzyme, spatial rejection is not conductive to phosphokinase binding. It indirectly prevents the phosphorylation of Y705 and the formation of Stat3 dimer. When the inhibitor binds to the DT1005 position, it obviously shortens the distance between DNA and DBD, enhances their binding capacity, and thereby reduces the degree of freedom required for transcription. This work not only provides the binding modes between Stat3 and quercetin, but also contributes to the optimization and design of such anti-cancer inhibitors.

In the earlier published article, the affiliations of the first author were not completely provided. The correct affiliations are provided above. New citation: Liu J, Li T, Wang X, Su S, Li Q, Yang W, et al. Volumetric-modulated arc therapy as an alternative to intensity-modulated radiotherapy for primary tumors of advanced non-small-cell lung cancer: A multicenter retrospective analysis based on propensity score matching. Trop J Pharm Res 2022; 21(10):2233-2240 doi: 10.4314/tjpr.v21i10.26 Erratum: 2023; 22(11): 2415 doi:10.4314/tjpr.v22i11.23 Earlier citation: Liu J, Li T, Wang X, Su S, Li Q, Yang W, et al. Volumetric-modulated arc therapy as an alternative to intensity-modulated radiotherapy for primary tumors of advanced non-small-cell lung cancer: A multicenter retrospective analysis based on propensity score matching. Trop J Pharm Res 2022; 21(10):2233-2240 doi: 10.4314/tjpr.v21i10.26

e20071 Background: There has been widespread reporting on predictive dose parameters for cardiac substructures in radiotherapy for non-small cell lung cancer (NSCLC). However, most advanced NSCLC patients are staged as N2-3, and there is a lack of research on the dose distribution, dose contribution and prognosis of the heart in conventional radiotherapy for N2-3 stage NSCLC. Methods: Retrospective analysis of 274 patients of stage N2-3 NSCLC treated with radiotherapy (RT) of prescription dose from 60Gy to 70Gy. Experienced radiation oncologists delineated the cardiac substructures. All patients were categorized according to different lymph node irradiation and tumor spatial locations. Spearman and linear regression were used for variation of dose-volume parameters, as well as the impact of different primary tumor locations and irradiated lymph nodes on the parameters of the entire heart and substructures. Receiver operating characteristic (ROC) curves, Kaplan-Meier, and Cox regression were performed on the influencing factors of adverse cardiac events after radiotherapy and prognosis analysis. Results: There are significant differences in the dose-volume parameters of the whole heart and its substructures. Mean heart doses (MHD),and the mean doses (Dmean) for the left atrium, right atrium, right ventricle, left ventricle and the left anterior descending coronary artery (LAD) were 15.7Gy (range 0.2-30.0Gy), 19.7Gy (range 0.3-55.0Gy), 9.7Gy (range 0.3-59.8Gy), 7.9Gy (range 0.1-48.2Gy), 6.4Gy (range 0.1-52.6Gy) and 5.2Gy (range 0.1-45.0Gy), respectively. The left atrium Dmean has the most significant impact on MHD compared to other substructures (B = 0.418, P < 0.05). Dose-volume parameters of the whole heart and the left atrium were positively correlated with the irradiation of the 7th lymph node region (P < 0.05). MHD and left atrium Dmean for tumors located in the lower region were significantly higher than those in the upper region (P < 0.001). Patients with LAD V30 ≥ 26.9% had a significantly higher risk of mortality compared to those with LAD V30 < 26.9% (P = 0.003, HR = 2.883, 95% CI = 1.436-5.788). Conclusions: With the dose distribution differences among the whole heart and its substructures. We observed the base of the heart received the highest dose, the dose to the left atrium is particularly required attention. The irradiation of different lymph nodes and different primary lesions has an impact on the dose variations of different cardiac structures. LAD V30 is an independent influencing factor of overall survival (OS) for N2-3 stage NSCLC. This study provides considerable information for the dose optimization of cardiac substructure in radiotherapy planning for N2-3 stage NSCLC.

Abstract Objective To explore the survival effect of thoracic gross tumor volume (GTV) in three‐dimensional (3D) radiotherapy for stage IV non‐small cell lung cancer (NSCLC). Methods The data cases were obtained from a single‐center retrospective analysis. From May. From 2008 to August 2018, 377 treatment criteria were enrolled. GTV was defined as the volume of the primary lesion and the hilus as well as the mediastinal metastatic lymph node. Chemotherapy was a platinum‐based combined regimen of two drugs. The number of median chemotherapy cycles was 4 (2–6), and the cut‐off value of the planning target volume (PTV) dose of the primary tumor was 63 Gy (30–76.5 Gy). The cut‐off value of GTV volume was 150 cm3 (5.83–3535.20 cm3). Results The survival rate of patients with GTV <150 cm3 is better than patients with GTV ≥150 cm3. Multivariate Cox regression analyses suggested that peripheral lung cancer, radiation dose ≥63 Gy, GTV <150 cm3, 4–6 cycles of chemotherapy, and CR + PR are good prognostic factors for patients with stage IV non‐small cell lung cancer. The survival rate of patients with GTV <150 cm3 was longer than patients with ≥150 cm3 when they underwent 2 to 3 cycles of chemotherapy concurrent 3D radiotherapy (p < 0.05). When performing 4 to 6 cycles of chemotherapy concurrent 3D radiotherapy, there was no significant difference between <150 cm3 and ≥150 cm3. Conclusions The volume of stage IV NSCLC primary tumor can affect the survival of patients. Appropriate treatment methods can be opted by considering the volume of tumors to extend patients' lifetime to the utmost.

e20607 Background: Although the targeted therapy and immunotherapy have become the first line options for selected stage IV non-small cell lung cancer (NSCLC) patients. However, there are instances where certain patients are not administered targeted therapy or immunotherapy due to a variety of factors, chemotherapy and radiotherapy remain the main way to treat such patients. This study aimed to construct a prognostic nomogram for patients with stage IV NSCLC treated with chemotherapy combined with high-dose (≥ 60 Gy) thoracic radiotherapy. Methods: The nomogram was based on a retrospective study of 335 patients with stage IV NSCLC who treated with chemotherapy combined with high-dose (≥ 60 Gy) thoracic radiotherapy were hospitalized between January 2010 and January 2018(patient did not receive TKI therapy or immunotherapy). The patients were randomly assigned to either a primary cohort (n = 234) or a validation cohort (n = 101) at a ratio of 7 : 3. In the primary cohort, a univariate analysis of the clinical or therapeutic factors that may predict OS was performed using a Cox regression model, with P < 0.05 indicating statistical significance. The variables from the univariate analysis that affected OS significantly were included in the Cox regression model for the multivariate analysis. A nomogram was then created based on the results of multivariate analysis and using the “rms,” “foreign,” and “survival” R version 4.0.3 software packages. The discriminatory ability of the nomogram was measured using the area under the curve (AUC) of a receiver operating curve (ROC). Results: Multivariate logistic regression analysis revealed that malignant pericardial effusion, adrenal metastasis, elevated lactate dehydrogenase levels, and excessive planning target volume were independent risk factors for poorer 1–3 year overall survival (OS), while a higher radiotherapy dose for the primary lesion was associated with better OS. Nomogram prediction models were constructed using these five variables. The AUC of the ROC for 1-year, 2-year, and 3-year OS in the primary cohort were 0.685, 0.729, and 0.816, respectively. In the validation cohort, the AUC of the ROC for 1-year, 2-year, and 3-year OS were 0.706, 0.749, and 0.797, respectively. The Kaplan-Meier survival analysis showed that differentiation between the high-risk group and low-risk group using the prediction model had a direct, significant effect on survival in both the primary cohort ( P < 0.001) and validation cohort ( P = 0.004). Conclusions: The nomogram model constructed in this study may be used to objectively predict the prognosis and OS of patients with stage IV NSCLC treated with chemotherapy and high-dose thoracic radiotherapy. Identify patients who may not benefit from high-dose thoracic radiotherapy prior to treatment to avoid overtreatment.

Background: EGFR-mutant (EGFR-M) and ALK-positive (ALK-P)are common in malignant pleural effusion (MPE) with metastatic non-small-cell lung cancer (NSCLC) (MPE-NSCLC). The impact of thoracic tumor radiotherapy on survival in such patients remains unclear. We aimed to investigate whether thoracic tumor radiotherapy could improve overall survival (OS) in such patients. Methods: According to whether or not patients accepted thoracic tumor radiotherapy, 148 patients with EGFR-M or ALK-P MPE-NSCLC treated with targeted therapy were classified into two groups: DT group without thoracic tumor radiotherapy and DRT group with thoracic tumor radiotherapy. Propensity score matching (PSM) was performed to balance clinical baseline characteristics. Overall survival was analyzed by Kaplan-Meier, compared by log--rank test, and evaluated using Cox proportional hazards model. Results: Median survival time (MST) was 25 months versus 17 months in the DRT group and DT group. The OS rates at 1, 2, 3, 5 years in the DRT group and DT group were 75.0%, 52.8%, 26.8%, 11.1% and 64.5%, 28.4%, 9.2%, 1.8%, respectively (.2 = 12.028, p = 0.001). Compared with DT group, the DRT group still had better survival after PSM (p = 0.007). Before and after PSM, factors associated with better OS through multivariable analysis were that thoracic tumor radiotherapy, radiotherapy, N0- -2, and ALK-TKIs. Grades 4-5 radiation toxicities were not observed in patients; 8 (11.6%) and 7 (10.1%) out of the DRT group suffered from Grade 3 radiation esophagitis and radiation pneumonitis, respectively. Conclusion: Our results for EGFR-M or ALK-P MPE-NSCLC showed that thoracic tumor radiotherapy may be crucial factor in improving OS with acceptable toxicities. Potential biases should not be neglected: Further randomized controlled trials are necessary to confirm this result.

PurposeActionable mutations are common in non-small cell lung cancer(NSCLC)with malignant pleural effusion(MPE)(MPE-NSCLC). The pattern of failure in MPE-NSCLC treated with targeted therapy after MPE control remains unclear. We aimed to investigate the failure pattern of such patients in a cohort study and explore the possibility of radiotherapy.Patients and methodsComputed tomography scans of 86 patients were reviewed in this study. We classified first pattern of failure after MPE control as initial disease sites only (IF), new distant sites only (NF), or IF and NF detected simultaneously (INF). Patients evaluated suitable for radiotherapy after disease progression were divided into two groups: D group without radiotherapy and RD group with radiotherapy. The Kaplan-Meier method and log-rank test were used for survival analyses.ResultsDisease progression after MPE control was observed in 42 patients with complete serial imaging. Median time to any progression was 9.5 months. Rate of the IF, NF and INF were 50%, 17% and 33% for all patients,60%,0% and 40% for patients with MPE recurrence (n=10,23.8%) and 47%, 22% and 31% for patients (n=32,76.2%) without MPE recurrence, respectively. Out of 10 patients(23.8%) with MPE recurrence, 7 patients simultaneous underwent primary tumor progression and 5 MPE were cytologically confirmed in 7 patients with examination. The overall survival (OS )rates at 1, 2, 3 years for the RD group and D group were 88.2%, 50.5%, 21.7% and 80.0%, 20.3%, 0%, respectively; the corresponding MST were 26.1 months and 17.5 months, respectively (χ2 = 4.959, p =0.026)ConclusionsOur data indicates that 50% of patients with actionable mutations MPE- NSCLC after MPE control are likely to fail at their initial sites of disease and the use of radiotherapy may bring OS benefits during the course of their disease. Multicenter RCT is necessary to confirm the result in the future.

Objective:To analyze the clinical characteristics of long-term survival patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy combined with primary tumor radiotherapy, and to establish a Nomogram prognostic model, aiming to provide a certain reference for making a decision about the treatment of advanced NSCLC.Methods:A retrospective analysis was made on the data of 260 NSCLC patients who participated in two prospective clinical studies from January 2003 to May 2012 and the data of 138 NSCLC patients admitted to the Affiliated Cancer Hospital of Guizhou Medical University from January 2014 to August 2020. The former 260 cases were used as a training set and the latter 138 cases were used as the validation set. The overall survival (OS) of ≥ 18 months was defined as long-term survival (LTS). The clinical characteristics of LTS patients were compared with those with OS less than 18 months. The clinical characteristics and treatment-related parameters between the two types of patients were compared using the χ2 test. A multivariate analysis was made using logistic regression, and a nomogram model was built using RStudio. Results:The median OS of the training set was 13.4 months (95% CI: 11.9-14.9), with 1-, 2-, and 3-year OS rates of 55.4%, 19.1%, and 11.9%, respectively. In the training set, 87 cases had LTS and were classified as the LTS group, while 173 cases had OS less than 18 months and were classified as the non-LTS group. The univariate analysis showed that the prognostic factors affecting LST included the KPS score, T status, the number of metastatic organs, the number of metastatic lesions, brain metastasis, bone metastasis, the number of chemotherapy cycles, the biologically effective dose (BED) to the primary tumor, hemoglobin level, platelet count, plasma D-dimer, fibrinogen level, lactate dehydrogenase, and lung immune prognostic index (LIPI; χ2=4.72-12.63, P < 0.05). The multivariable analysis showed that the independent prognostic factors of LTS included a number of chemotherapy cycles ≥ 4, BED ≥ 70 Gy, platelets ≤ 220×10 9/L, D-dimer ≤ 0.5 mg/L, and a good LIPI score ( P= 0.002, 0.036, 0.005, 0.008, and 0.002). A nomogram model was established using the meaningful parameters obtained in the multivariable analysis, determining that the training and validation sets had a consistency index (C-index) of 0.750 and 0.727, respectively. As shown by the analytical result of the corrected curves, for the advanced NSCLC patients treated with thoracic radiotherapy, their LTS probability predicted using the nomogram prognostic model was highly consistent with their actual LTS probability. Both the analytical result of the receiver operating characteristic (ROC) curves and the decision curve analysis (DCA) result showed that the composite prediction model was more beneficial than a single prediction model. Conclusions:For patients with advanced NSCLC treated with thoracic radiotherapy, the independent prognostic factors of LTS included the number of chemotherapy cycles, BED, platelet count, pre-chemotherapy D-dimer, and LIPI score. The Nomogram prognostic model built based on these prognostic factors is a convenient, intuitive, and personalized prediction model used to screen patients who can benefit from thoracic radiotherapy.

The purpose is to compare the clinical efficacy and toxicity of etoposide plus lobaplatin (EL) or etoposide plus cisplatin (EP) with concurrent thoracic radiotherapy during the treatment of limited-stage small cell lung cancer (LS-SCLC). Forty-two patients with LS-SCLC were randomly divided into EL ( n = 19) or EP ( n = 23) regimens combined with thoracic intensity-modulated radiotherapy. The primary endpoint was 1-year progression-free survival (PFS) rate. The 1-, 2-, and 3-year PFS rates in the EL and EP cohorts were 50.8, 38.1, and 12.7%; and 56.5, 43.5, and 29.0%, respectively ( P = 0.527), whereas the 1-, 2-, and 3-year overall survival (OS) rates were 72.2, 52.5, and 43.8%; and 73.9, 48.4, and 48.4%, respectively ( P = 0.923). The hematological toxicities were similar in two cohorts. However, gastrointestinal reactions were more severe in the EP group. The incidence of nausea and vomiting in EL and EP cohorts were 31.6% vs. 73.9% ( P = 0.006) and 20.1% vs. 60.9% ( P = 0.009), respectively. The two cohorts did not show ≥grade 4 radiation esophagitis and ≥grade 3 radiation pneumonitis. The incidence of acute radiation esophagitis in EL group was lower ( P = 0.038), both groups showed a similar incidence of radiation pneumonitis ( P = 1.000). EL or EP chemotherapy with concurrent thoracic radiotherapy showed similar PFS and OS. The EL group showed milder gastrointestinal toxicity and radiation esophagitis. Radiation pneumonitis and hematological toxicity were similar in the two regimens, which can be tolerated by patients.

Objective:To study the relationship between endoplasmic reticulum stress (ERS) and apoptotic protein and myocardial pathological changes in rats after endostar combined with low-dose X-ray irradiation.Methods:Forty SD rats were evenly divided into four groups: control group (intraperitoneal injection of equal volume physiological saline, once per day, 14 d), endostar group (intraperitoneal injection of endostar 6 mg/kg, once per day, 14 d), irradiation group (15 Gy divided into 3 times X-ray irradiation) and combination group (intraperitoneal injection of endostar after irradiation at the same dose and time as the endostar group). At 1 and 6 months after treatment, myocardial tissues of rats were prepared for HE staining and Masson staining to observe the myocardial histological changes. TUNEL assay was used to detect myocardial cell apoptosis, and ImageJ software was utilized to calculate myocardial collagen volume fraction (CVF). The expression levels of ERS and apoptotic protein glucose-regulated protein 78 (GRP78), protein kinase-like endoplasmic reticulum kinases (PERK), CCAAT/enhancer binding protein homologous protein (CHOP) and cysteine-containing aspartate-specific protease-12 (Caspase-12) were detected by Western blot. One-way ANOVA was conducted using GraphPad Prism 8.0.1 software, and comparison between two groups was conducted using t-test. Results:At 6 months after treatment, the myocardial interstitium in the irradiation and combination groups was widened, showing strip-like or reticular fibrosis changes, and the myocardial interstitium had diffuse collagen fiber deposition. Compared with the control group, CVF was increased significantly (both P<0.01). At 1 and 6 months after treatment, the apoptotic index of myocardial cells in the combination group was significantly higher than that in the control group ( P<0.05, <0.001). At 1 and 6 months after treatment, the expression levels of GRP78 protein in the irradiation and combination groups were increased (all P<0.01), and the expression levels of PERK and CHOP proteins in the combination group were increased compared to those in the control group (both P<0.05). At 6 months after treatment, the expression levels of PERK and CHOP proteins in the irradiation group were increased compared to those in the control group (both P<0.05). Compared with the control group, Caspase-12 expression levels at 1 and 6 months after treatment were increased in the endostar, irradiation and combination groups (all P<0.05). Conclusions:The expression levels of ERS and apoptotic proteins are related to cardiac injury caused by irradiation in rats. After low-dose X-ray combined with endostar treatment, ERS is aggravated and myocardial apoptosis is increased.

As a ubiquitous protein tyrosine phosphatase, SHP2 is involved in PD-1/PD-L1 mediated tumor immune escape and undergoes substantial conformational changes. Therefore, it is considered an ideal target for tumor intervention. However, the allosteric mechanisms of SHP2 binding PD-1 intracellular ITIM/ITSM phosphopeptides remain unclear, which greatly hinders the development of novel structure-based anticancer allosteric inhibitors. In this work, the open and closed structural models of SHP2 are first constructed based on this knowledge; next their motion modes are investigated via elastic network models such as the Gaussian network model (GNM), anisotropic network model (ANM) and adaptive anisotropic network model (aANM); and finally, a possible allosteric signaling pathway is proposed using a neural relational inference molecular dynamics (NRI-MD) simulation embedded with an artificial intelligence (AI) strategy. In GNM and ANM, the N-SH2, C-SH2 and PTP domains all exhibit distinct dynamics partitions, and the N-SH2/C-SH2 regions show a rigid rotation relative to PTP. According to a series of intermediate snapshots given by aANM, N-SH2 is first identified with pY223 specifically, inducing a D'E-loop to change from β-sheets to random coils, and then, C-SH2 serves as a fulcrum to drive N-SH2 to rotate 110° completely away from the original active sites of PTP. Finally, a possible allosteric signaling-transfer path for SHP2, namely R220-R138-T108-R32, is proposed based on NRI-MD sampling. This work provides a possible allosteric mechanism of SHP2, which is helpful for the following design of novel allosteric inhibitors and is expected to be used in clinical synergies with PD-1 monoclonal antibody.

Abstract ObjectiveTo investigate the alteration of subclinical lesions of subcutaneous xenograft tumors in nude mice after EGFR-TKI treatment. MethodsHuman lung adenocarcinoma cell lines were subcutaneously transplanted on the right hind legs of the nude mice in control and treatment groups. Three-dimensional pathological section was taken to observe the subclinical lesion areas when the tumors’ long diameters in the control group grew to specified length. In the Gefitinib treatment group, the subclinical lesions were observed likewise after tumor shrinkage. The results were compared. ResultsThe long diameters of transplanted tumors in group C were 5, 10, 15, and 20mm, the smallest infiltration range of subclinical lesions was 0.23, 0.78, 1.24, and 2.98mm. The edge of transplanted tumor was extended 5.14mm, to include 95% of subclinical lesions. The long diameter of the transplanted tumor in the T group shrank to 15, 10, 5, and 0mm, the smallest infiltration range was 5.74, 2.13, 2.13, and 0.11mm, the edge of the transplanted tumor was extended 8.99mm to include 95% of subclinical lesions. The extended range in T group was significantly larger than group C (P=0.000). ConclusionThe subclinical lesion receded after gefitinib treatment, but was wider than that of tumor of subclinical lesion without treatment. Even if the complete imaging response was achieved, there were still small infiltrating lesions.

Purpose: To investigate the effect of volumetric-modulated arc therapy (VMAT) versus intensity-modulated radiotherapy (IMRT) for advanced non–small-cell lung cancer (NSCLC). Methods: Cases in which the primary tumors were treated with IMRT or VMAT as initial intervention in stages III and IV NSCLC patients from September 2008 to March 2020 were retrospectively analyzed. Propensity Score Matching (PSM) was used to assess the efficacy and toxicity of the two radiotherapy techniques. Results: A total of 637 patients were included, out of which 483 cases were treated with IMRT, while 154 received VMAT. A total of 308 patients were selected after PSM. Patients who were having acute radiation esophagitis and pneumonia treated with VMAT had a lower percentage than those treated with IMRT (p < 0.05) before PSM. However, there was no significant difference in grades 3 - 4 toxicity (χ2 = 2.77, p = 0.096). There were also no significant differences in the primary endpoints between the two groups after PSM (p > 0.05), while for secondary endpoints, all lung V5, and V20, mean lung dose and heart V30, heart V40, mean heart dose in all patients and stage N2 patients in VMAT after PSM were significantly lower than those of IMRT (p < 0.05). Conclusion: Radiation therapy of A-NSCLC primary tumors using VMAT and IMRT seem to produce similar efficacy. The volume parameters of normal tissues and organs is significantly lower in VMAT, especially in patients with stage N2. Therefore, VMAT may be more beneficial for reducing radiation damage in normal tissues and organs.

Objective:To explore the characteristics of failure patterns of three-dimensional radiotherapy combined with first-line drug therapy for primary tumors of stage Ⅳ non-small cell lung cancer(NSCLC)and investigate the influence of radiotherapy-related factors.Methods:708 patients newly-diagnosed with stage Ⅳ NSCLC from March 2003 to July 2020 were selected. Chi-square test was used for univariate analysis of failure patterns. Kaplan-Meier method, Log-rank test and Cox regression model were employed for multivariate analysis. Results:The incidence of first-line treatment failure in 708 cases was 71.2%, and the incidence of treatment failure was 22.7%, 28.8%, 13.3%, and 6.4% for ≤6 months, >6-12 months, >12-24 months, and>24 months, respectively, and the median survival time was 7.2, 13.4, 22.2, and 37.6 months, which was significantly different( χ2=226.013, P<0.001). The incidence of recurrence failure(RF)was 21.3%.There was no significant difference in the incidence of RF between oligometastasis(OM)and non-oligometastasis(NOM). The incidence of DF was 66.3% and the order of incidence was brain>bone>lung>pleural cavity>liver>distant lymph nodes>adrenal gland>other sites, occurring in approximately 1/2 of AM and 1/3 of PSM cases. Metastatic status, time to treatment failure, pathological type, gender, combined treatment intensity were the independent influencing factors for predicting prognosis. Conclusions:The failure pattern of radiotherapy for primary tumors of stage Ⅳ NSCLC is different from that of first-line drug therapy, with significantly lower local failure and predominantly metastatic failure. The incidence of brain metastasis is the highest. The later time to treatment failure, the longer the overall survival(OS). OM, female, non-squamous cell carcinoma, late treatment failure, 4-6 cycles of chemotherapy over the same period ≥63 Gy are the independent prognostic factors for prolonging survival.