Background and objective Radiation therapy is one of the most common treatments for non-small cell lung cancer(NSCLC).However,the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients,and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge.This study aimed to identify the molecules associated with radioresistance in lung ad-enocarcinoma(LUAD),identified thyroid hormone receptor interactor 13(TRIP13)as the main target initially,and explored whether TRIP 13 is related to radioresistance in LUAD and the specific mechanism,with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic.Methods Three data-sets,GSE18842,GSE19188 and GSE33532,were selected from the Gene Expression Omnibus(GEO)database and screened for differentially expressed genes(|log FC|＞1.5,P＜0.05)in each of the three datasets using the R 4.1.3 software,and then Venn diagram was used to find out the differentially expressed genes common to the three datasets.The screened differential genes were then subjected to protein-protein interaction(PPI)analysis and module analysis with the help of STRING online tool and Cytoscape software,and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database,and the TRIP13 gene was identified as the main molecule for subsequent studies.Subsequently,the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line,H292DR.The radioresistance of H292DR cells was verified using cell counting kit-8(CCK-8)assay and clone formation assay.The expression levels of TRIP 13 in H292 and H292DR cells were measured by Western blot.Small interfering RNA(siRNA)was used to silence the expression of TRIP 13 in H292DR cells and Western blot assay was performed.The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing,followed by the detection of changes in the expression levels of proteins closely related to homologous recombination,such as ataxia telangiectasia mutated(ATM)protein.Results Screening of multiple GEO datasets,validation of external datasets and survival analysis revealed that TRIP 13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy.And the results of gene set enrichment analysis(GSEA)of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy.Experimentally,TRIP13 expression was found to be upregulated in H292DR,and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation.Conclusion TRIP13 is associated with poor prognosis in LUAD patients treated with radiation,possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

BACKGROUND: Low-density computed tomography (LDCT) improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data. Hence, accurate diagnosis of early-stage lung cancer remains challenging. The purpose of the study was to assess the feasibility of using circulating tumour cells (CTCs) to differentiate malignant from benign pulmonary nodules. METHODS: 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited. Peripheral blood samples were collected before surgery, and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis. Laser capture microdissection, MALBAC amplification, and whole-exome sequencing were performed on 8 samples. The diagnostic efficacy of CTCs counting, and the genomic variation profile of benign and malignant CTCs samples were analysed. RESULTS: Using 2.5 cells/5 mL as the cut-off value, the area under the receiver operating characteristic curve was of 0.651 (95% confidence interval: 0.538-0.764), with a sensitivity and specificity of 0.526 and 0.800, respectively, and positive and negative predictive values of 91.1% and 30.3%, respectively. Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples. TP53 mutations were identified in CTCs of four malignant cases; in particular, g.7578115T>C, g.7578645C>T, and g.7579472G>C were exclusively detected in all four malignant samples. CONCLUSIONS CTCs play an ancillary role in the diagnosis of pulmonary nodules. TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.
Humans ; Lung Neoplasms ; Exome Sequencing ; Multiple Pulmonary Nodules ; Carcinoma ; DNA Repair

BACKGROUND: It was believed that immunoglobulin G (IgG) was synthesized only by B cells. However, in recent years, researchers have found that a variety of cancer cells can also synthesize IgG (cancer-IgG) which promote the development of tumors. This study analyzed the expression and clinical significance of cancer-IgG in non-small cell lung cancer (NSCLC), and initially explored its mechanism. METHODS: The expression of IgG1 heavy chain gamma 1 (IGHG1) and cancer-IgG were detected by bioinformatics and immunohistochemistry in NSCLC; The gene set enrichment analysis (GSEA) method was used to explore the signaling pathways involved in IGHG1 regulation. RESULTS: The expression level of cancer-IgG in NSCLC was significantly higher than that in normal tissues. The high expression group had a poor prognosis and was associated with clinical stage (P=0.042), T stage (P=0.044) and metastasis (P=0.007). GSEA analysis showed that IGHG1 was associated with cell adhesion, cytokine interaction and chemokine signaling pathway. CONCLUSIONS High expression of cancer-IgG in NSCLC is a poor prognosis factor, which may be related to the promotion of tumor invasion and metastasis.
Adult ; Aged ; Biomarkers, Tumor ; metabolism ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Carrier Proteins ; genetics ; metabolism ; Computational Biology ; Female ; Humans ; Immunoglobulin G ; genetics ; metabolism ; Immunohistochemistry ; Lung Neoplasms ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Young Adult

Objective To analyze clinical significance of failure patterns and combined radiotherapy for advanced non-small cell lung cancer after EGFR-TKIs treatment.Methods A total of 111 patients who were treated with EGFR-TKIs for advanced non-small cell lung cancer (NSCLC) with EGFR exon mutation in Peking University Cancer Hospital from January 2009 to June 2013 were retrospectively analyzed.The impact of various failure patterns and combined radiotherapy on survial were analyzed with Kaplan-Meier method.Results Totally 111 patients were enrolled in the study.The median follow-up was 27.7 months (6.6-85.3 months).The median age,median PFS andmedian OS were 59 years (35-80 years old),10.3 months (6.2-30.5 months),and 29.8 months (7.1-90.7 months),respectively.The main failure mode was the progress of the original lesion (65 cases,58.6％) and the main failure site was the progress of intrathoracic lesions (57 cases,51.4％).The survival time of patients with oligoprogress (1-3 lesions during drug resistance) was significantly extended compared with the ones whose lesions were ≥ 4.The median OS were 32.5 months and 26.7 months,respectively (x2 =4.888,P＜0.05).For 43 patients with only intrathoracic progressed,there were 9 patients treated with radiotherapy and 34 patients treated without radiotherapy.The median PFS was 9.6 and 5.7 months,respectively.The median PFS of combined radiotherapy group was significantly prolonged (x2 =9.013,P＜0.05).And the median OS of retreatment after failure were 28.1 and 13.2 months,respectively,with no significant difference between two groups (P＞0.05).For 48 patients with oligo-progress,there were 12 patients treated with radiotherapy and 36 patients treated without radiotherapy.The median PFS were 9.6 and 4.2 months,respectively.The median PFS of the group treated with combined radiotherapy was significantly longer than that of the group without combined radiotherapy treatment (x2 =5.482,P＜0.05).And the median OS of retreatment after failure were 26.0 and 11.8 months,respectively.There was no significant difference between the two groups(P＞0.05).Conclusions Combined local radiotherapy can improve the PFS of patients who had only intrathoracic progress or oligo-progress after EGFR-TKIs treatment.Therefore,the patients whose T790 M mutation indicates negative or who are not in the position to perform coressoponding detection under the intrathoracic/oligo progress stage.The local intervention plays a very critical role for patients who have primary drug restisitance to GEN 1 EGFR-TKIs.

Objective To investigate the influence of enteral nutrition on body weight,nutritional status,treatment toxicities,and short-term outcomes in esophageal carcinoma patients treated with concurrent chemoradiotherapy(CCRT). Methods Eligible esophageal carcinoma patients were randomly assigned(2:1) to receive either CCRT combined with enteral nutrition (study group) or CCRT alone (control group). The primary endpoint was changes in the body weight during and after radiotherapy. The secondary endpoints were nutrition-related hematological parameters,the toxicities of chemoradiotherapy,the completion rate of treatment,and short-term outcomes. The differences was using χ2 or t-test. Results Between September 2014 and June 2017,203 patients were included in the study,consisting of 139 patients in the study group and 64 patients in the control group. Compared with the control group,the study group had significantly less body weight loss during and after radiotherapy (P<0.05) and significantly less decreases in serum albumin and hemoglobin (P<0.05),but there was no significant difference in the reduction in total lymphocyte count between the two groups (P>0.05).The study group had significantly lower incidence rates of grade ≥3 myelosuppression and infection and a significantly higher completion rate of chemoradiotherapy compared with the control group (P<0.05).The incidence of radiation pneumonitis and esophagitis showed no significant difference between the two groups (P>0.05).The study group had an insignificantly higher objective response rate than the control group (P>0.05). Conclusions For esophageal carcinoma patients treated with CCRT,enteral nutrition can reduce body weight loss during and after radiotherapy,improve nutritional status and treatment tolerance,and reduce toxicities.

Objective To understand the influence of the disease-based hierarchical medical system on inpatients flow covered by the new rural cooperative medical system ( NRCMS) , and that on the funding diversion and medical costs so incurred. Methods One county was selected from the eastern, central and western regions of China respectively, where the disease-based hierarchical medical system has been in place. Policy documents of the three counties were reviewed to analyze such changes as NRCMS inpatients flow, inpatients subsidy diversion, NRCMS fund surplus rate of the current year and medical costs per hospitalization before and after the system was in place. Results A comparison with 2014 found a 1. 26%drop of the out-of-county inpatients of county W of the western region, a 2. 00% increase of township hospitals inpatients of county D in the middle region, and the same ratio of out-of-county and in-county inpatients in county F of the eastern region in 2015. Compared with 2014, the fund surplus rate of county W increased 10. 46%, and the inpatient subsidy ratio of county D decreased 2. 51% for those in out-of-county medical institutions in 2015. Thanks for the quota payment of specific diseases under global budget in county W, the inpatient medical costs per hospitalization dropped at both county and township medical institutions. Conclusions The disease-based hierarchical medical system could optimize the NRCMS inpatients distribution among various medical institutions, conducive for establishment and operation of such a system.

Objective To investigate the consensus and controversies on the delineation of radiotherapy target volume for patients with locally advanced non-small cell lung cancer (LA-NSCLC).Methods Questionnaires including 15 questions on the delineation of radiotherapy target volume of NSCLC were sent to 12 radiation departments in China in November 2015.A patient with LA-NSCLC was selected by Fudan University Shanghai Cancer Center, and simulation CT images and medical history data were sent to the 12 radiation departments.Twelve radiation oncologists from the 12 radiation departments showed and explained the delineation of radiotherapy target volume of their own, and the patient was discussed by all experts in the sixth multidisciplinary summit forum of precise radiotherapy and chemotherapy for tumor and lung cancer.Results All receivers of the questionnaire answered the questions.The standard lung window width/level for the delineation of lung cancer was 800-1600/-600 to-750 HU, and the mediastinum window was 350-400/20-40 HU.Respiratory movement was measured by stimulator, 4D-CT, and stimulator+4D-CT with 2-5 mm expansion based on experience.The primary clinical target volume (CTV) was defined as gross target volume (GTV) plus 5-6 mm for squamous carcinoma/5-8 mm for adenocarcinoma.The metastatic lesion of mediastinal lymph nodes was delineated as 5 mm plus primary lesion in 6 departments and as primary lesion in another 6 departments.Of the 12 departments, 10 applied 5 mm of set-up error, 1 applied 3 mm, and 1 applied 4-6 mm.For V20 of the lungs, 10 departments defined it as<30%, 1 as<35%, and 1 as 28%.Nine departments defined the radiation dose of concurrent chemoradiotherapy (CCRT) for LA-NSCLC as 60 Gy in 30 fractions, 62.7 Gy in 33 fractions in 1 department, 50-60 Gy in 25-30 fractions in 1 department, and 60-70 Gy in 25-30 fractions in 1 department.For the delineation of target volume for the LA-NSCLC patient treated with CCRT, the primary planning target volume (PTV) was defined as GTV plus organ movement (IGTV) and set-up error (GTV→IGTV→PTV) in 3 departments, as CTV plus organ movement (ITV) and set-up error (GTV→CTV→ITV→PTV) in 8 departments, and as CTV plus set-up error/IGTV plus 5-6 mm for squamous carcinoma/5-8 mm for adenocarcinoma (CTV) and set-up error (GTV→CTV→PTV/GTV→IGTV→CTV→PTV) in 1 department.For the delineation of PTV in the mediastinal lymph node, GTV→IGTV→PTV was performed in 3 departments, GTV→CTV→ITV→PTV in 8 departments, and GTV→CTV→PTV in 1 department.For 10%-100% patients with LA-NSCLC, the radiation field needed to be replanned when 38-50 Gy was completed.There was no unified standard for the optimal standardized uptake value (SUV) of positron emission tomography (PET)-computed tomography (CT) simulation and delineation.Seven departments had applied magnetic resonance imaging (MRI) simulation and 10 departments had applied stereotactic body radiation therapy (SBRT) for the treatment of early-stage NSCLC.For the delineation of PTV for early-stage NSCLC (T1-2N0M0), GTV→IGTV→PTV was performed in 5 departments, IGTV→PTV in 3 departments, and GTV→CTV→ITV→PTV in 2 departments.In all the 12 departments, peripheral early-stage NSCLC was given 6.0-12.5 Gy/fraction, 3-12 fractions and central early-stage NSCLC was given 4.6-10.0 Gy/fraction, 5-10 fractions.The results of discussion on the delineation of target volume for the patient were as follows:respiratory movements should be measured by 4D-CT or simulator;the lung window width/level is 1600/-600 HU and the mediastinal window width/level is 400/20 HU;the primary controversy is whether the involved-field irradiation or elective nodal irradiation should be used for the delineation of CTVnd in the mediastinal lymph node.Conclusions Basic consensus is reached for the delineation of target volume in LANSCLC in these aspects:lung window width/level, respiratory movements and set-up error, primary lesion delineation, the radiation dose in CCRT, and the optimal time for replanning the radiation field.There are controversies on the optimal SUV in the delineation of target volume based on PET-CT simulation, the optimal dose fractionation in SBRT for early-stage NSCLC, and the delineation of CTVnd.

Objective To establish the methods for controlling quality of Yiqi Congming Pills, and to improve the quality standard for the pills. Methods Yiqi Congming Pills were sampled from the products of 3 mainpharmaceutical companies in China market, 2 batched from each company. Radix Puerariae, Radix Astragali, Fructus Viticis, Cortex Phellodendri Chinensis, Radix Codonopsis in Yiqi Congming Pills were observed under microscope for microscopic identification. Radix Astragali, Rhizoma Cimicifugae, Radix Paeoniae Alba, and Cortex Phellodendri Chinensis were identified by thin-layer chromatography (TLC) for qualitative differentiation. The contents of puerarin and paeoniflorin in Yiqi Congming Pills were determined by high performance liquid chromatography(HPLC). Results The microscopic characteristics of Radix Puerariae, Radix Astragali, Fructus Viticis, Cortex Phellodendri Chinensis, Radix Codonopsis in the pills were obvious and were easy for discrimination. The spots in thin-layer chromatography (TLC) chromatograms of Radix Astragali, Rhizoma Cimicifugae, Radix Paeoniae Alba, and Cortex Phellodendri Chinensis were clear without interference of negative reference. Puerarin had a good linearity in the range of 0.00112~3.50676μg, and the average recovery rate was 98.2%(sR=1.4%, N=9 ). Paeoniflorin had a good linearity in the range of 0.00333 ~ 3.328 μg, and the average recovery rate was 98.4%(sR = 1.8%, N = 9). Great differences existed in the contents of puerarin and paeoniflorin of Yiqi Congming Pills from the three pharmaceutical companies. Conclusion The established qualitative and quantitative methods are of accuracy, credibility and repeatability, and are effective for controling the quality of Yiqi Congming Pills.

Background and objective Twice-daily radiation concurrent with chemotherapy is one of the standard methods for limited-stage small cell lung cancer. hTe study was to evaluate the feasibility of chemotherapy concurrent with dose-escalating twice-daily radiotherapy by simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) approach in patients with limited-stage small cell lung cancer. Methods Patients with limited-stage small cell lung cancer were included, treated with twice-daily radiotherapy by SIB-IMRT concurrent with chemotherapy of etoposide plus cisplatin. Dose escalation was conducted by“classical”3+3 methods with three patients enrolled in each dose level. The therapeutic gross tumor volume (GTV) was treated according to three consecutive dose levels i.e., 45 Gy at 1.5 Gy twice daily, 50 Gy at 1.67 Gy twice daily and 54 Gy at 1.8 Gy twice daily. hTe planning target volume (PTV) received a dose of 45 Gy delivered in 30 fractions of 1.5 Gy. hTe primary endpoints were acute toxicities. hTe secondary endpoints included overall survival (OS), pro-gression-free survival (PFS) and loco-regional failure-free survival (LRFFS) at 1-year of follow-up. Results Twenty men and six women were included. hTe median age was 52 (30-68) months. 12 patients experienced grade 2 acute esophagitis, and 1 patient developed grade 3 acute esophagitis. Only 3 patients developed Grade 2 pneumonitis. Grade 3 or higher radiation-related pneumonia was not observed. None died of treatment-related causes. With median follow-up of 11.2 months (3.2-36.2 months), 1-year OS, PFS and LRFFS were 89.0%, 51.0%and 85.0%, respectively. Conclusion Dose escalation for twice-daily radiation concurrent with chemotherapy in LS-SCLC has been safely achieved up to 54 Gy for GTV using SIB-IMRT technique.

Background and objective Concurrent twice-daily radiotherapy with chemotherapy of EP regimen is one of the current standard treatments for limited-stage small cell lung cancer. However, the safely tolerated dose of standard chemotherapy for Chinese patients is not decided. hTis study was to evaluate the toxicity and the maximum tolerated dose (MTD) of etoposide and cisplatin concurrent with thoracic radiation therapy for patients with limited-stage small cell lung cancer. Methods Patients with histologically proven limited-stage small cell lung cancer (LS-SCLC) were eligible. hTe pa-tients underwent thoracic radiotherapy (45 Gy, 1.5 Gy bid, 30 fractions for 3 weeks) delivered concurrently with etoposide (100 mg/m2 iv, days 1-3) and cisplatin dose escalating from the two levels ( 70 mg/m2 and 75 mg/m2 on d1). hTe primary end-points were hematologic toxicities during treatment. hTe secondary endpoints were non-hematologic toxicities, overall survival (OS) and progression-free survival (PFS). According to Common Terminology Criteria for Adverse Events 4.0 (CTC-AE 4.0), maximum tolerant dosage (MTD) was deifned as the highest safely tolerated dose at which no more than one patient out of six experiences dose-limiting toxicity (Grades 4 hematologic), with the next higher dose having at least two out of six patients experience dose-limiting toxicity. Results From January 2013 to August 2016, 20 patients were enrolled in this study. hTe median age was 49.5 (30-68). Atfer the ifrst 6 patients were enrolled in Arm 1 (70 mg/m2 on d1), one patient had Grade 4 neu-tropenia. Another 14 patients were enrolled in Arm 2 (75 mg/m2 on d1), one patient had Grade 4 neutropenia. hTe MTD was determined to be etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1). 4 patients had≥Grade 3 neutropenia and 1 patients had≥Grade 3 acute esophagitis in Arm 1. 10 patients had≥Grade 3 neutropenia and no patient had≥Grade 3 acute esophagitis in Arm 2. All patients with a median follow-up time was 9.0 months, median OS and PFS were not achieved, 1-year OS and PFS were 91%and 61%, respectively. Conclusion hTe MTD of RT with concurrent chemotherapy of EP regi-men for patients with LS-SCLC was etoposide (100 mg/m2 iv, d1-d3) and cisplatin dose (75 mg/m2 on d1).