Clinical efficacy and prognostic influencing factors of radical surgery for duodenal gastro-intestinal stromal tumor: a multicenter retrospective study / 中华消化外科杂志

Objective:To investigate the clinical efficacy and prognostic influencing factors of radical surgery for duodenal gastrointestinal stromal tumor (GIST).Methods:The retrospective cohort study was conducted. The clinicopathological data of 741 duodenal GIST patients who under-went radical surgery in 17 medical centers, including 121 cases in Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 121 cases in Chinese PLA General Hospital, 116 cases in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 77 cases in Fudan University Shanghai Cancer Center, 77 cases in West China Hospital, Sichuan University, 31 cases in Guangdong Provincial People′s Hospital, 24 cases in Fujian Cancer Hospital, 22 cases in Fujian Medical University Union Hospital, 25 cases in Shengjing Hospital of China Medical University, 19 cases in Xiangya Hospital, Central South University, 23 cases in Zhejiang Cancer Hospital, 17 cases in Liaoning Cancer Hospital＆Institute, 17 cases in the First Affiliated Hospital of Xiamen University, 15 cases in Sun Yat-sen University Cancer Center, 14 cases in the First Affiliated Hospital of Nanjing Medical University, 14 cases in Zhongshan Hospital Affiliated to Xiamen University and 8 cases in General Hospital of Chinese People′s Liberation Army Air Force, from January 2010 to April 2020 were collected. There were 346 males and 395 females, aged 55(range, 17?86)years. Observation indicators: (1) neoadjuvant treatment; (2) surgical and postoperative situations; (3) follow-up; (4) stratified analysis. Follow-up was conducted using outpatient examination or telephone interview. Patients were followed up once every 3?6 months during neoadjuvant therapy and once every 6?12 months after radical surgery to detect tumor recurrence and survival of patient up to April 2022. Measurement data with normal distribution were represented as Mean± SD. Measurement data with skewed distribution were represented as M(range), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers or percentages, and comparison between groups was conducted using chi-square test or Fisher exact probability. The Kaplan-Meier method was used to draw survival curves and calculate survival rates. Log-rank test was used for survival analysis. The COX regression model was used for univariate and multivariate analyses. Propensity score matching was done by the 1∶1 nearest neighbor matching method, and the matching tolerance was 0.02. Results:(1) Neoadjuvant therapy. Of the 741 patients, 34 cases received neoadjuvant therapy for 8(range, 3?44)months. Cases assessed as partial response, stable disease and progressive disease before the radical surgery of the 34 cases were 21, 9, 4, respectively. The tumor diameter of the 34 patients before the neoadjuvant therapy and before the radical surgery were 8.0(range, 3.0?26.0)cm and 5.3(range, 3.0?18.0)cm, with the regression rate as 31.9%(range, ?166.7% to 58.3%). (2) Surgical and postoperative situations. Of the 741 patients, 34 cases underwent radical surgery after receiving neoadjuvant therapy, and 707 cases underwent radical surgery directly. All the 741 patients underwent radical surgery successfully, in which 633, 102 and 6 cases received open surgery, laparoscopic surgery and endoscopic treatment, respectively. Of the 633 cases receiving open surgery and the 102 cases receiving laparoscopic surgery, cases with surgical resection range as pancreatoduodenectomy (PD) was 238, and cases with surgical resection range as duodenal limited resection, including duodenal wedge resection, distal gastrectomy, segmental duodenal resection, local resection of duodenal tumor or segmental duodenum combined with subtotal gastrectomy, was 497, 226, 55, 204, 12. Of the 741 patients, 131 cases had post-operative complications including 113 cases with grade Ⅰ?Ⅱ complications and 18 cases with ≥ grade Ⅲ complications of the Clavien-Dindo classification. The duration of postoperative hospital stay of the 741 patients was 13(range, 4?120)days. Of the 707 patients receiving direct radical surgery, 371 cases were evaluated as extremely low risk, low risk, medium risk of the modified National Institutes of Health (NIH) risk classification after surgery, and 336 cases were evaluated as high risk in which 205 cases receive postoperative adjuvant imatinib therapy with the treatment time as 24(range, 6?110)months. (3) Follow-up. All the 741 patients were followed up for 58(range, 7?150)months. During the follow-up, 110 patients had tumor recurrence and metastasis. The 1-, 3-, 5-year overall survival rates and 1-, 3-, 5-year disease-free survival rates of the 741 patients were 100.0%, 98.6%, 94.5% and 98.4%, 90.9%, 84.9%, respectively. The 1-, 3-, 5-year overall survival rates and 1-, 3-, 5-year disease-free survival rates of the 707 patients receiving direct radical surgery were 100.0%, 98.5%, 94.3% and 98.4%, 91.1%, 85.4%, respectively. (4) Stratified analysis. ① Analysis of prognostic factors in patients undergoing radical surgery directly. Results of univariate analysis showed that primary tumor location, tumor diameter, mitotic count, modified NIH risk classification and tumor gene information were related factors affecting the overall survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=0.43, 0.18, 0.22, 0.06, 0.29, 95% confidence intervals as 0.20?0.93, 0.09?0.35, 0.10?0.50, 0.03?0.12, 0.09?0.95, P<0.05). The primary tumor location, tumor diameter, mitotic count, modified NIH risk classification were related factors affecting the disease-free survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=0.65, 0.25, 0.25, 0.10, 95% confidence intervals as 0.41?1.03, 0.17?0.37, 0.15?0.42, 0.07?0.15, P<0.05). Results of multivariate analysis showed that primary tumor located at the horizontal segment of duodenum, mitotic count >5/50 high power field, tumor gene KIT exon 9 mutation were independent risk factors affecting the overall survival of 365 patients with primary duodenal GIST after removing 342 patients without tumor gene information who underwent direct radical surgery ( hazard ratio=2.85, 2.73, 3.13, 95% confidence intervals as 1.12?7.20, 1.07?6.94, 1.23?7.93, P<0.05). Tumor diameter >5 cm and mitotic count >5/50 high power field were independent risk factors affecting the disease-free survival of 707 patients with primary duodenal GIST who underwent direct radical surgery ( hazard ratio=3.19, 2.98, 95% confidence intervals as 2.05?4.97, 1.99?4.45, P<0.05). ② Effect of postoperative adjuvant therapy on prognosis of high-risk patients of modified NIH risk classification. Of the 336 patients evaluated as high risk of the modified NIH risk classification, the 5-year overall survival rate and 5-year disease-free survival rate were 94.6% and 77.3% in the 205 cases with postoperative adjuvant therapy, versus 83.2% and 64.4% in the 131 cases without postoperative adjuvant therapy, showing significant differences between them ( χ2=8.39, 4.44, P<0.05). Of the 205 patients evaluated as high risk of the modified NIH risk classification who received postoperative adjuvant therapy, there were 106 cases receiving postoperative adjuvant therapy <36 months, with the 5-year overall survival rate and 5-year disease-free survival rate were 87.1% and 58.7%, and there were 99 cases receiving post-operative adjuvant therapy ≥36 months, with the 5-year overall survival rate and 5-year disease-free survival rate were 100.0% and 91.5%. There were significant differences in the 5-year overall survival rate and 5-year disease-free survival rate between the 106 patients and the 99 patients ( χ2=13.92, 29.61, P<0.05). ③ Comparison of clinical efficacy of patients with different surgical methods. Before propensity score matching, cases with primary tumor located at bulb, descending, horizontal, ascending segment of duodenum, cases with tumor diameter ≤5 cm and >5 cm were 95, 307, 147, 34, 331, 252, in the 583 patients receiving open surgery with complete clinical data, versus 15, 46, 17, 5, 67, 16 in the 83 patients receiving laparoscopic surgery with complete clinical data, showing no significant difference in the primary tumor location ( χ2=0.94, P>0.05), and a significant difference in the tumor diameter ( χ2=17.33, P<0.05) between them. After propensity score matching, the above indicator were 16, 39, 20, 8, 67, 16 in the 83 patients receiving open surgery, versus 15, 46, 17, 5, 67, 16 in the 83 patients receiving laparoscopic surgery, showing no significant difference between them ( χ2=1.54, 0.00, P>0.05). Cases with postoperative complications, cases with grade Ⅰ?Ⅱ complica-tions and ≥grade Ⅲ complications of the Clavien-Dindo classification, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate were 17, 12, 5, 11(range, 5?120)days, 92.0%, 100.0% in the 83 patients receiving open surgery, versus 9, 7, 2, 11(range, 5?41)days, 91.6%, 97.3% in the 83 patients receiving laparoscopic surgery, showing no signi-ficant difference in postoperative complications, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate ( χ2=2.91, Z=3 365.50, χ2=3.02, 1.49, P>0.05) between them. There was no significant difference in complications of the Clavien-Dindo classification between them ( P>0.05). ④ Comparison of clinical efficacy of patients with primary tumor located at the descending segment of duodenum who underwent surgery with different surgical resection scopes. Before propensity score matching, cases with tumor diameter ≤5 cm and >5 cm, cases with tumor located at opposite side of mesangium and mesangium were 71, 85, 28, 128 in the 156 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 92, 41, 120, 13 in the 133 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing significant differences between them ( χ2=16.34, 150.10, P<0.05). After propensity score matching, the above indicator were 28, 13, 16, 25 in the 41 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 28, 13, 16, 25 in the 41 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing no significant difference between them ( χ2=0.00, 0.00, P>0.05). Cases with postopera-tive complications, cases with grade Ⅰ?Ⅱ complications and ≥grade Ⅲ compli-cations of the Clavien-Dindo classification, duration of postoperative hospital stay, the 5-year overall survival rate and 5-year disease-free survival rate were 13, 11, 2, 15(range, 9?62)days, 94.2%, 64.3% in the 41 patients with primary tumor located at the descending segment of duodenum who underwent PD with complete clinical data, versus 9, 8, 0, 15(range, 7?40)days, 100.0%, 78.8% in the 41 patients with primary tumor located at the descending segment of duodenum who underwent duodenal limited resection with complete clinical data, showing no significant difference in post-operative complica-tions, the 5-year overall survival rate and 5-year disease-free survival rate ( χ2=0.99, 0.34, 1.86, P>0.05) between them. There was no significant difference in complications of the Clavien-Dindo classification ( P>0.05) and there was a significant difference in duration of postopera-tive hospital stay ( Z=614.50, P<0.05) between them. Conclusions:The clinical efficacy of radical surgery for duodenal GIST are ideal. Primary tumor located at the horizontal segment of duodenum, mitotic count >5/50 high power field, tumor gene KIT exon 9 mutation are independent risk factors affec-ting the overall survival of patients undergoing direct radical surgery and tumor diameter >5 cm and mitotic count >5/50 high power field are independent risk factors affecting the disease-free survival of patients. There is no significant difference in the short-term efficacy and long-term prognosis between patients undergoing open surgery and laparoscopic surgery. For patients with primary tumor located at the descending segment of duodenum, the duration of postoperative hospital stay is longer in patients undergoing PD compared with patients undergoing duodenal limited resection. For patients evaluated as high risk of the modified NIH risk classification, posto-perative adjuvant therapy and treatment time ≥36 months are conducive to improving the prognosis of patients.

Immune Microenvironment Comparation Study between EGFR Mutant and EGFR Wild Type Lung Adenocarcinoma Patients Based on TCGA Database / 中国肺癌杂志

BACKGROUND@#Lung cancer is a malignant with high incidence and mortality and adenocarcinoma is among the most popular subtypes. Epidermal growth factor receptor (EGFR) mutation is one of the most important driver mutations for lung adenocarcinoma and EGFR-tyrosine kinase inhibitor (TKI) will benefit those patients with sensitive EGFR mutations. Recently, immune checkpoint inhibitor (ICI) therapy, provide a new breakthrough treatment for lung cancer patients. Whereas immunotherapy as an emerging treatment does not benefit patients with EGFR mutations, for which mechanistic studies are poorly defined and focused on the link of EGFR mutations and programmed cell death-ligand 1 (PD-L1) expression, we speculate that the different immune microenvironment associated with the two classes of patients.@*METHODS@#Lung adenocarcinoma datasets were collected from the Cancer Genome Atlas (TCGA) database, and clinical information and gene expression profiles were downloaded. The immune related lymphocyte infiltration in TCGA database were generated through timer 2.0 GSEA was used to analyze the difference of pathway expression between EGFR mutant patients and wild type patients.@*RESULTS@#EGFR mutation was more frequently among women and never smokers. Immunoinfiltration analysis showed that patients with EGFR mutation tends to have more tumor associated fibroblasts, common myeloid progenitor cells, hematopoietic stem cells, effector CD4⁺ T cells and natural killer T cells infiltration, and less memory B cells, naïve B cells, plasma B cells, plasmacytoid dendritic cells, memory CD4⁺ T cells, CD4⁺ helper T cells 2, naive CD8⁺ T cells, CD8⁺ T cells and central memory CD8⁺ T cells infiltration. Moreover, patients with more infiltration of CD8⁺ T cells, natural killer T cells, memory B cells and hematopoietic stem cells, tends have better prognosis (Log-rank test, P=0.017, 0.0093, 0.018, 0.016). However, the patients with more CD4⁺ T th2 infiltration in the tumor tends to have worse prognosis (Log-rank test, P=0.016). Furthermore, the results of gene set enrichment analysis showed that compared with the lung adenocarcinoma patients with EGFR wild type, the three pathways positive regulation of natural killer (NK) cell-mediated immune response to tumor cells, NK cell activation involved in immune response, and NK cell-mediated immune response to tumor cells related to natural killer cells in patients with EGFR mutation were down regulated, while the pathway the positive regulation of cytokine secretion involved in immune response was up-regulated in EGFR mutation patients.@*CONCLUSIONS@#The tumour microenvironment of patients with EGFR mutations lacks potent tumour killing effector cells and appears dysfunctional with effector cells. This may be a potential reason for the poor efficacy of immunotherapy in patients with EGFR mutations.

Application value of transanal endoscopic partial intersphincteric resection for ultra-low rectal cancer / 中华消化外科杂志

Objective:To investigate the application value of transanal endoscopic partial intersphincteric resection for ultra-low rectal cancer.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 9 ultra-low rectal cancer patients undergoing transanal endoscopic partial intersphincteric resection at the First Affiliated Hospital of Xiamen University from December 2017 to August 2020 were collected. There were 8 males and 1 female, aged from 39 to 62 years, with a median age of 58 years. Observation indicators: (1) surgical and postoperative situations; (2) postoperative pathological examination; (3) follow-up. Follow-up was conducted using outpatient examination and telephone interview to detect postoperative tumor local recurrence and distant metastasis, survival of patients, ileostomy closure, anus function at 3 months after ileostomy closure, male urinary and sexual function and female sexual function at 6 months after rectal surgery. The follow-up was up to February 2021. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers. Results:(1)Surgical and postoperative situations: all 9 patients underwent surgery successfully, without conversion to open surgery. Seven of the 9 patients underwent transanal endoscopic partial intersphincteric resection and the rest of 2 patients with tumor close to the dentate line underwent transanal endoscopic modified partial intersphincteric resection. The operation time and volume of intraoperative blood loss of 9 patients were (267±48)minutes and 50 mL(range, 30?60 mL), respectively. Five of the 9 patients underwent transanal specimen extraction, and 4 patients underwent specimen extraction by an abdominal incision. All 9 patients underwent transanal hand-sewn coloanal anastomosis and protective ileostomy, and two pelvic drainage tubes were indwelled. Transanal drainage tube was placed after anastomosis in 3 of 9 patients. Three cases had intraoperative adverse events and there were no intraoperative adverse event reported in the remaining 6 cases. The time to postoperative initial stoma exhausting and time to postoperative first semi-liquid food intake of 9 patients were 3 days(range, 2?4 days) and 5 days(range, 4?7 days), respectively. One case had Clavien-Dindo grade Ⅰ complication and 2 cases had Clavien-Dindo grade Ⅱ complication during postoperative 30 days and the rest of 6 cases had no postoperative complication. No anastomotic stricture, hemorrhage or urinary retention occurred in 9 patients. The duration of postoperative hospital stay and cost of hospitalization of 9 patients were 11 days(range, 9?23 days) and (6.8±1.3)×10 4 yuan, respectively. (2) Postoperative pathological examination: the diameter of tumor, the distance of distal resection margin, the number of lymph node dissected and the number of positive lymph node of 9 patients were (3.2±1.4)cm, 0.6 cm(range, 0.5?1.5 cm), 17±7 and 0(range, 0?7), respectively. The tumor histopathological type was adenocarcinoma with negative tumor nodule and nerve infiltration in all 9 patients. Only 1 case of 9 patients was found vascular tumor thrombus. The surgical specimens of all 9 patients showed negative for distal and circumferential margins and complete mesorectum. Results of postoperative pathological TNM staging showed that of 6 cases with preoperative T1-T2 staging tumors, 3 cases were classified as pT2N0M0 stage, and 3 cases were classified as pT2N1M0 stage, pT2N2M0 stage or pT3N1M0 stage, respectively. Three cases with preoperative T3 staging tumors were classified as ypT0N0M0 stage, ypT2N0M0 stage or ypT3N0M0 stage, respectively. (3) Follow-up: all 9 patients were followed up for 6 to 13 months, with a median follow-up time of 9 months. No local recurrence, distant metastasis or tumor-related death was found during follow-up. Of the 9 patients, only 1 case did not receive stoma closure and undergo anus function assessment, and the rest of 8 cases underwent stoma closure. Results of postoperative anus function assessment showed 5 cases of accessibility, 2 cases of mild impairment and 1 case of severe impairment. Results of urogenital function assessment showed 6 cases of the 8 male patients of mild impairment, 1 case of moderate impairment and 1 case of severe impairment in micturition function, respectively, and 3 cases of accessibility, 2 cases of mild impairment and 3 cases of moderate impairment in sexual function, respectively. The female patient underwent accessibility of sexual function and the six-item version of the female sexual function index was 25. Conclusion:Transanal endoscopic partial intersphincteric resection can be used for the treatment of ultra-low rectal cancer.

Apatinib Combined with CCI-779 Inhibits the Proliferation and Migration of Small Cell Lung Cancer NCI-H446 Cells In Vitro / 中国肺癌杂志

BACKGROUND@#Lung cancer is the most common malignancy world-wide. Small cell lung cancer is the deadliest subtype of lung cancer, which features such as rapid growth, early metastasis, and high vascularization. Apatinib is a vascular endothelial growth factor receptor 2 inhibitor independently developed in China, which has a significant inhibition in a variety of solid tumors. The purpose of this study is to investigate the effects of Apatinib alone or Apatinib combined with mammalian target of rapamycin (mTOR) inhibitor, CCI-779, on small cell lung cancer cell line NCI-H446 in vitro.@*METHODS@#The small cell lung cancer cell line NCI-H446 was grew in vitro. The effects of Apatinib alone or Apatinib combined with CCI-779 on proliferation, apoptosis, cell cycle and migration of NCI-H446 small cell lung cancer cells were detected by CCK8; FACS and transwell assays were also carried out; Western blot assays were used to detect vascular endothelial growth factor and cell cycle related protein expression.@*RESULTS@#CCK8 assays showed that high concentration of Apatinib could inhibit the proliferation of NCI-H446 cells. Apoptosis assays showed that high concentration of Apatinib could induce NCI-H446 cell apoptosis. Transwell assays showed that high concentration of Apatinib could inhibit NCI-H446 cell migration. After combined with mTOR inhibitor CCI-779, low concentration of Apatinib could inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells and induce apoptosis.@*CONCLUSIONS@#Apatinib has a concentration-dependent effect on the small cell lung cancer cell line NCI-H446. High concentration of Apatinib can inhibit the proliferation and migration of NCI-H446 small cell lung cancer cells, induce apoptosis. Apatinib combined with the mTOR inhibitor CCI-779 can sensitize the NCI-H446 cells to Apatinib.

The Role of Plasma CDO1 Methylation in the Early Diagnosis of Lung Cancer / 中国肺癌杂志

BACKGROUND@#The incidence and mortality of lung cancer often rank first in all malignant tumors. DNA methylation, as one of epigenetics, often participates in the development and progression of tumors. CDO1 as a tumor suppressor gene always undergoes methylation changes early in tumor development. Therefore, this study aims to discuss the value of CDO1 methylation in the early diagnosis of lung cancer.@*METHODS@#Peripheral blood samples were collected from tumor patients and healthy people. Detection of the methylation level of CDO1 in plasma by sulfite modification and quantitative real-time PCR.@*RESULTS@#The level of gene methylation in peripheral blood of lung cancer patients was significantly higher than that of benign lung disease patients and healthy people. The methylation level of CDO1 was significantly different in the stratified comparison of gender, lymph node metastasis and tumor-node-metastasis (TNM) stage (P<0.05). The sensitivity and specificity of CDO1 were 52.2% and 78.6%, respectively. The overall accuracy of the diagnosis was significantly higher than that of the clinical tumor markers, and the sensitivity of CDO1 to stage I and II patients was the highest (40.8%, 47.1%). In addition, CDO1 could effectively increase the sensitivity of diagnosis in multiple joint examinations.@*CONCLUSIONS@#Detecting the methylation level of CDO1 has a potentially huge advantage for the early diagnosis of lung cancer.

Research Progress of Epigenetics in Pathogenesis and Treatment of Malignant Tumors / 中国肺癌杂志

Epigenetic modification is closely related to the occurrence and development of tumors. It mainly regulates gene function and expression level through DNA methylation, histone modification, regulation of non-coding RNA and chromatin structure reconstruction. At present, epigenetic drugs have been gradually applied to the treatment of malignant tumors. Common drug types include: DNA methyltransferase inhibitors and histone deacetylase inhibitors. However, these drugs still have many shortcomings and a wide range of clinical applications need further research. Encouragingly, the epigenetic drugs in combination with various anti-tumor drugs have shown great application potential. In this paper, we summarized the development mechanism of epigenetics in malignant tumors and the progress of related drugs.

Role of EZH2 Inhibitor Combined with Gefitinib in EGFR-TKIs Resistant Lung Cancer Cells / 中国肺癌杂志

BACKGROUND@#Lung cancer is one of the common malignant tumors that impair human health. With the development of epigenetics, the researchers found that enhancer of Zeste homolog 2 (EZH2) is highly expressed in lung cancer tissue and its expression is closely related to the prognosis. EZH2 inhibitor can also enhance the sensitivity of tumor cells to a variety of anti-tumor drugs. The purpose of this study is to investigate the effect of combination of EZH2 inhibitor and gefitinib on the proliferation, apoptosis and migration of Gefitinib-resistant lung cancer cells.@*METHODS@#PC9 and PC9/AB2 cells were used for this study. CCK-8 and EdU experiment were used to detect combined treatment on cell viability and proliferation activity; Wound healing assay and Transwell chamber experiment were used to determine the effects of combination therapy on cell migration ability; Flow cytometry was used to detect the effect of combination therapy on EZH2 and apoptosis; Western blot was used to observe the effect of combination therapy on epidermal growth factor receptor (EGFR) signaling pathway-related proteins expression.@*RESULTS@#In gefitinib-resistant cell line PC9/AB2, gefitinib combined with EZH2 inhibitor GSK343 can significantly inhibit cell viability, reduce cell migration and increase cell apoptosis. At the same time, combination therapy can significantly inhibit the expression of EZH2 and phosphorylation EGFR proteins.@*CONCLUSIONS@#The combination of EZH2 inhibitor GSK343 and gefitinib sensitize PC9/AB2 cell to gefitinib response. This study also suggests that synergistic therapy plays a role in the reversal of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) resistance in lung cancer.

Effect of Apatinib on Invasion and Migration of Lung Cancer Cells and Its Mechanism / 中国肺癌杂志

BACKGROUND@#Lung cancer is one of the most deadly cancers in the world for human. In recent years, the effect of targeted therapy has become increasingly significant. Apatinib is a multi-target anti-tumor drug that is currently under study. The purpose of this study is to investigate the effects of Apatinib on the biological characteristics of lung cancer cells and its possible mechanism.@*METHODS@#Lung cancer cell lines H1299 and H3255 were cultured in vitro. The effects of Apatinib on proliferation, migration and invasion of H1299 and H3255 cells were detected by cell proliferation assays wound healing assays and Transwell assays. The protein expression related to cancer angiogenesis and invasion was detected by Western blot.@*RESULTS@#Apatinib significantly inhibited the proliferation, migration and invasion of H1299 and H3255 in a concentration-dependent manner. Western blot showed that with the increasing of drug concentration, VEGF, VEGFR2, N-cadherin, MMP9, MMP2 and Vimentin were down-regulated, and E-cadherin were up-regulated.@*CONCLUSIONS@#Apatinib can inhibit the invasion and migration of lung adenocarcinoma cells H1299 and H3255. By regulation of epithelial-mesenchymal transition and the expression of matrix metalloproteinase-related proteins.

Study on the Difference of Gene Expression between Central and Peripheral Lung Squamous Cell Carcinoma Based on TCGA Database / 中国肺癌杂志

BACKGROUND@#Lung cancer is a malignant tumor disease with high morbidity and high mortality. The non-small cell lung cancer (NSCLC) is the most common type, among them, lung squamous cell carcinoma own special pathological type and specific treatment, is a subtype of non-small cell lung cancer and can be divided into peripheral type and central type according to clinical phenotype. This study explores the differences in gene levels and their potential values based on clinical differences between central and peripheral in lung squamous cell carcinoma.@*METHODS@#The lung squamous cell carcinoma dataset was collected from The Cancer Genome Atlas (TCGA) database, clinical information and the corresponding gene expression profiles were downloaded. Then we further sort and analyze all these data.@*RESULTS@#In clinical characteristics analysis, result showed that central lung squamous cell carcinoma was more likely to metastasis with lymph node than peripheral lung squamous cell carcinoma (46.2%, 67/145 vs 28.9%, 26/90; P=0.019), while there were no significant differences in gender, age, tumor size, distant metastasis, tumor node metastasis (TNM) stage, and EGFR mutation. Gene expression analysis showed 1,031 differentially expressed genes between central and peripheral lung squamous cell carcinoma, of which 629 genes were up-regulated and 402 genes were down-regulated (peripheral vs central). Further enrichment analysis showed differentially expressed genes were mainly riched in 6 signaling pathways. Among them, the neuroactive ligand-receptor interaction pathway was the main enrichment pathway of differentially expressed genes, and other differential expressed genes were mainly involved in lipid metabolism and glucose metabolism. The analysis of interaction network showed that hepatocyte nuclear factor 1 homeobox A (HNF1A) and cytochrome p450 family, Cytochrome P450 3A4 (CYP3A4) own widely effect in up-regulated genes, while ALB and APOA1 at the key positions of the network in down-regulated genes were CONCLUSIONS: Central and peripheral lung squamous cell carcinoma showed clinical phenotype difference not only reflected in the incidence of lymph node metastasis, but also in gene expression profiles. Among them, HNF1A, CYP3A4, ALB, APOA1 at the key position of the differential gene interaction network and maybe as regulatory factors in the phenotypic difference.

Role of PD 0332991 on the Proliferation and Apoptosis of Vascular Endothelial Cells / 中国肺癌杂志

BACKGROUND@#Angiogenesis is an important process in the development of tumor. PD 0332991, a cell cycle inhibitor, can specifically inhibit CD4/6 phosphorylation and cell cycle progression. In xeongraft mice models, PD 0332991 treated mice had significantly decreased angiogenesis and vascular density compared with the control group, but the mechanism remains unknown. The purpose of this study is to investigate the role and molecular mechanism of PD 0332991 on vascular endothelial cells.@*METHODS@#EA.hy926 cells, a kind of vascular endothelial cell, were used as the research model. The effects of PD 0332991 on the activity and proliferation of EA.hy926 cells were detected by the MTT, EdU assays. Wound-healing assays and transwell assays were used to determine the effects of PD 0332991 on the mobility of EA.hy926. The influence of PD 0332991 on cell cycle and apoptosis of endothelial cells was tested by flow cytometry, and the Western blot was applied to observe the expression of cell cycle related proteins in EA.hy926 cells treated by PD 0332991.@*RESULTS@#PD 0332991 significantly inhibited the proliferation and mobility of EA.hy926 cells, caused cell cycle arrest and apoptosis. At the same time, PD 0332991 inhibited the expression of CDK4/6 and phosphorylation of Rb, and thus inhibited the cell cycle progression of EA.hy926 cells.@*CONCLUSIONS@#PD 0332991 can inhibit the proliferation and activity of endothelial cells and induces apoptosis.

Thoracoscopic and laparoscopic radical resection for adenocarcinoma of the esophagogastric junction with side-to-side tubular gastroesophagostomy / 中华消化外科杂志

Objective To investigate the clinical efficacy of thoracoscopic and laparoscopic radical resection for adenocarcinoma of the esophagogastric junction (AEG) with side-to-side tubular gastroesophagostomy.Methods The retrospective and descriptive study was conducted.The clinicopathological data of 4 patients with AEG who were admitted to the First Affiliated Hospital of Xiamen University between November 2017 and June 2018 were collected.All the patients underwent thoracoscopic and laparoscopic radical resection for AEG using side-to-side tubular gastroesophagostomy and received 6 cycles of postoperative adjuvant chemotherapy with SOX regimen.Observation indicators:(1) surgical and postoperative recovery situations;(2) postoperative pathological examination;(3) follow-up and survival situations.The follow-up using outpatient examination and telephone interview was performed to detect postoperative adjuvant therapy situations and survival of patients up to Semptember 2018.Results (1) Surgical and postoperative recovery situations:4 patients successfully underwent thoracoscopic and laparoscopic radical resection for AEG using side-to-side tubular gastroesophagostomy,without conversion to thoracotomy,open surgery or perioperative death.Operation time,volume of intraoperative blood loss,time for postoperative fluid diet intake and postoperative drainage-tube removal time of case 1,2,3,4 were respectively 420 minutes,400 minutes,320 minutes,300 minutes and 100 mL,100 mL,150 mL,100 mL and 9 days,8 days,8 days,8 days and 11 days,10 days,10 days,10 days.Case 1 with mild pneumonia and hiccup and case 2 with mild pneumonia were improved by symptomatic treatment,case 3 and 4 didn't have complication.All the patients had postoperative patent anastomosis.Duration of postoperative hospital stay of case 1,2,3,4 were respectively 12 days,11 days,11 days,11 days.(2) Postoperative pathological examination:all the 4 patients had negative surgical margin.Number of lymph node dissected,number of positive lymph node,tumor diameter,Siewert type,depth of tumor infiltration,tumor histopathologic stage of case 1,2,3,4 were respectively 32,31,17,23 and 0,4,2,6 and 3.5 cm,5.0 cm,5.0 cm,4.0 cm and type Ⅱ,Ⅰ,Ⅱ,Ⅰ and subserosa,entire wall of the esophagogastric junction,subserosa,entire wall of the esophagogastric junction and Ⅱ A staging,Ⅲ B staging,Ⅱ B staging,Ⅲ A staging.Degree of tumor differentiation and pathological type were moderately differentiated adenocarcinoma in the 4 patients.(3) Follow-up and survival situations:4 patients were followed up for 3-10 months,with a median time of 5 months.During the follow-up,4 patients underwent chemotherapy and achieved disease-free survival.Conclusion Thoracoscopic and laparoscopic radical resection for AEG using side-to-side tubular gastroesophagostomy is safe and feasible.

Clinical effects and prognostic factors of transabdominal laparoscopic-assisted and open radical resection for Siewert type Ⅱ and Ⅲ adenocarcinoma of the esophagogastric junction / 中华消化外科杂志

Objective To investigate clinical effects and prognostic factors of transabdominal laparoscopic-assisted and open radical resection for Siewert type Ⅱ and Ⅲ adenocarcinoma of the esophagogastric junction (AEG).Methods The retrospective cohort and case-control studies were conducted.The clinicopathologieal data of 84 patients with Siewert type Ⅱ and Ⅲ AEG who were admitted to the First Affiliated Hospital of Xiamen University from January 2014 to January 2017 were collected.Among 84 patients,42 undergoing transabdominal laparoscopic-assisted radical gastectomy (LARG) were allocated into LARG group and 42 undergoing transabdominal open radical gastectomy (ORG) were allocated into ORG group.Observation indicators:(1) comparison of intraoperative and postoperative recovery situations between groups;(2)comparison of follow-up and survival situations between groups;(3) prognostic analysis of patients with Siewert type Ⅱ and Ⅲ AEG undergoing transabdominal radical resection.Follow-up using outpatient examination and telephone interview was performed to detect postoperative survival situations,tumor recurrence and metastasis of patients up to January 2018.Measurement data with normal distribution were representde as-x±s,and comparison between groups was analyzed using the t test.Measurement data with skewed distribution were described as M (range).Comparison of count data were analyzed using the ehi-square test or Fisher exact probability.Ordinal data were compared between groups using the Mann-Whitney U nonparametric test.The survival rate and curve were respectively calculated and drawn by the Kaplan-Meier method,and Log-rank test was used for survival and univariate analyses.Multivariate analysis was done by COX proportional hazard model.Results (1) Comparison of intraoperative and postoperative recovery situations between groups:patients with Siewert type Ⅱ and Ⅲ AEG in the LARG and ORG group underwent successful transabdominal radical resection,without conversion to thoracotomy.All patients in the LARG group underwent esophagojejunostomy with circular stapler device,38 and 4 patients in the ORG group underwent esophagojejunostomy with circular stapler and linear cut stapler respectively.Operation time,volume of intraoperative blood loss,length of incision,time of postoperative analgesia,cases with anastomotic bleeding,anastomotic leakage,abdominal bleeding,incisional infection,pulmonary infection,abdominal infection and reflux esophagitis of grade Ⅰ ～ Ⅱ postoperative complications and duration of postoperative stay were respectively (261±50)minutes,(119±111)mL,(7.8±1.6)cm,(2.1±1.3)days,1,1,0,0,1,0,0,(12.8 ± 1.9) days in LARG group and (216 ± 52) minutes,(230± 178) mL,(17.3± 1.8) cm,(3.4±1.2)days,2,0,2,2,2,1,2,(18.4±15.3)days in ORG group,with statistically significances between groups (t =2.357,2.960,2.195,2.013,x2 =5.486,t =2.125,P＜0.05).All patients with complications were improved by symptomatic treatment.(2) Comparison of follow-up and survival situations between groups:81 of 84patients including 41 in LARG group and 40 in ORG group were followed up for 6-48 months,with a median time of 29 months.The postoperative 2-year overall and tumor-free survival rates were respectively 85.1％ and 82.1％ of 41 patients in LARG group and 83.1％ and 79.3％ of 40 patients in ORG group,with no statistically significance between groups (x2 =0.013,0.049,P＞0.05).(3) Prognostic analysis of patients with Siewert type Ⅱ and Ⅲ AEG undergoing transabdominal radical resection:results of univariate analysis showed that tumor diameter,tumor TNM staging,tumor T staging,tumor N staging and postoperative adjuvant chemotherapy were related factors affecting prognosis of patients with Siewert type Ⅱ and Ⅲ AEG undergoing transabdominal radical resection (x2 =8.349,14.376,9.732,17.250,8.012,P＜0.05).Results of multivariate analysis showed that tumor TNM staging and postoperative adjuvant chemotherapy were independent factors affecting prognosis of patients with Siewert type Ⅱ and Ⅲ AEG undergoing transabdominal radical resection (risk ratio =4.305,0.031,95％ confidence interval:1.858-9.977,0.004-0.246,P＜0.05).Conclusions Transabdominal laparoscopicassisted radical resection for AEG is safe and feasible,with advantage of minimally invasiveness,having equivalent long-term effects compared to open surgery.Tumor TNM staging and postoperative chemotherapy are independent factors affecting prognosis of patients with Siewert type Ⅱ and Ⅲ AEG undergoing transabdominal radical resection.

Expression and Clinical Significance of LC-3 and P62 in Non-small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#LC-3 and P62, two of important autophagy-related proteins, were reported highly expressed in many kinds of human malignancies and associated with outcomes of the patients. The purpose of this study was to investigate the expression status of LC-3 and P62 in non-small cell lung cancer patients and define the clinical-pathologic features.@*METHODS@#66 cases of non-small cell lung cancer patients were employed. The expression of LC-3 and P62 were detected by immunohistochemistry.@*RESULTS@#LC-3 was positive stained in 27 out of 66 cases (40.9%) and P62 was positive stained in 43 out of 66 cases (65.2%). LC-3 positive staining was more frequently in squamous cell carcinoma patients (P<0.05); while P62 positive staining was more frequently in late-stage adenocarcinoma patients with metastasis (P<0.05). There was a significant negative correlation between LC-3 and P62 expressions in non-small cell lung cancer tissues (rs=-0.065, P<0.001). Kaplan-Meier analysis showed that patients with positive LC-3 expression had favorable clinical outcomes compared with the patients with negative LC-3 expression (P<0.05).@*CONCLUSIONS@#LC-3 and P62 showed abnormal expression in non-small cell lung cancer tissues, suggesting that autophagy is involved in the occurrence and development of NSCLC.

Application of golden section in development of digital resources based on the long tail theory / 中华医学图书情报杂志

The use of golden section was proposed as a beneficial supplementary method in development of digital resources based on the long tail theory according to its advantages and disadvantages in development of digital resources in library.Literature download by retrieving subject headings and classification number showed that golden section could be used as a marking point and a supplementary boundary point in development of digital resources based on the long tail theory, thus improving the efficiency, economy and feasibility in development of digital resources with the limited fund.

Effect of plumbagin on levels of Nox4/ROS andα-SMA in human hepatic stellate cells / 中国病理生理杂志

AIM:To observe the effect of plumbagin on the mRNA and protein expression of nicotinamide ade -nine dinucleotidephosphate oxidase 4 ( Nox4 ) , reactive oxygen species ( ROS ) level and protein expression of α-smooth muscle actin (α-SMA) in the HSC-LX2 cells stimulated with transforming growth factor β1 (TGF-β1) in vitro.METH-ODS:HSC-LX2 cells were cultured in vitro and divided into blank group, model group, high-, medium-and low-dose (2, 1.5 and 1 μmol/L) plumbagin groups .After incubated with each drug for 72 h, the mRNA expression of Nox4 was detec-ted by RT-PCR.ROS levels were tested by in situ loading probe method.The protein contents of Nox4 and α-SMA were measured by Western blot .RESULTS:Compared with model group , after treated with plumbagin for 72 h, the mRNA ex-pression of Nox4, ROS level and α-SMA protein were significantly decreased in high-and medium-dose plumbagin groups (P<0.01).CONCLUSION:Plumbagin inhibits the activation of HSC-LX2 cells via decreasing the expression of Nox4, thus decreasing ROS levels .

Association between TNF-α-308 genetic polymorphisms and increased risk of primary lung cancer in Chinese population:a case-control study / 中国肿瘤临床

Objective:Previous studies suggested that the-308G/A allele in the tumor necrosis factor-α(TNF-α) gene promoter (-308G/A) may be a potential risk factor for inflammatory diseases and tumor progression. However, only a few studies have focused on the-308 polymorphism of TNF-αgene with primary lung cancer in Chinese population. This study aims to evaluate the role of TNF-α-308G/A single nucleotide polymorphism (SNP) and the risk of primary lung cancer in Chinese population. Methods:A total of 250 patients and 447 healthy individuals (control group) were involved in this study. Genotyping was performed using TaqMan technology. Results:The frequencies of (GG), (A/G), and (A/G+AA) genotypes of-308G/A SNP in TNF-αgene were 183 (73.2%), 67 (26.8%), and 67 (26.8%) in the patients, and 406 (90.8%), 39 (8.7%), and 41 (9.2%) in the control group, respectively. The distribution of poly-morphism frequencies in the case group and the control group showed a statistically significant difference for the Chinese population (P<0.05). Conclusion:Results indicated that TNF-αgene polymorphism at position-308G/A is associated with susceptibility to lung cancer in Chinese Han population.

Application of right-to-lateral approach in laparoscopic-assisted radical gastrectomy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the technical feasibility, safety, and short-term clinical efficacy of right-to-lateral approach in laparoscopic-assisted radical gastrectomy.</p><p><b>METHODS</b>Clinicopathological data of 178 gastric cancer patients undergoing laparoscopic-assisted radical gastrectomy, including 92 patients with right-to-lateral approach(R-LG group) and 86 cases with left-to-lateral approach (L-LG group), in our department from October 2010 to September 2013 were analyzed retrospectively. Short-term efficacy and complication morbidity were compared between R-LG group and L-LG group according to body mass index (BMI).</p><p><b>RESULTS</b>For those patients with BMI ≥ 24 kg/m², the R-LG group (35 cases) had shorter mean operation time, less intraoperative blood loss, shorter painkiller used time than L-LG group (31 cases)[(227 ± 17) min vs. (262 ± 23) min, (73 ± 9) ml vs. (84 ± 8) ml and (2.1 ± 0.1) d vs. (2.6 ± 0.4) d, all P<0.05]. The average time to ambulation and recovery time of peristalsis in the R-LG group were faster than those in L-LG group [(2.2 ± 0.2) d vs. (2.8 ± 0.6) d and (3.6 ± 0.3) d vs. (4.2 ± 0.5) d, all P<0.05]. The R-LG group had more dissected lymph nodes per patient (35 ± 4) than the L-LG group (30 ± 5) with significant difference (P<0.05). There were no significances in postoperative hospital stay, postoperative complication morbidity and hospitalization expenses between R-LG and L-LG group (all P>0.05). For those patients with BMI<24 kg/m², there were no significant differences in all above parameters between R-LG group (57 cases) and L-LG group (55 cases). No mortality and recurrence was observed during follow-up of 3 to 24 months.</p><p><b>CONCLUSION</b>Right-to-lateral approach in laparoscopic-assisted radical gastrectomy is a safe and feasible procedure, especially for the obesity patients, which can shorten the operation time, decrease intraoperative blood loss, lead to a faster postoperative recovery and harvest more lymph nodes as compared to L-LG procedure.</p>

Evaluation of genechip for detecting isoniazid- and rifampicin-resistance of Mycobacterium tuberculosis in China: a Meta-analysis / 中华传染病杂志

Objective To evaluate the effect of genechip in detecting isoniazid-and rifampicinresistance of Mycobacterium tuberculosis (MTB) in China.Methods Studies of genechip in detecting MTB resistance to isoniazid and rifampicin in China,which were published from January 1995 to June 2013,were identified through searches of PubMed,Science Direct,CBMDISC,CNKI and Wanfang database.Meta-Disc1.4 software was used for all analyses.Results Totally 618 articles were identified.Fifteen articles published from 2004 to 2013 were finally included in the study.The pooled sensitivity and specificity of genechip in detecting MTB resistance to isoniazid was 0.79 (95 ％CI:0.77-0.81) and 0.94 (95％CI:0.93-0.95),respectively,with the area under curve (AUC) of 0.86.The pooled sensitivity and specificity of genechip in detecting MTB resistance to rifampin was 0.91 (95％CI:0.89-0.92) and 0.96 (95％CI:0.96-0.97),respectively,with the AUC of 0.97.The pooled sensitivity and specificity of genechip in detecting MTB resistance to multidrug was 0.75 (95％CI:0.72-0.78) and 0.97 (95％ CI:0.96-0.98),respectively.Conclusions The effect of genechip in detecting MTB resistance is moderate for isoniazid,while better for rifampin in China.More studies are needed to evaluate the effect of genechip in detecting multidrug resistance in MTB.

Effects of Total Alkaloids in Buxus microphylla Leaves on Aorta Smooth Muscle of Rats and Their Mechanisms / 中草药·英文版

Objective To investigate the effects of total alkaloids in Buxus microphylla leaves (ABML) on isolated rats thoracic aorta rings,and then to explore the possible mechanisms underlying the effects.MethodsThoracic aortas of Wistar rats were isolated,removed,and mounted onto an organ bath.The effects of ABML at different concentration on the contraction of isolated thoracic aorta rings (with and without endothelium) precontracted with KC1 or PE were observed with organ bath technique.Dose-effect curves of CaCl2 were recorded by organ bath technique.The concentration of intracellular Ca2+ ([Ca2+]i) increased by PE,KCI,and caffeine in the presence of ABML was determined using Ca2+ sensitive fluorescence indicator Fura-2/AM loaded thoracic aorta vascular smooth muscle (VSM) cells of rats.ResultsIn aorta rings precontracted with PE and KCI,ABML produced concentrationdependent relaxation in both intact and denuded endothelium ring groups.There was no difference in the inhibition of contraction between the intact and denuded endothelium ring groups at the same concentration.Exposure of isolated thoracic aorta rings to ABML led to a significant reduction in the contracting response induced by CaCI2,and shifted the cumulative concentration-response curves to right.ABML could significantly inhibit the extracellular Ca2+ influx induced by PE and KCI under [Ca2+]0 of 1.5 mmol/L,with inhibitory ratios of 40.2％ and 49.9％,respectively.In the case of Ca2+-free,ABML could significantly inhibit the intracellular Ca2+ release induced by PE,with inhibitory ratio of 72.4％.ConclusionABML relaxes thoracic aorta VSM cells by suppressing influx of extracellular Ca2+ via voltage-dependent Ca2+ channel and receptor-operated Ca2+ channel.

Effects of L-dopa methyl ester on the strabismic amblyopia cats / 中国药理学通报

Aim To observe the effects of the L-dopa methyl ester (LDME) on the pattern visual evoked potentials (P-VEP) and the expression of c-fos mRNA in neurons of the visual cortex of kittens with strabismic amblyopia, and explore the therapeutic effect of L-dopa methyl ester on amblyopia and its action mechanism.Methods 30 normal kittens were randomly divided into 6 groups: low dose of L-dopa methyl ester (20 mg·kg~(-1)), medium dose of L-dopa methyl ester (40 mg·kg~(-1)), and high dose of L-dopa methyl ester (80 mg·kg~(-1)),positive control (L-dopa 40 mg·kg~(-1)),normal control, and model control group.The surgery for producing iatrogenic convergent strabismus was performed on 4 weeks old kittens(normal control group excluded). After the confirmation of the development of amblyopia by pattern visual evoked potential,L-dopa methyl ester,L-dopa and normal saline were given to the corresponding animals, respectively. The P-VEP of amblyopia eyes was observed after one month, and the technique of in situ hybridization was used to detect the expression of c-fos mRNA.Results L-dopa methyl ester could reduce obviously the length of P100 peak latency of the cat strabismic amblyopes, and increase the amplitude of P100. The positive staining cells of strabismic cat visual cortex were less than those of normal cats, whose difference was significant (P<0.01).Positive staining cells in the treatment group were significantly increased when compared with that of the model group (P<0.01).Conclusion L-dopa methyl ester can significantly improve the conduction and sensory function in the model of strabismic amblyopia cats. The mechanism may be related to the increased amount of L-dopa methyl ester into the cerebral cortex and regulation of the expression of c-fos mRNA.