Research progress of DNA methylation in the diagnosis and treatment of nasopharyngeal carcinoma / 中华检验医学杂志

Nasopharyngeal carcinoma is a common malignant tumor in southern China, and its occurrence and development mechanism are still not fully understood. However, a large number of studies have shown that DNA methylation has important clinical application value in the screening, diagnosis, treatment and prognosis evaluation of nasopharyngeal carcinoma. DNA methylation affects the division cycle, growth, invasion and migration of nasopharyngeal carcinoma cells by regulating the transcription and protein expression levels of genes associated with tumorigenesis and development. In addition, there are significant differences in DNA methylation expression levels in different stages of nasopharyngeal carcinoma, which provides theoretical guidance and clinical reference for the early diagnosis, timely treatment and response evaluation of nasopharyngeal carcinoma. Current studies have shown that DNA methylation detection may provide a simple and efficient early screening method for nasopharyngeal carcinoma, and can also explore new ideas for the development of non-invasive screening methods.

The effect of cuproptosis related gene methylation on the prognosis of cervical cancer / 中华检验医学杂志

To investigate the differences in methylation levels of cuproptosis related genes in cervical cancer and their effects on clinical prognosis.Methods:The methylation data of 310 cervical tissue specimens were acquired from public databases. The UALCAN database was used to analyze the methylation level differences of 12 cuproptosis-related genes and study their level in different stages or grades of cervical cancer. Genes with statistically significant differences were selected for prognosis analysis using the EWAS datahub. Finally, gene-enrichment analysis, pathway analysis, immune infiltration analysis, the mutation rate and tumor mutation burden (TMB) of the genes in cervical cancer were analyzed using the cBioportal database. Two independent samples rank-sum test was used for differences in methylation levels and immune cell infiltration; comparative analyses of overall survival were performed using KM survival curves and Log-rank two-sided tests. TMB analyses were performed using the Wilcoxon Test for statistical analyses; Pearson correlation analysis was used for assessment in GSEA and pathway analyses.Results:The methylationβvalue of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A gene) in the cervical cancer tissues of patients was 0.075 which was significantly higher than the methylationβvalue of 0.049 in normal human tissues ( P=0.008). Dihydrolipoamide S-Acetyltransferase (DLAT gene) methylation with a β value of 0.102 was significantly higher than normal human tissue methylation with a β value of 0.08 ( P=0.002), and the methylation level β value of Lipoyltransferase 1 (LIPT1 gene) in cervical cancer tissues was 0.06,which was significantly lower than normal human tissue methylation value of 0.092 ( P=0.009). Patients with CDKN2A gene methylation levels≥0.199 had an overall survival of 14.75 years, which was lower than that of patients with methylation levels<0.199 (17.56 years) ( P=0.034).The results of gene enrichment analysis indicated that it mainly involves biological processes such as the response to type I interferon and DNA replication. The expression of CDKN2A gene is positively correlated with the number of neutrophils and dendritic cells in the tumor microenvironment( P<0.05), and negatively correlated with the number ofmacrophages( P<0.05). TMB was higher in the group of variants of the CDKN2A gene than in the group of non-variants ( P=0.019). Conclusion:CDKN2A methylation is a potential biomarker for predicting the prognosis of cervical cancer.

Establishment and evaluation of “integration of drug storage and dispensing”intelligent drug validity management system in outpatient pharmacy / 中国药房

OBJECTIVE To build an “integration of drug storage and dispensing” intelligent drug validity management system in outpatient pharmacy， and to evaluate the effect of this system. METHODS The information technology was used to connect the drug information in the primary storage， the intelligent secondary storage and the rapid dispensing machine； an “integration of drug storage and dispensing” intelligent drug validity management system was constructed. At the same time， the implementation effects of drug validity management system in outpatient pharmacy of our hospital were evaluated one year before and after the construction of the system. RESULTS By using information technology， intelligent closed-loop management of batch number and expiration date information throughout the entire process of drug circulation in outpatient pharmacy of our hospital had been achieved， making it easy to track and trace drug information. After the establishment of the intelligent system， the time spent on managing drug validity every month was reduced from 103 people·h to 8 people·h； the number of near-expired drugs per month had decreased from （30.67±1.10）types to （17.67±1.17）types（P＜0.05）. CONCLUSIONS The intelligent drug validity management system in outpatient pharmacy based on the mode of “integration of drug storage and dispensing” makes the drug validity management in the outpatient pharmacy more scientific， reasonable and efficient.

Analysis of the effect of cold snare endoscopic mucosal resection in the treatment of colorectal polyps / 中国医师进修杂志

Objective:To explore the effect of cold-strap endoscopic mucosal resection (CS-EMR) in patients with colorectal polyps.Methods:A prospective randomized clinical trial was conducted to 320 selected patients with colorectal polyps diagnosed by Shenzhen Luohu District People′s Hospital from May 2019 to June 2021. The patients were randomly divided into CS-EMR group and HS-EMR group with 160 cases each, using a random number table generated by Excel 2007. The main parameters for statistical analysis contain the process indicators of the two groups of surgical methods, the complete polypectomy rate of patients after surgery, the degree of postoperative pain and the recovery of gastrointestinal function, and the differences in surgical complications.Results:The polypectomy time of CS-EMR group was shorter than that of HS-EMR group: (4.11 ± 1.20) min vs. (4.42 ± 0.98) min, with a statistically significant difference ( P<0.05). The score of visual analogue pain scale (VAS) in CS-EMR group was lower than that in HS-EMR group at 4 and 12 hours after operation: (3.11 ± 0.78) scores vs. (3.48 ± 0.80) scores, (3.38 ± 0.80) scores vs. (3.61 ± 0.92) scores, with a statistically significant difference ( P<0.05). The first anal exhaust time and first defecation time in CS-EMR group were lower than those in HS-EMR group: (27.83 ± 5.01) h vs. (29.66 ± 4.84) h, (43.73 ± 7.80) h vs. (47.28 ± 8.14) h, with a statistically significant difference ( P<0.05). The complications in CS-EMR group were significantly lower than those in HS-EMR group: 5.63% (9/160) vs. 12.50% (20/160), with a statistically significant difference ( P<0.05). Conclusions:The effect of CS-EMR in the treatment of colorectal polyps is not different from that of HS-EMR, but the former has the advantages of short resection time, rapid recovery of gastrointestinal function after operation, light pain and less complications.

Recent progress in the application of circulating tumor cells in the diagnosis and treatment of colorectal cancer / 中华检验医学杂志

Colorectal cancer (CRC), as one of the most common gastrointestinal malignancy, is original from the epithelial/endothelial cells of colorectal tissues. CRC is one of the highest incidence and mortality rates of any malignancy in humans today. Moving forward the early diagnosis window of colorectal cancer, dynamic monitoring of the risk of postoperative recurrence and metastasis, early intervention is of great value in improving the diagnosis and treatment outcome of colorectal cancer. The clinical diagnosis of CRC via circulating tumor cells (CTC) has been considered as one of the fast, noninvasive, reproducible liquid biopsy methods, and it has been widely used in the early diagnosis, treatment monitoring and prognosis evaluation of colorectal cancer. This review systematically expounded the applied research values of CTC counting, protein expression (phosphatase of regenerating liver-3, matrix metalloproteinase, etc), molecular characterization (adenomatous polyp of colon, erb-b2 receptor tyrosine kinase, etc), mRNA expression profile and single cell sequencing in the diagnosis and treatment of colorectal cancer, in order to assist clinical in rational use of CTC monitoring indicators and provide support for improving the prognosis of colorectal cancer.

Efficacy of different laparoscopic surgeries for gastrointestinal stromal tumors of gastric cardia and fundus: a multicenter study / 中华消化外科杂志

Objective:To investigate the efficacy of different laparoscopic surgeries for gastrointestinal stromal tumors (GIST) of gastric cardia and fundus.Methods:The retrospective cohort study was conducted. The clinicopathological data of 251 patients with GIST of gastric cardia and fundus who underwent laparoscopic radical resection in 14 medical centers, including Guangdong Provincial People′s Hospital et al, from December 2007 to December 2021 were collected. There were 123 males and 128 females, aged 58(24,87)years. Observation indicators: (1) treatment; (2) clinicopathological data of patients undergoing different laparoscopic surgeries; (3) subgroup analysis for special laparoscopic techniques. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test or ANOVA. Measure-ment data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test or Kruskal-Wallis H test. Count data were described as absolute numbers or percentages. Comparison of ordinal data was conducted using the rank sum test. Results:(1) Treatment. Of the 251 patients,202 cases underwent gastric wedge resection, 26 cases underwent special laparoscopic techniques including 10 cases with serotomy and dissection and 16 cases with transluminal gastrectomy, 23 cases underwent structural gastrectomy including 6 cases with total gastrectomy and 17 cases with proximal partial gastrectomy. There were 24 patients had postoperative complications after surgery. (2) Clinicopathological data of patients undergoing different laparoscopic surgeries. The gender (male, female), age, tumor diameter, operation time, volume of intraoperative blood loss, length of incision, time to postoperative initial whole liquid food intake, time to postoperative initial semi-liquid food intake, duration of postoperative hospital stay, cases with perioperative complications, cases with mitotic count as ≤5/50 high power field, 6?10/50 high power field, >10/50 high power field, cases be classified as very low risk, low risk, medium risk, high risk according to the National Institutes of Health risk classification, cases with tumor located at fundus and gastric cardia were 93, 109, (59±11)years, 3.50(0.40,10.00)cm, 88.00(25.00,290.00)minutes,20.00(25.00,290.00)mL, 4.00(2.00,12.00)cm, 3.00(1.00,9.00)days, 4.00(1.00,16.00)days, 5.00(1.00,18.00)days, 14, 164, 31, 7, 47, 83, 50, 22, 30, 172 in patients undergoing gastric wedge resection, respectively. The above indicators were 19, 7, (49±14)years, 2.55(0.20,5.00)cm, 101.00(59.00,330.00)minutes, 27.50(2.00,300.00)mL, 4.50(0,6.00)cm, 2.50(1.00,10.00)days, 4.00(1.00,16.00)days, 6.00(1.00,18.00)days, 3, 20, 5, 1, 15, 5, 2, 4, 24, 2 in patients undergoing special laparos-copic techniques, and 11, 12, (52±10)years, 5.00(0.80,10.00)cm, 187.00(80.00,325.00)minutes, 50.00(10.00,300.00)mL, 6.00(4.00,12.00)cm, 4.00(2.00,8.00)days, 6.00(3.00,14.00)days, 8.00(2.00,18.00)days, 7, 11, 5, 7, 2, 6, 6, 9, 13, 10 in patients undergoing structural gastrectomy. There were significant differences in the above indicators among the three groups of patients ( χ2=6.75, F=10.19, H=17.71, 37.50, 35.54, 24.68, 16.09,20.20, 13.76, χ2=13.32, Z=28.98, 32.17, χ2=82.14, P<0.05). (3) Subgroup analysis for special laparoscopic techniques. The time to postoperative initial whole liquid food intake, time to postoperative initial semi-liquid food intake, classification of tumor location (endophytic type, exophytic type, parietal type) were 4.50(1.00,10.00)days, 8.00(3.00,12.00)days, 0, 8, 2 in patients undergoing serotomy and dissection, versus 2.00(1.00,4.00)days, 3.00(1.00,6.00)days, 16, 0, 0 in patients undergoing transluminal gastrectomy. There were significant differences in time to postoperative initial whole liquid food intake, time to postoperative initial semi-liquid food intake between them ( Z=-2.65, -3.16, P<0.05); and there was a significant difference in classification of tumor location between them ( P<0.05). Conclusions:Gastric wedge resection is the most commonly used laparoscopic technique for GIST of gastric cardia and fundus. The application of special laparoscopic techniques is focused on the GIST of cardia to preserve the function of the cardia.

The predicting value of pretreatment neutrophil count and lymphocyte-to-monocyte ratio in peripheral blood for the pathological tumor responses in patients with locally advanced gastric adenocarcinoma after preoperative therapy / 中华放射肿瘤学杂志

Objective:To analyze the predicting values of hematological indicators for the pathological response in patients with gastric adenocarcinoma after preoperative neoadjuvant therapy and radical surgery.Methods:The absolute count of neutrophils (NE), lymphocytes (LY) and monocytes (MO) of 102 patients with locally advanced gastric adenocarcinoma in a multi-center randomized phase Ⅲ clinical trial (NCT01815853) from June 2013 to Feburary 2019 were retrospectively analyzed. Patients were divided into the chemotherapy alone group (ChT, 3 cycles of XELOX regimen) and the chemoradiation group (CRT, 1 cycle of induced XELOX regimen and 4500 cGy/25f radiotherapy plus concurrent extenuated 2 cycles of XELOX regimen), 51 cases in each group. The pathological response indicators of tumors after radical surgery included tumor regression grade, pathological complete regression, pathological T stage (ypT), N stage (ypN) and TNM stage (ypTNM).Results:Univariate regression analysis and ROC curves demonstrated a significant association between the absolute neutrophil count (NE) and ypT, lymphocyte-to-monocyte ratio (LMR) and ypN 0, and LMR and ypTNM reduction in the entire cohort of patients. Multivariate regression analysis showed that higher NE (>4.10×10 9/L) was significantly associated with higher probability of ypT reduction ( OR=3.308, P=0.007). Higher LMR (>3.46) was significantly associated with higher ypN 0 probability ( OR=4.276, P=0.005) and better ypTNM reduction ( OR=2.805, P=0.019). In subgroup analysis, higher NE (>4.10) was significantly correlated with higher probability of ypT reduction ( OR=3.750, P=0.030) in the CRT group, and higher LMR (>3.46) was significantly associated with higher ypN 0 probability ( OR=8.500, P=0.050) and the probability of ypTNM stage reduction ( OR=4.000, P=0.026) in the ChT group. Conclusions:Pretreatment NE and LMR in the peripheral blood serve as independent predictors for tumor pathological responses after preoperative treatment, and immune condition is correlated with tumor regression after radical surgery in patients with locally advanced gastric cancer.

The relationship between Lauren classification and pathological response after preoperative chemoradiotherapy for locally advanced gastric cancer / 中华放射肿瘤学杂志

Objective:To investigate the correlation between Lauren classification and pathological response after preoperative chemoradiotherapy in patients with locally advanced gastric cancer.Methods:From 2013 to 2019, 98 patients with definite Lauren classification who were enrolled in Sun Yat-sen University Cancer Center 5010 Phase Ⅲ clinical trials. Among them, 46 patients received preoperative chemoradiotherapy (CRT), and the remaining 52 cases received preoperative chemotherapy (ChT) and radical surgery. After preoperative therapy, the correlation between pathological response including the tumor regression grade (NCCN-TRG 0-3) and the lymph node stage (ypN 0-3) and Lauren classification was analyzed. A favorable pathological response (FPR) was defined as TRG 0-2 and ypN 0. Results:In the CRT group, patients with intestinal type (IT) tumors had a higher rate of ypN 0( OR=6.8, 95% CI: 1.8-25.0, P=0.004) and FPR ( OR=8.0, 95% CI: 2.2-29.9, P=0.002) than their counterparts with diffuse or mixed type tumors. However, Lauren classification was not significantly correlated with pathological response in the ChT group ( P>0.05). For patients with IT tumors, those receiving CRT had a higher likelihood of achieving a TRG 0-2 response ( P=0.033), an ypN 0 nodal regression ( P<0.001), and a FPR ( P<0.001) than their counterparts receiving ChT, whereas pathological response was not significantly associated with preoperative therapeutic method in patients with diffuse or mixed tumors ( P>0.05). Conclusion:Lauren classification may be a reliable predictor of the clinical efficacy of preoperative chemoradiotherapy for locally advanced gastric cancer, which can be utilized to select and optimize preoperative treatment.

Updates and interpretation on NCCN clinical practice guidelines for gastric cancer 2017 version 5 / 中华胃肠外科杂志

The National Comprehensive Cancer Network (NCCN) issued the clinical practice guidelines for gastric cancer 2017 edition version 5, which has been fully updated for the treatment of gastric cancer, including systematic treatment, surgery and radiotherapy. This article review and summarize the updated NCCN clinical practice guidelines for gastric cancer in 2017 and try to interpret it. (1)Biomarkers: mismatch repair defect (dMMR) or high microsatellite instability (MSI-H), programmed death ligand 1 (PD-L1) and tumor Epstein Barr virus (EBV) status should be considered for patients with gastric cancer. (2)Treatment of advanced gastric cancer: the major update is the application of immunotherapy (Pembrolizumab, Nivolumab combined with Ipilimumab). (3)Adjuvant therapy after D2 resection and perioperative treatment: the guidelines recommended Capecitabine combined with Oxaliplatin as adjuvant therapy after radical operation, updated from category 2A to 1; although the 2017 edition of the NCCN guidelines have not yet been adopted, Docetaxel-based FLOT scheme has certain potential in adjuvant therapy for gastric cancer. (4) Radiotherapy: a more detailed definition of radiotherapy for gastric cancer in different locations, especially in high-risk lymphatic drainage areas, was updated. (5) Genetic risk assessment: the guidelines recommended genetic screening for gastric cancer, including hereditary diffuse gastric cancer (HDGC), Lynch syndrome, juvenile polyposis (JPS), Peutz-Jephers syndrome (PJS) and familial adenomatous polyposis (FAP). The NCCN guidelines continue to update based on new evidences, which is the embodiment of precision medicine in the treatment of gastric cancer. The biggest change in the 2017 gastric cancer guidelines is the updates of immunotherapy, which also suggests that the direction of the gastric cancer treatment began to turn to immunotherapy.

Risk factor analysis and prediction model establishment of lymph node metastasis in remnant gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To explore the risk factors and establish an effective model to predict lymph node metastasis (LNM) for remnant gastric cancer (RGC).</p><p><b>METHODS</b>Clinicopathological characteristics of 91 RGC patients undergoing radical gastrectomy at Sun Yat-sen University Cancer Center from January 2000 to December 2017 were retrospectively analyzed. RGC was defined as cancer detected in the remnant stomach >5 years for primary benign diseases or >10 years for malignant diseases following distal gastrectomy. Risk factors of LNM in RGC were identified using logistic regression (P<0.1). Covariates were then scored according to the β regression coefficient in the multivariate analysis, and a score model was established, in which higher score indicated higher risk of LNM. Finally, receiver operating characteristic(ROC) curve was used to evaluate the diagnostic efficacy of risk factors and the score model.</p><p><b>RESULTS</b>Among the 91 RGC patients, 84 were male and 7 were female with the age ranging from 47 to 82 years (63.7±8.5) years. Mean harvested lymph node (LN) was 16.0±11.8, including ≥15 LNs in 42(46.2%) patients and <15 LNs in 49(53.8%) patients. Forty-six (50.5%) patients were identified as LNM. Univariate analysis showed that tumor size ≥4 cm (χ=8.106, P=0.004), Borrmann III(-IIII( gross type (χ=6.129, P=0.013), increased CEA level (χ=4.041, P=0.044) and T3-4 stage (χ=17.321, P=0.000) were associated with LNM in RGC. In Logistic multivariate analysis, tumor size ≥4 cm (OR: 2.362, 95%CI: 0.829-6.730, P=0.100, β regression coefficient: 0.859) and T3-4 stage (OR: 7.914, 95%CI: 1.956-32.017, P=0.004, β regression coefficient: 2.069) remained as the independent risk factors for LNM, and were scored as 1 and 2 point in the final prediction model. In the final score model, LNM of patients with 0, 1, 2, 3 point were 11.1%(2/18), 1/5, 51.6%(16/31) and 73.0%(27/37), respectively. The AUC of the prediction model was 0.756 (P=0.000).</p><p><b>CONCLUSIONS</b>Increased CEA level, tumor size ≥4 cm, Borrmann III(-IIII( gross type, and deeper T stage are associated with LNM in RGC. Moreover, the score model combining with tumor size and T stage can effectively predict the LNM in RGC.</p>

A dose-effect analysis of organs at risk during preoperative chemoradiotherapy for gastric cancer / 中华放射肿瘤学杂志

Objective To investigate the clinical and dose-volume factors for damages to organs at risk(OARs)during preoperative chemoradiotherapy for gastric cancer, and to provide a reference for optimization of radiotherapy plans to avoid or reduce damages to OARs.Methods A total of 58 patients with locally advanced gastric adenocarcinoma undergoing neoadjuvant treatment were enrolled as subjects.In those patients,30 received preoperative chemoradiotherapy combined with surgery and adjuvant chemotherapy, while others received preoperative chemotherapy combined with surgery and adjuvant chemotherapy. The preoperative chemotherapy group received 2-3 cycles of xeloxregimen(capecitabine+oxaliplatin)before surgery and 3-4 cycles of xeloxregimen after surgery(a total of 6 cycles). The preoperative chemoradiotherapy group received preoperative radiotherapy(45 Gy in 25 fractions)combined with 2 cycles of concurrent xeloxchemotherapy at 14-21 days after the first cycle of xeloxregimen, as well as 3 cycles of xeloxchemotherapy after surgery. The analyses of clinical and dose-volume factors for damages to OARs were performed based on laboratory indices and clinical symptoms during the treatment. Results In all the patients,the incidence rates of liver injury(LI), renal injury(RI), and duodenum injury(DI)before surgery were 22%,48%,and 33%,respectively;the incidence rates of LI and RI after treatment were 35%and 49%, respectively. After appropriate treatment, neither LI nor DI affected the treatment of gastric cancer. RI healed without any special treatment. Compared with preoperative chemotherapy, preoperative chemoradiotherapy caused higher incidence of LI(P=0.00,0.03).RI was only associated with glomerular filtration rate before radiotherapy(P=0.08,0.13). A V3.5of ≤98.96% for the liver reduced LI, while a D2ccof ≤48 Gy for the duodenum reduced DI. Conclusions Preoperative chemoradiotherapy is safe for treating gastric cancer. Compared with preoperative chemotherapy, preoperative chemoradiotherapy does not increase the risk of RI. However,preoperative chemoradiotherapy tends to increase LI.Further studies are needed to improve the treatment method.

Danusertib induces autophagy of leukemia cells via Aurora kinase B/ribosomal protein p70S6 kinase/ribosomal protein 15 signaling pathway / 中华实用儿科临床杂志

Objective To investigate the effects of Danusertib on the changes in Aurora kinase B (Aurora B)/ribosomal protein p70S6 kinase (p70S6K)/ribosomal protein 15 (RPL15) signaling pathway and autophagy in human leukemia cells and its mechanism.Methods Myeloid leukemia cell lines THP-1 and K562 were selected as the research subjects.The experiment was divided into 2 phases.Phase 1:each cell line was treated with the concentration of Danusertib in 0.1 p mol/L,1.0 p mol/L and 5.0 μ mol/L.In control group,2 mL/L dimethyl sulfoxide (DMSO)was given.All the treated cells were cultured for 24 hours.The viability of each cell line was examined by methyhhiazoletrazolium assay and the autophagy was assessed by flow cytometry.In addition,the protein levels of p70S6K,AuroraB,phosphatidylinositol 3-kinase (PI3K),AKT(phosphorylated protein kinase B),mammalian target of rapamycin (mTOR),microtubule-associated protein (LC3),Beclin1 and RPL15 were determined by using Western blot.Part 2:Aurora B and RPL15 were down-regulated in THP-1 and K562 cells,respectively.DMSO was used to dissolve Danusertib(5.0 μ mol/L).The grouping was designed as following:DMSO group (blank control group),Danusertib treated group,empty plasmid group,small interfering RNA(siRNA) group,empty plasmid + Danusertib-treated group and siRNA + Danusertib treated group.The protein levels of Aurora B,p70S6K,RPL15,Beclinl and LC3 were detected by using Western blot.Results (1) Danusertib decreased the viability of THP-1 and K562 cells and the half maximal inhibitory concentration values were 26.9 pmol/L and 30.2 μmol/L for THP-1 and K562 cells,respectively.(2)The protein levels of p-Aurora B/Aurora B,p-p70S6K/p70S6K,RPL15,p-mTOR/mTOR and p-AKT/AKT decreased compared with control cells after being treated with 0.1 μmol/L,1.0 μ mol/L and 5.0 pmol/L of Danusertib in THP-1 and K562 cells,and the differences were statistically significant (all P ＜ 0.05).(3) In THP-1 cells,compared with the empty plasmid group,the protein levels of p70S6K and RPL15 decreased by 22.1％,61.3％ (F =18.1,P =0.001) and 55.4％,56.1％ (F =19.4,P =0.001) in siRNA group and siRNA + Danusertib-treated group after knockdown of Aurora B.In contrast,the protein levels of LC3 increased by 13.6％ and 17.1％ (F =15.4,P =0.001)compared with the empty plasmid group.In addition,the protein levels of Beclin1 and LC3 increased by 39.5％,92.3％ (F=25.2,P=0.001) and 40.2％,58.3％ (F=23.9,P=0.001) in siRNA group and siRNA + Danusertib treated group,compared with the empty plasmid group after down-regulation of RPL15.In K562 cells,compared with the empty plasmid group,the protein levels of p70S6K and RPL15 decreased by 24.2％,62.7％ (F =20.4,P=0.001) and 57.2％,60.1％ (F =23.9,P =0.001) in siRNA group and siRNA + Danusertib treated group after downregulation of Aurora B.But the protein levels of LC3 increased by 17.9％ and 56.7％ (F =20.9,P =0.001)compared with the empty plasmid group.Moreover,the protein levels of Beclin1 and LC3 were increased by 20.6％,98.4％ (F=22.4,P =0.001) and 41.5％,70.1％ (F=26.2,P =0.001) in siRNA group and siRNA + Danusertib treated group,compared with the empty plasmid group after downregulation of RPL15.Conclusion Danusertib can induce autophagy via inhibition of the PI3K/AKT/mTOR signaling pathway and can negatively regulate Aurora B/p70S6K/RPL15 axis in THP-1 and K562 cells.In addition,RPL15 may be a key target of Aurora B/p70S6K/RPL15signaling pathway in the inhibition of tumor proliferation.

Treatment of primary gastric lymphoma / 中华胃肠外科杂志

Stomach is the most common location of lymphoma in digestive tract, accounting for 50%-60% of gastrointestinal lymphomas. The most common histological types are low malignant mucosa-associated lymphoid tissue (MALT) lymphoma from non-Hodgkin lymphoma (NHL) and diffuse large B-cell and marginal zone B-cell lymphoma (DLBCL) from NHL. Chronic gastritis secondary to Helicobacter pylori(HP) infection has been considered a major predisposing factor for MALT lymphoma. At present, the most widely accepted initial therapy for localized disease is aimed at the eradication of HP using regimens combining antibiotics and proton-pump inhibitors. The irradiation has become the therapy of choice for patients with early stage MALT lymphoma without HP infection or with persistent lymphoma following antibiotic therapy. In all the patients with advanced disease, treatment options include chemotherapy and the use of monoclonal antibodies. Treatment of DLBCL in stomach is based on aggressive poly-chemotherapy that is usually combined with rituximab. The same guidelines followed for nodal aggressive lymphoma can also be applied to gastric lymphoma with aggressive histology as DLBCL. For localized stages (stages I( and II(), these guidelines suggest front-line therapy with 3 to 4 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) followed by radiotherapy. Advanced stage patients (stage IIII() usually undergo only 6 to 8 cycles of R-CHOP in order to obtain a complete remission rate. Nowadays surgery is limited to rare cases and radiotherapy combined or not with chemotherapy represents an effective therapeutic option ensuring long-term, organ-salvage benefits mainly in aggressive histological types.

Interpretation and evaluation of the American Joint committee on Cancer (AJCC) 8th Edition Staging System for patients with gastroenteropancreatic neuroendocrine tumors / 中华胃肠外科杂志

American Joint Committeeon Cancer (AJCC) released the eighth edition staging system manual in October 2016. Based on the shortcomings in the seventh edition of AJCC staging system, staging classifications for gastroenteropancreatic neuroendocrine tumor (GEP-NET) were updated. The changes are as follow: small intestinal NET was divided into two groups, duodenal and jejunoileal NET and lymphatic metastasis was redefined into N1 and N2 in jejunoileal NET; stages were condensed except colorectal NET; the staging classification for pancreatic NET proposed by European Neuroendocrine Tumor Society(ENETS) was adopted. However, problems still exist in the eighth edition AJCC staging classifications for GEP-NET. For instance, whether the definitions of N1 and N2 in jejunoileal NET are accurate in clinical management is still less understood. Thus, further clinical validations of the AJCC eighth edition staging system for GEP-NET are needed. Meanwhile, the eighth edition AJCC staging classifications for GEP-NET still did not step towards precision medicine and risks assessment models with high quality are still absent.

Updates on adjuvant therapy in gastrointestinal stromal tumor / 中华胃肠外科杂志

Surgery remains the primary treatment for patients with localized gastrointestinal stromal tumor (GIST), however, even after complete resection of the tumor, there is still a part of patients with tumor recurrence and metastasis. Imatinib, as adjuvant therapy in GIST patients with intermediate and high risk of recurrence, can significantly improve the disease-free survival, but whether it can prolong the overall survival is still unknown. It has reached a consensus that the intermediate and high risk patients should receive adjuvant therapy, but the duration for adjuvant therapy is still under investigation, especially for high-risk patients. Adjuvant therapy is recommended for at least 3 years, while in the end of adjuvant therapy, some patients still develop recurrence and metastasis. In 2017, results from PERSIST-5 study reported by the ASCO conference indicated that 5-year adjuvant therapy may further prolong disease-free survival of intermediate and high risk patients. In addition, adjuvant therapy is still not individualized based on the combination with different genotypes, and present adjuvant therapy is recommended for GIST patients with positive CD117 and intermediate-high risk of recurrence. It remains controversial whether different genotypes are associated with alternative adjuvant treatment options. Results of more researches are expected to provide better guidance for clinical treatment in the future.

Association between genetic polymorphisms and variation of imatinib pharmacokinetics in gastrointestinal stromal tumors / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the influence of metabolic enzymes polymorphisms on variations of imatinib (IM) pharmacokinetics in gastrointestinal stromal tumors (GIST) patients.</p><p><b>METHODS</b>Clinical data of 118 Chinese GIST patients receiving 400 mg/d IM at Sun Yat-sen University Cancer Center between 2014 and 2016 were retrospectively analyzed. The plasma concentration of imatinib mesylate(IM) and its main metabolic N-demethyl imatinib (NDI) were determined by LC-MS/MS. CYP3A4 rs2242480, CYP1A2 rs762551, CYP2C19 rs28399505 and NR1I2 rs3814057 were genotyped by MassArray system. Association between drug concentration and polymorphism was examined by Whitney U test. P≤0.05 indicated close association and 0.05<P<0.10 indicated marginal association.</p><p><b>RESULTS</b>Among 118 GIST patients, 63 were male and 55 were female with a median age of 55 (44 to 63) years. Primary lesion location was the stomach in 87 cases, intestine in 13 cases and other sites in 18 cases. All the patients received standard 400 mg/d IM. Concentration of IM (C) was (1 501.1±646.8) μg/L and concentration of NDI (C) was (221.7±92.5) μg/L. Association analysis showed that CYP2C19 rs28399505 was closely associated with concentration of IM and NDI(P=0.002 and 0.028). The concentration of IM and NDI in patients with TC heterozygote was significantly lower than those with wildtype TT [C: (695.4±202.9) μg/L vs. (1 518.9±716.8) μg/L, P=0.002; C:(133.3±59.8) μg/L vs. (244.5±99.1) μg/L, P=0.028]. NR1I2 rs3814057 was marginally associated with concentration of IM and NDI(C:P=0.079; C:P=0.082), while CYP3A4 rs2242480 and CYP1A2 rs762551 were not associated with concentration of IM or NDI(all P>0.10).</p><p><b>CONCLUSIONS</b>CYP2C19 may play an important role in IM metabolism. Detection of CYP2C19 polymorphism may be beneficial to clinical monitoring of IM and decision making of individualized treatment.</p>

Application of Cox model for analyzing prognosis factors of stage Ⅳ gastric cancer / 重庆医学

Objective To investigate the related prognostic factors of stage Ⅳ gastric cancer.Methods The clinical data of 248 patients with stage Ⅳ gastric cancer and intact follow up data in the Tumor Prevention and Treatment Center of Sun Yat-Sen University from 2000 to 2010 were retrospectively summarized.The twelve clinicopathological parameters served as the observation indicators,including age,sex,body mass reduction,H b,CEA,CA19-9,Borrmann type,tumor location,tumor size,pathological pattern,operative mode,metastatic sites and therapeutic model.The survival curve was drawn by using the Kaplan-Meier method.The median survival time was calculated.The univariate analysis was conducted with Log-rank test.The prognosis multivariate analysis was conducted by the Cox's proportional hazards regression analysis.Results MST in the patients of whole group was 254 d.The univariate analysis showed that sex,Borrmann type and therapeutic mode were the related factors afecting gastric cancer prognosis,while the Cox regression model revealed that above 3 indicators were also independent factors affecting the prognosis of the patients with stage Ⅳ gastric cancer in this group(P＜0.05).Conclusion The treatment mode is an important independent factor affecting the survival of stage Ⅳ gastric cancer,the translational medicine model of palliative chemotherapy combined with palliative operation conduces to improve the prognosis in the patients with stage Ⅳ gastric cancer.

The significance of preservation of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach / 中华耳鼻咽喉头颈外科杂志

Objective@#To evaluate the significance for the preservation of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach.@*Methods@#We retrospectively evaluated 168 patients who underwent unilateral endoscopic thyroidectomy via gasless anterior chest approach, with preservation of the medial branch of the supraclavicular nerve in 110 patients and not in other 58 patients. Semmes-Weinstein monofilament (SWM) test and a visual analogue scale (VAS) were used to assess the recovery of sensation in anterior chest within 1-12 months postoperatively. Difference in the scores of SWM or VAS between groups was tested with Mann-Whitney U test, and the rates of SWM and VAS scores returning to normal levels in individual periods after surgery was compared with Chi-square test.@*Results@#The preserved group showed more favorable results than the non-preserved group in both SMW and VAS scores. Compared to control group, SWM score in preserved group possessed a higher rate recovery to normal level at any period after operation, which was close to complete normality in 7-9 months postoperatively, and SWM score in non-preserved group was still partially normal in 10-12 months from surgery. Preferable results for VAS were also found in the preserved group, except no significant difference in VAS between groups in1-3 months or 10-12 months after operation.@*Conclusion@#Preservation of the medial branch of the supraclavicular nerve in endoscopic thyroidectomy via gasless anterior chest approach can improve sensation recovery in anterior chest, thus improving postoperative quality of life of patients.

Clinicopathological characteristics and prognostic factors of rectal neuroendocrine neoplasms / 中华普通外科杂志

Objective To analyze the clinicopathological characteristics and the related factors influencing the prognosis of rectal neuroendocrine neoplasms.Methods The clinical and follow-up data of 442 patients with rectal neuroendocrine neoplasms admitted between Sep 1993 and Dec 2015 in 5 hospitals in southern China were analyzed retrospectively.The univariate and multivariate analysis of survival prognosis were analyzed statistically.Results Of the 442 patients,the median age was 50 years and 64.7％ were males.The average tumor size was (1.4 ± 0.7) cm.NENs ＜ 1 cm accounted for 66.1％ cases,1-2 cm accounted for 17.2％ and ＞2 cm accounted for 16.7％ of the tumors.Stage Ⅰ,Ⅱ,Ⅲ and Ⅳ accounted for 73.5％,8.6％,7.2％,10.6％ of the tumors;G1,G2,G3 accounted for 76.5％,14.7％,8.8％ of the tumors;The median survival time for all 442 patients was 35 months (range,1-224 months).The overall 5-year survival rate was 85％.The 5-year survival rates for patients in stage Ⅰ-Ⅳ were 95％,94％,52％,36％ respectively.The 5-year survival rates for patients with G1-3 were 94％,80％,19％respectively.Univariate analysis showed that G grade,T stage,N stage,M stage,TNM stage,functional,gender,medication,surgical therapy,age,tumor sizes were statistically significant (all P ＜ 0.05).Multivariate analysis revealed that G grade (P =0.001),tumor sizes (P =0.012) and TNM stage (P =0.008) were the independent factors affecting the prognosis.Conclusion Patients with rectal neuroendocrine neoplasms have no specific clinical characteristics.G grade,tumor sizes and TNM stage were the independent factors affecting the prognosis.

Comparison of modified NIH and AFIP risk-stratification criteria for gastrointestinal stromal tumors: A multicenter retrospective study / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate and compare the value of Modified NIH criteria and AFIP criteria for the risk classification of gastrointestinal stromal tumors (GIST).</p><p><b>METHODS</b>Clinicopathological and follow-up data of 539 patients diagnosed as primary GIST with or without irregular tyrosine kinase inhibitors in the Nanfang Hospital(n=143), Sun Yat-sen University Cancer Center (n=138), Guangdong Provincial People's Hospital (n=102) and Wuhan Union Hospital (n=156) from January 2012 to December 2015 were retrospectively analyzed. Recurrence risks of these 539 patients were classified by the modified NIH criteria and AFIP criteria. Overall survival and tumor-free survival of patients with different risks were compared by Log-rank test and the accuracy of the two criteria in predicting postoperative recurrence was compared by receiver operating characteristic(ROC) curves.</p><p><b>RESULTS</b>Of 539 GIST patients, 283 were male and 256 were female; the age was (56.5±12.5) years old; tumors of 390 cases (72.4%) located in the stomach; tumor diameter of 178 cases (33.0%) was more than 5 cm; nuclear division number of 164 cases(30.4%) was more than 5/50 high magnification. The mean follow-up time was (37.5±13.6) months. According to the modified NIH criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 52.0, 57.0, 56.9 and 53.6 months respectively (P=0.002), and the mean tumor-free survival time was 56.0, 58.1, 58.2 and 51.2 months respectively (P=0.000). According to the AFIP criteria, the mean overall survival time of patients with very low, low, intermediate, and high risk was 54.1, 57.8, 55.5 and 52.0 months respectively(P=0.015), and the mean tumor-free survival time was 57.3, 56.6, 54.9 and 50.4 months respectively(P=0.000). While predicting the risk of postoperative recurrence, the ROC curve of AFIP criteria has a larger area under the curve compared to the curve of the modified NIH criteria(0.689 vs 0.641, P<0.05).</p><p><b>CONCLUSION</b>Compared with the modified NIH criteria, AFIP criteria predicts the risk postoperative recurrence more accurately in GIST patients.</p>