Clinicopathological features and survival analysis of gastric cancer patients with neuroendocrine differentiation after radical resection / 中华胃肠外科杂志

Objective: To compare the clinicopathological characteristics and the prognosis of gastric adenocarcinoma patients with and without neuroendocrine differentiation (NED) after radical gastrectomy plus D2 lymph node dissection. Methods: A retrospective cohort study was performed. The inclusion criteria were as follows: (1) patients who underwent radical resection of gastric cancer plus D2 lymph node dissection and were confirmed as gastric adenocarcinoma by postoperative pathology and received immunohistochemical examination of neuroendocrine markers Syn and/or CgA; (2) patients aged 20 to 75 years with normal organ function; (3) patients who did not receive neoadjuvant chemotherapy or radiotherapy before operation; (4) patients with postoperative pathological stage I to III according to the 8th edition of tumor staging system of American Joint Committee on Cancer (AJCC); and (5) patients who completed adjuvant chemotherapy according to the postoperative pathological stage. Those who had other malignant tumors in the past 5 years and who could not be followed up according to the required rules were excluded. According to the above criteria, the clinicopathological characteristics of gastric cancer patients who underwent radical resection plus D2 lymph node dissection in Zhongshan Hospital of Fudan University from January 2010 to June 2017 were collected and compared. All patients were followed up till June 2020. The disease-free survival (DFS) and overall survival (OS) between the patients with and without NED were compared, and the effect of NED on the prognosis was corrected by Cox proportional hazards model. The propensity score matching method was used for sensitivity analysis. Results: A total of 539 patients were enrolled in this study, including 35 with NED and 504 without NED. Compared with the patients without NED, the patients with NED were older [(65.0±7.5) years vs. (54.5±11.3) years, t=-7.681, P<0.001], had higher proportion of undergoing proximal gastrectomy [22.9% (8/35) vs. 7.6% (36/504), χ(2)=10.335, P=0.006], higher proportion of intestinal-type based on Lauren classification [77.1% (27/35) vs. 42.5% (214/504), χ(2)=14.553, P<0.001], and higher proportion of pathologic stage III [65.7% (23/35) vs. 27.6% (139/504), χ(2)=25.653, P<0.001]. The 3-year DFS of patients with NED and those without NED was 48.9% (95% CI: 33.8%-70.8%) and 37.4% (95% CI: 32.9%-42.5%) respectively, and no significant difference was found (P=0.44). The 3-year OS was 56.1% (95% CI: 39.9%-79.1%) and 64.3% (95% CI: 59.3%-69.7%) respectively, and no significant difference was found as well (P=0.32). Univariate and multivariate analyses showed that NED was not an independent risk factor for DFS and OS (all P>0.05). Sensitivity analysis showed that there was no significant difference in DFS and OS between the two groups after propensity score matching. Conclusion: Compared with patients without NED, patients with NED were older at onset, had a higher proportion of proximal gastrectomy, intestinal-type, and later diagnostic stage, but the survival prognosis had no significant difference with that of patients without NED.

Isobaric tags for relative and absolute quantitation-based quantitative proteomic analysis of X-linked inhibitor of apoptosis and H2AX in etoposide-induced renal cell carcinoma apoptosis / 中华医学杂志(英文版)

BACKGROUND@#X-linked inhibitor of apoptosis (XIAP) is a vital factor in the anti-apoptosis mechanism of tumors and is highly expressed in renal cell carcinoma (RCC). However, the mechanism through which XIAP regulates DNA damage repair is unknown. This study investigated the regulatory mechanism of XIAP in etoposide-induced apoptosis in two Caki-1 cell lines with high or low XIAP expression.@*METHODS@#The two cell lines were established using RNA interference technology. The differentially expressed proteins in the two cell lines were globally analyzed through an isobaric tags for relative and absolute quantitation-based quantitative proteomics approach. Proteomic analysis revealed 255, 375, 362, and 5 differentially expressed proteins after 0, 0.5, 3, and 12 h of drug stimulation, respectively, between the two cell lines. The identified differentially expressed proteins were involved in numerous biological processes. In addition, the expression of histone proteins (H1.4, H2AX, H3.1, H3.2, and H3.3) was drastically altered, and the effects of XIAP silencing were accompanied by the marked downregulation of H2AX. Protein-protein interactions were assessed and confirmed through immunofluorescence and Western blot analyses.@*RESULTS@#The results suggested that XIAP may act as a vital cell signal regulator that regulates the expression of DNA repair-related proteins, such as H2AX, and influences the DNA repair process.@*CONCLUSIONS@#Given these functions, XIAP may be the decisive factor in determining the sensitivity of RCC cell apoptosis induction in response to chemotherapeutic agents.

Dynamic imaging of autophagy-lysosomal pathway and autophagy function following pulmonary hypoxia/reoxygenation in vitro / 华中科技大学学报（医学）（英德文版）

Alterations of the autophagy-lysosomal pathway (ALP) and autophagy have been involved in lung ischemia-reperfusion (I/R) injury. However, dynamic imaging of ALP function under lung I/R injury particularly is not fully understood. Here we depicted the live-cell fluorescence imaging of autophagosome to monitor ALP activation and autophagy function. The pAsRed2-N1-LC3 vectors were transfected into CRL-2192 NR8383 (an alveolar macrophage cell line) and CCL149 (an alveolar epithelial cell line) successfully. 0-h, 2-h, 4-h, and 6-h hypoxia/0-h, 2-h, 4-h, and 6-h reoxygenation were then induced with an ALP inhibitor (3-MA) or activator (rapamycin) in the culture of transfected cells separately. ALP activation was conformed by up-regulating AMPK and beclin1 expression. Apoptosis was not obvious in 2-h hypoxia/2-h reoxygenation. pAsRed2-N1-LC3 CCL149 and pAsRed2-N1-LC3 NR8383 cells revealed gradually enhanced AsRed2 from 2-h to 6-h hypoxia/reoxygenation. AsRed2 varied sensitively to 3-MA and rapamycin interventions during 2-h hypoxia/reoxygenation. Our data provides a simple method of autophagosome imaging to monitor ALP activation and autophagy function in lung I/R injury.

Dynamic imaging of autophagy-lysosomal pathway and autophagy function following pulmonary hypoxia/reoxygenation in vitro / 华中科技大学学报（医学）（英德文版）

Alterations of the autophagy-lysosomal pathway (ALP) and autophagy have been involved in lung ischemia-reperfusion (I/R) injury. However, dynamic imaging of ALP function under lung I/R injury particularly is not fully understood. Here we depicted the live-cell fluorescence imaging of autophagosome to monitor ALP activation and autophagy function. The pAsRed2-N1-LC3 vectors were transfected into CRL-2192 NR8383 (an alveolar macrophage cell line) and CCL149 (an alveolar epithelial cell line) successfully. 0-h, 2-h, 4-h, and 6-h hypoxia/0-h, 2-h, 4-h, and 6-h reoxygenation were then induced with an ALP inhibitor (3-MA) or activator (rapamycin) in the culture of transfected cells separately. ALP activation was conformed by up-regulating AMPK and beclin1 expression. Apoptosis was not obvious in 2-h hypoxia/2-h reoxygenation. pAsRed2-N1-LC3 CCL149 and pAsRed2-N1-LC3 NR8383 cells revealed gradually enhanced AsRed2 from 2-h to 6-h hypoxia/reoxygenation. AsRed2 varied sensitively to 3-MA and rapamycin interventions during 2-h hypoxia/reoxygenation. Our data provides a simple method of autophagosome imaging to monitor ALP activation and autophagy function in lung I/R injury.

Efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer, mCRC / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC).</p><p><b>METHODS</b>Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed.</p><p><b>RESULTS</b>The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen.</p><p><b>CONCLUSIONS</b>BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.</p>

A pilot study of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer cells for advanced gastric cancer patients with ascites / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and safety of chemotherapy combined with intraperitoneal perfusion of cytokine-induced killer (CIK) cells for advanced gastric cancer patients with ascites.</p><p><b>METHODS</b>From January 2008 to December 2010, 42 advanced gastric cancer patients with ascites in Zhongshan Hospital of Fudan University were enrolled in the study. According to personal choice, patients were divided into 2 groups: XELOX chemotherapy alone (Capecitabine and Oxaliplatin) was applied in 22 patients (chemotherapy group) and XELOX combined with intraperitoneal perfusion of CIK cells in 20 patients (combination group). The efficacy, safety, and immunological function, including the time to progression (TTP), overall survival (OS), Karnofsky performance status (KPS) score, immunity index (CD4+/CD8+ ratio), volume of peritoneal fluid, were compared between two groups.</p><p><b>RESULTS</b>Compared with the chemotherapy group after treatment, the combination group had a higher KPS score (78.0±9.8 vs. 70.0±8.9, P=0.009), less volume of 2-cycle peritoneal fluid drainage [(4500±1218) ml vs. (5527±1460) ml, P=0.018 ], longer median TTP (4.0 vs. 2.5 months, P=0.001) and OS (11.0 vs. 6.0 months, P=0.006), higher ratio of CD4+/CD8+ (1.34±0.36 vs. 0.96±0.26, P=0.001). While no significant significances were found between the two groups in disease response rate (35.0% vs. 22.7%, P=0.499) and disease control rate (75.0% vs. 54.5%, P=0.209). There were no serious adverse reactions in the combination group.</p><p><b>CONCLUSIONS</b>As compared with XELOX chemotherapy alone, the combination immunological treatment of XELOX chemotherapy and intraperitoneal perfusion of CIK cells possesses better efficacy for the advanced gastric cancer patients with ascites, which can prolong the survival and enhance the immunological function with favorable safety.</p>

Efficacy of neoadjuvant chemotherpy in patients with locally advanced gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of neoadjuvant chemotherapy in patients with locally advanced gastric cancer, and to analyze the relevant factors of recurrent death of gastric cancer after adjuvant chemotherapy.</p><p><b>METHODS</b>Clinical data of 49 patients who underwent neoadjuvant chemotherapy for locally advanced gastric cancer between July 2007 and June 2011 were reviewed. Preoperative staging was determined by endoscopic ultrasonography and abdominal computer tomography (CT) or magnetic resonance imaging (MRI). Chemotherapy was administered for regimen of two or three drugs. Prognostic factors were analyzed by univariate and multivariate analysis with Cox proportional hazard model.</p><p><b>RESULTS</b>The response rate was 33.3% (16/48) and disease control rate was 93.8% (45/48). Forty-four (89.8%, 44/49) patients received curative resection after neoadjuvant chemotherapy, among whom 90.9% (40/44) underwent D2 lymphadenctomy. Thirty-two cases had pathological response and 2 patients had pathological complete response. The average hospital stay was 11.6 days and 2 patients had longer hospitalization because of postoperative pancreatic complications. The toxicities were most in grade 1-2. All the patients were followed up postoperatively and the median follow-up was 21.6 months. Median progression-free survival was 29.6 (95%CI:24.0-35.2) months and median overall survival was 34.6 months (95%CI:29.8-39.4). Imaging response (P=0.038, RR=0.168, 95%CI:0.031-0.904) and pathological response (P=0.007, RR=0.203, 95%CI:0.064-0.642) were identified as independent prognostic factors with COX multivariate analysis.</p><p><b>CONCLUSIONS</b>Neoadjuvant chemotherapy has quite high disease control rate and R0 resecting rate for patients with locally advanced gastric cancer. Imaging response and pathological response are most important prognostic factors in those patients.</p>

Chemotherapy selection through the process of gastric cancer / 中华胃肠外科杂志

The role of chemotherapy has become more and more important in the whole process of gastric cancer. S-1 or XELOX regimen is regarded as the standard treatment option in adjuvant chemotherapy. First-line chemotherapy in advanced gastric cancer has been established to improve survival, and the benefit from second-line chemotherapy is being acknowledged. More studies are needed to assess the neoadjuvant chemotherapy.

Impact of AJCC staging system (2010 edition) on the choice of postoperative adjuvant chemotherapy after radical resection of gastric cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate whether AJCC staging system(2010 edition) for gastric cancer has influence on the adoption of adjuvant chemotherapy.</p><p><b>METHODS</b>This was a cohort study and the data were collected from patients who underwent radical surgery and received adjuvant chemotherapy from January 2004 to December 2009. There were 48 patients with stage II( disease and 95 patients with stage III( disease according to TNM staging(2010 edition). Doublets were defined as 5-fluorouracil or capecitabine plus cisplatin or oxaliplatin, while triplets had epirubicin added. Ninety-six patients received doublet chemotherapy and 47 received triplet. All the patients were followed-up in the outpatient clinic until death or the censor time of May 2011.</p><p><b>RESULTS</b>The median follow-up time was 48 months in this cohort of 143 patients. The two groups had similar disease-free survival(DFS)(median, 23 months vs. 30 months, P>0.05). The median overall survival was 48 months in both groups. Subgroup analysis by TNM staging(2010 edition) showed that the median DFS of patients with stage III( gastric cancer was 15 months in the doublet group, significantly shorter than that of patients in the triplet group (18 months, P<0.05). However, the difference in overall survival was not statistically significant between the two groups. Patients with stage II( disease had comparable DFS and OS between the two groups(all P>0.05).</p><p><b>CONCLUSIONS</b>Triplets regimens (epirubicin, platins and fluorouracil) show benefit on disease-free survival for the stage III( gastric cancer patients staged by TNM staging 2010 edition.</p>

Adjuvant chemotherapy for gastric cancer: more drugs do not mean better efficacy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To compare oncologic outcomes between doublet and triplet adjuvant chemotherapy for gastric cancer patients undergoing radical resection.</p><p><b>METHODS</b>Patients with gastric cancer receiving adjuvant chemotherapy after radical resection from January 2004 to December 2008 were included. Doublet was defined as 5-FU 750 mg/m² (days 1-5) or capecitabine 1000 mg/m² (days 1-14) plus cisplatin 60 mg/m² (day 1) or oxaliplatin 130 mg/m² (day 1), while triplets had epirubicin 50 mg/m² (day 1) added. Chemotherapy was initiated 4-6 weeks after surgery, repeated every three weeks for 6 cycles. Patients were followed-up in the outpatient clinic until death or the most recent follow up(April 30, 2010). Cox proportional- hazard model and Chi-square test were used to test statistical difference.</p><p><b>RESULTS</b>A total of 316 patients (210 received doublets, 106 received triplets) had a median follow-up time of 47 months. Seventy-seven patients died at the end of the follow-up. Two groups were comparable except for age (median age of 57 in doublets, 51 in triplets, P<0.01). The two groups had similar disease-free survival (16 months vs. 23 months, P=0.656) and 3-year overall survival(59.6% vs. 64.8%, P=0.293). There was no significant difference in severe adverse side effects between the two groups (21.9% vs. 30.2%, P=0.107).</p><p><b>CONCLUSION</b>Triplet adjuvant chemotherapy appears not to be associated with superior efficacy than doublet regimen for patients with gastric cancer after radical resection.</p>

Cost-effectiveness analysis of different chemotherapeutical regimens in metastatic colorectal cancer / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To compare FOLFOX6 and FOLFIRI regimen in the treatment of metastatic colorectal cancer with cost-effective analysis.</p><p><b>METHODS</b>Cost-effective analysis was conducted based on the efficacy results of V308 clinical trial of FOLFOX6 and FOLFIRI regimen and the medical system price in Zhongshan hospital.</p><p><b>RESULTS</b>The minimal cost analysis showed FOLFIRI followed by FOLFOX6 had the cost of RMB 206365.78 Yuan for each patient during the whole treatment period, and RMB 170468.89 Yuan for the FOLFOX6 followed by FOLFIRI regimen. Incremental analysis showed FOLFIRI followed by FOLFOX6 regimen could prolong one month of overall survival with additional cost of RMB 39885.44 Yuan in each patient while compared with the regimen of FOLFOX6 followed by FOLFIRI.</p><p><b>CONCLUSIONS</b>Both FOLFOX and FOLFIRI regimens are able to prolong the survival time of patients with metastatic colorectal cancer, but cost of such treatments are still quite expensive for Chinese patients. FOLFOX6 regimen suggests better cost-effectiveness than FOLFIRI.</p>

Clinical values of extended lymph node dissection for gastric cancer:a meta-analysis for D1 versus D2 gastrectomy / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To evaluate the survival, complication and postoperative mortality after D(1) or D(2) lymph node dissection for gastric cancer.</p><p><b>METHODS</b>All the randomized clinical trials about nodal dissection for gastric cancer published within the last 20 years were collected. Quality assessment was done on each trial and relevant data were extracted from qualified trials. Meta-analysis was performed with the use of RevMan 4.2 (Cochrane) for statistic analysis.</p><p><b>RESULTS</b>Three hundred and ninety-four trials were yielded at the initial search. Four trials, recruited 1316 cases of gastric cancer in total, were included after quality assessment. Results of Meta-analysis showed that standard D(2) dissection could effectively improve patients' long-term survival [RR 1.35, 95%CI(1.12-1.62), NNT=9] as compared with D(1) dissection. If splenectomy (or pancreatico-splenectomy) was involved, D(2) dissection only improved the clinical outcome of T(3)-staged cases [RR 1.80,95%CI(1.03-3.15), NNT=13]. D(2) dissection produced higher rates of postoperative complication [RR 1.72,95%CI(1.46-2.03), NNT=6] and mortality [RR 2.12,95%CI(1.39-3.25), NNT=21] than D(1) dissection.</p><p><b>CONCLUSIONS</b>Standard D(2) dissection can increase the overall survival rate when compared with D(1) dissection. If splenectomy (or pancreatico-splenectomy) cases are involved,D(2) dissection can only improve the survival rate of T(3)-staged patients. D(2) dissection yields higher postoperative morbidity and mortality than D(1) dissection.</p>

Correlation between the activation of AP-1 signal transduction pathway and metastasis of colorectal carcinoma / 中华胃肠外科杂志

<p><b>OBJECTIVE</b>To investigate the binding activity of activator protein-1 (AP-1) with DNA probe in the colorectal carcinoma (CRC) tissues and surrounding tissues and explore the correlation between the activation of AP-1 signal transduction pathway and metastasis of CRC.</p><p><b>METHODS</b>The AP-1 DNA binding activities were investigated by electrophoretic mobility shift assay (EMSA) in CRC specimens (T), surrounding tissues including 2 cm (P(2)), 5 cm(P(5)) far away from primary tumor margin and distal resection margin of the specimens (N). The mRNA expression level of vascular endothelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9) were measured by quantitive reverse transcription polymerase chain reaction (Q- RT-PCR).</p><p><b>RESULTS</b>The AP-1 DNA binding activity in T was significantly higher than those in P(2), P(5) and N (P< 0.05) tissues. There were significantly positive correlations between AP-1 DNA binding activity in tumor and invasive degree, lymphatic metastasis respectively (P< 0.01), but no correlation with histological classification and differentiation (P> 0.05). The transcription levels of VEGF and MMP-9 in CRC were significantly higher than those in P(5) and N (P< 0.01, P< 0.05) tissues. The transcription levels of VEGF and MMP-9 were significantly correlated with increasing AP-1 DNA binding activity (P< 0.01).</p><p><b>CONCLUSIONS</b>AP-1 is significantly correlated to the invasion and metastasis in CRC. The activation of AP-1 signal transduction pathway might be involved in the angiogenesis and of degradation extracellular matrix during tumor metastasis.</p>

Down-regulation of osteopontin by siRNA on the biological behavior of gastric cancer cell lines / 中华消化杂志

Objective To explore the effects of down regulation of osteopontin(OPN)on the bio- logical behavior of MKN28 and SGC7901 cell lines.Methods OPN siRNA was designed according to the relevant literature and was transfected into the two cell lines.Fluorescent labeling was used to test the transfected efficiency.The down-regulation of OPN protein was measured by Western blot.Real- time PCR was used to test the ratio and time difference of down-regulation of OPN mRNA after siRNA transfection.The biological changes before and after OPN siRNA transfected into these two cell lines were tested by flow cytometry(to test cell cycle and apoptosis)and MTT method(to test the prolifera- tion for the consecutive seven days)and the difference between OPN siRNA transfected or non-transfect- ed cells was compared using mixed model.The capability of moving and invasion of cancer cells were tested by Transwell method and analyzed by t-test.Results The transfected efficiency of OPN siRNA were more than 90% in the two cell lines.OPN mRNA down-regulated to 47% at the 72th hour in SGC7901,while 40% at the 48th hour in MKN28.The expression of OPN protein was both down- regulated after siRNA transfection in the two cell lines.The proliferation decreased after transfected with OPN siRNA both in MKN28 andSGC7901(P