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Purpose: Published data have shown conflicting results about the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms (Arg399Gln and Arg194Trp) and clinical outcome of platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC). A meta-analysis is needed to provide a systematic review of the published findings.Experimental Design: We conducted a systematic review and meta-analysis to evaluate the predictive value of XRCC1 gene polymorphisms on clinical outcome up to October 1, 2010. The quality of each study was scored on the basis of predefined criteria.Results: A total of 13 eligible follow-up studies met all the inclusion criteria. The XRCC1194Trp allele was found to be significantly associated with a favorable response rate relative to 194Arg [Trp vs. Arg: OR, 1.88; 95% confidence interval (CI), 1.48–2.38]. XRCC1399Gln was less favorably associated with both response rate (Gln vs. Arg: OR, 0.67; 95% CI, 0.52–0.87) and overall survival (Gln vs. Arg: HR, 1.30; 95% CI, 1.04–1.63) than 399Arg in analyses using all available studies; but these associations became insignificant when only high-quality studies were used.Conclusion: These findings suggest a predictive role for XRCC1 gene polymorphisms in clinical outcome. However, the role of 399Gln could be considered controversial because its impact on clinical outcome was insignificant in high-quality studies. These findings show the importance of establishing suitable criteria, including genetic epidemiologic, phenotypic, and clinical criteria, to improve quality control of study design and methods in pharmacogenomic studies related to XRCC1 gene polymorphism. Clin Cancer Res; 18(14); 3972–81. ©2012 AACR.

XLSX file, 12KB, Random effects OR with the corresponding 95% CI and heterogeneity results for multiple pairwise comparisons of XRCC1Trp194Arg and response rate to chemotherapy.

XLSX file, 12KB, Random effects HR with the corresponding 95% CI and heterogeneity results for multiple pairwise comparisons of XRCC1Gln399Arg and 5-year survival to chemotherapy.

XLSX file, 13KB, Random effects OR with the corresponding 95% CI and heterogeneity results for multiple pairwise comparisons of XRCC1 Gln399Arg and response rate to chemotherapy.

To investigate the major causes and predictive factors of death in a middle-aged and elderly Chinese population. A total of 6591 residents aged ≥ 45 years from Shanghai Changfeng community were followed up for an average of 5.4 years. The causes of death were coded according to the 10th Revision of International Classification of Diseases. The mortality rate was calculated by person-years of follow up and age-standardized according to the 2010 Chinese census data. Multivariable-adjusted Cox proportional hazards model was performed to investigate the predictors of all-cause and cause-specific mortality. During the total follow-up of 35,739 person-years, 370 deaths were documented (157 from malignant neoplasms, 70 from heart diseases, 68 from cerebrovascular diseases, 75 from other causes). The age-standardized all-cause mortality rate was 798.2 per 100,000 person-years (927.9 among men and 716.7 among women). Results from multivariable analyses showed that aging, diabetes, and osteoporosis at baseline were independent predictors of all-cause mortality, with hazard ratios (HR) of 1.11 (95% CI 1.10–1.13), 1.91 (1.51–2.42), and 1.71 (1.24–2.35), respectively. The population attributable risk percent of diabetes and osteoporosis was 19.7% and 11.7%, respectively. Cigarette smoking was associated with a higher risk of all-cause mortality in men (HR and 95%CI 1.44, 1.01–2.06). In women, diabetes and osteoporosis were related to a higher risk of cardiovascular mortality (3.27, 1.82–5.88 and 1.89, 1.04–3.46, respectively). While in men, osteoporosis was related to a higher risk of malignant neoplasms mortality (2.39, 1.07–5.33). Malignant neoplasms, heart diseases, and cerebrovascular diseases are the leading causes of death. Aging, smoking, underweight, diabetes, and osteoporosis are independent predictors of premature death among middle-aged and elderly Chinese community population. Moreover, there may have been some differences in the causes and predictors of premature death between men and women.

Importance The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains uncertain given the lack of high-level clinical evidence. Objective To compare the safety of LTG for clinical stage I gastric cancer with that of conventional open total gastrectomy (OTG). Design, Setting, and Participants The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group CLASS02 study was a prospective, multicenter, open-label, noninferiority, randomized clinical trial that compared the safety of LTG vs OTG with lymphadenectomy for patients with clinical stage I gastric cancer. From January 2017 to September 2018, a total of 227 patients were enrolled. Final follow-up was in October 2018. Interventions Eligible patients were randomized to LTG (n = 113) or OTG (n = 114) by an interactive web response system. Main Outcomes and Measures The primary outcome was the morbidity and mortality within 30 days following surgeries between LTG and OTG with a noninferiority margin of 10%. The secondary outcomes were recovery courses and postoperative hospital stays. Results A total of 214 patients were analyzed for morbidity and mortality (105 patients in the LTG group and 109 patients in the OTG group). The mean (SD) age was 59.8 (9.4) years in the LTG group and 59.4 (9.2) years in the OTG group, and most were male (LTG group, 75 of 105 [71.4%]; OTG group, 80 of 109 [73.4%]). The overall morbidity and mortality rates were not significantly different between the groups (rate difference, −1.1%; 95% CI, −11.8% to 9.6%). Intraoperative complications occurred in 3 patients (2.9%) in the LTG group and 4 patients (3.7%) in the OTG group (rate difference, −0.8%; 95% CI, −6.5% to 4.9%). In addition, there was no significant difference in the overall postoperative complication rate of 18.1% in the LTG group and 17.4% in the OTG group (rate difference, 0.7%; 95% CI, −9.6% to 11.0%). One patient in the LTG group died from intra-abdominal bleeding secondary to splenic artery hemorrhage. However, there was no significant difference in mortality between the LTG group and the OTG group (rate difference, 1.0%; 95% CI, −2.5% to 5.2%), and the distribution of complication severity was similar between the 2 groups. Conclusions and Relevance The results of the CLASS02 trial showed that the safety of LTG with lymphadenectomy by experienced surgeons for clinical stage I gastric cancer was comparable to that of OTG. Trial Registration ClinicalTrials.gov Identifier:NCT03007550

Association between acute myocardial infarction (AMI) morbidity and ambient temperature has been examined with generalized linear model (GLM) or generalized additive model (GAM). However, the effect size by these two methods might be biased due to the autocorrelation of time series data and arbitrary selection of degree of freedom of natural cubic splines. The present study analyzed how the climatic factors affected AMI morbidity for older adults in Shanghai with Mixed generalized additive model (MGAM) that addressed these shortcomings mentioned. Autoregressive random effect was used to model the relationship between AMI and temperature, PM10, week days and time. The degree of freedom of time was chosen based on the seasonal pattern of temperature. The performance of MGAM was compared with GAM on autocorrelation function (ACF), partial autocorrelation function (PACF) and goodness of fit. One-year predictions of AMI counts in 2011 were conducted using MGAM with the moving average. Between 2007 and 2011, MGAM adjusted the autocorrelation of AMI time series and captured the seasonal pattern after choosing the degree of freedom of time at 5. Using MGAM, results were well fitted with data in terms of both internal (R2 = 0.86) and external validity (correlation coefficient = 0.85). The risk of AMI was relatively high in low temperature (Risk ratio = 0.988 (95% CI 0.984, 0.993) for under 12°C) and decreased as temperature increased and speeded up within the temperature zone from 12°C to 26°C (Risk ratio = 0.975 (95% CI 0.971, 0.979), but it become increasing again when it is 26°C although not significantly (Risk ratio = 0.999 (95% CI 0.986, 1.012). MGAM is more appropriate than GAM in the scenario of response variable with autocorrelation and predictors with seasonal variation. The risk of AMI was comparatively higher when temperature was lower than 12°C in Shanghai as a typical representative location of subtropical climate.

As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion.

Aim To investigate the association between mean fasting glucose (FG) and variability in visit-to-visit FG and risk of mortality in people with type 2 diabetes (T2D). Methods This retrospective cohort study included 48,077 Chinese men and women with T2D. The yearly mean and coefficient of variation for fasting glucose (mean-FG and FG-CV, respectively) were based on at least two measurements taken each year over a mean duration of 4.5 years. Deaths and their causes were identified using the Shanghai Vital Statistics registry. Mean-FG and FG-CV served as time-dependent variables in Cox models to estimate their associations with risk of mortality; hazard ratios (HRs) were adjusted for baseline risk factors. Potential non-linear associations were examined by restricted cubic splines. Results During an average 4.5 years of follow-up, 2095 men and 1923 women died. Men with low mean-FG and women with low or high FG were at greater risk of death. Mean-FG was not associated with either cardiovascular disease (CVD) or cancer-specific mortality, whereas higher yearly FG-CV was associated with all-cause and CVD-/cancer-specific mortality in both genders. Compared with a yearly FG-CV of 1.76 (5th percentile), men and women with an FG-CV of 14.14 (75th percentile) had HRs (95% CI) of 1.41 (1.24–1.61) and 1.44 (1.26–1.65), respectively, for all-cause mortality. Conclusion Variability of visit-to-visit FG may be a more sensitive predictor of risk of death than mean-FG in people with T2D.

Background Obesity and diabetes are two risk factors for cancer. To evaluate the association of body mass index (BMI) with cancer risk in diabetic patients may improve current understanding of potential mechanisms. Methods A retrospective cohort study was conducted in 51,004 newly diagnosed T2DM patients derived from an electronic health record (EHR) database of Minhang district in Shanghai, China. Incident cancer cases and all-cause deaths occurred before September 30, 2015 were identified by linking with the Shanghai Cancer Registry and the Shanghai Vital Statistics. To examine the potential non-linear and linear relationships of BMI and cancer risk, Cox proportional hazard models with and without restricted cubic spline functions were used, respectively. Results A non-linear association was observed between BMI and overall cancer incidence in men younger than 60 years old (p for non-linearity = 0.009). Compared with those having BMI of 25.0 kg/m2, the cancer risk increased in those with either lower or higher BMI. In women older than 60 years old, linear dose-response relationships were observed between BMI and the risk of both overall cancer and breast cancer. As each unit increase in BMI, the overall cancer risks elevated by 3% (95%CI: 1–5%) and the breast cancer risks increased by 7% (95%CI: 1–13%). No significant association was observed between BMI and other common cancer sites. Conclusions Our results show that the effect of BMI on cancer risk in Chinese patients with T2DM may vary by gender, age and cancer subtypes, suggesting different underlying biological mechanisms. Electronic supplementary material The online version of this article (10.1186/s12885-018-4675-0) contains supplementary material, which is available to authorized users.

AIM Although a minimum of 12 lymph nodes (LNs) has been recommended for examination in colorectal cancer patients there remains considerable debate with regard to rectal cancer. Inadequacy of examined LNs could lead to understaging and inappropriate treatment as a consequence. We describe a statistical tool that allows an estimate of the probability of false-negative nodes. METHOD A total of 26 778 patients diagnosed between 2004 and 2013 with rectal adenocarcinoma [tumour stage (T stage) 1-3] who did not receive neoadjuvant therapies and had at least one histologically assessed LN were extracted from the Surveillance, Epidemiology and End Results (SEER) database. A statistical tool using beta-binomial distribution was developed to estimate the probability of missing a positive node as a function of the total number of LNs examined and T stage. RESULTS The probability of falsely identifying a patient as node-negative decreased with increasing number of nodes examined for each stage. It was estimated to be 72%, 66% and 52% for T1, T2 and T3 patients, respectively, with a single node examined. To confirm an occult nodal disease with 90% confidence, 5, 9 and 29 nodes need to be examined for patients from stages T1, T2 and T3, respectively. CONCLUSION The false-negative rate of the examined LNs in rectal cancer was verified to be dependent preoperatively on the clinical T stage. A more accurate nodal staging score was developed to recommend a threshold for the minimum number of examined nodes with regard to the favoured level of confidence.

Summary We propose a flexible design for the identification of optimal dose combinations in dual-agent dose finding clinical trials. The design is called AAA, standing for three adaptations: adaptive model selection, adaptive dose insertion and adaptive cohort division. The adaptations highlight the need and opportunity for innovation for dual-agent dose finding and are supported by the numerical results presented in the proposed simulation studies. To our knowledge, this is the first design that allows for all three adaptations at the same time. We find that AAA enhances the chance of finding the optimal dose combinations and shortens the trial duration. A clinical trial is being planned to apply the AAA design and a Web tool is being developed for both statisticians and non-statisticians.

Background According to the current official guidelines, at least 12 lymph nodes (LNs) are qualified as an adequate sampling for colon cancer patients. However, patients evaluated with less nodes were still common in the United States, and the prevalence of positive nodal disease may be under-estimated because of the false-negative assessment. In this study, we present a statistical model that allows preoperative determination of the minimum number of lymph nodes needed to confirm a node-negative disease with certain confidence. Methods Adenocarcinoma colon cancer patients with stage T1-T3, diagnosed between 2004 and 2013, who did not receive neoadjuvant therapies and had at least one lymph node pathologically examined, were extracted from the Surveillance, Epidemiology and End Results (SEER) database. A beta binomial distribution was used to estimate the probability of an occult nodal disease is truly node-negative as a function of total number of LNs examined and T stage. Results A total of 125,306 patients met study criteria; and 47,788 of those were node-positive. The probability of falsely identifying a patient as node-negative decreased with an increasing number of nodes examined for each stage, and was estimated to be 72% for T1 and T2 patients with a single node examined and 57% for T3 patients with a single node examined. To confirm an occult nodal disease with 90% confidence, 3, 8, and 24 nodes need to be examined for patients from stage T1, T2, and T3, respectively. Conclusions The false-negative rate of diagnosed node negative, together with the minimum number of examined nodes for adequate staging, depend preoperatively on the clinical T stage. Predictive tools can recommend a threshold on the minimum number of examined nodes regarding to the favored level of confidence for each T stage. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3491-2) contains supplementary material, which is available to authorized users.

Background Neoadjuvant chemoradiation is not recommended as an approach for treatment of esophageal squamous cell carcinoma due to its significant postoperative mortality. However, it is assumed the combination of neoadjuvant chemoradiation with minimally invasive esophagectomy (MIE) may reduce postoperative mortality, which can revive preoperative chemoradiation. No randomized controlled studies comparing neoadjuvant chemoradiation plus MIE with neoadjuvant chemotherapy plus MIE have been performed so far. The present trial is initiated to obtain valid information whether neoadjuvant chemoradiation plus MIE yields better survival without worse postoperative morbidity and mortality in the treatment of locally advanced resectable esophageal squamous cell carcinoma(cT3-4aN0-1M0). Methods/design CMISG1701 is a multicenter, prospective, randomized, phase III clinical trial, investigating the safety and efficacy of neoadjuvant chemoradiation plus MIE compared with neoadjuvant chemotherapy plus MIE. Patients with locally advanced resectable esophageal squamous cell carcinoma (cT3-4aN0-1M0) are eligible for the study. A total of 264 patients are randomly assigned to neoadjuvant chemoradiation (arm A) or neoadjuvant chemotherapy (arm B) with a 1:1 allocation ratio. The primary outcome is overall survival assessed with a minimum follow-up of 36 months. Secondary outcomes are progression-free survival, recurrence-free survival, postoperative pathologic stage, treatment-related complications, postoperative mortality as well as quality of life. Discussion The objective of this trial is to identify the superior protocol with regard to patient survival, treatment morbidity/mortality and quality of life between neoadjuvant chemoradiation plus MIE and neoadjuvant chemotherapy plus MIE. Trial registration NCT03001596 (December 17, 2016). Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3446-7) contains supplementary material, which is available to authorized users.

// Yuntao Chen 1, 2, * , Zhenyi Shao 2, * , Wen Chen 2 , Hua Xie 2 , Zhenyu Wu 1, 2 , Guoyou Qin 1, 2 , Naiqing Zhao 1, 2 1 Department of Biostatistics, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 200032, China 2 Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China * Co-first authors Correspondence to: Guoyou Qin, email: gyqin@fudan.edu.cn Naiqing Zhao, email: nqzhao@shmu.edu.cn Keywords: CA19-9, pancreatic cancer, varying coefficient model, biomarker, prognosis Abbreviations: PC: pancreatic cancer; OS: overall survival; CA19-9: carbohydrate antigen 19-9; PH: proportional hazard; HR: hazard ratio. Received: August 16, 2016 Accepted: January 23, 2017 Published: February 21, 2017 ABSTRACT Purpose: To evaluate the relationship between serum CA19-9 and overall survival in patients with advanced pancreatic cancer. Methods: 109 advanced pancreatic cancer patients with gemcitabine based first-line chemotherapy were included. The effect of pretreatment CA19-9 level on overall survival was modeled by Cox proportional hazard regression. The effect of CA19-9 kinetics on overall survival was modeled by an extended Cox regression with a time varying coefficient and a time varying covariate. Results: Univariate analysis indicated that baseline CA19-9 correlated with OS (HR = 1.66, p < 0.01) and this association remained significant within multivariate analysis (HR = 1.56, P < 0.01). For the analysis of CA19-9 kinetics, the extended Cox model showed that the effect of CA19-9 on overall survival changed with time: increased in the first two months and reached the top at a HR of about 2, then decreased for the next two months to a HR of about 1.56 and finally tended to be stable. The combination of pretreatment CA19-9 and CA19-9 at 2 month may better evaluate the patients’ prognosis compared to pretreatment CA19-9 alone. Conclusion: Pretreatment CA19-9 and CA19-9 kinetics may serve as a useful serum biomarker in advanced pancreatic cancer.

Background. The theories of Shen-reinforcement and Qi-supplementation are important in asthma treatment based on traditional Chinese medicine theories. Early studies suggested that Invigorating Kidney and Supplementing Qi herbal formulae, Bu Shen Fang Chuan (BSFC) and Bu Shen Yi Qi (BSYQ), conveyed promising results in asthma treatment. However, the efficacy and safety of the formulae need to be further investigated by a randomized double-blind clinical trial. Methods. 328 eligible patients were randomly sent to BSFC, BSYQ, and placebo group. The two formulae were received as add-on therapy. The primary endpoints were rate of asthma exacerbation and Hamilton Rating Scale for Depression (HAM-D) score. The secondary endpoints included HPA axis function and inflammatory cytokine production profile. All indexes were measured before and after treatment. Results. The primary endpoints were not improved in both groups; however, the depression levels of subgroup patients with HAM-D score > 5 were improved in BSFC group. HPA axis functions and inflammatory cytokines level were also improved by two formulae. The incidences of adverse events were similar among groups. Conclusions. The two formulae had multiple advantage effects on neuroendocrine-immune system. They are worth used as a replacement therapy in asthma. Trial Registration. This trial is registered with clinical trial number ChiCTR-PRC-09000529.

Background: Accumulating evidence suggests that regulatory B cells (Bregs) play an important role in modulating the immune response to tumours. Our previous study indicated that a small percentage of peripheral CD19 + CD24 h CD27 + Breg cells slowed gastric cancer progression in XELOX-treated patients. Here, we further investigated the relationship between dynamic changes in circulating Breg cells and the clinical course in XELOX-treated gastric cancer patients. Methods: A total of 52 patients with advanced gastric cancer were enrolled in this study. The frequencies of CD19 + CD24 h CD27 + cells in peripheral blood were tested before (as a baseline) and 9 weeks after administration of oxaliplatin and capecitabine (XELOX). The primary endpoint of the study was progression-free survival time (PFS) of the patients. The overall survival (OS) and adverse events of chemotherapy were also recorded. Results: The median PFS of patients was 6 months (95% CI, 5.27-6.73) with effective rate of 46.2%. The percentage of CD19 + CD24 h CD27 + cells in lymphocytes ranged from 0.007% to 1.94%, with a median value of 0.45%. The median percentage of CD19 + CD24 h CD27 + lymphocytes was 0.59% (0.01%-6.02%) 9 weeks after treatment. There were no significant differences for this index. However, the patients with decreased Breg frequencies after XELOX treatment had a longer PFS time (7.0 months vs. 5.0 months, p =0.01) than those with increased Breg frequencies. Conclusion: Patients with downtrend of CD19 + CD24 h CD27 + B lymphocytes during early stages of chemotherapy relative to their initial values had longer PFS times, and this could be used to predict the efficacy of chemotherapy and help physicians adjust treatments accordingly.

Allergen-specific immunotherapy is widely used for allergic rhinitis and asthma treatment worldwide. This study explored the efficacy and safety of sublingual immunotherapy (SLIT) with the extracts...

Etanercept biosimilar recombinant human tumour necrosis factor-α receptor II: IgG Fc fusion protein (rhTNFR-Fc, trade name Yisaipu) has shown good efficacy in the treatment of moderate-to-severe plaque psoriasis. To compare the efficacy and safety of rhTNFR-Fc plus methotrexate (MTX) and rhTNFR-Fc plus placebo in Chinese patients with moderate-to-severe plaque psoriasis. In this multicentre, randomized, placebo-controlled trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned in a 1:1 ratio to receive rhTNFR-Fc plus MTX or rhTNFR-Fc plus placebo. The primary endpoint was the proportion of patients achieving Psoriasis Area and Severity Index improvement of at least 75% (PASI 75) from baseline at week 24. Adverse events (AEs) were recorded to evaluate safety. Efficacy analysis was performed using the intent-to-treat principle. A total of 466 patients were enrolled and randomly received rhTNFR-Fc plus MTX (combination group, n = 233) or rhTNFR-Fc plus placebo (monotherapy group, n = 233). PASI 75 at week 24 was significantly higher in the combination group than in the monotherapy group (81.86% vs. 65.50%, p

Chimeric antigen receptor T cells (CAR-T) with anti-CD19 have shown great promise in the treatment of relapsed and refractory non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Cytokine release syndrome (CRS) is the most significant and life-threatening side effect. This individual patient data (IPD) meta-analysis is to investigate the association of severe CRS with CAR-T dose and baseline factors. We collected the individual patient-level data of 237 patients with NHL or ALL from 16 published papers. A logistic model was used to analyze the association of severe CRS incidence with CAR-T dose and baseline factors including age and baseline tumor burden. A generalized additive model (GAM) with logit link function was used to estimate the nonlinear response for severe CRS incidence with CAR-T dose and baseline factors. Severe CRS incidence was positively associated with current proposed CAR-T treatment infusion dose at a range of 0.2 × 106–5.0 × 106 T cells per kg of body weight in patients less than or equal to 25 years old. For patients over 25 years old the association was not significant. Significant association between severe CRS incidence and baseline tumor burden was also shown in this study. Our results provide novel insights that association between CAR-T treatment dose and severe CRS incidence only exists in patients less than or equal to 25 years old. Severe CRS incidence is associated with baseline tumor burden which indicates that tumor burden needs to be controlled with induced chemotherapy before CAR-T treatment.

Forkhead box O3A (FOXO3a) is an important transcription factor involved in various human cancers. However, the role of FOXO3a in regulating the invasion and metastasis of gastric cancer cells has not been clarified. Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells. Silencing cathepsin L in these cells suppressed FOXO3a overexpression-induced cell migration and invasion. Mechanistic studies revealed that FOXO3a increased cathepsin L promoter activation, and cathepsin L overexpression repressed E-cadherin expression, causing gastric cancer cells to undergo epithelial-mesenchymal transition (EMT). Our data reveal a previously unexplored function of FOXO3a in gastric cancer invasion by regulating proteins involved in extracellular matrix (ECM) degradation and EMT. We suggest that FOXO3a may be of prognostic value and a potential therapeutic target in blocking tumor metastasis.

Objectives The optimal time to initiate adjuvant chemotherapy after surgery in patients with colon cancer is not clear. We investigated the benefit of combined intraportal chemotherapy administered during radical surgery with adjuvant chemotherapy for treating stage II and III colon cancer. Methods Patients were randomly assigned to OCTREE arm (intraportal chemotherapy plus mFOLFOX6) or a standard adjuvant chemotherapy arm (mFOLFOX6). The primary study endpoint was disease-free survival. The secondary endpoints included metastasis-free survival, overall survival, and safety. Results The intent-to-treat population comprised 237 patients. With a median follow-up of 44 months, the hazard ratio (OCTREE vs mFOLFOX6) was 0.66 (95% confidence interval, 0.43-0.90), a 34% risk reduction in favor of OCTREE (P = 0.016). The 3-year disease-free survival rate was 85.2% for OCTREE and 75.6% for mFOLFOX6 alone (P = 0.030). The 3-year metastasis-free survival rates were 87.6% for OCTREE and 78.0% for mFOLFOX6 (P = 0.035). Patients had lower distant metastatic rate in the OCTREE arm (12.7% vs 22.7%; P = 0.044), when compared with the mFOLFOX6 arm. The 3-year overall survival was no significant difference between 2 arms (P = 0.178). Neutropenia occurred in 12.7% of the patients receiving OCTREE and in 2.5% of the patients receiving mFOLFOX6 (P = 0.003) within 2 weeks of surgery, and grade 3 or 4 toxicity event was no difference between 2 regimens. Conclusions Combination of intraoperative intraportal chemotherapy with mFOLFOX6 reduced the occurrence of distant metastases and improved disease-free survival in patients with stage II and stage III colon cancer.

378 Background: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The aim of this study was to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG). Methods: From January 2017 to September 2018, a total of 227 patients with clinical stage T1N0-1M0/T2N0M0 gastric cancer were enrolled in this clinical trial and randomly assigned to Laparoscopic Gastrectomy group (LG, n=113) or Open Gastrectomy group (OG, n=114). The morbidity and mortality within 30 days following surgery, the recovery course, and the postoperative hospital stay between LG group (n=105) and OG group (n=109) were compared. Clavien-Dindo classification system was used to stratify surgical complications. Results: The overall morbidity rate was not significantly different in each group (LG group: 19.05%; OG group: 20.18%; Rate difference [RD]: -1.14%, 95%CI, -11.75%-9.58%). Intraoperative complications occurred in 3 (2.86%) patients in LG group and 4 (3.67%) patients in OG group (RD: -0.81%, 95%CI, -6.52%-4.85%). In addition, there was no significant difference in the overall postoperative complication rate of 18.10% in LG group and 17.43% in OG group (RD: 0.66%, 95%CI, -9.61%-11.01%). Each subtypes of postoperative complication were not significantly different between groups. One patient in LG group died of intra-abdominal bleeding from splenic artery, and there was no significant difference in mortality between LG group and OG group (RD: 0.95%, 95%CI, -2.54%-5.20%). The distribution of severity was similar between the two groups. Conclusions: Experienced surgeons can safely perform LTG with lymphadenectomy for clinical stage I gastric cancer. Clinical trial information: NCT03007550.

Associations between ferritin and insulin sensitivity have been described in recent studies. The possible association showed conflicting results by sex and menopausal status. We aimed to investigate the cross-sectional association of ferritin levels with insulin resistance and β-cell function. A total of 2518 participants (1033 men, 235 pre-menopausal women and 1250 post-menopausal women) were enrolled from the Changfeng Study. A standard interview was conducted, as well as anthropometric measurements and laboratory analyses, for each participant. The serum ferritin level was measured using electrochemiluminescence immunoassay. Insulin resistance and β-cell function indices were derived from a homeostasis model assessment. The results showed that the serum ferritin levels were 250·4 (sd 165·2), 94·6 (sd 82·0) and 179·8 (sd 126·6) ng/ml in the men, pre-menopausal and post-menopausal women, respectively. In fully adjusted models (adjusting for age, current smoking, BMI, waist:hip ratio, systolic blood pressure, diastolic blood pressure, TAG, HDL-cholesterol, LDL-cholesterol, log urine albumin:creatinine ratio, leucocytes, alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase), serum ferritin concentrations are significantly associated with insulin resistance in men and post-menopausal females, and the null association was observed in pre-menopausal females. Interestingly, an increased β-cell function associated with higher ferritin was observed in post-menopausal participants, but not in male participants. In conclusion, these results suggested that elevated serum ferritin levels were associated with surrogate measures of insulin resistance among the middle-aged and elderly male and post-menopausal women, but not in pre-menopausal women.

AIMS To examine the associations between BMI and the risks of all-cause, cardiovascular disease (CVD)-specific and cancer-specific mortality among people with Type 2 diabetes, and thus provide recommendations for weight management in the population. METHODS This retrospective cohort study was conducted among 52 763 people with newly diagnosed Type 2 diabetes between 1 January 2004 and 31 December 2014 in Shanghai, China. All cases of death were identified by linking to the Shanghai Vital Statistics. Some 52 488 people were included in the analysis. Survival curves for people with different BMI categories were plotted using the Kaplan-Meier method. Cox proportional hazard models within or without restricted cubic spline functions were applied to examine the potential non-linear or linear relationship between BMI and the risk of mortalities respectively. RESULTS A total of 4777 deaths were identified during an average of 6-year follow-up. An L-shaped association was observed between BMI and all-cause mortality in men (P for overall association < 0.001 and P for non-linearity < 0.001) while a U-shaped association was found in women (P for overall association < 0.001 and P for non-linearity< 0.001). In men, no significant association was observed for BMI with cancer-specific and CVD-specific mortality. In women, an increased risk of cancer-specific mortality was observed with increasing BMI, whereas decreasing BMI was associated with the increased CVD-specific mortality rate. CONCLUSION The increased all-cause mortality in men with low BMI and in women with either low or high BMI indicate the importance of keeping BMI in a normal range for Chinese adults with Type 2 diabetes.

Background: Elevated pretreatment lactate dehydrogenase (LDH) has been reported to be associated with poor survival in small cell lung cancer (SCLC). The present study aimed to investigate the continuous relationship between baseline LDH level and survival in patients with extensive-disease SCLC (ED-SCLC). Methods: Data were retrospectively collected from Shanghai Health Information Network. Patients primarily diagnosed as ED-SCLC from April 2011 to August 2014 were eligible for our study. Patients’ survival status was checked in March 2016. A multivariate Cox proportional hazard model was used to detect the association between baseline serum LDH and overall survival. The corresponding continuous relationship was analyzed by using natural spline functions in the Cox model. Results: A total of 132 eligible ED-SCLC patients were analyzed. Elevated LDH at baseline was associated with poor survival (HR =1.92; 95% CI, 1.29–2.86). An increment of LDH would still raise the risk of death even in abnormal range. Among patients with elevated LDH, those who had relatively higher LDH levels (>370 U/L) would have a poorer prognosis than those with moderately elevated LDH levels (245–370 U/L; median survival time, 114 vs . 274 days; P value of log rank test, 0.007). Conclusions: LDH is a significant prognostic biomarker for ED-SCLC patients. The interpretation of continuous relationship between LDH and patients’ survival can provide more accurate information for clinical practice.

Purpose : This meta-analysis aimed to systematically evaluate the efficacy of tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) for patients with brain metastases (BM) from nonsmall- cell lung cancer (NSCLC), and to compare this treatment modality to chemotherapy or radiotherapy. Methods : PubMed, EMBASE (OvidSP), the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ASCO Annual Meeting Abstracts were searched. Controlled clinical studies that compared the efficacy of EGFR-TKIs with chemotherapy or radiotherapy for NSCLC patients with BM were included in the analysis. Efficacy indicators included overall survival (OS), local progression-free survival (LPFS) and objective response rate (ORR). Results: The final sample consisted of 24,637 NSCLC patients with BM from 11 clinical studies. In primary efficacy analysis, it was found that EGFR-TKIs were significantly superior to chemotherapy or radiotherapy in terms of ORR (odds ratio (OR) = 2.10, p = 0.035), OS (hazard ratio (HR) = 0.78, p = 0.011) and LPFS (HR = 0.60, p < 0.001). Conclusion : Among the patients with BM from NSCLC, EGFR-TKIs exhibit a therapeutic advantage over chemotherapy or radiotherapy, which is reflected in the elevation of ORR and improvement in OS and LPFS. Keywords: Brain metastasis, Non-small-cell lung cancer (NSCLC), Protein kinase Inhibitors, Epidermal growth factor, Meta-analysis

The prognostic relevance of commonly used composite inflammation-based scores remains severely underdiscussed in pancreatic cancer (PC), especially for advanced PC. In this retrospective cohort study, we aimed to discuss the association between multiple inflammatory scores and the short-term overall survival (OS) of advanced pancreatic ductal adenocarcinoma (PDAC) patients. A total of 66 histologically confirmed PDAC patients were retrospectively analyzed. A multivariate Cox proportional hazards model was used to explore the association between 6 commonly used inflammatory scores measured right after diagnosis, Glasgow Prognostic Score (GPS), Modified Glasgow Prognostic Score (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), prognostic nutritional index (PNI), and the short-term OS of advanced PDAC. Analytical results revealed that among GPS, mGPS, NLR, PLR, PI and PNI only PLR was significantly associated with short-term OS of PDAC. For both 1-year and 2-year OS, every 10 increase of PLR value resulted in 1.10 (95% CI: 1.04, 1.16) folds hazard ratio (HR). Further analysis identified a statistically significant dose–response relationship between PLR and HR. Our study results probably suggested that PLR is a promising prognostic factor of advanced PDAC; maintaining normally ranged platelet count may gain short-term survival benefit among such patients.

Postmenopausal women are at increased risk of CVD: the increased serum ferritin level may be involved in the pathogenesis. The aim of the present study is to investigate the relationship of ferritin and carotid atherosclerosis in postmenopausal women. A total of 1178 postmenopausal women (mean age, 60·8 years) were enrolled from the Changfeng Study. A standard interview, anthropometric measurements and laboratory analyses were performed for each participant. Bilateral CIMT (carotid intima–media thickness) were measured using ultrasonography, and the presence of carotid plaques was assessed. Serum ferritin was measured using electrochemiluminescence immunoassay. The results showed that serum ferritin was 181·9 (sd 65·8) ng/ml in the postmenopausal women. Multivariate, linear, stepwise regression analysis demonstrated that age (standardised β = 0·233, PPPP= 0·003), Hb (standardised β = 0·080, P= 0·004) and PPG (2-h glucose levels following a 75-g oral glucose challenge) (standardised β = 0·079, P= 0·004) were independently associated with serum ferritin. Compared with the ferritin level of subjects in the first quartile, that in the fourth quartile had greater CIMT, and higher prevalence of carotid plaque. After adjusting for conventional CVD risk factors, Hb, leucocytes, log urine albumin:creatinine ratio and liver function, the ferritin level of postmenopausal women in the fourth quartile had a 1·587-fold increased risk of carotid plaques relative to those in the lowest quartile. In conclusion, these results suggest that serum ferritin is independently and positively associated with carotid atherosclerosis in postmenopausal women and that ferritin may be implicated in atherosclerosis.

Objective The ultrasound quantitative method for liver fat content (LFC) is a recent established method for non-invasive assessment of liver steatosis. Its use in clinical practice is further explored by investigating the quantitative relationships between LFC measured by quantitative ultrasonography and metabolic diseases in a middle-aged and elderly Chinese population. Methods Liver fat content was measured by the quantitative ultrasound method in 4,916 participants from the Shanghai Changfeng Community Study. The anthropometric and serum biochemical parameters related to glucose and lipid metabolism were detected for each participant. The carotid artery intima-media thickness (CIMT) was measured by ultrasonography. Results The LFC displayed a non-Gaussian and positively skewed distribution in the community population and was significantly correlated with body weight, serum glucose, lipid profile, and CIMT. The 95th percentile of LFC in the subgroup of participants without any metabolic disease was 10.8%, and a LFC ≥ 10% was correlated with remarkable increases in the risks for glucose and lipid metabolic diseases. Conclusions The quantitative ultrasound method that was developed for measuring LFC was useful in a population study. A LFC ≥ 10% might help to identify the subjects with an increased risk for metabolic diseases.

The XELOX regimen (capecitabine plus oxaliplatin) has been demonstrated as first-line chemotherapy for gastric cancer in China. However, the efficacy of XELOX varies in individuals. Some evidences indicate that the variable efficacy might be related to the distinct immune status not only in the tumor site but also in the systemic immune system, and further investigation is required. In this study, we collected 32 PBMC samples from 16 XELOX-treated patients with gastric cancer and analyzed the patterns of immune cells. At the end point, the proportion of CD24(hi)CD27(+)CD19(+) B cells in patients without progression revealed a significant decrease compared with that in patients with progression, but not other immune cells, such as T cells and NK cells. Furthermore, CD19(+) B cells were more sensitive to capecitabine plus oxaliplatin stimulation in vitro than other immune cells, displaying higher frequency of apoptosis in a dose-dependent way. Thus, our results suggested that the outcomes of XELOX chemotherapy were inversely correlated with peripheral B cell subsets, which might provide a more convenient method to predict gastric cancer progression of XELOX-treated patients.

Some newly published studies revealed that current smoking was associated with accelerated disease progression in diagnosed rheumatoid arthritis (RA) patients. The major aims of this study were to analyze the associated factors of current smoking in RA patients and explore the mediating role of depression in the associations between identified factors and smoking. RA patients were selected from NHANES databases 2005-2012. Current smoking was determined by race-specific serum cotinine levels. Depression was measured by the Depression Screener questionnaire. Totally, 848 RA patients were identified and included into final analysis. Logistic regression model founds that age, race, and socioeconomic status (SES) were associated with current smoking in RA patients: the odds ratios (ORs) of smoking were 0.29 (95 % CI 0.17, 0.49) and 0.39 (95 % CI 0.24, 0.62) in patients over 60 years old and of higher SES, respectively; non-Hispanic white patients with a pre-RA smoking history had an OR of 3.48 (95 % CI 1.35, 5.18) when compared with patients of other race with no pre-RA smoking history. Structural equation model identified a weak mediating role of depression, only accounted for 5 % of the total SES-smoking association. In this sample of diagnosed RA patients, age, SES, ethnicity, but not depression, were significantly associated with current smoking.