Xiaobin Zheng

PD-L1 expression as poor prognostic factor in patients with non-squamous non-small cell lung cancer

Objectives The role of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), especially according to histologic type, remains controversial. The purpose of this study was to assess PD-L1 expression and its association with overall survival (OS) and clinicopathologic characteristics in NSCLC. Materials and methods Formalin-fixed paraffin-embedded specimens were obtained from 108 patients with surgically resected primary NSCLC. PD-L1 expression was assessed via immunohistochemistry using a histochemistry score system. The relationship between OS or clinicopathologic characteristics and PD-L1 expression was evaluated via the Kaplan-Meier method and Cox proportional hazards model, respectively. Results Of 108 NSCLC specimens, 44 had high PD-L1 expression, which was highly associated with histologic type (p = 0.003). Patients without PD-L1 expression had remarkably longer OS than those with PD-L1 expression (median OS: 96 months vs. 33 months, p < 0.001). In the subgroup analysis of non-squamous cell carcinoma, OS was more favorable in those without PD-L1 expression than in those with PD-L1 expression (median OS: 113 months vs. 37 months, p < 0.001). Multivariate analysis revealed that PD-L1 expression (95% confidence interval 1.459-4.520, p < 0.001), male sex and higher tumor-node-metastasis stage were significantly correlated with shorter OS. Conclusions This study demonstrated that PD-L1 expression is an independent prognostic factor for poor survival in NSCLC patients, especially those with non-squamous NSCLC.OBJECTIVES The role of programmed cell death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), especially according to histologic type, remains controversial. The purpose of this study was to assess PD-L1 expression and its association with overall survival (OS) and clinicopathologic characteristics in NSCLC. MATERIAL AND METHODS Formalin-fixed paraffin-embedded specimens were obtained from 108 patients with surgically resected primary NSCLC. PD-L1 expression was assessed via immunohistochemistry using a histochemistry score system. The relationship between OS or clinicopathologic characteristics and PD-L1 expression was evaluated via the Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS Of 108 NSCLC specimens, 44 had high PD-L1 expression, which was highly associated with histologic type (p = 0.003). Patients without PD-L1 expression had remarkably longer OS than those with PD-L1 expression (median OS: 96 months vs. 33 months, p < 0.001). In the subgroup analysis of non-squamous cell carcinoma, OS was more favorable in those without PD-L1 expression than in those with PD-L1 expression (median OS: 113 months vs. 37 months, p < 0.001). Multivariate analysis revealed that PD-L1 expression (95% confidence interval 1.459-4.520, p < 0.001), male sex and higher tumor-node-metastasis stage were significantly correlated with shorter OS. CONCLUSIONS This study demonstrated that PD-L1 expression is an independent prognostic factor for poor survival in NSCLC patients, especially those with non-squamous NSCLC.

Survival improvement in patients with non–small cell lung cancer between 1983 and 2012: Analysis of the Surveillance, Epidemiology, and End Results database:

Non–small cell lung cancer is the most common malignancy in males; it constitutes the majority of lung cancer cases and requires massive medical resources. Despite improvements in managing non–small cell lung cancer, long-term survival remains very low. This study evaluated survival improvement in patients with non–small cell lung cancer in each decade between 1983 and 2012 to determine the impact of race, sex, age, and socioeconomic status on the survival rates in these patients. We extracted data on non–small cell lung cancer cases in each decade between 1983 and 2012 from the Surveillance, Epidemiology, and End Results registries. In total, 573,987 patients with non–small cell lung cancer were identified in 18 Surveillance, Epidemiology, and End Results registry regions during this period. The 12-month relative survival rates improved slightly across three decades, from 39.7% to 40.9% to 45.5%, with larger improvement in the last two decades. However, the 5-year-relative survival rates were very low, with 14.3%, 15.5%, and 18.4%, respectively, in three decades, indicating the urgency for novel comprehensive cancer care. In addition, our data demonstrated superiority in survival time among non–small cell lung cancer patients of lower socioeconomic status and White race. Although survival rates of non–small cell lung cancer patients have improved across the three decades, the 5-year-relative survival rates remain very poor. In addition, widening survival disparities among the race, the sex, and various socioeconomic status groups were confirmed. This study will help in predicting future tendencies of incidence and survival of non–small cell lung cancer, will contribute to better clinical trials by balancing survival disparities, and will eventually improve the clinical management of non–small cell lung cancer.

Survival changes in patients with small cell lung cancer and disparities between different sexes, socioeconomic statuses and ages

Small cell lung cancer (SCLC), as a proportion, makes up only 15–17% of lung cancer cases. The development of treatments for SCLC has remained stagnant for decades, and SCLC is expected to persist as a threat to human health. To date, no publications based on large populations have been reported. We calculated survival changes in patients with SCLC during each decade between 1983 and 2012 to determine the roles of race, sex, age, and socioeconomic status (SES) on survival rates based on the Surveillance, Epidemiology, and End Results (SEER) registries. In total, 106,296 patients with SCLC were identified, with the overall incidence per 100,000 decreasing each decade from 9.6 to 7.8 to 5.8. The median survival for SCLC remained 7 months, and the 12-month relative survival rates (RSRs) remained relatively stable at 32.9%, 33.2% and 33.2% during each decade. The 5-year RSRs significantly improved from 4.9% to 5.9% to 6.4% during each decade, but remained extremely low. In addition, a narrowing of the survival gaps among SES groups and stable survival gaps between sexes were observed. Although the incidence of SCLC decreased during each decade, the overall survival remained relatively stable, highlighting the urgency of developing novel treatments and the importance of prevention and early detection.

Chemotherapy plus dendritic cells co-cultured with cytokine-induced killer cells versus chemotherapy alone to treat advanced non-small-cell lung cancer: A meta-analysis

This study was aimed to investigate the efficacy and safety of the combination treatment of dendritic cells co-cultured with cytokine-induced killer cells and chemotherapy for patients with advanced non-small-cell lung cancer (NSCLC). Literatures were searched from the Cochrane Library Central, PubMed, Web of Science and EMBASE. The primary endpoint of interest was overall survival (OS), and secondary endpoints were disease control rate (DCR) and progression free survival (PFS). Finally 7 trials published between January 2005 and March 2016 met inclusion criteria and totally 610 patients were enrolled. The combination group showed advance in DCR (RR = 1.31, 95% CI = 1.13-1.52, p = 0.0004), 1-year OS (RR = 1.18, 95% CI = 1.05-1.33, p = 0.007), and 2-year OS (RR = 1.37, 95% CI = 1.10-1.70, p = 0.005), with statistical significance. The proportions of CD3+ T cells (p = 0.002), NK cells (p = 0.02) and NKT cells (p = 0.001) were significantly higher in the peripheral blood of combination group, compared with those of the control group. Moreover, adverse reactions were obviously decreased in the combination group. However, no significant difference was identified in ORR and PFS between two groups (p > 0.05). In conclusion, the combination therapy was safe and applicable for patients with advanced NSCLC.

Male gender is associated with an increased risk of anastomotic leak in rectal cancer patients after total mesorectal excision

Abstract Background The impact of a patient’s gender on the development of anastomotic leak (AL) in rectal cancer patients following total mesorectal excision (TME) remains controversial. The aim of this study was to evaluate the association between patients’ gender and the risk of AL. Methods All rectal cancer patients following TME with a primary anastomosis during the study period from 2010 to 2014 were examined. Comparisons of the post-operative AL incidence rate between male and female patients were performed. Results Of all patients examined (n = 956), 587 (61.4%) were males and 369 (38.6%) were females. Male patients were more likely to have a history of smoking and drinking alcohol, but less likely to have a history of abdominal surgery compared to female patients. A higher incidence rate of pre-operative bowel obstruction and larger tumor volume in male patients was observed in our study. Of all the patients, 81 (8.5%) developed post-operative AL. More male patients (n = 62, 10.6%) suffered from AL than females (n = 19, 5.1%) (P = 0.003). Multivariate logistic regression analyses confirmed the association between male gender and AL [odds ratio (OR): 2.41, 95% confidence interval (CI): 1.37–4.23, P = 0.002]. Similar results were also obtained in patients who underwent laparoscopic TME (OR: 2.11, 95% CI: 1.15–3.89, P = 0.016). Conclusions Male patents were found to have an increased risk for AL following TME with a primary anastomosis. A temporary protecting stoma may help to protect the anastomosis and lessen the risk for AL especially in male patients.

Enteral nutrition is associated with a decreased risk of surgical intervention in Crohn's disease patients with spontaneous intra-abdominal abscess

BACKGROUND The impact of enteral nutrition (EN) on surgical risk in Crohns disease (CD) patients suffering from spontaneous intra-abdominal abscess (IAA) was evaluated. METHODS CD patients diagnosed with spontaneous IAA from 2008 to 2015 were included in the study. The impact of EN on surgical risk was evaluated using both univariate and multivariate analyses. RESULTS A total of 87 patients were enrolled, 66 (75.9%) were male. The mean age at the development of an abscess was 30.2 ± 10.1 years and the median duration of illness from CD diagnosis until the development of an abscess was three (2-6) years. After a median follow-up of 1.9 (1.1-2.9) years, surgical intervention was performed in 42 patients (48.3%). Patients treated with EN were less likely to require surgical intervention (26.1% vs 56.3%, p = 0.01). Multivariate analysis showed that EN was an independent protective factor for the risk of surgery with a hazard ratio of 0.27 (95% confidence interval: 0.11-0.65, p = 0.004) after adjusting for abdominal pain, history of abdominal surgery, concomitant intestinal stenosis and prior use of antibiotics within three months. CONCLUSIONS Surgical intervention is common for CD patients with IAA. Appropriate application of EN may help obviate the need for surgical treatment.

Preoperative hypoalbuminemia is associated with an increased risk for intra-abdominal septic complications after primary anastomosis for Crohn’s disease

Abstract Objective The aim of this study was to evaluate the impact of preoperative hypoalbuminemia on the development of intra-abdominal septic complications (IASCs) after primary anastomosis for patients with Crohn’s disease (CD). Methods All CD patients undergoing bowel resection with a primary anastomosis during the study period from 2007 to 2015 were enrolled. The association of preoperative hypoalbuminemia (<30 g/L) with the risk for IASCs were assessed using both univariate and multivariate analyses. Results A total of 124 eligible patients were included, 117 (94.4%) of whom had available preoperative albumin level. Preoperative hypoalbuminemia occurred in 13 (11.7%) patients. The duration from diagnosis to surgery was longer for patients with preoperative hypoalbuminemia than those without (p = 0.012). Patients with preoperative hypoalbuminemia were more likely to have a history of preoperative use of 5-aminosalicylic acid (p = 0.013) and have an intraoperative finding of small bowel obstruction (p = 0.015). Of all patients, 24 (19.4%) developed postoperative IASCs. Univariate analysis showed that patients with preoperative hypoalbuminemia had an increased risk for IASCs (p = 0.012). Multivariate analysis confirmed the association between preoperative hypoalbuminemia and IASCs (odds ratio 4.67, 95% confidence interval: 1.28–17.04, p = 0.02). Similar findings were also obtained when preoperative albumin level was analysed as a continuous variable (p = 0.019). Conclusions Preoperative hypoalbuminemia is a significant predictor for the development of postoperative IASCs in CD patients after bowel resection with a primary anastomosis. Favorable preoperative nutrition status might lessen the risk for IASCs.

Engulfment and Cell Motility Protein 1 Protects Against DSS-induced Colonic Injury in Mice via Rac1 Activation

Background and Aims Mucosal healing is an emerging therapeutic goal that could result in clinical remission of inflammatory bowel disease [IBD]. We sought to determine the role of engulfment and cell motility protein 1 [ELMO1] in wound healing in vitro and in vivo and to investigate the underlying pathways. Methods RNA transcriptome sequencing was performed to detect the expression profiles of mRNA between inflamed tissues and corresponding non-inflamed tissues of IBD patients, followed by Gene Expression Omnibus [GEO] datasets and western blot analysis. The effects of ELMO1 overexpression or knockdown on cell migration and proliferation were determined. The dependence of these effects on Rac1 was assessed using a Rac1 inhibitor [NSC23766] and a Rac1 pull-down assay. We identified the underlying pathways involved by Gene Ontology [GO] analysis. A dextran sulphate sodium [DSS]-induced colitis model was established to evaluate the role of ELMO1 in colonic mucosal healing. Results ELMO1 was upregulated in inflamed tissues compared with corresponding non-inflamed tissues. ELMO1 overexpression increased cell migration in a Rac1-dependent manner. Depletion of ELMO1, or NSC23766 administration, abolished this effect. GO analysis revealed that ELMO1 overexpression preferentially affected pathways involved in cytoskeletal regulation and wound healing, which was demonstrated by enhanced F-actin staining and increased numbers of extending lamellipodia in cells overexpressing ELMO1. In DSS-induced colitis, systemic delivery of pSin-EF2-ELMO1-Pur attenuated colonic inflammation and promoted recovery from colonic injury. The protective effect of ELMO1 was dependent on Rac1 activation. Conclusions ELMO1 protects against DSS-induced colonic injury in mice through its effect on epithelial migration via Rac1 activation.

Conversion is a risk factor for postoperative anastomotic leak in rectal cancer patients - A retrospective cohort study

AIM The impact of conversion from laparoscopic surgery to laparotomy on the development of anastomotic leak (AL) in rectal cancer patients following laparoscopic low anterior resection (LAR) with total mesorectal excision (TME) has not been evaluated. The aim of this study was to evaluate the impact of conversion on the risk of AL and develop a prediction nomogram for postoperative AL. METHODS All rectal cancer patients following laparoscopic LAR with TME from January 2010 to October 2014 were enrolled in the primary cohort. Comparisons of the postoperative anastomotic leak incidence rate between converted patients and non-converted patients were performed using both univariate and multivariate logistic regression analyses. The result of multivariable analysis was used to develop the predicting model and the performance of nomogram was assessed with respect to its calibration, discrimination, and clinical usefulness. An independent validation cohort containing 200 patients from November 2014 to October 2015 was assessed. RESULTS Of all patients enrolled (n=646), 592 (91.6%) patients underwent totally laparoscopic surgery, and 54 (8.4%) were converted from laparoscopic surgery to laparotomy. Converted group patients were more likely to have a higher body mass index (BMI), prolonged length of stay (LOS), increased overall postoperative complication rates and advanced clinical T stage (T3 or T4), pathological N stage (N1 or N2) and pathological TNM stage (III or IV). The percentage of patients who had preoperative radiotherapy for rectal cancer was higher in non-converted patients. Patients who underwent conversion to laparotomy (n=10, 18.5%) were more likely to suffer from postoperative AL than those undergoing totally laparoscopic surgery (n=38, 6.4%) (P=0.004). Multivariate logistic regression analyses confirmed the association between conversion and postoperative AL (Odds ratio [OR], 95% confidence interval [CI]: 2.71 [1.31-5.63], P=0.007). Conversion, gender, and clinical N stage incorporated in the individualized prediction nomogram showed good discrimination, with a C-index of 0.697 (C-index, 0.621 and 0.772 through internal validation), and good calibration. In the validation cohort, the main results were consistent with the findings of the primary cohort, with a C-index of 0.670 (C-index, 0.562 and 0.777 through internal validation). Decision curve analysis demonstrated that the prediction nomogram was clinically useful. CONCLUSION Conversion during laparoscopic LAR was found to be associated with an increased risk for the postoperative AL in RC patients. A nomogram model incorporating conversion, gender and patients clinical N stage seems to offers a useful tool for predicting postoperative AL in these patients.

Bone marrow-derived CXCR4-overexpressing MSCs display increased homing to intestine and ameliorate colitis-associated tumorigenesis in mice

Abstract Background and Objective Increasing interest has developed in the therapeutic potential of bone marrow-derived mesenchymal stem cells (MSCs) for the treatment of inflammatory bowel disease (IBD) and IBD-induced cancer. However, whether MSCs have the ability to suppress or promote tumor development remains controversial. The stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis is well known to play a critical role in the homing of MSCs. In this study, we aimed to evaluate the role of CXCR4-overexpressing MSCs on the tumorigenesis of IBD. Methods MSCs were transduced with lentiviral vector carrying either CXCR4 or green fluorescent protein (GFP). Chemotaxis and invasion assays were used to detect CXCR4 expression. A mouse model of colitis-associated tumorigenesis was established using azoxymethane and dextran sulfate sodium (DSS). The mice were divided into three groups and then injected with phosphate buffer saline (PBS), MSC-GFP or MSC-CXCR4. Results Compared with the mice injected with MSC-GFP, the mice injected with MSC-CXCR4 showed relieved weight loss, longer colons, lower tumor numbers and decreased tumor load; expression of pro-inflammatory cytokines decreased, and signal transducer and activator of transcription 3 (STAT3) phosphorylation level in colon tissue was down-regulated. Conclusion CXCR4-overexpressing MSCs exhibited effective anti-tumor function, which may be associated with enhanced homing to inflamed intestinal tissues.