Jinlin Cao

Clinical Nomogram for Predicting Survival of Esophageal Cancer Patients after Esophagectomy.

The aim of this study was to construct an effective clinical nomogram for predicting the survival of esophageal cancer patients after esophagectomy. We identified esophageal cancer patients (n = 4,281) who underwent esophagectomy between 1988 and 2007 from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Clinically significant parameters for survival were used to construct a nomogram based on Cox regression analyses. The model was validated using bootstrap resampling and a Chinese cohort (n = 145). A total of 4,109 patients from the SEER database were included for analysis. The multivariate analyses showed that the factors of age, race, histology, tumor site, tumor size, grade and depth of invasion, and the numbers of metastases and retrieved nodes were independent prognostic factors. All of these factors were selected into the nomogram. The nomogram showed a clear prognostic superiority over the seventh AJCC-TNM classification (C-index: SEER cohort, 0.716 vs 0.693, respectively; P < 0.01; Chinese cohort, 0.699 vs 0.680, respectively; P < 0.01). Calibration of the nomogram predicted the probabilities of 3- and 5-year survival, which corresponded closely with the actual survival rates. This novel prognostic model may improve clinicians’ abilities to predict individualized survival and to make treatment recommendations.

Association between the TERT Genetic Polymorphism rs2853676 and Cancer Risk: Meta-Analysis of 76 108 Cases and 134 215 Controls

Background Several recent studies have identified that the TERT genetic polymorphism rs2853676 is associated with cancer risk, but presented inconsistent results. We investigated these inconclusive results by performing a meta-analysis to systematically evaluate the association. Methods We conducted a search in PubMed, Google Scholar and ISI Web of Science to select studies on the association between TERT rs2853676 and cancer risk. We conducted a stratified analysis using cancer type, ethnicity and source of controls. We calculated the odds ratios (OR) and 95% confidence intervals (CI). Article quality, heterogeneity, sensitivity, publication bias and statistical power were also assessed. Results 26 articles covering 76 108 cases and 134 215 controls met our inclusion criteria. A significant association between TERT rs2853676 allele A and cancer susceptibility was demonstrated under a per-allele risk analysis (OR = 1.08, 95% CI = 1.04-1.13). Stratification analysis revealed an increased cancer risk in subgroups of glioma, lung cancer and ovarian cancer. No significant increase was found in melanoma, breast cancer, pancreatic cancer and colorectal cancer. In a subgroup analysis of lung cancer, a statistically significant increase was only observed in adenocarcinoma. Moreover, a stratified analysis performed for ethnic groups revealed that the significant increase was only observed in Caucasians, whereas a non-significant increase was found in Asians. Conclusions This meta-analysis suggests that the TERT genetic polymorphism rs2853676 is associated with increased risk of glioma, lung adenocarcinoma and ovarian cancer among Caucasians. Further functional studies are warranted to validate this association and investigate further.

Clinical Characteristics and Prognostic Significance of TERT Promoter Mutations in Cancer: A Cohort Study and a Meta-Analysis

Background The prevalence of telomerase reverse transcriptase (TERT) promoter mutations (pTERTm) in non-small-cell lung cancer (NSCLC) have been investigated, but the results were inconsistent. In addition, several studies have analysed the role of pTERTm in the etiology of various types of cancers, however, the results also remain inconsistent. Methods The genomic DNA sequence of 103 NSCLC samples were analysed to investigate the frequency of pTERTm in these patients and to establish whether these mutations are associated with their clinical data. Furthermore, a meta-analysis based on previously published articles and our cohort study was performed to investigate the association of pTERTm with patient gender, age at diagnosis, metastasis status, tumour stage and cancer prognosis (5-year overall survival rate). Results In the cohort study, 4 patients had C228T and 2 had C250T, with a total mutation frequency up to 5.8%. Significant difference of clinical data between pTERTm carriers and noncarriers was only found in age at diagnosis. In the meta-analysis, We found that pTERTm carriers in cancer patients are older than noncarriers (Mean difference (MD) = 5.24; 95% confidence interval [CI], 2.00 to 8.48), male patients were more likely to harbour pTERTm (odds Ratios (OR) = 1.38; 95% CI, 1.22 to 1.58), and that pTERTm had a significant association with distant metastasis (OR = 3.78; 95% CI, 2.45 to 5.82), a higher tumour grade in patients with glioma (WHO grade III, IV vs. I, II: OR, 2.41; 95% CI, 1.88 to 3.08) and a higher tumour stage in other types of cancer (III, IV vs. I, II: OR, 2.48; 95% CI, 1.48 to 4.15). pTERTm was also significantly associated with a greater risk of death (hazard ratio = 1.71; 95% CI, 1.41 to 2.08). Conclusions pTERTm are a moderately prevalent genetic event in NSCLC. The current meta-analysis indicates that pTERTm is associated with patient age, gender and distant metastasis. It may serves as an adverse prognostic factor in individuals with cancers.

Wnt3a Expression Is Associated with Epithelial-Mesenchymal Transition and Impacts Prognosis of Lung Adenocarcinoma Patients

Background: Epithelial-mesenchymal transition (EMT) plays an important role in the invasion and migration during cancer metastasis. Wnt3a is one of the ligands in canonical Wnt/β-catenin signaling pathway, which contributes to the carcinogenesis and progression of lung cancer cell lines. The aim of this study was to evaluate the association between Wnt3a and EMT-related proteins (E-cadherin and N-cadherin), and to further investigate its impact on prognosis of lung adenocarcinoma patients. Methods: A total of 147 lung adenocarcinoma patients were included and their clinicopathological characteristics were collected in this retrospective study. The expression levels of Wnt3a, E-cadherin and N-cadherin in post-surgery cancerous and adjacent normal tissues were assessed by immunohistochemistry. The association between Wnt3a and EMT-related proteins and their prognostic values were systematically evaluated. HCC827 and PC9 cell lines were treated with Wnt3a to detect the expression of EMT-related and Wnt/β-catenin signaling-associated proteins, as well as the in vitro migration and invasion abilities. Results: High Wnt3a expression level was significantly associated with low E-cadherin (P<0.001) and high N-cadherin (P<0.001) expression levels in lung adenocarcinoma tissues. Besides, high Wnt3a level predicted poorer lung adenocarcinoma survival by univariate Cox analysis (P=0.001), while the multivariate result was not significant (P=0.355). Subgroup analysis suggested that the prognostic value of Wnt3a expression level was significant in stage T1-T2 (log rank P=0.003) and stage N0 (log rank P=0.031) patients. The multivariate Cox analysis suggested N-cadherin was an independent prognostic factor for lung adenocarcinoma patients (P=0.012). After including these markers into a nomogram, the Harrells C-index of the nomogram was 0.755. The decision-curve analysis of our nomogram performed net benefit at the threshold probability from 21.6% to 82.0%, and the current model had a better prognostic value than TNM-classification with a lower Akaike information criterion (AIC) value of 166.54. In vitro experiments suggested that Wnt3a could regulate EMT-related proteins and promotes in vitro invasion and migration abilities. Conclusions: Wnt3a could regulate EMT-related proteins and promote the migration and invasion process of lung adenocarcinoma. Although its value as an independent prognostic factor was limited, the combined model suggested good prognostic performance for lung adenocarcinoma patients.

Prognostic Impact of Lymphadenectomy on Outcomes of Sublobar Resection for Stage IA Non-Small Cell Lung Cancer ≤ 2 cm

Objective To investigate the prognostic impact of lymph node (LN) dissection on sublobar resection for stage IA non–small cell lung cancer (NSCLC) tumors ≤2 cm. Methods All patients who underwent sublobar resection for stage IA NSCLC tumors ≤2 cm were identified from the Surveillance, Epidemiology and End Results database. Patients were classified into no‐LN dissection and LN dissection groups, and the latter was subclassified by the extent of LN dissection (1‐3 regional LNs or ≥4 regional LNs). These groups were compared in terms of lung cancer–specific survival (LCSS) and overall survival (OS) rates. Propensity score–matched comparative analysis and a Cox regression model were used. Results A total of 3269 patients met our criteria, including 1459 (44.6%) who underwent no LN dissection, 891 (27.3%) who underwent dissection of 1 to 3 regional LNs, 919 (28.1%) who underwent dissection of ≥4 regional LNs. Compared with no LN dissection, LN dissection was associated with more favorable LCSS and OS rates in patients who underwent sublobar resection for stage IA tumors ≤2 cm. More extensive regional LN dissection (≥4 regional LNs) was associated with better LCSS and OS rates compared with less extensive regional LN dissection (1 to 3 regional LNs). A multivariable analysis of our patient population revealed independent associations of no LN dissection and less extensive regional LN dissection with poorer LCSS and OS rates compared with overall LN dissection and more extensive regional LN dissection, respectively. Conclusions This propensity score–matched analysis reveals an association of LN dissection, particularly more extensive regional LN dissection (≥4 regional LNs), with better survival rates in patients who undergo sublobar resection for stage IA NSCLC tumors ≤2 cm.

Survival Rates After Lobectomy, Segmentectomy, and Wedge Resection for Non-Small Cell Lung Cancer

BACKGROUND This study aimed to compare the survival rates after lobectomy, segmentectomy, and wedge resection for the eighth edition of the tumor, node, metastasis classification for stage IA non-small cell lung cancer (NSCLC). METHODS Patients who underwent lobectomy, segmentectomy, or wedge resection for stage IA NSCLC were identified from the Surveillance, Epidemiology, and End Results database. A Cox regression model and propensity-matched analysis were used. The overall survival (OS) rates and lung cancer-specific survival (LCSS) rates among the three groups were compared by tumor size. RESULTS A total of 16,819 patients met our criteria. Although the OS rate was better for lobectomy than for wedge resection, no statistical differences in the LCSS rate were identified among the three treatment groups of patients with tumors that were 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy showed no statistical differences in the LCSS rate, but both conferred better OS and LCSS rates than wedge resection. For tumors from 2.1 to 3.0 cm, the OS and LCSS rates were better for lobectomy than for segmentectomy or wedge resection, but similar for segmentectomy and wedge resection. CONCLUSIONS Lobectomy, segmentectomy, and wedge resection are comparable oncologic procedures for patients with stage IA NSCLC that is 1.0 cm or smaller. For tumors from 1.1 to 2.0 cm, lobectomy and segmentectomy could lead to equivalent survival rates but showed better survival rates than that observed with wedge resection. For tumors from 2.1 to 3.0 cm, lobectomy is still the standard surgical procedure; for patients who are unsuitable candidates for lobectomy, segmentectomy and wedge resection show similar survival rates.

Clinical, cellular, and bioinformatic analyses reveal involvement of WRAP53 overexpression in carcinogenesis of lung adenocarcinoma

Lung cancer, of which non-small cell lung cancer accounts for 80%, remains a leading cause of cancer-related mortality and morbidity worldwide. Our study revealed that the expression of WD repeat containing antisense to P53 (WRAP53) is higher in lung-adenocarcinoma specimens than in specimens from adjacent non-tumor tissues. The prevalence of WRAP53 overexpression was significantly higher in patients with tumor larger than 3.0 cm than in patients with tumor smaller than 3.0 cm. The depletion of WRAP53 inhibits the proliferation of lung-adenocarcinoma A549 and SPC-A-1 cells via G1/S cell-cycle arrest. Several proteins interacting with WRAP53 were identified through co-immunoprecipitation and liquid chromatography/mass spectrometry. These key proteins indicated previously undiscovered functions of WRAP53. These observations strongly suggested that WRAP53 should be considered a promising target in the prevention or treatment of lung adenocarcinoma.

The role of epithelial-mesenchymal transition in the post-lung transplantation bronchiolitis obliterans

BackgroundMany patients who receive lung transplantation (LT) operations develop varying degrees of bronchiolitis obliterans (BO) after the surgeries. Epithelial-mesenchymal transition (EMT) is considered to be related to the process of bronchiolitis obliterans. In this study we simulated the pathological process of post-lung transplantation bronchiolitis obliterans, and explored the correlation between BO and EMT of small airway epithelial cells.MethodsWe transplanted the left lungs of F344 rats to Lewis rats by the Tri-cuff anastomosis and established the allogeneic rat left lung orthotopic transplantation model. Cyclosporine and lipopolysaccharide were administrated appropriately after the surgery. The histological structure and the expression levels of the EMT markers was observed with the methods of HE staining, Masson staining and immunohistochemistry. The analysis of enumeration data was performed using Fisher’s Exact test and Spearman’s rank correlation was used for the correlation analysis.ResultsInflammatory cell infiltration, fibroplasia of bronchiole walls and significant lumen stenosis were found in the pulmonary mesenchyme of the transplanted lungs. The positive expression rate of E-cadherin in the transplanted lungs was 38.50% (5/13), significantly lower than that in the normal lung tissues [87.50% (7/8)] (P < 0.05), while the positive expression rate of Vimentin was 76.92% (10/13) which is significantly higher than that in the normal lung tissues [25.00% (2/8)] (P < 0.05). And a negative correlation existed between the expression levels of E-cadherin and Vimentin (r = −0.750, P < 0.01).ConclusionsIn the disease model we established in this study, we found pathological changes that met BO characteristics happened in the transplanted lungs. Meanwhile, the small airway epithelial cells of transplanted lungs underwent an epithelial-mesenchymal transition, which indicated a role of EMT in the BO airway remodeling.

Combination therapy of apatinib with icotinib for primary acquired icotinib resistance in patients with advanced pulmonary adenocarcinoma with EGFR mutation: Apatinib with icotinib combination

Multi‐targeted agents represent the next generation of targeted therapies for solid tumors, and patients with acquired resistance to EGFR‐tyrosine kinase inhibitors (TKIs) may also benefit from their combination with TKI therapy. Third‐generation targeted drugs, such as osimertinib, are very expensive, thus a more economical solution is required. The aim of this study was to explore the use of apatinib combined with icotinib therapy for primary acquired resistance to icotinib in three patients with advanced pulmonary adenocarcinoma with EGFR mutations. We achieved favorable oncologic outcomes in all three patients, with progression‐free survival of four to six months. Unfortunately, the patients ultimately had to cease combination therapy because of intolerable adverse effects of hand and foot syndrome and oral ulcers. Combination therapy of apatinib with icotinib for primary acquired resistance to icotinib may be an option for patients with advanced pulmonary adenocarcinoma with EGFR mutations, but physicians must also be aware of the side effects caused by such therapy.

Semi-quantitative Analysis of EBUS Elastography as a Feasible Approach in Diagnosing Mediastinal and Hilar Lymph Nodes of Lung Cancer Patients

This study aimed to semi-quantitatively evaluate the elastographic imaging color distribution of mediastinal and hilar lymph nodes (LNs), and explored its utility in helping define malignant and benign LNs for lung cancer patients. We prospectively collected patients who underwent preoperative mediastinal staging of suspected lung cancer by EBUS-TBNA. We analyzed the elastography color distribution of each LN and calculated the blue color proportion (BCP). The LN elastographic patterns were compared with the final EBUS-TBNA pathological results. A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of BCP. We sampled and analyzed 79 LNs from 60 patients. The average BCP in malignant LNs was remarkably higher than that in benign LNs (57.1% versus 30.8%, P < 0.001). The area under the ROC curve (AUC) for the BCP was 0.86 (95% CI: 0.78–0.94). The best cutoff BCP for differentiating between benign and malignant LNs was determined as 36.7%. All the 16 LNs (20.3%) with a BCP lower than 27.9% were diagnosed as benign tissues. Our study suggests that elastography is a feasible technique that may safely help to predict LN metastasis during EBUS-TBNA. We found a clear BCP cutoff value to help define positive and negative LNs.