Controversial role of γδ T cells in colorectal cancer.

Colorectal cancer (CRC) is the third most frequent type of cancer, and the second leading cause of cancer-related deaths worldwide. Current treatments for patients with CRC do not substantially improve the survival and quality of life of patients with advanced CRC, thus necessitating the development of new treatment strategies. The emergence of immunotherapy has revitalized the field, showing great potential in advanced CRC treatment. Owing to the ability of tumor cells to evade the immune system through major histocompatibility complex shedding and heterogeneous and low antigen spreading, only a few patients respond to immunotherapy. γδ T cells have heterogeneous structures and functions, and their key roles in immune regulation, tumor immunosurveillance, and specific primary immune responses have increasingly been recognized. γδ T cells recognize and kill CRC cells efficiently, thus inhibiting tumor progress through various mechanisms. However, γδ T cells can potentially promote tumor development and metastasis. Thus, given this dual role in prognosis, these cells can act as either a "friend" or "foe" of CRC. In this review, we explore the characteristics of γδ T cells and their functions in CRC, highlighting their application in immunotherapy.

Identification and validation of the model consisting of DDX49, EGFR, and T-stage as a possible risk factor for lymph node metastasis in patients with lung cancer.

INTRODUCTION: The lymph node metastasis stage of lung cancer is an important decisive factor in the need for postoperative adjuvant treatment and the difference between stage IIIa and stage IIIB that is the necessary information to distinguish whether surgery can be performed or not. The specificity of the clinical diagnosis of lung cancer with lymph node metastasis cannot meet the requirements of preoperative evaluation of surgical indications and prediction of surgical removal range in lung cancer. METHODS: This was an early experimental laboratory trial. The model identification data included the RNA sequence data of 10 patients from our clinical data and 188 patients with lung cancer from The Cancer Genome Atlas dataset. The model development and validation data consisted of RNA sequence data for 537 cases from the Gene Expression Omnibus dataset. We explore the predictive value of the model on two independent clinical data. RESULTS: A higher specificity of diagnostic model for patients with lung cancer with lymph node metastases consisted of DDX49, EGFR, and tumor stage (T-stage), which were the independent predictive factors. The area under the curve value, specificity, and sensitivity for predicting lymph node metastases were 0.835, 70.4%, and 78.9% at RNA expression level in the training group, and 0.681, 73.2%, and 75.7% at RNA expression level in the validation group as shown as in result part. To verify the predictive performance of the combined model for lymph node metastases, we downloaded the GSE30219 data set (n = 291) and the GSE31210 data set (n = 246) from the Gene Expression Omnibus (GEO) database as the training group and validation group, respectively. In addition, the model had a higher specificity for predicting lymph node metastases in independent tissue samples. CONCLUSIONS: Determination of DDX49, EGFR, and T-stage could form a novel prediction model to improve the diagnostic efficacy of lymph node metastasis in clinical application.

BDH1 promotes lung cancer cell proliferation and metastases by PARP1-mediated autophagy.

Lymph node metastases and distant metastases were the important limiting factor for therapy of unresectable locally advanced (IIIB stage) and oligotransduction (IVa stage) lung cancer. This study was undertaken to identify a novel predictive biomarker for predicting lymph node metastases of lung cancer. A total of 364 patients with lung cancer which comprised of 198 patients with transcriptome sequencing data, 110 cases with immunohistochemistry data and 66 patients with serum samples were included to identify and validate the candidate gene. Autophagy was measured by western blots, immunofluorescence and electron microscope. We found that 3-hydroxybutyrate dehydrogenase 1 (BDH1) was associated with proliferation and metastases of lung cancer. BDH1 expression in both tissue and serum samples was associated with lung cancer metastases. Mechanical studies revealed that the AMPK-mTOR signalling pathway mediated by PARP1 played an important role in BDH1-induced autophagy. Activation of mTOR pathway markedly increased the effect of BDH1 in cell proliferation and metastases. These results were verified by the knockdown of PARP1. Furthermore, in vivo administration of BDH1 effectively promoted tumour growth in H460 xenografts mice. Our finding not only suggested that BDH1 might be useful as a novel biomarker and therapeutic target for lung cancer metastases, but also imply that PARP1-mediated AMPK-mTOR signalling pathway might play a critical role in BDH1-induced autophagy and lung cancer proliferation and metastases.

Preoperative computed tomography diagnosis of non-recurrent laryngeal nerve in patients with esophageal carcinoma.

BACKGROUND: The non-recurrent laryngeal nerve (NRLN) is a rare but potentially serious anomaly that is commonly associated with the aberrant right subclavian artery (ARSA). It is easy to damage during surgical resection of esophageal cancer, leading to severe complications. METHODS: Preoperative enhanced thoracic computed tomography (CT) scans of 2697 patients with esophageal carcinoma treated in our hospital between January 2010 and December 2013 were examined. We classified the positional relationship between the right subclavian artery and the membranous wall of the trachea into two types and used this method to predicate NRLN by identifying ARSA. RESULTS: Twenty-six patients (0.96%) were identified with ARSA, all of which were cases of NRLN by CT. NRLN was identified during surgery in the 26 patients, and a normal right recurrent laryngeal nerve was observed in 2671 patients. The ARSA was detected on the dorsal side of the membranous wall of the trachea in all 26 NRLN cases, while it was detected on the ventral side in all 2671 recurrent laryngeal nerve cases. CONCLUSION: Enhanced CT scanning is a reliable method for predicting NRLN by identifying ARSA. Preoperative recognition of this nerve anomaly allows surgeons to avoid damaging the nerve and abnormal vessels during esophagectomy.

[MiRNA224 Regulation Role on RKIP Gene Expression and Methylation of miRNA224 Gene Promoter Region in Esophageal Squamous Cell Carcinoma].

OBJECTIVES: To study the expression levels of tumor suppressor gene RIKP and miRNA224 in esophageal squamous cell carcinoma (ESCC) tissues. To determine whether miRNA224 targets RKIP and the methylation status of miRNA224 gene promoter region in esophageal carcinoma. METHODS: The expression levels of RKIP and miRNA224 in ESCC and normal tissue were detected by using immunohistochemistry and real-time qPCR, respectively. Luciferase assay was used to determine the targeting of miRNA224 to RKIP. The methylation status of miRNA224 promoter region was studied by bisulfite sequencing PCR (BSP). RESULTS: In 40 cases of ESCC, RKIP expression was significantly lower than that of normal tissue; miRNA224 expression was higher in ESCC than in paracancerous tissue. Luciferase assay showed that miRNA224 targets RKIP 3'UTR thus inhibit its expression. The miRNA224 gene promoter region was hypomethylated in ESCC. CONCLUSIONS: Compared with normal tissue, in ESCC, RKIP was downregulated, while miRNA224 was upregulated, and the promoter region of miRNA224 gene was hypomethylated. RKIP is the target of miRNA224, which may be closely related to esophageal squamous cell carcinoma.

Effects of neutrophil elastase inhibitor in patients undergoing esophagectomy: a systematic review and meta-analysis.

AIM: To evaluate the benefit and safety of sivelestat (a neutrophil elastase inhibitor) administration in patients undergoing esophagectomy. METHODS: Online databases including PubMed, EMBASE, the Cochrane Library, Web of Knowledge, and Chinese databases (Wanfang database, VIP and CNKI) were searched systematically up to November 2013. Randomized controlled trials and high-quality comparative studies were considered eligible for inclusion. Three reviewers evaluated the methodological quality of the included studies, and Stata 12.0 software was used to analyze the extracted data. The risk ratio (RR) was used to express the effect size of dichotomous outcomes, and mean difference (MD) or standardized mean difference was used to express the effect size of continuous outcomes. RESULTS: Thirteen studies were included in this systematic review and nine studies were included in the meta-analysis. The duration of mechanical ventilation was significantly decreased in the sivelestat group on postoperative day 5 [I (2) = 76.3%, SMD = -1.41, 95%CI: -2.63-(-0.19)]. Sivelestat greatly lowered the incidence of acute lung injury in patients after surgery (I (2) = 0%, RR = 0.27, 95%CI: 0.08-0.93). However, it did not decrease the incidence of pneumonia, intensive care unit stay or postoperative hospital stay, and did not increase the incidence of complications such as anastomotic leakage, recurrent nerve palsy, wound infection, sepsis and catheter-related fever. CONCLUSION: A neutrophil elastase inhibitor is beneficial in patients undergoing esophagectomy. More high quality, large sample, multi-center and randomized controlled trials are needed to validate this effect.

Successful removal of a giant pulmonary hamartoma coexisting with an anomalous common pulmonary venous trunk.

We present an extremely rare case of a giant pulmonary hamartoma (PH) coexisting with an anomalous common pulmonary venous trunk (ACPVT). An asymptomatic 39-year-old man was referred for evaluation of a giant pulmonary lesion in his left thorax detected on chest X-ray during a routine medical examination. After clinical work-up, the patient underwent left exploratory thoracotomy. Since the extent of the tumor and coexistence of an ACPVT, a left pneumonectomy was performed. The specimen measured 28 cm × 18 cm × 17 cm and weighted for 2.1 kg. Histology revealed a blend of pieces of rounded cartilage separated by fibrous bands in which mature adipose tissue and cleft-like structures lined. The features were consistent with those of a chondromatous hamartoma. The patient made a satisfactory recovery and 10 months after the operation was asymptomatic.

Does tumour location influence postoperative long-term survival in patients with oesophageal squamous cell carcinoma?

OBJECTIVES: The seventh edition of the American Joint Committee on Cancer (AJCC) staging system introduced tumour location for the first time as an determinant of stage grouping in pathological T2N0M0 and T3N0M0 (pT2-3N0M0) oesophageal squamous cell carcinoma (OSCC). However, the new modification remains controversial. The objective of this study was to investigate the correlation between tumour location and postoperative long-term survival in patients with OSCC in China. METHODS: The clinicopathological data and over 10 years of follow-up results from a large cohort of 988 patients with OSCC undergoing radical-intent oesophagectomy from 1984 to 1995 without preoperative and postoperative chemoradiotherapy were reviewed, in which 632 patients were staged as pT2-3N0M0. Tumour location was redefined according to the seventh edition of the AJCC staging system. Survival was calculated by the Kaplan-Meier method; univariate log-rank and multivariate Cox proportional hazard models were used to further determine the impact of tumour location on long-term survival. RESULTS: Univariate analysis showed that OSCC tumour location was closely associated with long-term survival for the entire cohort of 988 patients (odds ratio [OR]: 0.82; 95% confidence interval [95% CI]: 0.67-0.99; P = 0.049), and for pT2-3N0M0 patients (OR: 0.63; 95% CI: 0.48-0.84; P = 0.001). The median survival times for patients with pT2-3N0M0 OSCC in the upper, middle and lower third of the oesophagus were 38.1, 46.6 and 66.0 months, respectively, with corresponding 5-year survival rates of 40.0, 51.8 and 66.2%, respectively. Overall survival rates among three categories of patients according to tumour location in the pT2-3N0M0 patients were statistically different (P = 0.004). Multivariate analysis demonstrated that tumour location was a significant independent predictor of long-term survival for pT2-3N0M0 patients (OR: 0.53; 95% CI: 0.42-0.67; P = 0.0001), but not for the entire cohort of 988 patients (OR: 0.99; 95% CI: 0.79-1.23; P = 0.90). CONCLUSIONS: Tumour location is an independent predictor of long-term survival for pathological T2-3N0M0 OSCC, and should be incorporated into the current staging system to predict long-term survival and identify high-risk postoperative patients.

A novel differential diagnostic model for multiple primary lung cancer: Differentially-expressed gene analysis of multiple primary lung cancer and intrapulmonary metastasis.

The incidence of synchronous multiple primary lung cancer (MPLC) is increasing. However, present diagnostic methods are unable to satisfy the individualized treatment requirements of patients with MPLC. The present study aimed to establish a quantitative mathematical model and analyze its diagnostic value for distinguishing between MPLC and cases of the histologically similar disease, intrapulmonary metastasis (IPM). The sum value of the differential expression ratios of four proteins, namely p53, p16, p27 and c-erbB2, was evaluated by immunohistochemically-staining specimens of primary cancers, second separate cancers, metastatic lymph nodes and metastatic cancers. The sum value of the differential expression ratio of the four proteins from the primary tumor and the lymph-node metastasis or metastatic cancer was <90 in the 11 patients with a single metastatic cancer and in the 30 patients with lymph-node metastasis, but was >90 in the 14 patients with different histological types of MPLC. Therefore, a quantitative differentially-expressed gene mathematical model was established as follows: Sum of the differential expression ratios = p16T1 - T + p27T1 - T2 + C-erbB2T1 - T2 + p53T1 - T2, where T1 is the primary cancer and T2 is the lymph node metastasis, metastatic cancer or the second separate cancer. The quantitative differentially-expressed gene mathematical model is considered to be a useful tool for distinguishing between MPLC and IPM.

Diagnosis and surgical treatment of esophageal carcinoma with coexistent intrathoracic vascular malformations.

BACKGROUND: The anomaly of intrathoracic large vessels might not only compress the esophagus resulting in dysphagia, but also hinder esophagectomy, even leading to uncontrolled massive hemorrhaging. This paper reviews our experience of seven patients with this diagnosis and their treatment. METHODS: From January 2007 through January 2012, among patients admitted with esophageal carcinoma, there were seven patients confirmed to have coexisted intrathoracic vascular anomalies. They were six men and one woman, aged 52 to 63 (mean 58.42). The vascular anomalies included aberrant right subclavian artery (ARSA) in three cases, post-aortic left innominate vein (PALIV) in two cases, and one case each of right aortic arch (RAA) and pseudoaneurysm of aortic isthmus (PAAI). Their diagnosis, surgical strategy, and outcome were reviewed. RESULTS: The vascular anomalies were missed by esophagography and endoscopy, but all identified by enhanced chest computed tomography (CT). Surgery was planned according to the anatomic features of the anomalies. ARSA did not need special management. RAA underwent left thoracotomy in order to dissect the aortopulmonary arterial ligament and to facilitate the mobilization of the esophagus. PAAI had preoperative aortic stenting to prevent unexpected aortic rupture. Prophylactic ligation of thoracic duct was performed on all patients and no postoperative chylothorax was documented. CONCLUSIONS: The coexistence of intrathoracic vascular malformations with esophageal carcinoma is rare, but easily missed in routine X-ray and endoscopy. Enhanced chest CT must be performed to confirm. Surgery should be designed individually in consideration of the anatomic features of the vascular anomalies. A routine prophylactic ligation of the thoracic duct is recommended.

[Meta-analysis on reconstructions of posterior mediastinal route and anterior mediastinal route after esophagectomy].

OBJECTIVE: To evaluate the efficacy and safety of posterior mediastinal route (PR) as compared with anterior mediastinal route (AR) after esophagectomy. METHODS: A systematic literature retrieval was carried out to obtain studies of randomized controlled trials (RCT) comparing PR with AR after esophagectomy before June 2012. Study selection, data collections and methodological quality assessments of retrieved studies were independently performed by two individual reviewers and meta-analysis was conducted using the RevMan 5.0 software. RESULTS: Six RCTs involving 376 patients (PR:197 cases, AR:179 cases) met the selection criteria. Meta-analysis showed that operative mortality (RR=0.49, 95%CI:0.18-1.36), anastomotic leaks (RR=0.95, 95%CI:0.44-2.07), cardiac morbidity (RR=0.51, 95%CI:0.25-1.04), pulmonary morbidity (RR=0.69, 95%CI:0.41-1.15), anastomotic strictures (RR=0.88, 95%CI:0.62-1.25), dysphagia (RR=1.26, 95%CI:0.75-2.11), 6-month body weight after esophagectomy were not significantly different between these two routes of reconstruction (all P>0.05). CONCLUSION: AR should be the choice of reconstruction in view of its potential advantages in the prevention of tumor recurrence within the gastric conduit and avoidance of conduit irradiation when undergoing postoperative radiotherapy. However, further studies are needed to confirm the difference of long-term efficacy between the two routes.

[Long-term survival of personalized surgical treatment of locally advanced non-small cell lung cancer based on molecular staging].

BACKGROUND AND OBJECTIVE: Approximately 35%-40% of patients with newly diagnosed non-small cell Lung cancer have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy. The aim of this study is to explore and summarize the probability of detection of micrometastasis in peripheral blood for molecular staging, and for selection of indication of surgical treatment, and beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in locally advanced lung cancer; to summarize the long-time survival result of personalized surgical treatment of 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. METHODS: CK19 mRNA expression of peripheral blood samples was detected in 516 lung cancer patients by RT-PCR before operation for molecular diagnosis of micrometastasis, personalized molecular staging, and for selection of indication of surgical treatment and the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in patients with locally advanced nonsmall cell lung cancer invaded heart, great vessels or both. The long-term survival result of personalized surgical treatment was retrospectively analyzed in 516 patients with locally advanced non-small cell lung cancer based on molecular staging methods. RESULTS: There were 322 patients with squamous cell carcinoma and 194 cases with adenocarcinoma in the series of 516 patients with locally advanced lung cancer involved heart, great vessels or both. There were 112 patients with IIIA disease and 404 cases with IIIB disease according to P-TNM staging. There were 97 patients with M-IIIA disease, 278 cases with M-IIIB disease and 141 cases with III disease according to our personalized molecular staging. Of the 516 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 256 cases; lobectomy combined with resection and reconstruction of partial left atrium was performed in 41 cases; Double sleeve lobectomy combined with resection and reconstruction of super vena cava was carried out in 90 cases; Lobectomy combined with resection and reconstruction of diaphragm was performed in 3 cases; Double sleeve lobectomy combined with resection and reconstruction of partial left atrium was performed in 30 cases; Bronchoplastic procedures and pulmonary artery reconstruction combined with reconstruction of aorta sheath was carried out in 10 cases; Right pneumonectomy combined with resection and reconstruction partial left atrium, total right diaphragm with Dacron, and post cava and right liver vein was performed in one case; Lobectomy combined with resection and reconstruction of carina was carried out in 10 cases; Bronchoplastic procedures and pulmonary artery reconstruction combined with resection and reconstruction of carina and superior vane cava, or combined with superior vena cava and left atrium, or with carina and left atrium was performed in 55 cases in this series. Five patients died of operative complications and the operative mortality was 0.97%. CK19 mRNA expression was found in 141 patients. The positive rate of CK19 mRNA expression was 27.3% in peripheral blood samples in the 516 cases. The positive rates of micrometastasis in peripheral blood was significantly related to histological classification, P-TNM staging and N staging of the cancer (P < 0.05), but not to age, sex, smoking status of the patients, and size of primary tumor, and locations of the tumor (P > 0.05). The median survival time was 43.74 months. The 1, 3, 5 and 10 year survival rates of the 516 cases was 89.1%, 39.3%, 19.8% and 10.4%, respectively. The postoperative survival rate was remarkably correlated with micrometastasis in peripheral blood, histological classification of the tumor, size of primary cancer and lymph mode involvement (P < 0.05). The results of multivariable Cox model analysis showed that "personalized molecular P-TNM staging", micrometastasis in peripheral blood, pathological types of the tumor and mediastinal lymph node metastasis of the cancer were the most significant factors for predicting prognosis in the patients with locally advanced nonsmall lung cancer. CONCLUSIONS: (1) Micrometastasis was existed in peripheral blood of patients with lung cancer, which can not be detected with conventional methods. (2) Detecting of CK19 mRNA expression in peripheral blood in lung cancer patients can be used for diagnosis of micrometastasis of lung cancer and "molecular staging" and "molecular P-TNM staging" for lung cancer patients. It will be helpful for selection of surgical treatment indication, the beneficiary of neoadjuvant chemotherapy and postoperative adjuvant therapy in the patients with locally advanced non-small cell lung cancer. (3) Personalized surgical treatment can significantly improve prognosis and increase curative rate and long-term survival rate of locally advanced nonsmall cell lung cancer based on personalized molecular staging.

[Detection of mRNA expression of CK-19 and MUC1 gene for diagnosis of lymph node micrometastasis in NSCLC patients by reverse transcriptase-polymerase chain reaction].

BACKGROUND: To investigate gene diagnosis of micrometastasis in lymph nodes in patients with non-small cell lung cancer (NSCLC) and the feasibility of mucin 1 (MUC1) mRNA and cytokeratin 19 (CK19) mRNA as molecular marker to detect micrometastasis of lung cancer. METHODS: Expression of MUC1 mRNA and CK19 mRNA was detected in 119 lymph nodes taken from 31 patients with NSCLC, 35 lymph nodes from 10 patients with pulmonary benign diseases as controls by nested reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In the 119 lymph nodes from lung cancer patients, CK19 mRNA expression was detected in 66 lymph nodes (55.5%) and MUC1 mRNA expression was detected in 65 lymph nodes (54.5%) by RT-PCR. Neither CK19 mRNA nor MUC1 mRNA expression was observed in all the 35 lymph nodes in the benign pulmonary lesion group. CONCLUSIONS: The results suggest that the detection of both MUC1 and CK19 mRNA might be helpful to diagnose NSCLC micrometastasis in lymph nodes. The establishment of this method may lead to an earlier diagnosis of metastasis for lung cancer.

[A study on the pericancerous tissue and vascular changes in non-small cell lung cancer with high-resolution CT].

BACKGROUND: To investigate the CT changes of pericancerous tissues with high-resolution CT (HRCT) and to explore the specific signs of CT in non-small cell lung cancer. METHODS: Thirty-one patients with non-small cell lung cancer and 12 patients with benign pulmonary nodules were analysed. An attention was paid on bronchovascular bundles, vessels and interlobular septa. HRCT films were read independently by two radiologists and results were statistically Chi-square tested. RESULTS: In the cancer group, 20 cases (64.5%) had thickening of bronchovascular bundles, 15 cases (48.4%) angiectasis of superior lobular arteries, 13 cases (41.9%) angiectasis of superior lobular veins, 16 cases (51.6%) thickening of interlobular septa, and 5 cases (16.1%) ground-glass opacity. In benign pulmonary lesion group, the values were 2 (16.7%) , 1 (8.3%), 2 (16.7%), 6 (50.0%) and 5 (41.7%) cases respectively. Significant differences were found between the two groups in the thickening of bronchovascular bundles and the angiectasis of superior lobular arteries. CONCLUSIONS: Thickening of bronchovascular bundles and angiectasis of superior lobular arteries are the specific signs of non-small cell lung cancer.