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Background A pathologically confirmed negative margin is required when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma. However, the optimal margin distance to ensure complete tumor resection while preserving healthy lung tissue remains unknown. We aimed to establish a reliable distance range for negative margins. Methods A total of 52 intraoperative para-cancer tissue specimens from patients with peripheral lung adenocarcinoma with pathological tumors ≤2 cm in size were examined. Depending on the distance from the tumor edge (D), the para-cancer tissues were divided into the following five groups: D Results Group V, in which the margin was the farthest from the tumor edge, was the safest. There were significant safety differences in between groups I and V (χ2 = 26.217, P 2 = 9.420, P P = 0.207; P = 0.610). Conclusions We suggest that when performing sublobar resection in patients with early stage peripheral lung adenocarcinoma with pathological tumor sizes ≤2 cm, the resection margin distance should be ≥1 cm to ensure a negative margin.

BackgroundLong intergenic non-protein coding RNA 1140 (LINC01140), a long non-coding RNA, is highly expressed in various cancers; however, its biological functions in lung cancer (LC) progression and immune escape are still unclear.MethodsHere, to elucidate LINC01140 function, 79 paired LC and paracancerous tissues were collected. LINC01140 expression levels were determined using fluorescence in situ hybridization and qPCR analysis. Cell counting kit-8 (CCK-8) assay and transwell assays were performed. The interaction between microRNAs (miRNAs) and LINC01140 was confirmed using an RNA immunoprecipitation assay. Cytokine-induced killer (CIK) cell phenotypes were analyzed by flow cytometry. Cytokine secretion levels were determined by ELISA. CIK cytotoxicity was assessed by measuring lactate dehydrogenase release. Besides, xenograft tumor mouse models were used to unveil the in vivo function of LINC01140.ResultsWe found that LINC01140 was highly expressed in human LC tissues and cell lines. High LINC01140 levels were associated with poor survival in patients with LC. LINC01140 upregulation promoted the proliferation, migration, and invasion of LC cells through direct interaction with miR-33a-5p and miR-33b-5p, thereby contributing to c-Myc expression and also inhibited cisplatin-induced cell apoptosis. In subcutaneous tumor xenograft mice, LINC01140 knockdown markedly reduced tumor growth and lung metastasis. Additionally, LINC01140 directly repressed miR-377-3 p and miR-155-5 p expression levels, resulting in the upregulation of their common downstream target programmed death-ligand 1 (PD-L1), a crucial target in LC immunotherapy. Notably, we proved that LINC01140 knockdown, along with CIK administration, suppressed the growth of subcutaneous LC xenografts by decreasing PD-L1 expression in severe combined immunodeficient mice.ConclusionsTaken together, LINC01140 overexpression protects c-Myc and PD-L1 mRNA from miRNA-mediated inhibition and contributes to the proliferation, migration, invasion, and immune escape of LC cells. These results provide a theoretical basis that LINC01140 is a promising target for LC treatment.

Background: The aim of this study was to compare the effects of currently available preoperative localization methods, including semi-rigid single hook-wire, double-thorn hook-wire, and microcoil, in localizing the pulmonary nodules, thus to select the best technology to assist video-assisted thoracoscopic surgery (VATS) for small ground glass opacities (GGO). Methods: Preoperative CT-guided localizing techniques including semi-rigid single hook-wire, double-thorn hook-wire and microcoil were used in re-aerated fresh swine lung for location experiments. The advantages and drawbacks of the three positioning technologies were compared, and then the most optimal technique was used in patients with GGO. Technical success and post-operative complications were used as primary endpoints. Results: All three localizing techniques were successfully performed in the re-aerated fresh swine lung. The median tractive force of semi-rigid single hook wire, double-thorn hook wire and microcoil were 6.5, 4.85 and 0.2 N, which measured by a spring dynamometer. The wound sizes in the superficial pleura, caused by unplugging the needles, were 2 mm in double-thorn hook wire, 1 mm in semi-rigid single hook and 1 mm in microcoil, respectively. In patients with GGOs, the semi-rigid hook wires localizations were successfully performed, without any complication that need to be intervened. Dislodgement was reported in one patient before VATS. No major complications related to the preoperative hook wire localization and VATS were observed. Conclusions: We found from our localization experiments in the swine lung that, among the commonly used three localization methods, semi-rigid hook wire showed the best operability and practicability than double-thorn hook wire and microcoil. Preoperative localization of small pulmonary nodules with single semi-rigid hook wire system shows a high success rate, acceptable utility and especially low dislodgement in VATS.

Lung cancer with highest morbidity and mortality seriously threatens human health worldwide. Long noncoding RNAs (lncRNAs) exert important biological functions by acting as microRNA, which is implicated in tumorigenesis and cancer development. Previous work has reported that lncRNA-ATB expression was significantly upregulated in lung adenocarcinoma tissues and promoted tumor progression; however, the mechanisms of lncRNA-ATB in lung squamous carcinoma (LSC) are still fairly elusive. In our study, lncRNA-ATB expression also markedly increases in LSC tissues and cell lines in comparison to the adjacent normal tissues and normal lung epithelial cells, respectively. Functional experiments indicate that lncRNA-ATB overexpression improves the proliferative, migratory, and invasive capabilities of normal lung epithelial cells compared with control group. Furthermore, the migratory and invasive abilities are strikingly inhibited in lncRNA-ATB silenced LSC cells. Mechanistically, lncRNA-ATB directly binds to microRNA-590-5p and downregulates microRNA-590-5p level, leading to the upregulation of NF-90 expression. In addition, lncRNA-ATB overexpression promotes the epithelial-mesenchymal transition process, where lncRNA-ATB overexpression facilitates the expression of mesenchymal phenotype related molecules N-cadherin and vimentin, while restrains the expression of epithelial phenotype related proteins E-cadherin and CK-19, compared to the control. Conversely, microRNA-590-5p mimics can reverse the results caused by lncRNA-ATB overexpression. Taken together, our initial data suggest that lncRNA-ATB overexpression may promote the progression of LSC by modulating the microRNA-590-5p/NF-90 axis.

Paraneoplastic autoimmune disorders (PAD) represent a group of autoimmune diseases associated with neoplasms. As a consequence of a remote autoimmunity-mediated effect, PAD are found in multiple organs or tissues, including the skin, blood and nervous system. Compared with non-paraneoplastic autoimmune diseases, PAD have different aetiologies, pathologies, disease symptoms and treatment responses. There are two main origins of autoimmunity in PAD: neoplasm-mediated dysregulated homeostasis in immune cells/organs and in autoantigens. Pathologically, PAD are mediated predominantly by either autoantibodies or autoreactive T-cells. In the past decade, significant progress has been achieved in increasing our understanding of the aetiology and pathology of PAD. In this review article, we aim to provide a comprehensive overview of the recent advances in this field.

// Jie Jiang 1 , Guojun Geng 1 , Xiuyi Yu 1 , Hongming Liu 1 , Jing Gao 1 , Hanxiang An 2 , Chengfu Cai 1 , Ning Li 1 , Dongyan Shen 3 , Xiaoqiang Wu 3 , Lisheng Zheng 4 , Yanjun Mi 1, 2 , Shuyu Yang 5 1 Department of Thoracic Surgery, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China 2 Department of Medical Oncology, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China 3 Biobank, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China 4 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China 5 Xiamen Diabetes Institution, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China Correspondence to: Shuyu Yang, email: yangshuyu2016@126.com Yanjun Mi, email: Myjgj_77@163.com Keywords: dihydroartemisinin, non-small-cell lung cancer, Warburg effect, metastasis, NF-κB Received: April 06, 2016 Accepted: November 02, 2016 Published: November 24, 2016 ABSTRACT Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment.

Brucea javanica oil (BJO), a traditional herbal medicine extracted from the seeds of B. javanica, has been clinically used to treat non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) in combination with chemotherapy or radiotherapy in China. However, how BJO exerts this antitumor effect is still largely unknown. Here, effects of BJO on the growth of NSCLC and SCLC cell lines were investigated by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenytetrazolium Bromide (MTT) assay, and the results showed that BJO inhibited the proliferation of A549 cells (NSCLC) and H446 cells (SCLC). Further studies revealed that BJO induced G0/G1 arrest partly via regulating p53 and cyclin D1 in these two cell lines. BJO also has pro-apoptotic effect on H446 and A549 cells through mitochondria/caspase-mediated pathway, which was initiated by the accumulation of intracellular reactive oxygen species (ROS). These findings thus revealed the molecular mechanisms underlying the antitumor effect of BJO on SCLC and NSCLC, which may benefit the further clinical application of BJO.

SRC-3 is widely expressed in multiple tumor types and involved in cancer cell proliferation and apoptosis. Histone deacetylase (HDAC) inhibitors are promising antitumor drugs. However, the poor efficacy of HDAC inhibitors in solid tumors has restricted its further clinical application. Here, we reported the novel finding that depletion of SRC-3 enhanced sensitivity of breast and lung cancer cells to HDAC inhibitors (SAHA and romidepsin). In contrast, overexpression of SRC-3 decreased SAHA-induced cancer cell apoptosis. Furthermore, we found that SRC-3 inhibitor bufalin increased cancer cell apoptosis induced by HDAC inhibitors. The combination of bufalin and SAHA was particular efficient in attenuating AKT activation and reducing Bcl-2 levels. Taken together, these accumulating data might guide development of new breast and lung cancer therapies.

3142 Background: Previous studies proved that mutation of POLD1 and POLE elevates base-substitution mutations and lead to the elevation of tumor mutation burden (TMB). Other signature needs to explore to identify driver mutations in these two genes. Methods: Using gene-panel target-capture next generation sequencing, we analyzed the TMB and POLD1/POLE mutation in 17383 tumor tissue or plasma ctDNA samples from different patients. Results: Tumor mutation burdens were calculated of all the 17383 samples. According to the present research and our panel, we use 10 and 100 Mut/Mb to define hypermutation and ultra-hypermutation. Samples with hypermutation possessed 18.8% (n = 3268) and ultra-hypermutation possessed 0.3% (n = 58). In unselected, hypermutation and ultra-hypermutation group, POLD1 or/and POLE mutations were identified in 3.5% (n = 625), 56.1% (n = 32) and 87.9%(n = 372) samples. There were 0.5% (n = 81), 17.0% (n = 73) and 87.7%(n = 51) identified more than one mutation. These results showed that POLD1 or/and POLE mutations were enriched in samples with high TMB. We screened every known POLE and POLD1 driver mutations. There were 22 ultra-hypermutation samples identified these mutations, including A456P(3), P286R(10), V411L(6), M444K(1), S459F(1) in POLE and R1016H(1) in POLD1. Interestingly, all of them were identified in microsatellite stable (MSS) samples, which suggest that driver mutation may enriched in MSS samples. These already known driver mutation was not detect in 24 high-level microsatellite instability (MSI-H) and ultra-hypermutation samples. We further analyzed 10 POLD1/POLE mutations in other 5 MSS and ultra-hypermutation samples. POLE L424V was a pathogenic germline mutation but not defined as a driver mutation clearly before. POLE P286C had not been biochemically characterized but had different residue with P286R in the same position. Others had not been biochemically characterized (R232H, A234T, V945M, S1064I, Y467H in POLD1, D462N and R749Q, E1956D in POLE). These mutations were potential driver mutations and further research need to be support. Conclusions: We found that not only POLD1 or/and POLE mutations were enriched in samples with high TMB, but also driver mutations were enriched in microsatellite stable tumors. Further researches need to continue to identify more driver mutations of POLD1 and POLE.

Description To The basic operation procedure of esophageal cancer radical surgery. Disclosure All authors have declared no conflicts of interest.

Background To study the advantages and disadvantages of 3D and 2D thoracoscope in the thoracic surgery of esophageal carcinoma. Methods Retrospectively analyze esophageal cancer cases between July 2013 and July 2017 of the first affiliated hospital to Xiamen University, depending on the different mode of Video-Assisted Thoracoscopic, which can be divided into 3D-VATS group 353 cases (observation group) and 2D-VATS group 351 cases (control group). Comparing the difference in operation time, intraoperative bleeding, lymph node transmission, volume of the drain by the first 24 hours, total volume of the drain, chest tube time and postoperative complications. Results All the 704 patients with esophageal cancer were performed under the video-assisted thoracoscope. In terms of surgery time, 3D-VATS group (51.4 ± 13.3min) was shorter than 2D-VATS group (65.7 ± 9.1min), with statistical significance (t = -9.751, P = 0.013); on blood loss, 3D-VATS group (34.1 ± 10.5ml) was less than 2D-VATS group (50.2 ± 9.4ml) with statistical significance (t = -9.274, P = 0.009); about lymph nodes transmission, 3D-VATS group (16.8 ± 3.2) was more than 2D-VATS group (13.1 ± 3.7), with statistical significance (t = 5.213, P = 0.007); in volume of the drain by the first 24 hours, 3D-VATS group (171.2.15 ± 20.2ml) was less slightly than 2D-VATS group (180.3 ± 35.2ml), no statistical difference (t = -1.347, P = 0.281); about total volume of the drain, 3D-VATS group (530.2 ± 53.4ml) was less slightly than 2D-VATS group (553.8 ± 57.5ml), no statistical difference (t = -1.911, P = 0.093); on chest tube time, 3D-VATS group (4.2 ± 0.7d) was less slightly than 2D-VATS group (4.9 ± 1.1d), no statistical difference (t = -1.806, P = 0.069); Postoperative complications in two groups including the incidence of arrhythmia, pulmonary infection, anastomotic leakage and recurrent laryngeal nerve injury has no obvious difference (P > 0.05). Conclusion Video-assisted thoracoscopic surgery of esophagectomy under 3D-mode has certain advantages in operation time, intraoperative bleeding and lymph nodes transmission over 2D-mode. While in the item of volume of the drain by 24 hours, total volume of the drain, chest tube time and postoperative complications, they have no obvious difference. Disclosure All authors have declared no conflicts of interest.

Background To explore the thoroughness and safety of a modified left recurrent laryngeal lymph nodes dissection in thoracoscopic esophageal carcinoma surgery. Methods Retrospectively analyzed the clinical data of 136 patients with the left recurrent laryngeal lymph nodes dissection from October 2015 to October 2017 in the First Hospital Affiliated to Xiamen University. 67 cases were divided to the traditional dissection group (double lumen endotracheal intubation, 90 ° lateral position) and 69 cases were classified to the modified dissection group (single cavity tracheal intubation, thoracic CO2 positive pressure ventilation, lateral prone position and esophageal suspension technology). Observed and compared the left laryngeal recurrent nerve lymph nodes cleaning and time, intraoperative complications including thoracic duct injury, tracheal injury, hoarseness and pneumonia. Results The cleaning time of the modified dissection group (23 + 8 min) was significantly less than that of the traditional cleaning group (32 plus or minus 5min) (P 0.05). Moreover, there was no significant difference in lymph nodes metastasis and complications incidence rate (P > 0.05). Conclusion The modified dissection method, including single cavity tracheal intubation, thoracic CO2 positive pressure ventilation, lateral prone position and using esophageal suspension technology, can achieve good operation field exposure, the left recurrent laryngeal lymph nodes ‘the whole block’ cleaning, and the greatest degree protection of laryngeal recurrent nerve, thoracic duct, trachea and other organs damage. It is worthy of clinical popularization and application. Disclosure All authors have declared no conflicts of interest.

Description To show the main operation procedure of the abdominal part of the radical operation of esophageal carcinoma. Disclosure All authors have declared no conflicts of interest.

Description The main steps of radical resection of esophageal carcinoma under 3D thoracoscope. Disclosure All authors have declared no conflicts of interest.

Background To investigate the feasibility and efficacy of cervical esophageal carcinoma operation through thoracoscope, laparoscopy combined with total laryngectomy. Methods Retrospect and analyze the data of 53 patients with cervical esophageal carcinoma undergone surgical treatment in Department of Thoracic Surgery, First Hospital Affiliated to Xiamen University from May.2010 to May.2017. Operation procedure: separate esophagus under thoracoscope, rebuild gastric tube, resect full throat, perform tracheostoma permanently, apply gastric-pharyngeal anastomosis. Results Thoracic operation time was 50 ∼ 65 min, average 57 min; abdominal operation time was 46 ∼ 62 min, average 54 min; neck surgery time was 117 ∼ 137 min, average 125 min. The amount of intraoperative bleeding was 78∼ 260 ml, average 180 ml. The postoperative hospital stay was 7 ∼ 15d, average 10d. All the cases were squamous cell carcinoma, 6 cases of high differentiated squamous cell carcinoma, 31 cases of squamous cell carcinoma, 10 cases of middle-low differentiated squamous cell carcinoma, 6 cases of low differentiated squamous cell carcinoma. All the resection edges had been proved no residual tumor left by pathological examination. In 53 cases, lymph node metastasis occurred in 48 cases, anastomotic fistula occurred in 1 cases, 2 cases of pulmonary infection, 1 cases of gastric emptying and 1 case anastomotic stenosis happed, and there is no death case. All the patients were followed up from 1 months to 5 years, the 1st, 3rd, 5th year survival rate was 83.8%, 51.2% and 23.1% respectively. Conclusion Cervical esophageal carcinoma operation treatment should be taken actively, Gastric pharyngeal anastomosis is an effective mean to treat cervical esophageal carcinoma. Disclosure All authors have declared no conflicts of interest.

Human esophageal cancer is a common occurring malignancy with high mortality rate partially due to lack of tools for early diagnosis. In this study, we have analysed tumour tissue from 50 cases of primary esophageal cancer. Our studies showed that the activity of monoamine oxidase (MAO) and the expression of MAO-A were strikingly decreased in the tumour tissues of 48 (96%) and 44 (88%) patients, respectively. These results suggest that the activity of MAO and the expression of MAO-A may be used as new diagnostic markers for esophageal cancers.

Despite recent advances in the therapy of non-small cell lung cancer (NSCLC), the chemotherapy efficacy against NSCLC is still unsatisfactory. Previous studies show the herbal antimalarial drug dihydroartemisinin (DHA) displays cytotoxic to multiple human tumors. Here, we showed that DHA decreased cell viability and colony formation, induced apoptosis in A549 and PC-9 cells. Additionally, we first revealed DHA inhibited glucose uptake in NSCLC cells. Moreover, glycolytic metabolism was attenuated by DHA, including inhibition of ATP and lactate production. Consequently, we demonstrated that the phosphorylated forms of both S6 ribosomal protein and mechanistic target of rapamycin (mTOR), and GLUT1 levels were abrogated by DHA treatment in NSCLC cells. Furthermore, the upregulation of mTOR activation by high expressed Rheb increased the level of glycolytic metabolism and cell viability inhibited by DHA. These results suggested that DHA-suppressed glycolytic metabolism might be associated with mTOR activation and GLUT1 expression. Besides, we showed GLUT1 overexpression significantly attenuated DHA-triggered NSCLC cells apoptosis. Notably, DHA synergized with 2-Deoxy-D-glucose (2DG, a glycolysis inhibitor) to reduce cell viability and increase cell apoptosis in A549 and PC-9 cells. However, the combination of the two compounds displayed minimal toxicity to WI-38 cells, a normal lung fibroblast cell line. More importantly, 2DG synergistically potentiated DHA-induced activation of caspase-9, -8 and -3, as well as the levels of both cytochrome c and AIF of cytoplasm. However, 2DG failed to increase the reactive oxygen species (ROS) levels elicited by DHA. Overall, the data shown above indicated DHA plus 2DG induced apoptosis was involved in both extrinsic and intrinsic apoptosis pathways in NSCLC cells.

Matrine, as a member of Sophora family, is an alkaloid found in plants, and produces plethora pharmacological effects, including anti-cancer effects. However, the mechanism involved remains largely unknown. This study is conducted to investigate the anti-cancer mechanisms of matrine in human esophageal cancer in vitro and in vivo. In human esophageal cancer cell Eca-109, matrine significantly decreased the cell viability in a dose-dependent manner, and induced apoptosis as well as cell cycle arrest in G0/G1 phase by up-regulation of P53 and P21. The expression of several apoptosis-related proteins in cells and tumor tissues were evaluated by Western blot analysis. We found that matrine induced cell apoptosis by down-regulation of the ratio of BCL-2/BID and increasing activation of caspase-9. Further studies indicated that matrine induced apoptosis of Eca-109 was through the mitochondria-mediated internal pathway, but not by death receptor-mediated extrinsic apoptotic pathway, which was confirmed by the fact that Bid translocated from the nucleus to mitochondria during the process of the apoptosis induced by matrine. In vivo study found that matrine effectively inhibited the tumor formation of Eca-109 cells in nude mice. Our study suggests that matrine could serve as a potential novel agent from natural products to treat esophageal cancer.