The protocol for the prehabilitation for thoracic surgery study: a randomized pragmatic trial comparing a short home-based multimodal program to aerobic training in patients undergoing video-assisted thoracoscopic surgery lobectomy.

BACKGROUND: Prehabilitation has been shown to have a positive effect on the postoperative recovery of functional capacity in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy. The optimal way to implement prehabilitation programs, such as the optimal forms of prehabilitation, duration, intensity, and methods to improve compliance, remained to be studied. This Prehabilitation for Thoracic Surgery Study will compare the effectiveness of multimodal and aerobic training-only programs in patients undergoing thoracoscopic lobectomy. METHODS: This randomized pragmatic trial will be conducted in Peking Union Medical College Hospital (PUMCH) and include 100 patients who are eligible to undergo VATS lobectomy. Patients will be randomized to a multimodal or aerobic training group. Prehabilitation training guidance will be provided by a multidisciplinary care team. The patients in the multimodal group will perform aerobic exercises, resistance exercises, breathing exercises, psychological improvement strategies, and nutritional supplementation. Meanwhile, the patients in the aerobic group will conduct only aerobic exercises. The interventions will be home-based and supervised by medical providers. The patients will be followed up until 30 days after surgery to investigate whether the multimodal prehabilitation program differs from the aerobic training program in terms of the magnitude of improvement in functional capability pre- to postoperatively. The primary outcome will be the perioperative 6-min walk distance (6MWD). The secondary outcomes will include the postoperative pulmonary functional recovery status, health-related quality of life score, incidence of postoperative complications, and clinical outcomes. DISCUSSION: Prehabilitation remains a relatively new approach that is not widely performed by thoracic surgery patients. The existing studies mainly focus on unimodal interventions. While multimodal prehabilitation strategies have been shown to be preferable to unimodal strategies in a few studies, the evidence remains scarce for thoracic surgery patients. The results of this study will contribute to the understanding of methods for thoracoscopic lobectomy patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04049942 . Registered on August 8, 2019.

Icotinib, an EGFR tyrosine kinase inhibitor, as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma: a multicenter, open-label, single-arm, phase II study (ICAPE).

The survival benefit of icotinib (an oral epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced lung cancer has been confirmed in several studies. This study (ICAPE) evaluated the efficacy of icotinib as adjuvant therapy for patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma. Patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma were enrolled in the multicenter, open-label, single-arm, phase II study. Eligible patients received oral icotinib 125 mg thrice daily for 1.5 years after complete surgical resection. The primary endpoint was disease-free survival (DFS). Between March 2014 and January 2018, 79 patients were enrolled. The median follow-up time was 39.7 months with a median DFS and overall survival (OS) of 41.4 months (95% CI: 33.6-51.8) and 67.0 months (95% CI: 21.2-not reached [NR]), respectively. The 1-year, 3-year, and 5-year OS rates were 100%, 83.3%, and 61.7%, respectively. No significant difference was found in the median DFS between patients with Bcl-2 interacting mediator of cell death (BIM) mutant-type and wild-type (NR vs. 41.7 months; p = 0.75). No significant difference was found in the median DFS according to EGFR mutation types. Icotinib as adjuvant therapy demonstrated a favorable survival benefit in patients with stage IIA-IIIA EGFR-mutant non-small-cell lung adenocarcinoma, indicating that icotinib might be a promising treatment option for this patient population. The optimal adjuvant duration of icotinib is still not clear and needs more incoming data to answer.

Ultrasensitive detection of circulating tumour DNA via deep methylation sequencing aided by machine learning.

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

Paclitaxel increases the sensitivity of lung cancer cells to lobaplatin via PI3K/Akt pathway.

[This retracts the article DOI: 10.3892/ol.2018.8086.].

Circ_0007142/miR-186/FOXK1 axis promoted lung adenocarcinoma progression.

Circular RNAs (circRNAs) are a class of non-coding RNAs could affect expression of specific genes which may induce tumor occurrence and progression. In this study, we identified 32 differentially expressed circRNAs between five pairs of lung adenocarcinoma and paracancerous tissues using circRNA microarray. And circ_0007142 expression was the most upregulated in five lung adenocarcinoma tissues. Meanwhile, circ_0007142 expression was remarkably over-expressed in lung adenocarcinoma tissues and cells. In addition, knockdown of circ_0007142 inhibited proliferation, migration, invasion and induced apoptosis of lung adenocarcinoma cells. Furthermore, knockdown of circ_0007142 inhibited the biological behavior of lung adenocarcinoma through miR-186/FOXK1 axis and inactivated the Wnt/ß-catenin signaling pathway. Altogether, our study suggests Circ_0007142/miR-186/FOXK1 axis may play as an important role in progression of lung adenocarcinoma, which provided a novel potential mechanism about this disease.

Circular RNA circMAGI3 accelerates the glycolysis of non-small cell lung cancer through miR-515-5p/HDGF.

The emerging roles of circular RNAs (circRNAs) in non-small cell lung cancer (NSCLC) have been convincingly proved. However, there are still numerous unknown circRNAs needing exploration. Here, present research performed a circRNA microarray analysis for the expression profile and identified a novel circRNA (circMAGI3, hsa_circ_0110498). Clinically, circMAGI3 was significantly up-regulated in NSCLC tissue and cells, which was closely correlated with unfavorable outcome for NSCLC patients. Functionally, circMAGI3 promoted the glycolysis and proliferation of NSCLC cells. Mechanistically, circMAGI3 functioned as a sponge for miR-515-5p to relieve its target gene HDGF expression, thereby accelerating the glycolysis of NSCLC. Collectively, this research identified the oncogenic role of circMAGI3 in the tumorigenesis through miR-515-5p/HDGF axis, providing a vital theoretical basis for treatment of NSCLC.

Mutational profiling of lung adenocarcinoma in China detected by next-generation sequencing.

PURPOSE: NSCLC is the most common type of lung cancers. The purpose of this study is to screen cancer-related mutations in early LUAD in China through NGS technology, determine their correlation with clinical characteristics and provide basis for treatment decisions. METHODS: In this study, we performed a 583 gene panel to detect the mutational spectrum of the tumors which were collected from 98 LUAD patients. The sequencing data and clinical characteristics were analyzed. RESULTS: Mutations were identified in 94.9% of patients. EGFR had the highest mutation frequency which was detected in 66% of the patients and was significantly associated with female gender and non-smoking history. Other genes with high mutation frequency were TP53 (37%), ERBB2 (24%), BCOR (22%), ZFHX3 (19%), BTG1 (17%), ATR (16%), WWTR1 (15%), etc. TP53 mutations were significantly associated with medium and low differentiation of tumors; BCOR and BLM mutations with gender; WWTR1 mutations with age; and ATR mutations with visceral pleura invasion were observed. 61% of the patients harbored at less one actionable alteration associated with FDA-recognized or investigational drugs. CONCLUSION: Multiple mutations in LUAD patients in this study have not previously been reported in NSCLC. Moreover, mutations in driver genes including EGFR, TP53, BCOR, BLM, WWTR1, and ATR were significantly related to clinical features. The panel used in this study is an effective approach for molecular analysis and can be applied in personalized treatment decision-making and drug development.

Hsa_circ_0018818 knockdown suppresses tumorigenesis in non-small cell lung cancer by sponging miR-767-3p.

To identify potential therapeutic targets in non-small cell lung cancer NSCLC, we conducted a bioinformatics analysis of circRNAs differentially expressed between NSCLC tissues and adjacent normal tissues. Cell proliferation and apoptosis was assessed using CCK-8 and flow cytometry, respectively. A connection between hsa_circ_0018818 and miR-767-3p was confirmed in dual luciferase reporter assays. Gene and protein expression in NSCLC cells were measured using quantitative PCR and Western-blotting, respectively. And a xenograft tumor model was established to assess the function of hsa_circ_0018818 in NSCLC in vivo. Hsa_circ_0018818 was greatly upregulated in NSCLC tumor tissues. Knocking down hsa_circ_0018818 using a targeted shRNA inhibited the proliferation and invasiveness of NSCLC cells and induced their apoptosis via the miR-767-3p/Nidogen 1 (NID1) signaling axis. Hsa_circ_0018818 knockdown also inactivated Epithelial-mesenchymal transition (EMT) process and PI3K/Akt signaling. In summary, hsa_circ_0018818 knockdown inhibited NSCLC tumorigenesis in vitro and in vivo, which suggests it could potentially serve as a target for the treatment of NSCLC.

Silencing of lncRNA XIST inhibits non-small cell lung cancer growth and promotes chemosensitivity to cisplatin.

Long noncoding RNAs (lncRNAs) play critical roles in tumour progression and metastasis. Emerging evidence indicates that the lncRNA X inactive-specific transcript (XIST) is dysregulated in several tumor types, including non-small cell lung cancer (NSCLC). However, in NSCLC and other cancers the oncogenic mechanism of XIST remains incompletely understood. Here, we confirmed that XIST is upregulated in human NSCLC specimens, and is especially overexpressed in tumors previously treated with cisplatin (cis-diamminedichloroplatinum(II); DDP). In vitro, XIST knockdown inhibited NSCLC cell growth and promoted DDP chemosensitivity by stimulating apoptosis and pyroptosis. Moreover, XIST's oncogenic effects and ability to promote DDP chemoresistance were largely related to its binding to the TGF-ß effector SMAD2, which inhibited its translocation to the nucleus and prevented the transcription of p53 and NLRP3, crucial regulators of apoptosis and pyroptosis, respectively. Using DDP-resistant NSCLC cells, mouse xenograft studies verified the oncogenic function of XIST and its ability to inhibit programmed cell death, thereby mediating DDP chemoresistance. These findings suggest that XIST expression may serve as a novel biomarker to predict DDP treatment efficacy, and may help in the design of new therapies to circumvent DDP chemoresistance in NSCLC and other tumor types.

Two-Week Multimodal Prehabilitation Program Improves Perioperative Functional Capability in Patients Undergoing Thoracoscopic Lobectomy for Lung Cancer: A Randomized Controlled Trial.

BACKGROUND: Patients with lung cancer often experience reduced functional capacity and quality of life after surgery. The current study investigated the impact of a short-term, home-based, multimodal prehabilitation program on perioperative functional capacity in patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for nonsmall cell lung cancer (NSCLC). METHODS: A randomized controlled trial was conducted with 73 patients. Patients in the prehabilitation group (n = 37) received a 2-week multimodal intervention program before surgery, including aerobic and resistance exercises, respiratory training, nutrition counseling with whey protein supplementation, and psychological guidance. Patients in the control group (n = 36) received the usual clinical care. The assessors were blinded to the patient allocation. The primary outcome was perioperative functional capacity measured as the 6-minute walk distance (6MWD), which was assessed at 1 day before and 30 days after surgery. A linear mixed-effects model was built to analyze the perioperative 6MWD. Other outcomes included lung function, disability and psychometric evaluations, length of stay (LOS), short-term recovery quality, postoperative complications, and mortality. RESULTS: The median duration of prehabilitation was 15 days. The average 6MWD was 60.9 m higher perioperatively in the prehabilitation group compared to the control group (95% confidence interval [CI], 32.4-89.5; P < .001). There were no differences in lung function, disability and psychological assessment, LOS, short-term recovery quality, postoperative complications, and mortality, except for forced vital capacity (FVC; 0.35 L higher in the prehabilitation group, 95% CI, 0.05-0.66; P = .021). CONCLUSIONS: A 2-week, home-based, multimodal prehabilitation program could produce clinically relevant improvements in perioperative functional capacity in patients undergoing VATS lobectomy for lung cancer.

XIST promote the proliferation and migration of non-small cell lung cancer cells via sponging miR-16 and regulating CDK8 expression.

Up-regulation of long non-coding RNA (lncRNA) XIST has been observed in the tissue samples of non-small cell lung cancer (NSCLC), however, the underlying mechanisms remain uncertain. The aim of this study is to investigate the roles of XIST in the pathogenesis of NSCLC and the underlying mechanism. We noted that XIST in NSCLC tumor tissue and cell lines was significantly up-regulated. XIST over-expression promoted the proliferation and migration, meantime, increased the proportion of cells in the S phase in NSCLC cell line A549 and H1299. Meantime, knockdown of XIST showed the opposite effects. In vivo study further revealed a oncogenic effect of XIST. In addition, we conducted bioinformatics analysis and luciferase activity assay to find out the potential target miR of XIST and the potential target gene of miR-16 which is CDK8. In conclusion, our findings proved that XIST can serve as a tumor promoter in the pathogenesis of NSCLC, suggesting that XIST has the potential to become a novel therapeutic target for the treatment of NSCLC.

Nodal promotes the malignancy of non-small cell lung cancer (NSCLC) cells via activation of NF-κB/IL-6 signals.

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer deaths worldwide. Understanding the mechanisms responsible for the malignancy of NSCLC cells is important for therapy and drug development. Nodal, an important embryonic morphogen, has been reported to modulate tumorigenesis. We found that Nodal can trigger the proliferation of NSCLC cells and decrease the sensitivity to doxorubicin (Dox) and cisplatin (CDDP) treatment. Targeted inhibition of Nodal can suppress the proliferation of NSCLC cells. Among the measured cytokines, Nodal can increase the expression of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGFA) in NSCLC cells. Inhibition of IL-6, while not VEGFA, attenuated Nodal induced cell proliferation, suggesting the essential roles of IL-6 in Nodal induced malignancy of NSCLC cells. Nodal can trigger the phosphorylation, nuclear translocation and transcriptional activities of p65, the key signal transducer of NF-κB. This was due to the fact that Nodal can increase the phosphorylation of IKKß/IκBα. The inhibitor of IKKß abolished Nodal induced activation of p65 and expression of IL-6. Collectively, we found that Nodal can increase the proliferation and decrease chemosensitivity of NSCLC cells via regulation of NF-κB/IL-6 signals. It indicated that Nodal might be a potential therapeutic target for NSCLC treatment.

Effects of mdig on proliferation and apoptosis of lung cancer cells.

Expression of mineral dust-induced gene (mdig) in lung cancer NCI-H1650 cells was detected to investigate the effects of mdig on proliferation and apoptosis of NCI-H1650 cells. NCI-H1650 lung cancer cells were cultured in vitro. The expression of mdig in NCI-H1650 cells was lowered using ribonucleic acid interference (RNAi) technique. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to detect the effects of mdig small interfering RNA (siRNA) on messenger RNA (mRNA) and the protein expression of mdig in lung cancer NCI-H1650 cells, respectively. The effect of mdig on the proliferation of NCI-H1650 cells was observed through 3-(4,5)-dimethylthiazol (-z-y1)-3,5-di-phenyl tetrazolium bromide (MTT) assay, and flow cytometry was used to detect the impact of mdig on cell cycle and apoptosis of NCI-H1650 cells. The influence of mdig on caspase-3 and poly (ADP-ribose) polymerase 1 (PARP1) proteins in NCI-H1650 cells were investigated via western blot analysis. The results of RT-qPCR and western blot analysis showed that mdig siRNA obviously inhibited the expression of mRNA and protein of mdig in NCI-H1650 cells. Results of the MTT assay showed mdig siRNA could significantly reduce the proliferation ability of NCI-H1650 cells. In addition cell cycle detection showed that mdig siRNA caused NCI-H1650 cell arrest at G1 phase. Apoptosis detection results indicated that mdig siRNA promoted apoptosis of NCI-H1650 cells. Western-blot analysis revealed that mdig siRNA upregulated the expression of cleaved caspase-3 and cleaved PARP1 proteins in NCI-H1650 cells. Mdig is highly expressed in lung cancer NCI-H1650 cells while mdig siRNA can inhibit proliferation of NCI-H1650 cells and accelerate apoptosis. The underlying mechanism may be related to inhibited cell cycle progression and upregulated expression of cleavage proteins (cleaved caspase-3 and cleaved PARP1).

Primary pulmonary malignant melanoma: Case report and literature review.

Primary malignant melanoma of the lung is an extremely rare pulmonary carcinoma. Only 45 cases have been reported in the literature. Herein, we report a case of a 46-year-old male patient with an O Rh negative blood type who presented with pulmonary bronchial symptoms and underwent lobectomy. Genetic testing was also performed but no targetable mutations were found, and the patient's PD-L1 RNA level was low. He developed brain metastasis four months after surgery and received radiotherapy but died 21 months after diagnosis. We review the published cases of this rare pulmonary lesion.

Primary lung carcinoma combined with pulmonary amyloidosis secondary to syphilis infection.

A 55-year-old female patient was found to have a pulmonary nodule combined with multiple lung cysts detected on CT scan. Video-assisted thoracoscopic surgery (VATS) lobectomy was performed and the nodule showed adenocarcinoma while the whole left upper lobe showed a heavy deposition of amyloid. Syphilis infection was detected and was suspected contributing to secondary pulmonary amyloidosis. Although very rare, pulmonary amyloidosis should be added to the differential diagnosis for solid pulmonary nodules. Furthermore, widespread lung cysts located apart from pulmonary nodules is especially rare in pulmonary amyloidosis secondary to syphilis infection.

Paclitaxel increases the sensitivity of lung cancer cells to lobaplatin via PI3K/Akt pathway.

The effect of paclitaxel combined with lobaplatin on the sensitivity of lung cancer cell line NCI-H446 through influencing the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated. The sensitivity of lobaplatin to NCI-H446 and the effect of paclitaxel and PI3K inhibitor LY294002 combined with lobaplatin on the sensitivity to NCI-H446 were detected via methyl thiazolyltetrazolium (MTT) assay. The effect of paclitaxel combined with lobaplatin on cell apoptosis was detected using flow cytometry, the effect of paclitaxel combined with lobaplatin on the cell migration was detected via cell wound scratch assay, and the effect of paclitaxel combined with lobaplatin on the cell invasion was detected via Transwell assay. Finally, the effect of paclitaxel on PI3K/Akt pathway was detected via western blotting. MTT assay showed that 30 µg/ml lobaplatin could significantly inhibit the growth of NCI-H446 (p<0.01). Lobaplatin group (group L), 2 µg/ml paclitaxel combined with lobaplatin group (group LP) and lobaplatin combined with 10 µmol/ml LY294002 group (group LL) were set up. The cell survival rates in group LP and group LL were significantly lower than that in group L (p<0.01), and the cell survival rate in group LP was similar to that in group LL (p>0.05). Flow cytometry revealed that the cell apoptotic levels in group LP and group LL were obviously higher than that in group L (p<0.01), and there was no statistically significant difference in the cell apoptotic level between group LP and group LL (p>0.05). Cell wound scratch assay showed that the cell migration capacity in group LP was significantly lower than those in group L and group LL (p<0.01, p<0.05), and the cell migration capacity in group LL was lower than that in group L (p<0.05). Besides, Transwell assay revealed that the cell invasion capacity in group LP was obviously lower than those in group L and group LL (p<0.01, p<0.05), and the cell invasion capacity in group LL was lower than that in group L (p<0.01). Finally, western blotting showed that the levels of PI3K, phosphorylated-Akt (p-Akt) and phosphorylated-glycogen synthase kinase 3ß (p-GSK3ß) in group LP and group LL were significantly lower than those in group L, and the differences were statistically significant (p<0.01). Paclitaxel can significantly increase the sensitivity of lobaplatin to lung cancer cell line NCI-H446. Moreover, paclitaxel can enhance the effect of lobaplatin on lung cancer cells and reduce the drug resistance through inhibiting PI3K/Akt pathway.

Video-Assisted Thoracoscopic Surgery Lobectomy Performed Satisfaction and Complications of Patients During Hands-On Training Courses.

AIM: It was aimed to concern about the satisfaction and procedural complications of patients during the thoracoscopy exist of hands-on training in this present study. PATIENTS AND METHODS: The patients with non-small-cell carcinoma underwent video-assisted thoracoscopic surgery (VATS) lobectomy during hands-on training courses at thoracoscopic center in our hospital and collected from January 2009 and December 2014. The rates of satisfaction and complications of patients were compared from hands-on training group and control group. Potential risk factors associated with post-VATS complications of patients and thoracoscopist-related variables were analyzed. There were 54 patients join in six meetings with hands-on thoracoscopy training in our center. RESULTS: There was no significant difference between patients for hands-on training group (n = 54) and control group (n = 54), including sex, age, BMI, smoking, PpoFEV1 and comorbidities. The satisfaction rate and the incidence of complication were similar between the two groups. CONCLUSION: Univariate analyses showed that elder age, heart disease, chronic obstructive pulmonary disease, long operative time, and first-time mentorship were significantly associated with post-VATS complications of patients in hands-on training group. We should pay more attention to the characteristics of patent and the experience of mentor before VATS hands-on training courses.

Network analysis of DEGs and verification experiments reveal the notable roles of PTTG1 and MMP9 in lung cancer.

Lung cancer, a malignant tumor, is the most frequently fatal cancer, with poor survival rates in the advanced stages. In order to improve the understanding of this disease, and to improve the outcomes of patients, additional studies are required. In the present study, differentially expressed genes (DEGs) in patients with lung cancer compared with controls were identified. To understand how these DEGs act together to account for the initiation of lung cancer, a protein interaction network and a transcriptional regulatory network were constructed to explore the clusters and pathways in lung cancer, and the results indicated that PTTG1 and MMP9 served major roles in the development of lung cancer in the regulatory system. Consistent with this, mRNA and protein expression levels of PTTG1 and MMP9 were significantly upregulated in lung cancer tissues compared with normal lung tissues. The overexpression of PTTG1 or MMP9 was induced in the human bronchial epithelial BEAS-2B cell line, indicating that increased PTTG1 or MMP9 alone may not only facilitate cell migration, proliferation and induce colony formation, but also suppress cell apoptosis. In summary, PTTG1 and MMP9 were identified as potential targets for therapeutic intervention through gene therapy in lung cancer.