Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy: Short-term Results of a Randomized Clinical Trial (RVlob Trial).

OBJECTIVE: To determine whether RAL affects perioperative outcomes and long-term efficacy in NSCLC patients, compared with traditional VAL. SUMMARY OF BACKGROUND DATA: RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated. METHODS: A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared. RESULTS: The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the 2 groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage {830 mL [interquartile range (IQR), 550-1130 mL] vs 685 mL [IQR, 367.5-1160 mL], P = 0.007} and hospitalization costs [$12821 (IQR, $12145-$13924) vs $8009 (IQR, $7014-$9003), P < 0.001] were significantly higher in the RAL group. RAL group had a significantly higher number of LNs harvested [11 (IQR, 8-15) vs 10 (IQR, 8-13), P = 0.02], higher number of N1 LNs [6 (IQR, 4-8) vs 5 (IQR, 3-7), P = 0.005], and more LN stations examined [6 (IQR, 5-7) vs 5 (IQR, 4-6), P < 0.001]. CONCLUSIONS: Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534).

Early Outcomes of Robot-Assisted Versus Thoracoscopic-Assisted Ivor Lewis Esophagectomy for Esophageal Cancer: A Propensity Score-Matched Study.

BACKGROUND: Both robot-assisted Ivor Lewis esophagectomy (RAILE) and conventional thoracoscopic-assisted Ivor Lewis esophagectomy (TAILE) are minimally invasive surgical techniques for the treatment of middle and distal esophageal cancer. However, no research studies comparing early outcomes between RAILE and TAILE have been reported. METHODS: A retrospective analysis was made of 184 patients, 76 in the RAILE group and 108 in the TAILE group, who underwent minimally invasive Ivor Lewis esophagectomy between December 2014 and June 2018. Propensity score-matched analysis was performed between the two groups based on demographics, comorbidities, American Society of Anesthesiologists score, tumor location, tumor size, and pathological stage. Perioperative outcomes were compared. RESULTS: Two conversions to thoracotomy occurred in the RAILE group. There was no 30-day in either group. Sixty-six matched pairs were identified for each group. Within the propensity score-matched cohorts, the operative time in the RAILE group was significantly longer than that in the TAILE group (302.0 ± 62.9 vs. 274.7 ± 38.0 min, P = 0.004). There was no significant difference in the blood loss [200.0 ml (interquartile range [IQR], 100.0-262.5 ml) vs. 200.0 ml (150.0-245.0 ml), P = 0.100], rates of overall complications (28.8 vs. 24.2%, P = 0.554), length of stay [9.0 days (IQR 8.0-12.3 days) vs. 9.0 days (IQR 8.0-11.3 days), P = 0.517], the number of total dissected lymph nodes (19.2 ± 9.2 vs. 19.3 ± 9.5, P = 0.955), and detailed categories of lymph nodes. CONCLUSIONS: RAILE demonstrated comparable early outcomes compared with TAILE and should be considered as an alternative minimally invasive option for treating esophageal cancer.

High-dimensional single-cell proteomics analysis of esophageal squamous cell carcinoma reveals dynamic alterations of the tumor immune microenvironment after neoadjuvant therapy.

BACKGROUND: Dynamic alterations of the tumor immune microenvironment in esophageal squamous cell carcinoma (ESCC) after different neoadjuvant therapies were understudied. METHODS: We used mass cytometry with a 42-antibody panel for 6 adjacent normal esophageal mucosa and 26 tumor samples (treatment-naïve, n=12; postneoadjuvant, n=14) from patients with ESCC. Single-cell RNA sequencing of previous studies and bulk RNA sequencing from The Cancer Genome Atlas were analyzed, flow cytometry, immunohistochemistry, and immunofluorescence analyses were performed. RESULTS: Poor tumor regression was observed in the neoadjuvant chemotherapy group. Radiotherapy-based regimens enhanced CD8+ T cells but diminished regulatory T cells and promoted the ratio of effector memory to central memory T cells. Immune checkpoint blockade augmented NK cell activation and cytotoxicity by increasing the frequency of CD16+ NK cells. We discovered a novel CCR4+CCR6+ macrophage subset that correlated with the enrichment of corresponding chemokines (CCL3/CCL5/CCL17/CCL20/CCL22). We established a CCR4/CCR6 chemokine-based model that stratified ESCC patients with differential overall survival and responsiveness to neoadjuvant chemoradiotherapy combined with immunotherapy, which was validated in two independent cohorts of esophageal cancer with neoadjuvant treatment. CONCLUSIONS: This work reveals that neoadjuvant therapy significantly regulates the cellular composition of the tumor immune microenvironment in ESCC and proposes a potential model of CCR4/CCR6 system to predict the benefits from neoadjuvant chemoradiotherapy combined with immunotherapy.

The Prognostic Value of Tumor Mutation Burden and Immune Cell Infiltration in Thymic Epithelial Tumors.

OBJECTIVE: The question of whether the tumor mutation burden (TMB) is associated with either improved survival outcomes or improvement of immunotherapies remains controversial in various malignancies. The aim of this study is to investigate the genomic landscape of the relationship between TMB and immune cell infiltration in thymic epithelial tumors (TETs). METHODS: We downloaded somatic mutation data, transcriptome sequencing data, and clinical information of TETs from the Cancer Genome Atlas (TCGA) database. We assessed the abundance of 22 immune fractions between low-TMB (TMB-L) and high-TMB (TMB-H) groups using the "CIBERSORT" package. RESULTS: Missense mutation had the highest frequency of mutation among the nine variant classifications in TETs. Higher TMB levels were associated with poor survival outcomes (P<0.05), and higher Masaoka stages (P<0.05). More importantly, TMB levels were much higher in the thymic cancer than in thymoma (P<0.01). The infiltration levers of naive CD4(+) T cells and regulatory T cells were significantly higher in the TMB-L group than in the TMB-H group, and this was further associated with better overall survival (OS) in patients with TETs. CONCLUSION: The present study indicates that the prognosis of TMB-H patients with TETs is significantly poorer than is that of TMB-L patients, which might result from the different levels of infiltration of naive CD4(+) T cells and regulatory T cells.

Beclin-1 is a Promising Prognostic Biomarker in a Specific Esophageal Squamous Cell Carcinoma Population.

The effects of autophagy and apoptosis in the prognostic assessment and treatment of Esophageal squamous cell carcinoma (ESCC) remain to be elucidated. Here, we conducted a retrospective study on the histopathology of ESCC, investigated the expression of Beclin-1 and Bcl-2 proteins (both autophagy- and apoptosis-related) in esophageal cancer tissue, and analyzed the significance of these proteins for the prognosis of ESCC. In the present study, the expression level of Beclin-1 in ESCC was significantly lower than that in adjacent tissues (p < 0.01), whereas the expression level of Bcl-2 showed the opposite pattern (p < 0.01). Furthermore, low expression of Beclin-1 was associated with more advanced ESCC stages and lymph node metastasis. However, high expression of Bcl-2 was associated with more advanced ESCC stages, deeper tumor invasion, and lymph node metastasis. Moreover, the relationship between Bcl-2 expression and OS was not significant (p > 0.05), whereas Beclin-1 expression was significantly associated with OS (p < 0.05). Subgroup analysis showed that Beclin-1 expression was significantly associated with OS in the high-Bcl-2-expression group but not in the low-Bcl-2-expression group. Importantly, Beclin-1 upregulation or downregulation significantly upregulated or downregulated invasion, respectively, in EC9706 cells in combination with high expression but not low expression of Bcl-2. These findings reveal that differences in autophagy and apoptotic states and their activities may promote malignant tumor differentiation, which could lead to a more aggressive esophageal squamous cell phenotype and a worse survival prognosis. Here, Beclin-1 was shown to be a promising prognostic biomarker and therapeutic target for patients with ESCC in the high-Bcl-2-expression population.

Development and validation of an autophagy-related prognostic signature in esophageal cancer.

BACKGROUND: Autophagy has a dual function in cancer, and its role in carcinogenesis of the esophagus remains poorly understood. In the present study, we explored the prognostic value of autophagy in esophageal cancer (ESCA), one of the leading causes of cancer-related deaths worldwide. METHODS: Using ESCA RNA-sequencing (RNA-Seq) data from 158 primary patients with ESCA, including esophageal adenocarcinoma and esophageal squamous cell carcinoma, were downloaded from The Cancer Genome Atlas (TCGA) for this study. We obtained differentially expressed autophagy-related genes (ARGs) by the "limma" package of R. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses unveiled several fundamental signaling pathways associated with the differentially expressed ARGs in ESCA. Univariate Cox regression analyses were used to estimate associations between ARGs and overall survival (OS) in the TCGA ESCA cohort. A Cox proportional hazards model (iteration =1,000) with a lasso penalty was used to create the optimal multiple-gene prognostic signature utilizing an R package called "glmnet". RESULTS: A prognostic signature was constructed with four ARGs (DNAJB1, BNIP1, VAMP7 and TBK1) in the training set, which significantly divided ESCA patients into high- and low-risk groups in terms of OS [hazard ratio (HR) =1.508, 95% confidence interval (CI): 1.201-1.894, P<0.001]. In the testing set, the risk score remained an independent prognostic factor in the multivariate analyses (HR =1.572, 95% CI: 1.096-2.257, P=0.014). The area under the curve (AUC) of the receiver operating characteristic (ROC) predicting 1-year survival showed a better predictive power for the prediction model. The AUC in training and testing cohorts were 0.746 and 0.691, respectively. Therefore, the prognostic signature of the four ARGs was successfully validated in the independent cohort. CONCLUSIONS: The prognostic signature may be an independent predictor of survival for ESCA patients. The prognostic nomogram may improve the prediction of individualized outcome. This study also highlights the importance of autophagy in the outcomes of patients with ESCA.

Next-generation sequencing in thymic epithelial tumors uncovered novel genomic aberration sites and strong correlation between TMB and MSH6 single nucleotide variations.

Thymic epithelial tumors (TET) including thymomas and thymic carcinomas are rare, but they are common primary tumors in the anterior mediastinum. The etiology and tumorigenesis of TET remain unclear. To better understand the novel aberrations of this rare tumor and provide more significant mutation sites for targeted therapy, we performed next-generation sequencing detection on 55 patients with TET. Our results showed that most genes in 12 core pathways harbored aberrations of indeterminate potential. In 4 genes (ARID1A, KMT2C, TGFBR2 and MAP3K1), the indel frequency was above 90%. Dozens of genes, including TGFBR2, KMT2C, PRKDC, ATR, CHD2, SDHA, KDM5A, CHEK1, MSH6 and POLE, possessed frameshift indel with different frequencies in different hotspot sites, which could be the new targets of therapy for TET. For the first time, we revealed a strong correlation between the tumor mutational burden and single nucleotide variations, but not frameshift, on DNA mismatch repair gene MSH6 in TET.

Endoscope-assisted mediastinal drainage therapy for anastomosis leakage after esophagectomy: a retrospective cohort study.

BACKGROUND: Anastomosis leakage after esophagectomy is a major threat which leads to many subsequent complications even mortality. But current diagnosis and treatment methods are inefficient. This retrospective study aims to evaluate the utilization of endoscope-assisted mediastinal drainage therapy in treatment for anastomosis leakage after esophagectomy. METHODS: Between January 2014 and June 2018, 51 patients were confirmed anastomosis leakage using gastroscopy. Of them, 23 patients were treated with endoscope-assisted mediastinal drainage therapy (drainage group); and the other 28 patients received endoscope-assisted biomedical fibrin glue occlusion (occlusion group). Short-term clinical outcomes were examined. Factors related to length of postoperative hospitalization (LPH) was analyzed. RESULTS: Endoscope provided highly accurate information on the condition of anastomosis leakage. And there was no evidence that early endoscopy could cause damage to the anastomosis or gastric conduit. One patient from drainage group and two from occlusion group discharged against medical advice. Other 48 patients were completely cured without reoperation or mortality. The median LPH was 32 days in drainage group (range from 17 to 80 days) and 81 days in occlusion group (range from 32 to 190 days), respectively (P<0.05). Linear regression indicated statistically significant correlation between LPH and length from diagnosis to drainage or occlusion (R=0.688, P<0.001). CONCLUSIONS: Endoscope-assisted mediastinal drainage therapy is a satisfactory treatment for anastomosis leakage. Early diagnosis and treatment may facilitate the recovery of anastomosis leakage and reduce LPH.

Detection of Epithelial-Mesenchymal Transition Status of Circulating Tumor Cells in Patients with Esophageal Squamous Carcinoma.

PURPOSE: To investigate the correlation between the status of epithelial-mesenchymal transition (EMT) of circulating tumor cells (CTCs) and esophageal squamous cell carcinoma (ESCC). METHODS: The demographic data and blood samples of 21 patients with ESCC were collected retrospectively. CTCs were enriched by using optimized CanPatrolTM CTC enrichment technique. CTCs were identified and characterized according to the EMT markers (e-CTCs: epithelial CTCs; mix-CTCs: epithelial-mesenchymal-mixed CTCs; m-CTCs: mesenchymal CTCs). The correlation between CTCs and demographic data was analyzed. RESULTS: Total 129 CTCs were detected in all the patients: 11(8.5%) CTCs of them were e-CTCs, 76(58.9%) were mix-CTCs, and 42(32.6%) were m-CTCs. The average number of CTCs from each patient was 6.1 ± 7.1 which included 0.5 ± 0.9 of e-CTCs, 3.6 ± 5.2 of mix-CTCs, and 2.0 ± 2.7 of m-CTCs; the difference between the three groups was significant (P = 0.017): the number of total CTCs was correlated with the number of mix-CTCs (R2 = 0.883, P < 0.01) and m-CTCs (R2 = 0.639, P < 0.01) but not e-CTCs (R2 = 0.012, P = 0.641) and the number of CTCs was correlated with the N stage and TNM stage in this study (R2 = 0.698 and R2 = 0.359). CONCLUSIONS: Mix-CTCs and m-CTCs might play an important role in progression of ESCC; the number of CTCs in ESCC might have the potential to be a predictor of prognosis.

Primary tracheal schwannoma treated by surgical resection: a case report.

The rarity and non-specific symptoms of benign primary tracheal tumors always leaded to misdiagnosis and delayed treatment, and also undefined the optimal treatment. In this case, a 45-year-old woman had a history of progressive shortness of breath and dry cough for several years, CT scan revealed an intra-luminal tracheal mass invaded the left side of tracheal wall. After being located by bronchoscope preoperatively, the tumor was removed by surgical resection. The tumor was 1.5 cm in diameter with intact capsule. The pathological result confirmed the diagnosis of schwannoma.

Effects of Chinese Medicine as Adjunct Medication for Adjuvant Chemotherapy Treatments of Non-Small Cell Lung Cancer Patients.

The aim was to evaluate the effects of traditional Chinese medicine (TCM) as a combination medication with adjuvant chemotherapy on postoperative early stage non-small cell lung cancer (NSCLC) patients. The 314 patients with completely resected stage IB, II or IIIA cancers were assigned into vinorelbine plus cisplatin/carboplatin (NP/NC) (control, n = 158) and NP/NC with additional TCM (intervention, n = 156) groups. The primary endpoint was QOL scores; secondary endpoints were the toxicity and safety of the regimens. The NP/NC regimen caused mild (grade 1 or 2) non-hematologic toxic effects in the patients comprising vomiting (43.6%), fatigue (36.9%), pain (23%), dry mouth (27.6%) and diarrhea (7.9%). The incidence of adverse events was significantly lower in the intervention group than in the control group (0.57% vs 4.02%, P = 0.037). Transient severe (grade 3 or 4) hematological toxic effects occurred less often (hemoglobin reduction (11.9 vs 22.5 percent) and total bilirubin increased (to 42.1 vs 46.2%) in the intervention compared to the control group during the 2nd chemotherapy cycle. When combined with adjuvant chemotherapy, TCM led to partial relief of symptoms in addition to a reduction of side-effects and adverse events caused by the NP/NC regimens.

Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor.

BACKGROUND: The study was to review the clinical manifestations and laboratory examinations of ectopic adrenocorticotropic hormone (ACTH) syndrome, and to analyze the efficacy of surgical treatment. METHODS: The clinical data, surgical therapy, and outcome of 23 cases of ectopic ACTH syndrome accompanied by intra-thoracic tumors were reviewed. The tumors were removed from all the patients according to the principles of radical resection. RESULTS: The tumors were confirmed as associated with ectopic ACTH secretion in 19 cases. Hyperglycemia and hypokalemia were recovered, while plasma cortisol, plasma ACTH and 24-hour urinary free cortisol (UFC) levels were significantly reduced after surgery in these 19 cases. Recurrences of the disease were found in six cases during following-up, and five of them died. CONCLUSIONS: The thoracic cavity should be a focus in routine examinations of patients with symptoms of Cushing's syndrome (CS), because ectopic ACTH-producing tumors are commonly found in bronchus/lung and mediastinum. Despite the incidence of the pulmonary nodule secondary to opportunistic infection in some cases, surgery is still the first choice if the tumor is localized. The surgical procedure should be performed according to the principles in resection of lung cancer and mediastinal tumor. The surgical efficacy is significant for short-term periods; however, the recurrence of the disease in long-term periods is in great part related to distal metastasis or relapse of the tumor.

MiR-25 is up-regulated in non-small cell lung cancer and promotes cell proliferation and motility by targeting FBXW7.

Increasing evidence showed that miR-25 is involved in the carcinogenesis and progression of various human cancers, while its role in non-small cell lung cancer (NSCLC) is still unclear. Here, we found that miR-25 is significantly up-regulated in NSCLC tissue samples and cell lines. Inhibition of miR-25 remarkably suppressed cell proliferation, migration and invasion in NSCLC cells, whereas enforced expression of miR-25 significantly increased NSCLC cells proliferation, migration and invasion. Moreover, we identified F-box and WD repeat domain-containing 7 (FBXW7) as a direct target of miR-25 and overexpression of FBXW7 partially attenuates the oncogenic effect of miR-25 on NSCLC cells. In conclusion, miR-25 is up-regulated in NSCLC and promotes NSCLC cells proliferation and motility partially by targeting FBXW7. Our data suggest that miR-25 might serve as a potential therapeutic target for NSCLC treatment in the future.

Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro.

Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. The role of AngII and ACE2 in the metastasis of non-small cell lung cancer (NSCLC) and the effects on matrix metalloproteinases (MMPs) are still unknown. In the present study, the anti-invasive effect and mechanism of ACE2 were investigated in vitro and in vivo. Results of a transwell assay showed that the overexpression of ACE2 reduces the invasive ability of A549 cells in vitro. According to the results of qRT-PCR and western blot analysis, the inhibitory role of ACE2 was mediated through the down-regulation of MMP-2 and MMP-9. Additionally, we confirmed that the overexpression of ACE2 inhibited cell growth and VEGFa production while simultaneously suppressing ACE and angiotensin II type 1 receptor (AT1R) expression in human lung cancer xenografts. These results suggest that the overexpression of ACE2 may potentially suppress the invasion and angiogenesis of NSCLC.

The angiotensin-converting enzyme 2 in tumor growth and tumor-associated angiogenesis in non-small cell lung cancer.

Angiotensin II (AngII) is a multifunctional bioactive peptide and previous studies have shown that the renin-angiotensin system (RAS) of both host and tumor are important in tumor growth and angiogenesis in lung cancer. Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS, with 42% amino acid homology to ACE. However, the expression and function of ACE2 in non-small cell lung cancer (NSCLC) are still unclear. In the present study, we analyzed ACE2 expression in NSCLC tissue by Western blot analysis and immunohistochemistry. AngII concentrations in the tissue homogenate were also detected using radio-immunoassay. We also examined the function of ACE2 by transducing A549 cells with MSCV-ACE2. We have shown for the first time that ACE2 expression decreased in NSCLC tissue in which AngII was higher than the matching non-malignant tissues. A concentration of 10(-6) mol/l of AngII significantly increased expression of vascular endothelial growth factor a (VEGFa) and AT1-R and decreased ACE2 expression. We also found that overexpression of ACE2 may have a protective effect by inhibiting cell growth and VEGFa production in vitro. ACE2 may become a target of novel strategies to treat NSCLC.