Clinicopathological and molecular characterization of resected lung adenocarcinoma: Correlations with histopathological grading systems in Chinese patients.

PURPOSE: Driver mutations inform lung adenocarcinoma (LUAD) targeted therapy. Association of histopathological attributes and molecular profiles facilitates clinically viable testing platforms. We assessed correlations between LUAD clinicopathological features, mutational landscapes, and two grading systems among Chinese cases. METHODS: 79 Chinese LUAD patients undergoing resection were subjected to targeted sequencing. 68 were invasive nonmucinous adenocarcinoma (INMA), graded via: predominant histologic pattern-based grading system (P-GS) or novel IASLC grading system (I-GS). Driver mutation distributions were appraised and correlated with clinical and pathological data. RESULTS: Compared to INMA, non-INMA exhibited smaller, well-differentiated tumors with higher mucin content. INMA grade correlated with size, lymph invasion (P-GS), and driver/EGFR mutations. Mutational spectra varied markedly between grades, with EGFR p.L858R and exon 19 deletion mutations predominating in lower grades; while high-grade P-GS tumors often harbored EGFR copy number variants and complex alterations alongside wild-type cases. I-GS upgrade of P-GS grade 2 to grade 3 was underpinned by ≥20 % high-grade regions bearing p.L858R or ALK fusions. Both systems defined tumors of distinctive phenotypic attributes and molecular genotypes. CONCLUSIONS: INMA represent larger, mucin-poor, molecularly heterogeneous LUAD with divergent grade-specific mutation profiles. Stronger predictor of clinicopathological attributes and driver mutations, P-GS stratification offers greater accuracy for molecular testing. A small panel encompassing EGFR and ALK captures the majority of P-GS grade 1/2 mutations whereas expanded panels are optimal for grade 3.

Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways.

BACKGROUND: The lncRNA PVT1 reportedly functions as a competing endogenous RNA (ceRNA) of miR-186 and miR-26b in different tissue types. In this study, we investigated the possible involvement of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways in the pathogenesis of hypoxia-induced PAH. METHODS: Expression of PVT1, miR-186, miR-26b, and Srf and Ctgf mRNAs were evaluated by real-time polymerase chain reaction. Protein expression of SRF, CTGF, LC3B-I, LC3B-II, and Beclin-I was evaluated using western blotting. The regulatory relationship between the lncRNA, miRNAs, and target mRNAs was explored using luciferase assays. Immunohistochemistry was used to evaluate the expression of SRF and CTGF in situ. MTT assay was performed to assess the proliferation of PASMCs. RESULTS: Exposure to hypoxia markedly altered the expression of PVT1, Srf, Ctgf, miR-186, and miR-26b in a rat model. MiR-186 binding sites in the sequences of Srf mRNA and PVT1 were confirmed by luciferase assays, indicating that miR-186 may interact with both PVT1 and Srf mRNA. Additionally, miR-26b binding sites were identified in the sequences of Ctgf mRNA and PVT1, suggesting that miR-26b may interact with both PVT1 and Ctgf mRNA. In line with this, we found that overexpression of PVT1 reduced expression of miR-26b and miR-186 but activated expression of Srf, Ctgf, LC3B-II, and Beclin-I. CONCLUSIONS: Upregulation of PVT1 by exposure to hypoxia promoted the expression of CTGF, leading to deregulation of autophagy and abnormal proliferation of PASMCs. Dysregulation of the miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways may be involved in the pathogenesis of hypoxia-induced PASMCs.

Patterns of care and prognostic evaluation for stage I-III upper esophageal squamous cell carcinoma: a population-based study.

Background: There is no strong evidence regarding the optimal treatment and specific prognosis prediction model for upper esophageal squamous cell carcinoma (UESCC). This study aimed to investigate the real-world treatment patterns and develop models to predict overall survival (OS) and esophageal cancer-specific survival (ECSS) in patients with stage I-III UESCC. Methods: Patients with T1-4N0-3M0 UESCC in the Surveillance, Epidemiology, and End Results (SEER) database were identified from 2010 to 2017, and randomized to a training cohort and a validation cohort. The effect of treatment patterns on survival were comprehensively analyzed. Nomograms were developed by incorporating independent prognostic factors analyzed by Cox regression in the training cohort and evaluated by the concordance index (C-index), receiver operating characteristic (ROC) curves, calibration curves, and decision curve analyses (DCA) in two cohorts. Results: A total of 677 patients were identified, including 452 in the training cohort and 225 in the validation cohort. Among all populations, 71.9% (487) received chemoradiotherapy without surgery, and chemoradiotherapy or/and surgery showed better survival than other treatments. However, surgery was rarely carried out for patients with stage II-III. T stage, N stage, surgery, chemotherapy, and radiotherapy were independent risks for both OS and ECSS, while age was also an independent risk for OS. The C-indexes for nomograms to predict OS (0.71 and 0.72) and ECSS (0.70 and 0.73) were greater than 7th AJCC staging system to predict OS (0.61 and 0.64) and ECSS (0.64 and 0.64) in both the training cohort and the validation cohort. Time-dependent ROC curves and DCA also suggested that nomograms performed consistently better than 7th AJCC staging system. The calibration curves demonstrated good consistency in predicting survival. Conclusions: Chemoradiotherapy was a major treatment with preferable survival for patients with stage I-III UESCC. We have firstly developed and validated prognostic nomograms in patients with stage I-III UESCC, which would play a supplementary role in the current staging system.

ARL14 as a Prognostic Biomarker in Non-Small Cell Lung Cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The mechanisms underlying NSCLC initiation and progression require further investigation. The purpose of this study was to investigate the role of ADP ribosylation factor-like GTPase 14 (ARL14) related to the progression of NSCLC. PATIENTS AND METHODS: We analyzed the correlation between clinical characteristics and ARL14 expression using data from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis was conducted to evaluate the prognostic value of ARL14 in NSCLC. Functions of ARL14 were identified by enrichment analysis. The relationship between ARL14 expression and immune cell infiltration was also studied. Furthermore, ARL14 expression was examined using immunohistochemistry, and its clinical significance was analyzed in 120 patients with NSCLC. RESULTS: Our study revealed that the expression level of ARL14 in patients with NSCLC was higher than that in normal tissues. Using TCGA data, higher ARL14 expression in lung adenocarcinoma was associated with residual tumor (P = 0.017), while it was associated with age (P = 0.003) and N stage (P = 0.009) in lung squamous cell carcinoma. Similar results were obtained from 120 patients with NSCLC. High ARL14 expression was associated with poor overall survival and progression-free survival in NSCLC. Multivariate analysis revealed that ARL14 was an independent risk factor for patients with NSCLC. Functional enrichment analysis indicated that ARL14 was related to the occurrence and development of tumors. CONCLUSION: Increased ARL14 expression was considerably correlated with poor survival in NSCLC, and it might be a promising prognostic biomarker for NSCLC.

Integrated analysis of the molecular mechanisms in idiopathic pulmonary fibrosis.

Rationale: Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonia. Some miRNAs may be associated with IPF and may affect the occurrence and development of IPF in various pathways. Many miRNAs and genes that may be involved in the development of IPF have been discovered using chip and high throughput technologies. Methods: We analyzed one miRNA and four mRNA databases. We identified hub genes and pathways related to IPF using GO, KEGG enrichment analysis, gene set variation analysis (GSVA), PPI network construction, and hub gene analysis. A comprehensive analysis of differentially expressed miRNAs (DEMs), predicted miRNA target genes, and differentially expressed genes (DEGs) led to the creation of a miRNA-mRNA regulatory network in IPF. Results: We found 203 DEGs and 165 DEMs that were associated with IPF. The findings of enrichment analyses showed that these DEGs were mainly involved in antimicrobial humoral response, antimicrobial humoral immune response mediated by antimicrobial peptide, extracellular matrix organization, cell killing, and organ or tissue specific immune response. The VEGFA, CDH5, and WNT3A genes overlapped between hub genes and the miRNA-mRNA regulatory network. The miRNAs including miR-199b-5p, miR-140-5p, miR-199a-5p, miR-125A-5p, and miR-107 that we predicted would regulate the VEGFA, CDH5, and WNT3A genes, which were also associated with IPF or other fibrosis-related diseases. GSVA indicated that metabolic processes of UTP and IMP, immune response, regulation of Th2 cell cytokine production, and positive regulation of NK cell-mediated immunity are associated with the pathogenesis and treatment of IPF. These pathways also interact with VEGFA, CDH5, and WNT3A. Conclusion: These findings provide a new research direction for the diagnosis and treatment of IPF.

Nivolumab monotherapy or combination therapy with ipilimumab for lung cancer: a systemic review and meta-analysis.

BACKGROUND: The high incidence and mortality of lung cancer have seriously affected human life and health. Nivolumab is a monoclonal antibody that can inhibit programmed death 1 (PD-1) and Ipilimumab is a monoclonal antibody against CTLA-4(cytotoxic T lymphocyte-associated antigen 4), both of which can prevent the immune escape of tumor cells. Our goal was to synthesize evidence from published randomized controlled trials involving the safety and efficacy of either Nivolumab alone or in combination for the treatment of unresectable lung cancer. METHODS: We searched the following electronic databases: PubMed, Embase, and Cochrane libraries, and screened the retrieved records for eligibility. We used the Stata16 software for the analyses. The results of the analysis are expressed as hazard ratios (HRs) or risk ratios (RRs) and their corresponding 95% confidence intervals (CI). RESULTS: The final analysis included seven trials involving 3817 patients. Among patients with advanced lung cancer, patients using immunotherapy had better overall survival (OS), progression-free survival (PFS), and an objective response rate (ORR) than patients receiving chemotherapy. The HR of Nivolumab monotherapy or combination therapy with OS was compared with that of chemotherapy (HR: 0.73, 95% CI 0.64-0.83; HR: 0.67, 95% CI 0.55-0.81), and the HR of PFS was (HR: 0.81, 95% CI 0.69-0.94; HR: 0.67, 95% CI 0.55-0.82). CONCLUSIONS: Immunotherapy has been shown to have more clinically meaningful survival benefits for patients with lung cancer, whether monotherapy or combination immunotherapy. CRD42020213440.

Mapping of Cervical and Upper Mediastinal Lymph Node Recurrence for Guiding Clinical Target Delineation of Postoperative Radiotherapy in Thoracic Esophageal Squamous Cell Carcinoma.

BACKGROUND: The lower neck and upper mediastinum are the major regions for postoperative radiotherapy (PORT) in thoracic esophageal squamous cell carcinoma (TESCC). However, there is no uniform standard regarding the delineation of nodal clinical target volume (CTVnd). This study aimed to map the recurrent lymph nodes in the cervical and upper mediastinal regions and explore a reasonable CTVnd for PORT in TESCC. METHODS: We retrospectively reviewed patients in our hospital with first cervical and/or upper mediastinal lymph node recurrence (LNR) after upfront esophagectomy. All of these recurrent lymph nodes were plotted on template computed tomography (CT) images with reference to surrounding structures. The recurrence frequency at different stations was investigated and the anatomic distribution of recurrent lymph nodes was analyzed. RESULTS: A total of 119 patients with 215 recurrent lymph nodes were identified. There were 47 (39.5%) patients with cervical LNR and 102 (85.7%) patients with upper mediastinal LNR. The high-risk regions were station 101L/R, station 104L/R, station 106recL/R, station 105 and station 106pre for upper TESCC and station 104L/R, station 106recL/R, station 105, station 106pre and station 106tbL for middle and lower TESCCs. LNR in the external group of station 104L/R was not common, and LNR was not found in the narrow spaces where the trachea was in close contact with the innominate artery, aortic arch and mediastinal pleura. LNR below the level of the cephalic margin of the superior vena cava was also not common for upper TESCC. CONCLUSIONS: The CTVnd of PORT in the cervical and upper mediastinal regions should cover station 101L/R, station 104L/R, station 106recL/R, station 105 and station 106pre for upper TESCC and station 104L/R, station 106recL/R, station 105, station 106pre and station 106tbL for middle and lower TESCCs. Based on our results, we proposed a useful atlas for guiding the delineation of CTVnd in TESCC.

Association Between NAT2 Polymorphism and Lung Cancer Risk: A Systematic Review and Meta-Analysis.

Lung cancer is the leading cause of cancer-related death worldwide and has a high incidence rate. N-Acetyltransferase 2 (NAT2) is a polymorphic xenobiotic enzyme, which can catalyze N-acetylation and O-acetylation of various carcinogens such as aromatic, heterocyclic amines and hydrazines. At present, many studies have explored the effects of NAT2 polymorphism on lung cancer, but we found inconsistent results. We researched 18 published studies, involving 4,016 patients and 5,469 controls, to more accurately assess the effects of NAT2 polymorphism on lung cancer risk and to investigate whether smoking is associated. We used STATA software to analyze the extracted data and used STATA for subgroup analysis, sensitivity analysis, and to perform publication bias tests. To determine the correlation, we used the crude odds ratio (ORs) with 95% confidence interval (CIs). Our study was prospectively registered in PROSPERO (CRD42020159737). The odds ratio was 1.53 (95% CI: 1.21-1.95, I² = 45.2%, P=0.104) for the NAT2 slow + intermediate phenotype versus rapid phenotype. The results suggested that people with NAT2 non-rapid (slow + intermediate) phenotype have a significantly increased risk of lung cancer. In addition, NAT2 rapid phenotype was significantly associated with reduced risk of lung cancer, compared with slow phenotype or intermediate phenotype (slow phenotype vs . rapid phenotype: OR: 1.61, 95% CI: 1.07-2.42, I²= 50%, P= 0.075; intermediate phenotype vs . rapid phenotype: OR: 1.47, 95% CI: 1.15-1.88, I²= 40.3%, P= 0.137).

Anatomy of lymphatic drainage of the esophagus and lymph node metastasis of thoracic esophageal cancer.

The lymphatic drainage of the inner layers (mucosa and submucosa) and the outer layers (muscularispropria and adventitia) of the thoracic esophagus is different. Longitudinal lymphatic vessels and long drainage territory in the submucosa and lamina propria should be the bases for bidirectional drainage and direct drainage to thoracic duct and extramural lymph nodes (LN). The submucosal vessels for direct extramural drainage are usually thick while lymphatic communication between the submucosa and intermuscular area is usually not clearly found, which does not facilitate transversal drainage to paraesophageal LN from submucosa. The right paratracheal lymphatic chain (PLC) is well developed while the left PLC is poorly developed. Direct drainage to the right recurrent laryngeal nerve LN and subcarinal LN from submucosa has been verified. Clinical data show that lymph node metastasis (LNM) is frequently present in the lower neck, upper mediastinum, and perigastric area, even for early-stage thoracic esophageal cancer (EC). The lymph node metastasis rate (LNMR) varies mainly according to the tumor location and depth of tumor invasion. However, there are some crucial LN for extramural relay which have a high LNMR, such as cervical paraesophageal LN, recurrent laryngeal nerve LN, subcarinal LN, LN along the left gastric artery, lesser curvature LN, and paracardial LN. Metastasis of thoracic paraesophageal LN seems to be a sign of more advanced EC. This review gives us a better understanding about the LNM and provides more information for treatments of thoracic EC.

The impact of adjuvant therapies on patient survival and the recurrence patterns for resected stage IIa-IVa lower thoracic oesophageal squamous cell carcinoma.

BACKGROUND: This study evaluated the impact of adjuvant therapies on patient survival and disease recurrence patterns to identify an effective adjuvant therapy for resected lower thoracic oesophageal squamous cell carcinoma (LTESCC). METHODS: Clinical data of 127 patients with stage IIa-IVa LTESCC with a minimum 2-year follow-up after oesophagectomy were analysed. The survival and recurrence patterns were compared among patients who received adjuvant radiotherapy, adjuvant chemotherapy, adjuvant chemoradiotherapy, or surgery alone. RESULTS: Eighty-eight patients (69.3%) were identified as having disease recurrence. The regional lymph node recurrence rate was 57.5%, and the recurrence rates were high in the lower neck, upper mediastinum, and upper abdomen. Compared to surgery alone, adjuvant radiotherapy or chemoradiotherapy significantly decreased the recurrence rate (p < 0.05). Adjuvant chemoradiotherapy significantly improved overall survival, disease-free survival, and locoregional recurrence-free survival compared to surgery alone (p = 0.01, 0.01, and 0.00, respectively). Pathologically positive lymph nodes (PPLNs) in the lower mediastinum represented a potential risk factor for cervical recurrence (HR 2.97, 95%CI 1.19-7.39). Multivariable analysis showed that postoperative radiotherapy (HR 0.30, 95%CI 0.13-0.68) and PPLNs in the upper mediastinum (HR 3.72, 95%CI 1.30-10.67) were independent risk factors for upper mediastinal recurrence, while postoperative radiotherapy (HR 0.37, 95%CI 0.16-0.85) and PPLNs in the abdomen (HR 2.57, 95%CI 1.12-5.92) were independent risk factors for abdominal recurrence. CONCLUSION: Adjuvant chemoradiotherapy was the most effective adjuvant therapy for resected stage IIa-IVa LTESCC. The lower neck, upper mediastinum, and upper abdomen were high-risk regions for postoperative radiotherapy. The regions of PPLNs may be important factors for individual targets.

A retrospective study of pattern of recurrence after radical surgery for thoracic esophageal carcinoma with or without postoperative radiotherapy.

The present study aimed to investigate the recurrence pattern of thoracic esophageal cancer (TEC) following radical surgery for guiding postoperative radiotherapy (PRT). Patterns of recurrence were analyzed in patients with recurrence for the first time after radical surgery at the First Affiliated Hospital of Anhui Medical University (Anhui, China) from January 2012 to December 2015. A total of 244 patients were reviewed in the study. The mean recurrence time for patients with PRT was >1 month longer than that for patients without PRT. The lymphatic, anastomotic and hematological recurrence ratios were 87.9 vs. 69.2%, 4.0 vs. 11.5% and 8.0 vs. 17.2%, respectively for patients without and with PRT. The most common recurrence regions were staion1 and station 2-4 (30.0 vs. 36.5% and 37.2% vs. 23.1%, respectively, for patients without and with PRT). The lymphatic recurrence of upper TEC was almost in station1 and station 2-4 (infield). The middle and lower TEC also had a high probability of lymphatic recurrence in station 1 and station 2-4 (totally 76.3 vs. 57.6% and 61.9 vs. 61.1%, respectively). The recurrence ratio significantly decreased in station 2-4 (infield) for middle TEC patients with PRT compared with patients without PRT (P=0.03), while no significant differences in the lymphatic recurrence ratios were observed in other regions (P>0.05). The differences of recurrence ratios in station 7, station 8 and celiac regions (infield) for lower TEC patients without and with PRT also demonstrated no statistical significance (P>0.05). The results of the present study indicated that the lower neck, supraclavicular regions and upper mediastinal regions (station 1, 2 and 4) should be included in the clinic target volume (CTV) for PRT, while lower mediastinal regions, celiac regions and anastomotic may not be included in CTV.

Endoscopic Management of Early Upper Gastrointestinal Bleeding After Minimally Invasive Ivor-Lewis Esophagectomy.

Minimally invasive esophagectomy is now accepted as a regular treatment modality for esophageal cancer. Upper gastrointestinal (GI) bleeding is a common postoperative adverse event of esophagectomy. However, there are very few reports in the literature on endoscopic management of early upper GI bleeding after an esophagectomy. Here, we report the successful management of such an early case of GI bleeding after thoracolaparoscopic esophagectomy by the use of endoscopic intrathoracic anastomosis.

Thoracoscopic purse string technique for minimally invasive Ivor Lewis esophagectomy.

OBJECTIVE: Thoracolaparoscopic esophagectomy with chest anastomosis (TLE-chest) is increasingly performed for middle and lower esophageal cancer; however, gastroesophageal anastomosis for this surgery remains both challenging and inefficient. To address this issue, we previously reported our MIE technique with Ivor-Lewis anastomosis. Here we present the video to introduce our TLE-chest operation procedures. METHODS: TLE-chest with a combined thoracoscopic and laparoscopic technique was performed by one group of surgeons. From October 2011 to September 2013, 80 esophageal cancer patients were treated with TLE-chest using this improved anastomotic technique. RESULTS: The surgery was successful for all patients, although the anastomosis in one patient required intraoperative manual repair. No patients required open conversion. In this video, dissociation of stomach, and dissection of lymph nodes, creation of gastric tube and staple line embedding, jejunostomy were carried out by laparoscopic surgery. Dissection of esophageal cancer and mediastinal lymph nodes were done through rib 3 or 4 by a 3-4 cm video-assisted right anterior minithoracotomy, then esophago-gastric anastomosis was performed in right thoracic cavity This video shows the R0 resection of T3N0M0 esophageal cancer. Totally, 36 lymph nodes were dissected, including 21 mediastinal lymph nodes and 15 abdominal lymph nodes. The patient recovered well and was discharged on day 8 after the surgery, with good short term outcomes. CONCLUSIONS: A safe, cost effective purse string stapled anastomotic technique has been presented for TLE-chest in our video. It is consistent with the oncology principles.

Pursestring stapled anastomotic technique for minimally invasive Ivor Lewis esophagectomy.

We describe a pursestring stapled anastomotic technique for minimally invasive Ivor Lewis esophagectomy, in which a pursestring is hand sewn through the muscular layer of the intact esophagus by using one piece of 3-0 Prolene suture. The anvil of a circular stapler is inserted through an esophageal incision, 2 to 3 cm distal to the pursestring, and secured by the pursestring. The esophagus is transected, and the mucosa of the proximal stump is retained 5 mm longer than the adjacent muscular layer. The gastroesophageal anastomosis is completed and embedded by using the previously reserved 2 cm of mediastinal pleura.

HIF-1α effects on angiogenic potential in human small cell lung carcinoma.

BACKGROUND: Hypoxia-inducible factor-1 alpha (HIF-1α) maybe an important regulatory factor for angiogenesis of small cell lung cancer (SCLC). Our study aimed to investigate the effect of HIF-1α on angiogenic potential of SCLC including two points: One is the effect of HIF-1α on the angiogenesis of SCLC in vivo. The other is the regulation of angiogenic genes by HIF-1α in vitro and in vivo. METHODS: In vivo we used an alternative method to study the effect of HIF-1a on angiogenic potential of SCLC by buliding NCI-H446 cell transplantation tumor on the chick embryo chorioallantoic membrane (CAM) surface. In vitro we used microarray to screen out the angiogenic genes regulated by HIF-1a and tested their expression level in CAM transplantation tumor by RT-PCR and Western-blot analysis. RESULTS: In vivo angiogenic response surrounding the SCLC transplantation tumors in chick embryo chorioallantoic membrane (CAM) was promoted after exogenous HIF-1α transduction (p < 0.05). In vitro the changes of angiogenic genes expression induced by HIF-1α in NCI-H446 cells were analyzed by cDNA microarray experiments. HIF-1α upregulated the expression of angiogenic genes VEGF-A, TNFAIP6, PDGFC, FN1, MMP28, MMP14 to 6.76-, 6.69-, 2.26-, 2.31-, 4.39-, 2.97- fold respectively and glycolytic genes GLUT1, GLUT2 to2.98-, 3.74- fold respectively. In addition, the expression of these angiogenic factors were also upregulated by HIF-1α in the transplantion tumors in CAM as RT-PCR and Western-blot analysis indicated. CONCLUSIONS: These results indicated that HIF-1α may enhance the angiogenic potential of SCLC by regulating some angiogenic genes such as VEGF-A, MMP28 etc. Therefore, HIF-1α may be a potential target for the gene targeted therapy of SCLC.