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Background: The first (1G) and second (2G) generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show differential inhibitory capacities towards EGFR T790M-mutated non-small-cell lung cancer (NSCLC) cells.Objective: To assess the ratio of the allele fractions of T790M (AFT790M) to EGFR-activating mutations (AFmEGFR) in patients treated with 1G and 2G EGFR TKIs who acquired T790M-mediated resistance and to determine the relationship between AF and the later efficacy of osimertinib.Patients and Methods: The efficacy of osimertinib was reviewed for 54 T790M-positive EGFR-mutated NSCLC patients grouped by the generation of prior EGFR TKI use (1G vs. 2G). AFmEGFR and AFT790M were determined by QuantStudio digital PCR using tissues obtained upon acquired resistance.Results: The progression-free survival (PFS; 20.3 vs. 11.6 months, p = 0.031) and the 1-year PFS rate (63.2 vs. 37.5%, p = 0.029) for osimertinib were significantly better for group 1G compared to group 2G. The ratio of AFT790M to AFmEGFR in group 1G was significantly higher than in group 2G (46.16 ± 5.40% vs. 25.86 ± 4.25%, p = 0.009). An unbiased analysis revealed three AF-associated clusters (ARCs) suggesting the ratio of AFT790M to AFmEGFR correlates with the efficacy of osimertinib. We found all patients in ARC2 having the highest ratio of AFT790M to AFmEGFR to have previously been treated with a 1G EGFR TKI and to show the longest osimertinib PFS compared to ARC3 (NR vs. 11.9 months, p = 0.060) and ARC1 (NR vs. 12.4 month, p = 0.045).Conclusions: Acquired T790M fraction of EGFR-mutated NSCLC is linked to different generations of prior EGFR TKI use and the later efficacy of osimertinib. [ABSTRACT FROM AUTHOR]

Purpose: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group.Methods: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images.Results: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP.Conclusions: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life. [ABSTRACT FROM AUTHOR]

Smoking leads to the presence of various elements, including toxic metals and metalloids, in tissues and fluids, thus contributing to cancer risk. This study assessed the concentrations of 14 elements (Ag, Al, As, Co, Cr, Cu, Fe, Ni, Mn, Mo, Pb, Sn, V, and Zn) and biochemical parameters (glucose, lactate dehydrogenase, and total protein) in the pleural effusion (PE) of patients with lung cancer. The potential association of these parameters with smoking was assessed. Total of 48 patients with lung cancer (26 non-smokers and 22 smokers) received thoracocentesis for PE removal. Analysis results revealed that among the biochemical parameters, only the glucose concentration was significantly higher in current smokers than in non-smokers; the other parameters showed no significant difference. The concentration of Zn in the PE was significantly lower in all smokers (10 former and 12 current smokers) than in non-smokers, but the other elements did not differ significantly between the two groups and smoker subgroups. Simultaneously, Zn correlated negatively with glucose concentrations in all smokers, positively with lactate dehydrogenase (LDH) concentration in current smoker, and positively with total protein (TP) concentrations in non-smokers. This is for the first time the relation between Zn and certain biochemical parameters in PE was found, the observation requiring further studies to explain the potential interactions between this element and glucose, LDH, and TP concentrations. [ABSTRACT FROM AUTHOR]

Purpose: Transthoracic thoracoscopic lobectomy is the preferred method of surgical treatment for early lung cancer. Current methods require a transthoracic approach and are associated with chronic postoperative pain in up to 25 % of patients. Single-port transumbilical uniport surgery may offer advantages over multiport surgery with less postoperative pain and better cosmetic results. The aim of this study was to evaluate the feasibility of a transumbilical anatomic lobectomy of the lung (TUAL) in a canine model. Methods: TUAL was performed in 12 beagle dogs using a 3-cm umbilical incision combined with a 2.5-cm diaphragmatic incision. Variables evaluated for surgical outcomes were operating time, operative complications, body rectal temperature, respiratory rate, white blood cell count, and arterial blood gases. Results: TUAL was successfully completed in ten animals. There were six bleeding complications related to surgery. In four animals, an avulsion of pulmonary vessel causes intraoperative bleeding, requiring simultaneous pulmonary artery and bronchus resections. In one animal, slipping of endoclip after vessel clipping caused perioperative bleeding. The other animal encountered bleeding complication during dissection of inferior pulmonary vein. Both animals required conventional thoracotomy to complete the surgery. Conclusions: TUAL in the canine model is feasible but associated with significant morbidity. With further development and refinement of instruments, comparative studies between the novel transumbilical lobectomy and the current video-assisted transthoracic lobectomy will clarify the role of transumbilical lobectomy in thoracic surgery. [ABSTRACT FROM AUTHOR]

Purpose: Transoral endoscopic surgery has been shown to be feasible and safe in both humans and animal models. The purpose of this study was to evaluate the safety and efficacy of transoral and conventional thoracoscopy for thoracic exploration, surgical lung biopsy, and pericardial window creation. Methods: The animals ( n = 20) were randomly assigned to the transoral endoscopic approach group ( n = 10) or conventional thoracoscopic approach group ( n = 10). Transoral thoracoscopy was performed with a flexible bronchoscope via an incision over the vestibulum oris. In conventional thoracoscopy, access to the thoracic cavity was obtained through a thoracic incision. Surgical outcomes (body weight, operating time, operative complications, and time to resumption of normal diet), physiologic parameters (respiratory rate, body temperature), inflammatory parameters [white blood cell (WBC) counts and C-reactive protein (CRP)], and pulmonary parameters (arterial blood gases) were compared for both procedures. Results: The surgical lung biopsy and pericardial window creation were successfully performed in all animals except one animal in the transoral group. There was no significant difference in operating times between the groups. The increase in WBC in the transoral thoracoscopy group was significantly smaller on postoperative day 1 than in the conventional thoracoscopy group ( p = 0.0029). The transoral group had an earlier return to preoperative body temperature ( p = 0.041) and respiratory rate ( p = 0.045) on day 7. With respect to pulmonary parameters, there was no significant difference in blood pH, pCO, or PaCO between the transoral and transthoracic groups. All animals survived without complications 14 days after surgery. Conclusions: This study demonstrated that the transoral approach was comparable to conventional thoracoscopic surgery for lung biopsy and pericardial window creation in terms of safety and efficacy. [ABSTRACT FROM AUTHOR]

Background: The feasibility of the transtracheal approach to the thoracic cavity has been demonstrated, but surgical lung biopsy via the tracheal approach still remains a challenge. This study aimed to evaluate the feasibility and outcome of transoral surgical lung biopsy under a single preoperative dose of parenteral antibiotics. Methods: Transoral thoracoscopy and surgical lung biopsy were performed for 10 anesthetized dogs after a single intravenous injection of cefazoline (20 mg/kg). A 12-mm transoral incision was created on the vestibulum, and a homemade metallic tube was advanced into the thoracic cavity via the pretracheal and substernal space under endoscopic guidance. After thoracic exploration, surgical lung biopsy was performed using an electrosurgical snare with a flexible bronchoscope inserted through the metallic tube. The resection margin of the lung was secured with a homemade endoloop. The animals were killed by day 14 after the surgery for gross and histologic evaluations. Results: The thoracic cavity was evaluated and lung biopsy was performed successfully (for 3 lobes in the right lung and 2 lobes in the left lung) in 9 of the 10 dogs. Neither mortality nor intraoperative complications were observed. The average time for the transoral thoracoscopy and surgical lung biopsy was 133.5 min. Postmortem examination showed complete healing, with fibrosis and moderate adhesion over the resection margin. No evidence of either mediastinitis or intrathoracic infection was observed. Conclusion: This study showed the feasibility of transoral thoracoscopy and surgical lung biospy in dogs. Moreover, single-dose prophylaxis with cefazoline in transoral surgical lung biopsy was found to be effective in preventing potential infection. [ABSTRACT FROM AUTHOR]

This corrects the article DOI: 10.1038/srep46667 [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease(COPD) is characterized by enhanced chronic inflammation in the airways, lung parenchyma, and circulation. We investigated whether SUV39H1, a histone methyltransferase, is causatively implicated in the abnormal inflammation observed in COPD. The SUV39H1 and H3K9me3 levels were reduced in peripheral blood mononuclear cells(PBMCs), primary human small airway epithelial cells(HSAEpCs) and lung tissues from COPD patients, which were correlated with poor lung function and the serum IL-8 and IL-6 levels. A specific SUV39H1 inhibitor, chaetocin, induced a distinct COPD panel of inflammatory cytokines in normal PBMCs. Mechanistically, chaetocin reduced the SUV39H1 and H3K9me3 levels in the native IL-8 promoter in normal HSAEpCs, which mimicked unstimulated COPD HSAEpCs and led to decreased HP-1α levels and increased RNA polymerase II levels. SUV39H1 knockdown reproduced the pattern of COPD inflammation, whereas SUV39H1 overexpression in COPD HSAEpCs rescued the H3K9me3 levels and suppressed inflammation. In COPD mice, chaetocin further repressed the SUV39H1/H3K9me3 levels and enhanced inflammation. SUV39H1 epigenetically controls a distinct panel of pro-inflammatory cytokines. Its reduction in COPD leads to a loss of the repressive chromatin mark H3K9me3 and confers an abnormal inflammatory response to stimulators. SUV39H1 and its regulatory pathways are potential therapeutic targets for COPD. [ABSTRACT FROM AUTHOR]