Optimizing Precision: A Trajectory Tract Reference Approach to Minimize Complications in CT-Guided Transthoracic Core Biopsy.

The advent of computed tomography (CT)-guided transthoracic needle biopsy has significantly advanced the diagnosis of lung lesions, offering a minimally invasive approach to obtaining tissue samples. However, the technique is not without risks, including pneumothorax and hemorrhage, and it demands high precision to ensure diagnostic accuracy while minimizing complications. This study introduces the Laser Angle Guide Assembly (LAGA), a novel device designed to enhance the accuracy and safety of CT-guided lung biopsies. We retrospectively analyzed 322 CT-guided lung biopsy cases performed with LAGA at a single center over seven years, aiming to evaluate its effectiveness in improving diagnostic yield and reducing procedural risks. The study achieved a diagnostic success rate of 94.3%, with a significant reduction in the need for multiple needle passes, demonstrating a majority of biopsies successfully completed with a single pass. The incidence of pneumothorax stood at 11.1%, which is markedly lower than the reported averages, and only 0.3% of cases necessitated chest tube placement, underscoring the safety benefits of the LAGA system. These findings underscore the potential of LAGA to revolutionize CT-guided lung biopsies by enhancing procedural precision and safety, making it a valuable addition to the diagnostic arsenal against pulmonary lesions.

Enhancing precision in lung tumor ablation through innovations in CT-guided technique and angle control.

BACKGROUND: This retrospective study aimed to evaluate the precision and safety outcomes of image-guided lung percutaneous thermal ablation (LPTA) methods, focusing on radiofrequency ablation (RFA) and microwave ablation (MWA). The study utilized an innovative angle reference guide to facilitate these techniques in the treatment of lung tumors. METHODS: This study included individuals undergoing LPTA with the assistance of laser angle guide assembly (LAGA) at our hospital between April 2011 and March 2021. We analyzed patient demographics, tumor characteristics, procedure details, and complications. Logistic regressions were employed to assess risk factors associated with complications. RESULTS: A total of 202 patients underwent ablation for 375 lung tumors across 275 sessions involving 495 ablations. Most procedures used RFA, especially in the right upper lobe, and the majority of ablations were performed in the prone position (49.7%). Target lesions were at a median depth of 39.3 mm from the pleura surface, and remarkably, 91.9% required only a single puncture. Complications occurred in 31.0% of ablations, with pneumothorax being the most prevalent (18.3%), followed by pain (12.5%), sweating (6.5%), fever (5.0%), cough (4.8%), hemothorax (1.6%), hemoptysis (1.2%), pleural effusion (2.0%), skin burn (0.6%), and air emboli (0.2%). The median procedure time was 21 min. Notably, smoking/chronic obstructive pulmonary disease emerged as a significant risk factor for complications. CONCLUSION: The LAGA-assisted LPTA enhanced safety by improving accuracy and reducing risks. Overall, this investigation contributes to the ongoing efforts to refine and improve the clinical application of these thermal ablation techniques in the treatment of lung tumors.

Puncture frequency predicts pneumothorax in preoperative computed tomography-guided lung nodule localization for video-assisted thoracoscopic surgery.

BACKGROUND: Iatrogenic pneumothorax is the most frequent complication in preoperative CT-guided localization (POCTGL) of lung nodules. We aimed to determine the predictive factors of iatrogenic pneumothorax. METHODS: We retrospectively analyzed data of consecutive POCTGL procedures in patients who received video-assisted thoracoscopic surgery (VATS) at our hospital between May 2015 and October 2019. All of our patients utilized laser angle guide assembly to aid in the localization procedures. RESULTS: In 610 consecutive POCTGL procedures, 40 (6.6%) patients developed iatrogenic pneumothorax, and complications occurred in 8.5%. Univariate analyses revealed that puncture frequency, male gender, puncture depth, left decubitus position, and nodule near fissure were factors associated with pneumothorax, while multivariate analysis showed that only male gender (odds ratio 3.58, p = 0.012) and puncture frequency (odds ratio 2.39/time, p = 0.0004) determined development of pneumothorax. Further collective analysis on puncture frequency revealed that tumor in a difficult zone (1.33 ± 0.71 vs. 1.19 ± 0.45, p = 0.002), especially adjacent to the mediastinum (1.41 ± 0.75 vs. 1.21 ± 0.52, p = 0.002), angle difference of plan-to-practice (r = 0.209, p = < 0.001), depth to skin (r = 0.152, p < 0.001), and depth to pleura (r = 0.164, p < 0.001) were factors related to increased puncture frequency in univariate analyses. Only angle difference of plan-to-practice was associated in multivariate analysis (odds ratio: 1.158, p = 0.008). CONCLUSIONS: Puncture frequency was the key factor in the development of iatrogenic pneumothorax from POCTGL. Other associated factors, especially angle difference, may have affected the puncture frequency and subsequently have some influence on the incidence of iatrogenic pneumothorax.

Identification of distinct slow mode of reversible adaptation of pancreatic ductal adenocarcinoma to the prolonged acidic pH microenvironment.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic neoplasm with high metastatic potential and poor clinical outcome. Like other solid tumors, PDAC in the early stages is often asymptomatic, and grows very slowly under a distinct acidic pHe (extracellular pH) microenvironment. However, most previous studies have only reported the fate of cancerous cells upon cursory exposure to acidic pHe conditions. Little is known about how solid tumors-such as the lethal PDAC originating within the pancreatic duct-acinar system that secretes alkaline fluids-evolve to withstand and adapt to the prolonged acidotic microenvironmental stress. METHODS: Representative PDAC cells were exposed to various biologically relevant periods of extracellular acidity. The time effects of acidic pHe stress were determined with respect to tumor cell proliferation, phenotypic regulation, autophagic control, metabolic plasticity, mitochondrial network dynamics, and metastatic potentials. RESULTS: Unlike previous short-term analyses, we found that the acidosis-mediated autophagy occurred mainly as an early stress response but not for later adaptation to microenvironmental acidification. Rather, PDAC cells use a distinct and lengthy process of reversible adaptive plasticity centered on the early fast and later slow mitochondrial network dynamics and metabolic adjustment. This regulates their acute responses and chronic adaptations to the acidic pHe microenvironment. A more malignant state with increased migratory and invasive potentials in long-term acidosis-adapted PDAC cells was obtained with key regulatory molecules being closely related to overall patient survival. Finally, the identification of 34 acidic pHe-related genes could be potential targets for the development of diagnosis and treatment against PDAC. CONCLUSIONS: Our study offers a novel mechanism of early rapid response and late reversible adaptation of PDAC cells to the stress of extracellular acidosis. The presence of this distinctive yet slow mode of machinery fills an important knowledge gap in how solid tumor cells sense, respond, reprogram, and ultimately adapt to the persistent microenvironmental acidification.

Preoperative computed tomography-guided pulmonary nodule localization augmented by laser angle guide assembly.

BACKGROUND: There is an increasing need for thoracic medicine specialists to master preoperative localizations after high rates of sub-centimeter nodules have been positively screened by low-dose CT. The Laser Angle Guide Assembly® (LAGA), an innovative angle reference device for CT-guided pulmonary invasive procedures, has been developed to safely and efficiently aid in the performance of preoperative CT-guided localizations (POCTGL). METHODS: The clinical and localization data of patients who received LAGA-assisted POCTGL for pulmonary nodules between May 2015 and June 2018 were collected and analyzed. RESULTS: One hundred and eighty-seven patients with 266 pulmonary nodules received LAGA-assisted POCTGL. The number of lung nodules localized for one surgery ranged from 1 to 5, with >1 for 22.1% of the surgeries. The median nodule size was 6 mm. A hookwire was inserted in 32 (12%) of the nodules. Most (83.1%) of the localizations were completed with a single puncture. The median angle was 18 degrees. The median and maximum depths of the nodule to pleura were 12 and 60 mm, respectively. The median procedure time was 19 minutes. The successful targeting and field targeting rates were 100% and 98.1%, respectively. Pneumothorax was noted in 17 (6.4%) localizations that did not require chest drainage. The multivariable analyses for pneumothorax showed odds ratios of 2.4 (95% confidence interval, 1.2-4.9) for puncture times/nodule and 10.1 (95% confidence interval, 2.3-41.7) for tumors adjacent to the fissure, respectively. There was no incidence of hookwire migration. CONCLUSIONS: LAGA enhanced the precision of POCTGL by optimizing targeting precision and decreasing repeated punctures, which minimized complications, such as pneumothorax.

Computed tomography-guided localization with laser angle guide for thoracic procedures.

Computed tomography (CT)-guided lung procedures such as preoperative localizations, biopsies, and ablations are associated with morbidity even mortality. Often, the puncture angle is determined by the 'experienced hand' without a precise guide. We describe here the Laser Angle Guide Assembly® to direct and steer the puncture angles precisely. It decreases procedure-related complications, saves time, reduces costs, avoids repeated punctures, and minimizes radiation exposures.

Quercetin and chrysin inhibit nickel-induced invasion and migration by downregulation of TLR4/NF-κB signaling in A549 cells.

Nickel exposure promotes the invasive potential of human lung cancer cells. Polyphenols such as quercetin, curcumin, chrysin, apigenin, and luteolin, present in many plant foods may suppress the development of cancers. However, whether these compounds inhibit the promoting effects of Nickel on cancer cell invasion and migration as well as the possible mechanisms are unclear. In the present study, we first showed that quercetin, curcumin, chrysin, apigenin, and luteolin at 5 µM, significantly suppressed the promoting effects of NiCl2 (Ni) on migration and invasion in H1975 and A549 human lung cancer cells. The five phytochemicals also significantly suppressed the secretion of cytokines, IL-1ß, IL-6, TNF-α and IL-10, induced by Ni in A549 cells. The overall efficiency of quercetin was the best, followed by chrysin and the other compounds. Furthermore, we found that quercetin and chrysin suppressed the mRNA and protein expression of TLR4 and Myd88. Consistently, quercetin and chrysin also decreased the phosphorylation of IKKß and IκB, the nuclear level of p65 (NF-κB) as well as the expression of MMP-9 in A549 cells exposed to Ni. In conclusion, these results suggest the potential preventive effects of the five phytochemicals on the promoting effect of Ni on human lung cancer cell invasion. In addition, the preventive effects are associated with downregulation of the TLR4/NF-κB signaling pathway, especially for quercetin and chrysin.

Dioscin overcome TKI resistance in EGFR-mutated lung adenocarcinoma cells via down-regulation of tyrosine phosphatase SHP2 expression.

Resistance to tyrosine kinase inhibitors (TKIs) results in tumor relapse and poor prognosis in patients with lung adenocarcinoma. TKI resistance caused by epidermal growth factor receptor (EGFR) mutations at T790M and c-Met amplification occurs through persistent activation of the MEK/ERK and PI3K/AKT signaling pathways. We therefore expected that dual inhibitors of both signaling pathways could overcome TKI resistance in lung adenocarcinoma. Here, dioscin was selected from a product library of Chinese naturally occurring compounds and overcame TKI resistance in EGFR-mutated lung adenocarcinoma cells. Mechanistically, dioscin may down-regulate the expression of SH2 domain-containing phosphatase-2 (SHP2) at the transcription level by increasing p53 binding to the SHP2 promoter due to reactive oxygen species (ROS). Simultaneous inhibition of MEK/ERK and PI3K/AKT activation via decreased SHP2 expression and its interaction with GAB1 may be responsible for dioscin-mediated TKI sensitivity. A higher unfavorable response to TKI therapy occurred more commonly in patients with high SHP2 mRNA expression than in patients with low SHP2 mRNA expression. Therefore, we suggest that dioscin may act as a dual inhibitor of the MEK/ERK and PI3K/AKT signaling pathways to overcome TKI resistance via dysregulation of SHP2 expression in lung adenocarcinoma.

Early Management of Retained Hemothorax in Blunt Head and Chest Trauma.

BACKGROUND: Major blunt chest injury usually leads to the development of retained hemothorax and pneumothorax, and needs further intervention. However, since blunt chest injury may be combined with blunt head injury that typically requires patient observation for 3-4 days, other critical surgical interventions may be delayed. The purpose of this study is to analyze the outcomes of head injury patients who received early, versus delayed thoracic surgeries. MATERIALS AND METHODS: From May 2005 to February 2012, 61 patients with major blunt injuries to the chest and head were prospectively enrolled. These patients had an intracranial hemorrhage without indications of craniotomy. All the patients received video-assisted thoracoscopic surgery (VATS) due to retained hemothorax or pneumothorax. Patients were divided into two groups according to the time from trauma to operation, this being within 4 days for Group 1 and more than 4 days for Group 2. The clinical outcomes included hospital length of stay (LOS), intensive care unit (ICU) LOS, infection rates, and the time period of ventilator use and chest tube intubation. RESULT: All demographics, including age, gender, and trauma severity between the two groups showed no statistical differences. The average time from trauma to operation was 5.8 days. The ventilator usage period, the hospital and ICU length of stay were longer in Group 2 (6.77 vs. 18.55, p = 0.016; 20.63 vs. 35.13, p = 0.003; 8.97 vs. 17.65, p = 0.035). The rates of positive microbial cultures in pleural effusion collected during VATS were higher in Group 2 (6.7 vs. 29.0%, p = 0.043). The Glasgow Coma Scale score for all patients improved when patients were discharged (11.74 vs. 14.10, p < 0.05). DISCUSSION: In this study, early VATS could be performed safely in brain hemorrhage patients without indication of surgical decompression. The clinical outcomes were much better in patients receiving early intervention within 4 days after trauma.

An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling.

High programmed cell death 1 ligand 1 (PD-L1) expression in tumour tissues was associated with poor outcomes in non-small cell lung cancer (NSCLC) due to evasion of tumour immune surveillance. However, the role of PD-L1 in tumour invasion and resistance to tyrosine kinase inhibitor (TKI) treatments is not fully understood. Here, we provide evidence to support the involvement of PD-L1 expression in the invasiveness and TKI resistance in NSCLC cells by increased Bcl-2-associated athanogene-1 (BAG-1) expression. The upregulation of BAG-1 transcription by PD-L1 was verified by constructing the BAG-1 promoters using the polymerase chain reaction (PCR) and deletion mutations for luciferase reporter assays. The results indicated that C/EBPß phosphorylation by extracellular signal-regulated kinase (ERK) signalling was responsible for PD-L1-mediated BAG-1 transcription. Mechanistically, the PD-L1-induced BAG-1 expression reciprocally increased PD-L1 expression due to persistent activation of ERK signalling, and it consequently conferred TKI resistance in NSCLC cells. The mechanistic action of this cell model was further confirmed by an animal model, affirming that PD-L1 conferred tumour invasiveness and TKI resistance via persistent activation of ERK signalling by the PD-L1/BAG-1 axis. We therefore suggest a combination of an ERK inhibitor with a TKI as a potential strategy for conquering PD-L1-mediated tumour invasion and TKI resistance in NSCLC patients whose tumours harbour high PD-L1/high BAG-1 expression.

PAK1 Is a Novel Therapeutic Target in Tyrosine Kinase Inhibitor-Resistant Lung Adenocarcinoma Activated by the PI3K/AKT Signaling Regardless of EGFR Mutation.

PURPOSE: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (TKI) treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance. EXPERIMENTAL DESIGN: Molecular manipulations were performed to verify whether TKI resistance mediated by p21-activated kinase (PAK1) could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-ß/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes was evaluated. RESULTS: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR-wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-ß/miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low-E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or low-E-cadherin tumors. CONCLUSIONS: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA-expressing tumors. Clin Cancer Res; 22(21); 5370-82. ©2016 AACR.

The enhancing effect of genistein on apoptosis induced by trichostatin A in lung cancer cells with wild type p53 genes is associated with upregulation of histone acetyltransferase.

Genistein has been shown to enhance the antitumor activity of trichostatin A (TSA) in human lung carcinoma A549 cells. However, whether the combined treatment exerts the same effect in other lung cancer cells is unclear. In the present study we first compared the enhancing effect of genistein on the antitumor effect of TSA in ABC-1, NCI-H460 (H460) and A549 cells. Second, we investigated whether the effects of genistein are associated with increased histone/non-histone protein acetylation. We found that the enhancing effect of genistein on cell-growth-arrest in ABC-1 cells (p53 mutant) was less than in A549 and H460 cells. Genistein enhanced TSA induced apoptosis in A549 and H460 cells rather than in ABC-1 cells. After silencing p53 expression in A549 and H460 cells, the enhancing effect of genistein was diminished. In addition, genistein increased TSA-induced histone H3/H4 acetylation in A549 and H460 cells. Genistein also increased p53 acetylation in H460 cells. The inhibitor of acetyltransferase, anacardic acid, diminished the enhancing effect of genistein on all TSA-induced histone/p53 acetylation and apoptosis. Genistein in combination with TSA increased the expression of p300 protein, an acetyltransferase, in A549 and NCI-H460 cells. Furthermore, we demonstrated that genistein also enhanced the antitumor effect of genistein in A549-tumor-bearing mice. Taken together, these results suggest that the enhancing effects of genistein on TSA-induced apoptosis in lung cancer cells were p53-dependent and were associated with histone/non-histone protein acetylation.

The surgical stabilization of multiple rib fractures using titanium elastic nail in blunt chest trauma with acute respiratory failure.

BACKGROUND: Blunt chest injuries are usually combined with multiple rib fractures and severe lung contusions. This can occasionally induce acute respiratory failure and prolong ventilations. In order to reduce the periods of ventilator dependency, we propose a less invasive method of fixing multiple rib fractures. METHODS: Since October 2009, we have developed a new method to fix fractured ribs caused by blunt trauma. Rib fixations were performed using 2.0- or 2.5-mm intramedullary titanium elastic nails (TEN), with the help of video-assisted thoracoscopic surgery (VATS) and minimal thoracic incisions. All the patients' demographics and postoperative data were collected. RESULTS: From January 2010 to December 2012, a total of 65 patients presenting with multiple rib fractures resulting in acute respiratory failure were included in the study. Twelve patients received the new surgical fixation. Rib fixations were performed at an average of 4 days after trauma. Patients were successfully weaned off ventilators after an average of 3 days. The average length of stay in the hospital and the intensive care unit (ICU) was shorter for the patients with fixation than for nonsurgical patients. All twelve patients returned to normal daily activities and work. CONCLUSIONS: In the reconstruction of an injured chest wall, the VATS with TENs fixation in multiple rib fractures is feasible. This method is also effective in decreasing the length of the surgical wound. Because the structure of the chest cage is protected, the period of mechanical ventilation is shortened and the length of stay in the hospital and the ICU can be reduced.

EGFR mutation and lobar location of lung adenocarcinoma.

The objective of this study was to investigate the associations among lung cancer location, and epidermal growth factor receptor (EGFR) mutation status. Treatment-naive, pathologically confirmed lung adenocarcinomas with tumor specimens available for genetic analysis were included from 2011 through 2014. Overall, 1771 patients with lung adenocarcinoma were included for analysis, after excluding those with carcinoma not otherwise specified, or synchronous multiple primary lung cancers. The median age was 64 years, and the female:male and never smoker:ever smoker ratios were 930:855 (52:48%) and 1167:604 (65:35%), respectively. The EGFR mutation rate was 56%. Among patients, 1093 (62%) had primary tumors in the upper lobes. Compared with the characteristics of the EGFR wild-type, tumors with EGFR activating mutations were more common in women (P < 0.001), never smokers (P < 0.001), and in the upper lobes (P = 0.004). Among EGFR activating mutations, compared with the EGFR exon 19 deletion, L858R mutation were more common in women (P = 0.002), never smokers (P = 0.038), and the upper lobes P < 0.0005). The present study is the first to address that different pulmonary lobar locations might harbor different EGFR mutation subtypes. We demonstrated that adenocarcinomas with L858R mutation, rather than exon 19 deletion or wild-type EGFR gene, prefer to locate over the upper lungs. This phenomenon was more significant in females and never-smokers, implying the result of complex interactions between genetic susceptibility and environmental factors. Therefore, EGFR L858R mutation and exon 19 deletion may not be identical disease entity from the point of carcinogenesis.

MicroRNA-184 Deregulated by the MicroRNA-21 Promotes Tumor Malignancy and Poor Outcomes in Non-small Cell Lung Cancer via Targeting CDC25A and c-Myc.

BACKGROUND: MicroRNA (miR)-184 has been reported to have a dual role in human cancers. However, the role of miR-184 in non-small cell lung cancer (NSCLC) remains unclear. METHODS: Wild-type or mutant CDC25A promoters were constructed by PCR and site-directed mutagenesis to verify whether miR-184 could inhibit CDC25A expression at post-transcription level. Boyden chamber assay was used to assess whether miR-184 could modulate cell invasiveness via targeting CDC25A and c-Myc. We utilized 124 tumors from NSCLC patients to determine miR-184, miR-21, PDCD4 mRNA, c-Myc mRNA, and CDC25A mRNA expression levels by means of real-time PCR analysis. The prognostic value of CDC25A, c-Myc, and miR-184 on overall survival (OS) and relapse-free survival (RFS) was evaluated by Kaplan-Meier and Cox regression analysis. RESULTS: MiR-184 suppressed CDC25A expression by enhancing the instability of its mRNA as a result of miR-184 binding to its coding region. An increase in CDC25A expression by means of a reduction in miR-184 promotes cell invasiveness. Moreover, a concomitant increase in CDC25A and c-Myc expression as a result of decreased miR-184 via the miR-21-mediated PDCD4 reduction is responsible for cell invasiveness. Among patients, miR-184 expression in lung tumors was found to correlate negatively with CDC25A mRNA, c-Myc mRNA, and miR-21 expression, but was positively related to PDCD4 mRNA expression. High-miR-184, High-CDC25A, or high-c-Myc mRNA tumors exhibited shorter OS and RFS periods than their counterparts. The worst OS and RFS were observed in low-miR-184/high-CDC25A/high-c-Myc tumors, followed by low-miR-184 /high-CDC25A, low-miR-184/high-c-Myc, high-c-Myc, and high-CDC25A tumors. CONCLUSIONS: MiR-184 as a tumor suppressor miR inhibits cell proliferation and invasion capability via targeting CDC25A and c-Myc. Low miR-184 level may predict worse prognosis in NSCLC patients.

Video-assisted thoracoscopic surgery for retained hemothorax in blunt chest trauma.

PURPOSE OF REVIEW: In the last decade, video-assisted thoracoscopic surgery (VATS) has become a popular method in diagnosis and treatment of acute chest injuries. Except for patients with unstable vital signs who require larger surgical incisions to check bleeding, this endoscopic surgery could be employed in the majority of thoracic injury patients with stable vital signs. RECENT FINDINGS: In the past, VATS was used to evacuate traumatic-retained hemothorax. Recent study has revealed further that lung repair during VATS could decrease complications after trauma. Management of fractured ribs could also be assisted by VATS. Early VATS intervention within 7 days after injury can decrease the rate of posttraumatic infection and length of hospital stay. In studies of the pathophysiology of animal models, N-acetylcysteine and methylene blue were used in animals with blunt chest trauma and found to improve clinical outcomes. SUMMARY: Retained hemothorax derived from blunt chest trauma should be managed carefully and rapidly. Early VATS intervention is a well tolerated and reliable procedure that can be applied to manage this complication cost effectively.

NKX2-1-mediated p53 expression modulates lung adenocarcinoma progression via modulating IKKß/NF-κB activation.

NKX2-1 plays a dual role in lung adenocarcinoma progression, but the underling mechanism is not fully understood. In the present study, we provide evidence that NKX2-1 directly regulates p53 transcription, and in turn, NKX2-1 elevates the mutant p53/NF-Y complex to up-regulate IKKß transcription in p53-mutant cells, but NKX2-1-mediated wild-type p53 down-regulates IKKß transcription via decreased Sp1 binding to IKKß promoter in p53-WT cells. The IKKß-mediated p65 nuclear localization and epithelial-to-mesenchymal transition (EMT) modulated by the NKX2-1/p53 axis is responsible for soft-agar growth, invasion, and xenograft tumour formation. Among patients, high-IKKß mRNA tumours had higher prevalence in p53-mutant or nuclear p65 tumours than their counterparts, but not related with NKX2-1 mRNA expression. However, when tumours were divided into p53-WT and p53-mutant subgroups, NKX2-1 mRNA expression was negatively correlated with IKKß mRNA in p53-WT subgroup, but positively related with IKKß mRNA expression in p53-mutant subgroup. Kaplan-Meier and Cox regression analysis indicated that high NKX2-1 mRNA tumours exhibited poorer overall survival and relapse free survival than low NKX2-1 mRNA tumours in p53-WT subgroup, but the opposite was observed in p53-mutant subgroup. Therefore, we suggest that NKX2-1 as a tumour suppressor or a tumour promoter in lung adenocarcinoma progression is dependent on p53 status.

Identification of five driver gene mutations in patients with treatment-naïve lung adenocarcinoma in Taiwan.

BACKGROUND: It is important to select appropriate targeted therapies for subgroups of patients with lung adenocarcinoma who have specific gene alterations. METHODS: This prospective study was a multicenter project conducted in Taiwan for assessment of lung adenocarcinoma genetic tests. Five oncogenic drivers, including EGFR, KRAS, BRAF, HER2 and EML4-ALK fusion mutations, were tested. EGFR, KRAS, BRAF and HER2 mutations were assessed by MALDI-TOF MS (Cohort 1). EML4-ALK translocation was tested by Ventana method in EGFR-wild type patients (Cohort 2). RESULTS: From August 2011 to November 2013, a total of 1772 patients with lung adenocarcinoma were enrolled. In Cohort 1 analysis, EGFR, KRAS, HER2 and BRAF mutations were identified in 987 (55.7%), 93 (5.2%), 36 (2.0%) and 12 (0.7%) patients, respectively. Most of these mutations were mutually exclusive, except for co-mutations in seven patients (3 with EGFR + KRAS, 3 with EGFR + HER2 and 1 with KRAS + BRAF). In Cohort 2 analysis, 29 of 295 EGFR-wild type patients (9.8%) were positive for EML4-ALK translocation. EGFR mutations were more common in female patients and non-smokers and KRAS mutations were more common in male patients and smokers. Gender and smoking status were not correlated significantly with HER2, BRAF and EML4-ALK mutations. EML4-ALK translocation was more common in patients with younger age. CONCLUSION: This was the first study in Taiwan to explore the incidence of five oncogenic drivers in patients with lung adenocarcinoma and the results could be valuable for physicians in consideration of targeted therapy and inclusion of clinical trials.

Combination of ß-carotene and quercetin against benzo[a]pyrene-induced pro-inflammatory reaction accompanied by the regulation of antioxidant enzyme activity and NF-κB translocation in Mongolian gerbils.

PURPOSE: We have previously shown that quercetin modulates the proinflammatory effect of ß-carotene (BC) induced by oral benzo[a]pyren (Bap) partly through the regulation of the JNK pathway. In the present study, we determined whether the combination of BC and quercetin regulates the antioxidant enzymes and the activation of NF-κB in Mongolian gerbils exposed to Bap. We also compared the combined effects of BC+ quercetin with that of BC+ ascorbic acid (C)+ α-tocopherol (E). METHODS: The gerbils were given BC (10 mg/kg) alone or in combination with quercetin (50 or 100 mg/kg) or C (13 mg/kg)+E (92 mg/kg) by gavage 3 times/week for 6 months. During the first 2 months, the gerbils were exposed to Bap by intratracheal instillation once/week. The levels of proinflammatory cytokines, thiobarbituric acid reactive substances, antioxidant enzymes and NF-κB activation in the plasma or the lungs were determined. RESULTS: Bap increased the level of proinflammatory cytokines and oxidative stress in the plasma or lungs, while it decreased the antioxidant systems. Bap also increased nuclear NF-κB levels in the lungs. BC partly recovered the Bap-induced decrease in antioxidant activity, antioxidant enzyme activities and glutathione levels but had no effect on proinflammatory cytokines and NF-κB translocation. BC in combination with quercetin or C+E suppressed all the harmful effects induced by Bap. All the effects of quercetin at 100 mg/kg were similar to the effect of C+E. CONCLUSION: BC in combination with quercetin or C+E rather than BC alone similarly suppresses the Bap-induced inflammatory reaction that was accompanied by the regulation of antioxidant enzymes and the translocation of NF-κB in vivo.

MnSOD overexpression confers cisplatin resistance in lung adenocarcinoma via the NF-κB/Snail/Bcl-2 pathway.

Manganese superoxide dismutase (MnSOD) has been shown to be associated with doxorubicin resistance in gastric cancer cells, but the underlying mechanism of MnSOD in drug resistance remains unclear. A recent study indicated that NF-κB activation by MnSOD promoted tumor malignancy in lung adenocarcinoma. Therefore, we hypothesized that MnSOD-mediated NF-κB activation might confer cisplatin resistance in lung adenocarcinoma via the NF-κB/Bcl-2/Snail pathway. Here, the inhibition concentration of cisplatin with 50% cell viability (IC50) was positively correlated with MnSOD expression and its activity in a panel of lung adenocarcinoma cells. The IC50 value was markedly increased and decreased by MnSOD overexpression and knockdown, respectively, in lung cancer cells. Mechanistically, an increase in Bcl-2 by MnSOD-mediated NF-κB activation confers greater cisplatin resistance than cIAP2, Bcl-xL, Mcl-1, and Snail. MnSOD-mediated cisplatin resistance can be overcome by a Bcl-2 antagonist (ABT-199) or IKKß inhibitor (curcumin) in cells and xenograft tumors. MnSOD expression was positively correlated with nuclear p65 protein and Bcl-2 mRNA expression in tumors from patients with lung adenocarcinomas. A retrospective study indicated that it was more common for MnSOD-positive, nuclear p65-positive, or high Bcl-2 mRNA tumors to have an unfavorable response to cisplatin-based chemotherapy than their counterparts. Therefore, we suggest that ABT-199 or curcumin may be potentially useful to improve tumor regression and chemotherapeutic response in patients with MnSOD/Bcl-2-positive tumors.