Persistent response of furmonertinib plus anlotinib in a lung adenocarcinoma patient with an EGFR exon 20 insertion mutation: A case report.

Insertions in exon 20 represent the third most common type of EGFR mutation following in-frame deletions in exon 19 and the point mutation L858R in exon 21. They are generally associated with primary resistance to EGFR-TKIs. Although mobocertinib and amivantamab were approved for adult patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, the efficacy of these two agents was rather moderate. Therefore, other more potent targeted agents are urgently needed. Here, we report a patient with advanced lung adenocarcinoma harboring an EGFR exon 20 insertion mutation (NM_005228: exon 20: c.2316_2321dup: p.773_774dup). After experiencing platinum-based chemotherapy, this patient received a combination of furmonertinib and anlotinib and achieved lasting stable disease (SD). The treatment was well tolerated, and only mild hand-foot syndrome was reported from the patient. To the best of our knowledge, this case firstly reported the encouraging efficacy of combined furmonertinib and anlotinib in an advanced lung adenocarcinoma patient with an EGFR exon 20 insertion mutation who was previously treated with platinum-based chemotherapy. In addition, we summarize the recent literature on therapies against NSCLC with EGFR exon 20 insertion mutations. This case might provide an alternative approach for clinical oncologists.

Endoscopic closure of refractory upper GI-tracheobronchial fistulas with a novel occluder: a prospective, single-arm, single-center study (with video).

BACKGROUND AND AIMS: Upper GI-tracheobronchial fistula is a morbid condition with high mortality. It is a challenge for endoscopists because currently available treatments have severe limitations. In this study we assessed the efficacy and safety of an occluder we invented for endoscopic closure of refractory upper GI-tracheobronchial fistulas. METHODS: This was a prospective, single-arm, single-center trial conducted between September 2020 and March 2022. All patients undergoing occluder placement were eligible to enroll. The primary endpoints were clinical success rate (CSR) and complete closure rate (CCR) at 3 months and safety. Secondary efficacy endpoints were technical success rates, CSRs and CCRs at 1 and 6 months, near-complete closure rates, change from baseline in body mass index (BMI), and health-related quality of life (HRQoL) at 1, 3, and 6 months. RESULTS: Twenty-eight patients (mean age, 63.2 years; 23 men) were enrolled. Eighteen through-the-scope occluders (TTSOs) and 10 through-the-overtube occluders (TTOOs) were implanted, with a technical success rate of 100%. The mean procedure time for the TTSO and TTOO groups were 28.0 ± 8.0 minutes and 31.8 ± 7.7 minutes, respectively. The CSRs at 1, 3, and 6 months were 92.9%, 96.4%, and 92.0% and the CCRs were 60.7%, 60.7%, and 60.0%, respectively. The mean BMI at 3 and 6 months and HRQoL at 1, 3, and 6 months were significantly increased compared with baseline (P < .05). Two completely occluded fistulas had 1-sided or complete healing by coverage of granulation tissue and re-epithelialized mucosa at a follow-up of 6 and 12 months. All 14 adverse events were either mild and transient or easily corrected. CONCLUSIONS: Our clinical outcomes suggest that this novel GI occluder is a safe and effective salvage option for patients with refractory upper GI-tracheobronchial fistulas. (Clinical trial registration number: ChiCTR2000038566.).

Efficacy and safety of flexible endoscopic intervention via laryngeal mask airway for endobronchial hamartoma removal.

OBJECTIVE: To evaluate the clinical characteristics, efficacy and safety of flexible endoscopic intervention for endobronchial hamartoma. MATERIAL AND METHODS: Thirteen patients with endobronchial hamartoma who underwent flexible endoscopic intervention at a single center were analyzed retrospectively. The clinical characteristics and efficacy of flexible endoscopic intervention were described. RESULTS: Nine patients were cured after one single flexible endoscopic intervention, three patients underwent second flexible endoscopic interventions due to late tumor recurrence, while one patient who eventually became stable with a 40% stenosis of the airway lumen, received a third intervention because of two relapses. Pneumothorax occurred in one patient who was cured after oxygen therapy. There were no serious complications such as massive hemorrhage, airway perforation, airway ignition and suffocation associated with the therapy. CONCLUSIONS: Flexible endoscopic intervention appeared to be safe and effective for the treatment of patients with endobronchial hamartoma.

Exosomal miR-660-5p promotes tumor growth and metastasis in non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) is still the commonest fatal malignancy worldwide. The relationship between miR-660-5p and progress of NSCLC has not been well confirmed in recent studies. This manuscript focused to the function of miR-660-5p during the appearance and progression of NSCLC. METHODS: To identify the expression level of miR-660-5p in NSCLC, patient plasma and exosomes, quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed. Cell proliferation and colony formation abilities were examined by Cell Counting Kit-8 (CCK-8) assay and colony formation assay. Then, the influence of miR-660-5p on migration and invasion was analyzed by transwell assay. Bioinformatics and Luciferase report assay were used to find potential target genes. Western blot was chosen to assess the expression level of KLF9. Stably transfected NSCLC cells (A549 and H1299) were injected into nude mice to identify the function of miR-660-5p in tumorigenesis in vivo. RESULTS: Compared with healthy controls, the release of miR-660-5p in plasma and exosomes was increased in patients with NSCLC (n=80). Knockdown of miR-660-5p significantly suppressed proliferation, migration, and invasion, whereas overexpression of miR-660-5p had the opposite effect. KLF9 might be a potential target of miR-660-5p. In addition, up-regulation of miR-660-5p promoted tumorigenesis in vivo, and the protein level of KLF9 also decreased in xenografts. CONCLUSIONS: Our current study suggests that miR-660-5p may control NSCLC proliferation, viability, and metastasis by targeting KLF9, which provides a potential therapeutic target for NSCLC.

The clinical feasibility of flexible bronchoscopy interventional therapy in patients with central airway stenosis and respiratory failure caused by malignancy.

OBJECTIVE: The aim of this study was to investigate the clinical effects and feasibility of using flexible bronchoscopy intervention in cases of malignancy that causes central airway stenosis and respiratory failure. METHODS: The clinical data of patients who were admitted to the Department of Respiratory Medicine at the First Affiliated Hospital of Nanjing Medical University and underwent treatment of a malignant tumor with central airway stenosis and respiratory failure by flexible bronchos-copy from February 2010 to May 2013 were analyzed using a retrospective method. The age, gender, location, extent of airway stenosis, interventional therapy, efficacy, and complications for 12 patients were collected and analyzed using the SPSS 13.0 software. RESULTS: After interventional therapy, the dyspnea index for all the patients improved signifi-cantly, and compared with before treatment, the difference was statistically significant (t=13.40, P<0.01). Eleven patients with respiratory failure were corrected, and only one patient was treated via tracheal intubation with mechanical ventilation. There were no severe complications, such as massive hemorrhaging or cardiac arrest in any case. CONCLUSION: Flexible bronchoscopy interventional treatment for central airway stenosis and respiratory failure caused by malignant tumors is an effective and safe method. It should be applied in clinical work.

Caffeic acid phenethyl ester alleviates asthma by regulating the airway microenvironment via the ROS-responsive MAPK/Akt pathway.

In the pathophysiology of asthma, structural cell dysfunction and concomitant microenvironment changes in airways are crucial to pathological progression, which involves oxidative stress. Caffeic acid phenethyl ester (CAPE) is an active anti-oxidative component obtained from propolis, and has been shown to have beneficial effects on several respiratory disorders, such as chronic obstructive pulmonary disease and lung cancer. However, the impact of CAPE on asthma is not well understood. Therefore, this study investigated the advantages of using CAPE to treat asthma and demonstrated the roles of CAPE in the regulation of airway microenvironments. In ovalbumin (OVA)-sensitized mice, CAPE treatments notably reduced airway hyperresponsiveness, attenuated extensive inflammatory cell infiltration and inhibited goblet cell hyperplasia and collagen deposition and fibrosis. In addition, CAPE improved the airway microenvironment in a dose-dependent manner by inhibiting OVA-induced increases in immunoglobulin E, tumor necrosis factor alpha (TNF-α), transforming growth factor-ß1 (TGF-ß1), interleukin (IL)-4 and IL-13 and suppressing matrix metalloproteinase-9 and alpha-smooth muscle actin expression as well as malondialdehyde production. To determine the underlying mechanisms responsible for these effects, we used TNF-α-stimulated BECs and TGF-ß1-challenged human ASMCs to explore the impacts of CAPE on pro-inflammatory proteins and ASMC proliferation. The results indicated that CAPE significantly limited the secretion of eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1 and dramatically inhibited the proliferation of ASMCs. These effects were shown to be associated with decreased reactive oxidant species (ROS) levels. The phosphorylation of Akt and Mitogen-Activated Protein Kinase (MAPK) caused by increased ROS was significantly decreased by CAPE, which implied a contribution of ROS-MAPK/Akt signaling to the attenuation of asthma. Our findings indicated for the first time that CAPE alleviates airway inflammation and remodeling in chronic asthma by balancing the airway microenvironment, which highlights a novel profile of CAPE as a potent agent for asthma management.

Morin Attenuates Ovalbumin-Induced Airway Inflammation by Modulating Oxidative Stress-Responsive MAPK Signaling.

Asthma is one of the most common inflammatory diseases characterized by airway hyperresponsiveness, inflammation, and remodeling. Morin, an active ingredient obtained from Moraceae plants, has been demonstrated to have promising anti-inflammatory activities in a range of disorders. However, its impacts on pulmonary diseases, particularly on asthma, have not been clarified. This study was designed to investigate whether morin alleviates airway inflammation in chronic asthma with an emphasis on oxidative stress modulation. In vivo, ovalbumin- (OVA-) sensitized mice were administered with morin or dexamethasone before challenge. Bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to perform cell counts, histological analysis, and enzyme-linked immunosorbent assay. In vitro, human bronchial epithelial cells (BECs) were challenged by tumor necrosis factor alpha (TNF-α). The supernatant was collected for the detection of the proinflammatory proteins, and the cells were collected for reactive oxygen species (ROS)/mitogen-activated protein kinase (MAPK) evaluations. Severe inflammatory responses and remodeling were observed in the airways of the OVA-sensitized mice. Treatment with morin dramatically attenuated the extensive trafficking of inflammatory cells into the BALF and inhibited their infiltration around the respiratory tracts and vessels. Morin administration also significantly suppressed goblet cell hyperplasia and collagen deposition/fibrosis and dose-dependently inhibited the OVA-induced increases in IgE, TNF-α, interleukin- (IL-) 4, IL-13, matrix metalloproteinase-9, and malondialdehyde. In human BECs challenged by TNF-α, the levels of proteins such as eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1, were consistently significantly decreased by morin. Western blotting and the 2',7'-dichlorofluorescein assay revealed that the increases in intracellular ROS and MAPK phosphorylation were abolished by morin, implying that ROS/MAPK signaling contributes to the relief of airway inflammation. Our findings indicate for the first time that morin alleviates airway inflammation in chronic asthma, which probably occurs via the oxidative stress-responsive MAPK pathway, highlighting a novel profile of morin as a potent agent for asthma management.

Administration of Pigment Epithelium-Derived Factor Inhibits Airway Inflammation and Remodeling in Chronic OVA-Induced Mice via VEGF Suppression.

PURPOSE: Pigment epithelium-derived factor (PEDF) is a recently discovered antiangiogenesis protein. PEDF possesses powerful anti-inflammatory, antioxidative, antiangiogenic, and antifibrosis properties. It has been reported that PEDF can regulate vascular endothelial growth factor (VEGF) expression. This study aimed to evaluate whether recombinant PEDF protein could attenuate allergic airway inflammation and airway remodeling via the negative regulation of VEGF using a murine model of chronic ovalbumin (OVA)-induced asthma and BEAS-2B human bronchial epithelial cells. METHODS: In an in vivo experiment, mice sensitized with OVA were chronically airway challenged with aerosolized 1% OVA solution for 8 weeks. Treated mice were given injections of recombinant PEDF protein (50 or 100 µg/kg body weight) via the tail vein. In an in vitro experiment, we investigated the effects of recombinant PEDF protein on VEGF release levels in BEAS-2B cells stimulated with IL-1ß. RESULTS: Recombinant PEDF protein significantly inhibited eosinophilic airway inflammation, airway hyperresponsiveness, and airway remodeling, including goblet cell hyperplasia, subepithelial collagen deposition, and airway smooth muscle hypertrophy. In addition, recombinant PEDF protein suppressed the enhanced expression of VEGF protein in lung tissue and bronchoalveolar lavage fluid (BALF) in OVA-challenged chronically allergic mice. In the in vitro experiment, VEGF expression was increased after IL-1ß stimulation. Pretreatment with 50 and 100 ng/mL of recombinant PEDF protein significantly attenuated the increase in VEGF release levels in a concentration-dependent manner in BEAS-2B cells stimulated by IL-1ß. CONCLUSIONS: These results suggest that recombinant PEDF protein may abolish the development of characteristic features of chronic allergic asthma via VEGF suppression, providing a potential treatment option for chronic airway inflammation diseases such as asthma.

Galangin attenuates airway remodelling by inhibiting TGF-ß1-mediated ROS generation and MAPK/Akt phosphorylation in asthma.

Galangin, a natural flavonol, has attracted much attention for its potential anti-inflammatory properties. However, its role in the regulation of airway remodelling in asthma has not been explored. The present study aimed to elucidate the effects of galangin on chronic inflammation and airway remodelling and to investigate the underlying mechanisms both in vivo and in vitro. Ovalbumin (OVA)-sensitised mice were administered with galangin 30 min before challenge. Our results showed that severe inflammatory responses and airway remodelling occurred in OVA-induced mice. Treatment with galangin markedly attenuated the leakage of inflammatory cells into bronchoalveolar lavage fluid (BALF) and decreased the level of OVA-specific IgE in serum. Galangin significantly inhibited goblet cell hyperplasia, collagen deposition and α-SMA expression. Lowered level of TGF-ß1 and suppressed expression of VEGF and MMP-9 were observed in BALF or lung tissue, implying that galangin has an optimal anti-remodelling effect in vivo. Consistently, the TGF-ß1-induced proliferation of airway smooth muscle cells was reduced by galangin in vitro, which might be due to the alleviation of ROS levels and inhibition of MAPK pathway. Taken together, the present findings highlight a novel role for galangin as a promising anti-remodelling agent in asthma, which likely involves the TGF-ß1-ROS-MAPK pathway.

Expression profiles and initial confirmation of long noncoding RNAs in Chinese patients with pulmonary adenocarcinoma.

BACKGROUND: The purpose of this study was to investigate differentially expressed long noncoding RNAs (lncRNAs) in pulmonary adenocarcinoma tissue and adjacent noncancerous tissue from Chinese patients using lncRNA expression microarray and preliminary analysis. METHODS: RNA extracted from three paired pulmonary adenocarcinoma tissue and adjacent noncancerous tissue specimens was used to synthesize double-stranded complementary DNA after labeling and hybridization. The complementary DNA was labeled and hybridized to the lncRNA expression microarray, and array data were analyzed for hierarchical clustering. Gene coexpression networks were constructed to identify interactions among genes. To validate the microarray findings, we measured the relative expression levels of four random differentially expressed lncRNAs in the same tissue used for microarray using real-time quantitative polymerase chain reaction. The expression level of one lncRNA, AK124939, in the paired pulmonary adenocarcinoma/adjacent noncancerous tissue of another 30 patients was measured using real-time quantitative polymerase chain reaction. The experimental data were further analyzed and compared with clinical features. RESULTS: Of 39,000 lncRNAs investigated, 704 were differentially expressed in pulmonary adenocarcinoma tissue; 385 were upregulated and 319 were downregulated compared with those in the adjacent noncancerous tissue (fold change ≥2 and ≤-2, P<0.05). AK124939 expression levels in poorly differentiated adenocarcinoma tissue were lower than those found in well to moderately differentiated adenocarcinoma tissue (P=0.05). CONCLUSION: There are significant differences in the lncRNA expression profiles in Chinese patients with pulmonary adenocarcinoma. LncRNAs such as AK124939 may be anticancer factors related to the progression of pulmonary adenocarcinoma.

Elimination of central sleep apnea by cardiac valve replacement: a continuous follow-up study in patients with rheumatic valvular heart disease.

BACKGROUND: Recent studies have suggested that cardiac surgery may affect sleep-disordered breathing (SDB) in chronic heart failure patients. However, the dynamic changes in sleep apnea and heart function after cardiac surgery and the mechanisms responsible for these changes remain unknown. METHODS: Patients with rheumatic valvular heart disease (RVHD) and SDB were enrolled and followed up at three, six and 12 months after cardiac valve replacement (CVR). Baseline and follow-up clinical data consisting of NYHA classification, 6min walk distance (6-MWD), medications, echocardiography, electrocardiography, chest X-ray, arterial blood gas, lung-to-finger circulation time (LFCT), and sleep data were collected and evaluated. RESULTS: Twenty-four central sleep apnea (CSA) patients and 15 obstructive sleep apnea (OSA) patients completed three follow-up assessments. Comparison of the baseline parameters between OSA patients and CSA patients showed that CSA patients had a worse baseline cardiac function assessed by higher NYHA class, shorter 6-MWD, larger left atrial diameter, longer LFCT, and enhanced chemosensitivity (higher pH and lower arterial carbon dioxide tension (PaCO2)). A continuous significant elevation in 6-MWD and left ventricular ejection fraction and decrease in NYHA class, plasma BNP, and left atrial diameter were found in both CSA and OSA patients. When comparing CSA and OSA patients, the CSA indices were remarkably reduced at month 3 post CVR and sustained throughout the trial, whereas there were no significant decreases in OSA index and hypopnea index. pH values and LFCT were markedly decreased and PaCO2 markedly increased in patients with CSA at the end of the third months following CVR. These changes were sustained until the end of the trial. CONCLUSIONS: CSA patients with RVHD had a worse baseline cardiac function, enhanced chemosensitivity and disordered hemodynamic as compared with OSA patients with RVHD. CSA were eliminated after CVR; however, there were no changes in OSA. The elimination of CSA, post CVR, is associated with the combined efficacies of improvement of cardiac function, normalized chemosensitivity, and stabilized hemodynamic.

Roles of Mir-144-ZFX pathway in growth regulation of non-small-cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung carcinoma (NSCLC) accounts for most of the lung cancer cases and the prognosis of this disease remains poor despite decades of intensive investigation. Thus new insights into underlying mechanisms by which NSCLC develops are avidly needed as the basis for development of new lines of therapeutic strategies. The past decade has witnessed a growing interest on the regulatory roles of micro RNAs on various categories of malignancies. Related data has been well documented in carcinogenesis and pathophysiology of a variety of malignancies. Even so, there is a relative lack of data on roles of mir-144 in tumor biology and there has been no report showing the involvement of mir-144 in NSCLC development. METHODS/PRINCIPAL FINDING: From human NSCLC tumor tissue samples and cell culture samples, we found that the expression of mir-144 is associated with malignant phenotype of NSCLC. Further investigations showed that ectopic mir-144 expression dramatically inhibits NSCLC tumor cell growth and induces apoptosis as manifested by elevated apoptotic protein markers and flowcytometry change. Moreover, we also found that ZFX protein expression is also associated with malignant phenotype of NSCLC and knockdown of ZFX protein results in a similar effect as of ectopic mir-144 expression. Finally, we found that ZFX expression is highly adjustable upon presence of mir-144 and ectopic expression of ZFX dramatically dampens mir-144 action of tumor inhibition. CONCLUSIONS: Our results for the first time showed mir-144-ZFX pathway is involved in the development of NSCLC, which sheds a light for further investigations on underlying mechanisms toward better understanding and management of NSCLC.

Galangin Abrogates Ovalbumin-Induced Airway Inflammation via Negative Regulation of NF-κB.

Persistent activation of nuclear factor κB (NF-κB) has been associated with the development of asthma. Galangin, the active pharmacological ingredient from Alpinia galanga, is reported to have a variety of anti-inflammatory properties in vitro via negative regulation of NF-κB. This study aimed to investigate whether galangin can abrogate ovalbumin- (OVA-) induced airway inflammation by negative regulation of NF-κB. BALB/c mice sensitized and challenged with OVA developed airway hyperresponsiveness (AHR) and inflammation. Galangin dose dependently inhibited OVA-induced increases in total cell counts, eosinophil counts, and interleukin-(IL-) 4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid, and reduced serum level of OVA-specific IgE. Galangin also attenuated AHR, reduced eosinophil infiltration and goblet cell hyperplasia, and reduced expression of inducible nitric oxide synthase and vascular cell adhesion protein-1 (VCAM-1) levels in lung tissue. Additionally, galangin blocked inhibitor of κB degradation, phosphorylation of the p65 subunit of NF-κB, and p65 nuclear translocation from lung tissues of OVA-sensitized mice. Similarly, in normal human airway smooth muscle cells, galangin blocked tumor necrosis factor-α induced p65 nuclear translocation and expression of monocyte chemoattractant protein-1, eotaxin, CXCL10, and VCAM-1. These results suggest that galangin can attenuate ovalbumin-induced airway inflammation by inhibiting the NF-κB pathway.

Invasive examinations in patients with suspected lung cancer: more may be too many.

The recent article entitled "Principles of biopsy in suspected lung cancer: priority still based on invasion in the era of targeted therapy?" published in Journal of Thoracic Disease by Chen et al., concluded the principles of biopsy in suspected lung cancer should be prioritized in sequence based on weight in clinical management, acquisition of tissue, invasion, efficiency and cost. We reported a patient with a 30-year history of pulmonary silicosis, had been found no evidence of tumor after receiving a series of invasive examinations. We conclude that invasive examinations should be limited in patients with suspected lung cancer who had a defined history of underlying disease. Minimal invasion with careful acquisition of the appropriate quantity and quality of tissue should be adequate.

[Flexible bronchoscopic intervention for endobronchial hamartoma].

OBJECTIVE: To evaluate the effectiveness and safety of interventional treatment in the removal of endobronchial hamartoma by flexible bronchoscopy. METHODS: A retrospective analysis was conducted in 8 inpatients with histologically confirmed endobronchial hamartoma , diagnosed between May 2009 to January 2012 in the First Affiliated Hospital of Nanjing Medical University. The clinical, radiological and bronchoscopic features of hamartoma, and the clinical outcomes after bronchoscopic intervention were described. The endoscopic interventional treatments included resection by electrosurgical snare, electrocautery, argon plasma coagulation (APC) and cryotherapy. Thoracic computed tomography(CT)and bronchoscopy were used to evaluate the airway stenosis during follow-up. RESULTS: The 8 patients, 7 males and 1 female, aged (62 ± 8) years, underwent 13 times of interventional treatment for endobronchial hamartoma. Four patients were cured after receiving a single endoscopic treatment, while 3 patients had recurrence after initial interventional treatment but were cured after the second treatment. Three times of interventional treatment was carried out in 1 patient who had two relapses but later became stable with a 40% stenosis of the airway lumen. The rates of cure and effectiveness were 87.5% and 100%, respectively. Following interventional treatment, pneumothorax occurred in 1 patient who was cured after oxygen therapy. There were no serious complications such as massive haemorrhage, airway perforation, airway ignition and suffocation. CONCLUSION: Interventional treatments through flexible bronchoscopy appear to be safe and effective for removing endobronchial hamartoma.

Coordinated regulation of IL-4 and IL-13 expression in human T cells: 3C analysis for DNA looping.

Asthma is a chronic allergic disorder characterised by chronic inflammation. The balance of type I and type II (CD4+) T helper cells is of critical importance. In asthma there is an overexpression of T(H)2 cytokines, such as IL-4, IL-5 and IL-13. The genes encoding these cytokines are located together the same chromosomal region, 5q31.1 in humans. Here we confirm a central role for the transcription factors NFAT and GATA3 in the regulation of human IL-4 and IL-13. Chromatin Conformation Capture (3C) demonstrated the formation of specific ligation products containing spliced IL-4 and IL-13 DNA sequences in human T(H)2 polarised HuT-78 cells. This suggests that co-ordinate expression of T(H)2 cytokines, under the control of GATA3 and NFAT1 is due to the formation of a chromatin hub by DNA looping.