Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Symptoms and General Pathology

Ear, Nose, and Throat Diseases

Rare Diseases

Lung Diseases, Obstructive

Pulmonary Disease, Chronic Obstructive

Lung Diseases

Laryngeal Diseases

Respiratory Tract Diseases

Chronic Disease

Disease Attributes

Chronic Graft Versus Host Disease

Laryngeal Cancer

Pharmaceutical Solutions

All Drugs and Chemicals

Anti-Arrhythmia Agents

Channel Blockers

Analgesics

Anticonvulsants

Central Nervous System Depressants

Reproductive Control Agents

Bone Density Conservation Agents

Magnesium Sulfate

Anesthetics

Calcium

Calcium Channel Blockers

Calcium, Dietary

Hormones

Tocolytic Agents

10% MgSO4 solution will be used, a loading dose of 30mg/kg over 20 min (equivalent to infusion rate of 0.9 ml/kg/hr for 20 min) will be given followed by continuous infusion of 10mg/kg/hr (equivalent to infusion rate of 0.1ml/kg/hr).

In control group, same rates of infusion for loading and maintenance will be applied using 0.9 normal saline.

intra-operative infusion of of 10% MgSO2 , stating by a laoding dose of 30be used, a loading dose of 30 mg/kg over 20 min followed by continuous infusion of 10 mg/kg/hr accomplish the total laryngectomy.

Magnesium Sulphate

Chronic Obstructive Pulmonary Disease \[COPD\] is a major cause of chronic morbidity and mortality worldwide. COPD is characterized by persistent progressive airflow limitation that adversely affects the ventilation/perfusion (V/Q) matching and mechanics of the respiratory muscles and leads to hypoventilation and reduced gas transfer. COPD was identified as a significant comorbidity associated with increased incidences of postoperative pulmonary complications and prolonged hospital stay. MgSO4 either intravenous or inhalational has been shown to promote bronchodilation and to improve lung function in asthmatic patients. MgSO4 either intravenous or inhalational has been shown to promote bronchodilation and to improve lung function in asthmatic patients. Administration of MgSO4 in patients with stable COPD was associated with reduced lung hyperinflation and improvement of respiratory muscle strength. This randomized control trial is designed to assess the effect of intravenous MgSO4 infusion on oxygenation and pulmonary mechanics and incidence of postoperative pulmonary complications and length of hospital stay in patients with COPD undergoing cancer larynx surgery.

Intra-operative intravenous infusion of magnesium sulphate in patients with chronic obstructive pulmonary diseases undergoing total laryngectomy and assess the influence on arterial oxygenation and pulmonary Mechanics in

Effect of Magnesium Sulphate Infusion on Lung Mechanics and Oxygenation in COPD Patients Undergoing Total Laryngeal

Effect of Intravenous Infusion of Magnesium Sulphate on Arterial Oxygenation and Pulmonary Mechanics in Patients With Chronic Obstructive Pulmonary Diseases Undergoing Cancer Larynx Surgery. A Randomized Controlled Trial

PaO2/FiO2 immediately after arrival to the PACU

Cairo University

Assistant Professor of Anesthesia and SICU - Faculty of Medicine - Cairo University

Neoplasms

Digestive System Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Stomach Neoplasms

Lung Neoplasms

Urinary Bladder Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Urinary Bladder Diseases

Urologic Diseases

Male Urogenital Diseases

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

Nicotine

Smokers of e-cigarettes containing nicotine only (non smoking traditional cigarettes and inhaling at least 50 puffs per week since six or more months). This group will be further split in the secondary analyses: never or former smokers of traditional cigarettes

Smokers of traditional cigarettes only (smokers of at least one traditional cigarette per day since six or more months). This group will be further split in the secondary analyses: recent and older smokers.

Smokers of both electronic and traditional cigarettes (at least one per day since six or more months). This group will be further split in the secondary analyses: mixed smokers who quit and who did not quit traditional cigarette smoking during follow-up

Lamberto Manzoli, MD, MPH

The main aim of this multicentric 5-year follow-up study is to evaluate for the first time the long-term efficacy and safety (in terms of smoking-related serious diseases requiring hospitalization) of e-cigarette smoking, comparing its health effects with those of traditional cigarette smoking and mixed electronic and traditional cigarette smoking.

The study will also permit to evaluate, over a 5-year follow-up, the self-reported quality of life, and the reported adverse events according to current and past smoking habit.

Finally, the study will also explore the long-term adherence to e-cigarette smoking and its efficacy of e-cigarettes in reducing and/or quitting traditional cigarette smoking.

The Efficacy and Safety of Electronic Cigarettes: a 5-year Follow-up Study

Multicentric 5-year Follow-up Study to Assess the Efficacy of E-cigarettes as a Tool for Smoking Cessation and to Compare the Risk of Smoking-related Diseases Among Electronic and Traditional Cigarette Smokers, and Smokers of Both.

Percentage of subjects that were current (in TC and Mixed groups) or former (in EC group) smokers reporting sustained smoking abstinence from traditional cigarette smoking at 60 months. Smoking abstinence is defined as complete abstinence from tobacco smoking (not even a puff) for the 30 days period prior to the visit. This outcome will be self-reported and checked using CO analyzer after breath.

Change in the average self-reported number of traditional cigarette smoked per day.

Percentage of subjects who had a hospital admission for one of the followings: cardiovascular diseases, chronic obstructive pulmonary diseases, cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Repeated admissions of the same subject will be counted once.

Mean number of hospital admissions for one of the followings: cardiovascular diseases, chronic obstructive pulmonary diseases, cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Each admissions of the same subject will be counted.

Mean number of hospital admissions for cardiovascular diseases. Each admissions of the same subject will be counted.

Mean number of hospital admissions for cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Each admissions of the same subject will be counted.

Change in the average quality of life according to EuroQol EQ-D3.

Time to hospital admission for one of the followings: cardiovascular diseases, chronic obstructive pulmonary diseases, cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Repeated admissions of the same subject will be counted once and the subject will be censored at the date of the first admission.

Self-reported side effects as measured by VAS and a structured report form.

Number of months of continued e-cigarette smoking in groups EC and Mixed.

The primary outcome measure is time to hospital admission for one of the followings: cardiovascular diseases, chronic obstructive pulmonary diseases, cancer of the lung, esophagus, larynx, oral cavity, bladder, pancreas, kidney, stomach, cervix, and myeloid leukemia. Repeated admissions of the same subject will be counted once and the subject will be censored at the date of the first admission.

Percentage of subjects reporting sustained smoking abstinence from traditional cigarette smoking. Smoking abstinence is defined as complete abstinence from tobacco smoking (not even a puff) for the 30 days period prior to the visit.

Percentage of subjects in all groups reporting sustained smoking abstinence from both traditional and electronic cigarette smoking at 12 months. Smoking abstinence is defined as complete abstinence from tobacco or electronic smoking (not even a puff) for the 30 days period prior to the visit.

University of Roma La Sapienza

Catholic University of the Sacred Heart

University of Turin, Italy

University of Catania

Mario Negri Institute for Pharmacological Research

Università degli Studi 'G. d'Annunzio' Chieti e Pescara

Associate Professor of Epidemiology and Public Health

Subject with histological confirmation of lung cancer

Subjects with no diagnosis of lung cancer

David CL LAM, MBBS, FRCP(Edin), FCCP, FACP

David CL Lam, MBBS, FRCP(Edin), FCCP, FACP

Lung cancer is the leading cause of cancer death in Hong Kong. Lung adenocarcinomas is the most common type, accounting for 70% of lung cancer and the molecular target of epidermal growth factor receptor (EGFR) gene mutation at exons 18 - 21 is present in about 50% of lung adenocarcinomas. The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras) mutations are commonly present in the other 50% that are EGFR wildtype. EGFR and K-ras mutations are found to be mutually exclusive in the same tumor. EGFR-tyrosine kinase inhibitor (TKI) can be used as treatment for EGFR mutated tumors while no specific targeted therapy can be recommended for EGFR wildtype tumors and these patients often receive chemoirradiation, which is toxic and clinical response is suboptimal. There is a need to find alternative molecular pathways/targets in EGFR wildtype lung adenocarcinomas.

Even with EGFR mutations, good clinical response to EGFR-TKI is achieved in about 70% of these patients. This would mean suboptimal targeting of the EGFR gene or the presence of alternative pathways mediating tumor progression and susceptibility to therapy. Exploration of molecular pathways in lung cancer may allow for discovery of new molecular targets for therapeutic development.

Neutrophil infiltration is frequently observed in lung cancer. Recognized similarities between neutrophils and cancer cells include (i) ability to circulate as single cells; (ii) target attachment via vascular system; (iii) target invasion. The major difference is that migrated neutrophils will undergo apoptosis while cancer cells can escape apoptosis.

This led to the postulation that neutrophils and cancer cells may share similar inflammatory cascades by secreting a similar panel of proteases, and one of these could be neutrophil elastase (NE). Animal studies demonstrated that NE from neutrophils moves into lung tumor cells and mediates lung tumor growth via degradation of Insulin receptor substrate-1 (IRS-1), leading to activation of intracellular phosphoinositide-3-kinase (PI3k) and the v-akt murine thymoma viral oncogene homolog 1 (Akt) signaling pathways and the intracellular tyrosine kinase of the platelet-derived growth factor receptor (PDGFR).

The aims of this study are to demonstrate NE activities and the subsequent signaling cascades activated in lung cancer cells, and to verify NE and its related pathway activation in clinical lung cancer specimen.

This study will conclude the roles of NE and the therapeutic potential of NE/IRS-1/PI3K/PDGFR pathways in EGFR wildtype lung adenocarinomas.

Objectives

1. To demonstrate the presence of NE in vitro and the entrance into lung adenocarcinoma cells
2. To identify the intracellular mechanisms through which NE mediates its tumor proliferating effects
3. To verify the activation of NE and its related pathway component in clinical lung adenocarcinoma specimens

Background of research

Lung Cancer in Hong Kong Lung cancer is the leading cause of cancer death in Hong Kong \[1\]. Surgical resection for early stage lung cancer is the only curative option and advanced stage lung cancer is treated with chemoirradiation or molecular targeted agents, one of which is Epidermal Growth Factor Receptor - Tyrosine Kinase Inhibitor (EGFR-TKI). Recent advances in molecular biology of lung cancer allowed for development of these targeted therapy. However, treatment response depends on the presence of activating EGFR gene mutation, and the median response period is usually maintained for nine to twelve months, after which the tumor usually become non-responsive or resistant to EGFR-TKI.

EGFR mutation vs EGFR wildtype lung adenocarcinomas

In Asian populations including Hong Kong, EGFR mutations at exons 18 - 21 are present in up to 50% of lung adenocarcinomas, while the other 50% are EGFR wild type lung adenocarcinomas and are usually bearing K-ras gene mutations \[2\]. Even with the presence of activating EGFR gene mutations at exons 18 - 21, clinical response was observed in only 70% of patients with tumors bearing EGFR mutations \[3\]. It is apparent that in a cohort of lung adenocarcinomas, there can be the following groupings according to their EGFR gene mutation status:

(i) EGFR mutated lung adenocarcinomas (\~50%)

1. with response to TKI treatment (\~35%)
2. but unresponsive to TKI treatment (\~15%) (ii) EGFR wildtype lung adenocarcinomas (\~50%) The presence of group (i)(b) tumors with EGFR but failed response to treatment would mean suboptimal targeting of EGFR and the presence of group (ii) EGFR wildtype tumors would imply alternative pathways mediating tumor progression and susceptibility to tumor therapy in lung cancer. Exploration of molecular pathways in lung adenocarcinomas may allow for discovery of new molecular targets for therapeutic development in lung cancer.

Neutrophils vs cancer cells

Neutrophil infiltration, and hence inflammatory infiltrate, is a frequently observed in lung cancer \[4\]. Recognized similarities between neutrophils and cancer cells include:

1. ability to circulate as single cells
2. target attachment via vascular system
3. target invasion Neutrophils achieve migration through pulmonary epithelial layers by secreting NE, which is readily balanced by the local action of secretory leukocyte peptidase inhibitor (SLPI). SLPI has also been detected in cancer tissues but the relevant function role in lung cancer has not been defined yet \[5\]. The major difference between neutrophils and cancer cells lies in the fact that migrated neutrophils will undergo apoptosis while cancer cells can escape apoptosis and are able to proliferate in target organs.

The possible roles of NE in lung cancer This has led to the speculation that neutrophils and cancer cells may share similar inflammatory cascades by secreting a similar panel of proteases, and one of these had been demonstrated to be neutrophil elastase (NE). The action of NE may happen at different cellular levels: (1) action on extracellular matrix to facilitate migration and tissue invasion; (2) action on cell surface signaling receptors; or (3) intracellular action on signaling pathways following uptake into signaling endosomes. There are recent evidence in animal studies that NE secreted by neutrophils actually moved into lung tumor cells and mediates lung tumor growth via degradation of Insulin receptor substrate-1 (IRS-1) and subsequent effects on the intracellular PI3K signaling pathways acting on the intracellular tyrosine kinase domain of the platelet-derived growth factor receptor (PDGFR)\[6\]. It is possible that neutrophils infiltrating lung tumor stromal tissues may be acting in collaboration with cancer cells via the direct and indirect actions of NE.

Work done by others Immunoreactive NE, both in free and in complex forms, can be demonstrated in breast cancer cell lines \[7\] and lung cancer cell lines \[8\]. NE activities has been further demonstrated in human breast cancer tissues \[9\] but not in human lung cancer tissues or normal lung tissues. These showed that NE is present at the tissue level but their intracellular action, whether enzymatically active or signaling active, has not been delineated clearly yet.

In breast cancer tissues, the higher the amount of extracted tissue NE, the worse was the prognosis \[9\] and similar prognostic significance was suggested for NE in non-small cell lung cancer \[10\].

When lung cancer cells were inoculated into severe combined immunodeficiency (SCID) mice, concomitant administration of NE inhibitor, ONO-5046, will completely suppressed tumor growth and appearance of metastatic foci \[11\]. The exact mechanism of action of ONO-5046 remains to be clarified.

NE has also been shown to cleave cell surface epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) \[12, 13\]. This may send aberrant signals to tumor cells EGF receptors and promote cancer cell proliferation in vitro.

TGF-α also induced NE expression in human cancer cell lines (breast and pancreas)

There were recent works by Houghton et al \[6\] demonstrating NE could influence lung cancer growth and development by:

1. permeating into lung tumor cells (A549 lung adenocarcinoma cell line with Kras mutation) and, via degradation of IRS-1, mediating tumor cell progression.
2. being blocked by specific inhibitors (ONO-5046), leading to aberrant intracellular signaling and then tumor cell growth arrest.

Work done by our groups NE in airway inflammation Our group had done work related to the roles of NE in airway inflammation and diseases and we have raised cancer and normal bronchial bronchial epithelial cell lines from local patients that would be appropriate models for testing the hypothesis in local patient populations.

Syndecan-1 was found to be able to bind NE in sputum sol of bronchiectasis, supporting the role of NE complexed with syndecan-1 in balance with antielastase \[14\]. We have also demonstrated shed syndecan-1 from human lymphoid cell line was able to bind to NE, disturbing the NE and anti-elastase balance in the airway environment, and thus could be playing a role in airway inflammation \[15\].

We have tried to unopposed NE in the airway fluids in a cigarette smoke-induced model of COPD in rats. Sulfated maltoheptaose to chelate NE was administered to rats and bronchoalveolar lavage fluid (BALF) and lung tissues were collected 3 days after administration that showed significant declines in NE activity and myeloperoxidase activity as compared to BALF of smoking rats not treated. Significant reduction in neutrophil accumulation was also observed in BALF and lung tissue sections. Airspace enlargement was significantly reduced following the treatment. All these results suggested that sulfated maltohepatose is a potential therapeutic against neutrophilic inflammation in the airways of patients with COPD. (unpublished data).

We have also tested the NE activity of a lung adenocarcinoma cell line A549 and found that radio-labelled cells migrate into lung cancer cells and is enzymatically inactive (unpublished data) Lung cancer cell lines and normal bronchial epithelial cells and clinical lung cancer tissue bank

We have recently established primary lung cancer and normal bronchial epithelial cell lines from local Chinese patients and they were characterized with in vitro growth kinetics, morphological and immunohistochemical studies and gene expression profiling \[16\]. At the moment, we have:

1. Four primary lung adenocarcinoma cell lines (HKULC 1 - 4) published \[16\] and six more newly established in various phase of characterization.
2. Two new normal bronchial epithelial cell lines immortalized with standard protocols with cdk4 and hTert infections \[17\].

These new cell lines were all derived from clinical specimen from the local Hong Kong Chinese patients and more are becoming established with continued accrual of clinical collection. The clinical data of the patients, including gender and smoking history, from which these primary lung adenocarcinoma cell lines originated were known. Together with 10 other ATCC lung adenocarcinoma cell lines and established normal bronchial epithelial lines (HBEC-KT 1 - 5) from John Minna MD, Tx, USA, these cell lines will provide invaluable materials to test for in vivo effects of NE on cancer cells.

With the collaboration of Queen Mary Hospital Cardiothoracic Surgical Department, we have also collected 40 pairs of resected lung adenocarcinomas and normal lung tissues that will allow for verification of in vitro findings in clinical specimens. Further collection accrual of clinical specimens is in progress

The research questions to be addressed (Figure 1) are:

1. What are the roles of NE in lung adenocarcinoma proliferation?
2. How are such roles of NE mediated at the intracellular signaling level? Is IRS-1/PI3K/PDGFR the most common axis involved in cancer cells? Or there will be 'cross-talk' with pathways such as EGFR or TNF-α in lung adenocarcinoma proliferation?
3. Can we verify such roles of NE in cancer proliferation in human lung adenocarcinoma tissues?

The aims of the study will be:

1. To determine the mode of entrance and site of action of labeled NE in lung adenocarcinoma cells
2. To study the activation of IRS-1/PI3K/PDGFR in lung adenocarcinoma cells after penetrance by NE and if there will be concurrent activation of other signaling pathways including the EGFR and TNF-α pathways
3. To study the effects of blocking NE with specific NE inhibitors on lung adenocarcinoma cell proliferation
4. To verify the above mechanisms of actions of NE in clinical lung adenocarcinoma specimens

Plan of study:

1. EGFR mutation profiling of lung adenocarcinoma cell lines and resected lung adenocarcinomas Genomic DNA will be extracted from available lung adenocarcinoma cell lines (20 specimens) as well as microdissected surgical lung adenocarcinoma specimens. Exons 18 - 21 will be PCR-amplified and directly sequenced to read for EGFR mutation in exons 18 - 21. This will characterize available lung adenocarcinomas cell lines and clinical tumor specimens with respect to EGFR gene mutation or EGFR wildtype for subsequent work, where experimental results will be compared between the two groups.
2. For aim (1) - (3), the mode of entrance and site of action of NE in lung adenocarcinoma cells will be studied.

   Live cell imaging Live cell imaging technique with Alex-Flour-488-labelled NE will be employed to localize and follow the path of NE entrance into lung adenocarcinoma cells. Eglin C, a proteolytic inhibitor, will be applied at the same time. Normal bronchial epithelial cell lines will be used for comparison. The intracellular location of entrance and possible activated structural changes will be recorded.

   NE-specific reverse transcription PCR cDNA amplified from total RNA will be amplified using RT-PCR with specific primers 5'-GAG GCA ATT CCG TGG ATT AG-3' and 5' ACG ACA TCG TGA TTC TCC AG-3' Western blotting NE-stimulated cells from (1) above will have proteins extracted by standard methods followed by immunoblotting with specific monoclonal antibodies to study related signaling pathways including pAkt, Akt, p85, IRS-1, IRS-2, PDGF, PDGF-α, pPDGF-α, p44/42 MAPK, phosphor-p44/42 MAPK as well as pEGFR and TNF-α. Anti-β-actin will be used as endogenous control. Reaction to individual markers will be done in triplicates Cell growth assay The effect of ONO-5046, a specific NE inhibitor, on cell growth and proliferation will be studied on lung adenocarcinoma cell lines compared to control (no drug administration).
3. For aims (4), we would like to study the activation of relevant signaling pathways upon NE stimulation

   1. Immunohistochemistry Immunohistochemical staining will be performed on clinical lung adenocarcinoma specimens with specific monoclonal antibodies against NE, PDGF, PDGFR, IRS-1 and EGFR. Concordance of staining pattern will be examined between IRS-1 and EGFR or PDGF respectively. The proportion of discordant cases will be compared with the proportion of concordant cases.
   2. NE assay in clinical lung cancer specimens from human subjects Clinical lung cancer specimens will be collected from patients with lung adenocarcinomas and NE activities assayed.

Small bronchial biopsy alongside with the corresponding Bronchoalveolar lavage and bronchial aspirate will be collected in the same one bronchoscopy session

The Roles of Neutrophil Elastase in Lung Cancer

The protein expression levels of phosphorylated Akt (pAkt), IRS-1, IRS-2, PDGF, mitogen activated kinase(MAPK) as well as phosphorylated EGFR (pEGFR) and TNF-α and β-actin will be assessed semi-quantitatively on electrophoretic blotting intensity.

Fields captured from four different fields from each stained (NE, IRS-1 and EGFR) lung tumor slides will be scored as 0 = absent, 1 = weak, 2 = strong and present. In NE positive cases, concordant and discordant cases of IRS-1 vs PDGF or EGFR staining will be observed. Likelihood ratio tests determining if proportion of discordant cases was significantly larger than half the cases will be presented

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Magnesium Sulphate Infusion on Lung Mechanics and Oxygenation in COPD Patients Undergoing Total Laryngeal	NCT03461328	Chronic Obstruc...	Magnesium Sulph...	40 Years - 80 Years	Cairo University
The Efficacy and Safety of Electronic Cigarettes: a 5-year Follow-up Study	NCT01785537	Cardiovascular ... Chronic Obstruc... Cancer of the L... Cancer of the B... Cancer of the S...		30 Years - 80 Years	Università degli Studi 'G. d'Annunzio' Chieti e Pescara
The Roles of Neutrophil Elastase in Lung Cancer	NCT01360931	Lung Cancer Chronic Obstruc...		18 Years - 80 Years	The University of Hong Kong

Spots Global Cancer Trial Database for chronic obstructive pulmonary diseases