[Show abstract][Hide abstract] ABSTRACT: Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is a commonly encountered yet loosely defined clinical entity. ACOS accounts for approximately 15-25% of the obstructive airway diseases and patients experience worse outcomes compared with asthma or COPD alone. Patients with ACOS have the combined risk factors of smoking and atopy, are generally younger than patients with COPD and experience acute exacerbations with higher frequency and greater severity than lone COPD. Pharmacotherapeutic considerations require an integrated approach, first to identify the relevant clinical phenotype(s), then to determine the best available therapy. The authors discuss the array of existing and emerging classes of drugs that could benefit those with ACOS and share their therapeutic approach. A consensus international definition of ACOS is needed to design prospective, randomized clinical trials to evaluate specific drug interventions on important outcomes such as lung function, acute exacerbations, quality of life and mortality.
Expert Review of Clinical Pharmacology 03/2013; 6(2):197-219.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the effect of tracheotomy tubes that enable suction immediately above the cuff on the development of ventilator-associated pneumonia (VAP).
Patients without preexisting pneumonia who required tracheotomy were randomly assigned to receive a tracheotomy tube with or without above-the-cuff suction. The suction tube provided 10 mm Hg of continuous wall suction while the tracheotomy tube cuff was inflated. Data regarding the development of VAP, time on the ventilator, and length of stay in the intensive care unit (ICU) were recorded and compared between groups.
Eighteen patients were randomized and prospectively evaluated. Nine patients received standard tracheotomy tubes, and 9 received suction-above-the-cuff tracheotomy tubes. The prevalences of VAP were 56% in the control group and 11% in the suction tracheotomy group (p = 0.02). The mean times on the ventilator were 18 +/- 14 days in the control group and 11 +/- 11 days in the suction group (p = 0.12). The mean lengths of ICU stay were 26 +/- 15 days in the control group and 18 +/- 15 days in the suction group (p = 0.14).
Use of suction-above-the-cuff tracheotomy tubes significantly decreases the incidence of VAP in ICU patients. There were trends toward decreased time on the ventilator and decreased length of stay in the ICU.
The Annals of otology, rhinology, and laryngology 01/2013; 122(1):3-8. · 1.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with severe asthma represent only a minority of the total asthma population; however, they account for the majority of the mortality, morbidity, and health care-related cost of this chronic illness. Bronchial thermoplasty is a novel treatment modality that employs radiofrequency energy to alter the smooth muscles of the airways. This therapy represents a radical change in our treatment paradigm from daily repetitive dosing of medications to a truly long-term and potentially permanent attenuation of perhaps the most feared component of asthma--smooth muscle-induced bronchospasm. A large, multicentered, double-blinded, randomized controlled trial employed the unprecedented (but now industry standard for bronchoscopic studies) approach of using sham bronchoscopy as a control. It demonstrated that bronchial thermoplasty is safe, improved quality of life, and decreased frequency of severe exacerbations in the treatment group compared to the control group. Although the mechanism of action of bronchial thermoplasty is not currently completely understood, it should be considered as a valid and potentially valuable option for patients who have severe persistent asthma and who remain symptomatic despite inhaled corticosteroids and long-acting beta-2 agonists. Such patients should however be carefully evaluated at centers with expertise in managing severe asthma patients and with physicians who have experience with this promising new treatment modality.
[Show abstract][Hide abstract] ABSTRACT: Argon plasma coagulation (APC) is a common and safe bronchoscopic technique used in the management of obstructing lesions and hemorrhage in the central airways. Complications of bronchoscopic APC are uncommon and include hemorrhage, perforation and fire in the airways. While bronchoscopic APC has been reported to cause systemic gas embolization and associated cardiovascular collapse, we report a case of cerebral gas embolization that occurred during bronchoscopic APC and highlight underappreciated potential risk factors for its occurrence.
[Show abstract][Hide abstract] ABSTRACT: Asthma in the adult patient is a complex clinical syndrome. Multiple patient phenotypes and subphenotypes exist that contribute to disease heterogeneity. Whether adult asthma begins in utero, develops in childhood, or manifests for the first time in adulthood is not completely understood, nor are the mechanisms fully delineated. In this chapter, we update definitions that apply to this group, emphasize epidemiologic factors and pathogenic mechanisms, diagnosis, therapeutic options, and controversies regarding drug safety. Finally, we provide a brief discussion of biomarker technologies and novel therapies with the potential to impact adult-onset asthma outcomes.
[Show abstract][Hide abstract] ABSTRACT: Racial disparities have been reported in non-small cell lung cancer (NSCLC) staging and therapeutic outcomes. We investigated whether such disparities exist in the era of modern noninvasive staging modalities, including positron emission tomography scan use.
NSCLC patients from the California Cancer Registry diagnosed between January 1, 1994, and December 31, 2004, were included. The likelihood of obtaining invasive (thoracoscopy, bronchoscopy, and mediastinoscopy) and noninvasive staging procedures (computed tomography, magnetic resonance imaging, and positron emission tomography scans), along with surgical resection, were analyzed using logistic regression adjusted for known confounders.
Of 13,762 NSCLC patients, 12,395 with adequate staging information were included. 10,217 patients (82%) were classified as white, 2178 patients (18%) were non-white, and 738 were black patients (6%). No association was seen between race and the use of either noninvasive (odds ratio [OR] = 1.02; p = 0.76) or invasive staging procedures (OR = 0.96; p = 0.44). However, compared with white patients, black patients had a lower likelihood of undergoing surgery, regardless of noninvasive (OR = 0.6; p <0.001) or invasive staging use (OR = 0.63; p = 0.02). There was no survival difference for those who underwent surgery between white and non-white patients, regardless of noninvasive (hazard ratio = 0.95; p = 0.45) or invasive staging (hazard ratio = 1.03; p = 0.79).
In contrast to prior published work, we found no difference in rates of both invasive and noninvasive staging between white and non-white patients. However, non-white patients-particularly blacks-were less likely to receive surgery. The reason for the apparent difference in surgical rates could not be explained by the variables we evaluated. Thus, other factors such as personal preference or access to care require further investigation.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 09/2010; 5(11):1772-8. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Complications of blind feeding tube (FT) placement include pneumothorax, pneumonia, empyema, and death. A safe and effective method of FT placement is desired. The Davis FT is a novel device that detachably couples to an ultrathin transnasal gastroscope. The objective of this study was to evaluate the safety and efficacy of Davis FT placement.
Fifty consecutive patients requiring transpyloric enteral tube feeding underwent placement of the Davis FT. Placement efficacy was evaluated with postplacement radiographs. Patient demographics, route of tube placement, use of sedation, and complications were abstracted.
The Davis FT was placed successfully in 50 patients. The mean age of the cohort was 52 (+/- 18) years. Sixty-two percent (31/50) were men. The success rate of nonpulmonary placement was 100% (50/50), and the postpyloric success rate was 96% (48/50). IV sedation was used in 72% (36/50) of placements. Eighty-six percent (43/50) of tubes were placed transnasally. The majority (62%) of esophagogastroduodenoscopies and Davis FT placements was performed by a pulmonologist. Forty-four percent (22/50) of patients had an endotracheal tube, 20% (10/50) had a tracheotomy, and 36% (18/50) had no breathing tube at the time of Davis FT placement. There were no complications.
Transpyloric placement of the Davis FT is safe (100%) and effective (96%). The tube can be placed transorally or transnasally with or without sedation. The data suggest that postplacement radiographs are not necessary to confirm placement. Pulmonologists were successful in performing EGD and Davis FT placement.
[Show abstract][Hide abstract] ABSTRACT: The diagnosis and management of a malignant pleural effusion can be one of the most vexing problems faced by physicians and their patients. Lung cancer is the most common primary tumor of origin with a prognosis that is limited, but variable and correlated with performance status (PS). Therefore, with a poor PS and known advanced lung cancer, establishing whether or not an effusion is malignant might not be necessary. Conversely, identifiable subsets of patients will have a much better survival, and establishing a definitive diagnosis could be of critical importance. In the great majority of cases, a diagnosis can be determined by serial thoracenteses with or without closed pleural biopsy. However, thoracoscopy is increasingly being utilized and can expedite the workup by obviating the need for repeated thoracenteses and/or closed pleural biopsy, while in the same setting providing definitive palliative treatment. Although studies comparing diagnostic and treatment strategies are limited, we will present the available data with the intention of providing the practicing oncologist with a practical strategy for the diagnosis and management of malignant pleural effusions due to lung cancer. The interventional pulmonologist can play an important role from diagnosis to palliation, greatly facilitating the care of patients with malignant pleural effusions.
Clinical Lung Cancer 12/2007; 8(9):535-47. · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A rare but serious complication of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is a lung injury syndrome commonly referred to as a drug-induced interstitial lung disease (ILD). It has a typical clinical presentation of rapidly progressive acute or subacute dyspnea and a histopathology of diffuse alveolar damage (DAD). The incidence, severity, and risk factors for EGFR TKI-induced ILD remain poorly understood. Whether concurrent chemotherapy increases its risk is also unclear. The primary focus of this blinded review was to determine the incidence of ILD leading to death in 1059 TRIBUTE patients randomized to chemotherapy plus erlotinib or placebo.
All fatal serious adverse events (SAEs) were reviewed by an independent three-person panel composed of a medical oncologist, radiologist, and pulmonologist not associated with the study and without knowledge of treatment assignment. Fatal respiratory SAEs were identified and assigned to one of four potential attributions: progressive cancer, concurrent illness, drug-induced ILD, or other toxicities not related to ILD. Each panel member first made an independent assignation; then each case was discussed jointly. If needed, consensus was reached by vote.
Fatal SAEs were reported in 80 of 1059 patients (7.6%): 53 of 526 patients on erlotinib (10.1%) and 27 of 533 on placebo (5.1%) (p < 0.05). Consensus assignation for 41 fatal respiratory SAEs was as follows: cancer, 18 (44%); concurrent illness, 15 (37%); other toxicities not related to ILD, five (12%); ILD, three (7%). All three ILD cases occurred in the erlotinib arm (3/526; 0.6%). The one biopsy-confirmed case of ILD revealed bronchiolitis obliterans organizing pneumonia, a histopathologic finding that has not previously been reported. All three cases of fatal ILD had a typical clinical presentation of acute or subacute onset of dyspnea with rapid progression to respiratory failure.
This independent blinded analysis of the TRIBUTE study identified fatal ILD in 0.6% of cases treated with the combination of erlotinib plus chemotherapy, possibly higher than previous reports of EGFR TKIs alone in the non-Japanese population. Fatal ILD alone does not fully account for the imbalance in fatal SAEs observed in TRIBUTE. EGFR TKI-induced fatal ILD typically presents with acute or subacute dyspnea with rapid progression and a typical histopathology of diffuse alveolar damage both consistent with the acute respiratory distress syndrome, but can also be associated with a histopathology of bronchiolitis obliterans organizing pneumonia. Further studies designed to better understand the underlying pathophysiology and risk factors for ILD are needed.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2007; 2(6):537-43. · 4.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung disease is a rare but serious complication of epidermal growth factor receptor tyrosine kinase inhibitor therapy. Although our understanding of this phenomenon remains incomplete, recently there have been significant insights made into the mechanisms of injury, incidence, risk factors, and its clinical manifestations. Japanese patients appear to be at a higher risk (1.6%-3.5%) than patients in the rest of the world (0.3%), and other risk factors, such as coincident interstitial lung disease, concurrent chemotherapy, previous radiation, preexisting pulmonary fibrosis, and male sex, have been identified. In the majority of cases, the histopathology, the acute and often dramatic clinical presentation, and the radiographic findings resemble acute respiratory distress syndrome. Aside from immediate cessation of the offending agent, the treatment is largely supportive, although corticosteroids appear to be of benefit. The mortality remains high at approximately 30%-50%. We present a review of the incidence, risk factors, clinical manifestations, diagnosis, management, and outcome of this disorder.
[Show abstract][Hide abstract] ABSTRACT: MOTIVATION: Global protein interaction network (interactome) analysis provides an effective way to understand the relationships between genes. Through this approach, it was demonstrated that the essential genes in yeast tend to be highly connected as well as connected to other highly connected genes. This is in contrast to the genes that are not essential, which share neither of these properties. Using a similar interactome-transcriptome approach, the topological features in the interactome of differentially expressed genes in lung squamous cancer tissues are assessed. RESULTS: This analysis reveals that the genes that are differentially elevated, as obtained from the microarray gene profiling data, in cancer are well connected, whereas the suppressed genes and randomly selected ones are less so. These results support the notion that a topological analysis of cancer genes using protein interaction data will allow the placement of the list of genes, often of the disparate nature, into the global, systematic context of the cell. The result of this type of analysis may provide the rationale for therapeutic targets in cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: •
Asthma in adults is composed of a complex group of reversible airway disorders in contrast to childhood asthma that is largely
allergic in nature.
Adult-onset asthma may be recently acquired in adulthood or represent various stages of long-standing disease. Atopic adults
may carry the genotype of childhood asthma symptomatically into adulthood only to have the phenotype finally expressed because
of a powerful trigger, e.g., specific aeroallergen(s) or infection.
Approximately 31 million Americans suffer from asthma. The majority of patients (71%) are adults, whereas fewer than 29% (8.9
million) are children less than 18 yr of age. More women than men are affected with severe adult-onset asthma. Estrogen replacement
therapy, respiratory infection with Chlamydia or Mycoplasma, certain occupations, tobacco smoking, gastroesophageal reflux,
obesity, and sleep disorders are important risk factors and comorbid conditions.
Asthma and active cigarette smoking interact to cause more severe symptoms, accelerated decline in lung function, and impaired
short-term therapeutic response to corticosteroids (CSs).
Simple spirometry, e.g., forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), detect expiratory flow limitations
and lung volumes. Demonstration of reversible obstructive airways disease with spirometry after using albuterol or ipratropium
in an adult older than 18 yr old does not alone diagnose adult-onset asthma. Methacholine challenge testing to exclude abnormal
airway hyperresponsiveness is safe in adult-onset asthma patients with FEV1 greater than 70% predicted.
High doses of inhaled CSs should be avoided in adult-onset asthma, particularly in the elderly or those with late-onset asthma.
The addition of long-acting β2-agonists or antileukotriene drugs is preferable to using high doses of inhaled CSs. All patients
using β2-agonists should be monitored for adverse effects, including paradoxical bronchoconstriction.
Given their demonstrated benefit in conditions such as heart failure, coronary artery disease, and hypertension, cardioselective
β1-blockers should not be withheld from adults with mild-moderate reversible airway disease.
Patient adherence with prescribed asthma therapy is poor, and it is clearly the overwhelming explanation for poor control
of asthma in adults, leading to exacerbations and hospitalizations. Compared with younger hospitalized adults, older hospitalized
adults had clear deficiencies, including lower use of peak flow meters and worse asthma self-management knowledge.
Factors independently associated with hospitalization included being female, nonwhite, less educated, and less physically
healthy and more frequent asthma symptoms. Chronological age was not an independent risk for hospitalization. Appropriate
care for older adults with asthma should address asthma symptoms as in children and younger adults.
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive pulmonary disease (COPD) exacts a heavy toll on society, yet its prevention, diagnosis and treatment receives inadequate attention from both the medical community and from society at large. Guidelines released in 2001 from the Global Initiative for Chronic Obstructive Lung Disease (GOLD) are aimed at redressing this inequity. In this review, we integrate information from the GOLD guidelines with recent updates on the prevention, treatment and management as related specifically to the most severe form of this disease. In order to help distinguish COPD from other disorders that may mimic or confound its treatment, we place particular emphasis on the definition, underlying pathophysiology and diagnosis of COPD. In addition, we discuss future directions in pharmacotherapy.
[Show abstract][Hide abstract] ABSTRACT: Recent advances in high-density DNA microarray technique allow the possibility to analyze thousands of genes simultaneously for their differential gene expression patterns in various biologic processes. Through clustering analysis and pattern recognition, the significance of these differentially expressed genes can be recognized and correlated with the biologic events that may take place inside the cell and tissue. High-density DNA microarray nylon membranes were used to explore gene expression and regulation associated with smoke- and hydrogen peroxide-induced injury and repair in differentiated human bronchial epithelial cells in vitro. At least three phases of change in gene expression could be recognized. The first phase seems to be an immediate event in response to oxidant injury. This phase includes the induction of bcl-2 and mdm2 genes that are involved in the regulation of apoptosis, and the mitogen-activated protein kinase phosphatase 1 that functions as a regulator for various mitogen-activated protein kinase activities. The second phase, usually 5 h later, includes the induction of various stress proteins and ubiquitin, which are important in providing the chaperone mechanism and the turnover of damaged macromolecules. The third phase, which is 5 to 10 h later, includes the induction of genes that seem to be involved in reducing oxidative stress by metabolizing the cellular level of reactive oxygen species. In this phase, enzymes associated with tissue and cell remodeling are also elevated. These results demonstrated a complex gene expression array by bronchial epithelial cells in response to a single insult of oxidants that are relevant to environmental pollutants.
Journal of the American Society of Nephrology 09/2003; 14(8 Suppl 3):S284-9. · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The effective palliation of endobronchial malignancies often involves the use of multiple modalities including surgery, external beam radiation, chemotherapy, or a variety of interventional bronchoscopic techniques. The authors discuss in detail recent advances in interventional bronchoscopy that enhance local tumor control. An integrated and individualized approach to the use of these complementary modalities can provide rapid palliation and may improve survival in a subset of patients.
Current opinion in pulmonary medicine 08/2003; 9(4):301-8. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human thioredoxin (Trx) is a 12-kD protein known to be involved in various reduction/oxidation reactions essential for cell growth and cellular injury repair. We previously demonstrated, based on nuclear run-on assay, that retinoic acid (RA) stimulated Trx gene expression in airway epithelial cells at the transcriptional level. Nucleotide sequencing of the 5'-flanking region of the human Trx gene revealed the presence of a TATA box at -28 and four RA response element (RARE)-like half sites at -426, -453, -507, and -626 nt. Transient transfection assays with a Trx promoter-reporter gene, chloramphenicol acetyltransferase (CAT), demonstrated a dose-dependent involvement of these four RARE-like half sites in RA-enhanced promoter activity. When the DNA fragment that flanks these four RARE-like half sites from -357 to -671 nt was introduced into a heterologous promoter of the tk-CAT2 vector, both basal and RA-stimulated CAT activities were observed. A site-directed mutagenesis approach demonstrated an essential role for RARE-I and RARE-II at -426 and -453 nt, respectively, and an auxiliary role for RARE-III at -507 nt in both basal and RA-stimulated CAT activities. Both in vivo and in vitro genomic footprinting experiments further demonstrated specific protein-DNA interactions in these "putative" RARE-I/II/III half sites. Gel electrophoretic mobility shift assays demonstrated specific interactions of these RARE-like half sites with the nuclear extracts obtained from RA-treated cultures. The anti-RAR-alpha antibody super-shift experiment further confirmed the interactions of RARE-I/II sites with RAR-alpha nuclear receptor. These results suggest a classic RARE/RAR interaction involved in RA-stimulated Trx gene expression in human airway epithelium.
American Journal of Respiratory Cell and Molecular Biology 06/2002; 26(5):627-35. · 4.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Development of the high-density DNA microarray technique permits the analysis of thousands of genes simultaneously for their differential expression patterns in various biological processes. Through clustering analysis and pattern recognition, the significance of differentially expressed genes can be recognized and correlated with biological events that may take place inside the cell and tissue. With this notion in mind, high-density DNA microarray nylon membrane with colorimetry detection was used to profile the expression of smoke- and hydrogen peroxide-inducible genes in a human bronchial epithelial cell line, HBE1. On the basis of the time course of expression, at least three phases of change in gene expression could be recognized. The first phase is an immediate event in response to oxidant injury. This phase includes induction of the bcl-2 and mdm-2 genes, which are involved in the regulation of apoptosis, and the mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) gene, that functions as a regulator of various mitogen-activated protein kinase activities. The second phase, usually 5 h later, includes the induction of various stress proteins and ubiquitin, which are important in providing the chaperone mechanism and the turnover of damaged macromolecules. The third phase, which is 5-10 h later, includes the induction of genes that are apparently involved in reducing oxidative stress by metabolizing reactive oxygen species. In this phase, enzymes associated with tissue and cell remodeling are also elevated. These results demonstrate a complex gene expression array by bronchial epithelial cells in response to the insult of oxidants that are relevant to environmental pollutants.
American Journal of Respiratory and Critical Care Medicine 12/2001; 164(10 Pt 2):S85-9. · 11.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increasing evidence indicates that intracellular redox status modulates the activity of various transcriptional factors, including nuclear factor (NF)-kappa B and activator protein-1. Our laboratory has been interested in characterizing the role thioredoxin (TRX) plays in regulating cellular redox status in airway epithelium. TRX is a small, ubiquitous protein with two redox-active half-cysteine residues, -Cys-Gly-Pro-Cys, in its active center. Using primary passage-1 human tracheobronchial epithelial cell cultures and an immortalized human bronchial epithelial cell line, HBE1, we observed that tumor necrosis factor (TNF)-alpha enhanced NF-kappa B transcriptional activity. This observation was based on gel mobility shift assays and interleukin (IL)-8 promoter-reporter gene transfection studies. TNF-alpha activation coincided with translocation of NF-kappa B p65 from the cytoplasm to the nucleus. Pretreatment with N-acetyl-cysteine (NAC) (1 to 10 mM) or glutathione (1 to 10 mM) inhibited TNF-alpha-induced activation of NF-kappa B transcriptional activity and IL-8 promoter-mediated reporter gene expression. In contrast, elevated TRX protein levels in cells enhanced TNF-alpha-dependent NF-kappa B transcriptional activity and IL-8 promoter activity. This observation was independent of the manner in which TRX was elevated in cells (e.g., by cotransfection with a FLAG-TRX expression clone, or by direct exposure to commercially available human TRX protein). Localization of TRX protein by anti-TRX antibody indicated an accumulation of TRX protein in the nucleus after TNF-alpha treatment. The nuclear localization phenomenon was different from the major cytosolic accumulation of glutathione and NAC. This is the first known report demonstrating movement of TRX into the nucleus of airway epithelial cells after an inflammatory stress. These results suggest a compartment effect of thiol chemicals in the regulation of redox-dependent transcriptional activity.
American Journal of Respiratory Cell and Molecular Biology 09/2001; 25(2):178-85. · 4.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mediastinal tumors are comprised of various benign and malignant neoplasms that share the same anatomic location within the thorax. The mediastinum is traditionally divided into three compartments: the anterior, middle, and posterior mediastinum. This division, based on lateral chest radiographs, helps clinicians establish appropriate differential diagnoses and plan further imaging, diagnostic, and treatment strategies. With the continued and complex advances in imaging, medical treatment, and surgery, we recommend a multidisciplinary approach to the management of mediastinal tumors. This discussion is intended to guide the pulmonary specialist through this potentially complex approach.
Current opinion in pulmonary medicine 08/2001; 7(4):226-33. · 3.12 Impact Factor