Ken Y. Yoneda

Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues

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.

The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations

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.

Independent Review of Interstitial Lung Disease Associated with Death in TRIBUTE (Paclitaxel and Carboplatin with or without Concurrent Erlotinib) in Advanced Non-small Cell Lung Cancer

Introduction: 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. Methods: 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. Results: 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. Conclusions: 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.

Cardiopulmonary Function in High Altitude Residents of Ladakh

We studied residents of high altitude in Ladakh, India, to determine the effects of altitude, age, gender, and ethnicity on gas exchange and pulmonary function. Physical examinations, including pulse oximetry, hemoglobin concentration, end-tidal PCO2, and pulmonary function, were conducted on resting Ladakhi and Tibetan subjects at altitudes of 3300, 4200, and 4500 m. A total of 574 men and women, ranging in age from 17 to 82, were studied. At 3300 m, Ladakhis had higher heart rates than Tibetans in both genders and higher PETCO2 in women. Above 4000 m, 21 of the 141 men studied (15%) had Hb concentrations higher than 20 g/dL, with one confirmed case of Monges disease. There was no gender difference in SaO2 at any altitude except for pregnant women. At 4600 m, Tibetans had significantly higher peak flows and lower PETCO2 than Ladakhis. Ladakhi men had higher diastolic BP than women (91 vs. 81), with no difference in systolic BP. There was no gender difference in BP for Tibetans. An important spirometry finding for both groups was high air flows, with mid-maximal expiratory flow (MMEF) at 130% to 150% of predicted values, compared with 85% for sojourner controls, and FEV1/FVC at 115%, compared with sojourner controls at 98%. Improved lung mechanics may be an important adaptation to the lifelong sustained increase in resting ventilation as well as to indoor biomass smoke and outdoor dust exposure of these populations at high altitude.

Application of high-density DNA microarray to study smoke- and hydrogen peroxide-induced injury and repair in human bronchial epithelial cells

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.

Systemic Metabolomic Changes in Blood Samples of Lung Cancer Patients Identified by Gas Chromatography Time-of-Flight Mass Spectrometry

Lung cancer is a leading cause of cancer deaths worldwide. Metabolic alterations in tumor cells coupled with systemic indicators of the host response to tumor development have the potential to yield blood profiles with clinical utility for diagnosis and monitoring of treatment. We report results from two separate studies using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) to profile metabolites in human blood samples that significantly differ from non-small cell lung cancer (NSCLC) adenocarcinoma and other lung cancer cases. Metabolomic analysis of blood samples from the two studies yielded a total of 437 metabolites, of which 148 were identified as known compounds and 289 identified as unknown compounds. Differential analysis identified 15 known metabolites in one study and 18 in a second study that were statistically different (p-values <0.05). Levels of maltose, palmitic acid, glycerol, ethanolamine, glutamic acid, and lactic acid were increased in cancer samples while amino acids tryptophan, lysine and histidine decreased. Many of the metabolites were found to be significantly different in both studies, suggesting that metabolomics appears to be robust enough to find systemic changes from lung cancer, thus showing the potential of this type of analysis for lung cancer detection.

Advances in the management of endobronchial lung malignancies

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.

A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with Gram-negative urosepsis

Evidence from in vitro experiments and animal and human studies indicate that antibiotic therapy may induce the release of endotoxin from the outer membrane of Gram-negative bacteria. Antibiotics that bind preferentially to penicillin-binding protein-2 (PBP-2) —such as imipenem — are associated with little release of endotoxin, while antibiotics that preferentially bind to PBP-3 — such as ceftazidime — are associated with far greater release of endotoxin. We conducted a randomized, multicenter, double-blind study comparing imipenem to ceftazidime in patients with urinary tract infections caused by Gram-negative bacilli associated with signs and symptoms of systemic inflammation. A total of 33 patients were randomized to receive either imipenem (n = 14) or ceftazidime (n = 19) for initial treatment for urosepsis. No differences in plasma endotoxin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) or urine endotoxin, IL-6 or IL-8 levels were found between the two treatment groups within the first 8 h after antibiotic administration. We conclude that, if differences exist with respect to endotoxin release by these two antimicrobial agents, these differences are not readily demonstrable in this clinical study with carefully defined patients with Gram-negative urinary tract infections.

Peritoneal and pleural ports for management of refractory ascites and pleural effusions: assessment of impact on patient quality of life and hospice/home nursing care.

PURPOSE Patients with end-stage malignancies often have refractory ascites or pleural effusions requiring repeated paracenteses or thoracenteses. Subcutaneous peritoneal and pleural port catheters are an alternative therapeutic option. We evaluate the clinical utility of this approach and the impact on quality of life (QOL) and home/hospice care. MATERIALS AND METHODS Thirty ports were placed, 16 peritoneal and 14 pleural, in patients with a mean age of 62 years. Retrospective chart review and interviews were held with patients and nursing care providers. Mean follow-up was 59 days. RESULTS On a 10-point scale, QOL improvement, compared to that prior to port placement, was rated a mean of 9.5 by patients and 9.0 by the nursing staff. Both patients and nurses reported a high degree of convenience (rated at 9.7 and 9.6, respectively) and improvement of symptoms and comfort (9.6 and 9.3, respectively). Nursing staff reported a high degree of comfort (9.9) using the aspiration ports. Six of 14 pleural ports were removed following pleurodesis. One pleural port was removed due to patient discomfort and another due to pneumothorax. Two patients with pleural ports developed tumor seeding in the subcutaneous tissues. Of 14 peritoneal ports, 3 required removal for leaking and probable chemical cellulitis. Four became temporarily occluded with patency restored using tissue plasminogen activator (TPA) infusion. CONCLUSIONS Peritoneal and pleural ports offer a convenient and relatively safe alternative to frequent paracenteses/thoracenteses in the management of refractory ascites and pleural effusions. This approach can improve the QOL for patients with end-stage disease.

Tracheotomy Tubes with Suction above the Cuff Reduce the Rate of Ventilator-Associated Pneumonia in Intensive Care Unit Patients:

Objectives: We evaluated the effect of tracheotomy tubes that enable suction immediately above the cuff on the development of ventilator-associated pneumonia (VAP). Methods: 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. Results: 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). Conclusions: 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.