Cell migration leads to spatially distinct but clonally related airway cancer precursors.

BACKGROUND: Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. METHODS: Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. RESULTS: We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. CONCLUSIONS: Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.

Diagnostic accuracy of biomarkers of oxidative stress in parapneumonic pleural effusions.

BACKGROUND: The imbalance between oxidants and antioxidants is referred to as oxidative stress and has been associated with various respiratory disorders. The aim of this study was the assessment of 8-isoprostane (8-iso-PGF(2α)) and Cu/Zn superoxide dismutase (Cu/Zn SOD) in exudative pleural effusions in order to examine the diagnostic accuracy of these markers in the differentiation between complicated and uncomplicated parapneumonic effusions. METHODS: The study included 214 consecutive patients with pleural effusions [68 parapneumonic (31 uncomplicated parapneumonic, 20 complicated parapneumonic, 17 empyemas), 24 tuberculous, 88 malignant and 34 transudates]. 8-Isoprostane and Cu/Zn SOD were determined by ELISA in pleural fluid and serum. RESULTS: Parapneumonic effusions were characterized by higher pleural fluid 8-isoprostane levels compared to transudative, malignant and tuberculous effusions. Pleural fluid Cu/Zn SOD levels were lower in transudates, while serum levels were higher in transudative compared to all exudative pleural effusions. Both pleural fluid 8-isoprostane and Cu/Zn SOD were higher in complicated parapneumonic effusions and empyemas compared to uncomplicated parapneumonic effusions. Pleural fluid 8-isoprostane was the most accurate test to differentiate between complicated and uncomplicated parapneumonic pleural effusions with a sensitivity of 100% and a specificity of 58·1% at a cut-off point of 35·1 (AUC = 0·848). CONCLUSIONS: Pleural fluid 8-isoprostane and Cu/Zn SOD may provide useful information for the differentiation between uncomplicated and complicated parapneumonic effusions and empyemas.

Matrix metalloproteinase levels in the differentiation of parapneumonic pleural effusions.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the escalation of fibrosis and remodeling which are central to the subsequent progression of a parapneumonic pleural effusion to empyema. OBJECTIVES: The aim of this study was the assessment of MMP-2, MMP-8 and MMP-9 in parapneumonic pleural effusions in order to examine their value in the differentiation between uncomplicated and complicated parapneumonic effusions. METHODS: The study included 208 consecutive patients with pleural effusions [60 parapneumonic (27 uncomplicated parapneumonic, 17 complicated parapneumonic, 16 empyemas), 24 tuberculous, 89 malignant and 35 transudates]. Concentrations of pleural fluid and serum MMP-2, MMP-8 and MMP-9 were determined by immunoassay. RESULTS: Pleural fluid MMP-8 and MMP-9 levels were higher in complicated parapneumonic effusions or empyema than in uncomplicated effusions, while their serum levels were higher in complicated parapneumonic effusions. MMP-2 levels were higher in uncomplicated than in complicated parapneumonic effusions or empyema. Pleural fluid MMP-2/MMP-9 ratio was the best marker to differentiate complicated from uncomplicated parapneumonic effusions, with a sensitivity of 94.1% and a specificity of 77.8% at a cut-off point of 1.32 (AUC = 0.887). CONCLUSIONS: Pleural fluid MMP-2, MMP-8 and MMP-9 may provide useful information for differentiating between uncomplicated and complicated parapneumonic effusions.

Matrix metalloproteinases in respiratory diseases: from pathogenesis to potential clinical implications.

Matrix metalloproteinases (MMPs) are zinc-endopeptidases responsible for degradation of the extracellular matrix (ECM) components including basement membrane collagen, interstitial collagen, fibronectin, and various proteoglycans, during normal remodeling and repair processes. The turnover and remodeling of ECM must be tightly regulated since excessive or inappropriate expression of MMPs may contribute to the pathogenesis of tissue destructive processes associated with lung inflammation and disease. Despite the fact that our knowledge in the field of MMP biology is rapidly expanding, the role of MMPs in the pathogenesis of lung diseases is still not clear. The aim of the present review is to present the basic principles of MMP biology and, subsequently, to focus on the clinical and experimental evidence related to MMP activity in various lung disorders, including lung cancer, pleural effusions, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and interstitial lung diseases.

Systemic oxidative stress in patients with pulmonary sarcoidosis.

BACKGROUND: A local redox imbalance has been reported in pulmonary sarcoidosis. However, so far no study has described a systemic redox imbalance in this context. The aim of the present study was to evaluate the systemic oxidative stress in patients with sarcoidosis and determine its relationship to treatment and indices of disease severity. METHODS: 35 patients with histologically proven pulmonary sarcoidosis and 13 healthy volunteers were included in the study. All patients were studied during a stable phase of their disease. Systemic oxidative stress was quantified in serum with the use of a commercially available spectrophotometric method (D-ROM test) which determines overall oxidative stress, by measuring total hydroperoxides. Oxidative stress was expressed in conventional units, i.e. Carratelli Units (UCarr), where 1 UCarr corresponds to 0.8 mg/L H(2)O(2). RESULTS: Serum oxidative stress levels were significantly higher in patients with sarcoidosis compared to those of normal subjects (390+/-25 vs 300+/-18 UCarr respectively, p=0.04). Patients not receiving systemic corticosteroids had higher levels of oxidative stress compared to steroid-treated patients (461.5+/-38 vs 315+/-20, p<0.01) and compared to controls (461.5+/-38 vs 300+/-18 UCarr, p<0.01). Oxidative stress did not correlate with diffusion lung capacity (DLCO), partial arterial oxygen tension (PaO(2)), MRC dyspnoea scale or chest X-ray stage. CONCLUSIONS: Systemic oxidative stress is increased in patients with stable pulmonary sarcoidosis who do not receive systemic corticosteroids. This finding suggests a sustained oxidative burden even when clinical, functional and radiological criteria indicate disease stability.

Acute phase markers for the differentiation of infectious and malignant pleural effusions.

Acute-phase markers, such as C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), have been studied in inflammatory and malignant disorders. We examined the diagnostic value of these markers for the differentiation among parapneumonic, tuberculous and malignant effusions. We studied 124 patients with pleural effusions, classified as exudates [total (n=97), parapneumonic (n=15), tuberculous (n=25), malignant (n=57)] and transudates due to congestive heart failure (n=27). CRP, IL-6 and TNF-alpha were measured in pleural fluid and serum. Pleural fluid CRP was higher in parapneumonic compared to tuberculous and malignant effusions, providing 100% sensitivity for a cut-off point of 5.3mg/dL. IL-6 was higher in both parapneumonic and tuberculous compared to malignant effusions. TNF-alpha was higher in tuberculous compared to malignant effusions, providing 96.0% sensitivity, and 93.0% specificity for a cut-off point of 88.1 pg/mL. Pleural fluid CRP levels were lower than serum in all groups, probably reflecting systemic inflammation, whereas IL-6 and TNF-alpha were higher in pleural fluid indicating local production. Our data suggest that these markers may provide useful information for the differentiation of infectious and malignant effusions in clinical practice. However, further studies are needed for the validation of these findings in usual clinical circumstances.

Adiposity and low-grade systemic inflammation modulate matrix metalloproteinase-9 levels in Greek children with sleep apnea.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) plasma levels correlate with C-reactive protein (CRP) concentrations and they are both increased in adults with obstructive sleep apnea (OSA). No studies have evaluated MMP-9 levels in children with sleep apnea and CRP is not consistently elevated in pediatric OSA. The aim of this investigation was to evaluate the association of severity of OSA, adiposity, and CRP with MMP-9 plasma levels in Greek children. METHODS: Consecutive children with snoring who underwent polysomnography and were found to have OSA (obstructive apnea-hypopnea index-OAHI > or = 1 episode/hr) were recruited. Subjects without OSA (OAHI < 1 episode/hr) were included for comparison. Morning plasma MMP-9 and CRP were measured. RESULTS: Twenty-nine children with moderate-to-severe OSA (age 5.4 +/- 1.5 years; OAHI 13.9 +/- 13.0 episodes/hr), 55 participants with mild OSA (6.4 +/- 2.6 years; OAHI 2.4 +/- 1.1 episodes/hr) and 22 subjects without OSA (6.8 +/- 2.6 years; OAHI 0.6 +/- 0.2 episodes/hr) were studied. Children with moderate-to-severe OSA were similar to those with mild OSA or without OSA regarding ln-transformed MMP-9 values (5.87 +/- 0.60 vs. 5.84 +/- 0.55 vs. 5.80 +/- 0.46; P > 0.05) and CRP concentrations (0.22 +/- 0.29 mg/dl vs. 0.21 +/- 0.36 vs. 0.13 +/- 0.16 mg/dl; P > 0.05). In multiple linear regression, body mass index (P = 0.027) and CRP levels (P = 0.008), but not OAHI or SpO(2) nadir (P > 0.05), were significantly related to MMP-9 values. CONCLUSIONS: Adiposity and systemic inflammation unrelated to OSA severity, modulate MMP-9 levels in Greek children.

Clinical, functional and biochemical changes during recovery from COPD exacerbations.

The pathways underlying chronic obstructive pulmonary disease exacerbations (ECOPD) remain unclear. This study describes the clinical, functional and biochemical changes during recovery from ECOPD. Thirty hospitalized patients with Anthonisen's type-I ECOPD were evaluated on days 0 (admission), 3, 10 and 40. A five-symptom score (TSS), performance status and quality of life were evaluated. Post-bronchodilator spirometry, blood gases, oxidative stress, C-reactive protein (CRP), serum amyloid-A (SAA), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and fibrinogen were also measured. Patients were classified as early- or late-recoverers, based on whether dyspnea had returned to pre-exacerbation level by day 10. Most clinical, functional and biochemical parameters improved during follow-up. CRP and IL-6 levels reduced on Day 3 (p<0.05), whereas SAA on Day 10 (p<0.01). TNF-alpha was reduced on Days 3 and 10, but on Day 40 its levels returned to baseline. Fibrinogen and WBC reduced only by day 40. TSS and dyspnea were correlated inversely with FEV(1) on days 3, 10 and 40. Although late-recoverers had lower FEV(1) on admission, none of the reported measurements on admission and day 3 predicted early recovery. During recovery from ECOPD, symptomatic improvement correlates only with post-bronchodilator FEV(1) whereas systemic inflammatory burden subsidence does not correlate with clinical and functional changes. Although late-recoverers have lower FEV(1) on admission, none of the measured parameters is able to predict early symptomatic recovery.

Urine concentrations of cysteinyl leukotrienes in children with obstructive sleep-disordered breathing.

BACKGROUND: Adenotonsillar tissue of children with obstructive sleep-disordered breathing (SDB) has increased content of cysteinyl leukotrienes (CysLTs) and expression of CysLTs receptors. Furthermore, CysLTs concentrations in the nasal exhaled breath condensate of children with sleep apnea are elevated. OBJECTIVE: To investigate the relationship between urine levels of CysLTs and severity of SDB in children. METHODS: Morning urine concentrations of CysLTs were measured in children with symptoms of SDB and in control subjects with recurrent tonsillitis and without snoring who underwent polysomnography and were expressed in pg/mL per mg/dL of urine creatinine. RESULTS: Nineteen children with moderate-to-severe SDB (mean [+/- SD] age, 5.4 +/- 1.6 years; obstructive apnea-hypopnea index [OAHI]: 14.4 +/- 9.6 episodes/h), 29 subjects with mild SDB (5.1 +/- 1.5 years; OAHI: 2.9 +/- 0.8 episodes/h), 26 children with primary snoring (PS) [7 +/- 2.6 years; OAHI: 1.1 +/- 0.3 episodes/h], and 18 control subjects (6.4 +/- 2.5 years; OAHI: 0.7 +/- 0.3 episodes/h) were studied. Children with moderate-to severe SDB had higher log-transformed urine CysLTs levels than those with mild SDB, PS, or control subjects (2.39 +/- 0.51 vs 2.06 +/- 0.26 vs 2.11 +/- 0.25 vs 1.86 +/- 0.28; p < 0.05). Log-transformed CysLTs concentration, tonsillar size, and body mass index z score were significant predictors of log-transformed OAHI (p < 0.01). CONCLUSIONS: Urine excretion of CysLTs is related to SDB severity in children. This finding indicates that 5-lipoxygenase pathway products participate in the pathogenesis of obstructive sleep apnea in childhood or alternatively that SDB promotes CysLTs biosynthesis.