Inflammatory cells and apoptosis in respiratory and limb muscles of patients with COPD.

Discrepancies exist regarding the involvement of cellular inflammation and apoptosis in the muscle dysfunction of chronic obstructive pulmonary disease (COPD) patients with preserved body composition. We explored whether levels of inflammatory cells and apoptosis were increased in both respiratory and limb muscles of COPD patients without nutritional abnormalities. In the vastus lateralis, external intercostals, and diaphragms of severe and moderate COPD patients with normal body composition, and in healthy subjects, intramuscular leukocytes and macrophage levels were determined (immunohistochemistry). Muscle structure was also evaluated. In the diaphragm and vastus lateralis of severe and moderate COPD patients and controls, apoptotic nuclei were explored using the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, electron microscopy, and caspase-3 expression. In COPD patients compared with controls, diaphragm and intercostal levels of inflammatory cells were extremely low and not significantly different. However, in the vastus lateralis of the severe patients, inflammatory cell counts, although also very low, were significantly greater. In those patients, TUNEL-positive nuclei levels were also significantly greater in diaphragms and vastus lateralis. A significant inverse relationship was found between quadriceps TUNEL-positive nuclei levels and muscle force. Ultrastructural apoptotic nuclei revealed no differences in respiratory or limb muscles between COPD patients and controls. Muscle caspase-3 expression did not differ between patients and controls. In severe COPD patients with preserved body composition, while increased apoptotic nuclei seems to be a contributor to their muscle dysfunction, cellular inflammation does not. The increased numbers of TUNEL-positive nuclei in their muscles suggest that they may also be exposed to a continuous repair/remodeling process.

Multiple independent primary cancers do not adversely affect survival of the lung cancer patient.

OBJECTIVE: Diagnosis of multiple independent primary cancers is increasing in many settings. Objectives of this study were to analyze clinical characteristics, organ location, and prognosis associated with the presentation of multiple independent primaries when a lung cancer is involved. METHODS: We analyzed all patients with a histology-proven diagnosis of lung cancer registered from January 1990 to December 2004 at the Tumor Registry of the Hospital del Mar, Barcelona. We compared 1686 patients presenting a lung cancer as unique primary versus 228 patients presenting a lung cancer and another independent primary. Cofactors included age, sex, smoking habit, lung cancer histology and stage, type and intention of treatment, organ location of the other cancer, and survival from the date of lung cancer diagnosis. RESULTS: Seventy percent of the other cancers were tobacco-related. Independent risk factors of cancer multiplicity were smoking (OR: 3.99; 95% CI: 1.4-11.2), lung cancer stages I (OR: 1.84; 95% CI: 1.2-2.9) and II (OR: 3.25; 95% CI: 1.7-6.3), and older age (OR: 3.11; 95% CI: 1.9-5.1). Once adjusted by age and sex, the main determinant of survival was lung cancer stage rather than cancer multiplicity. However, patients with multiple cancers presented a slightly better survival than patients with a lung cancer as unique primary. When analyzed by subgroups, survival was higher in patients with the lung cancer first (HR: 0.44; 95% CI: 0.24-0.80), and in patients with the other cancer first (HR: 0.80; 95% CI: 0.65-0.99), but it was not different in the patients with a lung cancer and a synchronous other cancer (HR: 0.80; 95% CI: 0.52-1.15). CONCLUSIONS: The risk of developing a second independent cancer was strongly associated with tobacco smoking. Cancer multiplicity was not associated with a worse prognosis. As a consequence, when a first primary tobacco-related cancer is treated with curative intention, patients should be closely followed up for an early diagnosis of a possible new independent cancer; and if diagnosed, treatment to cure should be considered as the first option.

Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease.

RATIONALE: Oxidative stress is involved in the skeletal muscle dysfunction observed in patients with severe chronic obstructive pulmonary disease (COPD). We hypothesized that the diaphragms of such patients might generate greater levels of oxidants than those neutralized by antioxidants. OBJECTIVES: To assess the levels of both oxidative and nitrosative stress and different antioxidants in the diaphragms of those patients, and to analyze potential relationships with lung and respiratory muscle dysfunctions. METHODS AND MEASUREMENTS: We conducted a case-control study in which reactive carbonyl groups, hydroxynonenal-protein adducts, antioxidant enzyme levels, nitric oxide synthases, and 3-nitrotyrosine formation were detected using immunoblotting and immunhistochemistry in diaphragm specimens (thoracotomy) obtained from six patients with severe COPD, six patients with moderate COPD, and seven control subjects. MAIN RESULTS: Diaphragms of patients with severe COPD showed both higher protein carbonyl groups and hydroxynonenal-protein adducts than control subjects. When only considering patients with COPD, negative correlations were found between carbonyl groups and airway obstruction, and between hydroxynonenal-protein adducts and respiratory muscle strength. Although diaphragmatic neuronal nitric oxide synthase did not differ among the three groups and no inducible nitric oxide synthase was detected in any muscle, muscle endothelial nitric oxide synthase was lower in patients with severe COPD than in control subjects. Muscle nitrotyrosine levels were similar in both patients with severe COPD and control subjects. CONCLUSIONS: This study shows that oxidative stress rather than nitric oxide is likely to be involved in the respiratory muscle dysfunction in severe COPD.

Clinical value of p53, c-erbB-2, CEA and CA125 regarding relapse, metastasis and death in resectable non-small cell lung cancer.

The prognostic value of p53 and c-erbB-2 immunostaining and preoperative serum levels of CEA and CA125 was investigated in a prospective multicentric study including 465 consecutive non-small cell lung cancer (NSCLC) patients with resectable tumors. Four end-points were used: lung cancer death, first relapse (either locoregional or metastasis), loco-regional recurrence and metastasis development. Standard statistical survival methods (Kaplan-Meier and Cox regression) were used. The specificity of the prognostic effect across different types of tumors was also explored, as had been planned in advance. Our results showed, once again, that pathological T and N classifications continue to be the strongest predictors regarding either relapse or mortality. Three of the studied markers seemed to add further useful information, however, but in a more specific context. For example, increased CEA concentration defined a higher risk population among adenocarcinomas but not among people with squamous tumors; and p53 overexpression implied a worse prognosis mainly in patients with well differentiated tumors. The analysis of type of relapse proved to be very informative. Thus, CA125 level was associated with a worse prognosis mainly related with metastasis development. Another interesting result was the influence of smoking, which showed a clear dose-response relationship with the probability of metastasis. For future studies, we recommend the inclusion of different endpoints, namely considering the relationship of markers with the type of relapse involved in lung-cancer recurrence. They can add useful information regarding the complex nature of prognosis.

Dual morphometrical changes of the deltoid muscle in patients with COPD.

The present study was specifically aimed at evaluating if the structure of the deltoid muscles is modified in patients with chronic obstructive pulmonary disease (COPD). Twenty-eight male volunteers (61+/-13 yr) were assigned, according to pulmonary function, to either the COPD (n=14, FEV(1)=22-74%pred) or control group (n=14, FEV(1)=83-121%pred). Biopsies from non-dominant deltoid muscle were obtained and processed for morphometric analysis of the fibre types. Both type I and type II muscle fibres were distributed in the typical mosaic pattern. The mean value of the fibre size was within the normal range. However, three differentiated modes were observed in the deltoid from COPD patients: a central mode of normal sized fibres, a mode of atrophic fibres and a mode of hypertrophic fibres. This observation was evident even within single fascicles and especially prevalent in the most severe COPD patients. We conclude that factors with opposite effect (promotion of either atrophy or hypertrophy) exert relevant roles in the histomorphometrical characteristics of the deltoid muscles in COPD patients.

Adaptación estructural del diafragma en pacientes con Enfermedad Pulmonar Obstructiva Crónica (EPOC)

Introducción: La función de los músculosrespiratorios de pacientes con enfermedad pulmonar obstructiva crónica (EPOC) está alterada, entre otros, por eventos mecánicos como la hiperinsuflación pulmonar, trastornos nutricionales (i.e., desnutrición) y cambios metabólicos (i.e., hipoxemia). Sin embargo, un estudio reciente postuló que el músculo puede compensar en alguna medida los efectos deletéreos de la hiperinsuflación. Objetivos: Describir los cambios ultraestructurales del diafragma humano en pacientes con EPOC y relacionarlos con el estado nutricional y la función pulmonar y muscular respectiva. Diseño: estudio observacional prospectivo y descriptivo (serie de casos). Pacientes y Métodos: Se estudiaron 22 pacientes llevados a toracotomía por neoplasia pulmonar localizada (estadio TMN I). Se evaluaron previos a la cirugía el estado nutricional, función pulmonar y mecánica del diafragma y de los demás músculos inspiratorios. Durante la intervención se tomaron muestras del diafragma costal que fueron procesadas para estudios histoquímicos y de microscopía electrónica. resultados: Los pacientes mostraron un volumen espiratorio en el primer segundo (FEV1) de 73+-16 por ciento pred; relación volumen residual/capacidad pulmonar total (RV/TLC), 43+-12 por ciento; y una presión transdiafragmática máxima de 93+-30 cmH2O. En las células musculares del diafragma se evidenciaron 56+-17 secciones mitocondriales por 100um2 (Nmit), una longitud sarcomérica (Lsar) de 2.15+-0.17um, y un área de depósitos de glicógeno (Agly) de 9.6+-4.4 por ciento del área celular total analizada. Se evidenciaron diferencias en elcontenido mitocondrial en asociación con el FEV1, ya que aquellos pacientes con el FEV1 menor de 75 porciento pred tenían mayor Nmit (63+-14 vs 46+-16 mit/100um2, p<0.05). El porcentaje FEV1 correlacionó en forma inversa con Nmit (r=0.53, p<0.01). Por otra parte, las muestras musculares de pacientes con una relación RV/TLC mayor de 35 por ciento mostraron mayores...