Validation of a Novel Compact System for the Measurement of Lung Volumes.

BACKGROUND: Current techniques for measuring absolute lung volumes rely on bulky and expensive equipment and are complicated to use for the operator and the patient. A novel method for measurement of absolute lung volumes, the MiniBox method, is presented. RESEARCH QUESTION: Across a population of patients and healthy participants, do values for total lung capacity (TLC) determined by the novel compact device (MiniBox, PulmOne Advanced Medical Devices, Ltd.) compare favorably with measurements determined by traditional whole body plethysmography? STUDY DESIGN AND METHODS: A total of 266 participants (130 men) and respiratory patients were recruited from five global centers (three in Europe and two in the United States). The study population comprised individuals with obstructive (n = 197) and restrictive (n = 33) disorders as well as healthy participants (n = 36). TLC measured by conventional plethysmography (TLCPleth) was compared with TLC measured by the MiniBox (TLCMB). RESULTS: TLC values ranged between 2.7 and 10.9 L. The normalized root mean square difference (NSD) between TLCPleth and TLCMB was 7.0% in healthy participants. In obstructed patients, the NSD was 7.9% in mild obstruction and 9.1% in severe obstruction. In restricted patients, the NSD was 7.8% in mild restriction and 13.9% in moderate and severe restriction. No significant differences were found between TLC values obtained by the two measurement techniques. Also no significant differences were found in results obtained among the five centers. INTERPRETATION: TLC as measured by the novel MiniBox system is not significantly different from TLC measured by conventional whole body plethysmography, thus validating the MiniBox method as a reliable method to measure absolute lung volumes.

Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy.

Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results: We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions: Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.

Effect of adding postoperative noninvasive ventilation to usual care to prevent pulmonary complications in patients undergoing coronary artery bypass grafting: a randomized controlled trial.

OBJECTIVE: We compared the efficacy of noninvasive ventilation with bilevel positive airway pressure added to usual care versus usual care alone in patients undergoing coronary artery bypass grafting. METHODS: We performed a 2-group, parallel, randomized controlled trial. The primary outcome was time until fit for discharge. Secondary outcomes were partial pressure of carbon dioxide, forced expiratory volume in 1 second, atelectasis, adverse events, duration of intensive care stay, and actual postoperative stay. RESULTS: A total of 129 patients were randomly allocated to bilevel positive airway pressure (66) or usual care (63). Three patients allocated to bilevel positive airway pressure withdrew. The median duration of bilevel positive airway pressure was 16 hours (interquartile range, 11-19). The median duration of hospital stay until fit for discharge was 5 days for the bilevel positive airway pressure group (interquartile range, 4-6) and 6 days for the usual care group (interquartile range, 5-7; hazard ratio, 1.68; 95% confidence interval, 1.08-2.31; P = .019). There was no significant difference in duration of intensive care, actual postoperative stay, and mean percentage of predicted forced expiratory volume in 1 second on day 3. Mean partial pressure of carbon dioxide was significantly reduced 1 hour after bilevel positive airway pressure application, but there was no overall difference between the groups up to 24 hours. Basal atelectasis occurred in 15 patients (24%) in the usual care group and 2 patients (3%) in the bilevel positive airway pressure group. Overall, 30% of patients in the bilevel positive airway pressure group experienced an adverse event compared with 59% in the usual care group. CONCLUSIONS: Among patients undergoing elective coronary artery bypass grafting, the use of bilevel positive airway pressure at extubation reduced the recovery time. Supported by trained staff, more than 75% of all patients allocated to bilevel positive airway pressure tolerated it for more than 10 hours.

Isogeneic comparison of primary and metastatic lung cancer identifies CX3CR1 as a molecular determinant of site-specific metastatic diffusion.

Metastatic diffusion is a major adverse prognostic determinant in lung cancer, that is ultimately responsible for significant morbidity, organ failure and death. Chemokine signaling pathways are known to guide site-specific metastatic spread in solid tumours. However, little is known about the contribution of CX3CR1 in the systemic dissemination of lung cancer. Syngeneic primary lung cancer/metastasis tissue microarray slides were constructed using 98 post-mortem specimens taken from patients with untreated lung cancer and immunostained for CX3CR1. Clinicopathological correlation between CX3CR1 expression and patient demographics, tumour histology, stage and pattern of metastatic spread was performed using χ2 test. CX3CR1 immunopositivity was significantly higher in non-small cell lung cancer (NSCLC) compared to small cell (SCLC) primary (p<0.001) and secondary tumours (p<0.001), with >75% of the metastatic sites staining positively in NSCLC. CX3CR1 positivity was significantly associated with stage and number of metastatic sites (p=0.03). At patients' death CX3CR1-negative lung adenocarcinomas were more likely to have spread to the brain and the liver (p=0.01). CX3CR1 is upregulated in NSCLC metastatic disease and its expression in primary lung tumours relates inversely to organotropic spread of cancer cells to the brain and the liver.

Inhaled therapy in elderly COPD patients; time for re-evaluation?

OBJECTIVE: chronic obstructive pulmonary disease (COPD) prevalence steadily increases with age. However, the effectiveness of inhaled therapy in the elderly COPD population has rarely been formally evaluated. We studied a group of elderly patients with COPD with a range of severity, selected from one General Practice register to measure peak inspiratory flow (PIF) and assess patient perceived benefit. METHODS: we recruited 53 randomly selected elderly patients with COPD (36 males) with a mean age of 73.5 years (range 65-89 years). The evaluation consisted of (i) information obtained from directed questions and (ii) objective measurements of the ability to generate adequate PIF for a variety of inhalers. Patients answered questions regarding ease of use, perceived benefit from and specific problems encountered with their inhaler. Three recordings of PIF were measured at varying inhaled resistances using the 'In-Check Dial'. RESULTS: thirty-five were classified as mild, 17 moderate and 1 severe COPD. All patients used a metered dose inhaler (pMDI), and 12 of the patients also used a dry powder inhaler (DPI). Forty six per cent of patients using a pMDI and 17% of those using a DPI rated their device difficult to use. No patient used a nebuliser. Thirty-one of the 53 patients using just a pMDI felt they were able to perceive benefit in comparison to 4 of the 12 DPI users. Even though most DPI users (10/12) had rated their inhaler as easy to use, 50% were 'unsure' as to whether they received any clinical benefit. Most patients were unable to generate sufficient inspiratory flow to use the higher resistance DPI's and patients with COPD who were able to generate adequate PIF were invariably mild. A significant negative correlation was found between age and the PIF achieved when assessed using the high resistance device setting (R = 0.84, P<0.0001). Multivariate analysis showed the effect of age on PIF was independent of the disease grade. CONCLUSIONS: elderly patients with COPD, even when in a stable clinical condition, may be unable to gain optimum benefit from their inhaler.

The effect of the steroid-sparing response to low-dose methotrexate on bone metabolism in glucocorticoid-dependent asthmatics.

BACKGROUND: The skeletal effects of low-dose methotrexate (MTX), in glucocorticoid-dependent asthmatics (GCDA), are unknown. METHODS: We studied 9 patients from a total of 26 chronic GCDA who completed 28 weeks of MTX (15 mg weekly, intramuscularly). Prednisolone dose was not altered during the first 12 weeks, and was then reduced between 12 and 28 weeks. Mean (S.E.M.) age of the patients was 54 (4.0) years. They had normal bone mineral density (BMD), were not taking medication that affected bone metabolism (except prednisolone and inhaled corticosteroids) and all achieved at least 50% reduction in prednisolone dose at 28 weeks. Blood and urine samples were obtained at baseline, 12, 28 and 40 weeks for measurement of serum osteocalcin (OC) and bone alkaline phosphatase (Bone-ALP) as formation markers and urinary deoxypyridinoline (DPD) and N-terminal cross-linked telopeptide of type I collagen (NTX-I) as resorption markers. RESULTS: Concurrently with the changes in prednisolone dosage serum OC levels increased significantly at 28 weeks (p<0.008) (8.1+/-1.0 ng/ml) compared to baseline (4.7+/-0.6 ng/ml) and 12 weeks (5.1+/-0.6 ng/ml), but trended back by 40 weeks (6.6+/-0.6 ng/ml). No significant changes were observed for the other bone markers between baseline and the other time points. CONCLUSIONS: The beneficial effects of steroid reduction on bone metabolism do not appear to be impaired by concomitant MTX treatment at least over 12 weeks.

Integrated approach for in vivo evaluation of respiratory muscles mechanics.

The respiratory muscles constitute the respiratory pump, which determines the efficacy of ventilation. Any functional disorder in their performance may cause insufficient ventilation. This study was designed to quantitatively explore the relative contribution of major groups of respiratory muscles to global lung ventilation throughout a range of maneuvers in healthy subjects. A computerized experimental system was developed for simultaneous noninvasive measurement of inspired/expired airflow, mouth pressure and up to 8 channels of EMG surface signals from major respiratory muscles which are located near the skin (e.g., sternomastoid, external intercostal, rectus abdominis and external oblique) during various respiratory maneuvers. Lung volumes values were calculated by integration of airflow data. Hill's muscle model was utilized to calculate the forces generated by the muscles from the acquired EMG data. Analysis of EMG measurements and respiratory muscles forces revealed the following characteristics: (a) muscle activity increased with increased breathing effort, (b) inspiratory muscles contributed to inspiration even at relatively low flow rates, while expiratory muscles are recruited at higher flow rates, (c) the forces generated by the muscle depended on the muscle properties as well as on their EMG performance and (d) the pattern of the muscle's force curves varied between subjects, but were generally consistent for the same subject regardless of breathing effort.

Pulmonary function after pectoralis major myocutaneous flap harvest.

OBJECTIVE: The pectoralis major myocutaneous flap is widely used in the reconstruction of surgical defects in the head and neck region. Pulmonary atelectasis has been reported in patients undergoing these procedures, and many of these patients are heavy smokers and drinkers and have associated cardiopulmonary disorders. Flap harvest and donor site closure may lead to impairment of pulmonary function before and after the use of pectoralis major myocutaneous (PMC) in surgical reconstruction in patients with cancer of the head and neck. METHODS: Patients undergoing extirpation of head and neck tumors with PMC reconstruction were prospectively evaluated. Patient age, smoking history (pack-years), anesthesia duration, percentage predicted pre- and postoperative FEV1, percentage-predicted pre- and postoperative FVC (forced vital capacity), and preoperative SaO2 (oxygen saturation) were evaluated. Preoperative FEV1/FVC ratio was calculated. Chest x-rays were reviewed. RESULTS: Only 11 patients, 5 of whom smoked, could be evaluated postoperatively. Preoperative FEV1/FVC was more than 70 and FEV1 more than 75% predicted in all patients. A decrease in FVC was observed in 7 of the 11 patients, which ranged between 2% and 27% without any clinically obvious respiratory manifestations. A baseline SaO2 of more than 96% was noted in all patients. Four of 9 postoperative chest x-rays demonstrated atelectasis. CONCLUSIONS: PMC harvest and donor site closure may lead to the recorded decrease in FVC measurements. These changes did not manifest clinically. Nevertheless, alternative methods of surgical defect closure should be considered in patients with severe preexisting pulmonary disorders.