Prevalence and Predictors of Obstructive Sleep Apnea in Patients with Chronic Obstructive Pulmonary Disease Undergoing Inpatient Pulmonary Rehabilitation.

The aim of our study was to evaluate the prevalence and predictors of obstructive sleep apnea (OSA) in patients with chronic obstructive pulmonary disease (COPD) undergoing inpatient pulmonary rehabilitation programs (PRPs). A retrospective data review of consecutive stable patients with a known diagnosis of COPD, admitted for PRP between January 2007 and December 2013. Full overnight polysomnography (PSG) and Epworth Sleepiness Scale (ESS) were assessed in all patients. Out of 422 evaluated patients, 190 (45%) showed an Apnea Hypopnea Index (AHI) ≥ 15 events/hour and underwent OSA treatment. Patients with OSA were significantly younger and had a less severe airway obstruction as compared to patients without OSA. There were no significant differences in cardiac comorbidities nor in arterial blood gases. As expected, patients with OSA showed significantly more severe diurnal symptoms, as assessed by the ESS and higher body mass index (BMI). However, only 69 out of 190 patients with OSA (36.3%) showed an ESS >10, whereas 25% of them had BMI ≤25 and 41% of them had a BMI <30. In all, 68% of patients with OSA were discharged with continuous positive airway pressure (CPAP), 15% with Bilevel ventilation, and 17% without any ventilatory treatment. In conclusion, in the population studied, the combination of OSA and COPD was frequent. BMI and ESS values commonly considered cutoff values for the prediction of OSA in the general population may not be accurate in a subgroup of patients with COPD.

The effect of continuous positive airway pressure on pulmonary function may depend on the basal level of forced expiratory volume in 1 second.

BACKGROUND: The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), also referred to as overlap syndrome (OS), is associated with a high rate of morbidity, COPD exacerbations and mortality. Treatment with continuous positive airway pressure (CPAP) has proven to significantly decrease the rate of these complications. However, data concerning the effect of CPAP on pulmonary function are scarce and conflicting. The aim of our study was to evaluate the effect of 1 year of CPAP treatment on arterial blood gases (ABGs) and pulmonary function tests in patients with OS and its potential relationship with the baseline severity of airway obstruction. A secondary aim was to search for predictors of changes in the evaluated parameters. METHODS: A retrospective study on a cohort of 92 patients (74 males) discharged from the Pulmonary Rehabilitation Unit of the Istituti Clinici Scientifici Maugeri in Pavia (Italy) from January 2013 to January 2016, with a diagnosis of OS and a prescription of CPAP, was conducted. Collected data at discharge were compared with 1-year follow-up data. RESULTS: After 1 year of CPAP, we observed the following: (I) a significant improvement in ABGs in all patients [median pO2 65.0 (59.0-70.0) vs. 71 (64.8-77.1) mmHg, pCO2 39.8 (36.2-43.5) vs. 38.3 (32.3-44.2) at baseline and after 1 year respectively, P<0.001], which was more pronounced in patients who were hypercapnic at baseline; (II) no significant change in respiratory function in the whole population; (III) a significant change in forced expiratory volume in 1 second (FEV1) only under and above a threshold of 79.1% of basal FEV1 with an opposite trend. In particular, patients with a basal FEV1 below that threshold significantly improved [median FEV1 70 (-70 to 200) mL, P=0.001], whereas patients with a basal FEV1 above the same threshold significantly worsened [median FEV1 -270 (-370 to -130) mL, P=3.05×10-5]. CONCLUSIONS: A population of overlap patients treated with CPAP may experience a different change in airflow obstruction after 1 year depending on the severity of baseline obstruction.

Long-Term Off-Line Extracorporeal Photochemotherapy in Patients with Chronic Lung Allograft Rejection Not Responsive to Conventional Treatment: A 10-Year Single-Centre Analysis.

BACKGROUND: Extracorporeal photochemotherapy (ECP) for chronic lung allograft dysfunction (CLAD) has been reported as beneficial in a few short-term studies. OBJECTIVES: In this retrospective cohort study on 48 CLAD patients treated by ECP (off-line technique) for a period of >8 years (compared to 58 controls), we explored potential predictors of survival and response. METHODS: Failures were defined as a decrease in forced expiratory volume in 1 s (FEV1) of >10% from ECP initiation. RESULTS: ECP patients were enrolled between February 2003 and December 2013; 14 (29.2%) with restrictive allograft syndrome (RAS) and 34 with bronchiolitis obliterans syndrome. Grade 1 severity was indicated in 58.3%, grade 2 in 20.8%, and grade 3 in 20.8% of patients. The median follow-up was 65 months (cumulative 2,284.4 person-months). Twenty (41.7%) patients died, including 17 (85%) CLAD-related deaths. Among the controls, there were 42 deaths (72.4%), of which 32 (76.2%) were CLAD related, over a median of 51 months (cumulative 3,066.5 person-months; p = 0.09). Among ECP patients, the FEV1 slope flattened out after a decline in the initial months (slope -19 ml/month in months 0-6, +4 in months 36-48 and later; p = 0.001). RAS was associated with poorer survival, whereas a 'rapid decline in the previous 6 months' was not. No ECP side effects or complications were observed. CONCLUSION: Long-term ECP for CLAD is safe and reduces FEV1 decline over time; the RAS phenotype might show a poorer response. ECP deserves to be evaluated in a randomized controlled trial.

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma.

BACKGROUND: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify 'druggable' pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus. METHODS: We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in 'hot spot' regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA). RESULTS: Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice. CONCLUSIONS: ERM and mTOR pathways are activated in MPM and 'druggable' by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM.

EGFR and KRAS mutational profiling in fresh non-small cell lung cancer (NSCLC) cells.

PURPOSE: Knowledge of tumor mutational status has become a priority for effective NSCLC-tailored treatment. NSCLC diagnosis is more often reached through biopsy; thus, there is a clear need to implement for routine tumor molecular profiling on small cytological samples. This work aims to screen and compare the EGFR and KRAS mutational prevalence in fresh tumor cells and in corresponding routinely processed samples derived from trans-thoracic fine-needle aspiration. The latter currently represents the most appropriate diagnostic procedure in case of peripheral lesions, such as adenocarcinomas, which account for almost 40% of all NSCLCs and for the highest EGFR mutational rates. METHODS: Two hundred and forty-four patients carrying peripheral lung masses underwent CT-guided aspiration. The obtained material was split, and a part was addressed to conventional histopathological analysis while the remaining one was stored at -20 °C. In case of confirmation of adenocarcinoma, tumor genomic DNA was extracted from both fresh and fixed material, and EGFR and KRAS sequencing was performed. RESULTS: We identified 136 adenocarcinomas; from 134, we could recover enough material for the study. A full match was demonstrated between EGFR/KRAS mutational prevalences through the two approaches tested. We found EGFR mutations in 13 patients (9.7%); 7 were females and 11 never or former smokers. KRAS mutations occurred in 20 (14.9%) patients. EGFR and KRAS mutations were mutually exclusive. CONCLUSIONS: Mutational screening on fresh cancer cells is an achievable, safe and cost-effective procedure which might allow routinely tumor molecular profiling as powerful integration of conventional histopathological analysis.

Targeting EGFR in non-small-cell lung cancer: lessons, experiences, strategies.

Cancer is a genetic disease and this concept is now widely exploited by both scientists and clinicians to design new targeted molecules. Indeed many data have already allowed us to ameliorate not only our knowledge about cancer onset, but also about patients treatment. Correlation between mutations in cancer alleles and drug response is a key point to identify drugs that match the genetic profile of each individual tumors. On the other hand, experience derived from inhibition of tyrosine kinase receptors has pointed out that targeted treatment is really successful only in a small subset of tumors. The latter are eventually addicted to those genetic alterations which are responsible for receptors activation and for the continued expression of their signalling. Overall these observations provide a strong rationale for a molecular-based diagnosis and patients selection for targeted therapies. This review analyses the current state of the art of molecularly-tailored pharmacological approach to lung cancer, one of the biggest killers among human solid tumors. Main relevance is addressed to genetic lesions activating the EGFR pathway transducers, focusing on their role as markers of targeted drug response.

Synchronous lung cancers: when same histological types feature different molecular profiles and response phenotypes.

We discuss the case of synchronous bilateral lung cancers which feature the same histological phenotype and a different EGFR mutational profile. Both histological and molecular characterizations were performed on specimens derived thorough CT-guided fine needle aspiration. A first-line chemotherapy was unsuccessful. Subsequent objective response to the EGFR inhibitor Erlotinib was clearly coherent with the sequencing data and the mutated nodule was effectively reduced (> 50%) after therapy, while the lesion assessed as EGFR wild type featured a slight response. This report has two relevant implications. It points out that in case of multiple malignant lesions at time of diagnosis, molecular profiling should be as extensive as possible and it might contribute to clarify the association between the lesions found. Besides the molecular analysis on cytology specimens could identify an accurate and safe diagnostic approach for clinical use.