Different pathways to lung cancer diagnosis in a real-life setting.

BACKGROUND: Most lung cancers are diagnosed at an advanced stage and therefore have a poor prognosis. One major challenge is to choose the most adapted sampling technique to obtain a rapid pathological diagnosis so as to start treatment as early as possible. A growing number of techniques have been developed in recent years. This study sought to assess the diagnostic efficiency of each, along with the respective duration of the diagnostic pathways. METHODS: This retrospective, bicentric, observational study enrolled patients with inoperable lung cancer (stage III or IV) diagnosed in 2018-2019. Diagnostic efficiency was assessed based on the different examinations performed to achieve a precise diagnosis (pathology, immunohistochemistry, and/or molecular biology). The time between the first medical contact and treatment initiation was also assessed. RESULTS: Overall, 625 patients were included (median age 67 years; men 67 %; adenocarcinoma 55 %). The most frequent examinations were bronchial endoscopy (n = 469, 75 %), followed by metastasis biopsy (n = 137, 21.9 %) and guided transthoracic core-needle biopsy (TCNB) (n = 116, 18.6 %). 372 patients had only one procedure (59.5 %), mainly bronchial endoscopy (n = 217, 34.7 %) and metastasis biopsy (n = 71, 11 %). The most efficient examination was thoracic surgery (surgical pleural biopsy, (n = 32, 100 %); mediastinoscopy (n = 26, 96.3 %); surgical pulmonary biopsy (n = 14, 93.3 %). The second most efficient examination was metastasis biopsy (n = 126, 94 %) followed by guided TCNB (n = 108, 93.1 %). The median time from first medical contact to first examination was 4 days (interquartile range 25 %-75 % 1-8). The median time from first medical contact to pathological result was 17 days (10-34). The median time from first medical contact to treatment start was 48 days (30-69). CONCLUSIONS: In order to make an accurate and rapid diagnosis of lung cancer, it is crucial to choose the most appropriate technique. Bronchial endoscopy remains the first-line examination for central lesions, as it is efficient and easily accessible. Guided TCNB and metastasis biopsy are the preferred techniques for peripheral lesions. The choice of the diagnostic technique should be part of a multidisciplinary approach and a dedicated pathway to optimize initial management.

Long-term outcomes of CPAP-treated sleep apnea patients: Impact of blood-pressure responses after CPAP initiation and of treatment adherence.

BACKGROUND AND OBJECTIVE: In randomized controlled trials, continuous positive airway pressure (CPAP) is reported as lowering blood pressure (BP) with a mean systolic blood pressure effect size of 2.5 mmHg. These trials have a median follow-up of less than 6 months. Whether this initial BP response during the first months of CPAP treatment translates into a reduction in long-term cardiovascular events and mortality is unknown. METHODS: This observational study addressed long-term hard cardiovascular outcomes and all-cause mortality in a well-defined population of 241 patients previously included in the AgirSASadom parallel randomized controlled trial (assessing whether fixed-pressure CPAP was superior to auto-adjusted CPAP in reducing BP (baseline evaluations 2010-2012)). Long-term outcomes were analyzed using a Cox survival model, and a logistic regression analysis was performed for long-term CPAP adherence. RESULTS: Sixty-nine cardiovascular events occurred in 61 patients during a median follow-up of 113 months (interquartile range [102 ; 124]) giving an incidence of 26 for 1000 person-years. Twenty-one (8.7%) patients died. BP values at baseline (i.e., office and 24-h BP) was a strong predictor of incident cardiometabolic events and mortality (p < 0.01) whereas initial BP response after the first four months of CPAP was not related to outcomes. Long-term CPAP adherence above 4 h/night was associated with a reduction in all-cause mortality (Log-rank P = 0.02) but not in the occurrence of long-term cardiovascular events. CONCLUSION: Independently of initial blood pressure response, long-term CPAP adherence is one of the prerequisites for reducing mortality.

RBM10-TFE3 fusions: A FISH-concealed anomaly in adult renal cell carcinomas displaying a variety of morphological and genomic features: Comprehensive study of six novel cases.

The accurate diagnosis of Xp11-translocation renal cell carcinoma (RCC) in adults is challenging. TFE3 (located on chromosome X) fuses with a partner gene generally located on another chromosome. In rare cases TFE3 may fuse with a neighboring gene: RBM10. Because TFE3 false-positive immunostaining is a common pitfall in many laboratories, demonstration of the chromosomal rearrangement is required in order to ascertain the diagnosis. Fluorescence in situ hybridization (FISH)-that has been considered as the gold standard method-reaches its limits for detecting small Xp11 paracentric inversions. We performed a comprehensive clinical, histological and genomic study of six novel cases of RCC with RBM10-TFE3 fusion. Using FISH, TFE3 rearrangement was equivocal in one case and negative in others. RBM10-TFE3 fusion was discovered using targeted RNA sequencing (RNASeq). As all the previously reported cases (mean age: 50), the six patients were adults (mean age: 42), suggesting an epidemiologic difference between RBM10-TFE3 RCC and tumors harboring some other partner genes, such as ASPSCR1 that rather occur in children. Array-comparative genomic hybridization showed several alterations, notably a gain of 17q in four cases with papillary features and loss of 3p in one case with clear cells. Our study demonstrates that, though rare among adult cases of RCC, RBM10-TFE3 fusion is not exceptional and warrants appropriate molecular detection. Notably, it would be worthy to systemically investigate by RNASeq challenging RCC with type-2 papillary features and 17q gain.

What are the barriers to the completion of a home-based rehabilitation programme for patients awaiting surgery for lung cancer: a prospective observational study.

OBJECTIVES: Home-based rehabilitation programmes (H-RPs) could facilitate the implementation of pulmonary rehabilitation prior to resection for non-small cell lung cancer (NSCLC), but their feasibility has not been evaluated. The aim of this study was to identify determinants of non-completion of an H-RP and the factors associated with medical events occurring 30 days after hospital discharge. DESIGN: A prospective observational study. INTERVENTION: All patients with confirmed or suspected NSCLC were enrolled in a four-component H-RP prior to surgery: (i) smoking cessation, (ii) nutritional support, (iii) physiotherapy (at least one session/week) and (iv) home cycle-ergometry (at least three times/week). OUTCOMES: The H-RP was defined as 'completed' if the four components were performed before surgery. RESULTS: Out of 50 patients included, 42 underwent surgery (80% men; median age: 69 (IQR 25%-75%; 60-74) years; 64% Chronic Obstructive Pulmonary Disease (COPD); 29% type 2 diabetes). Twenty patients (48%) completed 100% of the programme. The median (IQR) duration of the H-RP was 32 (19; 46) days. Multivariate analysis showed polypharmacy (n=24) OR=12.2 (95% CI 2.0 to 74.2), living alone (n=8) (single vs couple) OR=21.5 (95% CI 1.4 to >100) and a long delay before starting the H-RP (n=18) OR=6.24 (95% CI 1.1 to 36.6) were independently associated with a risk of non-completion. In univariate analyses, factors associated with medical events at 30 days were H-RP non-completion, diabetes, polypharmacy, social precariousness and female sex. CONCLUSION: Facing multiple comorbidities, living alone and a long delay before starting the rehabilitation increase the risk of not completing preoperative H-RP. TRIAL REGISTRATION NUMBER: NCT03530059.

Comparison of Auto- and Fixed-Continuous Positive Airway Pressure on Air Leak in Patients with Obstructive Sleep Apnea: Data from a Randomized Controlled Trial.

Auto-CPAP may cause sleep fragmentation due to variations in pressure and unintentional leaks. The aim of this study was to compare air leak between fixed-CPAP and auto-CPAP after 4 months of CPAP treatment. This study is an ancillary analysis of a randomized, double-blind, parallel, controlled trial over 4 months, comparing fixed- and auto-CPAP in newly diagnosed patients with OSA. The following data were extracted from the CPAP devices: mean and 90th percentile pressure, residual apnea-hypopnea index, mean CPAP use, and amount of leak. Within each arm, patients were also randomly allocated to use of one of the three different brands of devices. Since the leak was reported differently for each device, median leak value was determined for each brand and leaks were classified as "above the median" or "below the median". Data from 269 patients were analyzed. The univariate analysis showed that tobacco consumption, CPAP level, and oronasal masks were associated with leaks above the median value but not the type of CPAP. The multivariate analysis showed that only CPAP level and oronasal masks were associated with leaks below the median. There were no differences in the types of mask used between fixed- and auto-CPAP. There was no impact of the type of CPAP on leaks or the type of interface used. We used a method based on the median leak value to standardize comparisons across devices which report leaks with different definitions.

De Novo Malignancies Screening After Liver Transplantation for Alcoholic Liver Disease: A Comparative Opportunistic Study.

Patients having received a liver transplantation (LT) for alcoholic liver disease (ALD) have a high risk of de novo malignancies, especially in the upper aerodigestive tract and lungs due to their smoking and alcohol history. The aim of this retrospective study was to compare a group of patients transplanted for ALD who continue to smoke and who were included in an intensive screening program for tobacco-related cancers implemented at the Grenoble University Hospital and a group of similar patients followed according to usual practice (chest computed tomography [CT] scan every 5 years) at the Edouard Herriot Hospital in Lyon. The intensive screening program consisted of an annual checkup, including a clinical examination by an otorhinolaryngologist, a chest CT scan, and an upper digestive endoscopy. A total of 147 patients were included: 71 patients in Grenoble and 76 patients in Lyon. The cumulative incidence of a first tobacco-related cancer was 12.3% at 3 years, 20.6% at 5 years, 42.6% at 10 years, and 64.0% at 15 years. A curative treatment was possible in 80.0% of the patients in Grenoble versus 57.9% in Lyon (P = 0.068). The rates of curative treatment were 63.6% versus 26.3% (P = 0.062) for lung cancers, 100.0% versus 87.5% (P = 0.498) for lip-mouth-pharynx and larynx cancers, and 66.7% versus 100.0% (P = 1) for esophageal cancers, respectively. In addition, for lung cancers, regardless of study group, 68.7% received a curative treatment when the diagnosis was made by CT scan screening versus 14.3% when it was made because of symptoms (P = 0.008). In conclusion, our study strongly confirms the high rate of tobacco-related de novo malignancies in LT patients for ALD and suggests that the screening of lung cancer by annual chest CT scan could significantly increase the rate of curative treatment.

Severe central sleep apnoea associated with nalmefene: a case report.

Nalmefene, an opioid antagonist, has recently been approved for the treatment of alcohol dependence. We describe here the first case of a 52-year-old woman who developed a severe central sleep apnoea (CSA) 5 months after initiation of nalmefene. Scoring of ventilation during sleep recording revealed an apnoea-hypopnoea index of 67/h with 98.7% of central events and an apnoea index of 65/h. Nalmefene was withdrawn and a new polysomnography was performed which concluded that CSA has disappeared. Pathophysiology is still unclear but could involve the κ-opioid receptors. Physicians should be aware that CSA might affect patients treated with nalmefene. Further investigations are required to determine the pathophysiology, frequency, and treatment of CSA associated with nalmefene and other therapy for alcohol disorders.

Sarcoidosis, inorganic dust exposure and content of bronchoalveolar lavage fluid: the MINASARC pilot study.

Inhalation of mineral dust was suggested to contribute to sarcoidosis. We compared the mineral exposome of 20 sarcoidosis and 20 matched healthy subjects. Bronchoalveolar lavage (BAL) samples were treated by digestion-filtration and analyzed by transmission electron microscopy. The chemical composition of inorganic particles was determined by energy-dispersive X-ray (EDX) spectroscopy. Dust exposure was also assessed by a specific questionnaire. Eight sarcoidosis patients and five healthy volunteers had a high dust load in their BAL. No significant difference was observed between the overall inorganic particle load of each group while a significant higher load for steel was observed in sarcoidosis patients (p=0.029). Moreover, the building activity sub-score was significantly higher in sarcoidosis patients (p=0.018). These results suggest that building work could be a risk factor for sarcoidosis which could be considered at least in some cases as a granulomatosis caused by airborne inorganic dust. The questionnaire should be validated in larger studies. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 327-332).

Quadriceps muscle fat infiltration is associated with cardiometabolic risk in COPD.

PURPOSE: Losses of peripheral muscle mass and ectopic fat accumulation have been associated with cardiometabolic morbidity in COPD. We aimed at identifying the relationship between quadriceps muscle fat infiltration and cardiovascular risk. MATERIALS AND METHODS: From 2009 to 2014, 78 COPD patients (64 ± 8 years; 80% male) were prospectively included after having given written consent (ethical committee approval number: 2006-A00491-50). The cohort was divided into three groups (tertiles) according to body mass index (BMI), low [15 < BMI≤23·3], middle [23·3 < BMI≤27·6] and high [27·6 < BMI≤36] kg/m²). Measurements were respiratory function, plasmatic biomarkers and surrogate markers of cardiovascular risk (arterial stiffness and endothelial function). Mid-thigh quadriceps muscle volume and per cent of muscle fat infiltration, as assessed by 64-slice CT scanning, were compared between the tertiles. ANOVA or Kruskal-Wallis tests were used for statistical analyses with Bonferroni's correction for the 'post hoc' tests. RESULTS: Intramuscular fat volume was 52% [95% CI, 43 to 60%] of total quadriceps volume in high BMI vs. 47% [38 to 55%] and 34% [29 to 38%] in the middle and low-BMI groups, respectively (P<0·0001), without differences between groups in fat-free muscle volumes. Elevated muscle fat infiltration correlated with lower thiol to protein ratios in the whole population reflecting impaired antioxidant capacity (r = 0·50; P = 0·009). Furthermore, muscle fat infiltration was linked to endothelial dysfunction (r = -0·49, P = 0·01) in the low-BMI group. CONCLUSION: Skeletal muscle fat infiltration may be an indicator of increased cardiometabolic risk in both obese and lean COPD patients.

Differentiating pre- and minimally invasive from invasive adenocarcinoma using CT-features in persistent pulmonary part-solid nodules in Caucasian patients.

OBJECTIVE: To retrospectively investigate the diagnostic value of pre-operative CT-features between pre/minimally invasive and invasive lesions in part-solid persistent pulmonary ground glass nodules in a Caucasian population. MATERIALS AND METHODS: Retrospective review of two pre-operative CTs for 31 nodules in 30 patients. There were 10 adenocarcinomas in situ, 1 minimally invasive adenocarcinoma, 20 invasive adenocarcinomas. We analyzed the correlation between histopathology and the following CT-features: maximal axial diameter, maximal orthogonal axial diameter, height, density, size of solid component, air bronchogram, pleural retraction, nodule mass, disappearance rate and their evolution during follow-up. RESULTS: In univariate analysis, invasive adenocarcinomas had a higher maximal height, density, solid component size, mass, a lower disappearance rate and presented more often with pleural retraction (p<0.05). After logistic regression performed with the uncorrelated parameters using a method of selection of variables, only the size of solid component remained significant, with 100% sensitivity for invasive adenocarcinoma when larger than 5mm. CONCLUSION: Preoperative CT-features can help differentiating in situ and minimally invasive adenocarcinomas from invasive adenocarcinomas in Caucasian patients. A solid component larger than 5mm in diameter had 100% sensitivity for the diagnosis of invasive adenocarcinoma.

Rebiopsy during disease progression in patients treated by TKI for oncogene-addicted NSCLC.

All lung cancer patients with mutant epidermal growth factor receptor (EGFR) or rearranged EML4-ALK eventually develop acquired resistance to treatment. Rebiopsy may give insight into the resistance mechanisms and direct further lines of treatment. Here, we evaluate the potential interest and limitations of rebiopsy. Patients with mutant EGFR or rearranged EML4-ALK non-small cell lung cancer (NSCLC) and acquired resistance to tyrosine kinase inhibitors were included in a retrospective study to determine the percentage of patients who underwent rebiopsy and whether rebiopsy would have been possible, or not, in the remaining patients. In a cohort of 84 patients from 6 institutions, a biopsy had been performed in 39 cases. Biopsy samples were sufficient for histopathological or cytological examination in 35 cases (89.7 %). Complete or partial response had been observed in 84.5 % of patients whose cancer further progressed and who underwent rebiopsy. A biopsy could have been considered in 30 of the 45 remaining patients. Those with brain (N = 9) and bone (N = 2) metastases and/or with contraindications (N = 6) were excluded (two patients had both brain metastases and a contraindication). The rebiopsy target was thoracic in 62 % of cases and on distant metastases in 38 % of cases. Patients with NSCLC and an activating mutation could undergo a rebiopsy in 72 % of cases. A response to treatment does not preclude the possibility of rebiopsy at the time of progression.

Lung squamous cell carcinomas with basaloid histology represent a specific molecular entity.

PURPOSE: The basaloid carcinoma (pure) and the (mixed) basaloid variant of lung squamous cell carcinoma (SCC) have a dismal prognosis but their underlying specific molecular characteristics remain obscure and no therapy has proven to be efficient. EXPERIMENTAL DESIGN: To assess their molecular specificity among other lung SCCs we analyzed DNA copy number aberrations and mRNA expression pangenomic profiles of 93 SCCs, including 42 basaloid samples (24 pure, 18 mixed). RESULTS: Supervised analyses reveal that pure basaloid tumors display a specific mRNA expression profile, encoding factors controlling the cell cycle, transcription, chromatin, and splicing, with prevalent expression in germline and stem cells, while genes related to squamous differentiation are underexpressed. From this signature, we derived a 2-genes (SOX4, IVL) immunohistochemistry-based predictor that discriminated basaloid tumors (pure and mixed) from non-basaloid tumors with 94% accuracy in an independent series. The pure basaloid tumors are also distinguished through unsupervised analyses. Using a centroid-based predictor, the corresponding molecular subtype was found in 8 independent public datasets (n = 58/533), and was shown to be associated with a very poor survival as compared with other SCCs (adjusted HR = 2.45; P = 0.000001). CONCLUSION: This study enlightens the heterogeneity of SCCs that can be subclassified in mRNA expression subtypes. This study demonstrates for the first time that basaloid SCCs constitute a distinct histomolecular entity, which justifies its recognition and distinction from non-basaloid SCCs. In addition, their characteristic molecular profile highlights their intrinsic resistance to cytotoxic chemotherapy and could serve as a guide for targeted therapies.

Reduced six-minute walking distance, high fat-free-mass index and hypercapnia are associated with endothelial dysfunction in COPD.

This study investigated the determinants of endothelial function in patients with chronic obstructive pulmonary disease (COPD). Digital pulse amplitude augmentation was measured by post-ischemic reactive hyperemia (RH-PAT) in 44 COPD patients and analyzed with covariates: condition vs. exacerbation, fat-free mass index (FFMI), pulmonary function, blood pressure, inflammation, six-minute walking distance, muscle function, medications, diabetes and prevalent cardiovascular diseases. RH-PAT was 0.43 (-0.14 to 1.30) with 50% of patients exhibiting abnormal RH-PAT ≤ 0.40. After adjustment for age and sex, RH-PAT was linked to condition, FFMI, myocardial infarction history, FEV(1), PaCO(2), heart rate, bicarbonates, inflammation and walking distance (p<0.10). In multivariate analysis, walking distance, FFMI and PaCO(2) were independent contributors of RH-PAT explaining 49% of the variance (p<0.0001). Higher FFMI was associated with higher inflammation, oxidative stress and endothelial dysfunction. Six-minute walking distance which is a widely available marker of severity and functional capacity in COPD patients is a main predictor of endothelial dysfunction.

Effect of lung volume and gravity on the attenuation and size of a pure ground-glass nodule.

Detecting potentially malignant changes in a pure ground-glass nodule (GGN) is challenging. The development of a solid component is a known sign, which may help in differentiating benign from malignant GGN. We report the case of a 58-year-old man presenting with a pure GGN in the posterior segment of the right lower lobe. Follow-up computed tomographic scan after 1 year showed marked increase in attenuation (from -319 HU to +27 HU), whereas the average size of the nodule decreased (from 7 to 4.7 mm). On a computed tomographic scan in the prone position the nodule seemed larger (7.8 mm) and appeared as a pure GGN (-406 HU). Such changes were attributed to the reduction of lung volume and gravity.

Wegener granulomatosis revealed by pleural effusion.

Pulmonary signs are common in Wegener's granulomatosis (WG). However, an initial presentation including pleural effusion has not been described. We describe a case of WG in which pleural effusion was the first clinical manifestation. A 45-year-old man with dorsal pain presented with pleural thickening and effusion, and a visible nodule on a thoracic scan. A dense chronic inflammatory infiltrate was obtained by pleural biopsy and an open lung biopsy revealed necrotizing granulomatous vasculitis. Serologies were positive for antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies. A diagnosis of WG was conducted and the patient was started on cyclophosphamide and methylprednisolone as an initial treatment, with a favorable evolution. Although pleural effusion is rarely described in WG, this pathology must be considered in the presence of this clinical manifestation.

Cigarette smoking, preinvasive bronchial lesions, and autofluorescence bronchoscopy.

STUDY OBJECTIVES: Autofluorescence bronchoscopy (AFB), when used as an adjunct to standard white light bronchoscopy (WLB), enhances the bronchoscopist's ability to localize small neoplastic lesions, especially intraepithelial lesions. The current study was undertaken in order to define the population in which the rate of detection is higher using AFB. DESIGN AND PATIENTS: Two hundred forty-four consecutive patients, who were symptomatic smokers or patients who previously had been treated for lung cancer or head and neck cancers, underwent WLB and AFB. All patients with endoscopic abnormalities underwent biopsies. Data concerning smoking history were prospectively registered. RESULTS: We report the prevalence of high-grade or invasive lesions at the time of examination. On a lesion-by-lesion analysis, 92 low-grade lesions, 42 high-grade lesions (ie, moderate dysplasia, severe dysplasia, and carcinoma in situ), and 39 invasive carcinomas were diagnosed. There was no effect of age, gender, and age at smoking initiation on the prevalence of preinvasive or invasive lesions. The 10 patients who previously had undergone surgery for lung cancer and exhibited high-grade preinvasive lesions had a history of carcinoma of the epidermoid histologic type (p = 0.01). These 10 patients displayed multiple lesions in the bronchial tree (mean No. of lesions, 1.8 per patient). In current smokers, the prevalence of high-grade or invasive lesions were both related to the number of pack-years smoking had occurred (p = 0.01) and to the duration of smoking (p = 0.01). In contrast, the prevalence of preinvasive lesions in former smokers was related to a history of epidermoid carcinoma. CONCLUSIONS: AFB should be recommended in patients with a history of epidermoid carcinomas of the lung. Current smokers with a prolonged smoking history appear to comprise a population in which the rate of detection of preneoplastic lesions is high with AFB.