Clinical Outcomes Beyond 1L EGFR-TKI Progression in mNSCLC: Final Results of the Real-World Study 'LUNGFUL'.

BACKGROUND/AIM: Real-world data on the EGFR mutational profile upon progression after first/second-generation EGFR-TKI treatment in patients with advanced non-small-cell lung cancer (NSCLC) and treatment strategies employed thereon are needed. PATIENTS AND METHODS: This observational study was conducted in 23 hospital-based lung cancer Centers in Greece (protocol code: D133FR00126). Ninety-six eligible patients were consecutively enrolled between July-2017 and September-2019. Re-biopsy was performed in 18 of 79 patients who tested T790M-negative in liquid biopsy after progression in the first-line (1L) setting. RESULTS: Of the study population, 21.9% tested T790M-positive, while 72.9% proceeded to 2L treatment, mainly comprising of a third-generation EGFR-TKI (48.6%), a switch to chemotherapy (30.0%), or chemo-immunotherapy (17.1%). The objective response rate (ORR) in 2L was 27.9% in T790M-negative and 50.0% in T790M-positive patients. Of evaluable patients, 67.2% experienced disease progression; median progression-free survival (PFS) was 5.7 and 10.0 months among T790M-negative and positive patients, respectively. Among T790M-negative patients, longer median PFS and post-progression survival were observed with third-generation EGFR-TKI treatment. CONCLUSION: Mutational status and treatment strategy were identified as critical determinants of clinical outcomes in the 2L-setting of EGFR-mutated NSCLC patients in real-world settings in Greece, with early diagnosis, appropriate molecular testing and high-efficacy treatments at first lines positively affecting ORR and PFS.

Effect of compliance to continuous positive airway pressure on exacerbations, lung function and symptoms in patients with chronic obstructive pulmonary disease and obstructive sleep apnea (overlap syndrome).

INTRODUCTION: Patients with overlap syndrome (OS), that is obstructive sleep apnea (OSA) and chronic obstructive pulmonary disease (COPD), are at increased risk of acute exacerbations related to COPD (AECOPD). We assessed the effect of CPAP compliance on AECOPD, symptoms and pulmonary function in OS patients. METHODS: Consecutive OS patients underwent assessment at baseline and at 12 months under treatment with CPAP of: AECOPD and hospitalizations, COPD Assessment Test (CAT) and modified British Medical Research Council (mMRC) questionnaires, pulmonary function testing and 6-min walking test (6MWT). RESULTS: In total, 59 patients (54 males) with OS were followed for 12 months and divided post hoc according to CPAP compliance into: group A with good (≥4 h CPAP use/night, n = 29) and group B with poor (<4 h CPAP use/night, n = 30) CPAP compliance. At 12 months, group A showed improvements in FEV1 (p = 0.024), total lung capacity (p = 0.024), RV/TLC (p = 0.003), 6MWT (p < 0.001) and CAT (p < 0.001). COPD exacerbations decreased in patients with good CPAP compliance from baseline to 12 months (17 before vs. 5 after, p = 0.001), but not in those with poor compliance (15 before vs. 15 after, p = 1). At multivariate regression analysis, COPD exacerbations were associated with poor CPAP compliance (ß = 0.362, 95% CI: 0.075-0.649, p = 0.015). CONCLUSIONS: When compared to poorly compliant patients, OS patients with good CPAP compliance had a lower number of AECOPD and showed improved lung function and COPD related symptoms.

Pulmonary calcinosis associated with Alport syndrome.

We report the case of a 48-year-old woman under dialysis from chronic renal failure (CRF) since the age of 27, due to Alport syndrome. The patient underwent routine chest X-ray on which diffuse micronodules were shown. Chest computed tomography showed partially calcified micronodules with centrilobular distribution respecting the subpleural spaces and predominant in the upper lobar regions. Metastatic pulmonary calcinosis was confirmed by the bone scan with an overall course of 29 years. This is the first reported case of pulmonary calcinosis from CRF due to Alport syndrome.

Chest ultrasound findings in usual interstitial pneumonia patterns: a pilot study.

It is unknown what role chest ultrasound plays in distinguishing the various usual interstitial pneumonia (UIP) patterns of high-resolution chest tomography (HRCT). The purpose of this study was to see if there was a link between the results of chest ultrasound (u/s) and HRCT in patients with idiopathic pulmonary fibrosis (IPF). We performed chest u/s in 16 patients with UIP and probable UIP patterns to indeterminate UIP and alternative diagnosis patterns in this single center prospective study to determine any possible relationship with the HRCT findings. A chest radiologist reviewed each HRCT to determine the pattern in accordance with the American Thoracic Society (ATS) / European Respiratory Society (ERS) Guidelines. The local multidisciplinary committee validated the patients' diagnoses before they were included. When compared to the indeterminate for UIP or alternative diagnosis pattern group, there was a trend (p=0.07) toward the presence of more B lines in UIP or probable UIP patterns. There was no statistically significant difference in the presence of small, large, white lung, or pleural line thickening >5mm. Subgroup analysis revealed that patients with honeycombing were more likely to have a fragmented pleural line (p=0.04). To summarize, in our pilot study, chest u/s appears unable to differentiate UIP and probable UIP patterns from indeterminate UIP and alternative diagnosis patterns. However, it appears that this technique can be used to recognize the honeycombing pattern.

Prognostic role of immune microenvironment in pleural metastases from breast and lung adenocarcinomas.

Background: Pleural metastatic disease is a common disease with dismal prognosis. The immune microenvironment of metastatic pleural tissue remains largely unknown. Thus, we aimed to investigate the presence of different immune cell populations, and to compare them with clinical characteristics. Methods: We included 70 patients with lung and breast adenocarcinoma (ADC) diagnosed with pleural metastasis during a 2-year period with the primary endpoint to investigate if the main immune cell populations are present in pleural metastases and if they have any prognostic role. Secondary endpoints were to detect any differences in their presence between lung and breast primaries and to search for any correlation with the macroscopic (thoracoscopic) findings. We used immunohistochemical techniques for the detection of CD4+, CD8+, CD20+, CD163+ and S100+ cells in whole tissue pleural biopsies of lung and breast metastases. Results: Primary endpoint: all these populations are present in the biopsies from lung and higher stromal and intratumoral CD4 counts, as well as higher stromal CD20 cells were positive prognostic factors for lung cancer metastases, while higher S100 intratumoral counts were positive prognostic factors in lung and marginally breast cancer metastases. Secondary endpoints: significant higher values for the stromal CD163 group (P=0.04) and for the intratumoral S100 group (P=0.006) were seen in lung compared to breast metastases. Interesting correlations were also noted between thoracoscopic findings (nodules, masses, pachypleuritis) and the different factors studied. Conclusions: Our data show that the immune microenvironment may be important in this advanced tumoral setting and that possible targets of the nowadays numerous treatment strategies implicating the immune system may merit further exploration in this poor prognosis disease.

Two years progression-free survival under vinorelbine metronomic therapy of a patient with metastatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a very rare vascular tumor, originating from endothelial cells. The etiology of EHE is unknown, yet at the molecular level, different angiogenic stimulators may act as promoters of endothelial cell proliferation. The tumor affects more commonly the lung, the liver and the bones but it can affect any other organ. Due to its heterogeneous presentation and its rarity it is often misdiagnosed. No treatment is proved to be efficient in metastatic EHE and the median survival of patients with metastatic pleural disease is generally poor, less than one year. we report a case of a 57-year-old female with multiple metastatic EHE including pleural, diagnosed by medical thoracoscopy, with a progression-free survival of 24 months with oral vinorelbine as maintenance therapy after combination of cisplatin-vinorelbine. We believe that this therapy might be of value to test in this patient population as it has never been tested before.

Inflammation of the Pleural Cavity: A Review on Pathogenesis, Diagnosis and Implications in Tumor Pathophysiology.

Pleural effusions are a common respiratory condition with many etiologies. Nonmalignant etiologies explain most pleural effusions and despite being nonmalignant, they can be associated with poor survival; thus, it is important to understand their pathophysiology. Furthermore, diagnosing a benign pleural pathology always harbors the uncertainty of a false-negative diagnosis for physicians and pathologists, especially for the group of non-specific pleuritis. This review aims to present the role of the inflammation in the development of benign pleural effusions, with a special interest in their pathophysiology and their association with malignancy.

Review of the Physiology and Anesthetic Considerations for Pleuroscopy/Medical Thoracoscopy.

Pleuroscopy or medical thoracoscopy is the second most common utilized procedure after bronchoscopy in the promising field of interventional pulmonology. Its main application is for the diagnosis and management of benign or malignant pleural effusions. Entry into the hemithorax is associated with pain and patient discomfort, whereas concurrently, notable pathophysiologic alterations occur. Therefore, frequently procedural sedation and analgesia is needed, not only to alleviate the patient's emotional stress and discomfort by mitigating the anxiety and minimizing the pain but also for yielding better procedural conditions for the operator. The scope of this review is to present the physiologic derangements occurring in pleuroscopy and compare the various anesthetic techniques and sedative agents that are currently being used in this context.

A Real-World, Observational, Prospective Study to Assess the Molecular Epidemiology of Epidermal Growth Factor Receptor (EGFR) Mutations upon Progression on or after First-Line Therapy with a First- or Second-Generation EGFR Tyrosine Kinase Inhibitor in EGFR Mutation-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer: The 'LUNGFUL' Study.

Background: Real-world data on the molecular epidemiology of EGFR resistance mutations at or after progression with first- or second-generation EGFR-TKIs in patients with advanced NSCLC are lacking. Methods: This ongoing observational study was carried out by 23 hospital-based physicians in Greece. The decision to perform cobas®EGFR Mutation Test v2 in tissue and/or plasma at disease progression was made before enrollment. For patients with negative/inconclusive T790M plasma-based results, tissue re-biopsy could be performed. Results: Ninety-six (96) eligible patients were consecutively enrolled (median age: 67.8 years) between July-2017 and September-2019. Of the patients, 98% were tested upon progression using plasma and 2% using tissue/cytology biopsy. The T790M mutation was detected in 16.0% of liquid biopsies. Tissue re-biopsy was performed in 22.8% of patients with a T790M-negative plasma result. In total, the T790M positivity rate was 21.9%, not differing between patients on first- or second-generation EGFR-TKI. Higher (≥2) ECOG performance status and longer (≥10 months) time to disease progression following EGFR-TKI treatment initiation were associated with T790M positivity. Conclusions: Results from plasma/tissue-cytology samples in a real-world setting, yielded a T790M positivity rate lower than previous reports. Fewer than one in four patients with negative plasma-based testing underwent tissue re-biopsy, indicating the challenges in routine care settings.

The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.

Medical Thoracoscopy Implementation after a European Respiratory Society Course Held from 2003 to 2016: A Survey.

BACKGROUND: Medical thoracoscopy (MT) is an important procedure in the management of patients with pleural diseases. OBJECTIVES: We designed a survey to explore whether the participants of our courses implement MT at their hospital after attending the course as no real-life data exist. METHODS: We distributed by e-mail a questionnaire to the participants of the courses. The questionnaire included general information about the participants, the precourse experience on MT, the postcourse implementation of the technique, and the reasons for failure. RESULTS: Responses were obtained from 104 of 324 (32.3%) identified emails. Responders were males (76%), seniors (59.7%), respiratory physicians (91.3%), working in a public/university hospital (78.8%), and mostly beginners (65.3%) from 41 countries. Following the course, 58.6% of responders either created or modified a MT program in their workplace. The reasons for not performing MT before the course were as follows: patients' referral to a thoracic surgeon, not enough training, lack of funding, department understaffed, and refusal by the hospital/department. Overall, these reasons were significantly decreased (p = 0.002) after the course. CONCLUSIONS: Real-life data of our survey suggest that more than half of the responders have implemented the technique or modified their practice according to the skills they got from the course.

Local Anesthesia Thoracoscopy with versus without Midazolam: A Randomized Controlled Trial.

BACKGROUND: Medical thoracoscopy is the gold standard for the diagnosis of pleural diseases. To date, no consensus exists regarding the choice of sedative and analgesic agents in patients undergoing local anesthetic thoracoscopy (LAT), and questions are raised as to whether sedatives may add to respiratory side effects. OBJECTIVE: The aim of the study was to test the hypothesis that administration of midazolam associated with lidocaine versus lidocaine alone in patients with LAT adds to respiratory side effects. METHODS: We randomly assigned 80 patients to a 1:1 study to 2 groups: local anesthesia by lidocaine (n = 40) versus lidocaine and midazolam (n = 40), with the primary end point being the mean lowest oxygen saturation. The secondary end points were cardiovascular parameters, complications, days of drainage, hospital stay, and patients' quality of life (QoL) as assessed by a visual analog scale (VAS). RESULTS: The mean age of all patients was 66.6 ± 13.1 years. The study comprised 50 males (62.5%). No difference was observed in the demographics between the 2 groups. No significant difference was observed between the 2 groups in oxygen saturation (primary end point). A significant difference was observed in favor of the midazolam group regarding the QoL assessed by VAS. CONCLUSION: Midazolam does not add to respiratory side effects when it is used with lidocaine for LAT, while patients' QoL is actually improved in this group. Therefore, in our department, we changed our startegy in favor of the association of lidocaine and midazolam.

Chemotherapy-induced changes in bronchoalveolar lavage fluid CD4 + and CD8 + cells of the opposite lung to the cancer.

Published articles support the effect of chemotherapy in the immune environment of tumors, including lung carcinomas. The role of CD4 + T-cells is crucial for expansion and accumulation of other antigen-specific immune cells, and the participation of CD8 + cells in tumor killing activity has been confirmed by many studies. However, little is known about the effect of chemotherapy on the healthy lung parenchyma from lung cancer patients, and whether there are differences between the different chemotherapy compounds used to treat this patient population. The aim of our study was to explore the effect of chemotherapy on CD4 + and CD8 + cells in the bronchoalveolar lavage fluid (BALF) of the healthy lung in patients treated with standard chemotherapy regimens. Fifteen patients underwent BAL, in the healthy lung before and after six chemotherapy courses. Platinum-based regimens included vinolerbine (VN) in 6 patients, gemcitabine (GEM) in 4 patients and etoposide (EP) in 5 patients. All patients but one were males and smokers (93%). The median age of patients was 56 years (42-75). No significant difference was noted in the patients' age between the three treated groups. Furthermore, between the three groups, no significant changes in the means of CD4 + and CD8 + cells were noted. However, when we compared the mean CD4 + cells before and after chemotherapy within each group, changes were noted when comparing VN before versus after (p = 0.05), GEM before versus after (p = 0.03), and EP before versus after (p = 0.036). In our pilot study, changes were noted in BALF CD4 + cells for the three most applied regimens at the normal lung parenchyma.

Cell Therapy for Idiopathic Pulmonary Fibrosis: Rationale and Progress to Date.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive lung scarring due to unknown injurious stimuli ultimately leading to respiratory failure. Diagnosis is complex and requires a combination of clinical, laboratory, radiological, and histological investigations, along with exclusion of known causes of lung fibrosis. The current understanding of the disease etiology suggests an interaction between genetic factors and epigenetic alterations in susceptible, older individuals. Prognosis is dismal and current treatment options include anti-fibrotic agents that only slow down disease progression and carry considerable side effects that hamper patients' quality of life. Therefore, the need for new, more effective treatments, alone or in combination with existing pharmacotherapy, is sorely needed. Regenerative medicine, the potential use of cell therapies to treat destructive diseases that cause architectural distortion to the target organ, has also emerged as an alternative therapeutic for lung diseases with unfavorable prognosis such as IPF. Mesenchymal stem cells (MSCs) and type II alveolar epithelial cells (AEC2s) have been used and their safety has been demonstrated. In the case of MSCs, both homogenic and allogeneic sources have been used and both are considered viable options without immunosuppressive therapy, taking into consideration the absence of immunogenicity and HLA response. AEC2s have been used in one trial with promising results but their use requires a deceased donor and immunosuppressive pre-treatment. In this review, we briefly summarize the current state of knowledge regarding the pathogenesis of IPF, and the background and rationale for using MSCs or AEC2s as potential treatment options. We list and describe the clinical trials completed to date and provide a comparison of their methods and results as well as a possible way forward.

Clinical long-term outcome of non-specific pleuritis (NSP) after surgical or medical thoracoscopy.

BACKGROUND: Thoracoscopy, either "medical" or "surgical", is the gold standard to reveal the cause of pleural effusion by taking large biopsies. However, in some cases, the histology of pleural biopsies is inconclusive for a specific cause, describing a variable process of inflammation, encompassing for non-specific pleuritis (NSP). Questions are raised whether the surgical (or video-assisted thoracoscopic surgery, VATS) is doing better than the medical thoracoscopy (MT or pleuroscopy), but no direct comparison between the two techniques exist in the current bibliography. The aim of our retrospective study was to compare these two techniques to find whether there is any difference in the false negative cases of NSP. METHODS: We included in our study 295 patients with NSP, 179 patients who underwent VATS comparing to 116 patients who underwent MT for pleural effusion of initially undetermined cause, having a follow-up of at least one year. Analysis of patients' files, history, clinical examinations, further tests, and follow-up were recorded. RESULTS: The mean age of our patients was 58.5±19.1 and M/F gender was 216/79; no difference was observed between the two groups. The mean follow-up period was 47.3±20.7 months. After VATS, only one patient (0.55%) was finally diagnosed with pleural malignancy (false negative) while after MT 2 patients (1.7%). Negative predictive value for pleura-related malignancy for VATS was 0.994 and for MT 0.982. CONCLUSIONS: In patients with histological diagnosis of NSP both VATS and MT showed similar and excellent results of false negative cases and negative predictive value in excluding malignant pleural disease.

Metabolic Syndrome in Patients with Coexistent Obstructive Sleep Apnea Syndrome and Chronic Obstructive Pulmonary Disease (Overlap Syndrome).

Background: Evidence suggests that metabolic syndrome (MetS) is highly prevalent in patients with obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD). However, data on the prevalence of MetS in patients having both OSAS and COPD, or overlap syndrome (OS), are scarce. The aim of this study was to evaluate the prevalence and identify predictors of MetS in patients with OS. Methods: MetS was evaluated in consecutive patients who were diagnosed with OS by polysomnography and pulmonary function testing. Results: A total of 163 subjects (138 males and 25 females) were included. MetS was present in 38% of OS patients. Patients were divided into group A (OS without MetS group: 101 patients) and group B (OS with MetS group: 62 patients). Groups were similar in terms of pulmonary function and sleep parameters. In group B, abdominal obesity was the most prevalent component of MetS (100%), followed by hypertension (82.3%), hypertriglyceridemia (72.6%), and hyperglycemia (51.6%). Age (P = 0.009) and body mass index (P = 0.029) were independent predictors of MetS in patients with OS. Conclusions: An increased prevalence of MetS was observed in a group of patients with OS. Early identification and treatment of MetS may play a significant role in prevention of complications related to OS.

Increased risk for cardiovascular disease in patients with obstructive sleep apnoea syndrome-chronic obstructive pulmonary disease (overlap syndrome).

INTRODUCTION: Accumulating evidence suggests that cardiovascular disease (CVD) is highly prevalent among patients with concurrent obstructive sleep apnoea syndrome (OSAS) and chronic obstructive pulmonary disease, otherwise known as overlap syndrome (OS). OBJECTIVES: The aim of this study was to investigate the 10-year risk for CVD in OS patients compared with OSAS patients and controls. METHODS: Consecutive patients, referred for symptoms suggestive of OSAS, were evaluated with polysomnography and pulmonary function testing. Cardiovascular risk was assessed using the Framingham risk score (FRS) and systematic coronary risk evaluation (SCORE). RESULTS: Overall, 244 participants (184 males) without CVD and diabetes were divided into 3 groups: controls (n = 63), OSAS (n = 139) and OS (n = 42). Both FRS and SCORE were found to be elevated in the OS group compared with the OSAS and control groups (P < .001 for all). In multivariate analysis, age (ß = .461, P < .001), forced expiratory volume in first second (ß = -.285, P = .036) and oxygen desaturation index (ODI) (ß = .234, P = .007) were major determinants for the SCORE, whereas age (ß = .308, P < .001) and apnoea-hypopnoea index (ß = .252, P = .010) for the FRS. CONCLUSION: In our study, an increased risk for CVD was observed in a group of patients with OS at the time of their initial evaluation. Further studies are needed in the field of OS in order to investigate, prevent and manage early CVD in this population.