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Background The most commonly used topical hemostatic agents during flexible bronchoscopy (FB) are cold saline and adrenaline. Data on use of other agents such as tranexamic acid (TXA) for this purpose are limited. Research Question Is TXA effective and safe in controlling iatrogenic bleeding during FB compared with adrenaline? Study Design and Methods We conducted a cluster- randomized, double-masked, single-center trial in a tertiary teaching hospital. Patients were randomized in weekly clusters to receive up to three applications of TXA (100 mg, 2 mL) or adrenaline (0.2 mg, 2 mL, 1:10000) after hemostasis failure after three applications of cold saline (4°C, 5 mL). Crossover was allowed (for up to three further applications) before proceeding with other interventions. Bleeding severity was graded by the bronchoscopist using a visual analog scale (VAS ; 1 = very mild, 10 = severe). Results A total of 2, 033 FBs were performed and 130 patients were randomized successfully to adrenaline (n = 65) or TXA (n = 65), whereas 12 patients had to be excluded for protocol violations (two patients from the adrenaline arm and 10 patients from TXA arm). Bleeding was stopped in 83.1% of patients (54/65) in both groups (P = 1). The severity of bleeding and number of applications needed for bleeding control were similar in both groups (adrenaline: mean VAS score, 4.9 ± 1.3 [n = 1.8 ± 0.8] ; TXA: mean VAS score, 5.3 ± 1.4 [n = 1.8 ± 0.8]). Both adrenaline and TXA were more successful in controlling moderate bleeding (86.7% and 88.7%, respectively) than severe bleeding (40% and 58.3%, respectively ; P = .008 and P = .012, respectively) and required more applications for severe bleeding (3.0 ± 0 and 2.4 ± 0.5, respectively) than moderate bleeding (1.7 ± 0.8 and 1.7 ± 0.8, respectively) control (P = .006 and P = .002, respectively). We observed no drug- related adverse events in either group. Interpretation We found no significant difference between adrenaline and TXA for controlling noncatastrophic iatrogenic endobronchial bleeding after cold saline failure, adding to the body of evidence that TXA can be used safely and effectively during FB.

Lung transplantation is a therapeutic option for the treatment of advanced lung disease. The risk of pulmonary infections is increased in lung transplant recipients. We report a case of a pulmonary coinfection with Mycobacterium tuberculosis and Nocardia species in a lung transplant recipient.

Coronavirus disease 2019 (COVID-19) pandemic resulted in global healthcare crises and strained health resources, both in the acute and chronic phase of the disease. Similarly to post-acute viral syndromes described in survivors of other virulent coronavirus epidemics, there are increasing reports of persistent and prolonged symptoms after acute COVID-19. These reports and studies have helped contribute to the recognition of post-COVID-19, a syndrome characterized by persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of symptoms. Here, we provide a comprehensive review of different manifestations of post-COVID conditions and propose a framework for the identification of patients at higher risk for post- COVID and their coordinated management through dedicated COVID-19 outpatient clinics.

Aim To determine the diagnostic accuracy of pulmonary artery to aorta ratio in screening for pulmonary hyperten - sion in advanced chronic obstructive pulmonary disease (COPD) patients. Methods A prospective, diagnostic study was conducted in University Hospital Center Zagreb between January 2015 and March 2018. The study enrolled 100 patients who con - secutively underwent chest computed tomography (CT), echocardiographic exam, and right heart catheterization. Two independent observers measured pulmonary artery and ascending aorta diameters. The correlation between the ratio and mean pulmonary artery pressure, measured invasively, was assessed. Patients with echocardiographic signs of moderate systolic or diastolic left ventricular dys - function were excluded (n =44). Results Sixty-six patients (55.5% men), with a median age of 61, were identified. Median forced expiratory vol - ume during the first second (FEV1) was 34 ±12, FEV1/ forced vital capacity

Contains fulltext : 244079.pdf (Publisher’s version ) (Closed access) BACKGROUND: The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting. METHODS: We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records. RESULTS: Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003). CONCLUSION: The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.

The most commonly used topical hemostatic agents during flexible bronchoscopy (FB) are cold saline and adrenaline. Data on use of other agents such as tranexamic acid (TXA) for this purpose are limited.Is TXA effective and safe in controlling iatrogenic bleeding during FB compared with adrenaline?We conducted a cluster-randomized, double-masked, single-center trial in a tertiary teaching hospital. Patients were randomized in weekly clusters to receive up to three applications of TXA (100 mg, 2 mL) or adrenaline (0.2 mg, 2 mL, 1:10000) after hemostasis failure after three applications of cold saline (4°C, 5 mL). Crossover was allowed (for up to three further applications) before proceeding with other interventions. Bleeding severity was graded by the bronchoscopist using a visual analog scale (VAS; 1 = very mild, 10 = severe).A total of 2,033 FBs were performed and 130 patients were randomized successfully to adrenaline (n = 65) or TXA (n = 65), whereas 12 patients had to be excluded for protocol violations (two patients from the adrenaline arm and 10 patients from TXA arm). Bleeding was stopped in 83.1% of patients (54/65) in both groups (P = 1). The severity of bleeding and number of applications needed for bleeding control were similar in both groups (adrenaline: mean VAS score, 4.9 ± 1.3 [n = 1.8 ± 0.8]; TXA: mean VAS score, 5.3 ± 1.4 [n = 1.8 ± 0.8]). Both adrenaline and TXA were more successful in controlling moderate bleeding (86.7% and 88.7%, respectively) than severe bleeding (40% and 58.3%, respectively; P = .008 and P = .012, respectively) and required more applications for severe bleeding (3.0 ± 0 and 2.4 ± 0.5, respectively) than moderate bleeding (1.7 ± 0.8 and 1.7 ± 0.8, respectively) control (P = .006 and P = .002, respectively). We observed no drug-related adverse events in either group.We found no significant difference between adrenaline and TXA for controlling noncatastrophic iatrogenic endobronchial bleeding after cold saline failure, adding to the body of evidence that TXA can be used safely and effectively during FB.ClinicalTrials.gov; No.: NCT04771923; URL: www.gov.

To determine the frequency of common symptoms in long COVID and their effect on the quality of life, and to determine the factors contributing to a more severe long COVID.The study enrolled 266 patients who were either referred to long-COVID outpatient clinic or were inpatients undergoing rehabilitation. The data were collected between December 2020 and May 2021. We evaluated the symptoms experienced during acute and long COVID and comorbidities. Functional status was assessed with Post Covid Functional Status (PCFS).The final sample consisted of 261 patients. After acute COVID-19 period (4 weeks), almost 80% of patients had impaired functional status. Only 21.5% reported no functional impairment (0 on PCFS scale). A higher PCFS score was associated with female sex (P0.001) and oxygen therapy requirement during acute disease (P=0.001). However, it was not associated with having a pre-existing lung disease (P=0.749). Disease severity did not pose a risk for developing a more severe long COVID.Women were at greater risk for developing greater functional impairment in long COVID, although we have no explanation why. Malignant disease and hypertension also presented a risk factor for greater functional impairment. More studies are warranted to determine if patients with certain lung disease are more susceptible to long COVID.

Coronavirus-2 pandemic has changed the functioning of health systems worldwide. It is not yet fully known which symptoms of the disease are most commonly presented in patients referred for pulmonary rehabilitation. Our aim was to investigate the profile of patients referred for pulmonary rehabilitation; what symptoms they had during the acute phase of the disease and what symptoms were still present at the start of pulmonary rehabilitation.Study included ongoing symptomatic and post-COVID patients who attended standard, in person pulmonary rehabilitation program. Patients had COVID-19 disease at least four weeks before attending pulmonary rehabilitation. Patients completed questionnaires of self-reported somatic deficits during acute and post-COVID-19 stage as well as questionnaires regarding their psychological symptoms. Pulmonary function test, expiratory and inspiratory muscle strenght, hand grip strenght and six-minute walk test was performed prior and after pulmonary rehabilitation.Study included 63 patients (32 male, 31 female), with mean age of 52.9 years. During acute COVID-19, majority of patients complained of fatigue, cough, dyspnea, myalgia and headache. More than 85% of patients reported pulmonary deficits during ongoing symptomatic and post-COVID-19 stage. Emotional distress and anxiety levels were significantly elevated in acute stage, while depression, anger and the need for help was not significantly elevated. All reported symptoms were significantly reduced in post-COVID-19 stage. There was statistically significant difference in six-minute walk distance, inspiratory and expiratory muscle strenght and hand grip strenght between first and final testing.Results of our study are similar with previous studies, the most common symptoms during acute phase were fatigue, cough and dyspnea and fatigue and respiratory problems during ongoing symptomatic and post-COVID stage. Emotional distress diminishes signifiacantly in post-COVID stage. Further larger studies are needed to clarify which acute disease symptoms are predominant in patients referred to pulmonary rehabilitation and cause prolongued discomfort.

To determine the effect of lockdown measures on lung transplant patients during the COVID-19 pandemic.We collected data from Croatian lung transplant patients before and after the lockdown and analyzed changes in weight, BMI, lung function and blood lipid status.An average increase of 3.74 kg (+4.92%) body weight during the 4 month lockdown period was observed. Lung function values and blood lipid status remained stable.Such weight gain could have detrimental effects on the morbidity and mortality of lung transplant patients. Further follow up is needed to determine the long term impacts of this observation.

In most patients with acute respiratory distress syndrome (ARDS), invasive mechanical ventilation is an inevitable treatment measure. It should be applied respecting the principles of protective ventilation to minimize lung injury induced by mechanical ventilation. Ventilation of ARDS patients in prone position improves respiratory mechanics and oxygenation; consequently, it facilitates ventilation and reduces the risk of lung damage associated with the use of mechanical ventilation. Nevertheless, the prone position is still rarely used. We present a patient with ARDS in whom prone positioning resulted in a rapid and significant improvement in ventilation, which was directly recorded by the adaptive mode of mechanical ventilation. A 41-year-old woman was admitted to ICU with rightsided pneumonia, sepsis and type 1 respiratory failure. Empiric antibiotic therapy was administered immediately, along with all supportive therapy. During the next 48 hours, her condition progressed to ARDS and hypercapnic respiratory failure. This led us to initiate invasive mechanical ventilation using adaptive support ventilation (ASV). Achieved tidal volumes of 244 ml (3.9ml/kg of Ideal Body Weight)were insufficient despite optimized ventilator settings. The patient was placed in a completely prone position. Soon after the prone positioning, improvement of ventilation parameters were observed. Using the same ventilation settings, with even lower generated pressure support, tidal volumes increased to 451 ml (7ml/kg of Ideal Body Weight). In the further clinical course, the patient’s condition gradually improved until complete recovery. The presented course of treatment shows how prone positioning can significantly improve respiratory mechanics and facilitate the achievement of adequate mechanical ventilation, which has been clearly demonstrated using the adaptive ventilation modality.

Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation plays an important role in chronic obstructive pulmonary disease (COPD) pathogenesis and might be involved in ongoing chronic inflammation. This study aimed to determine interleukin-1beta (IL-1β) plasma concentration as well as IL1B, NLRP3 and caspase-1 (CASP1) gene expression in the Croatian COPD patients. 109 patients with stable COPD and age- and sex-matched 95 controls were included in the study. Plasma IL-1β concentration was measured by Luminex technology, and gene expression analysis was performed using TaqMan assays. It was shown that COPD patients had increased concentration of IL-1β and enhanced gene expression of IL1B, NLRP3 and CASP1 compared to controls. There was no difference in IL-1β or IL1B, NLRP3 and CASP1 in patients with COPD regarding airflow obstruction severity and smoking history. Finally, the diagnostic potential of the determined parameters was evaluated, and it was found that IL-1β correctly classified 89% of cases in the combination with common inflammatory biomarkers, white blood cell count and fibrinogen, showing a potential in COPD prediction. In conclusion, up-regulation of IL1B, NLRP3, CASP1 and increased IL-1β concentration suggest the activation of NLRP3 inflammasome in the systemic compartment of patients with stable COPD.

Background: Besides the burden of acute covid care, a fraction of patients report symptoms after the period of acute covid illness which affect quality of life and prolong recovery. Aim: To assess the profile of patients reporting to our post-covid clinic, their quality of life and frequency of persisting symptoms. Methods: Covid- 19 survivors, referred (at least a month after the acute illness) from December 2020 to January 2021 to our Centre’s post-covid clinic. Patients entered this study by filling out a questionnaire which also included current symptoms and standardised Post-Covid Functional Scale (PCFS) score. Results: 112 patients were included in the study. Males predominated (62.5% ; mean age 56) over females (37.5% ; mean age 48). In the acute phase, 72.3% were treated as outpatients, 27.6% at the ward and 7.1% in the ICU. Most common comorbidities were hypertension (21.4%), various chronic lung diseases (22.3%) and type 2 diabetes (5.4%). Corticosteroid therapy was given in 45.5% of patients, either in the acute phase, post-covid period, or both. The most frequent post- covid complaints were exhaustion (63.4%), shortness of breath (48.2%), muscle weakness (31.3%), dry cough (34.8%) and chest pain (25.0%). Of 110 patients with known PCFS value, 27 (24.5%) reported 0, while 34 (30.9%), 31 (28.2%), 17 (15.5%), and one (0.9%) patient reported scores of 1, 2, 3, and 4, respectively. Conclusion: Even though the majority of our patients were treated as outpatients in the acute phase and presumably had milder disease forms, three-quarters of them still experience impairment of life quality (PCFS >1) with pronounced respiratory symptoms months after the illness.

Background Patients with head and neck squamous cell carcinoma (HNSCC) can develop lung squamous cell carcinoma (LuSCC), which could be the second primary tumor or HNSCC metastasis. Morphologically it is difficult to distinguish metastatic HNSCC from a second primary tumor which presents a significant diagnostic challenge. Differentiation of those two malignancies is important because the recommended treatments for metastatic HNSCC and primary LuSCC differ significantly. We investigated if the quantification of the promotor methylation status in HNSCC and LuSCC differs. Methods Primary HNSCC (N = 36) and LuSCC (N = 17) were included in this study. Methylation status in the ASC/TMS1/PYCARD (apoptosis-associated speck-like protein containing a caspase recruitment domain; 8 CpG sites) and MyD88 (Myeloid differentiation primary response protein 88; 10 CpG sites) promoters was analyzed. Bisulfite converted DNA, isolated from tumor tissue was quantified using pyrosequencing. Results of pyrosequencing analysis were expressed as a percentage for each tested CpG site. Receiver-operating characteristic (ROC) curve analysis was used for the evaluation of the diagnostic properties of selected biomarkers. Results CpG sites located in the promoters of ASC/TMS1/PYCARD_CpG8 (− 65 upstream) and MyD88_CpG4 (− 278 upstream) are significantly hypermethylated in the HNSCC when compared with LuSCC (p ≤ 0.0001). By performing ROC curve analysis we showed that corresponding areas under the curve (AUC) were 85–95%, indicating that selected CpG sites are useful for a distinction between primary LuSCC and primary HNSCC. Conclusions Results of the present study indicate that there is a significant difference in the methylation status of tested genes between primary HNSCC and LuSCC. However, to prove this approach as a useful tool for distinguishing second primary LuSCC from HNSCC metastasis, it would be necessary to include a larger number of samples, and most importantly, metastatic samples.

The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting.We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records.Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003).The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.

Malignant pleural mesothelioma (MPM) is an aggressive tumor that develops from the mesothelial cells lining the pleural cavity. The most relevant risk factor is asbestos exposure. Despite therapy the median survival is poor ranging from four to 18 months. The aims and objectives of this study were to assess the clinical characteristics and survival of patients with MPM treated at UHC Zagreb. This study included 101 patients diagnosed and treated for MPM at UHC Zagreb from September 1999 to September 2012. We analyzed the overall survival (OS), progression free survival (PFS) and OS depending on histological subtype, clinical stage, age, treatment method and pleurodesis performed using the Kaplan-Meier method. Eighty-nine patients were male and 12 female with the median age of 62 years. Using the TNM staging system, 69.3% were stage IV, 26.73% were stage III and 3.96% were stage II. 73.26% of MPM were epitheloid, 4.95% sarcomatous and 20.79% were NOS (non otherwise specified) histological subtype. 14.85% of patients had surgery, 55.44% of patients received chemotherapy and 9.9% radiotherapy. Median OS was 11 months and PFS was ten months. OS by histological subtype was 11 months for epitheloid, 12.5 months for NOS and 5.5 months for sarcomatous MPM. OS by TNM stage was seven months for stage II, 17.5 months for stage III and 11 months for stage IV disease. Median OS was longer for patients younger than 65 (12 vs. 8.5 months, p=0.28), patients treated with pleurodesis (13 vs. 7.5 months, p=0.06) and patients who received chemotherapy (12.5 vs. 7.5 months, p=0.10). The overall survival and prognosis of patients with malignant pleural mesothelioma in Croatia is poor in accordance with the literature. The studied treatment methods offer only a modest survival benefit to our patients.

Background: Smoking is one of the major preventable risk factor for respiratory diseases and a global public health problem. Public awareness and access to smoking cessation schools should be one of the principal goals in disease prevention and public health initiatives. Cognitive-behavioral treatment has proven to be efficient in smoking cessation. Aim: The aim of this paper is to present the results of a two year ongoing smoking cessation school. Methods: Smoking cessation program started in 2017 as a public health interdisciplinary initiative. It consists of 12 visits, organized in a group, over one month, free of charge and accessible to all adult smokers motivated to quit. Education, psychoeducation, cognitive-behavioural techniques (self-monitoring, cognitive restructuring, reframing, breathing and progressive muscle relaxation, relapse prevention, etc.) and group counseling are included. It also includes measurement of exhaled CO at the beggining and end of the programme, and spirometry to screen for early stages of respiratory obstruction. Attendants evaluate the program in a written form on their last visit. Results: In two years, nine cycles of smoking cessation schools were completed. The program completed 91 person and 39 (42,9%) sucsessfuly quit smoking. Follow up at six months after the end of program showed a success rate reduction of 3% in average. Futher follow up is needed. Conclusion: Interdisciplinary, cognitive-behavioraly based, publicly accessible smoking cessation school represent an efficient way of smoking cessation. Due to its remarkable results so far, it is considered to be adopted as a nation–wide prevention program, during national lung cancer screening program.

Background: Dyspnea is traditionally considered as a physically caused phenomenon. Recent research suggests that being breathless has two components (sensoric and affective) and that factors other than biological are contributing to its subjective intensity. Aim: To determine the predictive value of biological, psychological and social factors in dyspnea intensity among patients with chronic obstructive pulmonary disease (COPD). Methods: Study included 74 COPD patients with following variables measured: biological - age, gender, smoking status, body mass index, pulmonary functions tests and blood oxygen saturation; psychological- anxiety sensitivity, positive/negative affect, personality traits, locus of control and coping strategies; social - education, working and socioeconomic status, marital status and percieved social support. Using stepwise linear regression data was analysed, with above mentioned variables included as predictors and dyspnea intensity as a criterion. Results: This combination of biopsychosocial predictors explained 29% of dyspnea intensity in COPD patients. The biggest contribution to dyspnea intensity was shown by psychological factors (14%), followed by biological (10%) and social factors (5%). This combination of psychosocial factors explained more of dyspnea intensity (19%) than did biological (10%). Method: Dyspnea is a complex, multidimensional sensation, affected not only by biological, but psychosocial factors too. By identifying and understanding all factors that play a role in dyspnea, we can better understand a specific patient needs, offer treatments which include psychosocial interventions to better target the psychosocial component of breathlessness.

Background. There is a lack of real-world data on the safety and efficacy of nivolumab in patients with previously treated advanced non-small-cell lung cancer (NSCLC) especially in South East Europe, a region with particularly high incidence and an unfavorable mortality-to-incidence ratio for lung cancer. Objectives. To evaluate the real-world safety and efficacy of nivolumab in patients with previously treated advanced squamous and nonsquamous NSCLC in South East Europe. Methods. This is a multicenter, retrospective cohort study on patients with stage IIIB or IV disease with at least one previous systemic treatment who received nivolumab through an expanded-access program between 2015 and 2017 in Croatia, Malta, and Hungary. The primary endpoint was the proportion of patients whose therapy was discontinued because of toxicity. Secondary endpoints were the incidence of adverse events (AEs), objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results. We analyzed data on 239 patients with a median (IQR) age of 62 (57–68), and 33% of them were women. Treatment was discontinued because of toxicity in 11.6% (95% CI 7.8% to 16.5%) of patients. The PFS was 6.4 (95% CI 5.2 to 8.6) months, and the median OS was 14.1 (10.6 to 18.0) months. Conclusions. The safety and efficacy of nivolumab in previously treated patients with advanced NSCLC in the real-world South East Europe clinical settings were consistent with the results of randomized clinical trials and comparable to the results from other countries.

Background: Carbohydrate sulfotransferases (CHST) were shown to be involved in carcinogenesis. The aim of the study was to assess the diagnostic value of serum CHST7 concentration in differentiation between lung cancer and non-malignant pulmonary inflammations. Methods: Clinical case-control study involving 125 participants was conducted: the control group containing cases of pneumonia and chronic obstructive pulmonary disease was compared to the lung cancer group composed of primary and metastatic cancers. Serum concentrations of CHST7 and routinely used markers including carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA 21-1) and neuron-specific enolase (NSE) were determined for each participant using immunochemical methods. Statistical association, receiver operating characteristic (ROC) analysis and cross-validation were used for the evaluation of CHST7 either as a standalone biomarker or as a part of a biomarker panel. Results: In comparison to the control group, serum CHST7 was elevated in lung cancer (p Conclusions: Serum CHST7 is a promising biomarker for the differentiation between lung cancer and non-malignant pulmonary inflammations.

We present unusual treatment outcome in a 59-year- old male diagnosed with metastatic lung adenocarcinoma with a very good response to ruxolitinib as monotherapy. In June 2017, this patient was diagnosed with myeloproliferative neoplasm - Janus-associated kinases 2 positive - and in December 2017 ruxolitinib therapy was started. At the same time, patient was diagnosed with lung adenocarcinoma in the left lower lobe with positive anaplastic lymphoma kinase mutation and with right lower lobe metastasis. Because of partial regression of tumor size noted on the computed tomography (CT) scans during tumor investigation, we did not apply any therapy for lung adenocarcinoma. A follow-up CT scan done in March 2018 showed further size reduction of tumor lesion in lower left lobe (91%), while follow-up CT scan done in June 2018 showed further size reduction of tumor lesion in lower right lobe (82%).

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC.

Lung cancer is the leading cause of cancer-related deaths worldwide. Despite growing efforts for its early detection by screening populations at risk, the majority of lung cancer patients are still diagnosed in an advanced stage. The management of lung cancer has dramatically improved in the last decade and is no longer based on the “one-fits-all” paradigm or the general histological classification of non-small cell versus small cell lung cancer. Emerging options of targeted therapies and immunotherapies have shifted the management of lung cancer to a more personalized treatment approach, significantly influencing the clinical course and outcome of the disease. Molecular biomarkers have emerged as valuable tools in the prognosis and prediction of therapy response. In this review, we discuss the relevant biomarkers used in the clinical management of lung tumors, from diagnosis to prognosis. We also discuss promising new biomarkers, focusing on non-small cell lung cancer as the most abundant type of lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death worldwide, with 5-year overall survival less than 15%. Therefore, it is essential to find biomarkers for early detection and prognosis. Aberrant DNA methylation is a common feature of human cancers and its utility is already recognized in cancer management. The aim of this study was to explore the diagnostic and prognostic value of the promoter methylation status of the ASC/TMS1/PYCARD and MyD88 genes, key adaptor molecules in the activation of the innate immune response and apoptosis pathways. METHODS: A total of 50 non-small cell lung cancer (NSCLC) patients were enrolled in the study. Methylation of bisulphite converted DNA was quantified by pyrosequencing in fresh frozen malignant tissues and adjacent non-malignant tissues. Associations between methylation and lung function, tumor grade and overall survival were evaluated using receiver-operating characteristics (ROC) analysis and statistical tests of hypothesis. RESULTS: Methylation level of tested genes is generally low but significantly decreased in tumor tissues (ASC/TMS1/PYCARD, P

Objective: Weight loss and an underweight status are serious problems in chronic obstructive pulmonary disease (COPD), independent of the degree of airflow obstruction. Body mass index (BMI), does not reflect changes in body composition that may occur with aging or with the level of disease. BIA is a simple, inexpensive, quick and non-invasive technique for measuring body composition, due to ability to identify malnutrition. Aim: To analyze values of BIA- Phase angle (PA), Fat Free Mass (FFM), Visceral Mass (VM) and obstruction level (FEV1) and their importance in the prediction of exercise capacity measured by six-minute-walking test (6MWT). Method: We analyzed results from 68 stable COPD male (44) and female (24) patients, aged M= 55.9 who attended standard PRP five days weekly, during four weeks. Nutritional status during rehabilitation was evaluated by BIA. Data analysis was performed using linear regression with following predictor variables: patient’s age, BIA values (PA, FFM, VM), FEV1 and 6MWT as a criterion variable. Results: Our results showed that chosen predictors explain a significant 40% (p Conclusion: Age, FEV1 and PA are significant predictors of exercise capacity. Therefore, PA as a measure of body composition status is an important tool in PRP to detect early changes in body composition in COPD patients so they can start immediately with nutrition support and pulmonary rehabilitation which in combination produce the best results regarding patient’s functionality.

Introduction: Clinical differences between M. avium and M. intracellulare haven’t been fully studied. Aims and Objectives: to asses the relevance of M. avium complex (MAC) members; record treatment outcomes and long term survival of MAC pulmonary disease (MAC-PD) patients. Methods: retrospective study on all Croatian residents with MAC respiratory isolates from 2006 to 2016 with follow up to 2018. ATS/IDSA guidelines were used to establish MAC-PD and evaluate treatment adequacy. Results: Medical records were available for 93/149 (62.4%) isolates. MAC-PD was diagnosed in 36/49 (73.4%) of M. avium and 24/44 (54.5%) of M. intracellulare isolates. Fibrocavitary form and smear positivity were more common with M. intracellulare than M. avium - 33.3 vs. 22.2% and 61 vs. 27.6%, respectively. Treatment was started in 23/36 (63.9%) of M. avium and 21/23 (91.3%) of M. intracellulare. Adequate regimen was administered in 26.1% (6/23) of M. avium and 55% (11/20) of M.intracellulare patients, and microbiological cure was achieved in 83.3% and 72.7% of cases, respectively. One-year mortality of M. avium patients was 19.4% compared to 8.3% of M. intracellulare. 5-year all-cause mortality amounted to 36% and 30% of M. avium and M. intracellulare cases, respectively (p=0.876). Conclusions: M. avium showed a higher percentage of isolates meeting the MAC-PD criteria. Still, M.intracellulare disease was more severe in its presentation, which partly explains the higher rate and adequacy of treatment. Although one-year mortality of M. avium cases was doubled compared to M. intracellulare, there were no differences in long term survival between the two groups.

Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by a progressive decline in lung function due to airflow limitation, mainly related to IL-1β-induced inflammation. We have hypothesized that single nucleotide polymorphisms (SNPs) in NLRP genes, coding for key regulators of IL-1β, are associated with pathogenesis and clinical phenotypes of COPD. We recruited 704 COPD individuals and 1238 healthy controls for this study. Twenty non-synonymous SNPs in 10 different NLRP genes were genotyped. Genetic associations were estimated using logistic regression, adjusting for age, gender, and smoking history. The impact of genotypes on patients’ overall survival was analyzed with the Kaplan–Meier method with the log-rank test. Serum IL-1β concentration was determined by high sensitivity assay and expression analysis was done by RT-PCR. Decreased lung function, measured by a forced expiratory volume in 1 s (FEV1% predicted), was significantly associated with the minor allele genotypes (AT + TT) of NLRP1 rs12150220 (p = 0.0002). The same rs12150220 genotypes exhibited a higher level of serum IL-1β compared to the AA genotype (p = 0.027) in COPD patients. NLRP8 rs306481 minor allele genotypes (AG + AA) were more common in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of group A (p = 0.0083). Polymorphisms in NLRP1 (rs12150220; OR = 0.55, p = 0.03) and NLRP4 (rs12462372; OR = 0.36, p = 0.03) were only nominally associated with COPD risk. In conclusion, coding polymorphisms in NLRP1 rs12150220 show an association with COPD disease severity, indicating that the fine-tuning of the NLRP1 inflammasome could be important in maintaining lung tissue integrity and treating the chronic inflammation of airways.

Extracellular Hsp70 (eHsp70) can act as pro- inflammatory mediator and is elevated in blood of chronic obstructive pulmonary disease (COPD) patients. Most of those patients are smokers, and it was suggested previously that cigarette smoke might induce Hsp70 secretion from the circulating cells. Therefore, we aimed to explore inflammation- associated effects of cigarette smoke extract (CSE) and its combinations with eHsp70 in monocyte-derived macrophages (MDMs) and THP-1 cell line, used as systemic component models of COPD We hypothesized that eHsp70 induces inflammation, but that it can also modulate cigarette smoke extract (CSE)- stimulated inflammatory responses. We assessed IL-8 secretion, TLR2, TLR4 and Hsp70 expressions, MAPKs and NF-κB activation, and cytotoxicity after treating the cells with CSE (2.5 and 5%) and its combinations with low-endotoxin recombinant human (rh) Hsp70, used to mimic eHsp70 effects. CSE induced IL-8 secretion from both cell types, but its combinations with rhHsp70 increased IL-8 release compared to CSE alone only from MDMs. In THP-1, combinations of rhHsp70 with 2.5% CSE induced TLR2 and TLR4 mRNA, while 5% CSE decreased TLR2 expression. In MDMs, CSE alone attenuated TLR2, while rhHsp70 increased TLR2 and lowered TLR4 gene expression. Hsp70 mRNA expression was suppressed in THP-1 with rhHsp70 and CSE ; however, the same treatments increased its level in MDMs. CSE had cytotoxic effect only on MDMs, but cytotoxicity was reduced in co-treatments with rhHsp70, which also triggered apoptosis. CSE and rhHsp70 activated p38 and JNK, while ERK was activated only by rhHsp70 in MDMs. In THP-1, 2.5% CSE activated ERK, and 5% CSE activated p38. Inhibition of NF-κB and JNK in MDMs, and ERK and JNK in THP-1 cells, attenuated IL-8 release after rhHsp70 treatment. In conclusion, rhHsp70 provoked pro- inflammatory effects and could also modulate inflammatory response to CSE on protein and gene expression levels in THP-1 cells and MDMs, which suggests that eHsp70 might be implicated in systemic inflammation induced by cigarette smoke.

Introducion: Lung carcinoid(LC)tumors account for 1–2% of all lung malignancies. They are classified as typical(TC)or atypical(AC)based on the mitotic index and/or the presence of necrosis. The utility of Ki-67 to differentiate between TCs and ACs has yet to be established and it is not presently recommended Aim: To investigate the predict value of Ki 67 indeks in overal survival, in multivariate analysis Methods: A cohort of 60 pts with LC treated in 5 year period in our department were analysed.LC were classified according to WHO histotype criteria after surgical resection Results: 6pts were excluded before the statistic analysis. Remaining 60pts;35 male(58.4%)and 25 female(41.6%);mean age of 53.6years. The histopathology revealed 44pts with TC and 16pts with AC. The mean Ki-67 indices for the TC(5.0)and theAC(18.4)were significantly different(p Conclusion: These findings don`t provide best evidence for the routine use of Ki-67 index to predict overall short-term survival in pts with LC

Cigarette smoke is one of the major risk factors for development of chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation. Bacterial infections can increase inflammatory responses and cause exacerbations in COPD. Extracellular Hsp70 (eHsp70) can act pro-inflammatory via Toll-like receptors (TLR) 2 or 4, and was found elevated in sera of COPD patients. We hypothesized that eHsp70 modulates the inflammatory response provoked by bacterial compounds and cigarette smoke. Therefore, we aimed to investigate the effect of eHsp70 present together with lipopolysaccharide (LPS), lipoteichoic acid (LTA) or cigarette smoke extract (CSE) on interleukin-8 (IL-8) secretion. We treated primary tracheo-bronchial epithelial cells (PBEC) isolated from healthy controls and COPD patients either with recombinant human (rh) Hsp70 (0.1, 1 and 3 µg/ml), 0.1 µg/ml LPS, 1 µg/ml LTA and CSE (2.5 and 15%) alone or with their combinations. IL-8 levels in cell-free supernatants were determined by ELISA. RhHsp70, LTA and CSE alone increased IL-8 secretion in PBEC both from healthy volunteers and COPD patients, while LPS had no significant effect. Instead of an additive effect, combined treatment with rhHsp70 reduced IL-8 levels compared to the presence of LPS, LTA or CSE alone in COPD-derived PBEC, but not those from healthy controls. In conclusion, rhHsp70 reduces the pro-inflammatory effects of bacterial components and CSE in PBEC cells from COPD patients. Their combined presence could lead to attenuation of pro-inflammatory epithelial responses in COPD patients, and Hsp70 could have a protective instead of detrimental effect in COPD.

Background: Asthma patients, due to their symptoms, often experience fear and anxiety when faced with daily activities. Such functional impairment over time causes lowered quality of life (QoL) and additional psychological distress expressed with depression, anxiety and stress symptoms. Objective: To evaluate the role of aerobic treadmill training among asthma patients attending pulmonary rehabilitation (PR) in their walking capacity (6 minute walking test - 6MWT), in improving QoL and reducing psychological distress. Method: We analyzed the results from 77 patients with persistent asthma divided in two groups. Patients in both groups had the same level of obstruction. They attended standard PR program five days weekly, during four weeks. In one group aerobic treadmill exercise training was added three times a week. Intensity was set at 60% of maximal work rate. Baseline and post PR status were evaluated by 6MWT in both groups, QoL, Depression (D), Anxiety (A) and Stress (S) symptoms. Results: All patients had a significant increase in 6MWT after PR (p

Introduction: Transbronchial criobiopsy is less invasive diagnostic technique for interstitial lung disease. According to published paper is safe with good diagnostic yield. Aim: to analyse safety and diagnostic yield of cryobiopsy in our centre. Methods: Prospective study which included 36 patients with clinical and radiographic features of interstitial lung disease who underwent transbronchial cryobiopsy without fluoroscopy. Results: Safety: Pneumothorax occurred in 2 patients (5,5%). There was no severe bleeding. In 26 cases (72%) there was mild bleeding and in 2 cases no bleeding. The mean number of samples was 4 (1-5) and mean diameter was 5,4 mm (5,4+/-2,3). Definitive diagnosis by pathologist was obtained in 14 (38%) cases (NSIP in 6 cases, 2 granulomatosis, 1 DAD, 1 UIP, 1 hypersensitivity pneumonitis, 1 drug related, 1 adenocarcinoma, 1 aspiration pneumonitis). In 15 cases cryobiopsy was inconclusive, in 5 cases nonspecific fibrosing changes were found and in 3 cases normal lung tissue. After multidisciplinary team discussion definitive diagnosis was obtained in 25 (69%) cases (6 NSIP, 4 IPF, 3 pulmonary manifestations of connective tissue disease, 3 chronic hypersensitivity pneumonitis, 2 sarcoidosis, 2 RB ILD, 2 cryptogenic organising pneumonia, 1 drug induced interstitial lung disease, 1 adenocarcinoma, 1 aspiration pneumonitis). Conclusion: Cryobiopsy is safe procedure with low incidence of serious complications (major bleeding or pneumothorax) even when it is performed without fluoroscopy. Results in our study showed lower proportion of definitive diagnosis established after cryobiopsy which can be partly explained with the lack of pathologist9s experience when we started the study.

Dyspnea or breathlessness is a term primarily used in respiratory medicine. Nevertheless, in the last fifteen years, studies from other fields focus on the affective component of this complex phenomenon due to the frequent observation that psychological states can cause or be caused by dyspnea. Research so far shows that besides the biological component, dyspnea has a strong emotional and psychosocial determinant. This means that apart from its biological factors, dyspnea and its intensity are affected by emotions, personality, anxiety and depression, etc. Individuals with psychiatric disorders, in the same conditions, will evaluate their dyspnea as more intense and disturbing compared to individuals without psychiatric comorbidity. Emotional states in healthy individuals can amplify the sense of dyspnea which is of extreme importance for clinical practice in order to consider the whole person and not just the symptom which is being presented. Also, dyspnea seems to be frequent complaint in some groups of patients with psychiatric disorders (e.g.panic disorder), where the fear of suffocation is presented as clinical symptom. Further research of dyspnea as a complex, multicomponent phenomenon, can contribute to better treatment options and better differential diagnosis concerning possible psychiatric background of physical symptoms.

Aim: to determine in-hospital and post-discharge mortality, readmission rates, and predictors of invasive mechanical ventilation (IMV) in patients treated at intensive care unit (ICU) due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Methods: a retrospective observational cohort study included all patients treated at a respiratory ICU for AECOPD during one year. A total of 62 patients (41 men) with mean age 68.4 ± 10.4 years were analyzed for outcomes including in-hospital and post-discharge mortality, readmission rates, and IMV. Patients’ demographic, hematologic, biochemical data and arterial blood gas (ABG) values were recorded on admission to hospital. Mean duration of followup time was 2.4 years. Results: of 62 patients, 7 (11.3%) died during incident hospitalization and 21 (33.9%) died during the follow-up. The overall 2.4-year mortality was 45.2%. Twenty nine (46.8%) patients were readmitted due to AECOPD. The average number of readmissions was 1.2. Multivariate analysis showed that blood pH, bicarbonate levels, low albumin, low serum chloride, and low hemoglobin were significant predictors of IMV during incident hospitalization (P < 0.001 for the overall model fit). Conclusion: high in-hospital and post-discharge mortality and high readmission rates in our patients treated due to AECOPD at ICU indicate that these patients represent a high risk group in need of close monitoring. Our results suggested that anemia, hypoalbuminemia, and elevated troponin levels were risk factors for the need of IMV in severe AECOPD. Identification of such high-risk patients could provide the opportunity for administration of an appropriate and timely treatment.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.

Introduction: Anxiety sensitivity (AS) is a stable personality trait characterized by fear of bodily symptoms that accompany anxiety. It is considered to be important in many chronic illnesses, especially respiratory, since the fear from the symptoms acts as an „symptom amplifier“. As such, it can worsen clinical manifestations of chronic illnesses. Aim: To compare asthma, lung cancer patients and healthy subjects in their sensitivity to anxiety symptoms. Method: Study included 121 subjects (N(A)asthma=52, N (Ca)Cancer=17, N(H)Healthy=52). To measure anxiety sensitivity we used a validated questionnaire Anxiety Sensitivity Index (ASI) consisting of 16 items evaluating fear of bodily and psychological symptoms and social threats. Patients completed ASI during outpatient check-ups. Healthy subjects were recruited through on-line survey. Group differences were analysed using ANOVA. Results: Results show significant difference between groups (F=7.513, p 0.05). Conclusions: Despite much more difficult course of lung cancer illness in comparison to asthma, fear of bodily symptoms and sensations seem to be similar in both illnesses. This finding poses a question of the importance of diseases onset and duration (adjustment period), person9s coping mechanisms and personality traits as manageable contributing factors in respiratory disease management.

Rossi A, Butorac-Petanjek B, Chilosi M, Cosío BG, Flezar M,Koulouris N, Marin J, Miculinic N, Polese G, Samaržija M,Skrgat S, Vassilakopoulos T, Vukić-Dugac A, Zakynthinos S,Miravitlles M. Int J Chron Obstruct Pulmon Dis. 2017;12:593–2610.Page 2604, Disclosure, the text “The authors report noconflicts of interest in this work” should read “BGC has received speaker fees from Chiesi, Novartis, Menarini,AstraZeneca, Esteve and Rovi; research grants from Chiesi and Boehringer; and served on advisory boards for Chiesi,Novartis, AstraZeneca and Esteve. MM has received speakerfees from Boehringer Ingelheim, Chiesi, Cipla, Menarini,Rovi, Bial, CSL, Behring, Grifols and Novartis; consultancyfees from Boehringer Ingelheim, Chiesi, GlaxoSmithKline,Bial, Gebro Pharma, CSL Behring, Laboratories Esteve,Mereo BioPharm, Verona Pharma, pH Pharma, Novartisand Grifols; and research grants from GlaxoSmithKline andGrifols. The authors report no other conflicts of interest inthis work”.Read the original article &nbsp

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, with high and growing prevalence. Its underdiagnosis and hence under-treatment is a general feature across all countries. This is particularly true for the mild or early stages of the disease, when symptoms do not yet interfere with daily living activities and both patients and doctors are likely to underestimate the presence of the disease. A diagnosis of COPD requires spirometry in subjects with a history of exposure to known risk factors and symptoms. Postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity = 80% predicted. In recent years, an elegant series of studies has shown that exclusive reliance on spirometry, in patients with mild airflow limitation, may result in underestimation of clinically important physiologic impairment. In fact, exercise tolerance, diffusing capacity, and gas exchange can be impaired in subjects at a mild stage of airflow limitation. Furthermore, growing evidence indicates that smokers without overt abnormal spirometry have respiratory symptoms and undergo therapy. This is an essential issue in COPD. In fact, on one hand, airflow limitation, even mild, can unduly limit the patient's physical activity, with deleterious consequences on quality of life and even survival; on the other hand, particularly in younger subjects, mild airflow limitation might coincide with the early stage of the disease. Therefore, we thought that it was worthwhile to analyze further and discuss this stage of mild COPD. To this end, representatives of scientific societies from five European countries have met and developed this document to stimulate the attention of the scientific community on COPD with mild airflow limitation. The aim of this document is to highlight some key features of this important concept and help the practicing physician to understand better what is behind mild COPD. Future research should address two major issues: first, whether mild airflow limitation represents an early stage of COPD and what the mechanisms underlying the evolution to more severe stages of the disease are; and second, not far removed from the first, whether regular treatment should be considered for COPD patients with mild airflow limitation, either to prevent progression of the disease or to encourage and improve physical activity or both., The authors acknowledge the scientific contribution of the following European Pulmonology Societies: AIPO - Italian Association of Hospital Pulmonologists, Croatian Pulmonology Society, Croatian Thoracic Society, HTS Hellenic Thoracic Society, SEPAR - Spanish Society of Pneumology and Thoracic Surgery, Slovenian Respiratory Society. The authors would like to thank the staff of AIPO Ricerche (Milan, Italy) for editing assistance. This consensus document has been funded through an unrestricted educational grant from Teva.

Incorrect catheter placement for drainage of malignant pericardial effusion in a 43-year-old woman with a metastatic lung adenocarcinoma.

The aim of this study was to investigate the consequences of insulin-like growth factors (IGF) and IGF receptor dysfunction in lung carcinomas. A correlation between increased expression (at mRNA and protein levels) for IGF-1 and IGF-1R and decreased apoptosis were found in large-cell carcinomas and adenocarcinomas. In 40% of informative adenocarcinomas expressing the highest values of IGF-2 and Ki-67 proteins, M6P/IGF-2R gene had LOH at one allele and a mutation in another allele. All four squamous cell carcinoma samples expressed LOH/mutation in the M6P/IGF-2R gene. The alphaIR3 strongly diminished proliferation and increased apoptosis in cultures established from squamous cell carcinomas overexpressing IGF-2 and IGF-1R. Telomerase activity was assessed in four squamous cell carcinomas. Cell treatment with IGF-1 increased telomerase activity. The opposite was observed when the cells were treated with alphaIR3, which inhibits the activity of IGF-1 receptors. Our findings suggest that disruption of the IGF/IGF receptors axis is involved in lung cancer formation.