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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.

Non–small cell lung cancer (NSCLC) has become the best example of precision oncology’s impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1–3) CRGA per patient. From the panel of recommended tests, KRAS, MET, and EGFR were the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.

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.

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.

Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin–angiotensin–aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.

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.

Here we retrospectively analyzed the post-COVID-19 register of University Hospital Zagreb, Clinic for Pulmonary Diseases Jordanovac in Croatia to compare COVID-19 incidence between smokers and nonsmokers. No significant differences among smokers and non-smokers were found regarding the severity of the disease. COVID-19 should be used as a chance to educate the public about adaptive, healthy stress-release methods and the necessity for smoking cessation, to prevent and preserve overall physical and psychical health.

Background and Aims: Limited number of studies investigated lipid profile in chronic obstructive pulmonary disease (COPD) with inconsistent results. This study aimed to investigate lipid parameters in sera of patients with stable COPD and their associations with disease severity, smoking, comorbidities and therapy. Methods and Results: The study included 137 COPD patients and 95 controls. Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were assessed. Non-HDL-C (NHC), atherogenic coefficient (AC), TG/HDL-C, atherogenic index of plasma (AIP), Castelli's risk index I and II (CRI- I, CRI-II), and monocyte to HDL ratio (MHR) were calculated. HDL-C and MHR were increased, while other lipid parameters and indices were decreased in COPD patients compared to healthy individuals. Smoking did not influence lipid parameters. However, lipid profile was altered only in more severe disease stages. AC, CRI-I and CRI-II showed positive association with lung function parameters in COPD patients, and negative with COPD multicomponent indices (ADO, BODCAT, BODEx, CODEx and DOSE). Combined model that included CRI-II, C- reactive protein, fibrinogen and white blood cells showed great diagnostic performances, and correctly classified 72% of study participants with an AUC of 0.800 (0.742 - 0.849), P < 0.001. Bronchodilator monotherapy and statins have opposite impact on TC, LDL-C and NHC, while TG, TG/HDL-C and AIP were increased in COPD patients with cardiovascular diseases. Conclusion: Lipid disbalance is present in COPD, and it seems to occur later as the disease progresses. Further studies are needed to illuminate the underlying mechanism of dyslipidaemia.

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: 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

Bolest uzrokovana novim koronavirusom 2019 (COVID-19) postala je prijetnja cijeloj svjetskoj populaciji. Njena česta komplikacija je upala pluća. Najčešći simptomi bolesti su povišena tjelesna temperatura, suhi kašalj, umor, iskašljavanje, zaduha. Rjeđi simptomi su glavobolja, suho grlo, probavne tegobe, simptomi gornjega dišnog puta, promjene u osjetu njuha i okusa. Starija dob i komorbiditeti kao što je visoki krvni tlak, šećerna bolest, kronične plućne bolesti, kardiovaskularne bolesti, srčane bolesti, pretilost predstavljaju značajni rizični faktor za bolesnike inficirane koronavirusom SARS-CoV-2. Uobičajeni laboratorijski nalazi uključuju limfopeniju, povišenu razinu C-reaktivnog proteina, feritina, aminotransferaza, laktat dehidrogenaze. Bolesnici koji razviju tešku kliničku sliku obično imaju brojne laboratorijske poremećaje što sugerira da SARS-CoV-2 infekcija može uzrokovati ozljedu stanične imunosti, aktivaciju koagulacije, oštećenje miokarda, jetre i bubrega. Najčešće komplikacije su akutni respiratorni distres sindrom, šok, aritmije, akutna ozljeda miokarda, akutno oštećenje bubrežne funkcije. Kompjuterizirana tomografija (CT) može biti korisna kao komplementarna metoda polimeraznoj lančanoj reakciji u realnom vremenu za dijagnozu COVID-19 pneumonije. Njezine glavne CT karakteristike su infiltrati tipa mliječnog stakla periferne i subpleuralne distribucije. Ova područja uzorka mliječnog stakla mogu se miješati s područjima žarišne konsolidacije i/ili se na njih superponiraju zadebljale intralobularne septe, što daje uzorak ludog popločenja., Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a clinical threat to the general population worldwide. Pneumonia is a common complication of COVID-19. Most common symptoms include fever, dry cough, fatigue, sputum production, dyspnea. Less common symptoms include headaches, sore throat, gastrointestinal symptoms, upper airway symptoms, alterations in smell or taste. Higher age and comorbidities, such as hypertension, diabetes mellitus, chronic lung disease, cardiovascular disease, cerebrovascular disease and obesity, pose significant risk for patients infected with SARS-CoV-2. Common laboratory findings include lymphopenia, elevated C-reactive protein, ferritin, aminotransferase levels and lactate dehydrogenase levels. Patients who develop severe disease typically have numerous laboratory abnormalities, which suggests that SARS-CoV-2 infection may be associated with cellular immune deficiency, coagulation activation, myocardial, hepatic and kidney injury. The most frequent complications include acute respiratory distress syndrome, shock, arrhythmias, acute cardiac injury and acute renal failure. Computed tomography (CT) may prove useful as a complementary method to real-time polymerase chain reaction for diagnosing COVID-19 pneumonia. The main CT feature of COVID-19 pneumonia is the presence of ground-glass opacities (GGO), typically with peripheral and subpleural distribution. These areas of GGO may be admixed with areas of focal consolidation and/or associated with superimposed intralobular reticulations, resulting in a crazy-paving pattern.

Introduction. Lung cancer is a complex disease and requires a multidisciplinary approach to achieve the best results in treatment, to increase the survival rate while preserving the quality of life of the sufferer. The nutritional status of the patient is an important factor affecting outcome and recovery from disease or injury. We question whether there is a link between nutritional status and malignant pain in lung cancer patients. Aim. A prospective trial was conducted to determine the distribution of respondents by frequency of pain according to a validated Visual Analog Scale (VAS), distribution of respondents who reported reduced food intake and distribution of factors that have led to the reduced food intake. Methods. A prospective trial was conducted at the Department for respiratory diseases Jordanovac, University Hospital Center Zagreb, Croatia, on a sample of patients with advanced non-small cell lung cancer to determine the frequency, characteristics and treatment of chronic malignant pain (N=76). These are the results from November 2013 to June 2014. For pain assessment, we used a validated VAS. For the identification of patients at risk of malnutrition we used Nutritional risk screening tool (NRS 2002). For a rough estimate of total body adiposity, we measured dermal thicknesses using a standard calliper. Monitoring of patients was documented in the form of nursing documentation. A component of nursing documentation was designed to monitor the nutritional status of cancer patients and has been implemented at the Department for respiratory diseases Jordanovac as required documentation. The component included collecting the following data: the stage and type of cancer and treatment, demographic characteristics, age, gender, vital signs, body weight and height, body mass index (BMI), subjective symptoms such as pain, fatigue and nausea, reduction ad rezones of food consumption. Results. During the study 417 measurements were made: 1) 32,1% of patients reported reduced food intake, and 67,9% of respondents indicated that have not reduced their regular diet; 2) as a reason for the reduced food intake 37,7% respondents stated loss of appetite, 31,2% fatigue and 24,6% pain; 3) 59,5% subjects mainly reported absence of pain, while none of the respondents reported the existence of the highest degree of pain. Conclusion. By regular monitoring of the intensity of the pain we achieved good control in malignant pain management, which is an important data in the assessment of nutritional status. The fact is that poorly controlled pain is present in 24% of patients and has been the reason for the reduced food intake., Uvod. Rak pluća jest kompleksna bolest i zahtijeva multidisciplinarni pristup kako bi se postigli što bolji rezultati u liječenju i povećala stopa preživljavanja uz istodobno očuvanje kvalitete života oboljelog. Nutritivni status bolesnika pokazao se važnim čimbenikom koji utječe na ishod i oporavak od bolesti ili ozljede. Postavljamo pitanje postoji li poveznica između nutritivnog statusa i maligne boli u bolesnika s rakom pluća. Cilj. Provedeno je prospektivno istraživanje kako bi se utvrdila raspodjela ispitanika prema učestalosti bolova prema validiranoj vizualnoj analognoj skali (VAS), raspodjela ispitanika koji su prijavili smanjeni unos hrane i raspodjela čimbenika koji su doveli do smanjenog unosa hrane. Metode. Istraživanje je provedeno na Zavodu za tumore pluća i sredoprsja Klinike za plućne bolesti Jordanovac Kliničkoga bolničkog centra Zagreb, na uzorku bolesnika s uznapredovalim rakom pluća nemalih stanica (N = 76). u periodu od studenoga 2013. do lipnja 2014. Za procjenu boli primijenjen je validirani VAS. Za identifikaciju pacijenata s rizikom od pothranjenosti primijenjen je alat za provjeru prehrambenih rizika (NRS 2002). Za grubu procjenu količine masnog tkiva koristili smo se kaliperom. Praćenje bolesnika dokumentirano je u obliku sestrinske dokumentacije. Sastavnica sestrinske dokumentacije osmišljena je za praćenje prehrambenog stanja oboljelih od karcinoma i implementirana je na Odjelu za respiratorne bolesti Jordanovac kao potrebna dokumentacija. Sastavnica je obuhvatila prikupljanje sljedećih podataka: stadij bolesti i tip karcinoma, tip i stadij liječenja, demografske karakteristike ispitanika, debljina kožnog nabora, standardizirani upitnik o pothranjenosti Nutritional NRS 20021, vitalni znakovi, tjelesna težina, tjelesna visina, indeks tjelesne mase, subjektivna procjena pacijenta; bol, umor i mučnina, razlozi smanjene prehrane. Rezultati. Tijekom provedenog istraživanja izvedeno je 417 mjerenja: 1) 32,1 % ispitanika prijavilo je smanjeni unos hrane, a 67,9 % istaknulo kako nisu smanjivali redovitu prehranu; 2) najučestaliji uzroci smanjenog unosa hrane u ispitanika su bili nedostatak apetita (37,7 %), prisutnost umora/slabosti (31,2 %) i prisutnosti boli (24,6 %); 3) 59,5 % ispitanika prijavilo je nepostojanje boli, dok nijedan ispitanik nije prijavio postojanje najvećeg stupnja boli. Zaključak. Redovitim praćenjem intenziteta boli ostvarena je dobra kontrola maligne boli kod ispitivane populacije, što je važan podatak kod procjene nutritivnog statusa. Činjenica je da je loše kontrolirana bol u 24 % ispitanika razlog smanjenog unosa hrane.

Lung cancer is the leading cause of cancer- related death worldwide. Squamous cell lung cancer (LUSC) accounts for 25-30% of all diagnosed lung cancer cases. It is known that interactions between cancer, immune and stromal cells can impact tumor proliferation and progression, however immune microenvironment of LUSC is still not well characterized. Omics approaches to cancer research started a new era of precision medicine, allowing analysis of large pools of available data. Identification of new predictive and prognostic biomarkers for LUSC using this approach could help optimize therapy decision, since only few targeted therapies were approved for treatment of LUSC specifically so far. In this study we examined mRNA expression profiles of 23 treatment naive patients diagnosed with primary LUSC and 3 healthy controls using RNA-sequencing approach. We determined total of 1535 differentially expressed genes between patients and controls and interrogated the role of those genes with Gene Ontology analysis. Gene Set Enrichment Analysis (GSEA) was used for further characterization of dysregulated genes. To characterize tumor microenvironment of LUSC, we used ESTIMATE package in R. Both immune and stromal scores, that represent the infiltration level of immune cells and presence of stroma in tumor tissue, showed different patterns in our samples. To elucidate this further we used GSVA (Gene Set Variation Analysis) to test enrichment of 17 immune-related gene sets in our samples. Our results show that upregulated genes in tumor samples are associated with DNA replication, DNA repair, mitotic cell-cycle process activity and signaling activity. Downregulated genes are associated with signal transduction, immune response activity, cell adhesion and migration activity. GSVA analysis coupled with hierarchical clustering showed four distinct patients subgroups (immune- subtypes) based on levels of immune cells infiltration. Identified immune-subtypes showed significantly different infiltration levels of macrophages, NK bright, NK dim cells, central memory T cells, effective memory T cells, CD8+ T cells and eosinophils. Additionally, in early stage cancer patients upregulation of inflammation-related genes was identified (e.g. CXCL13, CXCR5, IL36G, CXCR3, CCL19, CCR5, IRAK1, CXCL10).

Maligni pleuralni mezoteliom rijetka je i agresivna primarna novotvorina mezotelnih stanica pleure. Glavni rizični čimbenik je izloženost azbestu, najčešće uz latenciju od 30–50 godina. Unatoč terapiji medijan preživljenja je od 4 do 18 mjeseci, ovisno o izvoru. Cilj istraživanja bio je odrediti karakteristike bolesnika oboljelih od malignoga pleuralnog mezotelioma te ishode njihova liječenja na KBC Zagreb u razdoblju od 1999. do 2012. godine. Ispitane su karakteristike 101 bolesnika dijagnosticiranog i liječenog na KBC Zagreb u razdoblju od rujna 1999. do rujna 2012. Analizirali smo ukupno preživljenje (OS), preživljenje bez progresije bolesti (PFS) te preživljenje ovisno o histološkom podtipu tumora, dobi, kliničkom stadiju, pleurodezi talkom i modalitetu liječenja. Koristili smo Kaplan-Meierovu metodu za izradu krivulje preživljenja. 89 bolesnika bilo je muškog, 12 ženskog spola, a medijan dobi 62 godine. Prema TNM klasifikaciji stadij IV je utvrđen kod 69,3%, stadij III kod 26,73%, te stadij II kod samo 3,96% bolesnika. 73,26% bolesnika imalo je epiteloidni, 4,95% sarkomatoidni, 1% mješoviti te 20,79% NOS (nespecifirani) histološki podtip bolesti. Kirurški je liječeno 14,85% bolesnika, kemoterapijom 55,44%, dok je radioterapija primijenjena kod 9,9% bolesnika. Medijan OS iznosi 11 mjeseci, dok je PFS 10 mjeseci. Prema histološkom podtipu medijan OS iznosio je 11 mjeseci za epiteloidni, 12,5 za NOS te 5,5 za sarkomatoidni, a prema kliničkom stadiju 7 mjeseci za stadij II, 17,5 mjeseci za stadij III te 11 mjeseci za stadij IV. Medijan OS bio je dulji u skupini bolesnika mlađoj od 65 godina (12 naspram 8,5 mjeseci, p=0.28), skupini sa učinjenom pleurodezom (13 naspram 7,5 mjeseci, p=0.06) te u skupini liječenoj kemoterapijom (12,5 naspram 7,5 mjeseci, p=0.10). Očekivano preživljenje bolesnika oboljelih od malignoga pleuralnog mezotelioma u Republici Hrvatskoj u skladu je s podatcima iz literature. Ispitane metode liječenja relativno skromno utječu na preživljenje bolesnika., 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.

Novel hematological parameters such as immature granulocytes (IG), activated neutrophils (NEUT-GI, NEUT-RI) and lymphocytes (RE-LYMP, AS-LYMP) are shown to be valuable for detecting and monitoring infections and inflammations. Our aim was to assess the connection between these parameters and the severity and outcome of COPD exacerbations (AECOPD). 90 patients with AECOPD who visited our pulmonary emergency room from May to August 2018 were included in this retrospective study. Patients’ sex, age, therapy, smoking status, laboratory findings, comorbidities, spirometry results, blood gas analysis, hospitalization or discharge from the ER, duration of hospitalization and survival were evaluated. Hematological parameters were determined by flow cytometry method on a SYSMEX XN-1000 hematological analyzer. Pearson’s correlation test, Chi square and t-test were used for data analysis. 52 patients were male (58%) and 38 female (42%). There were 57 active smokers (64%), 5 former smokers (5.5%) and 28 non- smokers (31%). All patients had comorbidities, mostly hypertension (75, 5%) and diabetes (20%). 19 were admitted to the hospital (21%), and 4 died (4.4%). Correlation between CRP and IG (r=0.363) and NEUT-GI (r=0.230) was low positive, and between CRP and AS-LYMP (r=-0.068), RE-LYMP (r=-0.039) and NEUT-RI (r=-0.251) was low negative. There was no significant difference in these parameters between patients who were discharged from the ER and those who were hospitalized, as well as between patients who died and those who survived. In conclusion, further research on a larger number of patients is required, given these parameters could be promising new biomarkers of inflammation.

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.