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Supplementary Figure S6. Relation between TERT mRNA expression and MPM patient survival in the TCGA dataset.

Supplementary Material and Methods

Supplementary Table S6

Purpose:Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.Experimental Design:TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.Results:TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases.Conclusions:TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.

Supplementary Tables S1 to S9 with the exception of Supplementary Table S6

Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p

Background The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) were analyzed in various carcinomas and their potential prognostic significance was determined. The objective of present study was to determine the correlation between these parameters and the survival of patients with small cell lung cancer (SCLC), since very few studies have been published on this type of carcinoma. Patients and methods One hundred and forty patients diagnosed with SCLC at University Hospital Center Zagreb, between 2012 and 2016 were retrospectively analyzed. Extensive-stage disease (ED) was verified in 80 patients and limited-stage disease (LD) in 60 patients. We analyzed the potential prognostic significance of various laboratory parameters, including NLR, PLR, and LMR, measured before the start of treatment. Results Disease extension, response to therapy, chest irradiation and prophylactic cranial irradiation (PCI), as well as hemoglobin, monocyte count, C-reactive protein (CRP), and lactate dehydrogenase (LDH) showed a prognostic significance in all patients. When we analyzed the patients separately, depending on the disease extension, we found that only skin metastases as well as LDH and NLR values, regardless of the cut-off value, had a prognostic significance in ED. Meanwhile, the ECOG performance status, chest irradiation, PCI, and hemoglobin and creatinine values had a prognostic significance in LD. Conclusions NLR calculated before the start of the treatment had a prognostic significance for ED, while PLR and LMR had no prognostic significance in any of the analyzed groups of patients.

The Corona Virus Disease 2019 (COVID-19) as a unique disaster has stressed the extreme importance of the three issues for medicine, society and humanity in general: comorbidity, pandemic and syndemic. There are many reasons why the study of comorbidities and syndemics of COVID-19 is of great importance for researchers, clinicians and health policy makers who are responsible for health care organization and funding in a bid to develop more effective and efficient prevention and treatment. Thinking about COVID-19 through a syndemics concept and taking biological, psychological, social and spiritual dimensions into account, physicians could be more effective in clinical practice and community-based interventions. The outcome of SARS-CoV-2 infection is determined by the virus-host interaction, with pathogenicity of SARS-CoV-2 being related to the presence of comorbid diseases. The risk for severe COVID-19 clinical manifestations and death increases with age of patients and comorbidity. General mechanisms of multi-system dysfunction and multi-organ damage reported in COVID-19 are probably related to ubiquitous expression of ACE2 in many tissues and its important role in the renin-angiotensin-aldosterone system (RAAS) functioning. Physicians all over the world should be aware of COVID-19 related comorbidities, multisystem disorders and syndemics, as well as treatment and preventive strategies. COVID-19 age is a right time to reconsider the state of science and practice in comorbidity medicine field from the both epistemological and treatment perspective. Comorbidities and multimorbidities are indifferent to medical specializations, so the integrative and complementary medicine is an imperative in the both education and practice. Shifting the paradigm from vertical and mono-morbid interventions to comorbidity, multimorbidity and multi-system disease approaches enhances effectiveness and efficiency of human resources utilization. The aim of this review is to summarize the theoretical concepts and clinical experience and research regarding comorbidity in general, and specifically related to the COVID-19 pandemic, syndemics and infodemic.

Introduction: Lung cancer is one of the most diagnosed malignancies with increasing incidence worldwide. Immunotherapy is the main oncological treatment for advanced non-small cell lung cancer (NSCLC), for which the discovery of new efficient biomarkers is crucial. Scientific evidence points to the importance of the Lung Immune Prognostic Index (LIPI), but its predictive significance is unclear. Aim: The aim of this study was to investigate the clinical significance and predictive role of LIPI in patients with advanced NSCLC and PD-L1 mutation who are eligible for immunotherapy in combination with chemotherapy. In addition, to our knowledge, this is the first time that the association between COVID-19 infection and the course and outcome of oncologic treatment of NSCLC has been investigated. Patients and Methods: Patients were divided into four study groups according to strictly defined clinical parameters, therapeutic approach, and COVID-19 infection. LIPI was determined and its predictive power was evaluated in all studied groups, as well as overall survival (OS), progression-free survival (PFS), and disease control rate (DCR). Results: This study confirmed the understudied and uncertain predictive power and clinical relevance of LIPI as a biomarker in patients with advanced NSCLC. Patients infected with COVID-19 had a higher survival rate than uninfected patients despite the therapeutic approach, which may be attributed to their hospitalization and intensive medical management during the pandemic. Conclusions: Findings obtained in this study may help to determine treatment options according to the clinical condition of the patient by using LIPI values as a non-invasive, readily available and economically acceptable predictive biomarker in lung oncology.

Thymic epithelial tumors (TETs) are rare thymic neoplasms. There are approximately 1.5 cases per million TETs per year. They are the most common anterior mediastinal tumors in adults. Due to limited activity of available treatment options novel strategies and treatment options are needed and treatment with immune checkpoint inhibitors is an attractive option. Thymic epithelial tumors have one of the lowest tumor mutational burden among all cancer in adults, but high expression of PD-L1 on tumor cells and abundant CD8+ lymphocytes provide a strong rational for implementing immune checkpoint inhibitors (ICIs) which target PD-1/PD-L1 pathway in the treatment of TETs. Few small early stage clinical trials were published so far evaluating efficacy of pembrolizumab and avelumab in thymoma and thymic carcinoma patients. Al trials showed reasonable response rates and progression-free survival. Higher PD-L1 expression was predictor of response in all trials. However, increased incidence of immune-related adverse events was seen in TET patients treated with immune checkpoint inhibitors compared to patients with other cancers. At the moment, ICIs are not standard of care for patients with TET and larger trials are needed to establish the right role of ICIs regarding efficacy and safety of these agents.

The nutritional status in chronic obstructive pulmonary disease (COPD) patients is an important factor that influences the prognosis of the disease. The aim of this investigation was to study nutritional status in COPD patients and to investigate the association between nutritional status, disease severity and exercise capacity in four different regions of Croatia. In a multicentre study, 534 patients with COPD were recruited and their demographic characteristics were evaluated. Measurements included body composition by bioelectrical impedance analysis - fat free mass (FFM), fat free mass index (FFMI), sarcopenic index (SI), phase angle (PhA), pulmonary function tests and 6-minute walk test (6MWT). There were 325 (60, 9%) male and 209 (39, 1%) female patients with 66, 7±8, 4 years. FEV1 was 52±19, 3% (males) and 60±23, 8% (females), 6MWT was 396, 5±110, 8m. Body mass index (BMI) was 26, 3±5, 5kg/m2, FFM was 61, 8±10kg (males) and 46±8, 3kg (females), FFMI was 20, 6±2, 8kg/m2 (males) and 18, 6±3, 1kg/m2 (females), SI was 8, 2±1, 4kg/m2 (males) and 6, 9±1kg/m2 (females) with no statistical difference between centres (p=0.313 ; p=0.971 ; p=0.565 ; p=0.860 ; p=0.690 ; p=0.562). PhA was 6±1, 8° (males) and 5, 6±1, 7° (females). There were significant positive correlation of FEV1 with BMI (r=0, 148, p=0, 001), PhA (r=0, 256, p=0, 00), FFM (r=0.365, p=0, 00), SI (r=0, 238, p=0, 00), but no significant correlation of 6MWT with BMI (r=-0, 049, p=0, 254), FFM (r=0.065, p=0, 133) and SI (r=-0, 007, p=0, 867). Data showed that our patients are well-nourished and that there is no significant difference between centres in BMI, FFM, FFMI and SI. There is a significant correlation between nutritional status and disease severity.

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). ----- Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. ------ Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. ----- Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

Aims Malignant pleural mesothelioma (MPM) is a rare malignancy with a dismal prognosis. While the epithelioid type is associated with a more favourable outcome, additional factors are needed to further stratify prognosis and to identify patients who can benefit from multimodal treatment. As epithelioid MPM shows remarkable morphological variability, the prognostic role of the five defined morphologies, the impact of the nuclear grading system and the mitosis-necrosis score were investigated in this study. Methods and results Tumour specimens of 192 patients with epithelioid MPM from five European centres were histologically subtyped. Nuclear grading and mitosis-necrosis score were determined and correlated with clinicopathological parameters and overall survival (OS). Digital slides of 55 independent cases from The Cancer Genome Atlas (TCGA) database were evaluated for external validation. Histological subtypes were collapsed into three groups based on their overlapping survival curves. The tubulopapillary/microcystic group had a significantly longer OS than the solid/trabecular group (732 days versus 397 days, P = 0.0013). Pleomorphic tumours had the shortest OS (173 days). The solid/trabecular variants showed a significant association with high nuclear grade and mitosis-necrosis score. The mitosis-necrosis score was a robust and independent prognostic factor in our patient cohort. The prognostic significance of all three parameters was externally validated in the TCGA cohort. Patients with tubulopapillary or microcystic tumours showed a greater improvement in OS after receiving multimodal therapy than those with solid or trabecular tumours. Conclusions Histological subtypes of epithelioid MPM have a prognostic impact, and might help to select patients for intensive multimodal treatment approaches.

Aim: Alongside the proven efficacy, immunotherapy in treatment of malignant diseases can cause immune-related adverse events different from commonly known chemotherapy-related toxicities. Case presentation: During nivolumab treatment of metastatic squamous cell lung cancer, the patient developed a symptomatic inflammatory myositis confirmed with muscle biopsy and primary hypothyroidism. After initiation of corticosteroids and thyroid hormone replacement, the clinical and laboratory improvement occurred. To the best of our knowledge, this is the first description of a case of nivolumab-induced synchronous manifestation of immune-related myositis and hypothyroidism. Conclusion: Immunotherapy can trigger a wide spectrum of immune-related adverse events that could occur simultaneously. If not detected and treated, these events could become severe or even fatal and require clinicians’ awareness and routine check-ups.

Adie's syndrome (AS) and paraneoplastic sensorimotor neuropathy with cerebellar ataxia (PSN CA) are extremely rare, rapidly progressive, autoimmune diseases associated with the development of antibodies against neuronal- specific Hu proteins that are abnormally expressed in small-cell lung cancer (SCLC). We herein present the unique case of a 55-year-old obese woman, previous heavy smoker, who, during treatment with standard cisplatin-etoposide chemotherapy for limited-stage SCLC, developed simultaneous AS and worsening symptoms consistent with PSN CA that led to significant neurological disability and severe axonal electrophysiological pattern on nerve conduction studies. Serology confirmed the presence of low- titre type 1 antineuronal nuclear antibodies (ANNA-1), previously referred to as anti-Hu antibodies. Following plasmapheresis, immunosuppressive therapy and physical rehabilitation, the neurological symptoms progressively improved. The tumour completely regressed, with no recurrence detected on subsequent radiological examinations. The aim of this case was to highlight the importance of a multidisciplinary team approach for early recognition and rapid treatment of paraneoplastic neurological syndromes (PNS) as key to achieving significant recovery and marked improvement of the neurological deficit. This report extends the literature by confirming earlier studies showing that the presence of serum ANNA-1 in SCLC, an aggressive type of pulmonary carcinoma that is challenging to treat, may portend a more favourable prognosis and response to chemotherapy. Thus, patients with SCLC and new-onset neurological symptoms should be tested for ANNA-1. The role of a multimodality approach to treating PNS is also emphasized.

Purpose: Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns. Experimental Design: TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays. Results: TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases. Conclusions: TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.

Introduction: guidelines for nontuberculous mycobacterial pulmonary disease (NTMPD) treatment are mainly based on cohort studies and data on M. avium complex (MAC). Methods: retrospective analysis of all Croatian residents with respiratory NTM isolate from 2006 to 2016. ATS/IDSA guidelines were used for NTMPD definition. Cure was defined as multiple negative cultures at the end of treatment or at 12 months follow-up in case of shorter regimens. Regimens were grouped as: tuberculosis (TB), adequate NTM (NTM)

Lung cancer incidence in heart transplant patients is higher than in general population and correlates with smoking history. EGFR-mutations are more frequent in adenocarcinoma and among non-smoking women but incidence in solid organ transplanted patients is still not known. We present case of a 65-year-old ex-smoker male with history of heart transplantation and EGFR positive metastatic lung adenocarcinoma. At admission he was in a severe clinical condition and treatment with erlotinib was started. Initially he had good clinical and radiologic response to treatment with only grade 1 side effects. Data about drug interactions between cyclosporine and erlotinib are insufficient but we have to take this interaction into consideration during treatment because both drugs are substrates and inhibitors of CYP34A. In our case erlotinib was safe and well tolerated drug, there were no relevant toxicity, but close monitoring and dose reduction of cyclosporine was needed.

e21110 Background: In extensive stage small-cell lung cancer (ES-SCLC) immune check-point inhibitors, atezolizumab and durvalumab, when combined with chemotherapy in the first-line setting show better efficacy than chemotherapy alone with safety profile similar as the adverse events of individual agents. Methods: We administered atezolizumab, etoposide and platinum, either carboplatin or cisplatin, in the first-line treatment in 24 newly diagnosed patients with ES-SCLC. Patients were treated until disease progression or unacceptable toxicity. Results: Out of 24 treated patients 13 were males and 11 were females, median age 61 (ranging from 44 to 80). Majority of patients were ECOG 1. Median number of atezolizumab doses was 8 (ranging from 2 to 11). We observed median progression free survival of 6 months (95%CI 4,28-7,72), while median overall survival was not reached. 10 patients (41%) are still undergoing treatment and 9 patients (37%) have died. Immune-related adverse events occurred in 6 patients (25%). Four patients developed pneumonitis (all of them CTCAE grade 2), two patients colitis (CTCAE grade 2 and 3) and one patient rash, CTCAE grade 3. Median treatment pause was 5 weeks (ranging from 3 to 12 weeks). There were no treatment discontinuations due to adverse events nor treatment related deaths. Conclusions: Atezolizumab combined with chemotherapy in ES-SCLC showed good tolerability and effectiveness in real world setting. Our data are consistent with published clinical trial data. There was no new safety signal in our patient cohort. Limitations of our report are small sample size and short follow-up time.

Summary Background Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting. Methods In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150–400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636. Findings From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI −13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions. Interpretation Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment. Funding SciPharm Sarl.

Introduction: Global spread of carbapenem- resistant Enterobacteriacea is a critical healthcare challenge due to limited therapeutic options. We report a nosocomial outbreak of OXA- 48-producing Klebsiella pneumoniae in respiratory intensive care unit. Aims and Objectives: To investigate the outbreak of carbapenem-resistant K. pneumoniae using molecular methods and clinical data. Methods: All K. pneumoniae isolates were identified by MALDI-TOF mass spectrometry. Antimicrobial susceptibility was performed according to the European Committee on Antimicrobial Susceptibility Testing guidelines. Presence of the blaOXA-48 gene was detected by polymerase chain reaction. Molecular typing was performed with pulsed-field gel electrophoresis. Results: During November and December 2016, eight patients with OXA-48-producing K. pneumoniae isolates in BAL were identified. In all strains MIC for imipenem, meropenem and colistin was 4 µg/mL, 8 µg/mL, and 0, 25 µg/mL, respectively. Epidemiological data revealed that the first positive patient was transfered from foreign country. Typing of isolates showed that they were highly related. In all patients the same bronchoscope was used. The bronchoscope solutions taken for microbiological analysis remain negative. The usage of the suspected bronchoscope was discontinued and the outbreak was suspended. Conclusion: There are many potential modes of nosocomial infections transmission in ICU. Bronchoscopy should always be taken in to the consideration if oubreaks occur even without microbiological confirmation. Our report emphasizes the importance of careful bronchoscope reprocessing and introducing of single-use bronchoscopes as a possible solution.

Background: Significantly lower quality of life in transplanted patients has been reported in the domains of physical functioning, pain and health. [1] Aims: Are there any statistically significant difference among patients after lung transplantation and the general population in: 1) intensity, nature and quality of the pain 2) degree of the pain which interferes with the performance of various activities. Method: A prospective trial was conducted from Apr to Aug 2017 on a sample of patients after lung transplantation(N=30) and individuals from the general population–control group(N=30), to determine presence of pain in patients after lung transplantation. Criteria for the selection of transplanted patients: monitored by our clinic, 18–65 years of life, criteria for the control group to suit a group of transplanted by: age, sex and education. We used the following measuring instruments: painDETECT, Brief Pain Inventory. Results: 1)There was a statistically significant difference in the nature of the pain between study and control group, but no significant difference in intensity and quality of pain. 2)Brief Pain Inventory equally has been perceived by study and control groups. Conclusion: Transplanted patients had presence of pain that was different in its nature, but degree of the pain which interferes with the performance of various activities does not show statistically significant differences between the study and control group. Perhaps it can be assumed due to the strict rules of the lifestyle after lung transplantation in these patients, but further research are needed.

Objectives: Lung transplantation is a complex, high- risk, potentially life-saving therapy for the patient with the end-stage of cystic fibrosis (CF). The decision to pursue transplantation involves comparing the likelihood of survival with and without transplantation as well as assessing the effect of wait-listing and transplantation on the patient's quality of life. The aim of this study was to examine is there a difference in psychological status between CF patients who have not been transplanted and CF lung transplant recipients. Methods: Two patient groups, adult CF patients (N=22) and adult CF lung transplant recipients (N=6), participated in our study. The patients completed Patient Health Questionnaire-9 (PHQ 9) and the Generalized Anxiety Disorder 7-item scale (GAD 7). These data were compared to health status data, including pulmonary function testing and nutritional status measures. Results: In adult CF group, 52% of patients had mild to moderate anxiety and 95% mild to moderate depression. In adult CF lung transplant recipients group, 17% of subjects had minimal anxiety and 83% had minimal depression. Conclusion: In this study we find significant difference in the level of anxiety and depression between CF patients who have not been transplanted and CF lung transplant recipients. Lung transplantation in CF patient significantly contributed to the improvement of the psychological condition and quality of life.

Objectives: Living with chronic illness such as cystic fibrosis (CF) is accompanied by medical and psychological difficulties. To identify and treat depression and anxiety in CF, the CF Foundation and the European CF Society invited a panel of experts, including physicians, psychologists, psychiatrists, nurses, social workers, a pharmacist, parents and an individual with CF, to develop consensus recommendations for clinical care. The aim of this study was to assess anxiety and depression by using validated mental health survey data. Methods: CF patients were recruited from adult CF centre in Zagreb, Croatia from October 2016 to December 2017. 22 patients (13 female, 9 male, mean age 24, 18-33 years) completed the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder 7-item scale (GAD-7). Results: 82% and 59% of our patients had a normal anxiety and depression score (0-4), 41% of patients have symptoms of anxiety, and 18% of the patients have symptoms of depression (score between 5 and 9). No one had any serious anxiety and/or depression present. Conclusions: Anxiety and depression are serious complication of chronic illnesses such as cystic fibrosis. Our results highlight the need for improved early identification and management strategies for psychological illnesses in adult CF patients. Research efforts are needed to identify effective strategies for delivering anxiety and depression treatment in CF patients and to assess their risks and benefits. Furthermore, strategies that help patients maintain or even improve lung function may be an interesting topic for further studies to learn more about resources and successful coping strategies.

The deregulation of activin expression is often observed in various malignancies. Previous studies indicate that activin A plays a protumourigenic role in malignant pleural mesothelioma (MPM). The aim of the study was to evaluate circulating activin A level as a biomarker in MPM.Plasma samples were collected from 129 MPM patients in four institutions at the time of diagnosis or before surgical resection. Samples from 45 healthy individuals and from 16 patients with non-malignant pleural diseases served as controls. Circulating activin A was measured by enzyme-linked immunosorbent assay and correlated to clinicopathological variables.Plasma activin A level was significantly elevated in MPM patients (862 ± 83 pg/ml) when compared to healthy controls (391 ± 21 pg/ml; P 0.0001). Patients with pleuritis or fibrosis only showed a modest increase (versus controls; 625 ± 95 pg/ml; P = 0.0067). Sarcomatoid (n = 10, 1629 ± 202 pg/ml, P = 0.0019) and biphasic (n = 23, 1164 ± 233 pg/ml, P = 0.0188) morphology were associated with high activin A levels when compared to epithelioid histology (n = 94, 712 ± 75 pg/ml). The tumour volume showed a positive correlation with increased circulating activin A levels. MPM patients with below median activin A levels had a significantly longer overall survival when compared to those with high activin A levels (median survival 735 versus 365 d, P 0.0001). Importantly, circulating activin A levels were exclusively prognostic in epithelioid MPM.Our findings suggest that the measurement of circulating activin A may support the histological classification of MPM and at the same time help to identify epithelioid MPM patients with poor prognosis.

Background: This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients and methods: Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m2 on day 1) was administered alone or with ganetespib (150 mg/m2 on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Results: Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Conclusion: Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Introduction: Aims of the research was to determine: 1)The distribution of respondents by categories OSA according to measured value AHI, 2)OSA in interaction with specific cardiovascular outcomes. Method: These are the results for the year 2008 to 2010. The target group were all patients who came to the OSA treatment (N=277). OSA has been defined as negative AHI30. In each respondents, we recorded the AHI, BMI, age, sex, comorbidities. AHI is a result of polysomnography (PSG). All respondents made a complete full night PSG (ALICE IV or LE 5 Respironics). Results: 1)The distribution of respondents by categories OSA according to measured value AHI ; respondents with AHI30(32%) (N=277). 2)Display distribution of respondents by categories OSA according to measured value AHI with certain medical conditions (N=277): arterial hypertension ; AHI30(82%), cor hypertonicum ; AHI30(19%), history of myocardial infarction ; AHI30(7%), history of stroke ; AHI30(6%). Conclusion: We have demonstrated a high prevalence OSA in respondents. We noted that arterial hypertension and cor hypertonicum were in correlation with the degree of OSA. History of myocardial infarction and stroke reach their peak in study group with AHI 15–30, although this conditions were much higher present in overall respondents with OSA compered to respondents without OSA. We have confirmed by increasing degree of OSA increases the percentage of specific cardiovascular outcomes.

Background. Holistic scope in treating persons with chronic respiratory diseases is one of the main features of pulmonary rehabilitation program (PRP) at Zagreb University. Interventions are provided by a team made of physicians and other health care professionals - physiotherapists, respiratory therapists, nurses, psychologists, occupational therapists, social workers, behavioral specialists, among others. The program itself is tailored to attend to each person's specific needs through careful interdisciplinary examination and treatment planning, establishing commom ground to address disease severity, respiratory symptoms, comorbidities, psychological manifestations and specific limitations a person has in everyday activities. The focus of PRP is the whole person rather than just a person's disease.Aim. To show the impact of PRP's person-centered approach on patient's quality of life (QoL), anxiety, depression and stress levels.Method. Questionnaires designed to measure quality of life (single question scale), anxiety, depression and stress (DASS21) were administred to 54 patients at the beginning and at the end of a three-week pulmonary rehabilitation program. Each patient underwent an individualized program of education, respiratory exercises, nutrition consultation, and psychosocial/behavioral support and intervention.Results. Results showed significant improvement in all measured parameters – higher overall QoL (p

Background: Is there a statistically significant difference in quality of life between the patients after lung transplantation and the general population. Aim: To compare quality of life in patients after lung transplantation and individuals of general population. Method: A prospective trial was conducted at the Clinic for lung diseases on a sample of patients after lung transplantation (N=30) and individuals from the general population – control group (N=30), in order to determine quality of life of patients after lung transplantation. These are the results from April to July 2016. Criteria for the selection of transplanted patients: monitored by our clinic and 18 – 65 years of life, while the criteria for the control group to suit a group of transplanted by: age, sex and education. For the study were used the following measuring instruments: SF36 Questionnaire, Personal Wellbeing Index (PWI) and Questionnaire on demographic and socioeconomic characteristics of the respondents. Results: 1) There was no significant difference between the study and control groups. Personal level of wellbeing equally has been perceived by transplanted and control groups. 2) Component Score SF-36: Significantly lower quality of life in transplanted patients has been reported in the domains of physical functioning, pain and health. Conclusion: The quality of life of transplanted patients and subjects from the general population does not show statistically significant differences. Comparing the quality of life of these two groups came to the conclusion that respondents from the general population state better results only in the domain of physical health.

Background: It is well known that acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with increased morbidity, readmission rates and mortality, but few studies report rehospitalization and mortality rate after severe AECOPD treated in intensive care unit (ICU). The aim of our study was to assess two year readmission rates and mortality in AECOPD patients treated in ICU and to identify determinants of these outcomes. Methods: 55 patients (35 men) mean age 68.1 (±10.5) years successfully treated in respiratory ICU due to AECOPD and discharged from hospital were included in the study. Patients demographics, hematology, biochemistry and arterial blood gases on the first treating day were recorded. Results: During the median follow-up of 2.4 years, 29 (46.8%) patients had one or more readmissions due to AECOPD. The average number of readmissions was 1.2. Significant predictors for the time to next hospitalization were initial PaCO2, fibrinogen, proteins and alpha 2 globulins (p=0.001 for the overall model fit). Significant predictors for the number of readmissions were: age at admission, neutrophil count, serum sodium, bilirubin, coronary artery disease (p=0.001 for the overall model fit). During the follow-up, 21 (38.2%) patients died. Significant predictors for survival time after incident hospitalization were: BMI, monocyte count, serum LDH, cancer and hypertension (p

Introduction: Brain metastasis (BM) develops in about 50% of all patients with non-small cell lung cancer (Baik, C.S. et al. J Thorac Oncol 2015; 10(9): 1268-1278). Although targeted therapies with tyrosine-kinase inhibitors (TKI) are effective in systemic disease control of patients harbouring epidermal growth factor receptor (EGFR+) mutations, BM remains a clinical challenge. In Croatia, TKI is permitted in second line therapy for EGFR+ patients. Aims and Objectives: The purpose of this study was to investigate the clinical characteristics and overall survival (OS) between EGFR+ lung adenocarcinoma patients with and without BM. Methods: A retrospective review of the medical records for all patients with lung adenocarcinoma who underwent screening for EGFR mutations during 2014 until October 2015 was conducted. Results: A total of 116 EGFR+ patients were included. Most patients did not have BM (n= 92, 79.3%). In both BM and non-BM groups, the majority of EGFR+ patients were younger than 65 years of age, females, former-smokers or never-smokers, initially presented to the emergency department, and were in advanced stage (III/IV) at time of diagnosis of primary lung cancer. Oral TKI treatment was received by 33.3% of BM patients (n=8) and 50.6% (n=40) of non-BM patients in second line after progression of disease on standard chemotherapy. There was no significant difference (p = 0.133) in mOS between BM (20.1 months; censored n=7) and non-BM patients (19.7 months; censored n=41). Conclusions: In BM and non-BM EGFR+ patients, late stage of disease at presentation, as well as TKI in second line, may contribute to the similar clinical outcome.

Background: clinical relevance of M. xenopi in Croatia seems to differ to other countries. Aims and objectives: to assess clinical relevance of M. xenopi, and differences between patients colonized with M. xenopi and those with M. xenopi pulmonary disease (PD) and identify factors that may favor the disease. Methods: Retrospective analysis of all Croatian residents with pulmonary M. xenopi isolated in the period from 2006 to 2016. American Thoracic Society guidelines were used to establish the definition of M. xenopi PD or colonization. Results: medical records were available for 188/326 (57.7%) patients with M. xenopi isolate. Of those 188, 48 had certain PD, and 117 had no disease. Out of 117 classified as no disease, 20 cases of active tuberculosis (TB) co-infection were excluded from further risk analysis. Overall median follow up was 47 month. Patients with low body mass index (BMI), bronchiectasies, or inhalation corticosteroid (ICS) therapy had 6 (p

8505 Background: Multi-lineage myelosuppression is an acute toxicity of cytotoxic chemotherapy leading to hematologic adverse events and dose reductions and delays. Current therapies are lineage specific and administered after chemotherapy damage.Trilaciclib (T), a highly selective, reversible CDK4/6 inhibitor, is designed to preserve hematopoietic stem and progenitor cells and immune system function during chemotherapy (myelopreservation). We have shown that T mitigates myelosuppression in patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) receiving 1st-line chemotherapy. Methods: In this blinded, placebo-controlled, multicenter Phase 2 study, patients with previously treated ES-SCLC were randomized to T (240 mg/m2) + 0.75 mg/m2 topotecan, T (240 mg/m2) + 1.5 mg/m2 topotecan, or placebo (P) + 1.5 mg/m2 topotecan IV on days 1-5 of 21-day cycles. Patients had access to standard supportive care, except in cycle 1 where prophylactic growth factors were not allowed. Eligible patients had adequate organ function, measurable disease, ECOG PS 0-2, and disease progression during or after prior 1st/2nd-line chemotherapy. Objectives included safety, tolerability, measures of myelosuppression and tumor efficacy. Results: 91 patients were randomized: 30 patients received T + 0.75 mg/m2 topotecan, 32 patients received T + 1.5 mg/m2 topotecan and 28 patients received P + 1.5 mg/m2 topotecan. In patients receiving 1.5 mg/m2 topotecan, T treatment reduced occurrence [40.6% (T) vs 75.6% (P), p = 0.016], and duration in cycle 1 [2 days (T) vs 8 days (P), p = < 0.0001] of severe neutropenia. T-treated patients had fewer RBC transfusions on/after 5 weeks on study, GCSF administrations, and all-cause dose reductions. Chemotherapy efficacy was comparable in both arms (P and T) treated with 1.5 mg/m2 topotecan (median PFS (T) 4.2 months vs (P) 4.2 months, HR = 0.83). OS data is immature. Conclusions: T combined with topotecan mitigated chemotherapy-induced myelosuppression and improved tolerability of topotecan vs P. Results suggest the addition of T to cytotoxic chemotherapy for the treatment of ES-SCLC is clinically beneficial. Clinical trial information: NCT02514447.