Publications by authors named "Miroslav Samarzija"

69 Publications

Diagnostic, Predictive, and Prognostic Biomarkers in Non-Small Cell Lung Cancer (NSCLC) Management.

J Pers Med 2021 Oct 27;11(11). Epub 2021 Oct 27.

Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia.

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.
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http://dx.doi.org/10.3390/jpm11111102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624402PMC
October 2021

Diagnostic accuracy, sensitivity, and specificity of CT pulmonary artery to aorta diameter ratio in screening for pulmonary hypertension in end-stage COPD patients.

Croat Med J 2021 Oct;62(5):446-445

Kristina Gašparović, Department of Cardiovascular Diseases, University Hospital Center Zagreb, Kišpatićeva 12, 10000 Zagreb, Croatia,

Aim: To determine the diagnostic accuracy of pulmonary artery to aorta ratio in screening for pulmonary hypertension 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 consecutively 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 dysfunction were excluded (n=44).

Results: Sixty-six patients (55.5% men), with a median age of 61, were identified. Median forced expiratory volume during the first second (FEV1) was 34±12, FEV1/forced vital capacity <0.70. Patients with and without pulmonary hypertension had pulmonary artery diameter of 36±7 mm and 27±4.6 mm, respectively (P<0.001). Median pulmonary artery/aorta (PA/A) ratios for patients with and without pulmonary hypertension were 1.05 and 0.81, respectively (P<0.001). PA/A ratio above 0.95 was an independent predictor of pulmonary hypertension with a specificity of 100% and a sensitivity of 74.51% (area under the curve=0.882; standard error=0.041; P<0.001).

Conclusion: PA/A ratio as measured on chest CT images can be used as a screening tool instead of echocardiography.
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October 2021

Overview of Symptoms of Ongoing Symptomatic and Post-COVID-19 Patients Who Were Reffered to Pulmonary Rehabilitation - First Single-Centre Experience in Croatia.

Psychiatr Danub 2021 Spring-Summer;33(Suppl 4):565-571

Clinic for Lung Diseases Jordanovac, University Hospital Centre Zagreb, Jordanovac 104, 10000, Zagreb, Croatia, E-mail:

Background: 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.

Subjects And Methods: 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.

Results: 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.

Conclusions: 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.
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November 2021

Comorbidities and Syndemics in the COVID-19 Age: Challenges and Opportunities for Bringing Separated Branches of Medicine Closer to Each Other.

Psychiatr Danub 2021 Spring-Summer;33(Suppl 4):402-413

Department of Psychiatry and Psychological Medicine, University Hospital Centre Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia,

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.
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November 2021

Weight Gain in Lung Transplantation Patients during the COVID-19 Pandemic in Croatia.

Psychiatr Danub 2021 Sep;33(Suppl 10):137-139

Clinic for Respiratory Disease Jordanovac, University Hospital Center Zagreb, Jordanovac 104, 10000 Zagreb, Croatia.

Background: To determine the effect of lockdown measures on lung transplant patients during the COVID-19 pandemic.

Subjects And Methods: 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.

Results: 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.

Conclusion: 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.
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September 2021

Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells.

J Mol Biol 2021 11 16;433(23):167294. Epub 2021 Oct 16.

Drug Discovery Program, Ontario Institute for Cancer Research, Ontario, Canada; University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.1016/j.jmb.2021.167294DOI Listing
November 2021

Risk factors for nontuberculous mycobacterial pulmonary disease (NTM-PD) in Croatia.

Wien Klin Wochenschr 2021 Nov 17;133(21-22):1195-1200. Epub 2021 Aug 17.

Clinic for Respiratory diseases Jordanovac, University Hospital Centre Zagreb, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1007/s00508-021-01923-xDOI Listing
November 2021

Angiotensin-Converting Enzyme 2 (ACE2) as a Potential Diagnostic and Prognostic Biomarker for Chronic Inflammatory Lung Diseases.

Genes (Basel) 2021 07 9;12(7). Epub 2021 Jul 9.

Laboratory for Advanced Genomics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia.

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.
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http://dx.doi.org/10.3390/genes12071054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306334PMC
July 2021

Prognostic impact of PD-1 and PD-L1 expression in malignant pleural mesothelioma: an international multicenter study.

Transl Lung Cancer Res 2021 Apr;10(4):1594-1607

Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

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 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) 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.
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http://dx.doi.org/10.21037/tlcr-20-1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107750PMC
April 2021

CpG islands in MyD88 and ASC/PYCARD/TMS1 promoter regions are differentially methylated in head and neck squamous cell carcinoma and primary lung squamous cell carcinoma.

Diagn Pathol 2021 Feb 26;16(1):17. Epub 2021 Feb 26.

Division of Molecular Medicine, Laboratory for Advanced Genomics, Ruđer Bošković Institute, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1186/s13000-021-01078-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913417PMC
February 2021

Immunotherapy for thymoma.

J Thorac Dis 2020 Dec;12(12):7635-7641

School of Medicine, University of Zagreb, Zagreb, Croatia.

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.
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http://dx.doi.org/10.21037/jtd-2019-thym-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797835PMC
December 2020

Real-World Safety and Efficacy of Nivolumab in Advanced Squamous and Nonsquamous Non-Small-Cell Lung Cancer: A Retrospective Cohort Study in Croatia, Hungary, and Malta.

J Oncol 2020 29;2020:9246758. Epub 2020 Nov 29.

Department for Respiratory Disease "Jordanovac", University Hospital Center Zagreb, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1155/2020/9246758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738788PMC
November 2020

Lipid profile and atherogenic indices in patients with stable chronic obstructive pulmonary disease.

Nutr Metab Cardiovasc Dis 2021 01 5;31(1):153-161. Epub 2020 Aug 5.

University Hospital Centre Zagreb, Clinical Department for Pulmonary Diseases Jordanovac, Zagreb, Croatia; University of Zagreb, School of Medicine, Zagreb, Croatia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.numecd.2020.07.039DOI Listing
January 2021

Neutrophil-to-lymphocyte ratio can predict outcome in extensive-stage small cell lung cancer.

Radiol Oncol 2020 09 22;54(4):437-446. Epub 2020 Sep 22.

Laboratory for Advanced Genomics, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.

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.
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http://dx.doi.org/10.2478/raon-2020-0054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585340PMC
September 2020

Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup.

Clin Cancer Res 2020 07 21;26(14):3819-3830. Epub 2020 Apr 21.

Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

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 () gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.

Experimental Design: promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for immortalization. The respective MPM cell models ( = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.

Results: 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 promoter mutations were associated with enforced promoter activity and mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. promoter-mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While mutations/deletions were exclusive with promoter mutations, homozygous deletions at the and the loci were clearly enriched in mutated cases.

Conclusions: promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3573DOI Listing
July 2020

Comparative analysis of prognostic histopathologic parameters in subtypes of epithelioid pleural mesothelioma.

Histopathology 2020 Jul 25;77(1):55-66. Epub 2020 May 25.

2nd Institute of Pathology, Semmelweis University, Budapest, Hungary.

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.
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http://dx.doi.org/10.1111/his.14105DOI Listing
July 2020

A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Nat Chem Biol 2020 05 24;16(5):577-586. Epub 2020 Feb 24.

Department for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
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http://dx.doi.org/10.1038/s41589-020-0484-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123931PMC
May 2020

Promoter methylation status of is associated with decreased overall survival and TNM status in patients with early stage non-small cell lung cancer (NSCLC).

Transl Lung Cancer Res 2019 Dec;8(6):1000-1015

Ruđer Bošković Institute, Division for Molecular Medicine, Zagreb, Croatia.

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 and 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 (, P<0.0001; , P<0.0002), which correlates with increased protein expression. Three CpG sites were identified as promising diagnostic marker candidates; CpG11 (-63 position) in and CpG1 (-253 position) and 2 (-265 position) in . The association study showed that the methylation status of the CpG4 site (-34 position) in malignant and non-malignant tissues is associated with the overall survival (P=0.019) and the methylation status of CpG8 site (-92 position) is associated with TNM-stage (P=0.011).

Conclusions: The methylation status of the and promoters are promising prognostic biomarker candidates. However, presented results should be considered as a preliminary and should be confirmed on the larger number of the samples.
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http://dx.doi.org/10.21037/tlcr.2019.12.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976376PMC
December 2019

Ruxolitinib as monotherapy in a patient with anaplastic lymphoma kinase positive lung adenocarcinoma.

Anticancer Drugs 2019 11;30(10):1061-1063

Clinic for Lung Diseases Jordanovac.

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%).
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http://dx.doi.org/10.1097/CAD.0000000000000822DOI Listing
November 2019

Association of Coding Polymorphism with Lung Function and Serum IL-1β Concentration in Patients Diagnosed with Chronic Obstructive Pulmonary Disease (COPD).

Genes (Basel) 2019 10 9;10(10). Epub 2019 Oct 9.

Ruđer Bošković Institute, Division of Molecular Medicine, 10 000 Zagreb, Croatia.

Chronic obstructive pulmonary disease (COPD) is a chronic disease characterized by a progressive decline in lung function due to airflow limitation, mainly related to IL-1β-induced inflammation. We have hypothesized that single nucleotide polymorphisms (SNPs) in genes, coding for key regulators of IL-1β, are associated with pathogenesis and clinical phenotypes of COPD. We recruited 704 COPD individuals and 1238 healthy controls for this study. Twenty non-synonymous SNPs in 10 different genes were genotyped. Genetic associations were estimated using logistic regression, adjusting for age, gender, and smoking history. The impact of genotypes on patients' overall survival was analyzed with the Kaplan-Meier method with the log-rank test. Serum IL-1β concentration was determined by high sensitivity assay and expression analysis was done by RT-PCR. Decreased lung function, measured by a forced expiratory volume in 1 s (FEV% predicted), was significantly associated with the minor allele genotypes (AT + TT) of rs12150220 ( = 0.0002). The same rs12150220 genotypes exhibited a higher level of serum IL-1β compared to the AA genotype ( = 0.027) in COPD patients. rs306481 minor allele genotypes (AG + AA) were more common in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition of group A ( = 0.0083). Polymorphisms in (rs12150220; OR = 0.55, = 0.03) and (rs12462372; OR = 0.36, = 0.03) were only nominally associated with COPD risk. In conclusion, coding polymorphisms in rs12150220 show an association with COPD disease severity, indicating that the fine-tuning of the NLRP1 inflammasome could be important in maintaining lung tissue integrity and treating the chronic inflammation of airways.
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http://dx.doi.org/10.3390/genes10100783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826440PMC
October 2019

ADAPTATION AND VALIDATION OF THE CAMBRIDGE PULMONARY HYPERTENSION OUTCOME REVIEW (CAMPHOR) FOR CROATIA.

Acta Clin Croat 2019 Mar;58(1):3-12

1Department for Lung Diseases, Zagreb University Hospital Centre, Zagreb, Croatia; 2Galen Research, Manchester, UK; 3School of Medicine, University of Zagreb, Zagreb, Croatia; 4Dr. Andrija Štampar Teaching Institute of Public Health, Zagreb, Croatia; 5Faculty of Humanities and Social Science, University of Zagreb, Zagreb, Croatia.

Pulmonary hypertension (PH) is a chronic disease which severely impairs quality of life (QoL). The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first disease-specific tool to assess patient-reported symptoms, functioning and QoL in PH patients. The aim of this study was to adapt and validate the CAMPHOR for use in Croatia. The adaptation process involved three stages: translation (bilingual and lay panel), cognitive debriefing interviews with patients and psychometric validation. For the latter stage, a postal survey was conducted with 50 patients to examine the reliability and validity of the adapted scale. All three scales of the Croatian CAMPHOR demonstrated excellent internal consistency (Symptoms = 0.93; Activity limitations = 0.94; QoL = 0.92) and test-retest reliability correlations (Symptoms = 0.90; Activity limitations = 0.95; QoL = 0.90). Predicted correlations with the SF-36 scales provided evidence for construct validity of the CAMPHOR scales. Evidence for known group validity was shown by the ability of the scales to distinguish between participants based on patient-perceived general health and disease severity. The Croatian version of the CAMPHOR is a valid and reliable tool for use in clinical routine and clinical research.
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http://dx.doi.org/10.20471/acc.2019.58.01.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629211PMC
March 2019

Treatment of EGFR positive lung adenocarcinoma in a heart transplanted patient.

Monaldi Arch Chest Dis 2019 May 30;89(2). Epub 2019 May 30.

Department for Lung Diseases, University Hospital Centre Zagreb.

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.
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http://dx.doi.org/10.4081/monaldi.2019.1023DOI Listing
May 2019

Metastatic cancer mimics interstitial lung disease. Cases when we need fast diagnosis and treatment.

Monaldi Arch Chest Dis 2019 Jun 4;89(2). Epub 2019 Jun 4.

Department for Lung Diseases, University Hospital Centre Zagreb.

Interstitial lung diseases (ILD) are a heterogeneous group of diseases and one of the differential diagnosis which have to be excluded during diagnostic procedures are malignancies. We will present four patients who were referred to our Department because of suspicion of interstitial lung diseases according to radiology finding. In one case only, one of the radiologist's differential diagnosis was pulmonary lymphangitic carcinomatosis. All four patients had exertional dyspnea and dry cough which are nonspecific and can be first manifestation of ILD or obstructive lung diseases. After diagnostic evaluation in three cases, diagnosis was pulmonary lymphangitic carcinomatosis due to metastatic lung adenocarcinoma and in one due to metastatic adenocarcinoma of unknown primary origin. Patients with lymphangitic carcinomatosis have poor prognosis without treatment and usually die because of respiratory failure. With these four cases we want to highlight importance of thinking about malignancies when we have patients with suspicion of interstitial lung disease especially when reticular pattern is present on chest X ray. We also wanted to show how important is radiology finding and multidisciplinary approach, and how radiologist's differential diagnosis can be very helpful in making decisions in further investigations and way of clinicians thinking.
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http://dx.doi.org/10.4081/monaldi.2019.1041DOI Listing
June 2019

Effects of extracellular Hsp70 and cigarette smoke on differentiated THP-1 cells and human monocyte-derived macrophages.

Mol Immunol 2019 07 11;111:53-63. Epub 2019 Apr 11.

University of Zagreb, Faculty of Pharmacy and Biochemistry, Department of Medical Biochemistry and Hematology, Zagreb, Croatia. Electronic address:

Extracellular Hsp70 (eHsp70) can act as pro-inflammatory mediator and is elevated in blood of chronic obstructive pulmonary disease (COPD) patients. Most of those patients are smokers, and it was suggested previously that cigarette smoke might induce Hsp70 secretion from the circulating cells. Therefore, we aimed to explore inflammation-associated effects of cigarette smoke extract (CSE) and its combinations with eHsp70 in monocyte-derived macrophages (MDMs) and THP-1 cell line, used as systemic component models of COPD. We hypothesized that eHsp70 induces inflammation, but that it can also modulate cigarette smoke extract (CSE)-stimulated inflammatory responses. We assessed IL-8 secretion, TLR2, TLR4 and Hsp70 expressions, MAPKs and NF-κB activation, and cytotoxicity after treating the cells with CSE (2.5 and 5%) and its combinations with low-endotoxin recombinant human (rh) Hsp70, used to mimic eHsp70 effects. CSE induced IL-8 secretion from both cell types, but its combinations with rhHsp70 increased IL-8 release compared to CSE alone only from MDMs. In THP-1, combinations of rhHsp70 with 2.5% CSE induced TLR2 and TLR4 mRNA, while 5% CSE decreased TLR2 expression. In MDMs, CSE alone attenuated TLR2, while rhHsp70 increased TLR2 and lowered TLR4 gene expression. Hsp70 mRNA expression was suppressed in THP-1 with rhHsp70 and CSE; however, the same treatments increased its level in MDMs. CSE had cytotoxic effect only on MDMs, but cytotoxicity was reduced in co-treatments with rhHsp70, which also triggered apoptosis. CSE and rhHsp70 activated p38 and JNK, while ERK was activated only by rhHsp70 in MDMs. In THP-1, 2.5% CSE activated ERK, and 5% CSE activated p38. Inhibition of NF-κB and JNK in MDMs, and ERK and JNK in THP-1 cells, attenuated IL-8 release after rhHsp70 treatment. In conclusion, rhHsp70 provoked pro-inflammatory effects and could also modulate inflammatory response to CSE on protein and gene expression levels in THP-1 cells and MDMs, which suggests that eHsp70 might be implicated in systemic inflammation induced by cigarette smoke.
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http://dx.doi.org/10.1016/j.molimm.2019.04.002DOI Listing
July 2019

Hemothorax as the first manifestation of idiopathic pulmonary arteriovenous malformation.

Caspian J Intern Med 2018 ;9(4):406-409

Department of Respiratory Diseases 'Jordanovac', University of Zagreb, School of Medicine, Zagreb, Croatia.

Background: Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies and hemothorax as a presenting feature of PAVM is a very rare occurrence.

Case Presentation: A 45-year old woman presented with chest pain and breathlessness. A chest x-ray showed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation was shown. Diagnostic thoracocentesis revealed hemorrhagic exudate with negative cytology and microbiology findings. Thoracic drainage was performed resulting with complete regression of hemothorax. Three months later, patient was treated with transcatheter embolization of PAVM with good clinical outcome.

Conclusions: We have shown that management of PAVM related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM could lead to a successful outcome.
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http://dx.doi.org/10.22088/cjim.9.4.410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230461PMC
January 2018

Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial.

Lancet Respir Med 2019 03 23;7(3):239-248. Epub 2018 Nov 23.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address:

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 Sàrl.
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http://dx.doi.org/10.1016/S2213-2600(18)30367-9DOI Listing
March 2019

Achieving Thoracic Oncology data collection in Europe: a precursor study in 35 Countries.

BMC Cancer 2018 Nov 20;18(1):1144. Epub 2018 Nov 20.

University of Tirana, Service of Pulmonology, Tirana, Albania.

Background: A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire.

Methods: Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months.

Results: Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses.

Conclusion: Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.
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http://dx.doi.org/10.1186/s12885-018-5009-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247748PMC
November 2018

Serum carbohydrate sulfotransferase 7 in lung cancer and non-malignant pulmonary inflammations.

Clin Chem Lab Med 2018 07;56(8):1328-1335

Našice General Hospital, Našice, Croatia.

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<0.001), but no differences between the overall stages of primary cancers were detected (p=0.828). The differentiation performance in terms of ROC area under curve (AUC) was 0.848 making CHST7 superior biomarker to the NSE (p=0.031). In comparison to CEA and CYFRA 21-1, the performance differences were not detected. CHST7 was not correlated to other biomarkers, and its addition to the routine biomarker panel significantly improved the cross-validated accuracy (85.6% vs. 75.2%) and ROC AUC (p=0.004) of the differentiation using a machine learning approach.

Conclusions: Serum CHST7 is a promising biomarker for the differentiation between lung cancer and non-malignant pulmonary inflammations.
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http://dx.doi.org/10.1515/cclm-2017-1157DOI Listing
July 2018

Nivolumab-induced synchronous occurrence of myositis and hypothyroidism in a patient with squamous cell lung cancer.

Immunotherapy 2018 03;10(6):427-431

Department for Lung Diseases 'Jordanovac', University Hospital Centre Zagreb, Jordanovac 104, 10000 Zagreb, Croatia.

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.
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http://dx.doi.org/10.2217/imt-2017-0174DOI Listing
March 2018
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