Publications by authors named "Marko Jakopovic"

63 Publications

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

Wien Klin Wochenschr 2021 Aug 17. 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
August 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

Treatment patterns and real-world evidence for stage III non-small cell lung cancer in Central and Eastern Europe.

Radiol Oncol 2020 10 11;54(4):447-454. Epub 2020 Oct 11.

Department of Oncology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.

Background The aim of this project was to collect real-world evidence and describe treatment patterns for stage III non-small cell lung cancer in Central and Eastern Europe. Based on real-world evidence, an expert opinion was developed, and the unmet needs and quality indicators were identified. Patients and methods A systematic literature search and a multidisciplinary expert panel of 10 physicians from 7 countries used a modified Delphi process to identify quality indicators and unmet needs in patients with stage III non-small cell lung cancer. The profound questionnaire was used to characterize treatment patterns used for stage III non-small cell lung cancer, and a systematic review identified patterns in Central and Eastern Europe. The first questionnaire was completed by a group of medical oncologists, radiation oncologists and pneumologists. The panel of experts attended an in-person meeting to review the results of the questionnaire and to process a second round Delphi. An additional survey was then compiled and completed by the panel. Results A complete consensus was reached by the panel of experts on a set of evidence-based clinical recommendations. The experience-based questionnaire generated a highly variable map of treatment patterns within the region. A list of unmet needs and barriers to quality care were developed with near-unanimous consent of the panel of experts. Conclusions The current landscape of diagnostic and therapeutic approaches in Central and Eastern European countries is highly variable. We identified several significant barriers, mainly related to the availability of diagnostic and imaging methods and low rates of chemoradiotherapy with curative intention as initial treatment for unresectable stage III NSCLC.
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http://dx.doi.org/10.2478/raon-2020-0058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585343PMC
October 2020

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

Mitochondrial ROS Induce Partial Dedifferentiation of Human Mesothelioma via Upregulation of NANOG.

Antioxidants (Basel) 2020 Jul 10;9(7). Epub 2020 Jul 10.

Department of Pathology, University of Zagreb School of Medicine, 10 000 Zagreb, Croatia.

The expression of pluripotency factors is a key regulator of tumor differentiation status and cancer stem cells. The purpose of this study was to examine the expression of pluripotency factors and differentiation status of human mesothelioma and the role of mitochondria in their regulation. We tested the expression of OCT4/, NANOG, SOX2, PI3K-AKT pathway and BCL2 genes and proteins in 65 samples of human mesothelioma and 19 samples of normal mesothelium. Mitochondrial membrane potential, reactive oxygen species (ROS) generation and expression of pluripotency factors were also tested in human mesothelioma cell line. Human mesothelium and mesothelioma expressed SOX2, NANOG, PI3K and AKT genes and proteins and gene, whereby NANOG, SOX2 and phosphorylated (activated) AKT were upregulated in mesothelioma. NANOG protein expression was elevated in less differentiated samples of human mesothelioma. The expression of genes of PI3K-AKT pathway correlated with pluripotency factor genes. Mesothelioma cells had functional, but depolarized mitochondria with large capacity to generate ROS. Mitochondrial ROS upregulated NANOG and mitoTEMPO abrogated it. In conclusion, human mesothelioma displays enhanced expression of NANOG, SOX2 and phosphorylated AKT proteins, while elevated NANOG expression correlates with poor differentiation of human mesothelioma. Mitochondria of mesothelioma cells have a large capacity to form ROS and thereby upregulate NANOG, leading to dedifferentiation of mesothelioma.
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http://dx.doi.org/10.3390/antiox9070606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402173PMC
July 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

Access to Novel Drugs for Non-Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis.

Oncologist 2020 03 29;25(3):e598-e601. Epub 2019 Nov 29.

Vienna Cancer Center, Medical University of Vienna - General Hospital, Vienna, Austria and Central European Cooperative Oncology Group (CECOG).

Background: Treatment of non-small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune-oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries.

Material And Methods: The Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries.

Results: Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies-even for ALK inhibitors and checkpoint inhibitors in first-line-there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries.

Conclusion: The access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.
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http://dx.doi.org/10.1634/theoncologist.2019-0523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066717PMC
March 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

An extremely rare primary sarcoma of the lung with peritoneal and small bowel metastases: a case report.

World J Surg Oncol 2019 Aug 19;17(1):147. Epub 2019 Aug 19.

Department of Respiratory Diseases, UHC Zagreb, University of Zagreb School of Medicine, Jordanovac 104, 10000, Zagreb, Croatia.

Background: Primary sarcoma of the lung is a very rare malignant tumor accounting for less than 0.5% of all lung tumors and presenting diagnostic and treatment challenge. We describe a case of a patient diagnosed with primary lung undifferentiated pleomorphic sarcoma developing subsequent peritoneal and small bowel metastases, which stand for highly unusual disease presentation.

Case Presentation: A 57-year-old male presented with extensive partially necrotic tumor in the left upper lobe (LUL) of the lung that involved LUL bronchus and extended to the visceral pleura. There was no evidence of nodal or visceral dissemination. After initial presentation, the patient was admitted to the hospital's pulmonology department for further workup. The most likely diagnosis based on biopsy specimen was poorly differentiated sarcoma. Left pneumonectomy with mediastinal lymph node dissection was performed. The final pathohistological diagnosis (PHD) was undifferentiated pleomorphic sarcoma (UPS). Three months after lung surgery, a follow-up CT scan was done which showed a 60-mm obstructive metastatic intraabdominal lesion with small bowel infiltration and further separate peritoneal deposits. Unfortunately, an urgent surgery had to be performed as the patient developed signs of acute abdomen due to bowel perforation. Only 2 months later, the patient passed away at home.

Conclusions: Treatment options of UPS are based on algorithms used in treatment of extremity lesions with well-established role of surgery. However, the role of perioperative chemotherapy remains equivocal with no strong evidence-based data due to the rarity of the disease. Small bowel is an unexpected metastatic site, but of significant clinical relevance.
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http://dx.doi.org/10.1186/s12957-019-1691-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700993PMC
August 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

Prognostic value of cyclin A2 and B1 expression in lung carcinoids.

Pathology 2019 Aug 20;51(5):481-486. Epub 2019 Jun 20.

Medical University of Graz, Diagnostic and Research Institute of Pathology, Graz, Austria.

Carcinoid classification in the lung is still based on morphological criteria. Although there are many studies investigating the role of Ki-67 proliferation index in the classification of lung neuroendocrine tumours, it is still not used in routine diagnostics. Interestingly, cyclins, which have a crucial role in controlling the cell cycle, have not been thoroughly studied in lung neuroendocrine tumours. The aim of our study was to investigate the correlation of cyclin A2 and B1 expression with prognosis, Ki-67 proliferation index, and carcinoid morphology. A cohort of 134 resected typical and atypical carcinoids was stained with antibodies against Ki-67, cyclin A2 and B1. The positive nuclear reaction was assessed in hot spot areas and expressed as the percentage of tumour cells. Univariate analyses found the highest relative hazard between low and high cyclin A2 expression both with respect to overall survival [hazard ratio (HR)=16; 95% confidence interval (CI) 4.8-51; p=0.0000054], and relapse (HR=8; 95% CI 3.1-21; p=0.00002). In multivariate analysis for overall survival cyclin A2 (HR=10; 95% CI 2.5->100; p=0.0082) and B1 (HR=6.5; 95% CI 1.5-35; p=0.02) remained significant when adjusted for other risk factors, whereas Ki-67 was no longer significant (HR=0.64; 95% CI 0.003-5.5; p=0.65). This suggests that Ki-67 is closer to conventional risk factors for survival than cyclin A2 and B1. Furthermore, the analysis revealed 4 mitoses per 2 mm as a more powerful prognostic cut-off than currently accepted 2 mitoses. We have clearly demonstrated that application of cyclin A2 and cyclin B1 might bring additional value regarding the overall and progression-free survival of patients with carcinoids of the lung.
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http://dx.doi.org/10.1016/j.pathol.2019.03.011DOI Listing
August 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

Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial.

Lancet Respir Med 2019 07 15;7(7):569-580. Epub 2019 May 15.

Department of Thoracic/Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.

Background: Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma.

Methods: This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m) plus cisplatin (75 mg/m) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100.

Findings: Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8-7·3) in the nintedanib group and 5·1 months (2·7-7·8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6·8 months [95% CI 6·1-7·0]) and the placebo group (7·0 months [6·7-7·2]; HR 1·01 [95% CI 0·79-1·30], p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]).

Interpretation: The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported.

Funding: Boehringer Ingelheim.
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http://dx.doi.org/10.1016/S2213-2600(19)30139-0DOI 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

Noninvasive determination of the pulmonary artery input impedance.

Med Hypotheses 2018 Nov 9;120:7-13. Epub 2018 Aug 9.

Faculty of Mechanical Engineering and Naval Architecture, University of Zagreb, Ivana Lučića 5, 10000 Zagreb, Croatia.

A reliable noninvasive method for the estimation of pulmonary function in healthy and diseased subjects should be of great importance in the prognosis, diagnosis, and treatment of pulmonary hypertension. Here we propose such a method, which is based on the parameter identification of the five-element Windkessel model of pulmonary circulation. The method requires the following input variables: the heart rate, the stroke volume, the Doppler echocardiographic measurements of the tricuspid regurgitation and the pulmonary valve velocity profiles, and estimations of the right atrium and the pulmonary vein pressure. The stroke volume is calculated as a product of the left ventricle outflow tract area and the velocity-time integral measured at the same place. The model parameter identification procedure is based on minimization of the root mean square error between the pulmonary artery root pressure calculated from the aforementioned Doppler velocity profiles (from the Bernoulli equation applied during the ejection phase) and the pressure from the Windkessel model during the same period. The output from the model contains the calculated pulmonary artery input impedance (i.e. the model parameters: pulmonary vascular resistance, pulmonary artery proximal and distal compliances, inertance, and characteristic impedance) and the pulmonary artery pressure profile during the whole heart period. Our method is applied to a subject with pulmonary hypertension. The right heart Swan-Ganz catheterization has been performed in this subject. The results obtained by using this method show that the five-element Windkessel model reconstructs the main features of the pulmonary artery input impedance very well: its modulus shows the minimum where the phase angle changes its sign. The pulmonary vascular resistance, the systolic, diastolic and mean pulmonary artery pressures obtained from the method are in good agreement with the values obtained invasively from the catheterization. Sensitivity analysis shows that the mean pulmonary pressure is fairly insensitive to slight overestimation/ underestimation of all input parameters, except for the right atrium pressure. The absolute error in the mean pulmonary artery pressure is nearly the same as the error in the right atrium pressure. Since the proposed method offers a deeper insight into the pulmonary circulation than the catheterization itself because it provides the proximal and distal compliance, the inertance and the characteristic impedance, it seems that it can serve in clinical practice as a good substitute for catheterization.
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http://dx.doi.org/10.1016/j.mehy.2018.08.007DOI Listing
November 2018

Expression of plakophilin 3 in diffuse malignant pleural mesothelioma.

Histol Histopathol 2018 Sep 3;33(9):995-1004. Epub 2018 May 3.

Institute of Pathology, University of Zagreb, Zagreb, Croatia.

Diffuse malignant pleural mesothelioma (DMPM) is the most common primary malignant pleural neoplasm still posing major diagnostic, prognostic and therapeutic challenges. Plakophilins are structural proteins considered to be important for cell stability and adhesion in both tumor and normal tissues. Plakophilin 3 is a protein present in desmosomes of stratified and simple epithelia of normal tissues with presence in malignant cells of various tumors where it participates in the process of tumorigenesis. The aim of this study was to investigate the expression of plakophilin 3 protein in DMPM, but also to study its prognostic significance and relation to histologically accessible parameters of aggressive growth. Archival samples of tissue with established diagnosis of DMPM and samples of normal pleural tissue were used. Tumor samples were classified into three histological types of DMPM (epithelioid, sarcomatoid and biphasic). Additional subclassification of epithelioid mesotheliomas into nine patterns based on the prevalent histological component of the tumor was then performed. After immunohistochemical staining, cytoplasmic and membrane immunopositivity of tumor cells was assesed by scoring the intensity of the staining from 0 (no staining) to 4 (very strong staining). Prognostic value and expression of plakophilin 3 with consideration to histologically estimated aggression in tumor growth were then statistically analyzed using non- parametric tests. The results demonstrated higher level of plakophilin 3 expression in tumor samples with histologically more aggressive tumor growth, but no significant prognostic value. According to our study, plakophilin 3 appears to be involved in tumor invasion in malignant mesothelioma.
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http://dx.doi.org/10.14670/HH-11-996DOI Listing
September 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

Dyspnea from Neuropsychyatric Perspective: a Narrative Review.

Psychiatr Danub 2018 Mar;30(1):11-20

University Hospital Center Zagreb, Department for Respiratory Diseases, Jordanovac 104, 10000 Zagreb, Croatia,

Dyspnea or breathlessness is a term primarily used in respiratory medicine. Nevertheless, in the last fifteen years, studies from other fields focus on the affective component of this complex phenomenon due to the frequent observation that psychological states can cause or be caused by dyspnea. Research so far shows that besides the biological component, dyspnea has a strong emotional and psychosocial determinant. This means that apart from its biological factors, dyspnea and its intensity are affected by emotions, personality, anxiety and depression, etc. Individuals with psychiatric disorders, in the same conditions, will evaluate their dyspnea as more intense and disturbing compared to individuals without psychiatric comorbidity. Emotional states in healthy individuals can amplify the sense of dyspnea which is of extreme importance for clinical practice in order to consider the whole person and not just the symptom which is being presented. Also, dyspnea seems to be frequent complaint in some groups of patients with psychiatric disorders (e.g.panic disorder), where the fear of suffocation is presented as clinical symptom. Futher research of dyspnea as a complex, multicomponent phenomenon, can contribute to better treatment options and better differential diagnosis concerning possible psychiatric background of physical symptoms.
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http://dx.doi.org/10.24869/psyd.2018.11DOI Listing
March 2018

QuantiFERON-TB Gold In-Tube Test in the Diagnosis of Latent Tuberculosis Infection in Arthritis Patients Treated with Tumor Necrosis Factor Antagonists.

Acta Clin Croat 2017 Jun;56(2):203-209

Jordanovac Clinical Department of Respiratory Diseases, Zagreb University Hospital Centre.

The aim of this study was to investigate the role of the QuantiFERON-TB Gold In-Tube test (QFT-GIT) in detecting latent tuberculosis in immunocompromised patients before introducing tumor necrosis factor (TNF-α) antagonists. The study included 300 subjects of similar age. The study group comprised of 150 QuantiFERON (QFT) positive subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis, while control group comprised of 150 QFT negative respondents with the same diseases. Exhaustive medical history was documented for all patients. Screening tests were performed including QFT-GIT, tuberculin skin test (TST), chest radiography and detection of Mycobacterium tuberculosisin sputum culture 2 times. A positive QFT-GIT test result, regardless of TST result, was considered as an indication for latent tuberculosis infection (LTBI) treatment. Results of this study showed good correlation between the conclusive results of QFT-GIT and TST. All study group patients had normal clinical findings, normal radiologic findings and negative results of sputum microbiological analysis during the course of prophylaxis and after its completion and during the course of biological therapy. Conversion of positive QFT-GIT test to negative was observed in 4% of study group patients, while QFT negative respondents remained negative. There was a statistically significant positive correlation between QFTGIT, TST results and patient age, smoking habit and contact with tuberculosis. Study results showed that along with good clinical evaluation and detailed medical history, it is important to conduct testing in order to avoid disease progression or unnecessary isoniazid prophylaxis.
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http://dx.doi.org/10.20471/acc.2017.56.02.02DOI Listing
June 2017

Anemia, hypoalbuminemia, and elevated troponin levels as risk factors for respiratory failure in patients with severe exacerbations of chronic obstructive pulmonary disease requiring invasive mechanical ventilation.

Croat Med J 2017 Dec;58(6):395-405

Marina Labor, Department of Pulmonology, University Hospital Center Osijek, Faculty of Medicine, J.J. Strossmayer University of Osijek, 31000 Osijek, Croatia,

Aim: To determine in-hospital and post-discharge mortality, readmission rates, and predictors of invasive mechanical ventilation (IMV) in patients treated at intensive care unit (ICU) due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD).

Methods: A retrospective observational cohort study included all patients treated at a respiratory ICU for AECOPD during one year. A total of 62 patients (41 men) with mean age 68.4±10.4 years were analyzed for outcomes including in-hospital and post-discharge mortality, readmission rates, and IMV. Patients' demographic, hematologic, biochemical data and arterial blood gas (ABG) values were recorded on admission to hospital. Mean duration of follow-up time was 2.4 years.

Results: Of 62 patients, 7 (11.3%) died during incident hospitalization and 21 (33.9%) died during the follow-up. The overall 2.4-year mortality was 45.2%. Twenty nine (46.8%) patients were readmitted due to AECOPD. The average number of readmissions was 1.2. Multivariate analysis showed that blood pH, bicarbonate levels, low albumin, low serum chloride, and low hemoglobin were significant predictors of IMV during incident hospitalization (P<0.001 for the overall model fit).

Conclusion: High in-hospital and post-discharge mortality and high readmission rates in our patients treated due to AECOPD at ICU indicate that these patients represent a high risk group in need of close monitoring. Our results suggested that anemia, hypoalbuminemia, and elevated troponin levels were risk factors for the need of IMV in severe AECOPD. Identification of such high-risk patients could provide the opportunity for administration of an appropriate and timely treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778679PMC
http://dx.doi.org/10.3325/cmj.2017.58.395DOI Listing
December 2017

Incorrect catheter placement for drainage of malignant pericardial effusion.

Lancet Oncol 2016 10;17(10):e467

Jordanovac Clinic for Lung Diseases, University Hospital Centre Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1016/S1470-2045(16)30445-4DOI Listing
October 2016

Analysis of the frequency of EGFR, KRAS and ALK mutations in patients with lung adenocarcinoma in Croatia.

Diagn Pathol 2016 Sep 21;11(1):90. Epub 2016 Sep 21.

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

Background: Many studies have been published on the mutational status of patients with lung adenocarcinomas, and great population-based variability in mutation frequencies has been reported. The main objective of the present study was to analyze the EGFR, KRAS and ALK mutation status in a representative cohort of patients in Croatia with lung adenocarcinomas and to correlate the mutational status with clinical data.

Methods: All patients who were newly diagnosed within 6 months with histologically proven primary lung adenocarcinomas were included. Mutational analyses for EGFR and KRAS mutations were performed in a cobas z 480 analyzer. ALK immunohistochemistry was performed using the D5F3 clone on Benchmark XT instrument. Clinical data were obtained from the medical records.

Results: Of the 324 patients, 59.9 % were male. At the time of diagnosis, the patients ranged in age range from 35 to 88 years (median 63 years). Most of the patients were current smokers or former smokers (77.2 %). EGFR mutations were found in 15.7 % of the patients, and of these mutations, exon 19 deletion was the most common (45.1 %). KRAS mutations were present in 34.9 % of the patients, while 4.1 % of patients were ALK-positive. The statistical significance of the presence of mutations was detected for both gender and smoking.

Conclusion: The detected mutation rates demonstrated a slightly higher prevalence of KRAS mutations, but not a higher prevalence of EGFR mutations or ALK gene rearrangement, in comparison with the rates found in other European countries. EGFR and ALK mutational status showed a statistically significant correlation with gender as well as with smoking, while KRAS mutation status showed a statistically significant correlation only with smoking.
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http://dx.doi.org/10.1186/s13000-016-0544-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031347PMC
September 2016
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