Veljko Flego

Interferon-γ Gene (T874A and G2109A) Polymorphisms Are Associated With Microscopy-positive Tuberculosis

Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon‐γ (IFN‐γ) gene IFNG T+874A and IFNG G+2109A correlate with the IFN‐γ production in vitro, and the frequency of potential high IFN‐γ producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN‐γ gene and predisposition to tuberculosis. We analysed two IFNG SNPs (T+874A and G+2109A) in patients (n = 253) hospitalized in Rijeka (Croatia) and controls (n = 519) from the same area. One‐fifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case‐control study. However, T/T+874 (possible high IFN‐γ producer) and +874A/A (putative low producer) genotypes were associated with microscopically positive–negative forms of disease. Haplotypes (T+874A and G+2109A) based on a prediction by software phase and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at +874 (AA/AA; AA/AG and AG/AG) in microscopy‐ or bacterial culture‐positive groups compared with their negative counterparts. These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.

Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism in Lung Cancer Patients

Lung cancer is a complex disease, and many factors, including environmental and occupational exposure, cigarette smoking, and genetics, contribute to its progression. Angiotensin-converting enzyme (ACE) is an important regulator of blood pressure and cardiovascular homeostasis. Plasma levels of ACE depend on an insertion/deletion (I/D) polymorphism in its gene. Current correlation data between lung cancer and the ACE I/D polymorphism are contradictory or insufficient. We investigated whether the ACE I/D polymorphism is associated with a risk for lung cancer development in the Croatian population, representing the first report in a population of Slavic origin. A total of 308 lung cancer patients and 353 control subjects were genotyped for the ACE I/D polymorphism by polymerase chain reaction. The observed distribution of genotypes and alleles showed no significant difference between total patients and controls (p>0.050). However, in a subgroup of nonsmall cell lung cancer patients with squamous cell carcinoma, a significantly higher frequency of the DD genotype (37.7% vs. 27.8%, p=0.030, OR=1.57, 95% CI=1.05-2.36) and D allele was observed compared with the control group (61.3% vs. 52.8%, p=0.015, OR=1.41, 95% CI=1.07-1.87). The DD genotype of ACE may contribute to a higher risk of developing squamous cell carcinoma in the Croatian population.

Tumor necrosis factor-alpha gene promoter -308 and -238 polymorphisms in patients with lung cancer as a second primary tumor

Background Lung cancer is the most common second primary cancer. We investigated whether the TNF-α-308 and TNF-α-238 polymorphisms were associated with the susceptibility and severity of lung cancer as the second primary cancer (LC2). Material/Methods This study included 104 patients from the group LC2. The control subjects included 2 groups. The first control group (LC1) comprised 201 unrelated patients with lung cancer as a first primary cancer. The second control group (HC) comprised 230 healthy blood donors, matched for sex and age to the study group. Results The frequencies of the TNF-α-238 polymorphism GG genotype and the G allele were higher in the LC2 group than in the LC1 group, but the differences did not reach significance (p=0.054 and p=0.057, respectively). Similar differences were found in the TNF-α-238 polymorphism GG genotype and G allele between the LC2 group and the HC group (p=0.054 and p=0.057, respectively). In terms of the different types of lung cancer, patients with a second primary NSCLC (non-small cell lung cancer) more frequently had TNF-α-238 polymorphism GG genotypes and G alleles than patients with a first primary NSCLC (the differences approached statistical significance: p=0.060, p=0.064, respectively). All (100%) patients of group LC2 (n=104) had the GG genotype and the G allele. GG genotype was exclusive and no A allele was found in group LC2. Conclusions TNF-α-238 polymorphism GG genotype and the G allele could have a promotional effect on the development of NSCLC in the group of patients with LC2.

Association of the FAM46A gene VNTRs and BAG6 rs3117582 SNP with non small cell lung cancer (NSCLC) in Croatian and Norwegian populations

We analyzed for associations between a variable number of tandem repeat (VNTR) polymorphism in the Family with sequence similarity 46, member A (FAM46A) gene and a single nucleotide polymorphism (rs3117582) in the BCL2-Associated Athanogene 6 (BAG6) with non small cell lung cancer in Croatian and Norwegian subjects. A total of 503 (262 Croatian and 241Norwegian) non small cell lung cancer patients and 897 controls (568 Croatian and 329 Norwegian) were analyzed. We found that the frequency of allele b (three VNTR repeats) of FAM46A gene was significantly increased in the patients compared to the healthy controls in the Croatian and the combined Croatian and Norwegian subjects. Genotype frequencies of cd (four and five VNTR repeats) and cc (four VNTR repeats homozygote) of the FAM46A gene were significantly decreased in the patients compared to the healthy controls in the Croatian and Norwegian subjects, respectively. Logistic regression analyses revealed FAM46A genotype cc to be an independent predictive factor for non small cell lung cancer risk in the Norwegian subjects after adjustment for age, gender and smoking status. This is the first study to suggest an association between the FAM46A gene VNTR polymorphisms and non small cell lung cancer. We found also that BAG6 rs3117582 SNP was associated with non small cell lung cancer in the Norwegian subjects and the combined Croatian-Norwegian subjects corroborating the earlier finding that BAG6 rs3117582 SNP was associated with lung cancer in Europeans. Logistic regression analyses revealed that genotypes and alleles of BAG6 were independent predictive factor for non small cell lung cancer risk in the Norwegian and combined Croatian-Norwegian subjects, after adjustment for age and gender.

Pericardial effusion as the first manifestation of occupational tuberculosis in a health care worker

Abstract Tuberculosis (TB) is an infectious disease and, apart from protecting patients, attention must be given to protecting the persons who come in contact with them, especially nurses and medical practitioners. A 43-yearold immunocompetent male nurse developed occupationally disseminated TB after contact with patients affected by active TB (culture positive) while working in a psychiatric hospital. The first manifestation of the disease was exudative pericarditis with Mycobacterium tuberculosis (MT) confirmed two months after pericardiocentesis and evacuation of 1200 mL of pericardial effusion. Many lymph nodes showed histologic findings of granulomatous inflammation with necrosis. Treatment with antituberculosis drugs caused complications, including transient short-term medication-induced toxic hepatitis, prolonged fever, left pleural nonspecific effusion, and mononeuritis of the right peroneus nerve. The treatment lasted 14 months and led to permanent consequences, including fibrothorax with restrictive ventilation disorders and reduced diffusion of the alveolar-capillary membrane. This case highlights the need to improve the protection of health care workers who are in contact with TB patients, as well as the usefulness of the tuberculin skin test and QuantiFERON-TB test, which can be used to identify early latent TB Sažetak Tuberkuloza (TBC) zarazna je bolest, stoga je prijeko potrebno zaštititi ne samo bolesnike nego i osoblje koje dolazi u kontakt s njima, u prvom redu medicinske sestre i liječnike. Nakon kontakta s bolesnicima oboljelima od TBC-a (u kulturama pozitivne) 43-godišnji imunokompetentni medicinski tehničar, zaposlen u psihijatrijskoj bolnici, obolio je od profesionalnog diseminiranog TBC-a. Prva manifestacija bolesti bio je eksudativni perikarditis s dokazanim Mycobacterium tuberculosis (MT), dva mjeseca nakon perikardiocenteze i evakuacije 1200 mL perikardijalnog izljeva. Histološki nalaz limfnih čvorova na više lokalizacija pokazivao je granulomatoznu upalu s nekrozom. Liječenje antituberkuloticima bilo je praćeno komplikacijama. Došlo je do prolaznog, kratkotrajnog, medikamentozno toksičnog hepatitisa, dugotrajnog febriliteta, nespecifičnog ljevostranog pleuralnog izljeva i mononeuritisa desnog peronealnog živca. Liječenje je trajalo 14 mjeseci. Kao trajna posljedica razvio se fibrotoraks, koji je doveo do restriktivnih smetnji ventilacije i smanjene difuzije alveolarno-kapilarne membrane. Ovaj slučaj upozorava na potrebu poboljšanja zaštite zdravstvenih radnika koji su u kontaktu s oboljelima od tuberkuloze, kao i korisnost tuberkulinskog kožnog testa i QuantiFERON-TB testa, koji mogu rano otkriti latentni TBC

Diagnostic value of tumour markers in pleural effusions

Introduction We investigated whether tumour markers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cancer antigen 125 (CA-125), and cytokeratin 19 fragment (CYFRA 21-1) in pleural effusions and serum can be used to distinguish pleural effusion aetiology. Materials and methods During the first thoracentesis, we measured pleural fluid and serum tumour marker concentrations and calculated the pleural fluid/serum ratio for patients diagnosed with pleural effusion, using electrochemiluminescence immunoassays. Receiver operating characteristic (ROC) analysis was carried out and the Hanley and McNeil method was used to test the significance of the difference between the areas under ROC curves (AUCs). In order to detect which tumour marker best discriminates between malignant and non-malignant pleural effusions and to establish the predictive value of those markers, discriminant function analysis (DFA) and logistic regression analysis were utilized. Results Serum tumour markers CYFRA 21-1 and NSE as well as pleural NSE were good predictors of pleural effusion malignancy and their combined model was found statistically significant (Chi-square = 28.415, P < 0.001). Respective ROC analysis showed significant discrimination value of the combination of these three markers (AUC = 0.79). Conclusions Serum markers showed superiority to pleural fluid markers in determining pleural fluid aetiology. Serum CYFRA 21-1 and NSE concentrations as well as pleural fluid NSE values had the highest clinical value in differentiating between malignant and non-malignant pleural effusions. The combination of these three markers produced a significant model to resolve pleural effusion aetiology.

Pulmonary Histiocytic Sarcoma: A Case Report and Literature Review

Pulmonary histiocytic sarcoma is a rare, but highly malignant disease. Its low incidence imposes significant difficulties on physicians confronted with affected patients. The reported patient is a 24-year old male with histiocytic sarcoma of the lung. Left lower lobectomy was performed. Histologically, tumor cells had no features of carcinoma. Several entities were raised as differentials: large B or T cell lymphomas, metastatic melanoma, sarcoma, undifferentiated carcinoma, NK cell lymphoma. Immunohistochemically, melanoma, carcinoma, undifferentiated epithelioid sarcoma and also different types of lymphoma were excluded. Therefore, tumors of the histiocytic and dendritic cell lineage had to be considered. Tumors of the dendritic cell lineage were also immunohistochemically excluded, leaving histiocytic sarcoma by exclusion. The patient was followed for six years and six months, with no signs of recurrence of the tumor. Histiocytic sarcomas are tumors of uncertain behavior, with some progressing quickly, and others having a much slower course. As these tumors are rare, there is not much information, although a low number of mitosis might point to a less aggressive course. In the present patient with an unifocal disease, surgical excision was sufficient, without adjuvant radiotherapy and chemotherapy.

Primary spontaneous pneumothorax and mitral valve prolapse are not associated

ZusammenfassungEINLEITUNG: Mitralklappenprolaps ist eine häufige Diagnose bei Patienten mit primärem Spontanpneumothorax. Es wird davon ausgegangen, dass der Mitralklappenprolaps und der primäre Spontanpneumothorax eine Manifestation von systemischen Anomalien des Bindegewebes sein könnte. Ziel dieser Studie war es, die Prävalenz von Mitralklappenprolaps bei Patienten kroatischer Herkunft mit primären Spontanpneumothorax zu erheben und ihre mögliche Assoziation mit Bindgewebserkrankungen zu erfassen. Wir untersuchen umgekehrt auch die Prävalenz von primärem Spontanpneumothorax bei Patienten mit primärem Mitralklappenprolaps. METHODEN: Bei 32 Patienten mit primärem Spontanpneumothorax ohne bestehende Lungenerkrankungen oder Bindegewebserkrankungen wurde eine zweidimensionale transthorakale Echokardiografie von einem zertifizierten Kardiologen durchgeführt. Echokardiographische und demografische Merkmale wurden mittels deskriptiver Statistik analysiert. Ebenso haben wir medizinische Aufzeichnungen von 60 Patienten mit Mitralklappenprolaps ausgewertet. ERGEBNISSE: Es wurde bei keinem Patienten mit primärem Spontanpneumothorax ein Mitralklappenprolaps festgestellt. Alter, Geschlecht, Rauchen, Body Mass Index, Seite des Spontanpneumothorax , Häufigkeit des Auftretens und Familienanamnese entsprachen früheren Untersuchungen. Umgekehrt wurde auch bei keinem der 60 Patienten mit primärem Mitralklappenprolaps ein primärer Spontanpneumothorax diagnostiziert. SCHLUSSFOLGERUNG: Unter Anwendung neuer echocardiographischer Kriterien der Definition eines Mitralklappenprolaps, haben wir bei keinem Patienten kroatischer Herkunft mit primärem Spontanpneumothorax einen Mitralklappenprolaps gefunden. Auch haben wir keinen primären Spontanpneumothorax in einer Gruppe von Patienten mit Mitralklappenprolaps feststellen können. Die Herkunft der Patienten könnte einen Einfluss auf die Inzidenz eines Mitralklappenprolapses bei Patienten mit primärem Spontanpneumothorax, sowie auch umgekehrt auf die Inzidenz eines primären Spontanpneumothorax bei Patienten mit primärem Mitralklappenprolaps haben.SummaryBACKGROUND: Mitral valve prolapse (MVP) is a common diagnosis in patients with primary spontaneous pneumothorax (PSP). This description assumes that MVP and PSP might be manifestations of a systemic connective tissue abnormality. The purpose of this study was to determine the prevalence of MVP in PSP patients of Croatian origin and evaluate their relationship with connective tissue disorders. We also examined the prevalence of PSP in patients with primary MVP. METHODS: Thirty-two patients with PSP and without underlying pulmonary disease or connective tissue disease underwent two-dimensional transthoracic echocardiography performed by a certified cardiologist. Echocardiography and demographic features were analyzed using descriptive statistics. We also examined the medical records of 60 patients with primary MVP. RESULTS: MVP was found in none of the 32 patients suffering from PSP. The age, sex, smoking status, body mass index, side, rate, and family history were similar to previous investigations. Likewise, none of the 60 patients with primary MVP ever had PSP. CONCLUSION: By applying an updated definition of MVP, we found no MVP case among PSP patients of Croatian origin. We also found no PSP in the primary MVP group. Ethnicity may influence the occurrence of MVP in PSP patients, and PSP in primary MVP patients.