Aim: Here, we explored the role of NCAM/FGFR1 signaling and pro-fibrotic gene expression signatures as initiating or driving forces of EMT program in cultured human proximal tubular epithelial cells. Introduction: Epithelial-to-mesenchymal transition (EMT) contributes to maladaptive repair and parenchymal damage during renal fibrosis. Based on previous reports, neural cell adhesion molecule (NCAM) and fibroblast growth factor receptor 1 (FGFR1) are both considered to be mechanistically involved in the EMT process. Material and Methods: By using an established in vitro model of EMT of the human proximal tubular epithelial cells (HK-2 cells) in response to TGF-β1 (10ng/mL) exposure, NCAM/FGFR1 signaling responses were analyzed by light microscopy, immune-labelling, qRT-PCR and scratch assays. Modulation of FGFR1 was induced using PD173074 (100nM). Distribution of TGF-β1 downstream effectors was assessed in HK-2 cells of the EMT program as well as in 50 biopsies of different human kidney diseases to explore their in vivo correlation. Results: EMT associated with morphological changes started 48h after TGF-ß1 treatment of the HK-2 cells and was clearly apparent after 72 hours, associated with loss of CDH1 (encoding E-Cadherin) and transcriptional induction of SNAI1 (encoding SNAIL), SNAI2 (encoding SLUG), TWIST1, MMP2, MMP9, CDH2 (encoding N-Cadherin), ITGA5 (encoding integrin-α5), ITGB1 (encoding integrin-β1), ACTA2 (encoding α-SMA) and S100A4 (encoding FSP1). After 24 hours of TGF-β1 exposure at the early stage of SPECIJALNA SESIJA: SESIJA SPECIJALIZANATA 7 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. EMT program, transcriptional induction of several NCAM isoforms along with FGFR1 was observed, implicating a mechanistic link between NCAM/FGFR1 signaling and induction of EMT. These assumptions were further supported by the inhibition of the EMT program after specific blocking of FGFR1 signaling responses by PD173074. Moreover, there was evidence for an in vivo TGF-β1 pathway activation with EMT response signal signatures in diseased human kidneys in correlation to impaired renal excretory functions. Conclusion: Modulation of NCAM/FGFR1 signaling blocks the EMT program in cultured human proximal tubular epithelial cells. NCAM/FGFR1 signaling appears to be involved in initial phases of TGF-ß1 initiated EMT of tubular cells and thus could contribute to maladaptive repair and parenchymal damage during renal fibrosis.

Introduction: Primary sinovial sarcoma (PSS) is a very rare malignancy in lung, although lung is the most common organ-based site for metastatic synovial sarcoma. It is a high grade malignant mesenchymal neoplasm showing variable epithelial differentation and characterized by a balanced translocation t(X, 18). Case report: We report a case of a 67- year-old male presented with long lasting cough, chest pain and fever. Chest radiography and computer tomography scan revealed a large well defined lung mass invading hilum of the lung, which was indicated for the lung resection. Histopatological examination showed high-cellulare spindle cell malignant tumor. Immunohistochemically,neoplastic cells were positive for vimentin, TLE-1, Bcl-2, focally positive for cytokeratin AE1/AE3, cytokeratin 7, cytokeratin 18, cytokeratin 19, EMA, calponin and negative for CK 5/6, S100, STAT6, CD34, SMA, Desmin, CD99 and CD 117, which determinate a diagnosis of monophasic PSS of lung. Specific translocation t(X, 18) was detected by fluorescent in situ hybridization (FISH). Conclusion: Diagnosis of PSS in lung may create various diagnostic challenges. It can be established only after exclusion of metastatic sarcoma of other localizations and spindle cell primary lung malignancies. Molecular testing proved to be very helpful or necessary when spindle cell synovial sarcoma was recognized in uncommon sites.

Aim: The aim of the study is to investigate the effect of prenatal treatment of metronidazole on the process of cerebellar foliation in the guinea pig. Introduction: The use of metronidazole in pregnancy still occupies very different attitudes among doctors who prescribe them. Neurotoxicity is a common side effect in the use of metronidazole, but there is still no clear animal study. Materials and Method: We studied 42 guinea pig fetuses obtain from 12 pregnant guinea pig dams.  Dams were separated in experimental (6) and control6) group(K). Experimental group(E) received from 42-49 day of gestation at every PLENARY ORAL PRESENTATION 22 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. 12 hour (at 8 a.m. and 8 p.m.) subcutaneous injection od saline solution of metronidazole in concentration of 28 mg/kg.  Control group received using same time protocol just saline solution. At 50th day of gestation all dams were sacrified and fetuses were used for further analysis. In each  fetuses (22 in E, and 20 K group). Firstly we make gross picture of the brain and secondary we separated vermis region for further histological and immunohistochemical analysis. Results: An analysis of macroscopic images of the dorsal side of the cerebellum in the experimental group of individuals revealed malformations in 15 out of 22 fetuses (68.2%). The most affected folia was VII and characterized with aberrant diagonal positioning along the entire dorsal side of the vermis. Other folia were partial presence, with micro, and agyria changes. Conclusion: Prenatal use of metronidazole in guinea pigs during the 42-49th day of gestation cause disturbance in cerebellar foliation.

Aim: We present the case of a woman with endobronchial pulmonary synovial sarcoma. Introduction: Primary pulmonary synovial sarcoma is an extremely rare tumor that has the same histomorphological characteristics and chromosomal translocations as the synovial sarcoma of soft tissue origin. Material and Methods: A woman aged 58 years, the smoker, without the current symptoms of the disease, came to our institution because of the nodus that was seen on the CT chest. The polip (26 mm) was located in the lumen of the lower right lobar bronchus. The mediastinal and hilar lymph nodes were not increased. The radiological examination was done as part of a routine control after the meningeoma surgery three years ago. Right lower lobectomy and resection of regional lymph nodes were performed. Results: By a macroscopic examination, in the lumen of the bronchus for the lower right lobes, a clearly limited, nonencapsulated, grayish-white node of 2.6 x 2.6 x 1 cm was found. Histologically, the tumor was showed interweaving fascicular uniform spindle cell with ovoid, pale staining nuclei, and inconspicuous nucleoli, scant cytoplasm and the cell borders indistinct. Immunohistochemical tumor cells were positive for CD99, bcl2 and vimentin. Surgical margins and regional lymph nodes were not affected. A detailed clinical and radiological examination confirmed the primary lung origin of the diagnosed synovial sarcoma. A year after surgery the patient feels good. Conclusion: Morphological and immunohistochemical analysis with detailed clinical and radiological examination confirms the primary lung origin of synovial sarcoma

Aim: Reporting of autopsy case of fatal accidental poisoning by colchicine from meadow saffron. Introduction: Meadow saffron (Colchicum autumnale) is a perennial herbaceous plant similar to the edible wild garlic (Allium ursinum). Toxic substance in meadow saffron is alcaloid colchicine. Colchicine poisoning is a very dangerous condition, which can lead to fatal outcome. Case report: A 50-years-old male was admitted to the hospital complaining of weakness, abdominal pain, nausea, vomiting and diarrhea without blood. Day before he ate two plants thinking they’re wild garlic and seven hours after ingestion he felt first symptoms. During the course of the hospital stay, he had gastroenterocolitis, acute renal failure, hepatic lesion and cardiorespiratory insufficiency with fatal outcome. Post-mortem examination reveled:brain oedema, lung oedema and congestion, heart weighing 700 grams, ventricular hypertrophy, myocardial fibrosis, liver congestion and steatosis, spleen congestion, pancreatic fibrosis. Organs sections were taken for pathohistological analysis. Body fluids and parts of organs were toxicologically analyzed. Pathohistological findings:brain oedema, diffuse perivascular and interstitial myocardial fibrosis, myocardial haemorrhage, lungs congestion and edema, micro- and macrovesicular liver steatosis, centrilobular liver necrosis, lymphocytic inflammatory infiltrate in liver portions, spleen’s red pulp congestion, kidney congestion and interstitial bleeding, coagulation necrosis of the proximal tubules of the kidney. Toxicological analysis showed colchicine in blood-0.011 mg/L, urine-0.051 mg/L, liver with gallbladder-0.007 mg/ kg, kidney-0.008 mg/kg. Conclusion: Ingestion of the meadow saffron can lead to poisoning with fatal outcome due to colchicine. Colchicine intoxication should be suspected in patients with gastrointestinal symptoms after consuming wild plants.

Aim: The present a rare case intraocular primary malignant choroidal melanoma. Introduction: Melanoma choroideae is most common intraocular primary tumor of adults. Incidence is 7 cases per 1 million people per year and incidence of this tumor increases with age. Case report: We report 76 years old women who had progressive visual field defects at left eye at least two years. Diagnostic examination of eye was detected a greyish-brown mass of the posterior choroidal pole which was indication for enucleation. Macroscopically bulbus oculi was dimension 28x25x25mm, with optic nerve 5mm length. At the intersection on posterior pole nearby papila of optical nerve was detected ovoid dark lesion diameters 8x3mm. Histopathology examination was showed sharply demarcated solid tumor islands which consists of epithelioid tumor cells with pleomorphic, atypical nuclei, conspicuous nucleoli. Other type of cells were spindle look which formed fascicular shapes. Pigmentation was absent also. There was no significant vascularisation in tumor mass. Sclera was superficially infiltrated by tumor cells. Mitotic activity was absent (0/40HPHF). Immunohistochemistry staining was confirmed melanoma cells: S-100, MelanA , HMB-45 /-. Conclusion: Melanoma in this region is rare, indolent lesion, with bad prognosis. Early detection could prevent further dissemination of disease and many complications. Metastatic choroid melanoma is a highly malignant disease with a limited life expectancy.

Složeni problemi politraumatizovanih pacijenata su veliki izazov za lekare. Brojne povrede kod takvih pacijenata zahtevaju brzo reagovanje po principu prioriteta kojim se greške svode na minimum. Za lečenje trauma pacijenata neophodno je znanje, iskustvo i veština lekara da bi brzo i sveobuhvatno sagledao povređenog i da bi mu ukazao pravovremenu pomoć. Lečenje se izvodi fokusirajući se na prioritetne povrede pacijenta, prateći protokol postupaka koji lekara sistematski vodi tokom zbrinjavanja od najtežih ka lakšim povredama. Ovakve pacijente zbrinjava interdisciplinarni tim zdravstvenih radnika, u kome svako mora da zna svoje mesto i obaveze. Na čelu tima je najiskusniji lekar koji definiše redosled postupaka tokom inicijalnog zbrinjavanja. Samo organizovanim pristupom pandemijskom problemu trauma pacijenata može se pozitivno uticati na smanjenje neposrednog i odloženog mortaliteta i morbiditeta povređenih. U radu je revijalno prikazan pristup politraumatizovanom pacijentu uz inicijalno zbrinjavanje, baziran na prioritetima i prateći protokol koji obezbeđuje najveću efikasnost u lečenju.

Sarcomatoid differentiation in renal cell carcinoma (sarcomatoid renal cell carcinoma – sRCC) represents a dedifferentiated high grade neoplasm of the kidney that contains carcinomatous and sarcomatous component. sRCC is an uncommon tumor, with the incidence of 5-8% of renal carcinoma. Sarcomatoid differentiation is a result of divergent differentiation of malignant epithelial cells. During this process tumor cells lose their epithelial features, and acquire mesenchymal characteristics, which provides them higher APSTRAKTI 79 MATERIA MEDICA • Vol. 34 • Issue 1, suplement 1 • april 2018. capacity for migration and metastasis.This phenotype can be encountered in all RCC subtypes, including clear cell, papillary, chromophobe RCC, and carcinomaof collecting duct. Sarcomatoid component may resemble fibrosarcoma or undifferentiated pleomorphic sarcoma. Less often heterologous differentiation can be found, with histologic patterns resembling rhabdomyosarcoma, chondrosarcoma, or osteosarcoma. Rhabdoid phenotype is an aggressive form of divergent differentiation which has been described in clear cell RCC, papillary RCC, as well as in chromophobe RCC (CRRCC). CRRCC comprise about 6% of RCC, and has better prognosis compared to other RCC subtypes. Sarcomatoid differentiation is found in 8% of these tumors, and is an indicator of poor prognosis, as it is in other RCC types. Sarcomatoid component may represent terminally dedifferentiated clone which can arise from any RCC subtype, or can develop from a special clone. Although sRCC is most frequently found in high grade tumors, the occurrence of sarcomatoid differentiation in RCC, Fuhrman 1/2, detected in 30% of the cases, denies the claim that sarcomatoid differentiation is a continual process of classic RCC dedifferentiation, but a consequence of sarcomatoid stem cell activation within the tumor. In a case of sarcomatoid differentiation in renal carcinoma it is necessary to detect focuses of any morphological type of renal cell carcinoma, and to verify the immunohistochemical positivity of sarcomatoid component to epithelial and mesenchymal markers. Their epithelial origin is confirmed by the expression of cytokeratins, and EMA. PAX8, CAIX, and CD10 can be used to confirm the renal origin, which is of particular importance in finding of sarcomatoid cells in needle biopsy, as well as in metastatic RCC. CAIX, p53, and Bcl-2 can play a major role in transformation of RCC to highly malignant neoplasm with sarcomatoid differentiation. The expression of CAIX, p53, and Bcl-2 is indicator of poor prognosis and worse survival of the patients with sRCC. Significant micromorphological parameters that may influence the clinical course of the disease comprise percentage of sarcomatoid differentiation (>50%), presence of vascular invasion, extent of necrosis, and advanced TNM stage. Type and grade of sarcomatoid component, as well as RCC subtype do not influence the clinical outcome. The prognosis of patients with sRCC is worse compared to prognosis of other histologic forms of RCC. Sarcomatoid differentiation in RCC is a significant cause of mortality, with average survival of 4-9 months after diagnosis. The majority of unclassified RCCs contains variable percent of tumor cells with sarcomatoid morphology, without recognizable epithelial component. About 3% of RCC are exclusively sarcomatoid. These tumors are larger, more often invade adrenal glands and other adjacent organs, metastasize more frequently into regional lymph nodes and bones, and have significantly shorter survival (average is 4.3 months). Differential diagnosis of sRCC should exclude primary renal sarcoma, sarcomatoid urothelial carcinoma, and angiomyolipoma. Micromorphologically sRCC may resemble classic sarcoma, however it should be taken into account that primary renal sarcomas are extremely rare in adults, and comprise less than 1% of renal malignancies. The half of primary renal sarcomas are leiomyosarcomas, consisting of smooth muscle component, which is extremely rare in sRCC. In sarcomatoid urothelial carcinoma, the location of tumor is of significance, also the presence of carcinoma in situ, recurrence of urothelial carcinoma, and immunohistochemical positivity to CKhmw and p63. In angiomyolipoma, immunoreactivity to HMB45, as well as the presence of focuses with classic morphology, excludes sarcomatoid RCC. Conclusion: Sarcomatoid differentiation in renal cell carcinoma is a result of divergent differentiation of malignant epithelial cell, and can be found in all renal cell carcinoma subtypes. During this process tumor cells lose their epithelial features, and acquire mesenchymal characteristics, which provides them higher capacity for migration and metastasis. It is very important to recognize the presence of sarcomatoid differentiation in renal cell carcinoma, since it is an indicator of poor prognosis irrespective of RCC subtype.

Introduction: Hamartomas of the bile duct named von Meyenburg complex are benign liver lesions consisting of dilated bile duct structures with a surrounding fibrous stroma. Their incidence is age-dependent and they are observed about 1% in children and 5%-6% in adults. Von Meyenburg complexes are infrequently observed lesions, characterized by multiple small nodular lesions located below the Glisson’s capsule, and ranging from 0.1 to 1.0 centimeters in diameter. Von Meyenburg complex of the liver are usually detected during laparotomy or autopsies an incidental finding. Multilocular occurrence is possible although they are rarely spread throughout the whole liver, as it was observed in our patient. They are normally asymptomatic, and are incidental findings in asymptomatic patients. They may be found in normal liver tissue, but also in association with Caroli’s syndrome, congenital hepatic fibrosis, autosomal dominant polycystic renal diseas, cholangiocarcinomas and cholangitis. Cholangiocarcinoma which arise from these lesions are usually lower stage and better differentiations than other type of cholangiocarcinoma. The sonographic findings of von Meyenburg complex are variable, including multiple, small, hyperechogenic images, with poorly delimited margins, or even hypoechogenic images with a “target” pattern with a hyperechogenic center and a hypoechogenic periphery, and well delimited margins. A magnetic resonance cholangiography is the best imaging examination of hamartomas of the bile duct, which can distinguish the different forms of dilatation of the bile duct. Histology of von Meyenburg complexes consists of a variable number of dilated small bile ducts, embedded in a fibrous, sometimes hyalinizing stroma. Microscopically, they are characterized by cystic dilatations of the bile duct or clusters of mature bile duct of various sizes, peri-ductal glands, and encompassed by fibrous stroma. The ductules are lined by small cuboidal or flattened cells, with round to oval nuclei. Bile duct hamartomas contain cysts that are more irregularly shaped then normal ducts, and they may also contain eosinophilic debris or inspissated bile. Case report: A 68-year-old male patient with multiple hepatic lesion which ultrasonic and MSCT appearance suggestive of multiple liver metastases was accepted for surgical exploration and liver biopsy. The patient had one mounts symptoms of vomits and weight loss. During surgery numerous whitish irregular lesions of various sizes scattered in the hepatic surface imitating metastatic deposits were noted trough both liver lobe and trough all liver quadrants. Explorations of the rest of abdominal cavity not found any pathological changes or peritoneal carcinomatosis. Liver biopsy was done and taken three samples for analysis. Tissue was brown-yellow-gray color and medium-firm consistency. Histological analysis demonstrated multiple lesions composed of biliary ducts incorporated in fibrotic tissue (Figure 1).There are usually cystic dilatations of some intrahepatic biliary ducts with irregular shape lined with uniform epithelium (Figure 2). The epithel of biliary ducts in von Meyenburg complex were immunohistochemicaly Epithelial Membrane Antigen positive, Pan-Cytokeratin positive, Cytokeratin 7 negative, Cytokeratin 5/6 negative and Carcinoembryonic antigene negative. Also present were signs of cholestasis with small lakes of bile.Conclusion: Von Meyenburg complexes are an important differential diagnosis of liver metastases. Differential diagnosis of liver metastases also includes other benign liver lesions, including hemangiomas, adenomas or infectious lesions e.g. miliary tuberculosis. As the existence of liver metastases is crucial for therapeutic decision making in malignant diseases, this differential diagnosis must be carefully clarified. Since VMC are usually less than 5 mm in size, they can escape preoperative radiologic diagnostics. The macroscopic appearance of von Meyenburg complexes can mimic liver metastasis as demonstrated in our reported patients.

Stafilokokni toksični šok sindrom (STŠS) se obično javlja kod novorođenčadi i dece, ali se povremeno može javiti i kod odraslih. U tom slučaju, obično ukazuje na disfunkciju imunog sistema. Prikazan je slučaj kritično-obolelog odraslog muškarca sa STŠS i simptomima i znacima životno-ugrožavajuće sistemske infekcije (hemodinamska nestabilnost, akutna insuficijencija bubrega, konfuzija). Nakon završenog lečenja (anti-stafilokoni antibiotici, hemodijaliza, vazopresori, suportivna i simptomatska terapija), postignuta je potpuna remisija kod obolelog. Pravovremena dijagnostika i adekvatan tretman je glavno uporište u lečenju STŠS kod odraslih.