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Endemska nefropatija (EN) je kronična tubulointersticijska bolest bubrega kod koje se često javlja karcinom urotela gornjega urotrakta (UUC). Imunološki odgovor, u kojem ključnu ulogu imaju geni HLA, povezan je s nastankom brojnih bolesti. Cilj ovog rada bio je istražiti polimorfizam gena, alela i haplotipova lokusa HLA-A, -B i - DRB1 u skupini nesrodnih EN bolesnika (N=111; 52 bolesnika s UUC i 59 bolesnika bez UUC) u svrhu otkrivanja njihove moguće povezanosti s EN. Ispitana su i 52 zdrava srodnika i 190 zdravih nesrodnih osoba. Za određivanje polimorfizma HLA koristila se metoda lančane reakcije polimerazom u kombinaciji s oligunukleotidima specifičnih sekvenci (PCR-SSO) ili početnicama specifičnih sekvenci (PCR-SSP). Otkrivene su značajne razlike u zastupljenosti pojedinih alela HLA između skupine EN bolesnika i zdrave kontrole. U skupini EN bolesnika aleli HLA-A*01:01, B*57:01 i B*27:05 su bili značajno manje zastupljeni, dok je alel HLA-DRB1*04:02 bio značajno češće prisutan. Pozitivna povezanost s pojavom EN i UUC utvrđena je za haplotipove: HLA-B*18~DRB1*11 i HLA-B*44~DRB1*16 kao i produženi haplotip HLA-A*26:01~B*38:01~DRB1*04:02. Otkrivene su razlike u raspodjeli alela i haplotipova HLA s obzirom na dob pojave bolesti, kao i na preživljenje. Dobiveni rezultati ukazuju da su pojedini aleli i haplotipovi HLA potencijalno podložni, odnosno zaštitni genetski čimbenici za razvoj bolesti., Endemic nephropathy (EN) is a chronic tubulointerstitial kidney disease in which upper urothelial carcinoma (UUC) often occurs. The immune response and HLA genes have been linked with a number of diseases. Aim of this study was to analyze genes, alleles and haplotypes of HLA-A, -B and -DRB1 loci among EN patients (N=111; 52 patients with UUC and 59 patients without UUC) in order to investigate their possible role in EN etiology. In addition, analysis included 52 healthy relatives and 190 healthy unrelated individuals. HLA gene polymorphisms were determined by polymerase chain reaction methods in combination with oligonucleotides specific for HLA gene groups (PCR-SSO) or primers of specific sequences (PCR-SSP). Significant differences in distribution of several HLA alleles between EN patients and healthy controls were detected. The HLA-A*01:01, B*57:01 and B*27:05 alleles were significantly less present, while HLADRB1* 04:02 allele appeared significantly more frequently among EN patients. Positive corelation with the onset of EN and UUC was determined for HLAB* 18~DRB1*11 and HLA-B*44~DRB1*16 haplotypes, and HLAA* 26:01~B*38:01~DRB1*04:02 extended haplotype. Differences in distribution of alleles and haplotypes were also detected in correlation to age of disease onset and survival. Obtained data demonstrate that investigated HLA loci could be potential susceptibility/protection genetic markers for disesase development.

Endemska nefropatija (EN) je kronična tubulointersticijska bolest bubrega kod koje se često javlja karcinom urotela gornjega urotrakta (UUC). Imunološki odgovor, u kojem ključnu ulogu imaju geni HLA, povezan je s nastankom brojnih bolesti. Cilj ovog rada bio je istražiti polimorfizam gena, alela i haplotipova lokusa HLA-A, -B i - DRB1 u skupini nesrodnih EN bolesnika (N=111 ; 52 bolesnika s UUC i 59 bolesnika bez UUC) u svrhu otkrivanja njihove moguće povezanosti s EN. Ispitana su i 52 zdrava srodnika i 190 zdravih nesrodnih osoba. Za određivanje polimorfizma HLA koristila se metoda lančane reakcije polimerazom u kombinaciji s oligunukleotidima specifičnih sekvenci (PCR-SSO) ili početnicama specifičnih sekvenci (PCR-SSP). Otkrivene su značajne razlike u zastupljenosti pojedinih alela HLA između skupine EN bolesnika i zdrave kontrole. U skupini EN bolesnika aleli HLA-A*01:01, B*57:01 i B*27:05 su bili značajno manje zastupljeni, dok je alel HLA-DRB1*04:02 bio značajno češće prisutan. Pozitivna povezanost s pojavom EN i UUC utvrđena je za haplotipove: HLA- B*18~DRB1*11 i HLA-B*44~DRB1*16 kao i produženi haplotip HLA- A*26:01~B*38:01~DRB1*04:02. Otkrivene su razlike u raspodjeli alela i haplotipova HLA s obzirom na dob pojave bolesti, kao i na preživljenje. Dobiveni rezultati ukazuju da su pojedini aleli i haplotipovi HLA potencijalno podložni, odnosno zaštitni genetski čimbenici za razvoj bolesti.

Endemic nephropathy (EN) is a chronic kidney disease affecting populations in several countries, with an endemic focus in eastern Croatia with a population of about 10, 000 people. EN is a multifactorial disease with polygenic predis position to environmental risk agents. Recently, next generation sequencing nominated three genes tightly connected to process of angiogenesis as candidate genes for predispos tion to Balkan endemic nephropathy, one of them (KCNK5) being located on chromosome 6p21.2, in close proximity to the HLA region. Prompted by this finding, we investigated HLA-A, - B, and -DRB1 alleles and haplotypes in the popu lation of patients with EN (N=103) and matched healthy controls (N=190). All individuals were tested by PCR-SSO for low resolution typing and PCR-SSP to obtain a high- resolution typing. The results showed higher presence of HLA-DRB1*04:02 allele in EN (P=0.013, OR=3.006, 95% CI=1.28-7.07), in contrast to the lower frequency of HLA- A*01:01, B*57:01 and B*27:05 alleles (P=0.002, OR=0.373, 95% CI=0.19-0.72 ; P=0.032, OR=0.339, 95% CI=0.13-0.90 and P=0.006, OR=0.098, 95% CI=0.01-0.74, respectively). Moreover, when EN patient’s HLA haplotypes were compared to controls, two haplotypes were present with higher frequency within EN patient group, HLA- A*02:01~B*27:02~DRB1*16:01 and HLA- A*26:01~B* 38:01~DRB1*04:02 (P=0.002, OR=0 and P=0.054, OR=4.702, 95% CI=0.90-24.45, respectively) while HLA- A*02:01~B*57:01~DRB1*16:01 (P=0.031, OR=0) haplo- type showed a significantly lower frequency. HLA- A*02:01~B*27:05~DRB1*01:01 and HLA-A*01:01~B* 57:01~DRB1*07:01 haplotypes were also less frequent among EN patients but this difference did not reach statistical significance. In conclusion, our results point toward genetic susceptibility of EN and observed differences in both susceptible/protective HLA profiles indicate the necessity of further studies.

Aim: Endemic nephropathy (EN) is classified as a tubulointerstitial progressive chronic disease that affects kidneys with a slow clinical course. Disease occurs in rural communities along the river flows of the Danube river basin in Croatia, Bosnia and Herzegovina, Serbia, Bulgaria and Romania. In Croatia, the endemic focal point includes fourteen villages and affects population of about 10 000 people located in the BrodskoPosavska County on the Sava River bank, west of Slavonski Brod. Over the past period, the influence of hereditary and environmental factors on the appearance of EN (heavy metals, microelements, various viruses and bacteria, soil, drinking water, polycyclic hydrocarbons aromatic compounds) were investigated. Recently, next generation sequencing nominated three genes tightly connected to process of angiogenesis as candidate genes for predisposition to Balkan endemic nephropathy, one of them (KCNK5) being located on chromosome 6p21.2, in close proximity to the HLA region. Methods: Prompted by this finding, we investigated HLA-A, -B, and -DRB1 alleles and haplotypes in the population of patients with EN (N=103) and matched healthy controls (N=190). All individuals were tested by PCR-SSO for low resolution typing and PCR-SSP to obtain a high-resolution typing. Results: The results showed higher presence of HLA-DRB1*04:02 allele in EN (P=0.013, OR=3.006, 95% CI=1.28- 7.07), in contrast to the lower frequency of HLA- A*01:01, B*57:01 and B*27:05 alleles (P=0.002, OR=0.373, 95% CI=0.19-0.72 ; P=0.032, OR=0.339, 95% CI=0.13-0.90 and P=0.006, OR=0.098, 95% CI=0.01-0.74, respectively). Moreover, when EN patient’s HLA haplotypes were compared to controls, two haplotypes were present with higher frequency within EN patients group, HLA- A*02:01~B*27:02~DRB1*16:01 and HLA- A*26:01~B*38:01~DRB1*04:02 (P=0.002, OR=0 and P=0.054, OR=4.702, 95% CI=0.90- 24.45, respectively) while HLA-A*02:01~B*57:01~DRB1*16:01 (P=0.031, OR=0) haplotype showed a significantly lower frequency. Two other haplotypes, HLA- A*02:01~B*27:05~DRB1*01:01 and HLAA*01:01~B*57:01~DRB1*07:01, were also less frequent among EN patients, but this difference did not reach statistical significance. Conclusion: The results point toward genetic susceptibility to EN indicating the necessity of further studies.

Introductions: Endemic nephropathy (EN) is a chronic tubulointerstitial renal disease associated with the development of cancer of the upper urinary tract (UUC). The Human Leukocyte Antigen (HLA) plays role in immune response and its genes are involved in aetiology of autoimmune diseases as well as in carcinomas. The aim of this study was to investigate the differences between EN patients with and without UUC and HLA-DRB1 genes. Materials and methods: The study included 85 patients aged 58-88 years, with EN, treated at the Urology Department and Dialysis Department, General Hospital “Dr.Josip Benčević” Slavonski Brod, in the period from 2005 to 2018, and 150 healthy matched controls. Peripheral blood of all patients and controls was collected for HLA typing. All individuals were tested for HLA-DRB1 genes using Polymerase Chain Reaction – Sequence Specific Oligos (Luminex technology). Results: Thirteen different HLA-DRB1 genes were observed among EN patients as well as among controls. The most frequent HLA-DRB1 gene in patient’s group was HLA-DRB1*11 (20.7%), while among controls two HLA- DRB1* genes (DRB1*11 and DRB1*16 were observed with the same frequency (15.9%, each). Comparison between tested groups revealed significant P value for DRB1*16 which was significantly more present among patients in comparison to controls (15.9% vs. 8.3% ; P=0.0144). Conclusion: Our preliminary data demonstrated existence of positive association between DRB1*16 gene and EN in our population. The obtained data needs to be confirmed in future studies which should also investigate the distribution of HLA-DRB1 genes among patients with and without UUC, and include other HLA genes.

Uvod. Traumatska dislokacija testisa je rijedak događaj koji nastaje najčešće kao tupa direktna ozljeda skrotalne regije i za posljedicu ima dislokaciju jednog ili oba testisa izvan skrotuma. Dislokacija testisa može se previdjeti zbog opsežne traume ili nepotpunog kliničkog pregleda. Pravovremena dijagnoza i operativno zbrinjavanje ove ozljede najčešće ne ostalja trajne posljedice za testis. Prikaz slučaja. Politraumatizirani muškarac u dobi od 38 godina stradao kao motorist je primljen u našu Bolnicu 24 sata nakon primarnog zbrinjavanja ozljede u drugoj ustanovi. Petog dana po prijemu pregledom je ustanovljeno da u desnom skrotumu nema testisa. Na postavljeno pitanje o ranijem stanju desnog testisa bolesnik nije znao sa sigurnošću dati odgovor, stoga smo pretražili medicinsku dokumentaciju i našli uredan status genitala s oba testisa u skrotumu. Ustanovljena je luksacija desnog testisa u desnu ingvinalnu regiju smještenog u potkožnom tkivu, na palpaciju bezbolan, pomičan i dobrog tonusa. Nije nađena ingvinalna hernija. Ultrazvučnim pregledom se potvrdila radna dijagnoza dislociranog, a color dopplerom i uredna prokrvljenost desnog testisa. Nakon višekratnog operativnog zbrinjavanja prijeloma bolesnik je naknadno tek nakon devet mjeseci pristao na operativnu korekciju spuštanja desnog testisa u desnu polovicu skrotuma. Obzirom na duži vremenski period od traume i ranijih operativnih zahvata učini se CT zdjelice na kojem se prikaže testis desno ingvinalno, potkožno. Učini se operativna eksploracija ingvinalne regije i nađe se testis smješten u potkožnom tkivu, vitalan bez znakova torzije funikulusa te se spusti u desni skrotum i fiksira. Bolesnik se drugog postoperativnog dana dobrog općeg i lokalnog statusa otpušta na kućno liječenje. Na kontrolnom pregledu, nakon mjesec dana desni testis je smješten u skrotum, urednog palpatornog i ultrazvučnog nalaza. Diskusija. Traumatsku luksaciju testisa prvi puta spominje Clauby, 1818. godine. Od tada se navode literaturni podaci i pregledni članci o sveukupno malom broju obavljenih slučajeva. U jednoj studiji navode da je od ukupnog broja opće traumatiziranih bolesnika u njih 0, 37% nađena dislokacija testisa. Najčešće dislokacije su potkožno ingvinalno, suprapubično, penilno, ingvinalni kanal, intraabdominalno, perinealno, natkoljenično. Dijagnoza dislociranog testisa se često ne postavi pri prvom pregledu traumatiziranog bolesnika, a razlog tomu su politrauma, hematom skrotuma kao i nepotpun klinički pregled. Dijagnoza se postavlja ultrazvukom, ili CT-om, a color doppler-om se provjerava prokrvljenost tkiva testisa. Liječenje se može provesti ručnim pozicioniranjem testisa na mjesto što se ne preporuča zbog mogućnosti dodatnog oštećenja tkiva testisa, krivog smještaja ili torzije peteljke. Preporuča se operativno zbrinjavanje ozljede s fiksacijom testisa u skrotum. Zakašnjela dijagnoza i zbrinjavanje dislociranog testisa može za posljedicu imati djelomičan ili potpuni gubitak funkcije i samog testisa. Zaključak. Traumatska dislokacija testisa je rijedak događaj. Dijagnoza se postavlja kliničkim pregledom, ultrazvučnom sonografijom i CT-om. Ozljeda se zbrinjava otvorenim operativnih zahvatom te ako se učini na vrijeme najčešće ne ostavlja trajne posljedice za testis.

Uvod. Kamenci mokraćnog mjehura čine 5% od ukupne urolitijaze, a veliki kamenci mokraćnog mjehura teži od 100 grama su danas rijetkost. Najčešće su udruženi s infravezikalnom opstrukcijom, uroinfekcijom, neurogenim mokraćnim mjehurom, nefro i/ili ureterolitijazom i češći su u muškaraca. Prikaz slučaja. Bolesnica u dobi o 70 godina dolazi u urološku ambulantu nakon godinu dana učestalih uroinfekcija, dizurije, pritiska u mokraćnom mjehuru, inkontinencije i povremene hematurije. Na ultrazvučnom pregledu mokraćnog sustava se nađe veliki kamenac mokraćnog mjehura bez dilatacije šupljinskog sustava bubrega i bez kamenaca u oba bubrega. Na nativnoj rendgenskoj snimci urotrakta u projekciji mokraćnog mjehura vidi se mineralna sjena koja mjeri 100x90 mm. Laboratorijske vrijednosti krvne slike, bubrežne i jetrene funkcije su bili u granicama referentnih vrijednosti, a u sedimentu urina masa eritrocita i leukocita. Urinokultura je bila pozitivna na E.Coli. Uretrocistoskopija je učinjena kako bismo otklonili opstrukcijsku komponentu. Uretra je bila slobodna i prohodna, a cistoskopiju je bilo nemoguće učiniti radi veličine kamenca koji je zapremao gotovo cijelu šupljinu mokraćnog mjehura. Kod bolesnice smo napravili cistolitotomiju i odstranili kamenac ovalnog oblika dimenzija 100x90 mm, žuto smeđe boje i težine 580 grama. Bolesnica je otpuštena kući deveti dan nakon operativnog zahvata i vađenja urinarnog katetera bez postoperativnih komplikacija. U praćenju je 6 godina nakon operativnog zahvata bez recidiva urolitijaze. Učinjena je kontrolna urografija nakon dvije godine koja je bila uredna. Diskusija. Prevalencija urolitijaze kreće se između 3 i 20% u razvijenim zemljama svijeta, a od toga su kamenci mokraćnog mjehura oko 5%. Kamenci mokraćnog mjehura nastaju najčešće radi otežanog istjecanja urina iz mokraćnog mjehura, neurogene disfunkcije mokraćnog mjehura, stranog tijela u mokraćnom mjehuru ili uroinfekcije. Udruženi su često s nefro i/ili ureterolitijazom, retencijom, urgencijom ili inkontinencijom urina i uroinfekcijom. Dijagnoza velikih kamenaca mokraćnog mjehura se postavlja ultrazvučnim pregledom, rendgenskom nativnom snimkom urotrakta, kompjuteriziranom tomografijom urotrakta i cistoskopijom. Liječiti se mogu otvorenim zahvatom cistolitotomije ili endoskopski cistolitotripsijom. Zaključak. Namjera nam je bila prikazati ovaj slučaj velikog kamenca mokraćnog mjehura koji su danas rijetki, a dogodio se kod žene, bez udružene nefro i/ili ureterolitijaze, bez znakova opstrukcije gornjeg urotrakta kao niti infravezikalne opstrukcije, a u šestogodišnjem postoperativnom praćenju nije zabilježen recidiv litijaze.

ntroduction and Aims: Upper urinary tract urothelial cancers(UUC) are rare in general population but occur in almost 50% of patients with endemic nephropathy(EN)/aristolochic acid nephropathy (AAN). Aristolochic acid(AA) was proven as the etiological factor both for EN/AAN and UUC. The goal of this study was to identify tumor suppressor genes(TSG) and oncogenes(OG) involved in AA induced carcinogenesis and their posttranscriptional regulation mehanisms by microRNAs. Methods: Paired samples of tumors and adjacent normal urothelial tissues of 13 patients from Croatian and Bosnian endemic regions were analyzed. MiRNA profiling was performed by high- capacity quantitative PCR, while mRNA expression profiling of the same RNAs was done using microarray technology. Immunohistochemistry was performed on tissue microarrays. Results: The broad involvement of known cancer genes in the process of UUC tumorigenesis was revealed by expression profiling analysis of the tumors, implicating on many OG(35 up-regulated ; 54 down- modulated), and TSG(17 up-regulated ; 3 down- modulated). We studied whether the upregulation of specific OG (MYC, FGFR3, HRAS and KRAS) and down regulation of TSG (PTEN and PTCH1) might be augmented in UUC by coordinated action of miRNAs. Figure 1. shows a correlative network implicating numerous down-modulated miRNAregulators of these OG, including tumor suppressor miRNAs miR-23b, miR-143 and miR-145, and also a broad inhibition of PTCH1 by increased oncogenic miRNAs including miR-21, miR-18a and miR-9, and of PTEN by oncogenic miRNAs of the miR- 17-92 family. Both PTEN and PTCH1 appear commonly inhibited by essentially all the members of the miR-200 family. The elevated MYC then represents a central node in these processes, functioning as the activator of miR-17, miR-20 and miR-9 and inhibitor of miR-23b, the repressor of FGFR3 and KRAS, and the tumor- suppressor miRNA let-7c. By means of immunohistochemistry a trend of lower expression of PTEN protein was observed in tumor versus the normal tissue. Conclusions: AAN-associated UTUC carcinogenesis is characterized by a major deregulation of oncogenes and tumor suppressor genes, whose activity may be broadly and modulated by coordinate action of miRNAs.

Dietary intake of Aristolochia plants containing aristolochic acid (AA, IARC Group 1 carcinogen), leads to renal disease and to recurrent urinary tract transitional cell carcinomas (TCC). Mutation screens identified frequent A>T transversions, alterations underrepresented in other cancer types, as the signature of AA exposure. AA- associated TCC is a preventable cancer yet millions are estimated at risk due to unregulated medicinal use of Aristolochia. Here we present an ultra-low coverage modification of whole-exome sequencing (ULC-WES) as a novel molecular epidemiology method that reliably detects the AA mutation signature in small amounts of DNA from FFPE tumor tissues and can identify new exposed populations. DNA was isolated from paraffin sections of 18 TCC tumors from endemic nephropathy (EN) patients from regions in Croatia and Bosnia linked to exposure to AA. Four non-EN upper tract TCCs were used as controls. 250 ng of DNA was used for sequencing libraries and exome enrichment (Nimblegen, Roche). Libraries were sequenced on Illumina HiSeq2500 at 10-12x coverage. After data processing, GATK was used to call single nucleotide variants (SNV). To assess platform independence, 7 samples were run on SOLID 5500XL (Life), using proprietary chemistry and pipeline for data processing and variant calling. Normal genetic variants were filtered out after SNV annotation. ULC-WES at 10x identified the A>T predominance in 17 of 18 EN tumors (94%), and at T pattern in 14 (78%) samples. In contrast, the A>T presence was T mutations in the genome (R^2=0.83 for mutation count correlated with the chromosome length) but also identified recurrent non-synonymous A>T mutations in tumor suppressors and oncogenes including TP53, ARID1A, BRCA1/2, AXIN1, GATA3 and NRAS, DNMT1, FLT3, CSF1R and PIK3CA. We next detected recurrent A>T mutations in a number of histone and DNA modifiers suggesting epigenetic deregulation of genome activity in the AA-associated TCCs. In 2 patients, pairs of distinct TCCs from the same surgery had markedly overlapping mutation patterns (624 SNVs shared between same-side pelvic and ureteric tumors in one case, and 191 shared between renal pelvic and bladder tumors in the other). Thus, ULC-WES provided evidence supporting the concept of tumor cell seeding along the urinary tract as a mechanism of TCC spread and recurrence. We conclude that ULC-WES is a sensitive and specific method to identify AA exposure in tumor tissue and is directly applicable to identification of new populations at risk. The method can ultimately facilitate evidence-based preventive measures in the affected regions.

Endemic nephropathy is a syndrome that comprises two entities: chronic interstitial nephropathy and urothelial cell cancers predominantly of the upper urinary tract. The etiological agent for the disease is aristolochic acid, a compound found in the plants of Aristolochia spp. The development of urothelial cancers is characterized by the formation of aristolactam DNA adducts leading to mutations, predominantly A: T->T: A transversions. In order to comprehensively understand the gene regulation programs in upper urothelial cancers we performed integrated miRNA and mRNA expression profiling of paired tumours and unaffected urothelium samples. The obtained data will help us to understand the carcinogenesis caused by aristolochic acid and might be the source for the design of a diagnostic biomarker.

Endemska nefropatija sindrom je koji obuhvaća dva entiteta: kroničnu intersticijsku nefropatiju i urotelne karcinome, predominantno gornjeg dijela mokraćnog sustava. Etiološki agens za nastanak ove bolesti sada je poznat - aristolohična kiselina, sastojak biljaka reda Aristolochia. Nastanak urotelnih karcinoma karakteriziran je stvaranjem aristolaktam DNA adukata koji dovode do mutacija, prvenstveno A:T>T:A transverzije. Kako bi što bolje razumjeli programe genske regulacije u ovih tumora sproveli smo integrirano microRNA i mRNA ekspresijsko profiliranje tumora i priležećeg netumorskog urotelnog tkiva. Rezultati dobiveni ovim istraživanjem pomažu u razumijevanju karcinogeneze uzrokovane aristolohičnom kiselinom i mogli bi doprinijeti razvoju dijagnostičnog biomarkera.

Primjena laserske terapije u liječenju simptoma donjeg urinarnog trakta uzrokovanih benignom hiperplazijom prostate stječe sve veću popularnost. Kao osnovni razlog se ističe manja invazivnost postupka u odnosu na standardizirani operativni tretman, transuretralnu resekciju prostate (TURP). Učinak lasera se zasniva na vaporizaciji tkiva prostate što omogućava bolju kontrolu nad introperativnim krvarenjem. Posljedično se minimizira i broj komplikacija što opravdava epitet minimalno invazivnog zahvata. ovim radom prezentirat će se rezultati i iskustva operativne primjene lasera za liječenje benignog uvećanja prostate u Općoj bolnici "Dr. Josip Benčević" u Slavonskom Brodu. U razdoblju između siječnja 2010. i ožujka 2011. godine 15 pacijenata je liječeno transuretralnom laserskom vaporizacijom radi hiperplazije prostate. Korišten je diodni laser. Obavljena je analiza perioperativnih parametara (status pacijenta, trajanje zahvata, nužnost transfuzije krvi, komplikacije, trajanje kateterizacije i hospitalizacije) te su isti uspoređeni s podacima iz literature. Laserski tretman je efektivniji u odnosu na standardizirani operativni postupak TURP, ima manje intraoperativnih komplikacija, kraći je period kateterizacije i trajanje hospitalnog liječenja, a li je trajanje operacije dužwe i učestalije su kasne komplikacije. Evaluacija inicijalnih 15 slučajeva laserske vaporizacije prostate pokazuje da je postupak minimalno invazivan, te je terapija izbora u biranim skupinama pacijenata.

Endemic nephropathy (EN) and associated upper urothelial cancers (UUC) are a form of aristolochic acid nephropathy (AAN), in which ingestion of bread contaminated with Aristolochia leads to chronic dietary intoxication. This abstract presents the cases of 3 members of the same family who showed different EN clinical courses and pathological spectra. Although they shared the same household and familiar environment for 18 years and were therefore similarly exposed to aristolochic acid (AA), they exhibited different clinical courses. EN can present as renal insufficiency or UUC alone, or in combination, regardless of which develops first. Moreover, UUC commonly affects both the right and the left sides, and our study clearly showed this. The patient in Case 1 had UUC with typical EN histopathological signs, whereas that in Case 2 had right UUC without EN followed by left UUC with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. For Case 3, the appropriate tissue sample to detect adducts couldn’t have been obtained. This patient possibly had specific p53 mutations in exons that were not examined. The diverse clinical courses reported herein could be attributed to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.

Publications report on the Bosnian endemic focus as more active than the Croatian during the last decades. Our aim was to assess the current state and to compare upper urothelial cancer (UUC) patients’ characteristics between Bosnian and Croatian foci. Design and Methods: Study included 40 patients undergone surgery for UUC in the period from 2005 to 2010 in General Hospital „Josip Benčević“ in Slavonski Brod. The definition of UUC comprises calices, pyelon and/or ureter cancer. Aristolactam (AL-I)-DNA adducts were detected and quantified in renal cortex using 32P-postlabeling method and additionaly confirmed by mass spectrometry. Modified MDRD (Modification of Diet in Renal Disease) formula was used to calculate glomerular filtration rate, and patients were classified in chronic kidney disease (CKD) stages groups according to the KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines. Statistical analysis was performed using SPSS 16.0 at significance level p

Objectives and study: Approximately 50% of endemic nephropathy (EN) patients develop upper urothelial tract cancers (UUC) at some point during the course of their disease. Aristolochic acid (AA) was proven as the etiological factor both for EN and UUC. The goal of his study was to establish patterns of gene expression and posttranscriptional gene regulation mechanisms involved in AA induced carcinogenesis. Methods: Paired samples of tumors and adjacent normal urothelial tissues of 10 patients from Croatian endemic region were analyzed. miRNA profiling was performed by high-capacity qPCR using Applied Biosystems megaplex RT primer pools for 754 human miRNAs and the microfluidisc TagMan Low Density Arrays, while miRNA profiling of the same RNAs was performed using Affymetrix HG U133 Plus 2.0 arrays. Results: A signature of 50 miRNAs differentially modulated (19 elevated and 31 reduced) and 4801 significantly modulated mRNAs (2005 elevated and 2796 reduced) were identified in tumor vs. unaffected tissue. Using R-scripting, miRNA and mRNA dana were integrated, identifying 643 predicted, inversely correlated targets oft he 19 upregulated miRNAs and 483 predicted, inversely correlated targets oft he 31 downregulated miRNAs. Cancer-related miRNAs were upregulated in UUC while their tumor suppressor targets (PDCD4, PTEN, TPM1, PTCH1) were reduced. Additionally, the anti- metastatic miR-200 family was elevated in tumors, concurrently with low levels of its targets, the ZEB1/2 repressors of E cadherin. Inhibition of invasive/migratory process was documanted by increased miRNAs targeting cellular movement, migration and invasion (FGF1, COLIA2, CTGF, IGF1, MMP2, PTEN, RHOB, THBSI and TGFBR2). Comprehensive biological interpretation and mining oft he integrated miRNA:mRNA dana set (Ingenuity Pathway Analysis) identified high-scoring pathways of renal necrosis, renal damage and failure, cancer regulated cell growth and proliferation, G2/M DNA damage checkpoint regulation and DNA repair, inflammatory disease and suppression of cellular movement and migration. Conclusion: UUC tumorigenesis appears to involve primarily miRNA- mediated process of repression of tumor suppressor genes, tumor growth, induction of inflammatory processes and repression of anti- invasion/metastasis programs rendering the non- metastatic nature of these carcinomas.

Endemic (Balkan) nephropathy (EN) is characterized by an insidious onset, slow progression to end stage renal disease and a strong association with upper urinary tract cancers (UUC). EN occurs only in rural villages, situated near tributaries of the Danube River ; epidemiologic studies reveal a familial aggregation, but not an inherited disease. Various environmental agents, including ocratoxin A have been proposed as putative causative factors of EN but strong evidence in support of these hypotheses in lacking. We have proposed that chronic dietary exposure to aristolochic acid (AA) is genetically susceptible individuals is uniquely responsible for EN and UUC. This hypothesis is supported by the unquivocal detection of 7-(deoxyadenosin_N6-yl) aristolactam DNA adducts in renal cortical and UUC tissues of patients with EN and/or UUC.

The activation of protooncogenes and inactivation of tumor suppressor genes are considered to be the main molecular events in the multistep process of carcinogenesis. Mutations of the TP53 tumor suppressor gene have been found in nearly all tumor types and are estimated to contribute to more than 50% of all cancers. Most mutations lead to the synthesis of highly stable, inactive proteins that accumulate in the nucleus of cancer cells. Alterations of codons 175, 248, 273 and 282 correspond to 19 % of all mutations and are considered general hot spot mutations. Dietary exposure to aristolochic acid (AA), an established nephrotoxin and human carcinogen found in all Aristolochia species was shown to be the causative agent of aristolochic acid nephropathy (previously called Chinese herbs nephropathy). This syndrome is characterized by proximal tubular damage, renal interstitial fibrosis, slow progression to the end stage renal disease and a high prevalence of upper urinary tract urothelial carcinoma (otherwise a highly unusual location). AA preferentially binds to purines in DNA and is associated with a high frequency of A → T transversions in the p53 gene. Rats treated with AA develop A:T → T:A mutations in codon 61 of c-H-ras gene. The pathological and clinical features of endemic (Balkan) nephropathy closely resemble those associated with aristolochic acid nephropathy except for the slower progression to end stage renal disease and longer cumulative period before the appearance of urothelial cancer. Recently, we reported the presence of AA-DNA adducts in renal cortex and A → T p53 mutations in tumor tissue of patients from Croatia and Bosnia with endemic nephropathy. These data support the hypothesis that dietary exposure to AA is a major risk factor for endemic (Balkan) nephropathy.

It was known for several decades that populations of endemic areas have significantly higher risk for upper urothelial cancers than non-endemic populations.

The frequency of upper-urinary-tract tumor vs. bladder tumor is statistically significantly higher in patients from the EN area.