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Brahiterapija visokim brzinama doze (HDR–BT) predstavlja efikasan modalitet zračenja kod pacijenata sa lokalizovanim karcinomom prostate (CaP) svih rizika. Za razliku od transkutane radioterapije i brahiterapije niskim brzinama doze (LDR–BT), kod ove grupe pacijenata u intersticijalnoj HDR–BT još uvek nisu jednoznačno definisane ukupne doze zračenja, način frakcionisanja kod pacijenata sa lokalizovanim CaP različitih rizika. U periodu od 2009–2018.god. HDR–BT kao jedinim načinom lečenja (monoterapija) u Opštoj bolnici Medicinski sistem Beograd, lečeno je 35 pacijenata (6 (17,1%) pacijenata niskog rizika, 21 (60%) pacijent srednjeg rizika i 8 (22,9%) pacijenata visokog rizika) sa lokalizovanim CaP različitih rizika od relapsa i progresije bolesti. Grupe pacijenata sa srednjim i visokim rizikom spojene su u jednu grupu (grupa sa višim rizikom). Tehnika sprovođenja HDR–BT, osim u pojedinačnim specifičnim detaljima, bila je slična kao i kod LDR–BT. Aplikacija igala, segmentacija, delineacija i planiranje HDR–BT vršeno je korišćešem transrektalnog ultrazvuka (TRUS) i izocetričnog radioskopskog C–luka, a zračenje je sprovedeno na uređaju Microselectron HDR sa zatvorenim radioaktivnim izvorom 192Ir početne aktivnosti 370 GBq. Aplikovane terapijske doze (TD), u opsegu od 30–57 Gy frakcionisane su u 3–4 nezavisne frakcije sa razmakom od 2–3 nedelje između frakcija, a individualizovane su prema nivou rizika, stanju organa u riziku (OAR) i kvalitetu aplikacije (indeksu prekrivanja CTV sa planiranom terapijskom dozom (CI100%) i mogućnošću zaštite OAR). Uspešnost terapije ocenjivana je postignutom biohemijskom kontrolom (BFS – biochemical–free–survival), prema ASTRO i Phoenix kriterijumima, kao i ukupnim preživljavanjem u periodu od 5 godina (2–9 godina) posle sprovedene terapije. U niskorizičnoj grupi pacijenata lečenih HDR–BT, BFS je postignuta kod svih pacijenata kao i ukupno preživljavanje. U grupi pacijenata sa višim rizikom BFS je postignuta kod 95,8% lečenih pacijenata, a ukupno 5–to godišnje preživljavanje je 96,4%. BFS u ovom istraživanju se pokazala statistički značajnije bolja nego ona koju su prikazali drugi autori. Na osnovu rizika, nivoa PSA, TD i indeksa pokrivenosti CTV sa TD, izvršeno je modelovanje terapijskih parametara korišćenjem MANN (multilauyer artificial neural network). Određena optimalna doza zračenja (TD) u HDR–BT lokalizovanog CaP niskog rizika je 40,7 Gy za CI100% = 1,01. Kod viših rizika TD = 50,9 Gy za CI100% = 1,6. TD se frakcioniše u 4 nezavisne frakcije sa razmakom od 2–3 nedelje. Ovakav izbor parametara HDR–BT (TD, CI100%, i način frakcionisanja), uz individualizaciju i kontrolu u toku svake aplikacije, obezbedio bi prihvatljiv nivo kasnih postiradijacionih komplikacija gradusa G1–G3 na uretri (< 17% ukupnog broja lečenih pacijenata), uz minimimalne komplikacije na rektumu (pretežno G1–G2) i zanemarljive komplikacije na mokraćnoj bešici., High–dose rate brachytherapy (HDR–BT) is an effective therapy modality for patients with localized prostate cancer (CaP) of all risks. In contrast to an external beam radiotherapy and low–dose rate brachytherapy (LDR–BT), in these patients, the interstitial HDR–BT, the total radiation dose and fractionation is not unambiguously defined. Between 2009–2018 35 patients with localized CaP (6 (17.1%) low–risk patients, 21 (60%) patients medium–risk and 8 (22.9%) high–risk) were treated with HDR–BT, as the only treatment (monotherapy) in the General Hospital Medical System Belgrade. The group of patients with medium–risk and high–risk were merged into a single group (group with a higher–risk). Technique implementation of HDR–BT was similar as in the LDR–BT. Application of needles, segmentation, delineation, and planning of HDR–BT was performed with transrectal ultrasound (TRUS) and izocentrically mounted radioscopic C–arm. Irradiation was done on the Microselectron–HDR brachytherapy unit with a sealed radioactive source 192Ir (370 GBq). The dose (TD), in the range of 30–57 Gy was given fractionated in independent fractions (3–4) with a pause of 2–3 weeks between fractions. TD was individualized according to the risk, the conditions of organs at risk (OAR) and quality of the application (coverage index CI100%), as well as, the ability to protect OAR. Treatment result was evaluated by the achieved biochemical control (BFS – biochemical–free–survival) according to ASTRO and/or Phoenix criteria, as well as an overall survival in the period of 5 years (2–9 years) after the completion of the treatment. In the low–risk group, BFS has been achieved in all patients and overall survival rate is 100%. In the group of patients with higher risk BFS was achieved in 95.8% of treated patients, and 5–year survival rate was 96.4%. BFS in this study was proved to be statistically significantly better than showed by other authors. On the basis of the risk, the level of PSA, TD and CI100%, modeling was performed using the MANN (multilayer artificial neural network). The determined optimal dose TD for localized CaP of low risk is 40.7 Gy for CI100% = 1.0. At higher risk TD = 50.9 Gy for CI100% = 1.6. TD was given in 4 independent fractions with the interval of 2–3 weeks between each fraction. These HDR–BT parameters (TD, CI100%, and the fractionation scheme) with the individualization and control during each application would provide an acceptable level of late complications grade G1–G3 to the urethra (in less than 17% of treated patients), with minimum complications on the rectum (predominantly grade G1–G2) and insignificant complications rate on the urinary bladder.

Adenokarcinom prostate (PCa) je najčešći karcinom u muškaraca. Intraepitelne prostatične neoplazme visokog gradusa (HGPIN) su lezije koje prethode nastanku invazivnog karcinoma i podrazumevaju kompletno odsustvo bazalnih ćelija i invaziju strome malignim acinusima. Estrogeni receptor β (ERβ) se nalazi u jedrima bazalnih i sekretornih ćelija acinusa i delimično u stromalnim ćelijama. Cilj istraživanja je da prikaže i lokalizuje ERβ u različitim morfološkim lezijama prostate: hiperplaziji (BHP), PINu i u PCa sa različitim Gleason scorom. Pretpostavlja se da prekancerozne lezije u svojim različitim fazama evolucije ne koreliraju u potpunosti sa ekspresijom ERβ. LGPIN pokazuje ekspresiju, dok u HGPINu nema ekspresije. Takođe je pretpostavka da ekspresija ERβ postoji u većine srednje diferentovanih PCa, te da se ekspresija posmatranog receptora gubi sa porastom Gleason scora. Ispitivano je pet grupa bolesnika: kontrolna grupa sa BHP i četiri eksperimentalne grupe (PIN i 3 različite grupe PCa). Studija je sprovedena na muškarcima različite starosti u periodu 2010–2012. Nijedan pacijent nije prethodno primio hormonsku terapiju. Sekstant biopsije prostate su bojene na ERβ (Novocastra). Lokalizacija i intenzitet ERβ ekspresije prikazani su kroz skor: 0 = nula; 1 = 66%. Pozitivni fibroblasti i endotelne ćelije su korišćene za poređenje. Smanjena ekspresija ERβ primećena je kod malignih i premalignih lezija prostate naspram BHP. Ekspresija ERβ u epitelnim ćelijama acinusa bila je najslabija u dobro diferentovanim PCa. Kod BHP i dobro diferentovanih PCa bila je veća ekspresija ERβ u bazalnim ćelijama nego u sekretornim. Loše diferentovani PCa prikazali su smanjenje ekspresije ERβ u bazalnim ćelijama. Ukupna ćelijska ekspresija ERβ predstavlja složen i ponekad moguće paradoksalan nalaz, na osnovu čega primarni PCa zadržava ekspresiju ovog receptora, ali ipak značajno nižu u poređenju sa benignim epitelom i premalignim lezijama. Ovaj nalaz podupire stanovište o antiproliferativnoj ulozi ERβ u tkivu prostate., Adenocarcinoma of the prostate (PCa) is the most common cancer in men. High-grade prostatic intraepithelial neoplasia (HGPIN) are lesions that precede to invasive carcinomas and include complete absence of basal cells and stromal invasion by malignant acini. Estrogen receptor ß(ERß) is located in the nuclei of basal and secretory cells and partly in stromal ones.The aim of the research is to describe and localize ERß in different morphological lesions: prostate hyperplasia (BPH), PIN and PCa with different Gleason score. It is assumed that pre-cancerous lesions in different stages of their evolution not correlate completely with the expression ERß. LGPIN shows expression, while there is no expression in HGPIN. It is also an assumption that the expression ERß exists in most medium differentiated PCa, and that the expression of this receptor loses with increasing of Gleason score. Five groups of patient were investigated: control group with BPH and four experimental groups (PIN and 3 different groups of PCa). The study was conducted on men of different ages in the period 2010-2012. None of the patients received prior hormonal therapy. Sextant prostate biopsy were stained on ERß (Novocastra). ERß expression is shown through the score: 0 = zero; 1 = 66%. Positive fibroblasts and endothelial cells were used for comparison. Reduced expression was observed in malignant and premalignant lesions of the prostate versus BPH. ERß expression in the epithelial cells of acini was the weakest in well-differentiated PCa. In BPH and well differentiated PCa was greater expression in the basal cells than in secretory ones. Poorly differentiated PCa showed a decreased ERß expression in basal cells. Total cellular expression of ERß is a complex and sometimes paradoxical finding on the basis of which the primary PCa retains expression of this receptor, but significantly lower compared to benign epithelium and premalignant lesions. This finding supports the antiproliferative role of ERß in prostate tissue.

U eksperimantalnom postupku disertacije miševi NMRI soja su tretirani infuzom biljke Aristolochia clematitis. Sasušeni listovi, grane i plodovi biljke potopljeni su u ključalu vodu i ostavljeni 3-5 sati da stoje, a potom su profiltrirani kroz filter papir. Pravljen je rastvor biljke/vode od 10g/ 1000ml (1%), 20g/ 1000ml (2%) i 40g/ 1000ml (4%). Različite koncentracije infuza su date miševima da piju u neograničenoj količini u periodu od 7 nedelja. Tako su formirane tri ispitne grupe, prva koja je primala 1% infuz, druga 2% infuz i treća 4% infuz i kontrolna grupa koja je dobijala samo vodu da pije. U svakoj grupi je bilo 20 životinja. Tako je razvijen animalni model hronične toksičnosti. Na kraju eksperimenta je urađena patohistološka analiza bubrega, makroskopski pregled organa i merenje diureze tokom trajanja eksperimenta. Urađena je kompletna analiza urina koja podrazumeva utvrđivanje: boje, izgleda, pH, specifične težine, proteina i sedimenta urina. Analize urina ponavljane su na svakih 7 dana u toku 7 nedelja istraživanja. Na kraju eksperimenta urađena je analiza biohemijskih parametara (glukoza, urea, kreatinin, mokraćna kiselina, ukupni bilirubin, direktni bilirubin, ukupni tj. totalni proteini, natrijum i kalijum) i analiza kompletne krvne slike. Utvrđeno je da je Aristolochia clematitis izrazito nefrotoksična biljka. Utvrđene su patohistološke promene tubula i intersitcijuma NMRI miša, koje su bile najveće u ispitnoj grupi koja je primala najaču dozu. Ustanovljene patohistološke promene su slične opisanim patohistološkim promenama tubulointersticijuma bolesnika obolelih od Balkanske endemske nefropatije. Nije ustanovljeno postojanja karcinoma gornjeg urotrakta. Makroskopskim pregledom prilikom obdukcije eksperimentalnih životinja nisu ustanovljene značajnije promene bubrega. Došlo je prvo do izrazitog porasta diureze u prvoj, odnosno drugoj nedelji praćenja, kod druge i treće eksperimentalne grupe, da bi nakon 7 nedelja istaživanja diureza u svim ispitnim grupama bila manja od kontrolne grupe. Postoji porast ureje na kraju istraživanja, koji je dvostruko veći u trećoj eksperimentalnoj grupi u odnosu na kontrolnu. Postoji izrazit pad mokraćne kiseline na kraju istraživanja kod eksperimentalne grupe 3. Postoji izrazit pad granulocita u leukocitarnoj formuli u svim ispitnim grupama, a najveći je u trećoj ispitnoj grupi. Kako je došlo do pada relativnih vrednosti granulocita, tako je došlo do porasta relativnih vrednosti limfocita u prvoj i drugoj ispitnoj grupi. U trećoj ispitnoj grupi je pad granulocita praćen izrazito velikim povećanjem relativnog broja bazofilnih granulocita. Postoji značajan pad specifične težine urina na kraju istraživanja u drugoj i trećoj eksperimentalnoj grupi. Proteinurija je bila čest nalaz svim eksperimentalnim grupama, dok je bila odsutna ili samo u tragu u kontrolnoj grupi. Na kraju eksperimenta je utvrđen znatni porast broja kristala fosfata u eksperimentalnim grupama. Cilindri su se pojavljivali samo u nalazu urina u trećoj ispitnoj grupi. Najveći broj promena urina je utvrđen u trećoj eksperimentlanoj grupi., In the experimental procedure of dissertation, NMRI strain mice were treated with infusion of plants Aristolochia clematitis. Dried leaves, branches and fruit plants are submerged in boiling water and left to stand for 3-5 hours, and then filtered through filter paper. It was made a solution of the plant / water of 10g / 1000ml (1%), 20g / 1000ml (2%) and 40g / 1000ml (4%). Different concentrations of infusions were given to mice to drink an unlimited amount for a period of 7 weeks. So we formed the three test groups, the first who received 1% infusion, the second received 2% infusion and third received 4% infusion and a control group that received only water to drink. In each group there were 20 animals. Thus, developed an animal model of chronic toxicity. At the end of the experiment was performed histopathological analysis of kidneys, macroscopic examination of organs and measuring urine output during the experiment. We performed a complete analysis of urine, which is the determination of: color, appearance, pH, specific gravity, protein and urine sediment. Urinalysis were repeated every 7 days during the 7 weeks of the study. At the end of the experiment were analyzed for biochemical parameters (glucose, urea, creatinine, uric acid, total bilirubin, direct bilirubin, total proteins, sodium and potassium) and analysis of the complete blood count. It has been found that Aristolochia clematitis is extremely nephrotoxic plant. Identified histopathological changes of tubules and interstitium of NMRI mouse, which were the biggest in the test group receiving biggest dose. Established histopathological changes are similar to those described by pathological changes of tubulointerstitial injury of patients with Balkan endemic nephropathy. Not established the existence of cancer of the upper urinary tract. Macroscopic examination at autopsy of experimental animals, did not determine significant changes in the kidneys. There is first an enormous increase in diuresis in the first and second week of follow-up, in the second and third experimental groups retrospectively, that after 7 weeks of research, diuresis in all test groups was lower than the control group. There is an increase of urea at the end of the research, which is twice higher in the third experimental group compared to the control. There is a marked decrease in uric acid at the end of the research in the experimental group 3. There is a marked decrease in granulocytes in the leukocyte formula in all test groups, and the highest in the third test group. As the decline in the relative values of granulocytes, so there has been a rise in the relative values of lymphocite in the first and second test group. In the third test group, granulocyte drop was accompanied by a extremely large increase in the relative number of basophils. There is a significant drop in specific gravity of urine at the end of the research in the second and third experimental group. Proteinuria is a common finding to all experimental groups, while it was absent or only in traces in the control group. At the end of the experiment was determined to increase significantly the number of phosphate crystals in the experimental groups. The cylinders have appeared only in the urine in the third test group. The greatest number of changes in the urine is determined in the third experimental group.

Vitamin D ima antiproliferativno, proapoptotsko i prodiferencijaciono dejstvo. Dokazi o dejstvu na ćelije adenokarcinoma prostate su malobrojni i nekonzistentni. Cilj ispitivanja je određivanje stepena povezanosti između nivoa vitamina D, stadijuma adenokarcinoma prostate, prostata specifičnog antigena, Gleason grade i progresije oboljenja. Ispitivanje je prospektivno, sprovedeno na 120 ispitanika (90 pacijenata sa dijagnostikovanim karcinomom prostate i 30 kontrolnih, zdravih subjekata). Pacijenti sa dijagnostikovanim adenokarcinomom prostate podeljeni su prema stadijumu bolesti u dve grupe: lokalizovano (pT2cN0M0, prostata specifični antigen ≤ 20 ng/ml, Gleason 2-7) i metastatsko oboljenje (pT3-4, N1, M 0,1(a,b,c), prostata specifični antigen ≥ 20 ng/ml, Gleason ≥ 8), dok su prema ordiniranoj terapiji podeljeni u tri grupe: pacijenti koji su hemijski kastrirani, hirurški kastrirani i grupa kod koje je urađena radikalna prostatektomija. Uzorci za analizu nivoa vitamina D i prostata specifičnog antigen uzeti pre ordinirane terapije a nakon toga posle 6 i 12 meseci. Kako ne postoje definisane vrednosti unosa vitamina D i kalcijuma za ispitivano podneblje formirani smo Upitnik kojim smo evaluirali dnevni unos kod 90 zdravih subjekata muškog pola starijih od 50 godina koji nisu učestvovali u ispitivanju. Da bismo uočili ispitanike koji su hranom ili životnim navikama drastično uticali na vrednost vitamina D isti Upitnik su ispunili svi ispitanici uključeni u ispitivanje. Ustanovljena je očuvana godišnja oscilacija vitamina D kod ispitanika te smo statističkim modelom korigovali ovu varijablu. Rezultati pokazuju da grupa obolelih nema apsolutno niske vrednosti vitamina D i da su vrednosti kod obolelih niže u odnosu na kontrolne subjekte (64.12 nmol/l vs. 74.45 nmol/l). Nije uočena razlika u nivou vitamina D kod pacijenata sa lokalizovanim i metastatskim oboljenjem (62.90 nmol/l vs. 64,65 nmol/l). Odnos između prostata specifičnog antigena i vitamina D posmatran tokom perioda ispitivanja pokazuje da je kod obolelih pacijenata koji su hemijski ili hirurški kastrirani i kod pacijenata kod kojih je urađena radikalna prostektomija postoji pozitivna korelacija pre ordinirane terapije u sve tri grupe, nakon ordinirane terapije možemo uočiti inverznu korelaciju. Konrolna grupa ispitanika pokazuje stalnu pozitivnu korelaciju između nivoa vitamina D i prostata specifičnog antigena. Pacijenti kod kojih je došlo do progresije imaju niže vrednosti nivoa vitamina D u odnosu na pacijente kod kojih nije došlo do progresije. Nije ustanovljena korelacija između vremenskog intervala do progresije oboljenja i nivoa vitamina D., Vitamin D has antiproliferative, proapoptotic and prodifferentiational actions. There is a limited number of studies asessing influence of vitamin D on prostate cancer. Results of those available studies are inconsistent. This study hypothesizes with correlation of vitamin D, prostate cancer stage, prostate specific antigen, Gleason grade, stage, and disease progression. This prospective study included 120 subjects (90 subjects with diagnosed prostate cancer and 30 healthy, age adjusted controls). Patients with diagnosed prostate cancer formed two groups by criterion of disease advancement: localized (≤pT2cN0M0, prostate specific antigen ≤ 20 ng/ml, Gleason 2-7) and metastatic (≥pT3-4, N1, M 0,1(a,b,c), prostate specific antigen ≥ 20 ng/ml, Gleason ≥ 8. According to applied therapy subjects were devided in three groups: surgicaly castrated, medicamentous castrated and radical prostatectomy treated. Samples were obtained before therapy and after 6 and 12 months. As no defined value for vitamin D and calcium intake could be found we formed Questionnaire for vitamin D and calcium intake. Data were obtained from 90 healthy, age adjusted subjects, not included in this study. All subjects included in this study filed the Questionnarie and subjects with unusual vitamin D and calcium intake were excluded. Annual oscilation of vitamin D was observed, so we applied statistical model that excluded this variable. Subjects with diagnosed prostate cancer didn't have absolutely low vitamin D level. This level was lower in group of subjects whith diagnosed prostate cancer comparing to controls (64.12 nmol/l vs. 74.45 nmol/l). No differences in vitamin D level was observed in groups of patients with localised and metastatic disease (62.90 nmol/l vs. 64,65 nmol/l).Correlation of vitamin D and prostate specific antigen during 12 months period showed that castrated subjects and subjects in radical prostatectomy group showed possitive correlation before surgical treatment and inverse, negative correlation, after treatment. Control group showed possitive correlation of vitamin D and prostate specific antigen in all three measurements. Subjects with progression have significantly lower vitamin D level comparing to subjects without progression. No correlation between time to progression and vitamin D have been observed.