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Uvod: Serozni rak jajčnika visokega visokega gradusa (ang. high grade serous ovarian cancer, HGSC) je najpogostejši in najbolj agresiven histološki tip raka jajčnika. Običajno ga odkrijemo v napredovalem stadiju bolezni z izlivi v telesne votline, ki so pogosto prvi znak bolezni. Kljub napredku v diagnostiki in zdravljenju, se preživetje bolnic v zadnjih letih ni izboljšalo. Bioloških označevalcev s katerimi bi lahko zanesljivo napovedali potek bolezni in odgovor na zdravljenje zaenkrat še nimamo. V doktorski nalogi smo želeli preučiti tumorske sferoide ter imunske celice (ki sestavljajo tumorsko mikrookolje v izlivih bolnic s HGSC) kot potencialne napovedne dejavnike poteka bolezni, ovrednotiti izražanje PD-1 (receptor celične smrti 1) in PD-L1 (ligand PD-1) na imunskih in tumorskih celicah ter določiti morfološke, imunofenotipske in molekularne značilnosti tumorskih celic za takojšno in zanesljivo citopatološko diagnostiko. Cilji: V sklopu raziskave smo zastavili tri glavne cilje: 1) kvantificirati različne imunske celice v izlivih bolnic s HGSC in izražanje PD-1 in PD-L1 ter opredeliti njihovo napovedno vrednost preživetja 2) opisati tumorske sferoide v izlivih, s poudarkom na njihovih morfoloških značilnostih, sestavi celic (tumorskih, imunskih in endotelijskih celic) ter izražanju PD-1 in PD-L1 3) oceniti zanesljivost citopatologije za določanje imunofenotipskih značilnosti tumorskih celic in mutacij BRCA1/2 iz izlivov HGSC. Metode: V raziskavo smo vključili bolnice s histološko potrjenim HGSC in malignim izlivom. S pretočno citometrijo smo določili prisotnost (delež) različnih imunskih celic v izlivih: limfociti T (CD3+ in njihovih podskupin CD4+, CD8+), regulatorni limfociti T (Treg), NK T celice, CD103+ limfociti T, limfociti B, NK celice, makrofagi in dendritične celice ter izražanje PD-1 in PD-L1. Nizek in visok delež imunskih celic smo opredelili na osnovi mediane. Poleg tega smo v ramazih pobarvanih po Giemsi ocenili velikost in gostoto tumorskih sferoidov, določili mejno vrednost za razlikovanje bolnic z nizko in visoko gostoto tumorskih sferoidov, ki lahko napove boljše oz. slabše preživetje. Na citoblokih smo z imunocitokemijo (ICK) določili celično sestavo sferoidov. Poleg tega smo opazovali tudi izražanje PD-1 in PD-L1. Rezultate pretočno-citometrične analize imunskih celic in ICK analiz sferoidov smo uporabili za izračun morebitne korelacije s preživetjem brez napredovanja bolezni (ang. progression-free survival, PFS) ter celotnim preživetjem (ang. overall survival, OS). Na citospinih in citoblokih smo izvedli ICK barvanje za označevalce, značilne za HGSC histotip: PAX8, WT1, P53, P16 in Ki-67. S sekvenciranjem nove generacije (ang. next-generation sequencing, NGS) smo določili prisotnost zarodnih ali somatskih mutacij BRCA1/2 v izlivih. Rezultate ICK in NGS smo primerjali z rezultati imunohistokemije (IHK) in NGS iz vzorcev tkiva primarnega tumorja ter vzorcev krvi. Rezultati: Rezultati pretočne citometrije so pokazali, da so limfociti T prevladujoče imunske celice v izlivih (mediana 51%), medtem ko je drugih imunskih celic bistveno manj (mediana ?10%). PD-1 je bil izražen predvsem na limfocitih T (mediana 20%), manjše izražanje pa smo opazili tudi na drugih imunskih celicah. Izražanje PD-L1 nismo zaznani. Bolnice z visokim deležem CD103+ T limfocitov, NK celic, dendritičnih celic in PD-1+ Treg celic so imele statistično značilno boljši PFS in OS kot bolnice z nizkim deležem imunskih celic. Bolnice z visokim deležem CD8+ limfocitov T, makrofagov in PD1+ NK celic ter nizkim deležem CD4+ limfocitov T pa so imele le statistično značilno boljši OS. Poleg tega smo v razmazih pobarvanih po Giemsi opazili majhne, srednje velike in velike sferoide, vendar njihova velikost ni bila povezana s preživetjem. Določili smo 10% mejno vrednost gostote sferoidov, ki je bila povezna s statistično značilno boljšim oz. slabšim PFS in OS. Preučevali smo tudi sferoide v citoblokih, vendar le pri vzorcih, ki so vsebovali velike in številne sferoide. Rezultati ICK so potrdili, da so poleg tumorskih celic v sferoidih tudi limfociti, makrofagi in endotelijske celice. PD-1 je bil v sferoidih izražen predvsem na limfocitih, medtem ko smo opazili izražanje PD-L1 tako na tumorskih celicah kot tudi na imunskih celicah. Korelacije s preživetjem bolnic nismo uspeli pokazati. Rezultati ICC/IHC za PAX8, WT1, P53 in P16 so pokazali zelo dobro korelacijo med citospini, citobloki in tkivnimi bloki (? > 0,75), vendar korelacija za Ki-67 je bila slabša (? < 0,26 p < 0,001). Dodatno smo potrdili 100% korelacijo zarodnih mutacij BRCA1/2, ki so bile določene iz izlivov in primarnega tumorja, vendar to ni bilo opaženo pri somatskih mutacijah. Zaključek: Rezultati doktorske disertacije so pokazali, da imajo vzorci izlivov bolnic s HGSC velik potencial za preučevanje in razvoj novih prognostičnih označevalcev ter so enakovredni tkivnim vzorcem primarnega tumorja za postavitev zanesljive diagnoze HGSC. Introduction: High-grade serous ovarian cancer (HGSC) is the most common and aggressive histotype of ovarian cancer, often associated with effusions at presentation. Despite advancements in diagnosis and treatment, survival rates for HGSC patients have not improved in recent years. Currently, there is a need for new biological markers that can reliably predict the course of the disease and response to treatment. One potential source of such markers is the effusion that often accompanies HGSC. HGSC effusions contain tumor spheroids, dissociated tumor cells, and immune cells, and by studying the features and prognostic significance of these components, we may be able to identify new markers that can aid in the diagnosis and treatment of HGSC. However, there is a lack of quantitative data about the immune cells in HGSC effusions and data on their clinical importance. Furthermore, no study has yet investigated the presence of immune cells and endothelial cells in tumor spheroids and the expression of PD-1 and PD-L1. In general, cytopathology has also been underused as a modality to identify immunophenotypic and molecular features of HGSC. Objective: Three main objectives were established: 1) to quantify different immune cells in HGSC effusions, the expression of programmed death receptor-1 (PD-1) and its ligand (PD-L1) in both tumor and immune cells, and to calculate their correlation with patient progression-free survival (PFS) and overall survival (OS) 2) to study tumor spheroids within effusions with an emphasis on their morphological features, cell composition (tumor cells, immune cells, and endothelial cells), and PD-1 and PD-L1 expression, and 3) to evaluate the accuracy of cytopathology to identify immunophenotypic features of tumor cells and BRCA1/2 mutations from HGSC effusions. Methods: Patients with histologically confirmed HGSC and malignant effusions were included in the study. Flow cytometry analysis was performed to detect percentages of different immune cells in the effusions: T lymphocytes (CD3+ and their subsets CD4+, CD8+, regulatory T cells (Tregs), NK T (NKT) cells, and CD103+ T lymphocytes), B lymphocytes, NK cells, macrophages, and dendritic cells (DCs), as well as their expression of PD-1 and PD-L1. The cut-off of low and high percentages of different immune cells was determined by the median of the variables. Giemsa smears were used to evaluate the size and density of tumor spheroids in effusions, and a cut-off value for low and high density of tumor spheroids that could predict better/poorer survival outcomes was determined. Cytoblock immunocytochemistry (ICC) was used to describe the cell composition of the spheroids to establish if immune cells (T and B lymphocytes, and macrophages) and endothelial cells composed tumor spheroids together with the tumor cells, as well as PD-1 and PD-L1 expression within the spheroids. Flow-cytometric results on immune cells and morphological and immunophenotypic features of spheroids were used to calculate if there is any correlation with PFS and OS. ICC staining for PAX8, WT1, P53, P16, and Ki-67 was performed on cytospins and cytoblocks and compared with the results in tissue blocks of the primary tumor. Next-generation sequencing (NGS) was used to detect germline/somatic BRCA1/2 mutations in the effusions. Both ICC and NGS results were compared with immunohistochemistry (IHC) and NGS results from tissue blocks of the primary tumor and blood samples. Results: Flow-cytometric results showed that T lymphocytes were the predominant cells in the effusions (median 51%), while the presence of other immune cells was much lower (median 䁤10%). PD-1 was mainly expressed on T lymphocytes (median 20%), and lower expression was observed on other immune cells. PD-L1 expression was not detected in immune cells at all. Patients with high percentages of CD103+ T lymphocytes, NK cells, DCs, and PD-1+ Tregs were significantly associated with better PFS and OS than patients with low percentages of those immune cells, while high percentages of CD8+ T subsets, macrophages, and PD1+ NK cells, and low percentages of CD4+ T subsets associated with significantly better OS. The presence of small, medium, and large spheroids was observed in Giemsa smears but the size of the spheroids did not correlate with patients’ survival. A 10% cut-off for spheroid density in Giemsa smears was established, which significantly predicted the PFS and OS of the patients. The presence of spheroids was also observed in cytoblocks, but only in cases of big-sized and high-density spheroids (25/43 cytoblocks). ICC results confirmed the presence of spheroid-associated lymphocytes, macrophages, and endothelial cells in the spheroids. PD-1 was mainly expressed in spheroid-associated lymphocytes, while PD-L1 expression was seen in both spheroid-associated tumor cells and immune cells. No correlation with patient survival was observed. ICC/IHC results for PAX8, WT1, P53, and P16 showed good reliability between cytospins, cytoblocks, and tissue blocks (α > 0.75), whereas poor reliability and significant differences were observed for Ki-67 between effusions and tissue blocks (α < 0.26 p < 0.001). A 100% concordance was confirmed for the germline BRCA1/2 mutations between effusions and tissue blocks, but only 14% concordance for the somatic mutations. Conclusions: The results from the doctoral thesis highlight the potential of HGSC effusions to describe tumor and immune cells, explore their prognostic significance and the possibility of evolving new prognostic markers, as well as the importance of cytopathology to confirm HGSC histotype and BRCA1/2 mutations from effusions as reliable as from the primary tumor tissue.

Colorectal cancer (CRC) is still one of the most common types of cancer in the world, and the gut microbiome plays an important role in its development. The microbiome is involved in the carcinogenesis, formation and progression of CRC as well as its response to different systemic therapies. The composition of bacterial strains and the influence of geography, race, sex, and diet on the composition of the microbiome serve as important information for screening, early detection and prediction of the treatment outcome of CRC. Microbiome modulation is one of the most prospective new strategies in medicine to improve the health of individuals. Therefore, future research and clinical trials on the gut microbiome in oncology as well as in the treatment of CRC patients are warranted to determine the efficacy of systemic treatments for CRC, minimize adverse effects and increase survival rates. Nasl. z nasl. zaslona. Opis vira z dne 13. 12. 2021. Bibliografija na koncu prispevka. Abstract.

Izhodišča. O dejavnikih, ki določajo, kakšna bosta potek in izid klopnega meningoencefalitisa (KME), o (dolgo)trajnih posledicah prebolele bolezni (postencefalitisni sindrom) in o mehanizmih, ki so povezani z neugodnim potekom in izidom bolezni, je malo znanega. Namen. Namen raziskave je opredeliti klinične značilnosti akutne bolezni, ugotoviti, kateri klinični in/ali laboratorijski parametri so povezani s težjim potekom bolezni in/ali neugodnim izidom, oceniti (dolgo)trajne posledice, ki jih pušča prebolela bolezen, in osvetliti osnovne imunske značilnosti KME. Metode dela. V raziskavo smo vključili 717 odraslih bolnikov, ki so bili v obdobju od 1. 1. 2007 do 31. 12. 2012 na Kliniki za infekcijske bolezni in vročinska stanja zdravljeni zaradi KME. Pri podskupini 420 bolnikov, ki smo jih povabili na kontrolni pregled leta 2014, 2–7 let po prebolelem KME, smo ocenili dolgoročni izid bolezni. V raziskavo smo vključili tudi kontrolno skupino oseb, ki so se z bolniki ujemale glede na starost in v preteklosti niso prebolele KME. Imunske odzive smo v obdobju akutne bolezni ocenili v serumu in možganski tekočini, 2 meseca in 2–7 let po preboleli bolezni pa le v serumu. Določili smo koncentracije 24 citokinov/kemokinov, ki zastopajo prirojene ter pridobljene Th1-, Th17- ter B-celične odzive. Rezultati. Multipla regresija je pokazala, da so s težjim potekom KME značilno povezani višja starost bolnikov (razmerje obetov (RO) 1,26, 95 % interval zaupanja (IZ) 1,11–1,44 P = 0,001), predhodno cepljenje proti KME (RO 14,23, 95 % IZ 1,72–117,87 P = 0,014), nizka koncentracija protiteles IgG proti virusu KME v serumu (RO 0,85, 95 % IZ 0,75–0,96 P = 0,009), večja koncentracija levkocitov v krvi (RO 1,45, 95 % IZ 1,13–1,85 P = 0,004) ter večja koncentracija C-reaktivnega proteina v serumu (ocenjeni koeficient 1,20, 95 % IZ 0,48–1,91 P = 0,001). Pogostost postencefalitisnega sindroma se zmanjšuje s časom in se stabilizira 12 mesecev po preboleli bolezni, ko ima postencefalitisni sindrom tretjina bolnikov kasneje se zmanjšuje le še njegova teža. Neugoden izid 6 mesecev po preboleli bolezni je povezan s koncentracijo levkocitov v možganski tekočini (RO 1,43, 95 % IZ 1,07–1,93, P = 0,017), po 12 mesecih z izidom bolezni po 6 mesecih (RO 497,89, 95 % IZ 39,42–6289,16, P < 0,001) in 2–7 let po preboleli bolezni z izidom bolezni po 12 mesecih (RO 38,56, 95 % IZ 8,40–177,14, P < 0,001). Bolniki so 2&#8210 7 let po prebolelem KME navedli večje število nespecifičnih simptomov v primerjavi s kontrolnimi preiskovanci, ki niso preboleli KME, prisotnost vsakega od ponujenih simptomov pa bolj pogosto in bolj stalno. Slabše so ocenili tudi kakovost telesnega in duševnega zdravja, vendar so bile razlike med skupinama majhne in niso bile statistično značilne. Koncentracije velike večine citokinov/kemokinov v serumu in možganski tekočini se v času akutne bolezni značilno razlikujejo: koncentracije citokinov/kemokinov prirojenega in Th1-pridobljenega imunskega odziva so večje v možganski tekočini, tiste, povezane s pridobljenim Th17- in B-celičnim imunskim odzivom, pa v serumu. Večina predstavnikov prirojenega in pridobljenega Th1-imunskega odziva je povezana s težo akutne bolezni, z neugodnim izidom bolezni pa nismo dokazali statistično značilnih povezav. Sklep. Raziskava, temelječa na velikem številu dobro definiranih odraslih bolnikov s KME, je omogočila določitev dejavnikov, ki so povezani s težkim potekom in neugodnim izidom KME, ter oceno pogostosti in kliničnih značilnosti postencefalitisnega sindroma. Omogočila je tudi vpogled v imunske značilnosti akutne bolezni ter v vnetne parametre, povezane s težko akutno boleznijo in neugodnim izidom. Background. Information on parameters associated with the severity of tick-borne encephalitis (TBE), on the long-term outcome (post-encephalitic syndrome), and on the mechanisms responsible for the unfavorable clinical course and outcome of TBE are limited. Aims. The aims of the study were to describe the clinical characteristics of acute TBE, to determine the clinical and/or laboratory parameters associated with the severity of acute illness and/or unfavorable outcome, to assess the frequency and severity of post-encephalitic syndrome at different time points after TBE, and to highlight the basic immune characteristics of TBE. Methods. Seven hundred seventeen adult patients, diagnosed with TBE and hospitalized at the Department of Infectious Diseases, University Medical Centre Ljubljana, in the period from 1. 1. 2007 to 31. 12. 2012, qualified for the study. In a subgroup of 420 patients who participated in a follow-up visit in 2014, i.e. 2–7 years after TBE, we assessed the long-term outcome of the disease. The study also included control group of subjects of the same age (± 5 years). Immune responses were evaluated in serum and cerebrospinal fluid in the period of acute illness, and in the serum 2 months and 2–7 years after the onset of illness. The concentrations of 24 cytokines /chmokines that represent innate and adaptive Th1, Th17 and B cell responses were determined. Results. Multivariate regression showed that patient age (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.11–1.44 P = 0.001), previous vaccination against TBE (OR 14.23, 95% CI 1.72–117.87 P = 0.014), low level of specific TBE virus serum IgG antibodies (OR 0.85, 95% CI 0.75–0.96 P = 0.009), blood leukocyte count (OR 1.45, 95% CI 1.13–1.85 P = 0.004), and serum C-reactive protein level (estimated coefficient 1.20, 95% CI 0.48–1.91 P = 0.001) were associated with severe acute illness. The frequency of post-encephalitic syndrome diminished over time and stabilized 12 months after the acute illness when it was present in one-third of patients whereas the severity of post-encephalitis syndrome continued to decline. Unfavourable outcome at 6 months was associated with cerebrospinal fluid leukocyte count (OR 1.43, 95% CI 1.07–1.93, P = 0.017), at 12 months with the disease outcome at 6 months (OR 497.89, 95% CI 39.42–6289.16, P < 0.001), and at the final visit with disease outcome at 12 months (OR 38.56, 95% CI 8.40–177.14, P < 0.001). Unspecific symptoms 2–7 years after TBE were more frequent and more constant in patients than in the control group. Similarly, patients have poorly assessed their physical and mental health, but the differences between the groups were small and were not statistically significant. The concentrations of most cytokines/chemokines in serum and cerebrospinal fluid were significantly different during the time of acute illness: cytokines and chemokines associated with innate immune responses and Th1 adaptive immune responses were significantly higher in cerebrospinal fluid, whereas mediators associated with Th17 and B cell immune responses were generally higher in serum. The majority of studied cytokines/chemokines of innate and adaptive Th1 immune responses were associated with the severity of acute illness, while statistically significant correlations with the unfavorable outcome of the disease have not been found. Conclusion. A study based on a large number of well-defined adult patients with TBE enabled the identification of parametrs associated with the severity of acute illness and/or unfavourable (long-term) outcome of TBE, and the assessment of the frequency and severity of postencephalitic syndrome. It also provided an insight into the immune characteristics of acute illness and inflammatory parameters associated with severe acute illness and an unfavorable outcome of TBE.

The aim of the study was to determine predictive factors for live birth after in vitro fertilization with autologous oocytes in women ≥40 years of age.Authors conducted a retrospective analysis of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles performed at the Department of Reproductive Medicine and Gynecologic Endocrinology, University Medical Centre Maribor, Slovenia between January 2006 and December 2015 in women aged 40 or more. The characteristics of patients and cycles were compared regarding live birth as the final outcome.A total of 1920 IVF/ICSI cycles with egg retrieval in women ≥40 years of age were performed leading to 1591 embryo transfers. The live birth rate per embryo transfer was 17.3% at 40, 11.6% at 41, 8.2% at 42, 7.9% at 43, 1.9% at 44 and 0.0% at ≥45 years of age. The multivariate logistic regression model showed that besides women's age (OR 0.66, 95% CI: 0.55-0.78), the number of previous cycles (OR 0.88, 95% CI: 0.82-0.95), number of good quality embryos on day 2 (OR 1.19, 95% CI: 1.05-1.36), number of embryos transferred (OR 1.57, 95% CI: 1.19-2.07) and day 5 embryo transfer (OR 2.21, 95% CI: 1.37-3.55) were also independent prognostic factors for live birth.The chance of in vitro fertilization success in women ≥40 years of age should not be estimated only on the woman's age, but also on other predictive factors: number of previous cycles, number of good quality embryos on day 2, number of transferred embryos and blastocyst embry transfer.Namen raziskave je bil odkriti napovedne dejavnike za živorojenost po postopku zunajtelesne oploditve z lastnimi jajčnimi celicami pri ženskah, starih 40 let in več.Avtorji so v retrospektivno analizo zajeli postopke zunajtelesne oploditve, ki so jih opravili na Oddelku za reproduktivno medicino in ginekološko endokrinologijo Univerzitetnega kliničnega centra Maribor od januarja 2006 do decembra 2015 pri bolnicah, starih 40 let ali več. Primerjali so značilnosti bolnic in postopkov, ki so se končali s porodom, s tistimi, kjer je bil postopek neuspešen.Pri bolnicah, starih 40 let in več, so naredili 1.920 aspiracij foliklov, v 1.591 postopkih pa so prenesli zarodke v maternično votlino. Delež živorojenih na prenos zarodka je bil v starosti 40 let 17,3 %, v starosti 41 let 11,6 %, pri 42 let starih ženskah 8,2 %, v starosti 43 let 7,9 %, pri 44-letnih 1,9 % in 0,0 % v starosti ≥45 let. Multivariatni logistični regresijski model je pokazal, da so ob starosti ženske (RR 0,66, 95 % CI: 0,55–0,78) neodvisni napovedni dejavniki za porod še število predhodno opravljenih postopkov (RR 0,88, 95 % CI: 0,82– 0,95), število kakovostnih zarodkov na dan 2 (RR 1,19, 95 % CI: 1,05-1,36), število prenesenih zarodkov (RR 1.57, 95% CI: 1,19–2,07) in število prenosov 5 dni starih zarodkov (RR 2,21, 95 % CI: 1,37–3,55).Pri napovedi uspešnosti postopkov zunajtelesne oploditve pri ženskah, starih ≥40 let, je treba poleg starosti upoštevati tudi druge napovedne dejavnike: število predhodnih postopkov, število zarodkov dobre kakovosti na dan 2, število prenesenih zarodkov in prenos blastocist.

Namen: Rak na prostati (CaP) je najpogostejša rakasta bolezen pri moških in eden glavnih razlogov zbolevnosti in umrljivosti. V zadnjih letih je vse več raziskav o novih tumorskih označevalcih za zgodnjo diagnozo prostatičnega karcinoma. Z dokazanimi napovednimi vrednostmi novih markerjev bi bolje razumeli naravni potek bolezni, omogočili zgodnejše in zanesljivejše odkrivanje karcinoma ter pripomogli k natančnejši napovedi progresa in metastaziranja bolezni pri posamičnem bolniku. Bolniki in metode: Opravili smo retrospektivno raziskavo na vzorcih prostate 202 bolnikov, pri katerih smo zaradi dokazanega karcinoma prostate naredili laparoskopsko radikalno prostatektomijo na urološkem oddelku Splošne bolniš nice Slovenj Gradec. Bolniki so bili operirani v obdobju od januarja 2010 do julija 2011. Morfološke značilnosti in klasične napovedne dejavnike karcinomov smo zbrali iz histopatoloških izvidov in jih potrdili tudi z revizijo preparatov. Za raziskavo smo konstruirali tkivne mreže. Tako pripravljene preparate smo obdelali po metodi fluorescentne hibridizacije in situ. Rezultati: V tumorskem tkivu bolnikov smo odkrili tri glavne oblike preurejanja genov: fuzijo TMPRSS2:ERG smo našli pri 63 (42 %) bolnikih, cepitev TMPRSS2 pri dvanajstih in cepitev ERG pri osmih bolnikih. Fuzijo TMPRSS2:ERG in cepitev TMPRSS2 hkrati smo ugotovili le pri enem bolniku. Pri treh bolnikih smo odkrili istočasno fuzijo TMPRSS2:ERG in cepitev ERG. Ko smo primerjali skupino 63 bolnikov z gensko fuzijo TMPRSS2:ERG in Gleasonov stadij pred operacijo, smo uporabili Freeman-Haltonovo varianto Fisherjevega natančnega testa, pri tem pa med spremenljivkama nismo našli statistične povezave (p = 0,19). Če smo analizirali odnos med gensko fuzijo in stadijem pT v celi kohorti bolnikov, povezave nismo mogli ugotoviti. Ko pa smo razdelili bolnike v dve skupini, eno s stadijem pT2 in drugo s pT3, smo odkrili statistično značilno povezavo med stadijem pT3 in osnovno gensko fuzijo. Med 62 bolniki s stadijem pT3 smo našli gensko fuzijo pri 34 (55 %) bolnikih. Z uporabo Fisherjevega natančnega testa smo odkrili statistično zanesljivost s p = 0,01. Po uporabi Bonferronieve korekcije pa je bila vrednost p še vedno zanesljiva z vrednostjo 0,05. V naslednjem koraku smo preverili še povezavo med gensko fuzijo in stadijem pN. Bolnike z opravljeno elektivno disekcijo bezgavk smo razdelili v dve skupini, in sicer pN0 in pN1. Za ta del odvisnosti smo uporabili Freeman-Haltonovo raširitev Fisherjevega natančnega testa. Med obema spremenljivkama nismo našli statistične povezave (p = 0,66). Za analizo bolnikov z ugotovljenim stadijem N smo izbrali skupino s tumorskim stadijem pT3. Pokazalo se je, da je korelacija z gensko fuzijo statistično značilna (p = 0,02). Ko pa smo uporabili še Bonferronievo korekcijo, vrednost p ni dosegla 0,05. V nadaljnjih statističnih obdelavah smo skupino bolnikov s stadijem pT3 razdelili na dvoje ‒ v skupino z razširjeno limfadenektomijo in skupino brez tega posega. Pri bolnikih, kjer posega nismo opravili, smo gensko fuzijo odkrili v 25 (64 %) primerih. Povezava med gensko fuzijo in to značilnostjo je dosegla statistično vrednost p = 0,039. Zaključek: Na podlagi naših rezultatov pričakujemo, da bi pri bolnikih s fuzijo TMPRSS2:ERG, odkriti že na biopsiji prostate, dokazali stadij T3 po radikalni prostatektomiji v več kot polovici primerov (64 %). Podatek je pomemben predvsem za bolnike s predoperativno nizkimi PSA in GS, kar sicer kaže na rak z nizkim ali zmernim tveganjem, vendar bi tako resno podcenili razširjenost bolezni. Ker bi pri teh bolnikih torej pričakovali lokalno napredovano bolezen oziroma stadij-pT3, bi z radikalnejšim posegom dosegli nižji odstotek pozitivnih robov (ki v zadnjih smernicah še vedno dosegajo 33,5‒66 %). Pri bolnikih s klinič nim stadijem pT3 pričakujemo limfogene metastaze v 7,9‒49 odstotkih. Background: More specific diagnostic modalities, prognostic indicators of progression and a better understanding of prostate cancer biology are high priorities in prostate cancer research. Methods: The study cohort consisted of 202 operable prostate cancer Slovenian patients who underwent laparoscopic radical prostatectomy. We retrospectively constructed tissue microarrays of their prostatic specimens for fluorescense in situ hybridization study, obtaining appropriate signals for 148 patients. Results: The following genetic aberrations were found: TMPRSS2:ERG fusion, TMPRSS2 split (a non-ERG translocation) and ERG split (an ERG translocation without involvement of TMPRSS2). TMPRSS2:ERG gene fusion happened in 63 patients (42%), TMPRSS2 split in 12 patients and ERG split in 8 patients. The association between TMPRSS2:ERG gene fusion and pT stage was significant (p=0.01). Of 62 patients with pT3 stage, 34 (55%) had TMPRSS2:ERG gene fusion. In the group of patients with pT3 in which we did not perform an extended lymph node dissection, we detected TMPRSS2:ERG gene fusion in 25 patients (64%) with p=0.04. Conclusions: Our results indicate that it would be possible to predict pT3 stage at final histology from TMPRSS2:ERG gene fusion at initial core needle biopsy. This is important for patients with preoperative prostatic specific antigen and Gleason score values that indicate low or intermediate risk prostate cancer. Consistent with our findigs, we expect T3 stage at the final histology in these patients. Thus we would achieve a lower percentage of positive section margins and better functional and oncological results in patients with indication for nerve sparing prostatectomy.

Namen: Namen raziskave je bil ugotoviti, kateri bolezenski simptomi se najpogosteje pojavljajo pri odraslem prebivalstvu Slovenije in določiti njihovo prevalenco in dejavnike, ki nanjo vplivajo. Metode: Raziskava je bila presečna opazovalna in je potekala s pomočjo računalniško podprtega telefonskega anketiranja - CATI. Vključena sta bila 1002 prebivalca, stara med 15 in 90 let. Telefonski intervju je zajemal vprašanja o pojavnosti 23 bolezenskih simptomov, njihovem trajanju in o demografskih podatkih. Izsledki: Slovensko prebivalstvo ima najpogosteje težave z bolečinami v hrbtenici (409 oseb - 40,8 %), bolečinami v sklepih (334 oseb - 33,4 %), s prekomerno utrujenostjo (308 oseb - 30,7 %), z živčnostjo (285 oseb - 28,4 %), glavobolom (280 oseb - 27,9 %), razdražljivostjo (261 oseb - 26,1 %) in z nespečnostjo (259 oseb - 25,8 %). Statistično pogosteje so se bolezenski simptomi pojavljali pri ženskah, starejših, nižje izobraženih, ljudeh z nižjim osebnim dohodkom, nezaposlenih, upokojenih in tistih z znano kronično boleznijo. Neodvisna napovedna dejavnika za prisotnost vsaj enega bolezenskega simptoma sta ženski spol in prisotnost kronične bolezni. Sklepi: Slovensko prebivalstvo je znatno obremenjeno z bolezenskimi simptomi, saj 77,3 % vprašanih bremeni vsaj en bolezenski simptom. Raziskava je odkrila skupine prebivalstva, ki so bolezenskim simptomom še posebej podvržene (ženske, starejši, kronični bolniki, ljudje z nižjim socioekonomskim statusom) in katerim bi morala biti namenjena še posebna pozornost na ravni primarnega zdravstvenega varstva in preventivne dejavnosti. Objectives: The aim of this study was to determine the most common disease symptoms in the Slovenian adult population, to determine their prevalence and to identify the demographic and other factors associated with higher prevalence of the symptoms. Methods: A cross-sectional observational study was conducted using computer assisted telephone interviewing - CATI thatcovered questions about the prevalence of 23 disease symptoms in the past month, their duration and general demographic information. The sample included 1,002 interviewees (age 15 - 90). Results: The results showed that the most common symptoms among Slovenian people are back pain (409 interviewees - 40.8%), joint pain (334 interviewees - 33.4%), excessive fatigue (308 interviewees - 30.7%), nervousness (285 interviewees - 28.4%), headache (280 interviewees - 27.9%), irritability (261 interviewees - 26.1%) and insomnia (259 interviewees - 25.8%). Disease symptoms occurred more often in women, the elderly, people with lower education and lower income, theunemployed, retired people and people with a chronic disease. The independent predictive factors for the presence of any symptoms were female gender and chronic disease. Conclusions: The prevalence of disease symptoms troubling the adult Slovenian population is high, as 77.3% of people suffer from at least one symptom. The study showed the population groups thatare most heavily burdened (females, the elderly, chronic patients, people with lower socio-economic status) and to which more attention should be paid in primary health care and prevention.

Introduction: Choroidal melanoma is the most common primary malignancy of the eye, which frequently metastasizes. The Cancer Registry of Slovenia reported the incidence of choroid melanoma from 1983 to 2009 as stable, at 7.8 cases/million for men and 7.4/million for women. The aim of the retrospective study was to determinate the prognostic factors of survival for choroidal melanoma patients in Slovenia. Patients and methods: From January 1986 to December 2008 we treated 288 patients with malignant choroidal melanoma 127 patients were treated by brachytherapy with beta rays emitting ruthenium-106 applicators 161 patients were treated by enucleation. Results: Patients with tumours thickness < 7.2 mm and base diameter < 16 mm were treated by brachytherapy and had 5- and 10-year overall mortality 13% and 32%, respectively. In enucleated patients, 5- and 10-year mortality was higher, 46% and 69%, respectively, because their tumours were larger. Thirty patients treated by brachytherapy developed local recurrence. Twenty five of 127 patients treated by brachytherapy and 86 of 161 enucleated patients developed distant metastases. Patients of age >/= 60 years had significantly lower survival in both treatment modalities. For patients treated by brachytherapy the diameter of the tumour base and treatment time were independent prognostic factors for overall survival, for patients treated by enucleation age and histological type of tumour were independent prognosticators. In first few years after either of treatments, the melanoma specific annual mortality rate increased, especially in older patients, and then slowly decreased. Conclusions: It seems that particularly younger patients with early tumours can be cured, whereby preference should be given to eyesight preserving brachytherapy over enucleation.

Objectives. The aim of this study was to determine the most common disease symptoms in the Slovenian adult population, to determine their prevalence and to identify the demographic and other factors associated with higher prevalence of the symptoms. Methods. A cross-sectional observational study was conducted using computer assisted telephone interviewing - CATI thatcovered questions about the prevalence of 23 disease symptoms in the past month, their duration and general demographic information. The sample included 1,002 interviewees (age 15 - 90). Results. The results showed that the most common symptoms among Slovenian people are back pain (409 interviewees - 40.8%), joint pain (334 interviewees - 33.4%), excessive fatigue (308 interviewees - 30.7%), nervousness (285 interviewees - 28.4%), headache (280 interviewees - 27.9%), irritability (261 interviewees - 26.1%) and insomnia (259 interviewees - 25.8%). Disease symptoms occurred more often in women, the elderly, people with lower education and lower income, theunemployed, retired people and people with a chronic disease. The independent predictive factors for the presence of any symptoms were female gender and chronic disease. Conclusions. The prevalence of disease symptoms troubling the adult Slovenian population is high, as 77.3% of people suffer from at least one symptom. The study showed the population groups thatare most heavily burdened (females, the elderly, chronic patients, people with lower socio-economic status) and to which more attention should be paid in primary health care and prevention.