History of Urology at the Sestre Milosrdnice University Hospital Center.

The history of Croatian urology clearly shows its affiliation to the medical and civilizational circle of the Western world. The Department of Urology at the Sestre milosrdnice University Hospital Center is the oldest urology institution in the Republic of Croatia. The Department was established in 1894, when the new Sestre milosrdnice Hospital was open in Vinogradska cesta in Zagreb. It was then that doctor Dragutin Masek founded the so-called III Department, which, in addition to treating urology patients, also treated patients with conditions of the ear, nose and throat, eye diseases and dermatologic conditions. Dragutin Masek had already realized that medicine would soon be divided into fields and had assigned younger doctors joining the III Department to specific fields. As a result, urology was given to Aleksandar Blaskovic, who founded the first independent department of urology in Croatia in 1926. In 1927, he was appointed Professor of urology at the Zagreb School of Medicine, where he established the first department of urology and was giving lectures and practicals. Under his leadership, the Department of Urology was given the status of a Clinic, a teach-ing department, the first of its kind in Croatia. Owing to all his activities in the field of urology, the history remembers him as the "father of modern Croatian urology". Over the course of the following years, department chairs had changed, but luckily for the patients, approach to work had not. Conscientiousness, trust, competence and charity. After all, charity is the idea that the hospital carries even in its name, after the Sisters of Charity who had founded it. In all the decades, the Department of Urology has been following global development paths, objectively legging behind top facilities in the world by only a few years. Overall professional and scientific urology activities culminated in 1998, when the Clinic became the Reference Center of the Ministry of Health of the Republic of Croatia for prostate cancer, and in 2011, when it became the European Board of Urology Certified Center. All that has been achieved could not have been done without wholehearted help and cooperation of the nurses, as well as every other department employee from the beginnings of urology until today. Despite its rich history, the Department does not rest on laurels. Today, it is a modern urology department together with its European role models.

20 Years of the Reference Center for Prostate Tumors of the Ministry Of Health at the Department of Urology in Sestre Milosrdnice University Hospital Center.

The Department of Urology at the Sestre milosrdnice University Hospital Center is the oldest urological institution in the Republic of Croatia and this part of Europe. Today, the Department is a modern tertiary healthcare institution, where the most complex methods of urological practice are performed using modern medical devices and highly sophisticated technology. In 2011, our urology specialist education program was certified by the European Board of Urology (EBU) as the only one of its kind in Croatia. The program was recertified in 2017. The Department runs a program for the early detection of prostate cancer and performs more than 240 radical prostatectomies annually, which is the highest number of such interventions in Croatia. The aim of this study is to present the work and the activities of the Reference Center for Prostate Tumors of the Ministry of Health at the Department of Urology in Sestre milosrdnice University Hospital Center over the last 20 years. The database of the Reference Center for Prostate Tumors of the Ministry of Health at the Department of Urology in Sestre milosrdnice University Hospital Center was reviewed. During the twenty-year period, approximately 15,000 prostate interventions were performed due to benign and malignant diseases. Of this, 7,374 transrectal ultrasound guided prostate biopsies, 2,632 radical prostatectomies with open retropubic access, 3,988 transurethral prostate resections and 1,097 open suprapubic adenomectomies were performed. With the achieved scientific and professional results in monitoring, studying and improving the prevention, diagnosis and therapy of prostate tumors, as well as with the professional conditions and personnel, the Department of Urology in Sestre milosrdnice University Hospital Center truly justifies the title of the Reference Center for Prostate Tumors of the Ministry of Health of the Republic of Croatia awarded to it in 1998.

Epidemiology of Prostate Cancer in Croatia - Situation and Perspectives.

Prostate cancer represents a significant public health burden in Croatia, as well as in other developed countries. The aim of this paper was to present the current epidemiological situation in Croatia in comparison to other similar countries, using basic indicators such as incidence, mortality, prevalence and survival, and to discuss future possibilities in this field. The incidence of prostate cancer in Croatia has been rapidly increasing since the mid-nineties; recent data indicates that the trend is levelling off. Mortality data show constant increase since the 1960s, but mortality trends seem to be stabilizing in the recent period; however, Croatia is still in the top ten countries regarding prostate cancer mortality in Europe. Five-year prevalence in 2012 was estimated at 7,592 cases (426.7/100,000), ranking Croatia in the middle of European countries in the GLOBOCAN 2012 database. According to the CONCORD-2 study, five-year net survival in Croatia in the 2005-2009 period was 75.1%, which is lower than in similar European countries. The epidemiological pattern of prostate cancer in Croatia indicates a relatively low incidence, with significant room for improvement in mortality and survival data. Given the recent discussions regarding prostate cancer screening modalities, a debate is warranted and should be encouraged regarding the role of PSA testing in Croatia.

Diagnostic Value of Cognitive-Registration Multiparametric Magnetic Resonance Guided Biopsy for the Detection of Prostate Cancer after Initial Negative Biopsy.

The aim of this prospective clinical study was to determine the detection rate of prostate cancers by multiparametric magnetic resonance and transrectal ultrasound (mpMRI-TRUS) cognitive fusion biopsies in patients with a previously negative TRUS-guided biopsy. Between 1 October 2016 and 1 July 2017, in 101 consecutive patients with elevated antigen (PSA) and/or positive digital rectal examination and after a negative first TRUS biopsy, a second, repeated prostate biopsy was performed. In 24 patients, cognitive fusion mpMRI-TRUS biopsy of the prostate with 8-10 system cores and 1-3 target biopsies was performed, in line with the European Association of Urology guidelines. In 77 patients, only a classic, repeated TRUS guided biopsy was performed. In patients with mpMRI, the detection rate according to PIRADS-v2 reporting system was: PIRADS 1, n = 0; PIRADS 2, n = 0; PIRADS 3, n = 0; PIRADS 4, n = 6/8 (75%); and PIRADS 5, n = 2/3 (67%). In the group of patients with MR-TRUS cognitive fusion biopsy, the prostate cancer detection rate was 8/24 (33%), while in the control group the detection rate was 12/77 (16%), which was statistically significant (t test, p = 0.037, CI 95% is 0.01 to 0.37). Patients with PIRADS ≤ 3 (54%) could have avoided the biopsy.

Cost-Benefit Analysis of the Introduction of Mp-Mri Guided Biopsies in Croatia.

The objective of this study was to determine differential expression of TFF1, TFF2 and TFF3 genes and proteins in breast tumor subtypes. In addition, we investigated the correlation between TFF genes within tumor subgroups, and TFF genes with clinical and pathologic characteristics of the tumor. Study group included 122 patients with surgically removed breast tumors. Samples were investigated using qRT-PCR and immunohistochemistry. TFF1 and TFF3 genes and proteins were expressed in breast tumors, while the levels of TFF2 gene and protein expression were very low or undetectable. TFF1 was significantly more expressed in benign tumors, while TFF3 was more expressed in malignant tumors. Gene and protein expression of both TFF1 and TFF3 was greater in lymph node-negative tumors, hormone positive tumors, tumors with moderate levels of Ki67 expression, and in grade II tumors. A strong positive correlation was found between TFF1 and TFF3 genes, and the expression of both negatively correlated with Ki67 and the level of tumor histologic differentiation. Our results suggest that TFF1 and TFF3, but not TFF2, may have a role in breast tumor pathogenesis and could be used in the assessment of tumor differentiation and malignancy.

Incidental Prostate Cancer in Patients Treated for Benign Prostate Hyperplasia in the Period of 21 Years.

The aim of this study was to determine the incidence of incidental prostate cancer and its clinical significance among patients who underwent transurethral prostate resection or transvesical adenomectomy for benign prostate hyperplasia at the Department of Urology in Sestre milosrdnice University Hospital Center from January 1997 to December 2017. A total of 277/4,372 (6.34%) patients from our cohort were diagnosed with incidental prostate cancer (mean age 74.5 years). Due to incomplete data, 12 patents were excluded from further analysis. 44.91% (119/265 patents) of our cohort were stage T1a and 55.09% (146/265) were stage T1b. Clinically significant prostate cancer was found in 168/265 patients (63.40%). When divided into two groups, Gleason score ≤6 (mean age 73.58 years) and Gleason score ≥7 (mean age 75.77 years), the results showed that Gleason score ≥7 patients were significantly older (p=0.0104) and that the tumor extent among patients in this group (mean = 34.58%) was higher than that in Gleason score ≤6 group (mean = 11.11%) (p=0.0169). More than a half of patients in our cohort had T1b stage prostate cancer. We found that 63.4% of carcinomas were clinically significant, with 52/265 (19,62%) patients affected by ISUP grade 4 and 5 cancers. Based on our research, we cannot give any recommendations regarding incidental prostate cancer treatment due to lacking preoperative (PSA, DRE) and follow-up data.

Effect of histological inflammation on total and free serum prostate-specific antigen values in patients without clinically detectable prostate cancer.

PURPOSE: We are often confronted with patients in the "gray zone" (prostate-specific antigen [PSA]<10 ng/mL) whose biopsies reveal no malignancy but only inflammation. We investigated the relationship between histological inflammation and total PSA (tPSA), free PSA (fPSA), and percentage of free PSA (f/tPSA) levels in patients without prostate cancer (PC). MATERIALS AND METHODS: We studied 106 men with tPSA<10 ng/mL who had undergone biopsy that was negative for PC and who had no clinical prostatitis. Inflammation observed at biopsies was scored for inflammation type in each biopsy core by use of a four-point scale and was then correlated with tPSA, fPSA, and f/tPSA. RESULTS: Different patterns of inflammation were found in each set of biopsies. Regression factor analysis was used to form two groups according to inflammation type: more chronic and more acute. Median tPSA, fPSA, and f/tPSA levels in the more chronic and more acute inflammation groups were 6.4 ng/mL, 1.09 ng/mL, and 15%, and 7.3 ng/mL, 0.79 ng/mL, and l2%, respectively. A significant difference was found in fPSA (p=0.003) and f/tPSA (p<0.001), whereas the difference in tPSA was not significant (p=0.200). Total PSA correlated with fPSA (r=0.4, p<0.001) but not with inflammation type (r=0.12, p>0.010). A correlation existed between inflammation type and fPSA (r=-0.31, p=0.001) and f/tPSA (r=-0.43, p<0.001) in that the fPSA and f/tPSA were lower in the group with more acute inflammation. CONCLUSIONS: Subclinical inflammation has a significant influence on fPSA in patients with tPSA<10 ng/mL but without PC or clinical prostatitis. Subclinical inflammation is not characterized by elevated tPSA alone but also by a decreased fPSA, a tendency similar to that in PC.

[Cystine urolithiasis: recommendations for diagnosis, treatment and recurrence prevention]. / Cistinska urolitijaza: preporuke za dijagnostiku, lijecenje i prevenciju recidiva.

Cystine lithiasis is a diagnostic and therapeutic challenge. This consensus document has outgrown of discussion of experts in nephrology and urology. It is our hope that this document will be of use for all physicians who are facing this disturbing type of urolithiasis. So far, in our national literature there have been no comprehensive documents dealing with this entity and we believe that not only nephrologists and urologists will benefit, but also specialists in internal medicine and general practitioners.

The evolution of partial nephrectomy for kidney tumors--are we abandoning the basic principles of Robson's radical nephrectomy?

Fifty years ago, Robson introduced radical nephrectomy (RN) setting the gold standard for treating kidney tumors. Experience has shown that partial nephrectomy (PN) can be equally effective with the advantages of preserving kidney function and avoiding unnecessary nephrectomies for benign tumors. The purpose of this report is to demonstrate the evolution of clinical presentation and choice of treatment for patients with kidney tumors at our department, emphasizing changes in the PN utilization trends. Clinical data were abstracted for the years 2002, 2007 and 2012. We assessed annual trends for changes in the choice of operative treatment related to tumor size, pathologic stage and diagnosis. During the study, there was an increase in the share of T1 tumors, from 46.6% in 2002 to 69.8% in 2012. The rate of PN increased more than ten-fold, from 2.7% in 2002 to 31.7% in 2012. The annual rates of PN for T1 tumors increased even more, from 6.6% in 2002 to 46.7% in 2012. Opposite to RN group, there was an increase in the mean tumor size in PN group (from 1.8 cm in 2002 to 3.9 cm in 2012). The rate of RN for benign tumors was reduced impressively from 85.7% in 2002 to 23.1% in 2012. Our data argue strongly that PN should be expanded and not restricted. Robson's principles have been partially deserted over the last decade; however, proving that PN is superior to RN still remains to be elucidated.

Insulin receptor H1085H C>T and insulin receptor substrate 1 G972R polymorphisms and prostate cancer risk: a pilot study.

BACKGROUND: In recent years, numerous studies have focused their attention on genes that are part of the insulin/insulin-like growth factor 1 signaling pathway, such as the insulin receptor (INSR) and the insulin receptor substrate 1 (IRS1) genes. AIM: We aimed to examine the association of INSR H1085H C>T and IRS1 G972R polymorphisms with prostate cancer (PC). We also aimed to examine possible association with cancer severity assessed by Gleason score. MATERIALS AND METHODS: We have studied 180 consecutive patients referred for PC screening. The genotyping of two polymorphisms (INSR H1085H C>T and IRS1 G972R) was performed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: There was no difference in genotype (p=0.794) or allelic (p=0.621) frequency of the IRS1 G972R polymorphism between PC (n=119) and control (n=61) groups. However, a significant difference was found in INSR H1085H C>T polymorphism genotype and allelic distribution. Carriers of the polymorphic allele (C/T+T/T) were more frequent in control group patients than in the PC group (54.10% vs. 37.82%; p=0.040; odds ratio [95% confidence interval]=0.52 [0.28-0.96]). The IRS1 and INSR polymorphism distribution did not differ in subgroups according to Gleason score. CONCLUSION: INSR H1085H C>T polymorphism seems to be associated with PC risk, whereas IRS1 G972R is not. However, because of the limited power of this study, there is a possibility that some modest effects of the IRS1 G972R polymorphism on PC risk went undetected. Neither polymorphism is associated with the degree of PC malignancy.

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study.

OBJECTIVES: Methylation abnormalities appear to be important for the pathogenesis of many cancer types. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation process catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, C677T polymorphism, which decreases enzyme activity, may be associated with cancer susceptibility. The aim of this work was to investigate the distribution of MTHFR C677T polymorphism between various types of cancer and cancer-free controls and to assess if there is a difference in frequency. MATERIALS AND METHODS: 269 Cancer cases (95 prostate cancer, PC; 81 head and neck, HN; and 93 breast cancers, BC) and 102 healthy controls, free of cancer, were genotyped for C677T MTHFR polymorphism using the PCR-RFLP method. RESULTS: There was no overall difference in C677T genotype distribution between total cancer cohort and controls (p=0.064). However, a significant difference and protective OR was found for the C/T genotype (OR=0.574, 95% CI=0.352-0.935). In a comparison of different cancer types and respective controls, genotype frequencies were significantly different between head and neck carcinoma and controls (p=0.004), again with protective role of C/T genotype (OR=0.356, 95% CI=0.189-0.671). Moderate overrepresentation of C/T was found in respective male controls when compared with prostate cancer patients (p value was 0.074 for C/T vs. C/C comparison). The OR for heterozygous C/T genotype in prostate cancer group was 0.404, pointing to its putative protective role. Genotype and allelic frequencies did not differ significantly between 93 breast cancer patients and their 65 age-matched female controls. CONCLUSION: Our data indicate that the C677T MTHFR polymorphism does not significantly contribute to the inherited genetic susceptibility to breast and prostate cancer, while we show some evidence for possible genetic contribution of this polymorphism to the development of head and neck carcinoma.

Evolution of the clinical presentation and outcomes after radical prostatectomy for patients with clinically localized prostate cancer--changing trends over a ten year period.

We demonstrate the evolution of the clinical presentation and outcomes for patients with clinically localized prostate cancer (PC) treated with radical retropubic prostatectomy (RRP) at our department, emphasizing epidemiologic significance of changes during the 10-year period. We assessed the annual trends for changes in patients age, preoperative prostate specific antigen (PSA), preoperative versus postoperative stages and Gleason grades, organ confined status and surgical margin status. A total of 488 RRPs were performed from January 1996 to December 2005 with the annual frequency increased from 8 to 129 (1512.5%). Mean patient age increased from 61.5 to 66.12 years in 2005, with the percentage of men aged more than 70 years increased from 12.5 to 26.5%, respectively. The detection of PC based solely on pathological PSA levels (as indication for prostate biopsy) rose impressively from 25.5 to 70% and the rates of postoperative organ-confined disease also increased significantly from 25 to 74.7%. Mean preoperative PSA decreased from 16.7 to 9.89 ng/mL. On the contrary, there was an increase in percentage of patients with preoperative PSA values ranging from 4 to 10 ng/mL (from 20 to 65.4%). Positive surgical margin rate decreased from 49.4 to 25% and percent of patients receiving neoadjuvant therapy decreased from 78.5 to 5.4%. Proportion of patients who were undergraded decreased from 75.1 to 31.7%. The rates of understaging have remained relatively stable over the years. During the study period, PC was increasingly detected by prostate biopsy on the basis of a pathological PSA level only and shifted significantly to more organ-confined stages with more favourable outcomes for pathological variables due to a more accurate assessment of clinical stage prior to surgery, reduced use of neoadjuvant therapy and improved surgical technique. Our data also argue strongly that routine PSA testing should be expanded and not restricted.

[Second primary malignant tumors in patients with primary renal cell carcinoma]. / Ucestalost drugih primarnih tumora u bolesnika s primarnim karcinomom bubreznih stanica.

INTRODUCTION: Among multiple primary cancers in the same patient, renal cell carcinoma occurring either synchronously or metachronously is one of the most common. AIM: The aim of the study was to determine the frequency of second primary malignant tumor in patients with primary renal cell carcinoma. MATERIAL AND METHODS: Between 1992 and 2000, 447 patients underwent nephrectomy for primary renal tumor at the Department of Urology, Sestre milosrdnice University Hospital. Out of 447 patients 310 were registered at Cancer Registry of the Republic of Croatia. There were data on 297 patients with renal cell carcinoma, 197 male and 104 female patients, age group 24-91 (mean 59.9) years. RESULTS: Data on 24 (8.1%) patients with second primary malignant tumors were found in Hospital Registry and Croatian Cancer Registry during the study period. There were 13 male patients, age range 47-80 (median 65.1) years, and 11 female patients, age range 51-70 years (median 61.1) years with 26 second primary tumors. One male patient presented with four different primary tumors (kidney, prostate, urinary bladder and colon). The patients most commonly presented with prostate and colon carcinoma. The second malignant primary tumors occurred most commonly as antecedent to renal cell carcinoma, i.e. in 11 (42.3%) cases. CONCLUSION: Our results indicate that during the clinical follow-up of patients treated for primary renal cell cancer, a possibility of second primary cancers should always be considered. In order to upgrade detection of multiple cancer, the quality and completeness of cancer notification and registration from hospitals as well as collaboration between the National Cancer Registry and hospital cancer registries should be improved.

Correlation of periacinar retraction clefting in needle core biopsies and corresponding prostatectomy specimens of patients with prostatic adenocarcinoma.

One of the underemphasized supportive criteria for the diagnosis of prostatic cancer is the presence of retraction clefting around neoplastic glands. We analyzed a series of 152 prostatic cancer cases to determine the frequency, extent, and correlation of periacinar retraction clefting between needle core biopsies (NCB) and corresponding matched radical prostatectomy (RP) specimens. Clefting was significantly more frequent in neoplastic compared to nonneoplastic acini in NBC and RP (p<0.05). There was no significant difference in the frequency of retraction clefting in neoplastic acini between NCB and corresponding RP (p>0.05). We have also found a concordance in matched RP and NCB (Kappa=0.582). We conclude that periacinar retraction clefting appears more frequently in neoplastic acini and could serve as a reliable criterion in the diagnosis of prostatic adenocarcinoma.

Early diagnosis of prostate cancer in finasteride treated BPH patients.

A total of 37 patients with well-documented benign prostatic hypertrophy (BPH) were referred to finasteride. In all subjects the prostate volume was > 60 cc. Serum total PSA (TPSA) and free/total PSA (%FPSA) values were recorded at 3-month intervals. After 6 months of treatment, the patients were divided into two groups in accordance with the numerical values of these two parameters. In the first group (25 patients), a drop in TPSA approached 50% reduction while the %FPSA level remained at the initial level. No malignancy was detected in these patients after 9 months of finasteride treatment and in 4-18 months additional follow-up. The second group (12 patients), consisted of subjects with a less pronounced decrease in TPSA concentration (ca. 28%) and a significant reduction in %FPSA mostly to values < 18% (cut-off point dividing BPH from cancer) during a 6-month monitoring period. During the extended part of the investigation, prostate cancer was diagnosed in 7 out of 11 of these latter patients (63.6%), or overall in 7 out of 30 (23.3%) patients who reached the end-point of the study. Accordingly, serial assessments of total and free PSA are necessary and sufficient clinical means to detect early prostate cancer in patients with a large benign prostate referred to finasteride.

[Importance of determination of various histologic components in testicular germ cell tumors]. / Vaznost odredivanja razlicitih histoloskih sastavnica tumora zametnih stanica testisa.

Testicular germ cell tumors represent about 95% of all testicular tumors. They are often composed of many different components. Seminoma usually has a favorable course but the prognosis of mixed germ cell tumors is depending on the type and proportion of different histologic components. The aim of this study was to determine the proportion and histologic type of various components of testicular germ cell tumors diagnosed in the period 1992-2000. In this period there were 131 testicular germ cell tumors with 72 (55.0%) nonseminomatous and 59 (45.0%) seminomatous tumors. Of all nonseminomatous tumors, 4 were composed of one component only, and 68 contained different components. Nonseminomatous tumors contained most commonly embryonal carcinoma (91.7%), teratoma (70.8%) and yolk sac tumor (33.3%) components. The most frequent combination of mixed germ cell tumors was composed of teratoma and embryonal carcinoma in 28 (41.2%) cases. Seminoma was found in 59 cases as pure seminoma and in 19 (26.4%) additional cases represented a component of testicular mixed germ cell tumor. Analysis of deeper sections by means of HE stained slides and immunohistochemistry (cytokeratin, CD30, alpha-fetoprotein, beta-HCG, PLAP and hPL) revealed 20 cases with components that were not described in original biopsy findings. We may conclude that the analysis of many sections using immunohistochemistry is necessary to identify all tumor components.