Solitary Clear Cell Renal Cell Carcinoma Metastasis to the Eyelid: A Case Report.

Introduction: This study is a case of solitary clear cell renal cell carcinoma (ccRCC) eyelid metastasis in a 66-year-old man as the first sign of a primary tumor. ccRCC usually spreads to the lungs, mediastinum, bones, liver, and brain, while ocular metastases are rare. Case Presentation: Solitary metastasis presented as a solid mass in the central third of the upper eyelid, which has been growing for 3 weeks. Treatment included tumor removal and blepharoplasty. Histopathological examination showed metastasis of clear cell renal carcinoma. A thorough examination revealed a primary tumor on the lower pole of the right kidney. A right nephrectomy was performed, and histopathology showed ccRCC. Postoperative examinations showed no signs of local or systemic disease. Sunitinib malate was administered to the patient. Conclusion: The eyelid metastasis in this case was still solitary and had been discovered before the existence of the primary tumor was known. Ocular metastasis of renal carcinoma is a rare initial manifestation of the disease and therefore requires a multidisciplinary approach in the treatment of these patients.

CURRENT ROLE OF MAGNETIC RESONANCE IMAGING IN THE SCREENING, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER.

Prostate cancer is the most common cancer in men. Diagnosis of prostate cancer poses a significant challenge, due to several different key parameters that need to be evaluated, such as age, history of prostate specific antigen (PSA), clinical examination and more recently magnetic resonance imaging (MRI). The current diagnostic pathway for prostate cancer has resulted in overdiagnosis and overtreatment as well as underdiagnosis and missed diagnoses in many men. Multiparametric MRI (mp-MRI) of the prostate has been identified as a test that could alleviate these diagnostic errors. Before prostate cancer treatment pathological confirmation is mandatory. Prostate biopsy is an invasive procedure with rare but not negligible potential complications. There are several methods of prostate biopsy of which most common are systemic or planar prostate biopsy and cognitive or targeted MRI-guided prostate biopsy. Multiparametric MRI has demonstrated better accuracy and reproducibility in detecting, locating and evaluating prostate cancer and also sparing some men unnecessary biopsies. Recent studies have shown a mpMRI benefit for better procedure planning regarding prostate cancer location, extent of disease and length of the urethra. There are still some challenges ahead, such as ensuring high-quality execution and reporting of mpMRI and ensuring that this diagnostic pathway is cost-effective. According to the latest urological clinical guidelines mpMRI became fundamental tool in management of prostate cancer. The aim of this study is to give a brief insight in use of mpMRI in prostate cancer diagnosis and treatment.

COMPARISON OF GRADING ACCURACY OF PROSTATE CANCER IN SAMPLES ACQUIRED BY A TARGETED AND SYSTEMIC PROSTATE BIOPSY.

Introduction: All malignancies, including prostate cancer, require accurate diagnosing and staging before making a treatment decision. The introduction of targeted biopsies based on prostate MRI findings has raised prostate biopsy accuracy. Guided biopsies target the tumor itself during the biopsy instead of the most common tumor sites as is the case with a systemic biopsy. Some studies report that targeted biopsies should lower prostate cancer biopsy undergrading and overgrading. Goals: To determine the incidence of prostate cancer biopsy undergrading in patients who underwent a classic systemic biopsy compared to patients who underwent a mpMRI cognitive targeted biopsy. Materials and methods: We identified the patients from our database who underwent a radical prostatectomy at our institution from January 1st, 2021, to June 30th, 2021.There were 112 patients identified. Patients were stratified into two groups based on the type of biopsy that confirmed prostate cancer. The mpMRI (N=50) group had a mpMRI cognitive guided transrectal ultrasound (TRUS) prostate biopsy performed, and the non-mpMRI group (N=62) received a classic, systemic TRUS biopsy. We compared the biopsy results with the final pathological results, and searched for undergrading or overgrading in the biopsies compared to the final histological report. Results: The undergrading was found in 17,7% (N=11) cases in the non-mpMRI group and in 12,0% (N=6) of cases in the mpMRI group (p=0,02, Mann-Whitney U test). No overgrading was found in our cohort. All cases of undergrading had Grade Group 1 in the biopsy report and Grade Group 2 in the final specimen report. The charasteristics of patients are listed in Table 1. Discussion and conclusion: In our cohort, the patients who underwent a mpMRI targeted biopsy had a lower undergrading incidence. During a systemic TRUS biopsy, the urologist targets the areas of the prostate where cancer is most commonly located, which is usually the peripheral zone of the prostate. Since different areas of the tumor have different areas of differentiation, only a low-grade part of the tumor is sometimes biopsied, which results in a sampling error. Once the prostate is removed, the whole tumor is analyzed, so the obtained pathological results related to the removed prostate are far more accurate than the analysis of prostate cores obtained by biopsy.

cfDNA methylation in liquid biopsies as potential testicular seminoma biomarker.

Background: Seminoma is a testicular tumor type, routinely diagnosed after orchidectomy. As cfDNA represents a source of minimally invasive seminoma patient management, this study aimed to investigate whether cfDNA methylation of six genes from liquid biopsies, have potential as novel seminoma biomarkers. Materials & methods: cfDNA methylation from liquid biopsies was assessed by pyrosequencing and compared with healthy volunteers' samples. Results: Detailed analysis revealed specific CpGs as possible seminoma biomarkers, but receiver operating characteristic curve analysis showed modest diagnostic performance. In an analysis of panels of statistically significant CpGs, two DNA methylation panels emerged as potential seminoma screening panels, one in blood CpG8/CpG9/CpG10 (KITLG) and the other in seminal plasma CpG1(MAGEC2)/CpG1(OCT3/4). Conclusion: The presented data promote the development of liquid biopsy epigenetic biomarkers in the screening of seminoma patients.

Seminoma belongs to testicular cancer, which represents a common malignancy among men of reproductive age. Diagnosis of seminoma is a multistep process that also includes checking tumor biomarkers from blood. However, these biomarkers are not specific for seminoma and to conclude a definite diagnosis of seminoma immunohistochemical analysis is needed, which requires the removal of a whole or partial testicle. Therefore, there is a need for novel, noninvasive biomarkers. cfDNA is the most extensively investigated source of minimally invasive tumor markers. Therefore, this study investigated cfDNA methylation of six genes as potential noninvasive biomarkers for the management of seminoma patients. By examining CpG sites of selected genes by pyrosequencing, the authors detected significant differences. However, receiver operating characteristic curve analysis showed modest results. Therefore, the authors tested possible panels of significantly different CpGs and detected two possible DNA methylation panels for seminoma screening. These findings suggest the further investigation of possible epigenetic biomarkers for seminoma patient management from liquid biopsies.

New Insights into the Diagnosis, Molecular Taxonomy, and Treatment of Bladder Cancer.

This review aims to emphasize new insights into the diagnosis, classification, and therapy of bladder cancer (BC). Bladder cancer is a heterogeneous, complex disease on a morphological, molecular, diagnostic, and prognostic level. Cancer stage is still the most important attribute for prognosis and treatment, while early detection with optimal and rapid individual therapeutic and surveillance approach is crucial. The vast majority of patients have a superficial, non-muscle-invasive tumor associated with a good prognosis after resection and adjuvant intravesical maintenance immuno or chemotherapy if needed. On the other hand, muscle-invasive bladder cancer is a highly aggressive disease with high morbidity and mortality. However, it has become a model for oncology success over the last five years with many available targeted therapeutic modalities. Metastatic BC is now amenable to multimodal treatment combining cystectomy and neoadjuvant chemotherapy and immunotherapy and is a target for precision medicine. CONCLUSION: A new molecular taxonomy for bladder cancer has been proposed and provided insight into BC's carcinogenesis, with some possible effects on therapy decisions. However, this classification is still not applicable in routine clinical practice. It opens new questions regarding the interplay between tumor genetic signature, intratumoral heterogeneity, therapy implications, and tumor progression.

Refugee Status as a Possible Risk Factor for Childhood Enuresis.

This study investigated the influence of refugee status on the occurrence of enuresis. It was performed among school children aged 6 to 11 years and their parents in the Vukovarsko-srijemska County (eastern Croatia), which had many displaced persons and refugees (mostly women and children) in the 1990s due to the wars in Croatia and Bosnia and Herzegovina. A specially designed questionnaire (about the child's age and gender, the child's enuresis history and that of the parents, and data on parental refugee status in childhood) was completed by one of the parents. Adequate data were collected for 3046 children. The prevalence of enuresis among the studied children was quite low (2.3%) but the prevalence distribution according to gender, the decline by age, and the higher odds ratio for paternal enuresis were in line with the results of other studies. The prevalence of parental enuresis in childhood was higher than their children's enuresis (mothers: 5.8%, fathers: 3.6%, p < 0.001), and significantly higher among parents who had been refugees (mothers: p = 0.001, fathers: p = 0.04). Parental refugee status had no influence on the children's enuresis. The results suggest that refugee status is a risk factor for the occurrence of enuresis in childhood.

PROSTATE CANCER DIAGNOSIS IN 2019 - CHANGES IN EUROPEAN GUIDELINES AND IMPACT ON DAILY PRACTICE.

Changes in the diagnostic pathway for prostate cancer advised in the most recent Guidelines of the European Association of Urology bring many endeavors for everyday practice. Availability, costs and radiological expertise are still representing a challenge for the adoption of these guidelines in everyday clinical practice. In this article we discuss the current situation regarding these issues and future options.

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.

Role of Multiparametric Magnetic Resonance Imaging in Prostate Cancer Assessment.

Multiparametric magnetic resonance is assuming an increasingly important role in the diagnosis, initial assessment and monitoring of patients with prostate cancer. This paper offers a more complex insight into the application of magnetic resonance imaging with prostate cancer, with a current literature overview. The focus is on the problem of initial prostate cancer evaluation which strongly affects further decision-making and therapeutic interventions. Clinical suggestions based on the current guidelines are also offered.

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.

Histopathological Outcomes after Radical Prostatectomy for Prostate Cancer Based On a New Grading System.

One of the main reasons for the introduction of a new grading system was Gleason sum 7, which differed significantly in the prognosis of the disease depending on the primary Gleason. The aim of this study was to compare grade group 2 and grade group 3, and the impact of cancer percentages in final pathology reports after radical prostatectomy on the occurrence of T3 stage of the disease after radical prostatectomy of clinically localized prostate cancer. The study covered 365 patients with clinically localized prostate cancer who underwent radical retropubic prostatectomy (RRP) over the period of two years. The average percentage of carcinomas found in pathology reports after RRP was 20.1%. With the increase in the grade group, the average percentage of carcinomas in pathology reports increased significantly, p <0.001. With regard to grade groups 2 and 3, irrespective of cancer percentages in pathology reports, more cases of T3 stage were found in grade group 3 when compared to grade group 2, which was statistically significant (p <0.001). However, grade group 2 and grade group 3 patients with ≤10% cancer occurrences in final pathology reports after RRP did not show any statistical significance in the occurrence of T3 stage, p=0.96. Prognostic differences in grade group 2 and grade group 3 patients after RRP are significant, but not in all cases, because of their dependence on the percentage of cancer in the final pathology report after RRP of clinically localized prostate cancer.

Unfavorable Clinicopathological Features in Radical Prostatectomy Patients Who Were Spared Pelvic Lymphadenectomy.

Pelvic lymph node dissection (PLND) during radical prostatectomy (RP) is the most accurate staging modality for lymph node assessment in patients with prostate cancer. It is recommended in all patients with intermediate or high-risk disease undergoing radical prostatectomy. The goal of our study was to assess unfavorable clinicopathological characteristics in patients with omitted lymphadenectomy (PLND) during radical prostatectomy based on the nomogram proposed by Briganti and colleagues. In 2011, 200 patients undertook radical prostatectomy in our institution. Among them 53 patients who fulfilled Briganti criteria and in whom we omitted lymphadenectomy based on current guidelines. Unfavorable clinicopathological features considered were: stage T3, positive surgical margins or biochemical relapse (BCR). We registered biopsy Gleason score 6 in 34 patients, and 19 patients had Gleason score 7. Stage pT2 was seen in 49 patients, and pT3 in 4. Glea-son score after radical prostatectomy was upgraded from GS 6 to GS 7 in 20 patients (37%) and reduced in 1 patient (2%). After a median follow-up of 49 (44-56) months, there were 12 (22.6%) patients with BCR. Patients with biopsy Gleason score 6 (n=34) compared to biopsy Gleason 7 (n=19) patients showed no difference regarding positive margins (p=0.0738) and BCR (p=0,736) at 49 months follow-up. Thus, PLND according to current guidelines can be safely omitted in low-risk patients using Brigantinomogram.

Prostatic Artery Embolization as a New Option in the Treatment of Lower Urinary Tract Symptoms in Benign Prostatic Hyperplasia - Current Evidence.

Prostatic artery embolization is a minimally invasive endovascular treatment that improves lower urinary tract symptoms in men with benign prostatic hyperplasia. Although further randomized studies and long-term evidence is still needed for this method to be fully incorporated into treatment guidelines for benign prostatic hyperplasia, current studies show that this method can be an effective and safe alternative in patients with a significantly enlarged prostate gland who are not good surgical candidates. Therefore, we present the theory, technical details and potential benefits of this method as we review the current evidence on prostatic artery embolization.

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.

LOW RISK PROSTATE CANCER: ACTIVE TREATMENT OR ACTIVE SURVEILLANCE?

The widely used screening for prostate cancer with prostate specific antigen has resulted in identification of potentially lethal prostate cancers at a much more curable stage and has been associated with significant falls in prostate cancer mortality. In spite of the fact that prostate cancer is one of the deadliest malignancies in men, the advent of sensitive diagnostic testing has also resulted in detection of low risk cancers due to the high incidence of latent prostate cancer in aging men and prolonged natural history of the disease. This, in turn, has entailed the problem of cancer overdiagnosis and subsequent overtreatment. Approximately 6 times as many men will be diagnosed with the disease as will die from it. Active surveillance appeared as a response to the clearly documented risks of overdiagnosis and overtreatment of low risk prostate cancer for localized prostate cancer. It entails initial expectant management rather than immediate therapy, with 'curative-intent' treatment deferred until there is evidence that the patient is at an increased risk of disease progression. This approach attempts to balance the risks and side effects of overtreatment against the possibility of disease progression and lost opportunity for cure. A systematic literature review brings current knowledge on the subject.

CROATIAN UROLOGISTS' CLINICAL PRACTICE AND COMPLIANCE WITH GUIDELINES IN THE MANAGEMENT OF NON-NEUROGENIC MALE LOWER URINARY TRACT SYMPTOMS.

The aim of this study was to assess the Croatian urologists' management of non-neurogenic male lower urinary tract symptoms (LUTS) and their compliance with the European Association of Urology (EAU) guidelines. A cross-sectional survey included 51/179 Croatian urologists. We developed a questionnaire with questions addressing compliance with EAU guidelines. The rate of performing recommended evaluations on the initial assessment of patients with benign prostate hyperplasia (BPH)/LUTS varied from 8.0% (serum creatinine and voiding diary) to 100.0% (physical examination, prostate specific antigen and ultrasound). The international prostate symptom score was performed by 31%, analysis of urine sediment by 83%, urine culture by 53%, and serum creatinine by 8% of surveyed urologists. Only 8% of urologists regularly used bladder diary in patients with symptoms of nocturia. Our results indicated that 97% of urologists preferred alpha blockers as the first choice of treatment; 5-alpha reductase inhibitors (5ARI) were mostly prescribed (84%) in combination with an alpha-blocker, preferably as a continuous treatment, whilst 29% of urologists used to discontinue 5ARI after 1-2 years. Half of the Croatian urologists used antimuscarinics in the treatment of BPH/LUTS and recommended phytotherapeutic drugs in their practice. In conclusion, Croatian urologists do not completely comply with the guidelines available.