LGALS3 cfDNA methylation in seminal fluid as a novel prostate cancer biomarker outperforming PSA.

BACKGROUND: The unmet challenge in prostate cancer (PCa) management is to discriminate it from benign prostate hyperplasia (BPH) due to the lack of specific diagnostic biomarkers. Contemporary research on potential PCa biomarkers is directed toward methylated cell-free DNA (cfDNA) from liquid biopsies since epigenetic mechanisms are strongly involved in PCa development. METHODS: In the present research, cfDNA methylation of the LGALS3 gene in blood and seminal plasma of PCa and BPH patients was assessed using pyrosequencing, as well as LGALS3 DNA methylation in tissue biopsies. Liquid biopsy samples were taken from patients with clinical suspicion of PCa, who were subsequently divided into two groups, that is, 42 with PCa and 55 with BPH, according to the histopathological analysis. RESULTS: Statistically significant higher cfDNA methylation of LGALS3 in seminal plasma of BPH than in PCa patients was detected by pyrosequencing. ROC curve analysis showed that it could distinguish PCa and BPH patients with 56.4% sensitivity and 70.4% specificity, while PSA did not differ between the two patient groups. In contrast, there was no statistically significant difference in LGALS3 cfDNA methylation in blood plasma between the two patient groups. In prostate tumor tissue, there was a statistically significant DNA hypermethylation of LGALS3 compared to surrounding nontumor tissue and BPH tissue. CONCLUSIONS: The DNA hypermethylation of the LGALS3 gene represents an event specific to PCa development. In conclusion, LGALS3 cfDNA methylation in seminal fluid discriminates early PCa and BPH presenting itself as a powerful novel PCa biomarker highly outperforming PSA.

Methylation pattern of caveolin-1 in prostate cancer as potential cfDNA biomarker.

High prevalence and mortality of prostate cancer (PCa) are well known global health issues. Novel biomarkers for better identifying patients with PCa are the subject of extensive research. Prostate specific antigen (PSA) shows low specificity in screening and diagnostics, leading to unnecessary biopsies and health costs. Eighty patients with PCa and benign prostate hyperplasia (BPH) were included in the study. We analyzed CAV1 gene expression and methylation in tissue. CAV1 cfDNA methylation from blood and seminal plasma was accessed as a potential PCa biomarker. Although methylation in blood plasma did not differ between PCa and BPH patients, methylation in seminal plasma showed better PCa biomarker performances than tPSA (AUC 0.63 vs. AUC 0.52). Discrimination of BPH and Gleason grade group 1 PCa patients from patients with higher Gleason grade groups revealed very good performance as well (AUC 0.72). CAV1 methylation is useful biomarker with potential for further seminal plasma cfDNA research, but its diagnostic accuracy should be improved, as well as general knowledge about cfDNA in seminal plasma.

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.

Prostate Cancer-Focus on Cholesterol.

Prostate cancer (PC) is the most common malignancy in men. Common characteristic involved in PC pathogenesis are disturbed lipid metabolism and abnormal cholesterol accumulation. Cholesterol can be further utilized for membrane or hormone synthesis while cholesterol biosynthesis intermediates are important for oncogene membrane anchoring, nucleotide synthesis and mitochondrial electron transport. Since cholesterol and its biosynthesis intermediates influence numerous cellular processes, in this review we have described cholesterol homeostasis in a normal cell. Additionally, we have illustrated how commonly deregulated signaling pathways in PC (PI3K/AKT/MTOR, MAPK, AR and p53) are linked with cholesterol homeostasis regulation.

Psoas abscess during treatment with intravenous tocilizumab in a patient with rheumatoid arthritis: a case-based review.

Interleukin-6 receptor antagonist tocilizumab is a biologic drug used for treating patients with active rheumatoid arthritis (RA) who failed to respond to synthetic or other biologic disease-modifying antirheumatic drugs or where they were contraindicated. Interleukin-6 receptor blockade results in a decrease of disease activity but has some potential adverse effects, the most common being infections. We present a case of a 75-year-old female patient with long-lasting RA, several comorbidities and multiple prior therapies, who developed back pain and general malaise during tocilizumab intravenous treatment. The laboratory findings were typical of toxemia, and the imaging findings revealed large psoas muscle abscess. Surgical and antibiotic treatment was performed with a good outcome. To our knowledge, this has been the first case of a psoas abscess in a patient with RA treated with tocilizumab described in the literature so far. We also present a review of the literature regarding infection, and particularly abscess formation in patients treated with biological disease-modifying antirheumatic drugs, tocilizumab included.

Peritumoral Clefting and Expression of MMP-2 and MMP-9 in Basal Cell Carcinoma of the Skin.

BACKGROUND/AIM: Peritumoral clefting is one of the main histologic features of basal cell carcinoma of the skin (BCC). The aim of the study was to analyze the expression of MMP-2 and MMP-9 both in cells of basal cell carcinoma and in the adjacent stroma and to correlate the findings of immunohistochemical analysis with the presence of peritumoral clefting. PATIENTS AND METHODS: The study was made on archival material comprising 48 cases of BCC. These were scanned for the presence of peritumoral clefts. The results of immunohistochemical staining for MMP-2 and MMP-9 were determined semiquantitatively using immunohistochemical staining index (ISI). RESULTS: Peritumoral retractions were found in 40 BCC cases. Positive immunohistochemical reaction for MMP-2 in tumor cells was found in 47 cases and in all cases in the adjacent stroma. Positive immunostaining for MMP-9 in BCC tumor cells was observed in 37 cases and in all cases in the adjacent stroma. There was no statistically significant association between peritumoral retractions and expression of MMPs. A statistically significant correlation was found in the expression of both MMP-2 and MMP-9 between the tumor and the stroma. CONCLUSION: Tumor cells elaborate MMP-2 and -9, but they also produce some other factors that may induce production of MMPs in adjacent stromal cells. The role of MMPs in the development of peritumoral clefts could not be confirmed.

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.

PROSTATE-SPECIFIC ANTIGEN (PSA) VALUES IN PATIENTS WITH LOW- AND HIGH-RISK PROSTATIC ADENOCARCINOMA.

Prostatic adenocarcinoma (PC) comprises around 19% of malignancies in Croatian male population. On the basis of PSA value, Gleason score, grading group and clinical stage, PC can be classified into low- and high-risk groups which is significant for different therapeutic regimens and prognostic outcomes. In this retrospective study, we analyzed the difference in preoperative PSA value in a group of 272 patients who underwent radical prostatectomy and were diagnosed with PC adenocarcinoma in our institution in a period from January 1st, 2018 untill December 31st, 2018. Subsequently, they were divided into low- and high-risk prostatic adenocarcinoma groups. Our results demonstrated positive correlation in preoperative PSA values between the groups and therefore support the use of PSA as one of the parameters in defining low- and high-risk prostatic adenocarcinoma categories.

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.

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.

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.

Klebsiella Pneumoniaeoxa-48 in a Urology Patient: Case Report

We present an isolate of Klebsiella pneumoniae OXA-48 isolated in a 68-year-old man who underwent radical prostatectomy due to prostate cancer. The antibiotic susceptibility testing to a wide range of antibiotics was performed by disk diffusion method and determination of minimal inhibitory concentrations. The isolate was classified as multidrug-resistant. It showed intermediate susceptibility to imipenem and meropenem, resistance to ertapenem, and sensitivity only to colistin, amikacin, and trimethoprim-sulfamethoxazole. The isolate was positive for ESBLs, negative for AmpC. Polymerase chain reaction and sequencing revealed bla(OXA-48)', bla(CTX-M-15) and bla(SHV-11). The plasmid encoding OXA-48 ß-lactamase did not belong to any known PCR-based replicon typing. According to genotyping, the isolate belonged to ST37.

Validation of Epstein Biopsy Criteria for Insignificant Prostate Cancer in Contemporary Cohort of Croatian Patients.

Only few reports validated contemporary Epstein criteria for insignificant prostate cancer, and only one being from Europe. Patients with insignificant prostate cancer should be offered active surveillance and spared radical treatment. In our study we tested Epstein biopsy criteria for predicting unfavorable final pathology and biochemical relapse in low risk prostate cancer patients, who were eligible for active surveillance but where treated with radical prostatectomy. Between January 2003 and January 2008, 586 patients were subjected to radical prostatectomy in our institution. Among them, 106 where eligible for active surveillance according to Epstein biopsy criteria for insignificant prostate cancer. We analyzed the presence of adverse pathological findings in the final pathohistological specimen after radical prostatectomy which excludes low risk disease. Adverse pathohistological findings were noted in 41 (38.6%) patients, who could have been offered active surveillance. During the follow up of 48 (12-72) months, biochemical relapse was noted in 6 (5.6%) patients. Although active surveillance is becoming more popular because of the long natural course of prostate cancer and fear of overtreatment of patients with indolent course of disease, both doctors and patients must be aware of potentially significant disease in this group and limitations of current preoperative criteria defining low risk patients.

Intravesical foreign body as a result of self catheterization: case report.

Foreign bodies inside urinary tract are a relatively rare condition in our practice. There are several reports published and in most cases the reason for self insertion of an object was autoerotic stimulation or psychiatric illness. Self treatment by homemade instruments is a rarely seen scenario. A 62-year-old man presented to our department complaining of lower urinary tract symptoms. On examination, a foreign body was detected inside the urinary bladder. Urethral stricture was also detected for which the patient had been previously treated on several occasions. The patient stated that he had attempted self catheterization using a homemade catheter. He had succeeded in emptying his bladder; however, the catheter entered the bladder completely and was irretrievable to him. Sachse urethrotomy was performed following retrieval of the foreign body. No psychiatric illness was detected in our patient. The patient's postoperative course was uneventful.