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.

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.

Collecting duct carcinoma and endemic nephropathy - case reportS and literature review.

Although collecting duct carcinoma is a subtype of renal cell carcinoma, several studies implicate association with urothelial carcinoma. The coexistence of collecting duct carcinoma and another renal neoplasm is rare. Endemic nephropathy is a renal disease causing chronic renal failure. It is highly associated with urothelial neoplasm and occurs in endemic villages in Bosnia, Croatia, Bulgaria, Romania and Serbia. Recent studies have confirmed the important role of exposure to aristolochic acid as an etiologic factor. We present three cases of collecting duct carcinoma with literature overview. In one case, we describe collecting duct carcinoma with metachronous urothelial carcinoma of the pyelon and urinary bladder in an endemic nephropathy patient. To our knowledge, this is the first case report describing this coexistence. Certain similarities between collecting duct carcinoma and urothelial carcinoma were found, e.g., higher incidence in female compared to male, higher mean age, and multifocal and multicentric occurrence of the tumor. Our observations support the hypothesis that collecting duct carcinoma and urothelial carcinoma could be connected.

Molecular classification of muscle-invasive bladder cancer based on a simplified immunohistochemical panel using GATA3, CK5/6 and p16.

The choice of therapy for muscle-invasive bladder cancer (MIBC) could be influenced by the tumor's molecular subtype. Currently, well-defined consensus subtypes are based on tumor microarray mRNA data. Clearly defined and easy-to-use surrogate molecular subtypes, based on immunohistochemistry (IHC) performed on whole slides, are needed to make subtyping cost-effective and useful in routine work and future research. To aid in the development of a simple immunohistochemical classifier, a retrospective single-center series of 92 cases of localized bladder cancer was identified. Routine IHC for GATA3, cytokeratins 5 and 6 (CK5/6), and p16 was performed on whole tissue blocks containing muscle-invasive disease. Electronic medical records were retrieved and searched for clinical variables, treatment, and survival data. The mean age was 69.6 years, and 73% were males. Conservative treatment was used in 55% of cases, while cystectomy with chemotherapy was used in 45%. GATA3 and CK5/6 expression divided cases into broad luminal and basal subtypes, respectively, while p16 expression was used to subclassify luminal cases into luminal papillary and luminal unstable types according to the consensus molecular classification. When subtyped in this way, GATA3 and CK5/6 negative cases showed worse overall survival. Molecular subtyping of MIBC on whole slides containing muscle-invasive tumor using only three commonly used, consensus-based antibodies, is a feasible and cost-effective method for detecting subtypes of invasive bladder cancer. Future work combining morphological analysis and IHC is needed to fully translate the consensus molecular classification into a comprehensive, cost-effective subtyping strategy.

Genetics of Prostate Carcinoma.

The aim of this review is to provide a brief overview of some current approaches regarding diagnostics, pathologic features, treatment, and genetics of prostate carcinoma (PCa). Prostate carcinoma is the most common visceral tumor and the second most common cancer-related cause of death in males. Clinical outcomes for patients with localized prostate cancer are excellent, but despite advances in prostate cancer treatments, castrate-resistant prostate cancer and metastatic prostate cancer patients have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in prostate cancer. The meaning of these alterations needs to be validated in the specific prostate cancer molecular subtype context. Along these lines, there is a critical need for establishing genetically engineered mouse models, which would include speckle type BTB/POZ protein and isocitrate Dehydrogenase (NADP (+)) 1 mutant, as well as androgen receptor neuroendocrine subtypes of prostate cancer. Another urgent need is developing highly metastatic prostate cancer models, as only up to 17% of available models display bone metastases and exhibit a less typical neuroendocrine prostate cancer or sarcomatoid carcinoma. Moreover, androgen deprivation and relapse should be mimicked in the genetically engineered mouse models, as androgen independence may yield a better model for metastatic castrate-resistant prostate cancer. The development of such refined animal models should be guided by comparative genomics of primary versus corresponding metastatic tumors. Such an approach will have the potential to illuminate the key genetic events associated with specific molecular prostate cancer subsets and indicate directions for effective therapy. CONCLUSION: Despite excellent results in the treatment of localized prostatic carcinoma, castrate-resistant prostate cancer and metastatic prostate cancer have a poor prognosis. Advanced large-scale genomic studies revealed a large number of genetic alterations in PCa. Experimental models of prostate carcinoma in genetically modified mice could provide new data about the genetic changes in such cancers and help in developing better animal models for treatment resistant prostate carcinomas.

MiR-182-5p and miR-375-3p Have Higher Performance Than PSA in Discriminating Prostate Cancer from Benign Prostate Hyperplasia.

Prostate cancer (PCa) is the most commonly diagnosed neoplasm among men. Since it often resembles benign prostate hyperplasia (BPH), biomarkers with a higher differential value than PSA are required. Epigenetic biomarkers in liquid biopsies, especially miRNA, could address this challenge. The absolute expression of miR-375-3p, miR-182-5p, miR-21-5p, and miR-148a-3p were quantified in blood plasma and seminal plasma of 65 PCa and 58 BPH patients by digital droplet PCR. The sensitivity and specificity of these microRNAs were determined using ROC curve analysis. The higher expression of miR-182-5p and miR-375-3p in the blood plasma of PCa patients was statistically significant as compared to BPH (p = 0.0363 and 0.0226, respectively). Their combination achieved a specificity of 90.2% for predicting positive or negative biopsy results, while PSA cut-off of 4 µg/L performed with only 1.7% specificity. In seminal plasma, miR-375-3p, miR-182-5p, and miR-21-5p showed a statistically significantly higher expression in PCa patients with PSA >10 µg/L compared to ones with PSA ≤10 µg/L. MiR-182-5p and miR-375-3p in blood plasma show higher performance than PSA in discriminating PCa from BPH. Seminal plasma requires further investigation as it represents an obvious source for PCa biomarker identification.

A giant hemorrhagic adrenal pseudocyst: case report.

OBJECTIVE: To report a rare case of a giant hemorrhagic adrenal pseudocyst and highlight the importance of this entity to clinicians. CASE PRESENTATION: A 57-year-old woman presented with a 1-year history of abdominal pain and distension. Ultrasonography and multislice computed tomography revealed a giant cystic (partially solid) mass over the left suprarenal region measuring 20 x 17 x 15 cm. A complete endocrine workup failed to detect any hormonal hypersecretion. INTERVENTION: The patient was treated with tumor excision through transabdominal pararectal approach. Histopathological examination revealed a hemorrhagic adrenal pseudocyst. CONCLUSION: To our knowledge the case presented here appears to be one of the largest hemorrhagic adrenal pseudocysts reported so far. Radiological and clinical features of the tumor are nonspecific and histopathological examination is essential to establish definitive diagnosis. An open, laparotomic adrenalectomy is the preferred surgical technique for better control of such a large mass with active bleeding inside.

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.

Transobturator Advance® Sling Suspension for the Treatment of Postprostatectomy Stress Urinary Incontinence.

Stress urinary incontinence (SUI) continues to present a major complication after radical prostatectomy. Suburethral slings represent one of the less invasive options for postprostatectomy SUI, and a more recent addition is a transobturator sling, the AdVance®. We report our results with the AdVance® sling for the management of postoperative SUI. The evaluation was conducted on 47 patients with AdVance® implant for SUI in our institution (November 2010 - June 2017). Measurements included age, etiology of SUI, duration of SUI, follow-up and pad use per day (PPD) pre- and postoperatively. Patients were classified as cured if they used no pads or 1 PPD for security reasons, or as improved if 1-2 PPDs were used and if there was a 50% reduction in pad use per day postoperatively. In our series we observed a reduction of mean PPD of 5.1 (2-8) to 1.7 (0-4) postoperatively. After follow-up and according to our criteria, the cure rate was 51.1% (24/47) and the improvement rate 27.5% (13/47). The overall success rate was 78.6% (37/47). No improvement was observed in 21.4% (10/47) of patients. Failure rates after sling placement for patients with addi-tional treatments following prostatectomy were much higher (60% (3/10) for radiation therapy and 66.7% (4/10) for urethral stricture disease). Our results show favourable cure and improvement rates and are comparable to results from larger series. The most appropriate candidates for the AdVance® sling are patients with mild to moderate postprostatectomy SUI. The results may be even better in patients without additional treatment following prostatectomy, such as radiation therapy or surgery for stricture disease.

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.

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.

[Bilateral renal cell carcinoma and concomitant urothelial carcinoma of the renal pelvis and ureter: case report]. / Obostrani karcinom bubreznih stanica i istodobni urotelni karcinom nakapnice i mokracovoda: prikaz bolesnika.

We report a patient with ipsilateral synchronous renal cell carcinoma and urothelial carcinoma of the left renal pelvis and ureter. The patient underwent nephrectomy 9 years earlier due to renal cell cancer of the right kidney. Only 25 cases of ipsilateral synchronous renal cell carcinoma and urothelial carcinoma have been reported in the literature. The median age at diagnosis was 65 years, hematuria was the most common presentation and 24% of patients had metastases at first examination. Approximately one fourth of the patients had a history of cigarette smoking. There is no proof about higher histopathological grade of malignancy or specific histological pattern of these tumors when they occur synchronously. In the literature there is no report on the synchronous occurrence of renal cell carcinoma and urothelial carcinoma of both the renal pelvis and ipsilateral ureter.

A RARE CASE OF SQUAMOUS CELL CARCINOMA IN URINARY BLADDER DIVERTICULUM SUCCESSFULLY TREATED BY BLADDER-SPARING SURGERY.

The aim is to report a rare case of squamous cell carcinoma arising in a urinary bladder diverticulum and present recent literature overview of treatment options. A 56-year-old man presented with intermittent hematuria. Ultrasound examination indicated primary carcinoma in the urinary bladder diverticulum. Diagnosis was confirmed with cystoscopy and computed tomography. Transvesical diverticulectomy with regional lymphadenectomy was undertaken. Two years after initial treatment, the patient was well without evidence of tumor relapse. This report implicates that although aggressive surgical approach is recommended in the majority of bladder diverticulum tumors, simple diverticulectomy may be indicated in selected, confined cases.

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.

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.

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.

Management of fournier's gangrene: case report and literature review.

A 65-year-old man was referred to our department with clinical signs of septic shock and necrotizing soft tissue infection of the scrotal, perianal and right inguinal region. Initial presentation was a typical Fournier's gangrene. Because of the life-threatening condition, the initial treatment was extensive removal of necrotic tissue. Antibiotic therapy was administered and several debridements of the wound were done afterwards. Three weeks after the initial treatment, wide wound defects of the perianal, scrotal and inguinal regions were closed secondarily and the patient was discharged from the hospital. Fournier's gangrene is a surgical emergency. Although rare, it remains a life-threatening disease. Rapid and accurate diagnosis remains the key component in achieving successful outcome. Early aggressive surgical intervention together with fluid, hemodynamic and nutritional support and broad-spectrum antibiotics is the essential management to reduce mortality.

Posttraumatic high-flow priapism: case report, current management options and literature review.

A rare case of posttraumatic high-flow priapism is presented. A 20-year-old man underwent diagnostic procedure with color Doppler sonography and angiography. On color Doppler sonography and selective and supraselective angiographic images, arteriocavernosal fistula and pseudoaneurysm were detected in the proximal part of the right cavernous body. Complete detumescence of the penis was achieved by selective embolization with microcoil. No recurrence was observed and postoperative erectile function was incompletely restored. The clinical, diagnostic and therapeutic peculiarities of this rare condition are presented, along with review of the literature on the topic.