Trend analysis and regional tumor incidence in Germany for testicular cancer between 2003 and 2014.

BACKGROUND: Testicular germ cell tumor (TGCT) is one the most common solid tumors in men between the age of 15 and 35 with an overall incidence rate of 1-1.5 %. Epidemiologic studies have demonstrated different incidence patterns in western civilized countries with overall rising incidence trends. OBJECTIVE: To analyze differences in regional tumor incidence rates for TGCT and perform a trend analysis for TGCT between 2003 and 2014 in Germany. MATERIAL AND METHODS: TGCT cases in Germany which were diagnosed between 2003 and 2014 were provided by the Robert-Koch-Institute, Berlin. For statistical analysis, cluster and spatial scan tests according to Kulldorff were used for cases with seminoma and non-seminoma. Results are presented in administrative districts and graphically illustrated. We performed a trend-analysis in order to evaluate age-adjusted incidence trends in Germany. Tests were two-sided with a level of significance of α=0.05. RESULTS: In total we included 35,066 patients. Overall, 22,634 cases had newly diagnosed seminoma and 12,432 were diagnosed as non-seminoma. Maximum incidence of seminoma and non-seminoma was observed for age-group 38-40 years and 26-28 years, respectively. No second peak for the incidences of seminoma and non-seminoma with respect to age were observed. Cluster analysis revealed areas with high and low incidence rates as well as slightly different spatial distribution in Germany between seminoma and nonseminoma. Furthermore, there was no significant increase in age-adjusted incidence rates over the reviewed time period in both cohorts. DISCUSSION: In this study differences in reginal tumor incidence rates for seminoma and non-seminoma are reported with both tumor entities revealing distinct clusters. Furthermore, tumor incidence trends for seminoma and nonseminoma between 2003 and 2014 were stable which might indicate the beginning of a plateau phase for TGCT incidence rates in Germany. CONCLUSION: In this analysis we were able to identify regions with significantly higher tumor incidence rates for both seminoma and non-seminoma which were specific for these two subtypes. Furthermore, trend analysis revealed a steady incidence rate for testicular cancer in Germany.

[Urolithiasis 2016 : Reliable, effective and low radiation exposure]. / Steindiagnostik 2016 : Zuverlässig, effektiv und strahlungsarm.

BACKGROUND: Urolithiasis is a widespread disease. Diagnostic imaging plays an important role in the evaluation and management of patients with suspected urolithiasis. Furthermore, modern imaging methods may provide information on stone location, size, fragility and composition aiding the urologist to determine the appropriate treatment modality. PURPOSE: Based on the current literature and guidelines, this review reports on the various new and established diagnostic imaging modalities. RESULTS: Ultrasound should always be the initial imaging modality. Following ultrasound, noncontrast CT-principally using a low-dose protocol-is the imaging modality of choice in the evaluation of patients with acute flank pain and suspected urolithiasis. New imaging modalities like dual energy CT, Uro Dyna CT and digital tomosynthesis are currently under investigation but not yet part of daily clinical practice. Magnetic resonance imaging can be used to detect obstruction caused by urinary stones but is not a first-line imaging modality.

[Cystectomy in the elderly patient]. / Zystektomie im Alter.

Bladder cancer is a carcinoma of the elderly population. The highest incidence of bladder cancer is between the ages of 70 and 80 years old. Radical cystectomy remains the gold standard for muscle invasive bladder cancer treatment. In this article different aspects of radical cystectomy in elderly patients are reviewed. The Pubmed-MEDLINE database was searched using the following keywords: radical, cystectomy, elderly and age.

Resistance to the mTOR-inhibitor RAD001 elevates integrin α2- and ß1-triggered motility, migration and invasion of prostate cancer cells.

BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) might become a novel tool to treat advanced prostate cancer. However, chronic drug exposure may trigger resistance, limiting the utility of mTOR inhibitors. METHODS: Metastatic potential of PC3 prostate cancer cells, susceptible (PC3(par)) or resistant (PC3(res)) to the mTOR-inhibitor RAD001 was investigated. Adhesion to vascular endothelium or immobilised collagen, fibronectin and laminin was quantified. Motility, migration and invasion were explored by modified Boyden chamber assay. Integrin α and ß subtypes were analysed by flow cytometry, western blotting and real-time PCR. Integrin-related signalling, EGFr, Akt, p70S6kinase and ERK1/2 activation were determined. RESULTS: Adhesion was reduced, whereas motility, migration and invasion were enhanced in PC3(res). The α2 and ß1 integrin subtypes were dramatically elevated, integrins α1 and α6 were lowered, whereas α5 was nearly lost in PC3(res). Activation of the Akt signalling pathway was strongly upregulated in these cells. Treating PC3(par) cells with RAD001 reduced motility, migration and invasion and deactivated Akt signalling. Blocking studies revealed that α2 and ß1 integrins significantly trigger the motile behaviour of the tumour cells. CONCLUSION: Chronic RAD001 treatment caused resistance development characterised by distinct modification of the integrin-expression profile, driving prostate cancer cells towards high motility.

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro.

BACKGROUND: The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin ß subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose-dependently reduced tumor-cell growth but did not impair tumor-endothelium and tumor-matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated ß1-integrin in PC-3 and diminished ß4-integrin in PC-3 and DU-145 cells. CONCLUSIONS: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

Upgrading of Gleason score 6 prostate cancers on biopsy after prostatectomy in the low and intermediate tPSA range.

When offering watchful waiting or active monitoring protocols to prostate cancer (PCa) patients, differentiation between Gleason scores (GS) 6 and 7 at biopsy is important. However, upgrading after prostatectomy is common. We investigated the impact of different PSA levels on misclassification in the PSA range of 2-3.9 and 4-10 ng ml(-1). A total of 448 patients with GS 6 PCa on prostate biopsy were evaluated by comparing biopsy and prostatectomy GS. Possible over diagnosis was defined as GS <7, pathological stage pT2a and negative surgical margins, and possible under diagnosis was defined as pT3a or greater, or positive surgical margins; the percentage of over- or under diagnosis was determined for correctly and upgraded tumors after prostatectomy. A match between biopsy and prostatectomy GS was found in 210 patients (46.9%). Patients in the PSA range of 2.0-3.9 and 4.0-10.0 ng ml(-1) were upgraded in 32.6 and 44.0%, respectively. Over diagnosis was more common than under diagnosis (23.2% vs 15.6%). When upgraded there was a significant increase in under diagnosis. As almost 40% of GS 6 tumors on biopsy are GS 7 or higher after surgery with a significant rise in under diagnosis there is a risk of misclassification and subsequent delayed or even insufficient treatment, when relying on favorable biopsy GS.

Transrectal ultrasound as diagnostic tool for the detection of local recurrence following cystectomy and urinary diversion.

OBJECTIVE: Routine follow-up after cystectomy for bladder cancer detect patients with local recurrence late in the course of disease. We set out to determine the value of transrectal ultrasound (TRUS) as diagnostic tool to diagnose local failure. PATIENTS AND METHODS: Between 1986 and 2003, radical cystectomy for bladder cancer with orthotopic diversion was performed in 642 male patients. We identified all patients that simultaneously had transabdominal ultrasound, digital rectal examination, TRUS and CT/MRI of the pelvis at the diagnosis of local recurrence. RESULTS: Mean follow-up was 59.4 months. 83/642 patients (13%) had local failure of bladder cancer during follow-up. In 48/642 patients (7.5%) the local recurrence was the first site of recurrence. 35/642 patients (5.5%) developed local failure with concomitant distant disease. 31/83 patients met the inclusion criteria. The median time between cystectomy and diagnosis of local recurrence was 13 months (2-51 months). Routine follow-up detected local recurrence in 1 asymptomatic patient. 25/31, 3/31 and 2/31 patients had pain in the lower extremities/pelvis, hematuria and urinary retention, respectively. Digital rectal examination, transabdominal ultrasound, TRUS, and CT/MRI of the pelvis were suspicious for local recurrence in 9, 7, 26, and 29 patients, respectively. CONCLUSIONS: TRUS is a highly sensitive tool in detecting local recurrence following cystectomy. It is easy to perform and inexpensive. We recommend TRUS in short intervals in all patients with high risk for local recurrence in order to detect cancer early.

Extracellular microenvironment and cytokine profile of the ureterovesical junction in children with vesicoureteral reflux.

PURPOSE: Vesicoureteral reflux is caused by a defective valve mechanism of the ureterovesical junction. Previous studies have revealed structural and metabolic changes in the intravesical ureter, impairing its contractile properties. Smooth musculature and nerves are replaced by collagen, while matrix degrading enzymes are over expressed. We investigated the presence of regulating cytokines and the extracellular matrix composition to elucidate further the pathophysiology of vesicoureteral reflux. MATERIALS AND METHODS: Ureteral endings were obtained from 28 children during antireflux surgery, and 14 age matched autopsy specimens served as controls. Routine histological sections were immunostained for insulin-like growth factor-1, nerve growth factor, transforming growth factor-beta1, tumor necrosis factor-alpha and vascular endothelial growth factor. Smooth muscle staining was supplemented by tenascin C, tetranectin and fibronectin detection. Staining patterns were investigated using computer assisted, high power field magnification analyses. RESULTS: Tumor necrosis factor-alpha and transforming growth factor-beta1 were significantly more abundant in vesicoureteral reflux samples, whereas insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor were more prevalent in healthy controls. Fibronectin was intensely expressed in refluxing ureters, while it was scarce in healthy children. Tenascin C was notable within the urothelium of both groups. Only vesicoureteral reflux samples displayed tenascin C in the musculature and connective tissue. Tetranectin staining was only detected in vesicoureteral reflux. CONCLUSIONS: Several cytokines are differentially expressed in primary refluxing ureters, indicating an ongoing tissue remodeling process in the ureterovesical junction region. Additionally, the smooth muscle coat is widely lacking, while extracellular matrix proteins typical for tissue shrinkage and reorganization are over expressed. These alterations are likely to contribute to the malfunctioning active ureteral valve mechanism in primary vesicoureteral reflux.

The efficacy of dihydrotestosterone transdermal gel before primary hypospadias surgery: a prospective, controlled, randomized study.

PURPOSE: We sought to evaluate the efficacy of transdermal dihydrotestosterone treatment based on the results of hypospadias repair in children with primary hypospadias. MATERIALS AND METHODS: A total of 75 randomized consecutive children who were a mean of 33.4 +/- 3.7 months old and had primary hypospadias were included in the study between September 2004 and April 2006. While 37 children were treated with 2.5% transdermal gel daily, applied directly onto the penile shaft and glans for 3 months (group 1), 38 children did not receive any treatment preoperatively (group 2). All children underwent hypospadias repair using tubularized incised plate urethroplasty. Postoperative complications were analyzed using the Mann-Whitney U test with respect to fistulas, urethral strictures, diverticula, meatal stenosis, glanular dehiscence and scar formation according to the results at 1-year followup. RESULTS: Mean ages of the children in groups 1 and 2 were similar (30.8 +/- 5.4 months and 35.1 +/- 5.1 months, respectively). The urethral meatus was coronal in 70%, penile in 24% and penoscrotal in 5% of the patients in group 1, while it was coronal in 84% and penile in 16% of the patients in group 2. Postoperative complications included urethrocutaneous fistula in 4 patients (11%) in group 2, compared to 1 patient (3%) in group 1 (p >0.05). While 3 patients (8%) in group 2 had glanular dehiscence, no patient in the dihydrotestosterone group had this complication (p <0.05). There were 2 patients with meatal stenosis in group 2 (5%), and no patient with meatal stenosis in group 1 (p >0.05). In addition, there were 16 patients (42%) with moderate to severe postoperative scar formation in group 2, compared to only 2 patients (5%) in the dihydrotestosterone group (p <0.05). Finally, there was a significant difference between the overall reoperation rates of group 2 (9 patients, 24%) and group 1 (1 patient, 3%, p <0.05). None of our patients had signs or symptoms of urethral stricture or urethral diverticulum. CONCLUSIONS: Pretreatment with dihydrotestosterone transdermal gel was effective in decreasing the complications and improving the cosmetic results after hypospadias repair.

Transurethral ultrasonography-guided injection of adult autologous stem cells versus transurethral endoscopic injection of collagen in treatment of urinary incontinence.

In the last years preclinical studies have paved the way for the use of adult muscle derived stem cells for reconstruction of the lower urinary tract. Between September 2002 and October 2004, 42 women and 21 men suffering from urinary stress incontinence (age 36-84 years) were recruited and subsequently treated with transurethral ultrasonography-guided injections of autologous myoblasts and fibroblasts obtained from skeletal muscle biopsies. The fibroblasts were injected into the urethral submucosa, while the myoblasts were implanted into the rhabdosphincter. In parallel, 7 men and 21 women (age 39-83 years) also diagnosed with urinary stress incontinence were treated with standard transurethral endoscopic injections of collagen. Patients were randomly assigned to both groups. After a follow-up of 12 months incontinence was cured in 39 women and 11 men after injection of autologous myoblasts and fibroblasts. Mean quality of life score (51.38 preoperatively, 104.06 postoperatively), thickness of urethra and rhabdosphincter (2.103 mm preoperatively, 3.303 mm postoperatively) as well as contractility of the rhabdosphincter (0.56 mm preoperatively, 1.462 mm postoperatively) were improved postoperatively. Only in two patients treated with injections of collagen incontinence was cured. The present clinical results demonstrate that, in contrast to injections of collagen, urinary incontinence can be treated effectively with ultrasonography-guided injections of autologous myo- and fibroblasts.

Fetal distribution of 5alpha-reductase 1 and 5alpha-reductase 2, and their input on human prostate development.

PURPOSE: Human prostate development starts in the tenth week of gestation. Initial interactions between the epithelium and mesenchyma are stimulated by androgens. The transformation of circulating testosterone to 5alpha-dihydrotestosterone by tissue linked 5alpha-reductase is a key event in androgen metabolism. The 5alpha-dihydrotestosterone mediates androgen effects in the urogenital sinus and external genitalia, leading to the formation of a male phenotype and androgen mediated prostate growth. Supposedly 5alpha-reductase 2 is the predominant isoenzyme in human accessory sex tissue, whereas the function of 5alpha-reductase 1 remains unclear. We focused on the detection, distribution and effects of the 2 isoenzymes during gestation and infancy. MATERIALS AND METHODS: Serial sections from fetuses and infants were immunostained using antibodies directed against 5alpha-reductase 1 and 2. Additionally, to detect the downstream products of androgen synthesis reverse transcriptase-polymerase chain reaction analyses were done for 17 beta-hydroxysteroid dehydrogenase types 2, 3 and 7. RESULTS: Immunohistochemistry revealed positive staining for each isoenzyme throughout fetal development. Moreover, reverse transcriptase-polymerase chain reaction for 5alpha-reductase 1 and 2 confirmed these findings on the transcription level. Additionally, the most relevant enzymatic downstream products of cellular androgen synthesis (17 beta-hydroxysteroid dehydrogenase 2, 3 and 7) were also detected by reverse transcriptase-polymerase chain reaction. CONCLUSIONS: To our knowledge this is the first study revealing the expression and distribution of each 5alpha-reductase isoenzyme as well as the potential contribution of 5alpha-reductase 1 during fetal human prostate development.

Comparison of contrast enhanced color Doppler targeted biopsy to conventional systematic biopsy: impact on Gleason score.

PURPOSE: Prostate cancer grading with Gleason score is an important prognostic factor. This prospective randomized study compares ultrasound systematic biopsy vs contrast enhanced color Doppler targeted biopsy for the impact on Gleason score findings. MATERIALS AND METHODS: We examined 690 men (mean age 56 years, range 41 to 77) with a serum total prostate specific antigen of 1.25 ng/ml or greater, a free-to-total prostate specific antigen ratio less than 18% and/or a suspicious digital rectal examination. Contrast enhanced color Doppler targeted biopsies with a limited number of cores (5 or less) were performed in hypervascular areas of the peripheral zone during administration of the ultrasound contrast agent Sonovuetrade mark (Bracco, Milano, Italy). Ten systematic biopsies were obtained in a standard spatial distribution. Cancer detection rates and Gleason score were compared. RESULTS: Prostate cancer was identified in 221 of 690 subjects (32%) with a mean prostate specific antigen of 4.6 ng/ml (range 1.4 to 35.0). Prostate cancer was detected in 180 of 690 subjects (26%) with contrast enhanced color Doppler targeted biopsy and in 166 of 690 patients (24%) with systematic ultrasound biopsy. The Gleason score of all 180 cancers detected on contrast enhanced color Doppler targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected on systematic biopsy ranged from 4 to 6 and mean Gleason score was 5.4. Contrast enhanced color Doppler targeted biopsy detected significantly higher Gleason scores compared to systematic biopsy (Wilcoxon rank sum test p <0.003). CONCLUSIONS: Contrast enhanced color Doppler targeted biopsy detected cancers with higher Gleason scores and more cancer than systematic biopsy. Therefore, contrast enhanced color Doppler seems to be helpful in the grading of prostate cancer, which is important for defining prognosis and deciding treatment.

Structural changes of the intravesical ureter in children with vesicoureteral reflux-does ischemia have a role?

PURPOSE: Previous studies have revealed structural and metabolic changes in the distal most ureter, impairing its contractile properties, and, thus, having a role in the pathogenesis of vesicoureteral reflux. Musculature and nerves are replaced by interstitial collagen, while matrix degrading enzymes are over expressed. We investigated the microvessel architecture of the ureterovesical junction to elucidate further the pathophysiology of vesicoureteral reflux. MATERIALS AND METHODS: Ureteral endings were obtained from 28 children during antireflux surgery. Ureteral tissue from 14 age matched autopsy specimens served as control. Routine histological paraffin embedded sections were immunostained, detecting CD31 as an endothelial marker as well as vascular endothelial growth factor. Microvessel density and vascular endothelial growth factor expression were investigated based on computer assisted high power field magnification analyses. The t test and the Spearman rho test were applied for statistical evaluation. RESULTS: Overall, microvessel density was significantly reduced in cases of vesicoureteral reflux. While reflux grade and age were not correlated with microvessel density, it was particularly decreased in regions lacking smooth musculature. Vascular endothelial growth factor was observed in smooth muscle, endothelial and connective tissue cells. Additionally, cellular vascular endothelial growth factor expression was markedly abridged in cases of vesicoureteral reflux compared to healthy controls. CONCLUSIONS: Overall microperfusion is supposed to be impaired, leading to tissue ischemia due to reduction of vascular endothelial growth factor expression and subsequent microvessel density. Diminished ureteral perfusion is likely to induce and support smooth muscle dysfunction as well as subsequent extracellular matrix remodeling, including increased collagen deposition. These ongoing functional and structural alterations may further deteriorate the active valve mechanism of the ureterovesical junction, causing vesicoureteral reflux.

Neobladder emptying failure in males: incidence, etiology and therapeutic options.

PURPOSE: Neobladder reconstruction is considered the best option for patients requiring cystectomy. Limited information is available about incidence, etiology and therapeutic options for neobladder emptying failure in males. MATERIALS AND METHODS: In a retrospective study we analyzed the data of a consecutive series of 655 male patients (age range 23 to 82 years, median 63; followup range 0 to 208 months, median 36.5) who received an ileal neobladder following radical cystectomy at our institution. All patients had a complete followup until death or until December 2003. Data on all diagnostic and therapeutic procedures performed for neobladder emptying failure were collected. RESULTS: Of 655 patients 75 (11.5%) had at least 1 episode of failure emptying the neobladder requiring some form of therapy during followup. Failure was due to dysfunctional voiding in 23 patients (3.5%) and mechanical obstruction in 52 patients (8%). Causes of mechanical obstruction were benign strictures of the neovesicourethral anastomosis (23 patients, 3.5%) or the anterior urethra (11 patients, 1.7%), neoplastic obstruction by local tumor recurrence (13 patients, 2.0%) or a nonurological malignancy (1 patient, 0.2%), and obstruction by mucosal valves (3 patients, 0.5%) or a foreign body (1 patient, 0.2%). In 38 of 52 patients with mechanical obstruction of the neobladder outlet emptying was fully restored with endourological procedures, while in 14 of 52 patients long-term catheterization was necessary. Catheterization was the therapy of choice for all patients with dysfunctional voiding. CONCLUSIONS: Neobladder emptying failure is of major concern but is not an argument against orthotopic diversion. The overall rate of transient or permanent neobladder emptying failure in males is high but most of the mechanical causes can be managed endoscopically, while the rate of patients with long-term catheterization for dysfunctional voiding is relatively low.