MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer.

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa.

The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer.

BACKGROUND: Several randomized controlled trials assessed the outcomes of patients treated with neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP). The majority of them included mainly low and intermediate risk prostate cancer (PCa) without specifically assessing PCa-related death (PCRD). Thus, there is a lack of knowledge regarding a possible effect of NHT on PCRD in the high-risk PCa population. We aimed to analyze the effect of NHT on PCRD in a multicenter high-risk PCa population treated with RP, using a propensity-score adjustment. METHODS: This is a retrospective multi-institutional study including patients with high-risk PCa defined as: clinical stage T3-4, PSA >20 ng ml-1 or biopsy Gleason score 8-10. We compared PCRD between RP and NHT+RP using competing risks analysis. Correction for group differences was performed by propensity-score adjustment. RESULTS: After application of the inclusion/exclusion criteria, 1573 patients remained for analysis; 1170 patients received RP and 403 NHT+RP. Median follow-up was 56 months (interquartile range 29-88). Eighty-six patients died of PCa and 106 of other causes. NHT decreased the risk of PCRD (hazard ratio (HR) 0.5; 95% confidence interval (CI) 0.32-0.80; P=0.0014). An interaction effect between NHT and radiotherapy (RT) was observed (HR 0.3; 95% CI 0.21-0.43; P<0.0008). More specifically, of patients who received adjuvant RT, those who underwent NHT+RP had decreased PCRD rates (2.3% at 5 year) compared to RP (7.5% at 5 year). The retrospective design and lack of specific information about NHT are possible limitations. CONCLUSIONS: In this propensity-score adjusted analysis from a large high-risk PCa population, NHT before surgery significantly decreased PCRD. This effect appeared to be mainly driven by the early addition of RT post-surgery. The specific sequence of NHT+RP and adjuvant RT merits further study in the high-risk PCa population.

Older patients with low Charlson score and high-risk prostate cancer benefit from radical prostatectomy.

INTRODUCTION: The aim of the study was to identify the appropriate level of Charlson comorbidity index (CCI) in older patients (>70 years) with high-risk prostate cancer (PCa) to achieve survival benefit following radical prostatectomy (RP). METHODS: We retrospectively analyzed 1008 older patients (>70 years) who underwent RP with pelvic lymph node dissection for high-risk prostate cancer (preoperative prostate-specific antigen >20 ng/mL or clinical stage ≥T2c or Gleason ≥8) from 14 tertiary institutions between 1988 and 2014. The study population was further grouped into CCI < 2 and ≥2 for analysis. Survival rate for each group was estimated with Kaplan-Meier method and competitive risk Fine-Gray regression to estimate the best explanatory multivariable model. Area under the curve (AUC) and Akaike information criterion were used to identify ideal 'Cut off' for CCI. RESULTS: The clinical and cancer characteristics were similar between the two groups. Comparison of the survival analysis using the Kaplan-Meier curve between two groups for non-cancer death and survival estimations for 5 and 10 years shows significant worst outcomes for patients with CCI ≥ 2. In multivariate model to decide the appropriate CCI cut-off point, we found CCI 2 has better AUC and p value in log rank test. CONCLUSION: Older patients with fewer comorbidities harboring high-risk PCa appears to benefit from RP. Sicker patients are more likely to die due to non-prostate cancer-related causes and are less likely to benefit from RP.

[Urinary diversion in elderly patients]. / Harnableitung beim älteren Patienten.

BACKGROUND: Bladder cancer represents one of the ten most prevalent cancers worldwide. More than 400,000 people worldwide are newly diagnosed every year. Within 2 years after diagnosis, 80% of patients with muscle invasive bladder cancer without treatment die. METHODS: The aggressive local surgical approach with a cystectomy is the therapy of choice. The median age of patients with de novo bladder cancer is 70 years. Thus bladder cancer is a cancer of the elderly. For demographical reasons, the number of eldery patients undergoing radical cystectomy will rise in the next few years. The type of urinary diversion is a major factor influencing perioperative morbidity and quality of life in these patients. Incontinent urinary diversions are preferentially used in daily practice. CONCLUSIONS: There are only a few contraindications for orthotopic neobladder; however, age alone is not a contraindication. Patient selection and a nerve sparing approach are crucial in men and women to achieve excellent functional results with orthotopic neobladder in elderly patients.

Predicting prostate cancer-specific outcome after radical prostatectomy among men with very high-risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients.

BACKGROUND: The value of radical prostatectomy (RP) as an approach for very high-risk prostate cancer (PCa) patients is controversial. To examine the risk of 10-year cancer-specific mortality (CSM) and other-cause mortality (OCM) according to clinical and pathological characteristics of very high-risk cT3b/4 PCa patients treated with RP as the primary treatment option. METHODS: In a multi-institutional cohort, 266 patients with very high-risk cT3b/4 PCa treated with RP were identified. All patients underwent RP and pelvic lymph-node dissection. Competing-risk analyses assessed 10-year CSM and OCM before and after stratification for age and Charlson comorbidity index (CCI). RESULTS: Overall, 34 (13%) patients died from PCa and 73 (28%) from OCM. Ten-year CSM and OCM rates ranged from 5.6% to 12.9% and from 10% to 38%, respectively. OCM was the leading cause of death in all subgroups. Age and comorbidities were the main determinants of OCM. In healthy men, CSM rate did not differ among age groups (10-year CSM rate for ⩽64, 65-69 and ⩾70 years: 16.2%, 11.5% and 17.1%, respectively). Men with a CCI ⩾1 showed a very low risk of CSM irrespective of age (10-year CSM: 5.6-6.1%), whereas the 10-year OCM rates increased with age up to 38% in men ⩾70 years. CONCLUSION: Very high-risk cT3b/4 PCa represents a heterogeneous group. We revealed overall low CSM rates despite the highly unfavorable clinical disease. For healthy men, CSM was independent of age, supporting RP even for older men. Conversely, less healthy patients had the highest risk of dying from OCM while sharing very low risk of CSM, indicating that this group might not benefit from an aggressive surgical treatment. Outcome after RP as the primary treatment option in cT3b/4 PCa patients is related to age and comorbidity status.

[Approach to prostate cancer in men older than 75 years: active or passive?]. / Umgang mit dem Prostatakarzinom bei über 75-jährigen Männern : Aktiv oder passiv?

Based on the exponential aging of the population and the increasing life expectancy in industrialized western countries, prostate cancer (PCa) in elderly men is becoming a disease of increasing significance. Consensus exists that men over the age of 75 years should not be screened for PCa; however, higher age as a single parameter should not exclude men from being diagnosed with prostate cancer and treated accordingly. It is well-known that overdiagnosis and overtreatment are frequent in this age group. Competing mortality risks of men older than 75 years may supersede the risk of dying from PCa several fold. Both the treating physician and the patient himself should therefore balance the possible risks and benefits of diagnosing and treating prostate cancer concerning the impact on quality of life. This is of special importance when taking into account that the complication rates of curative treatment modalities are higher in older patients than in younger men and that hormonal treatment might have negative effects especially in older men.Age, existing comorbidities, cognitive and physical status in combination with specific tumor parameters are useful tools for an individualized treatment.Therapy should be considered for healthy, active men aged 75 years or older who present with high-risk PCa and/or with a PSA doubling time <12 months. Elderly men who are unfit or have low to intermediate risk PCa will most likely not benefit from treatment.

[Secondary malignancies in urinary diversions]. / Sekundärmalignome in Harnableitungen.

In contrast to ureterosigmoidostomy no reliable clinical data exist for tumor risk in different forms of urinary diversion using isolated intestinal segments.In 44 German urological departments, operation frequencies, indications, patient age, and operation dates of the different forms of urinary diversion, operated between 1970 and 2007, could be registered. The secondary tumors up to 2009 were registered as well and related to the numbers of the different forms of urinary diversions resulting in tumor prevalences.In 17,758 urinary diversions 32 secondary tumors occurred. The tumor risk in ureterosigmoidostomy (22-fold) and cystoplasty (13-fold) is significantly higher than in other continent forms of urinary diversion such as neobladders or pouches (p<0.0001). The difference between ureterosigmoidostomy and cystoplasty is not significant, nor is the difference between ileocecal pouches (0.14%) and ileal neobladders (0.05%) (p=0.46). The tumor risk in ileocecal (1.26%) and colonic neobladders (1.43%) is significantly higher (p=0.0001) than in ileal neobladders (0.5%). Of the 16 tumors that occurred following ureterosigmoidostomy, 16 (94%) developed directly at the ureterocolonic borderline in contrast to only 50% following urinary diversions via isolated intestinal segments.From postoperative year 5 regular endoscopic controls of ureterosigmoidostomies, cystoplasties, and orthotopic (ileo-)colonic neobladders are necessary. In ileocecal pouches, regular endoscopy is necessary at least in the presence of symptoms or should be performed routinely at greater intervals. Following neobladders or conduits, only urethroscopies for urethral recurrence are necessary.

[How should hormone therapy for castration-resistant prostate cancer be continued?]. / Wie soll die Hormontherapie beim kastrationsresistenten Prostatakarzinom fortgeführt werden?

After an average of 18-36 months under androgen suppression therapy by surgical castration, LHRH, and steroidal or non-steroidal antiandrogens, almost all patients with metastatic prostate cancer show PSA progression as a sign of androgen-independent but still androgen-sensitive tumor growth. Our understanding and the treatment of such castration-resistant prostate cancer has changed markedly. The introduction of new drugs like abiraterone and MDV3100 has shown that prostate cancer progression even in the"hormone-refractory" stage is driven by androgen receptor signaling. Based on this information the question of whether androgen deprivation therapy in castration-resistant prostate cancer should be continued or not is still of relevance. This review gives a critical overview of the literature and current guideline recommendations.

[Urethro-crural fistula to the adductor canal. Late complication following radiotherapy for recurrent prostate cancer]. / Urethrokrurale Fistel zum Adduktorenkanal. Spätfolge einer perkutanen Radiatio eines Prostatakarzinomrezidivs.

Urinary fistulas are rare (late) complications following radiotherapy for prostate cancer. We present the case of a urethro-crural fistula to the adductor canal 7 years after radiotherapy in a man who had previously undergone radical prostatectomy.

[Recto-vesico-cutaneous fistula following salvage cryotherapy of the prostate due to recurrent localized prostate cancer]. / Rektovesikokutane Fistel nach Salvagekryotherapie bei lokalem Prostatakarzinomrezidiv.

For patients with recurrent prostate cancer after initial external beam radiation salvage cryotherapy is considered as an alternative to salvage prostatectomy. We report a serious complication of salvage cryotherapy in a 72-year-old man suffering from a severe recto-vesico-cutaneous fistula 6 weeks after salvage cryotherapy. To manage this situation salvage cystoprostatectomy and continent urinary diversion with creation of an ileocaecal pouch with cutaneous stoma had to be performed.

[Interventional and surgical treatment of urethral strictures. End-to-end anastomosis]. / Interventionelle und operative Behandlung der Harnröhrenenge: End-zu-End-Anastomose.

Excision with primary anastomosis is an excellent reconstructive option for short bulbar and membranous urethral strictures. With adequate patient selection including history, physical examination, and radiographic staging success rates between 90 and 95% in appropriately selected patients can be achieved. Success with this reliable method is based on adequate excision of the complete urethral stricture and sufficient mobilization of the urethra with tension-free anastomosis. Complications affecting ejaculation or penile sensitivity are rare and might be avoided by appropriate surgical techniques. Resection of the stricture and urethral end-to-end anastomosis represents the "gold-standard" in the treatment of bulbar and membraneous strictures up to a length of 3 cm.

The role of exenterative surgery and urinary diversion in persistent or locally recurrent gynecological malignancy: complications and survival.

OBJECTIVE: Treatment options in patients with persistent or locally recurrent cervical cancer are limited. The aim of this study was to determine the chance of cure and associated morbidity following pelvic exenteration. PATIENTS AND METHODS: Consecutive patients who underwent pelvic exenteration between January 1992 and December 2006 at the University Hospital of Bern or the Karlsruhe Medical Center were evaluated. Time to recurrence, type of exenteration and urinary diversion, pathological stage, postoperative complications and survival were assessed. RESULTS: Initial therapy prior to diagnosis of persistent or locally recurrent disease included radiation therapy in 51%. Anterior exenteration was performed in 37 (86%) and total exenteration in 6 (14%). Half of the women underwent additional procedures. A continent urinary diversion was constructed in 16 and an ileal conduit in 27 patients. Early postoperative complications were generally minor and only 2 patients required surgical intervention. Four intestinal fistulas were successfully treated conservatively. Late complications were mainly tumor-related. Complication rates associated with the urinary diversion were low and there was no difference in complications between continent and incontinent diversions. The overall disease-specific 5-year survival rate after exenteration was 36.5%. Survival correlated significantly with surgical margin status. CONCLUSION: In patients with persistent or locally recurrent gynecological malignancy of the pelvis, exenteration is a viable option with long-term survival in over one third of patients. Continent urinary diversion did not show higher complication rates than an ileal conduit and should be considered even in irradiated patients. This may be of greater significance in younger patients in whom an intact body image can play an important role in quality of life.

[Renal transplantation and urinary diversion]. / Nierentransplantation und Harnableitung.

For patients with end-stage renal disease and dysfunctional or absent lower urinary tract, complex therapeutic strategies are necessary combining kidney transplantation and - if possible - continent urinary diversion. In this concept urinary diversion is the first step in a two-stage procedure followed by renal transplantation. Meticulous preoperative diagnostics, careful patient selection and life-long close surveillance are critical for the success of this concept. The published data concerning long-term graft and patient survival are promising.

[Complete resection of urothelial cancer metastases with curative intent]. / Metastasenchirurgie in kurativer Absicht beim Urothelkarzinom.

BACKGROUND: Recent publications suggest that a subgroup of patients can benefit from surgical removal of transitional cell carcinoma (TCC) metastases in addition to systemic chemotherapy. We report the combined experience and outcome of patients undergoing resection of TCC metastases at 15 uro-oncologic centers in Germany. MATERIALS AND METHODS: Forty-four patients with distant metastatic TCC of the bladder or upper urinary tract underwent resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008 in an attempt to be rendered free of disease. RESULTS: The resected metastatic sites consisted of retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). The treatment sequence included systemic chemotherapy in 35/44 (79.5%) patients before and/or after surgery. Median survival times from initial diagnosis of metastatic TCC and subsequent resection were as follows: overall survival, 35 and 27 months, respectively; cancer-specific survival, 38 and 34 months, respectively; and progression-free survival, 19 and 15 months, respectively. Overall 5-year survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up time of 8 months. Seven patients without disease progression survived for more than 2 years and remain free from tumor progression at a median of 63 months. CONCLUSION: The results in this selected cohort confirm that long-term cancer control and possibly cure can be achieved in a subgroup of patients following surgical removal of TCC metastases. However, prospective data to identify patients most likely to benefit from this aggressive therapeutic approach are lacking. Therefore, metastasectomy in patients with disseminated TCC remains investigational and should be offered only to those with limited disease as a combined-modality approach with systemic chemotherapy.

[Calcium oxalate stone formation. New pathogenetic aspects of an old disease]. / Kalziumoxalatsteinbildung. Neue pathogenetische Aspekte einer alten Erkrankung.

Calcium oxalate (CaOx) urolithiasis is a very common disorder. Surprisingly, the pathogenetic mechanisms leading to CaOx stone formation have been largely unknown so far. The long-accepted simple explanation by an exceeding of the solubility product of lithogenic substances in the urine cannot sufficiently describe the complex processes. Deviating from the hypothesis that proclaims that the initial crystal deposition takes place in the lumens of renal tubules, new insights suggest a primary plaque formation in the interstitial space of the renal papilla. Initially, calcium phosphate (CaPh) crystals and organic matrix are deposited along the basement membranes of the thin loops of Henle and extend further in the interstitial space to the urothelium, constituting the so-called Randall's plaques that can be regularly found during endoscopy of CaOx-stone-forming patients. These CaPh crystals seem to be the origin for the development of future CaOx stones, which form by the attachment of further matrix molecules and CaOx from the urine to the plaque. The driving forces, the exact pathogenetic mechanisms, and the involved matrix molecules remain largely unknown. Possibly, completely different pathomechanisms lead to the common clinical diagnosis of"CaOx stone former."

Bladder carcinoma during pregnancy.

INTRODUCTION: We report 3 cases of bladder cancer during pregnancy and give a review of the literature in an attempt to evaluate tumor at presentation, characteristics, maternal and fetal outcome. MATERIALS AND METHODS: The case history of 3 pregnant women treated for bladder cancer in 2001 together with the results of a MEDLINE search from 1966 to 2003. RESULTS: Out of 27 cases of nonbilharzial bladder carcinoma, 74% presented with transitional cell carcinoma. Five patients had muscle-invasive tumors. Major symptom was hematuria in 81%, which was initially mistaken as vaginal bleeding in 22%. Only half of the tumors were identified by ultrasonography. Although superficial bladder carcinoma was transurethrally resected alone, outcome and prognosis are good. But the prognosis of locally advanced bladder carcinoma is poor. None of the fetuses delivered before 30 weeks of gestation survived. Two of the 5 patients died from the disease and follow-up is only short in the rest. CONCLUSION: Any doubtful genital bleeding during pregnancy without definite proof of vaginal/cervical origin should be investigated by both ultrasonography of the upper urinary tract and urethrocystoscopy. Superficial bladder tumors can be most effectively treated by transurethral resection followed by cystoscopy, whereas the prognosis of muscle-invasive bladder carcinoma is poor and demands more radical treatment, depending on the stage of pregnancy.

[Penile fractures: controversy of surgical vs. conservative treatment]. / Konservative vs. operative Therapie der Penisfrakturen.

This paper reviews the current status of information on diagnostic and therapeutic management of penile fractures, focusing on the controversy between surgical vs. conservative treatment of this uncommon injury. Penile fracture, commonly defined as a rupture of the tunica albuginea and corpus cavernosum, is a serious urological disorder demanding surgical management. The diagnostic procedure classically consists of history taking, physical examination and urinary status. Determination of the extent of severity and location of the rupture in the tunica albuginea takes foremost priority and requires additional imaging procedures, such as ultrasound or cavernosography, which will impart enough diagnostic information for the correct choice of treatment. In some cases, the urethra is injured as well. Immediate surgical repair offers complete recovery for patients with penile fracture in most cases, even in the presence of urethral injury. Although penile fracture is easily recognized and can therefore be classified as a "first-look diagnosis", therapy remains controversial to date. The correct therapeutical approach is a vital factor in management, as the associated significant morbidity can result in complete loss of erectile function, painful erections or penis deviation. Early surgical treatment is strongly recommended because of the excellent results, shorter hospitalization, less morbidity and an early return to sexual activity.

[Postoperative radiologic evaluation in uroradiology. Part 2: Bladder, prostate, and testis]. / Postoperative Bildgebung in der Uroradiologie. Teil 2: Blase, Prostate und Hoden.

Radiologists, especially uroradiologists, must retain abreast of rapid developments in urologic therapy and operative techniques in order to critically assess postoperative changes. Part 2 of this review will cover therapy and postoperative evaluation in bladder surgery, surgery in prostate cancer, and retroperitoneal disease associated with testicular tumors. Using the appropriate modality at the appropriate time during the postoperative course is discussed. A variety of alternatives are available to perform urinary diversion after radical cystectomy. Knowledge of operative techniques and postoperative anatomy are mandatory for interpretation of postoperative radiologic findings.

[Postoperative evaluation in uroradiology. Part 1: Nephrolithiasis, renal tumors and diseases ot the ureter]. / Postoperativ Bildgebung in der Uroradioloie. Teil 1: Niere und ableitende Harnwege.

Therapeutic strategies and operative techniques in urology develop rapidly. In particular, surgery becomes more and more differentiated and complex. Radiologists, especially uroradiologists wil have to provide special knowledge about urologic therapy and operative techniques in order to critically look at postoperative changes. Part I of this review will cover therapy and postoperative evaluation in nephrolitiasis, renal tumors and disease of the ureter. Using the appropriate modality at the appropriate time in postoperative course is discussed. Typical postoperative changes are shown. There is a focus on evaluation and typical radiologic findings in postoperative complications.