Systemic therapy in metastatic renal cell carcinoma (mRCC): an evidence-based recommendation of the German interdisciplinary RCC guidelines group.

PURPOSE: The treatment landscape in metastatic renal cell carcinoma (mRCC) has evolved dramatically in recent years. Within the German guideline committee for RCC we evaluated current medical treatments and gave recommendations. METHODS: A systematic review of published evidence for medical treatment of mRCC was performed (July 2016-August 2019) to cover the duration from last guideline update in 2016. Evidence was graded according to SIGN ( http://www.sign.ac.uk/pdf/sign50.pdf ). Recommendations were made on the basis of a nominal group work with consensus approach and included patient advocates and shareholder of the German RCC treatment landscape. Each recommendation was graded according to its strength as strong recommendation (A) or recommendation (B). Expert statements were given, where appropriate. RESULTS: Strong first-line recommendations (IA) exist for axitinib + pembrolizumab (all risk categories) and ipilimumab + nivolumab (intermediate or poor risk only). Axitinib + avelumab is a recommended first-line treatment across patients with any risk category (IB). In patients who are not candidates for immune check point inhibitor (ICI) combinations, targeted agents should be offered as an alternative treatment. Subsequent treatment after ICI-based combinations remain ill-defined and no standard of care can be formulated. CONCLUSION: ICI-based combinations are the first-line standard of care and should be considered accordingly. There is an unmet medical need for pivotal studies that define novel standards in patients with failure of ICI-based combinations.

Safety and efficacy of vardenafil versus sertraline in the treatment of premature ejaculation: a randomised, prospective and crossover study.

We investigated safety and efficacy of vardenafil and sertraline in premature ejaculation (PE). Seventy-two men graded their primary PE on a scale of 0-8 (0 = almost never, 8 = almost always). Intravaginal ejaculatory latency time (IELT) was measured. Patients were included if they scored their PE as 4 or greater and their IELTs were less than 1.30 min. After 6 weeks of behavioural psychosexual therapy, 49 patients still had a PE of 4 or greater and an IELT less than 1.30 min and they were randomised: 6 weeks vardenafil (10 mg) or sertraline (50 mg). After a wash-out phase for 1 week, medication was changed in a cross-over design. Initially, all 72 men with PE received behavioural therapy. Twenty-three men were satisfied with treatment and excluded. The remaining 49 men graded their PE as 5.94 +/- 1.6 and IELT was 0.59 min and patients were randomised. Four men discontinued the study. Vardenafil improved PE grading: 2.7 +/- 2.1 (P < 0.01) and IELT increased to 5.01 +/- 3.69 (P < 0.001). PE grading improved 1.92 +/- 1.32, (P < 0.01) and IELT 3.12 +/- 1.89 (P < 0.001) with sertraline. It is concluded that vardenafil and sertraline are useful agents in the pharmacological treatment of PE.

[Is rehabilitation of erectile function following pelvic surgery reasonable? Review of the literature: from sports to PDE5 inhibitors]. / Ist eine Rehabilitation der erektilen Funktion nach beckenchirurgischen Eingriffen sinnvoll? Literaturübersicht vom Sport bis zur PDE-5-Inhibitoren-Gabe.

Increasingly, urologists are seeing patients with erectile dysfunction after pelvic operations. In most cases, radical prostatectomy is the cause. Even when a nerve-sparing procedure is performed, approximately 50% of the patients suffer from erectile dysfunction. This report discusses the causes and theoretical therapies, including lifestyle changes, strategies for neuroregeneration and the associated prevention of apoptosis of the smooth muscle of the corpus cavernosum and improvement of the corpora cavernosa by increased oxygenation. According to the international literature, many of these agents and lifestyle modifications display promise for treating impotence. Early treatment for patients recovering from pelvic operations seems to be reasonable. It is assumed that the natural recovery of erections may take as long as 18 to 24 months postsurgery or even longer; however, treatment modalities may reduce the time to erectile recovery.

Nebivolol induces eNOS activation and NO-liberation in murine corpus cavernosum.

Erectile function is critically dependent upon the activation of the endothelial nitric oxide synthase (eNOS) in the smooth muscle cells of penile corpus cavernosum tissue. Nebivolol is a beta(1)-selective beta-adrenoceptor blocker (beta-ARB) with additional vasodilating properties, which have been attributed to eNOS-activation. Our study investigated whether nebivolol is able to increase eNOS activity in erectile tissue. Murine penile tissue was incubated in an organ bath under control conditions and in the presence of nebivolol or metoprolol. Immunofluorescence staining was performed using specific antibodies against eNOS-activation or eNOS-serine 1177 phosphorylation. Corpus cavernosum smooth muscle tissue was identified using a smooth muscle actin antibody. In addition, slices of murine erectile tissue were incubated with diaminofluorescein (DAF), a specific fluorescence marker for NO-liberation. Under control conditions and after application of metoprolol, we observed a small eNOS-activation and serine 1177-phosphorylation in murine corpus cavernosum tissue. A significant increase in eNOS-activation and serine 1177-phosphorylation of eNOS was observed only in the presence of nebivolol (10 muM). These alterations of the eNOS protein induced after application of nebivolol were associated with a time-dependent increase in DAF fluorescence in murine erectile tissue. We conclude that beta-adrenoceptor blockers differentially influence erectile tissue. Since cardiovascular diseases are often associated with the development of erectile dysfunction, the nebivolol-induced eNOS-activation in corpus cavernosum may be beneficial when treating patients suffering from cardiovascular disease.

[Primary prevention, health promotion, and compression of morbidity. Perspectives for urology]. / Primärprävention, Gesundheitsförderung und Morbiditätskompression. Perspektiven für die Urologie.

Prevention and health promotion are interventions which achieve compression of morbidity. This is well-advised from the viewpoints of both health economics and quality of life in an aging society. Only when preventive and health-promoting strategies have become a matter of course in the health care system can the challenges posed by the altered disease spectrum be met. Because of the frequency of age-associated diseases encountered in urological practice and the considerable influence it wields on quality of life, urology is a focus of attention. Prevention and health counseling will prove to be major tasks in the practice of urology, especially in the private sector. Viewed systematically, primary prevention is more medical and individual in character while health promotion is an aspect of health science geared toward a specific echelon or group. The mission of health policy and medical associations must be to design and evaluate programs for prevention and health promotion. This is uncharted territory for urology. Economic aspects specific to professional groups should not constitute the sole center of attention, even though these interests are legitimate. It is essential that the approach to primary prevention efforts be directed at specific echelons and groups to also reach fringe groups and socially weak groups in the population.

[Secondary prevention after urological tumor diseases. Focusing on the kidneys, testes, and bladder]. / Sekundärprävention nach urologischen Tumorerkrankungen. Mit Fokus auf Niere, Hoden und Blase.

It is generally agreed upon that patients require a caring as well as careful medical follow-up after cancer treatment. The goal of secondary prevention is to recognize a recurrence at an early stage and to use the curative chance while the tumor mass is still small. There is evidence of a medically effective and successful follow-up for tumors of the testicle and the bladder. For quality reasons, these follow-up regimes should be adhered to for quality reasons. In other diseases, e.g., renal cell carcinoma, prospective randomized studies are missing which demonstrate the effectiveness of follow-ups. In these cases asymptomatic patients should be stratified to individualized follow-up care.

Why do patients with erectile dysfunction abandon effective therapy with sildenafil (Viagra)?

This prospective study determined the rate of abandonment of sildenafil therapy and assessed the reasons for abandonment. Between January 2001 and December 2002, 234 patients with erectile dysfunction (ED) at three independent centers successfully began therapy with sildenafil 50 or 100 mg. The rate of noncompliance was 31%. A telephone survey of these patients was conducted to determine the reasons for abandonment. The majority reported that they had had no opportunity or desire for sexual intercourse or that their partners had shown no sexual interest. Few patients stated that the high cost of the medication or that adverse events were the cause.

[Priapism: Current diagnostics and therapy]. / Priapismus : Aktuelle Diagnostik und Therapie.

Priapism is characterized by involuntary persistent penile erection after or independent of sexual stimulation. The diagnostic clarification, including patient history, physical findings, duplex ultrasonography and analysis of blood gases is decisive for the underlying pathophysiology and the appropriate therapeutic procedure. Non-hypoxic and non-acidotic blood gas parameters enable a conservative approach, hypoxic, hypercarbic and acidotic parameters may lead to fibrosis of the corpora cavernosa and, in turn, to a loss of penile function. Low-flow or ischemic (veno-occlusive) priapism is an emergency situation and can lead to irreversible erectile dysfunction within 4 h. Treatment consists of blood aspiration and possibly intracavernosal injection of sympathomimetic drugs. A distal shunt is necessary in the case of treatment failure (in rare cases a proximal shunt). Management of recurrent priapism (stuttering) includes self-injection of sympathomimetic drugs and preventive long-term administration of erection inhibitory and erection promoting substances. This concept still needs to be validated. High-flow or non-ischemic priapism does not necessitate immediate treatment measures and should be kept under observation. In cases of a detectable fistula selective artery embolization is often a successful option.

Fat-containing lesions of the liver: a pictorial essay.

The presence of fat within a hepatic lesion is unusual and can help to direct the radiologist's diagnosis. The aim of this iconographic review is to specify the various hepatic lesions that may contain fat and their appearance particularly on MRI. A histological correlation is also suggested for the most commonly found tumors. The identification of fat within a hepatic tumor, along with other radiological signs and reflection on the clinical and epidemiological context, can lead to a diagnosis being reached or suggested, with confirmation if necessary, by a pathological examination.

Urinary excretion of thromboxane B2 in patients with venous thromboembolic disease.

Platelet activation occurs in the initial phase of venous thrombus formation. To determine if thromboxanes (Tx) are released during this process and if Tx measurements are useful in the diagnosis, urinary immunoreactive TxB2 was measured by a rapid, inexpensive assay in 100 consecutive patients with suspected thromboembolic disease. Urinary iTxB2 was not increased in patients who took aspirin, nor in patients studied several weeks after onset of symptoms. Of the remaining patients, iTxB2 was increased in 11 of 15 with confirmed deep vein thrombosis and in seven of ten with confirmed pulmonary emboli. Of the 54 patients in whom acute thrombosis was excluded, iTxB2 was increased in only four (7 percent). A second study evaluated 25 additional patients with nondiagnostic lung scans who required pulmonary angiography; iTxB2 was increased in seven of ten with positive angiograms and in 0 of 15 with negative angiograms. The three patients with negative iTxB2 and positive angiograms were receiving heparin when studied. These data suggest that, in the absence of aspirin, platelet Tx is released during thrombus formation. In combination with other noninvasive tests, urinary iTxB2 is a useful adjunct to diagnosing acute thromboembolic disease.

Soluble guanylate cyclase and cGMP-dependent protein kinase I expression in the human corpus cavernosum.

Nitric oxide (NO) as a mediator in smooth muscle cells causes rapid and robust increases in cGMP levels. The cGMP-dependent protein kinase I has emerged as an important signal transduction mediator for smooth muscle relaxation. The purpose of this study was to examine the existence and distribution of two key enzymes of the NO/cGMP pathway, the cGMP-dependent kinase I (cGK I) and the soluble guanylate cyclase (sGC) in human cavernosal tissue. The expression of the enzymes were examined in corpus cavernosum specimens of 23 patients. Eleven potent patients suffered from penile deviations and were treated via Nesbit's surgical method. Nine long-term impotent patients underwent implantation of flexible hydraulic prothesis. Three potent patients underwent trans-sexual operations. Expression of the sGC and cGK I were examined immunohistochemically using specific antibodies. In all specimens of cavernosal tissue a distinct immunoreactivity was observed in different parts and structures. We found a high expression of sGC and cGK I in smooth muscle cells of vessels and in the fibromuscular stroma. The endothelium of the cavernosal sinus, of the cavernosal arteries, and the cavernosal nerve fibers showed an immunoreactivity against sGC. The distribution analysis of cGK I revealed a predominately vesicular localization in smooth muscle cells. The examination of the endothelium showed no clear immunoreactivity against cGK I. There was no distinct difference in immunoreactivity and cellular distribution between potent and impotent patients.

Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey'.

The last few decades have seen a marked increase in mean life expectancy in Central Europe. This has made elderly people and their quality of life a matter of ever-increasing medical concern. Available data from the United States and Scandinavia relating to erectile dysfunction (ED) do not enable us to draw valid conclusions about the current situation in Germany. The aim of the present study was to evaluate the epidemiology of male sexuality in Germany, and the proportion of men who need medical treatment because of increased suffering from this.A newly developed and validated questionnaire on male erectile dysfunction was mailed to a representative population sample of 8000 men, 30-80 y of age in the Cologne urban district. The response included 4489 evaluable replies (56.1%). The response rates in different age groups ranged from 49.2% to 68.4%. Regular sexual activity was reported by 96.0% (youngest age group) to 71.3% (oldest group). There were 31.5%-44% of responders who were dissatisfied with their current sex life. The prevalence of ED was 19.2%, with a steep age-related increase (2.3-53.4%) and a high co-morbidity of ED with hypertension, diabetes, pelvic surgery and 'lower urinary tract symptoms'. When treatment need was defined by co-occurrence of ED and dissatisfaction with sex life, 6.9% men required treatment for ED. Oral treatment of ED was preferred by 73.8% of respondents. There were 46.2% respondents who were willing to contribute more than DM 50 (25 Euro) per month for ED treatment. We conclude that regular sexual activity is a normal finding in advanced age. ED is a frequent disorder, contributing to dissatisfaction with sex life in a considerable proportion of men. The high burden of ED is reflected in willingness to pay for treatment. ED is frequently associated with chronic diseases. Therefore adequate diagnostic workup is essential, to offer patients individually adapted treatment. General non-reimbursability of treatment for ED appears to be unacceptable.

MAP kinase 1/2 (Erk 1/2) and serine/threonine specific protein kinase Akt/PKB expression and activity in the human corpus cavernosum.

Nitric oxide (NO) is an important mediator in the cavernosal smooth muscle relaxation that causes erections. The purpose of this study was to examine the existence, distribution and phosphorylation stage of two recently discovered key enzymes for NO regulation in human cavernosal tissue, the MAP Kinase 1/2 (Erk 1/2) and the serine/threonine specific protein kinase Akt/PKB. The expression of the enzymes was examined in corpus cavernosum specimens taken from both potent men and from patients with long-term impotence. There was a distinct difference in the activation stage of the MAP Kinase 1/2 (Erk 1/2) between endothelium and smooth muscle cells in potent patients. This finding gives evidence for a cell-type-specific regulation of the eNOS-dependent NO release. Furthermore, we found a higher basal level of active MAP Kinase 1/2 (Erk 1/2) in impotent patients. This finding gives the first evidence for an inhibitory influence of MAP Kinase 1/2 (Erk 1/2) on cavernosal eNOS activity.

Epidemiology of Peyronie's disease.

Francois Gigot de la Peyronie, surgeon to Louis XV of France, has become synonymous with the rather enigmatic though not uncommon condition of Peyronie's disease (PD), a localized connective tissue disorder of the penile tunica albuginea. The true prevalence of Peyronie's disease is unknown. Therefore, we decided to perform an evaluation of existing epidemiological data. A prevalence rate of 3.2% was determined in male inhabitants of the greater Cologne area. This is much higher than revealed by the data reported up to now, thus rendering the accepted prevalence rates of 0.3% to 1% untenable. The actual prevalence of Peyronie's disease may be even higher, considering many patients' reluctance to report this embarrassing condition to their physicians. Along these lines, most clinicians note that the number of Peyronie's patients has increased since the advent of oral sildenafil. Comparably high prevalences are known for diabetes and urolithiasis, suggesting a greater frequency of this rare disease than formerly believed.

Pneumatic v electrokinetic lithotripsy in treatment of ureteral stones.

Recently, a new device (Combilith) for electrokinetic lithotripsy (EKL) has become available which is very similar to the well-known device for pneumatic (ballistic) lithotripsy (Swiss Lithoclast). The Lithoclast uses air pressure to push a projectile within the handpiece against the end of a metal probe, which is thereby accelerated and thrown like a jackhammer against the stone. In principle, the same stroking movement of a small metal probe is provided by EKL; the difference is that instead of a projectile, a magnetic core within the handpiece is accelerated by the electromagnetic principle. This paper compares the clinical efficacy and the features of the two devices. Testing the devices on a stone model, taking into account stone propulsion, the systems turned out to equally effective regarding stone disintegration. However, stone displacement was more pronounced with the Lithoclast applied on easily breaking stones. In a second experiment, an optoelectronic movement-measuring apparatus (Zimmer camera) was employed to measure the range and velocity of the movement of the probe tip without any contact. The linear acceleration velocity ranged from 5 to a maximum of 12.5 m/sec with both systems, but the maximum height of the stroke was 2.5 mm with the Lithoclast and 1 mm with EKL. After the initial break-up of soft stones, further impact of the probe tip against the stone resulted merely in propulsion; thus, the greater probe stroke height is the cause of the stone displacement. In a clinical trial, 22 ureteral stones were treated with the Lithoclast and 35 with the EKL. The two devices were equally effective in terms of stone disintegration and safety margin. Fixation using a Dormia basket was necessary in 12 cases (8 Lithoclast, 4 EKL). Although a difference in probe stroke height was noted when comparing pneumatic and electrokinetic lithotripsy, there were no clinically significant differences in the efficacy of stone fragmentation or stone-free rates. At the current time, EKL is less costly.

Penetration of a single infusion of ampicillin and sulbactam into prostatic tissue during transurethral prostatectomy.

Antibiotic prophylaxis is recommended in endoscopic urological operations to diminish the rate of intraoperative septic complications and relevant urogenital infections. The objective of the study was to determine the tissue concentrations of preoperatively administered ampicillin and sulbactam in the human prostate in patients undergoing transurethral resection (TUR-P) for benign prostatic hyperplasia (BPH). In 19 patients (mean age 68.7 years) the serum and tissue concentrations of ampicillin and sulbactam were determined. For all patients the dosage was administered as a single infusion over 15 min at a 2:1 ratio, i.e. 2 g ampicillin and 1 g sulbactam. The serum and prostatic tissue samples were taken 15 to 55 min (mean 29.5 min) after infusion. Of transurethral resected prostatic chips 3 g were immediately collected after resection and stored at -70 degrees C. Ampicillin was determined by bioassay and sulbactam was determined by gas chromatography/mass spectrometry. Tissue concentrations of ampicillin ranged from 0.42 to 548.33 mg/kg (median 47 mg/kg). Tissue concentrations of sulbactam ranged from 0.15 to 249.74 mg/kg (median 19 mg/kg). Six (32%) of 19 patients showed a tissue concentration of ampicillin <4 mg/kg (MIC90), respectively 5 (26%) patients of sulbactam <8 mg/kg. The mean serum concentrations at tissue sampling time were 118.8+/-48.9 mg/l respectively 32.2+/-12.2 mg/l. There exists a high variability of intraprostatic concentrations of ampicillin and sulbactam after single infusion in patients with BPH. In a relevant part of patients both compounds do not exceed the minimal inhibitory concentrations (MIC) of important bacterial pathogens. A single shot infusion of 3 g ampicillin/sulbactam for intraoperative antibiotic prophylaxis is not sufficient in patients undergoing TUR-P. It seems that the prostate cannot be compared to other tissues in view of penetration of ampicillin/sulbactam.

Nitric oxide based influence of nitrates on micturition in patients with benign prostatic hyperplasia.

BACKGROUND: Nitric oxide (NO) is involved in the physiologic regulation of smooth muscle relaxation in the prostate. Organic nitrates act as NO donors. In this prospective open study we prove the influence of orally given nitrates on micturition. METHODS: Thirty-two patients underwent a urological medical check-up prior to starting nitrate medication for cardiovascular disease. We examined peak flow rates, residual urine, IPS-score, PSA level and prostate volume. Exact inclusion and exclusion criteria were defined. Fifteen patients suffered from obstructive symptoms, 17 patients reported no subjective micturition problems. Urological re-evaluation was performed two weeks and three months after nitrate medication. RESULTS: A significant improvement of peak urinary flow rates (+3.1 ml/s; p<0.05), IPS score and significant decrease of residual urine volume (-22 ml; p<0.05) were found in the symptomatic patients. No significant changes of micturition parameters were found in asymptomatic patients. PSA levels and prostate volumes did not change in either groups. CONCLUSIONS: Organic nitrates influence micturition parameters in patients with obstructive benign prostatic hyperplasia. This might be explained by the known mechanism of NO donation (smooth muscle relaxation) of nitrates. More functional controlled studies are necessary to describe the grade of influence of nitrates on the prostate. Concomitant oral medication with nitrates must be considered as a relevant bias factor on BPH in future clinical studies.

Sildenafil (Viagra): is there an influence on psychological performance?

BACKGROUND: Sildenafil (Viagra) is a well-introduced medicine for erectile dysfunction; many studies about effects and side effects are published. Beside these aspects of treatment the influence of sildenafil on psychophysical performance is of interest. cGMP is one of the most important second messengers in the central nervous system (CNS), so even very small changes of the intracellular cGMP-level caused by phosphodiesterases inhibition may be relevant for CNS-function. We wanted to verify the hypothesis whether sildenfail influences human psychomotor performance, especially under the aspect of traffic safety, or not. METHODS: Designed as a pilot study we tested 6 male healthy volunteers using a test battery of 7 different psychophysical performances tests. Each individual did the test battery twice, once without drug and once after a single oral dose of 100-mg sildenafil. 3 persons did the first and 3 others did the second experiment under the influence of drug (UID). All results (37 parameters) were analysed by t-test for paired samples using a confidence interval of 95%. RESULTS: Only two parameters of 2 different tests showed significant differences. In the simple choice reaction test (DR2) the mean reaction time got better in the group with sildenafil; in the multiple choice reaction test with stress induction (RST3) the amount of wrong answers indicated a weak influence of performance without statistical significance, six parameters (dominantly in the speed anticipation test (DEST)) represented an increase and one other (RST3 second part) showed a decrease UID. The uppermost parameters (76% of all items) stayed on equal levels for both groups. CONCLUSION: Sildenafil showed no important impairment of psychophysical performance, no strong improvement was found as well. With a look at the therapeutically indication of sildenafil the improvement in sexual activity may indicate no incapacity in traffic and other psychomotoric/psychophysical functions.