C. Börgermann

Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G protein-coupled receptors leads to phospholipase D stimulation.

The activation of the Ras-related GTPase R-Ras, which has been implicated in the regulation of various cellular functions, by G protein-coupled receptors (GPCRs) was studied in HEK-293 cells stably expressing the M3 muscarinic acetylcholine receptor (mAChR), which can couple to several types of heterotrimeric G proteins. Activation of the receptor induced a very rapid and transient activation of R-Ras. Studies with inhibitors and activators of various signaling pathways indicated that R-Ras activation by the M3 mAChR is dependent on cyclic AMP formation but is independent of protein kinase A. Similar to the rather promiscuous M3 mAChR, two typical Gs-coupled receptors also induced R-Ras activation. The receptor actions were mimicked by an Epac-specific cyclic AMP analog and suppressed by depletion of endogenous Epac1 by small interfering RNAs, as well as expression of a cyclic AMP binding-deficient Epac1 mutant, but not by expression of dominant negative Rap GTPases. In vitro studies demonstrated that Epac1 directly interacts with R-Ras and catalyzes GDP/GTP exchange at this GTPase. Finally, it is shown that the cyclic AMP- and Epac-activated R-Ras plays a major role in the M3 mAChR-mediated stimulation of phospholipase D but not phospholipase C. Collectively, our data indicate that GPCRs rapidly activate R-Ras, that R-Ras activation by the GPCRs is apparently directly induced by cyclic AMP-regulated Epac proteins, and that activated R-Ras specifically controls GPCR-mediated phospholipase D stimulation.

The Treatment of Stress Incontinence in Men: Part 2 of a Series of Articles on Incontinence

BACKGROUND Stress incontinence in men is a rare, usually iatrogenic condition. Its prevalence can be expected to rise in the future because of the increasingly common performance of radical prostatectomy. Most men who have undergone prostatectomy experience a transient disturbance of urinary continence. Such disturbances are only rarely due to structural damage to the sphincter apparatus and therefore have a good prognosis for spontaneous recovery. METHOD Selective literature review. RESULTS Pelvic floor training and/or pharmacotherapy can be used for more rapid restoration of subjectively satisfactory urinary continence. If the sphincter is intact, continence can also be regained in the early postoperative period through the submucosal injection of bulking agents. Incontinent patients whose urinary sphincter is dysfunctional because of denervation or direct injury to striated muscle can now be treated with a variety of surgical techniques. The implantation of an artificial sphincter is the gold standard of therapy. Properly selected and informed patients can also be treated with minimally invasive procedures, such as the creation of a male suburethral sling, although the experience with such procedures to date has not been extensive. CONCLUSION Post-prostatectomy incontinence has a good prognosis and should thus be treated conservatively at first. If it nonetheless persists, surgical treatment is indicated for patients who choose it after being fully informed about their options.

[Characterization of the EGF receptor status in penile cancer : retrospective analysis of the course of the disease in 45 patients].

INTRODUCTION Therapeutic success in metastasized squamous cell carcinoma is poor. Some entities, such as head-and-neck tumors or non-small-cell lung cancer, show an over expression of the EGF receptor. In latest studies target-specific substances against the EGF receptor have already been combined with chemotherapy or radiotherapy. Some studies showed a clear advantage of this combination concerning remission rates as well as survival. EGF receptor status has not yet been examined in penile cancer, therefore, a retrospective analysis of the receptor status was performed in patients treated over the last 14 years and correlations with the clinical course were investigated. PATIENTS AND METHODS The analysis included 45 patients, who underwent primary or secondary treatment at the Department of Urology of the University of Essen during 1990 to 2004. Histological preparations existed for 44 patients. Using immunohistochemistry the expression of EGF receptors was determined. RESULTS A total of 25 patients were primarily without positive lymph nodes (6 times cN0 and 19 times pN0), while 20 patients had pathologically proven lymph node metastases and 3 of them also had hematogeneous metastases. Out of 42 patients with follow-up 18 are still living of whom only 3 primarily had positive lymph nodes. These patients received adjuvant chemotherapy after resection. Out of the remaining 15 patients, 4 primarily N0 patients developed a lymphogenic recurrence, which was also resected and 3 patients also received adjuvant chemotherapy. Of the patients 24 died, 22 because of penile cancer. Of these 22 patients 16 primarily had positive lymph nodes and 5 of them also had an extensive primary tumor. Surgery was the treatment of choice in these cases and 10 patients also received chemotherapy. Nevertheless, 15 patients developed several recurrences. Distinguishing primarily node-negative and node-positive patients, the Kaplan-Meyer survival curves showed a significant difference (p<0.001). Median overall survival was 55.5 compared to 34 months and median 5-year survival was 76.9% compared to 15.8%. Of the tumors 40 out of 44 (91%) showed a positive or strong positive EGF receptor expression of the primary tumor as well as of the metastases. A correlation between EGF receptor expression and survival could not be shown. CONCLUSION Clinical data underline the prognostic value of the primary lymph node status as well as the therapeutic value of an ileoinguinal lymphadenectomy and adjuvant chemotherapy. It could also be shown that inductive chemotherapy is not very successful. EGF receptor expression was high and comparable to other squamous cell carcinomas, but there was no correlation to survival.

Correlation of pathological and cytological-cytometric grading of transitional cell carcinoma of the urinary tract.

Introduction: Cystoscopy and cytology are standard procedures for diagnosis and follow-up of patients with bladder cancer. Urinary cytodiagnosis is a descriptive method for tumor characterization. We correlated histopathologic diagnosis of noninvasive urothelial carcinomas with cytological evaluation and, furthermore, we validated cytology by cytometric analysis. Patients and Methods: 94 patients with a history of bladder cancer were included in the study. 25 patients were negative for tumors, 22 showed pTa G1 carcinomas, 25 had pTaG2 and 22 patients had G3 carcinomas. All patients underwent cytological and cytometric evaluation. Nuclear diameter and circumference were measured for 15 representative nuclei per specimen. Statistical evaluation was performed using Graph Pad Software. Results: Cytology showed excellent tumor detection for G2 and G3 carcinomas, with a sensitivity of 100% combined with a specificity of 100%. Using cytometry, we can significantly distinguish between unsuspicious patients and G1 carcinomas on the one hand and high-grade carcinomas on the other. Furthermore, in 6 of 25 patients (24%) with noninvasive G2 carcinomas, but G3 cytological evaluation, tumor progression occurred. Conclusions: Urinary cytology is an excellent instrument for detection of clinically relevant high-grade bladder cancer. Descriptive alterations of the cytopathology can be validated by objective data using cytometric analysis.

PSA Quo Vadis? It Is Reasonable to Start with Prostate-Specific Antigen Testing at the Age of 40!

Background: It is common to start with PSA (prostate-specific antigen)-testing at the age of 50. If patients with a PSA value greater than 4 ng/mL should be considered for prostate biopsy, approximately 20% of all men undergoing test are considered for biopsy at the time of first early-detection examination. Methods: We have screened 2,592 asymptomatic men younger than 45 years. With a short questionnaire, we assessed age, body mass index (BMI), concomitant diseases, last sexual intercourse, and last bicycle riding. We compared this cohort with a group of 11,656 men aged 45–75 years from a nationwide prostate cancer screening trial. Results: In this cohort, only 4 men with a PSA value greater than 4 ng/mL and 10 with a PSA greater than 3 ng/mL were identified. More than 99% of all men younger than 45 years had a PSA lesser than 4 ng/mL. Sexual intercourse, bicycle riding, or BMI had a significant but minimal influence on the PSA value. Conclusions: It is reasonable to start with PSA testing at the age of 40 years. The advantage of screening younger patients is that almost no one should be considered for biopsy at the time of first early-detection examination. We identified a baseline value at which only a minimal influence was exerted by benign prostatic hypertrophy. In comparison with many current guidelines, we gained a lead time of 10 years for observation of PSA dynamics. Impact: The importance of PSA velocity for stratification of patients at risk for development of significant prostate cancer will grow. Cancer Epidemiol Biomarkers Prev; 20(6); 1190–5. ©2011 AACR.

Charakterisierung des EGF-Rezeptorstatus beim Peniskarzinom

INTRODUCTION Therapeutic success in metastasized squamous cell carcinoma is poor. Some entities, such as head-and-neck tumors or non-small-cell lung cancer, show an over expression of the EGF receptor. In latest studies target-specific substances against the EGF receptor have already been combined with chemotherapy or radiotherapy. Some studies showed a clear advantage of this combination concerning remission rates as well as survival. EGF receptor status has not yet been examined in penile cancer, therefore, a retrospective analysis of the receptor status was performed in patients treated over the last 14 years and correlations with the clinical course were investigated. PATIENTS AND METHODS The analysis included 45 patients, who underwent primary or secondary treatment at the Department of Urology of the University of Essen during 1990 to 2004. Histological preparations existed for 44 patients. Using immunohistochemistry the expression of EGF receptors was determined. RESULTS A total of 25 patients were primarily without positive lymph nodes (6 times cN0 and 19 times pN0), while 20 patients had pathologically proven lymph node metastases and 3 of them also had hematogeneous metastases. Out of 42 patients with follow-up 18 are still living of whom only 3 primarily had positive lymph nodes. These patients received adjuvant chemotherapy after resection. Out of the remaining 15 patients, 4 primarily N0 patients developed a lymphogenic recurrence, which was also resected and 3 patients also received adjuvant chemotherapy. Of the patients 24 died, 22 because of penile cancer. Of these 22 patients 16 primarily had positive lymph nodes and 5 of them also had an extensive primary tumor. Surgery was the treatment of choice in these cases and 10 patients also received chemotherapy. Nevertheless, 15 patients developed several recurrences. Distinguishing primarily node-negative and node-positive patients, the Kaplan-Meyer survival curves showed a significant difference (p<0.001). Median overall survival was 55.5 compared to 34 months and median 5-year survival was 76.9% compared to 15.8%. Of the tumors 40 out of 44 (91%) showed a positive or strong positive EGF receptor expression of the primary tumor as well as of the metastases. A correlation between EGF receptor expression and survival could not be shown. CONCLUSION Clinical data underline the prognostic value of the primary lymph node status as well as the therapeutic value of an ileoinguinal lymphadenectomy and adjuvant chemotherapy. It could also be shown that inductive chemotherapy is not very successful. EGF receptor expression was high and comparable to other squamous cell carcinomas, but there was no correlation to survival.

Die Patientenaufklärung zur Prostatakarzinomfrüherkennung ist unzureichend

Men that undergo an early detection investigation should be informed of the advantages and disadvantages as well as of the therapeutic consequences. In this study the quality of information was checked using the state of scientific knowledge of the patients.An informative consultation was carried out before the early detection investigation using a clarification brochure and an examination by a urologist. A questionnaire was also filled out after the investigation. A total of 1,536 men were questioned. Although 47% of the men had previously undertaken a PSA at least once, only 55% knew their own test result. Subjectively 82% of men felt well informed. In contrast one-third did not know the significance of an increased PSA level. In the field of patient clarification for the early detection for prostate cancer there are considerable deficits but the information received was considered adequate by the participants. However, more than one-third did not understand the significance of the PSA level.

Management kutaner Metastasen

ZusammenfassungEine seltene Form des Tumorprogresses bei urologischen Tumoren ist die kutane Metastasierung. Sie ist ein Indiz für eine schlechte Prognose des Patienten. Die Erscheinungsform der kutanen Metastasen ist variabel, entscheidend in der Diagnostik ist es, eine kutane Metastasierung in die Differenzialdiagnose einzubeziehen. Die Therapie erfolgt meist in palliativer Intention, wobei die Lebensqualität des Patienten an erster Stelle stehen sollte. Im Vordergrund steht die Symptomkontrolle. Diese wird zu einem großen Anteil durch die lokale Wundpflege erreicht. Bei der Applikation einer Chemotherapie steht die Behandlung des systemischen Progresses im Vordergrund. Zur lokalen Tumorkontrolle findet die Metastasenchirurgie aber auch die lokale Strahlentherapie Einsatz.AbstractCutaneous metastases are rare and usually signify a poor prognosis. The manifestation of cutaneous metastases is variable; crucial to their diagnosis is their inclusion in the differential diagnosis. The therapy occurs mostly with palliative intention. The quality of life of the patient should take first priority. A combination chemotherapy is usually carried out because of systemic progress. For local tumor control and wound care, metastasis surgery and radiotherapy are used.

Von der Markerexpression zur individuellen Prognoseabschätzung urothelialer Neoplasien

Urothelial carcinoma of the bladder is a tumor entity with a heterogenous clinical course. At one end of the spectrum, patients are treated for low-grade carcinomas, which are likely to reccur but show low rates of tumor progression. At the other end, patients suffer from noninvasive or early invasive high-grade carcinomas. In these cases, risk-adapted treatment decisions are more complicated. The following article gives an overview of research activities on bladder cancer with the aim to individualize treatment of patients with bladder cancer.

Palliative Therapiekonzepte bei Patienten mit Urothelkarzinom der Harnblase

ZusammenfassungDas Harnblasenkarzinom ist ein Tumor des älteren Patienten. In zahlreichen Fällen handelt es sich bei klinischer Erstmanifestation um lokal fortgeschrittene oder metastasierte Karzinome. Aufgrund der Altersstruktur und den damit verbundenen Komorbiditäten treten nicht selten palliative Therapiekonzepte in den Mittelpunkt des Interesses. Nicht zu beherrschende Hämaturien lassen sich beispielsweise mit Aluminiumkaliumsulfatlösung oder Formalinspülung und mittels arterieller Embolisation behandeln. Harnabflussstörungen können mit selbst expandierenden Memotherm-Stents längerfristig versorgt werden. Der Stellenwert der palliativen Radiatio wird kontrovers diskutiert.AbstractUrothelial carcinoma usually occurs in older patients. At initial diagnosis, about 30% of all patients show muscle invasive tumor growth or metastases. Due to their advanced clinical stage, palliative therapy concepts become more and more interesting. Gross and intractable hematuria can be treated with special bladder irrigation or selective arterial embolization. Hydronephrosis can be treated in the long-term with self-expanding memotherm stents. Palliative pelvic radiation is still controversial.