Susanne Krege

Publications of Susanne Krege

• The Contemporary Role of Chemotherapy for Advanced Testis Cancer: A Systematic Review of the Literature.

  Authors: Fabio Calabrò, Peter Albers, Carsten Bokemeyer, Chris Martin, Lawrence H Einhorn, Alan Horwich, Susanne Krege, Hans Joachim Schmoll, Cora N Sternberg, Gedske Daugaard

  European urology. 03/2012;

  CONTEXT: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basisCONTEXT: Germ cell tumours (GCTs) of the testis are the most common cancer in young men; they are also one of the most curable cancers. Standard treatment of metastatic GCTs has evolved on the basis of randomised trials and prognostic factors. OBJECTIVE: This review summarises the evolving role of chemotherapy in the treatment of previously treated and untreated patients with metastatic GCTs and outlines the current standard treatment. EVIDENCE ACQUISITION: Randomised and nonrandomised trials of first-line, salvage, and palliative therapy were reviewed. EVIDENCE SYNTHESIS: Three cycles of standard bleomycin, etoposide, and platinum (BEP) can be considered the gold-standard treatment in good-risk patients, and four cycles of the same combination can result in cure in approximately 80% of intermediate-risk and 50% of poor-risk patients. The routine use of high-dose chemotherapy in patients with intermediate- or poor-prognosis GCT has not improved treatment outcome, but the role of tumour marker decline during the first cycles may provide useful prognostic information. Prognostic variables in patients who experience treatment failure after cisplatin-based chemotherapy can be used to guide salvage strategies, and many new drugs or combinations have shown activity in this setting. Patients and physicians should be aware of the risk of short- and long-term toxicity of treatments, and guidelines for screening and prevention of this risk should be established. CONCLUSIONS: A risk-based strategy offers the best chance of cure, even in patients with refractory GCT.

• Interdisciplinary evidence-based recommendations for the follow-up of early stage seminomatous testicular germ cell cancer patients.

  Authors: Rainer Souchon, Michael Hartmann, Susanne Krege, Anja Lorch, Frank Mayer, Maria De Santis, Silke Gillessen, Jörg Beyer, Richard Cathomas

  Strahlentherapie und Onkologie : Organ der Deutschen Röntgengesellschaft ... [et al]. 02/2011; 187(3):158-66.

  To provide guidance regarding follow-up procedures after initial treatment of early stage testicular seminoma (clinical stages (CS) I-II A/B) based on current published evidence complemented byTo provide guidance regarding follow-up procedures after initial treatment of early stage testicular seminoma (clinical stages (CS) I-II A/B) based on current published evidence complemented by expert opinion. An interdisciplinary, multinational working group consisting of urologists, medical oncologists, and radiation oncologists analyzed the published evidence regarding follow-up procedures in various stages of seminomatous and nonseminomatous testicular cancers. Focusing on radiooncological aspects, the recommendations contained herein are restricted to early stage seminoma (with radiotherapy being a standard treatment option). In particular, extent, frequency, and duration of imaging at follow-up were analyzed concerning relapse patterns, risk factors, and mode of relapse detection. Active surveillance, adjuvant carboplatin or radiotherapy are equally accepted options for CS I seminoma but they result in different relapse rates and patterns. Usually relapses occur within the first 2(-6) years. Routinely performed follow-up using computerized tomography (CT) after adjuvant treatment yield only low detection rates of recurrences. Therefore, there is no evidence to maintain routine examinations every 3-4 months. After treatment of stage IIA/B, detection rates of relapses or progression identified solely by routinely performed CT during follow-up are low. Considering lifelong cure rates of up to 99% for patients treated for seminoma CS I-IIA/B, the negative impact of unnecessary ionizing radiation exposure has to be considered. The presented recommendations for various follow-up scenarios for early stage seminoma strongly promote the restrictive use of imaging procedures that utilize ionizing radiation (especially CT), due to its potential to induce secondary malignancies.

• Interdisciplinary evidence-based recommendations for the follow-up of testicular germ cell cancer patients.

  Authors: Richard Cathomas, Michael Hartmann, Susanne Krege, Rainer Souchon, Anja Lorch, Frank Mayer, Maria De Santis, Silke Gillessen

  Onkologie. 01/2011; 34(1-2):59-64.

  Over the last years, clear treatment recommendations for patients with testicular cancer have been published. This has led to significant improvements in outcome and survival. Moreover, activeOver the last years, clear treatment recommendations for patients with testicular cancer have been published. This has led to significant improvements in outcome and survival. Moreover, active surveillance has become a cornerstone in the management of clinical stage I seminomatous and non-seminomatous germ cell tumors. On the other hand, the existing recommendations for the follow-up of testis cancer patients are unclear and differ widely. Follow-up recommendations in this young patient population have to be as evidence based as possible, feasible in order to ensure adherence, and must not be harmful. Therefore, attention has to be paid to the negative impact of unnecessary radiation exposure. Recently, new evidence became available regarding the relapse pattern of different disease stages of testicular cancer, the use of imaging at follow-up, and the risks of excessive radiation due to imaging, and in particular that of computed tomography (CT) scans. This article summarizes the recommendations for follow-up of testicular cancer patients of an interdisciplinary multinational working group consisting of urologists, medical oncologists, and radiation oncologists.

• Imaging studies in metastatic urogenital cancer patients undergoing systemic therapy: recommendations of a multidisciplinary consensus meeting of the Association of Urological Oncology of the German Cancer Society.

  Authors: Axel Heidenreich, Peter Albers, Johannes Classen, Markus Graefen, Jürgen Gschwend, Jörg Kotzerke, Susanne Krege, Jens Lehmann, Detlef Rohde, Heinz Schmidberger, Michael Uder, Hajo Zeeb

  Urologia internationalis. 01/2010; 85(1):1-10.

  Imaging studies are an integral and important diagnostic modality to stage, to monitor and follow-up patients with metastatic urogenital cancer. The currently available guidelines on diagnosis andImaging studies are an integral and important diagnostic modality to stage, to monitor and follow-up patients with metastatic urogenital cancer. The currently available guidelines on diagnosis and treatment of urogenital cancer do not provide the clinician with evidence-based recommendations for daily practice. To develop scientifically valid recommendations with regard to the most appropriate imaging technique and the most useful time interval in metastatic urogenital cancer patients undergoing systemic therapy. A systematic literature review was performed searching MedLine, Embase and Web of Science databases using the terms prostate, renal cell, bladder and testis cancer in combination with the variables lymph node, lung, liver, bone metastases, chemotherapy and molecular therapy, and the search terms computed tomography, magnetic resonance imaging and positron emission tomography were applied. A total of 11,834 records were retrieved from all databases. The panel reviewed the records to identify articles with the highest level of evidence using the recommendation of the US Agency for Health Care Policy and Research. Contrast-enhanced computed tomography remains the standard imaging technique for monitoring of pulmonary, hepatic and lymph node metastases. Bone scintigraphy is still the most widely used imaging technique for the detection and follow-up of osseous lesions. For clinical trials it might be replaced by either PET-CT or MRI of the skeletal axis. Response assessment for patients treated with cytotoxic regime is best performed by the RECIST/WHO criteria; treatment response to molecular triggered therapy is best assessed by CT evaluating decrease in tumor size and density. Cross-sectional imaging studies for response assessment might be obtained after each 2 cycles of systemic therapy to early stratify responders from non-responders.

• Burden or Relief: Do Second-Opinion Centers Influence the Quality of Care Delivered to Patients with Testicular Germ Cell Cancer?

  Authors: Mark Schrader, Lothar Weissbach, Michael Hartmann, Susanne Krege, Peter Albers, Kurt Miller, Axel Heidenreich

  European urology. 11/2009;

  BACKGROUND: To improve the quality of care, the German Testicular Cancer Study Group (GTCSG) has been publishing a series of testicular germ cell cancer guidelines since 1996. These guidelines wereBACKGROUND: To improve the quality of care, the German Testicular Cancer Study Group (GTCSG) has been publishing a series of testicular germ cell cancer guidelines since 1996. These guidelines were updated in the 2008 publication, "European Consensus on Diagnosis and Treatment of Germ Cell Cancer." Several studies have shown that published guidelines have a limited effect on clinical practice. For this reason, the GTCSG made a further effort in 2006 to improve the quality of care by establishing a national second-opinion system for therapy planning for patients who underwent orchiectomy and staging evaluations. OBJECTIVE: The primary aim was to analyze the influence of the second-opinion system on guideline implementation with a view to improving the quality of care. DESIGN, SETTING, AND PARTICIPANTS: An Internet data exchange was established between the urologist seeking advice and the second-opinion centers. Second-opinion centers were 18 clinics that had contributed toward developing treatment guidelines. MEASUREMENTS: Data sets included the primary clinical, radiologic, and pathohistologic data; the planned therapy; the therapy recommended by the second-opinion center; and the follow-up. RESULTS AND LIMITATIONS: From February 2006 to September 2008, 642 second opinions were requested. The therapy planned by the urologist seeking advice differed from that recommended by the second-opinion center in 32.3% of the cases. The discrepancy was significantly higher for nonseminomas than for seminomas (p=0.045) and showed a tendency to increase with advancing tumor stage (p=0.067). In cases of discrepancy, the applied therapy coincided with the second opinion in 71.8% of the cases. A discrepant second opinion prevented overtreatment in 40.3% and undertreatment in 26.5%. CONCLUSIONS: Approximately every sixth second opinion resulted in a relevant change in the scope of therapy. Published guidelines for germ cell cancer are applied only sporadically and should be supported by second-opinion systems.

• [18F]Fluorodeoxyglucose Positron Emission Tomography in Nonseminomatous Germ Cell Tumors After Chemotherapy: The German Multicenter Positron Emission Tomography Study Group.

  Authors: Karin Oechsle, Michael Hartmann, Winfried Brenner, Stephan Venz, Lothar Weissbach, Christiane Franzius, Sabine Kliesch, Stephan Mueller, Susanne Krege, Ruediger Heicappell, Roland Bares, Carsten Bokemeyer, Maike de Wit

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 12/2008;

  PURPOSE: In patients with metastatic nonseminomatous germ cell cancer (NSGCT), residual masses after chemotherapy (CTX) can consist of vital carcinoma, mature teratoma, or necrosis. This prospectivePURPOSE: In patients with metastatic nonseminomatous germ cell cancer (NSGCT), residual masses after chemotherapy (CTX) can consist of vital carcinoma, mature teratoma, or necrosis. This prospective trial has evaluated the accuracy of [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the prediction of histology compared with computed tomography (CT) and serum tumor markers (STM). PATIENTS AND METHODS: A total of 121 patients with stage IIC or III NSGCT scheduled for secondary resection after cisplatin-based CTX were included. FDG-PET was performed after completion of CTX. All results were confirmed by histopathology and correlated to STM and CT. RESULTS: Prediction of tumor viability with FDG-PET was correct in 56%, which did not reach the expected clinically relevant level of 70%, and was not better than the accuracy of CT (55%) or STM (56%). Sensitivity and specificity of FDG-PET were 70% and 48%. The positive predictive values were not significantly different (55%, 61%, and 59% for CT, STM, and PET, respectively). Judging only vital carcinoma as a true malignant finding, the negative predictive value increased to 83% for FDG-PET. CONCLUSION: The presence of vital carcinoma and mature teratoma is common (55%) in residual masses in patients with NSGCT, and CT and STM cannot reliably predict absence of disease. In contrast to prior studies, this prospective trial, which is the only with histologic confirmation in all patients, demonstrated that FDG-PET is unable to give a clear additional clinical benefit to the standard diagnostic procedures, CT and STM, in the prediction of tumor viability in residual masses.

• Surgery for Metastatic Urothelial Carcinoma with Curative Intent: The German Experience (AUO AB 30/05).

  Authors: Jan Lehmann, Henrik Suttmann, Peter Albers, Björn Volkmer, Jürgen E Gschwend, Guido Fechner, Martin Spahn, Axel Heidenreich, Axel Odenthal, Christoph Seif [......] Tilmann Kälble, Marc-Oliver Grimm, Claus Friedrich Fieseler, Susanne Krege, Margitta Retz, Heiner Schulte-Baukloh, Martin Gerber, Markus Hack, Jörn Kamradt, Michael Stöckle

  European urology. 12/2008;

  BACKGROUND: Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE: We report the combined experience and outcomeBACKGROUND: Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE: We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany. DESIGN, SETTING, AND PARTICIPANTS: Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008. INTERVENTION: Resected metastatic sites were the following: 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%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery. MEASUREMENTS: Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM. RESULTS AND LIMITATIONS: Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number. CONCLUSIONS: Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.

• Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I Nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group.

  Authors: Peter Albers, Roswitha Siener, Susanne Krege, Hans-Uwe Schmelz, Klaus-Peter Dieckmann, Axel Heidenreich, Peter Kwasny, Maik Pechoel, Jan Lehmann, Sabine Kliesch, Kai Uwe Köhrmann, Rolf Fimmers, Lothar Weissbach, Volker Loy, Christian Wittekind, Michael Hartmann

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 07/2008; 26(18):2966-72.

  PURPOSE: Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical stage I nonseminomatous germ cell tumors of the testisPURPOSE: Retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy are two adjuvant treatment options for patients with clinical stage I nonseminomatous germ cell tumors of the testis (NSGCT). Aim of this trial was to prove the advantage of one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy compared with RPLND in terms of recurrence. PATIENTS AND METHODS: Between 1996 and 2005, 382 patients were randomly assigned to receive either RPLND (n = 191) or one course of BEP (n = 191) after orchidectomy. The primary study end point was the rate of recurrence. The trial was powered to detect a 7% reduction (from 10% to 3%) of recurrence with chemotherapy compared with surgery. Results: After a median follow-up of 4.7 years, two and 15 recurrences were observed in the intention-to-treat population with chemotherapy and surgery, respectively (P = .0011). The difference in the 2-year recurrence-free survival rate between chemotherapy (99.46%; 95% CI, 96.20% to 99.92%) and surgery (91.87%; 95% CI, 86.87% to 95.02%) was 7.59% (95% CI, 3.13% to 12.05%). The hazard ratio to experience a tumor recurrence with surgery as opposed to chemotherapy was 7.937 (95% CI, 1.808 to 34.48). CONCLUSION: To our knowledge, this is the largest randomized trial investigating adjuvant treatment strategies in clinical stage I NSGCT, which showed the superiority of one course BEP over RPLND performed according to community standards to prevent recurrence. Although not standard treatment, one course of BEP is active in an unselected group of patients with clinical stage I disease and merits further investigation.

• European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus Group (EGCCCG): part II.

  Authors: Susanne Krege, Jörg Beyer, Rainer Souchon, Peter Albers, Walter Albrecht, Ferran Algaba, Michael Bamberg, István Bodrogi, Carsten Bokemeyer, Eva Cavallin-Ståhl [......] Niels E Skakkebaek, Aslam Sohaib, Sergei Tjulandin, Padraig Warde, Stefan Weinknecht, Lothar Weissbach, Christian Wittekind, Eva Winter, Lori Wood, Hans von der Maase

  European urology. 04/2008; 53(3):497-513.

  OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world.OBJECTIVES: The first consensus report that had been presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, The Netherlands. METHODS: Medical oncologists, urologic surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference and incorporated the new data into updated and revised guidelines. As for the first meeting the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The second part of the consensus paper includes the treatment of metastasised disease, residual tumour resection, salvage therapy, follow-up, and late toxicities. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early-stage as well as of advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

• European consensus conference on diagnosis and treatment of germ cell cancer: a report of the second meeting of the European Germ Cell Cancer Consensus group (EGCCCG): part I.

  Authors: Susanne Krege, Jörg Beyer, Rainer Souchon, Peter Albers, Walter Albrecht, Ferran Algaba, Michael Bamberg, István Bodrogi, Carsten Bokemeyer, Eva Cavallin-Ståhl [......] Niels E Skakkebaek, Aslam Sohaib, Sergei Tjulandin, Padraig Warde, Stefan Weinknecht, Lothar Weissbach, Christian Wittekind, Eva Winter, Lori Wood, Hans von der Maase

  European urology. 04/2008; 53(3):478-96.

  OBJECTIVES: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. InOBJECTIVES: The first consensus report presented by the European Germ Cell Cancer Consensus Group (EGCCCG) in the year 2004 has found widespread approval by many colleagues throughout the world. In November 2006, the group met a second time under the auspices of the Department of Urology of the Amsterdam Medical Center, Amsterdam, The Netherlands. METHODS: Medical oncologists, urological surgeons, radiation oncologists as well as pathologists from several European countries reviewed and discussed the data that had emerged since the 2002 conference, and incorporated the new data into updated and revised guidelines. As for the first meeting, the methodology of evidence-based medicine (EBM) was applied. The results of the discussion were compiled by the writing committee. All participants have agreed to this final update. RESULTS: The first part of the consensus paper describes the clinical presentation of the primary tumor, its treatment, the importance and treatment of testicular intraepithelial neoplasia (TIN), histological classification, staging and prognostic factors, and treatment of stage I seminoma and non-seminoma. CONCLUSIONS: Whereas the vast majority of the recommendations made in 2004 remain valid 3 yr later, refinements in the treatment of early- and advanced-stage testicular cancer have emerged from clinical trials. Despite technical improvements, expert clinical skills will continue to be one of the major determinants for the prognosis of patients with germ cell cancer. In addition, the particular needs of testicular cancer survivors have been acknowledged.

• The role of positron emission tomography in the evaluation of residual masses after chemotherapy for advanced stage seminoma.

  Authors: Stefan Hinz, Mark Schrader, Carsten Kempkensteffen, Roland Bares, Winfried Brenner, Susanne Krege, Christiane Franzius, Sabine Kliesch, Ruediger Heicappel, Kurt Miller, Maike de Wit

  The Journal of urology. 04/2008; 179(3):936-40; discussion 940.

  PURPOSE: Treatment in patients with seminoma who have residual or recurrent masses following chemotherapy is still a matter of debate. Surgical resection is currently the most common recommendationPURPOSE: Treatment in patients with seminoma who have residual or recurrent masses following chemotherapy is still a matter of debate. Surgical resection is currently the most common recommendation for masses greater than 3 cm, resulting in overtreatment in up to 70% of those affected. We analyzed the accuracy of preoperative positron emission tomography for predicting viable tumor residuals in patients with seminoma. MATERIALS AND METHODS: In a prospective, multicenter trial computerized tomography and FDG (2-(F-18)-fluoro-2-deoxy-D-glucose) positron emission tomography were performed before surgical resection for residual or recurrent masses in 20 patients who had undergone chemotherapy for stage IIb, IIc or III seminoma. Histopathological findings were directly correlated with positron emission tomography results. RESULTS: Of the patients 18 presented with residual masses and 2 had recurrent masses following chemotherapy. Histopathological assessment revealed viable tumor in 3 patients and benign lesions in 17. All patients with viable tumor were identified correctly by positron emission tomography. No false-negative results were observed but 9 patients had false-positive positron emission tomography results. This resulted in a negative predictive value of 1 (95% CI 0.63-1) and a positive predictive value of 0.25 (95% CI 0.05-0.57) for FDG-positron emission tomography in our patient cohort. CONCLUSIONS: Our data indicate that FDG-positron emission tomography is capable of excluding viable disease in residual masses, even those exceeding 3 cm. Therefore, it may be considered an additional tool to improve patient counseling. However, the decision to perform surgical resection of the residual mass should not be based exclusively on a positive positron emission tomography image since false-positive results appear to be common.

• Re: Winstanley AM, Mikuz G, Debruyne F, Schulman CC, Parkinson MC. Handling and reporting of biopsy and surgical specimens of testicular cancer. Eur Urol 2004;45:564-73.

  Authors: Klaus-Peter Dieckmann, Susanne Krege, Lothar Weissbach

  European urology. 11/2004; 46(4):538; author reply 539.

• Signal transduction underlying carbachol-induced contraction of human urinary bladder.

  Authors: Tim Schneider, Charlotte Fetscher, Susanne Krege, Martin C Michel

  The Journal of pharmacology and experimental therapeutics. 07/2004; 309(3):1148-53.

  The present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbachol-induced contraction of human urinary bladder and to investigate the underlying signalThe present study was designed to reexamine the muscarinic acetylcholine receptor subtype mediating carbachol-induced contraction of human urinary bladder and to investigate the underlying signal transduction. Based upon the nonselective tolterodine, the highly M(2)-selective (R)-4-[2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl]piperidine-1-carboxylic acid amide (Ro-320-6206), and the highly M(3)-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M(3) receptors. The phospholipase C inhibitor 1-(6-[([17beta]-3-methoxyestra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione (U 73,122) (1-10 microM) did not significantly affect carbachol-stimulated bladder contraction. The phospholipase D inhibitor butan-1-ol relative to its negative control butan-2-ol (0.3% each) caused small but detectable inhibition of carbachol-induced bladder contraction. The Ca(2+) entry blocker nifedipine (10-100 nM) strongly inhibited carbachol-induced bladder contraction. In contrast, 1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SK&F 96,365) (1-10 microM), an inhibitor of store-operated Ca(2+) channels, caused little inhibition. The protein kinase C inhibitor bisindolylmaleimide I (1-10 microM) did not significantly affected carbachol-induced bladder contraction. In contrast, trans-4-[(1R)-1-aminoethyl]-N-4-pyridinylcyclohexanecarboxamide (Y 27,632) (1-10 microM), an inhibitor of rho-associated kinases, concentration dependently and effectively attenuated the carbachol responses. We conclude that carbachol-induced contraction of human urinary bladder via M(3) receptors largely depends on Ca(2+) entry through nifedipine-sensitive channels and activation of a rho kinase, whereas phospholipase D and store-operated Ca(2+) channels contribute only in a minor way. Surprisingly, phospholipase C or protein kinase C do not seem to be involved to a relevant extent.

• Prediction of necrosis after chemotherapy of advanced germ cell tumors: results of a prospective multicenter trial of the German Testicular Cancer Study Group.

  Authors: Peter Albers, Lothar Weissbach, Susanne Krege, Sabine Kliesch, Michael Hartmann, Axel Heidenreich, Peter Walz, Markus Kuczyk, Rolf Fimmers

  The Journal of urology. 06/2004; 171(5):1835-8.

  PURPOSE: We evaluated the prognostic parameters of necrotic residual tumors after chemotherapy of advanced germ cell tumors to improve on the current indications for surgery. MATERIALS AND METHODS:PURPOSE: We evaluated the prognostic parameters of necrotic residual tumors after chemotherapy of advanced germ cell tumors to improve on the current indications for surgery. MATERIALS AND METHODS: Between January 1996 and January 2000, in 8 centers of the German Testicular Cancer Study Group, preoperative parameters were assessed to predict necrosis in the residual tumors of 261 patients with retroperitoneal residual tumor resection after first (92%) and second line (8%) chemotherapy. RESULTS: Of 232 evaluable patients 39 had pure seminoma and 5 had viable cancer (1 with seminoma) in the residual tumor. Of the remaining 193 patients with nonseminoma 35% had necrosis, 34% teratoma and 31% had viable carcinoma in the residual tumor. After multivariate analysis and exclusion of patients with seminoma, the 3 parameters independently predictive of necrosis were alpha-fetoprotein before chemotherapy less than 20 ng/ml, and tumor volume before and after chemotherapy. A mathematical model to predict necrosis yielded a test accuracy of 75%, a sensitivity to predict necrosis of 52% and a specificity of 87%. CONCLUSIONS: Patients with pure seminoma should not undergo residual tumor resection because 97% of patients who received adequate chemotherapy were found to have no residual seminoma. In cases of nonseminoma alpha-fetoprotein values before chemotherapy less than 20 ng/ml and a high percentage of shrinkage during chemotherapy reliably predicted only 19% of cases of necrosis. Therefore, this model is clinically irrelevant and patients with minimal residual disease should undergo surgery. New methods are necessary to improve the preoperative selection of patients after chemotherapy.

• Gender comparison of muscarinic receptor expression and function in rat and human urinary bladder: differential regulation of M2 and M3 receptors?

  Authors: Christian Kories, Claudia Czyborra, Charlotte Fetscher, Tim Schneider, Susanne Krege, Martin C Michel

  Naunyn-Schmiedeberg's archives of pharmacology. 06/2003; 367(5):524-31.

  Since symptoms of bladder dysfunction occur more frequently in women than in men and since muscarinic receptors are the physiologically most important system to mediate bladder contraction, we haveSince symptoms of bladder dysfunction occur more frequently in women than in men and since muscarinic receptors are the physiologically most important system to mediate bladder contraction, we have compared the number, subtype distribution and function of muscarinic receptors in bladders from male and female rats. Muscarinic receptor function was also assessed in bladder strips from male and female human bladder. Male and female rats expressed a similar number of muscarinic receptors (144+/-5 vs. 140+/-6 fmol/mg protein in saturation radioligand binding). While competition binding curves for the moderately M(2)-selective methoctramine were not consistently better fitted by a two-site model, most competition curves for the M(3)-selective darifenacin were biphasic and yielded 29+/-10% and 31+/-7% high affinity sites (corresponding to M(3) receptors) in male and females, respectively. Immunoreactivity of alpha-subunits of the G-proteins G(q/11), G(i1/2), G(i3) and G(s) did not significantly differ between both genders. The muscarinic receptor agonist carbachol similarly stimulated inositol phosphate accumulation in bladder slices from male and female rats with calculated maximum responses of 69+/-17 and 77+/-18% over basal and pEC(50) values of 4.90+/-0.45 and 4.40+/-0.46, respectively. While darifenacin inhibited carbachol-stimulated inositol phosphate formation approximately 100-fold more potently than methoctramine, each antagonist was similarly potent in both genders. Carbachol concentration-dependently contracted bladder strips with a pEC(50) of 5.66+/-0.05 and 5.72+/-0.06 and maximum effects of 4.3+/-0.1 and 4.2+/-0.2 mN/mg wet weight in male and female rats, respectively. The contractile effect of carbachol was concentration-dependently antagonised by the non-selective atropine (1-30 nM), the M(1)-selective pirenzepine (1-30 M), the M(2)-selective methoctramine (1-10 microM) and the M(3)-selective darifenacin (10-100 nM), with the latter exhibiting a partly unsurmountable antagonism. The overall potency of all four antagonists suggested that contraction was mediated predominantly if not exclusively by M(3) receptors with no appreciable differences between both male and female rats. Similarly, the maximum effects (4.4+/-0.6 vs. 4.4+/-2.4 mN/mg) and pEC(50) (6.07+/-0.05 vs. 6.32+/-0.14) of carbachol did not differ between genders in bladder samples from 25 consecutive patients. We conclude that number und function of muscarinic receptors and the relative roles of their M(2) and M(3) subtypes do not differ between urinary bladders of male and female rats; at least with regard to overall muscarinic responsiveness this situation appears to be similar in humans.

• Complications of primary nerve sparing retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell tumors of the testis: experience of the German Testicular Cancer Study Group.

  Authors: Axel Heidenreich, Peter Albers, Michael Hartmann, Sabine Kliesch, Kai-Uwe Kohrmann, Susanne Krege, Philipp Lossin, Lothar Weissbach

  The Journal of urology. 06/2003; 169(5):1710-4.

  PURPOSE: Nerve sparing retroperitoneal lymph node dissection has been the standard diagnostic and therapeutic approach to clinical stage I nonseminoma. However, the application of prognostic riskPURPOSE: Nerve sparing retroperitoneal lymph node dissection has been the standard diagnostic and therapeutic approach to clinical stage I nonseminoma. However, the application of prognostic risk factors and introduction of laparoscopy have recently called into question the clinical usefulness of nerve sparing retroperitoneal lymph node dissection. We assessed the therapeutic efficacy and associated complications of this procedure in patients with clinical stage I nonseminomatous germ cell tumor treated at 7 tertiary referral centers to evaluate its role in the modern management of low stage testis cancer. MATERIALS AND METHODS: Between January 1995 and September 2000, 239 patients with clinical stage I nonseminomatous germ cell tumor underwent nerve sparing retroperitoneal lymph node dissection in standardized fields of dissection. For retrospective analysis patient charts were reviewed. A minor complication did not prolong hospital stay and a major complication prolonged hospitalization for at least 2 days. Early complications developed within the first 30 days after retroperitoneal lymph node dissection and late complications occurred from postoperative day 31 and thereafter. RESULTS: Nerve sparing retroperitoneal lymph node dissection was performed unilaterally in 209 patients (88.2%) and bilaterally in 30 (11.8%). Median operative time was 214 minutes (range 90 to 395), mean hospital stay was 8 days (range 4 to 39) and mean blood loss was less than 150 ml. A mean of 18.5 lymph nodes (range 9 to 57) were dissected with metastases detected in 67 patients (28%). An average of 2.9 lymph nodes (range 1 to 14) with a mean diameter of 2.6 cm. (range 0.3 to 6.0) showed metastasis. Disease was pathological stage I in 172 patients (71.7%), 52 (17.6%) had 3 or fewer metastatic lymph nodes, and 15 (6.3%) had 4 to 5 and 10 (4.2%) had greater than 5 positive lymph nodes. Minor complications occurred in 14.2% of the cases and major complications were observed in 5.4%. Antegrade ejaculation was preserved in 93.3% of the patients, recurrence developed in 14 (5.8%) and retroperitoneal recurrence was observed in 3 (1.2%), including 1 in field and 2 out field. CONCLUSIONS: Primary diagnostic and therapeutic nerve sparing retroperitoneal lymph node dissection still has a role in the primary management of clinical stage I nonseminomatous germ cell tumor. Surgery is associated with low morbidity and patient followup is easy and cost-effective due to the concentration on extraretroperitoneal locations. Primary nerve sparing retroperitoneal lymph node dissection is curative in about 70% of clinical stage I nonseminoma cases with a maximum of 3 positive lymph nodes.

• Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German Testicular Cancer Study Group Trial.

  Authors: Peter Albers, Roswitha Siener, Sabine Kliesch, Lothar Weissbach, Susanne Krege, Christoph Sparwasser, Harald Schulze, Axel Heidenreich, Werner de Riese, Volker Loy, Erhard Bierhoff, Christian Wittekind, Rolf Fimmers, Michael Hartmann

  Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 05/2003; 21(8):1505-12.

  PURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to MayPURPOSE: To prospectively assess potential risk factors for relapse in clinical stage I nonseminomatous germ cell tumors of the testis (CS I NSGCT). PATIENTS AND METHODS: From September 1996 to May 2002, 200 patients with CS I NSGCT were prospectively assigned to retroperitoneal lymph node dissection (RPLND), and risk factor assessment was performed within a multicenter protocol. One hundred sixty-five patients had an adequate minimum follow-up of 12 months (mean, 34.5 months) or had pathologic stage II. RESULTS: Pathologic stage II disease was found in 27.9% of patients. Only 0.6% of patients relapsed in the retroperitoneum after confirmation of pathologic stage I disease. With reference pathology, vascular invasion (VI) was most predictive of stage in multifactorial analysis (accuracy, 65.1%). However, the positive predictive value (PPV) of VI to predict patients who have metastatic disease or relapse during follow-up was only 52.7%. With absent VI, low-risk patients had a negative predictive value (NPV) of 76.9%. With a combination of several risk factors, the PPV increased to 63.6% and the negative predictive value increased to 86.5%. CONCLUSION: Even with an optimal combination of prognostic factors and reference pathology, more than one third of patients predicted to have pathologic stage II or relapse during follow-up will not harbor metastatic disease and, therefore, would be overtreated with adjuvant therapy. However, patients at low risk may be predicted at an 86.5% level, and thus, surveillance in highly compliant patients would be a valuable option. For high-risk patients, further reduction of adjuvant treatment is necessary.

• Does gender or age affect the efficacy and safety of tolterodine?

  Authors: Martin C Michel, Tim Schneider, Susanne Krege, Mark Goepel

  The Journal of urology. 10/2002; 168(3):1027-31.

  PURPOSE: We compared the importance of patient age and gender relative to the intensity of baseline symptoms of overactive bladder in the therapeutic response to the muscarinic receptor antagonistPURPOSE: We compared the importance of patient age and gender relative to the intensity of baseline symptoms of overactive bladder in the therapeutic response to the muscarinic receptor antagonist tolterodine. MATERIALS AND METHODS: Data from an open label, observational study of 2,250 patients with overactive bladder treated for 12 weeks with tolterodine were analyzed for alterations in frequency, urgency and urge incontinence, and for global efficacy and tolerability using logistic regression analysis, stratifying for gender, age, baseline symptom intensity and tolterodine dose. RESULTS: Gender or tolterodine dose were not consistently associated with altered treatment efficacy. Greater age was associated with a slight but statistically significant decrease in treatment efficacy. Patients with great baseline symptom intensity had greater treatment associated improvement but a lesser chance to become symptom-free. Even with a large number of patients no statistically significant gender or age associated alterations in the tolerability of tolterodine treatment were detected. CONCLUSIONS: The extent of the therapeutic response to tolterodine is largely determined by the extent of baseline symptoms. While gender does not affect the efficacy or tolerability of tolterodine in a clinically relevant manner, advanced age is associated with a slight decrease in efficacy but not in tolerability.

• M(3) muscarinic receptors mediate contraction of human urinary bladder.

  Authors: Charlotte Fetscher, Marina Fleichman, Martina Schmidt, Susanne Krege, Martin C Michel

  British journal of pharmacology. 08/2002; 136(5):641-3.

  Since muscarinic receptors appear to be the physiologically most important control system for urinary bladder contraction, we have characterized the receptor subtype mediating contraction in responseSince muscarinic receptors appear to be the physiologically most important control system for urinary bladder contraction, we have characterized the receptor subtype mediating contraction in response to the muscarinic agonist carbachol in the human bladder. Experiments were based on four antagonists, the non-selective atropine, the M(1)-selective pirenzepine, the M(2)-selective methoctramine and the M(3)-selective darifenacin. All antagonists yielded Schild-plots with a slope close to unity. The order of potency (atropine> or =darifenacin>pirenzepine>methoctramine) as well as the estimated antagonist affinities suggested that contraction of the human bladder occurs predominantly if not exclusively via the M(3) receptor.

• An extract from the bark of Aspidosperma quebracho blanco binds to human penile alpha-adrenoceptors.

  Authors: Herbert Sperling, Annette Lorenz, Susanne Krege, Rainer Arndt, Martin C Michel

  The Journal of urology. 08/2002; 168(1):160-3.

  PURPOSE: We determined whether an extract from the bark of the tree Aspidosperma quebracho blanco, which is used as a prescription drug to treat erectile dysfunction in some countries, can bind toPURPOSE: We determined whether an extract from the bark of the tree Aspidosperma quebracho blanco, which is used as a prescription drug to treat erectile dysfunction in some countries, can bind to human penile alpha1 and alpha2-adrenoceptors, and cloned human alpha-adrenoceptor subtypes. MATERIALS AND METHODS: Competition binding studies were performed with alpha1 and alpha2-adrenoceptors with the extract and 4 subfractions prepared from it using [3H]prazosin (New England Nuclear, Dreieich, Germany) and [3H]RX 821002 (2-methoxy-idazoxam) (Amersham, Braunschweig, Germany) as the radioligands, respectively. RESULTS: In a concentration dependent manner the extract inhibited 2-methoxy-idazoxam binding to human penile alpha2-adrenoceptors. Somewhat less potently it inhibited [3H] prazosin binding to penile alpha1-adrenoceptors. The extract also inhibited binding to cloned alpha2-adrenoceptors more potently than to alpha1-adrenoceptors but did not discriminate among subtypes. Subfraction B was more potent than the others for all cloned alpha1-adrenoceptor subtypes and much more potent at all penile and all cloned alpha2-adrenoceptor subtypes. This fraction largely contained yohimbine, whereas the other fractions were devoid of yohimbine. Based on yohimbine competition binding experiments with penile and cloned alpha1 and alpha2-adrenoceptors, it appears that the inhibitory effects of the abstract and its subfractions can largely be explained by its yohimbine content. CONCLUSIONS: An alpha-adrenoceptor mediated component of the pro-erectile effects of Aspidosperma quebracho blanco bark extract may predominantly be caused by its yohimbine content. The alpha-adrenoceptor independent, pro-erectile effects of the extract could not be determined from this study.