Steffen Weikert

Publications of Steffen Weikert

• Impact of positive surgical margins on oncological outcome following laparoscopic radical prostatectomy (LRP): long-term results.

  Authors: Jonas Busch, Carsten Stephan, Annett Klutzny, Stefan Hinz, Carsten Kempkensteffen, Ergin Kilic, Michael Lein, Steffen Weikert, Kurt Miller, Ahmed Magheli

  World journal of urology. 05/2012;

  PURPOSE: The impact of positive surgical margins (PSM) on biochemical recurrence (BCR) has been heavily debated in laparoscopic radical prostatectomy (LRP). The aim of this study was to investigatePURPOSE: The impact of positive surgical margins (PSM) on biochemical recurrence (BCR) has been heavily debated in laparoscopic radical prostatectomy (LRP). The aim of this study was to investigate the impact of PSM on BCR following LRP in patients with extended follow-up. METHODS: Retrospective chart review of 1,845 patients who underwent LRP from 1999 to 2007. Predictors of PSM and BCR were identified utilizing univariate and multivariable logistic and Cox regression analyses, respectively. RESULTS: Five hundred and thirty-seven patients (29.1 %) had a PSM. Median postoperative follow-up was 56 months. 10-year BCR-free survival was 59.2 and 82.9 % for patients with and without PSM, respectively (p < 0.0001). Clinical stage T2 (OR 1.66; CI 1.23-2.25; p = 0.001), a biopsy Gleason sum > 7 (OR 1.84; CI 1.06-3.18; p = 0.031) and preoperative prostate-specific antigen (PSA) levels of 10-20 ng/mL (OR 1.58; CI 1.12-2.23; p = 0.010) and >20 ng/mL (OR 6.82; CI 3.51-13.27; p < 0.0001) were independent predictors of PSM. Prostate size was inversely associated with PSM (OR 0.99; CI 0.98-1.00; p = 0.002). On multivariable analysis, LRP Gleason score of 7 (HR 2.45; CI 1.67-3.40; p < 0.0001) and >7 (HR 4.76; CI 3.15-7.19; p < 0.0001), PSM (HR 1.49; CI 1.14-2.00; p = 0.003), advanced pathological stages (p < 0.001), and PSA 10-20 ng/mL (HR 1.46; CI 1.13-1.89; p = 0.004) were independent predictors of BCR. CONCLUSIONS: We demonstrated the independent predictive value of PSM for BCR in our LRP cohort with extended follow-up. Our results could potentially be transferred to robotic RP, in which long-term follow-up is lacking.

• Expression parameters of the metabolic pathway genes pyruvate dehydrogenase kinase-1 (PDK-1) and DJ-1/PARK7 in renal cell carcinoma (RCC).

  Authors: Daniel Baumunk, Uta Reichelt, Jannis Hildebrandt, Hans Krause, Jan Ebbing, Hannes Cash, Kurt Miller, Martin Schostak, Steffen Weikert

  World journal of urology. 04/2012;

  PURPOSE: Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways inPURPOSE: Metabolic adaptations, such as increases in glucose and energy metabolism, play a pivotal role in the biology of RCC. PDK-1 and DJ-1/PARK7 are thought to control metabolic pathways in cancer. We investigated the expression of PDK-1 and DJ-1/PARK7 in RCC and their prognostic relevance. METHODS: RCC tumor tissue and corresponding normal parenchyma samples were obtained from 91 patients with clear cell RCC. Expression of PDK-1 and DJ-1/PARK7 was determined on the mRNA and protein levels using quantitative RT-PCR and immunohistochemistry. Expression ratios tumor/normal were analyzed for associations with pathological stage and grade (Kruskal-Wallis ANOVA, chi-square test). Potential associations with progression-free and overall survival were analyzed using Cox regression models. RESULTS: PDK-1 mRNA expression was up-regulated as compared to normal tissue (p < 0.001). Differences were observed by tumor stage (p < 0.05) with a trend toward lower expression with increasing stage (p > 0.01). Expression ratio tumor/normal also showed differences by tumor stage with the lowest ratio observed in advanced (pT3) disease. MRNA expression data were confirmed on the protein level with the lowest protein expression in pT3 tumors. PDK-1 expression ratio tumor/normal was inversely associated with outcome after adjustment for stage and grade (HR, 0.54; 95 % CI, 0.31-0.94). No associations observed for DJ-1/PARK7 expression. CONCLUSIONS: PDK is up-regulated in RCC, but down-regulation may be associated with progression toward a metastasizing behavior. Given the role of PDK-1 in the control of glucose metabolism, aerobic glycolysis via up-regulation of PDK-1 may be an early event in RCC development, but less relevant for the progression toward an aggressive phenotype.

• Progression free survival of first line vascular endothelial growth factor-targeted therapy is an important prognostic parameter in patients with metastatic renal cell carcinoma.

  Authors: Christoph Seidel, Jonas Busch, Steffen Weikert, Sandra Steffens, Martin Fenner, Arnold Ganser, Viktor Grünwald

  European journal of cancer (Oxford, England : 1990). 03/2012;

  PURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuablePURPOSE: Intrinsic resistance in metastatic renal cell carcinoma (mRCC) was recently associated with poor overall survival (OS), suggesting that VEGF inhibitor sensitivity may represent a valuable prognostic marker. We explored the duration of progression free survival (PFS) in first-line treatment and other variables as prognostic markers in mRCC. METHODS: Medical records from 119 mRCC patients receiving first line treatment with tyrosine kinase inhibitors (TKI) were retrieved retrospectively. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analysed clinical parameters for their prognostic relevance. RESULTS: The median PFS of first line treatment was 8.4months (95% confidence interval 5.8-11) associated with a median OS of 28.2months (95% CI 20.9-35.4). Second line therapy with another TKI or mTOR-inhibitor was applied to 81 patients (68%). PFS of any second line therapy was 5.1 and 3.7months in first line treatment responders and non-responders (p=0.3), respectively. Univariate analyses revealed bone metastases, prior cytokine treatment, Memorial Sloan Kettering cancer centre (MSKCC) score, objective response rate, Eastern Cooperative Oncology Group (ECOG) performance status, first line PFS with 6months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6months (95% CI 0.154-0.641; HR 0.314), second line treatment (95% CI 0.162-0.657; HR 0.326), MSKCC score (95% CI 1.07-3.392; HR 1.905) and objective response rate (95% CI 0.358-0.989; HR 0.595) to be independent prognostic markers. CONCLUSIONS: The duration of first line PFS is an independent prognostic variable but not predictive for subsequent therapy.

• Selective Lymph Node Dissection for Castration-Resistant Prostate Cancer.

  Authors: Jonas Busch, Stefan Hinz, Carsten Kempkensteffen, Barbara Erber, Christian Klopf, Steffen Weikert, Kurt Miller, Ahmed Magheli

  Urologia internationalis. 03/2012;

  Background: No relevant data have been published on the impact of retroperitoneal lymph node dissection (LND) on clinical outcome in patients with castration-resistant prostate cancer. Methods: WeBackground: No relevant data have been published on the impact of retroperitoneal lymph node dissection (LND) on clinical outcome in patients with castration-resistant prostate cancer. Methods: We retrospectively studied the records of 6 patients with lymph node metastases from castration-resistant prostate cancer who underwent a retroperitoneal LND between 2005 and 2010. Complication rate and clinical outcome were examined. Results: Mean patient age was 69.2 (63-81) years. Primary therapy was radical prostatectomy, radiation therapy, or pelvic LND and androgen deprivation in 3, 2 and 1 cases, respectively. Mean prostate-specific antigen (PSA) at LND was 37.6 (20.3-139) ng/dl. LND was performed as a modified unilateral (n = 3), bilateral (n = 1) and bilateral extended (n = 2) approach with a median lymph node density of 0.739 (0.111-1). Preoperative Charlson index was 0 (n = 3) or 1 (n = 3). No intra- or postoperative complications occurred. The average postoperative decline of PSA was 39.3% (-99.4 to +31.3). Differences between mean pre- and postoperative PSA velocities and densities were 23.9 ng/ml/year and 11.2 months, respectively (p = 0.24 and p = 0.40). Four patients (67%) developed bone metastases after a mean period of 23.5 (5-58) months. Median bone metastases-free survival was 15.5 months and median overall survival after LND was 31.7 months on Kaplan-Meier analysis. Conclusions: A selective LND in castration-resistant prostate cancer patients could be safely performed. A positive effect on the PSA and PSA kinetics was accomplished for the majority of patients. This new surgical approach represents an alternative treatment option in the palliative setting of prostate cancer patients and could delay toxic systemic therapy up to 12 months.

• Time trends in prostate cancer surgery: data from an Internet-based multicentre database.

  Authors: Martin Schostak, Daniel Baumunk, Anita Jagota, Christian Klopf, Alexander Winter, Sebastian Schäfers, Robert Kössler, Volker Brennecke, Tom Fischer, Susanne Hagel, Steffen Höchel, Dierk Jäkel, Mike Lehsnau, Susanne Krege, Bernd Rüffert, Jana Pretzer, Eduard Becht, Thomas Zegenhagen, Kurt Miller, Steffen Weikert

  BJU international. 08/2011; 109(3):355-9.

  To report our experience with an Internet-based multicentre database that enables tumour documentation, as well as the collection of quality-related parameters and follow-up data, in surgicallyTo report our experience with an Internet-based multicentre database that enables tumour documentation, as well as the collection of quality-related parameters and follow-up data, in surgically treated patients with prostate cancer. The system was used to assess the quality of prostate cancer surgery and to analyze possible time-dependent trends in the quality of care. An Internet-based database system enabled a standardized collection of treatment data and clinical findings from the participating urological centres for the years 2005-2009. An analysis was performed aiming to evaluate relevant patient characteristics (age, pathological tumour stage, preoperative International Index of Erectile Function-5 score), intra-operative parameters (operating time, percentage of nerve-sparing operations, complication rate, transfusion rate, number of resected lymph nodes) and postoperative parameters (hospitalization time, re-operation rate, catheter indwelling time). Mean values were calculated and compared for each annual cohort from 2005 to 2008. The overall survival rate was also calculated for a subgroup of the Berlin patients. A total of 914, 1120, 1434 and 1750 patients submitted to radical prostatectomy in 2005, 2006, 2007 and 2008 were documented in the database. The mean age at the time of surgery remained constant (66 years) during the study period. More than half the patients already had erectile dysfunction before surgery (median International Index of Erectile Function-5 score of 19-20). During the observation period, there was a decrease in the percentage of pT2 tumours (1% in 2005; 64% in 2008) and a slight increase in the percentage of patients with lymph node metastases (8% in 2005; 10% in 2008). No time trend was found for the operating time (142-155 min) or the percentage of nerve-sparing operations (72-78% in patients without erectile dysfunction). A decreasing frequency was observed for the parameters: blood transfusions (1.9% in 2005; 0.5% in 2008), postoperative bleeding (2.6%; 1.2%) and re-operations (4.5%; 2.8%). The mean hospitalization time decreased accordingly (10 days in 2005; 8 days in 2008). The examined subcohort had an overall mortality of 1.5% (median follow-up of 3 years). An Internet-based database system for tumour documentation in patients with prostate cancer enables the collection and assessment of important parameters for the quality of care and outcomes. The participating centres show an improvement in the quality of surgical management, including a reduction of the complication rate.

• Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors.

  Authors: Jonas Busch, Christoph Seidel, Carsten Kempkensteffen, Manfred Johannsen, Ingmar Wolff, Stefan Hinz, Ahmed Magheli, Kurt Miller, Viktor Grünwald, Steffen Weikert

  European urology. 07/2011; 60(6):1163-70.

  The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. To describe the efficacy and toxicity of sequential everolimus (EV)The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. Sequence of systemic targeted treatment with sunitinib (n=85) or sorafenib (n=23) followed by EV (n=62) or another rTKI (n=46; sorafenib, n=35; sunitinib, n=11). We measured response rate (Response Evaluation Criteria in Solid Tumours 1.0) and toxicity. Survival analysis (Kaplan-Meier method and Cox regression) was conducted for progression-free survival (PFS) and overall survival (OS). Main patient characteristics did not significantly differ by sequence of treatment groups (rTKI-rTKI vs rTKI-EV). Response rate following first rTKI failure was not significantly different between sequential therapies with a disease control rate of 51.6% (EV) and 43.5% (rTKI). The corresponding median PFS was 3.6 mo (95% confidence interval [CI], 1.8-5.4) for EV and 4.0 mo (3.2-4.9) for rTKI treatment. The estimated OS was longer for the rTKI-EV group (43 mo; 95% CI, 33.9-52.1) than for the rTKI-rTKI group (29 mo; 95% CI, 18.6-39.5; p=0.03), but this difference lost statistical significance in multivariable-adjusted analyses. Intrinsic rTKI resistance was independently associated with inferior subsequent PFS (hazard ratio [HR]: 1.79; 95% CI, 1.15-3.62; p=0.015) and OS (HR: 6.54; 95% CI, 3.01-14.20; p<0.001). Limitations are the retrospective design, limited numbers of cases, and residual confounding factors. The sequence therapies rTKI-EV and rTKI-rTKI may be equally efficacious in terms of PFS and response rate, whereas a tendency towards superior survival was observed for the rTKI-EV sequence. These data, particularly the potential benefit of an early change of mode of action, need confirmation in randomised comparative trials.

• The epidemiology of renal cell carcinoma.

  Authors: Börje Ljungberg, Steven C Campbell, Han Yong Choi, Han Yong Cho, Didier Jacqmin, Jung Eun Lee, Steffen Weikert, Lambertus A Kiemeney

  European urology. 07/2011; 60(4):615-21.

  Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease.Kidney cancer is among the 10 most frequently occurring cancers in Western communities. Globally, about 270 000 cases of kidney cancer are diagnosed yearly and 116 000 people die from the disease. Approximately 90% of all kidney cancers are renal cell carcinomas (RCC). The causes of RCC are not completely known. We have reviewed known aetiologic factors. The data provided in the current review are based on a thorough review of available original and review articles on RCC epidemiology with a systemic literature search using Medline. Smoking, overweight and obesity, and germline mutations in specific genes are established risk factors for RCC. Hypertension and advanced kidney disease, which makes dialysis necessary, also increase RCC risk. Specific dietary habits and occupational exposure to specific carcinogens are suspected risk factors, but results in the literature are inconclusive. Alcohol consumption seems to have a protective effect for reasons yet unknown. Hardly any information is available for some factors that may have a high a priori role in the causation of RCC, such as salt consumption. Large collaborative studies with uniform data collection seem to be necessary to elucidate a complete list of established risk factors of RCC. This is necessary to make successful prevention possible for a disease that is diagnosed frequently in a stage where curative treatment is not possible anymore.

• Fluid intake and the risk of urothelial cell carcinomas in the European Prospective Investigation into Cancer and Nutrition (EPIC).

  Authors: Martine M Ros, H B Bas Bueno-de-Mesquita, Frederike L Büchner, Katja K H Aben, Ellen Kampman, Lars Egevad, Kim Overvad, Anne Tjønneland, Nina Roswall, Francoise Clavel-Chapelon [......] Börje Ljungberg, Naomi E Allen, Andrew W Roddam, Kay-Tee Khaw, Nick Wareham, Paolo Boffetta, Nadia Slimani, Dominique S Michaud, Lambertus A L M Kiemeney, Elio Riboli

  International journal of cancer. Journal international du cancer. 06/2011; 128(11):2695-708.

  Results from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in theResults from previous studies investigating the association between fluid intake and urothelial cell carcinomas (UCC) are inconsistent. We evaluated this association among 233,236 subjects in the European Prospective Investigation into Cancer and Nutrition (EPIC), who had adequate baseline information on water and total fluid intake. During a mean follow-up of 9.3 years, 513 first primary UCC occurred. At recruitment, habitual fluid intake was assessed by a food frequency questionnaire. Multivariable hazard ratios were estimated using Cox regression stratified by age, sex and center and adjusted for energy intake, smoking status, duration of smoking and lifetime intensity of smoking. When using the lowest tertile of intake as reference, total fluid intake was not associated with risk of all UCC (HR 1.12; 95%CI 0.86-1.45, p-trend = 0.42) or with risk of prognostically high-risk UCC (HR 1.28; 95%CI 0.85-1.93, p-trend = 0.27) or prognostically low-risk UCC (HR 0.93; 95%CI 0.65-1.33, p-trend = 0.74). No associations were observed between risk of UCC and intake of water, coffee, tea and herbal tea and milk and other dairy beverages. For prognostically low-risk UCC suggestions of an inverse association with alcoholic beverages and of a positive association with soft drinks were seen. Increased risks were found for all UCC and prognostically low-risk UCC with higher intake of fruit and vegetable juices. In conclusion, total usual fluid intake is not associated with UCC risk in EPIC. The relationships observed for some fluids may be due to chance, but further investigation of the role of all types of fluid is warranted.

• Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors.

  Authors: Steffen Weikert, Carsten Kempkensteffen, Jonas Busch, Manfred Johannsen, Viktor Grünwald, Kaja Zimmermann, Anne Flörcken, Jörg Westermann, Lisa Weinkauf, Kurt Miller, Ulrich Keilholz

  World journal of urology. 04/2011;

  PURPOSE: Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but dataPURPOSE: Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy. METHODS: Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed. RESULTS: Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1-10.4) and 18.0 months (12.6-23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13). CONCLUSIONS: Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.

• Red meat, dietary nitrosamines, and heme iron and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

  Authors: Paula Jakszyn, Carlos A González, Leila Luján-Barroso, Martine M Ros, H Bas Bueno-de-Mesquita, Nina Roswall, Anne M Tjønneland, Frederike L Büchner, Lars Egevad, Kim Overvad [......] Borje Ljungberg, Andrew Wilfred Roddam, Sheila A Bingham, Kay-Tee Khaw, Nadia Slimani, Paolo A Boffetta, Mazda Jenab, Traci Mouw, Dominique S Michaud, Elio Riboli

  Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 01/2011; 20(3):555-9.

  Previous epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and thePrevious epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and the risk of bladder cancer. We investigated the association between red meat consumption, dietary nitrosamines, and heme iron and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). Data on food consumption and complete follow-up for cancer occurrence were available for a total of 481,419 participants, recruited in 10 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, gender, and study center and adjusted for total energy intake, smoking status, lifetime intensity of smoking, duration of smoking, educational level, and BMI. After a mean follow-up of 8.7 years, 1,001 participants were diagnosed with bladder cancer. We found no overall association between intake of red meat (log2 HR: 1.06; 95% CI: 0.99-1.13), nitrosamines (log2 HR: 1.09; 95% CI: 0.92-1.30 and HR: 0.98; 95% CI: 0.92-1.05 for ENOC and NDMA, respectively) or heme iron (log2 HR: 1.05; 95 CI: 0.99-1.12) and bladder cancer risk. The associations did not vary by sex, high- versus low-risk bladder cancers, smoking status, or occupation (high vs. low risk). Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk.

• Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma.

  Authors: Jonas Busch, Christoph Seidel, Steffen Weikert, Ingmar Wolff, Carsten Kempkensteffen, Lisa Weinkauf, Stefan Hinz, Ahmed Magheli, Kurt Miller, Viktor Grünwald

  BMC cancer. 01/2011; 11:295.

  Data on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectivelyData on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague. We retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy. Thirty-five mRCC patients (male, 18; female, 11) with primary resistance to first rTKI therapy (sunitinib, n = 28; sorafenib, n = 7) and a median treatment interval of 2.4 months (1 - 4.6) were identified. In 22 patients, progressive disease (PD) was determined by a new metastatic lesion. Of these, 16 patients received subsequent therapy with 12 patients remaining refractory and 4 patients achieving disease stabilization. In 13 patients continuous growth of existing metastatic lesions determined PD. Of these, 9 received sequential therapy with 6 achieving disease stabilization. Altogether, 25 patients were treated sequentially (rTKI: n = 15; mTOR-inhibitor: n = 10) and achieved a median PFS of 3.2 months (range, 1-16.6). Fifteen patients failed to respond to either line of therapy. Disease control was not associated with type of subsequent therapy. Median OS was 14.9 months (CI: 5.5-24.4). Intrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.

• Efficacy of sunitinib re-exposure after failure of an mTOR inhibitor in patients with metastatic RCC.

  Authors: Viktor Grünwald, Steffen Weikert, Christoph Seidel, Jonas Busch, Antje Johannsen, Martin Fenner, Christoph Reuter, Arnold Ganser, Manfred Johannsen

  Onkologie. 01/2011; 34(6):310-4.

  The sequential use of tyrosine kinase inhibitors (TKI) followed by mTOR inhibitors (mTORi) has been recently established for the systemic treatment of metastatic renal cell carcinoma (mRCC). However,The sequential use of tyrosine kinase inhibitors (TKI) followed by mTOR inhibitors (mTORi) has been recently established for the systemic treatment of metastatic renal cell carcinoma (mRCC). However, subsequent treatment in mTORi-refractory disease remains undetermined. We analyzed the efficacy of sunitinib re-challenge after failure of an mTORi at 2 German centers. Thirteen patients who failed both sunitinib and an mTORi were analyzed, and all patients were re-exposed to sunitinib. Tumor assessment was performed every 2nd cycle of sunitinib or every 3 months. Tumor response was assessed according to RECIST criteria. Initial treatment with sunitinib was associated with a median progression free survival (PFS) of 21 months. Objective response consisted of 2 (15%) complete remissions and 7 (54%) partial remissions (PR) as best response. At the time of re-exposure, 12 of 13 (92%) patients again showed clinical benefit which was associated with a median PFS of 6.9 months and consisted of 2 (15%) PR and 10 (77%) disease stabilizations. In sunitinib-responsive patients, re-challenge with sunitinib has been successfully introduced after mTORi-refractory disease, underscoring the at least partially transient nature of TKI resistance in mRCC.

• Adverse events associated with testosterone administration.

  Authors: Cornelia Weikert, Tobias Pischon, Steffen Weikert

  The New England journal of medicine. 11/2010; 363(19):1865; author reply 1866-7.

• The tumour-targeting human L19-IL2 immunocytokine: preclinical safety studies, phase I clinical trial in patients with solid tumours and expansion into patients with advanced renal cell carcinoma.

  Authors: Manfred Johannsen, Gianluca Spitaleri, Giuseppe Curigliano, Jan Roigas, Steffen Weikert, Carsten Kempkensteffen, Andreas Roemer, Christian Kloeters, Patrik Rogalla, Gabriele Pecher [......] Alexander Berndt, Hartwig Kosmehl, Eveline Trachsel, Manuela Kaspar, Valeria Lovato, Reinerio González-Iglesias, Leonardo Giovannoni, Hans D Menssen, Dario Neri, Filippo de Braud

  European journal of cancer (Oxford, England : 1990). 11/2010; 46(16):2926-35.

  L19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker ofL19-IL2, a tumour-targeting immunocytokine composed of the recombinant human antibody fragment L19 (specific to the alternatively-spliced EDB domain of fibronectin, a well characterised marker of tumour neo-vasculature) and of human IL2, has demonstrated strong therapeutic activity in animal cancer models. This phase I/II trial was performed to evaluate safety, tolerability, recommended phase II dose (RD) and early signs of activity of L19-IL2. Five cohorts of patients with progressive solid tumours (n=21) received an intravenous infusion of L19-IL2 (from 5 to 30 Mio IU IL2 equivalent dose) on days 1, 3 and 5 every 3 weeks. This treatment cycle was repeated up to six times. In the following expansion phase, patients with metastatic renal cell carcinoma (RCC) (n=12) were treated at the RD of L19-IL2. Clinical data and laboratory findings were analysed for safety, tolerability and activity. Preclinical studies in rats and monkeys did not raise any safety concerns. The RD was defined to be 22.5 Mio IU IL2 equivalent. Pharmacokinetics of L19-IL2 was dose proportional over the tested range, with a terminal half-life of 2-3h. Toxicities were manageable and reversible with no treatment-related deaths. We observed stable disease in 17/33 patients (51%) and 15/18 with mRCC (83%) after two cycles. Median progression-free survival of RCC patients in the expansion phase of the study was 8 months (1.5-30.5). L19-IL2 can be safely and repeatedly administered at the RD of 22.5 Mio IU IL2 equivalent in advanced solid tumours. Preliminary evaluation suggests clinical activity of L19-IL2 in patients with mRCC.

• Deregulation of EZH2 expression in human spermatogenic disorders and testicular germ cell tumors.

  Authors: Stefan Hinz, Ahmed Magheli, Steffen Weikert, Wolfgang Schulze, Hans Krause, Mark Schrader, Kurt Miller, Carsten Kempkensteffen

  World journal of urology. 10/2010; 28(5):631-5.

  Enhancer of Zeste 2 (EZH2) is an epigenetic transcriptional repressor involved in cell cycle control and cell fate decisions. Since these processes play key roles during intact spermatogenesis,Enhancer of Zeste 2 (EZH2) is an epigenetic transcriptional repressor involved in cell cycle control and cell fate decisions. Since these processes play key roles during intact spermatogenesis, deregulation of EZH2 expression may contribute to the development and progression of benign and malignant testicular diseases. The objective of this study was to investigate the expression profile of EZH2 in testicular germ cell tumors (TGCT) and spermatogenic defects. Real-time RT-PCR was applied to quantify the m-RNA expression of EZH2 in 64 seminomas 36 non-seminomas, 4 carcinomas in situ (CIS), 40 samples harboring impaired spermatogenesis and 24 normal testicular reference biopsies. EZH2 was expressed in 99% of TGCT samples and in all biopsies with intact spermatogenesis. Its expression levels were highest in normal testicular tissue, and continuously decreased with malignant transformation to CIS and further progression to invasive TGCT (P < 0.001). EZH2 tumor levels were not related to the histological TGCT subtype or clinical tumor stage. Comparison of distinct stages of spermatogenic failure revealed an inverse association of EZH2 levels to the severity of the spermatogenic defect (P < 0.001). Our data strongly suggest that in TGCT EZH2 does not exert its often assumed oncogenic properties during malignant transformation and progression. High EZH2 levels in normal testicular tissue and the inverse association of its expression levels with the severity of spermatogenic failure point to its potential value as a molecular marker for spermatogenic defects and may indicate an important physiological role of EZH2 during intact spermatogenesis.

• Variety in vegetable and fruit consumption and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition.

  Authors: Frederike L Büchner, H Bas Bueno-de-Mesquita, Martine M Ros, Ellen Kampman, Lars Egevad, Kim Overvad, Anne Tjønneland, Nina Roswall, Françoise Clavel-Chapelon, Marie-Christine Boutron-Ruault [......] Börje Ljungberg, Tim J Key, Naomi E Allen, Kay-Tee Khaw, Nicholas Wareham, Nadia Slimani, Mazda Jenab, Paolo Boffetta, Lambertus A L M Kiemeney, Elio Riboli

  International journal of cancer. Journal international du cancer. 08/2010; 128(12):2971-9.

  Recent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which mayRecent research does not show an association between fruit and vegetable consumption and bladder cancer risk. None of these studies investigated variety in fruit and vegetable consumption, which may capture different aspects of consumption. We investigated whether a varied consumption of vegetables and fruits is associated with bladder cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Detailed data on food consumption and complete follow-up for cancer incidence were available for 452,185 participants, who were recruited from ten European countries. After a mean follow-up of 8.7 years, 874 participants were diagnosed with bladder cancer. Diet diversity scores (DDSs) were used to quantify the variety in fruit and vegetable consumption. Multivariable Cox proportional hazard models were used to assess the effect of the DDSs on bladder cancer risk. There was no evidence of a statistically significant association between bladder cancer risk and any of the DDSs when these scores were considered as continuous covariates. However, the hazard ratio (HR) for the highest tertile of the DDS for combined fruit and vegetable consumption was marginally significant compared to the lowest (HR = 1.30, 95% confidence interval: 1.00-1.69, p-trend = 0.05). In EPIC, there is no clear association between a varied fruit and vegetable consumption and bladder cancer risk. This finding provides further evidence for the absence of any strong association between fruit and vegetable consumption as measured by a food frequency questionnaire and bladder cancer risk.

• Contemporary epidemiology of renal cell carcinoma: perspectives of primary prevention.

  Authors: Steffen Weikert, Börje Ljungberg

  World journal of urology. 04/2010; 28(3):247-52.

  Epidemiological research of recent years has produced evidence for a role of lifestyle-associated risk factors in the etiology of renal cell carcinoma (RCC), the most common renal tumor. In thisEpidemiological research of recent years has produced evidence for a role of lifestyle-associated risk factors in the etiology of renal cell carcinoma (RCC), the most common renal tumor. In this review, we give an overview of recent trends in incidence and mortality and summarize the current knowledge on risk factors of RCC. Data on incidence and mortality in the literature were reviewed. Global incidence data were derived from the Globocan database. A literature review of epidemiological studies on risk factors of kidney cancer was performed, with special emphasis on recent studies with high level of evidence, i.e., meta-analyses and prospective cohort studies. The incidence of renal malignancies has increased over recent decades in the context of the more widespread use of diagnostic imaging. However, time trends and geographic variations in incidence and mortality may also relate to changes in the prevalence of risk factors. Cigarette smoking, excess body weight and uncontrolled blood pressure are the most important and modifiable risk factors for RCC with a high prevalence in the general population. Moreover, dietary habits associated with a Western lifestyle were proposed as potential risk factors, but no food or food group has consistently been related to RCC risk. Based on the current evidence, reductions in the prevalence of cigarette smoking, overweight and hypertension are preventive strategies for RCC. More research is needed to establish the underlying mechanisms linking these risk factors and renal carcinogenesis.

• Presence of gallstones or kidney stones and risk of type 2 diabetes.

  Authors: Cornelia Weikert, Steffen Weikert, Matthias B Schulze, Tobias Pischon, Andreas Fritsche, Manuela M Bergmann, Stefan N Willich, Heiner Boeing

  American journal of epidemiology. 02/2010; 171(4):447-54.

  Recent evidence suggests that gallstones and kidney stones are associated with insulin resistance, but the relation between stone diseases and the risk of developing type 2 diabetes mellitus is notRecent evidence suggests that gallstones and kidney stones are associated with insulin resistance, but the relation between stone diseases and the risk of developing type 2 diabetes mellitus is not clear. Participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study (Potsdam, Germany) provided information about the presence of gallstones and kidney stones at recruitment between 1994 and 1998. On biennial questionnaires, participants reported newly diagnosed type 2 diabetes mellitus, and confirmation was obtained from treating physicians. During a mean follow-up period of 7.0 years between 1994 and 2005, 849 incident cases of type 2 diabetes were identified among 25,166 participants. After adjustment for sex, age, waist circumference, and lifestyle risk factors, persons with reported gallstones (n = 3,293) had an increased risk of type 2 diabetes (relative risk = 1.42, 95% confidence interval: 1.21, 1.68). Among the 23,817 participants with information on reported kidney stones (784 cases of incident diabetes), those who developed kidney stones (n = 2,468) were not at increased risk of diabetes in multivariable-adjusted models (relative risk = 1.05, 95% confidence interval: 0.86, 1.27). These findings suggest that gallstones, but not kidney stones, may predict the risk of developing type 2 diabetes, providing physicians with an interventional opportunity to implement adequate prevention measures.

• Expression profile of the polycomb group protein enhancer of zeste homologue 2 and its prognostic relevance in renal cell carcinoma.

  Authors: Stefan Hinz, Steffen Weikert, Ahmed Magheli, Michèle Hoffmann, Rainer Engers, Kurt Miller, Carsten Kempkensteffen

  The Journal of urology. 12/2009; 182(6):2920-5.

  PURPOSE: EZH2 increases the proliferation rate and apoptosis resistance of renal cell carcinoma cell lines. To date its clinical impact on the outcome in patients with renal cell carcinoma is notPURPOSE: EZH2 increases the proliferation rate and apoptosis resistance of renal cell carcinoma cell lines. To date its clinical impact on the outcome in patients with renal cell carcinoma is not known. To our knowledge this is the first study of the association of EZH2 expression with histopathological features and disease outcomes in a large cohort of patients who underwent surgery for renal cell carcinoma. MATERIALS AND METHODS: Real-time reverse transcriptase-polymerase chain reaction was done to quantify EZH2 expression in malignant and adjacent benign renal tissue from a cohort of 119 patients with clear cell renal cell carcinoma. Median followup was 51 months. Immunohistochemistry was performed in a subset of samples. The impact of EZH2 expression on clinicopathological tumor features and outcome was investigated. RESULTS: EZH2 was over expressed in renal cell carcinoma compared to adjacent benign renal parenchyma (median 57.02, range 0 to 368.11 vs 0, range 0 to 280.87, p <0.001). Immunohistochemistry showed concordant results and revealed EZH2 protein predominantly located in the nucleus. EZH2 expression was not associated with histopathological tumor features and patient characteristics. High EZH2 levels predicted a lower disease recurrence rate on univariate and multivariate analysis (p = 0.047 and 0.037, respectively). CONCLUSIONS: These data support a role of EZH2 expression for renal cell carcinoma tumorigenesis rather than tumor progression. Contrary to previous EZH2 findings in cases of various human malignancies, high tumor EZH2 levels appear to indicate less aggressive tumor phenotypes with a favorable prognosis in renal cell carcinoma cases. Our findings suggest that EZH2 provides not only a potential therapeutic target, but also a molecular parameter for outcome prediction in patients with renal cell carcinoma.

• Metabolic profiling reveals key metabolic features of renal cell carcinoma.

  Authors: Gareth Catchpole, Alexander Platzer, Cornelia Weikert, Carsten Kempkensteffen, Manfred Johannsen, Hans Krause, Klaus Jung, Kurt Miller, Lothar Willmitzer, Joachim Selbig, Steffen Weikert

  Journal of cellular and molecular medicine. 10/2009;

  Abstract Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach wasAbstract Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumors. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. Alpha-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate, and glucose-1-phosphate contributed most to the tumor/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumor versus normal samples. Data on metastasized tumors suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil, and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid, and myoinositol, provide leads for the characterization of novel pathways in RCC.