Jonas Busch

Publications of Jonas Busch

• 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.

• 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.

• Residual tumor size and IGCCCG risk classification predict additional vascular procedures in patients with germ cell tumors and residual tumor resection: a multicenter analysis of the German Testicular Cancer Study Group.

  Authors: Christian Winter, David Pfister, Jonas Busch, Cigdem Bingöl, Ulrich Ranft, Mark Schrader, Klaus-Peter Dieckmann, Axel Heidenreich, Peter Albers

  European urology. 11/2011; 61(2):403-9.

  Residual tumor resection (RTR) after chemotherapy in patients with advanced germ cell tumors (GCT) is an important part of the multimodal treatment. To provide a complete resection of residual tumor,Residual tumor resection (RTR) after chemotherapy in patients with advanced germ cell tumors (GCT) is an important part of the multimodal treatment. To provide a complete resection of residual tumor, additional surgical procedures are sometimes necessary. In particular, additional vascular interventions are high-risk procedures that require multidisciplinary planning and adequate resources to optimize outcome. The aim was to identify parameters that predict additional vascular procedures during RTR in GCT patients. A retrospective analysis was performed in 402 GCT patients who underwent 414 RTRs in 9 German Testicular Cancer Study Group (GTCSG) centers. Overall, 339 of 414 RTRs were evaluable with complete perioperative data sets. The RTR database was queried for additional vascular procedures (inferior vena cava [IVC] interventions, aortic prosthesis) and correlated to International Germ Cell Cancer Collaborative Group (IGCCCG) classification and residual tumor volume. In 40 RTRs, major vascular procedures (23 IVC resections with or without prosthesis, 11 partial IVC resections, and 6 aortic prostheses) were performed. In univariate analysis, the necessity of IVC intervention was significantly correlated with IGCCCG (14.1% intermediate/poor vs 4.8% good; p=0.0047) and residual tumor size (3.7% size < 5 cm vs 17.9% size ≥ 5 cm; p < 0.0001). In multivariate analysis, IVC intervention was significantly associated with residual tumor size ≥ 5 cm (odds ratio [OR]: 4.61; p=0.0007). In a predictive model combining residual tumor size and IGCCCG classification, every fifth patient (20.4%) with a residual tumor size ≥ 5 cm and intermediate or poor prognosis needed an IVC intervention during RTR. The need for an aortic prosthesis showed no correlation to either IGCCCG (p=0.1811) or tumor size (p=0.0651). The necessity for IVC intervention during RTR is correlated to residual tumor size and initial IGCCCG classification. Patients with high-volume residual tumors and intermediate or poor risk features must initially be identified as high-risk patients for vascular procedures and therefore should be referred to specialized surgical centers with the ad hoc possibility of vascular interventions.

• Reference genes for the relative quantification of microRNAs in renal cell carcinomas and their metastases.

  Authors: Zofia Wotschofsky, Helmuth-Alexander Meyer, Monika Jung, Annika Fendler, Ina Wagner, Carsten Stephan, Jonas Busch, Andreas Erbersdobler, Alexander C Disch, Hans-Joachim Mollenkopf, Klaus Jung

  Analytical biochemistry. 10/2011; 417(2):233-41.

  To obtain accurate results in miRNA expression changes between different sample sets using real-time quantitative polymerase chain reaction (RT-qPCR) analyses, normalization to reference genes thatTo obtain accurate results in miRNA expression changes between different sample sets using real-time quantitative polymerase chain reaction (RT-qPCR) analyses, normalization to reference genes that are stably expressed across the sample sets is generally used. A literature search of miRNA expression studies in renal cell carcinoma (RCC) proved that non-miRNAs such as small RNAs or mRNAs have most frequently been used without preceding validation of their suitability. In this study, the most stably expressed miRNAs were ascertained from microarray-based data of miRNA expression in nonmalignant and malignant samples from clear cell RCC and from corresponding distant RCC metastases using the geNorm and NormFinder algorithms. Validation experiments with RT-qPCR were performed for the four best-ranked miRNAs (miR-28, miR-103, miR-106a, miR-151) together with the small RNU6B, RNU44, and RNU48 mostly described in literature. miR-28, miR-103, miR-106a, and RNU48 were proved as the most stably expressed genes. miR-28 is recommended as normalizer if only a single reference gene can be used, while the combinations of miR-28 and miR-103 or of miR-28, miR-103, and miR-106a, respectively, are preferred. RNU6B most frequently used as normalizer in miRNA expression studies should be abandoned in order to avoid misleading results.

• 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.

• 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.

• 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.

• Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors.

  Authors: Annika Schaefer, Carsten Stephan, Jonas Busch, George M Yousef, Klaus Jung

  Nature reviews. Urology. 04/2010; 7(5):286-97.

  MicroRNAs (miRNAs) are small, non-coding RNAs that have an important role in the regulation of carcinogenic pathways. The observations that miRNAs are differentially expressed in tumor versusMicroRNAs (miRNAs) are small, non-coding RNAs that have an important role in the regulation of carcinogenic pathways. The observations that miRNAs are differentially expressed in tumor versus corresponding normal tissue, and that they regulate important breakpoints during carcinogenesis, are of interest for urologic oncologists. As biomarkers, they might be helpful tools for diagnostic, prognostic and monitoring purposes. Furthermore, miRNAs might be potential targets for novel therapeutic strategies, especially in patients with tumor subtypes that do not respond to currently available therapies. In this Review, we will focus on the current proceedings of miRNA research in urologic tumors. In the past decade, the number of published articles related to miRNAs in urologic oncology has increased, highlighting the ongoing importance of miRNAs in this field. Current studies support the hypothesis that miRNA will gain influence in clinical practice. Here, therefore, we illustrate the current knowledge of miRNA function in urologic tumors and draw the attention of urologists to the future opportunities and challenges of this research field.

• Off-pump exchange of short-term percutaneous ventricular assist device (VAD) to long-term implantable VAD in severe coagulopathy and multi-organ failure.

  Authors: Jonas Busch, Zbiguiew Wojciechowski, Guillermo Torre-Amione, Matthias Loebe

  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 06/2008; 27(5):572-4.

  Ventricular support in patients with end-stage heart failure can be achieved using intracorporeal left ventricular assist device (LVAD) or percutaneous ventricular assist device (pVAD) systems.Ventricular support in patients with end-stage heart failure can be achieved using intracorporeal left ventricular assist device (LVAD) or percutaneous ventricular assist device (pVAD) systems. Multiple efforts have been made to minimize procedure-associated complications. We present a case report of an off-pump insertion of a MicroMed DeBakey VAD after Tandem Heart support using a previous sternotomy incision. A 47-year-old woman with end-stage heart failure after coronary artery bypass graft revascularization was admitted for pharmacologic treatment. She developed multi-organ failure and a severe coagulopathy with thromboembolic complications. Heparin-induced thrombocytopenia (HIT) was suspected. A percutaneous Tandem Heart was placed, the patient's condition stabilized, and finally a MicroMed DeBakey Child VAD was implanted off-pump, re-opening a previous sternotomy incision. To avoid the need for heparinization in the light of HIT and severe coagulopathy, the LVAD implantation was performed under Tandem Heart support without cardiopulmonary bypass. The patient has been anti-coagulated with angiomax ever since. Critically ill patients with end-stage heart disease, multi-organ failure, severe coagulopathy and a previous median sternotomy can be bridged from a Tandem Heart to MicroMed DeBakey VAD without cardiopulmonary bypass using the previous incision, provided there are few adhesions and stable hemodynamic conditions.

• TandemHeart Insertion via a Femoral Arterial GORE-TEX Graft Conduit in a High-Risk Patient.

  Authors: Jonas Busch, Guillermo Torre-Amione, George P Noon, Matthias Loebe

  Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 02/2008; 35(4):462-5.

  The TandemHeart(R) percutaneous ventricular assist device (pVAD), which provides temporary circulatory support of the left ventricle, can be used in high-risk and hemodynamically unstable patients.The TandemHeart(R) percutaneous ventricular assist device (pVAD), which provides temporary circulatory support of the left ventricle, can be used in high-risk and hemodynamically unstable patients. The easily inserted TandemHeart provides cardiac support superior to that from the use of intra-aortic balloon pumps. Herein, we discuss TandemHeart implantation via end-to-side femoral arterial grafting in a cardiac patient whose sepsis and multiorgan failure were complicated by coagulopathy and thromboembolism.A 47-year-old woman, on intra-aortic balloon and intravenous inotropic support after an acute myocardial infarction and emergency coronary artery bypass grafting, was transferred to our institution via helicopter. She developed sepsis and multiorgan failure. Her condition was further complicated by coagulopathy and a left-lower-extremity thromboembolism. After 6 weeks of aggressive pharmacologic and intermittent intra-aortic balloon treatment, the patient developed cardiogenic shock and received a TandemHeart pVAD for short-term circulatory support. A GORE-TEX(R) access graft, sewn end-to-side to the femoral artery because of the patient's leg ischemia and very small vessels, served as a conduit for the TandemHeart's femoral arterial inflow cannula. Her difficult circulatory, anatomic, and coagulopathic status stabilized after 2 weeks of TandemHeart support, and she was bridged to the long-term MicroMed DeBakey VAD(R) Child in anticipation of heart transplantation.The case of our patient shows that high-risk patients who have experienced cardiogenic shock with multiorgan failure and coagulopathy can benefit from the TandemHeart pVAD as a bridge to other therapeutic options, even when creative approaches to treatment and to TandemHeart insertion are required.