Jonas Busch

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377–1399; Krege S, Beyer J, Souchon R et al. 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. Eur Urol 2008; 53: 478–496; Krege S, Beyer J, Souchon R et al. 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. Eur Urol 2008; 53: 497–513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

Diagnostic, prognostic and therapeutic implications of microRNAs in urologic tumors

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 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.

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

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 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.

Diagnostic and prognostic potential of differentially expressed miRNAs between metastatic and non-metastatic renal cell carcinoma at the time of nephrectomy

BACKGROUND MicroRNAs are promising diagnostic and prognostic biomarkers in oncology. We aimed to evaluate the prognostic potential of selected microRNAs in primary clear cell renal cell carcinomas (ccRCC) as predictors of tumor recurrence after radical nephrectomy. METHODS miR-122, miR-141, miR-155, miR-184, miR-200c, miR-210, miR-224, and miR-514, validated as differentially expressed in a previous study, were measured by RT-PCR in matched malignant and non-malignant tumor samples after nephrectomy from 111 patients (89 without, 22 with metastases) and clinicopathological and outcome data were collected. Non-parametric statistical tests, receiver-operating characteristics, Kaplan-Meier-, and univariate as well as multivariate Cox regression analyses were performed. RESULTS Downregulation of miR-141/-184/-200c/-514 and upregulation of miR-122/-155/-210/-224 were not different between samples of non-metastatic and metastatic tumors except for miR-122 and miR-514. miR-514 was further downregulated in metastatic compared with non-metastatic tumors while the upregulation of miR-122 was significantly reduced in metastatic carcinomas. All miRNAs were suitable to discriminate malignant from non-malignant tissue. miR-122 and miR-514 were significantly related to the recurrence risk but only miR-514 provided independent prognostic information in the final model including relevant clinicopathological variables. CONCLUSIONS MiR-122 and miR-514 play a role in tumor recurrence after nephrectomy. Expression of miR-514 was particularly downregulated in primary metastatic tumor and those that recur and might be a suitable adjunct marker for predicting tumor recurrence.

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

BACKGROUND 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. OBJECTIVES The aim was to identify parameters that predict additional vascular procedures during RTR in GCT patients. DESIGN, SETTING, AND PARTICIPANTS 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. MEASUREMENTS 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. RESULTS AND LIMITATIONS 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). CONCLUSIONS 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.

Sequence Therapy in Patients with Metastatic Renal Cell Carcinoma: Comparison of Common Targeted Treatment Options Following Failure of Receptor Tyrosine Kinase Inhibitors

BACKGROUND The best sequence of targeted therapy in patients with metastatic renal cell carcinoma (mRCC) has not been sufficiently defined. OBJECTIVE To describe the efficacy and toxicity of sequential everolimus (EV) versus receptor tyrosine kinase inhibitor (rTKI) following failure of first rTKI treatment. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 108 patients receiving rTKI or EV after progression on rTKI therapy at two German academic centres. INTERVENTION 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). MEASUREMENTS 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). RESULTS AND LIMITATIONS 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. CONCLUSIONS 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.

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

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 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 8.4 months (95% confidence interval 5.8-11) associated with a median OS of 28.2 months (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 3.7 months 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 6 months taken as cut-off parameter and second line treatment as prognostic variables. Multivariate analyses proved first line PFS above 6 months (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.

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

Background: 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. Patients and Methods: 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. Results: 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. Conclusions: 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.

Iodinated contrast media cause endothelial damage leading to vasoconstriction of human and rat vasa recta

Contrast-induced acute kidney injury is an important clinical event with a worldwide increasing number of cases. Medullary hypoperfusion and hypoxia due to constriction of vasa recta are main factors in the pathophysiology of acute kidney injury. However, the mechanism of contrast media (CM)-induced vessel constriction is not known. We tested the hypothesis that vasa recta constriction is a consequence of endothelial dysfunction due to the cytotoxicity of CM. Human and rat descending vasa recta (DVR) were isolated and perfused with CM, and the luminal diameter was analyzed. For morphological analysis of the endothelium, renal arteries were CM perfused and then processed for electron microscopy. Transcellular electrical resistance was used to estimate CM-induced changes in the permeability of human umbilical vein endothelial cell (HUVEC) layers. Perfusion with CM constricted human and rat DRV (to 54.3 and 50.9% of initial diameter, respectively). This was blunted by adrenomedullin (77.7 and 77.1%, respectively). The ANG II response was enhanced by CM in rat DVR (reduction to 15.6 and 35.0% of initial diameter, respectively). Adrenomedullin blunted this effect (67.5%). CM led to endothelial damage of renal arteries characterized by a ragged surface, with sharply protruding intimal folds, spindle-like shape, and bulging in the lumen. These phenomena were reduced by adrenomedullin. The permeability of HUVEC cell layers was increased by CM, and this went along with increased myosin light chain phosporylation. Again, adremonedullin reduced the CM effect. Our study suggests that the constrictor effect of CM on the renal medullary microvasculature is a consequence of endothelial cell damage and the resulting endothelial dysfunction.

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

BackgroundData on sequential therapy in patients with metastatic renal cell carcinoma (mRCC) and intrinsic resistance to receptor tyrosine kinase inhibitor (rTKI) treatment remains vague.MethodsWe retrospectively studied treatment characteristics and outcome of mRCC patients refractory to first rTKI therapy.ResultsThirty-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).ConclusionIntrinsic resistance to rTKI is associated with a low chance of response to sequential therapy and a poor prognosis in mRCC patients.