@article{KotlyarKrebsSolimandoetal.2023,
  author    = {Kotlyar, Mischa J. and Krebs, Markus and Solimando, Antonio Giovanni and Marquardt, Andr{\´e} and Burger, Maximilian and K{\"u}bler, Hubert and Bargou, Ralf and Kneitz, Susanne and Otto, Wolfgang and Breyer, Johannes and Vergho, Daniel C. and Kneitz, Burkhard and Kalogirou, Charis},
  title     = {Critical evaluation of a microRNA-based risk classifier predicting cancer-specific survival in renal cell carcinoma with tumor thrombus of the inferior vena cava},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {7},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15071981},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311040},
  year      = {2023},
  abstract  = {(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC\(^{IVC}\)) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier — containing miR-21-5p, miR-126-3p and miR-221-3p expression — which significantly predicted the cancer-specific survival (CSS) of ccRCC\(^{IVC}\) patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC\(^{IVC}\), we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan-Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan-Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC\(^{IVC}\) according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC\(^{IVC}\) cohort.},
  language  = {en}
}
@article{EckhardtSbieraKrebsetal.2022,
  author    = {Eckhardt, Carolin and Sbiera, Iuliu and Krebs, Markus and Sbiera, Silviu and Spahn, Martin and Kneitz, Burkhard and Joniau, Steven and Fassnacht, Martin and K{\"u}bler, Hubert and Weigand, Isabel and Kroiss, Matthias},
  title     = {High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer},
  series = {Prostate Cancer and Prostatic Diseases},
  volume    = {25},
  journal   = {Prostate Cancer and Prostatic Diseases},
  number    = {3},
  issn      = {1476-5608},
  doi       = {10.1038/s41391-021-00431-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271819},
  pages     = {484-490},
  year      = {2022},
  abstract  = {Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25\%) and low in 219 (75\%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14\%) and at low levels in 249 (86\%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95\% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95\% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.},
  language  = {en}
}
@article{KrebsSolimandoKalogirouetal.2020,
  author    = {Krebs, Markus and Solimando, Antonio Giovanni and Kalogirou, Charis and Marquardt, Andr{\´e} and Frank, Torsten and Sokolakis, Ioannis and Hatzichristodoulou, Georgios and Kneitz, Susanne and Bargou, Ralf and K{\"u}bler, Hubert and Schilling, Bastian and Spahn, Martin and Kneitz, Burkhard},
  title     = {miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro},
  series = {Journal of Clinical Medicine},
  volume    = {9},
  journal   = {Journal of Clinical Medicine},
  number    = {3},
  issn      = {2077-0383},
  doi       = {10.3390/jcm9030670},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203168},
  year      = {2020},
  abstract  = {Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.},
  language  = {en}
}
@article{KrebsBehrmannKalogirouetal.2019,
  author    = {Krebs, Markus and Behrmann, Christoph and Kalogirou, Charis and Sokolakis, Ioannis and Kneitz, Susanne and Kruithof-de Julio, Marianna and Zoni, Eugenio and Rech, Anne and Schilling, Bastian and K{\"u}bler, Hubert and Spahn, Martin and Kneitz, Burkhard},
  title     = {miR-221 Augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1},
  series = {BioMed Research International},
  volume    = {2019},
  journal   = {BioMed Research International},
  doi       = {10.1155/2019/6392748},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202480},
  pages     = {6392748},
  year      = {2019},
  abstract  = {miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.},
  language  = {en}
}
@article{KienerChenKrebsetal.2019,
  author    = {Kiener, Mirjam and Chen, Lanpeng and Krebs, Markus and Grosjean, Joȅl and Klima, Irena and Kalogirou, Charis and Riedmiller, Hubertus and Kneitz, Burkhard and Thalmann, George N. and Snaar-Jagalska, Ewa and Spahn, Martin and Kruithof-de Julio, Marianna and Zoni, Eugenio},
  title     = {miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo},
  series = {BMC Cancer},
  volume    = {19},
  journal   = {BMC Cancer},
  doi       = {10.1186/s12885-019-5819-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325762},
  year      = {2019},
  abstract  = {Background Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. Methods miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4-2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. Results Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. Conclusions Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.},
  language  = {en}
}
@article{MorisVandenBroeckToscoetal.2016,
  author    = {Moris, Lisa and Van den Broeck, Thomas and Tosco, Lorenzo and Van Baelen, Anthony and Gontero, Paolo and Karnes, Robert Jeffrey and Everaerts, Wouter and Albersen, Maarten and Bastian, Patrick J. and Chlosta, Piotr and Claessens, Frank and Chun, Felix K. and Graefen, Markus and Gratzke, Christian and Kneitz, Burkhard and Marchioro, Giansilvio and Salas, Rafael Sanchez and Tombal, Bertrand and Van Der Poel, Henk and Walz, Jochen Christoph and De Meerleer, Gert and Bossi, Alberto and Haustermans, Karin and Montorsi, Francesco and Van Poppel, Hendrik and Spahn, Martin and Briganti, Alberto and Joniau, Steven},
  title     = {Impact of lymph node burden on survival of high-risk prostate cancer patients following radical prostatectomy and pelvic lymph node dissection},
  series = {Frontiers in Surgery},
  volume    = {3},
  journal   = {Frontiers in Surgery},
  organization    = {European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT)},
  issn      = {2296-875X},
  doi       = {10.3389/fsurg.2016.00065},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195721},
  year      = {2016},
  abstract  = {Aim To determine the impact of the extent of lymph node invasion (LNI) on long-term oncological outcomes after radical prostatectomy (RP). Material and methods In this retrospective study, we examined the data of 1,249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer-specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD. Results Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7\% (n = 671). Final Gleason score (GS) was 2-6 in 12.7\% (n = 158), 7 in 52\% (n = 649), and 8-10 in 35.4\% (n = 442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1,128 (90.3\%) had 0-3 positive LNs, while 126 (9.7\%) had ≥4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87 vs. 50\%; p < 0.0001). Similar results were obtained for OS, with a 72 vs. 37\% (p < 0.0001) survival at 10 years for patients with 0-3 vs. ≥4 positive LNs, respectively. At multivariate analysis, final GS of 8-10, salvage ADT therapy, and ≥4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS. Conclusion Four or more positive LNs, pathological stage pT4, and final GS of 8-10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having ≥4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied.},
  language  = {en}
}
@article{LitovkinVanEyndeJoniauetal.2015,
  author    = {Litovkin, Kirill and Van Eynde, Aleyde and Joniau, Steven and Lerut, Evelyne and Laenen, Annouschka and Gevaert, Thomas and Gevaert, Olivier and Spahn, Martin and Kneitz, Burkhard and Gramme, Pierre and Helleputte, Thibault and Isebaert, Sofie and Haustermans, Karin and Bollen, Mathieu},
  title     = {DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer},
  series = {PLoS ONE},
  volume    = {10},
  journal   = {PLoS ONE},
  number    = {6},
  doi       = {10.1371/journal.pone.0130651},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151705},
  pages     = {e0130651},
  year      = {2015},
  abstract  = {Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95\% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95\% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95\% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.},
  language  = {en}
}
@article{HailerGrunewaldOrthetal.2014,
  author    = {Hailer, Amelie and Grunewald, Thomas G. P. and Orth, Martin and Reiss, Cora and Kneitz, Burkhard and Spahn, Martin and Butt, Elke},
  title     = {Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration},
  series = {Oncotarget},
  volume    = {5},
  journal   = {Oncotarget},
  number    = {12},
  issn      = {1949-2553},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120540},
  pages     = {4144-53},
  year      = {2014},
  abstract  = {Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.},
  language  = {en}
}
@article{VerghoKneitzKalogirouetal.2014,
  author    = {Vergho, Daniel Claudius and Kneitz, Susanne and Kalogirou, Charis and Burger, Maximilian and Krebs, Markus and Rosenwald, Andreas and Spahn, Martin and L{\"o}ser, Andreas and Kocot, Arkadius and Riedmiller, Hubertus and Kneitz, Burkhard},
  title     = {Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava},
  doi       = {10.1371/journal.pone.0109877},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113633},
  year      = {2014},
  abstract  = {Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.},
  language  = {en}
}
@article{VerghoKneitzRosenwaldetal.2014,
  author    = {Vergho, Daniel and Kneitz, Susanne and Rosenwald, Andreas and Scherer, Charlotte and Spahn, Martin and Burger, Maximilian and Riedmiller, Hubertus and Kneitz, Burkhard},
  title     = {Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma},
  doi       = {10.1186/1471-2407-14-25},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110061},
  year      = {2014},
  abstract  = {Background Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. Methods Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). Results RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. Conclusions A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.},
  language  = {en}
}
@article{KneitzKalogirouSpahnetal.2013,
  author    = {Kneitz, Burkhard and Kalogirou, Charis and Spahn, Martin and Krebs, Markus and Joniau, Steven and Lerut, Evelyne and Burger, Maximilian and Scholz, Claus-J{\"u}rgen and Kneitz, Susanne and Riedmiller, Hubertus},
  title     = {MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer},
  series = {International Journal of Molecular Sciences},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms141121414},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97321},
  year      = {2013},
  abstract  = {The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70\% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.},
  language  = {en}
}
@article{SchubertSpahnKneitzetal.2013,
  author    = {Schubert, Maria and Spahn, Martin and Kneitz, Susanne and Scholz, Claus J{\"u}rgen and Joniau, Steven and Stroebel, Philipp and Riedmiller, Hubertus and Kneitz, Burkhard},
  title     = {Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer},
  series = {PLoS ONE},
  journal   = {PLoS ONE},
  doi       = {10.1371/journal.pone.0065064},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96825},
  year      = {2013},
  abstract  = {Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.},
  language  = {en}
}
@article{SchubertJoniauGonteroetal.2012,
  author    = {Schubert, Maria and Joniau, Steven and Gontero, Paolo and Kneitz, Susanne and Scholz, Claus-J{\"u}rgen and Kneitz, Burkhard and Briganti, Alberto and Karnes, R. Jeffery and Tombal, Bertrand and Walz, Jochen and Hsu, Chao-Yu and Marchioro, Giansilvio and Bader, Pia and Bangma, Chris and Frohneberg, Detlef and Graefen, Markus and Schr{\"o}der, Fritz and van Cangh, Paul and van Poppel, Hein and Spahn, Martin},
  title     = {The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis},
  series = {Advances in Urology},
  volume    = {2012},
  journal   = {Advances in Urology},
  doi       = {10.1155/2012/612707},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137712},
  year      = {2012},
  abstract  = {Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n=86 ) or no adjuvant ADT (group 2, n=86). Results. Only 11.6\% of the patients died, 2.3\% PCa related. Estimated 5-10-year clinical progression-free survival was 96.9\% (94.3\%) for group 1 and 73.7\% (67.0\%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.},
  language  = {en}
}