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To validate the risk stratification algorithm of the Prostate Imaging Reporting and Data System (PI-RADSv2) for intermediary risk lesions (PI-RADSv2 category 3) in the peripheral zone based on focal contrast enhancement and to compare cancer rates in category 3, upgraded category 4 and category 4 based on markedly low ADC value.We retrospectively analyze 172 consecutive patients undergoing prostate MRI with 315 histopathologically verified lesions. We select all lesions either assigned category 3 or category 4 in the peripheral zone for further analysis. We compare cancer rates with the two-sided chi-squared test. To determine inter-observer agreement about contrast enhancement two blinded radiologists evaluate the subset of category 3 lesions based on the diffusion weighted sequence.The frequency of peripheral PI-RADS 3, upgraded PI-RADS 4 and PI-RADS 4 lesions based on markedly low ADC value is 10.8%, 10.8% and 20.3%, respectively. Cancer rates (significant cancer only) in these subgroups are 8.8% (3/34), 23.5% (8/34) and 40.6% (26/64), P 0.01. Inter-observer agreement is moderate for evaluation of contrast enhancement with kappa values between 0.46 and 0.5.We demonstrate a trend of increasing cancer rate from PI-RADSv2 category 3 to upgraded category 4 to category 4 based on markedly low ADC value. Peripheral lesions of intermediary risk in the diffusion weighted sequence account for 21.6% of all prostate lesions encountered. Since it is likely that patient management recommendations will be linked to assessment categories in future versions of PI-RADS, cancer rates in upgraded category 4 and category 4 based on markedly low ADC values should be in a similar range. We conclude that in future studies of PI-RADSv2 upgraded category 4 and category 4 based on markedly low ADC value should be reported separately to generate a database for meta-analysis of cancer rates.

Accurate detection of prostate cancer lymph node metastases (LNM) through PET/CT before lymphadenectomy is crucial for successful therapy. PET/CT with choline derivatives used to be the standard tool for imaging metastases, whereas (68)Ga-PSMA (prostate-specific membrane antigen) PET/CT was introduced recently. Both PET techniques were investigated with respect to what extent the detection rate of LNM depends on the size of tumor deposits (TDs) within LNM. Methods: Documenting the switch from the use of (18)F-choline to (68)Ga-PSMA in 2014, we used 2 patient cohorts undergoing a template lymphadenectomy because of a PET/CT indicating LNM. Forty-four and 40 patients underwent PET/CT with (18)F-choline or (68)Ga-PSMA ligand, respectively. In total, 226 LNM (125 (18)F-choline, 101 (68)Ga-PSMA) originated from 73 salvage lymphadenectomies at biochemical recurrence and from 11 primary lymphadenectomies at radical prostatectomy. LNM eligible for direct correlation of PET/CT to histopathology were identified from lymphadenectomies conducted in small anatomic subregions, with 1 LNM (condition 1) or 1–2 LNM (condition 2). Longitudinal and short diameters of TD within LNM were determined by histopathology, allowing linking of the size of TD in LNM to the detection threshold of PET/CT. Diameters associated with a detection rate of 50% and 90% (d(50%), d(90%)) were calculated on the basis of logistic growth curve models fitted. Results: Gleason score, number of removed LNs, and subregions for lymphadenectomy per patient did not differ significantly between the (18)F-choline and (68)Ga-PSMA groups. The median prostate-specific antigen level at imaging and number of LNM per patient were significantly higher in the (18)F-choline group (3.4 ng/mL, n = 34) than in the (68)Ga-PSMA group (2.2 ng/mL, n = 28; both P < 0.05). Longitudinal and short diameters of TD in LNM to reach d(90%) were 11.2 and 7.4 mm, respectively, for (18)F-choline PET/CT and 6.3 and 4.9 mm, respectively, for (68)Ga-PSMA PET/CT. Corresponding diameters to reach d(50%) were 5.5 and 3.3 mm, respectively, for (18)F-choline PET/CT and 3.7 and 2.3 mm, respectively, for (68)Ga-PSMA PET/CT. Detection rates were significantly higher under (68)Ga-PSMA (P = 0.005 and 0.04 for longitudinal and short diameter). Conclusion: (68)Ga-PSMA PET/CT is superior to (18)F-choline PET/CT in the detection of LNM. Whether those results will lead to an improved patient outcome after (68)Ga-PSMA PET–guided therapy needs to be investigated by further studies.

To examine the diagnostic performance of PI-RADSv2 T2w and diffusion weighted imaging (DWI) based lexicon descriptors, inter-observer agreement for descriptor assignment and diagnostic accuracy of the PI-RADSv2 assessment categories for multiparametric prostate MRI.176 lesions in 79 consecutive patients are analyzed, lesions are histopathologically verified by MRI-ultrasound fusion biopsy. All lesions are rated according to the PI-RADSv2 lexicon, descriptors for T2w and DWI sequences and resulting assessment categories are assigned by two independent blinded radiologists. We perform receiver-operating-characteristic analysis using the assessment categories. To analyze inter-observer agreement, we calculate weighted kappa values for assessment category assignment and unweighted kappa values for descriptor assignment.PI-RADSv2 assessment categories yield an area under the curve of 0.76/0.74 (radiologist 1/radiologist 2), P0.05. Weighted kappa for agreement is 0.601 in the peripheral zone and 0.580 in the transition zone. We detect a difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone (32%) and transition zone (12%), P0.05. We obtain moderate agreement at most for descriptor assignment with kappa values ranging from 0.082 (T2w shape in the transition zone) to 0.407 (T2w signal intensity in the peripheral zone) and 0.493 (ADC pattern in the peripheral zone). Our analysis corroborates typical descriptors for benign/malignant lesions, but also reveals insights into potential pitfalls - T2w wedge shaped lesions in the peripheral zone have a considerable cancer rate, despite being labelled category 2 in the lexicon.Agreement for descriptor assignment in the PI-RADSv2 lexicon is at most moderate in our study. Typical descriptors for benign and malignant lesions are validated, whereas the discriminatory power of some descriptors is challenged. The difference in the cancer rate for PI-RADSv2 category 3 between peripheral zone and transition zone should be considered when management recommendations are linked to assessment categories in the future.

// Cordula A. Jilg 1 , Anett Ketscher 1, 2 , Eric Metzger 1 , Barbara Hummel 1 , Dominica Willmann 1 , Vanessa Russeler 1, 3 , Vanessa Drendel 4 , Axel Imhof 5 , Manfred Jung 6 , Henriette Franz 1 , Stefanie Holz 1, 2 , Malte Kronig 1 , Judith M. Muller 1 , Roland Schule 1, 7, 8 1 Urologische Klinik und Zentrale Klinische Forschung, Klinikum der Universitat Freiburg, Freiburg 79106, Germany 2 University of Freiburg, Faculty of Biology, Freiburg 79104, Germany 3 Universitatsklinikum Koln, Institut fur Pathologie, Koln 50937, Germany 4 Department of Pathology, University Medical Center, Freiburg, Germany 5 Adolf-Butenandt Institute and Munich Center of Integrated Protein Science (CIPS), Ludwig-Maximilians-University of Munich, Munich 80336, Germany 6 Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg 79104, Germany 7 BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg, Germany 8 Deutsches Konsortium fur Translationale Krebsforschung (DKTK), Standort Freiburg, Germany Correspondence to: R. Schule, e-mail: roland.schuele@uniklinik-freiburg.de Received: August 06, 2014 Accepted: October 26, 2014 Published: December 10, 2014 ABSTRACT The major threat in prostate cancer is the occurrence of metastases in androgen-independent tumor stage, for which no causative cure is available. Here we show that metastatic behavior of androgen-independent prostate tumor cells requires the protein-kinase-C-related kinase (PRK1/PKN1) in vitro and in vivo . PRK1 regulates cell migration and gene expression through its kinase activity, but does not affect cell proliferation. Transcriptome and interactome analyses uncover that PRK1 regulates expression of migration-relevant genes by interacting with the scaffold protein sperm-associated antigen 9 (SPAG9/JIP4). SPAG9 and PRK1 colocalize in human cancer tissue and are required for p38-phosphorylation and cell migration. Accordingly, depletion of either ETS domain-containing protein Elk-1 (ELK1), an effector of p38-signalling or p38 depletion hinders cell migration and changes expression of migration-relevant genes as observed upon PRK1-depletion. Importantly, a PRK1 inhibitor prevents metastases in mice, showing that the PRK1-pathway is a promising target to hamper prostate cancer metastases in vivo . Statement of significance Here we describe a novel mechanism controlling the metastatic behavior of PCa cells and identify PRK1 as a promising therapeutic target to treat androgen-independent metastatic prostate cancer.

Background: We examined whether or not extended prophylaxis with low molecular weight heparin (LMWH) would significantly reduce thromboembolic event (TEE) rates in germ cell cancer patients undergoing cisplatin-based chemotherapy. Patients and Methods: LMWH prophylaxis was given from the first day of chemotherapy until 21 days after completing the last chemotherapy cycle to 45 out of 93 (48.4%) patients (extended), and to 48 out of 93 (51.6%) patients during their hospitalization only (limited) between January 2008 and December 2013. Patients were analyzed retrospectively for TEEs such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) or peripheral arterial thrombosis. Results: A total of 22/93 (23.7%) patients experienced 30 TEE during chemotherapy: 12 out of 30 (40%) deep vein thrombosis, 4 out of 30 (13.3%) MI, 10 out of 30 (33.3%) PE and 4 out of 30 peripheral arterial thrombosis (13.3%). TEE rates in both groups did not differ significantly (extended: 26.7 vs. limited: 20.8%). Conclusions: The introduction of extended LMWH prophylaxis did not significantly reduce TEE rates in our patient cohort.

// Malte Kronig 1 , Max Walter 1 , Vanessa Drendel 2 , Martin Werner 2 , Cordula A. Jilg 1 , Andreas S. Richter 3, 4 , Rolf Backofen 3 , David McGarry 1 , Marie Follo 5 , Wolfgang Schultze-Seemann 1 , Roland Schule 1 1 Medical Center, University of Freiburg, Department of Urology, 79106 Freiburg, Germany 2 Medical Center, University of Freiburg, Department of Pathology, 79106 Freiburg, Germany 3 University of Freiburg, Department of Computer Science, 79110 Freiburg, Germany 4 Max Planck Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany 5 Medical Center, University of Freiburg, Department of Medicine I, 79106 Freiburg, Germany Correspondence to: Roland Schule, e-mail: roland.schuele@uniklinik-freiburg.de Keywords: prostate cancer, RNA detection, living cells, needle biopsy, gene expression, tumor heterogeneity Received: August 06, 2014 Accepted: November 11, 2014 Published: December 01, 2014 ABSTRACT A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer.

Nodal pelvic/retroperitoneal recurrent prostate cancer (PCa) after primary therapy can be treated with salvage lymph node dissection (salvage-LND) in order to delay disease progression and offer cure for a subset of patients. Whether adjuvant radiotherapy (ART) in affected regions improves the outcome by elimination of residual tumour burden remains unclear. A total of 93 patients with exclusively nodal PCa relapse underwent choline-positron-emission tomography-computed-tomography-directed pelvic/retroperitoneal salvage-LND; 46 patients had surgery only and 47 patients received ART in regions with proven lymph node metastases. In case of subsequent prostate specific antigen (PSA) progression, different imaging modalities were performed to confirm next relapse within or outside the treated region (TR). Mean follow-up was 3.2 years. Lymphatic tumour burden was balanced between the two groups. Additional ART resulted in delayed relapse within TR (5-year relapse-free rate 70.7 %) versus surgery only (5-year relapse-free rate 26.3 %, p

Objective In lethal primary metastatic prostate cancer, biopsy material is often the only accessible cancer tissue. Lack of tissue quantity limited the use of biopsy cores for analyzing higher numbers of molecular markers and standard histopathologic evaluation for clinical diagnosis simultaneously. Recent advances in single cell analytics have paved the way to characterize a tumor in more depth from minute input material such as biopsies. We therefore aimed to develop a biopsy needle, which generates two cores side by side from the same punch: one for standard histopathologic analysis to allow for routine diagnostics and the second one for single cell analytics. Methods On the basis of a conventional punch biopsy needle we have milled two parallel longitudinal rifts into the needles shat which are separated by a 100 µm thick metal sheet. Each rift can harbor a single tissue core. Results Two cores from the same punch were generated reproducibly from a radical prostatectomy specimen and showed congruent results in histopathologic analysis. Both cores yielded equally sufficient material for standard H&E staining and histopathological evaluation. Conclusion Our modified biopsy system will allow for simultaneous acquisition of tissue cores for diagnostic and scientific analysis from solid tumors or metastatic sites.