Wolfgang Schultze-Seemann

Von Hippel–Lindau disease (VHL) is a hereditary disorder associated with malignant tumors including clear cell renal cell carcinoma (ccRCC). Partial nephrectomy is complicated by multilocular tumor occurrence and a high recurrence rate. The aim of this study was to evaluate the potential of stereotactic body radiotherapy (SBRT) as an alternative treatment approach in VHL patients with multiple ccRCC. Patients with VHL and a diagnosis of ccRCC were enrolled. SBRT was conducted using five fractions of 10 Gy or eight fractions of 7.5 Gy. The primary endpoint was local control (LC). Secondary endpoints included alteration of renal function and adverse events. Seven patients with a total of eight treated lesions were enrolled. Median age was 44 years. Five patients exhibited multiple bilateral kidney cysts in addition to ccRCC. Three patients underwent at least one partial nephrectomy in the past. After a median follow-up of 43 months, 2-year LC was 100%, while 2-year CSS, 2-year PFS and 2-year OS was 100%, 85.7% and 85.7%, respectively. SBRT was very well tolerated with no acute or chronic toxicities grade ≥ 2. Mean estimated glomerular filtration rate (eGFR) at baseline was 83.7 ± 13.0 mL/min/1.73 m², which decreased to 76.6 ± 8.0 mL/min/1.73 m² after 1 year. Although the sample size was small, SBRT resulted in an excellent LC rate and was very well tolerated with preservation of kidney function in patients with multiple renal lesions and cysts.

Background: Systematic biopsy (SB) according to the Ginsburg scheme (GBS) is widely used to complement MRI-targeted biopsy (MR-TB) for optimizing the diagnosis of clinically significant prostate cancer (sPCa). Knowledge of the GBS’s blind sectors where sPCa is missed is crucial to improve biopsy strategies. Methods: We analyzed cancer detection rates in 1084 patients that underwent MR-TB and SB. Cancerous lesions that were missed or underestimated by GBS were re-localized onto a prostate map encompassing Ginsburg sectors and blind-sectors (anterior, central, basodorsal and basoventral). Logistic regression analysis (LRA) and prostatic configuration analysis were applied to identify predictors for missing sPCa with the GBS. Results: GBS missed sPCa in 39 patients (39/1084, 3.6%). In 27 cases (27/39, 69.2%), sPCa was missed within a blind sector, with 17/39 lesions localized in the anterior region (43.6%). Neither LRA nor prostatic configuration analysis identified predictors for missing sPCa with the GBS. Conclusions: This is the first study to analyze the distribution of sPCa missed by the GBS. GBS misses sPCa in few men only, with the majority localized in the anterior region. Adding blind sectors to GBS defined a new sector map of the prostate suited for reporting histopathological biopsy results.

Background/Aim: The combination of bevacizumab (BEV) plus interferon alpha-2a (IFN) constitutes an option for first-line treatment of metastatic renal cell carcinoma. Real-world data from routine clinical practice are rare and were, therefore, collected during this non-interventional study (NIS). Patients and Methods: A total of 359 patients received at least one dose of BEV (safety set population; SAF), 354 patients had at least one post-dose effectiveness assessment and formed the full analysis set (FAS) of the final analysis. Results: Progression-free survival (10.2 months, 95% CI=8.6-12.6) and overall response rate (27.2%) outcomes match the results from the phase III trials AVOREN and CALGB 90206. Longer overall survival (28.7 months, 95% CI=24.5-38.3) probably is an effect of patient characteristics and follow-up therapies. Safety findings were comparable to the results of the Phase III trials, although comprehensive severity assessments were not provided. Conclusion: Overall, efficacy and safety data from BEV plus IFN administered in routine clinical practice in an observational NIS are in line with results from the controlled phase III trials. (NCT02627144)

We evaluated the influence of comorbidity inferred risks for lymph node metastasis (pN1) and positive surgical margins (R1) after radical prostatectomy in order to optimize pretherapeutic risk classification. We analyzed 454 patients after radical prostatectomy (RP) between 2009 and 2014. Comorbidities were defined by patients’ medication from our electronic patient chart and stratified according to the ATC WHO code. Endpoints were lymph node metastasis (pN1) and positive surgical margins (R1). Rates for pN1 and R1 were 21.4% (97/454) and 29.3% (133/454), respectively. In addition to CAPRA and Gleason score, we identified diabetes as a significant medication inferred risk factor for pN1 (OR 2.9, p = 0.004/OR 3.2, p = 0.001/OR 3.5, p = 0.001) and beta-blockers for R1 (OR 1.9, p = 0.020/OR 2.9, p = 0.004). Patients with diabetes showed no statistically significant difference in Gleason score, CAPRA Score, PSA, and age compared to non-diabetic patients. We identified diabetes and beta1 adrenergic blockage as significant risk factors for lymph node metastasis and positive surgical margins in prostate cancer (PCa). Patients at risk will need intensive pretherapeutic staging for optimal therapeutic stratification.

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. 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. 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. Our modified biopsy system will allow for simultaneous acquisition of tissue cores for diagnostic and scientific analysis from solid tumors or metastatic sites.

Background CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer. Methods 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3–6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17. Results The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a]. Conclusions The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach. Trial registration EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009.

In a previous study we demonstrated that, based on 11C/18 F-choline positron emission tomography-computerized-tomography as a diagnostic tool, salvage lymph node dissection (LND) plus adjuvant radiotherapy (ART) is feasible for treatment of pelvic/retroperitoneal nodal recurrence of prostate cancer (PCa). However, the toxicity of this combined treatment strategy has not been systematically investigated before. The aim of the current study was to evaluate the acute and late toxicity and quality of life of ART after LND in pelvic/retroperitoneal nodal recurrent PCa. 43 patients with nodal recurrent PCa were treated with 46 LND followed by ART (mean 49.6 Gy total dose) at the sites of nodal recurrence. Toxicity of ART was analysed by physically examination (31/43, 72.1%), by requesting 15 frequent items of adverse events from the Common-Terminology-Criteria for Adverse Events Version 4.0-catalogue and by review of medical records. QLQ-C30 (EORTC quality of life assessment) and PR25 (prostate cancer module) questionnaires were used to investigate quality of life. Toxicity was evaluated before starting of ART, during ART (acute toxicity), after ART (mean 2.3 months) and at end of follow up (mean 3.2 years after end of ART) reflecting late toxicity. 71.7% (33/46) of 46 ART were treatment of pelvic, 10.9% (5/46) of retroperitoneal only and 28.3% (13/46) of pelvic and retroperitoneal regions. Overall 52 symptoms representing toxicities were observed before ART, 107 during ART, 88 after end of ART and 52 at latest follow up. Leading toxicities during ART were diarrhoea (19%, 20/107), urinary incontinence (16%, 17/107) and fatigue (16%, 17/107). The spectrum of late toxicities was almost equal to those before beginning of ART. No grade 3 adverse events or chronic lymphedema at extremities were observed. We observed no clear correlation between localisation of treated regions, technique of ART and frequency or severity of toxicities. Mean quality of life at final evaluation was 74%. ART after extended LND in PCa relapse is justifiable with respect to adverse effects and toxicity. The side effects were circumscribed and well tolerated. The spectrum of adverse events at latest follow up was almost equal to those before start of ART.

To evaluate the value of dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) without endorectal coil (EC) in the detection of local recurrent prostate cancer (PC) after radical prostatectomy (RP). Thirty-three patients with recurrent PC underwent DCE-MRI without EC before salvage radiotherapy (RT). At median 15 (mean 16±4.9, range 12-27) months after completion of RT all patients showed complete biochemical response. Additional follow up post RT DCE-MRI scans were available. Prostate specific antigen (PSA) levels at the time of imaging were correlated to the imaging findings. In 22/33 patients (67%) early contrast enhancing nodules were detected in the post-prostatectomy fossa on pre-RT DCE-MRI images. The average pre-RT PSA level of the 22 patients with positive pre-RT DCE-MRI findings was significantly higher (mean, 0.74±0.64 ng/mL) compared to the pre-RT PSA level of the 11 patients with negative pre-RT DCE-MRI (mean, 0.24±0.13 ng/mL) (p<0.001). All post-RT DCE-MRI images showed complete resolution of initial suspicious lesions. A pre-RT PSA cut-off value of ≥0.54 ng/ml readily predicted a positive DCE-MRI finding. This is the first study that shows that DCE-MRI without EC can detect local recurrent PC with an estimated accuracy of 83% at low PSA levels. All false negative DCE-MRI scans were detected using a PSA cut-off of ≥0.54 ng/mL.