Publications by authors named "Oliver W Hakenberg"

169 Publications

Flow-dependent differentiation of cultured adrenal cells under different stimuli.

Cell Tissue Res 2021 Mar 2. Epub 2021 Mar 2.

Division of Endocrinology and Metabolism, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057, Rostock, Germany.

It still remains unclear how the functional organisation of the adrenal cortex arises. One aim of this study was to create a setup which allows for the establishment of a concentration gradient in vitro. This was achieved by a continuous flow of medium through the culture flask which caused differences in glucose and cortisol concentrations as well as in pH values between the sites of inflow and outflow of medium. Using real-time polymerase chain reaction, we found that a continuous supply of 1 ml medium per hour significantly increased the expression of MC2R, CYP11B1 and CYP17A1 genes of NCI-H295R cells in the distal area of the flask as compared with the proximal part. The expression of the AT1R showed a reverse regulation. The addition of dexamethasone to the medium led to an increase in gene expression of MC2R while AT1R was downregulated. Moreover, we detected a higher expression of CYP11B2 and a decreased expression of CYP11B1 when endothelial cell-conditioned medium (ECCM) was added to the inflow. Our experiments show that a directed medium delivery system creates different gradients and affects the functional differentiation of the NCI-H295R cells. Also, our results emphasise that products of endothelial cells have additional effects on the differentiation of the cultured adrenal cortical cells. Our results are in support that the regulation of the adrenal zonation is possible through different concentration gradients.
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http://dx.doi.org/10.1007/s00441-021-03432-9DOI Listing
March 2021

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study.

Urol Int 2021 Feb 25:1-10. Epub 2021 Feb 25.

Department of Urology, Rostock University, Rostock, Germany.

Background: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice.

Objectives: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting.

Methods: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months.

Results: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%.

Conclusions: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.
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http://dx.doi.org/10.1159/000513073DOI Listing
February 2021

[Contemporary practice patterns in the treatment of Fournier's gangrene in German academic medicine and their implications for planning a registry study].

Urologe A 2021 Feb 9. Epub 2021 Feb 9.

Urologische Klinik und Poliklinik, Universitätsmedizin Rostock, Schillingallee 35, 18055, Rostock, Deutschland.

Background: Fournier's gangrene (FG) is a sporadic and life-threatening disease, but the outcome has not improved in recent years.

Objectives: The primary aim of this study was the description of current practice patterns in German academic medicine. The secondary aim was the identification of factors associated with a higher mortality rate. Furthermore, the data will be used for the planning of a registry study.

Materials And Methods: A 29-item nonvalidated questionnaire was sent to German University Medical Centers (Department of Urology), including three reminders from April through June 2020. Data management and analysis were performed with SPSS 26.0.

Results: The response rate was 88.9%. A median of 5 patients (median age 60.0 years) with FG were treated annually in German University Medical Centers. The contemporary practice patterns are very heterogeneous, especially in terms of empirical antibiotic treatment. Only one significant risk factor for a mortality rate higher than 20.0% was identified-intensive care treatment for ≥10 days (p = 0.039). In addition, 50% stated that outcome of FG has not improved in recent years. Furthermore, the majority of the respondents think that mortality is still too high. Consequently, 84.4% support a registry study. From the answers to the open questions we received a variety of suggestions for planning such a study, e.g., histological confirmation of the disease.

Conclusion: Treatment of FG is currently very heterogeneous. Furthermore, treatment outcomes are often unacceptable and difficult to predict.
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http://dx.doi.org/10.1007/s00120-021-01461-4DOI Listing
February 2021

Management of Germ Cell Tumours of the Testes in Adult Patients: German Clinical Practice Guideline, PART II - Recommendations for the Treatment of Advanced, Recurrent, and Refractory Disease and Extragonadal and Sex Cord/Stromal Tumours and for the Management of Follow-Up, Toxicity, Quality of Life, Palliative Care, and Supportive Therapy.

Urol Int 2021 22;105(3-4):181-191. Epub 2021 Jan 22.

Department of Urology, Universitätsklinikum Düsseldorf, Düsseldorf, Germany,

Objectives: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects.

Materials And Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements.

Results: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy.

Conclusion: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
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http://dx.doi.org/10.1159/000511245DOI Listing
January 2021

Management of Germ Cell Tumours of the Testis in Adult Patients. German Clinical Practice Guideline Part I: Epidemiology, Classification, Diagnosis, Prognosis, Fertility Preservation, and Treatment Recommendations for Localized Stages.

Urol Int 2021 7;105(3-4):169-180. Epub 2021 Jan 7.

Department of Urology, University Hospital Düsseldorf, Düsseldorf, Germany.

Introduction: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages.

Methods: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements.

Results: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma.

Conclusion: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
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http://dx.doi.org/10.1159/000510407DOI Listing
January 2021

Editorial.

Urol Int 2021 17;105(1-2). Epub 2020 Dec 17.

Klinikum der Universität, Rostock, Germany,

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http://dx.doi.org/10.1159/000513633DOI Listing
December 2020

Association Between Human Papillomavirus Infection and Outcome of Perioperative Nodal Radiotherapy for Penile Carcinoma.

Eur Urol Oncol 2020 Nov 13. Epub 2020 Nov 13.

San Raffaele Hospital and Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy; Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address:

Background: Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node-involved penile squamous-cell carcinoma (PSCC) are lacking.

Objective: To analyze the benefit from perioperative radiotherapy (RT) for PSCC according to HPV infection status.

Design, Setting, And Participants: In an international multicenter database of 1254 patients with PSCC who received inguinal lymph node dissection (ILND), 507 had suitable clinical information.

Intervention: ILND, with or without chemotherapy or RT for involved lymph nodes.

Outcome Measurements And Statistical Analysis: Kaplan-Meier and restricted mean survival time (RMST) analyses for overall survival (OS) were performed for all patients and after propensity score-matching (PSM; n = 136), for which patient age, histology, type of penile surgical procedure, pathological tumor and nodal stage, ILND laterality, pelvic LND, and perioperative treatment were taken into account when assessing differences between HPV and HPV- patients. Finally, we looked at genomic alterations in PSCC using data from the Foundation Medicine database (n = 199) to characterize HPV PSCC.

Results And Limitations: Patients with HPV PSCC (n = 86; 17%) had lower clinical N stage (p < 0.001) and inguinal lymph node metastasis density (p < 0.001). Perioperative RT was delivered in 49 patients (9.7%), with the vast majority receiving adjuvant RT (n = 40). HPV patients had similar median OS (p = 0.1) but longer RMST than HPV- patients at different time points. Nevertheless, HPV patients treated with perioperative RT exhibited longer median OS (p = 0.015) and longer RMST compared to HPV- patients. In the PSM cohorts, HPV status remained significantly associated with longer OS after RT. The HPV- PSCC group had a higher frequency of TP53 mutations compared to HPV PSCC (75% vs 15%; p < 0.001). The results are limited by the retrospective nature of the data.

Conclusions: Perioperative RT was more effective in the HPV PSCC subgroup. Reasons for the enhanced radiosensitivity may be related to the lack of TP53 mutations.

Patient Summary: We analyzed data from a large multicenter database for patients with penile cancer who had received inguinal lymph node dissection, with or without chemotherapy or radiotherapy. We found that for tumors positive for human papillomavirus (HPV), use of radiotherapy resulted in prolonged survival compared to HPV-negative tumors. On the basis of these results we are inspired to design studies on the use of radiotherapy in HPV-selected patients.
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http://dx.doi.org/10.1016/j.euo.2020.10.011DOI Listing
November 2020

A risk calculator predicting recurrence in lymph node metastatic penile cancer.

BJU Int 2020 11 7;126(5):577-585. Epub 2020 Aug 7.

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.

Objectives: To develop and externally validate a risk calculator for prediction of any cancer recurrence in patients with penile squamous cell carcinoma (pSCC) and inguinal lymph node metastases (ILNM), as to date no validated prognostic tool is available for patients with pSCC and ILNM.

Patients And Methods: The development cohort included 234 patients from seven referral centres. The external validation cohort included 273 patients from two additional referral centres. Cox regression identified predictors of any recurrence, which were used to develop a risk calculator. The risk-calculator grouped the development and the validation cohorts according to the individual risk of any recurrence at 24 months (24m-R). Adjuvant treatment effects were tested on overall survival (OS) according to the derived tertiles, within the development and validation cohorts.

Results: Positive surgical margins, pN , and ILNM ratio were associated with higher recurrence rate. The 2-year OS rates were lower for patients with high (>37%) and intermediate (19-37%) compared to low (<19%) 24m-R risk of recurrence, for both the development (43% and 58% vs 83%, P < 0.001) and validation cohort (44% and 50% vs 85%, P < 0.001). Results were confirmed in the subgroup of patients who did not receive adjuvant treatment (P < 0.001), but not in patients who did receive adjuvant treatments in both the development and validation cohorts (P > 0.1).

Conclusion: Adjuvant treatment planning is crucial in patients with pSCC with ILNM, where only weak evidence is available. The current tool proved to successfully stratify patients according to their individual risk, potentially allowing better tailoring of adjuvant treatments.
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http://dx.doi.org/10.1111/bju.15177DOI Listing
November 2020

Leflunomide in the treatment of BK polyomavirus associated nephropathy in kidney transplanted patients - A systematic review.

Transplant Rev (Orlando) 2020 10 21;34(4):100565. Epub 2020 Jun 21.

University Hospital Rostock, Dept. of Urology, Rostock, Germany.

BK polyomavirus (BKPyV) associated nephropathy (BKVAN) is seen in about 5% of renal transplant patients and can lead to chronic graft failure or graft loss. No effective therapy is available. Leflunomide has shown promising results in BKVAN. We performed a systematic review about the use of leflunomide for the treatment of BKVAN. The recommendations of the Cochrane Handbook of systematic Reviews were followed. Due to different study designs and endpoints no meta-analysis was performed. The literature search for primary studies yielded 274 results. Finally, twelve studies were included with a total of 267 patients. Clearance of BKPyV viremia was reported in 33.3% to 92.3% of cases and 27 graft losses (10.1%). The included studies were very heterogeneous, especially in terms of leflunomide dosing. Pharmacokinetics seem to have an important impact on the efficacy of leflunomide in BKVAN. There was no correlation between leflunomide serum levels and virus reduction. New adverse events of leflunomide have been described, e.g. haemolytic anaemia and thrombotic microangiopathy. Overall, the risk of bias in the studies was assessed as high and the quality of evidence was rated low. The role of leflunomide in BKVAN remains unclear, but further studies seem reasonable and should address pharmacokinetic aspects.
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http://dx.doi.org/10.1016/j.trre.2020.100565DOI Listing
October 2020

European Association of Urology Guidelines Office Rapid Reaction Group: An Organisation-wide Collaborative Effort to Adapt the European Association of Urology Guidelines Recommendations to the Coronavirus Disease 2019 Era.

Eur Urol 2020 Jul 27;78(1):21-28. Epub 2020 Apr 27.

Academic Urology Unit, University of Aberdeen, Aberdeen, UK.

The coronavirus disease 2019 (COVID-19) pandemic is unlike anything seen before by modern science-based medicine. Health systems across the world are struggling to manage it. Added to this struggle are the effects of social confinement and isolation. This brings into question whether the latest guidelines are relevant in this crisis. We aim to support urologists in this difficult situation by providing tools that can facilitate decision making, and to minimise the impact and risks for both patients and health professionals delivering urological care, whenever possible. We hope that the revised recommendations will assist urologist surgeons across the globe to guide the management of urological conditions during the current COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.eururo.2020.04.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183974PMC
July 2020

Loss of Mismatch-repair Protein Expression and Microsatellite Instability in Upper Tract Urothelial Carcinoma and Clinicopathologic Implications.

Clin Genitourin Cancer 2020 10 13;18(5):e563-e572. Epub 2020 Mar 13.

Institute of Pathology, University Medicine Rostock, Rostock, Germany.

Background: Upper tract urothelial carcinoma (UTUC) may arise in the setting of hereditary non-polyposis colorectal cancer (Lynch syndrome [LS]) or sporadically. Variable frequencies of microsatellite instability (MSI) were found in UTUC. For advanced solid MSI tumors, targeted therapy with programmed death-ligand 1 inhibitors is available. Therefore, we aimed to determine the prevalence of mismatch repair (MMR) protein loss and MSI in UTUC using a tissue microarray approach and further molecular and correlation analysis.

Materials And Methods: We studied the immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2 on tissue microarrays containing formalin-fixed, paraffin-embedded samples of 128 patients with UTUC. MSI analysis was performed in 79 cases with deficient MMR protein expression, and/or in patients aged 60 years and below, and/or other tumors possibly related to LS.

Results: Loss of MMR protein expression was seen in 24 (18.8%) of 128 cases. MSI analysis revealed MSI-high in 29, MSI-low in 7 cases. The Fisher exact test demonstrated significant differences between MSI and loss of MMR protein expression, clinically possible LS, tumor growth pattern, inverted growth pattern, and death (P < .001, P < .001, P = .002, P = .003, and P = .033, respectively). MSI does not appear to influence survival (overall and progression-free), but there was a significant shorter progression-free survival in MSI-high versus MSS patients who had received chemotherapy.

Conclusion: The frequency of MSI in UTUC was 36 (28.1%) of 128 patients with a good accuracy of immunohistochemistry. In daily practice, MSI screening especially is recommended in patients with advanced UTUC and inverted papillary tumor growth pattern with the aim of screening patients for possible targeted therapy.
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http://dx.doi.org/10.1016/j.clgc.2020.03.006DOI Listing
October 2020

Optimising the selection of candidates for neoadjuvant chemotherapy amongst patients with node-positive penile squamous cell carcinoma.

BJU Int 2020 06 1;125(6):867-875. Epub 2020 Apr 1.

University Hospital Rostock, Rostock, Germany.

Objectives: To identify predictors of poor overall survival (OS) amongst patients with penile squamous cell carcinoma (pSCC) with clinical inguinal lymphadenopathy (cN+), in order to define the best candidates for neoadjuvant chemotherapy (NAC).

Patients And Methods: Using an international, multicentre database of 924 patients with pSCC, we identified 334 men who harboured cN+ with available clinical and follow-up data. Lymph node involvement was defined either by the presence of palpable inguinal node disease or by preoperative computed tomography (CT) assessment. Fluorine-18 fluorodeoxyglucose positron-emission tomography ( F-FDG-PET)/CT scan was performed based on clinical judgment of the treating physician. Regression-tree analysis generated a risk stratification tool for prediction of 24-month overall mortality (OM). Kaplan-Meier explored the OS benefit related to the use of NAC according to the regression-tree-stratified subgroups.

Results: Overall, 120 (35.9%), 152 (45.5%), and 62 (18.6%) patients harboured cN1, cN2, and cN3 disease. F-FDG-PET/CT was performed in 48 (14.4%) patients, and 16 (4.8%) had inguinal and pelvic nodal PET detection. The median OS was 107 months, with a 24-month OS of 66%. At regression-tree analysis (area under the curve = 70%), patients with cN3 and cN2 with PET/CT-detected inguinal and pelvic nodal activity had a higher risk of 24-month OM (>50%). NAC was associated with improved 24-month OS rates (54% vs 33%) only in this subgroup of patients (P = 0.002), which was also confirmed after multivariable adjustment (hazard ratio 0.28, 95% confidence interval 0.13-0.62; P = 0.002).

Conclusion: Patients with pSCC with cN3 or cN2 and inguinal and pelvic 18F-FDG-PET/CT scan detected disease had higher 24-month OM rates according to our regression-tree model. NAC was associated with improved OS only in these subgroups of patients. Our novel decision model may help to stratify cN+ patients, and identify those who most likely will benefit from NAC prior to radical surgical resection.
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http://dx.doi.org/10.1111/bju.15054DOI Listing
June 2020

Prevention of Encrustation on Ureteral Stents: Which Surface Parameters Provide Guidance for the Development of Novel Stent Materials?

Polymers (Basel) 2020 Mar 3;12(3). Epub 2020 Mar 3.

Dept. of Cell Biology, Rostock University Medical Center, Schillingallee 69, 18057 Rostock, Germany.

Encrustations of ureteral stents are one of the biggest problems with urological implants. Crystalline biofilms can occur alone or in combination with bacterial biofilms. To identify which surface parameters provide guidance for the development of novel stent materials, we used an in vitro encrustation system. Synthetic urine with increasing pH to simulate an infection situation was pumped over the polymer samples with adjusted flow rates at 37 °C to mimic the native body urine flow. Chemical surface features (contact angle, surface charge), as well as encrustations were characterized. The encrustations on the materials were analyzed quantitatively (dry mass) and qualitatively using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and Fourier transform infrared spectroscopy (FTIR). The aim of this comparative study was to identify crucial surface parameters that might predict the quantity and type of mineral deposits in vitro and provide guidance for the development and screening of new polymer-based biomaterials for ureteral stent design. For the first time, we could identify that, within the range of our polymers, those materials with a slight hydrophilicity and a strong negative zeta potential (around -60 mV) were most favorable for use as ureteral stent materials, as the deposition of crystalline biofilms was minimized.
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http://dx.doi.org/10.3390/polym12030558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182952PMC
March 2020

First-in-human dosimetry of gastrin-releasing peptide receptor antagonist [Lu]Lu-RM2: a radiopharmaceutical for the treatment of metastatic castration-resistant prostate cancer.

Eur J Nucl Med Mol Imaging 2020 01 3;47(1):123-135. Epub 2019 Sep 3.

Department of Nuclear Medicine, Rostock University Medical Center, Gertrudenplatz 1, 18057, Rostock, Germany.

Purpose: Besides PSMA, prostate cancer cells also express gastrin-releasing peptide receptor (GRPr) which is therefore a promising target for theranostic approaches. The high affinity GRPr antagonist RM2 can be labeled with beta-emitting radiometals for therapeutic purposes. The aim of this study was to calculate absorbed doses for critical organs and tumor lesions for [Lu]Lu-RM2 therapy administered in a group of metastatic castration-resistant prostate cancer (mCRPC) patients who had insufficient PSMA expression or showed lower PSMA accumulation after previous cycles of [Lu]Lu-PSMA-617 therapy.

Methods: Thirty-five patients suffering from mCRPC without further treatment options for approved therapies were examined with [Ga]Ga-RM2-PET/CT. Out of these, 4 patients (mean age 68 years) were treated with [Lu]Lu-RM2; two of these also received a 2nd therapy cycle. Mean activity was 4.5 ± 0.9 GBq. For dosimetry, patients underwent planar WB-scintigraphy and SPECT/CT imaging of the upper and lower abdomen at approximately 1, 24, 48, and 72 h p.i. along with blood sampling. Absorbed doses for kidneys, pancreas, liver, spleen, gallbladder wall, and tumor lesions were derived based on quantitative SPECT/CT according to RADAR dosimetry scheme; individual organ masses were extracted from CT. Absorbed dose to bone marrow was calculated based on serial whole-body images and blood sampling according to the EANM guideline.

Results: Therapy was well tolerated by all patients and no side effects were observed. An increased uptake in tumor lesions and the pancreas was seen within the first 1 h. Mean absorbed organ doses were 1.08 ± 0.44 Gy/GBq in the pancreas, 0.35 ± 0.14 Gy/GBq in the kidneys, 0.05 ± 0.02 Gy/GBq in the liver, 0.07 ± 0.02 Gy/GBq in the gallbladder wall, 0.10 ± 0.06 Gy/GBq in the spleen, and 0.02 ± 0.01 Gy/GBq for the red bone marrow. The mean dose for tumor lesions was 6.20 ± 3.00 Gy/GBq.

Conclusions: Application of GRPr antagonist [Lu]Lu-RM2 is suitable for targeted radiotherapy of mCRPC as it shows high tumor uptake and rapid clearance from normal organs. Absorbed doses in tumor lesions are therapeutically relevant. The critical organ receiving the highest absorbed dose was the pancreas. Results suggest that the activity administered for each cycle could be increased to maximize the absorbed dose of tumors and metastases.
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http://dx.doi.org/10.1007/s00259-019-04504-3DOI Listing
January 2020

[Man, machine, medicine and economics].

Urologe A 2019 09;58(9):1003-1006

Urologische Klinik und Poliklinik, Universitätsmedizin Rostock, Ernst-Heydemann-Str. 6, 18057, Rostock, Deutschland.

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http://dx.doi.org/10.1007/s00120-019-01024-8DOI Listing
September 2019

Nomogram-based prediction of overall survival after regional lymph node dissection and the role of perioperative chemotherapy in penile squamous cell carcinoma: A retrospective multicenter study.

Urol Oncol 2019 08 1;37(8):531.e7-531.e15. Epub 2019 May 1.

Moffitt Cancer Center and Research Institute, Tampa, FL.

Objectives: To improve the prognostic allocation of patients with penile squamous-cell carcinoma (PSCC) receiving regional lymph node dissection (LND).

Patients And Methods: An international, multicenter, retrospective study was performed on patients with PSCC who received regional LND, with or without perioperative therapy, from 1980 to 2017. We first used a random forest (RF) method with missing data imputation. Additionally, data were modeled using Cox proportional hazard regression, and a Cox model was also fit including prespecified variables. Based on the latter model, a nomogram for estimating 12-month and 24-month overall survival (OS) was developed.

Results: There were 743 patients who received LND at 7 referral centers from Europe, the USA, Brazil, and China. Of these patients, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (P < 0.001), the pathologically involved/total removed LN ratio (P < 0.001), pN stage (overall P < 0.001), and NAC (P = 0.013). NAC and AC were ineffective in N1-2 patients (clinical and pathological, respectively), whereas they provided OS improvements in N3 patients. Finally, we developed a nomogram predicting 12- and 24-month OS based on prespecified variables (c-index: 0.75). The study is limited by its retrospective nature.

Conclusions: We propose a tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling whenever LND is needed for PSCC. Administration of NAC and AC should be restricted to clinical and pathological N3 patients, respectively.
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http://dx.doi.org/10.1016/j.urolonc.2019.04.003DOI Listing
August 2019

Prediction tools in non-muscle invasive bladder cancer.

Transl Androl Urol 2019 Feb;8(1):39-45

Department of Urology, University Medical Center Rostock, Rostock, Germany.

Non-muscle invasive bladder cancer (BCa) is the second most common genitourinary malignancy, burdened by high rates of recurrence and progression. Urologist are encouraged to stratify patients on the bases of recurrence and progression risks in order to define the best therapeutic approach and follow-up scheme. For these reasons, the aim of the present non-systematic review was to assess the literature on prediction tools in non-muscle invasive BCa. Currently, the most widely used tools remain the European Organization for Research and Treatment of Cancer (EORTC) and the Club Urologico Espanol de Tratamiento Oncologico (CUETO) risk tables, which are based on clinicopathologic features. Recent external validations, therefore, reported their low accuracy, probably related to the lack of the role of re-transurethral resection (TURBT), early instillations, chemotherapy and complete BCG schedules in the studies included to asses these scores. More recently several immunological, biochemical and genetics biomarkers have been tested by themselves and in combination with clinicopathologic features, and many of them resulted related with risk of recurrence and progression. Future perspectives will presumably include the update of EORTC and CUETO scores with newest guidelines' recommendations and their integration with biomarkers.
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http://dx.doi.org/10.21037/tau.2019.01.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414347PMC
February 2019

[Regulations from the German Federal Medical Chamber for specialization in urology: legal and occupational aspects].

Urologe A 2019 Feb;58(2):126-131

Klinik und Poliklinik für Urologie, Universitätsmedizin Rostock, Schillingallee 35, 18057, Rostock, Deutschland.

The new regulations of the German Federal Medical Chamber for the specialization in urology have been published in November 2018 and can now be transferred into official regulations by the different Medical Chambers of the German Länder. The new concept consists of different subjects which are each subdivided into different levels of competence. Required numbers for procedures have been kept to a minimum as the emphasis is on everyday procedures of outpatient urology. The scope of urology is well represented and all subspecialities have been incorporated with their basic contents. Higher qualifications in certain subspecialities are available.
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http://dx.doi.org/10.1007/s00120-018-0843-8DOI Listing
February 2019

Immunonutrition in radical cystectomy: a novel approach to reduce postoperative complications?

Transl Androl Urol 2018 Dec;7(Suppl 6):S718-S719

Department of Urology, University Medical Center Rostock, Rostock, Germany.

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http://dx.doi.org/10.21037/tau.2018.10.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323282PMC
December 2018

The Evidence Paradox of the Effectiveness between the Paediatric and Adult Stone-Forming Population: A Narrative Review.

Urol Int 2019 23;102(2):125-130. Epub 2019 Jan 23.

Aim/objective: To identify trends in the evidence base regarding the effectiveness of using α-blockers in children versus adults and compare outcomes.

Methods: A literature search up using the key words including urolithiasis/renal/ureteric stone in children/paediatric population, medical expulsive treatment (MET), α-blocker/alfuzosin/tamsulosin/doxazosin. Included were randomized or controlled clinical trials in paediatric stone formers (aged ≤18 years). Outcome measures for assessment included the overall stone expulsion rate, expulsion time, the number of pain episodes and adverse drug effects and/or reactions. Further comparison of efficacy levels using respective studies from the adult population was performed in order to identify trends, similarities and differences.

Results: A total of 8,259 articles were identified. Full text evaluation was possible for 28 articles. Although the picture is clearer in the paediatric group, the lack of reproducible results in adults certainly poses serious questions about data collection, analysis and interpretation in each individual study. The apparent paradox is due to the methodological differences between studies.

Conclusion: The effectiveness of α-blockers and other medication as MET needs to be studied in multi-institutional, double-blind, placebo-controlled studies that would aim to prove superiority to placebo in contemporary clinical situations, with realistic end points and standardized outcome measure determination.
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http://dx.doi.org/10.1159/000455157DOI Listing
July 2019

Randomised phase II study of second-line olaratumab with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer.

Eur J Cancer 2019 01 17;107:186-195. Epub 2018 Dec 17.

Eli Lilly and Company, Bridgewater, NJ, USA. Electronic address:

Introduction: Platelet-derived growth factor receptor-α (PDGFRα) is expressed in primary prostate adenocarcinoma and in associated skeletal metastases. Olaratumab is a fully human monoclonal antibody that binds PDGFRα and blocks downstream signalling. This phase II study assessed the efficacy and safety of olaratumab in combination with mitoxantrone and prednisone (M/P) versus M/P alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed after docetaxel.

Methods: Patients were randomised to receive 21-d cycles of olaratumab (15 mg/kg, Days 1 and 8) plus mitoxantrone (12 mg/m, Day 1) and prednisone (5 mg, twice daily) or M/P alone. Progression-free survival (PFS) was the primary end-point. Secondary end-points included overall survival (OS), safety, and circulating tumour cell (CTC) counts.

Results: A total of 123 patients were randomised, 63 to olaratumab + M/P and 60 to M/P. Median PFS was 2.3 months for olaratumab + M/P and 2.4 months for M/P (hazard ratio [HR] = 1.29; 95% confidence interval [CI] = 0.87-1.90). Median OS was 14.2 months for olaratumab + M/P and 12.8 months for M/P (HR = 1.08; 95% CI = 0.72-1.61). Both treatment arms had similar toxicity profiles; neutropenia (24% versus 15%), anaemia (13% versus 14%) and fatigue (11% versus 9%) (olaratumab + M/P versus M/P, respectively) were the most common grade ≥3 events. High CTC count was associated with poorer OS in both arms. Patients with very high cell counts (>37 cells/7.5 ml) exhibited improved OS with olaratumab + M/P (interaction P = 0.043).

Conclusions: Olaratumab + M/P had an acceptable safety profile but did not improve the efficacy of M/P chemotherapy. Further study with selected patient populations and earlier in the disease course might be considered.
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http://dx.doi.org/10.1016/j.ejca.2018.10.005DOI Listing
January 2019

Predicting 90-day and long-term mortality in octogenarians undergoing radical cystectomy.

BMC Urol 2018 Oct 22;18(1):91. Epub 2018 Oct 22.

Department of Urology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, D-01307, Dresden, Germany.

Background: Radical cystectomy bears a considerable perioperative mortality risk particularly in elderly patients. In this study, we searched for predictors of perioperative and long-term competing (non-bladder cancer) mortality in elderly patients selected for radical cystectomy.

Methods: We stratified 1184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated carcinoma of bladder into two groups (age < 80 years versus 80 years or older). Multivariable and cox proportional hazards models were used for data analysis.

Results: Whereas Charlson score and the American Society of Anesthesiologists (ASA) physical status classification (but not age) were independent predictors of 90-day mortality in younger patients, only age predicted 90-day mortality in patients aged 80 years or older (odds ratio per year 1.24, p = 0.0422). Unlike in their younger counterparts, neither age nor Charlson score or ASA classification were predictors of long-term competing mortality in patients aged 80 years or older (hazard ratios 1.07-1.10, p values 0.21-0.77).

Conclusions: This data suggest that extrapolations of perioperative mortality or long-term mortality risks of younger patients to octogenarians selected for radical cystectomy should be used with caution. Concerning 90-day mortality, chronological age provided prognostic information whereas comorbidity did not.
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http://dx.doi.org/10.1186/s12894-018-0402-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198515PMC
October 2018

Copy Number Alterations with Prognostic Potential in Clear Cell Renal Cell Carcinoma.

Urol Int 2018 18;101(4):417-424. Epub 2018 Sep 18.

Department of Urology, University Hospital Rostock, Rostock, Germany.

Objectives: To detect chromosomal aberrations in a genome-wide manner with potential value for prognosis in groups of patients with different histopathological grading in clear cell renal carcinoma (ccRCC).

Material And Methods: We performed a copy number alteration analysis using the Affymetrix platform and SNP 6.0 mapping arrays with samples from 48 ccRCC-patients. The data analysis was done using 3 different Software Platforms: Affymetrix Genotyping Console (version 4.1.3.840) and 2 open-source packages for validation: PennCNV and PICNIC.

Results: Consistent changes were found to divide the tumors into 4 groups: first group showed typical losses on 3p, second group losses on 3p plus gains on 5q, third group gains on chromosome 7 plus losses on chromosome 8; fourth group did not show any major changes. We selected the affected genes with the highest consistency and identified 13 different genes mapping in the SNP 6.0 results and Kyoto Encyclopedia of Genes and Genomes. Remarkable for further consideration were the phosphatidylinositol 3-kinase pathway, BRAF, MET, EGLN1; growth factors, for example, HGF, PGF and TGFB2.

Conclusion: A multimodal approach with a well-defined workflow for detecting genomic aberrations by using array technologies and comparing the findings with different comprehensive databases may provide insights into functional tumor processes and help to identify potential new targets for more individualized future treatment.
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http://dx.doi.org/10.1159/000493149DOI Listing
March 2019

Cross-Sectional Patient-Reported Outcome Measuring of Health-Related Quality of Life With Establishment of Cancer- and Treatment-Specific Functional and Symptom Scales in Patients With Penile Cancer.

Clin Genitourin Cancer 2018 12 11;16(6):e1215-e1220. Epub 2018 Aug 11.

Department of Urology, Medical Center of University of Rostock, Rostock, Germany.

Background: In the field of uro-oncology, the assessment of quality of life (QoL) is considered an integral part of clinical research. Because of the rarity of penile cancer, there is currently no cancer-specific questionnaire module available to assess the tumor-specific loss of function and symptoms in terms of influencing QoL. The aim of the study was to apply a validated questionnaire (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30) in a population of patients diagnosed with penile cancer and to compare these results to reference data of the general population. We also developed a new unvalidated questionnaire (Quality of Life Questionnaire-Penile Cancer-Rostock, HRO-PE29) in this population to promote QoL research in the field of uro-oncology.

Patients And Methods: Cross-sectional evaluation of patients with penile cancer after local surgical treatment (n = 76) was performed using EORTC QLQ-C30 and HRO-PE29. The QLQ-C30 provides information on QoL, functional scales, symptom scales, and 6 individual items (inappetence, insomnia, dyspnea, constipation, diarrhea, financial difficulties). Cancer-specific functional and symptom scales (HRO-PE29) were then established for use in different disease states and forms of treatment. These provide information on QoL as well as on cancer-specific function and symptom scores.

Results: The global QoL score was 54, which corresponds to an average QoL (score 0-100) and was well below the age-standardized average for German patients. For the general function scores, the following mean values were determined: physical (x¯ = 73), social (x¯ = 61), emotional (x¯ = 60), cognitive functioning (x¯ = 69), and role function (x¯ = 63). With regard to the general symptom scores and the individual items, the following values were found: fatigue (x¯ = 35), nausea (x¯ = 6), pain (x¯ = 27), dyspnea (x¯ = 23), insomnia (x¯ = 41), loss of appetite (x¯ = 25), constipation (x¯ = 19), diarrhea (x¯ = 10), and financial difficulties (x¯ = 25). The following mean values were found for the cancer-specific functional scores: voiding (x¯ = 77), sexuality (x¯ = 69, function and pleasure), body image (x¯ = 64), lymphedema (x¯ = 75), future prospects (x¯ = 72), and adverse effects of systemic treatment (x¯ = 73).

Conclusion: Defects of the external genitalia have implications for identity, personality, and interpersonal relationships. The mental stress of these patients results from the diagnosis of cancer as well as the partly mutilating treatment. Reconstructive surgery in penile cancer patients promises to maintain sexual and micturition function and thus improve QoL. Cancer-specific functional losses can be sufficiently named and their influence on QoL determined.
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http://dx.doi.org/10.1016/j.clgc.2018.07.029DOI Listing
December 2018

Gender and Mortality after Radical Cystectomy: Competing Risk Analysis.

Urol Int 2018 31;101(3):293-299. Epub 2018 Aug 31.

Departments of Urology, Dresden, Germany.

Background: Data on the impact of gender on mortality after radical cystectomy is conflicting. We investigated a large single center sample with long-term follow-up in order to determine the relationship between gender and outcome.

Patients And Methods: A total of 1,184 consecutive patients who underwent radical cystectomy for high risk superficial or muscle-invasive urothelial or undifferentiated bladder cancer between 1993 and 2015 were stratified by gender. Demographic data was compared using Mann-Whitney U test, chi-square test, or Fisher exact test. Cox proportional hazard models were used for the analysis of competing risks and logit models were used for the prediction of the receipt of adjuvant cisplatin-based chemotherapy.

Results: Female patients were older, healthier, less frequently current smokers and had more extravesical tumors. In the multivariate analyses, female gender was an independent predictor of (lower) non-bladder cancer (competing) mortality (hazards ratio [HR] 0.68, 95% CI 0.49-0.95, p = 0.0248) but no predictor of bladder cancer-specific mortality (HR in the full model 1.20, 95% CI 0.94-1.54, p = 0.15). Gender was no predictor of the receipt of adjuvant cisplatin-based chemotherapy.

Conclusions: Female gender was associated with an increased risk of extravesical disease but was no independent predictor of bladder cancer-specific mortality. Anatomical differences might be a plausible explanation for these observations.
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http://dx.doi.org/10.1159/000487445DOI Listing
April 2019

A brief overview of the development of robot-assisted radical prostatectomy.

Arab J Urol 2018 Sep 24;16(3):293-296. Epub 2018 Jul 24.

Department of Urology, Rostock University, Germany.

Robot-assisted radical prostatectomy (RP) has gained remarkable worldwide distribution and has become a standard procedure for localised prostate cancer, indeed a new 'gold standard'. There are proven advantages in reduced blood loss and shorter recovery time. Whilst case series publications often report improved functional outcomes, systematic hospital and healthcare data analyses mostly do not support these findings. Robotic surgery remains more costly. Its use has also increased knowledge about the anatomy of RP.
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http://dx.doi.org/10.1016/j.aju.2018.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104667PMC
September 2018

Re: Differences in Survival Associated with Lymph Node Dissection in Patients with Invasive Penile Cancer: Results from the National Cancer Database.

Eur Urol 2018 11 20;74(5):678-679. Epub 2018 Jul 20.

Department of Urology, Ludwig-Maximilians-University Munich, Munich, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.eururo.2018.07.016DOI Listing
November 2018

Hyperpolarization-Activated Cyclic Nucleotide-Gated Non-selective (HCN) Ion Channels Regulate Human and Murine Urinary Bladder Contractility.

Front Physiol 2018 19;9:753. Epub 2018 Jun 19.

Oscar Langendorff Institute of Physiology, University of Rostock, Rostock, Germany.

Hyperpolarization-activated cyclic nucleotide gated non-selective (HCN) channels have been demonstrated in the urinary bladder in various species. Since they play a major role in governing rhythmic activity in pacemaker cells like in the sinoatrial node, we explored the role of these channels in human and murine detrusor smooth muscle. In an organ bath, human and murine detrusor smooth muscle specimens were challenged with the HCN channel blocker ZD7288. In human tissue derived from macroscopically tumor-free cancer resections, the urothelium was removed. In addition, HCN1-deficient mice were used to identify the contribution of this particular isoform. Expression of HCN channels in the urinary bladder was analyzed using histological and ultrastructural analyses as well as quantitative reverse transcriptase polymerase chain reaction (RT-PCR). We found that the HCN channel blocker ZD7288 (50 μM) both induced tonic contractions and increased phasic contraction amplitudes in human and murine detrusor specimens. While these responses were not sensitive to tetrodotoxin, they were significantly reduced by the gap junction inhibitor 18β-glycyrrhetic acid suggesting that HCN channels are located within the gap junction-interconnected smooth muscle cell network rather than on efferent nerve fibers. Immunohistochemistry suggested HCN channel expression on smooth muscle tissue, and immunoelectron microscopy confirmed the scattered presence of HCN2 on smooth muscle cell membranes. HCN channels seem to be down-regulated with aging, which is paralleled by an increasing effect of ZD7288 in aging detrusor tissue. Importantly, the anticonvulsant and HCN channel activator lamotrigine relaxed the detrusor which could be reversed by ZD7288. These findings demonstrate that HCN channels are functionally present and localized on smooth muscle cells of the urinary bladder. Given the age-dependent decline of these channels in humans, activation of HCN channels by compounds such as lamotrigine opens up the opportunity to combat detrusor hyperactivity in the elderly by drugs already approved for epilepsy.
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http://dx.doi.org/10.3389/fphys.2018.00753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018223PMC
June 2018

Analysis of psychosocial stress factors in patients with renal cancer.

Ther Adv Urol 2018 Jun 18;10(6):175-182. Epub 2018 Feb 18.

Department of Urology, University of Rostock, Rostock, Germany.

Background: The experience of stress in patients with cancer through helplessness and the suppression of emotions correlates with unfavorable disease prognosis. Significant distress can reduce survival probability as well as subjectively perceived poor quality of life. Currently, there are few data on psychological stress in patients with renal cancer and most studies focus on survival time. The aim of the study was to evaluate the psychosocial stress of patients with renal cancer with screening questionnaires for an inpatient psychosocial treatment program.

Methods: Patients undergoing inpatient surgical or medical treatment for renal cancer were prospectively assessed for psychosocial stress with two standardized stress screening questionnaires used for the identification of the need for psychosocial care [NCCN Distress Thermometer (NCCN-DT), Hornheider Screening Instrument (HSI)].

Results: Seventy-four patients with a mean age of 65 years were assessed. The average NCCN-DT score was 4.8 (scale of 0-10) and did not correlate with tumor stage, sex or prognosis. According to the DT results, 27% of patients were in need of psychosocial care which was significantly higher than the self-reported need. The main stressors were anxiety (32%), pain (27%), nervousness (26%), sadness, worry and sleeping difficulties (20%).

Conclusions: There is a significant number of patients with renal cancer with increased psychological distress and a consecutive need for psychosocial care. This is underreported and largely unrecognized by patients as well as physicians and nurses. Easy-to-use assessment tools can be very helpful in identifying patients in need and this information can be used to implement psychological support and thus improve patient care.
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http://dx.doi.org/10.1177/1756287218754766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993071PMC
June 2018