Publications by authors named "Marcus Scharpf"

59 Publications

Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?

World J Urol 2021 Apr 21. Epub 2021 Apr 21.

Department of Urology, University Hospital, Tübingen, Germany.

Purpose: The value of bladder cancer (BC) substaging into macroscopic (pT3b) and microscopic (pT3a) perivesical fat extension in lymph node (Ln)-negative patients is controversially discussed and limited evidence for prognostic relevance of additional histopathological factors in pT3 BC exists. We evaluated the prognostic value of pT3 substaging and established pathological and clinical parameters with focus on tumor invasive front (TIF) and tumor size.

Methods: Specimens of 52 patients treated with radical cystectomy (RC) for pT3 a/b muscle-invasive BC were reviewed and re-evaluated by a pathologist specialized in uropathology. Clinical variables and standard histopathologic characteristics were assessed including TIF and tumor size. Their value as prognosticators for overall survival (OS) and recurrence-free survival (RFS) was evaluated.

Results: Mean age of patients was 67.55 years. Tumors were staged pT3a in 28 patients (53.8%) and pT3b in 24 (46.8%). Median OS was 34.51 months. Median tumor size was 3.2 cm, median TIF was 11.0 mm. Differences in OS between pT3a and pT3b were not significant (p = 0.45). Carcinoma in situ (CIS) and lymphovascular invasion (LVI) were significantly associated with pT3b tumors. Univariate analysis could not identify pathological prognosticators like TIF or tumor size for OS and RFS (p for all > 0.05).

Conclusion: No significant differences in OS or RFS were observed comparing Ln-negative pT3 BC following radical cystectomy. Additional pathologic variables like TIF could not be identified as prognosticator. Relevance of pT3 BC substaging needs reevaluation in larger prospective cohorts.
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http://dx.doi.org/10.1007/s00345-021-03697-3DOI Listing
April 2021

The prognostic value of fat invasion and tumor expansion in the hilar veins in pT3a renal cell carcinoma.

World J Urol 2021 Feb 27. Epub 2021 Feb 27.

Department of Urology, University of Tuebingen, Tübingen, Germany.

Purpose: The 7th TNM classification summarizes renal cell carcinoma (RCC) with perirenal (PFI) and/or sinus fat invasion (SFI) as well as hilar vein involvement (RVI) as pT3a tumors. In this study, we aimed to determine the prognostic value of fat invasion (FI) in the different compartments and RVI for medium-term cancer-specific-survival (CSS) in pT3a RCC.

Materials And Methods: Patients with pT3a RCC were identified using an institutional database. All original pathological reports were reclassified according to the 7th TNM edition. The prognostic value of FI as well as divided into PFI, SFI, combined PFI + SFI, and RVI for CSS was assessed using univariate and multivariate Cox-regression analysis. Survival was estimated using the Kaplan-Meier method.

Results: Median follow-up in 184 pT3a tumors was 38 months. FI was detectable in 153 patients (32.7% PFI, 45.1% SFI, 22.2% PFI + SFI), 31 patients showed RVI alone. Combined PFI + SFI increased the risk of cancer-related death compared to PFI (HR 3.11, p < 0.01), SFI (HR 1.84, p = 0.023) or sole RVI (HR 2.12, p = 0.025). In multivariate analysis, a combined PFI + SFI vs. PFI or SFI as the only compartment involved was confirmed as independent prognostic factor (HR 1.83, p = 0.029). Patients with FI and simultaneous RVI had significantly shorter CSS (HR 2.63, p < 0.01). In an unweighted model, the difference between patients with combined PFI + SFI and RVI and those with PFI alone was highest (HR 4.01, p = 0.029).

Conclusions: These results underline the subdivision of pT3a RCC depending on the location of FI and RVI for patient stratification.
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http://dx.doi.org/10.1007/s00345-021-03638-0DOI Listing
February 2021

Increased Expressions of Matrix Metalloproteinases (MMPs) in Prostate Cancer Tissues of Men with Type 2 Diabetes.

Biomedicines 2020 Nov 16;8(11). Epub 2020 Nov 16.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Type 2 diabetes (T2D) is associated with worse prognosis of prostate cancer (PCa). The molecular mechanisms behind this association are still not fully understood. The aim of this study was to identify key factors, which contribute to the more aggressive PCa phenotype in patients with concurrent T2D. Therefore, we investigated benign and PCa tissue of PCa patients with and without diabetes using real time qPCR. Compared to patients without diabetes, patients with T2D showed a decreased E-cadherin/N-cadherin (CDH1/CDH2) ratio in prostate tissue, indicating a switch of epithelial-mesenchymal transition (EMT), which is a pivotal process in carcinogenesis. In addition, the gene expression levels of matrix metalloproteinases () and CC chemokine ligands () were higher in prostate samples of T2D patients. Next, prostate adenocarcinoma PC3 cells were treated with increasing glucose concentrations to replicate hyperglycemia in vitro. In these cells, high glucose induced expressions of and , which showed significant positive associations with the proliferation marker proliferating cell nuclear antigen (). These results indicate that in prostate tissue of men with T2D, hyperglycemia may induce EMT, increase and gene expressions, which in turn activate invasion and inflammatory processes accelerating the progression of PCa.
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http://dx.doi.org/10.3390/biomedicines8110507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696165PMC
November 2020

Characterization of Hormone-Dependent Pathways in Six Human Prostate-Cancer Cell Lines: A Gene-Expression Study.

Genes (Basel) 2020 Oct 7;11(10). Epub 2020 Oct 7.

Department of Internal Medicine IV, Division of Diabetology, Endocrinology, and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest.
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http://dx.doi.org/10.3390/genes11101174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599530PMC
October 2020

Transcript Levels of Aldo-Keto Reductase Family 1 Subfamily C (AKR1C) Are Increased in Prostate Tissue of Patients with Type 2 Diabetes.

J Pers Med 2020 Sep 12;10(3). Epub 2020 Sep 12.

Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, 72076 Tübingen, Germany.

Aldo-keto reductase family 1 (AKR1) enzymes play a crucial role in diabetic complications. Since type 2 diabetes (T2D) is associated with cancer progression, we investigated the impact of diabetes on gene expression in the context of prostate cancer (PCa) development. In this study, we analyzed benign (BEN) prostate and PCa tissue of patients with and without T2D. Furthermore, to replicate hyperglycemia in vitro, we treated the prostate adenocarcinoma cell line PC3 with increasing glucose concentrations. Gene expression was quantified using real-time qPCR. In the prostate tissue of patients with T2D, and transcripts were higher compared to samples of patients without diabetes. In PC3 cells, high glucose treatment induced the gene expression levels of , and . Furthermore, both in human tissue and in PC3 cells, the transcript levels of and showed positive associations with oncogenes, which are involved in proliferation processes and HIF1α and NFκB pathways. These results indicate that in the prostate glands of patients with T2D, hyperglycemia could play a pivotal role by inducing the expression of and . The higher transcript level of was furthermore associated with upregulated HIF1α and NFκB pathways, which are major drivers of PCa carcinogenesis.
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http://dx.doi.org/10.3390/jpm10030124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564141PMC
September 2020

Prognostic impact of somatostatin receptor expression in advanced bladder cancer.

Urol Oncol 2020 12 7;38(12):935.e17-935.e28. Epub 2020 Aug 7.

Clinical Trial Unit, Studienpraxis Urologie, Nürtingen, Germany; Medical School, Eberhard-Karls-University Tübingen, Tübingen, Germany. Electronic address:

Introduction And Objectives: Somatostatin receptors (SSTR) recently have been identified as potential targets for treatment of solid tumors. Furthermore, they have been shown to be of high relevance for tumor biology and prognosis in various types of cancer. However, there is a lack of clinical data for SSTR in bladder cancer (BC). Aim of this study was to determine the expression of all relevant somatostatin receptor subtypes in benign urothelium and tumor tissue of patients with muscle invasive BC. Furthermore, their potential role as prognostic factor for cancer-specific survival (CSS) and overall survival (OS) was evaluated.

Methods: The collective included BC and benign urothelium tissue of 103 patients (Median age 69; range 32-84, 79 male, 24 female) who underwent a radical cystectomy. A tissue microarray with subsequent immunohistochemical staining was used to assess membranous expression of SSTR1-5. Results were correlated to clinical and histopathological data as well as CSS and OS.

Results: Expressions of SSTR1-4 were significantly decreased in BC compared to benign urothelium (P < 0.002 each), whereas SSTR5 expression was increased (P = 0.0017). Expression of SSTR1 was associated with organ-confined disease (≤pT2) (P = 0.0477). No correlation between SSTR1-5 expression and N- and M-stage was observed. Univariate analyses showed a significantly longer CSS and OS in patients with high expression of SSTR3 (P = 0.0316 and 0.0044). Multivariate analyses confirmed SSTR3 expression as independent marker of improved CSS and OS (P = 0.0324 and 0.0076).

Conclusions: The majority of somatostatin receptor subtypes exhibit decreased expression in BC compared to benign bladder tissue. Expression of SSTR3 is an indicator for favorable prognosis in patients with muscle-invasive BC. These results support preclinical investigations using somatostatin receptor analogues such as octreotide to influence BC growth.
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http://dx.doi.org/10.1016/j.urolonc.2020.07.005DOI Listing
December 2020

MR Thermometry Data Correlate with Pathological Response for Soft Tissue Sarcoma of the Lower Extremity in a Single Center Analysis of Prospectively Registered Patients.

Cancers (Basel) 2020 Apr 13;12(4). Epub 2020 Apr 13.

Department of Radiation Oncology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Str. 3, 72076 Tuebingen, Germany.

: There is a strong biologic rationale for using locoregional hyperthermia in soft tissue sarcoma and a randomized trial reported significant improvements with hyperthermia. The aim of this study was to describe the opportunities of magnetic resonance (MR)-based thermometry in a cohort of soft tissue sarcoma patients undergoing combined radiotherapy and locoregional hyperthermia. : For eleven evaluable patients, tumor volume (V) and a separate volume for temperature analysis with reliable temperature distribution (V) were contoured for every hyperthermia treatment (103 therapies). Temperature data were recorded for all tumors and were correlated with clinical features and pathologic response data. : Of 48 patients with high-risk soft tissue sarcomas treated with radio(chemo)therapy and locoregional hyperthermia, MR thermometry was possible in 11 (23%) patients. For all patients, the temperature superseded by 90% of V (T90(V)) and T90 (V) were in the range of 37-43 °C and 40-45 °C, respectively. Larger tumors tended to reach higher temperatures. For tumors showing a pathologic response in the resection specimen after preoperative treatment, temperature (T90 (V)) was significantly higher than in tumors without pathologic response. : Lower extremity sarcomas undergoing preoperative treatment with locoregional hyperthermia are especially suitable for MR thermometry. MR thermometry is a promising non-invasive way for temperature measurement during locoregional hyperthermia, showing a positive dose-response relationship.
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http://dx.doi.org/10.3390/cancers12040959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226612PMC
April 2020

Integrative -omics and HLA-ligandomics analysis to identify novel drug targets for ccRCC immunotherapy.

Genome Med 2020 03 30;12(1):32. Epub 2020 Mar 30.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

Background: Clear cell renal cell carcinoma (ccRCC) is the dominant subtype of renal cancer. With currently available therapies, cure of advanced and metastatic ccRCC is achieved only in rare cases. Here, we developed a workflow integrating different -omics technologies to identify ccRCC-specific HLA-presented peptides as potential drug targets for ccRCC immunotherapy.

Methods: We analyzed HLA-presented peptides by MS-based ligandomics of 55 ccRCC tumors (cohort 1), paired non-tumor renal tissues, and 158 benign tissues from other organs. Pathways enriched in ccRCC compared to its cell type of origin were identified by transcriptome and gene set enrichment analyses in 51 tumor tissues of the same cohort. To retrieve a list of candidate targets with involvement in ccRCC pathogenesis, ccRCC-specific pathway genes were intersected with the source genes of tumor-exclusive peptides. The candidates were validated in an independent cohort from The Cancer Genome Atlas (TCGA KIRC, n = 452). DNA methylation (TCGA KIRC, n = 273), somatic mutations (TCGA KIRC, n = 392), and gene ontology (GO) and correlations with tumor metabolites (cohort 1, n = 30) and immune-oncological markers (cohort 1, n = 37) were analyzed to characterize regulatory and functional involvements. CD8 T cell priming assays were used to identify immunogenic peptides. The candidate gene EGLN3 was functionally investigated in cell culture.

Results: A total of 34,226 HLA class I- and 19,325 class II-presented peptides were identified in ccRCC tissue, of which 443 class I and 203 class II peptides were ccRCC-specific and presented in ≥ 3 tumors. One hundred eighty-five of the 499 corresponding source genes were involved in pathways activated by ccRCC tumors. After validation in the independent cohort from TCGA, 113 final candidate genes remained. Candidates were involved in extracellular matrix organization, hypoxic signaling, immune processes, and others. Nine of the 12 peptides assessed by immunogenicity analysis were able to activate naïve CD8 T cells, including peptides derived from EGLN3. Functional analysis of EGLN3 revealed possible tumor-promoting functions.

Conclusions: Integration of HLA ligandomics, transcriptomics, genetic, and epigenetic data leads to the identification of novel functionally relevant therapeutic targets for ccRCC immunotherapy. Validation of the identified targets is recommended to expand the treatment landscape of ccRCC.
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http://dx.doi.org/10.1186/s13073-020-00731-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7106651PMC
March 2020

Simultaneous whole-body PET/MRI with integrated multiparametric MRI for primary staging of high-risk prostate cancer.

World J Urol 2020 Oct 6;38(10):2513-2521. Epub 2020 Jan 6.

Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.

Purpose: Whole-body positron emission tomography/magnetic resonance imaging (wbPET/MRI) is a promising diagnostic tool of recurrent prostate cancer (PC), but its role in primary staging of high-risk PC (hrPC) is not well defined. Thus, the aim was to compare the diagnostic accuracy for T-staging of PET-blinded reading (PBR) and PET/MRI.

Methods: In this prospective study, hrPC patients scheduled to radical prostatectomy (RPx) with extended lymphadenectomy (eLND) were staged with wbPET/MRI and either Ga-PSMA-11 or C-choline including simultaneous multiparametric MRI (mpMRI). Images were assessed in two sessions, first as PBR (mpMRI and wbMRI) and second as wbPET/MRI. Prostate Imaging Reporting and Data System criteria (PIRADS v2) were used for T-staging. Results were correlated with the exact anatomical localization and extension as defined by histopathology. Diagnostic accuracy of cTNM stage according to PBR was compared to pathological pTNM stage as reference standard.

Results: Thirty-four patients underwent wbPET/MRI of Ga-PSMA-11 (n = 17) or C-choline (n = 17). Twenty-four patients meeting the inclusion criteria of localized disease ± nodal disease based on imaging results underwent RPx and eLND, whereas ten patients were excluded from analysis due to metastatic disease. T-stage was best defined by mpMRI with underestimation of tumor lesion size by PET for both tracers. N-stage yielded a per patient sensitivity/specificity comparable to PBR.

Conclusion: MpMRI is the primary modality for T-staging in hrPC as PET underestimated T-stage in direct comparison to final pathology. In this selected study, cohort MRI shows no inferiority compared to wbPET/MRI considering N-staging.
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http://dx.doi.org/10.1007/s00345-019-03066-1DOI Listing
October 2020

Safety and effectiveness of a novel generator algorithm for bipolar vessel sealing: a randomised controlled chronic animal study.

BMC Surg 2019 Nov 5;19(1):160. Epub 2019 Nov 5.

Erbe Elektromedizin GmbH, Waldhoernlestrasse 17, 72072, Tuebingen, Germany.

Background: Electrosurgical vessel sealers are gradually replacing conventional techniques such as ligation and clipping. Algorithms that control electrosurgical units (ESU), known as modes, are important for applications in different surgical disciplines. This chronic porcine animal study aimed to evaluate the safety and effectiveness of the novel thermoSEAL electrosurgical vessel sealing mode (TSM). The BiClamp® mode (BCM) of the renowned VIO® 300 D ESU served as control. BCM has been widely available since 2002 and has since been successfully used in many surgical disciplines. The TSM, for the novel VIO® 3 ESU, was developed to reduce sealing time and/or thermal lateral spread adjacent to the seal while maintaining clinical success rates. The primary aim of this study was to investigate the long-term and intraoperative seal quality of TSM.

Methods: The BiCision® device was used for vessel sealing with TSM and BCM in ten German Landrace pigs which underwent splenectomy and unilateral nephrectomy during the first intervention of the study. The seals were cut with the BiCision® knife. Ninety-nine arteries, veins and vascular bundles were chronically sealed for 5 or 21 days. Thereafter, during the second and terminal intervention of the study, 97 additional arteries and veins were sealed. The carotid arteries were used for histological evaluation of thermal spread.

Results: After each survival period, no long-term complications occurred with either mode. The intraoperative seal failure rates, i.e. vessel leaking or residual blood flow after the first sealing activation, were 2% with TSM versus 6% with BCM (p = 0.28). The sealing time was significantly shorter with TSM (3.5 ± 0.69 s vs. 7.3 ± 1.3 s, p < 0.0001). The thermal spread and burst pressure of arteries sealed with both modes were similar (p = 0.18 and p = 0.61) and corresponded to the histological evaluation. The measured tissue sticking parameter was rare with both modes (p = 0.33). Tissue charring did not occur. Regarding the cut quality, 97% of the seals were severed in the first and 3% in the second attempt (both with TSM and BCM).

Conclusions: The novel TSM seals blood vessels twice as fast as the BCM while maintaining excellent tissue effect and clinical success rates.

Trial Registration: Not applicable.
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http://dx.doi.org/10.1186/s12893-019-0625-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833204PMC
November 2019

Assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation.

J Cancer Res Clin Oncol 2019 Jul 22;145(7):1835-1843. Epub 2019 Apr 22.

Department of Urology, Eberhard Karls University, Hoppe-Seyler- Strasse 3, 72076, Tuebingen, Germany.

Introduction: Based on the observation of beneficial effects on cancer metabolism, microenvironment, or VEGF-signaling, several non-anticancer drugs have been discussed as useful in renal cell carcinoma (RCC). In the present study, we investigated the prognostic impact of concomitant medication in RCC and correlated comedication with cell-cycle and proliferation activity in corresponding surgical specimen.

Methods: A total of 388 patients who underwent surgery for localized RCC were included. The individual medication was evaluated according to substance classes. Tissue microarrays from corresponding tumor specimen were immunohistochemically (IHC) stained for Cyclin D1 and Ki67 and semi-quantitatively evaluated. Uni- and multivariate analyses were used to compare survival outcomes. For the comparison of IHC expression according to medication subgroups, Kruskal-Wallis analysis was performed.

Results: Median follow-up was 57.93 months (95% CI 53.27-69.43) and median OS accounted for 181.12 months (129.72-237.17). Univariate analysis identified pathological standard variables (T-stage > T2, Grading > G2, L1, N1, M1, sarcomatoid subtype, necrosis) as significant determinants of OS. Moreover, statin use (p = 0.009) and sartan use (p = 0.032) were significantly associated with improved OS. Multivariate analysis identified M1-stage (p < 0.001), statin and sartan use (p = 0.003 and p = 0.033, respectively) as independent prognosticators of survival. Expression of Ki67 was significantly reduced in patients with statin use (p = 0.013), while Cyclin D1 expression showed no correlation with comedication.

Conclusions: Concomitant intake of statins and sartans identifies as an independent predictor of OS in RCC, and reduced Ki67 expression was significantly associated with statin use. Further evaluation of drug repurposing approaches with these substances in RCC appear warranted.
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http://dx.doi.org/10.1007/s00432-019-02914-2DOI Listing
July 2019

Transketolase like 1 (TKTL1) expression alterations in prostate cancer tumorigenesis.

Urol Oncol 2018 10 16;36(10):472.e21-472.e27. Epub 2018 Aug 16.

Department of Urology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany. Electronic address:

Background: Prostate cancer (CaP) is the most common nonepidermal cancer in elderly males. Due to its heterogeneity and high variability in regards to clinical outcome and therapeutic response, urologists' handling of this disease remains a challenge. The objective of this study was to assess Transketolase like 1 (TKTL1) expression in benign prostatic tissue, peritumoral tissue and in CaP (in different stages of disease), and its correlation with clinicopathological findings, in order to detect if TKTL1 expression is associated with CaP tumorigenesis.

Methods: In total, 100 tissue samples were included: (i) 22 benign specimens, (ii) 46 specimens with nonmetastatic CaP, and (iii) 32 specimens from patients with metastatic CaP. From the tissue microarray slides, we evaluated immunohistochemically the expression of the TKTL1 protein, using the H-score.

Results: The TKTL1 protein expression pattern ranges from a low level in benign prostatic tissue (100 [57.5-105]), moderately low in peritumoral tissue (135.42 [100-195.16]), moderate expression in nonmetastatic CaP (200 [172.19-254.38]) to high in metastatic CaP (300 [222.50-300]). A significant rise of TKTL1 mean expression was seen throughout disease progression. A significant difference was also found in TKTL1 expression between peritumoral tissue and benign tissue.

Conclusion: The results obtained in this study suggest that pentose phosphate pathway and its key enzyme TKTL1 is altered throughout the CaP tumorigenesis, and this pathway merits further investigation.
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http://dx.doi.org/10.1016/j.urolonc.2018.06.010DOI Listing
October 2018

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma.

Int J Cancer 2018 12 25;143(12):3181-3193. Epub 2018 Sep 25.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.
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http://dx.doi.org/10.1002/ijc.31741DOI Listing
December 2018

Clinical utility of the S3-score for molecular prediction of outcome in non-metastatic and metastatic clear cell renal cell carcinoma.

BMC Med 2018 07 5;16(1):108. Epub 2018 Jul 5.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany.

Background: Stratification of cancer patients to identify those with worse prognosis is increasingly important. Through in silico analyses, we recently developed a gene expression-based prognostic score (S3-score) for clear cell renal cell carcinoma (ccRCC), using the cell type-specific expression of 97 genes within the human nephron. Herein, we verified the score using whole-transcriptome data of independent cohorts and extend its application for patients with metastatic disease receiving tyrosine kinase inhibitor treatment. Finally, we sought to improve the signature for clinical application using qRT-PCR.

Methods: A 97 gene-based S3-score (S3) was evaluated in a set of 52 primary non-metastatic and metastatic ccRCC patients as well as in 53 primary metastatic tumors of sunitinib-treated patients. Gene expression data of The Cancer Genome Atlas (n = 463) was used for platform transfer and development of a simplified qRT-PCR-based 15-gene S3-score (S3). This S3-score was validated in 108 metastatic and non-metastatic ccRCC patients and ccRCC-derived metastases including in part several regions from one metastasis. Univariate and multivariate Cox regression stratified by T, N, M, and G were performed with cancer-specific and progression-free survival as primary endpoints.

Results: The S3-score was significantly associated with cancer-specific survival (CSS) in 52 ccRCC patients (HR 2.9, 95% Cl 1.0-8.0, P = 3.3 × 10) as well as progression-free survival in sunitinib-treated patients (2.1, 1.1-4.2, P = 2.2 × 10). The qRT-PCR based S3-score performed similarly to the S3-score, and was significantly associated with CSS in our extended cohort of 108 patients (5.0, 2.1-11.7, P = 5.1 × 10) including metastatic (9.3, 1.8-50.0, P = 2.3 × 10) and non-metastatic patients (4.4, 1.2-16.3, P = 1.6 × 10), even in multivariate Cox regression, including clinicopathological parameters (7.3, 2.5-21.5, P = 3.3 × 10). Matched primary tumors and metastases revealed similar S3-scores, thus allowing prediction of outcome from metastatic tissue. The molecular-based qRT-PCR S3-score significantly improved prediction of CSS by the established clinicopathological-based SSIGN score (P = 1.6 × 10).

Conclusion: The S3-score offers a new clinical avenue for ccRCC risk stratification in the non-metastatic, metastatic, and sunitinib-treated setting.
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http://dx.doi.org/10.1186/s12916-018-1088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6033218PMC
July 2018

Metabolic and Lipidomic Reprogramming in Renal Cell Carcinoma Subtypes Reflects Regions of Tumor Origin.

Eur Urol Focus 2019 07 13;5(4):608-618. Epub 2018 Feb 13.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Clinical Pharmacology, University Hospital Tuebingen, Tuebingen, Germany; Department of Pharmacy and Biochemistry, University of Tuebingen, Tuebingen, Germany. Electronic address:

Background: Renal cell carcinoma (RCC) consists of prognostic distinct subtypes derived from different cells of origin (eg, clear cell RCC [ccRCC], papillary RCC [papRCC], and chromophobe RCC [chRCC]). ccRCC is characterized by lipid accumulation and metabolic alterations, whereas data on metabolic alterations in non-ccRCC are limited.

Objective: We assessed metabolic alterations and the lipid composition of RCC subtypes and ccRCC-derived metastases. Moreover, we elucidated the potential of metabolites/lipids for subtype classification and identification of therapeutic targets.

Design, Setting, And Participants: Metabolomic/lipidomic profiles were quantified in ccRCC (n=58), chRCC (n=19), papRCC (n=14), corresponding nontumor tissues, and metastases (n=9) through a targeted metabolomic approach. Transcriptome profiling was performed in corresponding samples and compared with expression data of The Cancer Genome Atlas cohorts (patients with ccRCC, n=452; patients with papRCC, n=260; and patients with chRCC, n=59).

Outcome Measurements And Statistical Analysis: In addition to cluster analyses, metabolomic/transcriptomic data were analyzed to evaluate metabolic differences of ccRCC and chRCC using Welch's t test or paired t test as appropriate. Where indicated, p values were adjusted for multiple testing using Bonferroni or Benjamini-Hochberg correction.

Results And Limitations: Based on their metabolic profiles, RCC subtypes clustered into two groups separating ccRCC and papRCC from chRCC, which mainly reflected the different cells of origin. ccRCC-derived metastases clustered with primary ccRCCs. In addition to differences in certain lipids (lysophosphatidylcholines and sphingomyelins), the coregulation network of lipids differed between ccRCC and chRCC. Consideration of metabolic gene expression indicated, for example, alterations of the polyamine pathway at metabolite and transcript levels. In vitro treatment of RCC cells with the ornithine-decarboxylase inhibitor difluoromethylornithine resulted in reduced cell viability and mitochondrial activity. Further evaluation of clinical utility was limited by the retrospective study design and cohort size.

Conclusions: In summary, we provide novel insight into the metabolic profiles of ccRCC and non-ccRCC, thereby confirming the different ontogeny of RCC subtypes. Quantification of differentially regulated metabolites/lipids improves classification of RCC with an impact on the identification of novel therapeutic targets.

Patient Summary: Several subtypes of renal cell carcinoma (RCC) with different metastatic potentials and prognoses exist. In the present study, we provide novel insight into the metabolism of these different subtypes, which improves classification of subtypes and helps identify novel targets for RCC therapy.
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http://dx.doi.org/10.1016/j.euf.2018.01.016DOI Listing
July 2019

A prospective randomized experimental study to investigate the peritoneal adhesion formation after waterjet injection and argon plasma coagulation (HybridAPC) in a rat model.

Arch Gynecol Obstet 2018 04 23;297(4):961-967. Epub 2018 Jan 23.

Department of Obstetrics and Gynecology, University of Tuebingen, Calwerstr. 7, 72076, Tübingen, Germany.

Background: This prospective, randomized, controlled, single-blinded study investigates the peritoneal adhesion formation of HybridAPC (waterjet elevation of the peritoneum with subsequent argon plasma coagulation) versus only waterjet (elevation with the same instrument, but without subsequent argon plasma coagulation) in a rat model (24 female Wistar rats).

Materials And Methods: Bilateral lesions were created on the abdominal wall with HybridAPC on one sidewall and waterjet elevation on the other sidewall of the peritoneum in a standard fashion. After 10 days, the rats were euthanized to evaluate the peritoneal trauma sites.

Main Outcome Measure(s): Adhesion incidence, quantity, and quality were scored 10 days postoperatively and studied histopathologically.

Result(s): Incidence of adhesion formation was 2.3% for HybridAPC; no adhesions occurred for peritoneal elevation with saline (p = 1.00). Histologic evaluation revealed no acute inflammation in both groups. An overall moderate degree of granulation tissue formation and myonecrosis was observed in the HybridAPC group, whereas no chronic inflammation and myonecrosis occurred after elevation without thermal ablation (p < 0.0001).

Conclusion(s): This study investigates the effect of waterjet elevation of the peritoneum with and without subsequent thermal ablation on adhesion formation in a rat model for the first time. Peritoneal waterjet elevation with saline does not provide any risk of adhesion formation. Thermal coagulation with APC after waterjet elevation of the peritoneum creates advantageous peritoneal conditions due to a permanent moist tissue surface and the cooling effect of the injected solution, resulting in no significant difference in adhesion formation compared to peritoneal elevation without thermal ablation. HybridAPC can thus be regarded as a beneficial coagulation method with only minor adhesion formation due to positive tissue effects of the combined waterjet.
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http://dx.doi.org/10.1007/s00404-018-4661-4DOI Listing
April 2018

Higher prevalence of lymph node metastasis in prostate cancer in patients with diabetes.

Endocr Relat Cancer 2018 03 12;25(3):L19-L22. Epub 2018 Jan 12.

Department of Internal MedicineDivision of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.

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http://dx.doi.org/10.1530/ERC-17-0465DOI Listing
March 2018

Androgen receptor overexpression in prostate cancer in type 2 diabetes.

Mol Metab 2018 02 5;8:158-166. Epub 2017 Dec 5.

Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Disease, Nephrology and Clinical Chemistry, University of Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM), Helmholtz Center Munich, University of Tübingen, Germany; German Center for Diabetes Research (DZD), Munich-Neuherberg, Germany.

Objective: While prostate cancer does not occur more often in men with diabetes, survival is markedly reduced in this patient group. Androgen signaling is a known and major driver for prostate cancer progression. Therefore, we analyzed major components of the androgen signaling chain and cell proliferation in relation to type 2 diabetes.

Methods: Tumor content of 70 prostate tissue samples of men with type 2 diabetes and 59 samples of patients without diabetes was quantified by an experienced pathologist, and a subset of 51 samples was immunohistochemically stained for androgen receptor (AR). mRNA expression of AR, insulin receptor isoform A (IR-A) and B (IR-B), IGF-1 receptor (IGF1R), Cyp27A1 and Cyp7B1, PSA gene KLK3, PSMA gene FOLH1, Ki-67 gene MKI67, and estrogen receptor beta (ESR2) were analyzed by RT-qPCR.

Results: AR mRNA and protein expression were associated with the tumor content only in men with diabetes. AR expression also correlated with downstream targets PSA (KLK3) and PSMA (FOLH1) and increased cell proliferation. Only in diabetes, AR expression was correlated to higher IR-A/IR-B ratio and lower IR-B/IGF1R ratio, thus, in favor of the mitogenic isoforms. Reduced Cyp27A1 and increased Cyp7B1 expressions in tumor suggest lower levels of protective estrogen receptor ligands in diabetes.

Conclusions: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes.
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http://dx.doi.org/10.1016/j.molmet.2017.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985051PMC
February 2018

Targeted vs systematic robot-assisted transperineal magnetic resonance imaging-transrectal ultrasonography fusion prostate biopsy.

BJU Int 2018 05 15;121(5):791-798. Epub 2018 Jan 15.

Department of Urology, Eberhard Karls University, Tübingen, Germany.

Objective: To evaluate the performance of transperineal robot-assisted (RA) targeted (TB) and systematic (SB) prostate biopsy in primary and repeat biopsy settings.

Patients And Methods: Patients underwent RA biopsy between 2014 and 2016. Before RA-TB, multiparametric magnetic resonance imaging (mpMRI) was performed. Prostate lesions were scored (Prostate Imaging, Reporting and Data System, version 2) and used for RA-TB planning. In addition, RA-SB was performed. Available, whole-gland pathology was analysed.

Results: In all, 130 patients were biopsy naive and 72 had had a previous negative transrectal ultrasonography-guided biopsy. In total, 202 patients had suspicious mpMRI lesions. Clinically significant prostate cancer was found in 85% of all prostate cancer cases (n = 123). Total and clinically significant prostate cancer detection rates for RA-TB vs RA-SB were not significantly different at 77% vs 84% and 80% vs 82%, respectively. RA-TB demonstrated a better sampling performance compared to RA-SB (26.4% vs 13.9%; P < 0.001).

Conclusion: Transperineal RA-TB and -SB showed similar clinically significant prostate cancer detection rates in primary and repeat biopsy settings. However, RA-TB offered a 50% reduction in biopsy cores. Omitting RA-SB is associated with a significant risk of missing clinically significant prostate cancer.
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http://dx.doi.org/10.1111/bju.14089DOI Listing
May 2018

Ex vivo γH2AX radiation sensitivity assay in prostate cancer: Inter-patient and intra-patient heterogeneity.

Radiother Oncol 2017 09 14;124(3):386-394. Epub 2017 Sep 14.

Medical Faculty and University Hospital, Eberhard Karls University Tübingen, Radiation Oncology, Germany. Electronic address:

Introduction: The aim of the study is to assess inter-patient and intra-patient heterogeneity in tumour cell radiosensitivity using the ex vivo γH2AX assay in prostate cancer specimens.

Methods: Excised specimens from untreated prostate cancer patients were cultivated 24h in media, irradiated ex vivo and fixed after 24h. Residual γH2AX foci were counted and the slope of the dose response was calculated. Intra-patient heterogeneity was studied from three to seven different biopsies.

Results: In pathology-confirmed tumour samples from 21 patients the slope of residual γH2AX foci and radiation dose showed a substantial heterogeneity ranging from 0.82 to 3.17 foci/Gy. No correlation was observed between the slope values and the Gleason score (p=0.37), prostate specific antigen (p=0.48) and tumour stage (p=0.89). ANOVA indicated that only in 1 out of 9 patients, biopsies from different tumour locations yielded statistically significant differences. Variance component analysis indicated higher inter-patient than intra-patient variability. Bootstrap simulation study demonstrated that one biopsy is sufficient to estimate the mean value of residual γH2AX per dose level and account for intra-patient heterogeneity.

Conclusions: In prostate cancer inter-patient heterogeneity in tumour cell radiation sensitivity is pronounced and higher than intra-patient heterogeneity supporting the further development of the γH2AX ex vivo assay as a biomarker for individualized treatment.
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http://dx.doi.org/10.1016/j.radonc.2017.08.020DOI Listing
September 2017

Microvascular and lymphovascular tumour invasion are associated with poor prognosis and metastatic spread in renal cell carcinoma: a validation study in clinical practice.

BJU Int 2018 01 10;121(1):84-92. Epub 2017 Sep 10.

Department of Urology, Ernst-Moritz Arndt University of Greifswald, Greifswald, Germany.

Objective: To validate microvascular (MVI) and lymphovascular (LVI) invasion as prognostic factors in patients with renal cell carcinoma (RCC).

Patients And Methods: Data of patients with RCC who underwent radical or nephron-sparing surgery were prospectively collected from three academic centres. The occurrence of MVI and LVI was determined with standard staining protocols by experienced pathologists at the time of diagnosis. The association of MVI and LVI with clinicopathological data, metastatic spread, and cancer-specific survival (CSS) were evaluated with Fisher's exact tests, binary logistic regression analyses, and univariable and multivariable Cox proportional hazard regression models.

Results: MVI was present in 201 of 747 patients (26.9%) and was associated with advanced Tumour-Node-Metastasis (TNM) stages, high Fuhrman grades, and sarcomatoid features (all P < 0.001). MVI was associated with a higher rate of metastatic spread. LVI was present in 32 of 573 patients (5.5%) and was associated with advanced TNM stages, high Fuhrman grade, and sarcomatoid features (all P < 0.001). Two-thirds of LVI-positive patients died (P < 0.001). Both LVI and MVI were significantly associated with CSS in all patients, clear cell RCC (ccRCC), and localised RCC in univariable analysis (all P < 0.001). On multivariable analysis, presence of MVI was identified as an independent prognostic factor (hazard ratio 2.09; P = 0.001). Moreover, MVI [odds ratio (OR) 2.7; P = 0.001] and not macrovascular invasion (P = 0.895) was an independent predictor of sychronuous metastatic spread. LVI was the strongest factor associated with sychronous metastatic spread (OR 4.73, 95% confidence interval 1.84-12.14; P = 0.001) in all patients and in the subgroup of patients with ccRCC (P = 0.001).

Conclusions: The present study validated LVI and MVI as prognostic factors for poor outcome in RCC. These findings endorse an evaluation of both variables in the clinical routine setting to facilitate survival prognostication in follow-up protocols and for assignment to adjuvant treatment trials.
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http://dx.doi.org/10.1111/bju.13984DOI Listing
January 2018

The Value and Evaluability of the PCA3 Urine Assay in Prostate Carcinoma is Independent of the Tumor Localization.

Adv Ther 2017 04 13;34(4):966-974. Epub 2017 Mar 13.

Department of Urology, Eberhard-Karls-University of Tübingen, Tuebingen, Germany.

Introduction: The prostate cancer gene 3 (PCA3) test is based on the analysis of tumor cell mRNA in urine. As an exprimated urinary marker, its retrieval is subject to certain physical aspects like palpation pressure and detachment force during the squeezing of cells. Other potential factor of influence may be the distance the cells have to cover until they reach the urethra. Thus, it was investigated whether the localization of the tumors within the prostate with regard to the urethra and the seminal colliculus influences the PCA3 score.

Methods: Prostatectomy specimens of 55 organ-confined prostate cancer patients were processed according to the Stanford protocol. For each prostatectomy specimen, a three-dimensional reconstruction including the surface of the prostate, the tumor areas and the urethra was created. By model simulating, virtual concentric tubes were placed around the urethra and spherical volumes were virtually positioned around the seminal colliculus at diameters of 8, 16 and 32 mm. Depending on localization, tumor volumes may or may not protrude into the tubes or spherical volumes. For each respective diameter, PCA3 levels were compared between the subgroup with and without protrusion of tumor tissue into the tube or spherical ball.

Results: For none of the diameters, whether in tubes or spherical balls, were patients without intersection volumes-hence showing peripherally located tumors-found to have lower PCA3 levels. No clinical or histopathological parameter correlated with the PCA3 score.

Conclusion: The location of the tumor mass in the prostate with respect to the urethra or the seminal colliculus did not to affect the PCA3 score. Hence, the location of the tumor does not limit the validity of the PCA3 score, and even for exclusively peripherall y located tumors, this possible influencing factor did not lead to an artificial modulation of the PCA3 score.
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http://dx.doi.org/10.1007/s12325-017-0510-2DOI Listing
April 2017

Methylomes of renal cell lines and tumors or metastases differ significantly with impact on pharmacogenes.

Sci Rep 2016 07 20;6:29930. Epub 2016 Jul 20.

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany and University of Tuebingen, Auerbachstr. 112, 70376 Stuttgart, Germany.

Current therapies for metastatic clear cell renal cell carcinoma (ccRCC) show limited efficacy. Drug efficacy, typically investigated in preclinical cell line models during drug development, is influenced by pharmacogenes involved in targeting and disposition of drugs. Here we show through genome-wide DNA methylation profiling, that methylation patterns are concordant between primary ccRCC and macro-metastases irrespective of metastatic sites (rs ≥ 0.92). However, 195,038 (41%) of all investigated CpG sites, including sites within pharmacogenes, were differentially methylated (adjusted P < 0.05) in five established RCC cell lines compared to primary tumors, resulting in altered transcriptional expression. Exemplarily, gene-specific analyses of DNA methylation, mRNA and protein expression demonstrate lack of expression of the clinically important drug transporter OCT2 (encoded by SLC22A2) in cell lines due to hypermethylation compared to tumors or metastases. Our findings provide evidence that RCC cell lines are of limited benefit for prediction of drug effects due to epigenetic alterations. Similar epigenetic landscape of ccRCC-metastases and tumors opens new avenue for future therapeutic strategies.
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http://dx.doi.org/10.1038/srep29930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951699PMC
July 2016

Oncologic Impact of Renal Tissue Adjacent to Renal Cell Carcinoma.

Anticancer Res 2016 Jun;36(6):2865-9

Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany

Aim: The aim of the study was to investigate the clinical impact of the surgical margin width after nephron-sparing surgery (NSS) on the oncological course of renal cell carcinoma (RCC).

Patients And Methods: The study comprised of 126 RCC patients with NSS between 2002 and 2009. Inclusion criteria were negative resection margins and a tumor diameter of ≤100 mm with the possibility of a complete circumferential histopathological reevaluation. The minimal benign margin width was correlated to the patients' clinical course.

Results: Median safety margin width was revealed to be 1 mm. Nine of 126 patients (7.1%) developed recurrent disease (five local, four distant). All patients with local recurrence had safety margins ≤1 mm, whereas out of 49 patients with a margin >1 mm no one developed local recurrence (p=0.0245). Safety margin ≤1 mm showed associations with increased risk for overall recurrence in univariate and multivariate analysis (p=0.0531 and 0.0539, respectively).

Conclusion: Tumor adjacent renal parenchyma may have oncological relevance, corroborating the need for further molecular investigation of tumor-adjacent tissue in RCC.
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June 2016

Angiosarcoma arising in association with vascular Dacron grafts and orthopedic joint prostheses: clinicopathologic, immunohistochemical, and molecular study.

Ann Diagn Pathol 2016 Apr 11;21:21-8. Epub 2016 Jan 11.

Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.

Angiosarcoma may rarely arise near an inert foreign body material including vascular grafts and metal joint prostheses. Sixteen such cases have been reported since 1972 but mostly in the radiologic or surgical literature without detailed histologic or molecular analyses. We herein describe the clinicopathologic and molecular features of 2 new cases and reanalyzed 3 previously reported cases of angiosarcoma that developed in association with Dacron grafts for vascular repair (n=3) or related to orthopedic metal prostheses for joint replacement (n=2). All patients were men aged 50 to 84 years (median, 71 years). Mean time to development of angiosarcoma was 9 years (range, 4.6-17 years). Symptoms were recurrent bleeding/loosening of prosthesis for suspected infection (in the joint prosthesis cases) and fatigue, weight loss, and abdominal symptoms in the Dacron-associated cases. Four patients died of disease within 1 to 24 months (mean, 8 months). One patient was alive after radical surgery, radiochemotherapy, and embolization of pulmonary metastases (17 months). Histologically, all tumors were high-grade epithelioid neoplasms with a predominant solid growth pattern and variable vasoformation. All tumors expressed CD31, ERG, FLI-1, and variably pancytokeratin (diffuse in 3 cases), but none expressed D2-40, MDM2, or CDK4. Fluorescence in situ hybridization analysis revealed no MDM2 or CDK4 alterations. MYC was expressed in all cases, but only 1 case was MYC amplified by fluorescence in situ hybridization. Angiosarcomas are exceedingly rare fatal complications of long-standing metal and Dacron prostheses. Awareness of their morphology and frequent cytokeratin expression is necessary to avoid misdiagnosis as metastatic carcinoma. Limited awareness of their existence explains delayed clinical diagnosis in most of cases. Absence of MDM2/CDK4 alterations underlines their distinction from intimal-type sarcomas.
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http://dx.doi.org/10.1016/j.anndiagpath.2016.01.002DOI Listing
April 2016

Differential expression and clinical relevance of MUC1 in renal cell carcinoma metastasis.

World J Urol 2016 Dec 19;34(12):1635-1641. Epub 2016 Mar 19.

Department of Urology, Eberhard-Karls-University Tübingen, Hoppe-Seyler-Str.3, 72076, Tübingen, Germany.

Purpose: To determine the differential expression patterns and prognostic relevance of Mucin-1 (MUC1) expression in clear cell renal cell carcinoma (RCC) metastasis.

Methods: Tissue microarrays (TMA) from samples of 151 RCC metastases, 61 primary RCCs and corresponding benign renal tissues were immunohistochemically stained for MUC1 and semi-quantitatively evaluated by immunoreactivity scores (IRS). MUC1 differential expression in metastasis, primary RCC and normal tissue were comparatively analyzed. Patient characteristics and clinical follow-up for patients with metastatic RCC (mRCC) were recorded. Correlations of MUC1 expression with mRCC survival were determined.

Results: Median cytoplasmic expression was highest in benign tissue (IRS = 1.04). Primary RCC (0.50) and metastasis (0.12) showed significantly lower cytoplasmic staining intensity. Membranous expression in benign tissue was, however, significantly lower (0.21) compared with primary RCC (0.59) and metastasis (0.57). Notable differences of MUC1 cytoplasmic and membranous expression were observed between different metastasis sites. Significantly higher (P = 0.014) membranous expression was observed in pulmonary versus non-pulmonary lesions, while no significant differences of cytoplasmic MUC1 expression were observed. The prognostic relevance of MUC1 expression in metastatic RCC was limited.

Conclusions: MUC1 is differentially expressed in benign renal tissue, primary RCC and RCC metastasis. Membranous MUC1 expression was significantly elevated in pulmonary metastases compared to non-pulmonary lesions, which may reflect individual biology and putative response to MUC1-based anti-cancer therapy.
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http://dx.doi.org/10.1007/s00345-016-1804-8DOI Listing
December 2016

A Prospective Randomized Experimental Study to Investigate the Eradication Rate of Endometriosis after Surgical Resection versus Aerosol Plasma Coagulation in a Rat Model.

Int J Med Sci 2016 18;13(3):187-94. Epub 2016 Feb 18.

1. Department of Obstetrics and Gynaecology, University of Tuebingen, Calwerstr. 7, 72076 Tuebingen, Germany (Director: Prof. D. Wallwiener);

Purpose: To investigate the eradication rate of endometriosis after surgical resection (SR) vs. thermal ablation with aerosol plasma coagulation (AePC) in a rat model.

Methods: In this prospective, randomized, controlled, single-blinded animal study endometriosis was induced on the abdominal wall of 34 female Wistar rats. After 14 days endometriosis was either removed by SR or ablated by AePC. 14 days later the rats were euthanized to evaluate the eradication rate histopathologically. Intervention times were recorded.

Results: Eradication rate of endometriosis after 14 days did not significantly differ between AePC and SR (p=0.22). Intervention time per endometrial lesion was 22.1 s for AePC and 51.8 s for SR (p<0.0001).

Conclusions: This study compares the eradication rate of the new aerosol plasma coagulation device versus standard surgical resection of endometriosis in a rat model. Despite being a thermal method, AePC showed equality towards SR regarding eradication rate but with significantly shorter intervention time.
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http://dx.doi.org/10.7150/ijms.14246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773283PMC
December 2016

Ten Years of Complete Remission of Pulmonary Metastasis after Post-Cystectomy Palliative Cisplatin-Gemcitabine Chemotherapy with Gefitinib for Muscle Invasive Bladder Cancer: A Case Report.

Urol Int 2016 11;97(4):485-488. Epub 2016 Feb 11.

Department of Urology, Eberhard-Karls University, Tuebingen, Germany.

Muscle-invasive bladder cancer (MIBC) is considered one of the most lethal malignancies with high metastatic potential. Usually, metastatic bladder cancer carries worse prognosis with a median survival rate of approximately 6 months, which can be prolonged for up to 14 months with palliative systemic chemotherapy. We present the case of a 61-year-old male patient diagnosed with localized MIBC 10 years ago. He underwent nerve-sparing radical cystectomy with ileal neobladder, but developed pulmonary metastatic disease 7 months postoperatively. Six cycles of gemcitabine/cisplatin combination chemotherapy with an addition of gefitinib as daily oral medication were administered within a randomized phase II clinical trial; this resulted in complete remission of the pulmonary metastases. Until now, the patient is still on gefitinib daily without any side effects. Although, the addition of gefitinib to standard systemic chemotherapy has not been shown to improve the survival in metastatic urothelial cancer, this case represents a very pleasant albeit uncommon long-term outcome.
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http://dx.doi.org/10.1159/000441700DOI Listing
April 2018

Cytokeratin-positive interstitial reticulum cell tumor: recognition of a potential "in situ" pattern.

Hum Pathol 2016 Mar 26;49:15-21. Epub 2015 Oct 26.

Department of Pathology, University Hospital of Tübingen, D-72076 Tübingen, Germany.

Cytokeratin-positive interstitial reticulum cell (CIRC) tumor is a very rare accessory cell neoplasm of lymphoid organs derived from fibroblastic reticulum cells, which originate from mesenchymal stem cells. We describe the histologic, immunophenotypical, and molecular features of a CIRC tumor in a 67-year-old woman who underwent hysterectomy, bilateral adnexectomy, and pelvic lymphadenectomy for endometrial carcinoma. An enlarged pelvic node contained circumscribed neoplastic infiltrates in perifollicular and interfollicular areas consisting of large cells arranged in a reticular pattern with nuclear atypia, atypical mitoses, and apoptosis, but without glandular architecture or disruption of overall architecture. The atypical infiltrate coexpressed cytokeratin and vimentin, partially CD68, CD163, and lysozyme, but lacked markers of endometrial carcinoma, consistent with a diagnosis of CIRC tumor. Despite the obviously neoplastic cytological features, immunostains revealed the circumscribed and noninvasive pattern of the lesion, possibly representing an early "in situ" stage of CIRC tumor.
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http://dx.doi.org/10.1016/j.humpath.2015.10.001DOI Listing
March 2016

Prostate tumor overexpressed 1 expression in invasive urothelial carcinoma.

J Cancer Res Clin Oncol 2016 May 8;142(5):937-47. Epub 2016 Jan 8.

Department of Urology, University Hospital, Tübingen, Germany.

Purpose: To determine the expression patterns of the proliferation marker prostate tumor overexpressed 1 (PTOV1) in invasive urothelial cancer (UC).

Methods: Corresponding UC and benign samples from paraffin-embedded tissue of 102 patients treated with cystectomy for invasive UC were immunohistochemically (IHC) assessed for PTOV1. Expression was evaluated gradually separated for cytoplasmic and nuclear staining. Results were correlated to histological and clinical data. To correlate PTOV1 expression with molecular subtypes of UC, analysis of PTOV1 RNA expression data of the Cancer Genome Atlas UC cohort was performed.

Results: PTOV1 expression was present in UC and benign urothelium, whereby nuclear staining was significantly more frequent in UC tissue (p = 0.0004). Lower cytoplasmic expression was significantly associated with pathological stage >pT2 (p = 0.0014) and grade ≥G3 (p = 0.0041), respectively. IHC expression patterns did not show correlation to survival data. PTOV1 RNA expression correlated with features of the luminal UC subtype.

Conclusions: Subcellular distribution seems to be the most important feature of PTOV1 expression in UC. Nuclear localization of PTOV1 along with cytoplasmic decrease in PTOV1 expression was identified as putative surrogate for PTOV1-associated cellular proliferation and dedifferentiation in UC. The functional relevance as well as the potential role of PTOV1 as a biomarker in UC remains to be specified in future studies.
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http://dx.doi.org/10.1007/s00432-015-2107-yDOI Listing
May 2016