@article{SolimandoBittrichShahinietal.2023, author = {Solimando, Antonio G. and Bittrich, Max and Shahini, Endrit and Albanese, Federica and Fritz, Georg and Krebs, Markus}, title = {Determinants of COVID-19 disease severity - lessons from primary and secondary immune disorders including cancer}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms24108746}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319412}, year = {2023}, abstract = {At the beginning of the COVID-19 pandemic, patients with primary and secondary immune disorders — including patients suffering from cancer — were generally regarded as a high-risk population in terms of COVID-19 disease severity and mortality. By now, scientific evidence indicates that there is substantial heterogeneity regarding the vulnerability towards COVID-19 in patients with immune disorders. In this review, we aimed to summarize the current knowledge about the effect of coexistent immune disorders on COVID-19 disease severity and vaccination response. In this context, we also regarded cancer as a secondary immune disorder. While patients with hematological malignancies displayed lower seroconversion rates after vaccination in some studies, a majority of cancer patients' risk factors for severe COVID-19 disease were either inherent (such as metastatic or progressive disease) or comparable to the general population (age, male gender and comorbidities such as kidney or liver disease). A deeper understanding is needed to better define patient subgroups at a higher risk for severe COVID-19 disease courses. At the same time, immune disorders as functional disease models offer further insights into the role of specific immune cells and cytokines when orchestrating the immune response towards SARS-CoV-2 infection. Longitudinal serological studies are urgently needed to determine the extent and the duration of SARS-CoV-2 immunity in the general population, as well as immune-compromised and oncological patients.}, language = {en} } @article{KotlyarKrebsSolimandoetal.2023, author = {Kotlyar, Mischa J. and Krebs, Markus and Solimando, Antonio Giovanni and Marquardt, Andr{\´e} and Burger, Maximilian and K{\"u}bler, Hubert and Bargou, Ralf and Kneitz, Susanne and Otto, Wolfgang and Breyer, Johannes and Vergho, Daniel C. and Kneitz, Burkhard and Kalogirou, Charis}, title = {Critical evaluation of a microRNA-based risk classifier predicting cancer-specific survival in renal cell carcinoma with tumor thrombus of the inferior vena cava}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {7}, issn = {2072-6694}, doi = {10.3390/cancers15071981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311040}, year = {2023}, abstract = {(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC\(^{IVC}\)) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier — containing miR-21-5p, miR-126-3p and miR-221-3p expression — which significantly predicted the cancer-specific survival (CSS) of ccRCC\(^{IVC}\) patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC\(^{IVC}\), we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan-Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan-Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC\(^{IVC}\) according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC\(^{IVC}\) cohort.}, language = {en} } @article{MarquardtHartrampfKollmannsbergeretal.2023, author = {Marquardt, Andr{\´e} and Hartrampf, Philipp and Kollmannsberger, Philip and Solimando, Antonio G. and Meierjohann, Svenja and K{\"u}bler, Hubert and Bargou, Ralf and Schilling, Bastian and Serfling, Sebastian E. and Buck, Andreas and Werner, Rudolf A. and Lapa, Constantin and Krebs, Markus}, title = {Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers15020392}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305036}, year = {2023}, abstract = {(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.}, language = {en} } @article{HartrampfWeinzierlSeitzetal.2022, author = {Hartrampf, Philipp E. and Weinzierl, Franz-Xaver and Seitz, Anna Katharina and K{\"u}bler, Hubert and Essler, Markus and Buck, Andreas K. and Werner, Rudolf A. and Bundschuh, Ralph A.}, title = {Any decline in prostate-specific antigen levels identifies survivors scheduled for prostate-specific membrane antigen-directed radioligand therapy}, series = {The Prostate}, volume = {82}, journal = {The Prostate}, number = {14}, doi = {10.1002/pros.24414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318766}, pages = {1406 -- 1412}, year = {2022}, abstract = {Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS). Materials and Methods In this bicentric analysis, we included 184 mCRPC patients treated with \(^{177}\)Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50\% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan-Meier curves and log-rank comparison. Results A total of 114/184 patients (62.0\%) showed any PSA decline (PSA response >50\%, 55/184 [29.9\%]). For individuals exhibiting a PSA decline >50\%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95\% confidence interval [95\% CI] = 0.44-0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95\% CI = 0.25-0.60; p < 0.001). Conclusions In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50\%, RLT should be continued.}, language = {en} } @article{JordanBroeerFischeretal.2022, author = {Jordan, Martin C. and Br{\"o}er, David and Fischer, Christian and Heilig, Philipp and Gilbert, Fabian and H{\"o}lscher-Doht, Stefanie and Kalogirou, Charis and Popp, Kevin and Grunz, Jan-Peter and Huflage, Henner and Jakubietz, Rafael G. and Erg{\"u}n, S{\"u}leyman and Meffert, Rainer H.}, title = {Development and preclinical evaluation of a cable-clamp fixation device for a disrupted pubic symphysis}, series = {Communications Medicine}, volume = {2}, journal = {Communications Medicine}, number = {1}, doi = {10.1038/s43856-022-00227-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299800}, year = {2022}, abstract = {Background Traumatic separation of the pubic symphysis can destabilize the pelvis and require surgical fixation to reduce symphyseal gapping. The traditional approach involves open reduction and the implantation of a steel symphyseal plate (SP) on the pubic bone to hold the reposition. Despite its widespread use, SP-fixation is often associated with implant failure caused by screw loosening or breakage. Methods To address the need for a more reliable surgical intervention, we developed and tested two titanium cable-clamp implants. The cable served as tensioning device while the clamp secured the cable to the bone. The first implant design included a steel cable anterior to the pubic symphysis to simplify its placement outside the pelvis, and the second design included a cable encircling the pubic symphysis to stabilize the anterior pelvic ring. Using highly reproducible synthetic bone models and a limited number of cadaver specimens, we performed a comprehensive biomechanical study of implant stability and evaluated surgical feasibility. Results We were able to demonstrate that the cable-clamp implants provide stability equivalent to that of a traditional SP-fixation but without the same risks of implant failure. We also provide detailed ex vivo evaluations of the safety and feasibility of a trans-obturator surgical approach required for those kind of fixation. Conclusion We propose that the developed cable-clamp fixation devices may be of clinical value in treating pubic symphysis separation.}, language = {en} } @article{SolimandoKalogirouKrebs2022, author = {Solimando, Antonio Giovanni and Kalogirou, Charis and Krebs, Markus}, title = {Angiogenesis as therapeutic target in metastatic prostate cancer - narrowing the gap between bench and bedside}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.842038}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-263061}, year = {2022}, abstract = {Angiogenesis in metastatic castration-resistant prostate cancer (mCRPC) has been extensively investigated as a promising druggable biological process. Nonetheless, targeting angiogenesis has failed to impact overall survival (OS) in patients with mCRPC despite promising preclinical and early clinical data. This discrepancy prompted a literature review highlighting the tumor heterogeneity and biological context of Prostate Cancer (PCa). Narrowing the gap between the bench and bedside appears critical for developing novel therapeutic strategies. Searching clinicaltrials.gov for studies examining angiogenesis inhibition in patients with PCa resulted in n=20 trials with specific angiogenesis inhibitors currently recruiting (as of September 2021). Moreover, several other compounds with known anti-angiogenic properties - such as Metformin or Curcumin - are currently investigated. In general, angiogenesis-targeting strategies in PCa include biomarker-guided treatment stratification - as well as combinatorial approaches. Beyond established angiogenesis inhibitors, PCa therapies aiming at PSMA (Prostate Specific Membrane Antigen) hold the promise to have a substantial anti-angiogenic effect - due to PSMA´s abundant expression in tumor vasculature.}, language = {en} } @article{EckhardtSbieraKrebsetal.2022, author = {Eckhardt, Carolin and Sbiera, Iuliu and Krebs, Markus and Sbiera, Silviu and Spahn, Martin and Kneitz, Burkhard and Joniau, Steven and Fassnacht, Martin and K{\"u}bler, Hubert and Weigand, Isabel and Kroiss, Matthias}, title = {High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer}, series = {Prostate Cancer and Prostatic Diseases}, volume = {25}, journal = {Prostate Cancer and Prostatic Diseases}, number = {3}, issn = {1476-5608}, doi = {10.1038/s41391-021-00431-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271819}, pages = {484-490}, year = {2022}, abstract = {Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25\%) and low in 219 (75\%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14\%) and at low levels in 249 (86\%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95\% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95\% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.}, language = {en} } @article{MihatschBeissertPomperetal.2022, author = {Mihatsch, Patrick W. and Beissert, Matthias and Pomper, Martin G. and Bley, Thorsten A. and Seitz, Anna K. and K{\"u}bler, Hubert and Buck, Andreas K. and Rowe, Steven P. and Serfling, Sebastian E. and Hartrampf, Philipp E. and Werner, Rudolf A.}, title = {Changing threshold-based segmentation has no relevant impact on semi-quantification in the context of structured reporting for PSMA-PET/CT}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers14020270}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254782}, year = {2022}, abstract = {Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with \(^{18}\)F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV\(_{max}\), SUV\(_{peak}\), SUV\(_{mean}\)) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50\%). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories (p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV\(_{max}\) and SUV\(_{peak}\) compared to the entire PSMA-RADS-4 or -5 cohort (p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort (p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV\(_{max}\), p = 0.07; SUV\(_{peak}\), p = 0.08). SUV\(_{mean}\) (p = 0.30) and TL-PSMA (p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50\% MIT (p = 0.0066), which was driven by lymph nodes (p = 0.0239), but not bone lesions (p = 0.15). SUV\(_{max}\) was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in \(^{18}\)F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV\(_{mean}\) and TL-PSMA in contrast to PSMA-TV.}, language = {en} } @article{HartrampfKrebsPeteretal.2022, author = {Hartrampf, Philipp E. and Krebs, Markus and Peter, Lea and Heinrich, Marieke and Ruffing, Julia and Kalogirou, Charis and Weinke, Maximilian and Brumberg, Joachim and K{\"u}bler, Hubert and Buck, Andreas K. and Werner, Rudolf A. and Seitz, Anna Katharina}, title = {Reduced segmentation of lesions is comparable to whole-body segmentation for response assessment by PSMA PET/CT: initial experience with the keyhole approach}, series = {Biology}, volume = {11}, journal = {Biology}, number = {5}, issn = {2079-7737}, doi = {10.3390/biology11050660}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271191}, year = {2022}, abstract = {Simple Summary The calculation of PSMA-positive tumor volume (PSMA-TV) of the whole body from PSMA PET scans for response evaluation remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative tumor lesions. Changes in the whole-body PSMA-TV of 65 patients were comparable to the changes in PSMA-TV after including only the ten largest lesions. Moreover, changes in PSMA-TV correlated well with changes in PSA levels, as did the changes in PSMA-TV with the reduced number of lesions. We conclude that a response assessment using PSMA-TV with a reduced number of lesions is feasible and could lead to a simplified process for evaluating PSMA PET/CT. Abstract (1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV\(_{max}\) were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV\(_{maxall}\), ΔSUV\(_{max10}\), ΔSUV\(_{max5}\), ΔPSMA-TV\(_{all}\), ΔPSMA-TV\(_{10}\), ΔPSMA-TV\(_{5}\), ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV\(_{max10}\)/ΔSUV\(_{max5}\) or ΔPSMA-TV\(_{10}\)/ΔPSMA-TV\(_{5}\) compared to ΔSUV\(_{maxall}\) and ΔPSMA-TV\(_{all}\). For patients treated with taxanes, up to 6/21 (28.6\%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only up to 2/21 (9.5\%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). For patients treated with radioligand therapy (RLT), up to 5/28 (17.9\%) showed clinically relevant deviations between ΔSUV\(_{maxall}\) and ΔSUV\(_{max10}\) or ΔSUV\(_{max5}\), but only 1/28 (3.6\%) patients showed clinically relevant deviations between ΔPSMA-TV\(_{all}\) and ΔPSMA-TV\(_{10}\) or ΔPSMA-TV\(_{5}\). The highest correlations with ΔPSA were found for ΔPSMA-TV\(_{all}\) (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV\(_{10}\) (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV\(_{5}\) (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV\(_{maxall}\) (r = 0.60, p = 0.02) and with ΔSUV\(_{max10}\) (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV\(_{maxall}\) (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.}, language = {en} } @article{MarquardtKollmannsbergerKrebsetal.2022, author = {Marquardt, Andr{\´e} and Kollmannsberger, Philip and Krebs, Markus and Argentiero, Antonella and Knott, Markus and Solimando, Antonio Giovanni and Kerscher, Alexander Georg}, title = {Visual clustering of transcriptomic data from primary and metastatic tumors — dependencies and novel pitfalls}, series = {Genes}, volume = {13}, journal = {Genes}, number = {8}, issn = {2073-4425}, doi = {10.3390/genes13081335}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281872}, year = {2022}, abstract = {Personalized oncology is a rapidly evolving area and offers cancer patients therapy options that are more specific than ever. However, there is still a lack of understanding regarding transcriptomic similarities or differences of metastases and corresponding primary sites. Applying two unsupervised dimension reduction methods (t-Distributed Stochastic Neighbor Embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP)) on three datasets of metastases (n = 682 samples) with three different data transformations (unprocessed, log10 as well as log10 + 1 transformed values), we visualized potential underlying clusters. Additionally, we analyzed two datasets (n = 616 samples) containing metastases and primary tumors of one entity, to point out potential familiarities. Using these methods, no tight link between the site of resection and cluster formation outcome could be demonstrated, or for datasets consisting of solely metastasis or mixed datasets. Instead, dimension reduction methods and data transformation significantly impacted visual clustering results. Our findings strongly suggest data transformation to be considered as another key element in the interpretation of visual clustering approaches along with initialization and different parameters. Furthermore, the results highlight the need for a more thorough examination of parameters used in the analysis of clusters.}, language = {en} } @article{HartrampfWeinzierlSerflingetal.2022, author = {Hartrampf, Philipp E. and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Pomper, Martin G. and Rowe, Steven P. and Higuchi, Takahiro and Seitz, Anna Katharina and K{\"u}bler, Hubert and Buck, Andreas K. and Werner, Rudolf A.}, title = {Hematotoxicity and nephrotoxicity in prostate cancer patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I\&T}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers14030647}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254825}, year = {2022}, abstract = {(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [\(^{177}\)Lu]Lu-PSMA I\&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [\(^{177}\)Lu]Lu-PSMA I\&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [\(^{99m}\)Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22\%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67\%) according to eGFR. Only 5/42 (13\%) showed reduced TER, defined as <70\% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2\% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1\%; GFR, 1/49 (2\%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2\%); G3a to G3b, 2/49 (4.1\%)). After three cycles, follow-up eGFR correlated negatively with age (r = -0.40, p = 0.005) and the eGFR change with Gleason score (r = -0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2\%) (CTCAE I, 20/49 (41\%)) and CTCAE I thrombocytopenia in 7/49 (14\%), with an absolute decrease of 15.2\% and 16.6\% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20\%) (CTCAE I, 36/49 (73\%)) with a decrease in hemoglobin of 4.7\%. (4) Conclusions: After PSMA-targeted therapy using [\(^{177}\)Lu]Lu-PSMA I\&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.}, language = {en} } @article{SolimandoKrebsBittrichetal.2022, author = {Solimando, Antonio Giovanni and Krebs, Markus and Bittrich, Max and Einsele, Hermann}, title = {The urgent need for precision medicine in cancer and its microenvironment: the paradigmatic case of multiple myeloma}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {18}, issn = {2077-0383}, doi = {10.3390/jcm11185461}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288164}, year = {2022}, abstract = {No abstract available}, language = {en} } @article{SolimandoPalumboPragnelletal.2022, author = {Solimando, Antonio G. and Palumbo, Carmen and Pragnell, Mary Victoria and Bittrich, Max and Argentiero, Antonella and Krebs, Markus}, title = {Aplastic anemia as a roadmap for bone marrow failure: an overview and a clinical workflow}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms231911765}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290440}, year = {2022}, abstract = {In recent years, it has become increasingly apparent that bone marrow (BM) failures and myeloid malignancy predisposition syndromes are characterized by a wide phenotypic spectrum and that these diseases must be considered in the differential diagnosis of children and adults with unexplained hematopoiesis defects. Clinically, hypocellular BM failure still represents a challenge in pathobiology-guided treatment. There are three fundamental topics that emerged from our review of the existing data. An exogenous stressor, an immune defect, and a constitutional genetic defect fuel a vicious cycle of hematopoietic stem cells, immune niches, and stroma compartments. A wide phenotypic spectrum exists for inherited and acquired BM failures and predispositions to myeloid malignancies. In order to effectively manage patients, it is crucial to establish the right diagnosis. New theragnostic windows can be revealed by exploring BM failure pathomechanisms.}, language = {en} } @article{LuekeHallerUtpateletal.2022, author = {L{\"u}ke, Florian and Haller, Florian and Utpatel, Kirsten and Krebs, Markus and Meidenbauer, Norbert and Scheiter, Alexander and Spoerl, Silvia and Heudobler, Daniel and Sparrer, Daniela and Kaiser, Ulrich and Keil, Felix and Schubart, Christoph and T{\"o}gel, Lars and Einhell, Sabine and Dietmaier, Wolfgang and Huss, Ralf and Dintner, Sebastian and Sommer, Sebastian and Jordan, Frank and Goebeler, Maria-Elisabeth and Metz, Michaela and Haake, Diana and Scheytt, Mithun and Gerhard-Hartmann, Elena and Maurus, Katja and Br{\"a}ndlein, Stephanie and Rosenwald, Andreas and Hartmann, Arndt and M{\"a}rkl, Bruno and Einsele, Hermann and Mackensen, Andreas and Herr, Wolfgang and Kunzmann, Volker and Bargou, Ralf and Beckmann, Matthias W. and Pukrop, Tobias and Trepel, Martin and Evert, Matthias and Claus, Rainer and Kerscher, Alexander}, title = {Identification of disparities in personalized cancer care — a joint approach of the German WERA consortium}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {20}, issn = {2072-6694}, doi = {10.3390/cancers14205040}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290311}, year = {2022}, abstract = {(1) Background: molecular tumor boards (MTBs) are crucial instruments for discussing and allocating targeted therapies to suitable cancer patients based on genetic findings. Currently, limited evidence is available regarding the regional impact and the outreach component of MTBs; (2) Methods: we analyzed MTB patient data from four neighboring Bavarian tertiary care oncology centers in W{\"u}rzburg, Erlangen, Regensburg, and Augsburg, together constituting the WERA Alliance. Absolute patient numbers and regional distribution across the WERA-wide catchment area were weighted with local population densities; (3) Results: the highest MTB patient numbers were found close to the four cancer centers. However, peaks in absolute patient numbers were also detected in more distant and rural areas. Moreover, weighting absolute numbers with local population density allowed for identifying so-called white spots—regions within our catchment that were relatively underrepresented in WERA MTBs; (4) Conclusions: investigating patient data from four neighboring cancer centers, we comprehensively assessed the regional impact of our MTBs. The results confirmed the success of existing collaborative structures with our regional partners. Additionally, our results help identifying potential white spots in providing precision oncology and help establishing a joint WERA-wide outreach strategy.}, language = {en} } @article{HartrampfSeitzWeinzierletal.2022, author = {Hartrampf, Philipp E. and Seitz, Anna Katharina and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Schirbel, Andreas and Rowe, Steven P. and K{\"u}bler, Hubert and Buck, Andreas K. and Werner, Rudolf A.}, title = {Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [\(^{177}\)Lu]Lu-PSMA I\&T during long-term follow-up}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05853-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324573}, pages = {4262-4270}, year = {2022}, abstract = {Background Radioligand therapy (RLT) with \(^{177}\)Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [\(^{177}\)Lu]Lu-PSMA I\&T RLT in a long-term follow-up. Materials and methods Ninety-two mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (interval\(_{Diagnosis-RLT}\), per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan-Meier analyses. Results Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95\% CI 1.02-1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95\% CI 1.01-1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95\% CI 1.06-1.26; P = 0.001), and interval\(_{Diagnosis-RLT}\) (HR, 0.95, 95\% CI 0.91-0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and interval\(_{Diagnosis-RLT}\), 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval\(_{Diagnosis-RLT}\) (P ≤ 0.01, respectively). Conclusion In mCRPC patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [\(^{177}\)Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.}, language = {en} } @article{HartrampfBundschuhWeinzierletal.2022, author = {Hartrampf, Philipp E. and Bundschuh, Ralph A. and Weinzierl, Franz-Xaver and Serfling, Sebastian E. and Kosmala, Aleksander and Seitz, Anna Katharina and K{\"u}bler, Hubert and Buck, Andreas K. and Essler, Markus and Werner, Rudolf A.}, title = {mCRPC patients with PSA fluctuations under radioligand therapy have comparable survival benefits relative to patients with sustained PSA decrease}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {13}, doi = {10.1007/s00259-022-05910-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324562}, pages = {4727-4735}, year = {2022}, abstract = {Introduction In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy. Materials and methods In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan-Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle). Results Sixty-one out of one hundred seventy-six (34.7\%) patients showed a sustained increase and 86/176 (48.8\%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5\%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95\% CI 0.22-0.56; P < 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95\% CI 0.30-0.80; P < 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95\% CI 0.78-2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95\% CI 0.38-4.05; P = 0.68). Conclusion Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression.}, language = {en} } @article{HartrampfWeinzierlBucketal.2022, author = {Hartrampf, Philipp E. and Weinzierl, Franz-Xaver and Buck, Andreas K. and Rowe, Steven P. and Higuchi, Takahiro and Seitz, Anna Katharina and K{\"u}bler, Hubert and Schirbel, Andreas and Essler, Markus and Bundschuh, Ralph A. and Werner, Rudolf A.}, title = {Matched-pair analysis of [\(^{177}\)Lu]Lu-PSMA I\&T and [\(^{177}\)Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {9}, doi = {10.1007/s00259-022-05744-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324581}, pages = {3269-3276}, year = {2022}, abstract = {Background Labelled with lutetium-177, the urea-based small molecules PSMA I\&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [\(^{177}\)Lu]Lu-PSMA I\&T, and a matched cohort of 55 patients treated with [\(^{177}\)Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results Toxicity assessment revealed grade III anaemia in a single patient (1.8\%) for [\(^{177}\)Lu]Lu-PSMA I\&T and five (9.1\%) for [\(^{177}\)Lu]Lu-PSMA-617. In addition, one (1.9\%) grade III thrombopenia for [\(^{177}\)Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T did not differ significantly when compared to patients treated with [\(^{177}\)Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.}, language = {en} } @article{FussOtherHeinzeetal.2021, author = {Fuss, Carmina Teresa and Other, Katharina and Heinze, Britta and Landwehr, Laura-Sophie and Wiegering, Armin and Kalogirou, Charis and Hahner, Stefanie and Fassnacht, Martin}, title = {Expression of the chemokine receptor CCR7 in the normal adrenal gland and adrenal tumors and its correlation with clinical outcome in adrenocortical carcinoma}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250112}, year = {2021}, abstract = {Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients' survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.}, language = {en} } @article{MaasMischingerComperatetal.2021, author = {Maas, Moritz and Mischinger, Johannes and Comp{\´e}rat, Eva and Scharpf, Marcus and Fend, Falko and Todenh{\"o}fer, Timlan and Stenzl, Arnulf and Gakis, Georgios and Rausch, Steffen}, title = {Utility of pT3 substaging in lymph node-negative urothelial carcinoma of the bladder: do pathologic parameters add to prognostic sub-stratification?}, series = {World Journal of Urology}, volume = {39}, journal = {World Journal of Urology}, number = {11}, issn = {1433-8726}, doi = {10.1007/s00345-021-03697-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266535}, pages = {4021-4027}, year = {2021}, abstract = {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.}, language = {en} } @article{MarquardtSolimandoKerscheretal.2021, author = {Marquardt, Andr{\´e} and Solimando, Antonio Giovanni and Kerscher, Alexander and Bittrich, Max and Kalogirou, Charis and K{\"u}bler, Hubert and Rosenwald, Andreas and Bargou, Ralf and Kollmannsberger, Philip and Schilling, Bastian and Meierjohann, Svenja and Krebs, Markus}, title = {Subgroup-Independent Mapping of Renal Cell Carcinoma — Machine Learning Reveals Prognostic Mitochondrial Gene Signature Beyond Histopathologic Boundaries}, series = {Frontiers in Oncology}, volume = {11}, journal = {Frontiers in Oncology}, issn = {2234-943X}, doi = {10.3389/fonc.2021.621278}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232107}, year = {2021}, abstract = {Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups. Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256). Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients. Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.}, language = {en} } @article{KalogirouSchwingerKocotetal.2021, author = {Kalogirou, Charis and Schwinger, Marcel and Kocot, Arkadius and Riedmiller, Hubertus}, title = {Troubleshooting of failed continence mechanisms in the ileocecal pouch: Operative technique and long-term results of the intussuscepted ileal nipple valve}, series = {International Journal of Urology}, volume = {28}, journal = {International Journal of Urology}, number = {11}, doi = {10.1111/iju.14654}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259431}, pages = {1105-1111}, year = {2021}, abstract = {Objectives To provide a detailed step-by-step operative technique, and to report on long-term functional and metabolic outcomes in secondary continence mechanisms in the form of secondary intussuscepted ileal nipple valves in revisional surgery of ileocecal pouches. Methods From May 1997 to May 2015, 18 female and 10 male patients suffering from dysfunctional primary continence mechanisms of their ileocecal pouch underwent revisonal surgery to create a secondary ileal nipple valve at our tertiary referral center. The average follow-up period was 65.4 months. Results After surgery, 24 patients were continent by day and night, and four patients showed minor incontinence with the use of a safety pad. The average frequency of clean intermittent catheterization decreased both during the day and at night. The diameter of the catheters used for clean intermittent catheterization increased significantly. No patient showed stomal stenosis, change of stool habits or metabolic situation in the follow-up period. Furthermore, the creation of the secondary ileal nipple valves did not affect the capacity of the reservoir. In the long-term follow up, two patients required the construction of a third continence mechanism, making for an overall success rate of 92\% in the study group. Conclusion To our knowledge, this is the first study of long-term results after the creation of secondary ileal nipple valves. We provide evidence that the creation of a secondary ileal nipple valve is a safe and reliable procedure for continence restoration in ileocecal pouches with excellent functional and metabolic long-term outcomes.}, language = {en} } @article{HartrampfLapaSerflingetal.2021, author = {Hartrampf, Philipp E. and Lapa, Constantin and Serfling, Sebastian E. and Buck, Andreas K. and Seitz, Anna Katharina and Meyer, Philipp T. and Ruf, Juri and Michalski, Kerstin}, title = {Development of Discordant Hypermetabolic Prostate Cancer Lesions in the Course of [\(^{177}\)Lu]PSMA Radioligand Therapy and Their Possible Influence on Patient Outcome}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {17}, issn = {2072-6694}, doi = {10.3390/cancers13174270}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245168}, year = {2021}, abstract = {Simple Summary Discordant FDG-positive but PSMA-negative (FDG+/PSMA-) metastases constitute a negative prognostic marker of overall survival in patients undergoing PSMA radioligand therapy (RLT). The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA- lesions, which occur during or after PSMA RLT. In a retrospective bicentric analysis of 32 patients undergoing PSMA RLT and follow-up dual tracer staging with PSMA and FDG PET/CT, FDG+/PSMA- lesions occurred in a limited number of patients. However, the presence of FDG+/PSMA- lesions appears not to have a significant impact on the OS, but further studies are needed to establish the clinical relevance of such lesions. Abstract Introduction: Positron emission tomography/computer tomography (PET/CT) targeting the prostate-specific membrane antigen (PSMA) is crucial for the assessment of adequate PSMA expression in patients with metastatic castration-resistant prostate cancer (mCRPC) prior to PSMA radioligand therapy (PSMA RLT). Moreover, initial dual tracer staging using combined PSMA and [\(^{18}\)F]fluorodeoxyglucose (FDG) PET/CT provides relevant information, since discordant FDG-positive but PSMA-negative (FDG+/PSMA-) lesions constitute a negative prognostic marker of overall survival (OS) after PSMA RLT. However, little is known about the prognostic implications of dual tracer imaging for restaging at follow-up. The aim of this analysis was to investigate the prognostic implications of new FDG+/PSMA- lesions during or after PSMA RLT. Methods: This bicentric analysis included 32 patients with mCRPC who underwent both FDG and PSMA PET/CT imaging after two or four cycles of PSMA RLT. Patients with FDG+/PSMA- lesions prior to PSMA RLT were not considered. The presence of FDG+/PSMA- lesions was assessed with follow-up dual tracer imaging of patients after two or four cycles of PSMA RLT. Patients with at least one new FDG+/PSMA- lesion were compared to patients without any FDG+/PSMA- lesions at the respective time points. A log-rank analysis was used to assess the difference in OS between subgroups. Results: After two cycles of PSMA RLT, four of 32 patients (13\%) had FDG+/PSMA- metastases. No significant difference in OS was observed (p = 0.807), as compared to patients without FDG+/PSMA- lesions. Follow-up dual tracer imaging after the 4th cycle of PSMA RLT was available in 18 patients. Of these, four patients presented with FDG+/PSMA- findings (n = 2 already after two cycles). After the fourth cycle of PSMA RLT, no significant difference in OS was observed between patients with and without FDG+/PSMA- lesions (p = 0.442). Conclusion: This study shows that FDG+/PSMA- lesions develop in a limited number of patients undergoing PSMA RLT. Further studies are needed to establish the clinical relevance of such lesions.}, language = {en} } @article{D'AndreaSoriaGrotenhuisetal.2021, author = {D'Andrea, David and Soria, Francesco and Grotenhuis, Anne J. and Cha, Eugene K. and Malats, Nuria and Di Stasi, Savino and Joniau, Steven and Cai, Tommaso and Rhijn, Bas W. G. van and Irani, Jaques and Karnes, Jeffrey and Varkarakis, John and Baniel, Jack and Palou, Joan and Babjuk, Marek and Spahn, Martin and Ardelt, Peter and Colombo, Renzo and Serretta, Vincenzo and Dalbagni, Guido and Gontero, Paolo and Bartoletti, Riccardo and Larr{\´e}, Stephane and Malmstrom, Per-Uno and Sylvester, Richard and Shariat, Shahrokh F.}, title = {Association of patients' sex with treatment outcomes after intravesical bacillus Calmette-Gu{\´e}rin immunotherapy for T1G3/HG bladder cancer}, series = {World Journal of Urology}, volume = {39}, journal = {World Journal of Urology}, number = {9}, doi = {10.1007/s00345-021-03653-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-344486}, pages = {3337-3344}, year = {2021}, abstract = {Purpose To investigate the association of patients' sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette-Gu{\´e}rin (BCG) for T1G3/HG urinary bladder cancer (UBC). Materials and methods We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95\% confidence intervals (CI) for the association of patients' sex with HG-recurrence and disease progression. Results A total of 2170 (82\%) males and 465 (18\%) females were available for analysis. Overall, 1090 (50\%) males and 244 (52\%) females experienced recurrence, and 391 (18\%) males and 104 (22\%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95\%CI 1.01-1.56, p = 0.04) but not with recurrence (HR 1.06, 95\%CI 0.92-1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients' sex was not associated with recurrence (HR 0.99, 95\%CI 0.80-1.24, p = 0.96), HG-recurrence (HR 1.00, 95\%CI 0.78-1.29, p = 0.99) or disease progression (HR 1.12, 95\%CI 0.78-1.60, p = 0.55). Conclusion Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.}, language = {en} } @article{KrebsSolimandoKalogirouetal.2020, author = {Krebs, Markus and Solimando, Antonio Giovanni and Kalogirou, Charis and Marquardt, Andr{\´e} and Frank, Torsten and Sokolakis, Ioannis and Hatzichristodoulou, Georgios and Kneitz, Susanne and Bargou, Ralf and K{\"u}bler, Hubert and Schilling, Bastian and Spahn, Martin and Kneitz, Burkhard}, title = {miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm9030670}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203168}, year = {2020}, abstract = {Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.}, language = {en} } @article{BrumbergBecklDierksetal.2020, author = {Brumberg, Joachim and Beckl, Melanie and Dierks, Alexander and Schirbel, Andreas and Krebs, Markus and Buck, Andreas and K{\"u}bler, Hubert and Lapa, Constantin and Seitz, Anna Katharina}, title = {Detection Rate of \(^{68}\)Ga-PSMA Ligand PET/CT in Patients with Recurrent Prostate Cancer and Androgen Deprivation Therapy}, series = {Biomedicines}, volume = {8}, journal = {Biomedicines}, number = {11}, issn = {2227-9059}, doi = {10.3390/biomedicines8110511}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219301}, year = {2020}, abstract = {Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of \(^{68}\)Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and 68Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All \(^{68}\)Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7\% vs. 72.6\%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA (p < 0.01) and PSMA-derived tumor volume (p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.}, language = {en} } @article{HartrampfHeinrichSeitzetal.2020, author = {Hartrampf, Philipp E. and Heinrich, Marieke and Seitz, Anna Katharina and Brumberg, Joachim and Sokolakis, Ioannis and Kalogirou, Charis and Schirbel, Andreas and K{\"u}bler, Hubert and Buck, Andreas K. and Lapa, Constantin and Krebs, Markus}, title = {Metabolic Tumour Volume from PSMA PET/CT Scans of Prostate Cancer Patients during Chemotherapy — Do Different Software Solutions Deliver Comparable Results?}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {5}, issn = {2077-0383}, doi = {10.3390/jcm9051390}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205893}, year = {2020}, abstract = {(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods: \(^{68}\)Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland-Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible.}, language = {en} } @article{ArgentieroSolimandoKrebsetal.2020, author = {Argentiero, Antonella and Solimando, Antonio Giovanni and Krebs, Markus and Leone, Patrizia and Susca, Nicola and Brunetti, Oronzo and Racanelli, Vito and Vacca, Angelo and Silvestris, Nicola}, title = {Anti-angiogenesis and immunotherapy: novel paradigms to envision tailored approaches in renal cell-carcinoma}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {5}, issn = {2077-0383}, doi = {10.3390/jcm9051594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205846}, year = {2020}, abstract = {Although decision making strategy based on clinico-histopathological criteria is well established, renal cell carcinoma (RCC) represents a spectrum of biological ecosystems characterized by distinct genetic and molecular alterations, diverse clinical courses and potential specific therapeutic vulnerabilities. Given the plethora of drugs available, the subtype-tailored treatment to RCC subtype holds the potential to improve patient outcome, shrinking treatment-related morbidity and cost. The emerging knowledge of the molecular taxonomy of RCC is evolving, whilst the antiangiogenic and immunotherapy landscape maintains and reinforces their potential. Although several prognostic factors of survival in patients with RCC have been described, no reliable predictive biomarkers of treatment individual sensitivity or resistance have been identified. In this review, we summarize the available evidence able to prompt more precise and individualized patient selection in well-designed clinical trials, covering the unmet need of medical choices in the era of next-generation anti-angiogenesis and immunotherapy.}, language = {en} } @article{KrebsBehrmannKalogirouetal.2019, author = {Krebs, Markus and Behrmann, Christoph and Kalogirou, Charis and Sokolakis, Ioannis and Kneitz, Susanne and Kruithof-de Julio, Marianna and Zoni, Eugenio and Rech, Anne and Schilling, Bastian and K{\"u}bler, Hubert and Spahn, Martin and Kneitz, Burkhard}, title = {miR-221 Augments TRAIL-mediated apoptosis in prostate cancer cells by inducing endogenous TRAIL expression and targeting the functional repressors SOCS3 and PIK3R1}, series = {BioMed Research International}, volume = {2019}, journal = {BioMed Research International}, doi = {10.1155/2019/6392748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202480}, pages = {6392748}, year = {2019}, abstract = {miR-221 is regarded as an oncogene in many malignancies, and miR-221-mediated resistance towards TRAIL was one of the first oncogenic roles shown for this small noncoding RNA. In contrast, miR-221 is downregulated in prostate cancer (PCa), thereby implying a tumour suppressive function. By using proliferation and apoptosis assays, we show a novel feature of miR-221 in PCa cells: instead of inducing TRAIL resistance, miR-221 sensitized cells towards TRAIL-induced proliferation inhibition and apoptosis induction. Partially responsible for this effect was the interferon-mediated gene signature, which among other things contained an endogenous overexpression of the TRAIL encoding gene TNFSF10. This TRAIL-friendly environment was provoked by downregulation of the established miR-221 target gene SOCS3. Moreover, we introduced PIK3R1 as a target gene of miR-221 in PCa cells. Proliferation assays showed that siRNA-mediated downregulation of SOCS3 and PIK3R1 mimicked the effect of miR-221 on TRAIL sensitivity. Finally, Western blotting experiments confirmed lower amounts of phospho-Akt after siRNA-mediated downregulation of PIK3R1 in PC3 cells. Our results further support the tumour suppressing role of miR-221 in PCa, since it sensitises PCa cells towards TRAIL by regulating the expression of the oncogenes SOCS3 and PIK3R1. Given the TRAIL-inhibiting effect of miR-221 in various cancer entities, our results suggest that the influence of miR-221 on TRAIL-mediated apoptosis is highly context- and entity-dependent.}, language = {en} } @article{KienerChenKrebsetal.2019, author = {Kiener, Mirjam and Chen, Lanpeng and Krebs, Markus and Grosjean, Joȅl and Klima, Irena and Kalogirou, Charis and Riedmiller, Hubertus and Kneitz, Burkhard and Thalmann, George N. and Snaar-Jagalska, Ewa and Spahn, Martin and Kruithof-de Julio, Marianna and Zoni, Eugenio}, title = {miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo}, series = {BMC Cancer}, volume = {19}, journal = {BMC Cancer}, doi = {10.1186/s12885-019-5819-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325762}, year = {2019}, abstract = {Background Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. Methods miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4-2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. Results Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. Conclusions Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target.}, language = {en} } @article{AltieriSbieraDellaCasaetal.2017, author = {Altieri, Barbara and Sbiera, Silviu and Della Casa, Silvia and Weigand, Isabel and Wild, Vanessa and Steinhauer, Sonja and Fadda, Guido and Kocot, Arkadius and Bekteshi, Michaela and Mambretti, Egle M. and Rosenwald, Andreas and Pontecorvi, Alfredo and Fassnacht, Martin and Ronchi, Cristina L.}, title = {Livin/BIRC7 expression as malignancy marker in adrenocortical tumors}, series = {Oncotarget}, volume = {8}, journal = {Oncotarget}, number = {6}, doi = {10.18632/oncotarget.14067}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171887}, pages = {9323-9338}, year = {2017}, abstract = {Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R. The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression. Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability. In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy.}, language = {en} } @article{BluemelLinkeHerrmannetal.2016, author = {Bluemel, Christina and Linke, Fraenze and Herrmann, Ken and Simunovic, Iva and Eiber, Matthias and Kestler, Christian and Buck, Andreas K. and Schirbel, Andreas and Bley, Thorsten A. and Wester, Hans-Juergen and Vergho, Daniel and Becker, Axel}, title = {Impact of \(^{68}\)Ga-PSMA PET/CT on salvage radiotherapy planning in patients with prostate cancer and persisting PSA values or biochemical relapse after prostatectomy}, series = {EJNMMI Research}, volume = {6}, journal = {EJNMMI Research}, number = {78}, doi = {10.1186/s13550-016-0233-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147798}, year = {2016}, abstract = {Background Salvage radiotherapy (SRT) is clinically established in prostate cancer (PC) patients with PSA persistence or biochemical relapse (BCR) after prior radical surgery. PET/CT imaging prior to SRT may be performed to localize disease recurrence. The recently introduced \(^{68}\)Ga-PSMA outperforms other PET tracers for detection of recurrence and is therefore expected also to impact radiation planning. Forty-five patients with PSA persistence (16 pts) or BCR (29 pts) after prior prostatectomy, scheduled to undergo SRT of the prostate bed, underwent \(^{68}\)Ga-PSMA PET/CT. The median PSA level was 0.67 ng/ml. The impact of \(^{68}\)Ga-PSMA PET/CT on the treatment decision was assessed. Patients with oligometastatic (≤5 lesions) PC underwent radiotherapy (RT), with the extent of the RT area and dose escalation being based on PET positivity. Results Suspicious lesions were detected in 24/45 (53.3 \%) patients. In 62.5 \% of patients, lesions were only detected by 68Ga-PSMA PET. Treatment was changed in 19/45 (42.2 \%) patients, e.g., extending SRT to metastases (9/19), administering dose escalation in patients with morphological local recurrence (6/19), or replacing SRT by systemic therapy (2/19). 38/45 (84.4 \%) followed the treatment recommendation, with data on clinical follow-up being available in 21 patients treated with SRT. All but one showed biochemical response (mean PSA decline 78 ± 19 \%) within a mean follow-up of 8.12 ± 5.23 months. Conclusions \(^{68}\)Ga-PSMA PET/CT impacts treatment planning in more than 40 \% of patients scheduled to undergo SRT. Future prospective studies are needed to confirm this significant therapeutic impact on patients prior to SRT.}, language = {en} } @article{MorisVandenBroeckToscoetal.2016, author = {Moris, Lisa and Van den Broeck, Thomas and Tosco, Lorenzo and Van Baelen, Anthony and Gontero, Paolo and Karnes, Robert Jeffrey and Everaerts, Wouter and Albersen, Maarten and Bastian, Patrick J. and Chlosta, Piotr and Claessens, Frank and Chun, Felix K. and Graefen, Markus and Gratzke, Christian and Kneitz, Burkhard and Marchioro, Giansilvio and Salas, Rafael Sanchez and Tombal, Bertrand and Van Der Poel, Henk and Walz, Jochen Christoph and De Meerleer, Gert and Bossi, Alberto and Haustermans, Karin and Montorsi, Francesco and Van Poppel, Hendrik and Spahn, Martin and Briganti, Alberto and Joniau, Steven}, title = {Impact of lymph node burden on survival of high-risk prostate cancer patients following radical prostatectomy and pelvic lymph node dissection}, series = {Frontiers in Surgery}, volume = {3}, journal = {Frontiers in Surgery}, organization = {European Multicenter Prostate Cancer Clinical and Translational Research Group (EMPaCT)}, issn = {2296-875X}, doi = {10.3389/fsurg.2016.00065}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195721}, year = {2016}, abstract = {Aim To determine the impact of the extent of lymph node invasion (LNI) on long-term oncological outcomes after radical prostatectomy (RP). Material and methods In this retrospective study, we examined the data of 1,249 high-risk, non-metastatic PCa patients treated with RP and pelvic lymph node dissection (PLND) between 1989 and 2011 at eight different tertiary institutions. We fitted univariate and multivariate Cox models to assess independent predictors of cancer-specific survival (CSS) and overall survival (OS). The number of positive lymph node (LN) was dichotomized according to the most informative cutoff predicting CSS. Kaplan-Meier curves assessed CSS and OS rates. Only patients with at least 10 LNs removed at PLND were included. This cutoff was chosen as a surrogate for a well performed PNLD. Results Mean age was 65 years (median: 66, IQR 60-70). Positive surgical margins were present in 53.7\% (n = 671). Final Gleason score (GS) was 2-6 in 12.7\% (n = 158), 7 in 52\% (n = 649), and 8-10 in 35.4\% (n = 442). The median number of LNs removed during PLND was 15 (IQR 12-17). Of all patients, 1,128 (90.3\%) had 0-3 positive LNs, while 126 (9.7\%) had ≥4 positive LNs. Patients with 0-3 positive LNs had significantly better CSS outcome at 10-year follow-up compared to patients with ≥4 positive LNs (87 vs. 50\%; p < 0.0001). Similar results were obtained for OS, with a 72 vs. 37\% (p < 0.0001) survival at 10 years for patients with 0-3 vs. ≥4 positive LNs, respectively. At multivariate analysis, final GS of 8-10, salvage ADT therapy, and ≥4 (vs. <4) positive LNs were predictors of worse CSS and OS. Pathological stage pT4 was an additional predictor of worse CSS. Conclusion Four or more positive LNs, pathological stage pT4, and final GS of 8-10 represent independent predictors for worse CSS in patients with high-risk PCa. Primary tumor biology remains a strong driver of tumor progression and patients having ≥4 positive LNs could be considered an enriched patient group in which novel treatment strategies should be studied.}, language = {en} } @article{LitovkinVanEyndeJoniauetal.2015, author = {Litovkin, Kirill and Van Eynde, Aleyde and Joniau, Steven and Lerut, Evelyne and Laenen, Annouschka and Gevaert, Thomas and Gevaert, Olivier and Spahn, Martin and Kneitz, Burkhard and Gramme, Pierre and Helleputte, Thibault and Isebaert, Sofie and Haustermans, Karin and Bollen, Mathieu}, title = {DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0130651}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151705}, pages = {e0130651}, year = {2015}, abstract = {Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95\% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95\% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95\% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.}, language = {en} } @article{ArdeltEbbingAdamsetal.2015, author = {Ardelt, Peter U. and Ebbing, Jan and Adams, Fabian and Reiss, Cora and Arap, Wadih and Pasqualini, Renata and Bachmann, Alexander and Wetterauer, Ulrich and Riedmiller, Hubertus and Kneitz, Burkard}, title = {An anti-ubiquitin antibody response in transitional cell carcinoma of the urinary bladder}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0118646}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-143711}, pages = {e0118646}, year = {2015}, abstract = {Background To use combinatorial epitope mapping ("fingerprinting") of the antibody response to identify targets of the humoral immune response in patients with transitional cell carcinoma (TCC) of the bladder. Methods A combinatorial random peptide library was screened on the circulating pool of immunoglobulins purified from an index patient with a high risk TCC (pTa high grade plus carcinoma in situ) to identify corresponding target antigens. A patient cohort was investigated for antibody titers against ubiquitin. Results We selected, isolated, and validated an immunogenic peptide motif from ubiquitin as a dominant epitope of the humoral response. Patients with TCC had significantly higher antibody titers against ubiquitin than healthy donors (p<0.007), prostate cancer patients (p<0.0007), and all patients without TCC taken together (p<0.0001). Titers from superficial tumors were not significantly different from muscle invasive tumors (p = 0.0929). For antibody response against ubiquitin, sensitivity for detection of TCC was 0.44, specificity 0.96, positive predictive value 0.96 and negative predictive value 0.41. No significant titer changes were observed during the standard BCG induction immunotherapy. Conclusions This is the first report to demonstrate an anti-ubiquitin antibody response in patients with TCC. Although sensitivity of antibody production was low, a high specificity and positive predictive value make ubiquitin an interesting candidate for further diagnostic and possibly immune modulating studies.}, language = {en} } @article{HailerGrunewaldOrthetal.2014, author = {Hailer, Amelie and Grunewald, Thomas G. P. and Orth, Martin and Reiss, Cora and Kneitz, Burkhard and Spahn, Martin and Butt, Elke}, title = {Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration}, series = {Oncotarget}, volume = {5}, journal = {Oncotarget}, number = {12}, issn = {1949-2553}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120540}, pages = {4144-53}, year = {2014}, abstract = {Several studies have linked overexpression of the LIM and SH3 domain protein 1 (LASP1) to progression of breast, colon, liver, and bladder cancer. However, its expression pattern and role in human prostate cancer (PCa) remained largely undefined. Analysis of published microarray data revealed a significant overexpression of LASP1 in PCa metastases compared to parental primary tumors and normal prostate epithelial cells. Subsequent gene-set enrichment analysis comparing LASP1-high and -low PCa identified an association of LASP1 with genes involved in locomotory behavior and chemokine signaling. These bioinformatic predictions were confirmed in vitro as the inducible short hairpin RNA-mediated LASP1 knockdown impaired migration and proliferation in LNCaP prostate cancer cells. By immunohistochemical staining and semi-quantitative image analysis of whole tissue sections we found an enhanced expression of LASP1 in primary PCa and lymph node metastases over benign prostatic hyperplasia. Strong cytosolic and nuclear LASP1 immunoreactivity correlated with PSA progression. Conversely, qRT-PCR analyses for mir-203, which is a known translational suppressor of LASP1 in matched RNA samples revealed an inverse correlation of LASP1 protein and mir-203 expression. Collectively, our results suggest that loss of mir-203 expression and thus uncontrolled LASP1 overexpression might drive progression of PCa.}, language = {en} } @article{AlJanabiTaubertLohseFischeretal.2014, author = {Al-Janabi, Omar and Taubert, Helge and Lohse-Fischer, Andrea and Fr{\"o}hner, Michael and Wach, Sven and St{\"o}hr, Robert and Keck, Bastian and Burger, Max and Wieland, Wolf and Erdmann, Kati and Wirth, Manfred P. and Wullich, Bernd and Baretton, Gustavo and Magdolen, Viktor and Kotzsch, Mathias and F{\"u}ssel, Susanne}, title = {Association of Tissue mRNA and Serum Antigen Levels of Members of the Urokinase-Type Plasminogen Activator System with Clinical and Prognostic Parameters in Prostate Cancer}, series = {Biomed Research International}, journal = {Biomed Research International}, number = {972587}, issn = {2314-6141}, doi = {10.1155/2014/972587}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117967}, year = {2014}, abstract = {The objective was to determine the mRNA expression and protein levels of uPA system components in tissue specimens and serum samples, respectively, from prostate cancer (PCa) patients and to assess their association with clinicopathological parameters and overall survival (OS). The mRNA expression levels of uPA, its receptor (uPAR), and its inhibitor type 1 (PAI-1) were analyzed in corresponding malignant and adjacent nonmalignant tissue specimens from 132 PCa patients by quantitative PCR. Preoperative serum samples from 81 PCa patients were analyzed for antigen levels of uPA system members by ELISA. RNA levels of uPA system components displayed significant correlations with each other in the tumor tissues. A significantly decreased uP AmRNA expression in PCa compared to the corresponding nonmalignant tissue was detected. High uPA mRNA level was significantly associated with a high Gleason score. Elevated concentration of soluble uPAR (suPAR) in serum was significantly associated with a poor OS of PCa patients (P = 0.022). PCa patients with high suPAR levels have a significantly higher risk of death (multivariate Cox's regression analysis; IIR - 7.12, P - 0.027). The association of high suPAR levels with poor survival of PCa patients suggests a prognostic impact of suPAR levels in serum of cancer patients.}, language = {en} } @article{VerghoKneitzKalogirouetal.2014, author = {Vergho, Daniel Claudius and Kneitz, Susanne and Kalogirou, Charis and Burger, Maximilian and Krebs, Markus and Rosenwald, Andreas and Spahn, Martin and L{\"o}ser, Andreas and Kocot, Arkadius and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava}, doi = {10.1371/journal.pone.0109877}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113633}, year = {2014}, abstract = {Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.}, language = {en} } @article{VerghoKneitzRosenwaldetal.2014, author = {Vergho, Daniel and Kneitz, Susanne and Rosenwald, Andreas and Scherer, Charlotte and Spahn, Martin and Burger, Maximilian and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma}, doi = {10.1186/1471-2407-14-25}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110061}, year = {2014}, abstract = {Background Renal cell carcinoma (RCC) is marked by high mortality rate. To date, no robust risk stratification by clinical or molecular prognosticators of cancer-specific survival (CSS) has been established for early stages. Transcriptional profiling of small non-coding RNA gene products (miRNAs) seems promising for prognostic stratification. The expression of miR-21 and miR-126 was analysed in a large cohort of RCC patients; a combined risk score (CRS)-model was constructed based on expression levels of both miRNAs. Methods Expression of miR-21 and miR-126 was evaluated by qRT-PCR in tumour and adjacent non-neoplastic tissue in n = 139 clear cell RCC patients. Relation of miR-21 and miR-126 expression with various clinical parameters was assessed. Parameters were analysed by uni- and multivariate COX regression. A factor derived from the z-score resulting from the COX model was determined for both miRs separately and a combined risk score (CRS) was calculated multiplying the relative expression of miR-21 and miR-126 by this factor. The best fitting COX model was selected by relative goodness-of-fit with the Akaike information criterion (AIC). Results RCC with and without miR-21 up- and miR-126 downregulation differed significantly in synchronous metastatic status and CSS. Upregulation of miR-21 and downregulation of miR-126 were independently prognostic. A combined risk score (CRS) based on the expression of both miRs showed high sensitivity and specificity in predicting CSS and prediction was independent from any other clinico-pathological parameter. Association of CRS with CSS was successfully validated in a testing cohort containing patients with high and low risk for progressive disease. Conclusions A combined expression level of miR-21 and miR-126 accurately predicted CSS in two independent RCC cohorts and seems feasible for clinical application in assessing prognosis.}, language = {en} } @article{KunathKrauseWullichetal.2013, author = {Kunath, Frank and Krause, Steffen F. and Wullich, Bernd and Goebell, Peter J. and Engehausen, Dirk G. and Burger, Maximilian and Meerpohl, Joerg J. and Keck, Bastian}, title = {Bladder cancer - the neglected tumor: a descriptive analysis of publications referenced in MEDLINE and data from the register clinicaltrials.gov}, series = {BMC Urology}, volume = {13}, journal = {BMC Urology}, number = {56}, doi = {10.1186/1471-2490-13-56}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-122133}, year = {2013}, abstract = {Background: Uro-oncological neoplasms have both a high incidence and mortality rate and are therefore a major public health problem. The aim of this study was to evaluate research activity in uro-oncology over the last decade. Methods: We searched MEDLINE and ClinicalTrials.gov systematically for studies on prostatic, urinary bladder, kidney, and testicular neoplasms. The increase in newly published reports per year was analyzed using linear regression. The results are presented with 95\% confidence intervals, and a p value <0.05 was considered statistically significant. Results: The number of new publications per year increased significantly for prostatic, kidney and urinary bladder neoplasms (all <0.0001). We identified 1,885 randomized controlled trials (RCTs); also for RCTs, the number of newly published reports increased significantly for prostatic (p = 0.001) and kidney cancer (p = 0.005), but not for bladder (p = 0.09) or testicular (p = 0.44) neoplasms. We identified 3,114 registered uro-oncological studies in ClinicalTrials.gov. However, 85\% of these studies are focusing on prostatic (45\%) and kidney neoplasms (40\%), whereas only 11\% were registered for bladder cancers. Conclusions: While the number of publications on uro-oncologic research rises yearly for prostatic and kidney neoplasms, urothelial carcinomas of the bladder seem to be neglected despite their important clinical role. Clinical research on neoplasms of the urothelial bladder must be explicitly addressed and supported.}, language = {en} } @article{KneitzKalogirouSpahnetal.2013, author = {Kneitz, Burkhard and Kalogirou, Charis and Spahn, Martin and Krebs, Markus and Joniau, Steven and Lerut, Evelyne and Burger, Maximilian and Scholz, Claus-J{\"u}rgen and Kneitz, Susanne and Riedmiller, Hubertus}, title = {MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer}, series = {International Journal of Molecular Sciences}, journal = {International Journal of Molecular Sciences}, doi = {10.3390/ijms141121414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97321}, year = {2013}, abstract = {The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70\% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.}, language = {en} } @article{SchubertSpahnKneitzetal.2013, author = {Schubert, Maria and Spahn, Martin and Kneitz, Susanne and Scholz, Claus J{\"u}rgen and Joniau, Steven and Stroebel, Philipp and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0065064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96825}, year = {2013}, abstract = {Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.}, language = {en} } @article{PapoutsoglouBurgerRiedmiller2013, author = {Papoutsoglou, Nikolaos and Burger, Maximilian and Riedmiller, Hubertus}, title = {Persistent painless hemospermia due to metastatic melanoma of the right seminal vesicle}, series = {BMC Urology}, journal = {BMC Urology}, doi = {10.1186/1471-2490-13-43}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96254}, year = {2013}, abstract = {Background Metastatic melanoma of the seminal vesicles is a very rare clinical entity and has been reported only once until today in a patient suffering from concomitant HIV infection 12 years ago. Case presentation We report a case of persistent, painless hemospermia in a young Caucasian caused by metastatic malignant melanoma of the right seminal vesicle. The diagnosis was established by magnetic resonance imaging and transrectal ultrasound-guided biopsy. In the subsequent diagnostic workup the primary location of the tumor remained unknown but concomitant pulmonary, hepatic and supraclavicular lymph node metastases have been detected. Despite immediate chemotherapy initiation the patient finally succumbed to his progressive disease six months later. Conclusions Malignant melanoma should be considered as a rare differential diagnosis of hemospermia after common causes have been ruled out.}, language = {en} } @article{VerghoLoeserKocotetal.2012, author = {Vergho, Daniel Claudius and Loeser, Andreas and Kocot, Arkadius and Spahn, Martin and Riedm{\"u}ller, Hubertus}, title = {Tumor thrombus of inferior vena cava in patients with renal cell carcinoma - Clinical and oncological outcome of 50 patients after surgery}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75230}, year = {2012}, abstract = {Background: To evaluate oncological and clinical outcome in patients with renal cell carcinoma (RCC) and tumor thrombus involving inferior vena cava (IVC) treated with nephrectomy and thrombectomy. Methods: We identified 50 patients with a median age of 65 years, who underwent radical surgical treatment for RCC and tumor thrombus of the IVC between 1997 and 2010. The charts were reviewed for pathological and surgical parameters, as well as complications and oncological outcome. Results: The median follow-up was 26 months. In 21 patients (42\%) distant metastases were already present at the time of surgery. All patients underwent radical nephrectomy, thrombectomy and lymph node dissection through a flank (15 patients/30\%), thoracoabdominal (14 patients/28\%) or midline abdominal approach (21 patients/42\%), depending upon surgeon preference and upon the characteristics of tumor and associated thrombus. Extracorporal circulation with cardiopulmonary bypass (CPB) was performed in 10 patients (20\%) with supradiaphragmal thrombus of IVC. Cancer-specific survival for the whole cohort at 5 years was 33.1\%. Survival for the patients without distant metastasis at 5 years was 50.7\%, whereas survival rate in the metastatic group at 5 years was 7.4\%. Median survival of patients with metastatic disease was 16.4 months. On multivariate analysis lymph node invasion, distant metastasis and grading were independent prognostic factors. There was no statistically significant influence of level of the tumor thrombus on survival rate. Indeed, patients with supradiaphragmal tumor thrombus (n = 10) even had a better outcome (overall survival at 5 years of 58.33\%) than the entire cohort. Conclusions: An aggressive surgical approach is the most effective therapeutic option in patients with RCC and any level of tumor thrombus and offers a reasonable longterm survival. Due to good clinical and oncological outcome we prefer the use of CPB with extracorporal circulation in patients with supradiaphragmal tumor thrombus. Cytoreductive surgery appears to be beneficial for patients with metastatic disease, especially when consecutive therapy is performed. Although sample size of our study cohort is limited consistent with some other studies lymph node invasion, distant metastasis and grading seem to have prognostic value.}, subject = {Medizin}, language = {en} } @article{VanBaelenMottetSpahnetal.2012, author = {Van Baelen, Anthony and Mottet, Nicolas and Spahn, Martin and Briganti, Alberto and Gontero, Paolo and Joniau, Steven}, title = {Sense and Nonsense of an Extended Pelvic Lymph Node Dissection in Prostate Cancer}, series = {Advances in Urology}, volume = {2012}, journal = {Advances in Urology}, number = {983058}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-123990}, year = {2012}, abstract = {Lymph node metastases associated with prostate cancer (PCa) has been shown to be a poor prognostic factor. The role of pelvic lymph node dissection (PLND) itself in relation to survival remains unclear, however. A Medline search was conducted to address this issue. The following conclusions were drawn. Only recently, improved survival due to completion of radical prostatectomy (RP) (compared to abandoning RP) in known or presumed lymph-node-positive patients has been shown. Lymph node sampling can only be considered representative if an adequate number of nodes is removed. While several authors have suggested that a therapeutic benefit in patients undergoing RP is not provided by PLND, the reliability of these studies is uncertain. Contrary to this, several studies have indicated the possibility of long-term survival even in the presence of limited lymph node metastases. The role and timing of initiation of adjuvant androgen deprivation therapy (ADT) in patients who have node-positive disease after RP is controversial. Recent studies suggest that delaying ADT may not adversely impact survival.}, language = {en} } @article{OttoRubenwolfBurgeretal.2012, author = {Otto, Wolfgang and Rubenwolf, Peter C. and Burger, Maximilian and Fritsche, Hans-Martin and R{\"o}ßler, Wolfgang and May, Matthias and Hartmann, Arndt and Hofst{\"a}dter, Ferdinand and Wieland, Wolf F. and Denzinger, Stefan}, title = {Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {459}, doi = {10.1186/1471-2407-12-459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135679}, year = {2012}, abstract = {Background: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. Method: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. Results: 59\% of patients were shown to exhibit AQP3-positive tumours, whereas 41\% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20\% vs. 72\%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). Conclusions: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC.}, language = {en} } @article{SchubertJoniauGonteroetal.2012, author = {Schubert, Maria and Joniau, Steven and Gontero, Paolo and Kneitz, Susanne and Scholz, Claus-J{\"u}rgen and Kneitz, Burkhard and Briganti, Alberto and Karnes, R. Jeffery and Tombal, Bertrand and Walz, Jochen and Hsu, Chao-Yu and Marchioro, Giansilvio and Bader, Pia and Bangma, Chris and Frohneberg, Detlef and Graefen, Markus and Schr{\"o}der, Fritz and van Cangh, Paul and van Poppel, Hein and Spahn, Martin}, title = {The Role of Adjuvant Hormonal Treatment after Surgery for Localized High-Risk Prostate Cancer: Results of a Matched Multiinstitutional Analysis}, series = {Advances in Urology}, volume = {2012}, journal = {Advances in Urology}, doi = {10.1155/2012/612707}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137712}, year = {2012}, abstract = {Introduction. To assess the role of adjuvant androgen deprivation therapy (ADT) in high-risk prostate cancer patients (PCa) after surgery. Materials and Methods. The analysis case matched 172 high-risk PCa patients with positive section margins or non-organ confined disease and negative lymph nodes to receive adjuvant ADT (group 1, n=86 ) or no adjuvant ADT (group 2, n=86). Results. Only 11.6\% of the patients died, 2.3\% PCa related. Estimated 5-10-year clinical progression-free survival was 96.9\% (94.3\%) for group 1 and 73.7\% (67.0\%) for group 2, respectively. Subgroup analysis identified men with T2/T3a tumors at low-risk and T3b margins positive disease at higher risk for progression. Conclusion. Patients with T2/T3a tumors are at low-risk for metastatic disease and cancer-related death and do not need adjuvant ADT. We identified men with T3b margin positive disease at highest risk for clinical progression. These patients benefit from immediate adjuvant ADT.}, language = {en} } @article{JohanssenHahnerSaegeretal.2010, author = {Johanssen, Sarah and Hahner, Stefanie and Saeger, Wolfgang and Quinkler, Marcus and Beuschlein, Felix and Dralle, Henning and Haaf, Michaela and Kroiss, Matthias and Jurowich, Christian and Langer, Peter and Oelkers, Wolfgang and Spahn, Martin and Willenberg, Holger S. and Maeder, Uwe and Allolio, Bruno and Fassnacht, Martin}, title = {Deficits in the Management of Patients With Adrenocortical Carcinoma in Germany}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-85897}, year = {2010}, abstract = {Background: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. Methods: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical followup. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). Results: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21\% of them underwent no hormonal evaluation before surgery, and 59\% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48\% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13\% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11\% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. Conclusion: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers.}, language = {en} }