Search

OBJECTIVES: Although testicular cancer (TC) is the most common tumor in young men in Western countries, there is no official cancer detection/screening program for young men in Germany. The most important TC detection tool is self-examination of the testis. Hypothetically medical students may have a diagnosis lead time and detection superiority. This study was designed to analyze whether medical students have a possible knowledge advantage over students of other faculties concerning TC and to compare male and female cancer screening demeanor and mentality. METHODS: Male and female students of various faculties at the Goethe University Frankfurt/Main, Germany were invited to participate in this internet-based anonymous questionnaire with questions about TC awareness/knowledge, testicular (self) examination, and cancer screening behavior. RESULTS: In total 1,049 students (329 medical and 716 non-medical students) completed the questionnaire. In general, medical students had a significantly higher TC knowledge, especially in the more advanced stages of their medical studies (year 3-6). About 50% of medical students had knowledge of TC whereas only 21.3% of non-medical students knew about the disease (p < 0.01). In addition, medical students conducted scrotal examinations more frequently (34.7%) than non-medical students (18.8%). CONCLUSION: The knowledge about TC is low among students. In general, medical students are more aware of TC and perform more frequent testicular examinations compared to non-medical students. Female TC knowledge rises in the clinical part of studies to the same level as their male counterparts, with the result of more testicular partner examinations.

Aims: The study aimed to evaluate the prevalence of mental distress in patients with newly diagnosed bladder cancer, the cancer-information search behavior, and the influence of information seeking on distress. Methods: One hundred and one bladder cancer patients answered 2 established questionnaires (“Hospital Anxiety and Depression Scale” [HADS] and the “Fragebogen zur Belastung von Krebskranken” [FBK-R23]) for evaluation of mental distress and a self-developed questionnaire with questions concerning information seeking and socioeconomic facts. Results: Regarding risk group stratification, 57.4% were classified as high-risk and 42.6% as low-risk tumor-bearing patients. Analysis of mental distress showed that 23.2% had a score above the HADS-A cutoff, 25.3% above the HADS-D cutoff, and 21.4% showed a pathologic FBK-R23 score. Overall, 75% felt well informed about their illness. Risk group stratification did not correlate with HADS-A, HADS-D, or FBK-R23 score. Furthermore, active search for information or the use of the Internet did not correlate with the HADS-A, HADS-D, or FBK-R23 score. However, the quality of the urologist’s information and the feeling of being informed correlated with the grade of mental distress. Conclusion: Besides the treatment of bladder cancer, informing the patient about the disease in a psychologically wholesome manner and working together with psycho-oncologically trained psychologists are essential tasks for the treating urologist.

Alljahrlich werden auf dem Kongress der Deutschen Gesellschaft fur Urologie (DGU) die neuesten Entwicklungen und Studiendaten vorgestellt. Sieben Experten haben fur ihr jeweiliges Fachgebiet die zentralen Erkenntnisse aus Hamburg zusammengefasst: Was hat sich getan im Bereich ...?

Background Early detection of localized testicular cancer is associated with a significantly better prognosis compared to advanced tumor stages. Testicular cancer prevention campaigns like "Hodencheck.de" launched by the German Society of Urology or the international campaign "Movember Foundation" want to inform and raise awareness about testicular cancer and other male cancers. This study aimed to evaluate to which extent public prevention campaigns may influence the behavior of young men and women in Germany. Objectives Questionnaires were used to ask students at the University of Frankfurt, Germany, whether they are familiar with the currently most widespread testicular cancer prevention campaigns and whether testicular examinations for cancer screening were performed by themselves, a partner or a physician. Results Only a minority of the students were aware of the testicular cancer prevention campaigns "Hodencheck.de" and/or "Movember Foundation"; 79.9% of the male and 83.6% of female students had not heard of the two mentioned prevention campaigns. Significantly more male (35.2%) compared to female students (28.9%) knew that testicular cancer is the most common cancer in young men. Of the men, 48.9% had already palpated their testicles, while only 12.4% of the women had already palpated the partner's testicles for cancer screening. Students knowing about the testicular cancer prevention campaigns performed significantly more testicular examinations for screening purposes. Conclusions Our study demonstrates that current testicular cancer prevention campaigns are little known amongst German university students. However, the knowledge of testicular cancer prevention campaigns resulted in an increased awareness and an increased willingness for testicular (self-) examinations.

Incidence rates for urothelial carcinoma (UC) have been reported to differ between countries within the European Union (EU). Besides occupational exposure to chemicals, other substances such as tobacco and nitrite in groundwater have been identified as risk factors for UC. We investigated if regional differences in UC incidence rates are associated with agricultural, industrial and residential land use.Newly diagnosed cases of UC between 2003 and 2010 were included. Information within 364 administrative districts of Germany from 2004 for land use factors were obtained and calculated as a proportion of the total area of the respective administrative district and as a smoothed proportion. Furthermore, information on smoking habits was included in our analysis. Kulldorff spatial clustering was used to detect different clusters. A negative binomial model was used to test the spatial association between UC incidence as a ratio of observed versus expected incidence rates, land use and smoking habits.We identified 437,847,834 person years with 171,086 cases of UC. Cluster analysis revealed areas with higher incidence of UC than others (p=0.0002). Multivariate analysis including significant pairwise interactions showed that the environmental factors were independently associated with UC (p0.001). The RR was 1.066 (95% CI 1.052-1.080), 1.066 (95% CI 1.042-1.089) and 1.067 (95% CI 1.045-1.093) for agricultural, industrial and residential areas, respectively, and 0.996 (95% CI 0.869-0.999) for the proportion of never smokers.This study displays regional differences in incidence of UC in Germany. Additionally, results suggest that socioeconomic factors based on agricultural, industrial and residential land use may be associated with UC incidence rates.

The natural compound, amygdalin, is notably popular with prostate cancer patients as an alternative or complementary treatment option. However, knowledge about its mode of action is sparse. We investigated amygdalin's impact on prostate cancer adhesion and motile behavior. DU-145 and PC3 cancer cells were exposed to amygdalin. Adhesion to human vascular endothelium or immobilized collagen was then explored. The influence of amygdalin on chemotaxis and migration was also investigated, as well as amygdalin induced alteration to surface and total cellular α and β integrin expression. Integrin knockdown was performed to evaluate the integrin influence on chemotaxis and adhesion. Amygdalin significantly reduced chemotactic activity, migration, and adhesion of DU-145 but not of PC3 cells. Amygdalin elevated integrin α2 in both cell lines. Integrin α6 was reduced by amygdalin only in DU-145 cells, whereas β1 increased only in PC3 cells. Functional blocking revealed a negative association of α2 with PC3 and DU-145 chemotaxis. The β1 increase correlated with enhanced chemotaxis, the diminished α6 expression with reduced chemotaxis. Amygdalin acted on prostate cancer cells in vitro. It induced downregulation of α6 integrin in DU-145 but not in PC3 cells, suggesting that exposing certain prostate cancer cells to amygdalin might inhibit metastatic spread promoted by this particular integrin.

The natural compound amygdalin has gained high popularity among tumor patients as a complementary or alternative treatment option. However, due to metabolization of amygdalin to cyanide (HCN) following oral consumption, there could be a high risk of lactic acidosis caused by cyanide intoxication. The present retrospective study was undertaken to evaluate cyanide blood and lactate plasma levels of tumor patients (n = 55) before and after intravenous (i.v.) amygdalin infusion. All patients had also continuously ingested amygdalin tablets (3 x 500 mg/day), excepting on the days of i.v. administration. Each patient received one to five intravenous amygdalin treatments. The time period between each i.v. application ranged between 4–6 days. The initial i.v. dose was 6 mg (n = 28), 9 mg (n = 1), 15 mg (n = 1) or 18 mg (n = 25). The mean cyanide blood level before i.v. amygdalin administration was 34.74 μg/L, which increased significantly to a mean value of 66.20 μg/L after i. v. amygdalin application. In contrast, lactate decreased significantly from 1266 μmol/L pre-infusion to 868 μmol/L post-infusion. Increasing i.v. amygdalin by 1 mg was also associated with a significant increase in the cyanide level, while the lactate blood level significantly decreased. This is the first study evaluating cyanide levels under conditions employed by amygdalin administrators, i.e. after chronic oral amygdalin intake and then again after a closely subsequent intravenous amygdalin administration. Since lactate decreased, whilst cyanide increased, it is concluded that elevation of cyanide does not induce metabolic acidosis in terms of an increased lactate level.

Testicular germ cell cancer in a metastatic state is curable with a cisplatin‑based first line chemotherapy. However, 10‑15% of these patients are resistant to first line chemotherapy and are thus left with only palliative options. Immunotherapies and inhibition of angiogenesis used in multiple types of cancer; however, the molecular context of angiogenesis and immune checkpoints in the development and progression of testicular cancers is still unknown. Therefore, the present study performed tissue micro array based analysis of 84 patients with immunohistochemistry of programmed cell death protein 1 (PD‑1), programmed cell death ligand 1 (PD‑L1) and vascular endothelial growth factor receptor 2 (VEGFR2) of testicular cancer and corresponding normal appearing testis tissue, matching the results with clinical data. The results demonstrated that PD‑L1 was significantly upregulated in testicular tumors and that PD‑1 positive cells significantly infiltrated the testicular tumor when compared with normal testicular tissue. VEGFR2 was significantly upregulated in testicular cancer. It was indicated that PD‑1 expressing cytotoxic cells may require pathologic tumor vessels to pass the blood‑testis‑barrier in order to migrate into the tumor. Notably, when matching the clinical data for PD‑1, PD‑L1 and VEGFR2 there were no differences in expression in the different International Germ Cell Cancer Collaborative Group stages of non‑seminoma. These data suggested that the anti‑PD‑1/PD‑L1 immunotherapy and the anti‑angiogenic therapy, sequentially or in combination, may be a promising option in the treatment of testicular cancer.

Jens Mani,1 Eva Juengel,1 Ilhan Arslan,1 Georg Bartsch,1 Natalie Filmann,2 Hanns Ackermann,2 Karen Nelson,3 Axel Haferkamp,1 Tobias Engl,1,* Roman A Blaheta1,* 1Department of Urology, 2Institute of Biostatistics and Mathematical Modeling, 3Department of Vascular and Endovascular Surgery, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany *These authors contributed equally to this work Objective: Many patients use complementary and alternative medicine (CAM) as primary treatment or symptom relief for a variety of illnesses. This study was designed to investigate the influence of surgical removal of a tumor-bearing urogenital organ on CAM use.Methods: From 2007 to 2011, 350 patients underwent major urological surgery for kidney, prostate, or bladder cancer at the Goethe-University Hospital, Frankfurt, Germany. Data from 172 patients (49%), who returned a questionnaire, were retrospectively evaluated using the hospital information system along with the questionnaire to objectify CAM use 2 years before and after surgery.Results: From the 172 patients returning questionnaires, 56 (33%) used CAM before and/or after surgery and 116 (67%) never used CAM. Of the 56 CAM users, 30 (54%) used CAM presurgery and 53 (95%) used CAM postsurgery, indicating a significant change of mind about CAM use. Patients of German nationality used CAM significantly more than patients of other nationalities. Higher educational status (high-school diploma or higher) was a significant factor in favor of CAM use. The most common type of CAM used before/after surgery was an alternative medical system (63/49%), a manipulative and body-based method (50/19%), and a biological-based therapy (37/32%). Information about CAM, either provided by medical professionals or by other sources, was the main reason determining whether patients used CAM or not.Conclusion: The number of patients using CAM almost doubled after surgical removal of a cancer-bearing organ. Better awareness and understanding of CAM use by medical professionals could improve patient counseling. Keywords: complementary and alternative medicine, surgery, urologic cancer

BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (−)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer.

Molecular tumour targeting has significantly improved anti-cancer protocols. Still, the addition of molecular targeting to the treatment regime has not led to a curative breakthrough. Combined mammalian target of Rapamycin (mTOR) and histone deacetylase (HDAC) inhibition has been shown not only to enhance anti-tumour potential, but also to prevent resistance development seen under mono-drug therapy. This investigation was designed to evaluate whether cross-communication exists between mTOR signalling and epigenetic events regulated by HDAC. DU-145 prostate cancer cells were treated with insulin-like growth factor (IGF) to activate the Akt-mTOR cascade or with the HDAC-inhibitor valproic acid (VPA) to induce histone H3 and H4 acetylation (aH3, aH4). Subsequently, mTOR, Rictor, Raptor, p70s6k, Akt (all: total and phosphorylated), H3 and H4 (total and acetylated) were analysed by western blotting. Both techniques revealed a link between mTOR and the epigenetic machinery. IGF activated mTOR, Rictor, Raptor, p70s6k and Akt, but also enhanced aH3 and aH4. Inversely, IGFr blockade and knock-down blocked the Akt-mTOR axis, but simultaneously diminished aH3 and aH4. VPA treatment up-regulated histone acetylation, but also activated mTOR-Akt signalling. HDAC1 and 2 knock-down revealed that the interaction with the mTOR system is initiated by histone H3 acetylation. HDAC-mTOR communication, therefore, is apparent whereby tumour-promoting (Akt/mTOR(high), aH3/aH4(low)) and tumour-suppressing signals (Akt/mTOR(low) , aH3/aH4(high)) are activated in parallel. Combined use of an HDAC- and mTOR inhibitor might then diminish pro-tumour effects triggered by the HDAC- (Akt/mTOR(high)) or mTOR inhibitor (aH3/aH4(low)) alone.

Das Blasenkarzinom kommt v. a. bei Patienten zwischen dem 70. und 80. Lebensjahr vor. Die radikale Zystektomie stellt derzeit den Goldstandard bei der Therapie des muskelinvasiven Blasenkarzinoms dar. In diesem Beitrag wurden die verschiedensten Aspekte der radikalen Zystektomie im Alter untersucht. In der Datenbank von Pubmed-MEDLINE wurde nach Publikationen mit folgenden Schlusselwortern gesucht: „radical“, „cystectomy“, „elderly“, „age“.

Purpose This study compares early complications after cystectomy and urinary diversion (UD) stratified by the surgical focus and case load of two different department chairpersons in a single institution in two time periods. Creating clear data about complications that can affect the quality of life is an important tool for patients to decide whether and where to perform this extensive surgery. Hypothesis A team of surgeons with a clear focus on pelvic surgery leads to lower complication rates in radical cystectomy. Materials and methods Radical cystectomy was performed in two separate time periods under the patronage of two different chairmen in the same university hospital. The patient data were analyzed retrospectively and the complications 30 days after surgery were assessed using the Clavien–Dindo classification. Results Statistical analysis showed a significant difference in the severity of complications between the two time periods, A and B, in total (P70 years, P≤50.001) tumor grade (low grade, P

Jens Mani,1 Stefan Vallo,1Maximilian P Brandt,1 Kilian M Gust,1 Claudia Bartsch,1 Johannes Daechert,1 Igor Tsaur,1 Georg Bartsch,2,* Axel Haferkamp1,* 1Department of Urology, Goethe University Hospital, Frankfurt am Main, 2Department of Urology, Johannes Gutenberg University Hospital Mainz, Mainz, Germany *These authors contributed equally to this work Purpose: This study compares early complications after cystectomy and urinary diversion (UD) stratified by the surgical focus and case load of two different department chairpersons in a single institution in two time periods. Creating clear data about complications that can affect the quality of life is an important tool for patients to decide whether and where to perform this extensive surgery. Hypothesis: A team of surgeons with a clear focus on pelvic surgery leads to lower complication rates in radical cystectomy. Materials and methods: Radical cystectomy was performed in two separate time periods under the patronage of two different chairmen in the same university hospital. The patient data were analyzed retrospectively and the complications 30 days after surgery were assessed using the Clavien–Dindo classification. Results: Statistical analysis showed a significant difference in the severity of complications between the two time periods, A and B, in total (P70 years, P≤0.001) tumor grade (low grade, P

Pharmacologic options for patients with castration-resistant prostate cancer are limited. It has been suggested that targeting intracellular molecules, which have been altered during neoplastic development, may slow tumor growth. Therefore, the growth-blocking potential of the histone deacetylase-inhibitor LBH589 and the multiple tyrosine kinase-inhibitor TKI258, applied alone or in combination, was investigated in a panel of prostate cancer cell lines. PC-3, DU-145 or LNCaP cells were treated with various concentrations of LBH589 and/or TKI258. Tumor cell growth, cell cycle regulating proteins, HDAC3- and HDAC4-expression and histone H3 and H4 acetylation were then evaluated by MTT assay and Western blotting. LBH589 dose-dependently blocked prostate cancer cell growth. In contrast, TKI258 did not down-regulate tumor cell growth up to a 1,000 nM dosage. LBH589 elevated histone H3 and H4 acetylation. The cell cycle regulators cyclin B, cyclin D1, cdk1 and cdk4 were down-regulated in PC-3, whereas the suppressor proteins p21 and p27 were up-regulated in LNCaP by LBH589. TKI258 up-regulated p27 in PC-3 or p21 in LNCaP and additionally elevated cyclin B, cyclin D1, cdk1 and cdk4 in both cell lines. Presumably, the increase in cyclin and cdk caused by TKI258 counteracts the benefit of p21 or p27 up-regulation, resulting in TKI258 non-responsiveness. The LBH589/TKI258-combination was not superior to the LBH589 single-drug use in terms of growth reduction. Obviously, TKI258 did not enhance the sensitivity of prostate cancer cells towards an HDAC based regimen. Therefore, the LBH589/TKI258-combination probably does not provide an optimum strategy in fighting advanced prostate cancer.

The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated.PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin β subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots.ZA dose-dependently reduced tumor-cell growth but did not impair tumor-endothelium and tumor-matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated β1-integrin in PC-3 and diminished β4-integrin in PC-3 and DU-145 cells.ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue micro- arrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco‑regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue.

Information about the natural compound amygdalin, which is employed as an antitumor agent, is sparse and thus its efficacy remains controversial. In this study, to determine whether amygdalin exerts antitumor effects on renal cell carcinoma (RCC) cells, its impact on RCC metastatic activity was investigated. The RCC cell lines, Caki-1, KTC-26 and A498, were exposed to amygdalin from apricot kernels, and adhesion to human vascular endothelium, immobilized collagen or fibronectin was investigated. The influence of amygdalin on chemotactic and invasive activity was also determined, as was the influence of amygdalin on surface and total cellular α and β integrin expression, which are involved in metastasis. We noted that amygdalin caused significant reductions in chemotactic activity, invasion and adhesion to endothelium, collagen and fibronectin. Using FACScan analysis, we noted that amygdalin also induced reductions, particularly in integrins α5 and α6, in all three cell lines. Functional blocking of α5 resulted in significantly diminished adhesion of KTC-26 and A498 to collagen and also in decreased chemotactic behavior in all three cell lines. Blocking α6 integrin significantly reduced chemotactic activity in all three cell lines. Thus, we suggest that exposing RCC cells to amygdalin inhibits metastatic spread and is associated with downregulation of α5 and α6 integrins. Therefore, we posit that amygdalin exerts antitumor activity in vitro, and this may be linked to integrin regulation.

Background: Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (−)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (−)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown. Methods: Cisplatin (5637rCDDP1000, RT4rCDDP1000) and gemcitabine (5637rGEMCI20, RT4rGEMCI20) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637rGEMCI20 and 5637rCDDP1000 cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation. Results: Here we demonstrate that (−)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (−)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (−)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637rGEMCI20 and 5637rCDDP1000 cells. Conclusions: Our findings show for the first time that (−)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their "autophagy addiction" and acquired resistance to current therapy.

A significant proportion of men diagnosed with prostate cancer (PCa) eventually develop metastatic disease, which progresses to castration resistance, despite initial response to androgen deprivation. As anticancer therapy has become increasingly effective, acquired drug resistance has emerged, limiting efficacy. Combination treatment, utilizing different drug classes, exemplifies a possible strategy to foil resistance development. The effects of the triple application of the histone deacetylase (HDAC) inhibitor valproic acid (VPA), the mammalian target of rapamycin inhibitor everolimus and low dosed interferon alpha (IFNα) on PCa cell growth and dissemination capacity were investigated. For that purpose, the human PCa cell lines, PC-3, DU-145 and LNCaP were treated with the combined regimen or separate single agents. Cell growth was investigated by the MTT dye reduction assay. Flow cytometry served to analyse cell cycle progression. Adhesion to vascular endothelium or immobilized collagen, fibronectin and laminin was quantified. Migration and invasion characteristics were determined by the modified Boyden chamber assay. Integrin α and β subtypes were investigated by flow cytometry, western blotting and RT-PCR. Integrin related signalling, Epidermal Growth Factor Receptor (EGFr), Akt, p70S6kinase and extracellular signal-regulated kinases (ERK)1/2 activation were also assessed. The triple application of VPA, everolimus and low dosed IFNα blocked tumour cell growth and dissemination significantly better than any agent alone. Antitumour effects were associated with pronounced alteration in the cell cycle machinery, intracellular signalling and integrin expression profile. Combining VPA, everolimus and low dosed IFNα might be a promising option to counteract resistance development and improve outcome in PCa patients.

Background: Targeted therapies have improved therapeutic options of treating renal cell carcinoma (RCC). However, drug response is temporary due to resistance development. Methods: Functional and molecular changes in RCC Caki-1 cells, after acquired resistance to the mammalian target of rapamycin (mTOR)-inhibitor everolimus (Cakires), were investigated with and without additional application of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA). Cell growth was evaluated by MTT assay, cell cycle progression and apoptosis by flow cytometry. Target molecules of everolimus and VPA, apoptotic and cell cycle regulating proteins were investigated by western blotting. siRNA blockade was performed to evaluate the functional relevance of the proteins. Results: Everolimus resistance was accompanied by significant increases in the percentage of G2/M-phase cells and in the IC50. Akt and p70S6K, targets of everolimus, were activated in Cakires compared to drug sensitive cells. The most prominent change in Cakires cells was an increase in the cell cycle activating proteins cdk2 and cyclin A. Knock-down of cdk2 and cyclin A caused significant growth inhibition in the Cakires cells. The HDAC-inhibitor, VPA, counteracted everolimus resistance in Cakires, evidenced by a significant decrease in tumor growth and cdk2/cyclin A. Conclusion: It is concluded that non-response to everolimus is characterized by increased cdk2/cyclin A, driving RCC cells into the G2/M-phase. VPA hinders everolimus non-response by diminishing cdk2/cyclin A. Therefore, treatment with HDAC-inhibitors might be an option for patients with advanced renal cell carcinoma and acquired everolimus resistance.

Scientists who are members of an editorial board have been accused of preferentially publishing their scientific work in the journal where they serve as editor. Reputation and academic standing do depend on an uninterrupted flow of published scientific work and the question does arise as to whether publication mainly occurs in the self-edited journal. This investigation was designed to determine whether editorial board members of five urological journals were more likely to publish their research reports in their own rather than in other journals. A retrospective analysis was conducted for all original reports published from 2001–2010 by 65 editorial board members nominated to the boards of five impact leading urologic journals in 2006. Publications before editorial board membership, 2001–2005, and publications within the period of time as an editorial board member, 2006–2010, were identified. The impact factors of the journals were also recorded over the time period 2001–2010 to see whether a change in impact factor correlated with publication locality. In the five journals as a whole, scientific work was not preferentially published in the journal in which the scientists served as editor. However, significant heterogeneity among the journals was evident. One journal showed a significant increase in the amount of published papers in the ‘own’ journal after assumption of editorship, three journals showed no change and one journal showed a highly significant decrease in publishing in the ‘own’ journal after assumption of editorship.

To evaluate the prognostic relevance of different prostatic invasion patterns in pT4a urothelial carcinoma of the bladder (UCB) after radical cystectomy.Our study comprised a total of 358 men with pT4a UCB. Patients were divided in 2 groups-group A with stromal infiltration of the prostate via the prostatic urethra with additional muscle-invasive UCB (n = 121, 33.8%) and group B with continuous infiltration of the prostate through the entire bladder wall (n = 237, 66.2%). The effect of age, tumor grade, carcinoma in situ, lymphovascular invasion, soft tissue surgical margin, lymph node metastases, administration of adjuvant chemotherapy, and prostatic invasion patterns on cancer-specific mortality (CSM) was evaluated using competing-risk regression analysis. Decision curve analysis was used to evaluate the net benefit of including the variable invasion pattern within our model.The estimated 5-year CSM-rates for group A and B were 50.1% and 66.0%, respectively. In multivariable competing-risk analysis, lymph node metastases (hazard ratio [HR] = 1.73, P0.001), lymphovascular invasion (HR = 1.62, P = 0.0023), soft tissue surgical margin (HR = 1.49, P = 0.026), absence of adjuvant chemotherapy (HR = 2.11, P0.001), and tumor infiltration of the prostate by continuous infiltration of the entire bladder wall (HR = 1.37, P = 0.044) were significantly associated with a higher risk for CSM. Decision curve analysis showed a net benefit of our model including the variable invasion pattern.Continuous infiltration of the prostate through the entire bladder wall showed an adverse effect on CSM. Besides including these patients into clinical trials for an adjuvant therapy, we recommend including prostatic invasion patterns in predictive models in pT4a UCB in men.

348 Background: In the European Union (EU) differences in tumor incidence for urothelial cell carcinoma (UCC) have been reported. Besides occupational exposure, tobacco smoke and nitrite have been identified as risk factors for UCC. No study has evaluated the regional incidence of UCC in Germany in consideration of socioeconomic landscape. We investigated if a different allocation to agriculture (A), industrial use (I) and land settlement (S) are associated with the incidence of UCC. Methods: In collaboration with the German Centre for Cancer Registry Data, Robert Koch Institute, Berlin, all new cases of UCC between 2003 and 2010 were included, with partly dropped out information due to incomplete reporting. Kulldorff spatial cluster test was used to detect clusters with high incidence rates. Furthermore, information within the different administrative areas of Germany from 2010 for land use factors A, I and S were obtained from the Regional Database Germany, and calculated as both, a proportion of the total area of the respective administrative region and as a smoothed proportion including values from neighbouring regions. A negative binomial model was used to test the association of the area information in addition to the expected cases information for age and sex distribution. All tests were two-sided and a significance level of α=5% was used. Results: In a follow up of 437,847,835 person years, 171,086 incident cases of UCC were identified. Cluster analysis revealed areas with a significant higher incidence of UCC than others (p=0.0002). Multivariate analysis on land use (as smoothed proportion) in all available counties showed that each such factor is an independent risk factor for UCC (p< 0.00001, respectively). The interquartile range of the respective proportions and the relative risk (RR) for raising the respective proportion from first to third quantile of different land use were 35%-60% (RR 1.10), 0.5%-2.3% (RR 1.07) and 10%-29% (RR 1.21) for all three factors A, I, and S, respectively. Conclusions: This study displays regional differences in UCC incidence in Germany. Furthermore, results suggest that environmental exposure based on socioeconomic factors may present a relevant carcinogenic risk for UCC.

Background: In an earlier study we demonstrated the feasibility to create tissue engineered venous scaffolds in vitro and in vivo. In this study we investigated the use of tissue engineered constructs for ureteral replacement in a long term orthotopic minipig model. In many different projects well functional ureretal tissue was established using tissue engineering in animals with short-time follow up (12 weeks). Therefore urothelial cells were harvested from the bladder, cultured, expanded in vitro, labelled with fluorescence and seeded onto the autologous veins, which were harvested from animals during a second surgery. Three days after cell seeding the right ureter was replaced with the cell-seeded matrices in six animals, while further 6 animals received an unseeded vein for ureteral replacement. The animals were sacrificed 12, 24, and 48 weeks after implantation. Gross examination, intravenous pyelogram (IVP), H&E staining, Trichrome Masson's Staining, and immunohistochemistry with pancytokeratin AE1/AE3, smooth muscle alpha actin, and von Willebrand factor were performed in retrieved specimens. Results: The IVP and gross examination demonstrated that no animals with tissue engineered ureters and all animals of the control group presented with hydronephrosis after 12 weeks. In the 24-week group, one tissue engineered and one unseeded vein revealed hydronephrosis. After 48 weeks all tissue engineered animals and none of the control group showed hydronephrosis on the treated side. Histochemistry and immunohistochemistry revealed a multilayer of urothelial cells attached to the seeded venous grafts. Comclusions: Venous grafts may be a potential source for ureteral reconstruction. The results of so far published ureteral tissue engineering projects reveal data up to 12 weeks after implantation. Even if the animal numbers of this study are small, there is an increasing rate of hydronephrosis revealing failure of ureteral tissue engineering with autologous matrices in time points longer than 3 months after implantation. Further investigations have to prove adequate clinical outcome and appropriate functional long-term results.