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Iron nanoparticles encapsulated by carbon are protected from reactions with their environment avoiding oxidation in ambient conditions and thus, preserving their magnetic properties. Such particles are good candidates for magnetic fluid hyperthermia. When graphite shells are present, acidic treatments allow the formation of carboxylic groups on the nanoparticle surface. Those carboxylic groups can be used for further complexation with the drug cisplatin. We show the possibility of loading cisplatin on such nanoparticles and that the loading is dependent on the degree of surface functionalization. The drug release is dependent on time and temperature, making it ideal for applications involving hyperthermia. We show the possibility of applying hyperthermia in vitro using these nanoparticles. When loaded with cisplatin a stronger cytotoxic effect is observed. Such particles could be potentially used as multimodal anti-cancer agents for therapies based on the synergistic effect of chemotherapy and hyperthermia.

Study Type – Therapy (RCT) Level of Evidence 1b OBJECTIVE To evaluate the efficacy and tolerability of bicalutamide 150 mg once-daily as immediate hormonal therapy in patients with prostate cancer or as adjuvant to radical prostatectomy or radiotherapy. PATIENTS AND METHODS In all, 8113 patients with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) were enrolled in three complementary, double-blind, placebo-controlled trials. Patients were randomized to receive standard care plus either oral bicalutamide 150 mg once-daily or oral placebo. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Data were collated from individual trials and evaluated in a combined analysis. RESULTS Overall, at a median follow-up of 9.7 years, bicalutamide significantly improved PFS (hazard ratio 0.85, 95% confidence interval 0.79–0.91; P= 0.001). Compared with placebo there was no difference in OS (hazard ratio 1.01, P= 0.77). Patients who derived benefit from bicalutamide in terms of PFS were those with locally advanced disease, with OS significantly favouring bicalutamide in patients with locally advanced disease undergoing radiotherapy (P= 0.031). Patients with localized disease showed no clinically or statistically significant improvements in PFS; there was a survival trend in favour of placebo in patients with localized disease undergoing watchful waiting (P= 0.054). The overall tolerability of bicalutamide was consistent with previous analyses, with breast pain (73.7%) and gynaecomastia (68.8%) the most frequently reported adverse events in patients randomized to bicalutamide. CONCLUSIONS Bicalutamide 150 mg, either as monotherapy or adjuvant to standard care, improved PFS in patients with locally advanced prostate cancer, but not in patients with localized disease. A pre-planned subset analysis showed a benefit for OS in patients with locally advanced disease undergoing radiotherapy. Bicalutamide 150 mg might represent an alternative for patients with locally advanced prostate cancer considering androgen-deprivation therapy.

In a retrospective study, Touijer and co-workers investigated mortality in 1,338 patients with lymph-node positive prostate cancer who underwent radical prostatectomy between 1988 and 2010 in two centers in the US and one in Italy (1).

188 Background: (Stereotactic) Ablative radiotherapy (aRT) in patients with oligometastatic prostate cancer is safe, achieves high local control rates and its clinical benefit is currently being addressed in clinical trials. However, the selection of patients benefitting most from aRT remains unclear. Moreover, the highly specific and sensitive multimodality functional imaging modality, 68Ga-PSMA-PET-CT/-MR, is widely available. Therefore, we retrospectively evaluated the efficacy of PSMA-PET guided local aRT in low volume oligometastatic castration resistant prostate cancer (CRPC) patients. Methods: Fifteen patients with metachronous oligometastatic CRPC as diagnosed on PSMA-PET were treated with local aRT. Nine patients were treated with a conventionally fractionated regime (25 x 2 Gy) and six with stereotactic hypofractionated RT (3 x 10 Gy), while in all androgen deprivation was continued. The time to PSA-progression, i.e. PSA-nadir + 2 ng/ml (PSA+2) was estimated with the Kaplan-Meier method and compared to an individually estimated time to PSA+2 according to the individually calculated pre-RT PSA doubling time (PSA-DT). Results: At staging PSMA-PET, the median PSA was 3.4 ng/ml (range 1.3 -14.5) and the median PSA-DT was 3.2 months (range 0.6 - 15.3). In four patients no PSA-response after aRT was observed. The responding eleven patients (73%) had a mean decrease in PSA-level of 80% from baseline. The mean time to PSA-nadir was 10.7 months (range 4.5 - 11.5). The mean time to PSA+2 or last follow-up was 15.6 months [95%CI: 9.7 - 21.4] compared to 3.3 months [95%CI: 1.5 - 5.1] estimated PSA-DT without local aRT (p < 0.001). Conclusions: A relevant subset of patients with 68Ga PSMA-PET-detected oligometastatic low volume CRPC had a meaningful PSA-response with aRT. They were reverted into an earlier stage of their disease again. A prospective clinical trial on this clinically highly relevant question is being prepared.

Die radikale Prostatektomie (RP) ist die am haufigsten eingesetzte Therapie beim lokalisierten Prostatakarzinom. Im Gegensatz zu anderen Verfahren ist der Wert der RP beim lokal begrenzten Prostatakarzinom durch eine prospektiv randomisierte Studie (im Vergleich zu „watchful waiting“) untermauert; uber die Ergebnisse dieser Studie sollen Patienten laut S3-Leitlinie vor einer Therapieentscheidung aufgeklart werden. Als Ziele der Operation und damit Qualitatsindikatoren werden – in Anlehnung an die Vorgaben der Deutschen Krebsgesellschaft fur die Zertifizierung von Prostatakarzinomzentren – die Rate an R0-Resektion und der Erhalt der Harnkontinenz sowie Potenz herausgestellt. Bei Patienten mit „Low-risk-Tumoren“ (nach D’Amico-Kriterien) kann auf eine pelvine Lymphadenektomie verzichtet werden. Wird eine Lymphadenektomie durchgefuhrt, so sollten zumindest 10 Lymphknoten entnommen werden. Bei lokal fortgeschrittenen Tumoren sollte eine extendierte Lymphadenektomie empfohlen werden. Auch fur das lokal fortgeschrittene Prostatakarzinom stellt die RP eine Option dar. Bei Tumoren mit einem Gleason-Score ≥8 bzw. im klinischen Stadium cT3/4 sollte vor einer Therapieentscheidung allerdings eine Kernspintomographie des Beckens erfolgen. Praktisch keinen Stellenwert hat die (neo)adjuvante Therapie bei der RP (Ausnahme: adjuvante Therapie bei Lymphknotenmetastasen). Erstmalig werden durch die deutsche S3-Leitlinie mit dem Ziel der Qualitatssicherung Mindestmengen festgelegt. Die RP soll nur unter der Leitung eines erfahrenen Operateurs durchgefuhrt werden. Dies beinhaltet die Durchfuhrung von mindestens 50 Prostatektomien in einer Einrichtung pro Jahr sowie mindestens 25 pro Operateur pro Jahr sowie ein entsprechendes Ausbildungsprogramm.

Carbon-encapsulated magnetic nanoparticles are a new class of materials where the core magnetic nanoparticle is protected from reactions with its environment by graphite shells. Having a structure similar to carbon nanotubes, these nanoparticles could be potentially functionalized using methods which are already applied to those structures. We present the effects of acidic treatments based on HCl, HNO3, and H2SO4 on these nanoparticles highlighting the impact on their magnetic and surface properties. We show that acidic treatments based on HNO3 can be successfully applied for the generation of carboxylic groups on the surface of the nanoparticles. Using methylamine as a model, we demonstrate that these functional groups can be used for further functionalization with amino-containing biomolecules via diimide-activated amidation.

Due to their particular magnetic properties, nanoparticles of metallic iron are promising candidates for magnetic fluid hyperthermia when compared to the commonly used iron oxides. However, the difficulty of handling these structures in ambient conditions without oxidation hinders its practical application. In this work, iron filled carbon nanotubes non-covalently functionalized by human serum albumin are studied as potential agents for hyperthermia. Here the iron is encapsulated inside of the carbon shells and protected from reactions with its environment. Besides protecting the iron and biological environment against each other, the carbon shells can also work as an interface for conjugation with other biological molecules of interest. In order to assess if such structures could induce any toxic effect in human cell cultures, we have probed its biocompatibility on a dosage and time dependent manner by measuring metabolic activity, cell proliferation, cell cycle distribution and apoptosis. Our results have shown that those nanotubes strongly associate with cells within a short incubation period and do not pose any significant toxic effect. The magnetic properties of iron filled carbon nanotubes in biological environment, i.e., associated to cells, have been studied and a possible rotation as a function of the applied magnetic field is discussed. Our initial findings encourage the further study of these structures as potential hyperthermia agents.

Purpose Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Two randomized trials demonstrated an advantage for adjuvant radiotherapy (RT) compared with a wait-and-see policy. We conducted a randomized, controlled clinical trial to compare RP followed by immediate RT with RP alone for patients with pT3 prostate cancer and an undetectable prostate-specific antigen (PSA) level after RP. Methods After RP, 192 men were randomly assigned to a wait-and-see policy, and 193 men were assigned to immediate postoperative RT. Eligible patients had pT3 pN0 tumors. Patients who did not achieve an undetectable PSA after RP were excluded from treatment according to random assignment (n = 78; 20%). Of the remaining 307 patients, 34 patients on the RT arm did not receive RT and five patients on the wait-and-see arm received RT. Therefore, 114 patients underwent RT and 154 patients were treated with a wait-and-see policy. The primary end point was biochemical progression-free survival. Results Biochemical progression-free survival after 5 years in patients with undetectable PSA after RP was significantly improved in the RT group (72%; 95% CI, 65% to 81%; v 54%, 95% CI, 45% to 63%; hazard ratio = 0.53; 95% CI, 0.37 to 0.79; P = .0015). On univariate analysis, Gleason score more than 6 and less than 7, PSA before RP, tumor stage, and positive surgical margins were predictors of outcome. The rate of grade 3 to 4 late adverse effects was 0.3%. Conclusion Adjuvant RT for pT3 prostate cancer with postoperatively undetectable PSA significantly reduces the risk of biochemical progression. Further follow-up is needed to assess the effect on metastases-free and overall survival.

Summary. Background: Venous thromboembolism (VTE) is the most common non-surgical complication after major pelvic surgery. Little is known about the risk factors or the time of development of postoperative venous thrombosis. Methods: A cohort of 523 consecutive patients undergoing radical prostatectomy with lymphadenectomy was prospectively assessed by complete compression ultrasound at days )1, +8 and +21. Results: Complete data were available in 415 patients, while four patients had VTE before surgery and were excluded from the analysis. In the remaining 411 patients, 71 VTE events were found in 69 patients (16.8%). Most were limited to calf muscle veins (56.5%), followed by deep calf vein thrombosis (23.2%), proximal deep vein thrombosis (DVT, 14.5%) and pulmonary embolism (PE, 5.8%). Of the 14 patients with proximal DVT/PE, 11 patients (78.6%) developed VTE between days 8 and 21. Risk factors for VTE were a personal history of VTE (OR 3.0), pelvic lymphoceles (LCs) impairing venous flow (OR 2.8) and necessity of more than two units of red blood cells (OR 2.6). Conclusion: Venous thromboembolism is common after radical prostatectomy. A significant proportion develops after day 8, suggesting that prolonged heparin prophylaxis should be considered. Since LCs with venous flow reduction result in higher rates of VTE, hemodynamically relevant lymphoceles should be surgically treated.

To externally review a nomogram developed to predict the 10-year survival probability of men selected for radical prostatectomy.A total of 1910 consecutive patients who underwent radical prostatectomy from 1992 to 2004 were studied. The mean age was 64.2 years; the mean follow-up for the surviving patients was 6.3 years. The patients were classified according to age and the Charlson comorbidity score. The 10-year survival probability was estimated for each individual patient, applying a recently published nomogram incorporating these 2 variables. The survival rates estimated by the Kaplan-Meier method and the mean values of the nomogram-predicted survival probabilities were compared using 1-sample Wald tests. Subgroup analyses were done after stratification by age and Charlson score.Even including the prostate cancer-related mortality (accounting for 5.1% at 10 years), the 10-year overall survival rate in our sample was somewhat greater than predicted by the nomogram (84.9% vs 81.9%, P = .0222). Subgroup analyses revealed that this difference was attributable to a greater than predicted survival in patients with a Charlson score of 0 and agedor = 70 years (87.9% vs 74.7%, P.0001). In contrast, in the other subgroups, the predicted and Kaplan-Meier estimated survival rates did not differ meaningfully.Clinicians using this nomogram should be aware of a possible underestimation of survival in healthy men agedor = 70 years selected for radical prostatectomy.

After local therapy for prostate cancer, presumably isolated nodal recurrence is being detected in increasing numbers of patients by modern imaging techniques, especially by positron emission tomography (PET). The question arises whether lymphadenectomy may delay tumor progression.Conclusions concerning the value of PET/computed tomography, perioperative complications, and oncological outcome were derived from available studies and our own experiences. Six studies reported on 83 patients who underwent lymphadenectomy for suspected nodal recurrence. In cases with histological confirmation, no patient was cured.Hence, nodal recurrence in prostate cancer most likely represents a systemic affection instead of locally limited disease. If a drop in the prostate-specific antigen level occurs after lymphadenectomy, it can be assumed that the progression-free period is expected to be less than 12 months.The available data on oncological outcomes of this procedure are insufficient. Therefore, lymphadenectomy for nodal recurrence of prostate cancer remains an unproven approach.

Selected transcript markers as well as their combinations were analyzed on minimal prostate tissue specimens with regard to their diagnostic potential. Artificial prostate biopsies from RPE explants were used for evaluation and optimization of the techniques used followed by application to diagnostic prostate needle core biopsies. Minimal prostate specimens were cryopreserved and processed with standardized methods. The RNA amount of a half of each biopsy was sufficient for the analysis of 11 marker genes and one reference gene (TBP) using quantitative PCR assays.The relative transcript amounts obtained were included in several analyses including calculations for each single marker gene like median overexpression rate as well as marker combinations. Two optimized mathematical models based on relative expression levels of EZH2, hepsin, PCA3, prostein, and TRPM8 were evaluated with regard to their diagnostic potential. Compared to single marker analyses these models show higher sensitivity and specificity for prostate cancer detection.Thus biomolecular prostate cancer identification may represent a suitable diagnostic tool to supplement conventional techniques on prostate biopsies. Furthermore, an extension of this approach to PCa prognosis and the transfer to urine samples appear very promising.

Genetic aberrations are crucial in renal tumor progression. In this study, we describe loss of heterozygosity (LOH) and DNA-copy number abnormalities in clear cell renal cell carcinoma (cc-RCC) discovered by genome-wide single nucleotide polymorphism (SNP) arrays. Genomic DNA from tumor and normal tissue of 22 human cc-RCCs was analyzed on the Affymetrix GeneChip Human Mapping 10K Array. The array data were validated by quantitative polymerase chain reaction and immunohistochemistry. Reduced DNA copy numbers were detected on chromosomal arm 3p in 91%, on chromosome 9 in 32%, and on chromosomal arm 14q in 36% of the tumors. Gains were detected on chromosomal arm 5q in 45% and on chromosome 7 in 32% of the tumors. Copy number abnormalities were found not only in FHIT and VHL loci, known to be involved in renal carcinogenesis, but also in regions containing putative new tumor suppressor genes or oncogenes. In addition, microdeletions were detected on chromosomes 1 and 6 in genes with unknown impact on renal carcinogenesis. In validation experiments, abnormal protein expression of FOXP1 (on 3p) was found in 90% of tumors (concordance with SNP array data in 85%). As assessed by quantitative polymerase chain reaction, PARK2 and PACRG were down-regulated in 57% and 100%, respectively, and CSF1R was up-regulated in 69% of the cc-RCC cases (concordance with SNP array data in 57%, 33%, and 38%). Genome-wide SNP array analysis not only confirmed previously described large chromosomal aberrations but also detected novel microdeletions in genes potentially involved in tumor genesis of cc-RCC.

We identified an age range in which comorbidity is most closely associated with premature mortality after radical prostatectomy.A total of 1,302 patients selected for radical prostatectomy were stratified according to the Charlson score, the American Society of Anesthesiologists physical status classification, the New York Heart Association classification of heart insufficiency and the classification of angina pectoris of the Canadian Cardiovascular Society. Furthermore, patients were subdivided into several age groups. Comorbid mortality and overall mortality were the study end points. The prognostic relevance of the comorbidity classifications was assessed by comparing Mantel-Haenszel HRs, p values and 10-year overall survival rates.The discriminative capacity of all 4 investigated comorbidity classifications decreased when patients 70.0 years or older were included with decreasing HRs and increasing p values. Except for the American Society of Anesthesiologists classification HRs for comparing the high vs low risk groups tended to decrease and p values simultaneously tended to increase when patients younger than 63.0 years were included. In the age range of between 63.0 and 69.9 years 10-year overall survival rates differed by 14% to 28% between patients with a high vs low comorbid risk compared with 6% to 13% in the whole sample.The discriminative capacity of the investigated comorbidity classifications was greatest in the age group that was 63.0 to 69.9 years old. In patients younger than 63.0 or older than 70.0 years comorbidity classification seemed to contribute little to the prediction of comorbid mortality.

Objectives The absence of effective therapies for advanced prostate cancer has entailed an intensive search for novel treatments. This review presents an overview of specific immunotherapeutic strategies for prostate cancer. Methods Current literature was reviewed regarding the identification of tumor antigens and the design of T-cell– and antibody-based immunotherapy for prostate cancer. The PubMed database was searched using the key words antibodies, clinical trials, dendritic cells, immunotherapy, prostate cancer, and T cells. Results T cells and antibodies are powerful components of the specific antitumor immune response. CD8 + cytotoxic T lymphocytes (CTLs) efficiently destroy tumor cells. CD4 + T cells improve the antigen-presenting capacity of dendritic cells (DCs) and support the stimulation of tumor-reactive CTLs. Monoclonal antibodies exhibit their antitumor effects via antibody-dependent cellular cytotoxicity and complement activation. Consequently, much attention has been given to the identification of tumor antigens that represent attractive targets for specific immunotherapy. Several prostate cancer-related antigens were described and used in clinical trials. Such studies were based on the administration of peptides, proteins, or DNA. Furthermore, men with prostate cancer were vaccinated with peptide-, protein-, or RNA-loaded DCs, which display an extraordinary capacity to induce tumor-reactive T cells. Monoclonal antibodies directed against surface antigens were also used. Clinical trials revealed that immunotherapeutic strategies represent safe and feasible concepts for the induction of immunologic and clinical responses in men with prostate cancer. Conclusions Specific immunotherapy represents a promising treatment modality for prostate cancer. Further improvement of the current approaches is required and may be achieved by combining T-cell– and antibody-based vaccination strategies with radio-, hormone-, chemo-, or antiangiogenic therapy.

Es wurden 2200 Besucher der Mannergesundheitstage in verschiedenen deutschen Stadten darum gebeten, anhand eines einheitlichen Fragebogens die Qualitat der angebotenen Informationen zu beurteilen. Von den 51% der Besucher, die antworteten, gaben 80% eine uberwiegend positive Beurteilung ab, insbesondere zu einem begehbaren Prostatamodell sowie zu Expertenvortragen und Diskussionen. Die Besucher stellten in Bezug auf Alter (im Durchschnitt 64 Jahre), vorhandene Prostataerkrankung (51%) und Teilnahme am Fruherkennungsprogramm ein Teilsegment dar. Daher reprasentierten viele von ihnen nicht die Zielgruppe (gesund

Introduction: Extracorporeal shock wave lithotripsy (ESWL) is the standard stone treatment. Increased excretion of tubular enzymes and hypercalciuria has been reported after ESWL. We investigated the importance of renally induced hypercalciuria after ESWL. Material and Methods: 30 calcium oxalate stoneformers (23 men, 7 women), mean age 53.3 (range 30–71) years, were evaluated prospectively. Plasma calcium and creatinine concentrations and 8-hour overnight urine were measured before ESWL and on the 1st and 2nd days after ESWL. To estimate the changes of tubular reabsorption, the calcium/creatinine clearance ratios were calculated. Results: Hypercalciuria (>5 mmol/24 h) was seen in 5/30 (16.7%) before, in 12/30 (40.0%) on day 1 and in 13/30 (43.3%) on day 2 after ESWL. The mean plasma levels of calcium were significantly decreased from 2.36 mmol/l before to 2.28 mmol/l on day 2 after ESWL (p< 0.01). The mean calcium/creatinine clearance ratio was significantly increased from 0.012 before to 0.019 after ESWL (p< 0.01). Before and on day 2 after ESWL, the calcium/creatinine clearance ratio was significantly correlated with the age of the patients (r = 0.33, p< 0.04). Conclusion: Our data show an age-related significantly increased urine calcium excretion after ESWL possibly due to decreased tubular calcium reabsorption. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Die radikale Zystektomie mit regionaler Lymphknotendissektion stellt die Standardtherapie des muskelinvasiven Harnblasenkarzinoms dar. Untersuchungen zum klinischen Verlauf nach Zystektomie zeigen in Abhangigkeit vom Tumorstadium exzellente Langzeitergebnisse in Bezug auf das rezidivfreie und tumorspezifische Uberleben. Daruber hinaus zeichnet sich die Zystektomie gegenuber den anderen Therapieoptionen durch eine geringe Rate lokaler Rezidive aus. Verbesserungen der chirurgischen Technik, der Anasthesie und der perioperativen Uberwachung haben die Zystektomie zu einem Standardeingriff mit akzeptabler Morbiditat und Mortalitat gemacht. Trotzdem sollte die Indikation insbesondere bei alteren und multimorbiden Patienten kritisch gestellt werden. Die perioperative Mortalitat, postoperative Komplikationen sowie die Krankenhausverweildauer sind in Zentren mit hohem Zystektomie-Aufkommen und erfahrenen Operateuren besonders gering. Die Ersatzblase ist heute das am haufigsten gewahlte kontinente Harnableitungsverfahren. Der damit verbundene Erhalt von Kontinenz, Miktion auf naturlichem Wege und des „body image“ haben die Akzeptanz der Patienten fur ein radikales operatives Vorgehen zusatzlich erhoht.

Objectives This study assessed the usefulness of serial measurements of bone turnover markers in men with metastatic prostate cancer treated with zoledronic acid to detect disease progression. Methods Serum measurements of total alkaline phosphatase (tALP), bone-specific alkaline phosphatase (bALP), cross-linked N-terminal (NTx) and cross-linked C-terminal (CTx) telopeptides of type I collagen, amino-terminal procollagen propeptides of type I collagen (PINP), C-terminal telopeptides of type I collagen (ICTP), and prostate-specific antigen (PSA) were performed in 77 prostate cancer patients suffering from bone metastases and treated with zoledronic acid up to 15 mo. Fifty patients were with and 27 patients without objective evidence of metastatic bone progression during the administration of zoledronic acid. Results The baseline bone marker concentrations were not significantly different between the groups. After administration of zoledronic acid all bone markers except of ICTP decreased compared with baseline. CTx showed the greatest decrease. In patients with metastatic bone progression PINP, tALP, bALP, and ICTP were significantly higher at weeks 24, 36, 48, and 60 after starting treatment with zoledronic acid compared with patients without progression. In addition to the information of prostate-specific antigen as a monitoring parameter, the bone formation marker showed a better distinction between patients with and without disease progression. Conclusions Selected bone turnover markers provide valuable information regarding progression of bone metastasis in men with metastatic prostate cancer under bisphosphonate therapy. The clinical impact should be confirmed in prospective randomised studies.

The current EAU guidelines recommend continued androgen suppression in patients not treated by orchidectony and with HRPC, although few studies have addressed the benefits of this approach. The EAU recommendation was based primarily on evidence reported by Manni et al. [4], who conducted a small randomized trial to determine whether androgen priming potentiates the cytotoxic effects of chemotherapy. In all, 85 men with disease progression despite orchidectomy were randomly selected to receive androgen priming or chemotherapy alone. The median survival of men who received androgen priming (10 months) was significantly worse than that of men who did not (15 months; P = 0.005), a result indicating that continuous androgen blockade might be beneficial in men with HRPC.

Carbachol-induced detrusor contractions are mainly mediated via M 3 receptor subtype and depend not only on Ca 2+ release from the intracellular calcium stores but also on Ca 2+ influx via L-type Ca 2+ channels. The purpose of this study was to examine the different contributions of Ca 2+ influx and Ca 2+ release underlying muscarinic receptor-mediated contractions in human, porcine and murine urinary bladder. Detrusor contractions were measured in urothelium-denuded detrusor strips as responses to cumulatively increasing carbachol concentrations, release of intracellular Ca 2+ was determined in Chinese hamster ovary cells stably transfected with human muscarinic M 3 (hM 3 ) receptors. In human tissue, 1 μM of the L-type Ca 2+ -channel blocker nifedipine reduced carbachol contractions to 74%, in pig to 18% and in mouse to 27% of pre-drug controls. 2-Aminoethoxyphenyl borate (2-APB, 300 μM), which impairs inositol trisphosphate (IP 3 )-induced release of Ca 2+ , reduced carbachol responses in human detrusor to 60%, in pig to 35% and in mouse to 20%, whereas block of the Ca 2+ -induced Ca 2+ release with ryanodine had no significant effect on carbachol contractions in all three species. Carbachol-induced release of intracellular Ca 2+ in Chinese hamster ovary cells expressing muscarinic hM 3 receptors was completely prevented by 100 μM 2-APB. The direct intracellular IP 3 receptor antagonist xestospongin C (10 μM) reduced carbachol-stimulated intracellular Ca 2+ to 41% of the control value. Blockade of ATP-dependent Ca 2+ uptake into intracellular stores with thapsigargin was associated with a concentration-dependent increase of detrusor contraction, but limited on-top contractions with carbachol. In conclusion, carbachol-induced contractions in human, porcine and mouse detrusor depend differently on Ca 2+ influx, since potency of nifedipine reducing muscarinic receptor-mediated detrusor contraction is lower in human bladder. On the other hand, slight species differences are also found when inhibiting IP 3 -induced Ca 2+ release and Ca 2+ reuptake into intracellular stores. Taken together, our data show considerable species differences between human, porcine and murine detrusor regarding the relative contributions of Ca 2+ influx and maybe also carbachol-induced Ca 2+ release that could be of relevance when using different animal models.

The treatment of clinically locally advanced prostate cancer (cT3-4) is subject to controversies. Patients with lymph node metastases as well as patients with overstaged localized and thus curable disease fall into this category. Radical prostatectomy, external beam radiotherapy and early or deferred hormonal therapy are possible treatment options. Multimodal treatment (i.e., a combination of these options) is frequently used. After radical prostatectomy, Gleason score-adjusted disease-specific survival does not differ meaningfully between the tumor stages pT2 and pT3-4. In the case of lymph node metastases after radical prostatectomy, but not in node-negative disease, adjuvant hormonal treatment seems to improve survival. Adjuvant radiotherapy may improve biochemical and local control in locally advanced prostate cancer, a survival benefit has, however, not yet been proven. External beam radiotherapy alone provides unfavourable survival rates in locally advanced prostate cancer. Adjuvant hormonal treatment may improve outcome in this setting. When no curative treatment is chosen, early hormonal treatment seems to provide modest benefit compared with deferred therapy.

Objectives Abnormal gene activation in human tumours including bladder cancers (bCAs) may cause altered proliferation, maturation, and apoptosis as well as development of resistance to therapeutic interventions. Therefore, silencing of abnormally activated genes appears to be a rational approach for specific target-directed and sensitising therapies. Methods Of the available strategies for gene silencing, antisense-based techniques have attracted much attention and are the focus of this review. Putative target genes should be involved in essential tumour-promoting pathways, such as growth signalling, immortalisation, cell cycle regulation, apoptosis, angiogenesis, and development of therapy resistances. This review gives an overview of selected studies performed on bCA-derived cell lines and xenografts reporting down-regulation of potential target genes by antisense-based synthetic nucleic acids such as antisense oligodeoxynucleotides (AS-ODNs) and small interfering RNAs (siRNAs). Effects on proliferation of bCA cells and enhancement of the cytotoxic action of different chemotherapeutics were evaluated. Results Knock-down of the selected target genes frequently caused an impairment of growth of different bCA cell lines originating from cell cycle arrest or increased apoptosis. In numerous studies, the pretreatment with AS-ODNs or siRNAs provoked strong enhancement of subsequent chemotherapies, emphasising the effectiveness of these inhibition approaches. Conclusions The application of antisense-based inhibitors in combination with chemotherapeutics might represent an alternative strategy for the adjuvant treatment of superficial bCA. Nevertheless, translation of this technology to the clinic might be hampered by inestimable off-target effects caused by AS-ODNs and their behaviour after intravesical instillation has to be evaluated in preclinical and clinical trials.

Partial nephrectomy in solitary kidneys carries the risk of tumour progression as well as loss of renal function. We evaluated complications and outcome in patients with renal cell cancer in solitary kidneys who were treated by means of nephron-sparing surgery.Between 1993 and 2003, 38 patients with renal cell carcinoma in a solitary kidney underwent nephron-sparing surgery (partial nephrectomy, n = 37; work-bench resection, n = 1). Of these patients, 21 had asynchronous and eight had synchronous bilateral tumours and underwent contralateral radical nephrectomy. The variables examined were tumour size, disease progression, pre- and postoperative renal function and early (within 30 days of nephron-sparing surgery) and late complications.After a mean follow-up period of 41.7 months (range 8-93 months) the mean serum creatinine level had increased from 1.25 mg/dl preoperatively to 1.62 mg/dl postoperatively. Seventeen patients retained normal renal function and 21 developed some degree of renal insufficiency. New-onset chronic renal insufficiency after nephron-sparing surgery with creatinine levels2 mg/dl was the only late complication observed, occurring in 10 cases. None of the patients required dialysis. Transient urinary leakage was the most frequent early complication, occurring in four cases. Recurrence and/or progression were seen in six patients: four with local recurrence (three of whom also had distant metastases) and two with pure metastatic progression. Nephron-sparing surgery was repeated for the patient with isolated local tumour recurrence. The mean tumour size was 3.8 cm (range 0.7-9.9 cm). Tumour size was markedly greater in patients who developed disease progression (6.2 vs 3.5 cm) and in those who developed renal insufficiency (5.2 vs 3.3 cm).Nephron-sparing surgery for renal cell carcinoma involving a solitary kidney provides effective curative treatment for small tumours, with preservation of renal function. However, patients who undergo partial nephrectomy for locally extensive tumours are at high risk of disease progression.

To investigate the consistency of several comorbidity classifications and concomitant diseases at radical prostatectomy (RP) during a 10-year period.In 1,297 patients who underwent RP between 1993 and 2002, age and several comorbidity classifications were derived from patient records and assigned to the year of surgery. Trends were evaluated using the Cochran-Armitage trend test.Parallel to an increasing frequency of RPs and a shift toward more organ-confined tumors (P = 0.0094), the proportion of patients agedor =70 years increased (P = 0.0077). The proportion of the American Society of Anesthesiologists (ASA) Physical Status class 3 increased (P0.0001), whereas that of ASA class 1 decreased (P0.0001). A Charlson scoreor =1 has been assigned with an increasing frequency (P = 0.0008), whereas the trend with a Charlson score ofor =2 did not reach statistical significance (P = 0.07). In contrast to the latter 2 classifications, no significant trends were observed with classifications related to diabetes mellitus and heart disease.This study shows that the application of the ASA classification may change significantly over time, whereas cardiac and diabetes-related conditions, as well as the Charlson score were apparently less sensitive to changing classification standards in the RP setting.

Purpose: To evaluate the impact of adjuvant intravesical bacillus Calmette-Guérin (BCG) treatment in patients with high-grade transitional cell carcinoma of bladder. Patients and Methods: A total of 207 consecutive patients who underwent transurethral resection for high-grade T1 transitional cell carcinoma of bladder at our institution between January 1, 2005 and December 31, 2012. Of those patients, 77 underwent early cystectomy without BCG instillation and were excluded from the analysis. The overall survival and cancer-specific mortality were compared in 2 different therapy options groups (group of patients who received adjuvant BCG instillation vs. the group of patients who did not receive BCG therapy). Overall mortality was estimated by the Kaplan-Meier method, univariate comparisons were made with the log rank test. The cumulative incidence of deaths from bladder cancer (BC) was determined by univariate and multivariate competing risk analysis. Cox proportional hazard models for competing risks were used to study the combined effects of the variables on BC-specific mortality. Results: The 5-year overall survival in patients with BCG instillation vs. patients who did not receive BCG therapy was 74 vs. 28% (p = 0.0016). In the univariate analysis, the adjuvant intravesical BCG treatment was associated with decreased cancer-specific mortality (p = 0.0062). In the multivariable analysis, the age and the BCG instillation were independent factors of overall survival (hazard ratio 0.26, 95% CI 0.15-0.46, p < 0.0001) and cancer-specific mortality (hazard ratio 0.29, 95% CI 0.12-0.71, p = 0.0067). Conclusion: Dispensing from adjuvant intravesical BCG treatment is associated with increased overall- and disease-specific mortality in patients with T1 high-grade transitional cell carcinoma of bladder. This observation confirms that adjuvant BCG instillation is a crucial part of treatment in this patient population.

We describe a patient with rapid growth of a vena cava tumor thrombus from level I-II to level III within 1 month. This case illustrates that once the diagnosis of vena cava involvement is established in renal cell carcinoma, surgery should not be delayed without urgent reasons.

INTRODUCTION AND OBJECTIVES: Assessment of tumour aggressiveness is essential for accurate risk stratification in diagnostic and further counselling for treatment in patients with prostate cancer (PCa). Therefore, we compared MRI/ultrasound-fusion biopsy (fusionPBx) to systematic prostate biopsy (TRUS-PBx). METHODS: 263 consecutive patients with suspicion of PCa were investigated (repeat biopsy: n1⁄4 195; first biopsy: n1⁄468). All patients were examined by 3 Tesla multiparametric magnetic resonance imaging (mpMRI) applying the European Society of Urogenital Radiology (ESUR) criteria. All patients underwent transperineal fusion-PBx (mean 9 cores) and additionally a transrectal TRUS-PBx (mean 12 cores) during the same session. RESULTS: Median age was 66yrs, median PSA-level was 8.3ng/mL and median prostate volume was 50mL. Overall, PCa detection rate was 52% (137/263). Fusion-PBx detected more PCa than TRUS-PBx (44% (116/263) vs. 35% (91/263); p1⁄40.0023). In 74% (101/137) of biopsy-proven PCa, the Gleason Score (GS) was 7. In fusion-PBx (n1⁄4116) the distribution of GS was 28% for GS1⁄46 and 72% for GS 7. In TRUS-PBx (n1⁄491), 26% of tumours with GS1⁄46 and 74% with GS 7 were detected. 55% (n1⁄437) more tumours with GS 7 were detected by additional fusion-PBx compared to TRUS-PBx alone (GS 7 n1⁄467). Conversely, 21% (n1⁄418) more tumours with GS 7 were found by TRUS-PBx additionally to fusion-PBx (GS 7 n1⁄484). CONCLUSIONS: Fusion-PBx is associated with more tumourupgrading and therefore better prediction of tumour aggressiveness. But due to a high portion of tumours with GS 7 in fusion-PBx, TRUSPBx should still be performed in combination with fusion-PBx.

INTRODUCTION AND OBJECTIVES: The microRNA miR-224 is a putative regulator of alpha-methylacyl-CoA racemase (AMACR) which is known to be up-regulated in prostate cancer (PCa). Here, we analyzed the expression levels of miR-224 and its host gene gammaaminobutyric acid A receptor / epsilon subunit (GABRE). The functional role of miR-224 was then investigated in vitro. METHODS: Expression levels were analyzed by qPCR using 50 malignant (PCa) and matched non-malignant tissue samples from prostatectomy explants as well as 30 samples derived from patients with benign prostatic hyperplasia (BPH). AMACR expression data were used from a previous study on the same sample cohort. DU145, PC-3 and LNCaP PCa cells were transfected with 100 nM of miR-224 mimic or a control construct for 4 h. Protein and mRNA expression levels of AMACR as well as functional analyses (viability, proliferation, cell colony formation, apoptosis) were conducted 48 h after transfection. RESULTS: The expression of miR-224 was significantly decreased in PCa tissue samples by 3.5and 2.7-fold compared to matched non-malignant and BPH tissue samples, respectively. Concomitantly, GABRE mRNA expression was completely downregulated compared to either control group. The down-regulation of miR-224 significantly correlated with the down-regulation of its host gene GABRE (Spearman correlation coefficient: 0.442) as well as with the previously determined up-regulation of its target gene AMACR (Spearman correlation coefficient: 0.384). In vitro, miR-224 led to slight decreases of AMACR mRNA by 30% and protein by 20% only in PC-3 cells. MiR-224 marginally influenced cellular viability and proliferation in DU145 and LNCaP cells. In contrast, miR-224-treated PC-3 cells displayed a decrease in viability by 17% and proliferation by 34% compared to control. Cell colony formation was inhibited in both DU145 and PC-3 cells by 23% and 42%, respectively, following miR-224 administration. Furthermore, miR-224 produced a doubling of apoptosis-mediated cell death rate in PC-3 cells, whereas apoptosis rate remained unaffected in DU145 and LNCaP cells. CONCLUSIONS: Our findings indicate that the PCa-specific down-regulation of miR-224 correlates with the down-regulation of its host gene GABRE as well as with the up-regulation of its putative target gene AMACR. Depending on the cell line miR-224 could inhibit tumor cell viability and growth as well as induce apoptosis-mediated cell death which suggests a tumor-suppressive role for this microRNA in PCa.

Objectives: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. Patients and Methods: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ETA-receptor antagonist, BQ-123; ETB-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT1-receptor antagonist, candesartan; and NK1-receptor antagonist, L-703,606. Results: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. Conclusion: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.

Introduction: We aimed at developing and validating a pre-cystectomy nomogram for the prediction of locally advanced urothelial carcinoma of the bladder (UCB) using clinicopathological parameters. Materials and Methods: Multicenter data from 337 patients who underwent radical cystectomy (RC) for UCB were prospectively collected and eligible for final analysis. Univariate and multivariate logistic regression models were applied to identify significant predictors of locally advanced tumor stage (pT3/4 and/or pN+) at RC. Internal validation was performed by bootstrapping. The decision curve analysis (DCA) was done to evaluate the clinical value. Results: The distribution of tumor stages pT3/4, pN+ and pT3/4 and/or pN+ at RC was 44.2, 27.6 and 50.4%, respectively. Age (odds ratio (OR) 0.980; p < 0.001), advanced clinical tumor stage (cT3 vs. cTa, cTis, cT1; OR 3.367; p < 0.001), presence of hydronephrosis (OR 1.844; p = 0.043) and advanced tumor stage T3 and/or N+ at CT imaging (OR 4.378; p < 0.001) were independent predictors for pT3/4 and/or pN+ tumor stage. The predictive accuracy of our nomogram for pT3/4 and/or pN+ at RC was 77.5%. DCA for predicting pT3/4 and/or pN+ at RC showed a clinical net benefit across all probability thresholds. Conclusion: We developed a nomogram for the prediction of locally advanced tumor stage pT3/4 and/or pN+ before RC using established clinicopathological parameters.

Objectives To explore the views of experts about the development and validation of a robotic surgery training curriculum, and how this should be implemented. Materials and methods An international expert panel was invited to a structured session for discussion. The study was of a mixed design, including qualitative and quantitative components based on focus group interviews during the European Association of Urology (EAU) Robotic Urology Section (ERUS) (2012), EAU (2013) and ERUS (2013) meetings. After introduction to the aims, principles and current status of the curriculum development, group responses were elicited. After content analysis of recorded interviews generated themes were discussed at the second meeting, where consensus was achieved on each theme. This discussion also underwent content analysis, and was used to draft a curriculum proposal. At the third meeting, a quantitative questionnaire about this curriculum was disseminated to attendees to assess the level of agreement with the key points. Results In all, 150 min (19 pages) of the focus group discussion was transcribed (21 316 words). Themes were agreed by two raters (median agreement kappa 0.89) and they included: need for a training curriculum (inter-rater agreement kappa 0.85); identification of learning needs (kappa 0.83); development of the curriculum contents (kappa 0.81); an overview of available curricula (kappa 0.79); settings for robotic surgery training ((kappa 0.89); assessment and training of trainers (kappa 0.92); requirements for certification and patient safety (kappa 0.83); and need for a universally standardised curriculum (kappa 0.78). A training curriculum was proposed based on the above discussions. Conclusion This group proposes a multi-step curriculum for robotic training. Studies are in process to validate the effectiveness of the curriculum and to assess transfer of skills to the operating room.

Background: Epigenetic modifications are common in malignant tissues. Here we analyzed the methylation degree of plasminogen activator inhibitor 1 (PAI-1) gene in comparison to the methylation of glutathione-stransferase- π (GSTP1) gene in prostate cancer (PCa). Methods: PAI-1 hypermethylation was studied using methylation-sensitive high resolution melting (MS-HRM) analysis of bisulfite-modified DNA and methylation-sensitive restriction endonuclease based quantitative PCR (MSRE-qPCR) on unmodified genomic DNA. Results: Data, obtained by these two methods, correlate closely. Methylation levels of PAI-1 analyzed in tissue specimens and serum samples were nearly similar. The diagnostic performance of the MSRE-qPCR assay characterized by AUC values was 0.944 and 0.937 for PAI-1 and GSTP1, respectively. Combination of both markers resulted in higher values of AUC, sensitivity and specificity. Conclusion: MSRE-qPCR based methylation analysis of PAI-1 gene and especially - in combination with GSTP1 gene may have potential as epigenetic marker of PCa in biological fluids.

Context: Phase 3 trials have made major contributions to advances in prostate cancer (PCa). However, funding limitations and excess bureaucracy are now making it difficult to conduct trials. Objective: To describe the collaborative groups in Europe and their academic phase 3 PCa trials. Evidence acquisition: Leaders of collaborative groups from Scandinavia, the European Organisation for Research and Treatment of Cancer (EORTC), France, Spain, the United Kingdom, Germany, Switzerland, The Netherlands, and Ireland were asked to provide information. Evidence synthesis: Approximately 40 academic European phase 3 trials focussing on PCa have been completed, and about 10 are accruing patients. Cross-border trials have been successfully conducted led by EORTC (11), Scandinavian Prostate Cancer Group (9), European Association of Urology (1), Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficiency (STAMPEDE) (1), and the French Genito-Urinary Tumor Group (1). Among these studies were practise-changing trials showing the superiority of prostatectomy over watchful waiting in patients

Objectives To investigate several comorbidity classifications as possible predictors of mortality, because the value of comorbidity as a prognostic factor is uncertain in patients older than 70 years of age and radical prostatectomy in patients older than 70 years is controversial. Methods A total of 214 consecutive patients aged 70 years or older who underwent radical prostatectomy from December 1992 to December 2002 were stratified according to the Charlson score, American Society of Anesthesiologists physical status classification, New York Heart Association classification of cardiac insufficiency, classification of angina pectoris from the Canadian Cardiovascular Society, and age (70 to 72 versus 73 to 74 versus 75 years or older). The mean follow-up in the surviving patients was 5.1 years (range 1.3 to 12.5). A sample of 240 consecutive patients aged 67.0 to 69.9 years treated during the same period was used for comparison. The overall and comorbid mortality were the study endpoints. Mantel-Haenszel hazard ratios were calculated. Comparisons were made using the log-rank test. Results Unlike for patients aged 67.0 to 69.9 years, for those 70 years old or older, only one of the investigated stratifications reached significance as a predictor of mortality. A New York Heart Association classification of 2+ versus 0 was significant for overall mortality (hazard ratio 5.8, P = 0.021) and comorbid mortality (hazard ratio 15.9, P = 0.046). Conclusions Comorbidity is of limited prognostic value in patients selected for radical prostatectomy and 70 years old or older.

BACKGROUND. This study describes the evaluation of the expression patterns of prostaterelated transcripts in 106 matched prostate tissues from prostatectomies as predictors for prostate cancer (PCa). METHODS. Quantitative PCR (QPCR) assays with site-specific hybridization probes were established for four housekeeping genes (GAPDH, HPRT, PBGD, TBP) and nine prostaterelated genes (AibZIP, D-GPCR, EZH2, PCA3, PDEF, prostein, PSA, PSCA, TRPM8). RESULTS. TherelativemRNAexpressionlevelsofAibZIP,D-GPCR,EZH2,PCA3,PDEF,PSA, TRPM8 (all P

Aktuelle Studien ergaben, dass das bis dato als chemotherapieresistent angesehene Prostatakarzinom mit Docetaxel positiv beeinflusst werden kann. Im Rahmen eines Workshops fur Internisten und Urologen zur Chemotherapie bei fortgeschrittenem hormonrefraktarem Prostatakarzinom wurden die unterschiedlichen Ansichten zur dieser noch neuen Therapieform dargelegt, Gemeinsamkeiten diskutiert und erarbeitet, aber auch Kontroversen herausgestellt. In Therapieempfehlungen werden Vorschlage gemacht zu deren praktischer Durchfuhrung (Dosierung, Anwendung), zur begleitenden Medikation und Masnahmen sowie zur Kontrolle der Behandlung und des Therapieverlaufs. Hierbei wird insbesondere auf Untersuchungen zur Erfassung des Therapieeffekts und Kriterien fur ein Ansprechen auf die Behandlung, aber auch fur einen Abbruch derselbeneingegangen.

The prostate specific antigen level at which to recommend a bone scan after treatment of early prostate cancer is controversial. We identified the incidence of bone metastases at varying prostate specific antigen levels in asymptomatic men following radical prostatectomy, radiation therapy and watchful waiting.Data were obtained from the Early Prostate Cancer trial comparing placebo with bicalutamide in addition to standard care for localized prostate cancer. As part of the trial patients were required to have routine bone scans regardless of prostate specific antigen levels. The prostate specific antigen levels were divided into subgroups and the incidence of positive bone scans was calculated for each group.The incidence of positive bone scans in patients treated with watchful waiting and given bicalutamide or placebo was low (0.7% to 3.2%) at prostate specific antigen levels less than 20 ng/ml. At greater than this level the sample sizes were smaller but there was a significant increase in the incidence of positive bone scans. In the groups treated with radiation therapy or radical prostatectomy, regardless of the addition of bicalutamide, the incidence of positive bone scans was low (0.2% to 1.4%) at prostate specific antigen levels less than 5 ng/ml. The sample sizes were smaller at prostate specific antigen levels greater than 5 ng/ml so the results are harder to interpret.Bone scans can be confidently eliminated in the followup of patients with early prostate cancer after standard care of those with prostate specific antigen levels less than 5 ng/ml. This level can be increased to 20 ng/ml with caution in those patients treated with watchful waiting.