Objectives: To investigate the effects of serotonin and melatonin (MLT) on the regulation of malignant growth and the activity of serotonin receptors (5HTR1a/-1b) in prostate cancer (PCa) cell lines. Materials and Methods: In four PCa cell lines (LNCaP, 22RV1, PC3, DU145) and two reference cell lines 5HTR1a and -1b, relative mRNA expression levels were assessed. Different serotonin and MLT receptor agonists and antagonists were used in stimulation and inhibition experiments. Results: mRNA expression of 5HTR1b was higher than that of 5HTR1a in all PCa cell lines. Serotonin showed a significant growth stimulatory effect in all PCa lines. The 5HTR1a and -1b agonists/antagonists did not significantly affect viability. MLT inhibited viability only in PC3 cells. Similarly, the 5HTR1a antagonist induced apoptotic changes in PC3 cells only at 10–4M, while the 5HTR1b antagonist induced necrosis at 10–4M in all cell lines. Cell cycle alterations were seen in PC3 and DU145 cells under the influence of the 5HTR1a antagonist. Conclusions: Serotonin receptor antagonists and agonists as well as MLT influence viability and apoptosis of PCa cell lines at supraphysiologic concentrations. In contrast to other reports, our results do not support a regulatory role of serotonin or MLT receptor activation or inhibition in PCa growth. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The treatment of clinically locally advanced prostate carcinoma (stage cT3) remains controversial. One of the main reasons for this controversy results from the substantial staging error attached to the clinical diagnosis cT3 with overstaged T2 tumors and understaged node-positive cases. Treatment options in this situation include radical prostatectomy, external beam radiotherapy, immediate or delayed androgen deprivation treatment and the so-called ‘watchful waiting’. Acceptable and often surprisingly good tumor-specific survival rates have been reported for radical prostatectomy in pT3 series – based on good clinical case selection – approaching those of pT2 series. In lymph node-positive pT3 cases, adjuvant hormone deprivation seems to prolong survival which it does not in lymph node-negative pT3 disease. A benefit of adjuvant external beam radiotherapy after radical prostatectomy for pT3 cases in prolonging overall survival has not been shown, despite the fact that it can prevent or delay biochemical and local recurrence. External beam radiotherapy as the only treatment for cT3 disease results in unfavorable tumor-specific survival rates, which can be significantly improved with adjuvant hormonal treatment with LHRH agonists. If, in case of advanced age and/or significant comorbidity, primary hormonal treatment is chosen, early hormonal deprivation therapy seems to offer marginal benefits in survival compared to delayed treatment. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: To compare the clinical value of the measurement of complex and total PSA in the discrimination between benign prostatic hyperplasia (BPH) and prostate cancer. Methods: In serum samples collected from 166 men with histopathologically proven clinically localized prostate cancer and of 97 men with BPH, total prostate-specific antigen (PSA), complexed PSA and the free to total PSA ratio were determined. The statistical analysis was done by the comparison of the receiver operator characteristic (ROC) curves. Results: The areas under the ROC curves were 0.776 for total PSA, 0.799 for complexed PSA (total PSA vs. cPSA: p < 0.0001) and 0.812 for the free to total PSA ratio. With a cut-off of 3.0 ng/ml for complexed PSA, the sensitivity was 90%, the specificity 58%, the positive and the negative predictive values 79 and 78%, respectively. With a cut-off of 4.0 ng/ml for total PSA, the sensitivity was 87%, the specificity 59%, the positive and the negative predictive values were 78 and 72%, respectively. Conclusions: There was a statistically significant advantage for complexed PSA compared to total PSA in the discrimination between BPH and prostate cancer. The difference was, however, small and its clinical relevance is questionable. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Objectives: To investigate the prevalence and distribution of comorbidity and its association with perioperative complications in patients undergoing radical prostatectomy (RPE). Methods: In 431 unselected RPE patients, the American Society of Anesthesiologists Physical Status classification (ASA-PS), the New York Heart Association classification of cardiac insufficiency (NYHA), the classification of angina pectoris of the Canadian Cardiovascular Society (CCS), height, weight, the body mass index (BMI), and the number of concomitant diseases (NCD) were assessed and related to perioperative cardiovascular complications. Results: In RPE patients less than 70 years old, comorbidity rose nearly continuously with increasing age. However, after reaching an age of 70 years, the proportion of NYHA-0 patients increased (60–64 years, 86%; 65–69 years, 85%; ≥70 years, 87%). Furthermore, the severe comorbidities decreased in patients selected for RPE aged 70 or more years. There was a nonsignificant trend towards higher comorbidity in patients with perioperative cardiovascular complications. Conclusions: These data suggest that documentation of the distribution of ASA-PS, CCS, NYHA and of concomitant diseases might be helpful to characterize the general health status and the degree of selection of prostate cancer treatment populations especially in series with a high portion of patients aged 70 or more years. Concerning perioperative complications, the individual predictive value of comorbidity seems to be poor in the radical prostatectomy setting. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Transition zone biopsies have been found to increase the detection rates of cancer of the prostate in patients with negative digital rectal examination. There are however no data available whether the higher biopsy rate is associated with greater morbidity. The present study was therefore designed to evaluate the complication rate of extended sextant biopsy. In this prospective study, 162 consecutive patients who presented for prostatic evaluation were included. After starting prophylactic antibiotic treatment 48 h prior to the procedure, transrectal ultrasound-guided core biopsies were obtained from each lobe: three each from the peripheral zone (apex, mid-zone and base) and two from the transition zone of each prostatic lobe. In all patients a questionnaire was obtained 10–12 days after the procedure. Major complications occurred in 3 patients. In 2 of the 3 cases major macroscopic hematuria was treated by an indwelling catheter for 1 or 2 days and 1 patient developed fever >38.5°C for 1 day. Minor macroscopic hematuria was present in 68.5% of the patients. In 17.9% of these cases, the hematuria lasted for more than 3 days. Hematospermia was observed in 19.8% and minor rectal bleeding occurred in 4.9%. Ten-core biopsies did not lead to an increase in adverse effects or complications when compared to the results of sextant biopsies reported in the literature. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Evidence-based guidelines are important sources of knowledge in everyday clinical practice. In 2005, the German Society for Urology decided to develop a highquality evidence-based guideline for the early detection, diagnosis and treatment of the different clinical manifestations of prostate cancer. The guideline project started in 2005 and involved 75 experts from 10 different medical societies or medical organizations including a patient organization. The guideline was issued in September 2009 and consists of 8 chapters, 170 recommendations, and 42 statements. Due to the broad spectrum of clinical questions covered by the guideline and the high number of participating organizations and authors, the organizers faced several methodological and organizational challenges. This article describes the methods used in the development of the guideline and highlights critical points and challenges in the development process. Strategies to overcome these problems are suggested which might be beneficial in the development of new evidence-based guidelines in the future. / Evidenzbasierte Leitlinien sind wichtige Quellen komprimierten Wissens für die tägliche klinische Praxis. Die Deutsche Gesellschaft für Urologie beschloss im Jahr 2005, eine qualitativ hochwertige evidenzbasierte Leitlinie zur Früherkennung, Diagnose und Behandlung der verschiedenen klinischen Manifestationen des Prostatakarzinoms zu erstellen. Das Leitlinienprojekt begann im Jahr 2005 unter Mitwirkung von 75 Experten und Patientenvertretern aus 10 verschiedenen Fachgesellschaften und Organisationen. Die Leitlinie wurde im September 2009 veröffentlicht und besteht aus 8 Kapiteln mit insgesamt 170 Empfehlungen und 42 Statements. Das breite thematische Spektrum der Leitlinie und die hohe Zahl teilnehmender Autoren und Organisationen stellten die Organisatoren vor verschiedene methodische und logistische Herausforderungen. Dieser Beitrag stellt die angewendete Methodik bei der Leitlinienerstellung dar und betont kritische Punkte und Probleme der Erstellung. Die beschriebenen Lösungsansätze können bei der Planung und Durchführung künftiger evidenzbasierter Leitlinienprojekte hilfreich sein. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Prostate cancer is the most common malignancy afflicting Canadian men in 2011. Physicians use digital rectal exams (DRE), blood tests for prostate specific antigen (PSA) and transrectal ultrasound (TRUS)-guided biopsies for the initial diagnosis of prostate cancer. None of these tests detail the spatial extent of prostate cancer - information critical for using new therapies that can target cancerous prostate. With an MRI technique called proton magnetic resonance spectroscopic imaging (1H-MRSI), biochemical analysis of the entire prostate can be done without the need for biopsy, providing detailed information beyond the non-specific changes in hardness felt by an experienced urologist in a DRE, the presence of PSA in blood, or the “blind-guidance” of TRUS-guided biopsy. A hindrance to acquiring high quality 1H-MRSI data comes from signal originating from fatty tissue surrounding prostate that tends to mask or distort signal from within the prostate, thus reducing the overall clinical usefulness of 1H-MRSI data. This thesis has three major areas of focus: 1) The development of an optimized 1H-MRSI technique, called conformal voxel magnetic resonance spectroscopy (CV-MRS), to deal the with removal of unwanted lipid contaminating artifacts at short and long echo times. 2) An in vivo human study to test the CV-MRS technique, including healthy volunteers and cancer patients scheduled for radical prostatectomy or radiation therapy. 3) A study to determine the efficacy of using the 1H-MRSI data for optimized radiation treatment planning using modern delivery techniques like intensity modulated radiation treatment. Data collected from the study using the optimized CV-MRS method show significantly reduced lipid contamination resulting in high quality spectra throughout the prostate. Combining the CV-MRS technique with spectral-spatial excitation further reduced lipid contamination and opened up the possibility of detecting metabolites with short T2 relaxation times. Results from the in vivo study were verified with post-histopathological data. Lastly, 1H-MRSI data was incorporated into the radiation treatment planning software and used to asses tumour control by escalating the radiation to prostate lesions that were identified by 1H-MRSI. In summary, this thesis demonstrates the clinical feasibility of using advanced spectroscopic imaging techniques for improved diagnosis and treatment of prostate cancer.

Image guided radiation therapy (IGRT) is a new type of radiotherapy used to deliver lethal doses of radiation to mobile tumors, while preventing surrounding healthy structures from receiving high doses of radiation. It relies on image guidance to track the tumor and ensure its prescribed position in the radiation beam. The main goal of this work was to determine if a new three-dimensional ultrasound (3D US) image guidance device, called the Restitu System, could safely replace (or be used interchangeably with) an existing method involving x-ray images of implanted fiducial markers (FMs) for prostate IGRT. Using comparison statistics called 95 % limits of agreement (LOA), it was found that the new 3D US system did not produce measurements that agreed sufficiently closely to those made using the FM technique, and therefore, could not safely replace FMs for prostate IGRT. Ultrasound image quality and user variability were determined to have a significant impact on the agreement between the two methods. It was further shown that using the Restitu System offered no significant clinical advantages over a conventional patient re-positioning technique.

Abstract Objectives: To establish the prevalence of lower serum selenium status (<106 ng/ml) among the adult white American male population, to determine whether certain social, economic, geographic, physical, and dietary characteristics are risk factors for lower selenium status, and to identify a selenium augmentation strategy for white adult men deficient in this trace element. Design: An exploratory cross-sectional study using nationally representative data from the National Health and Nutrition Examination Survey III, 1988-1994 (NHANES III). Methods: 2989 white men, aged 20 or greater in the NHANES III dataset had recorded serum selenium values. These men were divided in two groups based on selenium status, those with values of less than 106 ng/ml (n=288) and those with a status greater than or equal to 106 ng/ml (n=2701). Various demographic, physical, and dietary variables were then compared between the two selenium status groups in a bivariate analysis. Multiple logistic regression was then performed to assess possible risk factors for lower selenium status. Results: This study estimated that 7.7% of white American adult men aged 20 years and older, a total of 4,751,618 individuals, had a selenium status less than 106 ng/ml. Several, of the more than forty, social, economic, geographic, physical and dietary characteristics examined were shown to be significantly associated with a lower selenium status. Risk factors for lower selenium status (<106 ng/ml) were, smoking, living in the Southern census region, being in either the 20-39 or the 60 years or older age groups, exercising less than their peers, having a lower income, and not consuming dark bread. Conclusion: It would appear that certain physical, geographic, dietary and demographic characteristics are significantly associated with lower selenium status. While, this work was unable to identify a suitable selenium fortification vehicle to reduce the prevalence of lower selenium status, it did identify risk factors that may contribute to this condition.

Biological processes in living organisms consist of a vast number of different molecular networks and interactions, which are complex and often hidden from our understanding. This work is focused on recovery of such details for two quite distant examples: acclimation to extreme freezing tolerance in Siberian spruce (Picea obovata) and detection of proteins associated with prostate cancer. The first biological system in the study, upon P. obovata, is interesting by this species ability to adapt and sustain extremely low temperatures, such as -60⁰C or below. Despite decades of investigations, the essential features and mechanisms of the amazing ability of this species still remains unclear. To enhance knowledge about extreme freezing tolerance, the metabolome and proteome of P. obovata’s needles were collected during the tree’s acclimation period, ranging from mid August to January, and have been analyzed. The second system within this study is the plasma proteome analysis of high risk prostate cancer (PCa) patients, with and without bone metastases. PCa is one of the most common cancers among Swedish men, which can abruptly develop into an aggressive, lethal disease. The diagnostic tools, including PSA-tests, are insufficient in predicting the disease’s aggressiveness and novel prognostic markers are urgently required. Both biological systems have been analyzed following similar steps: by two-dimensional difference gel electrophoresis (2D-DIGE) techniques, followed by protein identification using mass spectrometry (MS) analysis and multivariate methods. Data processing has been utilized for searching for proteins that serve as unique indicators for characterizing the status of the systems. In addition, the gas chromatography-mass spectrometry (GC-MS) study of the metabolic content of P.obovata’s needles, from the extended observation period, has been performed. The studies of both systems, combined with thorough statistical analysis of experimental outcomes, have resulted in novel insights and features for both P. obovata and prostate cancer. In particular, it has been shown that dehydrins, Hsp70s, AAA+ ATPases, lipocalin and several proteins involved in cellular metabolism etc., can be uniquely associated with acclimation to extreme freezing in conifers. Metabolomic analysis of P. obovata needles has revealed systematic metabolic changes in carbohydrate and lipid metabolism. Substantial increase of raffinose, accumulation of desaturated fatty acids, sugar acids, sugar alcohols, amino acids and polyamines that may act as compatible solutes or cryoprotectants have all been observed during the acclimation process. Relevant proteins for prostate cancer progression and aggressiveness have been identified in the plasma proteome study, for patients with and without bone metastasis. Proteins associated with lipid transport, coagulation, inflammation and immune response have been found among them.