Search

Aim: To analyze the potential of 14 cancer-associated genes, including six miRNAs, for bladder cancer (BC) diagnosis in urine., Patients & Methods: DNA methylation levels of 14 genes were analyzed in urine of 72 BC patients and 75 healthy controls using quantitative methylation-specific PCR. Multivariate logistic regression analysis was used to determine an optimal marker panel., Results: Ten genes were significantly hypermethylated in BC patients. The GHSR/MAL combination showed the best diagnostic performance, reaching a sensitivity of 92% (95% CI: 86-99) and a specificity of 85% (95% CI: 76-94)., Conclusion: We identified a novel two-gene panel with a high diagnostic accuracy for BC that can be applied in a noninvasive, urine-based test.

Aim: Several urinary hypermethylation-markers (hmDNA) have been described for bladder cancer (BC) detection, but none have been able to replace cystoscopy yet. We systematically reviewed and evaluated current literature on urinary hmDNA markers for BC diagnostics., Patients & Methods: A systematic search of PubMed, EMBASE.com and The Cochrane Library up to February 2017 using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, was conducted., Results: A total of 30/42 studies included compared gene panels, with varying sensitivities (52-100%) and specificities (0-100%). Considerable heterogeneity across studies was observed and most was case-control studies., Conclusion: Reported diagnostic accuracy of urinary hmDNA for BC detection is highly variable and there is a lack of validation studies. Recent studies indicate that complementary markers are needed to allow for clinical implementation.

Extracellular vesicles (EVs) secreted by prostate cancer (PCa) cells contain specific biomarkers and can be isolated from urine. Collection of urine is not invasive, and therefore urinary EVs represent a liquid biopsy for diagnostic and prognostic testing for PCa. In this study, we optimised urinary EV isolation using a method based on heat shock proteins and compared it to gold-standard ultracentrifugation. The urinary EV isolation protocol using the Vn96-peptide is easier, time convenient (≈1.5 h) and no special equipment is needed, in contrast to ultracentrifugation protocol (>3.5 h), making this protocol clinically feasible. We compared the isolated vesicles of both ultracentrifugation and Vn96-peptide by proteome profiling using mass spectrometry-based proteomics ( n  = 4 per method). We reached a depth of >3000 proteins, with 2400 proteins that were commonly detected in urinary EVs from different donors. We show a large overlap (>85%) between proteins identified in EVs isolated by ultracentrifugation and Vn96-peptide. Addition of the detergent NP40 to Vn96-peptide EV isolations reduced levels of background proteins and highly increased the levels of the EV-markers TSG101 and PDCD6IP, indicative of an increased EV yield. Thus, the Vn96-peptide-based EV isolation procedure is clinically feasibly and allows large-scale protein profiling of urinary EV biomarkers.

Objective: To design and demonstrate a customized tool to generate histologic sections of the prostate that directly correlate with needle-based optical coherence tomography pullback measurements., Materials and Methods: A customized tool was created to hold the prostatectomy specimens during optical coherence tomography measurements and formalin fixation. Using the tool, the prostate could be sliced into slices of 4 mm thickness through the optical coherence tomography measurement trajectory. In this way, whole-mount pathology slides were produced in exactly the same location as the optical coherence tomography measurements were performed. Full 3-dimensional optical coherence tomography pullbacks were fused with the histopathology slides using the 3-dimensional imaging software AMIRA, and images were compared., Results: A radical prostatectomy was performed in a patient (age: 68 years, prostate-specific antigen: 6.0 ng/mL) with Gleason score 3 + 4 = 7 in 2/5 biopsy cores on the left side (15%) and Gleason score 3 + 4 = 7 in 1/5 biopsy cores on the right side (5%). Histopathology after radical prostatectomy showed an anterior located pT2cNx adenocarcinoma (Gleason score 3 + 4 = 7). Histopathological prostate slides were produced using the customized tool for optical coherence tomography measurements, fixation, and slicing of the prostate specimens. These slides correlated exactly with the optical coherence tomography images. Various structures, for example, Gleason 3 + 4 prostate cancer, stroma, healthy glands, and cystic atrophy with septae, could be identified both on optical coherence tomography and on the histopathological prostate slides., Conclusion: We successfully designed and applied a customized tool to process radical prostatectomy specimens to improve the coregistration of whole mount histology sections to fresh tissue optical coherence tomography pullback measurements. This technique will be crucial in validating the results of optical coherence tomography imaging studies with histology and can easily be applied in other solid tissues as well, for example, lung, kidney, breast, and liver. This will help improve the efficacy of optical coherence tomography in cancer detection and staging in solid organs.

Purpose: Clinical outcomes prognostic markers are awaited in clear-cell renal carcinoma (ccRCC) to improve patient-tailored management and to assess six different markers' influence on clinical outcomes from ccRCC specimen and their incremental value combined with TNM staging., Materials and Methods: This is a retrospective, multicenter study. One hundred and forty-three patients with pT1b-pT3N0M0 ccRCC were included. Pathology specimens from surgeries were centrally reviewed, mounted on a tissue micro-array and stained with six markers: CAIX, c-MYC, Ki67, p53, vimentin and PTEN. Images were captured through an Ultra Fast Scanner. Tumor expression was measured with Image Pro Plus. Cytoplasmic markers (PTEN, CAIX, vimentin, c-MYC) were expressed as surface percentage of expression. Nuclear markers (Ki67, p53) were expressed as number of cells/mm 2 . Clinical data and markers expression were compared with clinical outcomes. Each variable was included in the Cox proportional multivariate analyses if p < 0.10 on univariate analyses. Discrimination of the new marker was calculated with Harrell's concordance index., Results: At median follow-up of 63 months (IQR 35.0-91.8), on multivariate analysis, CAIX under-expression and vimentin over-expression were associated with worse survival (recurrence, specific and overall survival). A categorical marker CAIX-/Vimentin+ with cutoff points for CAIX and vimentin of 30 and 50 %, respectively, was designed. The new CAIX-/Vimentin+ marker presented a good concordance and comparable calibration to the reference model. Limitations are the retrospective design, the need for external validation and the large study period., Conclusion: Using an automated technique of measurement, CAIX and vimentin are independent predictors of clinical outcomes in ccRCC.

Purpose: To reach standardized terminology in focal therapy (FT) for prostate cancer (PCa)., Methods: A four-stage modified Delphi consensus project was undertaken among a panel of international experts in the field of FT for PCa. Data on terminology in FT was collected from the panel by three rounds of online questionnaires. During a face-to-face meeting on June 21, 2015, attended by 38 experts, all data from the online rounds were reviewed and recommendations for definitions were formulated., Results: Consensus was attained on 23 of 27 topics; Targeted FT was defined as a lesion-based treatment strategy, treating all identified significant cancer foci; FT was generically defined as an anatomy-based (zonal) treatment strategy. Treatment failure due to the ablative energy inadequately destroying treated tissue is defined as ablation failure. In targeting failure the energy is not adequately applied to the tumor spatially and selection failure occurs when a patient was wrongfully selected for FT. No definition of biochemical recurrence can be recommended based on the current data. Important definitions for outcome measures are potency (minimum IIEF-5 score of 21), incontinence (new need for pads or leakage) and deterioration in urinary function (increase in IPSS >5 points). No agreement on the best quality of life tool was established, but UCLA-EPIC and EORTC-QLQ-30 were most commonly supported by the experts. A complete overview of statements is presented in the text., Conclusion: Focal therapy is an emerging field of PCa therapeutics. Standardization of definitions helps to create comparable research results and facilitate clear communication in clinical practice., Competing Interests: Compliance with ethical standards This is a report of a Delphi consensus project among experts only. No human or animal subjects were involved; therefore, no informed consent was collected. Conflict of interest O.U reports being a consultant for Sonacare Medical. A.A. reports consulting for Steba Biotech. A.Bl., M.S., R.S. and S.C. report being consultants for EDAP TMS. S.E. reports being a consultant for NxThera and Profound Medical. J.J. reports being consultant for Endocare. C.K. reports being a consultant for Elekta and organizing educational internships sponsored by Elekta, Siemens, Philips, Medicom and Hitachi. T.P. reports performing a clinical trial with Angiodynamics and being a consultant for Healthtronics. The other authors report no conflicts of interest.

Background and Objectives: Birt-Hogg-Dubé syndrome is an autosomal dominant disorder characterized by skin fibrofolliculomas, lung cysts, spontaneous pneumothorax and renal cell cancer due to germline folliculin (FLCN) mutations (Menko et al. in Lancet Oncol 10(12):1199-1206, 2009). The aim of this study was to evaluate the incidence of spontaneous pneumothorax in patients with BHD during or shortly after air travel and diving., Methods: A questionnaire was sent to a cohort of 190 BHD patients and the medical files of these patients were evaluated. The diagnosis of BHD was confirmed by FLCN mutations analysis in all patients. We assessed how many spontaneous pneumothoraces (SP) occurred within 1 month after air travel or diving., Results: In total 158 (83.2 %) patients returned the completed questionnaire. A total of 145 patients had a history of air travel. Sixty-one of them had a history of SP (42.1 %), with a mean of 2.48 episodes (range 1-10). Twenty-four (35.8 %) patients had a history of pneumothorax on both sides. Thirteen patients developed SP < 1 month after air travel (9.0 %) and two patients developed a SP < 1 month after diving (3.7 %). We found in this population of BHD patients a pneumothorax risk of 0.63 % per flight and a risk of 0.33 % per episode of diving. Symptoms possible related to SP were perceived in 30 patients (20.7 %) after air travel, respectively in ten patients (18.5 %) after diving., Conclusion: Based on the results presented in this retrospective study, exposure of BHD patients to considerable changes in atmospheric pressure associated with flying and diving may be related to an increased risk for developing a symptomatic pneumothorax. Symptoms reported during or shortly after flying and diving might be related to the early phase of pneumothorax. An individualized advice should be given, taking also into account patients' preferences and needs.

Unlabelled: Repeatable quantification is essential when using (18)F-fluoromethylcholine PET/CT to monitor treatment response in prostate cancer. It has been shown that SUV normalized to the area under the blood activity concentration curve (SUVAUC) provides a better correlation with full kinetic analysis than does standard SUV. However, the precision of SUVAUC is not known yet. The purpose of this study was to assess the repeatability of various semiquantitative (18)F-fluoromethylcholine parameters in prostate cancer., Methods: Twelve patients (mean age ± SD, 64 ± 8 y) with metastasized prostate cancer underwent two sets of (18)F-fluoromethylcholine PET/CT scans, on consecutive days. Each set consisted of a 30-min dynamic PET/CT scan of the chest after intravenous administration of 200 MBq of (18)F-fluoromethylcholine, followed by a whole-body PET/CT scan at 40 min. The dynamic scan was used to derive the area under the blood activity concentration curve. Lesion uptake was derived from the whole-body scan using various types of volumes of interest: maximum, peak, and mean. Each of these parameters was normalized to injected activity per body weight, area under the blood activity concentration curve, and blood concentration itself at 40 min, resulting in several types of SUVs: SUV, SUVAUC, and SUVTBR The test-retest repeatability of these metrics, as well as metabolic tumor volume (MTV) and total uptake of choline in the lesion, were studied. The level of agreement between test-retest data and reliability was assessed using Bland-Altman plots, repeatability coefficients, and intraclass correlation coefficients (ICCs)., Results: A total of 67 choline-avid metastases were identified: 44 bone lesions and 23 lymph node lesions. In the case of SUVmax, the repeatability coefficients for SUV, SUVAUC, and SUVTBR were 26% (ICC, 0.95), 31% (ICC, 0.95), and 46% (ICC, 0.89), respectively. Similar values were obtained for SUVpeak and SUVmean The repeatability of SUVAUC was comparable to that of SUVmax, SUVpeak, and SUVmean. Tissue type and tumor localization did not affect repeatability. An MTV of less than 4.2 cm(3) had larger variability than larger volumes (repeatability coefficient, 45% vs. 29%; P = 0.048). The repeatability coefficient did not significantly differ between lesions with SUVpeak above or below the median value of 8.3 (19% vs. 28%; P = 0.264)., Conclusion: The repeatability of SUVAUC was comparable to that of standard SUV. The repeatability coefficients of various semiquantitative (18)F-fluoromethylcholine parameters (SUV, MTV, and total uptake in the lesion) were approximately 35%. Larger differences are likely to represent treatment effects., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Renal cell cancer (RCC) represents 2-3% of all cancers and is the most lethal of the urologic malignancies, in a minority of cases caused by a genetic predisposition. Birt-Hogg-Dubé syndrome (BHD) is one of the hereditary renal cancer syndromes. As the histological subtype and clinical presentation in BHD are highly variable, this syndrome is easily missed. Lung cysts--mainly under the main carina--are reported to be present in over 90% of all BHD patients and might be an important clue in differentiating between sporadic RCC and BHD associated RCC. We conducted a retrospective study among patients diagnosed with sporadic RCC, wherein we retrospectively scored for the presence of lung cysts on thoracic CT. We performed FLCN mutation analysis in 8 RCC patients with at least one lung cysts under the carina. No mutations were identified. We compared the radiological findings in the FLCN negative patients to those in 4 known BHD patients and found multiple basal lung cysts were present significantly more frequent in FLCN mutation carriers and may be an indication for BHD syndrome in apparent sporadic RCC patients.

Aims and Objectives: To develop a patient decision aid and to prepare an overview of requirements for implementation., Background: We developed a decision aid that fits the preferences of patients and health care professionals to ensure adequate uptake in clinical practice., Design: A participatory design approach was used to acquire insight into preferences regarding the content and design of a decision aid and into barriers and aspects of the decision aid that facilitate implementation in clinical practice., Methods: Three focus group interviews with patients, their partners and health care professionals were conducted. A prototype of the decision aid was developed and presented to patients (n = 14) and health care professionals (n = 13) in semi-structured interviews. Patients (n = 5) participated in a usability study. Data were analysed by two independent coders., Results: Health care professionals considered medical information on treatments and side effects as the most important aspect to be included in the decision aid. Patients also focused on nonmedical considerations, such as location. Both expected the decision aid to support patients in making a treatment choice. According to health care professionals, the oncology nurse was the most suitable to discuss the decision aid with patients, while some patients preferred to discuss the patient decision aid with the urologist. The main barrier to implementation of the decision aid was said to be the expectation that it is time and money consuming, while the incorporation of the decision aid into clinical guidelines and basing the content on these guidelines, would promote implementation., Conclusions: By using a participatory design approach a patient decision aid was designed to meet patients' and health care professionals' needs. Insight was also gained on requirements for implementation., Relevance to Clinical Practice: Wide-scale implementation of decision aids is desirable. An overview is provided of requirements for implementation to successfully incorporate a decision aid into clinical practice., (© 2016 John Wiley & Sons Ltd.)

Urine exosomes (extracellular vesicles; EVs) contain (micro)RNA (miRNA) and protein biomarkers that are useful for the non-invasive diagnosis of various urological diseases. However, the urinary Tamm-Horsfall protein (THP) complex, which forms at reduced temperatures, may affect EV isolation and may also lead to contamination by other molecules including microRNAs (miRNAs). Therefore, we compared the levels of three miRNAs within the purified EV fraction and THP- protein-network. Urine was collected from healthy donors and EVs were isolated by ultracentrifugation (UC), two commercial kits or sepharose size-exclusion chromatography (SEC). SEC enables the separation of EVs from protein-complexes in urine. After UC, the isolation of EV-miRNA was compared with two commercial kits. The EV isolation efficiency was evaluated by measuring the EV protein markers, Alix and TSG101, CD63 by Western blotting, or miR-375, miR-204 and miR-21 by RT-qPCR. By using commercial kits, EV isolation resulted in either low yields or dissimilar miRNA levels. Via SEC, the EVs were separated from the protein-complex fraction. Importantly, a different ratio was observed between the three miRNAs in the protein fraction compared to the EV fraction. Thus, protein-complexes within urine may influence EV-biomarker studies. Therefore, the characterization of the isolated EV fraction is important to obtain reproducible results., Competing Interests: The authors report no conflict of interest.

Purpose: The purpose of the study was to compare image quality and quantitative accuracy of positron emission tomography/magnetic resonance imaging (PET/MRI) and PET/computed tomography (PET/CT) systems with time of flight PET gantries, using phantom and clinical studies., Procedures: Identical phantom experiments were performed on both systems. Calibration, uniformity, and standardized uptake value (SUV) recovery were measured. A clinical PET/CT versus PET/MRI comparison was performed using [(18)F]fluoromethylcholine ([(18)F]FCH)., Results: Calibration accuracy and image uniformity were comparable between systems. SUV recovery met EANM/EARL requirements on both scanners. Thirty-four lesions with comparable PET image quality were identified. Lesional SUVmax differences of 4 ± 26% between PET/MRI and PET/CT data were observed (R (2) = 0.79, slope = 1.02). In healthy tissues, PET/MRI-derived SUVs were 16 ± 11% lower than on PET/CT (R (2) = 0.98, slope = 0.86)., Conclusion: PET/MRI and PET/CT showed comparable performance with respect to calibration accuracy, image uniformity, and SUV recovery. [(18)F]FCH uptake values for both healthy tissues and lesions corresponded reasonably well between MR- and CT-based systems, but only in regions free of MR-based attenuation artifacts.

Purpose: The objective of the present study is to determine whether uptake of [(18)F]fluoromethylcholine ([(18)F]FCH) in comparison with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) accurately reflects chemotherapy efficacy at the tumor cell level in prostate cancer (PC)., Procedures: The effects of docetaxel and cabazitaxel on viable tumor cell number were explored in four PC cell lines. Cellular uptake of [(18)F]FDG and [(18)F]FCH was compared with the effects measured using sulforhodamine B (SRB) assay, cell counting and colony formation assay (CFA), as proximators of viable tumor cell number. Agreement between uptake and cell numbers was assessed by Bland-Altman plots., Results: [(18)F]FCH uptake in all PC cell lines significantly correlated to the cell numbers surviving the respective drug concentrations. Bland-Altman analysis showed that [(18)F]FDG uptake resulted in signal overestimation and higher variability after chemotherapy., Conclusions: [(18)F]FCH uptake correlates well with viable tumor cell numbers remaining after docetaxel and cabazitaxel exposure. Radiolabeled choline is a potential response monitoring biomarker after chemotherapy for PC.

Aim: To improve treatment of inoperable transmissible venereal tumors (TVTs) in dogs. Recently, we showed that TVT is sensitive to intratumoral treatment with interleukin-2 (IL2). In addition it is known that TVT is sensitive to intravenous treatment with vincristine. In the present study we tried to establish the therapeutic effect of intratumoral treatment with vincristine and IL2., Patients and Methods: We treated 12 dogs with TVT with 1-4 intratumoral treatments with vincristine and IL-2. Per treatment we used vincristine (0.5-0.7 mg/m(2)) and IL2 (2×10(6) units). The injections were given at weekly intervals., Results: Early therapeutic effects were: three complete regressions, four partial regressions, three stable disease, and two progressive disease. Late therapeutic effects were established 45-60 months after the first presentation; there were five complete regressions, no partial regressions, nor stable or progressive diseases. Interestingly, all five dogs with late therapeutic effects were in good health. No tumor recurrence was noted., Conclusion: Intratumoral treatment of TVT with vincristine and IL2 appears to have impressive therapeutic effects., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Unlabelled: Choline kinase is upregulated in prostate cancer, resulting in increased (18)F-fluoromethylcholine uptake. This study used pharmacokinetic modeling to validate the use of simplified methods for quantification of (18)F-fluoromethylcholine uptake in a routine clinical setting., Methods: Forty-minute dynamic PET/CT scans were acquired after injection of 204 ± 9 MBq of (18)F-fluoromethylcholine, from 8 patients with histologically proven metastasized prostate cancer. Plasma input functions were obtained using continuous arterial blood-sampling as well as using image-derived methods. Manual arterial blood samples were used for calibration and correction for plasma-to-blood ratio and metabolites. Time-activity curves were derived from volumes of interest in all visually detectable lymph node metastases. (18)F-fluoromethylcholine kinetics were studied by nonlinear regression fitting of several single- and 2-tissue plasma input models to the time-activity curves. Model selection was based on the Akaike information criterion and measures of robustness. In addition, the performance of several simplified methods, such as standardized uptake value (SUV), was assessed., Results: Best fits were obtained using an irreversible compartment model with blood volume parameter. Parent fractions were 0.12 ± 0.4 after 20 min, necessitating individual metabolite corrections. Correspondence between venous and arterial parent fractions was low as determined by the intraclass correlation coefficient (0.61). Results for image-derived input functions that were obtained from volumes of interest in blood-pool structures distant from tissues of high (18)F-fluoromethylcholine uptake yielded good correlation to those for the blood-sampling input functions (R(2) = 0.83). SUV showed poor correlation to parameters derived from full quantitative kinetic analysis (R(2) < 0.34). In contrast, lesion activity concentration normalized to the integral of the blood activity concentration over time (SUVAUC) showed good correlation (R(2) = 0.92 for metabolite-corrected plasma; 0.65 for whole-blood activity concentrations)., Conclusion: SUV cannot be used to quantify (18)F-fluoromethylcholine uptake. A clinical compromise could be SUVAUC derived from 2 consecutive static PET scans, one centered on a large blood-pool structure during 0-30 min after injection to obtain the blood activity concentrations and the other a whole-body scan at 30 min after injection to obtain lymph node activity concentrations., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Aim: To improve the treatment of transmissible venereal tumors (TVTs) in dogs with intratumoral injections of interleukin-2 (IL-2)., Patients and Methods: We treated 13 dogs with 18 natural TVTs with IL-2. The tumors were treated with intratumoral application of 2×10(6) units IL-2., Results: Three months after injection of IL-2, the tumors in 2/13 dogs had regressed completely, those in 1/13 had regressed partially, and 4/13 dogs had stable disease., Conclusions: Local IL-2 treatment of TVT is therapeutically effective, as indicated by complete regression (CR), partial regression (PR) and stable disease (SD) of the tumors of 7 out of 13 dogs. In addition, we observed that the intratumoral treatment with IL-2 did not cause any toxic side-effects., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The development and natural course of lung cysts in patients with Birt-Hogg-Dubé syndrome (BHD) is still unclear, and the relationship between lung cysts and pneumothorax is not fully clarified. Based on the follow-up results of thoracic imaging in six patients with BHD, we hypothesize that decreased potential for stretching of the cysts' wall and extensive contact with the visceral pleura are probably responsible for rupture of the cyst wall resulting in increased risk for pneumothorax., (© 2014 Asian Pacific Society of Respirology.)

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominantly inherited disorder caused by germline mutations in the folliculin (FLCN) gene. Clinical manifestations of BHD include skin fibrofolliculomas, renal cell cancer, lung cysts and (recurrent) spontaneous pneumothorax (SP). All clinical manifestations usually present in adults > 20 years of age., Case Presentations: Two non-related patients with (recurrent) pneumothorax starting at age 14 accompanied by multiple basal lung cysts on thoracic CT underwent FLCN germline mutation analysis. A pathogenic FLCN mutation was found in both patients confirming suspected BHD. The family history was negative for spontaneous pneumothorax in both families., Conclusion: Although childhood occurrence of SP in BHD is rare, these two cases illustrate that BHD should be considered as cause of SP in children.

Prophylactic vaccination is arguably the most effective medical preventative method. After local inoculation, vaccines induce antigen-specific systemic immunity, protecting the whole body. Systemic antitumour immunity can cure advanced cancer, but will therapeutic vaccination suffice? A vaccine for castration-refractory prostate cancer (CRPC) was approved by regulatory authority, but its evidence is disputed. We critically reviewed the clinical efficacy of therapeutic cancer vaccines for prostate cancer, including the results of 31 clinical studies employing vaccines-only, and another 10 studies combining vaccines with immune co-stimulation. Vaccinations yielded immunological responses, but no study showed evidence for clinically relevant therapeutic improvement. Clinical failure of therapeutic vaccination is discussed in the light of immunological dogmas and mechanisms of antitumour therapies. We propose that cancer immunotherapy might be improved by immunological danger, i.e. disturbing tumour homeostasis by destroying the tumour tissue or inducing local inflammation. Such danger might override immunological tolerance, and thereby allow clinically relevant anticancer results., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Major disadvantages are associated with the early diagnostics of prostate cancer; for this reason routine determination of PSA level is not recommended in the Netherlands. If, after guidance, the patient still wants further investigations and rectal examination is not abnormal, the Dutch College of General Practitioners guideline 'Micturition problems in men' recommends that a PSA test should be done. The cut-off PSA level for referring patients for secondary care has been lowered from 4 ng/ml to 3 ng/ml, meaning that this guideline is now in accordance with the Dutch Society for Urology's multidisciplinary guideline "Prostate Carcinoma". Using the Prostate Cancer Risk Calculator (Prostaatwijzer-3), the PSA level and ultrasound-guided measurement of prostate volume can be used to calculate the risk of prostate cancer. The risk calculated is then used a starting point in determining if invasive follow-up diagnostic tests should be implemented.

Birt-Hogg-Dubé (BHD) syndrome is a cancer disorder caused by a pathogenic FLCN mutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax.

Background: Cancer cells are able to change the protein expression and behavior of non-cancerous surrounding cells. Exosomes, secreted by prostate cancer (PCa) cells, may have a functional role in cancer metastasis and present a promising source for protein biomarkers. The aim of the present study was to identify which proteins in exosomes can influence non-cancerous cells, and to determine whether we can use urine exosomal proteins to identify high-risk PCa patients., Method: Exosomes were isolated by ultracentrifugation. Migration and invasion were studied by the transwell (invasion) assay. Proteomics was performed by LC-MS/MS and identified proteins were validated by Western blotting. Cellular uptake of fluorescent labeled PKH67-exosomes was measured by FACS., Results: Based on comparative protein profiling by mass spectrometry-based proteomics of LNCaP- and PC3-exosomes, we selected ITGA3 and ITGB1, involved in migration/invasion, for further analyses. Inhibition of exosomal ITGA3 reduced the migration and invasion of non-cancerous prostate epithelial cells (prEC) almost completely. Cellular uptake of exosomes by prEC was higher with PC3-exosomes compared to LNCaP exosomes. Finally, ITGA3 and ITGB1 were more abundant in urine exosomes of metastatic patients (p<0.05), compared to benign prostate hyperplasia or PCa., Conclusion: These data indicate exosomal ITGA3 and ITGB1 may play a role in manipulating non-cancerous surrounding cells and that measurement of ITGA3 and ITGB1 in urine exosomes has the potential to identify patients with metastatic PCa in a non-invasive manner.

Background: Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with low-dose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity., Methods: BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatment-naive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade ≥3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade ≥3 AEs and bevacizumab/IFN-related grade 1-2 AEs occurring from first administration until 28 days after last treatment were reported., Results: A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade ≥3 IFN-associated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7-18.0] and 30.7 months (95% CI: 25.7-not reached), respectively. The ORR was 28.8%., Conclusions: Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757].

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition due to germline FLCN (folliculin) mutations, characterized by skin fibrofolliculomas, lung cysts, pneumothorax and renal cancer. We identified a de novo FLCN mutation, c.499C>T (p.Gln167X), in a patient who presented with spontaneous pneumothorax. Subsequently, typical skin features and asymptomatic renal cancer were diagnosed. Probably, de novo FLCN mutations are rare. However, they may be under-diagnosed if BHD is not considered in sporadic patients who present with one or more of the syndromic features. Genetic and immunohistochemical analysis of the renal tumour indicated features compatible with a tumour suppressor role of FLCN. The finding that mutant FLCN was expressed in the tumour might indicate residual functionality of mutant FLCN, a notion which will be explored in future studies.

Introduction: Brachytherapy may be complicated by serious obstructive voiding symptoms (OVS). Only conservative treatment options are available in the first 6 months after brachytherapy. We evaluated safety, efficacy and patient tolerance of the Memokath prostatic stent (MPS)., Material and Methods: A MPS was placed in 10 patients with OVS after brachytherapy. Evaluation included uroflowmetry, international prostate symptom score (IPSS), prostate volume and urethrocystoscopy before and 3 months after placement of the stent., Results: Both the IPSS and uroflowmetry results significantly improved after stent insertion. The mean IPSS decreased from 29/5 to 11/1 and the mean Qmax from the uroflowmetry improved from 4.7 to 11.2 ml/s. The 5 patients who were catheter dependent voided spontaneously with a mean Qmax of 15 ml/s. Two stents migrated towards the bladder, and those patients needed a second stent which was placed without complications. Removal of the stent was easy to perform. Adverse effects were minor with perineal pain and irritative voiding symptoms occurring in 5 patients mainly in the first weeks after insertion. This did not negatively influence quality of life and all patients were more satisfied with the stent than without., Conclusions: The MPS provides a safe, effective, and completely reversible treatment for patients with OVS after brachytherapy and was well tolerated.

Objective: To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer., Materials and Methods: A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated., Results: The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men., Conclusion: Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: Comparison of the therapeutic effect of treatment of non-muscle invasive bladder carcinoma (NMIBC) after intravesical Interleukin-2 (IL-2) instillations in the presence and absence of a marker tumour., Materials and Methods: Two pilot studies were performed in patients with NMIBC. The first study (10 patients) was performed in Krakow (Poland), the second (26 patients) in Vilnius (Lithuania). In Krakow the tumours were treated with incomplete transurethral resection (TUR) leaving a marker tumour of 0.5-1.0-cm followed by IL-2 instillations (3 × 10(6) IU IL-2) on five consecutive days. In Vilnius the tumours were treated with complete TUR, followed by IL-2 instillations (9 × 10(6) IU IL-2) on five consecutive days., Results: During 30 months follow-up, the recurrence-free survival was 5/10 (50%) and 6/26 (23%) after incomplete and complete TUR, respectively. So, the ratio of the recurrence-free survival after incomplete/complete TUR of 50/23=2.2. The median of the recurrence-free survival is >20.5 months and 7 months after incomplete and complete TUR, respectively. So, this ratio was >20.5/7= >2.9. The hazard ratio which combines both the chance of the disease recurrence and its timing for both censored and uncensored cases was 0.53, again confirming the better outcome after incomplete TUR., Conclusion: A possible explanation for the better therapeutic effects after incomplete TUR compared with complete TUR is that the marker tumour has tumour-associated antigens (TAA) that could lead to an immune reaction that is stimulated by local application of IL-2. After complete TUR, no TAA are available to initiate and to stimulate an immune reaction; consequently, local IL-2 therapy is less effective after complete TUR. The results of these two pilot studies have led to the recent start of a randomised prospective clinical trial in which therapeutic effects of local IL-2 therapy after complete and incomplete TUR are compared.

Purpose: Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings., Methods: In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily., Results: Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth., Conclusions: Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.

Background: This study aimed to investigate cabazitaxel efficacy in a model for docetaxel-resistant prostate cancer cells and to evaluate the involvement of ATP-cassette binding protein 4 (ABCC4) with regard to multidrug resistance., Materials and Methods: Docetaxel and cabazitaxel sensitivity was measured in PC3 and R3327-MATLyLu (MLL) cell lines, using the sulforhodamine B (SRB) assay. ABCC4 expression was examined by western blotting and its functional involvement in drug sensitivity by blocking with MK571 inhibitor., Results: The docetaxel-resistant MLL cells (4.5-fold compared to cabazitaxel; p<0.001) were shown to express high levels of ABCC4, while non-resistant PC3 cells had no detectable ABCC4 expression. Functional inhibition of ABCC4 in MLL cells resulted in a two-fold decrease in effective concentration of docetaxel and had no effect on toxicity of cabazitaxel., Conclusion: Cabazitaxel showed an improved therapeutic efficacy over docetaxel in ABCC4-expressing prostate cancer cells. ABCC4 appears to be an important determinant of docetaxel resistance, since its inhibition almost completely reversed resistance.

Background: It is important to identify markers that predict whether prostate cancer will metastasise. The adjacent noncancerous cells (influenced by the tumour cells) may also express potential markers. The objective of this study was to determine the influence of cancer cells on noncancerous cells and to assess the value of the cell-communication protein connexin-26 (Cx26) as a marker to predict the development of metastasis., Methods: The effect of conditioned medium (CM) from PrCa cells on in vitro noncancerous cell proliferation, migration and invasion and Cx26 expression was determined. Connexin-26 expression was investigated in prostatectomy tissues from 51 PrCa patients by immunohistochemistry and compared with various clinicopathological parameters., Results: Proliferation, migration and invasion of noncancerous cells were influenced by CM from the PrCa cell lines. Importantly, a clear relation was found between low Cx26 expression in the noncancerous tissue in prostatectomy sections and the risk of development of metastasis (P<0.0002). Kaplan-Meier analysis showed a relation between low Cx26 expression in noncancerous tissues and time to biochemical recurrence (P=0.0002)., Conclusion: Measuring Cx26 expression in the adjacent noncancerous tissues (rather than cancer tissues) of prostatectomy sections could help to identify high-risk patients who may benefit from adjuvant therapy to decrease the risk of metastasis.

Background: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288., Findings: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab., Interpretation: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted., Funding: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range., Materials and Methods: Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined., Results: All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group., Conclusions: Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined., (Copyright © 2012 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome characterized by skin piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer caused by germline mutations in the fumarate hydratase (FH) gene. Previously, we proposed renal imaging for FH mutation carriers starting at the age of 20 years. However, recently an 18-year-old woman from a Dutch family with HLRCC presented with metastatic renal cancer. We describe the patient and family data, evaluate current evidence on renal cancer risk and surveillance in HLRCC and consider the advantages and disadvantages of starting surveillance for renal cancer in childhood. We also discuss the targeted therapies administered to our patient.

Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Purpose: To investigate whether time-trends of enhanced [(18)F]Fluoromethylcholine ([(18)F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice., Procedures: 25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [(18)F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUV(max) and SUV(meanA50), determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [(18)F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant., Results: Analysis of 54 nodes showed that LN status, time-trends, and 'late' (30 min p.i.) SUV(max) and SUV(meanA50) parameters were strongly associated (P<0.0001). SUV(max) relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [(18)F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type., Conclusions: Time-trends of enhanced [(18)F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.

Background: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD., Methods: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families., Results: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas., Conclusion: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Objective: • To compare survival after prostate brachytherapy in patients aged ≤60 years with patients aged >60 years., Patients and Methods: • We analysed 419 locally confined prostate cancer patients, treated between 1989 and 2001 with I-125 implantation monotherapy. • Endpoints were biochemical failure (BF) according to the +2 ng/mL definition, disease-specific and overall survival. • Patients were subdivided into age ≤60 years and age >60 years. • Cox proportional-hazards regression analyses were performed to study the independent effect of age on BF and disease-specific survival., Results: • The younger cohort consisted of 87 patients (21%), with smaller prostate volumes and a lower average prostate cancer risk class than the older cohort, consisting of 332 patients (79%). Mean follow-up was 9.1 years (±sd 2.8) for the younger cohort and 8.3 years (±sd 2.9) for the older cohort. • The 10-year (95% CI) freedom from BF, disease-specific survival and overall survival rates were 63% (51-75), 87% (78-96) and 81% (69-89), respectively, for the younger cohort and 46% (39-54), 83% (78-89) and 60% (54-66), respectively, for the older patient cohort. • Although a trend for better freedom from BF and disease-specific survival was observed in younger patients, the difference proved not clinically significant., Conclusion: • Prostate cancer risk group and the year of treatment relate to outcome, but not age. With respect to prostate cancer curability, there seems no objection to offer brachytherapy to patients aged 60 years and younger., (© 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.)

Background: The objective of this study was to evaluate the recurrence-preventing effect of intravesical instillations of interleukin-2 (IL-2) in patients with non-muscle-invasive bladder carcinoma. In addition, this study aimed to determine the significance of immune parameters for recurrence-free interval., Patients and Methods: Twenty-six patients with non-muscle-invasive bladder carcinoma were treated with intravesical instillations of IL-2 (Proleukin®, Novartis, formerly Chiron) in doses of 9 × 10(6) IU on 5 consecutive days, beginning on the second day after transurethral resection (TUR) of tumours. CD8(high)CD57(+) lymphocytes in peripheral blood were determined before TUR and compared with the recurrence-free interval after treatment., Results: The multivariate analysis showed that CD8(high)CD57(+) lymphocytes had a prognostic significance in combination with number of bladder tumours, prior recurrence rate and age of patients., Conclusion: Peripheral blood CD8(high)CD57(+) lymphocytes have prognostic significance for recurrence-free survival in patients with non-muscle-invasive bladder carcinoma after TUR and intravesical IL-2.

OBJECTIVE To present a new concept for non-invasive renal tumour ablation using real-time magnetic resonance imaging (MRI)-guided radiation therapy. All currently available treatment techniques for localized renal cell carcinoma (RCC) have to be performed in a laparoscopic or percutaneous way. MATERIALS AND METHODS A technical prototype MRI-accelerator which performs real-time 1.5 T MRI imaging during the irradiation has been constructed. We performed a technical feasibility study on real-time MRI-guided arc therapy using repeated breath-holds for renal tumour ablation by (i) investigating renal mobility during breath-holding, (ii) performing dose calculation and (iii) measuring the radiation delivery time on a phantom. The renal mobility during free breathing and end-expiration breath-holding during 15 s was investigated for three patients with renal tumour appearance. Conventional MRI screening data of four patients was used for arc therapy dose calculation. Tumour and normal tissues were delineated and a tumour margin of 3 mm was applied. The radiation delivery time of a 25-Gy arc therapy plan was measured on a phantom. RESULTS Renal mobility during free breathing varied from 10 to 25 mm, whereas breath-holding resulted in nearly non-moving kidneys (0 to 2 mm) for all patients. Arc therapy dose calculation resulted in an adequate tumour coverage. The radiation delivery time of the arc therapy plan was about 10 min. This means that 20 to 40 repeated breath-holds of 15 to 30 s will be needed for a single session treatment. A higher maximum dose rate would reduce the number of breath-holds needed and improve patient comfort. A phase I study will be started to proof the clinical feasibility. CONCLUSION Real-time MRI-guided radiation therapy using an MRI-accelerator might become a valuable non-invasive alternative to the current RCC treatment options., (© 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.)

Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management., (© 2010 John Wiley & Sons A/S.)

Background and Purpose: This study presents an overview of the experience with transrectal and transperineal implantations of fiducial markers for position verification in prostate radiotherapy, regarding the practical feasibility, procedure-related toxicity and influence on quality of life (QoL)., Material and Methods: Since 2001, 914 patients scheduled for intensity-modulated radiotherapy (IMRT) have received gold markers in the prostate. The incidence of severe toxicity, defined by the CTCAE v3.0, was evaluated retrospectively. The influence on QoL was measured prospectively in 36 patients using a combination of three validated questionnaires: the Rand-36, the EORTC QLQ-C30(+3) and the prostate cancer-specific EORTC QLQ-PR25. Next, the incidence of marker migration was assessed., Results: From 2001 to 2005, 402 patients received markers via the transrectal route. Two of these patients developed urosepsis (grade 3 toxicity). Since 2005, 512 patients received markers via the transperineal route. No grade 3 or 4 toxicity occurred in this group. No significant and clinically relevant differences were found in QoL between pre- and post-implant measures. In 5 patients marker migration led to discontinuation of the marker-based IMRT., Conclusions: Clinical use of transperineal-implanted fiducial gold markers for position verification in external beam radiotherapy for prostate cancer is a feasible and safe procedure without influencing patients' QoL., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Evaluation of bladder-preserving treatment protocol., Objective: To evaluate the long-term results of iridium-192 brachytherapy-based bladder-sparing treatment strategy in patients with solitary invasive bladder tumours., Design, Setting, and Participants: We performed a retrospective analysis of 111 patients with solitary T1G3-T2Gall bladder tumours (< or = 5 cm), who were treated with iridium-afterloading brachytherapy between February 1988 and May 2007., Intervention: After transurethral tumour resection, external beam radiotherapy (28 Gy; 12 fractions) was given, followed by brachytherapy (Iridium-192; 40 Gy). Partial cystectomy was part of the treatment strategy in nine patients. In five of those patients a T3 tumour was found, and they were included in the analysis., Measurements: The 5-, 10- and 15-yr overall survival rate (OS); disease-specific survival rate (DSS); and disease-free survival rate (DFS) estimates were determined using the Kaplan-Meier method., Results and Limitations: Mean follow-up period was 6.2 yr (range: 0.2-16.3 yr). At the last follow-up 75 patients were alive without evidence of disease, whereas 17 patients had died without evidence of disease. Nineteen patients died of bladder cancer after a mean follow-up period of 2.9 yr (range: 0.5-9.0). OS rates at 5 yr, 10 yr, and 15 yr were 70%, 55%, and 51%, respectively. DSS rates at 5 yr, 10 yr, and 15 yr were 82%, 73% and 73%, respectively. DFS rates at 5 yr, 10 yr, and 15 yr were 60%, 47%, and 23%, respectively. Higher tumour stage (T3 vs T1) was negatively associated with DSS (hazard ratio [HR]:19.8; p=0.01) and DFS (HR: 4.67; p=0.02). No prognostic factor was found for OS. Local recurrence occurred in 27% of patients and salvage cystectomy was performed in 9% of patients. Bladder function was able to be preserved in 99 of 111 patients (89%)., Conclusions: In patients with solitary stage T1-T2 bladder cancer (< or = 5 cm) who refuse radical cystectomy or who are poor candidates for major surgical procedures, this modality is a valuable treatment alternative.

Raman spectroscopy has the ability to provide differential diagnosis of different cancers with high sensitivity and specificity. A major limitation in its clinical application is the weak nature of Raman signal, which inhibits scanning large surface areas of tissues. In bladder cancer diagnosis, fluorescence-guided endoscopy with 5-aminolevulinic acid (5-ALA) has gained interest as a technique that can provide such spatial differentiation, thus improving early detection and more complete removal of superficial tumors. However, several studies have demonstrated the poor specificity of this modality. Combining fluorescence with Raman spectroscopy could improve its diagnostic capability. However, little is known about the effect of agents such as 5-ALA on Raman spectra of tissue. In this paper, we present measuring Raman spectroscopy from benign and malignant bladder tissues in the presence of 5-ALA and attempt to evaluate the potential to discriminate between different pathologies. Raman spectra were recorded from 92 bladder biopsies without 5-ALA and 38 biopsies with 5-ALA using a Raman microspectrometer system at 830nm excitation. Empirical and multivariate statistical techniques were used for data analysis. Algorithms were developed to determine the effect of 5-ALA on tissue and its influence on the prediction ability of a preliminary benign/malignant prediction model. In samples with 5-ALA, an overall decrease in Raman intensity was observed when compared to the Raman spectra from samples without 5-ALA. Additionally, differences in relative intensities at 1270 and 1330cm(-1) were also noted. However, significant differences were observed in the Raman spectra of benign and malignant samples with 5-ALA indicating the potential of using Raman spectroscopy for discriminating bladder cancer in the presence of 5-ALA. The Principal-Component fed Linear-Discriminant Analysis (PCA/LDA) algorithm derived from biopsies in the absence of 5-ALA used to predict biopsies in the presence of 5-ALA resulted in an overall sensitivity and specificity of 42.6% and 71.1%, respectively. This suggests the presence of 5-ALA in tissue affects the Raman spectra. A PCA/LDA algorithm based on fluorescence information (i.e. PpIX fluorescence positive or negative) and the Raman spectrum of 5-ALA biopsies, had a sensitivity and specificity of 100% and 80.8%, respectively. This study demonstrates that applying 5-ALA affects the Raman spectra of bladder tissues. However, benign/malignant differentiation can be accomplished with a preliminary PCA/LDA algorithm, suggesting the potential of a combined diagnostic modality in vivo.

Spontaneous pneumothorax can be due to Birt-Hogg-Dubé syndrome (BHD syndrome), an autosomal dominant predisposition for fibrofolliculomas, multiple lung cysts, pneumothorax and renal cancer. The syndrome is the result of germline mutations in the FLCN (folliculin) gene. Its clinical presentation is highly variable. Consequently, this syndrome is probably under-diagnosed. An illustrative kindred is presented in which the index patient, a man aged 26, had recurrent episodes of pneumothorax without apparent skin lesions or renal abnormalities. He had bilateral mostly basally-located lung cysts. There was a family history of fibrofolliculomas, lung cysts, pneumothorax and clear cell renal cancer. Recognition of BHD is important since carriers of the mutation can be offered surveillance for early detection and treatment of renal cancer.

We report unusual magnetic resonance imaging findings of a 20-year-old pregnant woman at 18 weeks of gestation who was diagnosed with metastatic renal cell cancer (RCC) with a large liver metastasis.

--A national, multidisciplinary practice guideline was developed concerning diagnosis and treatment of patients with prostate cancer. Because of the lack of sufficient scientific evidence at this moment no practice guideline on screening is included. --The diagnosis of prostate cancer is made by transrectal ultrasound-guided prostate biopsies. The Gleason score is used for histological grading. --In localized prostate cancer and comorbidity 'active surveillance' is advised if the life expectancy is < 10 years. In healthy patients radical prostatectomy, external and internal radiotherapy are equivalent treatment options. The final decision is made after the patient has received adequate counselling. --In locally advanced prostate cancer in a patient with a life expectancy > or = 10 years external beam radiotherapy is the preferred treatment whether or not in combination with hormonal therapy. --In locally recurring prostate cancer following radical prostatectomy and prostate-specific antigen (PSA) < 1.0 ng/ml salvage radiotherapy can be advised. Recurrence following external beam radiotherapy may be treated by salvage radical prostatectomy or brachytherapy in selected cases. --In metastatic prostate cancer androgen deprivation therapy is advised, i.e. surgical castration, luteinizing hormone-releasing hormone (LH-RH) analogues, or parenteral estrogens. --In hormone resistant prostate cancer palliative treatment of painful metastases is advised, e.g. painkillers, local radiotherapy, or radionuclides. The role of docetaxel-based chemotherapy should be discussed. --During follow-up PSA is determined; digital rectal examination and imaging are performed whenever indicated.