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Purpose: Therapy with the alpha-emitter radium-223 chloride (Ra) is an innovative therapeutic option in patients with metastasized, castration-resistant prostate cancer. However, radiotherapy can lead to hematopoietic toxicity. The aim of this study was to determine if Ra therapy induces an impairment of cellular antimicrobial immune responses. Methods: In 11 patients receiving Ra treatment, lymphocyte proliferation and the production of pro- and anti-inflammatory cytokines (interferon-γ and interleukin-10) were determined, using lymphocyte transformation testing and ELISpot, respectively. Lymphocyte function after stimulation with mitogens and microbial antigens was assessed prior to therapy and at day 1, 7 and 28 after therapy. Results: Lymphocyte proliferation and the production of interferon-γ and interleukin-10 towards mitogens and antigens remained unchanged after therapy. Consistent with these in vitro data, we did not observe infectious complications after treatment. Conclusions: The results argue against an impairment of lymphocyte function after Ra therapy. Thus, immune responses against pathogens should remain unaffected. [ABSTRACT FROM AUTHOR]

In the era of personalized medicine, there is an urgent need for non-invasive biomarkers to optimize the individual treatment of cancer patients. Epigenetic alterations, including DNA methylation and non-coding RNAs, are a hallmark of malignant tumors. The detection of many of these epigenetic conditions is feasible in bodily fluids, that is, blood plasma and serum, and may therefore be used for liquid biopsy. In this review, we summarize and discuss the current state of research on circulating epigenetic alterations (DNA methylation, miRNA and long non-coding RNA) in serum and plasma of patients with bladder cancer, prostate cancer, renal cell carcinoma and testicular germ cell cancer. [ABSTRACT FROM AUTHOR]

Objectives: To identify an appropriate reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Methods: Serum from patients with prostate cancer ( n = 24), bladder cancer ( n = 24), renal cell carcinoma ( n = 24) and control subjects ( n = 48) was spiked with cel-miR-39, and then ribonucleic acid was isolated. Quantitative real-time polymerase chain reaction was used to determine the levels of candidate reference genes ( RNU1-4, RNU6-2, SNORD43, SNORD44, SNORD48, S NORA74A, miR-let-7a-1, miR-106a). Reference gene stability was determined using the NormFinder, geNorm and comparative delta-Ct algorithm. The effect of normalization was tested with miR-21 as the target gene, as this was previously suggested to be upregulated in cancer patients' serum. Results: Recovery of cel-miR-39 (mean 11.6%, range 1-56%) was similar in control subjects and cancer patients. SNORD44 and SNORD74A levels were around the detection limit of the assay and were thus omitted. All remaining candidates showed satisfying stability; SNORD43 was the most stable reference gene using all three algorithms. A combination of two genes ( SNORD43, RNU1-4) increases the stability somewhat. The level of miR-21 was similar in cancer patients and healthy controls, irrespective of the normalization strategy. Conclusions: SNORD43 is a suitable reference gene for the analysis of circulating micro-ribonucleic acid in patients with urological malignancies. Our study questions the suitability of miR-21 as a biomarker for uro-oncological patients. [ABSTRACT FROM AUTHOR]

Global histone modification patterns have been shown to be a predictive factor of recurrence in various cancers. We analyzed global histone-3-lysine-27 (H3K27) methylation in prostate cancer (PCA) tissues. H3K27 mono-, di-, and tri-methylation patterns were different in nonmalignant prostate tissue, localized PCA, metastatic PCA, and castration-resistant PCA. H3K27 mono-methylation was correlated with pT-stage, capsular penetration, seminal vesicle infiltration, and Gleason score in localized PCA and may therefore indicate adverse prognosis. [ABSTRACT FROM AUTHOR]

Abstract: The presence of small amounts of circulating DNA in plasma was demonstrated 60 years ago. Since then, cell-free DNA has been tested for quantity, fragmentation pattern, and tumor-specific sequences in patients with various malignancies. Recent studies have shown that cell-free DNA levels are distinctly increased in most patients with prostate cancer (PCA) and that the DNA fragmentation pattern is different from healthy individuals and patients with benign prostate disease. The origin of this circulating DNA remains largely unknown, but it is established that a small fraction of the DNA is derived from the tumor itself, and genetic (allelic imbalances) and epigenetic (DNA methylation) alterations are regularly detected in patients with PCA. The detection of increased DNA levels and tumor-specific DNA sequences may provide diagnostic and prognostic information. The recent findings in the emerging field of cell-free DNA will be discussed. [Copyright &y& Elsevier]

OBJECTIVE To investigate the role of circulating mitochondrial DNA (mtDNA) in patients with localized prostate cancer, as recent reports show that patients with advanced cancer have increased levels of mtDNA. PATIENTS AND METHODS DNA was isolated from the serum of 100 patients with prostate cancer and 18 with benign prostate hyperplasia (BPH). A quantitative real-time polymerase chain reaction was used to amplify 79 bp and 230 bp fragments of the mitochondrial 16s-RNA gene, the short fragment representing total mtDNA, including mtDNA truncated by apoptosis, and the long fragment representing mostly mtDNA from other cell death entities. mtDNA integrity was defined as the ratio of long to short mtDNA fragments. RESULTS The short and long mtDNA levels, and mtDNA integrity, were similar in patients with BPH and cancer ( P = 0.940, 0.211 and 0.441, respectively), and were not correlated with clinical or pathological variables, e.g. age, prostate-specific antigen (PSA) level, cT stage, pT stage, seminal vesicle infiltration, lymph node invasion, or Gleason score ( P = 0.075 to 0.961). However, patients with high levels of short mtDNA (>75th percentile) had a greater risk of PSA progression and this variable was the strongest predictor of PSA recurrence in a multivariate Cox analysis ( P = 0.023; hazard ratio 0.31; 95% confidence interval 0.113–0.851). CONCLUSION Circulating mtDNA levels did not distinguish between patients with prostate cancer or BPH. However, there was a significant increase in short mtDNA fragments in patients with early PSA recurrence after radical prostatectomy. [ABSTRACT FROM AUTHOR]

Androgen deprivation is a common treatment option in patients with locally advanced or metastatic prostate cancer. No case of long term treatment with an intermittent approach with only low dose bicalutamide (50 mg daily) has been described yet. We report a 60-year-old patient, initially presenting with a PSA elevation of 19.2 ng/mL in 1996. After diagnosis of well to moderately differentiated prostate cancer by transrectal biopsy, the patient underwent an open radical prostatectomy. Final diagnosis was adenocarcinoma of the prostate, classified as pT3a, pR1, pV0, and pL1. Adjuvant intermittent androgen deprivation therapy with flutamide 250 mg was applied, which was changed to bicalutamide 50 mg once daily when it became available in 2001. Six on-phases were performed and PSA values never exceeded 20 ng/mL. The patient did not experience any serious side effects. To date, there are no clinical or radiological signs of progression. Current PSA value is 3.5 ng/mL. [ABSTRACT FROM AUTHOR]

The spindle cell rhabdomyosarcoma is a rare variant of the embryonal rhabdomyosarcoma, mostly occurring in childhood. Only a few cases are described in adults. To date, no case of the spindle cell subtype of the prostatic embryonal rhabdomyosarcoma has been published. We report on a 23-year-old man, initially presenting with obstructive micturition problems, perineal pain and night sweat. After diagnosis by transrectal biopsy of the prostate, radiochemotherapy within the CWS 2002 P study was applied: nine cycles of vincristine, doxorubicin, actinomycin D, ifosfamide, and fractionated radiotherapy of the tumor and suspect lymph nodes (final dose 50.4 Gy). The tumor initially shrank, but an early local recurrence arose. Second-line chemotherapy was applied, followed by a salvage radical cytoprostatectomy. The patient died of disseminated disease 14 months after diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Cell-free circulating mitochondrial DNA (mtDNA) has been proposed as universal diagnostic and prognostic biomarker in cancer patients. Patients and methods: Cell-free DNA was isolated from 1 ml serum from patients with bladder cancer (BCA, n = 84), renal cell carcinoma (RCC, n = 33), and prostate cancer (CaP, n = 23), and compared with healthy individuals (n = 79). Quantitative real-time PCR was used to analyze the levels of a 79 bp (mtDNA-79), and 220 bp (mtDNA-220) fragment of the mitochondrial specific 16S-RNA. The mitochondrial DNA integrity (mtDNA-integrity) was defined as ratio of mtDNA-220 to mtDNA-79 fragments. Results: In healthy controls, mtDNA-79 levels were increased in male volunteers; mtDNA-230 levels and mtDNA-integrity were correlated with age. Neither mtDNA levels nor mtDNA-integrity were correlated with age or gender in cancer patients. Circulating mtDNA-79 (median 8.75 × 106 vs. 0.43 × 106 copies/ml) and mtDNA-230 (8.11 × 106 vs. 0.27 × 106 copies/ml) levels were significantly increased in cancer patients and allowed sensitive (84%) and specific (97%) discrimination from healthy controls. mtDNA levels were unequally distributed among the different cancer entities (mtDNA-79: BCA 9.54 × 106 vs. RCC 6.69 × 106 vs. CaP 4.48 × 106 copies/ml; mtDNA-230: BCA 9.78 × 106 vs. RCC 6.74 × 106 vs. CaP 1.94 × 106 copies/ml). The mtDNA-integrity was increased in RCC and BCA patients compared to control subjects and CaP patients. Serum mtDNA-integrity was correlated with pathological stage in RCC and with tumor grade in BCA patients. Conclusion: Circulating mtDNA levels are associated with gender and age in healthy individuals, but not in cancer patients. Quantification of circulating mtDNA may help identify patients with urologic malignancies. [Copyright &y& Elsevier]

High-quality management of prostate cancer is needed in the fields of clinics, research, and education. The objective of this project was to develop the concept of "European Prostate Cancer Centres of Excellence" (EPCCE), with the specific aim of identifying European centres characterised by high-quality cancer care, research, and education. A task force of experts aimed at identifying the general criteria to define the EPCCE. Discussion took place in conference calls and by e-mail from March 2017 to November 2017, and the final consensus meeting named "European Association of Urology (EAU) Prostate Cancer Centre Consensus Meeting" was held in Barcelona on November 16, 2017. The required criteria were grouped into three main steps: (1) clinics, (2) research, and (3) education. A quality control approach for the three steps was defined. The definition of EPCCE consisted of the following steps: (1) clinical step—five items were identified and classified as core team, associated services, multidisciplinary approach, diagnostic pathway, and therapeutic pathway; (2) research step—internal monitoring of outcomes was required; clinical data had to be collected through a prespecified database, clinical outcomes had to be periodically assessed, and prospective trials had to be conducted; (3) educational step—it consists of structured fellowship programmes of 1 yr, including 6 mo of research and 6 mo of clinics; and (4) quality assurance and quality control procedures, related to the quality assessment of the previous three steps. A limitation of this project was that the definition of standards and items was mainly based on a consensus among experts rather than being an evidence-based process. The EAU Prostate Cancer Centre Consensus Meeting defined the criteria for the identification of the EPCCE in the fields of clinics, research, and education. The inclusion of a quality control approach represents the novelty that supports the excellence of these centres. A task force of experts defined the criteria for the identification of European Prostate Cancer Centres of Excellence , in order to certify the high-quality centres for prostate cancer management. The European Association of Urology Prostate Cancer Centre Consensus Meeting defined the criteria for the identification of European Prostate Cancer Centres of Excellence in the field of clinics, research, and education. The inclusion of a quality control approach represents the novelty that supports the excellence of these centres. [ABSTRACT FROM AUTHOR]

Summary The Prostate Cancer Programme of the European School of Oncology developed the concept of specialised interdisciplinary and multiprofessional prostate cancer care to be formalized in Prostate Cancer Units (PCU). After the publication in 2011 of the collaborative article “The Requirements of a Specialist Prostate Cancer Unit: A Discussion Paper from the European School of Oncology”, in 2012 the PCU Initiative in Europe was launched. A multiprofessional Task Force of internationally recognized opinion leaders, among whom representatives of scientific societies, and patient advocates gathered to set standards for quality comprehensive prostate cancer care and designate care pathways in PCUs. The result was a consensus on 40 mandatory and recommended standards and items, covering several macro-areas, from general requirements to personnel to organization and case management. This position paper describes the relevant, feasible and applicable core criteria for defining PCUs in most European countries delivered by PCU Initiative in Europe Task Force. [ABSTRACT FROM AUTHOR]

Abstract: Gene silencing by epigenetic mechanisms is frequent in prostate cancer (PCA). The link between DNA hypermethylation and histone modifications is not completely understood. We chose the GSTP1 gene which is silenced by hypermethylation to analyze the effect of the histone deacetylase inhibitor depsipeptide on DNA methylation and histone modifications at the GSTP1 promoter site. Prostate cell lines (PC-3, LNCaP, and BPH-1) were treated with depsipeptide; apoptosis (FACS analysis), GSTP1 mRNA levels (quantitative real-time PCR), DNA hypermethylation (methylation-specific PCR), and histone modifications (chromatin immunoprecipitation) were studied. Depsipeptide induced apoptosis in PCA cells, but not a cell cycle arrest. Depispeptide reversed DNA hypermethylation and repressive histone modifications (reduction of H3K9me2/3 and H3K27me2/3; increase of H3K18Ac), thereby inducing GSTP1 mRNA re-expression. Successful therapy requires both, DNA demethylation and activating histone modifications, to induce complete gene expression of epigenetically silenced genes and depsipeptide fulfils both criteria. [Copyright &y& Elsevier]

Abstract: Objectives: To evaluate CpG island hypermethylation in a set of candidate genes in prostate cancer (pCA) and its relationship to clinicopathologic parameters and a nomogram predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy. Materials and methods: Tissues of 78 prostate carcinomas, 32 benign prostate hyperplasias (BPHs), and prostate cell lines (LNCaP, DU145, PC3, BPH-1) were examined with MethyLight polymerase chain reaction at 13 gene loci (APC, CDC6, CTNNB1, E-Cadherin, EDNRB, FGFR2, GSTP1, NAB2, PKCmu, PTGS2, RAR-beta, RASL11A, WWOX). Results: APC, RAR-beta, PTGS2, GSTP1, EDNRB, and CTNNB1 (83%, 71%, 65%, 33%, 14%, 9%, respectively) were methylated in pCA but rarely or not methylated in BPH. NAB2 and CDC6 were hypermethylated frequently in pCA (92%, 67%, respectively) and in BPH (91%, 59%, respectively). FGFR2, WWOX, E-Cadherin, PKCmu, and RASLL1A did not display noteworthy methylation in pCA (0–1%) or in BPH. CpG island hypermethylation at APC, retinoic acid receptor beta (RAR-beta), and PTGS2 discriminated with a sensitivity of 65–83% and a specificity of 97–100% between BPH and pCA. The combination of various genes increased the diagnostic expressiveness. PTGS2 hypermethylation correlated with seminal vesicle infiltration (p =0.047), capsular penetration (p =0.004), and pT stage (p =0.014). RAR-beta methylation was accompanied by a higher cumulative Gleason score (p =0.042). The probability of PSA-free-survival calculated with a Kattan nomogram correlated inversely with CpG island hypermethylation at EDNRB, RAR-beta, and PTGS2. All prostate cancer cell lines displayed a varying degree of demethylation after 5-aza-2′deoxycytidine treatment. Conclusions: CpG island hypermethylation at various gene loci is frequent in prostate cancer and can distinguish between neoplastic and noncancerous tissue. Furthermore, hypermethylation at PTGS2, RAR-beta, and EDNRB inversely correlated with PSA-free-survival according to a Kattan nomogram and has potential prognostic value. [Copyright &y& Elsevier]

Abstract Background Global histone modifications have been implicated in the progression of various tumour entities. Our study was designed to assess global methylation levels of histone 4 lysine 20 (H4K20me1-3) at different stages of prostate cancer (PCA) carcinogenesis. Methods Global H4K20 methylation levels were evaluated using a tissue microarray in patients with clinically localized PCA (n = 113), non-malignant prostate disease (n = 27), metastatic hormone-naive PCA (mPCA, n = 30) and castration-resistant PCA (CRPC, n = 34). Immunohistochemistry was performed to assess global levels of H4K20 methylation levels. Results Similar proportions of the normal, PCA, and mPCA prostate tissues showed strong H4K20me3 staining. CRPC tissue analysis showed the weakest immunostaining levels of H4K20me1 and H4K20me2, compared to other prostate tissues. H4K20me2 methylation levels indicated significant differences in examined tissues except for normal prostate versus PCA tissue. H4K20me1 differentiates CRPC from other prostate tissues. H4K20me1 was significantly correlated with lymph node metastases, and H4K20me2 showed a significant correlation with the Gleason score. However, H4K20 methylation levels failed to predict PSA recurrence after radical prostatectomy. Conclusions H4K20 methylation levels constitute valuable markers for the dynamic process of prostate cancer carcinogenesis.

Objective: Noncoding RNAs play an important role in carcinogenesis; a number of tRNA-halves are expressed in response to androgen stimulation and are involved in prostate cancer (CaP) initiation and progression. In this study, we evaluated the expression profile of androgen-dependent tRNA-halves in CaP.Materials and Methods: Total RNA was isolated from formalin-fixed paraffin-embedded 58 CaP, and 25 benign prostate hyperplasia tissues. We also studied the expression in serum from 49 localized and 21 metastatic castration-resistant CaP samples. The ligation of a RNA adaptor molecule to the tRNA-halves allowed the specific amplification of 3'/5'-tRNA-halves using quantitative TaqMan reverse transcription polymerase chain reaction. The expression levels were correlated with clinicopathological parameters as well as prostate-specific antigen recurrence free survival.Results: 5'-tRNA-Asp-GUC-half and 3'-tRNA-Asp-GUC-half were up-regulated in CaP tissues compared with benign prostate hyperplasia tissues. An increased expression level of all the 5 candidate tRNA-halves was associated with adverse clinicopathological parameters (pT-stage, pN-stage, prostate-specific antigen, International Society of Urological Pathology /ISUP grade) and a shorter time to biochemical relapse. In serum, 5'-tRNA-Glu-CUC-half was circulating at a higher level in metastatic castration-resistant CaP patients compared to patients with localized CaP.Conclusions: The androgen-dependent tRNA-halves can potentially act as biomarkers to monitor and predict the progression of CaP. [ABSTRACT FROM AUTHOR]

Objectives: To analyze circulating microRNAs (miRNA) in serum as non-invasive biomarker in patients with localized prostate cancer (PCA), benign prostate hyperplasia (BPH) and healthy individuals (HI). Methods: Total RNA was isolated from serum samples and the circulating levels of different RNA species (miRNA, miR-16; small nuclear RNA, RNU1A-1; messenger RNA, HPRT1), as well as of 4 oncogenic miRNAs (miR-26a, miR-32, miR-195, miR-let7i), were determined using a quantitative real-time polymerase chain reaction. We also evaluated miRNA levels in a second cohort of 10 PCA patients in cancer/nonmalignant tissue, and pre- and post-prostatectomy serum samples. Results: The levels of miR-16 and RNU1A-1were reliably measured, whereas HPRT1 levels were often below the detection limit of our assay. Circulating oncogenic miRNA levels were different, and especially the miR-26a level allowed sensitive (89%) discrimination of PCA and BPH patients at a moderate specificity (56%; area under the curve [AUC]: 0.703); the analysis of oncogenic miRNAs in combination increased the diagnostic accuracy (sensitivity: 78.4%; specificity: 66.7%; AUC: 0.758). Despite the low number of patients limiting the statistical power of the study, we observed correlations with clinical-pathologic parameters: miR-16, miR-195, and miR-26a were significantly correlated with surgical margin positivity; miR-195 and miR-let7i were significantly correlated with the Gleason score. Tissue miRNA levels were correlated with preprostatectomy miRNA levels in serum, and serum miRNA decreased after prostatectomy, thereby indicating tumor-associated release of miRNA. Conclusions: Tumor-associated miRNAs in serum allow noninvasive discrimination of PCA and BPH. [ABSTRACT FROM AUTHOR]