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Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive SPOP-mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion sampling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in SPOP-mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. Significance: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.

Objectives: We conducted a phase I/II prospective trial to determine whether stereotactic dose escalation to the dominant intra-prostatic nodule (DIN) up to 50 Gy incorporating a rectal balloon spacer is safe, does not affect patient quality of life, and preserves local control in patients with intermediate-high risk PCa. Methods: Eligible patients included males with stage ≤T3b localized disease, a prostate-specific antigen (PSA) level ≤50 , International Prostate Symptom Score (IPSS) ≤14, and a gland volume ≤70 cm3. Patients underwent perirectal spacer placement, followed by a planning MRI and were subsequently treated with SBRT doses of 36.25 Gy in five fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image visible DIN up to 50 Gy. Primary endpoint: safety. Secondary endpoints: biochemical control, quality of life (QofL), and dosimetry outcome. Results: Nine patients were treated in the Phase I part of the study. Dose limiting toxicities (DLTs) were not observed. Further characterization of tolerability and efficacy was conducted in the subsequent 24 patients irradiated at the recommended Phase II dose (50 Gy, RP2D). At a median follow-up of 61 months, biochemical control is 69%. Grade 1 and 2 acute GU and GI toxicity was 57.5 and 15%, and 24.2 and 6.1%, respectively. Grade 1 and 2 late GU and GI toxicity was 66.6 and 12.1%, and 15.1 and 3%, respectively. No Grade 3 or higher toxicity was reported. QofL data confirmed physician’s reported side effects. Dosimetry analysis showed adherence to the doses prescribed in the protocol. Conclusions SBRT of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN, when combined with a peri-rectal balloon spacer, was tolerable and established the RP2D. QofL analysis showed minimal negative impact in GU, GI, and sexual domains. Advances in knowledge: Extreme hypofractionated prostate radiation therapy with focal dose escalation to the DIN is well tolerated with efficacy comparable to normal fractionated radiation therapy.

Introduction High-resolution micro-ultrasound (micro-US) is a novel precise imaging modality that allows targeted prostate biopsies and multiparametric magnet resonance imaging (mpMRI) fusion. Its high resolution relying on a 29 MHz transducer allows real-time visualisation of prostate cancer lesions; this might overcome the inaccuracy of conventional MRI-US fusion biopsy strategies. We compared cancer detection rates in patients who underwent transrectal (TR-B) versus transperineal (TP-B) MR-micro-US fusion biopsy. Materials and methods 1:2 propensity score matching was performed in 322 consecutive procedures: 56 TR-B and 266 TP-B. All prostate biopsies were performed using ExactVuTM micro-US system with mpMRI image fusion. Clinically significant disease was defined as grade group ≥2. The primary objective was to evaluate the detection of clinically significant disease according to access route. The secondary outcomes were to compare the respective detection rates of random and targeted biopsies stratified per access route and to evaluate micro-US for its potential added value. Results 47 men undergoing TR-B and 88 undergoing TP-B were matched for age, PSA, clinical stage, prostate volume, PIRADS score, number of mpMRI-visible lesions and indication to biopsy. The detection rates of clinically significant and of any prostate cancer did not differ between the two groups (45% TR-B vs 42% TP-B; p = 0.8, and 57% TR-B vs 59% TP-B; p = 0.9, respectively). Detection rates also did not differ significantly between random (p = 0.4) and targeted biopsies (p = 0.7) stratified per access route. Micro-US targeted biopsy detected 36 MRI-invisible lesions in 33 patients; 19% of these lesions were positive for clinically significant disease. Overall, micro-US targeted biopsies upgraded 2% of patients to clinically significant disease that would have been missed otherwise. Conclusions MR-micro-US-fusion TR-B and TP-B have similar diagnostic yields in terms of detection rates of clinically significant prostate cancer. Micro-US targeted biopsy appears to have an additional diagnostic value over systematic and MRI-targeted biopsies.

The androgen receptor (AR) is a prostate master transcription factor. It binds to genetic enhancers, where it regulates gene activity and plays a fundamental role in prostate pathophysiology. Previous work has demonstrated that AR-DNA binding is systematically and consistently reprogrammed during prostate tumorigenesis and disease progression. We charted these reprogrammed AR sites and identified genes proximal to them. We were able to devise gene lists based on AR status within specific histological contexts: normal prostate epithelium, primary prostate tumor, and metastatic prostate cancer. We evaluated expression of the genes in these gene sets in subjects from two distinct clinical cohorts—men treated with surgery for localized prostate cancer and men with metastatic prostate cancer. Among men with localized prostate cancer, expression of genes proximal to AR sites lost in the transition from normal prostate to prostate tumor was associated with clinical outcome. Among men with metastatic disease, expression of genes proximal to AR sites gained in metastatic tumors was associated with clinical outcome. These results are consistent with the notion that AR is fundamental to both maintaining differentiation in normal prostate tissue and driving de-differentiation in advanced prostate cancer. More broadly, the study demonstrates the power of incorporating context-dependent epigenetic data into genetic analyses.

Adding abiraterone acetate (AA) plus prednisolone (P) to standard of care (SOC) improves survival in newly diagnosed advanced prostate cancer (PC) patients starting hormone therapy. Our objective was to determine the value for money to the English National Health Service (NHS) of adding AAP to SOC. We used a decision analytic model to evaluate cost-effectiveness of providing AAP in the English NHS. Between 2011–2014, the STAMPEDE trial recruited 1917 men with high-risk localised, locally advanced, recurrent or metastatic PC starting first-line androgen-deprivation therapy (ADT), and they were randomised to receive SOC plus AAP, or SOC alone. Lifetime costs and quality-adjusted life-years (QALYs) were estimated using STAMPEDE trial data supplemented with literature data where necessary, adjusting for baseline patient and disease characteristics. British National Formulary (BNF) prices (£98/day) were applied for AAP. Costs and outcomes were discounted at 3.5%/year. AAP was not cost-effective. The incremental cost-effectiveness ratio (ICER) was £149,748/QALY gained in the non-metastatic (M0) subgroup, with 2.4% probability of being cost-effective at NICE’s £30,000/QALY threshold; and the metastatic (M1) subgroup had an ICER of £47,503/QALY gained, with 12.0% probability of being cost-effective. Scenario analysis suggested AAP could be cost-effective in M1 patients if priced below £62/day, or below £28/day in the M0 subgroup. AAP could dominate SOC in the M0 subgroup with price below £11/day. AAP is effective for non-metastatic and metastatic disease but is not cost-effective when using the BNF price. AAP currently only has UK approval for use in a subset of M1 patients. The actual price currently paid by the English NHS for abiraterone acetate is unknown. Broadening AAP’s indication and having a daily cost below the thresholds described above is recommended, given AAP improves survival in both subgroups and its cost-saving potential in M0 subgroup.

IntroductionRadiotherapy is the most common curative treatment for non-metastatic prostate cancer; however, up to 13% of patients will develop local recurrence within 10 years. Patients can undergo further and potentially curative treatment including salvage surgery, brachytherapy (BT), external beam radiotherapy, high-intensity focused ultrasound and cryotherapy. Systematic review shows that high-dose-rate (HDR) BT and stereotactic body radiotherapy (SBRT) have the best outcomes in terms of biochemical control and lowest side effects. The reirradiation options for previously irradiated prostate cancer (RO-PIP) trial aims to determine the feasibility of recruitment to a trial randomising patients to salvage HDR-BT or SBRT and provide prospective data on patient recorded toxicity outcomes that will inform a future phase III trial.Methods and analysisThe primary endpoint of the RO-PIP feasibility study is to evaluate the patient recruitment potential over 2 years to a trial randomising to either SBRT or HDR-BT for patients who develop local recurrence of prostate cancer following previous radiation therapy. The aim is to recruit 60 patients across 3 sites over 2 years and randomise 1:1 to SBRT or HDR-BT. Secondary objectives include recording clinician and patient-reported outcome measures to evaluate treatment-related toxicity. In addition, the study aims to identify potential imaging, genomic and proteomic biomarkers that are predictive of toxicity and outcome based on hypoxia status, a prognostic marker of prostate cancer.Ethics and disseminationThis study has been approved by the Yorkshire and The Humber—Bradford Leeds Research Ethics Committee (Reference: 21/YH/0305, IRAS: 297060, January 2022). The results will be presented in national and international conferences, published in peer-reviewed journals and will be communicated to relevant stakeholders. A plain English report will be shared with the study participants, patients’ organisations and media.Trial registration numberISRCTN 12238218 (Amy Ackroyd NIHR CPMS Team).

Background Multiparametric MRI (mpMRI) became recognised in investigating those with suspected prostate cancer between 2010 and 2012; in the USA, the preventative task force moratorium on PSA screening was a strong catalyst. In a few short years, it has been adopted into daily urological and oncological practice. The pace of clinical uptake, born along by countless papers proclaiming high accuracy in detecting clinically significant prostate cancer, has sparked much debate about the timing of mpMRI within the traditional biopsy-driven clinical pathways. There are strongly held opposing views on using mpMRI as a triage test regarding the need for biopsy and/or guiding the biopsy pattern. Objective To review the evidence base and present a position paper on the role of mpMRI in the diagnosis and management of prostate cancer. Methods A subgroup of experts from the ESUR Prostate MRI Working Group conducted literature review and face to face and electronic exchanges to draw up a position statement. Results This paper considers diagnostic strategies for clinically significant prostate cancer; current national and international guidance; the impact of pre-biopsy mpMRI in detection of clinically significant and clinically insignificant neoplasms; the impact of pre-biopsy mpMRI on biopsy strategies and targeting; the notion of mpMRI within a wider risk evaluation on a patient by patient basis; the problems that beset mpMRI including inter-observer variability. Conclusions The paper concludes with a set of suggestions for using mpMRI to influence who to biopsy and who not to biopsy at diagnosis. Key Points • Adopt mpMRI as the first, and primary, investigation in the workup of men with suspected prostate cancer. • PI-RADS assessment categories 1 and 2 have a high negative predictive value in excluding significant disease, and systematic biopsy may be postponed, especially in men with low-risk of disease following additional risk stratification. • PI-RADS assessment category lesions 4 and 5 should be targeted; PI-RADS assessment category lesion 3 may be biopsied as a target, as part of systematic biopsies or may be observed depending on risk stratification. Electronic supplementary material The online version of this article (10.1007/s00330-019-06166-z) contains supplementary material, which is available to authorized users.

Purpose: To determine the value of a three-dimensional (3D) greyscale transrectal ultrasound (TRUS)-guided prostate biopsy system and biopsy core pre-embedding method on concordance between Gleason scores of needle biopsies and radical prostatectomy (RP) specimens. Methods: Retrospective analysis of prostate biopsies and subsequent RP for PCa in the Jeroen Bosch Hospital, the Netherlands, from 2007 to 2016. Two cohorts were analysed: conventional 2D TRUS-guided biopsies and RP (2007–2013, n = 266) versus 3D TRUS-guided biopsies with pre-embedding (2013–2016, n = 129). The impact of 3D TRUS-guidance with pre-embedding on Gleason score (GS) concordance between biopsy and RP was evaluated using the κ-coefficient. Predictors of biopsy GS 6 upgrading were assessed using logistic regression models. Results: Gleason concordance was comparable between the two cohorts with a κ = 0.44 for the 3D cohort, compared to κ = 0.42 for the 2D cohort. 3D TRUS-guidance with pre-embedding, did not significantly affect the risk of biopsy GS 6 upgrading in univariate and multivariate analysis. Conclusions: 3D TRUS-guidance with biopsy core pre-embedding did not improve Gleason concordance. Improved detection techniques are needed for recognition of low-grade disease upgrading.

Background Active surveillance (AS) of low-risk prostate cancer (PCa) is an accepted alternative to active treatment. However, the conventional diagnostic trans-rectal ultrasound guided biopsies (TRUS-bx) underestimate PCa aggressiveness in almost half of the cases, when compared with the surgical specimen. Purpose To investigate if additional multi-parametric magnetic resonance imaging (mpMRI) of the prostate and MRI-guided in-bore biopsies (MRGB) at AS inclusion would improve selection of patients for active treatment. Material and Methods All patients enrolled in AS programs at two Danish centers, from October 2014 to January 2016, were offered an mpMRI 8–12 weeks after the initial diagnostic TRUS-bx. Candidates had low-risk disease (PSA 6 or GS 6 (3 + 3) lesions with ≥ 6 mm maximal cancer core length (MCCL). Results A total of 78 patients were included and in 21 patients a total of 22 PIRADS-score 4 or 5 lesions were detected. MRGB pathology revealed that 17 (81%) of these and 22% of the entire AS population harbored significant cancers at AS inclusion. In eight (38%) cases, the GS was upgraded. Also, nine patients (43%) had GS 6 (3 + 3) foci with MCCL ≥ 6 mm. Conclusion In an AS cohort based on TRUS and TRUS-bx diagnostic strategies, supplemental mpMRI and in-bore MRGB were able to efficiently reclassify a substantial number of patients as candidates for immediate active treatment.

Deferred active treatment (DAT) strategies, including active surveillance and active monitoring, are a recognised management option for men with localised low-risk prostate cancer. However, there is uncertainty due to heterogeneity of patient selection criteria, follow-up and monitoring characteristics, reclassification thresholds, and which outcome measures should be prioritised. This protocol describes a study led by the European Association of Urology (EAU) Prostate Cancer Guidelines Panel in conjunction with other guideline organisations and societies to develop consensus statements for all domains of deferred active treatment. The project is divided into 3 sequential phases: (1) Systematic review of studies reporting on DAT in order to summarise and define range of heterogeneity regarding all domains; (2) Two-round Delphi online survey involving a large, international panel of healthcare professionals (HCPs) and patients to initiate consensus; and (3) Consensus group meeting involving representatives from HCP and patient stakeholder groups to finalise the consensus process. The consensus statements are expected to be adopted by clinical practice guidelines in order to standardise and guide practice for clinicians and researchers until better evidence emerges. Patient summary: We describe a project aimed at standardising elements of practice in active surveillance/monitoring for early localised prostate cancer, because currently there is great variation and uncertainty regarding how best to conduct them. This will be achieved through a structured process of agreement (i.e. consensus) amongst a large, international panel of healthcare professionals and patients.

The immune system plays a central role in cancer development, showing both anti-tumor and pro-tumor activities depending on the immune cell subsets and the disease context. While CD8 T cells are associated with a favorable outcome in most cancers, only T helper type 1 (Th1) CD4 T cells play a protective role, in contrast to Th2 CD4 T cells. Double positive (DP) CD4 + CD8 + T cells remain understudied, although they were already described in human cancers, with conflicting data regarding their role. Here, we quantified and phenotypically/functionally characterized DP T cells in blood from urological cancer patients. We analyzed blood leukocytes of 24 healthy donors (HD) and 114 patients with urological cancers, including bladder (n = 54), prostate (n = 31), and kidney (n = 29) cancer patients using 10-color flow cytometry. As compared to HD, levels of circulating DP T cells were elevated in all urological cancer patients, which could be attributed to increased frequencies of both CD4 high CD8 low and CD4 + CD8 high DP T-cell subsets. Of note, most CD4 high CD8 low DP T cells show a CD8αα phenotype, whereas CD4 + CD8 high cells express both CD8α and CD8β subunits. Functional properties were investigated using ex-vivo generated DP T-cell clones. DP T cells from patients were skewed toward an effector memory phenotype, along with enhanced Th2 cytokine production. Interestingly, both CD8αα and CD8αβ DP T cells were able to trigger Th2 polarization of naïve CD4 T cells, while restraining Th1 induction. Thus, these data highlight a previously unrecognized immunoregulatory mechanism involving DP CD4 + CD8 + T cells in urological cancers.

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients., Notch signalling is involved in prostate cancer progression and therapeutic resistance. Here, the authors show that loss of PTEN in prostate cancer models results in increased Notch1 cleavage and activation through CUX1-mediated transactivation of ADAM17.

Tumorigenesis is a multistep process involving co-operation between several deregulated oncoproteins. In this study, we unravel previously unrecognized interactions and crosstalk between Pim kinases and the Notch signaling pathway, with implications for both breast and prostate cancer. We identify Notch1 and Notch3, but not Notch2, as novel Pim substrates and demonstrate that for Notch1, the serine residue 2152 is phosphorylated by all three Pim family kinases. This target site is located in the second nuclear localization sequence (NLS) of the Notch1 intracellular domain (N1ICD), and is shown to be important for both nuclear localization and transcriptional activity of N1ICD. Phosphorylation-dependent stimulation of Notch1 signaling promotes migration of prostate cancer cells, balances glucose metabolism in breast cancer cells, and supports in vivo growth of both types of cancer cells on chick embryo chorioallantoic membranes. Furthermore, Pim-induced growth of orthotopic prostate xenografts in mice is associated with enhanced nuclear Notch1 activity. Finally, simultaneous inhibition of Pim and Notch abrogates the cellular responses more efficiently than individual treatments, opening up new vistas for combinatorial cancer therapy.

// Karine Lefort 1 , Paola Ostano 2 , Maurizia Mello-Grand 2 , Valerie Calpini 1 , Maria Scatolini 3 , Antonella Farsetti 4, 5 , Gian Paolo Dotto 1, 6 , Giovanna Chiorino 2 1 Department of Biochemistry, University of Lausanne, Lausanne, Switzerland 2 Laboratory of Cancer Genomics, Fondazione “Edo ed Elvo Tempia Valenta”, Biella, Italy 3 Laboratory of Molecular Oncology, Fondazione “Edo ed Elvo Tempia Valenta”, Biella, Italy 4 Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy 5 Internal Medicine Clinic III, Goethe University, Frankfurt am Main, Germany 6 Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA, USA Correspondence to: Giovanna Chiorino, email: giovanna.chiorino@fondazionetempia.org Karine Lefort, email: karine.lefort@unil.ch Keywords: Notch, prostate cancer Received: January 15, 2016 Accepted: June 12, 2016 Published: June 30, 2016 ABSTRACT Adenocarcinomas of the prostate arise as multifocal heterogeneous lesions as the likely result of genetic and epigenetic alterations and deranged cell-cell communication. Notch signaling is an important form of intercellular communication with a role in growth/differentiation control and tumorigenesis. Contrasting reports exist in the literature on the role of this pathway in prostate cancer (PCa) development. We show here that i) compared to normal prostate tissue, Notch1 expression is significantly reduced in a substantial fraction of human PCas while it is unaffected or even increased in others; ii) acute Notch activation both inhibits and induces process networks associated with prostatic neoplasms; iii) down-modulation of Notch1 expression and activity in immortalized normal prostate epithelial cells increases their proliferation potential, while increased Notch1 activity in PCa cells suppresses growth and tumorigenicity through a Smad3-dependent mechanism involving p21 WAF1/CIP1 ; iv) prostate cancer cells resistant to Notch growth inhibitory effects retain Notch1-induced upregulation of pro-oncogenic genes, like EPAS1 and CXCL6, also overexpressed in human PCas with high Notch1 levels. Taken together, these results reconcile conflicting data on the role of Notch1 in prostate cancer.

Background The French West-Indies rank first for both prostate cancer incidence and mortality rates. Analyzing diagnostic and therapeutic procedures among patients with prostate cancer, using data from a population-based cancer registry, is essential for cancer surveillance and research strategies. Methods This retrospective observational cohort study was based on data from the Martinique Cancer Registry. Records of 452 patients diagnosed with prostate cancer in 2013 were retrieved from the registry. Data extracted were: socio-demographic and clinical characteristics, circumstances of diagnosis, PSA level at diagnosis, Gleason score and risk of disease progression. Stage at diagnosis and patterns of care among prostate cancer patients were analyzed. Results Mean age at diagnosis was 67 ± 8 years; 103 (28.5%) were symptomatic at diagnosis. Digital rectal exam was performed in 406 (93.8%). Clinical stage was available in 385 (85.2%); tumours were localized in 322/385 (83.6%). Overall, 17.9% were at low risk, 36.4% at intermediate and 31.9% at high risk; 13.8% were regional/metastatic cancers. Median PSA level at diagnosis was 8.16 ng/mL (range 1.4–5000 ng/mL). A total of 373 patients (82.5%) received at least one treatment, while 79 (17.5%) had active surveillance or watchful waiting. Among patients treated with more than one therapeutic strategy, the most frequent combination was external radiotherapy with androgen deprivation (n = 102, 22.6%). Conclusions This study provides detailed data regarding the quality of diagnosis and management of patients with prostate cancer in Martinique. Providing data on prostate cancer is essential for the development of high-priority public health measures for the Caribbean.

PURPOSE: To date no guidelines are available for contouring prostate cancer inside the gland, as visible on multiparametric (mp-) MRI. We assessed inter-institutional differences in interpretation of mp-MRI in the multicenter phase III FLAME trial. METHODS: We analyzed clinical delineations on mp-MRI and clinical characteristics from 260 patients across three institutes. We performed a logistic regression analysis to examine each institute's weighting of T2w, ADC and Ktrans intensity maps in the delineation of the cancer. As reviewing of all delineations by an expert panel is not feasible, we made a selection based on discrepancies between a published tumor probability (TP) model and each institute's clinical delineations using Areas Under the ROC Curve (AUC) analysis. RESULTS: Regression coefficients for the three institutes were -0.07, -0.27 and -0.11 for T2w, -1.96, -0.53 and -0.65 for ADC and 0.15, 0.20 and 0.62 for Ktrans, with significant differences between institutes for ADC and Ktrans. AUC analysis showed median AUC values of 0.92, 0.80 and 0.79. Five patients with lowest AUC values were reviewed by a uroradiologist. CONCLUSION: Regression coefficients revealed considerably different interpretations of mp-MRI in tumor contouring between institutes and demonstrated the need for contouring guidelines. Based on AUC values outlying delineations could efficiently be identified for review. ispartof: RADIOTHERAPY AND ONCOLOGY vol:128 issue:2 pages:321-326 ispartof: location:Ireland status: published

Background: When managing patients with cancer, lymphedema of the lower limbs (LLL) is commonly reported as secondary to the surgical excision and/or irradiation of lymph nodes (LNs). In the framework of lymphoscintigraphic imaging performed to evaluate secondary LLL, some lympho-nodal presentations have been observed that could not be explained by the applied treatments, suggesting that these LLL might be primary. Therefore, all our lymphoscintigraphic examinations that were performed in patients for LLL after surgery for gynecological or urological cancer were retrospectively analyzed in order to evaluate the frequency in which these LLL might not be secondary (either completely or partially) but primary in origin. Methods: Lymphoscintigraphies performed in 33 patients who underwent LN dissection (limited to the intra-abdominal LN) with or without radiotherapy for histologically confirmed ovarian cancer (n = 6), uterine cancer (n = 14 with cervical cancer and n = 7 with endometrial cancer), or prostate cancer (n = 6) were compared to lymphoscintigraphies obtained in primary LLL. Results: In 12 (33% of the) patients (3 men plus 9 women, 4 with cervical cancer and 5 with endometrial cancer), scintigraphy of the lower limbs revealed lympho-nodal presentation that did not match with the expected consequences of the surgical and/or radiological treatments and were either suggestive or typical of primary lymphedema. Conclusions: This retrospective analysis of a limited but well-defined series of patients suggests that the appearance of LLL might not be related to cancer treatment(s) but that these LLL may represent the development of a primary lymphatic disease latent prior to the therapeutic interventions., SCOPUS: ar.j, info:eu-repo/semantics/published

Contains fulltext : 215808.pdf (Publisher’s version ) (Open Access) PURPOSE: Along with a number of other malignancies, the term "oligometastatic" prostate cancer has recently emerged. It represents an attempt to define a subtype of cancer with a limited metastatic load that might perform more favorably than a distinctly disseminated disease, or even one that may be managed in a potentially curative way. Since there is currently a knowledge gap of what imaging modalities should be utilized to classify patients as having this type of tumor, we aimed to shed light on the role of conventional and marker-based imaging in the setting of synchronous oligometastatic prostate cancer as well as summarize the available evidence for its clinical application. METHODS: A literature search on December 15th 2017 was conducted using the Pubmed database. RESULTS: Functional imaging techniques like (68)Ga PSMA. (68)Ga PSMA PET-CT has currently been shown the best detection rates for the assessment of nodal, bone and visceral metastases, especially for smaller lesions at low PSA levels. CONCLUSIONS: Functional imaging helps detect low-burden disease metastatic patients. However, these imaging modalities are not available in every center and thus clinicians may be prone to prescribe systemic treatment rather than referring patients for cytoreductive treatments. We hope that the ongoing prospective trials will help guide clinicians in making a more personalized management of synchronous metastatic patients.

Although salvage radiotherapy (SRT) for PSA recurrence after radical prostatectomy provides better oncological outcomes when delivered early, in the absence of detectable disease many patients are treated for macroscopic locally recurrent tumors. Due to limited data from prospective studies, we hypothesized an important variability in the SRT management of these patients. Our aim was to investigate current practice patterns of SRT for local macroscopic recurrence after radical prostatectomy. A total of 14 Swiss radiation oncology centers were asked to complete a survey on treatment specifications for macroscopic locally recurrent disease including information on pretherapeutic diagnostic procedures, dose prescription, radiation delivery techniques and androgen deprivation therapy (ADT). Treatment recommendations on ADT were analyzed using the objective consensus methodology. The majority of centers recommended pretreatment magnetic resonance imaging (MRI) of the pelvis and choline positron emission tomography (PET). The median prescribed dose to the prostate bed was 66 Gy (range 65-72 Gy) with a boost to the macroscopic lesion used by 79% of the centers with a median total dose of 72 Gy (range 70-80 Gy). Intensity-modulated rotational techniques were used by all centers and daily cone beam computed tomography (CT) was recommended by 43%. The use of concomitant ADT for any macroscopic recurrence was recommended by 43% of the centers while the remaining centers recommended it only for high-risk disease, which was not consistently defined. We observed a high variability of treatment paradigms when SRT is indicated for macroscopic local recurrences after prostatectomy. These data reflect the need for more standardized approaches and ultimately further research in this field.

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Activation of the PTEN-PI3K-mTORC1 pathway consolidates metabolic programs that sustain cancer cell growth and proliferation,. Here we show that mTORC1 regulates polyamine dynamics, a metabolic route that is essential for oncogenicity. Through the use of integrative metabolomics in a mouse model and human biopsies of prostate cancer, we identified alterations in tumours impacting on the production of decarboxylated S-adenosylmethionine (dcSAM) and polyamine synthesis. Mechanistically, this metabolic rewiring stems from mTORC1-dependent regulation of S-adenosylmethionine decarboxylase 1 (AMD1) stability. This novel molecular regulation was validated in murine and human cancer specimens. AMD1 was upregulated in prostate cancer specimens with activated mTORC1. Conversely, samples from a clinical trial with the mTORC1 inhibitor everolimus exhibited a predominant decrease in AMD1 immunoreactivity that was associated to a decrease in proliferation, in line with the requirement of dcSAM production for oncogenicity. These findings provide fundamental information about the complex regulatory landscape controlled by mTORC1 to integrate and translate growth signals into an oncogenic metabolic program.

Background Pre-treatment magnetic resonance imaging (MRI) can give patient-specific evaluation of 25 suspected pathologically-involved volumes in the seminal vesicles (SV) in prostate cancer patients. By 26 targeting this suspicious volume we hypothesize that radiotherapy is more efficient without introducing more 27 toxicity. In this study we evaluate the concept of using MRI-defined target volumes in terms of tumor 28 control probability (TCP) and rectal normal tissue complication probability (NTCP). Materials and methods Twenty-one high-risk prostate cancer patients were included. Pre-treatment CT 30 images, T2 weighted (T2w) MRI and two multi-parametric MRI were acquired. Overlap between a 31 suspicious volume in the SV observed on T2w images and a suspicious volume observed on either multi-32 parametric MRI was assumed to reflect a true malignant region (named “MRI positive”). In addition the 33 entire SV on the CT-scan was delineated. Three treatment plans of 2Gyx39 fractions were generated per 34 patient: one covering the MRI positive volume in SV and prostate with margin of 11 mm to the MRI positive 35 in the SV and two plans covering prostate and SV using 11mm and 7mm SV margin, respectively. All plans 36 prescribed the same PTV mean dose. Rectal NTCP grade≥2 was evaluated with the Lyman-Kutcher-Burman 37 model and TCP was estimated by a logistic model using the combined MRI positive volume in SV and 38 prostate as region-of-interest. Results 14/21 patients were classified as MRI positive, 6 of which had suspicious volumes in all three MRI 40 modalities. On average TCP for the plan covering prostate and the MRI positive volume was 3% higher (up 41 to 11%) than the two other plans which was statistically significant. The increased TCP was obtained without 42 increasing rectal NTCP grade≥2. Conclusion Using functional MRI for individualized target delineation in the seminal vesicles may improve 44 the treatment outcome in radiotherapy of prostate cancer without increasing the rectal toxicity.

Background: Data regarding the natural history of biochemical recurrence (BCR) after radical prostatectomy (RP) and adjuvant radiotherapy (aRT) are limited. Objective: To evaluate cancer-specific (CSM) and other-cause mortality (OCM) in prostate cancer patients with BCR after RP and aRT. Design, setting, and participants: We identified 336 patients with BCR treated between 1990 and 2006 at two tertiary care centers. Intervention: All patients underwent RP plus aRT. Outcome measurements and statistical analysis: Cox regression analyses were used to evaluate the association between clinicopathologic variables and CSM. The coefficients of CSM-independent predictors were used to develop a novel nomogram. Patients were stratified into groups according to nomogram-calculated CSM probability and median age. Competing-risks survival analyses were used to estimate CSM and OCM for each group. Results and limitations: Ten-year CSM and OCM were 21.5 and 21.7%, respectively. On multivariable analyses, short time to BCR, pathologic Gleason score >= 8, and positive lymph node count of more than two at RP were significantly associated with increased CSM rate (all p 10-30% versus >30%. On competing-risks analysis, 10-yr CSM rate for these groups was 6%, 15%, and 42%, respectively, for patients aged 68 yr. Likewise, 10-yr OCM rate was 24%, 9%, and 10%, respectively, for patients aged 68 yr. The study is limited by its retrospective design. Conclusions: Short time to BCR, pathologic Gleason score >= 8, and more than two positive lymph nodes were independent predictors of CSM in patients with BCR after RP and aRT. Men with these features may benefit from additional secondary therapies, ideally, in a clinical trial setting. (C) 2013 European Association of Urology. Published by Elsevier B. V. All rights reserved.

Objectives: The rationale for directing targeted biopsy towards the centre of lesions has been questioned in light of prostate cancer grade heterogeneity. In this study, we assess the assumption that the maximum cancer Gleason grade (Gleason grade hotspot) lies within the maximum dimension (volume hotspot) of a prostate cancer lesion. Methods: 3-D histopathological models were reconstructed using the outputs of the 5-mm transperineal mapping (TPM) biopsies used as the reference test in the pilot phase of Prostate Mri Imaging Study (PROMIS), a paired validating cohort study investigating the performance of multi-parametric magnetic resonance imaging (MRI) against transrectal ultrasound (TRUS) biopsies. The prostate was fully sampled with 5 mm intervals; each core was separately labelled, inked and orientated in space to register 3-D cancer lesions location. The data from the histopathology results were used to create a 3-D interpolated reconstruction of each lesion and identify the spatial coordinates of the largest dimension (volume hot spot) and highest Gleason grade (Gleason grade hotspot) and assess their concordance. Results: Ninety-four men, with median age 62 years (interquartile range, IQR= 58–68) and median PSA 6.5 ng ml−1 (4.6–8.8), had a median of 80 (I69–89) cores each with a median of 4.5 positive cores (0–12). In the primary analysis, the prevalence of homogeneous lesions was 148 (76%; 95% confidence interval (CI) ±6.0%). In all, 184 (94±3.2%) lesions showed concordant hotspots and 11/47 (23±12.1%) of heterogeneous lesions showed discordant hotspots. The median 3-D distance between discordant hotspots was 12.8 mm (9.9–15.5). These figures remained stable on secondary analyses using alternative reconstructive assumptions. Limitations include a certain degree of error within reconstructed models. Conclusions: Guiding one biopsy needle to the maximum cancer diameter would lead to correct Gleason grade attribution in 94% of all lesions and 79% of heterogeneous ones if a true hit was obtained. Further correlation of histological lesions, their MRI appearance and the detectability of these hotspots on MRI will be undertaken once PROMIS results are released.

Background We did a randomised phase 3 trial assessing the benefit of addition of long-term androgen suppression with a luteinising-hormone-releasing hormone (LHRH) agonist to external irradiation in patients with prostate cancer with high metastatic risk. In this report, we present the 10-year results. Methods For this open-label randomised trial, eligible patients were younger than 80 years and had newly diagnosed histologically proven T1-2 prostatic adenocarcinoma with WHO histological grade 3 or T3-4 prostatic adenocarcinoma of any histological grade, and a WHO performance status of 0-2. Patients were randomly assigned (1:1) to receive radiotherapy alone or radiotherapy plus immediate androgen suppression. Treatment allocation was open label and used a minimisation algorithm with institution, clinical stage of the disease, results of pelvic-lymph-node dissection, and irradiation fields extension as minimisation factors. Patients were irradiated externally, once a day, 5 days a week, for 7 weeks to a total dose of 50 Gy to the whole pelvis, with an additional 20 Gy to the prostate and seminal vesicles. The LHRH agonist, goserelin acetate (3.6 mg subcutaneously every 4 weeks), was started on the first day of irradiation and continued for 3 years; cyproterone acetate (50 mg orally three times a day) was given for 1 month starting a week before the first goserelin injection. The primary endpoint was clinical disease-free survival. Analysis was by intention to treat. The trial is registered at ClinicalTrials.gov, number NCT00849082. Findings Between May 22,1987, and Oct 31,1995,415 patients were randomly assigned to treatment groups and were included in the analysis (208 radiotherapy alone, 207 combined treatment). Median follow-up was 9.1 years (IQR 5.1-12.6). 10-year clinical disease-free survival was 22.7% (95% CI 16.3-29.7) in the radiotherapy-alone group and 47.7% (39.0-56.0) in the combined treatment group (hazard ratio [HR] 0.42,95% CI 0.33-0.55, p

Background: The role of extended pelvic lymph node dissection (ePLND) in treating prostate cancer (PCa) patients with lymph node invasion (LNI) remains controversial. Objective: The relationship between the number of removed lymph nodes (RLNs) and cancer-specific mortality (CSM) was tested in patients with LNI. Design, setting, and participants: We examined data of 315 pN1 PCa patients treated with radical prostatectomy (RP) and anatomically ePLND between 2000 and 2012 at one tertiary care centre. All patients received adjuvant hormonal therapy with or without adjuvant radiotherapy (aRT). Outcome measurements and statistical analysis: Univariable and multivariable Cox regression analyses tested the relationship between RLN number and CSM rate, after adjusting to all available covariates. Survival estimates were based on the multivariable model; patients were stratified according to RLN number using points of maximum separation. Results and limitations: The average number of RLNs was 20.8 (median: 19; interquartile range: 14–25). Mean and median follow-up were 63.1 and 54 mo, respectively. At 10-yr, the CSM-free survival rate was 74.7%, 85.9%, 92.4%, 96.0%, and 97.9% for patients with 8, 17, 26, 36, and 45 RLNs, respectively. By multivariable analyses, the number of RLNs independently predicted lower CSM rate (hazard ratio [HR]: 0.93; p = 0.02). Other predictors of CSM were Gleason score 8–10 (HR: 3.3), number of positive nodes (HR: 1.2), and aRT treatment (HR: 0.26; all p 0.006). The study is limited by its retrospective nature. Conclusions: In PCa patients with LNI, the removal of a higher number of LNs during RP was associated with improvement in cancer-specific survival rate. This implies that ePLND should be considered in all patients with a significant preoperative risk of harbouring LNI. Patient summary: We found that removing more lymph nodes during prostate cancer surgery can significantly improve cancer-specific survival in patients with lymph node invasion.

PURPOSE: To understand the reasons for differences in the delineation of target volumes between physicians. MATERIAL AND METHODS: 18 Swiss radiooncology centers were invited to delineate volumes for one prostate and one head-and-neck case. In addition, a questionnaire was sent to evaluate the differences in the volume definition (GTV [gross tumor volume], CTV [clinical target volume], PTV [planning target volume]), the various estimated margins, and the nodes at risk. Coherence between drawn and stated margins by centers was calculated. The questionnaire also included a nonspecific series of questions regarding planning methods in each institution. RESULTS: Fairly large differences in the drawn volumes were seen between the centers in both cases and also in the definition of volumes. Correlation between drawn and stated margins was fair in the prostate case and poor in the head-and-neck case. The questionnaire revealed important differences in the planning methods between centers. CONCLUSION: These large differences could be explained by (1) a variable knowledge/interpretation of ICRU definitions, (2) variable interpretations of the potential microscopic extent, (3) difficulties in GTV identification, (4) differences in the concept, and (5) incoherence between theory (i.e., stated margins) and practice (i.e., drawn margins).

DNA typing was requested to investigate a presumptive cancer diagnosis error by confirming whether benign and cancerous prostatic tissue in the same presurgical haematoxylin and eosin stained slide belonged to the same person. After independent histological re-examination of the slide by a pathologist, manual slide dissection was used to guarantee independent and high recovery DNA isolation from each tissue section, avoiding carryover and background contamination. Nuclear DNA quantification performed by real time polymerase chain reaction (PCR) revealed the absence of human DNA for short tandem repeat (STR) typing. Mitochondrial DNA was only obtained by performing PCR of very short fragments ( approximately 100 bp), indicating high DNA degradation. Different low frequency hypervariable region I haplotypes were obtained from each tissue section (normal tissue section haplotype: 16224C, 16234T, 16311C, 16356C; cancer tissue section haplotype: 16256T, 16270T, 16293G). Only the normal tissue section haplotype matched that obtained from the patient's blood sample, indicating that the cancer tissue section originated from an unknown patient. These results supported the hypothesis of sample mix up during block processing or slide preparation by a carryover mechanism. Mitochondrial genetic typing is recommended to exclude the possibility of carryover artefacts when low DNA content and high degradation compromise conventional STR typing.

29歳男.肉眼的血尿と排尿時痛を自覚し受診, 検尿にて膿尿を認め, 出血性膀胱炎と診断された.排泄性尿路造影およびMRIを施行され, 膀胱右壁に広基性腫瘤が認められ, 浸潤性膀胱癌を疑われた.尿細胞診はclass V, CTおよびMRI上, 膀胱右側壁から前立腺にかけて径6×3cmの腫瘤を認めた.膀胱鏡では膀胱右壁から前立腺にかかる単発の非乳頭状広基性腫瘤を認め, 生検が行われた.なお, 球部尿道に尿道狭窄を認め, 尿道切開刀とYAGレーザーにて尿道切開術を施行した.病理学的検査で腫瘍が筋層内に浸潤増生する像を認め, 移行上皮癌grade 3と診断した.また, 右側前立腺内にも同様の異型細胞を認めており, T4aN0M0と診断した.妊孕性を考慮し, 補助化学療法前に精子凍結保存を施行した後, 術前化学療法としてMEG療法を3コース施行した.腫瘍はCT画像上消失したが, 根治的膀胱全摘除術を施行した.病理組織学的検索では筋深層部に及ぶ分化度の低い移行上皮癌(G3)細胞をわずかに認め, pT2b pNOMOであった.術後18ヵ月, 再発, 転移は認められない, A 29-year-old male with bladder cancer was referred to our hospital. Histological examination of transurethral biopsy showed transitional cell carcinoma with invasion into prostate (T4aN0M0, grade 3). Nerve-sparing radical cystectomy with ileal neobladder reconstruction was performed after 3 courses of neoadjuvant chemotherapy with Methotrexate, Epirubicin and Cisplatin. Continence and erectile function were preserved and no recurrence has been observed for 18 months after the operation. This is the sixth case of an invasive bladder cancer in Japanese patients under 30 years old.

78歳男.陰茎腫脹を主訴とし, 近医で陰茎悪性黒色腫疑いと診断され, 精査加療目的で入院した.包皮から亀頭と陰茎根部に黒色, 結節状, 悪臭のある腫瘤性病変を認め, 両側の鼠径リンパ節を数個触知した.膀胱鏡では尿道への浸潤, 陰茎部MRIでは海綿体, 尿道, 前立腺への浸潤, 腹部CTでは内腸骨リンパ節腫脹を認めた.血液検査では腫瘍マーカー5-S-システイニルドーパ(CD)の高値を認めた.陰茎原発悪性黒色腫と診断し, 膀胱全摘, 陰茎全摘, 両側睾丸摘出, 骨盤内・両側鼠径リンパ節郭清を施行した.病理診断は結節型悪性黒色腫であった.術直後はCDが正常範囲に低下した.その後, 化学療法と免疫療法の併用を行い, 一旦は退院したが, 脳への多発性転移を認め, 術後12ヵ月目には腹膜転移を生じ死亡した, A 79-year-old male presented in December. In January, 2001, with complaints of black nodules and bleeding from the glans of the penis to the foreskin. Inguinal lymph nodes were palpable bilaterally. Clinical diagnosis was penile malignant melanoma. Cystoscopy and urethrography revealed urethral invasion of malignant melanoma, and magnetic resonance imaging (MRI) of the penis revealed invasion to prostate, and pelvic lymph node metastases in abdominal compuled tomography (CT) but no organ metastases. Total cystectomy, total penectomy, bilateral inguinal and pelvic lymph node dissection and bilateral ureterocutaneostomy were performed in February, 2002. The pathological findings were nodular malignant melanoma, pT4bN2bM1a, and the surgical margin was positive. After these therapies, chemotherapy was performed. Five months later, CT revealed multiple lung and brain metastases, and radiation therapy and chemotherapy were performed. Twelve months after the operation, he died of cancer. Review of the literature revealed that our patient is the thirtieth reported case of penile malignant melanoma in Japan since 1924. In 30 cases, stage III, IV were 20 cases and 16 cases performed operation.