OBJECTIVE: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. PATIENTS AND METHODS: Men aged 50-69\u2009years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6\u2009years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. RESULTS: Treatment-received analyses revealed different impacts of treatments over 6\u2009years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6\u2009years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6\u2009years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6\u2009years, and after EBRT this was reported by 69% and 74%, respectively (P\u2009
\n \n\n \n \nIn prostate cancer, loss of the tumour suppressor gene, Retinoblastoma (Rb), and consequent activation of transcription factor E2F1 typically occurs at a late-stage of tumour progression. It appears to regulate a switch to an androgen-independent form of cancer, castration-resistant prostate cancer (CRPC), which frequently still requires androgen receptor (AR) signalling. We have previously shown that upon mating, binucleate secondary cells (SCs) of the Drosophila melanogaster male accessory gland (AG), which share some similarities with prostate epithelial cells, switch their growth regulation from a steroid-dependent to a steroid-independent form of Ecdysone Receptor (EcR) control. This physiological change induces genome endoreplication and allows SCs to rapidly replenish their secretory compartments, even when ecdysone levels are low because the male has not previously been exposed to females. Here, we test whether the Drosophila Rb homologue, Rbf, and E2F1 regulate this switch. Surprisingly, we find that excess Rbf activity reversibly suppresses binucleation in adult SCs. We also demonstrate that Rbf, E2F1 and the cell cycle regulators, Cyclin D (CycD) and Cyclin E (CycE), are key regulators of mating-dependent SC endoreplication, as well as SC growth in both virgin and mated males. Importantly, we show that the CycD/Rbf/E2F1 axis requires the EcR, but not ecdysone, to trigger CycE-dependent endoreplication and endoreplication-associated growth in SCs, mirroring changes seen in CRPC. Furthermore, Bone Morphogenetic Protein (BMP) signalling, mediated by the BMP ligand Decapentaplegic (Dpp), intersects with CycD/Rbf/E2F1 signalling to drive endoreplication in these fly cells. Overall, our work reveals a signalling switch, which permits rapid growth of SCs and increased secretion after mating, independently of previous exposure to females. The changes observed share mechanistic parallels with the pathological switch to hormone-independent AR signalling seen in CRPC, suggesting that the latter may reflect the dysregulation of a currently unidentified physiological process.
\n \n\n \n \nOBJECTIVES: To evaluate different scenarios for the management of early diagnosis of cancer (PCa) in men at high genetic risk, using recently developed blood and urinary molecular biomarkers in combination with clinical information alongside multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: A total of 322 patients with a high genetic risk (familial or personal history of cancers or a predisposing germline variant) were included in this study. The primary outcome was the detection rates of PCa (positive biopsy) or clinically significant PCa (biopsy with International Society of Urological Pathology [ISUP] grade >1). Clinical parameters included age, body mass index, ancestry, and germline mutational status,\u00a0mpMRI, prostate-specific antigen density (PSAD), Prostate Health Index and urinary markers (Prostate Cancer Associated 3, SelectMdx\u2122 and T2:ERG score) were assessed. Sensitivity (Se) and specificity (Sp) for each marker at their recommended cut-off for clinical practice were calculated. Comparison between diagnoses accuracy of each procedure and scenario was computed using mutual information based and direct effect contribution using a supervised Bayesian network approach. RESULTS: A mpMRI Prostate Imaging-Reporting and Data System (PI-RADS) score \u22653 showed higher Se than mpMRI PI-RADS score \u22654 for detection of PCa (82% vs 61%) and for the detection of ISUP grade >1 lesions (96% vs 80%). mpMRI PI-RADS score \u22653 performed better than a PSA level of \u22653\u2009ng/mL (Se 96%, Sp 53% vs Se 91%, Sp 8%) for detection of clinically significant PCa. In case of negative mpMRI results, the supervised Bayesian network approach showed that urinary markers (with the same accuracy for all) and PSAD of \u22650.10\u2009ng/mL/mL were the most useful indicators of decision to biopsy. CONCLUSIONS: We found that screening men at high genetic risk of PCa must be based on mpMRI without pre-screening based on a PSA level of >3\u2009ng/mL, to avoid missing too many ISUP grade >1 tumours and to significantly reduce the number of unnecessary biopsies. However, urinary markers or a PSAD of \u22650.10\u2009ng/mL/mL when mpMRI was negative increased the detection of ISUP grade >1 cancers. We suggest that a baseline mpMRI be discussed for men at high genetic risk from the age of 40\u2009years.
\n \n\n \n \nPURPOSE: Improved early diagnosis and determination of aggressiveness of prostate cancer (PC) is important to select suitable treatment options and to decrease over-treatment. The conventional marker is total prostate specific antigen (PSA) levels in blood, but lacks specificity and ability to accurately discriminate indolent from aggressive disease. EXPERIMENTAL DESIGN: In this study, we sought to identify a serum biomarker signature associated with metastatic PC. We measured 157 analytes in 363 serum samples from healthy subjects, patients with non-metastatic PC and patients with metastatic PC, using a recombinant antibody microarray. RESULTS: A signature consisting of 69 proteins differentiating metastatic PC patients from healthy controls was identified. CONCLUSIONS AND CLINICAL RELEVANCE: The clinical value of this biomarker signature requires validation in larger independent patient cohorts before providing a new prospect for detection of metastatic PC.
\n \n\n \n \nBACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
\n \n\n \n \nProstate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature.
\n \n\n \n \nPatients not yet receiving medication provide insight to drug-na\u00efve early physiology of Parkinson's Disease (PD). Wearable sensors can measure changes in motor features before and after introduction of antiparkinsonian medication. We aimed to identify features of upper limb bradykinesia, postural stability, and gait that measurably progress in de novo PD patients prior to the start of medication, and determine whether these features remain sensitive to progression in the period after commencement of antiparkinsonian medication. Upper limb motion was measured using an inertial sensor worn on a finger, while postural stability and gait were recorded using an array of six wearable sensors. Patients were tested over nine visits at three monthly intervals. The timepoint of start of medication was noted. Three upper limb bradykinetic features (finger tapping speed, pronation supination speed, and pronation supination amplitude) and three gait features (gait speed, arm range of motion, duration of stance phase) were found to progress in unmedicated early-stage PD patients. In all features, progression was masked after the start of medication. Commencing antiparkinsonian medication is known to lead to masking of progression signals in clinical measures in de novo PD patients. In this study, we show that this effect is also observed with digital measures of bradykinetic and gait motor features.
\n \n\n \n \nCystic echinococcosis is a zoonosis caused by the larvae of Echinococcus granulosus . Pulmonary disease may be asymptomatic until the cyst ruptures or becomes secondarily infected. We report a case of pulmonary cystic echinococcosis presenting in the United Kingdom, with discussion on management: optimum antihelminthic agent, length of treatment and type of operative intervention. Treatment should be individualized to the clinical scenario.
\n \n\n \n \n