The effect of dutasteride on MRI-defined prostate cancer lesions: MAPPED (Magnetic resonance imaging in Primary Prostate Cancer after Exposure to Dutasteride) - a randomized placebo-controlled, double-blind clinical trial

PURPOSE: Dutasteride is licensed for symptomatic benign prostatic hyperplasia, and has been associated with a lower progression rate in low-risk prostate cancer. We have evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted Magnetic Resonance Imaging (MRI). MATERIALS AND METHODS: In this randomized, double-blind, placebo-controlled trial, men with biopsy-proven low-intermediate risk prostate cancer (up to Gleason 3+4 and PSA up to 15 ng/ml) who had an MR visible lesion of >/= 0.2ml on T2-weighted sequences were randomized to daily dutasteride 0.5mg or placebo for 6 months. Lesion volume was assessed at baseline, 3 and 6 months, with an image-guided biopsy to the lesion at study exit. The primary endpoint was percentage reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18). RESULTS: Forty-two men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55ml and 0.38ml respectively, and the average percentage reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65ml and 0.76ml respectively, and the average percentage reduction was -12%. The difference in percentage reductions between groups was 48% (95% CI 27.4-68.3%. p< 0.0001). The most common adverse event was deterioration in erectile function (25% in men randomized to dutasteride, 16% in men randomized to placebo). CONCLUSIONS: Dutasteride was associated with a significant reduction in prostate cancer volume on T2 weighted MRI images compared to placebo

Evaluating the Trade-offs Men with Localised Prostate Cancer Make Between the Risks and Benefits of Treatments: The COMPARE Study

PURPOSE: COMPARE (COMparing treatment options for ProstAte cancer) aimed to evaluate and quantify the trade-offs patients make between different aspects of active surveillance and definitive therapy. METHODS: A Discrete Choice Experiment (DCE) tool was used to elicit patients' preferences for different treatment characteristics in 34 urology departments. Patients with localised prostate cancer completed the DCE within one week of being diagnosed and before they made treatment decisions. The DCE was pre-tested (N=5) and piloted (n=106) with patients. Patients chose their preferred treatment profile based on six characteristics: treatment type (active surveillance, focal therapy, radical therapy), return to normal activities, erectile function, urinary function, not needing more cancer treatment and 10-15 year cancer-specific survival. Different tools were designed for low-intermediate (n=468) and high-risk (n=166) patients. An error-components conditional logit model was used to estimate preferences and trade-offs between treatment characteristics. RESULTS: Low-intermediate risk patients were willing to trade 6.99% absolute decrease in survival to have active surveillance over definitive therapy. They were willing to trade 0.75%, 0.46% and 0.19% absolute decrease in survival for a one-month reduction in time-to-return to normal activities, and 1% absolute improvements in urinary and sexual function, respectively. High-risk patients were willing to trade 3.10%, 1.04% and 0.41% absolute decrease in survival for a one-month reduction in time-to-return to normal activities and 1% absolute improvements in urinary and sexual function, respectively. CONCLUSIONS: Patients with low-intermediate risk prostate cancer preferred active surveillance to definitive therapy. Patients of all risks were willing to trade-off cancer-specific survival for improved quality-of-life.Registration:clinicaltrials.gov Registration Identifier NCT01177865Funding:Medical Research Council (UK) (grant reference: G1002509)

Haloperidol differentially modulates prepulse inhibition and p50 suppression in healthy humans stratified for low and high gating levels

Schizophrenia patients exhibit deficits in sensory gating as indexed by reduced prepulse inhibition (PPI) and P50 suppression, which have been linked to psychotic symptom formation and cognitive deficits. Although recent evidence suggests that atypical antipsychotics might be superior over typical antipsychotics in reversing PPI and P50 suppression deficits not only in schizophrenia patients, but also in healthy volunteers exhibiting low levels of PPI, the impact of typical antipsychotics on these gating measures is less clear. To explore the impact of the dopamine D2-like receptor system on gating and cognition, the acute effects of haloperidol on PPI, P50 suppression, and cognition were assessed in 26 healthy male volunteers split into subgroups having low vs high PPI or P50 suppression levels using a placebo-controlled within-subject design. Haloperidol failed to increase PPI in subjects exhibiting low levels of PPI, but attenuated PPI in those subjects with high sensorimotor gating levels. Furthermore, haloperidol increased P50 suppression in subjects exhibiting low P50 gating and disrupted P50 suppression in individuals expressing high P50 gating levels. Independently of drug condition, high PPI levels were associated with superior strategy formation and execution times in a subset of cognitive tests. Moreover, haloperidol impaired spatial working memory performance and planning ability. These findings suggest that dopamine D2-like receptors are critically involved in the modulation of P50 suppression in healthy volunteers, and to a lesser extent also in PPI among subjects expressing high sensorimotor gating levels. Furthermore, the results suggest a relation between sensorimotor gating and working memory performance

Prostate Radiofrequency Focal Ablation (ProRAFT) Trial: A Prospective Development Study Evaluating a Bipolar Radiofrequency Device to Treat Prostate Cancer

PURPOSE: To determine early efficacy of bipolar radiofrequency ablation with a coil design (bRFA) for focal ablation of clinically significant localised prostate cancer (sPCa)visible at mpMRI. MATERIAL AND METHODS: A prospective IDEAL phase 2 development study (NCT02294903) recruited treatment naive patients with a single focus of localised sPCa (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multi-parametric MRI. Intervention was a focal ablation with a bRFA system (Encage®, Trod Medical) encompassing the lesion and a predefined margin using nonrigid MRI-ultrasound fusion. Primary outcome was the proportion of men with absence of sPCa on biopsy at 6 months. Trial follow up comprised serum PSA, mpMRI at 1 week, 6 and 12 months post ablation. Validated patient reported outcome measures (PROMs) for urinary, erectile and bowel functions and adverse events monitoring system were used. Analyses were done on a per-protocol basis. RESULTS: 20 of 21 patients recruited received the intervention. Baseline characteristics were a median age of 66 years (IQR 63-69), pre-operative median PSA of 7.9 ng/ml (5.3-9.6), 18 (90%) had Gleason 7 with median maximum cancer of 7 mm (IQR 5-10) for a median 2.8 cc mpMRI lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores=6, IQR 5-8) showed absence of sPCa in 16/20 men (80%), concordant with mpMRI. There was a low profile of side effects at PROMs analysis and no serious adverse events. CONCLUSIONS: Focal therapy of sPCa associated with an MRI lesion using bRFA showed early efficacy to ablate cancer with low rates of genitourinary and rectal side-effects

The ReIMAGINE Multimodal Warehouse: Using Artificial Intelligence for Accurate Risk Stratification of Prostate Cancer

Introduction. Prostate cancer (PCa) is the most frequent cancer diagnosis in men worldwide. Our ability to identify those men whose cancer will decrease their lifespan and/or quality of life remains poor. The ReIMAGINE Consortium has been established to improve PCa diagnosis. / Materials and methods. MRI will likely become the future cornerstone of the risk-stratification process for men at risk of early prostate cancer. We will, for the first time, be able to combine the underlying molecular changes in PCa with the state-of-the-art imaging. ReIMAGINE Screening invites men for MRI and PSA evaluation. ReIMAGINE Risk includes men at risk of prostate cancer based on MRI, and includes biomarker testing. / Results. Baseline clinical information, genomics, blood, urine, fresh prostate tissue samples, digital pathology and radiomics data will be analysed. Data will be de-identified, stored with correlated mpMRI disease endotypes and linked with long term follow-up outcomes in an instance of the Philips Clinical Data Lake, consisting of cloud-based software. The ReIMAGINE platform includes application programming interfaces and a user interface that allows users to browse data, select cohorts, manage users and access rights, query data, and more. Connection to analytics tools such as Python allows statistical and stratification method pipelines to run profiling regression analyses. / Discussion. The ReIMAGINE Multimodal Warehouse comprises a unique data source for PCa research, to improve risk stratification for PCa and inform clinical practice. The de-identified dataset characterized by clinical, imaging, genomics and digital pathology PCa patient phenotypes will be a valuable resource for the scientific and medical community

Protocol for a feasibility randomised controlled trial of targeted oxygen therapy in mechanically ventilated critically ill patients

IntroductionOxygen is the most commonly administered drug to mechanically ventilated critically ill adults, yet little is known about the optimum oxygen saturation (SpO2) target for these patients; the current standard of care is an SpO2of 96% or above. Small pilot studies have demonstrated that permissive hypoxaemia (aiming for a lower SpO2than normal by using a lower fractional inspired oxygen concentration (FIO2)) can be achieved in the critically ill and appears to be safe. This approach has not been evaluated in a National Health Service setting. It is possible that permissive hypoxaemia may be beneficial to critically ill patients thus it requires robust evaluation.Methods and analysisTargeted OXygen therapY in Critical illness (TOXYC) is a feasibility randomised controlled trial (RCT) to evaluate whether recruiting patients to a study of permissive hypoxaemia is possible in the UK. It will also investigate biological mechanisms that may underlie the links between oxygenation and patient outcomes. Mechanically ventilated patients with respiratory failure will be recruited from critical care units at two sites and randomised (1:1 ratio) to an SpO2target of either 88%–92% or ≥96% while intubated with an endotracheal tube. Clinical teams can adjust FIO2and ventilator settings as they wish to achieve these targets. Clinical information will be collected before, during and after the intervention and blood samples taken to measure markers of systemic oxidative stress. The primary outcome of this study is feasibility, which will be assessed by recruitment rate, protocol adherence and withdrawal rates. Secondary outcomes will include a comparison of standard critical care outcome measures between the two intervention groups, and the measurement of biomarkers of systemic oxidative stress. The results will be used to calculate a sample size, likely number of sites and overall length of time required for a subsequent large multicentre RCT.Ethics and disseminationThis study was approved by the London - Harrow Research Ethics Committee on 2 November 2017 (REC Reference 17/LO/1334) and received HRA approval on 13 November 2017. Results from this study will be disseminated in peer-reviewed journals, at medical and scientific meetings, in the NIHR Journals Library and patient information websites.Trial registration numberNCT03287466; Pre-results.</jats:sec

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial

Objectives To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. Methods We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. Results A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs –0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). Conclusions Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

The ReIMAGINE prostate cancer risk study protocol: A prospective cohort study in men with a suspicion of prostate cancer who are referred onto an MRI-based diagnostic pathway with donation of tissue, blood and urine for biomarker analyses

INTRODUCTION: The ReIMAGINE Consortium was conceived to develop risk-stratification models that might incorporate the full range of novel prostate cancer (PCa) diagnostics (both commercial and academic). METHODS: ReIMAGINE Risk is an ethics approved (19/LO/1128) multicentre, prospective, observational cohort study which will recruit 1000 treatment-naive men undergoing a multi-parametric MRI (mpMRI) due to an elevated PSA (≤20ng/ml) or abnormal prostate examination who subsequently had a suspicious mpMRI (score≥3, stage ≤T3bN0M0). Primary outcomes include the detection of ≥Gleason 7 PCa at baseline and time to clinical progression, metastasis and death. Baseline blood, urine, and biopsy cores for fresh prostate tissue samples (2 targeted and 1 non-targeted) will be biobanked for future analysis. High-resolution scanning of pathology whole-slide imaging and MRI-DICOM images will be collected. Consortium partners will be granted access to data and biobanks to develop and validate biomarkers using correlation to mpMRI, biopsy-based disease status and long-term clinical outcomes. RESULTS: Recruitment began in September 2019(n = 533). A first site opened in September 2019 (n = 296), a second in November 2019 (n = 210) and a third in December 2020 (n = 27). Acceptance to the study has been 65% and a mean of 36.5ml(SD+/-10.0), 12.9ml(SD+/-3.7) and 2.8ml(SD+/-0.7) urine, plasma and serum donated for research, respectively. There are currently 4 academic and 15 commercial partners spanning imaging (~9 radiomics, artificial intelligence/machine learning), fluidic (~3 blood-based and ~2urine-based) and tissue-based (~1) biomarkers. CONCLUSION: The consortium will develop, or adjust, risk models for PCa, and provide a platform for evaluating the role of novel diagnostics in the era of pre-biopsy MRI and targeted biopsy