Ectodermal origins of the skin-brain axis: a novel model for the developing brain, inflammation, and neurodevelopmental conditions.

Early life development and its divergence is influenced by multiple genetic, neurological, and environmental factors. Atypical neurodevelopment, such as that observed in autism spectrum disorder, likely begins in early gestation during a period of entwined growth between the brain and epithelial barriers of the skin, gastrointestinal tract, and airway. This review coalesces epidemiological and neuroinflammatory evidence linking cutaneous atopic disease with both reduced skin barrier integrity and determinants of neurodivergence. We consider the shared developmental origin of epidermal and neural tissue with related genetic and environmental risk factors to evaluate potential pre- and postnatal modifiers of the skin-brain connection. Initial postnatal skin barrier integrity may provide a useful marker for both cortical integrity and meaningful subgroups of children showing early neurodevelopmental delays. It may also modify known risk factors to neurodevelopment, such as pathogen caused immune system activation. These novel insights of a skin-brain-neurodevelopment connection may advance detection and intervention opportunities.

The diagnosis and management of male genital lichen sclerosus: a retrospective review of 301 patients.

INTRODUCTION: Male genital lichen sclerosus (MGLSc) is an acquired, chronic, inflammatory skin disease that is associated with significant morbidity and squamous cell carcinoma of the penis (PSCC). However, some clinical, diagnostic and management controversies endure, including the relationship with penile intraepithelial neoplasia (PeIN). OBJECTIVES: To clarify clinical presentations, diagnostic approaches, histological findings, response to treatment and the relationship with PeIN. METHODS: Retrospective review of patients with a diagnosis of MGLSc who attended a specialist male genital dermatoses clinic. RESULTS: 301 patients were identified: 260 had isolated MGLSc and 41 both MGLSc and PeIN. Referrals were made from the local Urology and Andrology departments (128), primary care (89), GUM (54), other dermatology departments (28) and other specialties (2). In isolated MGLSc, 94.6% were diagnosed clinically with 93.5% accuracy (based on data from subsequent circumcisions). In combined MGLSc/PeIN, 85.4% were diagnosed following diagnostic biopsy and 14.6% retrospectively after circumcision. In isolated MGLSc, 50% were treated topically, and 50% required surgery. In MGLSc/PeIN, 78% required surgical interventions. In isolated MGLSc, 92.2% achieved resolution of symptoms, 3.5% were awaiting procedures, and 4.8% were receiving ongoing topical therapy. In MGLSc/PeIN, 90.2% achieved clearance, 2.4% were waiting surgery, and 7.3% were treated topically. Only 2.7% reported ongoing symptoms, all in patients treated surgically. None progressed to PSCC. DISCUSSION: MGLSc is generally a disease of the uncircumcised; the majority of cases of MGLSc are accurately diagnosed clinically; suspected PeIN or PSCC requires histological confirmation; circumcision histology can be non-specific; most men are either cured by topical treatment with ultrapotent corticosteroid (53.1%) or by circumcision (46.9%); surgical intervention is required in most cases of concomitant MGLSc and PeIN; the majority of patients with MGLSc alone or with MGLSc and PeIN remit with this approach; effective management appears to negate the risk of malignant transformation to PSCC.

Epinephrine syringe exchange events in a paediatric cardiovascular ICU: analysing the storm.

Introduction Haemodynamically unstable patients can experience potentially hazardous changes in vital signs related to the exchange of depleted syringes of epinephrine to full syringes. The purpose was to determine the measured effects of epinephrine syringe exchanges on the magnitude, duration, and frequency of haemodynamic disturbances in the hour after an exchange event (study) relative to the hours before (control). Materials and methods Beat-to-beat vital signs recorded every 2 seconds from bedside monitors for patients admitted to the paediatric cardiovascular ICU of Texas Children's Hospital were collected between 1 January, 2013 and 30 June, 2015. Epinephrine syringe exchanges without dose/flow change were obtained from electronic records. Time, magnitude, and duration of changes in systolic blood pressure and heart rate were characterised using Matlab. Significant haemodynamic events were identified and compared with control data. RESULTS: In all, 1042 syringe exchange events were found and 850 (81.6%) had uncorrupted data for analysis. A total of 744 (87.5%) exchanges had at least 1 associated haemodynamic perturbation including 2958 systolic blood pressure and 1747 heart-rate changes. Heart-rate perturbations occurred 37% before exchange and 63% after exchange, and 37% of systolic blood pressure perturbations happened before syringe exchange, whereas 63% occurred after syringe exchange with significant differences found in systolic blood pressure frequency (p<0.001), duration (p<0.001), and amplitude (p<0.001) compared with control data. CONCLUSIONS: This novel data collection and signal processing analysis showed a significant increase in frequency, duration, and magnitude of systolic blood pressure perturbations surrounding epinephrine syringe exchange events.

The Prevalence of Clinically Significant Prostate Cancer According to Commonly Used Histological Thresholds in Men Undergoing Template Prostate Mapping Biopsies.

PURPOSE: Transrectal prostate biopsies are inaccurate and, thus, the prevalence of clinically significant prostate cancer in men undergoing biopsy is unknown. We determined the ability of different histological thresholds to denote clinically significant cancer in men undergoing a more accurate biopsy, that of transperineal template prostate mapping. MATERIALS AND METHODS: In this multicenter, cross-sectional cohort of men who underwent template prostate mapping biopsies between May 2006 and January 2012, 4 different thresholds of significance combining tumor grade and burden were used to measure the consequent variation with respect to the prevalence of clinically significant disease. RESULTS: Of 1,203 men 17% (199) had no previous biopsy, 38% (455) had a prior negative transrectal ultrasound biopsy, 24% (289) were on active surveillance and 21% (260) were seeking risk stratification. Mean patient age was 63.5 years (SD 7.6) and median prostate specific antigen was 7.4 ng/ml (IQR 5.3-10.5). Overall 35% of the patients (424) had no cancer detected. The prevalence of clinically significant cancer varied between 14% and 83% according to the histological threshold used, in particular between 30% and 51% among men who had no previous biopsy, between 14% and 27% among men who had a prior negative biopsy, between 36% and 74% among men on active surveillance, and between 47% and 83% among men seeking risk stratification. CONCLUSIONS: According to template prostate mapping biopsy between 1 in 2 and 1 in 3 men have prostate cancer that is histologically defined as clinically significant. This suggests that the commonly used thresholds may be set too low.

Eczema and related atopic diseases are associated with increased symptom severity in children with autism spectrum disorder.

Growing evidence indicates that autism spectrum disorder (ASD) has diverse genetic, neurological, and environmental factors that contribute to its neurodevelopmental course. Interestingly, childhood ASD is often accompanied by skin disorders, such as eczema, and other related atopic manifestations. This link may be due to the shared embryonic origin of epidermal and neural tissue. Accordingly, we consider the potential influence of a skin-brain co-vulnerability and ensuing atopic cascade on ASD symptomatology by investigating whether atopic disorders (asthma, allergies, eczema and hay fever) are associated with increased symptom severity in children with ASD. Overall, 45 atopic and 93 non-atopic children with ASD were assessed using the ADOS-2 on scores of total, social and non-social symptoms. Differences in ASD symptom severity were further evaluated as a function of atopic disease type. Atopic children displayed greater symptom severity overall and in the social domain, relative to non-atopic participants. Atopic children were 2.4 times more likely to experience overall impairments classified within the ADOS-2 highest-level severity bracket and 2.7 times more likely to show social difficulties in this range. Moreover, those reporting comorbid eczema displayed increased symptom severity relative to both their non-atopic peers and those reporting asthma and allergies. Taken together, findings indicate that atopic disorders, and particularly comorbid eczema, are associated with increases in ASD symptom severity. Findings provide grounds for future investigations into this link between childhood skin diseases and ASD symptom severity to advance our understanding of neurodevelopment and to develop targeted assessment and intervention opportunities.

The management of penile intraepithelial neoplasia (PeIN): clinical and histological features and treatment of 345 patients and a review of the literature.

INTRODUCTION: Penile intraepithelial neoplasia (PeIN) is a histological term for precancerous penile lesions. PeIN is important due to the high morbidity and mortality associated with progression to penile squamous cell carcinoma (PSSC). But PeIN is rare, contributing to a limited evidence-base for the relative efficacy of available treatment options. OBJECTIVES & METHODS: To consolidate and expand knowledge about PeIN and its treatment, we describe the clinical and histological characteristics, treatments and outcomes of 345 patients with PeIN, managed by our multidisciplinary team. Our results are compared and contrasted with those in the literature, following comprehensive review. RESULTS: 8.7% of patients had concomitant, invasive PSCC, whilst 91.3% demonstrated PeIN alone. 84% had undifferentiated PeIN, and 10.7% differentiated PeIN (5.2%, not specified). Clinical or histological evidence of HPV alone was present in 58%; features of lichen sclerosus alone in 12%; features of both in 29.4%. Only 14.4% of patients could be treated solely with topical agents or cryotherapy, whereas the remaining 85.6% underwent some form of surgical intervention, circumcision being the mainstay. Just 2.6% progressed to PSCC. CONCLUSIONS: Clinical management of PeIN can be rationally optimized with excellent outcomes. Circumcision is important. Topical treatments alone are disappointing.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

Structural Characterization of the Reaction and Substrate Specificity Mechanisms of Pathogenic Fungal Acetyl-CoA Synthetases.

Acetyl CoA synthetases (ACSs) are Acyl-CoA/NRPS/Luciferase (ANL) superfamily enzymes that couple acetate with CoA to generate acetyl CoA, a key component of central carbon metabolism in eukaryotes and prokaryotes. Normal mammalian cells are not dependent on ACSs, while tumor cells, fungi, and parasites rely on acetate as a precursor for acetyl CoA. Consequently, ACSs have emerged as a potential drug target. As part of a program to develop antifungal ACS inhibitors, we characterized fungal ACSs from five diverse human fungal pathogens using biochemical and structural studies. ACSs catalyze a two-step reaction involving adenylation of acetate followed by thioesterification with CoA. Our structural studies captured each step of these two half-reactions including the acetyl-adenylate intermediate of the first half-reaction in both the adenylation conformation and the thioesterification conformation and thus provide a detailed picture of the reaction mechanism. We also used a systematic series of increasingly larger alkyl adenosine esters as chemical probes to characterize the structural basis of the exquisite ACS specificity for acetate over larger carboxylic acid substrates. Consistent with previous biochemical and genetic data for other enzymes, structures of fungal ACSs with these probes bound show that a key tryptophan residue limits the size of the alkyl binding site and forces larger alkyl chains to adopt high energy conformers, disfavoring their efficient binding. Together, our analysis provides highly detailed structural models for both the reaction mechanism and substrate specificity that should be useful in designing selective inhibitors of eukaryotic ACSs as potential anticancer, antifungal, and antiparasitic drugs.

Isolated groin recurrence in vulval squamous cell cancer (VSCC). The importance of node count.

OBJECTIVE: To determine whether there is a node count which can define an adequate inguinofemoral lymphadenectomy (IFL) in primary VSCC. METHODS: A retrospective and prospective review of patients with node negative VSCC who had a full staging IFL. Detection of isolated groin recurrences (IGR) would allow groins with higher risk of groin recurrence to be identified. RESULTS: The median node count of 228 IFLs in 139 patients was eight (0-24). There were six IGR (4.3%). Increased rate of IGR was present in patients with increased age, tumour diameter and depth of invasion, lymphovascular space invasion, unilateral IFL, and moderate/poor tumour grade. In the 138 groins with node counts of eight or greater there were no IGRs compared to six in the patients with either undissected groins or groin node counts less than eight (p = 0.030) Interval to IGR was significantly shorter than other sites of recurrence. Both disease-specific and overall survival were significantly reduced in IGR. CONCLUSIONS: An inadequate IFL is a nodal count of less than eight per groin; both these groins and undissected groins are at increased risk of IGR and should have close surveillance.

Mucinous ovarian cancer.

Mucinous epithelial ovarian cancer (mEOC) accounts for approximately 10% of EOCs. Patients presenting with early-stage disease have an excellent prognosis, however, those with advanced disease have a poor outcome with relative resistance to standard ovarian cancer chemotherapy. Molecular and genetic studies demonstrate differences between mucinous and serous EOC supporting the concept that these tumors develop along separate pathways. Together with the observed differences in clinical behavior and outcome for mEOC, there is a need to develop specific therapeutic strategies for this histologic subtype. The relative rarity of advanced mEOC has resulted in few patients enrolled in major ovarian cancer trials. The results of such trials may not necessarily reflect those specific to mEOC. Separate trials testing alternative chemotherapeutics are required. Metastatic mucinous tumors from other sites such as the gastrointestinal tract may present with ovarian involvement. For all mucinous tumors of the ovary, establishing primary as opposed to metastatic cancers is important. Clinical presentation, tumor markers, histologic, and immunohistochemical features are helpful in distinguishing most cases.

TOR complex 2-regulated protein kinase Ypk1 controls sterol distribution by inhibiting StARkin domain-containing proteins located at plasma membrane-endoplasmic reticulum contact sites.

In our proteome-wide screen, Ysp2 (also known as Lam2/Ltc4) was identified as a likely physiologically relevant target of the TOR complex 2 (TORC2)-dependent protein kinase Ypk1 in the yeast Saccharomyces cerevisiae. Ysp2 was subsequently shown to be one of a new family of sterol-binding proteins located at plasma membrane (PM)-endoplasmic reticulum (ER) contact sites. Here we document that Ysp2 and its paralogue Lam4/Ltc3 are authentic Ypk1 substrates in vivo and show using genetic and biochemical criteria that Ypk1-mediated phosphorylation inhibits the ability of these proteins to promote retrograde transport of sterols from the PM to the ER. Furthermore, we provide evidence that a change in PM sterol homeostasis promotes cell survival under membrane-perturbing conditions known to activate TORC2-Ypk1 signaling. These observations define the underlying molecular basis of a new regulatory mechanism for cellular response to plasma membrane stress.

Magnetic resonance imaging targeted transperineal prostate biopsy: a local anaesthetic approach.

BACKGROUND: Despite high rates of disease misclassification and sepsis, the use of transrectal biopsy remains commonplace. Transperineal mapping biopsies mitigate these problems but carry increased cost and patient burden. Local anaesthetic, multiparametric magnetic resonance imaging (MRI)-targeted transperineal biopsy may offer an alternative. Here, we aim to determine the feasibility, tolerability and detection rates of clinically significant prostate cancer using a local anaesthetic, transperineal, MRI-targeted biopsy technique. METHODS: Tertiary referral centre in which 181 consecutive men underwent local anaesthetic, transperineal MRI-targeted prostate biopsy (September 2014 to January 2016). A standardized local anaesthetic technique was used to obtain targeted biopsies using visual estimation with the number of targeted cores determined by each of a number of users. We assessed adverse events, patient visual analogue pain scores and detection rates of clinically significant cancer (defined by University College London (UCL) definitions one and two and separately by the presence of dominant and non-dominant Gleason pattern 4). We secondarily assessed detection of any cancer, rates of detection by MRI (Likert) score and by presenting PSA. Differences were assessed using Chi-squared tests (P<0.05). RESULTS: One hundred eighty-one men with 243 lesions were included. There were no episodes of sepsis or re-admissions and one procedure was abandoned owing to patient discomfort. Twenty-three out of 25 (92%) men would recommend the procedure to another. Median visual analogue pain score was 1.0 (interquartile range: 0.0-2.4). A total 104/181 (57%) had UCL definition 1 disease (Gleason ⩾4+3 and/or maximum cancer length ⩾6 mm) and 129/181 (71%) had UCL definition 2 cancer (Gleason ⩾3+4 and/or maximum cancer length ⩾4 mm). Fifty-four out of 181 (30%) and 124/181 (69%) had dominant and non-dominant pattern 4 disease or greater (irrespective of cancer length). Any cancer was detected in 142/181 (78%). Significant disease was more likely in higher MRI-scoring lesions and in men with PSAs ⩾10 ng ml-1. CONCLUSIONS: This approach to prostate biopsy is feasible, tolerable and can be performed in ambulatory settings.

Selective immunosuppression in mice of natural killer cell activity by ochratoxin A.

Ochratoxin A, a naturally occurring mycotoxin, has recently been shown to cause renal and hepatic carcinomas in mice. In the present studies, the effects of ochratoxin A on immune mechanisms associated with tumor resistance were examined in mice using dose levels similar to those that cause neoplasia. Ochratoxin A was shown to specifically inhibit natural killer (NK) cell activity and increase the growth of transplantable tumor cells without altering T-cell- or macrophage-mediated antitumor activity. In contrast, ochratoxin B, a much less toxic ochratoxin, did not influence immune function. Polyinosinic:polycytidylic induced interferon was markedly reduced in mice following exposure to ochratoxin A although total serum protein levels were slightly increased. Injection of polyinosinic:polycytidylic enhanced NK activity in the presence of ochratoxin A, although the level of enhancement was slightly lower than that produced by the agent in the absence of ochratoxin A. Thus, ochratoxin appears to suppress NK cell activity by inhibiting production of basal interferon. Additionally, these findings suggest a possible role for altered NK cell function in the development of mycotoxin-induced carcinogenesis.

The concordance between the volume hotspot and the grade hotspot: a 3-D reconstructive model using the pathology outputs from the PROMIS trial.

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.

Transperineal Magnetic Resonance Imaging-targeted Biopsy versus Transperineal Template Prostate Mapping Biopsy in the Detection of Localised Radio-recurrent Prostate Cancer.

AIMS: Multi-parametric magnetic resonance imaging (mpMRI) may identify radio-recurrent intra-prostatic cancer accurately. We aimed to compare visually directed MRI-targeted biopsies (MRI-TB) to an accurate reference standard - transperineal prostate mapping (TPM) biopsies with 5 mm sampling - in the detection of clinically significant cancer in men with biochemical failure after radiotherapy. MATERIALS AND METHODS: A retrospective registry analysis between 2006 and 2014 identified 77 men who had undergone mpMRI followed by MRI-TB and TPM. Clinical significance was set at two definitions of disease. Definition 1 was Gleason ≥ 4+3 and/or maximum cancer core length ≥ 6 mm. Definition 2 was Gleason ≥ 3+4 and/or maximum cancer core length ≥ 4 mm. RESULTS: Of the 77 patients included, the mean age was 70 years (range 61-82; standard deviation 5.03). The median prostate-specific antigen (PSA) at the time of external beam radiotherapy (EBRT) was 14 ng/ml (interquartile range 7.83-32.50). The most frequent EBRT dose given was 74 Gy over 37 fractions. Eight patients had iodine-seed implant brachytherapy or high dose rate brachytherapy. Neoadjuvant/adjuvant hormonal therapy use was reported in 38. The time from EBRT to biochemical recurrence was a median of 60 months (interquartile range 36.75-85.00). The median PSA at the time of mpMRI was 4.68 ng/ml (interquartile range 2.68-7.60). The median time between mpMRI and biopsy was 2.76 months (interquartile range 1.58-4.34). In total, 2392 TPM and 381 MRI-TB cores were taken with 18% and 50% cancer detection, respectively. Detection rates of definition 1 clinically significant cancer were 52/77 (68%) versus 55/77 (71%) for MRI-TB and TPM, respectively. MRI-TB was more efficient requiring 1 core versus 2.8 cores to detect definition 2 cancer. CONCLUSION: MRI-TB seems to have encouraging detection rates for clinically significant cancer with fewer cores compared with TPM, although TPM had higher detection rates for smaller lower grade lesions.

Aggressive Angiomyxoma of the Bladder Neck Requiring Local Excision and Mitrofanoff Formation.

Aggressive angiomyxoma is a rare mesenchymal tumour predominantly affecting the female pelvis and perineum but has also been described in males. This tumour can often present a diagnostic challenge and has a propensity for local recurrence after surgical excision. We present an unusual case of aggressive angiomyxoma arising from the bladder of a female patient which required local excision and Mitrofanoff formation.

The FORECAST study - Focal recurrent assessment and salvage treatment for radiorecurrent prostate cancer.

BACKGROUND: One-third of men may experience biochemical failure by 8years following radical radiotherapy for localised prostate cancer. Over 90% of men are started on androgen deprivation therapy (ADT) which is non-curative and confers systemic side-effects. Focal salvage therapy (FST) limits collateral tissue damage and may improve therapeutic ratios. In order to deliver FST, distant disease must be ruled-out and intra-prostatic disease must be accurately detected, localised and characterised. AIM: FORECAST - Focal Recurrent Assessment and Salvage Treatment - is a study designed to evaluate a novel imaging-based diagnostic and therapeutic complex intervention pathway for men who fail radiotherapy. METHODS: Men with biochemical failure following radical prostate radiotherapy, prior to salvage therapy will be recruited. They will undergo whole-body multi-parametric MRI (WB-MRI), choline PET/CT, bone-scan and pelvic-mpMRI and then MRI transperineal-targeted biopsies (MRI-TB) and Transperineal Template Prostate Mapping Biopsy (TPM). Those suitable for FST will undergo either high intensity focused ultrasound (HIFU) or cryotherapy. RESULTS: Primary outcome measures: a) the accuracy of WB-MRI to detect distant metastatic disease; b) accuracy of prostate mpMRI in local detection of radiorecurrent prostate cancer; c) detection accuracy of MRI-TB; and d) rate of urinary incontinence following FST. CONCLUSION: Focal salvage therapy may confer lower rates of morbidity whilst retaining disease control. In order to deliver FST, intra- and extra-prostatic disease must be detected early and localised accurately. Novel diagnostic techniques including WB-MRI and MRI-TB may improve the detection of distant and local disease whilst reducing healthcare burdens compared with current imaging and biopsy strategies.