Publications by authors named "Alex Freeman"

175 Publications

Clinical Impact of the Predict Prostate Risk Communication Tool in Men Newly Diagnosed with Nonmetastatic Prostate Cancer: A Multicentre Randomised Controlled Trial.

Eur Urol 2021 Sep 4. Epub 2021 Sep 4.

Department of Surgery, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Background: Predict Prostate is a freely available online personalised risk communication tool for men with nonmetastatic prostate cancer. Its accuracy has been assessed in multiple validation studies, but its clinical impact among patients has not hitherto been assessed.

Objective: To assess the impact of the tool on patient decision-making and disease perception.

Design, Setting, And Participants: A multicentre randomised controlled trial was performed across eight UK centres among newly diagnosed men considering either active surveillance or radical treatment. A total of 145 patients were included between 2018 and 2020, with median age 67 yr (interquartile range [IQR] 61-72) and prostate-specific antigen 6.8 ng/ml (IQR 5.1-8.8).

Intervention: Participants were randomised to either standard of care (SOC) information or SOC and a structured presentation of the Predict Prostate tool.

Outcome Measurements And Statistical Analysis: Validated questionnaires were completed by assessing the impact of the tool on decisional conflict, uncertainty, anxiety, and perception of survival.

Results And Limitations: Mean Decisional Conflict Scale scores were 26% lower in the Predict Prostate group (mean = 16.1) than in the SOC group (mean = 21.7; p = 0.027). Scores on the "support", "uncertainty", and "value clarity" subscales all favoured Predict Prostate (all p < 0.05). There was no significant difference in anxiety scores or final treatment selection between the two groups. Patient perception of 15-yr prostate cancer-specific mortality (PCSM) and overall survival benefit from radical treatment were considerably lower and more accurate among men in the Predict Prostate group (p < 0.001). In total, 57% of men reported that the Predict Prostate estimates for PCSM were lower than expected, and 36% reported being less likely to select radical treatment. Over 90% of patients in the intervention group found it useful and 94% would recommend it to others.

Conclusions: Predict Prostate reduces decisional conflict and uncertainty, and shifts patient perception around prognosis to be more realistic. This randomised trial demonstrates that Predict Prostate can directly inform the complex decision-making process in prostate cancer and is felt to be useful by patients. Future larger trials are warranted to test its impact upon final treatment decisions.

Patient Summary: In this national study, we assessed the impact of an individualised risk communication tool, called Predict Prostate, on patient decision-making after a diagnosis of localised prostate cancer. Men were randomly assigned to two groups, which received either standard counselling and information, or this in addition to a structured presentation of the Predict Prostate tool. Men who saw the tool were less conflicted and uncertain in their decision-making, and recommended the tool highly. Those who saw the tool had more realistic perception about their long-term survival and the potential impact of treatment upon this.

Take Home Message: The use of an individualised risk communication tool, such as Predict Prostate, reduces patient decisional conflict and uncertainty when deciding about treatment for nonmetastatic prostate cancer. The tool leads to more realistic perceptions about survival outcomes and prognosis.
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http://dx.doi.org/10.1016/j.eururo.2021.08.001DOI Listing
September 2021

Which Prostate Cancers are Undetected by Multiparametric Magnetic Resonance Imaging in Men with Previous Prostate Biopsy? An Analysis from the PICTURE Study.

Eur Urol Open Sci 2021 Aug 15;30:16-24. Epub 2021 Jun 15.

Department of Urology, Imperial College Healthcare NHS Trust, London, UK.

Background: Multiparametric magnetic resonance imaging (mpMRI) has improved risk stratification for suspected prostate cancer in patients following prior biopsy. However, not all significant cancers are detected by mpMRI. The PICTURE study provides the ideal opportunity to investigate cancer undetected by mpMRI owing to the use of 5 mm transperineal template mapping (TTPM) biopsy.

Objective: To summarise attributes of cancers systematically undetected by mpMRI in patients with prior biopsy.

Design Setting And Participants: PICTURE was a paired-cohort confirmatory study in which men requiring repeat biopsy underwent mpMRI followed by TTPM biopsy.

Outcome Measurements And Statistical Analysis: Attributes were compared between cancers detected and undetected by mpMRI at the patient level. Four predefined histopathological thresholds were used as the target condition for TTPM biopsy. Application of prostate-specific antigen density (PSAD) was explored.

Results And Limitations: When nonsuspicious mpMRI was defined as Likert score 1-2, 2.9% of patients (3/103; 95% confidence interval [CI] 0.6-8.3%) with definition 1 disease (Gleason ≥ 4 + 3 of any length or maximum cancer core length [MCCL] ≥ 6 mm of any grade) had their cancer not detected by mpMRI. This proportion was 6.5% (11/168; 95% CI 3.3-11%) for definition 2 disease (Gleason ≥ 3 + 4 of any length or MCCL ≥ 4 mm of any grade), 4.8% (7/146; 95% CI 2.0-9.6%) for any amount of Gleason ≥ 3 + 4 cancer, and 9.3% (20/215; 95% CI 5.8-14%) for any cancer. Definition 1 cancers undetected by mpMRI had lower overall Gleason score ( = 0.02) and maximum Gleason score ( = 0.01) compared to cancers detected by mpMRI. Prostate cancers undetected by mpMRI had shorter MCCL than cancers detected by mpMRI for every cancer threshold: definition 1, 6 versus 8 mm ( = 0.02); definition 2, 5 versus 6 mm ( = 0.04); any Gleason ≥ 3 + 4, 5 versus 6 mm ( = 0.03); and any cancer, 3 versus 5 mm ( = 0.0009). A theoretical PSAD threshold of 0.15 ng/ml/ml reduced the proportion of patients with undetected disease on nonsuspicious mpMRI to 0% (0/105; 95% CI 0-3.5%) for definition 1, 0.58% (1/171; 95% CI 0.01-3.2%) for definition 2, and 0% (0/146) for any Gleason ≥ 3 + 4.

Conclusions: Few significant cancers are undetected by mpMRI in patients requiring repeat prostate biopsy. Undetected tumours are of lower overall and maximum Gleason grade and shorter cancer length compared to cancers detected by mpMRI.

Patient Summary: In patients with a previous prostate biopsy, magnetic resonance imaging (MRI) overlooks few prostate cancers, and these tend to be smaller and less aggressive than cancer that is detected.
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http://dx.doi.org/10.1016/j.euros.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277581PMC
August 2021

Inter-reader agreement of the PI-QUAL score for prostate MRI quality in the NeuroSAFE PROOF trial.

Eur Radiol 2021 Jul 29. Epub 2021 Jul 29.

Department of Radiology, University College London Hospital NHS Foundation Trust, London, UK.

Objectives: The Prostate Imaging Quality (PI-QUAL) score assesses the quality of multiparametric MRI (mpMRI). A score of 1 means all sequences are below the minimum standard of diagnostic quality, 3 implies that the scan is of sufficient diagnostic quality, and 5 means that all three sequences are of optimal diagnostic quality. We investigated the inter-reader reproducibility of the PI-QUAL score in patients enrolled in the NeuroSAFE PROOF trial.

Methods: We analysed the scans of 103 patients on different MR systems and vendors from 12 different hospitals. Two dedicated radiologists highly experienced in prostate mpMRI independently assessed the PI-QUAL score for each scan. Interobserver agreement was assessed using Cohen's kappa with standard quadratic weighting (κw) and percent agreement.

Results: The agreement for each single PI-QUAL score was strong (κw = 0.85 and percent agreement = 84%). A similar agreement (κw = 0.82 and percent agreement = 84%) was observed when the scans were clustered into three groups (PI-QUAL 1-2 vs PI-QUAL 3 vs PI-QUAL 4-5). The agreement in terms of diagnostic quality for each single sequence was highest for T2-weighted imaging (92/103 scans; 89%), followed by dynamic contrast-enhanced sequences (91/103; 88%) and diffusion-weighted imaging (80/103; 78%).

Conclusion: We observed strong reproducibility in the assessment of PI-QUAL between two radiologists with high expertise in prostate mpMRI. At present, PI-QUAL offers clinicians the only available tool for evaluating and reporting the quality of prostate mpMRI in a systematic manner but further refinements of this scoring system are warranted.

Key Points: • Inter-reader agreement for each single Prostate Imaging Quality (PI-QUAL) score (i.e., PI-QUAL 1 to PI-QUAL 5) was strong, with weighted kappa = 0.85 (95% confidence intervals: 0.51 - 1) and percent agreement = 84%. • Interobserver agreement was strong when the scans were clustered into three groups according to the ability (or not) to rule in and to rule out clinically significant prostate cancer (i.e., PI-QUAL 1-2 vs PI-QUAL 3 vs PI-QUAL 4-5), with weighted kappa = 0.82 (95% confidence intervals: 0.68 - 0.96) and percent agreement = 84%. • T2-weighted acquisitions were the most compliant with the Prostate Imaging Reporting and Data System (PI-RADS) v. 2.0 technical recommendations and were the sequences of highest diagnostic quality for both readers in 95/103 (92%) scans, followed by dynamic contrast enhanced acquisition with 81/103 (79%) scans and lastly by diffusion-weighted imaging with 79/103 (77%) scans.
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http://dx.doi.org/10.1007/s00330-021-08169-1DOI Listing
July 2021

Cellular senescence as a possible link between prostate diseases of the ageing male.

Nat Rev Urol 2021 Jul 22. Epub 2021 Jul 22.

UCL Division of Surgery & Interventional Science, University College London, London, UK.

Senescent cells accumulate with age in all tissues. Although senescent cells undergo cell-cycle arrest, these cells remain metabolically active and their secretome - known as the senescence-associated secretory phenotype - is responsible for a systemic pro-inflammatory state, which contributes to an inflammatory microenvironment. Senescent cells can be found in the ageing prostate and the senescence-associated secretory phenotype and can be linked to BPH and prostate cancer. Indeed, a number of signalling pathways provide biological plausibility for the role of senescence in both BPH and prostate cancer, although proving causality is difficult. The theory of senescence as a mechanism for prostate disease has a number of clinical implications and could offer opportunities for targeting in the future.
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http://dx.doi.org/10.1038/s41585-021-00496-8DOI Listing
July 2021

Tumour growth rates of prostate cancer during active surveillance: is there a difference between MRI-visible low and intermediate-risk disease?

Br J Radiol 2021 Jul 8:20210321. Epub 2021 Jul 8.

Department of Radiology, University College London Hospital NHS Foundation Trust, London, UK.

Objectives: The aim of this study was to evaluate the changes in lesion volume on serial multiparametric magnetic resonance (mpMRI) during active surveillance for prostate cancer.

Methods: A total of 160 patients with a targeted biopsy-confirmed visible lesion on mpMRI, stratified by low- and intermediate-risk disease (Gleason Grade Group 1 vs Gleason Grade Group 2), were analysed. The % change per year was calculated using the formula: .

Results: There was no significant difference in the annual median percentage change between Gleason Grade Group 1 (18%) and Gleason Grade Group 2 (23%) disease (p = 0.16), and between ≤ 10% (23%) and > 10% (22%) of Gleason pattern 4 (p = 0.78).Assuming a spherical lesion, these changes corresponded to annual increases in mean tumour diameter of 6% and 7% for Gleason Grade Group 1 and Gleason Grade Group 2 respectively, which may be less than the interscan variability of serial mpMRI.

Conclusion: In an active surveillance cohort, we did not see a significant difference in the annual growth rate of Gleason Grade Group 1 and 2 tumours.

Advances In Knowledge: In patients on active surveillance, the measured growth rates for visible tumours in Gleason Grade Groups 1 and 2 were similar. The annual growth rate was small in most cases and this may have implications for the MRI follow-up interval in active surveillance.
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http://dx.doi.org/10.1259/bjr.20210321DOI Listing
July 2021

Multidisciplinary Approach for the Management of Penoscrotal Extramammary Paget's disease -An eUROGEN study.

Urol Oncol 2021 08 27;39(8):501.e1-501.e10. Epub 2021 Jun 27.

Male Genital Cancer Centre, Institute of Andrology, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK; Male Genital Cancer Centre, Institute of Andrology, NIHR Biomedical Research Centre UCLH, 235 Euston Road, London, NW1 2BU, UK; Division of Surgery and Interventional Science, UCL, University College London Hospital, 235 Euston Road, London, NW1 2BU, UK. Electronic address:

Introduction: We reviewed the medical and surgical management and long-term outcomes for patients diagnosed with penoscrotal extramammary Pagets disease (EMPD) within an eUROGEN centre.

Patients And Methods: Retrospective review of cases from an institutional database with biopsy proven penoscrotal EMPD.

Results: A total of 10 patients were identified with penoscrotal EMPD over a 10-year period. Two patients had a previous history of gastrointestinal and urogenital cancers (20%) and no synchronous or metachronous cancers were identified. Eight patients with non-invasive EMPD (80%) underwent wide local excision of the affected skin, with at least a 5mm macroscopic resection margin and in selected cases simultaneous multiple mapping biopsies around the lesion were performed. Residual disease was present at the margins in seven patients (87.5%), of which three required further surgical excision or adjuvant topical immunotherapy (42.8%). Recurrence after complete excision was 12.5% and was successfully treated with topical imiquimod immunotherapy and CO laser therapy. Two patients (20%) had invasive carcinoma and metastatic disease at diagnosis.

Conclusion: Reported recurrence rates of non-invasive penoscrotal EMPD are high and residual disease is present in most cases requiring either close clinical surveillance or adjuvant treatment. We propose an algorithm in the management of this rare disease.
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http://dx.doi.org/10.1016/j.urolonc.2021.05.018DOI Listing
August 2021

Mapping Contemporary Biopsy Zones to Traditional Prostatic Anatomy: The Key to Understanding Relationships Between Prostate Cancer Topography, Magnetic Resonance Imaging Conspicuity, and Clinical Risk.

Eur Urol 2021 Aug 28;80(2):263-265. Epub 2021 May 28.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/j.eururo.2021.05.017DOI Listing
August 2021

Clinical outcomes associated with prostate cancer conspicuity on biparametric and multiparametric MRI: a protocol for a systematic review and meta-analysis of biochemical recurrence following radical prostatectomy.

BMJ Open 2021 05 5;11(5):e047664. Epub 2021 May 5.

UCL Division of Surgery & Interventional Science, University College London, London, UK

Introduction: There is an increasing body of evidence to suggest that visibility of prostate cancer on magnetic resonance (MRI) may be related to likelihood of adverse pathological outcomes. Biochemical recurrence (BCR) after radical prostatectomy remains a significant clinical challenge and a means of predicting likelihood of this prior to surgery could inform treatment choice. It appears that MRI could be a potential candidate strategy for BCR prediction, and as such, there is a need to review extant literature on the prognostic capability of MRI. Here, we describe a protocol for a systematic review and meta-analysis of the utility of biparametric MRI (bpMRI) and multiparametric MRI (mpMRI) in predicting BCR following radical prostatectomy for prostate cancer treatment.

Methods And Analysis: PubMed, MEDLINE, Embase and Cochrane databases will be searched and screening will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In order to meet the inclusion criteria, papers must be English-language articles involving patients who have had bpMRI or mpMRI for suspected prostate cancer and have undergone radical prostatectomy as definitive therapy. Patients must have had prostate-specific antigen monitoring before and after surgery. All relevant papers published from July 1977 to October 2020 will be eligible for inclusion. The Newcastle-Ottawa score will be used to determine the quality and bias of the studies. This protocol is written in-line with the PRISMA protocol 2015 checklist.

Ethics And Dissemination: There are no relevant ethical concerns. Dissemination of this protocol will be via peer-reviewed journals as well as national and international conferences.

Prospero Registration Number: CRD42020206074.
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http://dx.doi.org/10.1136/bmjopen-2020-047664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103365PMC
May 2021

Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial.

Cancers (Basel) 2021 Apr 20;13(8). Epub 2021 Apr 20.

Centre for Medical Imaging, University College London, London WC1E 6BT, UK.

: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging-Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. : 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. : The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.
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http://dx.doi.org/10.3390/cancers13081985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074769PMC
April 2021

Patient Perspectives and Understanding of MRI-directed Prostate Cancer Diagnosis.

Urology 2021 Jul 3;153:6-7. Epub 2021 Apr 3.

UCL Division of Surgery and Interventional Science, University College London, London, United Kingdom; Department of Urology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

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http://dx.doi.org/10.1016/j.urology.2021.03.031DOI Listing
July 2021

The prevalence of human leucocyte antigen and human papillomavirus DNA in penile intraepithelial neoplasia in England 2011-2012.

Int J STD AIDS 2021 04 12;32(5):388-395. Epub 2021 Feb 12.

Dermatology Department, University College Hospital, Chelsea and Westminster Hospital, London, UK.

Background: The pathogenesis of penile intraepithelial neoplasia (PeIN) is unclear but human papillomavirus (HPV) infection and polymorphisms in human leucocyte antigen (HLA).

Objectives: To examine the prevalence of HPV DNA and HLA in PeIN.

Methods: Adult Caucasian men with a clinical and histological diagnosis of PeIN, that is, Bowenoid papulosis (BP), Bowen's disease of penis (BDP) and erythroplasia of Queyrat (EQ) were selected and phenotyped from the clinical records. DNA was extracted from blood and paraffin-embedded sections for HLA and HPV typing, respectively. Human leucocyte antigen allele frequencies were compared with those derived from the UK-based Caucasian population.

Results: Seventy-two cases of PeIN (20 BP, 34 BDP and 18 EQ) were studied. Human papillomavirus DNA was identified in 65/72 (90.2%) PeIN; types were detected in 62/72 (85%) followed by types in 9/72 (12.5%) and cutaneous types in 7/72 (9.7%); HPV16 was the most prevalent genotype at 35/72 (48.6%) followed by HPV33 at 7/72 (9.7%); multiple infections were seen in 18/72 (25%) PeIN. HLA-C*15 (Bonferroni corrected = 0.049) confers susceptibility to PeIN, whereas HLA-DQA1*01 (corrected = 0.02) protects against PeIN. HPV16-associated PeIN cases showed no statistically significant association with HLA genotype after multiple corrections.

Conclusion: Human papillomavirus is involved in the pathogenesis of PeIN. Immunogenotype may play a role in the pathogenesis of PeIN.
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http://dx.doi.org/10.1177/0956462420970727DOI Listing
April 2021

Mixed acinar and macrocystic ductal prostatic adenocarcinoma.

Lancet Oncol 2021 01;22(1):e37

Department of Urology, University College London Hospital NHS Foundation Trust, London, UK; Division of Surgery & Interventional Science, University College London, London, UK.

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http://dx.doi.org/10.1016/S1470-2045(20)30435-6DOI Listing
January 2021

A Modified Newcastle-Ottawa Scale for Assessment of Study Quality in Genetic Urological Research.

Eur Urol 2021 03 26;79(3):325-326. Epub 2020 Dec 26.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

Our modification of the traditional Newcastle-Ottawa scale enables urological researchers to effectively appraise and communicate the quality of genetic-based research in urology.
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http://dx.doi.org/10.1016/j.eururo.2020.12.017DOI Listing
March 2021

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

J Urol 2021 04 14;205(4):1090-1099. Epub 2020 Dec 14.

Division of Surgery and Interventional Sciences, University College London, London, United Kingdom.

Purpose: We determined the early efficacy of bipolar radiofrequency ablation with a coil design for focal ablation of clinically significant localized prostate cancer visible at multiparametric magnetic resonance imaging.

Materials And Methods: A prospective IDEAL phase 2 development study (Focal Prostate Radiofrequency Ablation, NCT02294903) recruited treatment-naïve patients with a single focus of significant localized prostate cancer (Gleason 7 or 4 mm or more of Gleason 6) concordant with a lesion visible on multiparametric magnetic resonance imaging. Intervention was a focal ablation with a bipolar radiofrequency system (Encage™) encompassing the lesion and a predefined margin using nonrigid magnetic resonance imaging-ultrasound fusion. Primary outcome was the proportion of men with absence of significant localized disease on biopsy at 6 months. Trial followup consisted of serum prostate specific antigen, multiparametric magnetic resonance imaging at 1 week, and 6 and 12 months post-ablation. Validated patient reported outcome measures for urinary, erectile and bowel functions, and adverse events monitoring system were used. Analyses were done on a per-protocol basis.

Results: Of 21 patients recruited 20 received the intervention. Baseline characteristics were median age 66 years (IQR 63-69) and preoperative median prostate specific antigen 7.9 ng/ml (5.3-9.6). A total of 18 patients (90%) had Gleason 7 disease with median maximum cancer 7 mm (IQR 5-10), for a median of 2.8 cc multiparametric magnetic resonance imaging lesions (IQR 1.4-4.8). Targeted biopsy of the treated area (median number of cores 6, IQR 5-8) showed absence of significant localized prostate cancer in 16/20 men (80%), concordant with multiparametric magnetic resonance imaging. There was a low profile of side effects at patient reported outcome measures analysis and there were no serious adverse events.

Conclusions: Focal therapy of significant localized prostate cancer associated with a magnetic resonance imaging lesion using bipolar radiofrequency showed early efficacy to ablate cancer with low rates of genitourinary and rectal side effects.
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http://dx.doi.org/10.1097/JU.0000000000001567DOI Listing
April 2021

Prostate Cancer Undetected by mpMRI: Tumor Conspicuity is Reliant Upon Optimal Scan Timing and Quality.

Urology 2021 Feb 2;148:316-317. Epub 2020 Dec 2.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1016/j.urology.2020.11.037DOI Listing
February 2021

Histopathological features of prostate cancer conspicuity on multiparametric MRI: protocol for a systematic review and meta-analysis.

BMJ Open 2020 10 22;10(10):e039735. Epub 2020 Oct 22.

UCL Division of Surgery and Interventional Science, University College London, London, UK.

Introduction: Multiparametric MRI (mpMRI) has improved risk stratification for men with suspected prostate cancer. Indeed, mpMRI-visible tumours tend to be larger and of higher pathological grade than mpMRI-invisible tumours; however, concern remains around significant cancer that is undetected by mpMRI. There has been considerable recent interest to investigate whether tumour conspicuity on mpMRI is associated with additional histopathological features (including cellular density, microvessel density and unusual prostate cancer subtypes), which may have important clinical implications in both diagnosis and prognosis. Furthermore, analysis of these features may help reveal the radiobiology that underpins the actual mechanisms of mpMRI visibility (and invisibility) of prostate tumours. Here, we describe a protocol for a systematic review of the histopathological basis of prostate cancer conspicuity on mpMRI.

Methods And Analysis: A systematic search of the MEDLINE, PubMed, Embase and Cochrane databases will be conducted. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines will be used to guide screening, thematic reporting and conclusions drawn from all eligible studies. Included papers will be full-text, English-language articles, comparing the histopathological characteristics of mpMRI-visible lesions and mpMRI-invisible tumours. All studies published between January 1950 and January 2020 will be eligible for inclusion. Studies using confirmatory immunohistochemistry for the identification of immune subsets or structural components will be included. Study bias and quality will be assessed using a modified Newcastle-Ottawa scale. To ensure methodological rigour, this protocol is written in accordance with the PRISMA Protocol 2015 checklist. If appropriate, a meta-analysis will be conducted comparing histopathological feature frequency between mpMRI-visible and mpMRI-invisible disease.

Ethics And Dissemination: No ethical approval will be required as this is an academic review of published literature. Findings will be disseminated through publications in peer-reviewed journals and presentations at national and international conferences.

Prospero Registration Number: CRD42020176049.
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http://dx.doi.org/10.1136/bmjopen-2020-039735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583062PMC
October 2020

Immunogenetics and human papillomavirus (HPV) in male genital lichen sclerosus (MGLSc).

Int J STD AIDS 2020 12 21;31(14):1334-1339. Epub 2020 Oct 21.

Dermatology Department, University College Hospital, Chelsea and Westminster Hospital, London, UK.

The pathogenesis of male genital lichen sclerosus (MGLSc) is controversial. Incriminated factors include infection with human papillomavirus (HPV) and autoimmunity (e.g. Human Leukocyte Antigen [HLA]). To address the roles of HLA and HPV in MGLSc we studied adult Caucasian males with a clinical and histological diagnosis of MGLSc. The men in the study attended two specialised Male Genital Dermatoses Clinics between July 2011 and September 2012 and were selected and phenotyped from the clinical records. DNA was extracted from blood and paraffin-embedded biopsy sections, for HLA and HPV typing, respectively. HLA allele frequencies were compared with those derived from the UK-based Caucasian population. Eighty-eight cases of MGLSc were identified. HPV DNA was detected in 33/88 (37.5%) cases of MGLSc. HPV16 was the most prevalent type found: 11/88 (12.5%) MGLSc. No statistically significant HLA associations were established but HLA-B*35, -B*51, -C*15, -DRB1*04, -DRB1*10 (predisposition) and -DQA1*01 (protection) were revealed as alleles of interest. HPV16-associated MGLSc cases showed no statistically significant association with HLA genotype. The relationship between HPV and MGLSc suggests a passenger effect rather than a pathogenic role. HLA is not associated with MGLSc nor co-existent HPV16.
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http://dx.doi.org/10.1177/0956462420949395DOI Listing
December 2020

A critical evaluation of visual proportion of Gleason 4 and maximum cancer core length quantified by histopathologists.

Sci Rep 2020 10 14;10(1):17177. Epub 2020 Oct 14.

Department of Urology, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.

Gleason score 7 prostate cancer with a higher proportion of pattern 4 (G4) has been linked to genomic heterogeneity and poorer patient outcome. The current assessment of G4 proportion uses estimation by a pathologist, with a higher proportion of G4 more likely to trigger additional imaging and treatment over active surveillance. This estimation method has been shown to have inter-observer variability. Fifteen patients with Prostate Grade Group (GG) 2 (Gleason 3 + 4) and fifteen patients with GG3 (Gleason 4 + 3) disease were selected from the PROMIS study with 192 haematoxylin and eosin-stained slides scanned. Two experienced uropathologists assessed the maximum cancer core length (MCCL) and G4 proportion using the current standard method (visual estimation) followed by detailed digital manual annotation of each G4 area and measurement of MCCL (planimetric estimation) using freely available software by the same two experts. We aimed to compare visual estimation of G4 and MCCL to a pathologist-driven digital measurement. We show that the visual and digital MCCL measurement differs up to 2 mm in 76.6% (23/30) with a high degree of agreement between the two measurements; Visual gave a median MCCL of 10 ± 2.70 mm (IQR 4, range 5-15 mm) compared to digital of 9.88 ± 3.09 mm (IQR 3.82, range 5.01-15.7 mm) (p = 0.64) The visual method for assessing G4 proportion over-estimates in all patients, compared to digital measurements [median 11.2% (IQR 38.75, range 4.7-17.9%) vs 30.4% (IQR 18.37, range 12.9-50.76%)]. The discordance was higher as the amount of G4 increased (Bias 18.71, CI 33.87-48.75, r 0.7, p < 0.0001). Further work on assessing actual G4 burden calibrated to clinical outcomes might lead to the use of differing G4 thresholds of significance if the visual estimation is used or by incorporating semi-automated methods for G4 burden measurement.
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http://dx.doi.org/10.1038/s41598-020-73524-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561724PMC
October 2020

False Positive Multiparametric Magnetic Resonance Imaging Phenotypes in the Biopsy-naïve Prostate: Are They Distinct from Significant Cancer-associated Lesions? Lessons from PROMIS.

Eur Urol 2021 01 10;79(1):20-29. Epub 2020 Oct 10.

UCL Division of Surgery & Interventional Science, University College London, London, UK; Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK.

Background: False positive multiparametric magnetic resonance imaging (mpMRI) phenotypes prompt unnecessary biopsies. The Prostate MRI Imaging Study (PROMIS) provides a unique opportunity to explore such phenotypes in biopsy-naïve men with raised prostate-specific antigen (PSA) and suspected cancer.

Objective: To compare mpMRI lesions in men with/without significant cancer on transperineal mapping biopsy (TPM).

Design, Setting, And Participants: PROMIS participants (n=235) underwent mpMRI followed by a combined biopsy procedure at University College London Hospital, including 5-mm TPM as the reference standard. Patients were divided into four mutually exclusive groups according to TPM findings: (1) no cancer, (2) insignificant cancer, (3) definition 2 significant cancer (Gleason ≥3+4 of any length and/or maximum cancer core length ≥4mm of any grade), and (4) definition 1 significant cancer (Gleason ≥4+3 of any length and/or maximum cancer core length ≥6mm of any grade).

Outcome Measurements And Statistical Analysis: Index and/or additional lesions present in 178 participants were compared between TPM groups in terms of number, conspicuity, volume, location, and radiological characteristics.

Results And Limitations: Most lesions were located in the peripheral zone. More men with significant cancer had two or more lesions than those without significant disease (67% vs 37%; p< 0.001). In the former group, index lesions were larger (mean volume 0.68 vs 0.50 ml; p< 0.001, Wilcoxon test), more conspicuous (Likert 4-5: 79% vs 22%; p< 0.001), and diffusion restricted (mean apparent diffusion coefficient [ADC]: 0.73 vs 0.86; p< 0.001, Wilcoxon test). In men with Likert 3 index lesions, logPSA density and index lesion ADC were significant predictors of definition 1/2 disease in a logistic regression model (mean cross-validated area under the receiver-operator characteristic curve: 0.77 [95% confidence interval: 0.67-0.87]).

Conclusions: Significant cancer-associated MRI lesions in biopsy-naïve men have clinical-radiological differences, with lesions seen in prostates without significant disease. MRI-calculated PSA density and ADC could predict significant cancer in those with indeterminate MRI phenotypes.

Patient Summary: Magnetic resonance imaging (MRI) lesions that mimic prostate cancer but are, in fact, benign prompt unnecessary biopsies in thousands of men with raised prostate-specific antigen. In this study we found that, on closer look, such false positive lesions have different features from cancerous ones. This means that doctors could potentially develop better tools to identify cancer on MRI and spare some patients from unnecessary biopsies.
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http://dx.doi.org/10.1016/j.eururo.2020.09.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772750PMC
January 2021

Natural history of prostate cancer on active surveillance: stratification by MRI using the PRECISE recommendations in a UK cohort.

Eur Radiol 2021 Mar 30;31(3):1644-1655. Epub 2020 Sep 30.

Division of Surgery & Interventional Science, University College London, 3rd Floor, Charles Bell House, 43-45 Foley St., London, W1W 7TS, UK.

Objectives: The PRECISE recommendations for magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer (PCa) include repeated measurement of each lesion, and attribution of a PRECISE radiological progression score for the likelihood of clinically significant change over time. We aimed to compare the PRECISE score with clinical progression in patients who are managed using an MRI-led AS protocol.

Methods: A total of 553 patients on AS for low- and intermediate-risk PCa (up to Gleason score 3 + 4) who had two or more MRI scans performed between December 2005 and January 2020 were included. Overall, 2161 scans were retrospectively re-reported by a dedicated radiologist to give a PI-RADS v2 score for each scan and assess the PRECISE score for each follow-up scan. Clinical progression was defined by histological progression to ≥ Gleason score 4 + 3 (Gleason Grade Group 3) and/or initiation of active treatment. Progression-free survival was assessed using Kaplan-Meier curves and log-rank test was used to assess differences between curves.

Results: Overall, 165/553 (30%) patients experienced the primary outcome of clinical progression (median follow-up, 74.5 months; interquartile ranges, 53-98). Of all patients, 313/553 (57%) did not show radiological progression on MRI (PRECISE 1-3), of which 296/313 (95%) had also no clinical progression. Of the remaining 240/553 patients (43%) with radiological progression on MRI (PRECISE 4-5), 146/240 (61%) experienced clinical progression (p < 0.0001). Patients with radiological progression on MRI (PRECISE 4-5) showed a trend to an increase in PSA density.

Conclusions: Patients without radiological progression on MRI (PRECISE 1-3) during AS had a very low likelihood of clinical progression and many could avoid routine re-biopsy.

Key Points: • Patients without radiological progression on MRI (PRECISE 1-3) during AS had a very low likelihood of clinical progression and many could avoid routine re-biopsy. • Clinical progression was almost always detectable in patients with radiological progression on MRI (PRECISE 4-5) during AS. • Patients with radiological progression on MRI (PRECISE 4-5) during AS showed a trend to an increase in PSA density.
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http://dx.doi.org/10.1007/s00330-020-07256-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880925PMC
March 2021

Genetic Landscape of Prostate Cancer Conspicuity on Multiparametric Magnetic Resonance Imaging: A Systematic Review and Bioinformatic Analysis.

Eur Urol Open Sci 2020 Jul;20:37-47

UCL Division of Surgery & Interventional Science, University College London, London, UK.

Context: Multiparametric magnetic resonance imaging (mpMRI) detects most, but not all, clinically significant prostate cancer. The genetic basis of prostate cancer visibility and invisibility on mpMRI remains uncertain.

Objective: To systematically review the literature on differential gene expression between mpMRI-visible and mpMRI-invisible prostate cancer, and to use bioinformatic analysis to identify enriched processes or cellular components in genes validated in more than one study.

Evidence Acquisition: We performed a systematic literature search of the Medline, EMBASE, PubMed, and Cochrane databases up to January 2020 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The primary endpoint was differential genetic features between mpMRI-visible and mpMRI-invisible tumours. Secondary endpoints were explanatory links between gene function and mpMRI conspicuity, and the prognostic value of differential gene enrichment.

Evidence Synthesis: We retrieved 445 articles, of which 32 met the criteria for inclusion. Thematic synthesis from the included studies showed that mpMRI-visible cancer tended towards enrichment of molecular features associated with increased disease aggressivity, including phosphatase and tensin homologue () loss and higher genomic classifier scores, such as Oncotype and Decipher. Three of the included studies had accompanying publicly available data suitable for further bioinformatic analysis. An over-representation analysis of these datasets revealed increased expression of genes associated with extracellular matrix components in mpMRI-visible tumours.

Conclusions: Prostate cancer that is visible on mpMRI is generally enriched with molecular features of tumour development and aggressivity, including activation of proliferative signalling, DNA damage, and inflammatory processes. Additionally, there appears to be concordant cellular components and biological processes associated with mpMRI conspicuity, as highlighted by bioinformatic analysis of large genetic datasets.

Patient Summary: Prostate cancer that is detected by magnetic resonance imaging (MRI) tends to have genetic features that are associated with more aggressive disease. This suggests that MRI can be used to assess the likelihood of aggressive prostate cancer, based on tumour visibility.
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http://dx.doi.org/10.1016/j.euros.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497895PMC
July 2020

NeuroSAFE frozen section during robot-assisted radical prostatectomy: peri-operative and histopathological outcomes from the NeuroSAFE PROOF feasibility randomized controlled trial.

BJU Int 2021 06 29;127(6):676-686. Epub 2021 Mar 29.

Division of Surgery and Interventional Science, University College London, London, UK.

Objectives: To report on the methods, peri-operative outcomes and histopathological concordance between frozen and final section from the NeuroSAFE PROOF feasibility study (NCT03317990).

Patients And Methods: Between May 2018 and March 2019, 49 patients at two UK centres underwent robot-assisted radical prostatectomy (RARP). Twenty-five patient were randomized to NeuroSAFE RARP (intervention arm) and 24 to standard RARP (control arm). Frozen section was compared to final paraffin section margin assessment in the 25 patients in the NeuroSAFE arm. Operation timings and complications were collected prospectively in both arms.

Results: Fifty neurovascular bundles (NVBs) from 25 patients in the NeuroSAFE arm were analysed. When analysed by each pathological section (n = 250, average five per side), we noted a sensitivity of 100%, a specificity of 99.2%, and an area under the curve (AUC) of 0.994 (95% confidence interval [CI] 0.985 to 1; P ≤0.001). On an NVB basis (n = 50), sensitivity was 100%, specificity was 92.7%, and the AUC was 0.963 (95% CI 0.914 to 1; P ≤0.001). NeuroSAFE RARP lasted a mean of 3 h 16 min (knife to skin to off table, 95% CI 3 h 2 min-3 h 30 min) compared to 2 h 4 min (95% CI 2 h 2 min-2 h 25 min; P ≤0.001) for standard RARP. There was no morbidity associated with the additional length of operating time on in the NeuroSAFE arm.

Conclusion: This feasibility study demonstrates the safety, reproducibility and excellent histopathological concordance of the NeuroSAFE technique in the NeuroSAFE PROOF trial. Although the technique increases the duration of RARP, this does not cause short-term harm. Confirmation of feasibility has led to the opening of the fully powered NeuroSAFE PROOF randomized controlled trial, which is currently under way at four sites in the UK.
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http://dx.doi.org/10.1111/bju.15256DOI Listing
June 2021

Prostate cancer measurements on serial MRI during active surveillance: it's time to be PRECISE.

Br J Radiol 2020 Dec 21;93(1116):20200819. Epub 2020 Sep 21.

Division of Surgery & Interventional Science, University College London, London, UK.

Objective: The PRECISE criteria for reporting multiparametric MRI in patients on active surveillance (AS) for prostate cancer (PCa) score the likelihood of clinically significant change over time using a 1-5 scale, where 4 or 5 indicates radiological progression. According to the PRECISE recommendations, the index lesion size can be reported using different definitions of volume (planimetry or ellipsoid formula) or by measuring one or two diameters. We compared different measurements using planimetry as the reference standard and stratified changes according to the PRECISE scores.

Methods: We retrospectively analysed 196 patients on AS with PCa confirmed by targeted biopsy who had two MR scans (baseline and follow-up). Lesions were measured on weighted imaging (WI) according to all definitions. A PRECISE score was assessed for each patient.

Results: The ellipsoid formula exhibited the highest correlation with planimetry at baseline (ρ = 0.97) and follow-up (ρ = 0.98) imaging, compared to the biaxial measurement and single maximum diameter. There was a significant difference ( < 0.001) in the yearly percentage volume change between radiological regression/stability (PRECISE 2-3) and progression (PRECISE 4-5) for planimetry (39.64%) and for the ellipsoid formula (46.78%).

Conclusion: The ellipsoid formula could be used to monitor tumour growth during AS. Evidence of a significant yearly percentage volume change between radiological regression/stability (PRECISE 2-3) and progression (PRECISE 4-5) has been also observed.

Advances In Knowledge: The ellipsoid formula is a reasonable surrogate for planimetry in capturing tumour volume changes on WI in patients on imaging-led AS. This is also associated with radiological changes using the PRECISE recommendations.
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http://dx.doi.org/10.1259/bjr.20200819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716009PMC
December 2020

Conspicuity of prostate cancer on multiparametric magnetic resonance imaging: A cross-disciplinary translational hypothesis.

FASEB J 2020 11 13;34(11):14150-14159. Epub 2020 Sep 13.

UCL Division of Surgery & Interventional Science, University College London, London, UK.

Pre-biopsy multiparametric magnetic resonance imaging (mpMRI) has transformed the risk stratification and diagnostic approach for suspected prostate cancer. The majority of clinically significant prostate cancers are visible on pre-biopsy mpMRI, however, there are a subset of significant tumors that are not detected by mpMRI. The radiobiological mechanisms underpinning mpMRI-visibility and invisibility of these cancers remain uncertain. Emerging evidence suggests that mpMRI-visible tumors are enriched with molecular features associated with increased disease aggressivity and poor clinical prognosis, which is supported by short-term endpoints, such as biochemical recurrence following surgery. Furthermore, at the histopathological level, mpMRI-visible tumors appear to exhibit increased architectural and vascular density compared to mpMRI-invisible disease. It seems probable that the genomic, pathological, radiological, and clinical features of mpMRI-visible and mpMRI-invisible prostate cancers are interrelated. Here, we propose a novel cross-disciplinary theory that links genomic and molecular evidence with cellular and histopathological appearances, elucidating both the mpMRI visibility and clinical status of significant prostate cancer.
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http://dx.doi.org/10.1096/fj.202001466RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436756PMC
November 2020

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer.

Sci Rep 2020 09 1;10(1):14380. Epub 2020 Sep 1.

Molecular Diagnostics and Therapeutics Group, University College London, London, UK.

PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies.
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http://dx.doi.org/10.1038/s41598-020-71263-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463239PMC
September 2020
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