Multiparametric ultrasound versus multiparametric MRI to diagnose prostate cancer (CADMUS): a prospective, multicentre, paired-cohort, confirmatory study.

BACKGROUND: Multiparametric MRI of the prostate followed by targeted biopsy is recommended for patients at risk of prostate cancer. However, multiparametric ultrasound is more readily available than multiparametric MRI. Data from paired-cohort validation studies and randomised, controlled trials support the use of multiparametric MRI, whereas the evidence for individual ultrasound methods and multiparametric ultrasound is only derived from case series. We aimed to establish the overall agreement between multiparametric ultrasound and multiparametric MRI to diagnose clinically significant prostate cancer. METHODS: We conducted a prospective, multicentre, paired-cohort, confirmatory study in seven hospitals in the UK. Patients at risk of prostate cancer, aged 18 years or older, with an elevated prostate-specific antigen concentration or abnormal findings on digital rectal examination underwent both multiparametric ultrasound and multiparametric MRI. Multiparametric ultrasound consisted of B-mode, colour Doppler, real-time elastography, and contrast-enhanced ultrasound. Multiparametric MRI included high-resolution T2-weighted images, diffusion-weighted imaging (dedicated high B 1400 s/mm2 or 2000 s/mm2 and apparent diffusion coefficient map), and dynamic contrast-enhanced axial T1-weighted images. Patients with positive findings on multiparametric ultrasound or multiparametric MRI underwent targeted biopsies but were masked to their test results. If both tests yielded positive findings, the order of targeting at biopsy was randomly assigned (1:1) using stratified (according to centre only) block randomisation with randomly varying block sizes. The co-primary endpoints were the proportion of positive lesions on, and agreement between, multiparametric MRI and multiparametric ultrasound in identifying suspicious lesions (Likert score of ≥3), and detection of clinically significant cancer (defined as a Gleason score of ≥4 + 3 in any area or a maximum cancer core length of ≥6 mm of any grade [PROMIS definition 1]) in those patients who underwent a biopsy. Adverse events were defined according to Good Clinical Practice and trial regulatory guidelines. The trial is registered on ISRCTN, 38541912, and ClinicalTrials.gov, NCT02712684, with recruitment and follow-up completed. FINDINGS: Between March 15, 2016, and Nov 7, 2019, 370 eligible patients were enrolled; 306 patients completed both multiparametric ultrasound and multiparametric MRI and 257 underwent a prostate biopsy. Multiparametric ultrasound was positive in 272 (89% [95% CI 85-92]) of 306 patients and multiparametric MRI was positive in 238 patients (78% [73-82]; difference 11·1% [95% CI 5·1-17·1]). Positive test agreement was 73·2% (95% CI 67·9-78·1; κ=0·06 [95% CI -0·56 to 0·17]). Any cancer was detected in 133 (52% [95% CI 45·5-58]) of 257 patients, with 83 (32% [26-38]) of 257 being clinically significant by PROMIS definition 1. Each test alone would result in multiparametric ultrasound detecting PROMIS definition 1 cancer in 66 (26% [95% CI 21-32]) of 257 patients who had biopsies and multiparametric MRI detecting it in 77 (30% [24-36]; difference -4·3% [95% CI -8·3% to -0·3]). Combining both tests detected 83 (32% [95% CI 27-38]) of 257 clinically significant cancers as per PROMIS definition 1; of these 83 cancers, six (7% [95% CI 3-15]) were detected exclusively with multiparametric ultrasound, and 17 (20% [12-31]) were exclusively detected by multiparametric MRI (agreement 91·1% [95% CI 86·9-94·2]; κ=0·78 [95% CI 0·69-0·86]). No serious adverse events were related to trial activity. INTERPRETATION: Multiparametric ultrasound detected 4·3% fewer clinically significant prostate cancers than multiparametric MRI, but it would lead to 11·1% more patients being referred for a biopsy. Multiparametric ultrasound could be an alternative to multiparametric MRI as a first test for patients at risk of prostate cancer, particularly if multiparametric MRI cannot be carried out. Both imaging tests missed clinically significant cancers detected by the other, so the use of both would increase the detection of clinically significant prostate cancers compared with using each test alone. FUNDING: The Jon Moulton Charity Trust, Prostate Cancer UK, and UCLH Charity and Barts Charity.

Determination of optimal drug dose and light dose index to achieve minimally invasive focal ablation of localised prostate cancer using WST11-vascular-targeted photodynamic (VTP) therapy.

OBJECTIVE: To determine the optimal drug and light dose for prostate ablation using WST11 (TOOKAD Soluble) for vascular-targeted photodynamic (VTP) therapy in men with low-risk prostate cancer. PATIENTS AND METHODS: In all, 42 men with low-risk prostate cancer were enrolled in the study but two who underwent anaesthesia for the procedure did not receive the drug or light dose. Thus, 40 men received a single dose of 2, 4 or 6 mg/kg WST11 activated by 200 J/cm light at 753 nm. WST11 was given as a 10-min intravenous infusion. The light dose was delivered using cylindrical diffusing fibres within hollow plastic needles positioned in the prostate using transrectal ultrasonography (TRUS) guidance and a brachytherapy template. Magnetic resonance imaging (MRI) was used to assess treatment effect at 7 days, with assessment of urinary function (International Prostate Symptom Score [IPSS]), sexual function (International Index of Erectile Function [IIEF]) and adverse events at 7 days, 1, 3 and 6 months after VTP. TRUS-guided biopsies were taken at 6 months. RESULTS: In all, 39 of the 40 treated men completed the follow-up. The Day-7 MRI showed maximal treatment effect (95% of the planned treatment volume) in men who had a WST11 dose of 4 mg/kg, light dose of 200 J/cm and light density index (LDI) of >1. In the 12 men treated with these parameters, the negative biopsy rate was 10/12 (83%) at 6 months, compared with 10/26 (45%) for the men who had either a different drug dose (10 men) or an LDI of <1 (16). Transient urinary symptoms were seen in most of the men, with no significant difference in IPSS score between baseline and 6 months after VTP. IIEF scores were not significantly different between baseline and 6 months after VTP. CONCLUSION: Treatment with 4 mg/kg TOOKAD Soluble activated by 753 nm light at a dose of 200 J/cm and an LDI of >1 resulted in treatment effect in 95% of the planned treatment volume and a negative biopsy rate at 6 months of 10/12 men (83%).

Multiparametric MR imaging for detection of clinically significant prostate cancer: a validation cohort study with transperineal template prostate mapping as the reference standard.

PURPOSE: To evaluate the diagnostic performance of multiparametric (MP) magnetic resonance (MR) imaging for prostate cancer detection by using transperineal template prostate mapping (TTPM) biopsies as the reference standard and to determine the potential ability of MP MR imaging to identify clinically significant prostate cancer. MATERIALS AND METHODS: Institutional review board exemption was granted by the local research ethics committee for this retrospective study. Included were 64 men (mean age, 62 years [range, 40-76]; mean prostate-specific antigen, 8.2 ng/mL [8.2 µg/L] [range, 2.1-43 ng/mL]), 51 with biopsy-proved cancer and 13 suspected of having clinically significant cancer that was biopsy negative or without prior biopsy. MP MR imaging included T2-weighted, dynamic contrast-enhanced and diffusion-weighted imaging (1.5 T, pelvic phased-array coil). Three radiologists independently reviewed images and were blinded to results of biopsy. Two-by-two tables were derived by using sectors of analysis of four quadrants, two lobes, and one whole prostate. Primary target definition for clinically significant disease necessary to be present within a sector of analysis on TTPM for that sector to be deemed positive was set at Gleason score of 3+4 or more and/or cancer core length involvement of 4 mm or more. Sensitivity, negative predictive value, and negative likelihood ratio were calculated to determine ability of MP MR imaging to rule out cancer. Specificity, positive predictive value, positive likelihood ratio, accuracy (overall fraction correct), and area under receiver operating characteristic curves were also calculated. RESULTS: Twenty-eight percent (71 of 256) of sectors had clinically significant cancer by primary endpoint definition. For primary endpoint definition (≥ 4 mm and/or Gleason score ≥ 3+4), sensitivity, negative predictive value, and negative likelihood ratios were 58%-73%, 84%-89%, and 0.3-0.5, respectively. Specificity, positive predictive value, and positive likelihood ratios were 71%-84%, 49%-63%, and 2.-3.44, respectively. Area under the curve values were 0.73-0.84. CONCLUSION: Results of this study indicate that MP MR imaging has a high negative predictive value to rule out clinically significant prostate cancer and may potentially have clinical use in diagnostic pathways of men at risk.

A biopsy simulation study to assess the accuracy of several transrectal ultrasonography (TRUS)-biopsy strategies compared with template prostate mapping biopsies in patients who have undergone radical prostatectomy.

UNLABELLED: What's known on the subject? and What does the study add? Transrectal ultrasonography (TRUS)-guided biopsies can miss prostate cancer and misclassify risk in a diagnostic setting; the exact extent to which it does so in a repeat biopsy strategy in men with low-intermediate risk prostate cancer is unknown. A simulation study of different biopsy strategies showed that repeat 12-core TRUS biopsy performs poorly. Adding anterior sampling improves on this but the highest accuracy is achieved using transperineal template prostate mapping using a 5 mm sampling frame. OBJECTIVE: To determine the effectiveness of two sampling strategies; repeat transrectal ultrasonography (TRUS)-biopsy and transperineal template prostate mapping (TPM) to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL using computer simulation on reconstructed three-dimensional (3-D) computer models of radical whole-mount specimens. PATIENTS AND METHODS: Computer simulation on reconstructed 3-D computer models of radical whole-mount specimens was used to evaluate the performance characteristics of repeat TRUS-biopsy and TPM to detect and exclude lesions of ≥0.2 mL or ≥0.5 mL. In all, 107 consecutive cases were analysed (1999-2001) with simulations repeated 500 times for each biopsy strategy. TPM and five different TRUS-biopsy strategies were simulated; the latter involved a standard 12-core sampling and incorporated variable amounts of error, as well as the addition of anterior cores. Sensitivity, specificity, negative and positive predictive values for detection of lesions with a volume of ≥0.2 mL or ≥0.5 mL were calculated. RESULTS: The mean (SD) age and PSA concentration were 61 (6.4) years and 8.5 (5.9) ng/mL, respectively.In all, 53% (57/107) had low-intermediate risk disease. In all, 665 foci were reconstructed; there were 149 foci ≥0.2 mL and 97 ≥ 0.5 mL in the full cohort and 68 ≥ 0.2 mL and 43 ≥ 0.5 mL in the low-intermediate risk group. Overall, TPM accuracy (area under the receiver operating curve, AUC) was ≈0.90 compared with AUC 0.70-0.80 for TRUS-biopsy. In addition, at best, TRUS-biopsy missed 30-40% of lesions of ≥0.2 mL and ≥0.5 mL whilst TPM missed 5% of such lesions. CONCLUSION: TPM under simulation conditions appears the most effective re-classification strategy, although augmented TRUS-biopsy techniques are better than standard TRUS-biopsy.

Characterizing clinically significant prostate cancer using template prostate mapping biopsy.

PURPOSE: Definitions of prostate cancer risk are limited since accurate attribution of the cancer grade and burden is not possible due to the random and systematic errors associated with transrectal ultrasound guided biopsy. Transperineal prostate mapping biopsy may have a role in accurate risk stratification. We defined the transperineal prostate mapping biopsy characteristics of clinically significant disease. MATERIALS AND METHODS: A 3-dimensional model of each gland and individual cancer was reconstructed using 107 radical whole mount specimens. We performed 500 transperineal prostate mapping simulations per case by varying needle targeting errors to calculate sensitivity, specificity, and negative and positive predictive value to detect lesions 0.2 ml or greater, or 0.5 ml or greater. Definitions of clinically significant cancer based on a combination of Gleason grade and cancer burden (cancer core length) were derived. RESULTS: Mean±SD patient age was 61±6.4 years (range 44 to 74) and mean prostate specific antigen was 9.7±5.9 ng/ml (range 0.8 to 36.2). We reconstructed 665 foci. The total cancer core length from all positive biopsies for a particular lesion that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 10 mm or greater and 6 mm or greater, respectively. The maximum cancer core length that detected more than 95% of lesions 0.5 ml or greater and 0.2 ml or greater was 6 mm or greater and 4 mm or greater, respectively. We combined these cancer burden thresholds with dominant and nondominant Gleason pattern 4 to derive 2 definitions of clinically significant disease. CONCLUSIONS: Transperineal prostate mapping may provide an effective method to risk stratify men with localized prostate cancer. The definitions that we present require prospective validation.

The "Is mpMRI Enough" or IMRIE Study: A Multicentre Evaluation of Prebiopsy Multiparametric Magnetic Resonance Imaging Compared with Biopsy.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is now recommended prebiopsy in numerous healthcare regions based on the findings of high-quality studies from expert centres. Concern remains about reproducibility of mpMRI to rule out clinically significant prostate cancer (csPCa) in real-world settings. OBJECTIVE: To assess the diagnostic performance of mpMRI for csPCa in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: A multicentre, retrospective cohort study, including men referred with raised prostate-specific antigen (PSA) or an abnormal digital rectal examination who had undergone mpMRI followed by transrectal or transperineal biopsy, was conducted. Patients could be biopsy naïve or have had previous negative biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary definition for csPCa was International Society of Urological Pathology (ISUP) grade group (GG) ≥2 (any Gleason ≥7); the accuracy for other definitions was also evaluated. RESULTS AND LIMITATIONS: Across ten sites, 2642 men were included (January 2011-November 2018). Mean age and PSA were 65.3yr (standard deviation [SD] 7.8yr) and 7.5ng/ml (SD 3.3ng/ml), respectively. Of the patients, 35.9% had "negative MRI" (scores 1-2); 51.9% underwent transrectal biopsy and 48.1% had transperineal biopsy, with 43.4% diagnosed with csPCa overall. The sensitivity and negative predictive value (NPV) for ISUP GG≥2 were 87.3% and 87.5%, respectively. The NPVs were 87.4% and 88.1% for men undergoing transrectal and transperineal biopsy, respectively. Specificity and positive predictive value of MRI were 49.8% and 49.2%, respectively. The sensitivity and NPV increased to 96.6% and 90.6%, respectively, when a PSA density threshold of 0.15ng/ml/ml was used in MRI scores 1-2; these metrics increased to 97.5% and 91.2%, respectively, for PSA density 0.12ng/ml/ml. ISUP GG≥3 (Gleason ≥4+3) was found in 2.4% (15/617) of men with MRI scores 1-2. They key limitations of this study are the heterogeneity and retrospective nature of the data. CONCLUSIONS: Multiparametric MRI when used in real-world settings is able to rule out csPCa accurately, suggesting that about one-third of men might avoid an immediate biopsy. Men should be counselled about the risk of missing some significant cancers. PATIENT SUMMARY: Multiparametric magnetic resonance imaging (MRI) is a useful tool for ruling out prostate cancer, especially when combined with prostate-specific antigen density (PSAD). Previous results published from specialist centres can be reproduced at smaller institutions. However, patients and their clinicians must be aware that an early diagnosis of clinically significant prostate cancer could be missed in nearly 10% of patients by relying on MRI and PSAD alone.

Accuracy of multiparametric magnetic resonance imaging in detecting recurrent prostate cancer after radiotherapy.

OBJECTIVE: To assess the role of multiparametric magnetic resonance imaging (mp-MRI) of the prostate in evaluating local recurrence of prostate cancer, using transperineal template-guided 5 mm-spaced biopsies as a reference standard, in men treated with external beam radiotherapy (EBRT) for prostate cancer. PATIENTS AND METHODS: The study included 13 patients with evidence of biochemical recurrence after EBRT who had undergone mp-MRI and prostate mapping. Each MRI scan (consisting of T1/T2 weighting, dynamic contrast enhancement and diffusion weighting) was reported by two expert uro-radiologists. Each prostate was divided into four regions of interest (ROI), generating 52 paired datasets for analysis. RESULTS: The mean (range) age of the men was 65.5 (55-70) years, the mean prostate-specific antigen (PSA) level before EBRT was 36.6 (4.5-150) ng/mL, the mean time from EBRT to biochemical recurrence was 5.7 (3-10) years and the mean PSA level at the time of recurrence was 7.1 (0.83-27.9) ng/mL. Eleven men had histological evidence of recurrence, with 23 of 52 ROIs involved with cancer. Overall accuracy, as expressed by the area under a receiver-operator curve, was 0.77 and 0.89 for all cancer, with accuracies of 0.86 and 0.93 for those cancers with ≥3 mm biopsy core length. Inter-observer variability was measured by calculating κ coefficients, which showed fair and moderate agreement between radiologists. CONCLUSIONS: Interpretation of mpMRI of the prostate after previous EBRT is challenging. Our results show that the accuracy is good using an accurate reference standard. These results need verification in more patients, but have implications for determining presence or absence of local recurrence and subsequent local salvage therapy.

Photodynamic therapy for focal ablation of the prostate.

Although in early stages of clinical development, photodynamic therapy (PDT) shows promise in delivering focal treatment of both primary and post-radiotherapy prostate cancer. This article will review the mechanism of action of PDT, previous research using PDT for treating prostate cancer including the development of newer vascular-acting photosensitizers, and the potential advantages and disadvantages of PDT in delivering focal therapy.

A three-centre experience of orthotopic neobladder reconstruction after radical cystectomy: revisiting the initial experience, and results in 104 patients.

OBJECTIVE: To assess, in a retrospective three-centre series, a second analysis of the initial experience and results of patients undergoing radical cystectomy (RC) and orthotopic neobladder reconstruction (ONR) after an additional 4 years of follow-up. PATIENTS AND METHODS: The medical records of 104 suitable consecutive patients undergoing RC and ONR between June 1994 and April 2003 were reviewed retrospectively. The complications, mortality, continence and cancer control rates were all recorded. RESULTS: The median (range) follow-up was 88 (52-156) months; 90 patients had reconstruction with a 'Studer' neobladder, 12 with a Hautmann W pouch and 2 with a 'T pouch' ileal neobladder. There were 24 early complications, and one death after surgery. There were 32 late complications. The daytime continence rate was 98% and the nocturnal continence rate was 76%. Ten patients required intermittent self-catheterization (ISC). In all, 30 patients had local and/or distant recurrences, all of whom died. Seven patients died from other causes. CONCLUSIONS: ONR provides excellent long-term continence rates and both acceptable complication and mortality rates. Suitable patients undergoing RC should be offered ONR.

Simultaneous Rupture of the Bladder and Pelvicaliceal System Because of Blunt Abdominal Trauma: A Rare Case.

We present a unique case of simultaneous rupture of the bladder and left renal pelvis after blunt trauma to the lower abdomen. To the best of our knowledge, this has not yet been reported in the literature. Another unusual aspect of this case was that the bladder rupture was bilateral, with both an extra- and intraperitoneal component. The management of this case was challenging. This involved an emergency laparotomy to repair the bladder tear, followed by a nephrostomy. This was followed by left ureteral stent insertion using a rendezvous technique. The case also highlights the role of expectant conservative management relating to the concurrent left renal pelvic rupture.

Introduction of an enhanced recovery protocol for radical cystectomy.

OBJECTIVE: To describe and assess an enhanced recovery protocol (ERP) for the peri-operative management of patients undergoing radical cystectomy (RC), which was started at our institution on 1 October 2005, as RC is associated with increased morbidity and longer inpatient stays than other major urological procedures. PATIENTS AND METHODS: An ERP was introduced in our institution that focused on reduced bowel preparation, and standardized feeding and analgesic regimens. In all, 112 consecutive patients were compared, i.e. 56 before implementing the ERP and 56 since introducing the ERP. The primary outcome measures were duration of total inpatient stay and interval from surgery to discharge, and the morbidity and mortality. Data were analysed retrospectively from cancer network and hospital records. RESULTS: The demographics of the two groups showed no significant difference in age, gender distribution, American Society of Anesthesiologists grade, or type of urinary diversion. Re-admission, mortality and morbidity rates showed no statistically significant difference between the groups. The median (interquartile range) duration of hospital stay was 17 (15-23) days in the no-ERP group, and 13 (11-17) days in the ERP group (significantly different, P < 0.001, Wilcoxon rank-sum test). The median duration of recovery after RC was 15 (13-21) days in the no-ERP group and 12 (10-15) days in the ERP group (significantly different, P = 0.001, Wilcoxon rank-sum test). CONCLUSION: The introduction of an ERP was associated with significantly reduced hospital stay, with no deleterious effect on morbidity or mortality.

Antegrade versus retrograde stenting in laparoscopic pyeloplasty.

PURPOSE: To compare operative times between retrograde and antegrade ureteral stenting as part of laparoscopic pyeloplasty. PATIENTS AND METHODS: Laparoscopic pyeloplasty procedures from January 2002 to January 2007 were identified through a prospective database. Procedures on 126 patients were performed using the same transperitoneal technique apart from the method of stent placement, which was performed in either a retrograde manner before laparoscopy or an antegrade manner during the laparoscopic portion of the procedure. RESULTS: A total of 45 patients underwent antegrade stenting, 53 had retrograde stenting, 20 patients already had a stent in place, and 8 patients had retrograde pyelography followed by antegrade stenting. Operative time in patients with antegrade stent placement was significantly faster than in those with retrograde stent placement (median 185 v 245 min, P < 0.0001 [two-way analysis of variance]), even when the variability of the operative surgeon was taken into account. There was no difference in the complication rates. CONCLUSION: Antegrade stent placement results in a significantly faster overall operative time when compared with retrograde stent placement.

Acute scrotal pain needs prompt investigation.

Scrotal pain must first be differentiated as either acute or chronic in nature. In acute pain, it is important to identify and specifically treat the aetiology. In chronic scrotal pain, if a potential cause is found on examination or investigation, where possible it should be treated first. Often, chronic scrotal pain does not have an easily identifiable aetiology and management can be difficult. Initially, conservative measures should be tried. If these treatments fail, the patient should be referred to a urologist for further evaluation and a multidisciplinary team approach should be used. Surgical intervention may be needed for cases of idiopathic chronic pain.

What Burden of Prostate Cancer Can Radiologists Rule Out on Multiparametric Magnetic Resonance Imaging? A Sensitivity Analysis Based on Varying the Target Condition in Template Prostate Mapping Biopsies.

OBJECTIVE: To evaluate the minimum disease burden of prostate cancer at which multiparametric magnetic resonance imaging (MRI) optimally performs. METHODS: Between 2006 and 2008, 64 men underwent multiparametric MRI imaging (index test) followed by template prostate mapping biopsy (reference test). Three radiologists independently reported each quadrant of every prostate on a scale of 1 to 5: highly likely benign, likely benign, equivocal, likely malignant, highly likely malignant (≥3 or ≥4 was considered positive). There were 256 prostate sectors; bootstrapping adjustment was used to account for nonindependence. The target condition indicating cancer on biopsies was varied by changing the maximum cancer core length (MCCL) and total cancer core length (TCCL) within each sector from 1 mm to 10 mm. The sensitivity, specificity, and positive (PPVs) and negative predictive values (PPVs) were calculated for each MCCL and TCCL. Gleason ≤3+3 and Gleason ≥3+4 cancers were analyzed separately. RESULTS: Mean age was 62 years (range, 40-76 years), and mean prostate-specific antigen level was 8.2 µg/L (range, 2.1-43 µg/L). Fifty percent of quadrants (127 of 256) had prostate cancer, of which 65% (83 of 127) were Gleason ≤3+3. For Gleason ≤3+3, multiparametric MRI had an NPV of ≥95% at an MCCL of ≥5 mm and at a TCCL of ≥7 mm (MRI score ≥3). For Gleason ≥3+4, an NPV of ≥95% was seen at an MCCL of ≥5 mm (MRI score ≥3) and TCCL ≥6 mm. CONCLUSION: Multiparametric MRI may allow areas of the prostate which test negative to avoid biopsy. Whether multiparametric MRI can be used as a "triage" test before the first biopsy requires results from ongoing prospective validating cohort studies.