No abstract

Reviewer #4: The authors are still failing to take the problem of heterogeneity seriously. The latest response was "well, yes, the results are all over the place, but most results are pretty good". First off, it is not at all clear to this reviewer that a negative predictive value of 85%, the threshold used by the authors, is acceptable. Would most patients be happy to be told that they only have a 15% risk of high-grade cancer, so not to worry about it? That is approximately the risk for a PSA of 10. How many urologists would argue against giving a biopsy to a man with a PSA of 10?Second, the point about heterogeneity is absolutely not to find out where the majority of results lie. For instance, if this was a meta-analysis of complication risk after abortion, and there was gross heterogeneity, with most clinics having very low rates and a few having very high rates, I'm pretty sure the conclusion wouldn't be only that "abortion is a safe procedure". More likely, there would be something about there being some unsafe clinics, and then an analysis to determine the characteristics of those clinics (e.g. solo practice) or a call for further research to determine why some clinics have poor outcomes. The current paper reads as if the authors came up with the conclusion first and then went through the motions of reporting forest plots and I2 statistics and so on. The conclusion that "Multiparametric MRI of the prostate is an accurate test for ruling-out clinically significant prostate cancer" is simply not an appropriate reflection of the data presented by the authors.Formatted: Font: Bold Commented [AL1]: I know we'd already done it but we don't need to point that out to AV. Hopefully he'll think we've now spotted the wisdom of his words and made the change requested. Don't want to give him any reason to dig his heals in.

To assess the feasibility of local anaesthetic transperineal (LATP) technique using a single-freehand transperineal (TP) access device, and report initial prostate cancer (PCa) detection, infection rates, and tolerability. Patients and methodsObservational study of a multicentre prospective cohort, including all consecutive cases. LATP was performed in three settings: (i) first biopsy in suspected PCa, (ii) confirmatory biopsies for active surveillance, and (iii) repeat biopsy in suspected PCa. All patients received pre-procedure antibiotics according to local hospital guidelines. Local anaesthesia was achieved by perineal skin infiltration and periprostatic nerve block without sedation. Ginsburg protocol principles were followed for systematic biopsies including cognitive magnetic resonance imaging-targeted biopsies when needed using the PrecisionPoint TM TP access device. Procedure-related complications and oncological outcomes were prospectively and consecutively collected. A validated questionnaire was used in a subset of centres to collect data on patient-reported outcome measures (PROMs). ResultsSome 1218 patients underwent LATP biopsies at 10 centres: 55%, 24%, and 21% for each of the three settings, respectively. Any grade PCa was diagnosed in 816 patients (67%), of which 634 (52% of total) had clinically significant disease. Two cases of sepsis were documented (0.16%) and urinary retention was observed in 19 patients (1.6%). PROMs were distributed to 419 patients, with a 56% response rate (n = 234). In these men, pain during the biopsy was described as either 'not at all' or 'a little' painful by 64% of patients. Haematuria was the most common reported symptom (77%). When exploring attitude to re-biopsy, 48% said it would be 'not a problem' and in contrast 8.1% would consider it a 'major problem'. Most of the patients (81%) described the biopsy as a 'minor or moderate procedure tolerable under local anaesthesia', while 5.6% perceived it as a 'major procedure that requires general anaesthesia'. ConclusionOur data suggest that LATP biopsy using a TP access system mounted to the ultrasound probe achieves excellent PCa detection, with a very low sepsis rate, and is safe and well tolerated. We believe a randomised controlled trial comparing LATP with transrectal ultrasound-guided biopsy (TRUS) to investigate the relative trade-offs between each biopsy technique would be helpful.

BackgroundMultiparametric magnetic resonance imaging (mpMRI) is now recommended pre-biopsy 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. ObjectiveTo assess the diagnostic performance of mpMRI for csPCa in a real-world setting. Design, Setting, and ParticipantsA multicentre, retrospective cohort study including men referred with a raised PSA or abnormal digital rectal exam who had undergone mpMRI followed by transrectal or transperineal biopsy. Patients could be biopsy naïve or have had previous negative biopsies. Outcome Measurements and Statistical AnalysisThe primary definition for csPCa was defined as ISUP Grade Group 2 or higher (any Gleason >/=7); the accuracy for other definitions was also evaluated. Results and LimitationsAcross 10 sites 2642 men were included (January/2011-November/2018). Mean age and PSA were 65.3 years (SD 7.8 years) and 7.5ng/ml (SD 3.3ng/ml). 35.9% had a 'negative' MRI' (score 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 5 ISUP GG >/=2 were 87.3% and 87.5%, respectively. The NPV was 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% when a PSA-density threshold 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 score 1-2. They key limitation of this study is the heterogeneity and retrospective nature of the data. ConclusionsmpMRI when used in real-world settings is able to accurately rule-out csPCa suggesting that about one-third of men might avoid an immediate biopsy. Men should be counselled about the risk of missing some significant cancers.