Background:The aim of this study was to investigate the hypothesis that changes in circulating microRNAs (miRs) represent potentially useful biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer.Methods:Real-time polymerase chain reaction analysis of 742 miRs was performed using plasma-derived circulating microvesicles of 78 prostate cancer patients and 28 normal control individuals to identify differentially quantified miRs.Results:A total of 12 miRs were differentially quantified in prostate cancer patients compared with controls, including 9 in patients without metastases. In all, 11 miRs were present in significantly greater amounts in prostate cancer patients with metastases compared with those without metastases. The association of miR-141 and miR-375 with metastatic prostate cancer was confirmed using serum-derived exosomes and microvesicles in a separate cohort of patients with recurrent or non-recurrent disease following radical prostatectomy. An analysis of five selected miRs in urine samples found that miR-107 and miR-574-3p were quantified at significantly higher concentrations in the urine of men with prostate cancer compared with controls.Conclusion:These observations suggest that changes in miR concentration in prostate cancer patients may be identified by analysing various body fluids. Moreover, circulating miRs may be used to diagnose and stage prostate cancer.

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.

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Cit a tio n fo r fin al p u blis h e d ve r sio n: H a m dy, F r e d di e C., Do n ov a n, Je n ny L., La n e, J. Ath e n e , M e t c alf e, C h ri s, D avis, Mi c h a el, T u r n er, E m m a L., M a r ti n, Ric h a r d M .