Unblinded Operator Bias in Multimodal Prostate Ultrasound: The Case for Independent Validation

We read with great interest the study by Jiang et al1 on prostate cancer (PCa) detection using a multimodal ultrasound strategy. The authors innovatively integrated whole-gland contrast-enhanced transrectal ultrasound (CETRUS) with fixed-plane flash-replenishment imaging (FRI) to evaluate their combined efficacy, an approach that may enhance the identification of PCa-related microvascular perfusion abnormalities. However, we believe there are still methodological shortcomings in the study that warrant further discussion. Firstly, the unblinded single-operator design introduces important methodological bias and limits generalizability. This design increases the risk of detection bias. If the operator interpreting CETRUS was aware of lesions identified on conventional transrectal ultrasound (TRUS), the diagnostic assessment was not independent. This raises concerns according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool, which emphasizes blinding to reduce bias in diagnostic accuracy studies.2 Future studies should therefore use blinded, independent interpretation by at least 2 operators and report inter-rater agreement. Second, the absence of validation against magnetic resonance imaging (MRI)-directed diagnostic pathways limits the strength of the evidence. The VISION meta-analysis showed that MRI with or without targeted biopsy detects more clinically significant prostate cancer (csPCa) and reduces overdiagnosis of insignificant disease compared with systematic TRUS biopsy.3 MRI is currently considered the optimal imaging modality for the diagnosis of PCa. Without direct comparison with MRI-based pathways, the incremental diagnostic value of the combined CETRUS and FRI approach remains uncertain. Third, subgroup analyses could better identify patients most likely to benefit from multimodal ultrasound. As demonstrated in the PROTECT study,4 over 3-quarters of men had low-risk disease, meaning that many men without csPCa underwent unnecessary biopsies. Currently, the blood flow grade on CETRUS is considered to be significantly correlated with histopathological findings from biopsy samples, and a CETRUS cutoff value of ≥4 offers the highest diagnostic differentiation for PCa.5 Therefore, performing stratified analyses based on CETRUS blood flow scores (≤3 versus 4–5) would provide greater clinical reference value for men with high-risk features. These patients stand to benefit more from multimodal ultrasound as a triage tool to reguide biopsy decisions and reduce unnecessary procedures. In conclusion, Jiang et al have confirmed the incremental value of multimodal ultrasound strategies in visualizing prostatic microvasculature. The combined ultrasound strategy of CETRUS and FRI shows promising potential for PCa detection. However, independent blinded validation and prospective comparison with MRI-based diagnostic strategies are needed before broader clinical adoption can be justified. At present, its use may be more appropriate in research settings than in routine practice. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.