Editorial: Combining multiple non-invasive images and/or biochemical tests to predict prostate cancer aggressiveness

COPYRIGHT © 2023 Mayer, Raman and Simone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. TYPE Editorial PUBLISHED 14 February 2023 DOI 10.3389/fonc.2023.1156649


Introduction
This Special Topics Issue in Frontiers in Oncology, Genitourinary Oncology compiles research articles that noninvasively assess prostate tumors through combining multiple disparate independent quantitative data. The contributions to the Special Topics discuss the performance of more common resources and methods that have been employed in the medical arena, such as biomarkers, clinical data, visual inspection of multi-parametric MRI (mpMRI), as well as adapting and applying novel approaches derived from other fields that quantitatively assess spatially registered multi-parametric MRI (SRMP-MRI).
Background "What's past is prologue," William Shakespeare, The Tempest "The past is a stepping stone, not a mill stone," Robert Plant Quantifiable research endeavors can benefit from combining multiple independent pieces of information or variables (1)(2)(3) to describe or ascertain a given condition or predict an outcome. The sources of input information may be garnered from biomarkers, clinical factors, meta information, human intelligence, detectors and/or images. Having multiple input factors that supplement and/or complement each other without mere duplication improves the accuracy of the predicted outcome. To aid combining disparate data in the clinic, nomograms (4) have provided a graphical tool for computing the likelihood of an effect due to a number of input variables. Standard measures can establish the significance of the input information for evaluating or achieving a desired goal. Extracting information, however, may burden and harm the patient (5). For prostate cancer, a 6-12 core transrectal ultrasoundbased needle biopsy supplemented by MRI has been the principal means of diagnosis and patient risk stratification. Aside from possible under sampling the prostate (6, 7), such an invasive procedure carries the risks of pain, hemorrhage, and infection for the patient (8). Although the widely implemented non-invasive PSA indicator has significantly reduced PCa mortality, its low specificity lead to under and overtreatment and loss quality of life for the patient (9).
To improve PCa diagnosis, grading, and alleviate patient suffering, non-invasive strategies have been developed, such as the Prostate Imaging Reporting and Data System (PI-RADS) (9). PI-RADS (10) is a protocol for radiologists to visually inspect multiple MRI sequences and combine the assessments to determine the prostate tumor's aggressiveness. However, such a qualitative approach depends on the training and experience of the radiologists.
Only one study (Jia et al.) in this compilation applies Artificial Intelligence (AI) methods to find image texture features and combine them to predict outcomes. AI harnesses the available image data and the growing computing power, is fashionable, and successful. However, there are drawbacks to the AI, such as overtraining of models lead to low accuracy, require fixed measurement conditions such as magnetic field, and textures are unconnected to physiology. The studies in this issue mostly avoid these pitfalls. Table 1 Table 1, does not use multiple features to predict an outcome. Instead, Mayer et al. studied an anomaly detector that finds deviant voxels within the normal prostate through processing the SRMP-MRI and examines a variety of statistical methods to manipulate the covariance matrix in order to generate an optimized AUC. Further studies are warranted that compared the anomaly detection with a radiologist tumor contouring of the SRMP-MRI tumors.

Future research
"The best way to predict the future is to create it." Abraham Lincoln "The past is in your head, the future is in your hands." Margaret Atwood The works presented in this issue directly suggested future refinements, such as more patients, prospective studies, application to greater number of clinics, but hints at more ambitious projects such as:

New biomarkers.
A number of studies in Special Topics showed that adding PSA to mpMRI boosts sensitivity and specificity for reliably determining csPCa. New biomarkers, beyond PSA (11,12), show promise in identifying the presence of prostate tumors with fewer false positives than PSA. Future studies might combine these novel biomarkers with PI-RADS or mpMRI for further improvement.

Directed proton therapy
Due to the increasing prevalence of proton beam therapy and its ability to more precisely deliver radiation therapy (13), imaging (14,15) may reveal that certain patients benefit from exposing only a portion of the prostate, rather than the entire prostate, to irradiation, thus reducing possible side effects from unnecessarily exposing nearby normal tissues. To date, only treatment planning studies (13) suggest the feasibility of using mpMRI for this purpose.

Qualitative/quantitative color maps.
Currently radiologists (10) visually inspect individual greyscale images to discern and interpret lesions. An alternative coloring schemes assigns red, green, blue to components in SRMP-MRI and generate a composite color image that can be quantified (16)(17)(18). Color in this case codes for PCa and normal tissue physiology. This coloring is not equivalent to false or pseudo coloring applied to individual images to show relative intensities within a given image. Future research (18) may clinically test employing tumor color display for patient care management and possibly derive new quantitative metrics for assessing tumors.

Cross-clinic transformation
MRI scanning conditions (magnetic field strength, pulse sequences etc.), can vary among clinics which hinders AI-based techniques from generalization. Previously (19), "whitening-dewhitening" transformed target signatures for supervised target detections to handle the changes in conditions. Similarly (20), signatures based on Gleason score status were transformed. Future research may transform prostate tumor signatures across multiple clinics. A single library may hold multiple tumor signatures in the future.

mpMRI and genomics
Other research directions may combine multiple data input or images to infer tumor genomics. A meta-analysis (21) found that mpMRI-visible cancer related to genotype, phenotype, physiology (proliferative signaling, DNA damage, and inflammatory processes). Others (22,23) correlated mpMRI visibility with aggressive genomic and proteomic features. Further research incorporating all mpMRI modalities may further discriminate among genomic metrics or find more markers.
Magnetic resonance spectroscopy MRS uses many bands, similar to airborne hyperspectral imagers. However, MRS suffers from crude spatial resolution (MRS (24) is 0.25 cm 3 versus mpMRI is 0.006 cm 3 ) causing sampling issues. The limited MRS sample number precludes exploiting the statistical analysis due to background covariance matrix inversion non-singularity. Covariance matrix regularization can mitigate the insufficient sampling. Elevating the MRS spatial resolution by degrading the spectral resolution may enable MRS statistical analysis similar to remote sensing. Remote sensing proved the value of making the tradeoffs and possibly help the clinic.

Author contributions
Conception and design: RM, CS. Administrative support: RM, CS. Collection and assembly of data: RM. Data analysis and interpretation: RM. Writing of manuscript: RM, SR, CS. All authors (RM, SR, CS) listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.