Reply to Paraskevaidi et al.: Epithelial and microenvironment characterization is key to understanding and improving diagnoses

First, we thank Paraskevaidi et al. (1) for their kind comments and assessment of the potentially significant impact of our work (2). Their letter recognizes that our study could reduce the caseloads of pathologists/surgeons but that it may not directly benefit patients. Surgeons, pathologists, and technologists all strive to improve outcomes for patients; indeed, diagnosis is the gateway to therapy (and better outcomes). The speed and one-shot tumor and microenvironment measurement focus of our study are aimed precisely toward providing new information that is useful while being compatible with how diagnoses are actually made—via pathology.

Second, Paraskevaidi et al. (1) propose that earlier detection and less-invasive tools can potentially be more useful. Most certainly, we agree. Early detection is the key to earlier diagnoses and better outcomes. The studies cited by the authors on biological fluids and using fiber optics are of great potential interest. Indeed, if they can prove effective, new avenues for spectral screening and point-of-care diagnoses (3) may be enabled. In vivo methods, combined with approaches like stainless staining (4), may prove similarly beneficial. We note that these new approaches and our study’s method are all enabled by the advent of new light sources (5), new concepts in imaging science (6), and progressive advances in technology and applications (7, 8). While technological advancement is heartening, we caution against assuming biological effectiveness of all fluid biomarkers. The use of famous first-line biomarkers; for example, prostate-specific antigen, remains debated after decades of use (9). The major issues of overdetection and overtreatment, induction of needless patient anxiety, and unnecessary biopsies transcend technology development and remain to be addressed.

We also agree wholeheartedly with Paraskevaidi et al. (1) on the importance of in vivo imaging for detection, diagnosis, and treatment. Many studies incorporating fiber probes have performed in vivo imaging in the visible to near-IR wavelengths, but measured mid-IR wavelengths only with point spectroscopy (10). While a handheld mobile probe that can be used in the operating environment is an excellent advance, the data from it must either be definitive in its own native record (i.e., spectrum) or provide images that relate to pathology knowledge. While the former has not yet been definitely established in a trial, significant challenges remain for the latter. One challenge is speed of data acquisition. While our study shows a speed advance compared with other works for a high image quality, significant further advances are needed to make it fast enough for in vivo use. Finally, focusing on in vivo use to improve patient outcome with a new technique may be premature until such an advance is shown ex vivo. Characterization of altered stromal response has been demonstrated to be crucial for predicting breast cancer outcomes (11). However, there are limited practical means of recording the same. Measuring the microenvironment is not only useful for adding value to diagnostic pathology, as we proposed, but is also a step toward adding novelty to the tools proposed by Paraskevaidi et al. (1). We agree with Paraskevaidi et al. that comprehensive (tumor and microenvironment) spectroscopic imaging in vivo remains a laudable goal.