Non-invasive detection of pre-malignant lesions using sub-ablative, deep ultraviolet laser-tissue interactions coupled with endogenous tissue fluorescence: Proof-of-concept, computational modeling, and detection-theory strategies for clinical instrument design and testing.

摘要

Half of all cancers are superficial in nature, originating in the stratified squamous epithelia including cervical, colorectal, skin, and oral cancer. Some of these diseases have seen a dramatic reduction in lethality due to the benefits of improved screening and diagnosis promoting earlier interdiction. Others, while treatable if caught at an early stage, have overall five year survival rates below 50% because they are challenging to identify early. These superficial carcinomas provide an opportunity for technological approaches to early detection due to the nature of their development: malignancy is invariably preceded by dysplastic precancerous cellular changes, which are often confined to the epithelial layer. These earliest changes are often not detectable visually, but are accessible using in vivo spectroscopy.;Optical spectroscopies have been widely investigated as techniques for identifying pathological tissue; however, unrelated subject-to-subject variations in spectra complicate interpretation and consequently clinical adaptation has been limited. In this dissertation a new biosensing technique, differential laser-induced perturbation spectroscopy (DLIPS), is described and evaluated. This technique combines fluorescence probing (pre- and post-perturbation) with sub-ablative deep UV perturbation and difference spectroscopy to provide a new spectral dimension, facilitating two improvements over traditional techniques. First, this technique eliminates significant variations in absolute fluorescence within subject populations. Second, UV perturbations alter superficial protein layers, directly coupling the response to the spatio-biomolecular structure.;This work is focused on the confluence of this innovation and the unmet clinical need for tools to detect pre-cancerous transformations earlier and with greater accuracy. In a proof-of-concept study, this technique is shown to work at least as well as fluorescence spectroscopy alone in detecting cancer but couples more specifically to changes induced by the dysplastic state, and putative relationships are drawn between tissues spectra and their biomolecular basis. To further understand the benefits of this technique, Monte Carlo modeling of DLIPS tissue spectroscopy is also presented, demonstrating that excimer perturbation enhances the returned molecular signatures from tissue layers and specifically emphasizes important disease biomarkers. Finally in a pre-clinical model of both oral dysplasia and benign pathology, detection performance and optimization of DLIPS and fluorescence technologies are considered from a detection-theory perspective.