Probe-based confocal endomicroscopy: technical challenges and clinical applications
Creators: name: Newton, Richard
Publisher: name: Imperial College London
Year: 2013

description: Probe based confocal laser endomicroscopy (pCLE) is an in vivo device which acquires high resolution superficial optical biopsies. Despite encouraging data on neoplasia identification in colorectal polyps and Barrett’s oesophagus, there are many hurdles to pCLE advancement beyond the research arena. This thesis defines these challenges, and via 5 experimental chapters expounds four key requirements: 1) the effect of probe contact force upon the tissue needs assessing and harnessing; 2) the probe’s diagnostic accuracy needs to be improved; 3) the probe’s site of optical biopsy acquisition needs improved tracking; and 4) the ergonomics of pCLE optical biopsy need development. These challenges are elucidated and elaborated upon using two short clinical studies. A library is created describing the differences between normal, inflammatory and neoplastic endobronchial pCLE images from 16 pCLE bronchoscopies, but an inability to distinguish between endobronchial carcinoma and carcinoma-in-situ is shown. The tolerability of pCLE imaging of the colorectum over five sessions during chemoradiotherapy for advanced rectal cancer is explored, and possible morphological changes are described. The accuracy of bronchoscopic pCLE for diagnosing peripheral lung diseases is investigated. In 116 bronchopulmonary segments in 43 subjects pCLE safely provided video sequences for comparison with computed tomography, transbronchial biopsy, and bronchoalveolar lavage. With pCLE, non-emphysematous peripheral diseases tend to create diminishment of the distinct elastin alveolar microstructure, and distinction between microvessels and septal walls becomes more difficult. Alveolar septal wall density is reduced in severe emphysema, and the pleura is demonstrated beyond bullae in two patients. Though assessors have some consistency, they are shown to be unable to accurately judge the category of emphysema severity in this small study. Intravenous fluorescein is shown to cause “white-out” and thus provide no advantage for pCLE imaging of the pulmonary lobule. At least in the laboratory, this thesis demonstrates that mucosal distension/colonic inflation and probe contact force significantly affect the consistency of pCLE images in terms of gland diameter and intergland separation. It also introduces the concept of pCLE elastography: if a device attaches to the probe to enable it to produce a sinusoidal force upon the tissue, the amount with which the glands individually expand/shrink and separate is altered if the mucosa is artificially stiffened to mimic disease. It suggests there is potential for improving pCLE ergonomics, and tracking (at least within peripheral lung). A transvaginal flexible endoscopic robot is predicted to reach 88% of a human peritoneal cavity for pCLE periteoneoscopy; a porcine feasibility study provides interpretable abdominal cavity images. Probe tracking in the peripheral lung is especially difficult and important in heterogeneously distributed disease. A study using ex vivo porcine lung assesses the predictability of probe tip destination; it shows that only half of the probe deployments beyond the most distally visible bronchus have a single possible path. Finally, a role for pCLE evaluation of chronic radiation proctopathy is proposed. 26 patients with symptomatic disease are pCLE sigmoidoscoped with correlative pinch biopsy. Macroscopically severe disease is associated with pCLE sequences showing glandular disruption and vasculopathy (dilated or absent vessels; “dilabscence”). A score from 16 histological features correlates with pCLE vessel dilabscence and glandular disruption suggesting pCLE may have a role in the longitudinal monitoring of this unpleasant disease. Overall, the thesis approaches pCLE challenges from several angles in both laboratory and clinical settings, and the data are often descriptive and preliminary. However, it significantly expands upon the understanding of pCLE in peripheral and endobronchial lung disease, describes two novel clinical roles for pCLE (radiation proctopathy and evaluation of neoadjuvant therapy response), and contains the first description of two technical pCLE developments (elastographic interrogation and robotic actuation). The time is fast approaching when one of these clinical niches capitalises on pCLEs enormous potential for mainstream deployment.