Research Highlights

The goal of this study was to assess non-invasive Optical Coherence Tomography (OCT) and Optical Doppler Tomography (ODT) for early detection and evaluation of chemotherapy-induced oral mucositis. Cheek pouches of 10 Syrian Golden hamsters were imaged using OCT/ODT during development of chemotherapy-induced mucositis. Intra-peritoneal injections of 5-fluorouracil and mechanical irritation induced oral lesions. At 2, 4, 7, 11 days, 1 hamster was sacrificed and processed for histopathology. OCT images were visually examined; ODT results were semi-quantified. Imaging data were compared with histologic findings. During the development of mucositis, OCT/ODT identified the following events: (1) change in epithelial thickness (beginning on day 2), (2) loss of surface keratinized layer continuity (beginning on day 4), (3) loss of epithelial (day 4 onwards) and submucosal integrity (day 7 onwards), (4) Changes in axial blood flow velocity (increased day 2,4; decreased day 7), (5) changes in blood vessel size (diameter doubled day 2; quadrupled day 4; unchanged day 7). The semi-quantitative imaging-based scoring system identified the severity of mucositis as defined by histopathology.

The combination of imaging criteria used allowed for the detection of early, intermediate and late mucositic changes. Imaging data gave higher scores compared to clinical scores early on, suggesting that the imaging-based diagnostic scoring was more sensitive to early mucositic change than the clinical scoring system. Once mucositis was established, imaging and clinical scores converged.

Although OCT/ODT technology is currently limited in its availability to clinicians, its accessibility is increasing rapidly as its costs diminish and turn-key systems can readily be purchased. Clinical and research implications of the imaging-based scoring system are considerable, and include the following:

1. Accurate scoring of the level of mucositis will permit effective communication between treating physicians, and will improve the ability to assess the severity of therapy-induced mucositis and the effectiveness of interventional.
2. The ability to quantify epithelial, connective tissue and vascular change (which is currently impossible) will lead to a better understanding of the mucositic process, of patient susceptibility and of the mechanisms and effectiveness.
3. Imaging-based diagnostics will permit very early identification of at risk patients, early initiation (and greater success) of the most appropriate interventions, as well as monitoring of interventional effects and effectiveness. While not assessed in this study it is likely that healing may be visible on OCT/ODT prior to clinical evidence of resolution of tissue damage. The tailoring of interventions, for example by using a preventive agent initially followed by a healing promoter at the appropriate time point, based on the in vivo imaging data, is very attractive. The high cost of managing mucositis adds to the urgency for instituting imaging-based diagnostics in patients receiving cancer therapy.
4. The accurate mapping of the epithelial, connective tissue and vascular components of mucositis will greatly enhance our understanding of the mechanisms involved in the interventions currently under investigation. For example, some interventions such as KGF are thought to have vascular or epithelial effects.

OCT/ODT identified chemotherapy-induced oral changes prior to their clinical manifestation, and the proposed scoring system for oral mucositis was validated for the semi-quantification of mucositic change.

Figures 1A, B and C show non-invasive in vivo OCT image, H&E stained sections of healthy hamster cheek pouch prior to the commencement of mucositis induction. In the OCT image, the keratinized epithelial surface layer (KESL), the basement membrane (BM), underlying connective tissues (CT) and blood vessels (BV) as well as the muscle layer (ML) are clearly visible. Corresponding structures are seen in the stained tissue section in B and C. Figures 1D, E and F show non-invasive in vivo OCT image, H&E stained sections of hamster cheek pouch after 11 days mucositis induction. In the OCT image, the epithelium is only present in small patches, the keratinized epithelial surface layer (KESL) is almost completely lost. The tissues appear swollen and indistinct with extensive areas of tissue degeneration. A blood vessel (BV) is visible, it appears partly collapsed. In the stained tissue section in E and F: considerable epithelial destruction is apparent, and the surface keratinized layer is mostly lost. Areas of liquefaction degeneration and collagen degeneration are visible, an infiltration of lymphocytes, polymorphonuclear leukocytes and macrophages is noted.

Figure 2 (a) Total Imaging Score (SE) over Time and (b) Clinical Score (mod. OMAS) (SE) over Time.

Figure 3. (a) Change in Epithelial Thickness, (b) Loss of Epithelial Surface Integrity, (c) Loss of Subsurface Integrity, (d) Change in Blood Flow Velocity and Blood Vessel Size.

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