Optimising the management of dysplastic lesions in the oesophagus with photodynamic therapy

The outcome of patients suffering from adeno and squamous carcinoma of the oesophagus remains poor. In the west, the incidence of adenocarcinoma has increased dramatically, with most cases occurring in association with Barrett's oesophagus (BE). Both adeno and squamous carcinoma are believed to progress through worsening degrees of dysplasia. This thesis assesses the role of Elastic Scattering Spectroscopy (ESS) as an objective diagnostic test for dysplasia and Photodynamic Therapy (PDT) with 5-aminolevulinic acid (ALA) as a less invasive treatment option. It also looks for a better understanding of the factors influencing mucosal healing after PDT. Using ESS, the sensitivity and specificity was 83% for distinguishing HGD/cancer from LGD/non dysplastic BE. Low dose ALA (30mg/kg) PDT eradicated 38% of HGD in BE compared with 67% eradication with a higher dose (60mg/kg). The higher dose also decreased the length of BE. In a study comparing red with green light (fixed light doses) for treating HGD, at 30 mg/kg ALA, 63% and 13 % of patients were clear of HGD with red and green laser respectively. At 60 mg/kg, the corresponding figures were 78% and 33% for the same light dose. 5 of 5 patients with LGD in BE and 4 of 5 patients with HGD in squamous mucosa had their dysplasia eradicated with ALA PDT. Successful PDT involves healing by regeneration of normal squamous mucosa. My in vitro studies created a PDT wound model using malignant oesophageal cell lines to assess the role of different cytokines in healing. Keratinocyte Growth Factor (KGF) was found to promote wound healing after PDT and significantly encouraged (p 0.001) the development of squamous cell lines. In conclusion: 1. ESS can differentiate dysplasia and early cancer from non-dysplastic and normal mucosa (sensitivity and specificity 83%). 2. PDT using high dose (60mg/kg) ALA (but not low dose) is effective in eradicating HGD in BE using red light. 3. The cytokine, KGF may promote healing with squamous mucosa after PDT. 4. Larger scale clinical trials are now required to confirm these results

Engineering data.

<p>Engineering data.</p

The figure of displacement of L-strut and the maximum values of displacement.

<p>(<i>a</i>) Explanation of displacement of L-strut. (<i>b</i>) Graph of the maximum values of displacement at point 1 (the inner angle area of the L-strut) according to the FA-2 condition.</p

Redefining the Septal L-Strut to Prevent Collapse

<div><p>During septorhinoplasty, septal cartilage is frequently resected for various purposes but the L-strut is preserved. Numerous materials are inserted into the nasal dorsum during dorsal augmenation rhinoplasty without considering nasal structural safety. This study used a finite element method (FEM) to redefine the septal L-strut, to prevent collapse as pressure moved from the rhinion to the supratip breakpoint on the nasal dorsum and as the contact percentage between the caudal L-strut and the maxillary crest changed. We designed a 1-cm-wide L-strut model based on computed tomography data. At least 45% of the width of the L-strut in the inferior portion of the caudal strut must be preserved during septoplasty to stabilize the septum. In augmentation rhinoplasty, the caudal L-strut must either be preserved perfectly or reinforced to prevent collapse or distortion of the L-strut. The dorsal augmentation material must be fixed in an augmentation pocket to prevent movement of graft material toward the supratip breakpoint, which can disrupt the L-strut. We conducted a numerical analysis using a FEM to predict tissue/organ behavior and to help clinicians understand the reasons for target tissue/organ collapse and deformation.</p></div

Maximum stress at each point in the L-strut.

<p><b>A</b>. The stress was constant at point 1 (pressure exertion region), regardless of the applied load location and the contact percentage with the maxillary crest. <b>B</b>. Stress at point 2 decreased gradually after an initial increase, according to changes in the applied load caudally from the rhinion. In particular, the maximum L-strut stress occurred at point 2 under the location 5 and 6 load conditions, regardless of changes in contact percentage. <b>C</b>. The stress at point 3 increased when the location of the applied load was changed from the rhinion to the supratip breakpoint.</p

Boundary conditions of the L-strut for stress, strain energy, and displacement analysis.

<p>(<i>a</i>) 100% FA-2 fixation condition. (<i>b</i>) 20% FA-2 fixation condition.</p

Assumptions for the L-strut condition.

<p><b>A</b>. External pressure (0.01N) was applied to the dorsal L-strut in a vertical direction from the rhinion (location 1) to the supratip breakpoint (location 9) at a 2-mm distance. The load was exerted in the 2-mm-wide dorsal segment. The location 9 load condition is the region of the superior point of the L-strut inner corner. <b>B</b>. Fixation area 1 is the bonding area with the perpendicular plate of the ethmoid bone (PPE) in the dorsal L-strut. Fixation area 2 is the bonding area with the maxillary crest. The contact percentage in fixation area 2 was assumed to range from 100% to 20%. The 100% condition of fixation area 2 was when the intact 1-cm-wide caudal strut was in contact with the maxillary crest. This simulation was based on partial resection of the caudal septal segment posterior of the anterior nasal spine (ANS) during actual septorhinoplasty. <b>C</b>. The 20% condition of fixation area 2 was the 2-mm-wide caudal strut in contact with the maxillary bone posterior to the ANS.</p

Design of the septal L-strut.

<p><b>A</b>. Schematic diagram of the L-strut on the nasal septum in sagittal view. <b>B</b>. Point 1 is the location of pressure application. Point 2 is the inner corner of the L-strut. Point 3 is the contact region between the maxillary crest and the caudal septal L-strut.</p

L-strut stress distribution.

<p>Red and blue indicate the highest and lowest stresses, respectively. Relatively high stress occurred at point 1 (applied load), point 2 (L-strut inner corner), and point 3 (contact between maxillary bone and the L-strut). Increased stress on the L-strut occurred as the location of the applied load moved caudally (supratip breakpoint) and the contact percentage decreased. <b>A</b>. Stress distribution according to the location of the applied load. As the applied load increased near the supratip breakpoint, the stress value increased at point 2 and around point 2. <b>B</b>. The stress distribution according to the contact percentage between the L-strut and the maxillary crest. Increased stress occurred in the caudal segment between points 2 and 3 as the contact percentage decreased.</p

Results for 100% contact between the caudal L-strut and the maxillary crest.

<p><b>A</b>. Stress at points 2 and 3 based on the applied load location. Maximum stress occurred at point 3 under the location 8 and 9 loading conditions; stress values at point 2 were higher than those at point 3, with the highest values seen under the location 7 loading condition. <b>B</b>. Displacement at point 2 according to the applied load location. As the applied load location changed from location 1 to location 9 (from the rhinion caudally), displacement increased, and maximum values were seen under the location 8 and 9 load conditions (supratip breakpoint).</p