Pacifico, M.; (2005) Improving outcome in melanoma by early detection and identification of novel prognostic markers. Doctoral thesis , University of London.

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Abstract

The incidence of cutaneous melanoma continues to rise rapidly. Problems are faced throughout its management and this thesis addresses them as follows: secondary prevention, prediction of prognosis and early detection of metastatic disease. Secondary prevention has been shown to be an effective strategy for improving survival in other cancers. A study of the rapid access, early detection, pigmented lesion clinic at Mount Vernon Hospital demonstrates for the first time that such an approach improves outcome in melanoma. Refining current prognostic capability in melanoma is essential for improving disease management. Tissue microarray was used to investigate 480 specimens from 120 primary melanomas for novel prognostic markers. Several markers were identified, including MCAM, CD44v3, Nm23 and P-cadherin, which showed a significant bearing on melanoma patient outcome. Their identification reveals valuable markers for predicting outcome and potential targets for therapeutic manipulation. Immunoscintigraphy is the use of radiolabeled tumour-specific antibodies to detect disease. Previously the whole monoclonal antibody LHM2, directed against the high molecular weight melanoma-associated antigen was studied. Whilst being highly melanoma-specific, its use in melanoma detection is limited. Its large size (150 kDa) results in background accumulation in normal organs, reducing image quality and hindering metastasis detection. The single chain Fv fragment (scFv) is the smallest part of the whole monoclonal antibody that maintains full antigen- binding capability. Its potential superiority over whole monoclonal antibodies has been demonstrated however it requires further refinement before routine use in patients. Two methods of improving tumour targeting with scFvs were investigated: use of a cocktail of scFvs binding different epitopes and use of scFv multimers. The use of a scFv cocktail improved tumour targeting in the spleen and muscle. Dimeric scFvs were shown to improve tumour retention whilst maintaining rapid blood clearance, leading to overall improved tumour targeting compared with monomers.

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