Novel biomarkers in two gastrointestinal malignancies - the potential of early detection and identification of new therapies

Sagar, Vandana Mridhu (2019). Novel biomarkers in two gastrointestinal malignancies - the potential of early detection and identification of new therapies. University of Birmingham. M.D.

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Abstract

Currently, there are no sufficient biomarkers that can be utilised in hepatocellular cancer (HCC) and neuroendocrine tumours (NETs) that can help in making an early diagnosis, or recognise serious complications that can be associated with the tumour. HCC is usually diagnosed at an advanced stage when curative treatment options are limited. There is no recommended biomarker to use in clinical practice to diagnose early HCC at present. NETs can occur in different sites, but the gastroenteropancreatic NETs are the commonest sites of origin. Serious complications can be associated with this cancer due to the underlying gastrointestinal and cardiac valve fibrosis, including intestinal obstruction and ischaemia, and carcinoid heart disease (CHD).

Within this thesis the suitability of prothrombin induced by vitamin K absence-II (PIVKA-II) as a biomarker in HCC will be presented. The aims of this study are to compare PIVKA-II to the traditional marker alpha-fetoprotein (AFP) in diagnosing early HCC, as well as a combination of both biomarkers, assess PIVKA-II levels in patients undergoing ablation therapy, and assess if levels of PIVKA-II increase with disease progression of HCC. The second project in this thesis describes the suitability of vascular adhesion-protein 1 (VAP-1) as a biomarker in NETs and CHD. The aims of this project are to compare the levels of soluble VAP-1 (sVAP-1) in different NET cohorts and healthy volunteers and compare levels of sVAP-1 pre- and post-treatment in midgut NETs. I also aim to study the tissue expression of VAP-1 in midgut NET tissue and CHD.

AFP has been the traditional marker used in HCC surveillance. PIVKA-II was not found to be a superior marker to AFP in diagnosing early HCC, and the combination of both markers was only slightly better compared to AFP alone. However, on explant histology, pre-transplant serum PIVKA-II levels were found to be significantly higher in the presence of microvascular invasion and also in moderately- or poorly- differentiated HCC. This was not seen with AFP. In the longitudinal data analysis, PIVKA-II shows a promising role in the surveillance of recurrent HCC post-ablation.

Tissue expression of VAP-1 was present in midgut NETs and in the CHD valves, associated with the presence of a dense stromal and collagen network. Significantly higher % area of tissue expression of VAP-1 was seen in CHD valves compared to control valves. Across the healthy controls, midgut NETs and CHD groups, significantly higher levels of circulating sVAP-1 was seen with highest levels found in CHD. The longitudinal data analysis did not show any significant change in the sVAP-1 levels between the pre- and post-treatment samples, similar to the markers currently used in clinical practice (chromogranin A, 24 hour urinary 5-hydroxyindole acetic acid and N-terminal pro b-type natriuretic peptide).

PIVKA-II could therefore be a prognostic marker in HCC and may support patient stratification for therapy. Despite a small number in the longitudinal data analysis, PIVKA-II shows a promising role in the surveillance of recurrent HCC post-ablation therapy. The VAP-1 study identifies the presence of VAP-1, both in a circulating form and tissue expression in midgut NETs and in CHD, and therefore could be a potential biomarker and treatment target in NETs.

Type of Work:

Thesis (Doctorates > M.D.)

Award Type:

Doctorates > M.D.

Supervisor(s):