Enhancing clinical care and investigating a novel therapeutic approach for multiple paragangliomas
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Paragangliomas (PGLs) are rare tumours of the autonomic nervous system that cause high morbidity and mortality. Diagnosis and management can be challenging and no consensus on pre-operative management exists. PGLs arise in sporadic and familial forms and have the potential for malignant transformation. Despite significant advances in identification of genetic causes there is still a lack of understanding in the pathogenesis of the different clinical phenotypes. Surgical resection is the only cure, but once metastases have occurred treatment options are limited. This thesis aims to address some of these issues with the overall objective of improving clinical care for affected patients and their relatives. The first part of this research focuses on pre-operative management. Using home blood pressure monitoring and personalised titration of medications, the presented data show improved compliance with alpha-blockade medication. Duration of treatment appears to be an important factor in intra- and post-operative haemodynamic instability. Analysis of bioimpedance and serum inflammatory markers demonstrated that medical therapy is potentially able to reverse the inflammatory and catabolic effects of catecholamine excess. Part two focuses on mutations within the Succinate Dehydrogenase (SDH) genes. Mutations in any of these can cause disruption in SDH enzymatic function, but penetrance, clinical presentation and tumour aggressiveness differ between subunits. A model for surveillance monitoring is proposed based on collated data. The final part investigates the immune cell composition of the tumour microenvironment (TME). Emerging evidence suggests that the TME correlates with clinical outcome, however, little is known about the TME of PGLs. Immune cells in the TME were assessed using immunohistochemistry. There was a higher proportion of immune cells in tumour tissue compared to non-pathological medulla, with a predominance of macrophages. Differences in the TME were observed between aggressive and benign tumours. These observations could potentially be exploited as an aid in predicting tumour behaviour.
Authors
TUFTON, NCollections
- Theses [4241]