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Elucidating the pathological role of obesity, inflammation and immunity in cancer-related arcopenia in upper gasteointestinal cancers

Cachexia is an understudied debilitating consequence of cancer, affecting up to 80% of all cancer patients and solely responsible for 20% of all cancer deaths. Cachexia is defined as the ongoing involuntary loss of muscle mass (sarcopenia) with or without the loss of fat, which cannot be fully reversed, leading to functional impairment, poor quality of life, reduced efficacy of chemotherapies and increased mortality. While inflammatory mediators have been identified as driving factors in sarcopenia, there are currently no laboratory tools to assess or monitor patients who are at risk of developing or have ongoing sarcopenia. Oesophageal cancer has a strong association with obesity, which is an inflammatory state and many oesophageal cancer patients are overweight or obese at diagnosis, despite underlying muscle loss, which may not be physically evident. Oesophageal cancer patients are particularly affected by cachexia and this study aims to determine to what extent muscle loss and muscle quality are associated with obesity, the systemic inflammatory response and the oesophageal cancer patient’s response to neo-adjuvant treatment. We will develop a serum panel of known and novel inflammatory and muscle degradation markers with gender and obesity cut-off values, which could be used from diagnosis and for repeated monitoring. This panel will be validated in an independent cohort of oesophageal cancer patients. Lastly, we will assess the sarcopenic muscle to determine what gene pathways are affected and profile the inflammatory and immune cell infiltrate to identify potential new immunotherapeutic targets to maintain muscle health. Interventional treatments have been somewhat successful only during early cachexia phases, therefore developing a cost effective, reliable tool to identify and monitor patients will have significant clinical, economic and societal benefits. In addition, a deeper understanding of the role of inflammation and immunity plays within the muscle may offer new avenues for targeted therapies.