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Title: Oral effects of radiotherapy in head and neck cancer patients : aetiology and pathophysiology linked to management
Author: Gonzalez Agurto, Maria
ISNI:       0000 0004 9357 4395
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Radiotherapy (RT), the mainstay treatment for head & neck cancer (HNC), is associated with salivary gland dysfunction. Intensity-modulated radiotherapy (IMRT) helps mitigate the severity of side effects. This is of particular note with oral mucositis being a very frequent side effect of head and neck cancer radiation therapy treatment having a clinical impact on patients being a limiting factor for cancer treatment, compromising its effectiveness. In addition, there is a lack of adequate treatment to reverse, control or prevent this side effect. The aim of this study was to analyse and evaluate the longitudinal nature of IMRT oral side effects and changes in nine salivary protein composition, as well as their possible associations, in order to develop a clinical and laboratory-based model, built on these connections, for the prediction of the incidence and severity of oral mucositis. Samples were obtained from 40 head and neck cancer patients prior to IMRT (T0) at Guy’s Hospital London in the Special Dental Care Unit, afterwards they were seen at six months post IMRT (T1) and 12 months post IMRT (T2). Unstimulated whole saliva samples were used to quantify flow rate and were analysed for total protein content using the Bicinchoninic Acid Assay (BCA), Periodic Acid Schiff (PAS) staining determined glycoprotein concentration, including mucin 5B and mucin 7, α-amylase activity was determined by kinetic assay, targeted Enzyme-Linked Immunosorbent Assays (ELISA) were used to quantified IgA, albumin cystatin S, acidic proline-rich peptides and statherin. Coomassie Brilliant blue was employed to detect carbonic anhydrase VI protein (CA VI) band. In agreement with previous studies using conventional RT, IMRT resulted in decreased saliva flow rate and composition, along with xerostomia, taste variation reported by patients and oral mucositis score showed a significant, transient alteration. Significant reductions in total protein secretion rate were identified for individuals on IMRT compared to baseline. Protein concentration for mucin 5B and mucin 7 were significantly elevated, concentration levels of IgA did not vary at any time point following IMRT. α-amylase activity and cystatin S were statistically decreased post-IMRT. Albumin concentration was significantly increased at T1, PRP and statherin reduction was not significant post IMRT. There were reported significant associations among protein composition, secretion rate and this reduced flow rate as well as dry mouth feeling reported by patients and taste acuity. Additionally, it was observed significant association between oral mucositis onset/severity and saliva total protein concentration and secretion rate along with specific salivary proteins mucin 5B, mucin 7 and IgA as a part of the mucosal protection barrier and hydration layer, as well as amylase that play a role in bacterial colonization, cystatin S as an antibacterial protein and part of pellicle, and albumin as marker of inflammatory processes. These associations between clinical and biochemical data allowed the determination of potential cases that can serve as a reference for monitoring oral response to therapy. The current study proposed the use of novel salivary protein predictive model for the early diagnosis and potential severity of oral mucositis in head and neck cancer patients based on the analysis of ROC curves. The specific proteins concentration and secretion rate cut off points were selected regarding their sensitivity and specificity to target this condition and classify patients susceptible to develop severe mucositis prior to IMRT in a routine clinical situation.
Supervisor: Banerjee, Avijit ; Watson, Timothy F. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available