Ex vivo human pancreatic cancer avatars; an in-line personalised therapeutic response assessment platform

A paradigm shift in long-term survival rates for patients with Pancreatic Ductal Adenocarcinoma (PDAC) has yet to be witnessed. Long-term survival is only achieved in a small minority of patients. Systemic control of the disease can be secured with chemotherapy, however PDAC harbours high rates of chemotherapeutic resistance. Within current clinical practice, chemotherapeutic treatment strategies for PDAC are dictated by the patients’ level of fitness. There is no assessment of the individual’s tumour biology or acknowledgement of the significant heterogeneity that exists across tumours. Precision therapy incorporates individual tumour phenotype and biological characteristics and utilises this information to guide future management. Such an approach may improve the outcome for patients with PDAC. Whilst several different models for precision therapies have been reported, they all possess weaknesses that limit their use within a clinical setting. Within this thesis, I present the creation of patient derived cancer avatars as a method for delivering precision therapy for patients with PDAC. This approach allows for the creation of individual and miniature versions of a patient’s tumour for detailed cellular profiling in addition to an opportunity to perform a therapeutic drug screen. This approach overcomes several of the limitations of other models of precision therapy notably the preservation of the cellular diversity of the primary tumour and can be implemented within a clinically meaningful time frame. I further investigated as to whether long-term ex vivo culture of patient avatars can be achieved through utilising novel perfusion culture. To date, we are the first group to describe the use of perfusion culture of PDAC tissue slices. We demonstrated that perfusion culture is associated with a physiological benefit as we were able to maintain both glucose and lactate levels at a constant level during 12 days of ex vivo culture (p < 0.001 and p<0.0001 respectively). Native functional biological processes within the avatars were preserved ex vivo through the use of perfusion culture. Avatars that were cultured with perfusion culture ex vivo maintained a significantly higher proliferation rate (p < 0.01) and demonstrated reduced rates of cell death as per cleaved caspase 3 activation (p < 0.01). The metabolic activity of the avatars (mTOR) was preserved with perfusion culture (p < 0.01). Our model system also preserved native immune cells present within the tumour during ex vivo culture. Our initial experience with ex vivo chemotherapy treatment of avatars demonstrated a correlation with the patients’ clinical response to adjuvant therapy. Therefore, the avatar response to treatment may provide a unique opportunity and a window of insight into the future response of the patient to systemic treatment. This information can be harnessed and utilised to create individual, personalised treatment regimes for each patient. This in turn would change the historic approach to systemic therapy for PDAC, evolving from a generic, standardised treatment approach for all patients to establishing an individual, customisable regime for an individual tumour for each patient. Such an approach may finally translate into prolonging survival for patients with this lethal disease

Evaluating the evidence for a liver shrinkage diet for obese patients prior to laparoscopic cholecystectomy: A systematic review and meta-analysis

Patients and Methods: A systematic review and meta-analysis was performed (PROSPERO ID CRD42022374610). The primary outcome was to determine the impact of pre-operative VLCD on the operative findings and ease of dissection during laparoscopic cholecystectomy (LC). Results: Two studies were included with a total of 84 patients. VLCD was associated with a significantly easier Calot's dissection (MD: −0.58 (95% confidence interval [CI] [ −1.03, -0.13], P = 0.01) and was associated with a significantly higher rate of pre-operative weight loss (MD; 2.92 (95% CI [2.23, 3.62], P = 0.00001). Conclusions: The published evidence regarding VLCD before cholecystectomy in obese patients is limited. After acknowledging the limitations of the data, VLCD is associated with a significantly higher rate of weight loss preoperatively and directly impacts the ease of intraoperative dissection of Calot's triangle. Routine use of VLCD should be considered for all obese patients undergoing elective LC

Predicting Early Disease Recurrence of Pancreatic Cancer following Surgery: Determining the Role of NUDT15 as a Prognostic Biomarker

Surgical resection remains the only curative treatment strategy for Pancreatic Ductal Adenocarcinoma (PDAC). A proportion of patients succumb to early disease recurrence post-operatively despite receiving adjuvant chemotherapy. The ability to identify these high-risk individuals at their initial diagnosis, prior to surgery, could potentially alter their treatment algorithm. This unique patient cohort may benefit from neo-adjuvant chemotherapy, even in the context of resectable disease, as this may secure systemic control over their disease burden. It may also improve patient selection for surgery. Using the Cancer Genome Atlas dataset, we first confirmed the poor overall survival associated with early disease recurrence (p &lt; 0.0001). The transcriptomic profiles of these tumours were analysed, and we identified key aberrant signalling pathways involved in early disease relapse; downregulation across several immune signalling pathways was noted. Differentially expressed genes that could serve as biomarkers were identified (BPI, C6orf58, CD177, MCM7 and NUDT15). Receiver operating characteristic curves were constructed in order to identify biomarkers with a high diagnostic ability to identify patients who developed early disease recurrence. NUDT15 expression had the highest discriminatory capability as a biomarker (AUC 80.8%). Its expression was confirmed and validated in an independent cohort of patients with resected PDAC (n = 13). Patients who developed an early recurrence had a statistically higher tumour expression of NUDT15 when compared to patients who did not recur early (p &lt; 0.01). Our results suggest that NUDT15 can be used as a prognostic biomarker that can stratify patients according to their risk of developing early disease recurrence

Predicting Early Disease Recurrence of Pancreatic Cancer following Surgery: Determining the Role of NUDT15 as a Prognostic Biomarker

Surgical resection remains the only curative treatment strategy for Pancreatic Ductal Adenocarcinoma (PDAC). A proportion of patients succumb to early disease recurrence post-operatively despite receiving adjuvant chemotherapy. The ability to identify these high-risk individuals at their initial diagnosis, prior to surgery, could potentially alter their treatment algorithm. This unique patient cohort may benefit from neo-adjuvant chemotherapy, even in the context of resectable disease, as this may secure systemic control over their disease burden. It may also improve patient selection for surgery. Using the Cancer Genome Atlas dataset, we first confirmed the poor overall survival associated with early disease recurrence (p n = 13). Patients who developed an early recurrence had a statistically higher tumour expression of NUDT15 when compared to patients who did not recur early (p < 0.01). Our results suggest that NUDT15 can be used as a prognostic biomarker that can stratify patients according to their risk of developing early disease recurrence

The Cambridge History of Welsh Literature

This is the first comprehensive, single-volume history of the literature of Wales. The volume contains chapters covering the whole range of Welsh literature, from post-Roman Britain to post-devolution Wales, with many of the later chapters providing holistic accounts of literature in Welsh and literature in English within a single genre or a single period of literary production