Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by a stubbornly low 5-year survival which is essentially unchanged in the past 5 decades. Despite recent advances in chemotherapy and surgical outcomes, progress continues to lag behind that of other cancers. The PDAC microenvironment is characterised by a dense, fibrotic stroma of which cancer-associated fibroblasts (CAFs) are key players. CAFs and fibrosis were initially thought to be uniformly tumour-promoting, however this doctrine is now being challenged by a wealth of evidence demonstrating CAF phenotypic and functional heterogeneity. Recent technological advances have allowed for the molecular profiling of the PDAC tumour microenvironment at exceptional detail, and these technologies are being leveraged at pace to improve our understanding of this previously elusive cell population. In this review we discuss CAF heterogeneity and recent developments in CAF biology. We explore the complex relationship between CAFs and other cell types within the PDAC microenvironment. We discuss the potential for therapeutic targeting of CAFs, and we finally provide an overview of future directions for the field and the possibility of improving outcomes for patients with this devastating disease.

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study.

BACKGROUND: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors. METHODS: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012-2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded. RESULTS: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20-0.60 95% CI and 0.47; 0.25-0.88, respectively). CONCLUSION: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur.

Improving lesion localisation at colonoscopy: an analysis of influencing factors.

PURPOSE: Colonoscopy detects colorectal cancer and determines lesion localisation that influences surgical planning. However, published work suggests that the accuracy of lesion localisation can be low as 60%, with implications for both the surgeon and the patient. This work aims to identify potential influencing factors at colonoscopy that could lead to improved lesion localisation accuracy. METHODS: A multi-centred, prospective, observational study was performed that identified patients who were undergoing planned curative resection for a colorectal lesion. Localisation of a lesion at colonoscopy was compared to the intra-operative lesion localisation to determine accuracy of colonoscopic localisation. Patient factors and colonoscopic factors were recorded to determine any influencing factors on lesion localisation at colonoscopy. RESULTS: One hundred and eleven patients were analysed: mean age 67.4 years (range 27-89); male:female ratio 1.3:1; symptomatic referrals (n = 78, 70.3%); and previous abdominal surgery in 27 patients (24.3%). Complete colonoscopy was recorded in 78 patients (70.3%). In 88 patients (79.3%), colonoscopic lesion localisation matched the intra-operative location. Pre-operative CT imaging was unable to identify the tumour in 24 cases (21.8%). Potential influencing patient and colonoscopic factors on accurate lesion localisation at colonoscopy found complete colonoscopy to be the only significant factor (p = 0.008). CONCLUSION: Colonoscopic lesion localisation was found to be inaccurate in 79.3% cases, and with pre-operative CT unable to detect all lesions, this study confirms that accurate lesion localisation in the modern era is increasingly reliant on colonoscopy. Incomplete colonoscopy was the only significant factor that influenced inaccurate lesion localisation at colonoscopy.