The desmoplastic stroma of pancreatic cancer is a barrier to immune cell infiltration

This is an Accepted Manuscript of an article published by Taylor & Francis in OncoImmunology on 1 Dec 2013, available online: https://doi.org/10.4161/onci.2678

Fibroblast growth factor family as a potential target in the treatment of hepatocellular carcinoma.

Hepatocellular cancer (HCC) is currently the third leading cause of cancer death worldwide. The prognosis of patients diagnosed with late-stage disease is dismal due to high resistance to conventional systemic therapies. The introduction of sorafenib, despite its limited efficacy, as the standard systemic therapy for advanced HCC has paved a way for targeted molecular therapies for HCC. Fibroblast growth factor (FGF) signaling plays an important role in the developing embryo and the adult. The FGF signaling pathway is often hijacked by cancer cells, including HCC. Several alterations in FGF signaling correlate with poor outcome in HCC patients, suggesting that this family of signaling molecules plays an important role in the development of HCC. Multikinase inhibitors targeting FGF signaling are currently under investigation in clinical trials. This review discusses the current understanding of the biological and clinical implications of aberrant FGF signaling in the prognosis, diagnosis, and treatment of HCC

Longitudinal profiling of circulating tumour DNA for tracking tumour dynamics in pancreatic cancer.

BACKGROUND: The utility of circulating tumour DNA (ctDNA) for longitudinal tumour monitoring in pancreatic ductal adenocarcinoma (PDAC) has not been explored beyond mutations in the KRAS proto-oncogene. Here, we aimed to characterise and track patient-specific somatic ctDNA variants, to assess longitudinal changes in disease burden and explore the landscape of actionable alterations. METHODS: We followed 3 patients with resectable disease and 4 patients with unresectable disease, including 4 patients with ≥ 3 serial follow-up samples, of whom 2 were rare long survivors (> 5 years). We performed whole exome sequencing of tumour gDNA and plasma ctDNA (n = 20) collected over a ~ 2-year period from diagnosis through treatment to death or final follow-up. Plasma from 3 chronic pancreatitis cases was used as a comparison for analysis of ctDNA mutations. RESULTS: We detected > 55% concordance between somatic mutations in tumour tissues and matched serial plasma. Mutations in ctDNA were detected within known PDAC driver genes (KRAS, TP53, SMAD4, CDKN2A), in addition to patient-specific variants within alternative cancer drivers (NRAS, HRAS, MTOR, ERBB2, EGFR, PBRM1), with a trend towards higher overall mutation loads in advanced disease. ctDNA alterations with potential for therapeutic actionability were identified in all 7 patients, including DNA damage response (DDR) variants co-occurring with hypermutation signatures predictive of response to platinum chemotherapy. Longitudinal tracking in 4 patients with follow-up > 2 years demonstrated that ctDNA mutant allele fractions and clonal trends were consistent with CA19-9 measurements and/or clinically reported disease burden. The estimated prevalence of 'stem clones' was highest in an unresectable patient where changes in ctDNA dynamics preceded CA19-9 levels. Longitudinal evolutionary trajectories revealed ongoing subclonal evolution following chemotherapy. CONCLUSION: These results provide proof-of-concept for the use of exome sequencing of serial plasma to characterise patient-specific ctDNA profiles, and demonstrate the sensitivity of ctDNA in monitoring disease burden in PDAC even in unresectable cases without matched tumour genotyping. They reveal the value of tracking clonal evolution in serial ctDNA to monitor treatment response, establishing the potential of applied precision medicine to guide stratified care by identifying and evaluating actionable opportunities for intervention aimed at optimising patient outcomes for an otherwise intractable disease

A Case Report on Longitudinal Collection of Tumour Biopsies for Gene Expression-Based Tumour Microenvironment Analysis from Pancreatic Cancer Patients Treated with Endoscopic Ultrasound Guided Radiofrequency Ablation.

BACKGROUND: Most patients with pancreatic ductal adenocarcinoma (PDAC) are metastatic at presentation with dismal prognosis warranting improved systemic therapy options. Longitudinal sampling for the assessment of treatment response poses a challenge for validating novel therapies. In this case study, we evaluate the feasibility of collecting endoscopic ultrasound (EUS)-guided longitudinal fine-needle aspiration biopsies (FNABs) from two PDAC patients and conduct gene expression studies associated with tumour microenvironment changes associated with radiofrequency ablation (RFA). METHODS: EUS-guided serial/longitudinal FNABs of tumour were collected before and after treatment from two stage III inoperable gemcitabine-treated PDAC patients treated with targeted RFA three times. Biopsies were analysed using a custom NanoString panel (144 genes) consisting of cancer and cancer-associated fibroblast (CAFs) subtypes and immune changes. CAF culture was established from one FNAB and characterised by immunofluorescence and immunoblotting. RESULTS: Two-course RFA led to the upregulation of the CD1E gene (involved in antigen presentation) in both patients 1 and 2 (4.5 and 3.9-fold changes) compared to baseline. Patient 1 showed increased T cell genes (CD4-8.7-fold change, CD8-35.7-fold change), cytolytic function (6.4-fold change) and inflammatory response (8-fold change). A greater than 2-fold upregulation of immune checkpoint genes was observed post-second RFA in both patients. Further, two-course RFA led to increased PDGFRα (4.5-fold change) and CAF subtypes B and C genes in patient 1 and subtypes A, B and D genes in patient 2. Patient 2-derived CAFs post-first RFA showed expression of PDGFRα, POSTN and MYH11 proteins. Finally, RFA led to the downregulation of classical PDAC subtype-specific genes in both patients. CONCLUSIONS: This case study suggests longitudinal EUS-FNAB as a potential resource to study tumour and microenvironmental changes associated with RFA treatment. A large sample size is required in the future to assess the efficacy and safety of the treatment and perform comprehensive statistical analysis of EUS-RFA-based molecular changes in PDAC

Lymphoepithelial Cyst of the Pancreas.

The final, published version of this article is available at doi: 10.1159/000445373Lymphoepithelial cyst (LEC) of the pancreas is an extremely rare, benign pancreatic cystic lesion that is difficult to differentiate preoperatively from other cystic pancreatic lesions. LEC may have malignant potential. Here, we describe a case of LEC of the pancreas - initially suspected to be a mucinous cyst neoplasm - in an elderly man presenting with abdominal pain, who went on to have a distal pancreatectomy and splenectomy. We also review the relevant literature and discuss implications for the diagnosis and management of this rare lesion

Alteration in emergency theatre prioritisation does not alter outcome for acute appendicitis: comparative cohort study.

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.BACKGROUND: Despite dedicated emergency theatre, emergency surgery can be often delayed due to competing urgencies, suggesting a need for innovative theatre time management. AIM: To investigate if a change in the emergency theatre prioritisation affects outcomes for a common urgent operation such as appendicectomy. METHODS: We prospectively recorded data from 67 patients undergoing appendicectomy, for two cohorts of patients: before and after change in theatre prioritisation: Group 1 (Jan-Mar) and 2 (Aug-Oct) respectively. Demographic and peri-operative data, time from admission to surgery, postoperative length of stay and total length of stay and complications were compared. RESULTS: The two groups were comparable with regards to gender, age, time of admission and histological confirmation of appendicitis. No differences between the two groups were found regarding time from admission to surgery (24.4 (95% CI 11.2;27.6) hours versus 16.1 (95% CI 10.4;21.7) hours, Mann-Whitney U test, p = 0.35), postoperative length of stay (90.8 (95% CI 61.4;120.1) hours versus 70 (95% CI 48.3;91.6) hours, Mann-Whitney U test, p = 0.25) and total length of stay (115.2 (95% CI 84.6;145.7) hours versus 86 (95% CI 61.6;110.4) hours, Mann-Whitney U test, p = 0.07) as well as complication or re-admission rates. CONCLUSION: A change in the emergency theatre prioritisation does not affect outcome for appendicectomy. Provision of a second emergency theatre could be a solution to reduce the delays in acute surgical operations