Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy

The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1-2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review

A case-control study comparing the incidence of early symptoms in pancreatic and biliary tract cancer.

Pancreatic ductal adenocarcinoma (PDAC) and biliary tract cancers (BTC) are often diagnosed late and at an advanced stage. Population-based screening programmes do not exist and diagnosis is primarily dependent on symptom recognition. Recently symptom-based cancer decision support tools (CDSTs) have been introduced into primary care practices throughout the UK to support general practitioners (GPs) in identifying patients with suspected PDAC. However, future refinement of these tools to improve their diagnostic accuracy is likely to be necessary

Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint.

PURPOSE: Cdc7 is a serine/threonine kinase which is responsible for the 'firing' of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer. EXPERIMENTAL DESIGN: Cdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491). RESULTS: Cdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491. CONCLUSIONS: Our findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase

Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in biliary brush cytology

Background: Biliary brush cytology is the standard method of evaluating biliary strictures, but is insensitive at detecting malignancy. In pancreaticobiliary cancer minichromosome maintenance replication proteins (MCM 2–7) are dysregulated in the biliary epithelium and MCM5 levels are elevated in bile samples. This study aimed to validate an immunocolorimetric ELISA assay for MCM5 as a pancreaticobiliary cancer biomarker in biliary brush samples. methods: Biliary brush specimens were collected prospectively at ERCP from patients with a biliary stricture. Collected samples were frozen at −80 °C. The supernatant was washed and lysed cells incubated with HRP-labelled anti-MCM5 mouse monoclonal antibody. Test positivity was determined by optical density absorbance. Patients underwent biliary brush cytology or additional investigations as per clinical routine. results: Ninety-seven patients were included in the study; 50 had malignant strictures. Median age was 65 years (range 21–94) and 51 were male. Compared with final diagnosis the MCM5 assay had a sensitivity for malignancy of 65.4% compared with 25.0% for cytology. In the 72 patients with paired MCM5 assay and biliary brush cytology, MCM5 demonstrated an improved sensitivity (55.6% vs 25.0%; P=0.0002) for the detection of malignancy. conclusions: Minichromosome maintenance replication protein5 is a more sensitive indicator of pancreaticobiliary malignancy than standard biliary brush cytology

Determination of optimal ultrasound planes for the initialisation of image registration during endoscopic ultrasound-guided procedures

PURPOSE: Navigation of endoscopic ultrasound (EUS)-guided procedures of the upper gastrointestinal (GI) system can be technically challenging due to the small fields-of-view of ultrasound and optical devices, as well as the anatomical variability and limited number of orienting landmarks during navigation. Co-registration of an EUS device and a pre-procedure 3D image can enhance the ability to navigate. However, the fidelity of this contextual information depends on the accuracy of registration. The purpose of this study was to develop and test the feasibility of a simulation-based planning method for pre-selecting patient-specific EUS-visible anatomical landmark locations to maximise the accuracy and robustness of a feature-based multimodality registration method. METHODS: A registration approach was adopted in which landmarks are registered to anatomical structures segmented from the pre-procedure volume. The predicted target registration errors (TREs) of EUS-CT registration were estimated using simulated visible anatomical landmarks and a Monte Carlo simulation of landmark localisation error. The optimal planes were selected based on the 90th percentile of TREs, which provide a robust and more accurate EUS-CT registration initialisation. The method was evaluated by comparing the accuracy and robustness of registrations initialised using optimised planes versus non-optimised planes using manually segmented CT images and simulated ([Formula: see text]) or retrospective clinical ([Formula: see text]) EUS landmarks. RESULTS: The results show a lower 90th percentile TRE when registration is initialised using the optimised planes compared with a non-optimised initialisation approach (p value [Formula: see text]). CONCLUSIONS: The proposed simulation-based method to find optimised EUS planes and landmarks for EUS-guided procedures may have the potential to improve registration accuracy. Further work will investigate applying the technique in a clinical setting

Endoscopic versus percutaneous drainage of symptomatic pancreatic fluid collections: a 14-year experience from a tertiary hepatobiliary centre

INTRODUCTION: Endoscopic transmural drainage (ED) or percutaneous drainage (PD) has mostly replaced surgery for the initial management of patients with symptomatic pancreatic fluid collections (PFCs). This study aimed to compare outcomes for patients undergoing ED or PD of symptomatic PFCs. METHODS: Between January 2000 and December 2013, all patients who required PD or ED of a PFC were included. Rates of treatment success, length of hospital stay, adverse events, re-interventions and length of follow-up were recorded retrospectively in all cases. RESULTS: In total, 164 patients were included in the study; 109 patients underwent ED; and 55 had PD alone. During the 14-year study period, the incidence of ED increased and PD fell. In the 109 patients who were managed by ED, treatment success was considerably higher than in those managed by PD (70 vs. 31 %). Rates of procedural adverse events were higher in the ED cohort compared to the PD group (10 vs. 1 %), but patients managed by ED required fewer interventions (median of 1.8 vs. 3.3) had lower rates of residual collections (21 vs. 67 %) and need for surgical intervention (4 vs. 11 %). In the ED group, treatment success was similar for walled-off pancreatic necrosis (WOPN) and pseudocysts (67 vs. 72 %, P = 0.77). There were no procedure-related deaths. CONCLUSION: Compared with PD, ED of symptomatic PFCs was associated with higher rates of treatment success, lower rates of re-intervention, including surgery and shorter lengths of hospital stay. Outcomes in WOPN were comparable to those in patients with pseudocysts

The use of transdermal optical coherence tomography to image the superficial temporal arteries

PURPOSE: The diagnosis of Giant Cell Arteritis (GCA) is an area of major challenge. This is the first reported use of the directed use of transdermal optical coherence tomography (OCT) to image the superficial temporal artery (STA). METHODS: This proof of concept study used a commercially available transdermal OCT instrument to identify and image the STA in eight patients (suspected GCA, confirmed GCA, and in healthy controls). Three cases are presented to demonstrate the preliminary imaging findings. RESULTS: In all eight cases the STA was identified. Imaging findings from three cases are presented. A hyper-reflective signal was seen, which distinguishes the artery from vein. In two cases, a ratio of band thickness (BT) to arterial lumen diameter (ALD) could be calculated (BT : ALD ratio) where the whole circumference of the artery was imaged. DISCUSSION: Using dermal OCT to image the temporal arteries is a novel concept. With ongoing advances in resolution, penetration, and blood flow detection; this non-invasive technology warrants further investigation to determine its role in Giant Cell Arteritis

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR

Sociodemographic Trends in the Incidence of Pancreatic and Biliary Tract Cancer in UK Primary Care

The UK incidence of pancreatic ductal adenocarcinoma (PDAC) is approximately 9/100,000 population compared with 1-2/100,000 for biliary tract cancer (BTC). This study explores the incidence of these cancers over time and the influence of socio-demographic and geographic factors in a UK primary care cohort