Concurrent use of two dual-combination drenches containing monepantel/abamectin and oxfendazole/levamisole in sheep: effect on marker residues 21 and 28 days after administration.

AIMS: To determine the concentration, in comparison with the maximum residue limit (MRL), of anthelmintic marker residues in the target tissues (liver and fat) of sheep treated concurrently with two oral drenches, one containing monepantel and abamectin and the other oxfendazole and levamisole. METHODS: On day 0 of the study, 12 sheep (six male and six female; 8-9-months old) were dosed according to individual body weight determined the day prior. Zolvix Plus (dual-active oral drench containing 25 g/L monepantel and 2 g/L abamectin) was administered to all animals prior to administration of Scanda (dual-active oral drench containing 80 g/L levamisole hydrochloride and 45.3 g/L oxfendazole). Six sheep (three male and three female) were slaughtered 21 and 28 days after treatment and renal fat and liver samples were collected.Using validated methods, analyses for monepantel sulfone, abamectin, levamisole and oxfendazole (expressed as total fenbendazole sulfone following conversion of the combined concentrations of oxfendazole, fenbendazole and fenbendazole sulfone) were performed on liver samples while renal fat specimens were analysed for monepantel sulfone and abamectin residues only. Detected concentrations were compared to the established MRL in sheep for each analyte determined by the Ministry for Primary Industries. RESULTS: All residues detected in samples of liver and fat collected 21 and 28 days after treatment were below the MRL for each analyte. All liver samples collected on day 21 had detectable monepantel sulfone (mean 232 (min 110, max 388) µg/kg) and oxfendazole (mean 98.7 (min 51.3, max 165) µg/kg) residues below the MRL (5,000 and 500 µg/kg, respectively). Monepantel sulfone (mean 644 (min 242, max 1,119) µg/kg; MRL 7,000 µg/kg) residues were detected in 6/6 renal fat samples. Levamisole residues were detected in 3/6 livers (mean 40.0 (min 14.3, max 78.3) µg/kg; MRL 100 µg/kg), and abamectin residues in 1/6 livers (0.795 µg/kg; MRL 25 µg/kg) and 2/6 fat samples, (mean 0.987 (min 0.514, max 1.46) µg/kg; MRL 50 µg/kg) 21 days after treatment. CONCLUSION AND CLINICAL RELEVANCE: These results suggest that concurrent administration of Zolvix Plus and Scanda to sheep is unlikely to result in an extended residue profile for any of the active ingredients, with all analytes measured being under the approved New Zealand MRL 21 days after treatment. This work was not completed in line with guidance for establishing official residue profiles, nor is it sufficient to propose a new withholding period.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy.

BACKGROUND: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification. METHODS: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure. RESULTS: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group. CONCLUSION: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge.

Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions.

BACKGROUND: Semiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA. PATIENTS AND METHODS: This single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS-FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome. RESULTS: 91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01-43.94 95% CI vs 44.00; 32.42-55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison. CONCLUSION: Semiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging.

Outcome after surgical resection for duodenal adenocarcinoma in the UK.

BACKGROUND: Factors influencing long-term outcome after surgical resection for duodenal adenocarcinoma are unclear. METHODS: A prospectively created database was reviewed for patients undergoing surgery for duodenal adenocarcinoma in six UK hepatopancreaticobiliary centres from 2000 to 2013. Factors influencing overall survival and disease-free survival (DFS) were identified by regression analysis. RESULTS: Resection with curative intent was performed in 150 (84·3 per cent) of 178 patients. The postoperative morbidity rate for these patients was 40·0 per cent and the in-hospital mortality rate was 3·3 per cent. Patients who underwent resection had a better median survival than those who had a palliative surgical procedure (84 versus 8 months; P < 0·001). The 1-, 3- and 5-year overall survival rates for patients who underwent resection were 83·9, 66·7 and 51·2 per cent respectively. Median DFS was 53 months, and 1- and 3-year DFS rates were 80·8 and 56·5 per cent respectively. Multivariable analysis revealed that node status (hazard ratio 1·73, 95 per cent c.i. 1·07 to 2·79; P = 0·006) and lymphovascular invasion (hazard ratio 3·49, 1·83 to 6·64; P = 0·003) were associated with overall survival. CONCLUSION: Resection of duodenal adenocarcinoma in specialist centres is associated with good long-term survival. Lymphovascular invasion and nodal metastases are independent prognostic indicators.

Exploiting inflammation for therapeutic gain in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

'Do we know if we need to reduce head impact exposure?': A mixed-methods study highlighting the varied understanding of the long-term risk and consequence of head impact exposure across all stakeholders at the highest level of rugby union.

Background: One strategy to prevent and manage concussion is to reduce head impacts, both those resulting in concussion and those that do not. Because objective data on the frequency and intensity of head impacts in rugby union (rugby) are sparse, stakeholders resort to individual perceptions to guide contact training. It is unknown whether there is a level of contact training that is protective in preparing elite players for contact during matches. Objectives: This study aimed to describe how contact training is managed in elite male rugby, and how staff and players perceive contact training load and head impact load. Methods: This was a sequential explanatory mixed-methods study. Forty-four directors of rugby, defence coaches, medical and strength/conditioning staff and 23 players across all 13 English Premiership Rugby Union clubs and the National senior team participated in semi-structured focus groups and completed two bespoke questionnaires. Results: The study identified the varied understanding of what constitutes head impact exposure across all stakeholder groups, resulting in different interpretations and a range of management strategies. The findings suggest that elite clubs conduct low levels of contact training; however, participants believe that some exposure is required to prepare players and that efforts to reduce head impact exposure must allow for individualised contact training prescription. Conclusion: There is a need for objective data, possibly from instrumented mouthguards to identify activities with a high risk for head impact and possible unintended consequences of reduced exposure to these activities. As data on head impact exposure develop, this must be accompanied with knowledge exchange within the rugby community.

Novel Antarctic yeast adapts to cold by switching energy metabolism and increasing small RNA synthesis.

The novel extremophilic yeast Rhodotorula frigidialcoholis, formerly R. JG1b, was isolated from ice-cemented permafrost in University Valley (Antarctic), one of coldest and driest environments on Earth. Phenotypic and phylogenetic analyses classified R. frigidialcoholis as a novel species. To characterize its cold-adaptive strategies, we performed mRNA and sRNA transcriptomic analyses, phenotypic profiling, and assessed ethanol production at 0 and 23 °C. Downregulation of the ETC and citrate cycle genes, overexpression of fermentation and pentose phosphate pathways genes, growth without reduction of tetrazolium dye, and our discovery of ethanol production at 0 °C indicate that R. frigidialcoholis induces a metabolic switch from respiration to ethanol fermentation as adaptation in Antarctic permafrost. This is the first report of microbial ethanol fermentation utilized as the major energy pathway in response to cold and the coldest temperature reported for natural ethanol production. R. frigidialcoholis increased its diversity and abundance of sRNAs when grown at 0 versus 23 °C. This was consistent with increase in transcription of Dicer, a key protein for sRNA processing. Our results strongly imply that post-transcriptional regulation of gene expression and mRNA silencing may be a novel evolutionary fungal adaptation in the cryosphere.

Accuracy of endoscopic ultrasound elastography used for differential diagnosis of focal pancreatic masses: a multicenter study.

BACKGROUND AND STUDY AIMS: Endoscopic ultrasound (EUS) elastography represents a new imaging procedure that might characterize the differences of hardness and strain between diseased tissue and normal tissue. The aim of this study was to assess the efficiency of EUS elastography for the differentiation of focal masses in chronic pancreatitis and pancreatic cancer. PATIENTS AND METHODS: The study group comprised 258 patients with focal pancreatic masses included prospectively at 13 participating centers. Qualitative analysis of the diagnoses made by two expert doctors using all recorded video clips was performed in order to test the interobserver variability. A post-processing software analysis was used to examine the EUS elastography videos by calculating average-hue histograms of individual elastography images. The quantitative information was used to calculate intra-observer variability and the accuracy of the method. RESULTS: Qualitative analysis of the recorded videos revealed a kappa value of 0.72. Intra-observer variability analysis revealed that the single measure intraclass correlation ranged between 0.86 and 0.94. The average-hue histogram analysis of the data indicated a sensitivity of 93.4 %, a specificity of 66.0 %, a positive predictive value of 92.5 %, a negative predictive value of 68.9 %, and an overall accuracy of 85.4 %, based on a cut-off value of 175. Area under the receiver operating characteristic curve (AUROC) was 0.854 ( P < 0.0001) with a confidence interval of 0.804 - 0.894. CONCLUSION: The value of quantitative analysis of EUS elastography recordings was proven by good reproducibility of the videos, as well as good parameters of the AUROC analysis. (Clinical Trials.gov identifier: CT00909103).