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.

Are there missed opportunities for vaccinating against hepatitis B among people who inject drugs in the UK?

Sustaining the impact of hepatitis B virus (HBV) vaccination on incidence and prevalence of HBV infection requires increasing and maintaining the uptake of vaccine among those at risk. In recent years, the level of vaccine uptake among people who inject drugs (PWID) in the UK has levelled-off. Data (2015-2016) from the national unlinked-anonymous monitoring survey of PWID, an annual survey that collects data from PWID across England, Wales and Northern Ireland, were used to examine HBV vaccine uptake. Data from participants who had injected drugs during the previous year were used to investigate sources of hepatitis B vaccine doses as well as factors associated with vaccine uptake. Among the 3175 anti-HBc-negative participants, 3138 (99%) reported their vaccination status; 23% (714) reported no vaccine uptake. Among those not vaccinated, 447 (63%) reported being sexually active and 116 (16%) reported sharing needles and syringes. Majority of those not vaccinated reported accessing services in the previous year that could have provided hepatitis B vaccine doses. These missed opportunities for vaccinating of PWID indicate a need for additional targeted interventions.

Tumour stage and resection margin status are independent survival factors following partial pancreatoduodenectomy for duodenal adenocarcinoma.

INTRODUCTION: There is limited published evidence on duodenal carcinoma due to its rarity. This study aimed to evaluate gastric outlet obstruction and obstructive jaundice along with pathological variables as survival factors in patients with duodenal adenocarcinoma following resection. METHODS: Survival factor analysis was undertaken in patients undergoing duodenal cancer surgery from 1997 to 2015 in a single centre. RESULTS: There were 57 patients of whom 18 had gastric outlet obstruction and 14 had obstructive jaundice. Fifty-three had a partial pancreatoduodenectomy and four had palliative bypass. Perioperative mortality and morbidity were 4% (2/53) and 47% (25/53) respectively in resected patients. With a median (95% confidence interval, CI) follow-up of 72 (57-86) months, median overall and recurrence-free survival was 38 months (95% CI 28-113) and 27 months (95% CI 18-83) respectively. The 1 and 3-year overall survival rates were 84% (95% CI 74-95) and 52% (95% CI 39-69) respectively. Median overall survival was 19 months in patients with gastric outlet obstruction vs 53 months in those without (p = 0.026) and 28 months in patients with obstructive jaundice vs 38 months in those without (p = 0.611). Univariate analysis revealed that tumour stage, resection margin status, pre-operative albumin status, gastric outlet obstruction and age were associated with poorer overall and recurrence-free survival but multivariate analysis confirmed only tumour stage and resection margin status to be significant. CONCLUSION: Whereas gastric outlet obstruction in duodenal cancer appeared to be an important survival factor following partial pancreatoduodenectomy, multivariate analysis showed that only tumour stage and resection margin status were the key independent survival factors. Further multicentre studies are required to elucidate further characteristics of duodenal carcinoma and develop neoadjuvant/adjuvant management strategies.

The Liverpool duodenum-and spleen-preserving near-total pancreatectomy can provide long-term pain relief in patients with end-stage chronic pancreatitis.

PURPOSE: Total pancreatectomy may improve symptoms in patients with severe end-stage chronic pancreatitis. This might be achieved whilst preserving both the duodenum- and spleen-(DPSPTP). Mature clinical outcomes of this approach are presented. METHODS: Single-centre prospective cohort study performed between September 1996 and May 2016. Demographic, clinical details, pain scores and employment status were prospectively recorded during clinic attendance. RESULTS: Fifty-one patients (33 men, 18 women) with a median (interquartile range) age of 40.8 (35.3-49.4) years, a median weight of 69.8 (61.0-81.5) Kg and a median body mass index of 23.8 (21.5-27.8), underwent intended duodenum-and spleen-preserving near-total pancreatectomy for end-stage chronic pancreatitis. Aetiology was excess alcohol in 25, idiopathic (no mutation) in 15, idiopathic (SPINK-1/CFTR mutations) in two, hereditary (PRSS1 mutation) in seven and one each post-necrotising pancreatitis and obstructive pancreatic duct divisum in 1. The main indication for surgery was severe pain. Findings included parenchymal calcification in 79% and ductal calculi in 24%, a dilated main pancreatic duct in 57% and a dilated main bile duct in 17%, major vascular involvement in 27% and pancreato-peritoneal fistula in 2%. Postoperative complications occurred in 20 patients with two deaths. Median pain scores were 8 (7-8) preoperatively and 3 (0.25-5.75) at 5 years (p = 0.013). Opiate analgesic use was significantly reduced postoperatively (p = 0.048). Following surgery, 22 (63%) of 38 patients of working age re-entered employment compared with 12 (33%) working preoperatively (p = 0.016). CONCLUSION: Duodenum-and spleen-preserving near-total pancreatectomy provided long-term relief in adult patients with intractable chronic pancreatitis pain, with improved employment prospects.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Assessment of the comparability of CLSI, EUCAST and Stokes antimicrobial susceptibility profiles for Escherichia coli uropathogenic isolates.

BACKGROUND: As many clinical laboratories convert between Stokes, Clinical and Laboratory Standards Institute (CLSI) and European Committee for Antimicrobial Susceptibility Testing (EUCAST) methods, the problem of comparing differently derived sets of antimicrobial susceptibility testing (AST) data with each other arises, owing to a scarcity of knowledge of inter-method comparability. The purpose of the current study was to determine the comparability of CLSI, EUCAST and Stokes AST methods for determining susceptibility of uropathogenic Escherichia coli to ampicillin, amoxicillin-clavulanate, trimethoprim, cephradine/cephalexin, ciprofloxacin and nitrofurantoin. METHODS: A total of 100 E. coli isolates were obtained from boric acid urine samples from patients attending GP surgeries. For EUCAST and CLSI, the Kirby-Bauer disc diffusion method was used and results interpreted using the respective breakpoint guidelines. For the Stokes method, direct susceptibility testing was performed on the urine samples. RESULTS: The lowest levels of agreement were for amoxicillin-clavulanate (60%) and ciprofloxacin (89%) between the three AST methods, when using 2017 interpretive guidelines for CLSI and EUCAST. A comparison of EUCAST and CLSI without Stokes showed 82% agreement for amoxicillin-clavulanate and 94% agreement for ciprofloxacin. Discrepancies were compounded by varying breakpoint susceptibility guidelines issued during the period 2011-2017, and through the inclusion of a definition of intermediate susceptibility in some cases. CONCLUSIONS: Our data indicate that the discrepancies generated through using different AST methods and different interpretive guidelines may result in confusion and inaccuracy when prescribing treatment for urinary tract infection.

In vitro suppression of drug-induced methaemoglobin formation by Intralipid(®) in whole human blood: observations relevant to the 'lipid sink theory'.

To provide further evidence for the lipid sink theory, we have developed an in vitro model to assess the effect of Intralipid® 20% on methaemoglobin formation by drugs of varying lipid solubility. Progressively increasing Intralipid concentrations from 4 to 24 mg.ml⁻¹ suppressed methaemoglobin formation by the lipid soluble drug glyceryl trinitrate in a dose-dependent manner (p < 0.001). Both dose and timing of administration of Intralipid to blood previously incubated with glyceryl trinitrate for 10 and 40 min resulted in significant suppression of methaemoglobin formation (p < 0.0001 and p < 0.05, respectively). Mathematical modelling demonstrated that the entire process of methaemoglobin formation by glyceryl trinitrate was slowed down in the presence of Intralipid. Intralipid did not significantly suppress methaemoglobin formation induced by 2-amino-5-hydroxytoluene (partially lipid soluble) or sodium nitrite (lipid insoluble; both p > 0.5). This work may assist determination of the suitability of drugs taken in overdose for which Intralipid might be deployed.

Mycobacterium avium infection associated with sterile polyarthritis in a dog.

A 1-year-old male neutered Portuguese Podengo dog was presented for lameness, inappetence, pyrexia, diarrhoea and abdominal moderate to severe lymphadenomegaly. Cytology of synovial fluid revealed neutrophilic inflammation in multiple joints suggestive of immune-mediated polyarthritis. Cytology of fine-needle-aspiration material obtained from lymph nodes revealed macrophages with intracytoplasmic, rod-like Ziehl-Neelsen positive staining structures, indicative of mycobacteria. Four-month treatment with enrofloxacin, rifampicin and clarithromycin resulted in clinical improvement and resolution of polyarthritis as evidenced on repeat synoviocentesis, but diarrhoea recurred, Ziehl-Neelsen positive organisms were again found on lymph node cytology and analysis of the 16S rRNA-gene using the Basic Local Alignment Search Tool facility resulted in a match to Mycobacterium avium with 100% sequence identity. Treatment was adjusted to include pradofloxacin, doxycycline, rifampicin and ethambutol and 3 months later the dog is clinically normal. Based on the literature search, this is the first time canine Mycobacterium avium infection associated with immune-mediated polyarthritis is reported. Based on scoping searches, this is the first report of canine Mycobacterium avium infection associated with immune-mediated polyarthritis.

CTSim: Changing teaching practice in radiography with simulation.

INTRODUCTION: Simulation offers radiography students the possibility to experiment with Computed Tomography (CT) in a way not possible in clinical practice. The aim of this work was to test a newly developed simulator 'CTSim' for effectiveness in teaching and learning. METHODS: The simulator was tested in two phases. The first phase used a test-retest methodology with two groups, a group that experienced a Simulation based learning intervention and one which did not. The second phase subsequently tested for changes when the same intervention was introduced as part of an existing CT training module. RESULTS: Phase 1 demonstrated statistically significant improvement of mean scores from 58% to 68% (P < .05) for students who experienced the intervention against no change in scores for the control group. Phase 2 saw mean scores improve statistically significantly in a teaching module from 66% to 73% (P < .05) following the application of the intervention as an active learning component. CONCLUSION: The use of the CTSim simulator had a demonstrable effect on student learning when used as an active learning component in CT teaching. IMPLICATIONS FOR PRACTICE: Simulation tools have a place in enhancing teaching and learning in terms of effectiveness and also introduce variety in the medium by which this is done.

Carbohydrate antigen 19.9 accurately selects patients for laparoscopic assessment to determine resectability of pancreatic malignancy.

BACKGROUND: Laparoscopy with laparoscopic ultrasonography (L-LUS) may be useful in the selection of patients for surgery to resect peripancreatic malignancy in addition to contrast-enhanced computed tomography (CE-CT). The present prospective study assessed the strategy of using carbohydrate antigen 19.9 (CA19.9) levels to select patients for L-LUS. METHODS: Patients with suspected peripancreatic malignancy that appeared resectable on CE-CT were selected for immediate surgery if CA19.9 was low (up to 150 kU/l, or up to 300 kU/l if serum bilirubin was above 35 micromol/l), or to L-LUS if CA19.9 was high (over 150 kU/l, or over 300 kU/l if serum bilirubin was above 35 micromol/l). Data were assessed to determine the clinical utility of this strategy. RESULTS: A total of 94 patients went straight to surgery, of whom 65 proved resectable: 63 of 80 with a low CA19.9 level but only two of 14 with a high CA19.9 level and gastric outlet obstruction. From 55 patients with high CA19.9 levels, L-LUS correctly identified 26 of 31 resectable tumours and eight of 24 unresectable tumours. CONCLUSION: Using CA19.9 levels to help select patients with pancreatic malignancy for immediate surgery or L-LUS for further assessment of resectability effectively increased resection rates and reduced unnecessary laparotomies.

Cytokine and Chemokine Concentrations as Biomarkers of Feline Mycobacteriosis.

Mycobacteriosis is an emerging zoonotic disease of domestic cats and timely, accurate diagnosis is currently challenging. To identify differential cytokine/chemokine concentrations in serum/plasma of cats, which could be diagnostic biomarkers of infection we analysed plasma/serum from 116 mycobacteria-infected cats, 16 healthy controls and six cats hospitalised for unrelated reasons was analysed using the Milliplex MAP Feline Cytokine Magnetic Bead multiplex assay. Three cytokines; sFAS, IL-13 and IL-4 were reduced while seven; GM-CSF, IL-2, PDGF-BB, IL-8, KC, RANTES and TNF-α were elevated in mycobacteria-infected cats compared to healthy controls. However, IL-8 and KC concentrations were not significantly different from cats hospitalised for other reasons. Elevations in TNF-α and PDGF-BB may have potential to identify M. bovis and M. microti infected cats specifically while GM-CSF, IL-2 and FLT3L were increased in MTBC infected cats. This study demonstrates potential use of feline tuberculosis as a spontaneously occurring model of this significant human disease. Cytokine profiling has clear diagnostic potential for mycobacteriosis of cats and could be used discriminate tuberculous from non-tuberculous disease to rapidly inform on zoonotic risk. Future work should focus on the in-field utility of these findings to establish diagnostic sensitivity and specificity of these markers.

No longer 'written off' - times have changed for the BBV-infected dental professional.

There is a recognised potential risk of transmission of blood-borne viruses (BBVs) from infected healthcare workers to patients during exposure prone procedures (EPPs). The restrictions placed on performance of EPPs by infected clinicians in the UK have had a particularly significant impact on dentists because of the exposure-prone nature of most dental procedures and the difficulties in identifying alternative career pathways in the profession that do not involve EPPs. More recently, the significant positive impact of antiviral drugs on viral load, together with a re-categorisation of EPPs in dentistry have resulted in evolution of the guidance with a consequent significant improvement to the career prospects of dentists infected with BBVs. This paper provides an update for practitioners on the progress that has been made and outlines the current position with respect to practice restrictions.

The predictive utility of behavior-based interviewing compared with traditional interviewing in the selection of radiology residents.

RATIONALE AND OBJECTIVES: This study compares the predictive use of measures based on traditional faculty and resident interviews of residency applicants with measures obtained through behavior-based interviewing. A special emphasis was placed on predicting residents' noncognitive abilities. METHODS: One hundred fifty-one resident applicants, over a 3-year period, were interviewed using standard interviews by faculty and residents. These residents also were interviewed with an experimental behavior-based accomplishment interview. Four years later, during their diagnostic radiology residency, evaluations of performance were gathered on these applicants from their residency director. RESULTS: Results indicated that scores based on responses given during the accomplishment interviews added considerable predictive utility to the low prediction demonstrated by traditional interviews. CONCLUSIONS: These findings imply that improving unstructured faculty and resident interviews to obtain, in a more rigorous manner, desired information about noncognitive abilities may be a key to successful resident selection.

Evaluation of resident applicants by letters of recommendation: a comparison of traditional and behavior-based formats.

RATIONALE AND OBJECTIVES: Traditional, narrative letters of recommendation solicited by medical students applying for radiology residency are widely used as a selection tool. Letters of recommendation are considered a source of reliable information about the attitudes and behaviors (non-cognitive variables) of the resident applicant. However, in many instances, this information is not present or is highly encoded and cannot be extracted. This study attempted to document the deficiencies of traditional letters of recommendation and determine the effectiveness of a structured letter of recommendation in obtaining information regarding noncognitive variables. METHODS: One hundred thirteen randomly selected letters of recommendation were analyzed by two radiologists with experience in residency selection. Deficiencies in inclusion of information or the ability to extract information about noncognitive variables were documented. A standard behavioral assessment was sent to the writers of these letters of recommendation and these results tabulated. RESULTS: The traditional letters of recommendation were frequently deficient in data regarding the noncognitive variables. In letters that contained such data, two experienced reviewers could not reliably extract the information. The structured form produced clearly identifiable information about the letter writer's assessment of noncognitive variables. CONCLUSIONS: Traditional letters of information are frequently deficient in data regarding noncognitive variables. A standardized statement is effective in eliciting information on noncognitive variables related to applicant performance.

Gene therapy for pancreatic cancer--current and prospective strategies.

Pancreatic ductal adenocarcinoma is one of the most common causes of cancer death in the developed world. Long-term survival is currently only achieved through surgical resection. Most patients have locally advanced or metastatic disease at the time of diagnosis and are therefore not amenable to resection, whilst chemotherapy and radiotherapy are by and large ineffective. Gene therapy offers an alternative to current adjuvant strategies. With approximately two-thirds of all gene therapy trials worldwide directed at cancer, the gene therapy approaches that are currently being explored for pancreatic cancer are specifically examined. Gene delivery systems, genetic targets, and combined gene delivery with chemotherapy are discussed in the context of pancreatic cancer treatment.

The efficacy of preparation for surgery and invasive medical procedures.

In this article, we review published research evaluating the effectiveness of preparation interventions for adult patients undergoing surgery or invasive medical procedures. This review is meant to assist practitioners in selecting or designing an intervention. In general, preparation interventions have been shown to be effective across a range of health outcomes. However, the relative efficacy of different strategies has been difficult to assess, as has the contribution of several patient variables to outcome. Considering interventions used prior to surgery, there is not a clear demonstration of effectiveness, in part because large numbers of outcome variables have been used. In contrast, the preparation intervention literature using adult patients facing invasive medical procedures has shown the relative superiority of modeling procedures and coping strategies. In this review, we consider methodological weaknesses in previous research, and make suggestions for improving future research.