Activation of protein kinase Cδ leads to increased pancreatic acinar cell dedifferentiation in the absence of MIST1.

Pancreatic ductal adenocarcinoma (PDAC) has a 5 year survival rate post-diagnosis of < 5%. Individuals with chronic pancreatitis (CP) are 20-fold more likely to develop PDAC, making it a significant risk factor for PDAC. While the relationship for the increased susceptibility to PDAC is unknown, loss of the acinar cell phenotype is common to both pathologies. Pancreatic acinar cells can dedifferentiate or trans-differentiate into a number of cell types including duct cells, ß cells, hepatocytes and adipocytes. Knowledge of the molecular pathways that regulate this plasticity should provide insight into PDAC and CP. MIST1 (encoded by Bhlha15 in mice) is a transcription factor required for complete acinar cell maturation. The goal of this study was to examine the plasticity of acinar cells that do not express MIST1 (Mist1(-/-) ). The fate of acinar cells from C57Bl6 or congenic Mist1(-/-) mice expressing an acinar specific, tamoxifen-inducible Cre recombinase mated to Rosa26 reporter LacZ mice (Mist1(CreERT/-) R26r) was determined following culture in a three-dimensional collagen matrix. Mist1(CreERT/-) R26r acini showed increased acinar dedifferentiation, formation of ductal cysts and transient increases in PDX1 expression compared to wild-type acinar cells. Other progenitor cell markers, including Foxa1, Sox9, Sca1 and Hes1, were elevated only in Mist1(-/-) cultures. Analysis of protein kinase C (PKC) isoforms by western blot and immunofluorescence identified increased PKCε accumulation and nuclear localization of PKCδ that correlated with increased duct formation. Treatment with rottlerin, a PKCδ-specific inhibitor, but not the PKCε-specific antagonist εV1-2, reduced acinar dedifferentiation, progenitor gene expression and ductal cyst formation. Immunocytochemistry on CP or PDAC tissue samples showed reduced MIST1 expression combined with increased nuclear PKCδ accumulation. These results suggest that the loss of MIST1 is a common event during PDAC and CP and events that affect MIST1 function and expression may increase susceptibility to these pathologies.

Support as a complement, intrusion and right--evidence from ageing and disability support service users in Sweden and Australia.

How service users conceptualise their personal support services is under researched, even though this understanding is important for responsive policy development and service implementation. This paper tests the proposition that service users understand formal support in three ways: support is a complement to their other arrangements, an intrusion into their personal life and a right. These three concepts were identified using discourse analysis in a Swedish study of older people wanting in-home support services. To test generalisability of these concepts, they were applied to data from an Australian study of people using disability personal support. The analysis found that the three concepts were core to people's views of their support, although the construction of the concepts differed in the two countries. Service users in Sweden asserted their right to services more forcefully than those in Australia, and they had higher expectations that their support needs would be met. These differences reflect the impact of each country's social policy environment on service users' expectations. The analysis suggests that service users and their families want to control their formal support arrangements to complement their informal care and their life preferences and to minimise the intrusive aspects of formal support. The findings imply that the three concepts have utility for theorising service users' perspectives, informing policy and developing implementation strategies which enhance peoples' quality of life.

The Utility of Endoscopic Biopsies in Patients with Normal Upper Endoscopy.

Background and Aims. Upper endoscopy is a valuable tool in the workup of gastrointestinal (GI) complaints. The purpose of this study is to determine cost and yield of taking biopsies in a normal upper GI tract. Methods. This is a retrospective study where all upper GI biopsies were identified between May 2012 and April 2013, at a tertiary care center. Clinical, procedural, and pathology reports were reviewed to identify patient demographics, procedure information, and pathology diagnosis. Results. Biopsies of the upper GI tract were taken in 1297 patients with normal upper endoscopies. In patients with normal upper endoscopy, 22% of esophageal, 44% of gastric, and 12% of duodenal biopsies were abnormal. The most frequent abnormality was reflux esophagitis in 16% of esophageal biopsies, chronic gastritis in 23% of gastric biopsies, and increased intraepithelial lymphocytes in 6% of duodenal biopsies. The additional cost for taking biopsies in a normal upper GI tract for a diagnosis of eosinophilic esophagitis was $2963 Canadian (CAD), H. pylori associated gastritis was $1404 CAD, and celiac disease was $3024 CAD. Conclusions. The yield of biopsy in normal upper endoscopy varied with location, but the additional expense can be costly and should be tailored to appropriate clinical situations.

Negative colorectal polyp biopsies: the utility of cutting deeper levels.

The objectives of this study were to determine the frequency with which deeper levels reveal a lesion in polyp biopsies where no polyp was found on initial sections and to identify features that predict such occult (histologically unapparent) lesions. All initially negative biopsy specimens were accumulated over an 18-month period. Following standard sections, three to ten levels were cut, 50 µm apart. The presence of any lesion, the level at which it was found, the location, number and size of fragments, number of levels obtained, presence of any lymphoid aggregate, endoscopic size and appearance, and bowel preparation quality were recorded. There were 214 specimens, mean patient age 61.4 years (range 27-86 years). Deeper levels revealed a lesion in 52/214 (24.3 %) cases; 76.9 % were tubular adenomas (TA), 21.2 % were hyperplastic polyps, and one was a leiomyoma. All TAs were negative for high-grade dysplasia and malignancy. The mean level at which TAs were found was 1.85 (range 1-9). Male sex (p = 0.021) and right-sided location (p = 0.0075) were statistically significant predictors of an occult TA. As the presence of an adenoma affects screening, pathologists should consider "pursuing" polyps when initial sections reveal no lesion, after ascertaining the incidence of occult lesions in their own practice.

Three dimensional transrectal ultrasound imaging of the prostate: initial experience with an emerging technology.

PURPOSE: A three-dimensional ultrasound system (3-D US) was evaluated for its clinical utility in transrectal prostate imaging, in comparison with the current standard 2-dimensional transrectal ultrasound (TRUS) imaging system. METHODS AND MATERIALS: The computer program developed in our laboratory was coupled with a commercially available ultrasound transducer. Geometric validation and volumetric assessment was performed with "stretched-string" wire models and solution-containing balloons respectively. Anatomic correlation of 3-D TRUS images was performed with cadaveric prostates. Intraprostatic lesion localization by 3D-TRUS was assessed clinically by 2 observers in 11 patients prior to radical prostatectomy and the data compared with those yielded by 2-D TRUS. RESULTS: Geometric assessment by 3D TRUS in comparison with the "between strings in the phantom" model (true dimensions) had an error of up to 1.2%. Volume measurement by 3-D TRUS had an error, compared to the true volume, of 0.9%. The correlation coefficient (r) was 0.99985 for the end-firing probe and 0.978 for side firing. The 3-D images provided accurate representation of the true anatomy in the sagittal, transverse and most uniquely, the coronal plane. Two observers achieved better diagnostic accuracies with intraprostatic abnormalities using 3-D instead of standard 2-D TRUS. The negative predictive value and the specificity were improved. CONCLUSION: 3-D TRUS appears to provided accurate representation of the true anatomy with geometric and volumetric validation. Areas of potential clinical application of 3-D TRUS include treatment monitoring with volume measurements and various intervention and therapeutic procedures for both benign and malignant prostatic disorders.

Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

BACKGROUND: Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. METHODS: A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. RESULTS: The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg/kg to 4.78 mg/kg/day. CONCLUSIONS: Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

Recurrent hepatocellular carcinoma after transplantation: use of a pathological score on explanted livers to predict recurrence.

Milan and University of California at San Francisco (UCSF) criteria are used to select patients with hepatocellular carcinoma (HCC) for liver transplantation (LT). Recurrent HCC is a significant cause of death. There is no widely accepted pathological assessment strategy to predict recurrent HCC after transplantation. This study compares the pathology of patients meeting Milan and UCSF criteria and develops a pathological score and nomogram to assess the risk of recurrent HCC after transplantation. All explanted livers with HCC from our center over the 18-yr period 1985 to 2003 were assessed for multiple pathological features and relevant clinical data were recorded; multivariate analysis was performed to determine features associated with recurrent HCC. Using pathological variables that independently predicted recurrent HCC, a pathological score and nomogram were developed to determine the probability of recurrent HCC. Of 75 cases analyzed, 50 (67%) met Milan criteria, 9 (12%) met only UCSF criteria and 16 (21%) met neither criteria based on explant pathology. There were 20 cases of recurrent HCC and the mean follow-up was 8 yr. Recurrent HCC was more common (67 vs. 12%; P < 0.001) and survival was lower (15 vs. 83% at 5 yr; 15 vs. 55% at 8 yr; P < 0.001) with those who met only UCSF criteria, compared to those who met Milan criteria. Cryptogenic cirrhosis (25 vs. 5%; P = 0.015), preoperative AFP >1,000 ng/mL (20 vs. 0%; P < 0.001) and postoperative OKT3 use (40 vs. 15%; P = 0.017) were more common among patients with recurrent HCC. While microvascular invasion was the strongest pathological predictor of recurrent HCC, tumor size >or=3 cm (P = 0.004; odds ratio [OR] = 7.42), nuclear grade (P = 0.044; OR = 3.25), microsatellitosis (P = 0.020; OR = 4.82), and giant/bizarre cells (P = 0.028; OR = 4.78) also predicted recurrent HCC independently from vascular invasion. The score and nomogram stratified the risk of recurrent HCC into 3 tiers: low (<5%), intermediate (40-65%), and high (>95%). In conclusion, compared to patients meeting Milan criteria, patients who meet only UCSF criteria have a worse survival and an increased rate of recurrent HCC with long-term follow-up, as well as more frequent occurrence of adverse histopathological features, such as microvascular invasion. Application of a pathological score and nomogram could help identify patients at increased risk for tumor recurrence, who may benefit from increased surveillance or adjuvant therapy.