Screening for undiagnosed pancreatic exocrine insufficiency (PEI) in a cohort of diabetic patients using faecal elastase testing and PEI scoring system.

INTRODUCTION: Type 1 and type 2 diabetes mellitus (DM) are often accompanied by mild forms of pancreatic exocrine insufficiency (PEI). The prevalence rates of PEI in diabetic patients are unclear and variable depending on the testing modality and the studies published. The clinical consequences of PEI in diabetics are also not well defined. AIM: We aimed to determine the prevalence of PEI in a diabetic cohort using the faecal elastase-1 (FE-1) assay as a screening test and to validate a patient-reported symptom-based scoring system, the (PEI-S) for diagnosing PEI within this patient population. METHODS: Two hundred and three diabetic patients attending diabetic and gastroenterology outpatients of a university hospital without previously known PEI were recruited for the study. Demographic parameters, PEI score (PEI-S), and glycated hemoglobin (HBA1c) were documented in standardized data sheets, and a stool sample was obtained. A FE-1 value < 200 µg/g and or a PEIS of > 0.6 was used as the screening cut-off for PEI. RESULTS: One hundred sixty-six patients returned faecal samples. The prevalence of PEI, as measured by low FE-1, was 12%. Smoking was associated with an increased risk of developing PEI in this diabetic population. No other independent risk factors were identified. The PEI-S system did not differentiate between people with diabetes having a normal and low FE1. CONCLUSION: 12% of this mixed, real-life cohort of type 1 and 2 DM patients had undiagnosed PEI, as defined by an FE-1 score of less than 200 µg/g. While this may appear low, given the rising prevalence of type 2 DM worldwide, there is likely an unrecognized burden of PEI, which has long-term health consequences for those affected. The PEI-S, a symptom-scoring system for patients with PEI, did not perform well in this patient group.

A systematic review of the effects of temperature and precipitation on pollen concentrations and season timing, and implications for human health.

Climate and weather directly impact plant phenology, affecting airborne pollen. The objective of this systematic review is to examine the impacts of meteorological variables on airborne pollen concentrations and pollen season timing. Using PRISMA methodology, we reviewed literature that assessed whether there was a relationship between local temperature and precipitation and measured airborne pollen. The search strategy included terms related to pollen, trends or measurements, and season timing. For inclusion, studies must have conducted a correlation analysis of at least 5 years of airborne pollen data to local meteorological data and report quantitative results. Data from peer-reviewed articles were extracted on the correlations between seven pollen indicators (main pollen season start date, end date, peak date, and length, annual pollen integral, average daily pollen concentration, and peak pollen concentration), and two meteorological variables (temperature and precipitation). Ninety-three articles were included in the analysis out of 9,679 articles screened. Overall, warmer temperatures correlated with earlier and longer pollen seasons and higher pollen concentrations. Precipitation had varying effects on pollen concentration and pollen season timing indicators. Increased precipitation may have a short-term effect causing low pollen concentrations potentially due to "wash out" effect. Long-term effects of precipitation varied for trees and weeds and had a positive correlation with grass pollen levels. With increases in temperature due to climate change, pollen seasons for some taxa in some regions may start earlier, last longer, and be more intense, which may be associated with adverse health impacts, as pollen exposure has well-known health effects in sensitized individuals.

A novel value-based scoring system for endoscopic ultrasound-guided drainage of pancreatic fluid collections: a single-centre comparative study of plastic and lumen-apposing metal stents (NOVA study).

OBJECTIVE: Healthcare resources are finite. Value in healthcare can be defined as patient health outcomes achieved per monetary unit spent. Attempts have been made to quantify the value of luminal endoscopy, but there is little in the medical literature describing the value of the complex therapeutic endoscopic activity. This study aimed to characterise the value of endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) with either plastic or lumen-apposing metal stents (LAMSs). METHODS: This is a single-centre, retrospective-prospective comparative study of 39 patients, who underwent EUS-guided PFC drainage between 2009 and 2018. Procedure value was calculated using the formula Q/(T/C), where Q is the quality of procedure adjusted for complications, T procedure duration and C is the complexity adjustment. Quality and complexity were estimated on a 1-4 Likert scale based on the American Society for Gastrointestinal Endoscopy criteria. Time (in minutes) was recorded from the patient entering and leaving the procedure room. Endoscopy time calculated from procedure time was considered a surrogate marker of cost as individual components of procedure cost were not itemized. RESULTS: Of 39 identified patients who underwent EUS-guided PFC drainage, 11 received double pigtail plastic stents (DPPSs) and 28 received LAMSs. The two groups were comparable in age, gender and aetiology. Nearly 40% of the LAMS interventions were considered high value but only 11% of the plastic stent interventions achieved the same. The difference predominantly was due to a higher rate of complications and longer procedure time. CONCLUSION: In this single-centre study, EUS-guided PFC drainage using LAMS was found to be a higher value procedure compared to the use of DPPS.

Conservative management of complete traumatic pancreatic body transection; A case report.

INTRODUCTION: Isolated pancreatic body transection secondary to blunt abdominal trauma is a very rare injury associated with poor outcomes. Almost all previously reported cases were managed by emergency distal pancreatectomy, which is associated with high morbidity and mortality. To our knowledge, this is the first reported case of complete transection of the pancreas at the body that was successfully treated by conservative management in an adult patient. PRESENTATION OF CASE: A 19-year-old male was found to have complete transection of the pancreatic body on computed tomography (CT) following blunt force abdominal trauma. Given that he was haemodynamically stable without evidence of haemorrhage or bile leakage on imaging, a trial of conservative management was initiated. He remained well through his admission, gradually improving clinically and biochemically with stable appearances on serial imaging. He remains asymptomatic as of six months since discharge from the hospital and continues to be monitored in the outpatient setting. DISCUSSION: Management of pancreatic trauma with ductal injury has typically been with emergency distal pancreatectomy, which is associated with high morbidity and mortality. The decision to operate should not be purely based on radiological findings, and should take into account clinical status, haemodynamic stability, coexisting injuries and evidence of active haemorrhage or bile leak. CONCLUSION: In select cases, it is reasonable to trial conservative management in isolated traumatic pancreatic body fracture by means of close clinical observation and serial imaging. This may allow the patient to avoid a high-risk emergency distal pancreatectomy.

Trends in the Use of Laparoscopic Versus Open Paediatric Appendicectomy: A Regional 12-Year Study and a National Survey.

BACKGROUND: In adult patients, it is generally accepted that laparoscopic appendicectomy (LA) is the predominant operative pathway in treating acute appendicitis. The case for a similar pathway utilising LA in children is less clear. We investigate usage, trends and complications after LA in children in a single co-located adult/paediatric centre with contemporaneous adults as controls. METHODS: A retrospective case-control study was conducted over 12 years including patients who underwent appendicectomy, and the paediatric series (<16 years) was divided into age-groups-based quartiles. An anonymous questionnaire-based national survey was circulated among general and paediatric surgeons. RESULTS: Of the 5784 appendicectomy patients, 2960 were children. LA rate in paediatric appendicitis was 65%. Yearly trends in LA reached a steady state in both groups after 2010 (Δ 0-1%/year). Rates of LA and LA IAA (respectively) differed significantly between age groups: 60, 3% (0-9 years); 65, 1% (10-13 years); 71, 2% (14-16 years) and 93, 3% (>16 years) (p = 0.001, 0.02). The national survey showed respondents believed LA was not superior to OA in paediatric patients except in terms of cosmesis. There was strong support in the use of LA in older children and children >40 kg. CONCLUSION: The use of LA in paediatric appendicectomies in the study region is similar to international rates, but not increasing over time. Irish surgeons still favour OA in younger children and prefer a case-by-case approach rather LA being the preferred pathway. This is despite the regional and international evidence showing favourable outcomes with LA in children.

Preoperative CT in patients with surgically resectable pancreatic adenocarcinoma: does the time interval between CT and surgery affect survival?

PURPOSE: The preoperative imaging-to-surgery time interval (ISI) influences the risk of unexpected progression (UP) found at surgery for pancreatic adenocarcinoma. We aimed to assess whether ISI influences disease recurrence and/or survival. METHODS AND MATERIALS: A single-institution, ethics board-approved retrospective analysis of all patients who underwent attempted resection of pancreatic (PDAC) or periampullary adenocarcinoma (AmpAC) between 1st January 2010 and 31st December 2015 was performed. All patients underwent preoperative abdominal computed tomography (CT). Exclusion criteria were borderline resectable disease and neoadjuvant chemo/radiotherapy. Patients were followed up until 30th June 2016. The population was divided into ISI ≥/<25 days. Kaplan-Meier and Cox regression survival analyses were performed. RESULTS: 239 patients underwent surgical exploration. UP was found in 29 (12.1%) and these patients had longer ISI (median 46 vs. 29 days, p < 0.05). When intention-to-treat analysis was performed, there was no difference in overall survival (OS) between patients with ISI ≥/<25. In those who underwent resection, ISI did not influence disease-free survival (DFS) or OS for PDAC (n = 174). For AmpAC (n = 36), ISI ≥ 25 days was associated with longer OS (p < 0.05) but did not influence DFS. Longer ISI was independently associated with improved OS on regression analysis for AmpAC. CONCLUSION: Performing surgery for resectable pancreatic adenocarcinoma within 25 days of abdominal CT reduces the chance of UP but does not confer a survival benefit. For those who undergo resection of AmpAC, a longer ISI was associated with longer OS. This probably represents a more biologically indolent disease in this cohort.

Step by step guide to do a systematic review and meta-analysis for medical professionals.

INTRODUCTION: Systematic review and meta-analysis are statistical tools used to review researches performed on a same topic. They extract the collective effect of the studies performed on the topic of interest after statistically analysing the data of all the studies included. AIMS AND OBJECTIVES: Systematic reviews and meta-analysis are getting more and more popular in the medical field. Statistics is never the strong aspect of medical professionals, and facing a large number of statistical tests and values could be quite confusing for them. The aim of this article is to simplify these two very important research modalities for medical professionals. CONCLUSION: This article will provide a step-to-step guide for the medical colleagues to perform a meta-analysis if they are interested.

Attitudes of oncology healthcare practitioners towards smoking cessation: A systematic review of the facilitators, barriers and recommendations for delivery of advice and support to cancer patients.

OBJECTIVES: A systematic review of the literature was conducted. The review was conducted using a search of the literature for all years up to October 2016. Statements that identified facilitators, barriers or recommendations surrounding smoking cessation delivery were extracted and analogous statements aggregated to enable thematic analysis. After searching multiple databases and the application of exclusion and inclusion criteria, a total of 19 acceptable studies were identified. KEY FINDINGS: Delivery of cessation by oncology professionals was impacted by their own knowledge and views, their perception of the benefits to patient health and by the workplace procedures within their institution. CONCLUSION: Oncology practitioners worldwide face similar issues in delivering smoking cessation advice. By improving training programs that address the attitudes and beliefs which facilitate or block delivery of smoking cessation and by implementing systemic changes within cancer centres, delivery of smoking cessation should be enabled.

Postoperative exercise training is associated with reduced respiratory infection rates and early discharge: A case-control study.

INTRODUCTION: Pulmonary complications are a significant cause of morbidity, mortality and increased hospital stay following complex abdominal surgery. We investigated whether postoperative early aerobic activity with a pedal exerciser reduced respiratory morbidity and length of stay and improved pulmonary function. METHODS: A prospective case-control study on 30 cases and 30 case matched controls aged 18 years or more who underwent major surgery was conducted. Controls were case-mix matched prospectively from a similar general surgical service not utilising postoperative exercising. Thirty consecutive cases were started on a twice-daily aerobic exercise program with pedal exerciser post-operatively day 2 or from when sitting independently. Primary outcome measures were respiratory tract infection (RTI), deep vein thrombosis (DVT) or pulmonary embolus (PE). Secondary outcome measure was subjective breathlessness and Length of Stay (LOS) postoperatively. RESULTS: The rate of RTI was only 16.6% in the exercise group and 43.3% in the control group (P = 0.024). None of the cases or controls suffered from a DVT or PE. Median postoperative length of stay in the control group was 11 ± 7.5 days whereas in the cases it was 8.5 ± 5.00 days (P = 0.049). The Borg subjective breathlessness score in the cases group showed a decline in the subjective breathlessness on postoperative day 4 (P = 0.002). CONCLUSIONS: Early aerobic activity with a pedal exerciser halves the rate of postoperative RTI and postoperative hospital stay after complex abdominal surgery. Subjective breathlessness was also reduced with the use of pedal exerciser, signifying potential to improve exercise endurance in the postoperative patient.

The nutritional management of type 3c (pancreatogenic) diabetes in chronic pancreatitis.

Type 3c diabetes mellitus (T3cDM), also known as pancreatogenic diabetes, refers to diabetes caused by disease of the exocrine pancreas. T3cDM is not commonly recognised by clinicians and frequently it is misclassified as T1DM, or more commonly, T2DM. T3cDM can be difficult to distinguish from T1DM and T2DM, and it often co-exists with the latter. The aim of this review is to describe T3cDM, along with its complications, diagnosis and management. We focus on the nutritional implications of T3cDM for those with chronic pancreatitis, and provide a practical guide to the nutritional management of this condition.

Spontaneous resolution of avascular necrosis of femoral heads following cure of Cushing's syndrome.

UNLABELLED: Avascular necrosis (AVN) is a rare presenting feature of endogenous hypercortisolism. If left untreated, complete collapse of the femoral head may ensue, necessitating hip replacement in up to 70% of patients. The majority of the described patients with AVN due to endogenous hypercortisolaemia required surgical intervention. A 36-year-old female, investigated for right leg pain, reported rapid weight gain, bruising and secondary amenorrhoea. She had abdominal adiposity with violaceous striae, facial plethora and hirsutism, atrophic skin, ecchymosis and proximal myopathy. Investigations confirmed cortisol excess (cortisol following low-dose 48h dexamethasone suppression test 807nmol/L; 24h urinary free cortisol 1443nmol (normal<290nmol)). Adrenocorticotrophic hormone (ACTH) was <5.0pg/mL. CT demonstrated subtle left adrenal gland hypertrophy. Hypercortisolaemia persisted after left adrenalectomy. Histology revealed primary pigmented micronodular adrenal disease. Post-operatively, right leg pain worsened and left leg pain developed, affecting mobility. MRI showed bilateral femoral head AVN. She underwent right adrenalectomy and steroid replacement was commenced. Four months after surgery, leg pain had resolved and mobility was normal. Repeat MRI showed marked improvement of radiological abnormalities in both femoral heads, consistent with spontaneous healing of AVN. We report a case of Cushing's syndrome due to primary pigmented nodular adrenocortical disease, presenting with symptomatic AVN of both hips. This was managed conservatively from an orthopaedic perspective. Following cure of hypercortisolaemia, the patient experienced excellent recovery and remains symptom free 4 years after adrenalectomy. This is the first report of a favourable outcome over long-term follow-up of a patient with bilateral AVN of the hip, which reversed with treatment of endogenous hypercortisolaemia. LEARNING POINTS: AVN of femoral head can be a presenting feature of hypercortisolism, both endogenous and exogenous.Rarely, treatment of hypercortisolaemia can reverse AVN without the need for orthopaedic intervention.Primary pigmented nodular adrenal disease is a rare cause of ACTH-independent Cushing's syndrome.

The Impact of Social Work Intervention in Alcohol-Induced Pancreatitis in Ireland: a Single-Center Experience.

AIM: To evaluate the effect on recurrent admission for alcohol-induced pancreatitis (that can be up to 48%) of a brief social work intervention for alcohol dependence in a single center in Ireland METHODS: Retrospective cohort study of patients admitted with acute alcohol-induced pancreatitis to a tertiary hospital in Ireland from January 2009 to December 2012. RESULTS: The relapse rate in the cohort of 160 patients with alcohol-induced pancreatitis was 28.1%. There was no difference in the relapse rate of those patients who received a social work intervention compared with those who did not (ANOVA, P = 0.229). The employment status was a significant risk factor for relapse (ANOVA, P = 0.027), but did not differ between those who did, and did not, receive the intervention. CONCLUSION: Although the cohort size did not allow great statistical power, it appears that our hospital's current social work intervention for alcohol-induced pancreatitis is ineffective in preventing relapse. Long-term prospective studies are required to formulate and better implement more efficacious interventions for such patients.

Segmental duodenal resection: indications, surgical techniques and postoperative outcomes.

INTRODUCTION: Segmental duodenal resections (DR) have been increasingly performed for the treatment of primary duodenal tumours. The aim of the study is to review the indications for, clinical and operative details, and outcomes of patients undergoing elective DR. MATERIAL AND METHODS: We retrospectively reviewed all patients who underwent elective segmental DR for the treatment of primary duodenal tumours, at a single institution between January 2007 and December 2013. Demographic data, clinical presentation, preoperative investigations, operative details, postoperative complications/mortality and histopathological results were recorded. RESULTS: In the study period, 11 duodenal resections were performed (7 male, median age 61 years). Thirty-six percent of the patients presented with anaemia. Surgical resection included two or more segments in seven patients. The most frequently resected part of the duodenum was segment 3 (n = 7). Median operative time was 191 min and blood loss was 675 ml. End-to-end and end-to-side anastomoses were performed in equal numbers. The pathology of resected specimens included adenocarcinoma (n = 4), gastrointestinal stromal tumour (GIST) (n = 1), adenoma (n = 5) and lymphoma (n = 1). Median hospital stay was 14 days. Overall, 30-day morbidity rate was 82% (78% Clavien 2 or less). CONCLUSIONS: Segmental duodenal resection is a safe and effective surgical technique for the resection of primary duodenal tumours.

Augmented efficacy with the combination of blockade of the Notch-1 pathway, bortezomib and romidepsin in a murine MT-1 adult T-cell leukemia model.

Adult T-cell leukemia (ATL) is an aggressive malignancy caused by human T-cell lymphotropic virus-1. There is no accepted curative therapy for ATL. We have reported that certain ATL patients have increased Notch-1 signaling along with constitutive activation of the nuclear factor-κB pathway. Physical and functional interaction between these two pathways provides the rationale to combine the γ-secretase inhibitor compound E with the proteasome inhibitor bortezomib. Moreover, romidepsin, a histone deacetylase inhibitor, has demonstrated major antitumor action in leukemia/lymphoma. In this study, we investigated the therapeutic efficacy of the single agents and the combination of these agents in a murine model of human ATL, the MT-1 model. Single and double agents inhibited tumor growth as monitored by tumor size (P<0.05), and prolonged survival of leukemia-bearing mice (P<0.05) compared with the control group. The combination of three agents significantly enhanced the antitumor efficacy as assessed by tumor size, tumor markers in the serum (human soluble interleukin-2 receptor-α and ß2-microglobulin) and survival of the MT-1 tumor-bearing mice, compared with all other treatment groups (P<0.05). Improved therapeutic efficacy obtained by combining compound E, bortezomib and romidepsin supports a clinical trial of this combination in the treatment of ATL.

Time to surgical review: an assessment of the traditional model of emergency surgical care.

BACKGROUND: The traditional model for emergency surgical care consists of an on-call team providing service to the emergency department, while simultaneously balancing the demands of elective work. Various newer models, such as the "surgeon of the week" aim to reduce the conflict between elective and emergency duties. Despite the recent focus on newer models, there remains no data on the effectiveness of the traditional model. We aim to assess the efficacy of the traditional model in a large regional hospital. METHODS: A retrospective study between July 2009 and March 2010 was performed. Primarily, we assessed the initial time to surgical consultation after emergency department referral. Secondarily, we evaluated the impact of time periods, days of week, and case-mix etiology on this consultation time. RESULTS: The overall median time to surgical consultation after emergency department referral was 30 min (N = 860, P = 0.709). However, the median time to consultation was 60, 30, and 20 min for daytime, evening and night time, respectively (*P < 0.001). Trauma cases had a median time of 15 min, vascular had 45 min, neoplasm had 120 min, while other categories (upper and lower gastroenterology, and skin related) were 30 min (*P = 0.025). DISCUSSION: Newer models of acute surgical care have desirable outcomes in consultation times. However, regional and economical implications have a substantial impact on which model is feasible at local levels. We demonstrated that the traditional model still remains effective in a large sized tertiary referral unit.

Pancreatic metastasectomy: experience of the Irish National Surgical Centre for Pancreatic Cancer.

BACKGROUND: Metastatic tumours of the pancreas are rare and the optimal management of these tumours remains unclear, given the paucity of data existing in the literature. We report our experience of pancreatic metastasectomy. METHODS: Data were reviewed on all patients who underwent pancreatic resection for pathologically confirmed metastatic lesions over a consecutive 7-year period. RESULTS: Seven patients (two men and five women) underwent a pancreatectomy for a metastatic pancreatic tumour. The primary tumours were renal cell carcinoma (n = 3), colorectal carcinoma (n = 2) and leiomyosarcoma (n = 2). There was no operative mortality. Postoperative morbidities occurred in two patients. The median follow-up was 49 months (range 17-76). Overall 1- and 2-year survivals were 100 and 86 %, respectively, with a 2-year disease-free survival of 72 %. CONCLUSIONS: Our series further supports that pancreatic metastasectomy can be performed safely and achieves acceptable survival outcomes.

Pancreatectomy for metastatic disease: a systematic review.

AIM: Tumours rarely metastasise to the pancreas. While surgical resection of such metastases is believed to confer a survival benefit, there is limited data to support such management. We present a systematic review of case series of pancreatic metastasectomy and analysis of survival outcomes. METHODS: A literature search was performed using the PubMed and Cochrane databases and the reference lists of relevant articles, searching for sizeable case series of pancreatic metastasectomy with curative intent. Data extracted included basic demographics, histological primary tumour, presentation, operative management, complications and survival, while the MINORS index was used to assess study quality. RESULTS: 18 studies were found which met our inclusion criteria, involving 399 patients. Renal cell carcinoma (RCC) was the commonest malignancy metastasising to the pancreas, responsible for 62.6% of cases, followed by sarcoma (7.2%) and colorectal carcinoma (6.2%). While survival data was not uniformly reported, the median survival post-metastasectomy was 50.2 months, with a one-year survival of 86.81% and five-year survival of 50.02%. Median survival for RCC was 71.7 months with 70.4% five-year survival. Median survival was similar in patients with synchronous and metachronous pancreatic metastases, but patients with additional extrapancreatic metastases had a significantly shorter survival than patients with isolated pancreatic metastases (26 versus 45 months). Study quality was poor, with a median MINORS score of 10/16. CONCLUSIONS: Within the limitations of a review of non-randomised case series, it would appear that pancreatic metastasectomy confers a survival benefit in selected patients. Better evidence is required, but may prove difficult to acquire.

A transatlantic survey of nutrition practice in acute pancreatitis.

BACKGROUND: Many guidelines exist for the nutritional management of acute pancreatitis; however, little is known regarding current practice. We aimed to investigate feeding practices, including the use of parenteral/enteral nutrition. METHODS: The study design was a cross-sectional, descriptive survey. Electronic surveys were sent to dietitians in the UK, the Republic of Ireland and Canada. Of 253 dietitians surveyed, 204 saw patients with acute pancreatitis regularly or occasionally and were included in the analyses. RESULTS: Most dietitians (92.8%) considered early feeding to mean <48 h after presentation. Over half (54.2%) favoured early feeding in severe disease, less in obesity (42%) and more with pre-existing malnutrition (81.9%). There was a tendency to feed earlier in university hospitals (P = 0.015), especially in obesity (P = 0.011). There was a tendency towards enteral (versus parenteral) nutrition in university hospitals (P = 0.000). The majority preferred the jejunal route (64.2%), although this was lower in the UK (43.8%) than in Canada (77.8%) or Ireland (54.2%). Under one-quarter of UK dietitians (23.2%) reported the existence of a pancreatic multidisciplinary team in their institutions, although this was lower in Ireland and Canada. CONCLUSIONS: Despite guidelines, there are gaps in the nutritional management of acute pancreatitis, including a continued reliance on parenteral feeding.

Invasive markers identified by gene expression profiling in pancreatic cancer.

BACKGROUND: Molecular profiling has proven utility as a diagnostic and predictive tool in clinical oncology. However, a clinically relevant gene expression profile in pancreatic cancer remains elusive. METHODS: Primary and metastatic pancreatic cancer cell lines (BxPC-3 and AsPC-1), were stimulated with phorbol-12-myristate 13-acetate (PMA), a known inducer of cell invasion. Affymetrix gene expression microarray analysis was performed, comparing gene expression to unstimulated controls. Differential expression was identified using ArrayAssist, and confirmed using quantitative real-time PCR. Bioinformatic analysis was performed using Pathway Studio and GOstat. The derived gene expression was further validated in fresh frozen pancreatic tumour samples. The ability of the derived 3 gene expression markersto differentiate between pancreatic adenocarcinoma (PDAC) and other neoplasms, and its association with clinicopathological variables was examined. RESULTS: PMA-induced significant changes in cell line gene expression, from which distinctive 3 potential invasive markers were derived. Expression of these genes, uPA, MMP-1 and IL1-R1 was confirmed in human pancreatic tumours, and was found to differentiate PDAC from other pancreatic neoplasms. The expression of IL1-R1 in PDAC is a novel finding. We found that the expression of MMP-1 was associated with high-grade PDAC (p = 0.035, Wilcoxon rank sum). CONCLUSION: We have identified three potential invasive markers, uPA, MMP-1 and IL1-R1, whose gene expression may differentiate PDAC from other pancreatic neoplasms, and potentially reflect a more invasive phenotype.

NPM-ALK signals through glycogen synthase kinase 3ß to promote oncogenesis.

Anaplastic large cell lymphoma (ALCL) is the most common type of pediatric peripheral T-cell lymphoma. In 70-80% of cases, the chromosomal aberration t(2;5)(p23;q35) results in the juxtaposition of anaplastic lymphoma kinase (ALK) with nucleophosmin (NPM) and the subsequent expression of the NPM-ALK fusion protein. NPM-ALK is a chimeric tyrosine kinase, which induces numerous signaling pathways that drive proliferation and abrogate apoptosis. However, the mechanisms that lead to activation of downstream growth regulatory molecules have not been completely elucidated. Using a mass spectrometry-based phosphoproteomic screen, we identified GSK3ß as a signaling mediator of NPM-ALK. Using a selective inhibitor of ALK, we demonstrated that the tyrosine kinase activity of ALK regulates the serine-9 phosphorylation of GSK3ß. Expression of NPM-ALK in 293T cells led to an increase of pS(9)-GSK3ß (glycogen synthase kinase 3 beta) compared with kinase-defective K210R mutant NPM-ALK, but did not affect total GSK3ß levels. Phosphorylation of pS(9)-GSK3ß by NPM-ALK was mediated by the PI3K/AKT signaling pathway. ALK inhibition resulted in degradation of GSK3ß substrates Mcl-1 and CDC25A, which was recovered upon chemical inhibition of the proteasome (MG132). Furthermore, the degradation of Mcl-1 was recoverable with inhibition of GSK3ß. ALK inhibition also resulted in decreased cell viability, which was rescued by GSK3ß inhibition. Furthermore, stable knockdown of GSK3ß conferred resistance to the growth inhibitory effects of ALK inhibition using viability and colony formation assays. pS(9)-GSK3ß and CDC25A were selectively expressed in neoplastic cells of ALK+ALCL tissue biopsies, and showed a significant correlation (P<0.001). Conversely, ALK-ALCL tissue biopsies did not show significant correlation of pS(9)-GSK3ß and CDC25A expression (P<0.2). Our results demonstrate that NPM-ALK regulates the phosphorylation of S(9)-GSK3ß by PI3K/AKT. The subsequent inhibition of GSK3ß activity results in accumulation of CDC25A and Mcl-1, which confers the advantage of growth and protection from apoptosis. These findings provide support for the role of GSK3ß as a mediator of NPM-ALK oncogenesis.