Follow-up of asymptomatic pancreatic cysts in clinical practice: A vignette questionnaire

Background/ObjectivesIn absence of evidence-based guidelines of pancreatic cystic neoplasms (PCN), the management might vary among physicians. The aim of this survey was to assess the attitude of Dutch gastroenterologists (GE) towards the management of asymptomatic PCNs.MethodsAn anonymous online questionnaire was distributed to all practicing GE (n = 381) in The Netherlands, in which four vignette patients with PCN were presented.ResultsIn total 45% of GE responded. Most respondents would perform surveillance for a 10 mm PCN (78%) mainly with an interval of one year (57%). A shorter interval of three (26%) or six (57%) months was chosen for a 25 mm BD-IPMN. Ultrasound was recommended for surveillance by 19% for a 10 mm cyst. GE with EUS experience were more likely to apply EUS for surveillance of 10 mm cyst than those without (56% vs 28%; p < 0.001). The presence of a branch-duct intraductal mucinous neoplasm (BD-IPMN) with a mural nodule, dilated pancreatic duct (8 mm) or increased serum CA 19.9 (300 U/ml) were considered an indication for resection by respectively 88%, 68% and 51% of respondents.ConclusionDutch GE demonstrate substantial variability in the management of asymptomatic PCNs. A significant proportion of general GE still use ultrasound for surveillance of small PCNs, while GE with EUS experience were more likely to perform EUS. The presence of risk factors for malignant degeneration of IPMN were not recognized by a substantial proportion of GE. Data on the natural history of PCNs is required to provide input for evidence-based guidelines, which should lead to a more uniform approach.     

MUC2 expression and prevalence of high-grade dysplasia and invasive carcinoma in mixed-type intraductal papillary mucinous neoplasm of the pancreas

Background/objectivesMorphological types and mucin protein expressions classify intraductal papillary mucinous neoplasms (IPMNs). Main duct (MD)-IPMN mostly consists of intestinal type (I-type), which expresses MUC2. Branch duct (BD)-IPMN mostly consists of gastric type (G-type), which does not express MUC2. However, the definition of mixed-type IPMN has yet to be clarified and it contains various histological types. The aim of this study was to investigate the relationship between MUC2 expression and the presence of high-grade dysplasia (HGD) and invasive carcinoma, especially in mixed-type IPMN.MethodsThis retrospective study included 101 consecutive patients with surgically resected IPMNs between April 2001 and October 2012. All patients were morphologically classified into four distinct types (I-type, G-type, PB-type: pancreatobilliary, O-type: oncocytic) and immunohistochemical reactivity of various anti-mucin antibodies were investigated.ResultsAccording to the classification of the 2012 international guidelines, the numbers (and histomorphological types: I/G/PB/O) of MD, mixed-type, and BD-IPMNs were 16 (12/4/0/0), 45 (16/28/1/0), and 40 (0/38/1/1). Prevalence of MUC2 expression in MD, mixed-type, and BD-IPMNs were 75% (12/16), 36% (16/45), and 0% (0/40). In mixed-type IPMN, the prevalence of HGD and/or invasive carcinoma in MUC2-positive IPMN was significantly higher than that of MUC2-negative IPMN (HGD + invasive carcinoma: 88% vs. 38%, p = 0.0017; invasive carcinoma: 50% vs. 21%, p = 0.042). Multivariate analysis showed that MUC2 expression is an independent predictive factor of HGD and invasive carcinoma in mixed IPMN (odds ratio 14.6, 95% CI 2.5–87.4, p = 0.003).ConclusionsIn mixed-type IPMN, MUC2 expression clearly identified HGD and invasive carcinoma and may provide most appropriate surgical indication.     

Predictive value of low serum pancreatic enzymes in invasive intraductal papillary mucinous neoplasms

BackgroundDespite evidence suggesting a role of chronic pancreatitis in pancreatic carcinogenesis, its relationship with invasive intraductal papillary mucinous neoplasms (IPMN) remains unclear. Low levels of pancreatic enzymes are predictive markers of advanced chronic pancreatitis. We investigated whether low pancreatic enzyme levels were associated with a higher incidence of invasive IPMN.MethodsThis study included 146 consecutive patients who underwent surgical resection of IPMN between April 2001 and October 2014. Multivariable logistic regression analysis was conducted to assess the association between serum pancreatic enzymes and the incidence of invasive IPMN, with adjustment for clinical characteristics including alcohol consumption. The association of serum pancreatic enzymes with pathological pancreatic atrophy and inflammation in areas adjacent to or distant from the tumor was also evaluated.ResultsLow serum levels of pancreatic amylase and lipase were associated with a higher incidence of invasive IPMN (multivariable odds ratio [OR] = 9.6, 95% confidence interval [CI] = 2.99 to 35.1, P = 0.0001; OR = 14.2, 95% CI = 2.77 to 112, P = 0.001, respectively). Low serum pancreatic amylase and lipase levels were also associated with higher grade pancreatic atrophy in areas adjacent to the tumor (P = 0.011 and P = 0.017, respectively) and in areas distant from the tumor (P = 0.0002 and P = 0.001, respectively). Furthermore, low serum pancreatic amylase and lipase levels were associated with higher grade inflammation in areas distant from the tumor (P < 0.0001 and P = 0.001, respectively).ConclusionsLow serum pancreatic enzymes may be a predictive marker of invasive IPMN. Excessive alcohol consumption did not influence the association of low pancreatic enzyme levels with invasive IPMN.     

Requirement of a single high-risk feature as an indication for EUS for the diagnosis of asymptomatic pancreatic cysts

Background and aimsEndoscopic ultrasound (EUS) is widely used to evaluate pancreatic cysts. Recent American Gastroenterological Association (AGA) guideline limits EUS for evaluation of cysts with at-least two high-risk features (size ≥ 3 cm, dilated main pancreatic duct or presence of a solid component). We have investigated the impact of this guideline on sensitivity of EUS for pancreatic cancer and the reduction of EUS procedures for pancreas cysts.MethodsEUS procedures performed between 2004 and 2015 and related patient records were retrospectively reviewed to determine the presence or absence of high-risk features, and for the results of fine needle aspiration cytology.ResultsTwo hundred ten patients (108 males) underwent EUS for diagnostic evaluation of pancreatic cysts. Four patients (1.9%), all with at-least one high-risk feature, were diagnosed with cytologically-proven pancreatic cancer. Only 2 patients with cancer had at-least two high-risk features that would have warranted EUS examination based on the new AGA guideline. The requirement for at-least two high-risk features would have decreased the number of EUS procedures by 91%, but reduced the sensitivity for pancreatic malignancy to 50%. If only one high-risk feature was required, EUS procedures would have been decreased by 67%, with a sensitivity of 100%.ConclusionLimiting EUS to patients with pancreatic cysts with 2 or more high-risk features may substantially reduce the sensitivity for pancreatic malignancy. Performing EUS in patients with at least one high-risk feature may substantially decrease the need of invasive procedures without reducing sensitivity for detecting malignancy.     

Monitoring and functional characterization of the lymphocytic compartment in pancreatic ductal adenocarcinoma patients

Background/ObjectivesPancreatic ductal adenocarcinoma (PDAC) still has a poor prognosis and current treatments including immunotherapy often fail. This might be due to the pronounced immunosuppressive milieu impairing infiltration and function of immune effector cells. This study aimed at a comprehensive analysis of immune cells in PDAC patients by determining absolute and relative peripheral blood cell numbers of immune cell subsets along with their functional capacity.MethodsWhole blood cells or isolated peripheral blood mononuclear cells were characterized by flow cytometry. PDAC tissues were analyzed by immunohistochemistry. Anti-tumor activity of immune effector cells was determined by RTCA system.ResultsOur data demonstrate that relative CD4⁺ memory- and regulatory T cell numbers were enhanced, whereas determination of absolute cell numbers revealed generally lower immune cell numbers in PDAC patients compared to healthy controls. γδ T cells accumulated at higher numbers compared to αβ T cells in the malignant ductal epithelium of PDAC tissues indicating that γδ T cells infiltrate into the tumor. Cytotoxicity against tumor cells of even small numbers of T- and NK cells could be induced by a bispecific antibody targeting CD3⁺ T cells to human epidermal growth factor receptor (HER)2 expressing PDAC cells or Trastuzumab. Importantly, a critical number of γδ T cells was required for significant tumor cell killing by a bispecific antibody engaging the γδ T cell receptor on γδ T cells and HER2 on tumor cells.ConclusionMonitoring immune cells along with the determination of their functional capacity provides a comprehensive assessment as a prerequisite for a personalized immunotherapeutic PDAC treatment.     

Measures of trainee performance in advanced endoscopy: A systematic review

IntroductionThe diversity, technical skills required, and risk inherent to advanced endoscopy techniques all contribute to complex training curricula and steep learning curves. Since trainees develop endoscopy skills at different rates, there has been a shift towards competency-based training and certification. Validated endoscopy performance measures for trainees are, therefore, necessary. The aim of this systematic review was to describe and critically assess the existing evidence regarding measures of performance for trainees in advanced endoscopy.MethodsA systematic review of the literature from January 1980 to January 2016 was carried out using the MEDLINE, EMBASE, CENTRAL, and ISI Web of knowledge databases. MeSH terms related to 'advanced endoscopy' and 'performance' were applied to a highly sensitive search strategy. The main outcomes were face, content, and construct validity, as well as reliability.ResultsThe literature search yielded 1,662 studies and 77 met the inclusion criteria after abstract and full-text review (endoscopic retrograde cholangiopancreatography (ERCP) = 23, endoscopic ultrasound (EUS) = 30, colonoscopic polypectomy (CP) = 11, balloon-assisted enteroscopy (BAE) = 7, luminal stenting = 3, radiofrequency ablation (RFA) = 2, and endoscopic muscosal resection (EMR) = 1). Good validity and reliability were found for measurement tools of overall performance in ERCP, EUS and CP, with applications for both patient-based and simulator training models. A number of specific technical skills were also shown to be valid measures of performance. These include: selective biliary cannulation, sphincterotomy, biliary stent placement, stone extraction and procedure time for ERCP; pancreatic solid mass T-staging, EUS-guided fine needle aspiration (EUS-FNA) procedure time, number of EUS-FNA passes and puncture precision for EUS; procedure time and en bloc resection rate for CP; retrograde fluoroscopy time for BAE; and mean number of endoscopy sessions required to achieve complete eradication of intestinal metaplasia (CIEM) for RFA. The evidence for EMR and luminal stenting is of insufficient quality to make recommendations.ConclusionsWe have identified multiple valid and readily available performance measures for advanced endoscopy trainees for ERCP, EUS, CP, BAE and RFA procedures. These tools should be considered in advanced endoscopy training programs wishing to move away from apprenticeship-based training and towards competency-based learning with the help of patient-based and simulator tools.     

Simulator training in gastrointestinal endoscopy – From basic training to advanced endoscopic procedures

Simulator-based gastrointestinal endoscopy training has gained acceptance over the last decades and has been extensively studied. Several types of simulators have been validated and it has been demonstrated that the use of simulators in the early training setting accelerates the learning curve in acquiring basic skills. Current GI endoscopy simulators lack the degree of realism that would be necessary to provide training to achieve full competency or to be applicable in certification. Virtual Reality and mechanical simulators are commonly used in basic flexible endoscopy training, whereas ex vivo and in vivo models are used in training the most advanced endoscopic procedures. Validated models for the training of more routine therapeutic interventions like polypectomy, EMR, stenting and haemostasis are lacking or scarce and developments in these areas should be encouraged.     

Cdkn1a is a key mediator of rat pancreatic stellate cell senescence

Background/objectivesCompletion of pancreatic wound healing requires termination of pancreatic stellate cell (PSC) activation to prevent fibrosis. Besides induction of apoptosis and return to a quiescent phenotype, senescence of PSC followed by immune cell-mediated cytolysis represents a potential mechanism. Here, we have studied if the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21/Waf1), expression of which is increased in senescent rat PSC, plays a causative role in the senescence process.MethodsSenescence was induced by doxorubicin treatment. The functions of Cdkn1a were analyzed using two approaches, treatment of primary rat PSC with siRNA and tetracycline-regulated overexpression of Cdkn1a in immortalized rat cells. Expression of senescence-associated β-galactosidase (SA β-Gal) was used as a surrogate marker of senescence.ResultsThe knockdown of Cdkn1a significantly attenuated the growth-inhibitory effect of doxorubicin and strongly diminished the portion of SA β-Gal-positive cells. Overexpression of Cdkn1a enhanced both the antiproliferative effect of doxorubicin and induction of senescence. In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker α-smooth muscle actin (α-SMA), p53, Cdk1 and Rad54 was diminished. The application of Cdkn1a siRNA specifically antagonized the effects of doxorubicin on the expression of p53, Cdk1 and Rad54 but not IL-6 and α-SMA, while MMP-9 expression and also activity were even enhanced.ConclusionsCdkn1a plays a direct role in the process of rat PSC senescence. Additional Cdkn1a-independent pathways may contribute to the partial maintenance of a gene expression profile typical of senescent PSC.     

The relationship between pancreatic atrophy after steroid therapy and diabetes mellitus in patients with autoimmune pancreatitis

Background/objectivesMany patients with autoimmune pancreatitis (AIP) have an association with diabetes mellitus. It has not been clarified whether steroid therapy for AIP improves or worsens the condition of diabetes mellitus. The aim of this study was thus to investigate the relationship between pancreatic atrophy after steroid therapy and the clinical course of diabetes.MethodsThirty-one AIP patients, who were treated by steroid therapy, were included in this study during December 2005 to March 2013. Pancreatic atrophy 6 months after the beginning of steroid therapy was defined to be present when the width of the pancreatic body was less than 10 mm. The relationships between pancreatic atrophy and patient characteristics as well as the course of diabetes were examined.ResultsSteroid therapy was effective in all treated patients. Pancreatic atrophy was observed in 12 patients and not in 19 patients after the steroid therapy. AIP patients with pancreatic atrophy showed higher incidences of diabetes mellitus (p = 0.001, 9/12 vs. 2/19), diabetes control worsening (p = 0.007, 7/12 vs. 2/17), and new onset of diabetes (p = 0.02, 5/7 vs. 1/18) than those without atrophy. It was not associated with gender, other organ involvement, pattern of pancreas swelling (diffuse/focal), serum IgG4 level, alcohol intake, and pancreatic calcification on CT. Patients with new onset of diabetes needed insulin therapy, even in the maintenance therapy of AIP.ConclusionsAIP patients with pancreatic atrophy after steroid therapy have a high incidence of diabetes mellitus. New onset of diabetes is closely associated with pancreatic atrophy after steroid therapy.     

Relationship between QRS characteristics and delayed-enhancement cardiac magnetic resonance in patients with ischemic cardiomyopathy

BackgroundWe explored the relationship between QRS characteristics and myocardial phenotype by delayed-enhancement cardiac magnetic resonance (DE-CMR) in patients with coronary heart disease (CHD).Methods and resultsEighty five consecutive patients with CHD that were referred for DE-CMR evaluation constituted the study population. Of a total of 1445 left ventricular (LV) segments evaluated, 346 (23.9%) segments had fibrosis.Compared to patients without pathological Q waves, patients with pathological Q waves showed a higher number of segments with fibrosis (5.9 ± 3.1 vs. 2.7 ± 2.8, p < 0.001), and lower left ventricular ejection fraction (LVEF) (42.9 ± 13.6% vs. 51.8 ± 18.3, p = 0.01); whereas no significant differences were observed regarding LV size.When discriminated in according to the QRS duration tertiles, no significant differences were observed regarding the number of segments with fibrosis (p = 0.34), whereas the highest QRS tertile was related to the presence of a low LVEF (p = 0.005) and larger LV size (p = 0.01). QRS fragmentation (fQRS), defined as the presence of an R′ or notching in the nadir of the R wave or the S wave, or the presence of >1 R′ in 2 contiguous leads, was significantly related to LV size (LV end diastolic volume 153.6 ± 81.6 ml, vs. 111.5 ± 41.4 ml, p = 0.003), function (LVEF 43.2 ± 15.9% vs. 53.6 ± 16.3%, p = 0.005), and extent of fibrosis (5.1 ± 3.4 segments vs. 3.2 ± 3.1 segments, p = 0.01).ConclusionsIn the present study, fQRS was the only QRS-derived variable systematically and more closely related to LV size, LV systolic function, and to the presence and extent of fibrosis.     

Myeloperoxidase levels predict accelerated progression of coronary atherosclerosis in diabetic patients: Insights from intravascular ultrasound

ObjectiveWhile inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied.MethodsWe investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated.ResultsMPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline.ConclusionsIncreasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease.     

Prevalence of exocrine pancreatic insufficiency in type 2 diabetes mellitus with poor glycemic control

ObjectivesTo evaluate the relationship between exocrine pancreatic insufficiency and the level of glycemic control in diabetes (DM).MethodsPatients with type 2 DM treated in our clinic were prospectively recruited into the study. Pancreatic diabetes was excluded. Cases with HbA1c ≥7% formed Group A (n = 59), and with HbA1c <7% Group B (n = 42). The fecal level of pancreatic elastase (PE-1) was measured and morphological examinations of the pancreas were performed.ResultsThe PE-1 level was significantly lower in Group A than in Group B (385.9 ± 171.1 μg/g, vs. 454.6 ± 147.3 μg/g, p = 0.038). The PE-1 level was not correlated with HbA1c (r = −0.132, p = 0.187), the duration of DM (r = −0.046, p = 0.65), age (r = 0.010, p = 0.921), BMI (r = 0.203, p = 0.059), or pancreatic steatosis (r = 0.117, p = 0.244). The size of the pancreas did not differ significantly between Groups A and B.ConclusionsAn exocrine pancreatic insufficiency demonstrated by fecal PE-1 determination is more frequent in type 2 DM patients with poor glycemic control. The impaired exocrine pancreatic function cannot be explained by an alteration in the size of the pancreas or by pancreatic steatosis.     

Improved survival of Korean patients with idiopathic pulmonary arterial hypertension after the introduction of targeted therapies

ObjectivesWe compared the survival of patients with idiopathic pulmonary arterial hypertension (IPAH), receiving conventional and targeted therapies.BackgroundIPAH is an incurable disease with high mortality. To manage IPAH, several targeted therapies have been used in Korea.MethodsWe performed a retrospective study of 71 patients diagnosed with IPAH in a tertiary hospital between January 1994 and February 2013. Patients were classified into “conventional therapy group” (treated with conventional therapies and/or beraprost) and “targeted therapy group” (treated with targeted therapies other than beraprost).ResultsThe median age of the patients was 33 years and 50 patients were female. The survival rate at 1, 3, 5, and 10 years was 80.1% 62.0%, 51.5%, and 26.8%, respectively. The survival rate in the targeted therapy group was greater than in the conventional therapy group (p-value = 0.026).ConclusionsWe believe targeted therapies would improve survival benefits in IPAH patients.     

Early management of acute pancreatitis

Acute pancreatitis is the most common gastro-intestinal indication for acute hospitalization and its incidence continues to rise. In severe pancreatitis, morbidity and mortality remains high and is mainly driven by organ failure and infectious complications. Early management strategies should aim to prevent or treat organ failure and to reduce infectious complications. This review addresses the management of acute pancreatitis in the first hours to days after onset of symptoms, including fluid therapy, nutrition and endoscopic retrograde cholangiography. This review also discusses the recently revised Atlanta classification which provides new uniform terminology, thereby facilitating communication regarding severity and complications of pancreatitis.     

Specific increase in serum core-fucosylated haptoglobin in patients with chronic pancreatitis

Background/ObjectivesPancreatic ductal adenocarcinoma (PDAC) has the worst prognosis of all malignancies, and its diagnosis in early stages is the most important prognostic factor. Chronic pancreatitis (CP), a common background of PDAC occurrence, is morphologically defined as progressive pancreatic fibrosis and inflammation accompanied by pancreatic exocrine cell atrophy. We recently found that inflammation and fibrosis are independent characteristic histological changes in noncancerous lesions in PDAC patients despite the absence of a past history of clinical CP. Subclinical CP is an important background for PDAC occurrence. Therefore, there is an urgent need to develop a noninvasive and reliable biomarker for CP diagnosis.MethodsFifty-nine healthy volunteers (HV), 159 patients with CP, and 83 patients with PDAC were enrolled in this study. We measured serum total fucosylated haptoglobin (Fuc-Hpt) and core-Fuc-Hpt levels using lectin-antibody enzyme-linked immunosorbent assay kits that we developed. In these kits, total Fuc-Hpt and core-Fuc-Hpt were measured using Aleuria aurantia lectin and Pholiota squarrosa lectin, respectively.ResultsSerum Fuc-Hpt levels were significantly increased in CP patients compared to HV (P < 0.0001) and were further increased in PDAC patients (P < 0.0001). Interestingly, serum core-Fuc-Hpt levels were significantly higher in CP patients compared to HV (P < 0.0001) and PDAC patients (P < 0.0001). Multivariate analyses demonstrated that total serum core-Fuc-Hpt was an independent determinant for CP diagnosis, but Fuc-Hpt was not.ConclusionsA dramatic change in oligosaccharides was observed in serum haptoglobin between CP and PDAC. Serum core-Fuc-Hpt may be a novel and useful biomarker for CP diagnosis.