Kwang Hyuck Lee

High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer.

The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300–0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC.

A prospective, comparative trial to optimize sampling techniques in EUS-guided FNA of solid pancreatic masses

BACKGROUNDnThere is no standardization of the use of suction during puncturing of a target in pancreatic EUS-guided FNA (EUS-FNA). It is also debatable whether expressing aspirates from the needle by the traditional method of reinserting the stylet is more effective than by air flushing, which is easier and safer.nnnOBJECTIVEnTo optimize sampling techniques in pancreatic EUS-FNA.nnnDESIGNnProspective, comparative trial.nnnSETTINGnTertiary-care referral center.nnnPATIENTSnEighty-one consecutive patients with solid pancreatic masses.nnnINTERVENTIONnFour punctures were performed for each mass in random order by a 2 × 2 factorial design. Sample quality and diagnostic yield were compared between samples with suction (S+) versus no suction (S-) and expressed by reinserting the stylet (RS) versus air flushing (AF).nnnMAIN OUTCOME MEASUREMENTSnSample quality by the number of diagnostic samples, cellularity, bloodiness, and air-drying artifact; diagnostic yield by accuracy, sensitivity, and specificity.nnnRESULTSnThe number of diagnostic samples (72.8% vs 58.6%; P = .001), cellularity (odds ratio [OR] 2.12; 95% confidence interval [CI], 1.37-3.30; P < .001), bloodiness (OR 1.46; CI, 1.28-1.68; P < .001), accuracy (85.2% vs 75.9%; P = .004), and sensitivity (82.4% vs 72.1%; P = .005) were higher in S+ than in S-. Bloodiness was lower in AF than in RS (OR 1.16; CI, 1.03-1.30; P = .017).nnnLIMITATIONSnSingle-center trial, 2 kinds of needle gauges, and no immediate cytopathology evaluation.nnnCONCLUSIONnPuncturing with suction and expressing by air flushing may be used preferentially in pancreatic EUS-FNA because they were more effective and convenient techniques. (nnnCLINICAL TRIAL REGISTRATION NUMBERnNCT01354795.).

Clinicopathologic features of intraductal papillary neoplasm of the bile duct according to histologic subtype.

OBJECTIVES:Despite an increase in the reports of intraductal papillary neoplasm of the bile duct (IPN-B), the clinical characteristics and long-term prognosis of this disease are not well known compared with those of intraductal papillary mucinous neoplasms of the pancreas. The objective of our study was to compare the clinical features, radiologic findings, and clinical outcomes of IPN-B according to histologic subtype.METHODS:A retrospective analysis was performed on the medical records of 97 patients diagnosed with IPN-B by pathologic analysis of their surgical specimens between May 1995 and May 2010. We compared the clinical manifestations, radiological findings, pathologic grade, curative resection rate, recurrence, and overall survival according to four histologic subtypes: gastric (n=15), intestinal (n=46), pancreaticobiliary (n=33), and oncocytic (n=3), which were classified on the basis of hematoxylin and eosin staining and the immunohistochemical profile of mucin core proteins.RESULTS:Mucin hypersecretion was significantly more frequent in patients with gastric and intestinal types than it was in those with oncocytic and pancreaticobiliary types (P=0.014). There were no significant differences between groups regarding the presence of bile duct stones or tumor location. The frequency of invasive carcinoma in the pancreaticobiliary type was significantly higher than those in the gastric and intestinal types (72.7 vs. 26.7 and 32.6%, P<0.001 and P<0.001). When comparing the survival curves according to histologic subtype, patients with pancreaticobiliary type demonstrated significantly worse survival compared to those with gastric and intestinal types (P=0.035).CONCLUSIONS:Gastric and intestinal types of IPN-B have similar clinical characteristics compared with the pancreaticobiliary type, which has a worse prognosis.

Preventive effects of ulinastatin on post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients: a prospective, randomized, placebo-controlled trial.

Objectives: Previous studies have shown that ulinastatin may be effective at preventing pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, routine administration of ulinastatin is unlikely to be cost-effective. So the aim of this prospective study was to evaluate the effectiveness of low-dose ulinastatin at preventing pancreatitis in patients at high risk of post-ERCP pancreatitis. Methods: A total of 227 patients (mean age, 63 years; 54% men) were randomized to receive placebo (n = 108) or active drug (n = 119) immediately after ERCP and received active drug (100,000 U of ulinastatin) or placebo. Occurrence of post-ERCP pancreatitis and hyperamylasemia were compared between the 2 groups. Results: The overall incidence of pancreatitis was 6.2%, and no significant differences were observed between placebo- and ulinastatin-treated patients in terms of the frequencies of pancreatitis (5.6% vs 6.7%), abdominal pain, or hyperamylasemia. Pancreatic duct acinarization, papillectomy of ampulla of Vater adenoma, difficult cannulation, and female sex were identified as risk factors for pancreatitis in univariate analysis. Conclusions: Low-dose prophylactic treatment with ulinastatin immediately after ERCP did not show a beneficial influence on the incidence of post-ERCP pancreatitis and hyperamylasemia in high-risk patients.

Efficacy of low‐calorie, partial meal replacement diet plans on weight and abdominal fat in obese subjects with metabolic syndrome: a double‐blind, randomised controlled trial of two diet plans – one high in protein and one nutritionally balanced

Background:u2002 Little is known about the relative efficacy of high‐protein vs. conventional diet plans that include partial meal replacements on body fat loss in obese subjects with metabolic syndrome.

The clinical epidemiology and outcomes of bacteremic biliary tract infections caused by antimicrobial-resistant pathogens.

OBJECTIVES:The prevalence of antibiotic-resistant pathogens continues to increase steadily. The aim of this study was to analyze the changing patterns and risk factors of antibiotic resistance in patients with bacteremic biliary tract infections (BTIs). In addition, prognostic factors related to survival in patients with a bacteremic BTI were evaluated.METHODS:Five hundred fifty-six biliary bacteremic events in 411 patients, treated from January 2000 to April 2010, were retrospectively analyzed. In addition, biliary bacteremic events were divided into nosocomial infections (N=396) and community-acquired infections (N=160).RESULTS:The resistance rate to third-generation cephalosporin was higher in 2005–2009 (35 out of 140, 25%, vs. 72 out of 151, 47.7%). The prevalence of extended-spectrum β-lactamase-producing organisms of Escherichia coli and Klebsiella strains increased markedly from 2.3% (2 out of 86) in 2000–2004 to 43.9% (58 out of 132) in 2005–2009. Nosocomial infection, hospital days before bacteremia, previous hospitalization within 90 days, previous use of antibiotics within 90 days, and an indwelling biliary drainage catheter were found to be independently associated with antibiotic resistance. However, no association was found between antibiotic resistance and mortality in patients with biliary bacteremia.CONCLUSIONS:Antibiotic resistance in bacteremic BTI has increased markedly during the past 10 years. Almost half of nosocomial bacteremic BTI caused by common Gram-negative pathogens during 2005–2009 (58.5%) could not be treated with third-generation cephalosporin. Clinical outcomes were found to be associated with bacteremia severity and underlying illness rather than antibiotic resistance.

Spontaneous activation of pancreas trypsinogen in heat shock protein 70.1 knock-out mice.

Objectives: Heat shock proteins (Hsps) protect cellular proteins in response to injury, and the role of Hsp70 in experimental pancreatitis was recently described. To find out the possible role of Hsp70 in pancreatitis, we used Hsp70 knock-out mice (Hsp70.1−/−) and wild-type mice (Hsp70.1+/+). Methods: We studied enzymes activities, Hsp70 protein levels, and histologies in cerulein-induced pancreatitis of Hsp70.1−/− and Hsp70.1+/+ mice. Results: In the basal state, Hsp70 protein levels were higher in Hsp70.1+/+ than in Hsp70.1−/− mice, and trypsin activity was higher in Hsp70.1−/− than in Hsp70.1+/+ mice. The zymogen/lysosome ratio of cathepsin B activity before cerulein injection was higher in Hsp70.1−/− than in Hsp70.1+/+ mice. The expression level of Hsp70 in the pancreas increased in both of Hsp70.1−/− and Hsp70.1+/+ mice after hyperthermia because of the Hsp70.3 gene left intact in Hsp70.1−/− mice. After cerulein hyperstimulation, trypsin activity increased 2-fold in Hsp70.1+/+ mice, but cerulein did not further increase basally elevated trypsin activity in Hsp70.1−/− mice. Hyperthermia pretreatment not only blocked cerulein-induced trypsinogen activation, pancreatic edema, and vacuolization in Hsp70.1+/+ mice, but also decreased basally elevated trypsin activity in Hsp70.1−/− mice. Conclusions: Hsp70 can be responsible for inhibition of cerulein-induced pancreatitis and prevention of spontaneous trypsinogen activation in mice by inhibiting the colocalization of zymogen and lysosomal enzymes.

RGS16 and FosB underexpressed in pancreatic cancer with lymph node metastasis promote tumor progression.

Lymph node (LN) metastasis is one of the most important adverse prognostic factors for pancreatic cancer. The aim of this study was to identify novel lymphatic metastasis-associated markers for pancreatic cancer. DNA microarray analysis was used to determine and compare the expression profiles of 17 pancreatic cancer tissues with LN metastasis and 17 pancreatic cancer tissues without LN metastasis. The microarray results were validated by real-time reverse transcription-polymerase chain reaction and immunohistochemistry. Only 58 genes were differentially expressed between the two groups with a difference in signal intensity ratio greater than a 1.5-fold change. Of these genes, 30 were significantly down-regulated in the LN metastasis group. Among five selected down-regulated genes for validation using real-time PCR, the expression of DST, FosB, RGS16, and CXCL12 was significantly lower in the LN metastasis group. Immunohistochemical analysis confirmed RGS16 and FosB underexpression in pancreatic cancer tissues with LN metastasis. RGS16 and FosB underexpression was associated with poor patient survival. Our findings show that RGS16 and FosB are underexpressed in pancreatic cancer with lymph node metastasis and associated with reduced survival, suggesting that RGS16 and FosB might be prognostic markers for pancreatic cancer.

Intratumoral heterogeneity of 18 F-FDG uptake predicts survival in patients with pancreatic ductal adenocarcinoma

PurposeTo assess whether intratumoral heterogeneity measured by 18F-FDG PET texture analysis has potential as a prognostic imaging biomarker in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsWe evaluated a cohort of 137 patients with newly diagnosed PDAC who underwent pretreatment 18F-FDG PET/CT from January 2008 to December 2010. First-order (histogram indices) and higher-order (grey-level run length, difference, size zone matrices) textural features of primary tumours were extracted by PET texture analysis. Conventional PET parameters including metabolic tumour volume (MTV), total lesion glycolysis (TLG), and standardized uptake value (SUV) were also measured. To assess and compare the predictive performance of imaging biomarkers, time-dependent receiver operating characteristic (ROC) curves for censored survival data and areas under the ROC curve (AUC) at 2xa0years after diagnosis were used. Associations between imaging biomarkers and overall survival were assessed using Cox proportional hazards regression models.ResultsThe best imaging biomarker for overall survival prediction was first-order entropy (AUCu2009=u20090.720), followed by TLG (AUCu2009=u20090.697), MTV (AUCu2009=u20090.692), and maximum SUV (AUCu2009=u20090.625). After adjusting for age, sex, clinical stage, tumour size and serum CA19-9 level, multivariable Cox analysis demonstrated that higher entropy (hazard ratio, HR, 5.59; Pu2009=u20090.028) was independently associated with worse survival, whereas TLG (HR 0.98; Pu2009=u20090.875) was not an independent prognostic factor.ConclusionIntratumoral heterogeneity of 18F-FDG uptake measured by PET texture analysis is an independent predictor of survival along with tumour stage and serum CA19-9 level in patients with PDAC. In addition, first-order entropy as a measure of intratumoral metabolic heterogeneity is a better quantitative imaging biomarker of prognosis than conventional PET parameters.

Role of SpyGlass Peroral Cholangioscopy in the Evaluation of Indeterminate Biliary Lesions

BackgroundAccurate diagnosis of indeterminate biliary lesions is essential for treatment planning. The currently available techniques have some limitations in evaluating indeterminate biliary lesions. SpyGlass single-operator peroral cholangioscopy system has been developed to overcome these limitations.AimThe aim of this retrospective study was to evaluate the diagnostic accuracy of SpyGlass visual assessment and SpyBite biopsy in patients with indeterminate biliary lesions.MethodsWe conducted a retrospective analysis of data from 36 patients with indeterminate biliary strictures or filling defects who had inconclusive results on the cross-sectional imaging study from September 2010 to October 2013. Four patients were excluded because of the presence of a metastatic mass and an ampulla of Vater cancer.ResultsThirty-two patients (19 men, mean age 63.7xa0years) with indeterminate biliary lesions underwent SpyGlass cholangioscopy. The cholangioscopy procedure with SpyGlass was technically successful in all of the cases except for one case because of the intraprocedural breakage of the SpyGlass optic probe (96.8xa0%, 31/32). The biopsy specimens from nineteen patients were obtained using SpyBite forceps. The sensitivity, specificity, and overall accuracy of SpyGlass visual assessment and SpyBite biopsy for the diagnosis of malignancy were 100xa0% (21/21) and 64.2xa0% (9/14), 90xa0% (9/10) and 100xa0% (5/5), and 96.7xa0% (30/31) and 73.6xa0% (14/19), respectively. Procedure-related complications were noted in three cases; postsphincterotomy bleeding in one case and mild pancreatitis in two cases.ConclusionsSpyGlass cholangioscopy with SpyBite biopsy is highly accurate and safe for differentiating malignant lesions from benign lesions in patients with indeterminate biliary lesions.