Kyu-hyun Paik

High Expression of MicroRNA-196a Indicates Poor Prognosis in Resected Pancreatic Neuroendocrine Tumor.

AbstractThere is limited data on miRNA expression in pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to identify miRNAs that could be potential prognostic biomarkers of PanNETs in patients who underwent curative surgery.For miRNA target screening, 2 primary PanNETs and corresponding liver metastases were screened for miRNA expression by the NanoString nCounter analysis. Candidate miRNAs were selected by ≥2-fold difference of expression between metastatic versus primary tumor. For miRNA target validation, quantitative real-time PCR was performed for candidate miRNAs on 37 PanNETs and matched nonneoplastic pancreata, and the miRNA levels were correlated with the clinicopathological features and patient survival data.Eight miRNAs (miRNA-27b, -122, -142–5p, -196a, -223, -590–5p, -630, and -944) were selected as candidate miRNAs. Only miR-196a level was significantly associated with stage, and mitotic count. When PanNETs were stratified into high (n = 10) and low (n = 27) miRNA-196a expression groups, miRNA-196a-high PanNETs were significantly associated with advanced pathologic T stage (50.0% vs 7.4%), N stage (50.0% vs 3.7%), higher mitotic counts (60.0% vs 3.7%), and higher Ki-67-labeling indices (60.0% vs 22.2%). In addition, high miRNA-196a expression was significantly associated with decreased overall survival (P = 0.046) and disease-free survival (P < 0.001) during a median follow-up of 37.9 months with the hazard ratio for recurrence of 16.267 (95% confidence interval = 1.732–153.789; P = 0.015).MiRNA-196a level may be a promising prognostic marker of recurrence in resected PanNETs, although further experimental investigation would be required.

Initial Metastatic Site as a Prognostic Factor in Patients With Stage IV Pancreatic Ductal Adenocarcinoma.

Abstract Few studies have evaluated the presence of hepatic or peritoneal metastasis as a prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). This study aimed to elucidate the prognostic value of the initial metastatic, extrahepatic, or hepatic site in patients with metastatic PDAC. Between January 2007 and December 2013, the medical records of 343 patients with metastatic PDAC treated at Seoul National University Bundang Hospital were retrospectively reviewed. Patients were classified as having extrahepatic metastasis alone (EH), hepatic metastasis alone (LV), and both hepatic and extrahepatic metastasis (BOTH). The median age was 67 years; 207 patients were men. Patients were classified as having EH (111 patients), LV (106), and BOTH (126). Totally, 212 patients underwent chemotherapy with a FOLFIRINOX (23 patients) or gemcitabine-based regimen (189). On multivariate analysis, an ECOG score ≥2 (hazard ratio [HR]: 3.2, 95% confidence interval [CI]: 2.2–4.5), albumin < 35 g/L (HR: 1.6, 95% CI: 1.1–2.3), C-reactive protein > 10 mg/L (HR: 2.3, 95% CI: 1.6–3.2), neutrophil-lymphocyte ratio > 5 (HR: 1.4, 95% CI: 1.0–2.0), no chemotherapy (HR: 2.0, 95% CI: 1.0–4.1), and metastatic site (LV, HR: 2.1, 95% CI: 1.4–3.1; BOTH, HR: 2.2, 95% CI: 1.6–3.2) were significantly associated with shorter overall survival (OS). Considering the initial metastatic site, the median OS of patients with EH, LV, and BOTH were 7.5 (95% CI: 6.3–8.8), 4.8 (95% CI: 4.1–5.5), and 2.4 (95% CI: 1.9–2.9) months, respectively. The initial metastatic site is significantly and independently associated with OS in patients with metastatic PDAC, serving as an effective prognostic factor.

Adjunctive role of preoperative liver magnetic resonance imaging for potentially resectable pancreatic cancer.

Background: The adjunctive role of magnetic resonance imaging of the liver before pancreatic ductal adenocarcinoma has been unclear. We evaluated whether the combination of hepatic magnetic resonance imaging with multidetector computed tomography using a pancreatic protocol (pCT) could help surgeons select appropriate candidates and decrease the risk of early recurrence. Methods: We retrospectively enrolled 167 patients in whom complete resection was achieved without grossly visible residual tumor; 102 patients underwent pCT alone (CT group) and 65 underwent both hepatic magnetic resonance imaging and pCT (magnetic resonance imaging group). Results: By adding hepatic magnetic resonance imaging during preoperative evaluation, hepatic metastases were newly discovered in 3 of 58 patients (5%) without hepatic lesions on pCT and 17 of 53 patients (32%) with indeterminate hepatic lesions on pCT. Patients with borderline resectability, a tumor size >3 cm, or preoperative carbohydrate antigen 19–9 level >1,000 U/mL had a greater rate of hepatic metastasis on subsequent hepatic magnetic resonance imaging. Among 167 patients in whom R0/R1 resection was achieved, the median overall survival was 18.2 vs 24.7 months (P = .020) and the disease‐free survival was 8.5 vs 10.0 months (P = .016) in the CT and magnetic resonance imaging groups, respectively (median follow‐up, 18.3 months). Recurrence developed in 82 (80%) and 43 (66%) patients in the CT and magnetic resonance imaging groups, respectively. The cumulative hepatic recurrence rate was greater in the CT group than in the magnetic resonance imaging group (P < .001). Conclusion: Preoperative hepatic magnetic resonance imaging should be considered in patients with potentially resectable pancreatic ductal adenocarcinoma, especially those with high tumor burden.

Comparison of Endoscopic Ultrasonography, Computed Tomography, and Magnetic Resonance Imaging for Pancreas Cystic Lesions.

AbstractConsensus regarding which modality is optimal for the measurement of pancreas cystic lesions (PCLs) was not achieved although cyst size is important for clinical decisions. This study aimed to evaluate the properties of endoscopic ultrasonography (EUS) compared with computed tomography (CT) and magnetic resonance imaging (MRI) in measuring the size of PCL.A total of 34 patients who underwent all 3 imaging modalities within 3 months before surgery were evaluated retrospectively. The size measured by each modality was compared with the pathologic size as a reference standard using Bland–Altman analysis and intraclass correlation coefficients (ICCs).The mean size difference was 1.76 mm (ICC 0.86), 7.35 mm (ICC 0.95), and 8.65 mm (ICC 0.93) in EUS, CT, and MRI. EUS had the widest range of 95% limits of agreement (LOA) (−17.54 to +21.07), compared with CT (−6.21 to +20.91), and MRI (−6.82 to +24.12). The size by EUS tended to be read smaller in tail portion, while those by CT and MRI did not. When the size was more than 4 cm, the size on EUS was estimated to be smaller than on pathology (r = 0.492; P = 0.003).Although 3 modalities showed very good reliability for the size measurement on PCL compared with corresponding pathologic size, EUS had the lowest level of agreement, while CT showed the highest level among the 3 modalities. Therefore, the size estimated by EUS has to be interpreted with caution, especially when it is located in tail and relevantly large.

Serum interleukin-6 is associated with pancreatic ductal adenocarcinoma progression pattern

Abstract Several reports showed that interleukin-6 (IL-6) or -8 (IL-8) might be useful inflammatory biomarkers for pancreatic ductal adenocarcinoma (PDAC), although these clinical impact is still open to debate. The aim of this study was to elucidate whether serum levels of IL-6 and IL-8 at diagnosis could predict the tumor progression pattern of PDAC, especially in extensive hepatic metastasis. According to the tumor burden of hepatic metastasis at the last follow-up, tumor progression pattern was defined as follows: no or limited (unilobar involvement and 5 or less in the within liver, limited group) and extensive hepatic metastasis (bilobar or more than 5, progressed group). Fifty-three PDAC patients with initially no or limited hepatic metastasis were enrolled retrospectively. Around 42 (79.2%) were included in the limited and 11 (20.8%) in the progressed group. The median serum level of IL-6 in the progressed group was elevated significantly compared with the limited group. However, the median serum level of IL-8 was not. Furthermore, multivariate analysis revealed that the elevated serum level of IL-6 was an independent risk factor for progression to extensive hepatic metastasis (odds ratio 1.928, 95% confidence interval 1.131–3.365, P = 0.019), but IL-8 was not. However, higher IL-6 did not predict shorter survival. High serum IL-6 can be an independent risk factor for progression to extensive hepatic metastasis in PDAC patients.

Risk Factors for Gallstone Formation in Resected Gastric Cancer Patients

AbstractPrevious studies reported increased incidence of gallstone formation after gastrectomy. However, there were few reports about factors other than surgical technique. The purpose of this study is to investigate the spectrum of risk factors of gallstone formation after gastrectomy.From June 2003 to December 2008, 1480 patients who underwent gastrectomy due to gastric cancer but had no gallstones before surgery were identified. Electronic medical records were retrospectively reviewed. Gallstones were assessed by computerized tomography or ultrasound performed as surveillance for recurrence.There were 987 men (66.7%) and the median age was 59.0 years. The median follow-up period was 47.0 months. According to the surgical technique, 754 (50.9%), 459 (31.1%), and 267 (18.0%) underwent subtotal gastrectomy with Billroth I (STG B-I) and Billroth II (STG B-II) anastomosis, and total gastrectomy (TG). Within the follow-up period, gallstone formation occurred in 106 of 1480 patients (7.2%), the only 9 patients (0.6%) experienced symptomatic cholecystitis. By multivariate Cox regression analysis, age (HR 1.02, 95% CI 1.00–1.04), male (1.65, 1.02–2.67), diabetes mellitus (2.15, 1.43–3.24), ≥4% decrease of body mass index after surgery (1.66, 1.02–2.70), STG B-II (1.63, 1.03–2.57), and TG (2.35, 1.43–3.24) compared with STG B-I were associated with gallstone formation. Common bile duct stone formation occurred in 20 of 1480 patients (1.4%) and was only associated with gallstones.After gastrectomy, there were considerable numbers of patients with newly developed gallstones; however, prophylactic cholecystectomy should not be routinely recommended. Gastrectomy (STG B-II or TG), old age, male sex, diabetes mellitus, and decreased body mass index were associated with gallstones.

The Efficacy of Clinical Predictors for Patients with Intermediate Risk of Choledocholithiasis.

Background/Aims: For the suspected choledocholithiasis, the American Society for Gastrointestinal Endoscopy has proposed guidelines to assign risk based on clinical predictors. The study aimed to assess the usefulness of clinical predictors of choledocholithiasis set forth by the guidelines in patients with intermediate risk of choledocholithiasis. Methods: In 2014, 109 patients with intermediate risk of choledocholithiasis underwent endoscopic ultrasound. Their medical records were retrospectively reviewed. The gold standard for choledocholithiasis was endoscopic retrograde cholangiopancreatography or clinical follow-up. Results: Based on endoscopic ultrasound findings, choledocholithiasis was suspected in 18 patients, and it was removed in 17 patients. Choledocholithiasis was absent in the remaining 91 who did not show any signs from endoscopic ultrasound. Among the 2 strong (common bile duct (CBD) diameter >6 mm and bilirubin 1.8-4 mg/dl) and 3 moderate (abnormal liver biochemical test other than bilirubin, age >55 years and gallstone pancreatitis) clinical predictors, 28.8% of patients with one of the strong predictors had choledocholithiasis; however, only 3.5% of patients with any one of the moderate predictors had choledocholithiasis. As a result, only strong clinical predictors showed predictability: increased bilirubin level (OR 3.23; 90% CI 0.85-12.28) and dilated CBD diameter (OR 5.83; 90% CI 1.93-17.57). Conclusion: Only strong clinical predictors of choledocholithiasis showed predictability for patients with intermediate risk of choledocholithiasis.

Adjunctive role of preoperative liver magnetic resonance imaging added to computed tomography among resected pancreatic cancer patients.

207 Background: Multi-detector computed tomography using pancreatic protocol (pCT) has been a preferred diagnostic imaging modality before resection of the pancreatic ductal adenocarcinoma (PDAC), because an adjunctive role of liver magnetic resonance imaging (MRI) is still unclear. The current study evaluated whether liver MRI added to pCT can help to select proper surgical candidates, and reduce the risk of early recurrence, eventually result in longer survival in resected PDAC patients. Methods: Among 197 PDAC patients who underwent curative-intended surgery, 167 patients who achieved complete resection with no grossly visible tumor were enrolled retrospectively. All patients had no metastatic lesions on pCT and/or MRI, preoperatively. Among them, 102 patients underwent pCT alone (CT group), and 65 patients liver MRI as well as pCT (MRI group). Results: By adding the liver MRI, hepatic metastases were newly discovered in 3 of 58 patients (5.2%) with no hepatic lesions on pCT and in 17 of 53 patients (3...

Clinical impact of neoadjuvant treatment in resectable pancreatic cancer: a systematic review and meta-analysis protocol.

Introduction Although the only curative strategy for pancreatic cancer is surgical resection, up to 85% of patients relapse after surgery. The efficacy of neoadjuvant treatment in resectable pancreatic cancer (RPC) remains unclear and there is no systematic review focusing fully on this issue. Recently, two prospective trials of neoadjuvant treatment in RPC were terminated early because of slow recruiting and existing randomised controlled trials (RCTs) have too small sample sizes. Therefore, to overcome probable biases, it would be more reasonable to include both RCTs and non-randomised studies (NRSs) with selected criteria. This review aims to investigate the effect of neoadjuvant chemotherapy (CTx) and chemoradiation therapy (CRT) in RPC using RCTs and specific NRSs. Method and analysis This systematic review will include conventional RCTs as group I, and quasi-randomised controlled trials, non-randomised controlled trials and prospective cohort studies as group II. Two groups will be assessed and analysed separately. Comprehensive literature search will use Medline, Embase, Cochrane library and Scopus databases. Additionally, we will search references from relevant studies and abstracts from major conferences. Two authors will independently identify, screen, include studies, extract data and assess the risk of bias. Discrepancies will be resolved by consensus with another author. An independent methodologist will categorise and assess NRSs to minimise heterogeneity. In each study group, meta-analysis will be conducted using a random-effect model and statistical heterogeneity will be evaluated using I2-statistics. Publication bias will be visualised with contour-enhanced funnel plots and analysed with Eggers test. In group I, cumulative meta-analysis will be considered because the CTx regimen and CRT protocol have changed. The quality of evidence will be summarised using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Ethics and dissemination This review does not use primary data, and formal ethical approval is not required. Findings will be disseminated through peer-reviewed journals and committee conferences. Trial registration number CRD42015023820.

715PDOES REDUCED DOSE OF FOLFIRINOX GUARANTEE TUMOR RESPONSE IN UNRESECTABLE PANCREATIC CANCER? : SUGGESTION FOR THE MINIMAL RELATIVE DOSE INTENSITY

ABSTRACT Aim: Since PRODIGE4-ACCORD11 trial showed the superior activity of FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) than gemcitabine, FOLFIRINOX has been widely applied to the patients with pancreatic cancer as the first-line chemotherapy. Recently there have been published several reports about modified FOLFIRINOX as a concept of dose reduction. However, it is still unclear how much reduction would be promising as a minimal threshold of effective dose. The aim of this study is to investigate minimal relative dose intensity of FOLFIRINOX to expect tumor response in unresectable pancreatic cancer. Methods: A total of 44 patients who were diagnosed with unresectable pancreatic adenocarcinoma from 2012 to 2014 were retrospectively reviewed. All patients were treated with FOLFIRINOX as 1st-line treatment. Assuming four cycles of standard FOLFIRINOX dose as a 100% dose, actually delivered cumulative dose of each patient was converted to relative dose intensity (RDI, %) during the first 8 weeks. Patients were divided into three groups depending on RDI; group A, RDI ≥ 80%; group B, 70 ≤ RDI Results: Of 44 patients, total 27 were eligible. Among 27 eligible patients, the number of group A, B and C was 8 (30%), 12 (44%) and 7 (26%), respectively. There was no difference between groups in terms of mean age, performance status and stage. The response rates in first 8 weeks were 50%, 42% and 0% in group A, B, C, respectively. The number of grade 4 neutropenia within the 8 weeks was 13%, 16%, and 14%, respectively. The incidence of grade 3/4 diarrhea or nausea was 25%, 33%, and 29%, respectively. There was no statistical difference between group A and B in terms of response rate, whereas group B and C showed significant difference. Grade 3 or more toxicities were not statistically different among three groups. Conclusions: Dose reduction of FOLFIRINOX might be effective to control unresectable pancreatic cancer. However, less than 70% of RDI of FOLFIRINOX showed significantly low response rate, whereas there was no change in terms of severe side effects. We suggest the 70% of RDI as minimal relative dose intensity to expect tumor response in unresectable pancreatic cancer. Disclosure: All authors have declared no conflicts of interest.