Ki Byung Song

A Combination of Molecular Markers and Clinical Features Improve the Classification of Pancreatic Cysts

BACKGROUND & AIMS The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. METHODS We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. RESULTS We identified molecular markers and clinical features that classified cyst type with 90%-100% sensitivity and 92%-98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. CONCLUSIONS We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Matched Case-Control Analysis Comparing Laparoscopic and Open Pylorus-preserving Pancreaticoduodenectomy in Patients With Periampullary Tumors.

OBJECTIVES To evaluate the safety, feasibility, and oncologic outcomes of laparoscopic pylorus-preserving pancreaticoduodenectomy (L-PPPD) to treat periampullary tumors. The clinical outcomes of L-PPPD were compared with open pylorus-preserving pancreaticoduodenectomy (O-PPPD). BACKGROUND Despite recent advances in laparoscopic pancreatic surgery, few studies have compared L-PPPD with O-PPPD. The safety, short-term clinical benefits, and oncologic outcomes of L-PPPD remain controversial. METHODS Between January 2007 and December 2012, a total of 2192 patients diagnosed with periampullary tumors were treated with curative resection at our institution. Of these patients, 137 underwent a laparoscopic approach and 2055 an open technique. A retrospective study was performed to evaluate the safety, feasibility, and oncologic outcomes of L-PPPD compared with O-PPPD. RESULTS The mean operation time for the L-PPPD group was longer than for the O-PPPD group (P < 0.001). Estimated blood loss was similar, as was the incidence of complications, such as pancreatic fistula and delayed gastric empting (P > 0.05). The mean number of analgesic injections administered was lower in the L-PPPD group than in the O-PPPD group (P < 0.001), and the mean duration of the postoperative hospital stays was shorter (P < 0.001). The surgical resection margins and the number of lymph nodes in the resected specimens did not differ between the 2 groups, and there was no significant difference in overall survival curves. CONCLUSIONS L-PPPD had the typical advantages of minimally invasive abdominal procedures, such as less pain, shorter hospital stay, and quicker recovery. It is technically safe and feasible, and has favorable oncologic outcomes in comparison with O-PPPD in patients with periampullary tumors.

Validation of the 2012 International Consensus Guidelines Using Computed Tomography and Magnetic Resonance Imaging: Branch Duct and Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Objective:To validate the 2012 guidelines for intraductal papillary mucinous neoplasm (IPMN) of the pancreas and to compare diagnostic performances of computed tomography (CT) and magnetic resonance imaging (MRI) for differentiating malignant from benign IPMN. Background:As IPMN has variable risks of malignancy and management of this entity is closely related to its malignant potential, it is important to predict risks of IPMN malignancy. Methods:This retrospective study included 158 patients with surgically confirmed IPMN of the pancreas who underwent both preoperative CT and MRI. Two radiologists evaluated the “high-risk stigmata” and “worrisome features” of the 2012 guidelines for branch duct (BD)-IPMN and main duct (MD)-IPMN. Univariate and multivariable analyses were used to identify significant predictors of malignancy in IPMN. The diagnostic performance was compared between CT and MRI. Results:Malignant IPMN was seen in 8 of 60 patients (13.3%) with BD-IPMN and 44 of 98 patients (44.9%) with MD-IPMN. Presence of mural nodule was the most important predictor in BD-IPMN and MD-IPMN (odds ratios, 9.2 and 7.6, respectively, P = 0.01 on CT; and odds ratios, 5.7 and 13.3, respectively, P ⩽ 0.04 on MRI), whereas mural nodule size and lymphadenopathy were significant only in MD-IPMN (P < 0.05). The diagnostic performance of CT and MRI for significant findings was not statistically different in both types of IPMN (P > 0.34). Conclusions:The presence of mural nodule was the most important predictor of malignancy in both types of IPMN. Mural nodule size and lymphadenopathy were also significant predictors in MD-IPMN. Computed tomography and MRI showed similar diagnostic performances for differentiating malignant from benign IPMN.

Surgical outcomes of pancreatic arteriovenous malformation in a single center and review of literature.

Objective Pancreatic arteriovenous malformation (P-AVM) is an extremely rare condition that can be accompanied by fatal complications. We have attempted to identify the possible management guidelines based on our and others’ clinical experience. Methods We retrospectively analyzed our findings including clinical characteristics, imaging modalities, and treatment in 12 patients. Sporadic reports of 69 patients with P-AVM were surveyed for representative characteristics and treatment strategy. Results The mean age at diagnosis was 49.8 years (range, 44–64 years), and all 12 were male. The mean body mass index was 21.5 kg/m2 (range, 18.3–24.3 kg/m2) and 6 (50%) were heavy smokers (mean, 30.9 pack-years; range, 7.5–120 pack-years). The most common clinical symptom is gastrointestinal bleeding, followed by abdominal pain. All patients were diagnosed with abdominal disease using computed tomography. Of the 12 patients, 11 underwent pancreatic resection and 1 patient was managed conservatively. No patient experienced any major postoperative complications during the median follow-up of 37 months. Conclusions In patients with symptomatic P-AVM, surgical resection of the affected pancreas showed a successful result. When a patient is at a high risk for surgical treatment, transjugular intrahepatic portosystemic shunt, transarterial embolization, and radiation therapy might be other treatment options.

Alternative lengthening of telomeres in primary pancreatic neuroendocrine tumors is associated with aggressive clinical behavior and poor survival

Purpose: Alternative lengthening of telomeres (ALT), a telomerase-independent telomere maintenance mechanism, is strongly associated with ATRX and DAXX alterations and occurs frequently in pancreatic neuroendocrine tumors (PanNET). Experimental Design: In a Korean cohort of 269 surgically resected primary PanNETs and 19 sporadic microadenomas, ALT status and nuclear ATRX and DAXX protein expression were assessed and compared with clinicopathologic factors. Results: In PanNETs, ALT or loss of ATRX/DAXX nuclear expression was observed in 20.8% and 19.3%, respectively, whereas microadenomas were not altered. ALT-positive PanNETs displayed a significantly higher grade, size, and pT classification (all, P < 0.001). ALT also strongly correlated with lymphovascular (P < 0.001) and perineural invasion (P = 0.001) and the presence of lymph node (P < 0.001) and distant metastases (P = 0.002). Furthermore, patients with ALT-positive primary PanNETs had a shorter recurrence-free survival [HR = 3.38; 95% confidence interval (CI), 1.83–6.27; P < 0.001]. Interestingly, when limiting to patients with distant metastases, those with ALT-positive primary tumors had significantly better overall survival (HR = 0.23; 95% CI, 0.08–0.68; P = 0.008). Similarly, tumors with loss of ATRX/DAXX expression were significantly associated with ALT (P < 0.001), aggressive clinical behavior, and reduced recurrence-free survival (P < 0.001). However, similar to ALT, when limiting to patients with distant metastases, loss of ATRX/DAXX expression was associated with better overall survival (P = 0.003). Conclusions: Both primary ALT-positive and ATRX/DAXX-negative PanNETs are independently associated with aggressive clinicopathologic behavior and displayed reduced recurrence-free survival. In contrast, ALT activation and loss of ATRX/DAXX are both associated with better overall survival in patients with metastases. Therefore, these biomarkers may be used as prognostic markers depending on the context of the disease. Clin Cancer Res; 23(6); 1598–606. ©2016 AACR.

Branch duct intraductal papillary mucinous neoplasm of the pancreas: single-center experience with 324 patients who underwent surgical resection

Backgrounds/Aims International treatment guidelines for branch duct intraductal papillary mucinous neoplasm (BD-IPMN) of the pancreas have been proposed, for features associated with malignancy and invasiveness. We investigated the clinicopathological characteristics that are predictive of malignancy or invasiveness and disease recurrence. Methods A review of 324 patients with resected and pathologically confirmed BD-IPMN, between March 1997 and December 2013, was conducted. Results There were 144 (44.4%) low grade dysplasia (LGD), 138 (42.6%) intermediate grade dysplasia (IMGD), 17 (5.3%) high grade dysplasia (HGD), and 25 (7.7%) invasive carcinoma (invIPMC) cases. The 5-year survival rates were 98.1% for LGD, 95.3% for IMGD, 100% for HGD, and 71.8% for invIPMC. Through a univariate analysis, the male sex was associated with malignancy, and CA19-9 was related to both malignant and invasive IPMN. The high risk or worrisome features of the international guidelines were associated with both malignant and invasive IPMN: the total bilirubin of the head/uncinate lesion, tumor size, mural nodule, and the size of the main pancreatic duct (MPD). Through a multivariate analysis, the male sex, elevated CA19-9, mural nodule, and dilated MPD diameter were independently correlated with the malignant IPMN. The elevated CA19-9 and dilated MPD diameter were also correlated with invasive carcinoma. The patient age and the initial pathological diagnosis were strongly associated with disease recurrence following surgical resection. Conclusions The high risk or worrisome features in the current treatment guidelines for BD-IPMN are confined to the morphological characteristics of the disease. Patient factors and biological features should also be considered in order to develop optimal therapeutic or surveillance strategies.

The DPC4/SMAD4 genetic status determines recurrence patterns and treatment outcomes in resected pancreatic ductal adenocarcinoma: A prospective cohort study

Objectives The objective of this study was to investigate the role of genetic status of DPC4 in recurrence patterns of resected pancreatic ductal adenocarcinoma (PDAC). Methods Between April 2004 and December 2011, data on patients undergoing surgical resection for PDAC were reviewed. Genetic status of DPC4 was determined and correlated to recurrence patterns and clinical outcomes. Results Analysis of 641 patients revealed that genetic status of DPC4 was associated with overall survival and was highly correlated with recurrence patterns, as inactivation of the DPC4 gene was the strongest predictor of metastatic recurrence (odds ratio = 4.28). Treatment modalities for recurrent PDAC included chemotherapy alone and concurrent chemotherapy along with local control. For both locoregional and metastatic recurrence, local control resulted in improved survival; however, for groups subdivided according to recurrence patterns and genetic status of DPC4, local control contributed to improved survival in locoregional recurrences of patients with expressed DPC4, while chemotherapy alone was sufficient for others. Conclusions Genetic status of DPC4 contributes to the recurrence patterns following pancreatectomy, and patients with an initially expressed DPC4 gene receive a greater benefit from intensive local control for locoregional recurrence. The DPC4 gene, therefore, may aid the establishment of treatment strategies for initial adjuvant treatment or for recurrent PDAC.

Prognostic Value of Somatostatin Receptor Subtypes in Pancreatic Neuroendocrine Tumors.

Objectives Studies on the expression of somatostatin receptor (SSTR) subtypes in pancreatic neuroendocrine tumors (PNETs) are rare. The aim of this study was to determine the expression of the SSTR subtypes via immunohistochemistry analyses and assess the correlation between SSTR subtype expression and prognosis. Methods We examined 199 patients with PNET who underwent surgical resection between January 1995 and December 2010 at the Asan Medical Center. For all cases, medical records, including demographic data, clinical symptoms, radiological findings, postoperative treatment outcomes, and expression of SSTR subtypes, were carefully reviewed. Results In total, 162 (81.4%) PNETs expressed more than 1 SSTR subtype. Functioning PNET expressed significantly more SSTR subtypes, compared to nonfunctioning PNET. The SSTR2(+) and SSTR5(+) groups had better prognosis than the SSTR2(−) (P = 0.009) and SSTR5(−) groups (P = 0.03), respectively. In the grade 2 PNET of 2010 World Health Organization classification, the SSTR(+) group had better prognosis than SSTR(−) group. Conclusions The expression of SSTR 2 and 5 were related with good prognosis of PNET. In World Health Organization grade 2 PNET, the SSTR(+) group had better prognosis than SSTR(−) group. The SSTR expression(+) by immunohistochemistry might be related with good prognosis of the patients with surgically resected PNET.

Clinical usefulness of portal venous stent in hepatobiliary pancreatic cancers

Treatment options for patients with portal vein (PV) stenosis or occlusion after surgery are limited. The purpose of this study was to investigate the efficacy and safety of PV stent placement in patients with portal vein occlusion or stenosis after radical operation for hepatobiliary pancreatic malignant tumour.

Appraisal of Laparoscopic Distal Pancreatectomy for Left-Sided Pancreatic Cancer: A Large Volume Cohort Study of 152 Consecutive Patients

Background The aim of this study was to appraise the value of laparoscopic distal pancreatectomy (LDP) for left-sided pancreatic cancer based on a large volume cohort study. Methods We reviewed data for all consecutive patients undergoing LDP for left-sided pancreatic cancer at Asan Medical Center (Seoul, Korea) between December 2006 and December 2014. Results A total of 91 male and 61 female patients, with a median age of 62.7 years were included in this study. The median operative duration was 234 minutes. Pathological reports revealed the following: a median tumor size of 3.0 cm (range, 0.4–10.0), T stages (T1 in 7.9%, T2 in 5.3%, T3 in 86.8%, and no T4), the tumor differentiation (well differentiated in 16.4%, moderately differentiated in 75.4%, and poorly differentiated in 8.2%), and R0 resection in 126 patients (82.9%). After pancreatectomy, 96 patients (63.2%) received adjuvant chemotherapy, and the median time to chemotherapy was 30 days. The median length of hospital stay was 8 days (range, 5–31), and the median time to diet resumption was 1 day. Grade B or C postoperative pancreatic fistula occurred in 14 patients (9.2%) and grade II or III complications occurred in 27 (17.7%). The median overall survival was 43.0 months. A Cox proportional hazards model showed that tumor size, N1 stage, combined resection, and incompleteness of planned adjuvant chemotherapy affect patient survival. Conclusions LDP for left-sided pancreatic cancer is reasonable within selected indications. An international consensus on laparoscopic surgery for pancreatic cancer would be desirable and timely.