Long-term outcomes of endoscopic papillectomy for ampullary adenoma with high-grade dysplasia or adenocarcinoma: a propensity score-matched analysis.

BACKGROUND: Evidence of endoscopic papillectomy (EP) for ampullar adenoma with high-grade dysplasia (HGD) or adenocarcinoma is insufficient. Here we investigated the long-term outcomes of the advanced ampullary tumors treated by EP with careful surveillance comparing to subsequent surgery after EP. METHODS: Patients treated with EP for ampullary adenoma with HGD or adenocarcinoma from the multi-center retrospective Korean cohort of ampulla of Vater tumor were categorized into EP alone versus EP with subsequent surgery groups. The overall survival (OS) and recurrence-free survival (RFS) were analyzed for unmatched and matched cohorts using propensity score with nearest neighbor method. RESULTS: During a median 43.3 months of follow-up, 5-year OS was not significantly different between the EP alone and EP surgery groups (91.9% vs. 82.3%, P = 0.443 for unmatched cohort; 89.2% vs. 82.3%, P = 0.861 for matched cohort, respectively). Furthermore, 5-year RFS was not significantly different between the two groups (82.1% vs. 86.7%, P = 0.520 for unmatched cohort; 66.1% vs. 86.7%, P = 0.052 for matched cohort, respectively). However, the patients with positive both (lateral and deep) margins showed significantly poorer survival outcomes than those with negative margins within the EP alone group (P = 0.007). CONCLUSION: EP alone with careful surveillance showed comparable survival outcomes to those of EP with subsequent surgery for ampullar HGD or adenocarcinoma. Resection margin status could be a parameter to determine whether to perform subsequent radical surgery after EP.

Increased incidence of indeterminate pancreatic cysts and changes of management pattern: Evidence from nationwide data.

BACKGROUND: Pancreatic cysts are common. However, most studies are based on data collected from individual centers. The present study aimed to evaluate the changes of management patterns for pancreatic cystic lesions (PCLs) by analyzing large epidemiologic data. METHODS: Between January 2007 and December 2018, information regarding pancreatic cystic lesions was acquired from the nationwide Health Insurance Review and Assessment Service database in Korea. RESULTS: The final number of patients with pancreatic cysts was 165 277 among the total claims for reimbursement of 855 983 associated with PCLs over 12 years. The total number of claims were increased from 19 453 in 2007 to 155 842 in 2018 and the prevalence increased from 0.04% to 0.23%. For 12 years, 2874 (1.7%) had pancreatic cancer and 8212 (5.0%) underwent surgery, and 36 had surgery for twice (total 8248 pancreatectomy). After ruling out claims from the first 3 years of washout period, the incidence increased from 9891 to 24 651 and the crude incidence rate of PCLs expanded from 19.96 per 100 000 to 47.77 per 100 000. Compared to specific neoplasm codes (D136 or D377), the use of pancreatic cyst code (K862) has been remarkably increased and the most common since 2010. The annual number of pancreatectomies increased from 518 to 861 between 2007 and 2012, and decreased to 596 until 2018. The percentage of pancreatic cancer in patients who received pancreatectomy increased from 5.6% in 2007 to 11.7% in 2018. CONCLUSIONS: The incidence of PCLs is rapidly increasing. Among PCLs, indeterminate cyst is increasing outstandingly. A trend of decreasing in the number of resections and increasing cancer rates among resected cysts may be attributed to the updated international guidelines.

Tumor resectability and response on CT following neoadjuvant therapy for pancreatic cancer: inter-observer agreement study.

OBJECTIVES: First, to measure inter-observer agreement regarding tumor resectability and response, and second, to measure diagnostic performance in predicting negative resection margin, on re-staging CTs of patients who received neoadjuvant therapy for pancreatic cancer. METHODS: This retrospective study included patients who received neoadjuvant therapy for borderline resectable pancreatic cancer from 2017 to 2020. Six readers independently evaluated initial staging and re-staging CT images. They categorized the resectability on re-staging CT based on the NCCN guideline, and evaluated tumor response to neoadjuvant therapy according to our proposed criteria on a 5-grade scale. For inter-observer agreement, Gwet's agreement coefficients were used. A crossed random effect model was used to pool the sensitivity and specificity of six readers in predicting negative resection margin. RESULTS: Seventy-seven patients with the median age of 66 (59-70) were included. The pooled agreement for tumor resectability was 0.64 (95% CI, 0.56-0.71) for differentiating the three categories, and 0.84 (0.77-0.91) for differentiating resectable or borderline resectable cancer vs. unresectable cancer. Agreement for tumor response grade was 0.89 (0.85-0.92). The pooled sensitivity and specificity for predicting negative resection margin were 48% (43-52%) and 61% (57-64%), respectively, when only "resectable" on re-staging CT was considered as index test positive. When either "resectable"' or "borderline resectable" was considered as positive, the pooled sensitivity and specificity were 91% (89-94%) and 5% (4-6%), respectively. CONCLUSION: CT can be used reliably with a high inter-observer agreement in selecting candidates for surgery after neoadjuvant therapy of pancreatic cancer. KEY POINTS: • On CT following neoadjuvant therapy of pancreatic cancer, six readers showed high agreement in differentiating resectable or borderline resectable vs. unresectable cancer (Gwet's coefficient, 0.84). • Inter-observer agreement was also high for our proposed tumor response grade (Gwet's coefficient, 0.89). • Specificity was very low (5%) while sensitivity was high (91%) when either resectable or borderline resectable cancer on re-staging CT was considered as predictive of negative resection margin status.

Prediction model using clinical factors for radiation exposure during endoscopic retrograde cholangiopancreatography.

BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) requires radiation. This study aimed to assess the clinical factors influencing radiation exposure and devise a scoring model for predicting high-dose radiation exposure. METHODS: Endoscopic retrograde cholangiopancreatography cases recorded between 2016 and 2019 in a single tertiary teaching hospital were retrospectively reviewed. A scoring model was created by bootstrap method in a derivation cohort (2016-2018) and was assessed in a validation cohort (2019). RESULTS: Out of 4223 ERCPs, 2983 and 1240 cases were included in the derivation and validation cohorts, respectively. In the derivation cohort, 746 cases (top 25%) comprised the high-dose exposure group, and 2237 cases (bottom 75%) comprised the low-dose exposure group. Nine clinical parameters associated with high-dose exposure were male, pancreatic sphincterotomy, balloon dilatation, biliary or pancreatic drainage, procedures with contrast dye, endoscopist, in-hospital ERCP, and spot image. Stone removal was included by bootstrap analysis. As presented in a nomogram, the weight score of each variable was as follows: male, 1; pancreatic sphincterotomy, 3; balloon dilatation, 7; stone removal, 3; biliary or pancreatic drainage, 5; procedures with contrast dye, 1; endoscopist B, 4; endoscopist C, 5; in-hospital procedure, 3; and spot image, 3. A total score ≥ 15 suggested a high-dose radiation exposure. The sensitivity and specificity of the model for high-dose exposure were 0.562 and 0.813, respectively. In the validation cohort, the model showed reasonable predictability. CONCLUSIONS: Various factors were associated with radiation exposure. The simple scoring system in this study could guide endoscopists in predicting the risk of high-dose radiation exposure.

Tailored adjuvant gemcitabine versus 5-fluorouracil/folinic acid based on hENT1 immunohistochemical staining in resected pancreatic ductal adenocarcinoma: A biomarker stratified prospective trial.

BACKGROUND: The study aimed to evaluate the clinical outcomes of tailored adjuvant chemotherapy according to human equilibrative nucleoside transporter 1 (hENT1) expression in resected pancreatic ductal adenocarcinoma (PDA). METHODS: Patients who underwent pancreatectomy for PDA were enrolled prospectively. According to intra-tumoral hENT1 expression, the high hENT1 (≥50%) group received gemcitabine and the low hENT1 (<50%) group received 5-fluorouracil plus folinic acid (5-FU/FA). The propensity score-matched control consisted of patients who received hENT1-independent adjuvant chemotherapy. The primary outcome was recurrence free survival (RFS) and the secondary outcomes were overall survival (OS) and toxicities. RESULTS: Between May 2015 and June 2017, we enrolled 44 patients with resected PDA. During a median follow-up period of 28.5 months, the intention-to-treat population showed much longer median RFS [22.9 (95% CI, 11.3-34.5) vs. 10.9 (95% CI, 6.9-14.9) months, P = 0.043] and median OS [36.2 (95% CI, 26.5-45.9) vs. 22.1 (95% CI, 17.7-26.6) months, P = 0.001] compared to the controls. Among 5 patients in the low hENT1 group who discontinued treatment, 2 patients receiving 5-FU/FA discontinued treatment due to drug toxicities (febrile neutropenia and toxic epidermal necrolysis). CONCLUSION: Tailored adjuvant chemotherapy based on hENT1 staining provides excellent clinical outcomes among patients with resected PDA. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02486497.

Malignant potential of small pancreatic neuroendocrine neoplasm and its risk factors: A multicenter nationwide study.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PNENs) show heterogeneous biological behavior, and most small PNENs show indolent features. Consequently, selected cases can be considered for observation only, according to the National Comprehensive Cancer Network guideline, however, supporting clinical evidence is lacking. We investigated the clinical course of small PNENs and their risk factors for malignant potential. METHODS: A total of 158 patients with small pathologically confirmed PNENs ≤2 cm in initial imaging were retrospectively enrolled from 14 institutions. The primary outcome was any metastasis or recurrence event during follow-up. RESULTS: The median age was 57 years (range, 22-82 years), and 86 patients (54%) were female. The median tumor size at initial diagnosis was 13 mm (range, 7-20 mm). PNENs were pathologically confirmed by surgery in 137 patients and by EUS-guided fine needle aspiration biopsy (EUS-FNAB) in 21 patients. Eight patients underwent EUS-FNAB followed by surgical resection. The results of WHO grade were available in 150 patients, and revealed 123 grade 1, 25 grade 2, and 2 neuroendocrine carcinomas. A total of 145 patients (92%) underwent surgical resection, and three patients had regional lymph node metastasis. During the entire follow-up of median 45.6 months, 11 metastases or recurrences (7%) occurred. WHO grade 2 (HR 13.97, 95% CI 2.60-75.03, p = 0.002) was the only predictive factor for malignant potential in multivariable analysis. CONCLUSIONS: WHO grade is responsible for the malignant potential of small PNENs ≤2 cm. Thus, EUS-FNAB could be recommended in order to provide early treatment strategies of small PNENs.

The clinical significance of preoperative C-reactive protein/albumin ratio in patients with resected extrahepatic bile duct cancer.

PURPOSE: The C-reactive protein (CRP)/albumin ratio has been identified as a potential prognostic factor for several malignancies. We, therefore, assessed the prognostic role of the CRP/albumin ratio in resected extrahepatic cholangiocarcinoma (EC). MATERIALS AND METHODS: A total of 235 patients were retrospectively analyzed between March 2005 and December 2017. The correlations among the preoperative CRP/albumin ratio, clinicopathological factors, and clinical outcomes were investigated. RESULTS: There were 143 males (60.8%), and the median age at the diagnosis was 70.1 (range 41.0-85.5) years. Patients were diagnosed with perihilar bile duct cancer (n = 61) and distal bile duct cancer (n = 174). The median recurrence-free survival and overall survival were 32.7 and 38.7 months, respectively. The optimal prognostic cut-off point of the CRP/albumin ratio for the survival was 0.18 (× 103). According to the Kaplan-Meier analysis with a log-rank test, the high CRP/albumin ratio group (≥ 0.18) had a significantly shorter overall survival than the low CRP/albumin ratio group (< 0.18) (29.8 vs. 54.6 months, p = 0.002). A multivariate logistic regression analysis for the overall survival showed that CA19-9 ≥ 37 and a high CRP/albumin ratio were associated with a shorter overall survival. CONCLUSION: A high CRP/albumin ratio appears to be significantly associated with clinically worse outcomes in patients with resected EC.

Serum fibrinogen as a diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma.

BACKGROUND/OBJECTIVES: Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is important as PDAC can lead to mortality; however, no specific biomarker has been identified for its early diagnosis. We previously identified fibrinogen α chain as a promising biomarker for differentiating between patients with and without PDAC using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Here, we aimed to validate the clinical usefulness of serum fibrinogen as a biomarker for PDAC. METHODS: From 2009 to 2011, blood samples of 67 PDAC patients and 43 healthy adults (controls) were prospectively collected. Serum fibrinogen levels and their clinical significances were evaluated. RESULTS: Mean fibrinogen levels were significantly higher in the PDAC group than in the control group (3.08 ± 0.565 vs. 2.54 ± 0.249 log10 ng/mL, P < 0.001). In the receiver operating characteristic analysis, overall sensitivity, and specificity of serum fibrinogen levels for differentiating PDAC patients from control patients were 67.4% and 83.6%, respectively, with a 427-ng/mL cutoff value. Serum fibrinogen levels were significantly higher in PDAC patients with distant metastasis than in those without distant metastasis (3.38 ± 0.581 vs. 2.93 ± 0.499 log10 ng/mL, P = 0.002). Median overall survival was significantly longer in PDAC patients with low fibrinogen levels (<1000 ng/mL) than in those with high fibrinogen levels (≥1000 ng/mL) [489 days (95% confidence interval, 248.1-729.9) vs. 172 days (58.4-285.6) (P = 0.008)]. Although serum fibrinogen levels were poorly correlated with carbohydrate antigen 19-9 levels, these two biomarkers together predicted survival better. CONCLUSIONS: Serum fibrinogen levels may be a useful biomarker for diagnosing and predicting PDAC prognosis.

Tolerability and safety of EUS-injected adenovirus-mediated double-suicide gene therapy with chemotherapy in locally advanced pancreatic cancer: a phase 1 trial.

BACKGROUND AND AIMS: Locally advanced pancreatic cancer (LAPC) is challenging. Here, we aimed to evaluate the tolerability and safety of Ad5-yCD/mutTK(SR39)rep-ADP (Ad5-DS), a replication-competent adenovirus-mediated double-suicide gene therapy in combination with gemcitabine in patients with LAPC. METHODS: Patients with newly diagnosed LAPC were enrolled in this single-center, open-label, 3 + 3 dose-escalation phase 1 trial. Ad5-DS was injected into the pancreatic mass with EUS-guided fine needles combined with oral 5-fluorocytosine and valganciclovir, and a standard dose of intravenous gemcitabine. The doses of Ad5-DS in cohorts 1 to 3 were 1 × 1011, 3 × 1011, and 1 × 1012 viral particles (vp)/mL, respectively. Patients were observed for dose-limiting toxicity (DLT) for 8 weeks after Ad5-DS injection. Toxicity within 12 weeks, tumor response in 12 weeks, disease progression in 6.5 months, and detection of adenoviral DNA particles in 8 weeks were also assessed. RESULTS: Among the 11 enrolled patients, 9 completed the evaluation period and 2 withdrew their consent. No DLT was reported; thus, the maximum tolerated dose was not reached. No additional toxicity was reported in 9 to 12 weeks. One patient showed a partial response and 8 showed stable disease at 12 weeks. Two patients showed disease progression at 6.5 months (median progression-free survival, 11.4 months). At 8 weeks, serum adenoviral DNA particles were detected in 4 patients (median, 55 days). CONCLUSION: A combination of intratumoral Ad5-DS and gemcitabine is safe and well tolerated in patients with LAPC. This warrants further investigation in a larger clinical trial. (Clinical trial registration number: NCT02894944.).

Programmed cell death ligand-1 (PD-L1) expression in extrahepatic biliary tract cancers: a comparative study using 22C3, SP263 and E1L3N anti-PD-L1 antibodies.

AIMS: Pembrolizumab has shown promising results for patients with programmed cell death ligand-1 (PD-L1)-positive advanced biliary tract cancer in an ongoing clinical trial. However, data on PD-L1 expression in bile duct cancers is limited, and the frequency of PD-L1 positivity varies, which may be partly due to the assay used. The aim of this study was to evaluate PD-L1 expression status in bile duct cancers by using 22C3, SP263 and E1L3N antibodies. METHODS AND RESULTS: We evaluated PD-L1 expression in tissue microarrays of 183 extrahepatic bile duct cancers, including 89 perihilar and 94 distal bile duct cancers, by using 22C3, SP263 and E1L3N. When the 22C3 assay was used, tumoral PD-L1 was shown to be expressed in 16.9% of cases at a 1% threshold. When the SP263 and E1L3N assays were used, tumoral PD-L1 was shown to be expressed in 26% and 7.1% of cases, respectively. When whole tissue sections were examined, 59.6% of PD-L1-positive cases showed a low percentage (<10%) of positive tumour cells. Tumoral PD-L1 positivity was associated with poor histological differentiation (P = 0.017) and the biliary epithelial phenotype (P = 0.041). High tumoral PD-L1 expression (≥10%) was associated with worse overall survival (OS) and disease-free survival (DFS) (OS, P = 0.012; DFS, P = 0.042). CONCLUSIONS: PD-L1 was expressed in a small subset of patients with bile duct cancer, and the percentage of positive tumour cells was low in PD-L1-positive cases. The SP263 assay showed the highest PD-L1 positivity in both tumour cells and immune cells, followed by the 22C3 and E1L3N assays. High PD-L1 expression was associated with a poor prognosis in extrahepatic bile duct cancer patients.

Duct-obstructive pancreatitis with granulocytic epithelial lesion in a patient with ulcerative colitis: An atypical manifestation of type 2 autoimmune pancreatitis?

Type 2 autoimmune pancreatitis (AIP) typically presents with diffuse or focal enlargement of the pancreas; however, its diverse clinical presentation has not yet been clarified. We herein described a 46-year-old man with a 1-month history of ulcerative colitis who presented with imaging features of a mass-like lesion in the pancreatic body with upstream duct dilatation and serum CA19-9 elevation. He underwent laparoscopic distal pancreatectomy with splenectomy for suspected malignancy. Histologically, the area radiologically suspected to be duct dilatation consisted of necrotic tissue, in which the disrupted main pancreatic duct was involved. The area radiologically suspected to be the mass lesion showed features of pancreatitis without discrete mass. In addition, several ducts showed neutrophilic duct injury similar to granulocytic epithelial lesions observed in type 2 AIP. Immunohistochemistry revealed the aberrant expression of IL-8 in the pancreatic ductules and infiltrating CD3-positive T-lymphocytes, findings recently identified in type 2 AIP. The present case is not typical for either type 2 AIP or other known conditions, but extreme examples of type 2 AIP may present with ductal obstruction because of severe neutrophilic duct injury. IL-8 immunostaining may also assist in establishing a diagnosis of type 2 AIP with an atypical presentation.

Effects of Saline Irrigation of the Bile Duct to Reduce the Rate of Residual Common Bile Duct Stones: A Multicenter, Prospective, Randomized Study.

OBJECTIVES: In clinical practice, recurrent cholangitis due to residual common bile duct (CBD) stone occurs frequently even after endoscopic stone removal. This study aimed to determine whether preventive saline irrigation of the bile duct (PSIB) after endoscopic removal of CBD stones would decrease the residual CBD stones. METHODS: In this multicenter, prospective, randomized study, patients who received endoscopic retrograde cholangiopancreatography for removal of CBD stone were randomized to either receiving PSIB after stone removal (PSIB group) or not receiving PSIB (non-PSIB group). Patients were prospectively followed up and the presence of residual CBD stones was evaluated within 6 months after endoscopic stone removal. RESULTS: A total of 148 patients were enrolled and completed follow-up (73 in PSIB group and 75 in non-PSIB group). The two groups were similar with regard to baseline characteristics. Residual CBD stones were detected in 22 patients (14.9%). The incidences of residual CBD stones were 6.8% in PSIB group and 22.7% in non-PSIB group (P=0.010). Multivariate analysis revealed that the performance of PSIB and the presence of only a single-CBD stone were the significant factors for the decrease of the occurrence of the residual CBD stones. Although, procedure time was slightly longer in PSIB group (22.0 vs 19.2 min, P=0.037), no significant difference was observed in the procedure-related complications between the two groups. CONCLUSIONS: PSIB could reduce the residual CBD stones without increasing complications. Considering the efficacy and safety, routine PSIB after endoscopic CBD stone removal seems to be preferred (ClinicalTrials.gov identifier: NCT01425177).

Predictive factors of therapeutic intervention in on-call endoscopy for suspected gastrointestinal bleeding.

BACKGROUND AND AIMS: Performing an endoscopy out of hours confer significant burdens on limited health-care resources. However, not all on-call endoscopies lead to therapeutic interventions. The purpose of the present study was to analyze predictive factors for performing therapeutic intervention in patients with suspected gastrointestinal bleeding. METHODS: We reviewed and analyzed electronic medical records regarding on-call endoscopy that were prospectively collected for quality control. The subjects were patients with suspected gastrointestinal bleeding who underwent on-call endoscopies at night, on weekends and on holidays between April 2013 and January 2017 in Seoul National University Bundang Hospital. To determine predictive factors for performing therapeutic intervention, the following variables were analyzed: symptoms, patient status, coexisting disease, laboratory findings and medications. To clarify the association between the likelihood of therapeutic intervention in on-call endoscopy and AIMS65 score, the included variables were divided by cutoffs. RESULTS: A total of 270 patients (male: 72.6%, mean age: 62.6 years) with suspected gastrointestinal bleeding had on-call endoscopies and 153 (56.7%) patients had therapeutic intervention. Gastroscopy, colonoscopy and both endoscopic techniques were performed in 215, 42 and 13 patients, respectively. In the multivariate analysis, hematemesis (p < .001, odds ratio [OR], 2.484) and prolonged prothrombin time-international normalized ratio (PT-INR) (p = .033; OR, 1.958) were correlated with performing therapeutic intervention in on-call endoscopy. AIMS65 score with a cutoff of 2 was associated with the likelihood of intervention (p = .043). CONCLUSIONS: Hematemesis and prolonged PT-INR were predictive factors of therapeutic intervention when on-call endoscopy was performed in patients with suspected gastrointestinal bleeding.

It is necessary to exam bottom and top slide smears of EUS-FNA for pancreatic cancer.

BACKGROUND: Despite many reports on the diagnostic yield of cytology from endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), inter-slide differences are unknown. This prospective study aimed to compare diagnostic yield and cellular characteristics of bottom slides (BS) and top slides (TS) from EUS-FNA cytology performed without an on-site cytopathologist. METHODS: In patients with suspected pancreatic cancer on previous imaging explorations, a single endoscopist performed EUS-FNA and obtained 2 sets of cytology slide (8 BS and 8 TS), 1 cellblock slide, and 1 biopsy slide. Both slide sets were randomly assigned. A cytopathologist with more than 10 years of expertise in pancreatic cytopathology blindly inspected and compared two slide sets. RESULTS: In total, 73 specimens [42 head (57.5%), 16 body (21.9%), and 15 tail (20.5%)] were acquired for final analysis. Seventy-one cases were finally diagnosed with pancreatic cancer. The sensitivity and specificity of BS were 80.3% and 100.0%; and of TS 78.9% and 100.0%, respectively. In analyzing inter-slide difference, 66 cases (90.4%) showed consistent results between BS and TS. However, seven (9.6%) were positive only in one slide sets (4 BS and 3 TS). The proportions of specimens more than moderate and high cellularity were 75.3% and 60.3% in both slide sets (P> 0.99), and the proportion of artifact-free sets were 50.7%, and 52.1% for the BS and TS, respectively (P= 0.869). CONCLUSIONS: Although BS and TS exhibited highly consistent diagnostic yields in cytologic smears from EUS-FNA, the proportion of inter-slide discordance is clinically considerable. Both slide sets need to be examined if there is no on-site cytopathologist.

The prognostic significance of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma.

Cancer-associated fibroblasts are abundant in the desmoplastic stroma of pancreatic ductal adenocarcinomas and are considered to play important roles in tumor progression. In this study, we investigated the expression status of secreted protein acidic and rich in cysteine, periostin, fibroblast-activated protein, and the newly developed proCOL11A1 antibody in the stroma of surgically resected pancreatic ductal adenocarcinomas and their prognostic implications. Tissue microarrays were constructed from 155 surgically resected pancreatic ductal adenocarcinomas and paired non-neoplastic pancreata and from another independent set of 48 normal/benign pancreata, and immunohistochemical stains were performed for proCOL11A1, fibroblast-activated protein, secreted protein acidic and rich in cysteine, and periostin. The immunohistochemical stain results were correlated with clinicopathological features and survival data. proCOL11A1, fibroblast-activated protein, secreted protein acidic and rich in cysteine, and periostin expression was significantly increased in the intratumoral stroma of pancreatic ductal adenocarcinomas compared to paired non-neoplastic pancreata (proCOL11A1: 145/155 (93.5%) vs 26/154 (16.9%); fibroblast-activated protein: 139/143 (97.2%) vs 82/132 (62.1%); secreted protein acidic and rich in cysteine: 113/150 (75.3%) vs 49/132 (37.1%); periostin: 135/151 (89.4%) vs 45/135 (33.3%); p < 0.001, all). While the four markers were expressed at lower levels in normal/benign pancreata, there were no significant differences in the expression frequencies among normal pancreas, acute pancreatitis, and chronic pancreatitis. Interestingly, on survival analysis, low intratumoral fibroblast-activated protein+ cancer-associated fibroblast counts (<100/high-power field) were associated with a significantly reduced overall survival compared to those with high fibroblast-activated protein+ cancer-associated fibroblast counts (p = 0.010; hazard ratio 5.2 (95% confidence interval 1.3-21.3)). Similar patterns were seen for proCOL11A and secreted protein acidic and rich in cysteine and overall and disease-free survival, although not statistically significant. In conclusion, we demonstrate that the presence of cancer-associated fibroblasts in the tumor stroma may not always be associated with a poor prognosis as suggested in many studies; on the contrary, it may even be associated with prolonged survival, supporting the recent experimental findings that tumor stroma may have a protective role rather than enhance aggressive behavior.

Percutaneous transhepatic versus EUS-guided gallbladder drainage for malignant cystic duct obstruction.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been proposed as an alternative management strategy for acute cholecystitis caused by malignant cystic duct obstruction in patients for whom surgery is not an option. This study aimed to compare the results of EUS-GBD with those of percutaneous transhepatic gallbladder drainage (PTGBD) for palliative management of malignant cystic duct obstruction with acute cholecystitis or symptomatic gallbladder hydrops. METHODS: Between November 2013 and November 2015, 14 patients with acute cholecystitis or symptomatic gallbladder hydrops as a result of malignant cystic duct obstruction underwent EUS-GBD with covered metal stents. Nineteen patients with acute cholecystitis as a result of malignant cystic duct obstruction who received PTGBD served as a control group. Patients' medical records were reviewed retrospectively. RESULTS: The technical and clinical success rates of EUS-GBD were 85.7% (12/14) and 91.7% (11/12) and of PTGBD were 100% (19/19) and 86.4% (17/19), respectively. The groups had similar adverse event rates (28.5% and 21.1%, respectively). The average duration of stent patency in patients with EUS-GBD was 130.3 ± 35.3 days, and no patient required an additional procedure before death. In 6 of 17 patients (35.3%) with clinically successful PTGBD, the catheter was not removed until the end stage of life. CONCLUSIONS: EUS-GBD is a feasible, safe, and effective modality for the treatment of malignant cystic duct obstruction in patients who are not indicated for surgery. It enables improved long-term quality of life in patients with advanced-stage cancer.

Percutaneous biliary approach as a successful rescue procedure after failed endoscopic therapy for drainage in advanced hilar tumors.

BACKGROUND AND AIM: Palliative endoscopic or percutaneous biliary drainage is used for unresectable advanced hilar cancer (HC). The best option for drainage in Bismuth type III or IV HC has not been established. The aims of this study are to identify factors predictive of endoscopic stenting failure and evaluate the effectiveness of rescue percutaneous stenting in patients with advanced HC. METHODS: Data from 110 patients with inoperable advanced HC were retrospectively reviewed. All received bilateral self-expandable metallic stents. Patients were divided into three groups: I, successful initial endoscopic stenting; II, unsuccessful initial endoscopic stenting, followed by percutaneous stenting; and III, initial percutaneous stenting. We analyzed clinical results and radiologic tumor characteristics. RESULTS: Baseline characteristics and clinical outcomes of all groups were similar, except the hospital stay was longer in group III than group I. Technical success rate was higher in groups II and III (100%) than in group I (72.4%). The functional success rate, stent patency time, patient survival time, and complication rate were similar between groups. Endoscopic stenting failed because of guide-wire passage failure (n = 12) or stent passage failure (n = 7). The only factor significantly associated with endoscopic failure was a smaller left intrahepatic duct-common bile duct angle. CONCLUSIONS: As clinical outcomes were generally similar between approaches, percutaneous stenting is recommended for patients with Bismuth type III or IV advanced HC. Acute left intrahepatic duct-common bile duct angulation predicts endoscopic stenting failure. If endoscopic stenting fails, immediate conversion to the percutaneous approach is a necessary and effective rescue method.

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.

Presence of pancreatic intraepithelial neoplasia-3 in a background of chronic pancreatitis in pancreatic cancer patients.

The clinical significance of pancreatic intraepithelial neoplasia (PanIN) lesions in non-neoplastic pancreata of pancreatic ductal adenocarcinoma (PDAC) patients remains controversial. As chronic inflammation has been recently demonstrated to promote dissemination of in situ precancerous lesions, we investigated the prognostic significance of PanINs associated with chronic pancreatitis (CP) in PDAC patients. This retrospective study analyzed 125 curatively resected PDAC specimens for the presence of PanIN and CP. Univariate and multivariate analyses were performed to identify significant predictive factors for poor disease-free survival (DFS) and overall survival (OS). Immunohistochemical staining for E-cadherin and S100A4, markers of epithelial-mesenchymal transition, was performed on resected specimens containing PanIN-3 lesions. CP was observed in 27.2% (34/125) and PanIN-3 in 25.6% (32/125) of specimens. In the presence of CP, PanIN-3 was significantly associated with decreased survival (DFS: 4.3 vs 15.5 months, P = 0.021; OS: 16.3 vs 30.9 months, P = 0.004). PanIN-3 was not a prognostic factor in the absence of CP. The presence of both PanIN-3 and CP was associated with a reduced survival compared to the other cases, in both univariate (DFS: P = 0.039; OS: P = 0.023) and multivariate (DFS: P = 0.020; OS: P = 0.076) analyses. Furthermore, E-cadherin loss and S100A4 expression were more frequently observed in PanIN-3 lesions of CP specimens than in those of non-CP specimens, although not statistically significant. PanIN-3 in association with CP is a significant prognostic factor for decreased survival in PDAC patients, suggesting that chronic inflammation may accelerate the progression of preinvasive high-grade PanIN.

Predictors of malignancy in pure branch duct type intraductal papillary mucinous neoplasm of the pancreas: A nationwide multicenter study.

BACKGROUND/OBJECTIVES: Prediction of malignancy in patients with BD-IPMNs is critical for the management. The aim of this study was to elucidate predictors of malignancy in patients with 'pure' BD-IPMNs who had a main pancreatic duct (MPD) diameter of ≤5 mm according to the most recent international consensus criteria and in whom MPD involvement was excluded on postoperative histology. METHODS: We identified 177 patients with 'pure' BD-IPMNs based on preoperative imaging and postoperative histology from 15 tertiary referral centers in Korea. BD-IPMNs with low-grade (n = 72) and moderate-grade (n = 66) dysplasia were grouped as benign and BD-IPMNs with high-grade dysplasia (n = 10) and invasive carcinoma (n = 29) were grouped as malignancy. RESULTS: On univariate analysis, particular symptoms (jaundice and clinical pancreatitis), CT findings (cyst size > 3 cm, the presence of enhancing mural nodules) and EUS features (the presence of mural nodules, the mural nodule size > 5 mm) were significant risk factors predicting malignant BD-IPMNs. Multivariate analysis revealed that the cyst size > 3 cm (odds ratio = 9.9), the presence of enhancing mural nodules on CT (odds ratio = 19.3) and the mural nodule size > 5 mm on EUS (odds ratio = 14.9) were the independent risk factors for the presence of malignancy in BD-IPMNs (p < 0.001). CONCLUSIONS: The cyst size > 3 cm, the presence of enhancing mural nodules on CT, the mural nodule size > 5 mm on EUS are three independent predictors of malignancy in patients with 'pure' BD-IPMNs.