Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications.

BACKGROUND: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging. METHODS: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations. RESULTS: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs. CONCLUSION: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

Establishment of a patient-specific avatar organoid model derived from EUS-guided fine-needle biopsy for timely clinical application in pancreatic ductal adenocarcinoma (with video).

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate among tumors. At the time of diagnosis, more than 80% of PDACs are considered to be surgically unresectable, and there is an unmet need for treatment options in these inoperable PDACs. This study aimed to establish a patient-derived organoid (PDO) platform from EUS-guided fine-needle biopsy (EUS-FNB) collected at diagnosis and to determine its clinical applicability for the timely treatment of unresectable PDAC. METHODS: Patients with suspected PDAC were prospectively enrolled at the Samsung Medical Center from 2015 to 2019. PDAC tissues were acquired by means of EUS-FNB to establish PDAC PDOs, which were comprehensively analyzed for histology, genomic sequencing, and high-throughput screening (HTS) drug sensitivity test. RESULTS: PDAC PDOs were established with a success rate of 83.2% (94/113). It took approximately 3 weeks from acquiring minimal EUS-FNB specimens to generating sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and genomic sequencing. The high concordance between PDAC tissues and matched PDOs was confirmed, and whole-exome sequencing revealed the increased detection of genetic alterations in PDOs compared with EUS-FNB tissues. The HTS drug sensitivity test showed clinical correlation between the ex vivo PDO response and the actual chemotherapeutic response of the study patients in the real world (13 out of 15 cases). In addition, whole-transcriptome sequencing identified candidate genes associated with nab-paclitaxel resistance, such as ITGB7, ANPEP, and ST3GAL1. CONCLUSIONS: This PDAC PDO platform allows several therapeutic drugs to be tested within a short time window and opens the possibility for timely personalized medicine as a "patient avatar model" in clinical practice.

Bleeding after endoscopic papillectomy and its risk factors: A single center experience of 196 cases.

BACKGROUND: Endoscopic papillectomy (EP) is an effective method to remove an ampulla of Vater (AoV) adenoma with minimal invasiveness. We reviewed the clinical outcomes and prognosis of patients undergoing EP, including tumor recurrence and adverse events. METHODS: A total of 196 patients who underwent EP from January 2004 to December 2017 were included. Clinical information was collected through electronic medical records, and risk factors to predict post-procedural bleeding were analyzed using a multivariate logistic regression model. RESULTS: A total of 93.9% patients (184/196) underwent complete resection. During the follow-up period, 14.7% patients (27/184) experienced tumor recurrence, and two of seven surgically resected tumors were malignant. A total of 45.4% patients (89/196) experienced adverse events related to EP. Delayed bleeding occurred in 16.3% of the patients (32/196), and they were all successfully treated with endoscopic hemostasis and conservative management. The most frequent site of delayed bleeding was the distal end of the papillary orifice, and 56.2% (18/32) patients of delayed bleeding were classified as having mild severity, the others had moderate severity. Familial adenomatous polyposis (FAP) [odds ratio (OR) = 3.80, 95% confidence interval (CI): 1.01-14.29; P < 0.05] and male sex (OR = 2.82, 95% CI: 1.04-7.63; P = 0.04) showed statistical significance in predicting delayed post-EP bleeding. CONCLUSIONS: EP for AoV adenoma was a highly effective and safe procedure. The risk of post-EP delayed bleeding was increased in patients with FAP syndrome and male patients, and post-EP bleeding occurred most commonly in the distal part of the AoV.

Genetic assessment of pathogenic germline alterations in lysosomal genes among Asian patients with pancreatic ductal adenocarcinoma.

BACKGROUND: Lysosomes are closely linked to autophagic activity, which plays a vital role in pancreatic ductal adenocarcinoma (PDAC) biology. The survival of PDAC patients is still poor, and the identification of novel genetic factors for prognosis and treatment is highly required to prevent PDAC-related deaths. This study investigated the germline variants related to lysosomal dysfunction in patients with PDAC and to analyze whether they contribute to the development of PDAC. METHODS: The germline putative pathogenic variants (PPV) in genes involved in lysosomal storage disease (LSD) was compared between patients with PDAC (n = 418) and healthy controls (n = 845) using targeted panel and whole-exome sequencing. Furthermore, pancreatic organoids from wild-type and KrasG12D mice were used to evaluate the effect of lysosomal dysfunction on PDAC development. RNA sequencing (RNA-seq) analysis was performed with established PDAC patient-derived organoids (PDOs) according to the PPV status. RESULTS: The PPV in LSD-related genes was higher in patients with PDAC than in healthy controls (8.13 vs. 4.26%, Log2 OR = 1.65, P = 3.08 × 10-3). The PPV carriers of LSD-related genes with PDAC were significantly younger than the non-carriers (mean age 61.5 vs. 65.3 years, P = 0.031). We further studied a variant of the lysosomal enzyme, galactosylceramidase (GALC), which was the most frequently detected LSD variant in our cohort. Autophagolysosomal activity was hampered when GALC was downregulated, which was accompanied by paradoxically elevated autophagic flux. Furthermore, the number of proliferating Ki-67+ cells increased significantly in pancreatic organoids derived from Galc knockout KrasG12D mice. Moreover, GALC PPV carriers tended to show drug resistance in both PDAC cell line and PDAC PDO, and RNA-seq analysis revealed that various metabolism and gene repair pathways were upregulated in PDAC PDOs harboring a GALC variant. CONCLUSIONS: Genetically defined lysosomal dysfunction is frequently observed in patients with young-onset PDAC. This might contribute to PDAC development by altering metabolism and impairing autophagolysosomal activity, which could be potentially implicated in therapeutic applications for PDAC.

Intraductal placement of non-flared fully covered metallic stent for refractory anastomotic biliary strictures after living donor liver transplantation: Long-term results of prospective multicenter trial.

BACKGROUND AND AIM: Fully covered self-expandable metallic stent (FCSEMS) may be an effective modality for managing anastomotic biliary stricture (ABS) after liver transplantation. However, stent migration and stent-induced ductal injury are the main limitations. The objective of this study was to evaluate the usefulness of an unflared, intraductal FCSEMS that was designed to minimize migration and ductal injury for refractory ABS after living donor liver transplantation (LDLT). METHODS: A total of 32 consecutive patients with symptomatic ABS after LDLT unresolved by plastic stents with or without balloon dilation at four tertiary medical centers were prospectively enrolled. A short (3 or 5 cm) FCSEMS having long lasso (10 cm) used in this study had unflared convex ends to minimize tissue hyperplasia and smaller center portion to prevent migration. The FCSEMS was placed above the papilla and removed at 3-4 months after stenting. RESULTS: Technical and clinical success rates of intraductal placement with FCSEMS were 100% (32/32) and 81.2% (26/32), respectively. Early stent migration was observed in five (15.6%) patients. However, three patients with early stent migration had stricture resolution without needing additional intervention. Intended stent removal was successful in 27 (100%) patients (median, 101 days; range, 23-118 days). No stent-induced ductal change was observed in all patients. Stricture recurrence was observed in 11.5% (3/26) of patients during 639 days of median duration of follow-up (range, 366-2079 days). CONCLUSIONS: Intraductal placement of an unflared short FCSEMS may be a promising option for refractory ABS after LDLT with minimal stent-induced ductal injury and stent migration.

Efficacy of a paclitaxel-eluting biliary metal stent with sodium caprate in malignant biliary obstruction: a prospective randomized comparative study.

BACKGROUNDS: The placement of a self-expandable metal stent (SEMS) is widely used in patients with unresectable malignant biliary obstructions, but SEMSs are susceptible to occlusion by tumor ingrowth or overgrowth. The efficacy and safety of a novel paclitaxel-eluting biliary metal stent incorporating sodium caprate (MSCPM-III) were compared prospectively with those of a covered metal stent (CMS) in patients with malignant biliary obstructions. METHODS: Patients with unresectable distal malignant biliary obstructions (n = 106) were prospectively enrolled in this study at multiple treatment centers. Stents were placed endoscopically: MSCPM-III in 54 patients and CMS in 51 patients. The patients received systemic chemotherapy regimens according to their disease characteristics. RESULTS: The two groups did not differ significantly in basic characteristics or mean follow-up period. Stent occlusion occurred in 14 patients who received MSCPM-III and in 11 patients who received CMS. Time to recurrent biliary obstruction (RBO) and survival time did not differ significantly between the two groups (P  = 0.84 and P = 0.29, respectively). However, tumor size at 2 months after stent insertion was significantly decreased in patients in the MSCPM-III group with bile duct cancers or those who experienced stent migration compared with the CMS group. Complications, including cholangitis and pancreatitis, were found to be acceptable in both groups. CONCLUSIONS: Although compared with a CMS the MSCPM-III did not significantly influence time to RBO or survival duration in patients with malignant biliary obstructions, MSCPM-III reduced tumor volume and was used safely in humans.

Prognosis and prognostic factors in patients with advanced biliary tract cancer depending on its anatomical location.

Objective: Previous studies have revealed that biliary tract cancer (BTC) has different clinical characteristics depending on its anatomical location. However, clinical studies about the prognosis of BTC according to its anatomical location are lacking. We aimed to compare the prognosis of BTC according to its anatomical location. Methods: We retrospectively reviewed records of 311 patients with advanced BTC who received gemcitabine based palliative chemotherapy from January 2006 to December 2015 at Samsung medical Center. Results: During median follow-up of 7.67 months, the median overall survival (OS) times for patients with gallbladder (GB) cancer, intrahepatic cholangiocellular carcinoma (ICCC) and extrahepatic cholangiocellular carcinoma (ECCC) were 8.1 months, 7.7 months and 13.4 months, respectively. Median progression free survival (PFS) times for those with GB cancer, ICCC and ECCC were 4.1 months, 5.4 months and 7.2 months respectively. In multivariate analysis, anatomical location of cancer was a statistically significant factor for OS and PFS (p < .001). Prognostic factors associated with OS were also different according to the anatomical location of cancer: CA 19-9 and chemotherapy response for GB cancer; disease status, albumin and chemotherapy response for ICCC; performance status and chemotherapy response for ECCC. Conclusions: Prognosis and prognostic factors of BTC were significantly different depending on its anatomical location.

Long-term outcome and recurrence factors after percutaneous cholecystostomy as a definitive treatment for acute cholecystitis.

BACKGROUND AND AIM: Percutaneous cholecystostomy (PC) has been frequently used as an alternative treatment for acute cholecystitis in seriously ill patients unfit for surgery. The aim of this study was to investigate the recurrence rate and risk factors of recurrence. METHODS: Medical records of 102 patients who were followed up for more than 1 year after PC tube removal among 716 patients who underwent PC for acute cholecystitis treatment were retrospectively analyzed. RESULTS: The recurrence rate of acute cholecystitis after PC tube removal was 20.6% (21/102), and the mean time to recur was 660 days. Underlying cancer (odds ratio [OR]: 3.369; 95% confidence interval [CI]: 1.006-11.282; P = 0.0489), PC duration shorter than 44 days (OR: 5.596; 95% CI: 1.35-23.201; P = 0.0176), and the presence of common bile duct stone in initial imaging studies (OR: 24.393; 95% CI: 2.696-220.746; P = 0.0045) were positively correlated with recurrence. Tubogram before PC tube removal did not significantly lower the recurrence. However, PC tube clamping for several days significantly lowered the recurrence (OR: 0.108; 95% CI: 0.015-0.794; P = 0.0288). Fifty-nine (57.8%) had acalculous cholecystitis. Calculous cholecystitis was negatively correlated with recurrence (OR: 0.267; 95% CI: 0.074-0.967; P = 0.0444). Receiver operating characteristic curve of the prediction model for recurrence verified its accuracy (area under the curve: 0.8475). CONCLUSION: We should try to keep PC more than 6 weeks and clamp for 1-2 weeks before removal. For those with the presence of common bile duct stones, calculous cholecystitis, and underlying malignancy, we should keep PC for longer duration and carefully observe symptoms and signs of recurrence.

Efficacy of EUS-guided and ERCP-guided biliary drainage for malignant biliary obstruction: prospective randomized controlled study.

BACKGROUND AND AIMS: ERCP-guided biliary drainage (ERCP-BD) is a criterion standard treatment for malignant biliary obstruction when curative surgery is not an option. Alternative methods such as percutaneous transhepatic biliary drainage would significantly lower the quality of life. EUS-guided biliary drainage (EUS-BD) has been developed and performed by experienced endoscopists. Therefore, the aims of this study were to evaluate the efficacy and safety of EUS-BD compared with ERCP in malignant biliary obstruction. METHODS: The prospective randomized controlled study was conducted, and 30 patients were enrolled: 15 for each EUS-BD and ERCP-BD arms. The technical success, procedural time, clinical success, and adverse events were evaluated. RESULTS: Thirty patients had extrahepatic malignant biliary tract obstruction (19 men, 11 women). Twenty-seven patients had unresectable pancreatic ductal adenocarcinomas, 1 patient had distal common bile duct cancer, and 2 patients had metastatic malignant lymphadenopathy. There were no significant differences both in terms of technical success rate and clinical success rate (100% vs 93% and 93% vs 100% in ERCP-BD vs EUS-BD, respectively; P = 1.00, P = 1.00). Four patients (31%) had tumor ingrowth-caused stent dysfunction in the ERCP-BD group, whereas 2 patients had food impaction and 2 patients had stent migration in the EUS-BD group. No significant procedure-related adverse events occurred in either group. CONCLUSIONS: This prospective randomized controlled study suggests that EUS-BD has similar safety to ERCP-BD. EUS-BD was not superior to ERCP-BD in terms of relief of malignant biliary obstruction. EUS-BD may have fewer cases of tumor ingrowth but may also have more cases of food impaction or stent migration. (Clinical trial registration number: NCT01421836.).

Preoperative EUS-guided FNA: effects on peritoneal recurrence and survival in patients with pancreatic cancer.

BACKGROUND AND AIMS: EUS-guided FNA (EUS-FNA) is an accurate and relatively safe tissue confirmation method for pancreatic cancer. However, there is concern that this procedure may spread tumor cells along the needle track or within the peritoneum. We aimed to estimate the effect of preoperative EUS-FNA on the risk of peritoneal recurrence and long-term outcomes in resected pancreatic cancer. METHODS: We retrospectively reviewed records of patients diagnosed with pancreatic cancer who had undergone curative resection between 2009 and 2013 to investigate the overall survival, cancer-free survival, and peritoneal recurrence. Peritoneal recurrence was diagnosed based on image findings or cytology-confirmed ascites. RESULTS: Of 411 patients, 90 underwent preoperative EUS-FNA (EUS-FNA group), whereas 321 did not (non-EUS-FNA group). The median length of follow-up was 16.2 months (range, 2-46). Peritoneal recurrence occurred in 131 patients: 30% (27/90) in the EUS-FNA group versus 32% (104/321) in the non-EUS-FNA group (P = .66). Cancer-free survival or overall survival was not significantly different between the 2 groups: median overall survival of 25.3 months in the EUS-FNA group versus 23.7 months in the non-EUS-FNA group (P = .36) and median cancer-free survival of 12.7 months in the EUS-FNA group versus 11.6 months in the non-EUS-FNA group (P = .38). CONCLUSIONS: Preoperative EUS-FNA for pancreatic cancer was not associated with an increased rate of peritoneal recurrence or mortality. Therefore, EUS-FNA is an accurate and safe method to obtain suspicious pancreatic mass tissue.

Predictive Model for Neoplastic Potential of Gallbladder Polyp.

GOAL: To provide the statistical predictive model for neoplastic potential of gallbladder polyp (GBP). BACKGROUND: Many studies have attempted to define the risk factors for neoplastic potential of GBP. It remains difficult to precisely adapt the reported risk factors for the decision of surgery. Estimating the probability for neoplastic potential of GBP using a combination of several risk factors before surgical resection would be useful in patient consultation. STUDY: We collected data of patients confirmed as GBP through cholecystectomy at Samsung Medical Center between January 1997 and March 2015. Those with a definite evidence for malignancy, such as adjacent organ invasion, metastasis on preoperative imaging studies, polyp >15 mm, and absence of proper preoperative ultrasonographic imaging were excluded. A total of 1976 patients were enrolled. To make and validate the predictive model, we divided the cohort into the modeling group (n=979) and validation group (n=997). Clinical information, ultrasonographic findings, and blood tests were retrospectively analyzed. RESULTS: Clinical factors of older age, single lesion, sessile shape, and polyp size showed statistical significance for neoplastic potential of GBP in the modeling group. A predictive model for neoplastic potential of GBP was constructed utilizing the statistical outcome of the modeling group. Statistical validation was performed with the validation group to determine the optimal clinical sensitivity and specificity of the predictive model. Optimal cut-off value for neoplastic probability was 7.4%. CONCLUSIONS: The predictive model for neoplastic potential of GBP may support clinical decisions before cholecystectomy.

Long term outcome of EUS-based strategy for suspected choledocholithiasis but negative CT finding.

OBJECTIVES: The American Society for Gastrointestinal Endoscopy (ASGE) guidelines offered the risk-stratified approach in suspected choledocholithiasis. Previous studies have raised concern about the insufficient accuracy of the guideline, especially in high probability group. The purposes of this study were to authenticate the stratification and clinical predictors of the guidelines for suspected choledocholithiasis with no visible choledocholithiasis on computed tomography (CT) and to make clear the clinical strategy of endoscopic ultrasonography (EUS). MATERIALS AND METHODS: We carried out the retrospective single-center study of 156 patients with suspected choledocholithiasis but negative findings on CT who underwent EUS for about 8 years at Samsung Medical Center. We assessed the clinical predictors of the ASGE guidelines in predicting the presence of choledocholithiasis and the outcome of the EUS. RESULTS: Fifty-three of the 156 patients had positive findings on EUS that included choledocholithiasis (n = 43, 27.6%) or obstructive papillitis (n = 10, 6.4%). Among the 53 patients, 51 (96.2%) had choledocholithiasis or obstructive papillitis on ERCP. The 101 patients of 103 patients with negative finding on EUS did not show biliary events during follow-up period. EUS accuracy was 98.7% (sensitivity 100%; specificity 98.1%). Among the 49 patients with high probability, 21 (42.9%) had choledocholithiasis on ERCP. In 107 patients who were classified as intermediate probability, 30 (27.3%) had choledocholithiasis. There were no complications related to EUS. CONCLUSIONS: Not only intermediate probability group but also high probability group without definite acute cholangitis may require EUS. Application of EUS for suspected choledocholithiasis is highly accurate, safe and reduces unnecessary invasive ERCP in 57.1% of patients with high probability group.

Comparison of 22-gauge standard fine needle versus core biopsy needle for endoscopic ultrasound-guided sampling of suspected pancreatic cancer: a randomized crossover trial.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is effective for tissue diagnosis of pancreatic mass. To improve diagnostic yield and drawbacks, 22-gauge (G) core biopsy (FNB) needle has been developed. This study aims to compare 22G FNA and FNB needles for EUS-guided sampling of suspected pancreatic cancer. METHODS: This is a randomized controlled crossover trial. A total of 60 patients with suspected unresectable pancreatic cancer referred for EUS-guided sampling were randomly assigned to two groups. Both groups had 22G FNA and FNB needles performed in a randomized order. The primary endpoint was the cytological, histological and overall diagnostic accuracy of pancreatic cancer. RESULTS: FNA and FNB needles reported similar level of diagnostic accuracy (FNA needle 95% vs. FNB needle 93.3%; p = .564), and it was not statistically different. However, cytological cellularity was significantly higher in the FNB needles compared to FNA needles (odds ratio 2.75, 95% confidence interval (CI)). There were no procedure-related complications in both needles. CONCLUSIONS: The diagnostic accuracy of EUS-guided sampling for pancreatic cancer using 22G FNA is comparable to FNB needles. The cytological quality of specimen is better in the FNB needle.

22G versus 25G biopsy needles for EUS-guided tissue sampling of solid pancreatic masses: a randomized controlled study.

BACKGROUND/OBJECTIVES: No comparative study of 22-gauge biopsy needles (PC22) and 25-gauge biopsy needles (PC25) has been conducted. We prospectively compared the diagnostic accuracy of PC22 and PC25 in patients with pancreatic and peripancreatic solid masses. METHODS: We conducted a randomized noninferiority clinical study from January 2013 to May 2014 at Samsung Medical Center. A cytological and histological specimen of each pass was analyzed separately by an experienced pathologist. The primary outcome was to assess the diagnostic accuracy using the PC22 or PC25. Secondary outcomes included the optimal number of passes for adequate diagnosis, core specimen yield, sample adequacy, and complication rates. RESULTS: Diagnostic accuracy of combining cytology with histology in three cumulative passes was 97.1% (100/103) for the PC22 and 91.3% (94/103) for the PC25 group. Thus, noninferiority of PC25 to PC22 was not shown with a 10% noninferiority margin (difference, -5.8%; 95% CI, -12.1 to -0.5%). In a pairwise comparison with each needle type, two passes was non-inferior to three passes in the PC22 (96.1% vs. 97.1%; difference, -0.97%; 95% CI -6.63 to 4.69%) but noninferiority of two passes to three passes was not shown in the PC25 group (87.4% vs. 91.3%; difference, -3.88%; 95% CI, -13.5 to 5.7%). CONCLUSIONS: Non-inferiority of PC25 to PC22 diagnostic accuracy was not observed for solid pancreatic or peripancreatic masses without on-site cytology. PC22 may be a more ideal device because only two PC22 needle passes was sufficient to establish an adequate diagnosis, whereas PC25 required three or more needle passes.

SpyGlass cholangioscopy-assisted guidewire placement for post-LDLT biliary strictures: a case series.

BACKGROUND AND AIMS: Anastomotic biliary strictures are common in patients that undergo living donor liver transplantation. Although endoscopic management has the advantage over percutaneous approaches, the initial success rate for the endoscopic management is unsatisfactory. The SpyGlass system can be a useful device in patients with a severe anastomotic stricture. METHODS: The SpyGlass cholangioscopy-assisted guidewire placement was performed in 15 patients with a difficult guidewire placement in which the guidewire could not transverse the stricture with conventional methods for 10 min or more. RESULTS: The visualization rate of the stricture orifice was 93.3 % (14 of 15 patients). The total success rate of the SpyGlass cholangioscopy-assisted guidewire placement was 60 % (9 of 15 patients). No procedure-related complications occurred during or after the SpyGlass cholangioscopy-assisted guidewire placement. CONCLUSIONS: This series demonstrated that the SpyGlass cholangioscopy-assisted guidewire placement is a useful method when the guidewire passage of the strictures site is impossible by conventional methods.

Novel flower-type covered metal stent to prevent cholecystitis: experimental study in a pig model.

BACKGROUND: Covered self-expandable metal stent (CSEMS) has the risk of obstruction of the cystic duct, and the main and branch pancreatic ducts due to strong radial force and covering material, which results in cholecystitis and pancreatitis. A flower-type covered self-expandable metal stent (F-CSEMS) having a five-petal-shaped design with side grooves was constructed to prevent the obstruction of the cystic duct orifice. This study investigated the value of the F-CSEMS in protection for cholecystitis in a pig model. METHODS: Fourteen pigs randomly underwent endoscopic placement of either F-CSEMS or conventional CSEMS (C-CSEMS). The stent was placed across the cystic duct orifice to impede bile drainage from the gallbladder. Drainage was checked at 24, 48, 120 and 168 h after implantation. Blood was collected at baseline, on days 2 and 7 following implantation. The animals were killed for histologic evaluation on day 7. RESULTS: All stents were successfully inserted into bile duct without any procedure-related complications. At 48 h, the rate of contrast drainage from the gallbladder was higher in the F-CSEMS group than the C-CSEMS group without significant difference (71.4 vs. 28.6% p = 0.28). C-CSEMS was associated with higher levels of C-reactive protein (35.2 vs. 20.5 µg/dl, p = 0.03) and histologic inflammatory scores of gallbladder (score 4 vs. 2; p = 0.03). CONCLUSION: The F-CSEMS appears safe and helpful to prevent cholecystitis without disturbance of bile flow in a pig model.

A Prospective Multicenter Study Evaluating Secondary Adrenal Suppression After Antiemetic Dexamethasone Therapy in Cancer Patients Receiving Chemotherapy: A Korean South West Oncology Group Study.

BACKGROUND: In a previous pilot study, adrenal suppression was found to be common after antiemetic dexamethasone therapy in cancer patients. The objective of this large prospective multicenter study was to confirm the incidence and factors associated with secondary adrenal suppression related to antiemetic dexamethasone therapy in cancer patients receiving chemotherapy. METHODS: Chemotherapy-naïve patients who were scheduled to receive at least three cycles of highly or moderately emetogenic chemotherapy with dexamethasone as an antiemetic were enrolled. Patients with a suppressed adrenal response before chemotherapy or those administered corticosteroids within 6 months of enrollment in the study were excluded. RESULTS: Between October 2010 and August 2014, 481 patients receiving chemotherapy underwent the rapid adrenocorticotropic hormone (ACTH) stimulation test to assess eligibility; 350 of these patients were included in the final analysis. Fifty-six patients (16.0%) showed a suppressed adrenal response in the rapid ACTH stimulation test at 3 or 6 months after the start of the first chemotherapy. The incidence of adrenal suppression was affected by age, performance status, stage, and use of megestrol acetate in univariate analysis. Multivariate analysis revealed that secondary adrenal suppression associated with antiemetic dexamethasone therapy was significantly associated with megestrol acetate treatment (odds ratio: 3.06; 95% confidence interval: 1.60 to 5.86; p < .001). CONCLUSION: This large prospective study indicates that approximately 15% of cancer patients receiving chemotherapy with a normal adrenal response show suppressed adrenal responses after antiemetic dexamethasone therapy. This result was particularly significant for patients cotreated with megestrol acetate.

Comparison of endoscopic retrograde cholangiopancreatography with papillary biopsy and endoscopic ultrasound-guided pancreatic biopsy in the diagnosis of autoimmune pancreatitis.

BACKGROUND: International consensus diagnostic criteria (ICDC) have been proposed for the diagnostic criteria and algorithm of autoimmune pancreatitis (AIP). Although endoscopy is important in the diagnosis of AIP, practical patterns of its usage vary considerably worldwide. This study aimed to compare endoscopic retrograde cholangiopancreatography (ERCP) with papillary biopsy and endoscopic ultrasound (EUS)-guided pancreatic biopsy for diagnosing AIP using ICDC. METHODS: We retrospectively reviewed and classified 165 Korean patients diagnosed by Korean criteria from June 2007 to October 2013. Among them, 61 patients underwent ERCP with duodenal papillary biopsy (group A) and 62 patients underwent EUS-guided pancreatic biopsy (group B). We analyzed the diagnostic criteria and levels of each criterion, and type of AIP before and after endoscopic procedures. RESULTS: ERCP with papillary biopsy increased the diagnostic sensitivity from 65.6% (40/61) to 95.1% (58/61) (P < 0.01). EUS-guided pancreatic biopsy increased the diagnostic sensitivity from 50.0% (27/62) to 88.7% (55/62) (P < 0.01). The increases of diagnostic sensitivity in two endoscopic methods were not different statistically. In diagnosing definite AIP, EUS-guided pancreatic biopsy was more useful than ERCP with papilla biopsy (sensitivity; 79.0% vs. 65.6%, P < 0.01). EUS-guided pancreatic biopsy was helpful to classify type 1 and type 2 AIP in some patients. Procedure-related complication (mild pancreatitis) developed in one patient (1.6%) in group A and two patients (3.2%) in group B. ERCP with papillary biopsy was less expensive than EUS-guided pancreatic biopsy. CONCLUSIONS: Both ERCP with papillary biopsy and EUS-guided pancreatic biopsy are safe and play important roles in diagnosing AIP according to the ICDC.

Role of SpyGlass peroral cholangioscopy in the evaluation of indeterminate biliary lesions.

BACKGROUND: Accurate 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. AIM: The aim of this retrospective study was to evaluate the diagnostic accuracy of SpyGlass visual assessment and SpyBite biopsy in patients with indeterminate biliary lesions. METHODS: We 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. RESULTS: Thirty-two patients (19 men, mean age 63.7 years) 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 (96.8%, 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 100% (21/21) and 64.2% (9/14), 90% (9/10) and 100% (5/5), and 96.7% (30/31) and 73.6% (14/19), respectively. Procedure-related complications were noted in three cases; postsphincterotomy bleeding in one case and mild pancreatitis in two cases. CONCLUSIONS: SpyGlass cholangioscopy with SpyBite biopsy is highly accurate and safe for differentiating malignant lesions from benign lesions in patients with indeterminate biliary lesions.

Long-term outcomes of autoimmune pancreatitis: a multicentre, international analysis.

OBJECTIVE: Autoimmune pancreatitis (AIP) is a treatable form of chronic pancreatitis that has been increasingly recognised over the last decade. We set out to better understand the current burden of AIP at several academic institutions diagnosed using the International Consensus Diagnostic Criteria, and to describe long-term outcomes, including organs involved, treatments, relapse frequency and long-term sequelae. DESIGN: 23 institutions from 10 different countries participated in this multinational analysis. A total of 1064 patients meeting the International Consensus Diagnostic Criteria for type 1 (n=978) or type 2 (n=86) AIP were included. Data regarding treatments, relapses and sequelae were obtained. RESULTS: The majority of patients with type 1 (99%) and type 2 (92%) AIP who were treated with steroids went into clinical remission. Most patients with jaundice required biliary stent placement (71% of type 1 and 77% of type 2 AIP). Relapses were more common in patients with type 1 (31%) versus type 2 AIP (9%, p<0.001), especially those with IgG4-related sclerosing cholangitis (56% vs 26%, p<0.001). Relapses typically occurred in the pancreas or biliary tree. Retreatment with steroids remained effective at inducing remission with or without alternative treatment, such as azathioprine. Pancreatic duct stones and cancer were uncommon sequelae in type 1 AIP and did not occur in type 2 AIP during the study period. CONCLUSIONS: AIP is a global disease which uniformly displays a high response to steroid treatment and tendency to relapse in the pancreas and biliary tree. Potential long-term sequelae include pancreatic duct stones and malignancy, however they were uncommon during the study period and require additional follow-up. Additional studies investigating prevention and treatment of disease relapses are needed.