Simultaneous establishment of pancreatic cancer organoid and cancer-associated fibroblast using a single-pass endoscopic ultrasound-guided fine-needle biopsy specimen.

Considering the critical roles of cancer-associated fibroblasts (CAFs) in pancreatic cancer, recent studies have attempted to incorporate stromal elements into organoid models to recapitulate the tumor microenvironment. This study aimed to evaluate the feasibility of patient-derived organoid (PDO) and CAF cultures by using single-pass endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) samples from prospectively enrolled pancreatic cancer patients. The obtained samples were split into two portions for PDO and CAF cultures. PDOs and CAFs were cultured successfully in 54.4% (31/57) and 47.4% (27/57) of the cases, respectively. Both components were established in 21 cases (36.8%). Various clinicopathologic factors, including the tumor size, tumor location, clinical stage, histologic subtype, and tumor differentiation, did not influence the PDO establishment. Instead, the presence of necrosis in tumor samples was associated with initial PDO generation but no further propagation beyond passage 5 (P = 0.024). The "poorly cohesive cell carcinoma pattern" also negatively influenced the PDO establishment (P = 0.018). Higher stromal proportion in tumor samples was a decisive factor for successful CAF culture (P = 0.005). Our study demonstrated that the coestablishment of PDOs and CAFs is feasible even with a single-pass EUS-FNB sample, implying an expanding role of endoscopists in future precision medicine.

WT1 Pulsed Human CD141+ Dendritic Cell Vaccine Has High Potential in Solid Tumor-Targeted Immunotherapy.

Dendritic cells (DC) are powerful cells that play critical roles in anti-tumor immunity, and their use in cancer immunotherapy unlocks hidden capabilities as an effective therapeutic. In order to maximize the full potential of DC, we developed a DC vaccine named CellgramDC-WT1 (CDW). CDW was pulsed with WT1, an antigen commonly expressed in solid tumors, and induced with zoledronate to aid DC maturation. Although our previous study focused on using Rg3 as an inducer of DC maturation, problems with quality control and access led us to choose zoledronate as a better alternative. Furthermore, CDW secreted IL-12 and IFN-γ, which induced the differentiation of naïve T cells to active CD8+ T cells and elicited cytotoxic T lymphocyte (CTL) response against cancer cells with WT1 antigens. By confirming the identity and function of CDW, we believe CDW is an improved DC vaccine and holds promising potential in the field of cancer immunotherapy.

Mechanistic loop resolution strategy for short-type single-balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y reconstruction after gastrectomy (with video).

BACKGROUND: Endoscopic access to the targeted site is a major challenge for the endoscopic retrograde cholangiopancreatography (ERCP) in patients undergoing Roux-en-Y (R-Y) reconstruction after total or subtotal gastrectomy. We aimed to evaluate the feasibility, reproducibility, and safety of mechanistic loop resolution strategies using a short-type single-balloon enteroscopy (short SBE) system. METHODS: Between February 2020 and March 2022, consecutive patients with a previous R-Y gastrectomy requiring ERCP were prospectively enrolled. Different mechanistic loop resolution strategies for two-dimensional loops, three-dimensionally rotated loops, and loops making a cane or S-shape were applied during the SBE approach. RESULTS: Forty-three short SBE-ERCP procedures were performed on 37 patients, with an approach success rate of 100.0% (43/43). The mean time to reach the jejunojejunal anastomosis and target site were 8.0 (6.0-11.0) minutes and 26.0 (16.0-36.0) minutes, respectively. The major challenges for the approach were the cane or S-shaped loop in the jejunojejunal anastomosis or Treitz ligament. The retroflex positioning of a SBE in front of the papilla was achieved in 86.0% (37/43), and the cannulation success rate in patients with an intact papilla was 90.9% (30/33). The initial, overall therapeutic successes, median total procedure time, and adverse event rate were 87.8%, 92.7%, 77.0 (IQR 56-100.5) minutes, and 11.6%, respectively. CONCLUSIONS: Short SBE-ERCP using standardized mechanistic loop resolution strategies is effective and reproducible in patients with R-Y reconstruction after gastrectomy. TRIAL REGISTRATION: ClinicalTrial.gov (NCT04847167).

The value of drain fluid amylase as a predictor of postoperative pancreatic fistula after pancreaticogastrostomy.

BACKGROUND: Drain fluid amylase is commonly used as a predictor of pancreatic fistula after pancreaticoduodenectomy (PD). This study aimed to determine the ideal cut-off value of drain fluid amylase on postoperative day 1 (DFA1) for predicting pancreatic fistula after pancreaticogastrostomy (PG). METHODS: Prospective data of 272 consecutive patients undergoing PG between 2010 and 2020 was collected and analysed to determine the postoperative pancreatic fistula (POPF) risk factors. RESULTS: The incidence of POPF was 143 cases (52.6%). The median DFA1 in patients with POPF was significantly higher than that of patients with NO-POPF (5483 versus 311, P < 0.001). DFA1 correlated with POPF in the area under the curve (AUC) of 0.84 (P < 0.001). When DFA1 was 2300 U/L, Youden index was the highest, with a sensitivity of 72.7% and a specificity of 82.9%. Logistic regression analysis showed that DFA1 ≥ 2300 U/L was an independent predictor of POPF (P < 0.001; OR: 12.855; 95% CI: 7.019-23.544). The AUC of DFA1 and clinically relevant postoperative pancreatic fistula (CR-POPF) was 0.674 (P < 0.001). CONCLUSION: DFA1 ≥ 2300 U/L can be used as an independent predictor of POPF after PG. DFA1 ≥ 3000 U/L can predict the occurrence of CR-POPF, when DFA1 ≥ 3000 U/L, the patients should be observed closely active for complications.

Diagnostic Yield of Transabdominal Ultrasonography for Evaluation of Pancreatic Cystic Lesions Compared with Endoscopic Ultrasonography.

Detection rates of pancreatic cystic lesions (PCLs) have increased, resulting in greater requirements for regular monitoring using imaging modalities. We aimed to evaluate the capability of ultrasonography (US) for morphological characterization of PCLs as a reference standard using endoscopic ultrasonography (EUS). A retrospective analysis was conducted of 102 PCLs from 92 patients who underwent US immediately prior to EUS between January 2014 and May 2017. The intermodality reliability and agreement of the PCL morphologic findings of the two techniques were analyzed and compared using the intraclass correlation coefficient and κ values. The success rates of US for delineating PCLs in the head, body, and tail of the pancreas were 77.8%, 91.8%, and 70.6%, respectively. The intraclass correlation coefficient for US and the corresponding EUS lesion size showed very good reliability (0.978; p < 0.001). The κ value between modalities was 0.882 for pancreatic duct dilation, indicating good agreement. The κ values for solid components and cystic wall and septal thickening were 0.481 and 0.395, respectively, indicating moderate agreement. US may be useful for monitoring PCL growth and changes in pancreatic duct dilation, but it has limited use in the diagnosis and surveillance of mural nodules or cystic wall thickness changes.

Outcomes and Loop Pattern Analysis of a Road-Map Technique for ERCP with Side-Viewing Duodenoscope in Patients with Billroth II Gastrectomy (with Video).

Endoscopic retrograde cholangiopancreatography (ERCP) in patients who have undergone a Billroth II gastrectomy is a major challenge. This study aimed to evaluate the outcomes of the road-map technique for duodenal intubation using a side-viewing duodenoscope for ERCP in Billroth II gastrectomy patients with naïve papilla, and to analyze the formation and release patterns of common bowel loops that occur when the duodenoscope navigates the afferent limb. The duodenoscopy approach success rate was 85.8% (97/113). In successful duodenoscopy approach patients, there were five bowel looping patterns that occurred when the preceding catheter-connected duodenoscope was advanced into the duodenum: (1) reverse É£-loop (29.9%), (2) fixed reverse É£-loop (5.2%), (3) simple U-loop (22.7%), (4) N-loop (28.9%), and (5) reverse alpha loop (13.4%). The duodenoscopy cannulation and duodenoscopy therapeutic success rates were 81.4% (92/113) and 80.5% (91/113), respectively, while the overall cannulation and therapeutic success rates were 92.0% (104/113) and 87.6% (99/113), respectively. Bowel perforation occurred in three patients (2.7%). The road-map technique may benefit duodenoscope-based ERCP in Billroth II gastrectomy patients by minimizing the tangential axis alignment between the duodenoscopic tip and driving of the afferent limb, and by predicting and counteracting bowel loops that occur when the duodenoscope navigates the afferent limb.

Factors affecting the diagnostic yield of endoscopic transpapillary forceps biopsy in patients with malignant biliary strictures.

BACKGROUND AND AIM: Transpapillary biliary forceps biopsy (TBFB) is a common method to obtain histological evidence for the differential diagnosis of biliary stricture. This study aimed to evaluate the factors associated with a positive cancer diagnosis from TBFB and the number of tissue samples required to increase the diagnostic yield in patients with malignant biliary strictures. METHODS: A total of 376 patients who underwent TBFB for investigation of biliary stricture were included. Factors affecting the diagnostic yield of TBFB were determined using univariate analysis and multivariate logistic regression analyses. RESULTS: Bile duct cancer (odds ratio [OR] = 3.50, P = 0.002), intraductal growing type (OR = 9.01, P = 0.001), and number of tissue samples (n < 5 vs 5 ≤ n < 10, OR = 4.13, P = 0.01; n < 5 vs n ≥ 10, OR = 12.25, P < 0.001; 5 ≤ n < 10 vs n ≥ 10, OR = 2.97, P = 0.046) were significant factors associated with positive results for malignancy. In patients with periductal infiltrating-type bile duct cancer, the number of tissue samples was a significant factor for diagnostic sensitivity (54.3% in the n < 5 group, 83.3% in the 5 ≤ n < 10 group and 98.2% in the n ≥ 10 group) (P < 0.001). CONCLUSIONS: Bile duct cancer, intraductal growing type, and five or more tissue samples were significant predictors of positive TBFB results in patients with malignant biliary stricture. Increasing the number of tissue samples by five or more led to higher sensitivity in bile duct cancer patients with the periductal infiltrating type.

Tips for Dealing with Common Beginner's Mistakes Made during Endoscopic Ultrasound-Guided Gallbladder Drainage.

Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has been performed as an alternative to percutaneous drainage in surgically high-risk patients. Technical failures of EUS-GBD made by beginners are often attributed to failure of over-the-wire insertion of a fistula-dilating device or stent delivery system into the gallbladder, or stent misplacement in the final technical step. We herein report technical tips to prevent the failure of fistula dilation and provide tricks to avoid inward or outward stent misplacement.

Significance of Hepatectomy in Patients Diagnosed With T2 Gallbladder Cancer.

BACKGROUND: A radical surgery is mandatory for advanced gallbladder cancer. However, the appropriate surgical procedure for T2 gallbladder cancer remains controversial because of the difficulty associated with accurate preoperative diagnosis. The aims of the study were to analyze the clinicopathologic features of patients diagnosed with T2 gallbladder cancer and to identify the survival benefit of hepatectomy for such cases. METHODS: Eighty-four patients, who were diagnosed with pT2 gallbladder cancer from January 1995 to December 2012, were included in this study. Patients were divided into nonhepatectomy and hepatectomy groups. RESULTS: Partial hepatectomies were performed in 36 of 84 patients (42.9%). A significant difference in age was observed between the nonhepatectomy and hepatectomy groups (P=0.027). However, no significant differences were observed in sex, tumor size, or pathologic outcome between the 2 groups. No significant difference in survival rate was observed between the 2 groups (5-year survival rate, 60.4% vs. 66.6%). Of the 23 patients who underwent cholecystectomy, 11 (47.8%) were treated with extended surgery as a second operation with curative intent. No remnant tumor was detected at the hepatectomy site in any patient. However, the second operation revealed lymph node metastasis in 2 patients (18.2%). In terms of recurrence, 8 patients (34.7%) had hepatic metastasis. However, the metastatic tumor was away from the resection margin. No significant difference in survival rate was found between the peritoneal and the hepatic side groups (5-year survival rate, 62.5% vs. 73.0%). CONCLUSIONS: Hepatectomy is not associated with a better survival rate after surgery for T2 gallbladder cancer. Moreover, no recurrence near the gallbladder fossa is observed. In case of T2 gallbladder cancer confirmed by first operation, however, a second operation should be recommended on the basis of accurate nodal staging and additional therapy.

Balloons larger than 15 mm can increase the risk of adverse events following endoscopic papillary large balloon dilation.

BACKGROUND AND AIM: Although endoscopic papillary large balloon dilation (EPLBD) has been widely used to facilitate the removal of difficult common bile duct stones, however, the outcomes have not yet been investigated in terms of the diameter of the balloon used. We aimed to compare the clinical outcomes between EPLBD using smaller (12-15 mm, S-EPLBD) and larger balloons (> 15 mm, L-EPLBD). METHODS: Six hundred seventy-two patients who underwent EPLBD with or without endoscopic sphincterotomy for common bile duct stone removal were enrolled from May 2004 to August 2014 at four tertiary referral centers in Korea. The outcomes, including the initial success rate, the success rate without endoscopic mechanical lithotripsy, the overall success rate, and adverse events between S-EPLBD and L-EPLBD groups, were retrospectively compared. RESULTS: The initial success rate, the success rate without mechanical lithotripsy, the overall success rate, and the overall adverse events were not significantly different between the two groups. The rate of severe-to-fatal adverse events was higher in the L-EPBLD group than in the S-EPLBD group (1.6% vs 0.0%, 0.020). One case of severe bleeding and two cases of fatal perforation occurred only in the L-EPLBD group. In the multivariate analysis, the use of a > 15-mm balloon was the only significant risk factor for severe-to-fatal adverse events (>0.005, 23.8 [adjusted odds ratio], 2.6-214.4 [95% confidence interval]). CONCLUSIONS: L-EPLBD is significantly related to severe-to-fatal adverse events compared with S-EPLBD for common bile duct stone removal.

A Proposal for Modification of the Barcelona Clinic Liver Cancer Staging System Considering the Prognostic Implication of Performance Status.

Background/Aims: Barcelona Clinic Liver Cancer (BCLC) C stage demonstrates considerable heterogeneity because it includes patients with either symptomatic tumors (performance status [PS], 1-2) or with an invasive tumoral pattern reflected by the presence of vascular invasion (VI) or extrahepatic spread (EHS). This study aimed to derive a more relevant staging system by modification of the BCLC system considering the prognostic implication of PS. Methods: A total of 7,501 subjects who were registered in the Korean multicenter hepatocellular carcinoma (HCC) registry database from 2008 to 2013 were analyzed. The relative goodness-of-fit between staging systems was compared using the Akaike information criterion (AIC) and integrated area under the curve (IAUC). Three modified BCLC (m-BCLC) systems (#1, #2, and #3) were devised by reducing the role of PS. Results: As a result, the BCLC C stage, which includes patients with PS 1-2 without VI/EHS, was reassigned to stage 0, A, or B according to their tumor burden in the m-BCLC #2 model. This model was identified as the most explanatory and desirable model for HCC staging by demonstrating the smallest AIC (AIC=70,088.01) and the largest IAUC (IAUC=0.722), while the original BCLC showed the largest AIC (AIC=70,697.17) and the smallest IAUC (IAUC=0.705). The m-BCLC #2 stage C was further subclassified into C1, C2, C3, and C4 according to the Child-Pugh score, PS, presence of EHS, and tumor extent. The C1 to C4 subgroups showed significantly different overall survival distribution between groups (p<0.001). Conclusions: An accurate and relevant staging system for patients with HCC was derived though modification of the BCLC system based on PS.

Improvement of Nonalcoholic Fatty Liver Disease Reduces the Risk of Type 2 Diabetes Mellitus.

Background/Aims: Little evidence is available about the effect of change in nonalcoholic fatty liver disease (NAFLD) status on risk of diabetes mellitus (DM) development. In this study, we tried to analyze the DM risk according to change in NAFLD status over time. Methods: Among a total of 10,141 individuals for whom routine healthcare assessment was performed, 2,726 subjects were selected according to the inclusion/exclusion criteria. NAFLD status change was determined by using serial abdominal ultrasonography and fatty liver index (FLI) during the follow-up period. Results: Subjects were categorized according to change in NAFLD status as follows: 670 subjects in the persistent NAFLD group, 155 subjects in the resolved NAFLD group, 498 subjects in the incident NAFLD group, and 1,403 subjects in the no NAFLD group. Multivariate Cox regression analysis revealed that incident NAFLD (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.08 to 3.50; p=0.026) and persistent NAFLD (HR, 3.59; 95% CI, 2.05 to 6.27; p<0.001) were independent risk factors for predicting DM development, whereas the risk with resolved NAFLD was not significantly different from that with no NAFLD. FLI could reproduce the results acquired by ultrasonography. Conclusions: This study demonstrated that future DM risk could be influenced by changes in NAFLD status over time. Resolution of NAFLD could reduce the risk of future DM development, while the development of new NAFLD could increase the risk of DM development.

Comparisons of the Mucosal Healing Process between Flat and Protruded Type after Endoscopic Submucosal Dissection for Gastric Neoplasms.

BACKGROUND/AIMS: The mucosal healing process after endoscopic submucosal dissection (ESD) is mostly scarring change (flat type), but a protruded lesion is occasionally found. We investigated the factors influencing the mucosal healing process, such as the flat and protruded types. METHODS: A total of 2,096 ESD cases were performed from February 2005 to December 2013, and 1,757 underwent follow-up endoscopy after 3 months to check the healing type of the ulceration. We retrospectively reviewed the medical charts to analyze demographic, endoscopic, and pathological findings between the 2 groups. RESULTS: Forty-eight cases were of the protruded type and 1,709 were of the flat type. In univariate analysis, the protruded type was found more in the antrum, anterior wall, and greater curvature (p < 0.001). In protruded types, the Helicobacter pylori (H. pylori) infection rate was lower (p < 0.017), the mean length of ESD specimen was shorter (p < 0.012), the fibrosis rate was lower (p < 0.033), and the mean number of hot biopsy and clips during ESD were less (p < 0.008 and p < 0.001 respectively). CONCLUSIONS: The healing type of mucosal ulceration after ESD seemed to be influenced by location, specimen size, and the presence of an H. pylori infection.

Analysis of endoscopic features for histologic discrepancies between biopsy and endoscopic submucosal dissection in gastric neoplasms: 10-year results.

BACKGROUND AND AIM: The histologic discrepancies between preoperative endoscopic forceps biopsy (EFB) and endoscopic submucosal dissection (ESD) specimens sometimes confuse the endoscope operator. This study aimed to analyze the limitation of the biopsy-based diagnosis before ESD and to evaluate which factors affect the discordant pathologic results between EFB and ESD. METHODS: A total of 1427 patients, who were diagnosed with gastric adenoma by EFB, were enrolled. Cancer confirmed on EFB was excluded (n = 513). We retrospectively reviewed cases and compared histologic diagnoses in the biopsy sample with the final diagnosis in the endoscopically resected specimen. RESULTS: The diagnosis was upgraded (from low-grade dysplasia to high-grade dysplasia or adenocarcinoma, or from high-grade dysplasia to adenocarcinoma) in 328 cases (23.0%), concordant in 944 (66.1%), and downgraded (from high-grade dysplasia to low-grade dysplasia or non-neoplasia, or from low-grade dysplasia to non-neoplasia) in 155 (10.9%). Multivariate logistic regression analysis showed that surface ulceration and depressed lesions were associated with significant risk factors for upgrading. Age younger than 60 years and size <1 cm were associated with significant factors for downgrading. CONCLUSIONS: Careful endoscopic observation should consider size, ulceration, and depression to ensure accurate diagnosis when a gastric neoplasm is suspected.

Cyclic Change of Sphincter of Oddi Motility and Its Relationship with Small Bowel Migrating Motor Complex in Humans.

BACKGROUND: Several animal and human studies have reported that sphincter of Oddi (SO) motility shows cyclical changes during the fasting state. However, to date, the relationship between the SO motility and the migrating motor complex (MMC) of the small bowel (SB) remains unclear in humans. AIMS: We observed SO motility over a long study period and evaluated its relationship with the MMC of the SB in humans using percutaneous long-term manometry. METHODS: Our study included patients with hepatolithiasis who required percutaneous transhepatic catheter placement and subsequently underwent choledochoscopy and stone removal. Long-term percutaneous transhepatic SO manometry was performed after complete stone removal. SO and SB motility were simultaneously recorded. RESULTS: SO motility showed cyclical phasic changes with periodic high-frequency contractions similar to the MMC contractions of the SB. All high-frequency contractions of the SO coincided with phase III contractions of the MMC of the SB. The proportions of phase III contractions of SO and SB were similar, but the proportions of phase I (P = 0.001) and phase II (P = 0.002) contractions were significantly different. The mean basal SO pressure was observed to significantly increase in phase III compared to phase I (P = 0.001) and phase II (P = 0.001) contractions. CONCLUSIONS: SO motility in humans showed cyclical phasic changes closely coordinated with the MMC of the SB in a fasting state; however, the proportion of phases differed between the SO and the SB. The basal pressure significantly increased during physiological high-frequency phase III contractions of the SO.

Prospective Multicenter Study of the Challenges Inherent in Using Large Cell-Type Stents for Bilateral Stent-in-Stent Placement in Patients with Inoperable Malignant Hilar Biliary Obstruction.

Background/Aims: Although endoscopic bilateral stent-in-stent placement is challenging, many recent studies have reported promising outcomes regarding technical success and endoscopic re-intervention. This study aimed to evaluate the technical accessibility of stent-in-stent placement using large cell-type stents in patients with inoperable malignant hilar biliary obstruction. Methods: Forty-three patients with inoperable malignant hilar biliary obstruction from four academic centers were prospectively enrolled from March 2013 to June 2015. Results: Bilateral stent-in-stent placement using two large cell-type stents was successfully performed in 88.4% of the patients (38/43). In four of the five cases with technical failure, the delivery sheath of the second stent became caught in the hook-cross-type vertex of the large cell of the first stent, and subsequent attempts to pass a guidewire and stent assembly through the mesh failed. Functional success was achieved in all cases of technical success. Stent occlusion occurred in 63.2% of the patients (24/38), with a median patient survival of 300 days. The median stent patency was 198 days. The stent patency rate was 82.9%, 63.1%, and 32.1% at 3, 6, and 12 months postoperatively, respectively. Endoscopic re-intervention was performed in 14 patients, whereas 10 underwent percutaneous drainage. Conclusions: Large cell-type stents for endoscopic bilateral stent-in-stent placement had acceptable functional success and stent patency when technically successful. However, the technical difficulty associated with the entanglement of the second stent delivery sheath in the hook-cross-type vertex of the first stent may preclude large cell-type stents from being considered as a dedicated standard tool for stent-in-stent placement.