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.

Alteration of the fecal microbiome in patients with cholecystectomy: potential relationship with postcholecystectomy diarrhea - before and after study.

BACKGROUND: Bile acid (BA) is a crucial determinant of the gut microbiome, and cholecystectomy can alter the physiology of BA. Physiological changes in BA resulting from cholecystectomy can also influence the gut microbiome. We aimed to identify the specific taxa associated with perioperative symptoms, including postcholecystectomy diarrhea (PCD), and to evaluate the effect of cholecystectomy on the microbiome by investigating the fecal microbiome of patients with gallstones. METHODS: We analyzed the fecal samples of 39 patients with gallstones (GS group) and 26 healthy controls (HC group) to evaluate their gut microbiome. We also collected fecal samples from GS group 3 months postcholecystectomy. Symptoms of patients were evaluated before and after cholecystectomy. Further, 16S ribosomal RNA amplification and sequencing were performed to determine the metagenomic profile of fecal samples. RESULTS: The microbiome composition of GS differed from that of HC; however, the alpha diversity was not different. No significant microbiome alterations were observed before and after cholecystectomy. Moreover, GS group showed a significantly lower Firmicutes to Bacteroidetes ratio before and after cholecystectomy than the HC group (6.2, P< 0.05). The inter-microbiome relationship was lower in GS than in HC and tended to recover 3 months after surgery. Furthermore, ~28.1% ( n =9) of patients developed PCD after surgery. The most prominent species among PCD (+) patients was Phocaeicola vulgatus. Compared with the preoperative state, Sutterellaceae , Phocaeicola , and Bacteroidals were the most dominant taxa among PCD (+) patients. CONCLUSION: GS group showed a different microbiome from that of HC; however, their microbiomes were not different 3 months after cholecystectomy. Our data revealed taxa-associated PCD, highlighting the possibility of symptom relief by restoring the gut microbiome.

Multimodal Characterization of Cardiac Organoids Using Integrations of Pressure-Sensitive Transistor Arrays with Three-Dimensional Liquid Metal Electrodes.

Herein, we present an unconventional method for multimodal characterization of three-dimensional cardiac organoids. This method can monitor and control the mechanophysiological parameters of organoids within a single device. In this method, local pressure distributions of human-induced pluripotent stem-cell-derived cardiac organoids are visualized spatiotemporally by an active-matrix array of pressure-sensitive transistors. This array is integrated with three-dimensional electrodes formed by the high-resolution printing of liquid metal. These liquid-metal electrodes are inserted inside an organoid to form the intraorganoid interface for simultaneous electrophysiological recording and stimulation. The low mechanical modulus and low impedance of the liquid-metal electrodes are compatible with organoids' soft biological tissue, which enables stable electric pacing at low thresholds. In contrast to conventional electrophysiological methods, this measurement of a cardiac organoid's beating pressures enabled simultaneous treatment of electrical therapeutics using a single device without any interference between the pressure signals and electrical pulses from pacing electrodes, even in wet organoid conditions.

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).

In situ diagnosis and simultaneous treatment of cardiac diseases using a single-device platform.

The in situ diagnosis of cardiac activities with simultaneous therapeutic electrical stimulation of the heart is key to preventing cardiac arrhythmia. Here, we present an unconventional single-device platform that enables in situ monitoring even in a wet condition and control of beating heart motions without interferences to the recording signal. This platform consists of the active-matrix array of pressure-sensitive transistors for detecting cardiac beatings, biocompatible, low-impedance electrodes for cardiac stimulations, and an alginate-based hydrogel adhesive for attaching this platform conformally to the epicardium. In contrast to conventional electrophysiological sensing using electrodes, the pressure-sensitive transistors measured mechanophysiological characteristics by monitoring the spatiotemporal distributions of cardiac pressures during heart beating motions. In vivo tests show mechanophysiological readings having good correlation with electrocardiography and negligible interference with the electrical artifacts caused during cardiac stimulations. This platform can therapeutically synchronize the rhythm of abnormal heartbeats through efficient pacing of cardiac arrhythmia.

Comparison of the Malignant Predictors in Intrahepatic and Extrahepatic Intraductal Papillary Neoplasm of the Bile Duct.

Background: Intraductal papillary neoplasm of the bile duct (IPNB) is a precancerous lesion of cholangiocarcinoma, for which surgical resection is the most effective treatment. We evaluated the predictors of malignancy in IPNB according to anatomical location and the prognosis without surgery. Methods: A total of 196 IPNB patients who underwent pathologic confirmation by surgical resection or endoscopic retrograde cholangiography or percutaneous transhepatic cholangioscopic biopsy were included. Clinicopathological findings of IPNB with invasive carcinoma or mucosal dysplasia were analyzed according to anatomical location. Results: Of the 116 patients with intrahepatic IPNB (I-IPNB) and 80 patients with extrahepatic IPNB (E-IPNB), 62 (53.4%) and 61 (76.3%) were diagnosed with invasive carcinoma, respectively. Multivariate analysis revealed that mural nodule > 12 mm (p = 0.043) in I-IPNB and enhancement of mural nodule (p = 0.044) in E-IPNB were predictive factors for malignancy. For pathologic discrepancy before and after surgery, IPNB has a 71.2% sensitivity and 82.3% specificity. In the non-surgical IPNB group, composed of nine I-IPNB and seven E-IPNB patients, 43.7% progressed to IPNB with invasive carcinoma within 876 days. Conclusions: E-IPNB has a higher rate of malignancy than I-IPNB. The predictive factor for malignancy is mural nodule > 12 mm in I-IPNB and mural nodule enhancement in E-IPNB.

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.

Clinical outcome of endoscopic retrograde cholangiopancreatography for choledocholithiasis in end-stage renal disease patients on hemodialysis.

BACKGROUND/AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is used as a curative method for choledocholithiasis, but little is known about ERCP for patients with end-stage renal disease (ESRD) on hemodialysis (HD). The aim of the current study was to evaluate the efficacy and safety of ERCP for patients with ESRD on HD and to identify the risk factors of ERCP-related bleeding. MATERIALS AND METHODS: The medical records of 61 ESRD patients with choledocholithiasis who underwent ERCP were retrospectively investigated with respect to successful bile duct stone removal and procedure-related adverse events such as pancreatitis, bleeding, and cholangitis. RESULTS: For the study subjects, the overall stone removal success rate was 96.7%, and the overall ERCP-related adverse event rate was 21.3% (pancreatitis, 4.9%; bleeding, 13.1%; cholangitis, 6.6%). Endoscopic sphincterotomy (EST) was found to be associated with hemorrhage (p=0.02), and the occurrence of hemorrhage in patients who underwent EST with or without endoscopic papillary balloon dilation (EPBD) was significantly higher than that in patients who underwent EPBD alone (Odds ratio 1.27, 95% confidence interval 1.075-1.493, p=0.02). CONCLUSION: ERCP for ESRD patients was found to be feasible and safe. However, EST was significantly related to hemorrhagic events. EPBD reduced the risk of hemorrhage and was as effective as EST in terms of stone removal.

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.

Treatment and prognosis of hepatic epithelioid hemangioendothelioma based on SEER data analysis from 1973 to 2014.

BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular origin with an unknown etiology, a low incidence, and a variable natural course. We evaluated the management and prognosis of HEH from the Surveillance, Epidemiology and End Results (SEER) program and changes in treatment modalities of HEH over 30 years. METHODS: From 1973 to 2014 in the SEER database, we selected patients diagnosed with HEH. We analyzed the clinical characteristics, patterns of management, and clinical outcomes of patients with HEH. RESULTS: We identified 79 patients with HEH (median age: 54.0 years; male to female ratio: 1:2.6). The initial extent of disease was local in 22 (27.8%) patients, regional metastasis in 22 (27.8%), distant metastasis in 31 (39.2%) and unknown in 4 (5.1%). The median size of primary tumor was 3.85 cm (interquartile range, 2.50-7.93 cm). Among 74 patients with available management data, the most common management was no treatment (29/74, 39.2%), followed by chemotherapy only (22/74, 29.7%), liver resection-based (13/74, 17.6%), and transplantation-based therapy (6/74, 8.1%). The 5-year cancer-specific survival rate was 57.8%. Patients who underwent surgical treatment had significantly higher survival than those who underwent non-surgical treatment (5-year survival; 88% vs. 49%, P = 0.019). Multivariate analysis revealed that surgical therapy was the only independent prognostic factor for survival (hazard ratio: 0.20, P = 0.040). CONCLUSIONS: Resection or liver transplantation is worth considering for treatment of patients with HEH.

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.