Preoperative risk factors for skeletal muscle mass loss in patients with biliary tract cancer.

BACKGROUND: Endoscopic retrograde cholangiography (ERC)-related procedures, usually performed before biliary tract cancer (BTC) surgery, are associated with increased risk for various complications, which can cause sarcopenia. No study has previously elucidated the relationship between preoperative ERC-related procedures and sarcopenia/skeletal muscle mass loss. METHODS: Patients with BTC who underwent radical surgical resection following ERC-related procedures were included. Skeletal muscle mass was evaluated using the psoas muscle mass index (PMI), which was determined using computed tomography images, and the change in PMI before the initial pre-ERC and surgery (ΔPMI) was calculated. Risk factors for advanced skeletal muscle mass loss, defined as a large ΔPMI, were evaluated. RESULTS: The study cohort included 90 patients with a median age of 72 (interquartile range, 65-75) years. The median PMI pre-ERC and surgery was 4.40 and 4.15 cm2/m2, respectively (p < .01). The median ΔPMI was -6.2% (interquartile range, -10.9% to 0.5%). By multivariate analysis, post-ERC pancreatitis and cholangitis before surgery were independent predictive factors for large PMI loss (odds ratio, 4.57 and 3.18, respectively; p = .03 and p = .02, respectively). CONCLUSIONS: Skeletal muscle mass decreases preoperatively in most patients with BTC undergoing ERC. Post-ERC pancreatitis and cholangitis before surgery were independent risk factors for large skeletal muscle mass loss.

ERCP using balloon-assisted endoscopes versus EUS-guided treatment for common bile duct stones in Roux-en-Y gastrectomy.

BACKGROUND AND AIMS: We compared ERCP using a balloon-assisted endoscope (BE-ERCP) with EUS-guided antegrade treatment (EUS-AG) for removal of common bile duct (CBD) stones in patients with Roux-en-Y (R-Y) gastrectomy. METHODS: Consecutive patients who had previous R-Y gastrectomy undergoing BE-ERCP or EUS-AG for CBD stones in 16 centers were retrospectively analyzed. RESULTS: BE-ERCP and EUS-AG were performed in 588 and 59 patients, respectively. Baseline characteristics were similar, except for CBD diameter and angle. The technical success rate was 83.7% versus 83.1% (P = .956), complete stone removal rate was 78.1% versus 67.8% (P = .102), and early adverse event rate was 10.2% versus 18.6% (P = .076) in BE-ERCP and EUS-AG, respectively. The mean number of endoscopic sessions was smaller in BE-ERCP (1.5 ± .8 vs 1.9 ± 1.0 sessions, P = .01), whereas the median total treatment time was longer (90 vs 61.5 minutes, P = .001). Among patients with biliary access, the complete stone removal rate was significantly higher in BE-ERCP (93.3% vs 81.6%, P = .009). Negative predictive factors were CBD diameter ≥15 mm (odds ratio [OR], .41) and an angle of CBD <90 degrees (OR, .39) in BE-ERCP and a stone size ≥10 mm (OR, .07) and an angle of CBD <90 degrees (OR, .07) in EUS-AG. The 1-year recurrence rate was 8.3% in both groups. CONCLUSIONS: Effectiveness and safety of BE-ERCP and EUS-AG were comparable in CBD stone removal for patients after R-Y gastrectomy, but complete stone removal after technical success was superior in BE-ERCP.

Metabolomics of Duodenal Juice for Biliary Tract Cancer Diagnosis.

The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.

Significance of Shear Wave Dispersion Slope Values Before Versus After Biliary Drainage in Patients With Obstructive Jaundice: A Single-Center Prospective Observational Cohort Study.

ABSTRACT: The shear wave dispersion (SWD) slope has become available in the clinical practice and is related to tissue viscosity. However, clinical evaluation using SWD was not yet performed for obstructive jaundice. We aimed to evaluate the change of SWD values between before and after biliary drainage in patients with obstructive jaundice. This prospective observational cohort study evaluated 20 patients with obstructive jaundice who underwent biliary drainage. The SWD and liver elasticity values were measured before versus after biliary drainage, comparing between days -5 and 0 (day 0), days 1 and 3 (day 2), and days 6 and 8 (day 7). The mean ± SD values of SWD measured at day 0, day 2, and day 7 were 15.3 ± 2.7, 14.2 ± 3.3, and 13.3 ± 2.4 m/s/kHz, respectively. Dispersion slope values were decreased significantly from day 0 to day 2, from day 2 to day 7, and from day 0 to day 7 ( P < 0.05). Liver elasticity levels and serum hepatobiliary enzymes were additionally decreased significantly over time after biliary drainage. The correlations between SWD and liver elasticity values were strong ( r = 0.91, P < 0.01). In conclusion, t he SWD values decreased significantly over time after biliary drainage concomitant with liver elasticity.

Suprapapillary placement of plastic versus metal stents for malignant biliary hilar obstructions: a multicenter, randomized trial.

BACKGROUND AND AIMS: The efficacy of the suprapapillary placement of inside plastic stents (iPSs) for unresectable malignant hilar biliary obstructions (MHOs) is unknown compared with that of uncovered inside metal stents (iMSs). This randomized controlled trial was designed to evaluate the outcomes of endoscopic placement of these stents for unresectable MHOs. METHODS: This open-label, randomized study was conducted at 12 Japanese institutions. The enrolled patients with unresectable MHOs were allocated to iPS and iMS groups. The primary outcome was defined as the time to recurrent biliary obstruction in patients for whom the intervention was both technically and clinically successful. RESULTS: Among 87 enrollments, 38 patients in the iPS group and 46 patients in the iMS group were analyzed. Technical success rates were 100% (38 of 38) and 96.6% (44 of 46), respectively (P = 1.00). After transferring 1 unsuccessful iMS-group patient to the iPS group (since iPSs were deployed), the clinical success rates were 90.0% (35 of 39) for the iPS group and 88.9% (40 of 45) for the iMS group from a per-protocol analysis (P = 1.00). Among the patients with clinical success, the median times to recurrent biliary obstruction were 250 (95% confidence interval, 85-415) and 361 (95% confidence interval, 107-615) days (log-rank test, P = .34). No differences were detected in rates of adverse events. CONCLUSIONS: This Phase II randomized trial did not show any statistically significant difference in stent patency between suprapapillary plastic versus metal stents. Considering the potential advantages of plastic stents for malignant hilar obstruction, these findings suggest that suprapapillary plastic stents could be a viable alternative to metal stents for this condition.

Clinical significance of dispersion imaging by shear wave elastography in the treatment and diagnosis of pancreatic cancer.

BACKGROUND AND AIM: Recently, dispersion imaging by shear wave elastography has been developed to visualize a tissue viscosity-related factor by measuring the dispersion slope. However, clinical significance of dispersion imaging in the field of pancreatic cancer is unknown. This study aimed to investigate the clinical significance of dispersion imaging in the treatment and diagnosis of pancreatic cancer. METHODS: We measured shear wave dispersion slope (SWD) (m/s/kHz) and shear wave elasticity (SWE) (kPa) in patients with pancreatic ductal adenocarcinoma (PDA). The primary endpoint was the relationship between the changes in SWD and SWE values before and after chemotherapy and the response to chemotherapy. Secondary endpoints included SWD and SWE values in relation to differences between PDA and non-PDA sites and histopathological scores of stroma, inflammation, fibrosis, and necrosis in endoscopic ultrasound-guided fine-needle aspiration specimens. RESULTS: Fifty-six patients were included, 30 of whom underwent chemotherapy. There was no relationship between the changes of SWD and SWE values and chemotherapy responses. In 56 patients, the median SWD value was 12.20 m/s/kHz (interquartile range [IQR]: 10.88-13.61) at PDA sites and 13.57 m/s/kHz (IQR: 12.28-16.20) at non-PDA sites (P = 0.005). The median SWE value was 8.18 kPa (IQR: 7.00-9.74) at PDA sites and 6.14 kPa (IQR: 5.40-6.77) at non-PDA sites (P < 0.001). Histopathological evaluation revealed that inflammation scores were correlated with SWD values (rs  = 0.42, P < 0.001). CONCLUSIONS: Dispersion imaging in pancreatic cancer would be useful for diagnosis and assessing inflammation.

Genetic Analyses of Cell-Free DNA in Pancreatic Juice or Bile for Diagnosing Pancreatic Duct and Biliary Tract Strictures.

Poor prognosis of pancreaticobiliary malignancies is attributed to intrinsic biological aggressiveness and the lack of reliable methods for early diagnosis. This study aimed to evaluate the feasibility and availability of pancreatic juice- and bile-derived cell-free DNA (cfDNA) for diagnosing pancreaticobiliary strictures. From October 2020 to February 2022, pancreatic juice or bile was obtained from 50 patients with pancreaticobiliary strictures during endoscopic retrograde cholangiopancreatography. cfDNAs extracted from the samples were analyzed using next-generation sequencing and a cancer gene panel. The obtained cfDNAs, genetic data and clinical information were analyzed for diagnosis. cfDNA concentrations in pancreatic juice were higher in the intraductal papillary mucinous neoplasm group than in the other groups, whereas those in bile were similar in all groups. In pancreatic juice, the sensitivity, specificity and positive and negative predictive values of cfDNA analyses were 33%, 100%, 100% and 71.4%, respectively, whereas those of cytological analyses were 0%, 100%, 0% and 62.5%, respectively. In bile, those of cell-free DNA analyses were 53%, 75%, 89.5% and 28.6%, respectively, whereas those of cytological analyses were 19%, 100%, 100% and 16%, respectively. In conclusion, pancreatic juice- and bile-derived cfDNA is a novel liquid biopsy tool that can diagnose pancreaticobiliary strictures.

Epigenetic regulation of pancreatic adenocarcinoma in the era of cancer immunotherapy.

Pancreatic adenocarcinoma is a lethal cancer with poor response to chemotherapy and immune checkpoint inhibitors. Recent studies suggest that epigenetic alterations contribute to its aggressive biology and the tumor microenvironment which render it unresponsive to immune checkpoint blockade. Here, we review our current understandings of epigenetic dysregulation in pancreatic adenocarcinoma, its effect on the tumor immune microenvironment, and the potential for epigenetic therapy to be combined with immune checkpoint inhibitors.

Analysis of the Pancreatic Cancer Microbiome Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration-Derived Samples.

OBJECTIVES: Most previous studies have analyzed bacteria in tumors using resected pancreatic cancer (PC) tissues, because it is difficult to obtain tissue samples from unresectable advanced PC. We aimed to determine whether minimal tissue obtained by endoscopic ultrasound-guided fine-needle aspiration is useful for microbiome analysis. METHODS: Thirty PC and matched duodenal and stomach tissues (N = 90) were prospectively collected from 30 patients who underwent endoscopic ultrasound-guided fine-needle aspiration. Bacterial DNA was extracted, and 16S rRNA sequencing was performed. The primary outcome was the success rate of bacterial detection in tumors. Bacterial diversity and structure were investigated. RESULTS: The bacterial detection rates were 80%, 100%, and 97% in PC, gastric, and duodenal samples, respectively. Pancreatic cancer tissues showed a lower α-diversity and a significantly different microbial structure than stomach and duodenal tissues. Proteobacteria were more abundant, whereas Firmicutes, Bacteroidetes, and Fusobacteria were less abundant in PC tissues than in stomach and duodenal tissues. Acinetobacter was more abundant in PC tissues than in stomach and duodenal tissues, and Delftia was more frequently detected in resectable PC. CONCLUSIONS: Endoscopic ultrasound-guided fine-needle aspiration samples were valuable for PC microbiome analysis, revealing that the bacterial composition of PC is different from that of the stomach and duodenum.

Promising Genomic Testing for Biliary Tract Cancer Using Endoscopic Ultrasound-Guided Fine-Needle Aspiration/Biopsy Specimens.

The undesired prognosis of biliary tract cancer is mainly attributed to the difficult detection of cancer lesions, including intraepithelial neoplasia and no standard examination for screening. In addition, pathological diagnosis of biliary stricture, whether it is malignant or benign, is not so easy, because of difficult optimal sampling by forceps biopsy and brush cytology, although various devices and methods for pathological diagnosis have been reported. Furthermore, we have to be careful about post-endoscopic retrograde cholangiography pancreatitis when we approach the biliary tract lesion via a transpapillary route. In order to improve the diagnostic accuracy, there have been several studies that indicate the feasibility and efficacy of genomic analysis for accurate diagnosis of biliary tract cancer by using pathological specimens, including endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) samples. For efficient and precision medicine for patients with biliary tract cancer, future diagnosis and treatment should also be based on molecular and genetic analyses. In this article, we review and summarize the past knowledge and cutting edge of genomic testing for biliary tract cancer, using EUS-FNA/FNB specimens, and indicate some ingenuities in sample processing to promote effective clinical practice and future perspectives.

Placental growth factor promotes tumour desmoplasia and treatment resistance in intrahepatic cholangiocarcinoma.

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. DESIGN: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. RESULTS: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

Possible reasons for the regrettable results of patency of an inside stent in endoscopic transpapillary biliary stenting.

Endoscopic biliary decompression is a minimally invasive procedure for cholestasis since the first endoscopic retrograde cholangiopancreatography-guided biliary stenting performed by Soehendra and Reynders-Frederix. Among the endoscopic biliary decompression, endoscopic transpapillary biliary stenting (EBS), is a mainstream choice and presently has two methods of placement: stenting above the sphincter of Oddi (SO) (suprapapillary) and stenting across the SO (transpapillary). Stent patency is the most important concern for patients, endoscopists and physicians because it can affect both the life prognosis and treatment schedule of patients. Biliary stent occlusion can occur because of several factors. Among them, direct food impaction, biofilm formation, and sludge formation play important roles and are presumed to be theoretically overcome by EBS above the SO. Thus, EBS above the SO is expected to result in a longer patency than EBS across the SO. In the literature, there have been six comparative studies on EBS for distal biliary obstruction in which the stent was placed above or across the SO, including two randomized controlled trials (RCTs) with negative results of stenting above the SO. With respect to EBS for hilar biliary obstruction, there have been no RCTs, whereas four retrospective comparative studies with negative results and four retrospective comparative studies showing positive results of stenting above the SO have been reported. In this review, we focused on EBS above and across the SO, and summarized the positive and negative results of the two types of stenting to promote effective clinical practice and to provide a basis for future studies.

A Prospective Multicenter Study of "Inside Stents" for Biliary Stricture: Multicenter Evolving Inside Stent Registry (MEISteR).

BACKGROUND: Endoscopic biliary stent placement is the standard of care for biliary strictures, but stents across the papilla are prone to duodenobiliary reflux, which can cause stent occlusion. Preliminary studies of "inside stents" placed above the papilla showed encouraging outcomes, but prospective data with a large cohort were not reported. METHODS: This was a prospective multicenter registry of commercially available inside stents for benign and malignant biliary strictures. Primary endpoint was recurrent biliary obstruction (RBO). Secondary endpoints were technical success of stent placement and removal, adverse events, and stricture resolution. RESULTS: A total of 209 inside stents were placed in 132 (51 benign and 81 malignant) cases with biliary strictures in 10 Japanese centers. During the follow-up period of 8.4 months, RBO was observed in 19% of benign strictures. The RBO rate was 49% in malignant strictures, with the median time to RBO of 4.7 months. Technical success rates of stent placement and removal were both 100%. The adverse event rate was 8%. CONCLUSION: This prospective multicenter study demonstrated that inside stents above the papilla were feasible in malignant and benign biliary strictures, but a randomized controlled trial is warranted to confirm its superiority to conventional stents across the papilla.

Trial protocol: a randomised controlled trial to verify the non-inferiority of a partially covered self-expandable metal stent to an uncovered self-expandable metal stent for biliary drainage during neoadjuvant therapy in patients with pancreatic cancer with obstructive jaundice (PUN-NAC trial).

INTRODUCTION: Neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (NAC/NACRT) for resectable/borderline resectable pancreatic cancers was recently performed to improve clinical outcomes and led to good results, although it remains controversial whether NAC/NACRT is beneficial for resectable pancreatic cancer. A few recent studies revealed longer patency and lower cost related to the stent occlusion of a metal stent than those of a plastic stent during NAC/NACRT. It also remains controversial which type of self-expandable metal stent (SEMS) is the most suitable for patients with resectable/borderline resectable pancreatic cancer during NAC/NACRT: an uncovered SEMS (USEMS), a fully covered SEMS (FCSEMS) or a partially covered SEMS (PCSEMS). So far, two randomised controlled trials indicated that a USEMS and an FCSEMS were similar in preoperative stent dysfunction and adverse event rate. Thus, we aimed to verify the non-inferiority of a PCSEMS to a USEMS in this multicentre randomised controlled trial. METHODS AND ANALYSIS: We designed a multicentre randomised controlled trial, for which we will recruit 100 patients with resectable/borderline resectable pancreatic cancer and distal biliary obstruction scheduled for NAC/NACRT from 13 high-volume institutions. Patients will be randomly allocated to the PCSEMS group or USEMS group. The primary outcome measure is the preoperative biliary event rate. Data will be analysed after completion of the study. We will calculate the 95% CIs of the incidence of preoperative biliary events in each group and analyse whether the difference between them is within the non-inferiority margin (10%). ETHICS AND DISSEMINATION: This study has been approved by the institutional review board of Hokkaido University Hospital. The results will be submitted for presentation at an international medical conference and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: UMIN000041737; jRCT1012200002.

Efficacy of a novel ultra-sharp dilation device for dilating bare metal stent mesh in patients with hilar malignant biliary obstruction.

The placement of additional stents in patients with hilar malignant biliary obstruction can be challenging when a metal stent already exists because occasionally, the catheter and delivery system of the additional stent cannot pass through the mesh of the formerly placed stent. We studied ten consecutive patients with hilar malignant biliary obstruction who underwent mesh dilation using a novel ultra-sharp dilation device (ES dilator) to assess the efficacy and safety of the ES dilator for mesh dilation. Mesh dilation using the ES dilator was successful in eight patients (8/10; 80.0%), which was the same rate as that of patients with pre-dilation using a Soehendra biliary dilation catheter (4/5, 80.0%) and patients without pre-dilation (4/5, 80.0%). In the two patients with dilation failure, the angle of the hilar bile duct branch was too steep to permit the passage of a stiff dilation device. Nonetheless, stent placement was uncomplicated in all mesh-dilated patients (8/8, 100.0%), and no adverse events related to the ES dilator were observed. The efficacy of an ultra-sharp dilation device appears promising for metallic stent mesh dilation, especially in patients where conventional methods are unsuccessful. However, additional data are necessary to confirm our findings.

A Prospective Multicenter Study of Partially Covered Metal Stents in Patients Receiving Neoadjuvant Chemotherapy for Resectable and Borderline Resectable Pancreatic Cancer: BTS-NAC Study.

Background/Aims: The aim of this study was to evaluate the safety and efficacy of partially covered self-expandable metallic stents (PCSEMS) in patients undergoing neoadjuvant chemo(radio) therapy (NAC) for pancreatic cancer (PC). Methods: This was a prospective multicenter study to evaluate the safety and efficacy of PCSEMS in patients receiving NAC for resectable and borderline resectable PC. The primary endpoint was the rate of recurrent biliary obstruction (RBO). Results: Twenty-six patients with PC (three with resectable PC and 23 with borderline resectable PC) who underwent NAC at seven Japanese centers were included in the analysis. Both the technical and functional success rates of PCSEMS placement were 100%. Early stent-related complications were observed in three patients (11.5%): mild pancreatitis (n=2) and mild liver abscess (n=1). The median time to surgery or palliation was 4.0 months. Surgical resection was eventually performed in 73.1% of patients, and stent removal during surgery was successful in all patients. RBO was observed in nine patients (34.6%): seven with stent occlusion, one with kinking and one with migration. The RBO rates in resected cases and nonresected cases were 36.8% and 28.6%, respectively. Conclusions: Biliary drainage by PCSEMS was safe and feasible in patients undergoing NAC for resectable and borderline resectable PC.