Clinical predictors of significant findings on EUS for the evaluation of incidental common bile duct dilation.

BACKGROUND AND AIMS: Although EUS is highly accurate for the evaluation of common bile duct (CBD) dilation, the yield of EUS in patients with incidental CBD dilation is unclear. METHODS: Serial patients undergoing EUS for incidental, dilated CBD (per radiologist, minimum of >6 mm objectively) from 2 academic medical centers without active pancreaticobiliary disease or significantly elevated liver function test results were evaluated. Multivariable logistic regression identified predictors of EUS with significant findings and a novel prediction model was derived from one center, internally validated with bootstrapping, and externally validated at the second center. RESULTS: Of 375 patients evaluated, 31 (8.3%) had significant findings, including 26 choledocholithiasis, 1 ampullary adenoma, and 1 pancreatic mass. Predictors of significant findings with EUS included age of ≥70 years (odds ratio [OR], 3.7; 95% confidence interval [CI], 1.5-10.0), non-biliary-type abdominal pain without chronic pain (OR, 6.1; 95% CI, 2.3-17.3), CBD diameter of ≥15 mm or ≥17 mm with cholecystectomy (OR, 6.9; 95% CI, 2.7-18.7), and prior ERCP (OR, 6.8; 95% CI, 2.1-22.5). A point-based novel clinical prediction model was created: age of ≥70 years = 1, non-biliary-type abdominal pain without chronic pain = 2, prior ERCP = 2, and CBD dilation = 2. A score of <1 had 93% (development) and 100% (validation) sensitivity and predicted a <2% chance of having a significant finding in both cohorts while excluding the need for EUS in ∼30% of both cohorts. Conversely, a score of ≥4 was >90% specific for the presence of significant pathology. CONCLUSIONS: Less than 10% of patients undergoing EUS for incidental CBD dilation had pathologic findings. This novel, externally validated, clinical prediction model may reduce low-yield, invasive evaluation in nearly one-third of patients.

Biliary Duct Dilatation: AJR Expert Panel Narrative Review.

Biliary duct dilatation is a common incidental finding in practice, but it is unlikely to indicate biliary obstruction in the absence of clinical symptoms or elevated levels on liver function tests (LFTs). However, the clinical presentation may be nonspecific, and LFTs may either be unavailable or difficult to interpret. The goal of this AJR Expert Panel Narrative Review is to highlight a series of topics fundamental to the management of biliary duct dilatation, providing consensus recommendations in a question-and-answer format. We start by covering a basic approach to interpreting LFT results, the strengths and weaknesses of the biliary imaging modalities, and how and where to measure the extrahepatic bile duct. Next, we define the criteria for biliary duct dilatation, including patients with prior cholecystectomy and advanced age, and discuss when and whether biliary duct dilatation can be attributed to papillary stenosis or sphincter of Oddi dysfunction. Subsequently, we discuss two conditions in which the duct is pathologically dilated but not obstructed: congenital cystic dilatation (i.e., choledochal cyst) and intraductal papillary neoplasm of the bile duct. Finally, we provide guidance regarding when to recommend obtaining additional imaging or testing, such as endoscopic ultrasound or ERCP, and include a discussion of future directions in biliary imaging.

Prrx1 isoform switching regulates pancreatic cancer invasion and metastatic colonization.

The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.

Phase Ib and Expansion Study of Gemcitabine, Nab-Paclitaxel, and Ficlatuzumab in Patients With Metastatic Pancreatic Cancer.

BACKGROUND: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. METHODS: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination. RESULTS: Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose-limiting toxicities were identified (N = 7 pts) and ficlatuzumab at 20 mg/kg was chosen as the maximum tolerated dose. Among the 21 patients treated at the MTD, best response by RECISTv1.1: 6 (29%) partial response, 12 (57%) stable disease, 1 (5%) progressive disease, and 2 (9%) not evaluable. Median progression-free survival and overall survival times were 11.0 months (95% CI, 7.6-11.4 months) and 16.2 months (95% CI, 9.1 months to not reached), respectively. Toxicities attributed to ficlatuzumab included hypoalbuminemia (grade 3, 16%; any grade, 52%) and edema (grade 3, 8%; any grade, 48%). Immunohistochemistry for c-Met pathway activation demonstrated higher tumor cell p-Met levels in patients who experienced response to therapy. CONCLUSION: In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.

AGA Clinical Practice Update on Interventional EUS for Vascular Investigation and Therapy: Commentary.

DESCRIPTION: The purpose of this AGA Institute Clinical Practice Update is to review the available evidence supporting and examine opportunities for future research in endoscopic ultrasound-guided vascular investigation and therapies. METHODS: This Clinical Practice Update was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the Clinical Practice Updates Committee and external peer review through standard procedures of Clinical Gastroenterology and Hepatology. This expert commentary incorporates important as well as recently published studies in this field, and it reflects the experiences of the authors who are advanced endoscopists with expertise in endoscopic ultrasound-guided vascular investigation and therapy.

Two StAR-related lipid transfer proteins play specific roles in endocytosis, exocytosis, and motility in the parasitic protist Entamoeba histolytica.

Lipid transfer proteins (LTPs) are the key contributor of organelle-specific lipid distribution and cellular lipid homeostasis. Here, we report a novel implication of LTPs in phagocytosis, trogocytosis, pinocytosis, biosynthetic secretion, recycling of pinosomes, and motility of the parasitic protist E. histolytica, the etiological agent of human amoebiasis. We show that two StAR-related lipid transfer (START) domain-containing LTPs (named as EhLTP1 and 3) are involved in these biological pathways in an LTP-specific manner. Our findings provide novel implications of LTPs, which are relevant to the elucidation of pathophysiology of the diseases caused by parasitic protists.

Synthesis of Functionalized Five-Membered Heterocycles from Epoxides: A Hydrogen-Bond Donor Catalytic Approach.

The synthesis of highly functionalized five-membered oxa- and aza-heterocycles has been reported utilizing hydrogen-bond donor (HBD) catalysis. In this method, an epoxide was taken as a substrate and reacted with functionalized arylidene/alkylidene malononitrile derivatives in the presence of a newly designed HBD catalyst. In all the cases, the products 2,5-disubstituted tetrahydrofurans (2,5-THFs) were obtained in good to excellent yields (up to 86%) with high diastereoselectivity (dr up to 99:1) as a single regioisomer. The stereochemistry at the 2- and 5-positions of the five-membered ring has been confirmed by single-crystal X-ray analysis, and cis is found to be the major product. The same strategy has been further utilized to obtain substituted oxazolidines whenever the epoxide has been reacted with isocyanate as an electrophile. In order to induce enantioselectivity, a chiral epoxide has been reacted with both the electrophiles in the presence of the same catalyst system to afford the single stereoisomer of the final products. This synthetic methodology involves a low catalyst loading and ambient reaction condition and has been generalized with various substituents present in the starting electrophiles to produce the resultant products in acceptable yields and stereoselectivity.

Functional characterization of phospholipase B enzyme from Giardia lamblia.

The microaerotolarent amitochondriate protozoan Giardia lamblia causes Giardiasis and produces a unique enzyme called Phospholipase B (PLB) in contrast to higher eukaryotes. The enzyme is produced upon induction with oxidative (H2O2) stress, thus leading to prostaglandin E2 (PGE2) production. It exists in dimeric form, and its molecular weight is 56 kDa. This PLB was extracellularly cloned in the pET21d vector. The ORF is 1620 bp (Genbank accession no. -OM939681) long and codes for a protein 539 amino acid long, with a 15 amino acid long amino-terminal signal peptide. The highest enzyme activity of PLB was identified at pH 7.5 and 35 °C. This specific enzyme was also active at 50 °C pH 10, but activity was low. We also analyzed the expression of PLB protein in G. lamblia, which was significantly induced under increased oxidative stress.

Development of a simple PCR-RFLP technique for detection and differentiation of E. histolytica, E. dispar and E. moshkovskii.

Epidemiological studies on amoebic infections are complicated by morphological overlap between the pathogenic E. histolytica, the commensal E. dispar and the amphizoic E. moshkovskii, necessitating molecular identification. The present study developed a simple and economical 18S PCR-RFLP method for the simultaneous detection and differentiation of the three species. PCR products were differentiated by Tat1 restriction digestion generating three different RFLP patterns. Validation was conducted by screening 382 faecal samples from human patients from Kolkata, India, hospitalized for diarrhoea. Analysis indicated that the PCR-RFLP could successfully differentiate between the three species and was confirmed by sequence analysis. This method could prove useful for clinical and epidemiological studies of amoebiasis.

Investigating genetic polymorphism in E. histolytica isolates with distinct clinical phenotypes.

Amoebiasis is an infection caused by enteric protozoa, most commonly Entamoeba histolytica, and is globally considered a potentially severe and life-threatening condition. To understand the impact of the parasite genome on disease outcomes, it is important to study the genomes of infecting strains in areas with high disease prevalence. These studies aim to establish correlations between parasite genotypes and the clinical presentation of amoebiasis. We employ a strain typing approach that utilizes multiple loci, including SREHP and three polymorphic non-coding loci (tRNA-linked array N-K2 and loci 1-2 and 5-6), for high-resolution analysis. Distinct clinical phenotype isolates underwent amplification and sequencing of studied loci. The nucleotide sequences were analysed using Tandem Repeats Finder to detect short tandem repeats (STRs). These patterns were combined to assign a genotype, and the correlation between clinical phenotypes and repetitive patterns was statistically evaluated. This study found significant polymorphism in the size and number of PCR fragments at SREHP and 5-6 locus, while the 1-2 locus and NK2 locus showed variations in PCR product sizes. Out of 41 genotypes, two (I6 and I41) were significantly associated with their respective disease outcomes and were found in multiple isolates. We observed that I6 was linked with a symptomatic outcome, with a statistically significant p-value of 0.0183. Additionally, we found that I41 was associated with ALA disease outcome, with a p-value of 0.0089. Our study revealed new repeat units not previously reported, unveiling the genetic composition of E. histolytica strains in India, associated with distinct disease manifestations.

Non-Vesicular Lipid Transport Machinery in Leishmania donovani: Functional Implications in Host-Parasite Interaction.

Eukaryotic cells have distinct membrane-enclosed organelles, each with a unique biochemical signature and specialized function. The unique identity of each organelle is greatly governed by the asymmetric distribution and regulated intracellular movement of two important biomolecules, lipids, and proteins. Non-vesicular lipid transport mediated by lipid-transfer proteins (LTPs) plays essential roles in intra-cellular lipid trafficking and cellular lipid homeostasis, while vesicular transport regulates protein trafficking. A comparative analysis of non-vesicular lipid transport machinery in protists could enhance our understanding of parasitism and basis of eukaryotic evolution. Leishmania donovani, the trypanosomatid parasite, greatly depends on receptor-ligand mediated signalling pathways for cellular differentiation, nutrient uptake, secretion of virulence factors, and pathogenesis. Lipids, despite being important signalling molecules, have intracellular transport mechanisms that are largely unexplored in L. donovani. We have identified a repertoire of sixteen (16) potential lipid transfer protein (LTP) homologs based on a domain-based search on TriTrypDB coupled with bioinformatics analyses, which signifies the presence of well-organized lipid transport machinery in this parasite. We emphasized here their evolutionary uniqueness and conservation and discussed their potential implications for parasite biology with regards to future therapeutic targets against visceral leishmaniasis.

Radiologic Predictors of Increased Number of Necrosectomies During Endoscopic Management of Walled-off Pancreatic Necrosis.

GOALS: No established methods exist to predict who will require a higher number of endoscopic necrosectomy sessions for walled-off necrosis (WON). We aim to identify radiologic predictors for requiring a greater number of necrosectomy sessions. This may help to identify patients who benefit from aggressive endoscopic management. MATERIALS AND METHODS: This is a multicenter retrospective study of patients with WON at 3 tertiary care centers. WON characteristics on preintervention computed tomography imaging were evaluated to determine if they were predictive of requiring more endoscopic necrosectomy. RESULTS: A total of 104 patients were included. Seventy patients (67.3%) underwent endoscopic necrosectomy, with median of 2 necrosectomies. WON largest transverse diameters (P=0.02), largest coronal diameters (P=0.01), necrosis pattern [likelihood ratio (LR)=17.85, P<0.001], spread (LR=11.02, P=0.01), hemorrhage (LR=8.64, P=0.003), and presence of disconnected pancreatic duct (LR=6.80, P=0.01) were associated with undergoing ≥2 necrosectomies. Patients with septations/loculations were significantly less likely to undergo ≥2 necrosectomies (LR=4.86, P=0.03). CONCLUSIONS: Several computed tomography radiologic features were significantly associated with undergoing ≥2 necrosectomies. These could help identify patients who will undergo a higher number of endoscopic necrosectomy sessions.

Endoscopic ultrasound-guided biliary drainage in benign biliary pathology with normal foregut anatomy: a multicenter study.

BACKGROUND AND AIMS: Biliary drainage using endoscopic ultrasound (EUS-BD) has been developed as a novel technique to obtain biliary access and drainage when ERCP fails. Numerous studies have demonstrated its safety and efficacy specifically pertaining to those with malignant distal biliary obstruction or altered foregut anatomy. The aim of this study is to evaluate the safety and efficacy of EUS-BD in benign indications in patients with normal foregut anatomy. METHODS: We performed a retrospective comparative study from 5 academic medical centers (2008-2018) involving patients with benign biliary obstruction and native foregut anatomy who had an initial failed ERCP with subsequent attempt at biliary decompression via EUS-BD or by repeating ERCP. RESULTS: 36 patients (mean age 61.6 ± 2.2, 38.9% female) who underwent attempted EUS-BD following initial failed ERCP were compared to 50 patients (mean age 62.7 ± 2.3, 73.5% female) who underwent repeat ERCP following an initial failed cannulation. EUS-BD was technically successful in 28 (77.8%) patients with rendezvous being the most common approach (86.1%). A higher level of pre-procedural bilirubin was found to be associated with technical success of EUS-BD (3.65 ± 0.63 versus 1.1 ± 0.4, p value 0.04). Success of repeat ERCP following failed cannulation was 86%. Adverse events were significantly more frequent in the EUS-BD cohort when compared to the repeat ERCP (10 (27.8%) versus 4 (8.0%), p = 0.02, OR 4.32. CONCLUSIONS: EUS-BD remains a viable therapeutic option in the setting of benign biliary disease, with success rates of 77.8%. Adverse events were significantly more common with EUS-BD vs. repeat ERCP, emphasizing the need to perform in expert centers with appropriate multidisciplinary support and to strongly consider the urgency of biliary decompression before considering same session EUS-BD after failed initial biliary access.

Validation of choledocholithiasis predictors from the "2019 ASGE Guideline for the role of endoscopy in the evaluation and management of choledocholithiasis."

BACKGROUND AND AIMS: Identifying patients likely to have CDL is an important clinical dilemma because endoscopic retrograde cholangiopancreatography (ERCP), carries a 5-7% risk of adverse events. The purpose of this study was to compare the diagnostic test performance of the 2010 and 2019 ASGE criteria used to help risk stratify patients with suspected CDL. METHODS: Consecutive patients evaluated for possible CDL from 2013 to 2019 were identified from surgical, endoscopic, and radiologic databases at a single academic center. Inclusion criteria included all patients who underwent ERCP and/or cholecystectomy with intraoperative cholangiogram (IOC) for suspected CDL. We calculated the diagnostic test performance of criteria from both guidelines and compared their discrimination using the receiver operator curve. Univariate and multivariate analysis was used to identify the strongest component predictors. RESULTS: 1098 patients [age 57.9 ± 19.0 years, 62.8% (690) F] were included. 66.3% (728) were found to have CDL on ERCP and/or IOC. When using the 2019 guidelines, the sensitivity, specificity, PPV, NPV, and accuracy are 65.8, 78.9, 86.3, 54.1, and 70.4%, respectively. Using the 2010 guidelines, the sensitivity, specificity, PPV, NPV, and accuracy are 50.5, 78.9, 82.5, 44.8, and 60.1%, respectively. The AUC for high-risk criteria using the 2019 guidelines [0.726 (0.695, 0.758)] was greater than for the 2010 guidelines [0.647 (0.614, 0.681)]. The key difference providing the increased discrimination was the inclusion of stones on any imaging modality, which increased the sensitivity to 55.0% from 29.1%. Not including CDL on imaging or cholangitis, a dilated CBD was the strongest individual predictor of CDL on multivariate analysis (OR 3.70, CI 2.80, 4.89). CONCLUSION: Compared to 2010, the 2019 high-risk criterion improves diagnostic test performance, but still performs suboptimally. Less invasive tests, such as EUS or MRCP, should be considered in patients with suspected CDL prior to ERCP.

Endoscopic Diagnosis and Management of Gastrointestinal Trauma.

Trauma affects all sociodemographic profiles and is a major cause of morbidity and mortality particularly in patients less than forty years of age. A variety of endoscopic tools and techniques initially used for iatrogenic etiologies (post-operative bile or pancreatic duct leaks, intra-procedural perforation) have been adopted for use in the gastrointestinal trauma victim. The purpose of this review is to highlight a variety of gastrointestinal traumatic complications where endoscopy can serve a complement and/or definitive management strategy.

Performance and Predictors of Migration of Partially and Fully Covered Esophageal Self-Expanding Metal Stents for Malignant Dysphagia.

BACKGROUND & AIMS: Self-expanding metal stents (SEMS) are routinely used to palliate malignant dysphagia. However esophageal SEMS can migrate or obstruct due to epithelial hyperplasia. The aim of this study was to evaluate the rates and factors predicting migration and obstruction, and the nutritional outcomes in partially covered (pc) vs. fully covered (fc) SEMS vs. fcSEMS with antimigration fins (AF) placed for malignant dysphagia. METHODS: A retrospective review of consecutive patients undergoing SEMS placement for malignant dysphagia at three academic medical centers. RESULTS: Among 357 patients, there were 55 (15.4%) stent migrations, 45 (12.6%) obstructions from epithelial hyperplasia, and 20 (5.6%) food impactions. Median overall survival was 79 days (IQR 41,199). The percent weight change/change in albumin at 30 and 60 days after SEMS placement were -2.24%/-0.544 g/dL and -2.98%/-0.55 g/dL, respectively. Stent migration occurred significantly more often with fcSEMS than pcSEMS (25.3% vs 10.9%; P < .003), but there was no difference when either group was compared to fcSEMS-AF (19.3%). The overall rate of epithelial hyperplasia resulting in stent obstruction was low (12.6%) and not different between stent types. Factors associated with increased risk of SEMS migration on multivariable logistic regression included stricture traversability with a diagnostic endoscope (OR, 2.37; 95% CI, 1.29-4.35) and use of fcSEMS (OR, 2.56; 1.31-5.00) or fcSEMS-AF (OR, 2.30, 1.03-5.14). CONCLUSIONS: Traversability of a malignant esophageal stenosis predicts SEMS migration. In these patients with a limited overall survival, pcSEMS are associated with lower rates of stent migration and similar rates of obstruction compared to fcSEMS.

Cross Validation of the Monoclonal Antibody Das-1 in Identification of High-Risk Mucinous Pancreatic Cystic Lesions.

BACKGROUND & AIMS: Although pancreatic cystic lesions (PCLs) are frequently and incidentally detected, it is a challenge to determine their risk of malignancy. In immunohistochemical and enzyme-linked immunosorbent assay (ELISA) analyses of tissue and cyst fluid from pancreatic intraductal papillary mucinous neoplasms, the monoclonal antibody Das-1 identifies those at risk for malignancy with high levels of specificity and sensitivity. We aimed to validate the ability of Das-1 to identify high-risk PCLs in comparison to clinical guidelines and clinical features, using samples from a multicenter cohort. METHODS: We obtained cyst fluid samples of 169 PCLs (90 intraductal papillary mucinous neoplasms, 43 mucinous cystic neoplasms, and 36 non-mucinous cysts) from patients undergoing surgery at 4 tertiary referral centers (January 2010 through June 2017). Histology findings from surgical samples, analyzed independently and centrally re-reviewed in a blinded manner, were used as the reference standard. High-risk PCLs were those with invasive carcinomas, high-grade dysplasia, or intestinal-type intraductal papillary mucinous neoplasms with intermediate-grade dysplasia. An ELISA with Das-1 was performed in parallel using banked cyst fluid samples. We evaluated the biomarker's performance, generated area under the curve values, and conducted multivariate logistic regression using clinical and pathology features. RESULTS: The ELISA for Das-1 identified high-risk PCLs with 88% sensitivity, 99% specificity, and 95% accuracy, at a cutoff optical density value of 0.104. In 10-fold cross-validation analysis with 100 replications, Das-1 identified high-risk PCLs with 88% sensitivity and 98% specificity. The Sendai, Fukuoka, and American Gastroenterological Association guideline criteria identified high-risk PCLs with 46%, 52%, and 74% accuracy (P for comparison to Das-1 ELISA <.001). When we controlled for Das-1 in multivariate regression, main pancreatic duct dilation >5 mm (odds ratio, 14.98; 95% confidence interval, 2.63-108; P < .0012), main pancreatic duct dilation ≥1 cm (odds ratio, 47.9; 95% confidence interval, 6.39-490; P < .0001), and jaundice (odds ratio, 6.16; 95% confidence interval, 1.08-36.7; P = .0397) were significantly associated with high-risk PCLs. CONCLUSIONS: We validated the ability of an ELISA with the monoclonal antibody Das-1 to detect PCLs at risk for malignancy with high levels of sensitivity and specificity. This biomarker might be used in conjunction with clinical guidelines to identify patients at risk for malignancy.