Comparison of lumen-apposing metal stents versus endoscopic balloon dilation for the management of benign colorectal anastomotic strictures.

BACKGROUND AND AIMS: Limited data exist evaluating lumen-apposing metal stents (LAMSs) with endoscopic balloon dilation (EBD) for the treatment of benign colorectal anastomotic strictures (BCASs). This study compares outcomes of both interventions. METHODS: Patients with left-sided BCAS treated with LAMSs versus EBD were identified retrospectively. The primary outcome was a composite of crossover to another intervention to achieve clinical success or recurrence requiring reintervention. RESULTS: Twenty-nine patients (11 LAMS and 18 EBD) were identified with longer follow-up in the EBD group (734 vs 142 days; P = .003). No significant differences were found in the composite outcome, technical success, clinical success, or components of composite outcome. With LAMS, there was a nonsignificant trend toward fewer procedures (2.4 vs 3.3; P = .06) and adverse events (0% vs 16.7%; P = .26). CONCLUSIONS: LAMS appears to be as effective as EBD for the treatment of BCAS but may require fewer procedures and may be safer than EBD.

KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. EXPERIMENTAL DESIGN: We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. RESULTS: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. CONCLUSIONS: Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.

Multimodal Mapping of the Tumor and Peripheral Blood Immune Landscape in Human Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8+ T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8+ T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT, a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer.

Recent advances in understanding and managing acute pancreatitis.

This review highlights advances made in recent years in the diagnosis and management of acute pancreatitis (AP). We focus on epidemiological, clinical, and management aspects of AP. Additionally, we discuss the role of using risk stratification tools to guide clinical decision making. The majority of patients suffer from mild AP, and only a subset develop moderately severe AP, defined as a pancreatic local complication, or severe AP, defined as persistent organ failure. In mild AP, management typically involves diagnostic evaluation and supportive care resulting usually in a short hospital length of stay (LOS). In severe AP, a multidisciplinary approach is warranted to minimize morbidity and mortality over the course of a protracted hospital LOS. Based on evidence from guideline recommendations, we discuss five treatment interventions, including intravenous fluid resuscitation, feeding, prophylactic antibiotics, probiotics, and timing of endoscopic retrograde cholangiopancreatography (ERCP) in acute biliary pancreatitis. This review also highlights the importance of preventive interventions to reduce hospital readmission or prevent pancreatitis, including alcohol and smoking cessation, same-admission cholecystectomy for acute biliary pancreatitis, and chemoprevention and fluid administration for post-ERCP pancreatitis. Our review aims to consolidate guideline recommendations and high-quality studies published in recent years to guide the management of AP and highlight areas in need of research.

Endoscopic suture fixation is associated with reduced migration of esophageal fully covered self-expandable metal stents (FCSEMS).

BACKGROUND: Esophageal fully covered self-expandable metal stents (FCSEMS) are indicated for the management of benign and malignant conditions of the esophagus including perforations, leaks, and strictures. FCSEMS are resistant to tissue ingrowth and are removable; however, stent migration occurs in 30-55% of cases. Endoscopic suture fixation of FCSEMS has been utilized to decrease the risk of stent migration though data supporting this practice remain limited. The primary aim of this study was to compare clinical outcomes and migration rate of patients who underwent placement of esophageal FCSEMS with and without endoscopic suture fixation. METHODS: Our single-center, retrospective, cohort study includes patients who underwent esophageal FCSEMS placement with and without endoscopic suture fixation between January 1, 2012, and November 11, 2015. Baseline patient characteristics, procedural details, and clinical outcomes were abstracted. Logistic regression was performed to identify clinical and technical factors associated with outcomes and stent migration. RESULTS: A total of 51 patients underwent 62 FCSEMS placements, including 21 procedures with endoscopic suture fixation and 41 without. Suture fixation was associated with reduced risk of stent migration (OR 0.13, 95% CI 0.03-0.47). Prior stent migration was associated with significantly higher risk of subsequent migration (OR 6.4, 95% CI 1.6-26.0). Stent migration was associated with lower likelihood of clinical success (OR 0.21, 95% CI 0.06-0.69). There was a trend toward higher clinical success among patients undergoing suture fixation (85.7 vs. 60.9%, p = 0.07). CONCLUSIONS: Endoscopic suture fixation of FCSEMS was associated with a reduced stent migration rate. Appropriate patient selection for suture fixation of FCSEMS may lead to reduced migration in high-risk patients.

Transpapillary Gallbladder Stents Can Stabilize or Improve Decompensated Cirrhosis in Patients Awaiting Liver Transplantation.

GOALS: To describe the short-term and long-term outcomes in 34 consecutive decompensated cirrhotic patients with symptomatic gallbladder disease undergoing transpapillary gallbladder stent (TGS) placement. BACKGROUND: Endoscopic TGS placement is a minimally invasive means of treating symptomatic gallbladder disease in poor surgical candidates. STUDY: Between June 2005 and June 2011, 34 patients with cirrhosis and symptomatic gallbladder disease underwent attempted TGS placement. RESULTS: Median patient age was 52 years, 56% were hospitalized, and 48% were listed for liver transplantation. The median model for end-stage liver disease (MELD) score was 15 (range, 6 to 40) and 88% were Child-Turcotte-Pugh class B/C. A double pigtailed stent was successfully placed in 94% of the patients. At 1-month follow-up, clinical improvement was noted in 82% of the treated subjects and the MELD scores in 14 of 22 (64%) evaluable subjects improved or stabilized. Actuarial transplant-free survival was 53% in the liver transplant candidates with a mean follow-up of 352 days, whereas survival was 44% in the 18 nontransplant candidates with a mean follow-up of 1.5 years. Periprocedural complications included pancreatitis in 5 patients, cholangitis in 3, and 1 patient with cystic duct perforation. In addition, 2 subjects had symptomatic bleeding from traumatic duodenal ulcerations 2 years after TGS placement that necessitated stent removal. CONCLUSIONS: Endoscopic TGS placement was technically feasible in 94% of decompensated cirrhotics and was associated with a relatively low rate of periprocedural (26%) and long-term complications (6%). Stabilization or improvement in clinical status and MELD scores was seen in the majority of treated patients.

Endoscopic approach to the diagnosis and treatment of pancreatic disease.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on the diagnosis and treatment of pancreatic disorders using endoscopy. RECENT FINDINGS: The role of endoscopy in the diagnosis and management of pancreatic disorders continues to increase in importance. The use of post-endoscopic retrograde cholangio-pancreatography (ERCP) provides therapy for many pancreatic disorders, including in the treatment of pancreatitis, its complications and pancreatic neoplasia. In recent years, there has been a focus on improving its safety in the prevention of post-ERCP pancreatitis. Pancreatic endotherapy by ERCP for the treatment of biliary strictures and chronic pain in chronic pancreatitis will also be reviewed. Endoscopic ultrasound (EUS) has a vital diagnostic role in pancreatic disorders; however, much of the recent focus has been on its therapeutic role for simple and complex pancreatic fluid collections. As for the role of EUS in pancreatic cancer, recent technical advances in conjunction with on-site cytopathology service continue to improve pancreatic cancer diagnosis. EUS has an increasing role in treatment with fiducial placement for stereotactic body radiation therapy. SUMMARY: In this review, I will examine the literature over the last year in ERCP and EUS as they apply to specific pancreatic disorders.

Risk models for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP): smoking and chronic liver disease are predictors of protection against PEP.

OBJECTIVES: We investigated which variables independently associated with protection against or development of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and severity of PEP. Subsequently, we derived predictive risk models for PEP. METHODS: In a case-control design, 6505 patients had 8264 ERCPs, 211 patients had PEP, and 22 patients had severe PEP. We randomly selected 348 non-PEP controls. We examined 7 established- and 9 investigational variables. RESULTS: In univariate analysis, 7 variables predicted PEP: younger age, female sex, suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate-difficult cannulation (MDC), pancreatic stent placement, and lower Charlson score. Protective variables were current smoking, former drinking, diabetes, and chronic liver disease (CLD, biliary/transplant complications). Multivariate analysis identified seven independent variables for PEP, three protective (current smoking, CLD-biliary, CLD-transplant/hepatectomy complications) and 4 predictive (younger age, suspected SOD, pancreatic sphincterotomy, MDC). Pre- and post-ERCP risk models of 7 variables have a C-statistic of 0.74. Removing age (seventh variable) did not significantly affect the predictive value (C-statistic of 0.73) and reduced model complexity. Severity of PEP did not associate with any variables by multivariate analysis. CONCLUSIONS: By using the newly identified protective variables with 3 predictive variables, we derived 2 risk models with a higher predictive value for PEP compared to prior studies.

Pancreas divisum.

We review important new clinical observations in pancreas divisum (PD) made since 2007. PD is common and has the same prevalence in the general population and idiopathic pancreatitis (IP). Up to 53% of patients with PD and IP have underlying idiopathic chronic pancreatitis (CP), and in rigorous prospective clinical follow-up and/or natural history studies, many with idiopathic recurrent acute pancreatitis (IRAP) have idiopathic CP. According to retrospective studies, PD does not modify the natural course of nonalcoholic or alcoholic CP. CFTR and/or SPINK1 gene mutations associate with IP (idiopathic CP and IRAP) independently of the presence of PD. More than one third of patients with pancreatitis or presumed pancreaticobiliary pain respond to placebo. Authors of uncontrolled studies report a significant symptomatic response to surgery and endotherapy in patients with IP and PD, but the response remains unproven and is largely limited to those with IRAP and not idiopathic CP or chronic pain.

Type of pain, pain-associated complications, quality of life, disability and resource utilisation in chronic pancreatitis: a prospective cohort study.

OBJECTIVE: To compare patients with chronic pancreatitis (CP) with constant pain patterns to patients with CP with intermittent pain patterns. METHODS: This was a prospective cohort study conducted at 20 tertiary medical centers in the USA comprising 540 subjects with CP. Patients with CP were asked to identify their pain from five pain patterns (A-E) defined by the temporal nature (intermittent or constant) and the severity of the pain (mild, moderate or severe). Pain pattern types were compared with respect to a variety of demographic, quality of life (QOL) and clinical parameters. Rates of disability were the primary outcome. Secondary outcomes included: use of pain medications, days lost from school or work, hospitalisations (preceding year and lifetime) and QOL as measured using the Short Form-12 (SF-12) questionnaire. RESULTS: Of the 540 CP patients, 414 patients (77%) self-identified with a particular pain pattern and were analysed. Patients with constant pain, regardless of severity, had higher rates of disability, hospitalisation and pain medication use than patients with intermittent pain. Patients with constant pain had lower QOL (by SF-12) compared with patients who had intermittent pain. Additionally, patients with constant pain were more likely to have alcohol as the aetiology for their pancreatitis. There was no association between the duration of the disease and the quality or severity of the pain. CONCLUSIONS: This is the largest study ever conducted of pain in CP. These findings suggest that the temporal nature of pain is a more important determinant of health-related QOL and healthcare utilisation than pain severity. In contrast to previous studies, the pain associated with CP was not found to change in quality over time. These results have important implications for improving our understanding of the mechanisms underlying pain in CP and for the goals of future treatments and interventions.

Combining fine needle aspiration with brushing cytology has improved yields in diagnosing pancreatic ductal adenocarcinoma.

The aim of this retrospective study is to evaluate the diagnostic yields of combining fine needle aspiration (FNA) with brushing cytology (BC) in clinical work-up of pancreatic ductal adenocarcinoma. The study included a total of 97 patients who underwent both FNA and BC along with histologic/clinical follow-up (F/U). Cytologic diagnoses were categorized as negative for neoplasm (NEG), atypical/favor neoplasm (AN), and suspicious or positive for neoplasm (POS). Based on the cytologic diagnoses, the cohort was divided as follows: 23 had concordant FNA and BC diagnoses of POS/AN, all were neoplasms on F/U; 34 had disconcordant (POS/AN vs. NEG) FNA and BC diagnoses, all but 2 were neoplasms on F/U; The remaining 40 were NEG on both FNA and BC, F/U revealed that 10 were neoplasms and 30 were chronic pancreatitis. Overall, FNA rendered more true positive diagnoses than BC. However, BC but not FNA detected neoplasms in 10 patients. Most of the neoplasms identified on F/U were ductal adenocarcinoma (59 of 65). Diagnostic sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 69.2, 93.8, 95.7, 60, and 77.3% for FNA alone, 50.8, 100, 100, 50.0, and 67.0% for BC alone, and 84.6, 100, 100, 76.2, and 89.7% for combining FNA with BC. In conclusion, both EUS-guided FNA and BC are valuable modalities in the preoperative diagnosis of pancreatic ductal adenocarcinoma. When used in combination, the two modalities complement each other and achieve better diagnostic yield in pancreatic ductal adenocarcinoma than either FNA or BC alone.

Alcohol use and cigarette smoking as risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND & AIMS: Alcohol use and cigarette smoking are associated with various pancreatic diseases, but it is not known whether they associate with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). We performed a retrospective case-control study to determine if these activities increase the risk of PEP. METHODS: We identified 7638 patients who had undergone ERCP in the University of Michigan Health System and applied exclusion criteria to identify 123 with PEP. We randomly selected 308 age- and sex-stratified controls (2.5-fold case sample); after applying exclusion criteria 248 remained. In a masked fashion, we collected data for alcohol use, cigarette smoking, and 5 internal control variables: suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate/difficult cannulation, 2 or more pancreatic injections, and pancreatic stent placement. RESULTS: The univariate model showed an increased frequency of PEP in current drinkers (P < .001), former drinkers (P < .001), and former smokers (P < .001), as well as patients who were suspected of having SOD (P < .001), had undergone pancreatic sphincterotomy (P < .001), had a moderate/difficult cannulation (P = .001), and/or had 2 or more pancreatic injections (P = .007). The frequency of PEP was reduced in current smokers (P < .001). The multivariate model showed that the only independent significant predictors of PEP were current drinking (odds ratio [OR], 4.70; 95% confidence interval [CI], 2.60-8.50; P < .0001), former cigarette smoking (OR, 3.29; 95% CI, 1.28-8.44; P < .013), suspected SOD (OR, 3.69; 95% CI, 1.94-7.02; P < .001), and pancreatic sphincterotomy (OR, 5.91; 95% CI, 2.04-17.14; P = .001). CONCLUSIONS: Current alcohol use and potentially former cigarette smoking are new risk factors for PEP. It is important to consider these variables in designing PEP prevention trials.

Updates in biliary endoscopy 2006.

PURPOSE OF REVIEW: Endoscopic retrograde cholangiopancreatography is reserved primarily for therapeutic reasons. Recent literature continues to support therapeutic uses of the technique. This review addresses the literature in the field of biliary endoscopy for the year 2006 and is intended to assist gastroenterologists and gastrointestinal surgeons in everyday practice. RECENT FINDINGS: Endoscopic management of choledocholithiasis in gallstone pancreatitis, a newer approach in the endoscopic management of malignant biliary strictures, the broadening therapeutic indications including the use of gallbladder stenting and the performance of endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y gastric bypass are discussed. Safety of the technique continues to be addressed. The risks of pancreatitis after endoscopic retrograde cholangiopancreatography as well as morbidity in the elderly are addressed. SUMMARY: Major updates in the management of biliary tract disease using biliary endoscopy are discussed over a broad range of biliary tract diseases. The literature emphasizes the broadening therapeutic role of endoscopic retrograde cholangiopancreatography as well as improvements in our understanding of risk factors for complications and the potential for their prevention.

Updates in biliary endoscopy.

PURPOSE OF REVIEW: Endoscopic retrograde cholangiopancreatography is a non-surgical approach to diseases of the pancreaticobiliary system that dates back to the late 1960s. Initially, endoscopic retrograde cholangiopancreatography was purely a diagnostic procedure. After the first report of endoscopic sphincterotomy in 1974, therapeutic uses were possible for diseases that previously required surgery. As therapeutic indications broaden, our understanding of complications has tempered the initial excitement. Non-invasive imaging in many circumstances has replaced the diagnostic utilization of endoscopic retrograde cholangiopancreatography which is now reserved primarily for therapeutic indications. This review is intended to address biliary therapeutics with an update on the recent directions of this field. RECENT FINDINGS: Advancements in the endoscopic retrograde cholangiopancreatography medical literature in the last year have concentrated on the management of difficult common bile duct stones using electrohydraulic lithotripsy, chronic pancreatitis and pancreatic cancer-induced biliary strictures, postoperative bile leaks, the use of newer methods of biliary access and finally the use of ulinastatin for the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis. SUMMARY: This is an update of the work in the field of biliary endoscopy over the last year. The goal of this review is to address specific management concerns in the field of biliary endoscopy from the literature published in 2005.

Fluorescence in situ hybridization for the detection of malignant bile duct strictures: has FISH found a new pond?

Routine cytology for the diagnosis of biliary and pancreatic malignancies has exceptionally poor sensitivity and has spurred a search for new technology in the evaluation of these diseases. The recent study by Kipp et al. in this issue of the Journal, compares one of these novel techniques (fluorescence in situ hybridization to standard cytology) for the detection of malignant biliary strictures. Although larger studies are indicated, the modality shows considerable promise for future clinical use.

EUS detection of pancreatic endocrine tumors in asymptomatic patients with type 1 multiple endocrine neoplasia.

BACKGROUND: EUS is highly sensitive, specific, and cost-effective for localization of pancreatic neuroendocrine tumors. EUS screening of asymptomatic patients with multiple endocrine neoplasia type 1 has not been described. METHODS: EUS was used to evaluate all patients with known or suspected pancreatic neuroendocrine tumors. Asymptomatic patients with either a confirmed genetic or clinical diagnosis of multiple endocrine neoplasia type 1 were evaluated with EUS. The results were correlated with surgical and histopathologic findings. RESULTS: A total of 65 patients with multiple endocrine neoplasia type 1 underwent 132 EUS procedures over an 8-year period, including 13 asymptomatic patients. Five of the 13 asymptomatic patients had normal serum gastrin levels, and 8 had levels less than 4 times the upper limit of normal. EUS demonstrated pancreatic neuroendocrine tumors in 11 of these patients, ranging in size from 0.4 to 4 cm (mean 10 mm). Ten of the 11 patients with tumors at EUS underwent surgical exploration, and 23 of 28 (82%) tumors removed surgically had been identified by EUS. At a mean follow-up of 44 months, no liver or lymph node metastases were demonstrated in any patient. CONCLUSIONS: In this first cohort study of asymptomatic patients with multiple endocrine neoplasia type 1 undergoing screening EUS, pancreatic neuroendocrine tumors were identified before the development of significant biochemical test abnormalities. Aggressive early surgical treatment may improve the prognosis for these patients.