Payal Saxena

Human bile contains MicroRNA‐laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis

Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR‐based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR‐based disease markers in bile. Finally, we report on the development of a novel bile‐based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility. (Hepatology 2014;60:896–907)

Efficacy and Safety of Peroral Endoscopic Myotomy for Treatment of Achalasia After Failed Heller Myotomy

BACKGROUND & AIMS: In patients with persistent symptoms after Heller myotomy (HM), treatment options include repeat HM, pneumatic dilation, or peroral endoscopic myotomy (POEM). We evaluated the efficacy and safety of POEM in patients with achalasia with prior HM vs without prior HM. METHODS: We conducted a retrospective cohort study of 180 patients with achalasia who underwent POEM at 13 tertiary centers worldwide, from December 2009 through September 2015. Patients were divided into 2 groups: those with prior HM (HM group, exposure; n = 90) and those without prior HM (non‐HM group; n = 90). Clinical response was defined by a decrease in Eckardt scores to 3 or less. Adverse events were graded according to criteria set by the American Society for Gastrointestinal Endoscopy. Technical success, clinical success, and rates of adverse events were compared between groups. Patients were followed up for a median of 8.5 months. RESULTS: POEM was technically successful in 98% of patients in the HM group and in 100% of patients in the non‐HM group (P = .49). A significantly lower proportion of patients in the HM group had a clinical response to POEM (81%) than in the non‐HM group (94%; P = .01). There were no significant differences in rates of adverse events between the groups (8% in the HM group vs 13% in the non‐HM group; P = .23). Symptomatic reflux and reflux esophagitis after POEM were comparable between groups. CONCLUSIONS: POEM is safe and effective for patients with achalasia who were not treated successfully by prior HM. Although the rate of clinical success in patients with prior HM is lower than in those without prior HM, the safety profile of POEM is comparable between groups.

Comprehensive Analysis of Adverse Events Associated with per Oral Endoscopic Myotomy in 1826 Patients: An International Multicenter Study

Objectives:The safety of peroral endoscopic myotomy (POEM) is still debated since comprehensive analysis of adverse events (AEs) associated with the procedure in large multicenter cohort studies has not been performed. To study (1) the prevalence of AEs and (2) factors associated with occurrence of AEs in patients undergoing POEM.Methods:Patients who underwent POEM at 12 tertiary-care centers between 2009 and 2015 were included in this case–control study. Cases were defined by the occurrence of any AE related to the POEM procedure. Control patients were selected for each AE case by matching for age, gender, and disease classification (achalasia type I and II vs. type III/spastic esophageal disorders).Results:A total of 1,826 patients underwent POEM. Overall, 156 AEs occurred in 137 patients (7.5%). A total of 51 (2.8%) inadvertent mucosotomies occurred. Mild, moderate, and severe AEs had a frequency of 116 (6.4%), 31 (1.7%), and 9 (0.5%), respectively. Multivariate analysis demonstrated that sigmoid-type esophagus (odds ratio (OR) 2.28, P=0.05), endoscopist experience <20 cases (OR 1.98, P=0.04), use of a triangular tip knife (OR 3.22, P=0.05), and use of an electrosurgical current different than spray coagulation (OR 3.09, P=0.02) were significantly associated with the occurrence of AEs.Conclusions:This large study comprehensively assessed the safety of POEM and highly suggests POEM as a relatively safe procedure when performed by experts at tertiary centers with an overall 7.5% prevalence of AEs. Severe AEs are rare. Sigmoid-type esophagus, endoscopist experience, type of knife, and current used can be considered as predictive factors of AE occurrence.

The role of endoscopic ultrasound in pancreatic cancer screening.

Pancreatic cancer (PC) is a highly lethal cancer. Despite a significant advancement in cancer treatment, the mortality rate of PC is nearly identical to the incidence rates. Early detection of tumor or its precursor lesions with dysplasia may be the most effective approach to improve survival. Screening strategies should include identification of the population at high risk of developing PC, and an intense application of screening tools with adequate sensitivity to detect PC at an early curable stage. Endoscopic ultrasound (EUS) and magnetic resonance imaging (MRI) seem to be the most promising modalities for PC screening based on the data so far. EUS had an additional advantage over MRI by being able to obtain tissue sample during the same examination. Several questions remain unanswered at this time regarding the age to begin screening, frequency of screening, management of asymptomatic pancreatic lesions detected on screening, timing of resection, and extent of surgery and impact of screening on survival. Novel techniques such as needle-based confocal laser endomicroscopy (nCLE), along with biomarkers, may be helpful to identify pancreatic lesions with more aggressive malignant potential. Further studies will hopefully lead to the development of strategies combining EUS with other technological/biological advancements that will be cost-effective and have an impact on survival.

Predictors of success for double balloon assisted endoscopic retrograde cholangiopancreatography in patients with Roux-en-Y anastomosis.

Endoscopic retrograde cholangiopancreatography (ERCP) in patients with roux‐en‐Y anastomosis (REYA) is challenging. Use of double balloon enteroscope‐assisted ERCP (DBE‐ERCP) has been successful. We aim to determine predictors of successful biliary cannulation with DBE‐ERCP in patients with REYA.

Education and Imaging. Hepatobiliary and pancreatic: Glycogenic hepatopathy: a reversible condition.

Glycogenic hepatopathy is an under recognised condition, described as a pathological overloading of hepatocytes with glycogen in patients with poorly controlled type 1 diabetes mellitus. Clinical presentations can include abdominal pain, tender hepatomegaly, nausea and elevated transaminases. We report a case of a 33 year old woman, with poorly controlled type 1 diabetes mellitus (HbA1c 13.7%) who was referred for evaluation of diarrhoea and abnormal liver enzymes, to highlight the diagnostic challenges of glycogenic hepatopathy. Physical examination revealed a diffusely tender abdomen. Liver enzymes were significantly elevated at ALP 205 U/L, GGT 88 U/L, AST 428 U/L and ALT 404 U/L. Bilirubin and liver synthetic function were normal, and screening for other causes of liver disease was negative. Ultrasound examination suggested fatty infiltration of the liver. The degree of liver enzyme elevation led to a liver biopsy. The biopsy showed enlarged, swollen hepatocytes with no evidence of steatosis, inflammation, fibrosis or necrosis (Figure 1). Mallory hyaline bodies were not seen. The enlarged hepatocytes showed intense cytoplasmic staining with Periodic Acid-Schiff stain, and negative staining with Periodic Acid-Schiff Diastase. This is suggestive of glycogen accumulation (Figure 2), and consistent with glycogenic hepatopathy. At 12 month follow-up, the patient had achieved significant improvement in glycaemic control (HbA1c 9.3%), with normalisation of liver enzymes. Fibroscan (non-invasive method of measuring liver elastography), was performed on our patient. A mean reading of 5.3 Kpa was found, suggesting early fibrosis. The literature suggests that glycogenic hepatopathy is reversible with improved glycaemic control. This is certainly demonstrated in our patient with normalisation of liver enzymes, though the early fibrosis evident on Fibroscan does not correlate with this picture. Repeat liver biopsy would be needed for confirmation. Cases similar to ours have been described amongst the paediatric and adult population. However there are no reports of Fibroscans on these patients. The hallmark of this condition is its reversibility with improved glycaemic control, unlike hepatic steatosis. Glycogen overload is not known to progress to fibrosis, distinct from fatty liver disease. However, Fibroscan findings propose this may not be the case. More studies of similar cases with both liver biopsies and Fibroscan readings would be needed to clarify this further. The condition remains under recognised by clinicians, pathologists and radiologists. Diabetic patients are frequently diagnosed with fatty liver disease as it is indistinguishable unless biopsy is performed. Awareness of the condition is important, particularly as imaging is not diagnostic, and is likely a reversible condition.

Update on therapeutic interventions for the management of achalasia.

Achalasia is a primary esophageal motility disorder. It is the absence of peristalsis in the esophageal body and inability of the lower esophageal sphincter to relax, which characterizes this rare condition. Its features typically include dysphagia, regurgitation, chest pain, and weight loss. The ultimate goal in treating achalasia is to relieve the patients symptoms, improve esophageal emptying, and prevent further dilatation of the esophagus. Current treatment modalities targeted at achalasia include pharmacological therapy, endoscopic therapy, and surgery. This review focuses on the current therapeutic options and explores the role of peroral endoscopic myotomy in the management armamentarium.

Hepatobiliary and Pancreatic: Glycogenic hepatopathy: A reversible condition

Glycogenic hepatopathy is an under recognised condition, described as a pathological overloading of hepatocytes with glycogen in patients with poorly controlled type 1 diabetes mellitus. Clinical presentations can include abdominal pain, tender hepatomegaly, nausea and elevated transaminases. We report a case of a 33 year old woman, with poorly controlled type 1 diabetes mellitus (HbA1c 13.7%) who was referred for evaluation of diarrhoea and abnormal liver enzymes, to highlight the diagnostic challenges of glycogenic hepatopathy. Physical examination revealed a diffusely tender abdomen. Liver enzymes were significantly elevated at ALP 205 U/L, GGT 88 U/L, AST 428 U/L and ALT 404 U/L. Bilirubin and liver synthetic function were normal, and screening for other causes of liver disease was negative. Ultrasound examination suggested fatty infiltration of the liver. The degree of liver enzyme elevation led to a liver biopsy. The biopsy showed enlarged, swollen hepatocytes with no evidence of steatosis, inflammation, fibrosis or necrosis (Figure 1). Mallory hyaline bodies were not seen. The enlarged hepatocytes showed intense cytoplasmic staining with Periodic Acid-Schiff stain, and negative staining with Periodic Acid-Schiff Diastase. This is suggestive of glycogen accumulation (Figure 2), and consistent with glycogenic hepatopathy. At 12 month follow-up, the patient had achieved significant improvement in glycaemic control (HbA1c 9.3%), with normalisation of liver enzymes. Fibroscan (non-invasive method of measuring liver elastography), was performed on our patient. A mean reading of 5.3 Kpa was found, suggesting early fibrosis. The literature suggests that glycogenic hepatopathy is reversible with improved glycaemic control. This is certainly demonstrated in our patient with normalisation of liver enzymes, though the early fibrosis evident on Fibroscan does not correlate with this picture. Repeat liver biopsy would be needed for confirmation. Cases similar to ours have been described amongst the paediatric and adult population. However there are no reports of Fibroscans on these patients. The hallmark of this condition is its reversibility with improved glycaemic control, unlike hepatic steatosis. Glycogen overload is not known to progress to fibrosis, distinct from fatty liver disease. However, Fibroscan findings propose this may not be the case. More studies of similar cases with both liver biopsies and Fibroscan readings would be needed to clarify this further. The condition remains under recognised by clinicians, pathologists and radiologists. Diabetic patients are frequently diagnosed with fatty liver disease as it is indistinguishable unless biopsy is performed. Awareness of the condition is important, particularly as imaging is not diagnostic, and is likely a reversible condition.

Endoscopic modalities for upper gastrointestinal leaks, fistulae and perforations.

Endotherapy techniques are a recent addition to the suite of non‐surgical and minimally invasive strategies to manage patients with perforations, leaks and fistulae. The emergency nature of these conditions and the heterogeneity of pathologies encountered create difficulties when trying to select appropriate tools in these complex situations. The purpose of this article is to review experience at a tertiary academic centre, describe the various endoscopic tools available and the situations where they can be considered for use.

Refining the care of patients with pancreatic cancer: the AGITG pancreatic cancer workshop consensus

A meeting of the Australasian Gastro‐Intestinal Trials Group (AGITG) was held to develop a consensus statement defining when a patient with pancreatic cancer has disease that is clearly operable, is borderline, or is locally advanced/inoperable. Key issues included the need for multidisciplinary team consensus for all patients considered for surgical resection. Staging investigations, to be completed within 4 weeks of presentation, should include pancreatic protocol computed tomography, endoscopic ultrasound, and, when possible, biopsy. Given marked differences in outcomes, the operability of tumours should be clearly identified by categories: those clearly resectable by standard means (group 1a), those requiring vascular resection but which are clearly operable (group 1b), and those of borderline operability requiring vascular resection (groups 2a and 2b). Patients who may require vascular reconstruction should be referred, before exploration, to a specialist unit. All patients should have a structured pathology report with standardised reporting of all seven surgical margins, which identifies an R0 (no tumour cells within a defined distance of the margin) if all surgical margins are clear from 1 mm. Neo‐adjuvant therapy is increasingly recommended for borderline operable disease, while chemotherapy is recommended as initial therapy for patients with unresectable loco‐regional pancreatic cancer. The value of adding radiation after initial chemotherapy remains uncertain. A small number of patients may be downstaged by chemoradiation, and trimodality therapy should only be considered as part of a clinical trial. Instituting these recommendations nationally will be an integral part of the process of improving quality of care and reducing geographic variation between centres in outcomes for patients.