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Cholangiocarcinoma and pancreatic cancer are the most common causes of malignant biliary obstruction. The majority of patients are diagnosed at a late stage when surgical resection is rarely possible. In these cases, palliative chemotherapy and radiotherapy provide only limited benefit and are associated with poor survival. Radiofrequency ablation (RFA) is a procedure for locoregional control of tumours, whereby a high-frequency alternating current turned into thermal energy causes coagulative necrosis of the tissue surrounding the catheter. The subsequent release of debris and tumour antigens by necrotic cells can stimulate local and systemic immunity. The development of endoluminal RFA catheters has led to the emergence of endoscopically delivered RFA, a treatment mainly used for malignant biliary strictures to prolong survival and/or stent patency. Other indications include recanalisation of occluded biliary stents and treatment of intraductal ampullary adenoma or benign biliary strictures. This article presents a comprehensive review of endobiliary RFA, mainly focusing on its use in patients with malignant biliary obstruction. The available data suggest that biliary RFA may be a promising modality, having positive impacts on survival and stent patency and boasting a reasonable safety profile. However, further studies with better characterised and stratified patient populations are needed before the method becomes accepted within routine clinical practice.

Funder: British Society of Interventional Radiology, PURPOSE: The purpose of this study was to evaluate the predictive value of a 'Modified Karnofsky Scoring System' on outcomes and provide real-world data regarding the UK practice of biliary interventions. MATERIALS AND METHODS: A prospective multi-centred cohort study was performed. The pre-procedure modified Karnofsky score, the incidence of sepsis, complications, biochemical improvement and mortality were recorded out to 30 days post procedure. RESULTS: A total of 292 patients (248 with malignant lesions) were suitable for inclusion in the study. The overall 7 and 30 day mortality was 3.1% and 16.1%, respectively. The 30 day sepsis rate was 10.3%. In the modified Karnofsky 'high risk' group the 7 day mortality was 9.7% versus 0% for the 'low risk' group (p = 0.002), whereas the 30 day mortality was 28.8% versus 13.3% (p = 0.003). The incidence of sepsis at 30 days was 19% in the high risk group versus 3.3% at the low risk group (p = 0.001) CONCLUSION: Percutaneous biliary interventions in the UK are safe and effective. Scoring systems such as the Karnofsky or the modified Karnofsky score hold promise in allowing us to identify high risk groups that will need more careful consideration and enhanced patient informed consent but further research with larger studies is warranted in order to identify their true impact on patient selection and outcomes post biliary interventions.

BACKGROUND Liver tumors with dual differentiations [combined hepatocellular carcinoma (HCC) and cholangiocarcinoma] are common. However, liver tumors that exhibit hepatocellular, biliary, and neuroendocrine differentiation are exceedingly rare, with only three previous case reports in the literature. CASE SUMMARY A 65-year-old female with a previous history of hepatitis C and a distant history of low grade, well-differentiated rectal neuroendocrine tumor was found to have two liver lesions in segment 4 and segment 7 on imaging. Serum alpha-fetoprotein and chromogranin A were elevated. Biopsy of the larger lesion in segment 4 revealed a high-grade tumor, with morphologic and immunohistochemical features of a neuroendocrine tumor. Given the previous history of rectal neuroendocrine tumor, imaging investigation, serologic markers, and biopsy findings, metastatic neuroendocrine tumor was considered. Subsequent regional resection of these hepatic lesions revealed the segment 4 lesion to be a HCC with additional biliary and neuroendocrine differentiation and the segment 7 lesion to be a cholangiocarcinoma with neuroendocrine differentiation. Follow-up of the patient revealed disease recurrence in the dome of the liver and metastasis in retro-pancreatic lymph nodes. The patient eventually expired due to complications of chemotherapy. CONCLUSION HCC cases with additional biliary and neuroendocrine differentiation are exceedingly rare, posing a diagnostic challenge for clinicians and pathologists.

The synchronous presentation of multifocal pancreatobiliary tumors is a rare occurrence and can prove to be a significant diagnostic and therapeutic challenge. We describe the case of a 70-year-old female who presented with a 2-week history of jaundice, reduced appetite, and mild epigastric discomfort of insidious onset. Radiological evaluation with computed tomography and magnetic resonance imaging demonstrated features consistent with a hilar cholangiocarcinoma , also known as a Klatskin tumor, involving both the cystic duct and gallbladder neck. In addition to this, a pancreatic neoplasm with associated splenic vein occlusion and metastatic deposits in the liver and lung were identified. The patient was managed with percutaneous transhepatic external biliary drainage and stenting by interventional radiology. Cytology results from the brushings obtained from the aforementioned procedure were nondiagnostic. Core biopsies were performed of the pancreatic lesion; the histopathological results of which were in keeping with pancreatic ductal adenocarcinoma . The patient was scheduled for chemotherapy however unfortunately deteriorated clinically prior to commencement. This case highlights the diagnostic and management challenges of synchronous pancreatobiliary malignancies.

Biliary ascariasis is a rare disease in a non-endemic area. However, it is one of the possible etiological factors for retarded growth as well as malnutrition in children. It may cause intestinal obstruction, appendicitis, biliary obstruction, liver abscess, hepatolithiasis, and pancreatitis in adults. Herein, we report a patient with ascending cholangitis secondary to biliary ascariasis who was successfully managed with Endoscopic Retrograde Cholangio Pancreaticography.

BACKGROUND: Hepatopancreatoduodenectomy (HPD) is an aggressive operation for treatment of advanced bile duct and gallbladder cancer associated with high perioperative morbidity and mortality, and uncertain oncological benefit in terms of survival. Few reports on HPD from Western centers exist. The purpose of this study was to evaluate safety and efficacy for HPD in European centers.METHOD: Members of the European-African HepatoPancreatoBiliary Association were invited to report all consecutive patients operated with HPD for bile duct or gallbladder cancer between January 2003 and January 2018. The patient and tumor characteristics, perioperative and survival outcomes were analyzed.RESULTS: In total, 66 patients from 19 European centers were included in the analysis. 90-day mortality rate was 17% and 13% for bile duct and gallbladder cancer respectively. All factors predictive of perioperative mortality were patient and disease-specific. The three-year overall survival excluding 90-day mortality was 80% for bile duct and 30% for gallbladder cancer (P = 0.013). In multivariable analysis R0-resection had a significant impact on overall survival.CONCLUSION: HPD, although being associated with substantial perioperative mortality, can offer a survival benefit in patient subgroups with bile duct cancer and gallbladder cancer. To achieve negative resection margins is paramount for an improved survival outcome.

Gallstone-related disease can have significant associated morbidity and mortality worldwide. The incidence of gallstone-related disease in the Western world is on the increase. There are multiple different pathological manifestations of gallstone disease: the presentation, diagnosis and associated complications of which vary significantly depending on anatomical location. The role of imaging in gallstone-related disease is broad with radiology playing an essential role in the diagnosis, management and follow-up of gallstone-related pathologies. This paper distills the broad range of gallstone-related pathologies into an anatomical map, discussing the disease processes involved at each point along the biliary tree and reviewing the strengths and weaknesses of different imaging modalities for each distinct disease process.

Systemic sclerosis (SSc) is a chronic systemic disease of unknown etiology characterized by vasculopathy, excessive accumulation of extracellular matrix, and fibrosis of the skin and other internal organs. Although its etiology remains elusive, approximately one third of SSc patients presents with additional autoimmune disease, which suggests that an autoimmune mechanism is a major component of the underlying pathophysiology. On the other hand, primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are two main autoimmune liver diseases. A 41-year-old female previously diagnosed with PBC/AIH overlap syndrome presented with multiple, painful brownish to erythematous firm patches on the hands, arms, axillae, neck, abdomen, and thighs. Laboratory work-up yielded positive results for anti-nuclear antibody, anti-Ro/Sjogren's-syndrome-related antigen A autoantibodies, and perinuclear anti-neutrophil cytoplasmic antibodies while punch biopsy of her left hand showed characteristics that are consistent with scleroderma. Herein, we report the first case of a patient with diffuse cutaneous SSc and concurrent PBC/AIH overlap syndrome and suggest that this coexistence of multiple autoimmune diseases is not a coincidence but rather that a common autoimmune pathogenesis may exist.

Introduction Intertumor and intratumor heterogeneity may explain the diagnostic challenge and limited efficacy of chemotherapy for primary sclerosing cholangitis-associated cholangiocarcinoma (PSC-CCA). In this study, tumor heterogeneity was assessed through p53 and p16 protein expression analysis and next-generation sequencing (NGS) of TP53 and CDKN2A genetic alterations in PSC-associated CCA. Methods Formalin-fixed paraffin-embedded tissue samples from resection material of patients with PSC-CCA or patients with PSC diagnosed with biliary dysplasia were selected. Sections with CCA and foci with dysplastic epithelium were identified by 2 independent gastrointestinal pathologists. Immunohistochemical evaluation of p53 and p16 protein expression and NGS of TP53 and CDKN2A genetic alterations were performed. Results A total of 49 CCA and 21 dysplasia samples were identified in the resection specimens of 26 patients. P53 protein expression showed loss of expression, wild type, and overexpression in 14%, 63%, and 23% CCA and in 19%, 62%, and 19% dysplasia samples, respectively. P16 protein expression showed negative, heterogeneous, and positive results in 31%, 57%, and 12% CCA and in 33%, 53%, and 14% dysplasia samples, respectively. NGS showed high intertumor and intratumor heterogeneity of TP53 mutations and CDKN2A loss. Nearly 70% of the samples with a TP53 missense mutation demonstrated p53 overexpression, whereas all samples with a TP53 nonsense mutation demonstrated loss of p53 protein expression. Discussion PSC-associated CCA is characterized by high intertumor and intratumor heterogeneity of both p53/p16 protein expression and genetic alterations in TP53/CDKN2A, indicating that these tumors consist of multiple subclones with substantially different genetic makeup. The high intertumor and intratumor heterogeneity in PSC-CCA should be acknowledged during the development of diagnostic and therapeutic strategies.

Gastroduodenal artery (GDA) pseudoaneurysms are rare clinical entities that typically develop in the setting of chronic inflammation of the pancreas, although idiopathic pseudoaneurysms can occur. Although GDA pseudoaneurysms carry the risk of rupture with resultant hemorrhage, they seldom are reported to cause biliary obstruction. We report a unique case of biliary obstruction secondary to extrinsic compression of the bile duct by a GDA pseudoaneurysm successfully managed by nonoperative means.

We have recently introduced multiple reaction monitoring (MRM) mass spectrometry as a novel tool for glycan biomarker research and discovery. Herein, we employ this technique to characterize the site-specific glycan alterations associated with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Glycopeptides associated with disease severity were also identified. Multinomial regression modelling was employed to construct and validate multi-analyte diagnostic models capable of accurately distinguishing PBC, PSC, and healthy controls from one another (AUC=0.93±0.03). Finally, to investigate how disease-relevant environmental factors can influence glycosylation, we characterized the ability of bile acids known to be differentially expressed in PBC to alter glycosylation. We hypothesize that this could be a mechanism by which altered self-antigens are generated and become targets for immune attack. This work demonstrates the utility of the MRM method to identify diagnostic site-specific glycan classifiers capable of distinguishing even related autoimmune diseases from one another.

ATP-binding cassette, sub-family B member 11 (ABCB11) is an efflux transporter for bile acids on the liver canalicular membrane. The expression of this transporter is reduced in cholestasis; however, the mechanisms contributing to this reduction are unclear. In this study, we sought to determine whether miR-199a-5p contributes to the depletion of ABCB11/Abcb11 in cholestasis in mice. In a microRNA (miRNA) screen of mouse liver after common bile duct ligation (CBDL), we found that miR-199a-5p was significantly upregulated by approximately 4-fold. In silico analysis predicted that miR-199a-5p would target the 3'-untranslated region (3'-UTR) of ABCB11/Abcb11 mRNA. The expression of ABCB11-3'-UTR luciferase construct in Huh-7 cells was markedly inhibited by cotransfection of a miRNA-199a-5p mimic, which was reversed by a miRNA-199a-5p mimic inhibitor. We also show treatment of mice after CBDL with the potent nuclear receptor FXR agonist obeticholic acid (OCA) significantly increased Abcb11 mRNA and protein and decreased miR-199a-5p expression. Computational mapping revealed a well-conserved FXR-binding site (FXRE) in the promoter of the gene encoding miR-199a-5, termed miR199a-2. Electromobility shift, chromatin immunoprecipitation, and miR199a-2 promoter-luciferase assays confirmed that this binding site was functional. Finally, CBDL in mice led to depletion of nuclear repressor NcoR1 binding at the miR199a-2 promoter, which facilitates transcription of miR199a-2. In CBDL mice treated with OCA, NcoR1 recruitment to the miR199a-2 FXRE was maintained at levels found in sham operated mice. In conclusion, we demonstrate that miR-199a-5p is involved in regulating ABCB11/Abcb11 expression, is aberrantly upregulated in obstructive cholestasis, and is downregulated by the FXR agonist obeticholic acid.

Post Endoscopic Retrograde Cholangiopancreatography (ERCP) pancreatitis is one of the most serious complications of ERCP. Our study aims to investigate the risk, predisposing factors and prognosis of pancreatitis after ERCP in elderly patients. Patients referred to the ERCP unit between April 2008 and 2012 and admitted to the hospital at least 1 day after the ERCP procedure were included to the study. Information including patient’s demographics, diagnosis, imaging findings, biochemical analysis, details of the ERCP procedure and complications were recorded. The severity of post ERCP pancreatitis (PEP) was determined by revised Atlanta Criteria as well as APACHE II and Ranson scores. A total of 2902 ERCP patients were evaluated and 988 were included to the study. Patients were divided into two groups as ≥ 65 years old (494 patients, 259 F, 235 M) and

PICO question In dogs with an uncomplicated gallbladder mucocele, is the long-term survival when surgically managed superior, inferior, or equal to those medically managed? Clinical bottom line Category of research question Treatment and prognosis The number and type of study designs reviewed Three papers were critically reviewed. All of the studies were retrospective analyses of medical records, two of which were cohort studies, and one which was a case control study Strength of evidence Weak Outcomes reported There is some evidence that surgical management of gallbladder mucoceles is associated with longer survival times than medically managed cases, although there is no direct analysis of uncomplicated vs complicated cases Conclusion We cannot clearly make a conclusion based on the available evidence. To date, there is only one retrospective analysis that directly compares the long-term survival of cases medically vs surgically managed, but this study does not separate uncomplicated vs complicated cases of gallbladder mucocele. In order to more accurately determine which type of treatment should be recommended for uncomplicated cases of gallbladder mucoceles, a prospective study comparing long-term survival with each treatment should be performed. These studies should also standardise medical management in order to more accurately compare survival time to surgical treatment How to apply this evidence in practice The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources. Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.

The altered anatomy of patients after Roux-en-Y gastric bypass (RYGB) surgery creates technical challenges for endoscopic and surgical treatment of gallstones. We present a unique case of a post-RYGB patient with complicated gallbladder surgery requiring coiling and embolization of the cystic duct for bile leak. The cystic duct coils migrated out into the bile duct forming a nidus for infection and biliary obstruction, which was resolved using the novel endoscopic ultrasound–directed transgastric routine endoscopic retrograde cholangiopancreatography technique, with successful transpapillary removal of cystic duct coils in RYGB anatomy.

Biliary varices (BVs) are an infrequent complication of chronic portal hypertension. Most cases of BVs are asymptomatic and are likely underdiagnosed. We present a case of a 34-year-old woman with Budd-Chiari syndrome who was found to have BVs caused by a significant inferior vena cava (IVC) stenosis. This case demonstrates that preprocedure imaging for variceal screening should be considered before biliary tract procedures to prevent complications.

Highlights • Incidental finding of primary gallbladder paraganglioma on routine laparoscopic cholecystectomy. • Finding of gallbladder paraganglioma in setting of biliary colic. • Rarity of gallbladder paraganglioma. • Sufficient treatment of gallbladder paraganglioma with cholecystectomy., Introduction Paragangliomas are tumors arising from paraganglia of the autonomic nervous system. They are rare tumors and occurrence inside the gallbladder is exceptionally rare. Biliary paragangliomas are thought to be associated with the parasymphathetic fibers and are therefore non-functioning and benign. There are less than 10 cases reported in literature and majority are found incidentally upon cholecystectomy. There is no specific treatment for these tumors and resection is considered sufficient. Case presentation 63 year old female presented with recurrent bliary colic exacerbated by fatty food. She underwent imaging work up that was consistent with biliary dyskinesia. She underwent uneventful elective laparoscopic cholecystectomy and was doing well post-operatively. Pathology report was significant for chronic cholecystitis, no calculi, and a small focus of paraganglioma. Discussion Little is known about primary gallbladder paragangliomas. Due to the non-functioning nature of these tumors there are felt to be benign. We know the paraganglia of the gallbladder consists of both parasymphathetic and sympathetic fibers. The sympathetic paragangliomas tend to act similar to pheochromocytomas and thus have malignant potential. Conclusion We presented a case in which a primary gallbladder paraganglioma was identified incidentally in a patient who presented with symptomatic biliary dyskinesia. Due to the rarity of primary gallbladder paraganglioma and limited reported cases, optimal follow up remains unknown.

Background/Aims: Biliary strictures remain one of the most challenging aspects after living donor liver transplantation (LDLT). The aim of this study was to assess long-term out ­come of endoscopic treatment of biliary strictures occurring after LDLT and to identify risk factors of recurrent biliary stric­ tures following endoscopic retrograde biliary drainage (ERBD) in LDLT. Methods: A total of 1,106 patients underwent LDLT from May 1995 to May 2014. We compared the risk factors between patients with and without recurrent biliary strictures. Results: Biliary strictures developed in 24.0% of patients. Technical success rate of ERBD for biliary stricture after LDLT was 66.2% (145/219). Among 145 patients managed by endoscopic drainage, stricture resolution occurred in 69 with median duration of stent indwelling of 13.6 months (range, 0.5 to 67.3 months), and stricture recurrence was seen in 20 (21.3%) out of 94. The median recurrence-free duration after final endoscopic success was 13.1 months (range, 0.5 to 67.3 months). Older donor age (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03 to 1.17; p=0.004) and non-B, non-C liver cirrhosis (HR, 5.10; 95% CI, 1.10 to 25.00; p=0.043) were associated with higher recurrence of biliary stricture. Conclusions: Long-term stricture resolution rate after ERBD insertion for biliary stricture occurring after LDLT was 73.4%. Clinicians should pay careful attention during following-up to decide when to remove ERBD in patients who have factors associated with recurrent biliary strictures. (Gut Liver 2020;14:125-134)

Background & Aims The role of 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) in the diagnosis and staging of patients with biliary tract cancers (BTCs) remains controversial, so we aimed to provide robust information on the utility of 18FDG-PET in the diagnosis and management of BTC. Methods This systematic review and meta-analysis explored the diagnostic test accuracy of 18FDG-PET as a diagnostic tool for diagnosis of primary tumour, lymph node invasion, distant metastases and relapsed disease. Subgroup analysis by study quality and BTC subtype were performed. Changes in management based on 18FDG-PET and impact of maximum standardised uptake values (SUVmax) on prognosis were also assessed. A random effects model was used for meta-analyses. Results A total of 2,125 patients were included from 47 eligible studies. The sensitivity (Se) and specificity (Sp) of 18FDG-PET for the diagnosis of primary tumour were 91.7% (95% CI 89.8–93.2) and 51.3% (95% CI 46.4–56.2), respectively, with an area under the curve (AUC) of 0.8668. For lymph node invasion, Se was 88.4% (95% CI82.6–92.8) and Sp was 69.1% (95% CI 63.8–74.1); AUC 0.8519. For distant metastases, Se was 85.4% (95% CI 79.5–90.2) and Sp was 89.7% (95% CI86.0–92.7); AUC 0.9253. For relapse, Se was 90.1% (95% CI 84.4–94.3) and Sp was 83.5% (95% CI 74.4–90.4); AUC 0.9592. No diagnostic threshold effect was identified. Meta-regression did not identify significant sources of heterogeneity. Sensitivity analysis revealed no change in results when analyses were limited to studies with low risk of bias/concern. The pooled proportion of change in management was 15% (95% CI 11–20); the majority (78%) due to disease upstaging. Baseline high SUVmax was associated with worse survival (pooled hazard ratio of 1.79; 95% CI 1.37–2.33; p Conclusions There is evidence to support the incorporation of 18FDG-PET into the current standard of care for the staging (lymph node and distant metastases) and identification of relapse in patients with BTC to guide treatment selection; especially if the identification of occult sites of disease would change management, or if diagnosis of relapse remains unclear following standard of care imaging. The role for diagnosis of the primary tumour remains controversial due to low sensitivity and 18FDG-PET should not be considered as a replacement for pathological confirmation in this setting. Lay summary A positron emission tomography (PET scan), using 18F-fluorodeoxyglucose (18FDG), can help doctors identify areas of cancer in the body by highlighting "hot spots". These hotspots may be cancerous (true positive) but may also be non-cancerous, like inflammation (false positive). We show that PET scans are useful to assess how far advanced the cancer is (by assessing spread to lymph glands and to other organs) and also to identify if the cancer has recurred (for example after surgery), thus helping doctors to make treatment decisions. However, a biopsy is still needed for the initial diagnosis of a biliary tract cancer, because of the high chance of a "false positive" with PET scans.

Background and Aim The two most common etiologies of acute pancreatitis (AP) are alcohol and gallstone. Whether etiology contributes to the outcome in patients with AP is an unresolved issue, more so in the severe form of the disease. The aim is to study the effects of the etiological factors of alcohol and gallstone on the disease course and the role of etiology in the subgroup of severe AP. Methods Consecutive patients of AP with alcohol or gallstone etiology were included. Various severity parameters and various outcome measures, such as need for organ support, intensive care, surgical or radiological intervention, hospital stay, and mortality, were evaluated between the two groups. Results Of the 759 patients, alcoholic pancreatitis was seen in 368 (48.5%), while gallstone disease was observed in 246 (32.4%). Gallstone pancreatitis occurred in older age (P

Highlights • Left side gallbladder is more often discovered intraoperatively. • A lot of anatomical variations are described. • The three-dimensional reconstruction can better highlight intra and extraparenchimal anatomy. • The knowledge of this anomaly could be useful both in cholecystectomy technique and liver resection., Introduction Left sided gallbladder is a rare congenital abnormality more often discovered as incidental finding during laparoscopic cholecystectomy requiring surgical challenge to prevent complication. We present a case of a true left sided gallbladder treated with laparoscopic cholecystectomy. Case A 90 y/o woman with acute abdominal pain was hospitalised and underwent a laparoscopic cholecystectomy. A preoperative CT scan didn't show the variation. Intraoperative finding revealed a true left sided gallbladder that was carefully dissected at the Calot's triangle with identification of the cystic duct and artery. After a complete separation of the gallbladder from the liver, the cystic duct and the artery were safely clipped and transected. CT scan reconstruction reveal agenesis of the right superior sector with simultaneous absence of the right biliary duct. Discussion True left sided gallbladder is defined as one attached in the left of the ligamentum teres and falciform ligament. This abnormality predispose to a numerous anatomical variation. Unfortunately its finding is more often incidentally during intervention and recognition of such variation could be difficult that can be of high risk for surgical injury. Conclusion Left sided gallbladder presents a significant challenge to the surgeon and makes it even more difficult to avoid postoperative complications. Therefore, a careful dissection of Calot’s triangle and the complete mobilisation of the gallbladder should be done before clipping the cystic duct and artery. However, if a preoperative finding suggests a left sided gallbladder, then an in-depth preoperative anatomical study is advocated.

Published histologic studies of the hilar plate or entire biliary remnant at the time of Kasai portoenterostomy (KHPE) have not provided deep insight into the pathogenesis of biliary atresia, relation to age at surgery, prognosis or the basis for successful drainage. We report detailed histologic findings in 172 centrally reviewed biliary remnants with an average of 6 sections per subject. Active lesions were classified as either necroinflammatory (rare/clustered in a few subjects) or active concentric fibroplasia with or without inflammation (common). Inactive lesions showed bland replacement by collagen and fibrous cords with little or no inflammation. Heterogeneity was common within a given remnant; however, relatively homogenous histologic patterns, defined as 3 or more inactive or active levels in the hepatic ducts levels, characterized most remnants. Homogeneity did not correlate with age at KHPE, presence/absence of congenital anomalies at laparotomy indicative of heterotaxy and outcome. Remnants from youngest subjects were more likely than older subjects to be homogenously inactive suggesting significantly earlier onset in the youngest subset. Conversely remnants from the oldest subjects were often homogenously active suggesting later onset or slower progression. More data are needed in remnants from subjects

Cholangiocarcinoma (CCC) is the second most common primary malignancy of the liver and is typically diagnosed at advanced disease stages. Among curative treatment options for CCC, radical surgical resection with extrahepatic bile duct resection, hepatectomy, and en-bloc lymphadenectomy are considered the mainstay of curative therapy. The assessment of the functional liver reserve by dynamic liver function tests and the estimation of the remaining future liver volume (future liver remnant, FLR) are of paramount importance. The introduction of novel interventional and surgical techniques, such as portal vein embolization, associating liver partition, and portal vein ligation for staged hepatectomy (ALPPS), have enabled clinicians to achieve resectability even in patients previously deemed unresectable. Radiofrequency ablation (RFA) shows acceptable results in small intrahepatic cholangiocarcinoma (IHCC) in liver cirrhosis and should be evaluated if cirrhosis precludes surgical treatment. Transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) alone or in combination with systemic therapy may be applied in cases of surgical irresectability. According to recent results of the British BILCAP trial, adjuvant therapy may be considered after surgical resection in curative intent.

Gallbladder volvulus is a rarely reported and diagnosed condition. We present a case of an elderly female with right lower quadrant pain mimicking acute appendicitis without conclusive imaging; however, due to worsening serological laboratory findings and sepsis picture, an exploratory laparotomy was performed. A necrotic gallbladder was removed, diagnosing gallbladder volvulus. A systemic literature review showed the difficulty in making a diagnosis and the uniqueness of our patient presentation. A high level of clinical suspicion for gallbladder volvulus must be maintained and should be included in the differential diagnosis in elderly women with an acute abdomen, as complications can be severe.

INTRODUCTION: This study investigated the risk of depression in Korean adults who underwent cholecystectomy and appeared for subsequent long-term follow-ups. A national population-based data set was used for analysis. METHODS: All patients (n = 111,934) aged 40 years and older who underwent cholecystectomy between 2010 and 2015 and a control population (n = 223,868), matched for age and sex, were identified from the database of the Korean National Health Insurance Corporation. The hazard ratio (HR) and 95% confidence interval (CI) of depression were estimated after cholecystectomy, and a Cox regression analysis was performed. RESULTS: The incidence of depression in the cholecystectomy group was 27.3 per 1,000 person-years and that in the control group was 20.3 per 1,000 person-years. Patients who underwent cholecystectomy showed an increased risk of major depressive disorder (MDD) with an adjusted HR (aHR) of 1.34 (95% CI: 1.31–1.37, P < 0.001). The mean follow-up period after a 1-year lag was 3.67 ± 1.79 years. In the subgroup analysis, the risk of developing MDD after cholecystectomy was relatively high in patients aged 40–49 years (aHR 1.51, 95% CI: 1.44–1.58) and in participants without diabetes mellitus (aHR: 1.36, 95% CI: 1.33–1.39), hypertension (aHR: 1.38, 95% CI: 1.34–1.42), or dyslipidemia (aHR: 1.35, 95% CI: 1.32–1.38). DISCUSSION: Compared with the control population, patients who underwent cholecystectomy exhibited an increased incidence of MDD. Thus, physicians should implement an enhanced program of MDD screening for at least several years after cholecystectomy.

Immune-related adverse events (irAEs) of immune checkpoint inhibitors can potentially affect every organ system, are sometimes challenging, and require a multidisciplinary approach. Most common irAEs are very well characterized, but some other such rare autoimmune liver diseases are probably underdiagnosed and less explored. We present here the case of a 69-year-old man with metastatic melanoma developing a severe primary biliary cirrhosis under pembrolizumab, and of a 52-year-old woman with metastatic melanoma with granulomatous hepatitis in the context of an immune-related multiorgan inflammatory reaction due to ipilimumab and nivolumab. Both cases were in part steroid refractory and required a complex diagnostic assessment and long-term therapeutic management. The liver biopsy was crucial for ensuring a correct diagnosis. Clinicians should be aware of rare liver diseases in the context of increased liver enzymes under immune checkpoint inhibitors, especially if not responding to corticosteroids. The primary diagnostic workup should localize the liver damage (biliary or parenchymal) and distinguish irAEs from other pathologic conditions such as metastasis, second benign and malignant tumors, viral hepatitis, and cholelithiasis. If in doubt, a liver biopsy should be performed. Early diagnosis and accurate assessment of hepatic adverse events is necessary for prompt and effective treatment, with reduction of inappropriate discontinuation of immunotherapy, morbidity, and mortality.

Hemangioma of the gallbladder is rare, with less than 10 cases reported in the literature. It may represent a hamartomatous proliferation of connective tissue in the gallbladder or may be congenital in origin. Although liver hemangiomas rarely present with spontaneous rupture, it has not been documented in gallbladder hemangiomas. This report presents a case of gallbladder hemangioma that ruptured spontaneously and presented with hemoperitoneum.

Background & aims Liver fibrosis holds a relevant prognostic meaning in primary biliary cholangitis (PBC). Non-invasive fibrosis evaluation using vibration-controlled transient elastography (VCTE) is routinely performed. However, there is limited evidence on its accuracy at diagnosis in PBC. We aimed to estimate the diagnostic accuracy of VCTE in assessing advanced fibrosis at disease presentation in PBC. Approach & results We collected data from 167 consecutive treatment-naive PBC patients who underwent liver biopsy(LB) at diagnosis at six Italian centers. VCTE examinations were completed within 12 weeks of LB. Biopsies were scored by two blinded expert pathologists, according to Ludwig system. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves(AUROCs) for advanced fibrosis (Ludwig stage≥III). The effects of biochemical and clinical parameters on liver stiffness measurement (LSM) were appraised. Derivation cohort consisted of 126 patients with valid LSM and LB, VCTE identified patients with advanced fibrosis with AUROC of 0.89. LSM cut-offs ≤6.5kPa and >11.0kPa enabled to exclude and confirm, respectively, advanced fibrosis (negative predictive value[NPV]=0.94, positive predictive value[PPV]=0.89, error rate=5.6%). These values were externally validated in an independent cohort of 91 PBC patients(NPV=0.93, PPV=0.89, error rate=8.6%). Multivariable analysis found the only parameter affecting LSM was fibrosis stage. No association was found with BMI and liver biochemistry. Conclusions In a multicenter study of treatment-naive PBC patients, we identified two cut-offs (LSM≤6.5kPa and>11.0kPa) able to discriminate at diagnosis the presence or the absence, respectively, of advanced fibrosis in PBC patients, with external validation. In patients with LSM between these two cut-offs, VCTE is not reliable and liver biopsy should be evaluated for accurate disease staging. BMI and liver biochemistry did not affect LSMs.

[BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC., 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28.

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Background: Treatment of cholangitis complicating choledocholithiasis includes biliary sphincterotomy and stone extraction. In certain cases of elderly comorbid patients with high risk for definitive endoscopic treatment, biliary stenting is the only measure for relieving biliary obstruction. Aim: We aimed to report the safety of retained biliary stone. Methods: a multi-center, retrospective case-control study conducted at two Israeli medical centers from January 2013 to December 2018 including all patients 18 years of age or older who underwent ERCP and biliary stent insertion for the treatment of acute cholangitis due to choledocholithiasis. Results: Three-hundred and eight patients were identified. Eighty-three patients had retained long-term biliary stents of more than 6 months (group A) from insertion compared to 225 patients whose biliary stents were removed within a 6-month period (group B). The mean follow-up in group A was 66.1&plusmn, 16.3 vs. 11.1 &plusmn, 2.7 weeks in group B. Overall complications during the follow-up were similar between groups A and B (6% vs. 4.9%, OR 1.24, Chi square 0.69). Similarly, the rate of each complication alone was not different when comparing group A to group B (3.6%, 1.2% and 1.2% vs. 2.7%, 0.44% and 1.8%) for cholangitis, stent related pancreatitis and biliary colic, respectively (Chi square 0.85). Even after 12 months, the rates of overall complications and each complication alone were not higher compared to less than 12 months (Chi square 0.72 and 0.8, respectively). Conclusion: endoscopic biliary stenting for cholangitis complicating choledocholithiasis is safe for the long-term period without increase in stent related complications.

Sump syndrome is a rare complication of choledochoenterotomy. Patients with sump syndrome often have abdominal pain, recurrent cholangitis, pancreatitis, malabsorption, fever, an abnormal liver function test, and, rarely, hepatic abscess. Roux-en-Y choledochojejunostomy or hepaticojejunostomy has been advocated to prevent sump syndrome. We report an 80-year-old man who presented with a hepatic abscess secondary to sump syndrome 26 years after a Roux-en-Y choledochojejunostomy for recurrent cholangitis. Sump syndrome should be considered for patients who underwent biliary diversion surgery, regardless of the type of procedure or time from surgery.

Percutaneous transhepatic cholangiodrainage is an intervention for obstructive jaundice that, although effective in decreasing bilirubin levels, often leads to depletion of regular bile acids that subsequently cause malabsorption, diarrhea, and acute kidney injury. Bile reinfusion (BR) is a method of enteral refeeding of biliary secretions to replenish innate bile acids to the patient. In addition, BR is a low-cost alternative to exogenous bile acid replacement and abates the need for inpatient fluid resuscitation. We report oral BR in a patient with percutaneous transhepatic cholangiodrainage due to choledocholithiasis and review the literature on BR.

Acute choledocholithiasis results when stones form in the gallbladder and then pass into the common bile duct, where they may become lodged and cause obstruction. To our knowledge, very few cases are reported in which multiple imaging techniques had failed to detect the presence of gallstones, as per current literature review. We report a case of a 73-year-old woman with nausea, vomiting, and jaundice who was found to have choledocholithiasis with negative imaging on abdominal ultrasound (US), CT, and magnetic resonance cholangiopancreatography (MRCP).

Isolated gallbladder tuberculosis is a rare entity, even in endemic zones. Preoperative diagnosis is usually not possible, with most of the cases being diagnosed either as cholecystitis or malignancy. Histopathological examination of the resected specimen clinches the diagnosis. We present a middle-aged man with obstructive jaundice who was diagnosed to have gallbladder malignancy clinically and radiologically and on microscopy, and was diagnosed as gallbladder tuberculosis with the involvement of the common bile duct.

A 29-year-old woman with developmental delay presented with 2.5 weeks of jaundice of the skin with accompanying microcytic anemia (hemoglobin 6.8 g/dL, mean corpuscular volume 70.5 fL), elevated liver enzymes (aspartate aminotransferase 77 U/L, alanine aminotransferase 95 U/L, alkaline phosphatase 362 U/L), total bilirubin (9.5 mg/dL; 4.4 mg/dL direct), lipase (325 U/L), and cancer antigen 19-9 (68 U/mL). The patient had no prior gastrointestinal or liver disease. CT of the chest/abdomen/pelvis found a large lobulated non-fully obstructing mass in the second and third part of the duodenum, with endoscopic biopsies yielding an invasive, well-differentiated adenocarcinoma positive for cytoplasmic-stained cells to antibody to beta-human chorionic gonadotropin (hCG) antigen, suggesting a duodenal choriocarcinoma. Treatment included biliary drainage with a percutaneous transhepatic catheter and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy, but a repeat CT scan five months later revealed an increase in tumor size and invasion; the patient died shortly thereafter. Beta-hCG-secreting choriocarcinomas are rare, rapidly growing, highly invasive malignant tumors and are uncommonly present at extragonadal sites.

Here, we report a case of coexistence of a duplicate gallbladder and choledochal cyst, which was overlooked preoperatively and confirmed via intraoperative inspection and pathological examination. We concluded that a high index of suspicion is required to diagnose a double gallbladder, and special attention should be paid to preoperative radiological imaging when treating patients with choledochal cysts because these patients present a higher incidence of biliary anomalies.

Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC were identified from the Netherlands Cancer Registry. Patients were grouped according to time period (2005–2009/2010–2016) and disease stage. Trends in treatment and overall survival (OS) were analyzed. In total 1834 patients were included: 661 (36%) patients with resected, 278 (15%) with non-resected non-metastatic, and 895 (49%) with metastatic GBC. Use of radical versus simple cholecystectomy (12% vs. 26%, p < 0.001) in early (pT1b/T2) GBC increased. More patients with metastatic GBC received chemotherapy (11% vs. 29%, p < 0.001). OS improved from 4.8 months (2005–2009) to 6.1 months (2010–2016) (p = 0.012). Median OS increased over time (2005–2009 vs. 2010–2016) in resected (19.4 to 26.8 months, p = 0.038) and metastatic (2.3 vs. 3.4 months, p = 0.001) GBC but not in unresected, non-metastatic GBC. In early GBC, patients with radical cholecystectomy had a median OS of 76.7 compared to 18.4 months for simple cholecystectomy (p < 0.001). Palliative chemotherapy showed superior (p < 0.001) survival in metastatic (7.3 versus 2.1 months) and non-resected non-metastatic (7.7 versus 3.5 months) GBC. In conclusion, survival of GBC remains poor. Radical surgery and palliative chemotherapy appear to improve prognosis but remain under-utilized.

Gallstone ileus is a rare entity, and an obstructing gallstone in the left colon is even less frequent. A 78-year-old man was evaluated for abdominal distension and pain, associated with a lack of bowel movements in the past 5 days. An abdominal computed tomography showed a cholecystocolonic fistula associated with a gallstone in the descending colon. During the operation, the gallstone was retrieved through a longitudinal colotomy proximal to the impaction site, which was then closed.

Schwannomas are benign tumors which arise in the Schwann cells of the peripheral nerves. They develop anywhere in the human body but are less frequent found in the digestive tract. A 67-year-old female patient was referred to our tertiary HPB department with a asymptomatic mass of the gallbladder. Contrast‐enhanced computed tomography revealed a rather homogeneous, well-circumscribed, high-density ovoid mural mass. An open cholecystectomy was performed. A final diagnosis of schwannoma with degenerative atypia, so-called “ancient schwannoma”, was made. Clinical recovery and follow-up was uneventful, with no signs of recurrence.

Background & Aims: Total bilirubin is a predictor of survival in primary biliary cholangitis, with the main elevated component being direct bilirubin. The purpose of this post hoc analysis was to assess the efficacy and safety of obeticholic acid across quartiles of varying baseline levels of direct bilirubin in the phase 3, randomized, placebo-controlled Primary Biliary Cholangitis Obeticholic Acid International Study of Efficacy. Methods: This analysis assessed patients on the basis of their baseline direct bilirubin level (divided by quartile). Biochemistry and safety outcomes were evaluated within each quartile over time. Results: In the quartile with the highest baseline direct bilirubin (>5.47µmol/L), there was a significant reduction in both direct and total bilirubin at Month 12 compared with placebo. Least squares mean (standard error) change from baseline in direct bilirubin at Month 12 was 4.17 (1.42) µmol/L for placebo, −3.48 (1.63) µmol/L for obeticholic acid 5-10mg and −3.66 (1.51) µmol/L for obeticholic acid 10mg (P&nbsp

Background & Aims: Primary sclerosing cholangitis (PSC) is a rare, cholestatic liver disease with no currently approved therapies. Obeticholic acid (OCA) is a potent farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis. We investigated the efficacy and safety of OCA in patients with PSC. Methods: AESOP was a phase II, randomized, double-blind, placebo-controlled, dose-finding study. Eligible patients were 18 to 75 years of age with a diagnosis of PSC and serum alkaline phosphatase (ALP) ≥2× the upper limit of normal (ULN) and total bilirubin, Lay summary Primary sclerosing cholangitis (PSC) is a long-term disease that damages the bile ducts in the liver over time. In the AESOP clinical study in patients with PSC, obeticholic acid reduced serum alkaline phosphatase (a potential marker of disease severity) during an initial 24-week treatment period. The result was sustained during the 2-year, long-term extension of the study. The most common side effect of obeticholic acid in the study was itchy skin, which is consistent with earlier clinical studies., Graphical Abstract

Background: Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).Methods: Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 mu M for 48 h. PI3K pathway activation was assessed through protein kinase B (Akt) phosphorylation and antifibrotic efficacy was determined via a spectrum of fibrosis markers at the transcriptional and translational level.Results: During incubation of PCTS the PI3K pathway was activated and incubation with omipalisib prevented Akt phosphorylation (IC50 = 20 and 1.5 nM for mouse and human, respectively). Viability of mouse and human liver PCTS was compromised only at the high concentration of 10 and 1-5 mu M, respectively. However, viability of jejunum PCTS decreased with 0.1 (mouse) and 0.01 mu M (human). Spontaneously increased fibrosis related genes and proteins were significantly and similarly suppressed in mouse and in human liver PCTS.Conclusions: Omipalisib has antifibrotic properties in ex vivo mouse and human liver PCTS, but higher concentrations showed toxicity in jejunum PCTS. While the PI3K/mTOR pathway appears to be a promising target for the treatment of liver fibrosis, PCTS revealed likely side effects in the intestine at higher doses.

Background: Intracholecystic papillary–tubular neoplasm (ICPN) is a relatively new entity which includes neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm. This study is done to evaluate the pathological features of ICPN and to find out the factors associated with invasion. Materials and Methods: This is a 5-year retrospective study in a referral pathology center. A total of 19 cases of ICPN are found. The cases are analyzed for age and sex distribution, clinical suspicion, stages, histological architecture, differentiation, and grade of dysplasia. Descriptive statistics and test of significance by Chi-square and t-test are used in the study. Results: ICPN comprises 23.5% of all gallbladder neoplasms. Two-thirds of the cases were suspected radiologically. Age range is 26–65 years with mean age of 50 years. They are 2.8 times more common in female. Approximately one-third of the cases show invasion. The most common histological pattern is papillary, followed by papillary–tubular and finally by tubular pattern. Pyloric and biliary are the most common differentiation pattern followed by oncocytic and intestinal pattern. About three-fourths of the cases are associated with high-grade dysplasia mostly diffuse high-grade dysplasia. Conclusion: We have found the younger age of presentation, less proportion of invasive tumors, fewer tumors with biliary phenotypes, and fewer tumors with high-grade dysplasia as compared to previous studies. Factors significantly associated with invasion are grade and extent of dysplasia particularly diffuse high-grade dysplasia.

Eosinophilic cholangitis (EC) is an uncommon, benign, self-limiting disease, which typically causes bile duct stricture with eosinophil infiltration. We report the case of a 70-year-old woman who presented with abdominal pain diagnosed with EC after treatment for eosinophilic esophagitis. All previous reported cases of EC had bile duct stricture seen on magnetic resonance cholangiopancreatography or cholangiogram during endoscopic retrograde cholangiopancreatography, but only wall thickness of the common bile duct was noted in our case. Although rare, EC should be considered when wall thickening of the bile duct is observed, even without stricture.

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney for renal elimination. Many common drugs are organic anions. The major liver uptake transporters for organic anion drugs are organic anion transporter polypeptides (OATP1B1 or SLCO1B1, OATP1B3 or SLCO1B3), whereas in the kidney they are organic anion transporters (OAT1 or SLC22A6, OAT3 or SLC22A8). Since these particular OATPs are overwhelmingly found in the liver but not the kidney, and these OATs are overwhelmingly found in the kidney but not liver, it is possible to use chemoinformatics, machine learning (ML) and deep learning to analyze liver OATP-transported drugs versus kidney OAT-transported drugs. Our analysis of &gt, 30 quantitative physicochemical properties of OATP- and OAT-interacting drugs revealed eight properties that in combination, indicate a high propensity for interaction with “liver” transporters versus “kidney” ones based on machine learning (e.g., random forest, k-nearest neighbors) and deep-learning classification algorithms. Liver OATPs preferred drugs with greater hydrophobicity, higher complexity, and more ringed structures whereas kidney OATs preferred more polar drugs with more carboxyl groups. The results provide a strong molecular basis for tissue-specific targeting strategies, understanding drug–drug interactions as well as drug–metabolite interactions, and suggest a strategy for how drugs with comparable efficacy might be chosen in chronic liver or kidney disease (CKD) to minimize toxicity.

Background Acute pancreatitis (AP) is a significant cause of acute abdominal pain, morbidity and hospitalisation. There was previously a dearth of studies exploring the incidence, risk factors and outcome of AP in the Caribbean region. Materials and methods All patients with a diagnosis of AP admitted to the University Hospital of the West Indies (UHWI) between 2006 and 2012 were reviewed. The epidemiological profile, risk factors, clinical presentation and outcomes of patients with AP were retrospectively studied. Results There were 70 females and 21 males with a median age of 44 years (range 2–86). The median age of males was significantly higher than that of females (p = 0.041). The incidence of AP was 74 per 100,000 admissions per year. Vomiting and abdominal tenderness were noted in the majority of patients. The most common aetiology was biliary disease (71.4%), idiopathic (12%), post-ERCP (6.6%) and alcohol (5.5%). Alcoholic pancreatitis was only seen in males whereas idiopathic and post-ERCP pancreatitis only occurred in females. The mean duration of hospitalisation was 9.51 ± 8.28 days. Disease severity was mild in 61.1%, moderately severe in 26.7%, and severe in 12.2% of patients. Factors associated with more severe disease included overweight/obesity, idiopathic aetiology and post-ERCP status. The case fatality rate was 2%. Conclusion The incidence of AP was 74/100,000 hospital admissions annually. There was an unusual female preponderance, with biliary pancreatitis being the most common type occurring at an equal frequency among males and females. Only 12.2% of the total cases seen were severe. The case fatality rate was 2%. Local health policy should target timely interventions for biliary pancreatitis and should also address the local factors affecting disease severity., Highlights • This is the first known epidemiological study on acute pancreatitis in the Caribbean and found a case fatality rate of 2%. • This is the first report of a female preponderance in acute pancreatitis. • Biliary pancreatitis was the predominant aetiology in both males and females. • Transfer status, overweight/obesity, idiopathic aetiology and post-ERCP status increased duration of hospitalisation. • Disease severity was mild in 61.1%, and severe in 12.2% of patients, with severe cases more likely to have an idiopathic aetiology, post-ERCP status and higher burden of overweight/obesity.

Background Bacterial cholecystitis often is diagnosed by combination of gallbladder ultrasound (US) findings and positive results of bile culture. The value of gallbladder US in determining the likelihood of bile bacterial infection in cats and dogs with suspected biliary disease is unknown. Hypothesis/Objectives To determine the value of gallbladder US in predicting bile bacterial culture results, identify most common bacterial isolates from bile, and describe complications after cholecystocentesis in cats and dogs with suspected hepatobiliary disease. Animals Cats (70) and dogs (202) that underwent an abdominal US and submission of bile for culture were included in the study. Methods A cross-sectional study design was used to determine the association of gallbladder US abnormalities and the results of bile cultures, and complications of cholecystocentesis. Results Abnormal gallbladder US had high sensitivity (96%) but low specificity (49%) in cats with positive and negative results of bile bacterial culture, respectively. Cats with normal gallbladder US findings were unlikely to have positive bile bacterial culture (negative predictive value of 96%). Gallbladder US had lower sensitivity (81%), specificity (31%), positive predictive value (20%), and negative predictive value (88%) in dogs. The most common bacterial isolates were of enteric origin, the prevalence being higher in cats. Incidence of complications after cholecystocentesis was 3.4%. Conclusions and clinical importance Gallbladder US has a high negative predictive value for bile culture results in cats. This modality is less predictive of infection in dogs. Percutaneous US-guided cholecystocentesis has a low complication rate.

AIM To investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD). METHODS We administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis. RESULTS This study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity. CONCLUSION The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.