Bile acids drive the newborn's gut microbiota maturation.

Following birth, the neonatal intestine is exposed to maternal and environmental bacteria that successively form a dense and highly dynamic intestinal microbiota. Whereas the effect of exogenous factors has been extensively investigated, endogenous, host-mediated mechanisms have remained largely unexplored. Concomitantly with microbial colonization, the liver undergoes functional transition from a hematopoietic organ to a central organ of metabolic regulation and immune surveillance. The aim of the present study was to analyze the influence of the developing hepatic function and liver metabolism on the early intestinal microbiota. Here, we report on the characterization of the colonization dynamics and liver metabolism in the murine gastrointestinal tract (n = 6-10 per age group) using metabolomic and microbial profiling in combination with multivariate analysis. We observed major age-dependent microbial and metabolic changes and identified bile acids as potent drivers of the early intestinal microbiota maturation. Consistently, oral administration of tauro-cholic acid or ß-tauro-murocholic acid to newborn mice (n = 7-14 per group) accelerated postnatal microbiota maturation.

Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors.

The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration.

Analysis of TNF-α and interleukin-6 in seroma of patients undergoing mastectomy with or without flap fixation: is there a predictive value for seroma formation and its sequelae?

BACKGROUND: Seroma formation is a common complication after mastectomy. Flap fixation has the potential to prevent seroma formation, but identifying patients that are at risk of developing seroma, remains challenging. The aim of this study was to assess the association between pro-inflammatory cytokines in seroma fluid one day after surgery and seroma formation and it sequelae. METHODS: Patients undergoing mastectomy were randomized into one of three groups: no flap fixation, flap fixation using sutures or flap fixation using tissue glue. Seroma samples from 40 consecutive patients undergoing mastectomy were collected on the first postoperative day for analysis of interleukin-6 and tumor necrosis factor-α. Seroma formation and its sequelae were assessed in the outpatient clinic ten days, six weeks and three months after surgery. RESULTS: TNF-α concentrations were not detectable in the seroma samples of any of the 40 patients. BMI (p = 0.001) and weight of the resected surgical specimen (p = 0.003) were associated with higher IL-6 levels in seroma on the first postoperative day after mastectomy. A higher seroma concentration of IL-6 was associated with significantly fewer patients with clinical seroma formation three months after surgery (p = 0.027). CONCLUSION: IL-6 is associated with clinical seroma formation three months after surgery. There is however no evident association between IL-6 and complications related to seroma formation. Higher IL-6 levels are predictive of less long-term seroma formation. Application of flap fixation does not seem to influence the level of IL-6.

Patient-derived organoid models help define personalized management of gastrointestinal cancer.

BACKGROUND: The prognosis of patients with different gastrointestinal cancers varies widely. Despite advances in treatment strategies, such as extensive resections and the addition of new drugs to chemotherapy regimens, conventional treatment strategies have failed to improve survival for many tumours. Although promising, the clinical application of molecularly guided personalized treatment has proven to be challenging. This narrative review focuses on the personalization of cancer therapy using patient-derived three-dimensional 'organoid' models. METHODS: A PubMed search was conducted to identify relevant articles. An overview of the literature and published protocols is presented, and the implications of these models for patients with cancer, surgeons and oncologists are explained. RESULTS: Organoid culture methods have been established for healthy and diseased tissues from oesophagus, stomach, intestine, pancreas, bile duct and liver. Because organoids can be generated with high efficiency and speed from fine-needle aspirations, biopsies or resection specimens, they can serve as a personal cancer model. Personalized treatment could become a more standard practice by using these cell cultures for extensive molecular diagnosis and drug screening. Drug sensitivity assays can give a clinically actionable sensitivity profile of a patient's tumour. However, the predictive capability of organoid drug screening has not been evaluated in prospective clinical trials. CONCLUSION: High-throughput drug screening on organoids, combined with next-generation sequencing, proteomic analysis and other state-of-the-art molecular diagnostic methods, can shape cancer treatment to become more effective with fewer side-effects.

Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases.

BACKGROUND: The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres. METHODS: PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001). CONCLUSION: An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.

Study protocol on the role of intestinal microbiota in colorectal cancer treatment: a pathway to personalized medicine 2.0.

PURPOSE: Investigate in patients with metastatic and/or irresectable colorectal cancer treated with systemic treatment with capecitabine or TAS-102 whether: 1. Intestinal microbiota composition can act as a predictor for response. 2. Intestinal microbiota composition changes during systemic treatment and its relation to chemotoxicity. BACKGROUND: Gut microbiota and host determinants evolve in symbiotic and dependent relationships resulting in a personal ecosystem. In vitro studies showed prolonged and increased response to 5-fluorouracil, a fluoropyrimidine, in the presence of a favorable microbiota composition. Capecitabine and TAS-102 are both fluoropyrimidines used for systemic treatment in colorectal cancer patients. METHODS: An explorative prospective multicenter cohort study in the Maastricht University Medical Centre+ and Zuyderland Medical Centre will be performed in 66 patients. Before, during, and after three cycles of systemic treatment with capecitabine or TAS-102, fecal samples and questionnaires (concerning compliance and chemotoxicity) will be collected. The response will be measured by CT/MRI using RECIST-criteria. Fecal microbiota composition will be analyzed with 16S rRNA next-generation sequencing. The absolute bacterial abundance will be assessed with quantitative polymerase chain reaction. Multivariate analysis will be used for statistical analysis. CONCLUSIONS: We aim to detect a microbiota composition that predicts if patients with metastatic and/or irresectable colorectal cancer will respond to systemic treatment and/or experience zero to limited chemotoxicity. If we are able to identify a favorable microbiota composition, fecal microbiota transplantation might be the low-burden alternative to chemotherapy switch in the future.

The influence of sarcopenia on survival and surgical complications in ovarian cancer patients undergoing primary debulking surgery.

BACKGROUND: Sarcopenia, severe skeletal muscle loss, has been identified as a prognostic factor in various malignancies. This study aims to investigate whether sarcopenia is associated with overall survival (OS) and surgical complications in patients with advanced ovarian cancer undergoing primary debulking surgery (PDS). METHODS: Ovarian cancer patients (n = 216) treated with PDS were enrolled retrospectively. Total skeletal muscle surface area was measured on axial computed tomography at the level of the third lumbar vertebra. Optimum stratification was used to find the optimal skeletal muscle index cut-off to define sarcopenia (≤38.73 cm2/m2). Cox-regression and Kaplan-Meier analysis were used to analyse the relationship between sarcopenia and OS. The effect of sarcopenia on the development of major surgical complications was studied with logistic regression. RESULTS: Kaplan-Meier analysis showed a significant survival disadvantage for patients with sarcopenia compared to patients without sarcopenia (p = 0.010). Sarcopenia univariably predicted OS (HR 1.536 (95% CI 1.105-2.134), p = 0.011) but was not significant in multivariable Cox-regression analysis (HR 1.362 (95% CI 0.968-1.916), p = 0.076). Significant predictors for OS in multivariable Cox-regression analysis were complete PDS, treatment in a specialised centre and the development of major complications. Sarcopenia was not predictive of major complications. CONCLUSION: Sarcopenia was not predictive of OS or major complications in ovarian cancer patients undergoing primary debulking surgery. However a strong trend towards a survival disadvantage for patients with sarcopenia was seen. Future prospective studies should focus on interventions to prevent or reverse sarcopenia and possibly increase ovarian cancer survival. Complete cytoreduction remains the strongest predictor of ovarian cancer survival.

Effect of obeticholic acid on liver regeneration following portal vein embolization in an experimental model.

BACKGROUND: The bile salt-activated transcription factor farnesoid X receptor (FXR) is a key mediator of proliferative bile salt signalling, which is assumed to play a role in the early phase of compensatory liver growth. The aim of this study was to evaluate the effect of a potent FXR agonist (obeticholic acid, OCA) on liver growth following portal vein embolization (PVE). METHODS: Rabbits were allocated to receive daily oral gavage with OCA (10 mg/kg) or vehicle (control group) starting 7 days before PVE (n = 18 per group), and continued until 7 days after PVE. PVE of the cranial liver lobes was performed using polyvinyl alcohol particles and coils on day 0. Caudal liver volume (CLV) was analysed by CT volumetry on days -7, -1, +3 and +7. Liver function was determined by measuring mebrofenin uptake using hepatobiliary scintigraphy. Additional parameters analysed were plasma aminotransferase levels, and histological scoring of haematoxylin and eosin- and Ki-67-stained liver sections. RESULTS: Three days after PVE of the cranial lobes, the increase in CLV was 2·2-fold greater in the OCA group than in controls (mean(s.d.) 56·1(20·3) versus 26·1(15·4) per cent respectively; P < 0·001). This increase remained greater 7 days after PVE (+1·5-fold; P = 0·020). The increase in caudal liver function at day +3 was greater in OCA-treated animals (+1·2-fold; P = 0·017). The number of Ki-67-positive hepatocytes was 1·6-fold higher in OCA-treated animals 3 days after PVE (P = 0·045). Plasma aminotransferase levels and histology did not differ significantly between groups. CONCLUSION: OCA accelerated liver regeneration after PVE in a rabbit model. OCA treatment might increase the efficacy of PVE and, thereby, resectability. Surgical relevance Liver failure is the most feared complication after liver surgery, with no effective treatment options. Liver regeneration is essential to avoid liver failure, and recently bile acid signalling was implicated in the initiation of liver regeneration through the nuclear bile acid receptor farnesoid X receptor (FXR). In this study, the potent FXR agonist obeticholic acid accelerated liver regeneration following portal vein embolization in a rabbit model, in terms of liver volume, liver function and proliferation. Obeticholic acid treatment could enhance the efficacy of portal vein embolization, thereby increasing resectability, and could reduce the interval to surgery. In addition, obeticholic acid might have a place in the prevention of liver failure after liver surgery.

Alternatives to antibiotics for prevention of surgical infection.

BACKGROUND: Surgical-site infection (SSI) is still the second most common healthcare-associated infection, after respiratory tract infection. SSIs are associated with higher morbidity and mortality rates, and result in enormous healthcare costs. In the past decade, several guidelines have been developed that aim to reduce the incidence of SSI. Unfortunately, there is no consensus amongst the guidelines, and some are already outdated. This review discusses the recent literature regarding alternatives to antibiotics for prevention of SSI. METHODS: A literature search of PubMed/MEDLINE was performed to retrieve data on the prevention of SSI. The focus was on literature published in the past decade. RESULTS: Prevention of SSI can be divided into preoperative, perioperative and postoperative measures. Preoperative measures consist of showering, surgical scrubbing and cleansing of the operation area with antiseptics. Perioperative factors can be subdivided as: environmental factors, such as surgical attire; patient-related factors, such as plasma glucose control; and surgical factors, such as the duration and invasiveness of surgery. Postoperative measures consist mainly of wound care. CONCLUSION: There is a general lack of evidence on the preventive effectiveness of perioperative measures to reduce the incidence of SSI. Most measures are based on common practice and perceived effectiveness. The lack of clinical evidence, together with the stability of the high incidence of SSI (10 per cent for colorectal procedures) in recent decades, highlights the need for future research.

Human splanchnic amino-acid metabolism.

Plasma levels of several amino acids are correlated with metabolic dysregulation in obesity and type 2 diabetes. To increase our understanding of human amino-acid metabolism, we aimed to determine splanchnic interorgan amino-acid handling. Twenty patients planned to undergo a pylorus preserving pancreatico-duodenectomy were included in this study. Blood was sampled from the portal vein, hepatic vein, superior mesenteric vein, inferior mesenteric vein, splenic vein, renal vein, and the radial artery during surgery. The difference between arterial and venous concentrations of 21 amino acids was determined using liquid chromatography as a measure of amino-acid metabolism across a given organ. Whereas glutamine was significantly taken up by the small intestine (121.0 ± 23.8 µmol/L; P < 0.0001), citrulline was released (-36.1 ± 4.6 µmol/L; P < 0.0001). This, however, was not seen for the colon. Interestingly, the liver showed a small, but a significant uptake of citrulline from the circulation (4.8 ± 1.6 µmol/L; P = 0.0138) next to many other amino acids. The kidneys showed a marked release of serine and alanine into the circulation (-58.0 ± 4.4 µmol/L and -61.8 ± 5.2 µmol/L, P < 0.0001), and a smaller, but statistically significant release of tyrosine (-12.0 ± 1.3 µmol/L, P < 0.0001). The spleen only released taurine (-9.6 ± 3.3 µmol/L; P = 0.0078). Simultaneous blood sampling in different veins provides unique qualitative and quantitative information on integrative amino-acid physiology, and reveals that the well-known intestinal glutamine-citrulline pathway appears to be functional in the small intestine but not in the colon.

Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome.

Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.

Sinusoidal obstruction syndrome (SOS): A light and electron microscopy study in human liver.

AIMS: Oxaliplatin is an important chemotherapeutic agent, used in the treatment of hepatic colorectal metastases, and known to induce the sinusoidal obstruction syndrome (SOS). Pathophysiological knowledge concerning SOS is based on a rat model. Therefore, the aim was to perform a comprehensive study of the features of human SOS, using both light microscopy (LM) and electron microscopy (EM). METHODS AND RESULTS: Included were all patients of whom wedge liver biopsies were collected during a partial hepatectomy for colorectal liver metastases, in a 4-year period. The wedge biopsy were perfusion fixated and processed for LM and EM. The SOS lesions were selected by LM and details were studied using EM. Material was available of 30 patients, of whom 28 patients received neo-adjuvant oxaliplatin. Eighteen (64%) of the 28 patients showed SOS lesions, based on microscopy. The lesions consisted of sinusoidal endothelial cell detachment from the space of Disse on EM. In the enlarged space of Disse a variable amount of erythrocytes were located. CONCLUSION: Sinusoidal endothelial cell detachment was present in human SOS, accompanied by enlargement of the space of Disse and erythrocytes in this area. These findings, originally described in a rat model, were now for the first time confirmed in human livers under clinically relevant settings.

Effects of postoperative morbidity on long-term outcome following surgery for colorectal liver metastases.

BACKGROUND: The impact of postoperative complications on long-term outcomes after surgery for colorectal liver metastases (CRLM) remains controversial. During the last decade, advances in surgical as well as non-surgical treatment have increased resectability and altered outcomes. We sought to determine the influence of postoperative morbidity on disease-free (DFS) and overall survival (OS). METHODS: All patients undergoing liver resection for CRLM for the first time between 2000 and 2011 were retrospectively identified from a prospective database. Postoperative morbidity was classified according to Dindo-Clavien grade. A Dindo-Clavien grade ≥ 3a was considered a major complication. Primary outcomes were DFS and OS depending on the presence or absence of postoperative morbidity. RESULTS: Of the 266 included patients, 97 patients (37 %) developed postoperative complications, of whom 61 (23 %) had major complications. Median DFS and OS (5-year) were 17 and 53 months (42 %). The occurrence of postoperative morbidity did not significantly shorten OS (p = 0.130) and DFS (p = 0.101). However, major morbidity reduced DFS significantly (p < 0.05). CONCLUSION: In the present study, the occurrence of major postoperative complications was associated with diminished DFS. However, the effect of (major) complications on OS did not reach statistical significance.

ESPEN endorsed recommendations. Definition and classification of intestinal failure in adults.

BACKGROUND & AIMS: Intestinal failure (IF) is not included in the list of PubMed Mesh terms, as failure is the term describing a state of non functioning of other organs, and as such is not well recognized. No scientific society has yet devised a formal definition and classification of IF. The European Society for Clinical Nutrition and Metabolism guideline committee endorsed its "home artificial nutrition and chronic IF" and "acute IF" special interest groups to write recommendations on these issues. METHODS: After a Medline Search, in December 2013, for "intestinal failure" and "review"[Publication Type], the project was developed using the Delphi round methodology. The final consensus was reached on March 2014, after 5 Delphi rounds and two live meetings. RESULTS: The recommendations comprise the definition of IF, a functional and a pathophysiological classification for both acute and chronic IF and a clinical classification of chronic IF. IF was defined as "the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth". CONCLUSIONS: This formal definition and classification of IF, will facilitate communication and cooperation among professionals in clinical practice, organization and management, and research.

Glutathione S-transferase M1-null genotype as risk factor for SOS in oxaliplatin-treated patients with metastatic colorectal cancer.

BACKGROUND: Oxaliplatin is used as a neo-adjuvant therapy in hepatic colorectal carcinoma metastasis. This treatment has significant side effects, as oxaliplatin is toxic to the sinusoidal endothelial cells and can induce sinusoidal obstruction syndrome (SOS), which is related to decreased overall survival. Glutathione has an important role in the defence system, catalysed by glutathione S-transferase (GST), including two non-enzyme producing polymorphisms (GSTM1-null and GSTT1-null). We hypothesise that patients with a non-enzyme producing polymorphism have a higher risk of developing toxic injury owing to oxaliplatin. METHODS: In the nontumour-bearing liver, the presence of SOS was studied histopathologically. The genotype was determined by a semi-nested PCR. RESULTS: Thirty-two of the 55 (58%) patients showed SOS lesions, consisting of 27% mild, 22% moderate and 9% severe lesions. The GSTM1-null genotype was present in 25 of the 55 (46%). Multivariate analysis showed that the GSTM1-null genotype significantly correlated with the presence of (moderate-severe) SOS (P=0.026). CONCLUSION: The GSTM1-null genotype is an independent risk factor for SOS. This finding allows us, in association with other risk factors, to conceive a potential risk profile predicting whether the patient is at risk of developing SOS, before starting oxaliplatin, and subsequently might result in adjustment of treatment.

The introduction of a laparoscopic liver surgery programme: a cost analysis of initial experience in a university hospital.

BACKGROUND AND AIMS: In the era of expanding costs of healthcare, this study was conducted to perform a cost analysis of introducing a laparoscopic liver surgery programme for left sided liver lesions. MATERIALS AND METHODS: Consecutive patients treated by laparoscopic liver resections of left lateral segments were included. Controls were a group of 14 patients undergoing open resection for similar pathology. Primary outcomes were costs. Secondary outcomes were complications, conversions, blood loss, length of operation, and length of hospital stay. RESULTS: The laparoscopic approach for hepatic left lateral resection (bisegmentectomy 2 and 3) was performed in fourteen patients (group I, median age 54 [range 26-82] years). In the open group, fourteen patients from a prospectively collected database with the same type of resection were selected (group II, median age 64 [range 29-76] years). Costs of theatre usage in the laparoscopic group were significantly lower (p=0.031). No significant differences in costs of disposable instruments, ward stay and total costs were observed between the two groups. There were three complications in the laparoscopic group compared with two complications in the open group. In the laparoscopic group there were 2 conversions (14%). Median blood loss was significantly lower in the laparoscopic group (50 mls [range 0-750], (p=0.001) versus the open group (500 mls [range 150-750]). Furthermore, operation time was also significantly lower in the laparoscopic group (116 [range 85-261] minutes) versus the open group (165 [range 96-217] minutes, p=0.016). Median length of stay was 6 [range 4-11] days in group I versus 6 [range 5-13] days in group II (p=0.508). CONCLUSION: Costs of laparoscopic liver resections proved to be equivalent to open surgery. Furthermore, implementation of a laparoscopic liver resection programme seems feasible and safe with reduced blood loss and operation time and comparable morbidity and length of stay.

Overnight glucose infusion suppresses renal ammoniagenesis and reduces hyperammonaemia induced by a simulated bleed in cirrhotic patients.

BACKGROUND: A simulated upper gastrointestinal (UGI) bleed in cirrhotic patients has been shown to induce hyperammonaemia. The kidney was the site of this exaggerated ammoniagenesis with alanine as substrate. Administration of alanine to decompensated cirrhotic patients did not change hepatic gluconeogenesis, but resulted in increased ammoniagenesis. We hypothesise that reduced hepatic glycogen stores result in hyperglucagonaemia which may drive increased renal gluconeogenesis and therefore alanine uptake and renal ammoniagenesis. AIM: To determine whether an overnight glucose infusion lowers renal ammoniagenesis by reducing hyperglucagonaemia and renal ammoniagenesis. METHODS: Patients with decompensated cirrhosis were studied in a cross-over design. An UGI bleed was simulated via intragastric administration of an amino acids mixture mimicking the haemoglobin molecule after a 12-h overnight fast (F-group) or after a 12-h treatment with 20% glucose solution (G-group). RESULTS: Before the simulated bleed the glucagon levels were 21 (15-31) pmol/L in the F-group and 15 (9-21) pmol/L in the G-group (P < 0.01). After the simulated bleed, arterial ammonia levels increased in both groups [F-group: 73-118 µmol/L (P = 0.01); G-group 64-87 µmol/L (P = 0.01)]. The enhancement of hyperammonaemia was significantly higher in the F-group (45 [19-71] µmol/L) compared with the G-group (23 [13-39] µmol/L) (P = 0.01). The difference in renal ammoniagenesis during the simulated bleed in the F-group was 399 (260-655) nmol/kg/bwt/min and was significantly higher than in the G-group 313 (1-498) nmol/kg/bwt/min (P = 0.05). CONCLUSIONS: Overnight glucose infusion results in reduced renal ammoniagenesis and attenuates ammonia levels. These observations have implications for the development of nutritional strategies in hyperammonaemic patients.

Coil migration--a rare complication of endovascular exclusion of visceral artery pseudoaneurysms and aneurysms.

INTRODUCTION: We describe a case of metallic, angiographic coil migration, following radiological exclusion of a gastroduodenal artery pseudoaneurysm secondary to chronic pancreatitis. PATIENTS AND METHODS: A 55-year-old man presented to the out-patient clinic with chronic, intermittent, post-prandial, abdominal pain, associated with nausea, vomiting and weight loss. He was known to have chronic pancreatitis and liver disease secondary to alcohol abuse and previously underwent angiographic exclusion of a gastroduodenal artery pseudoaneurysm. During subsequent radiological and endoscopic investigation, an endovascular coil was discovered in the gastric pylorus, associated with ulceration and cavitation. This patient was managed conservatively and enterally fed via naso-jejunal catheter endoscopically placed past the site of the migrated coil. This patient is currently awaiting biliary bypass surgery for chronic pancreatitis, and definitive coil removal will occur concurrently. CONCLUSIONS: Literature review reveals that this report is only the eighth to describe coil migration following embolisation of a visceral artery pseudoaneurysm or aneurysm. Endovascular embolisation of pseudoaneurysms and aneurysms is generally safe and effective. More common complications of visceral artery embolisation include rebleeding, pseudoaneurysm reformation and pancreatitis.

Review article: surgical, neo-adjuvant and adjuvant management strategies in biliary tract cancer.

BACKGROUND: The majority of patients with cholangiocarcinoma present with advanced, irresectable tumours associated with poor prognosis. The incidence and mortality rates associated with cholangiocarcinoma continue to rise, mandating the development of novel strategies for early detection, improved resection and treatment of residual lesions. AIM: To review the current evidence base for surgical, adjuvant and neo-adjuvant techniques in the management of cholangiocarcinoma. METHODS: A search strategy incorporating PubMed/Medline search engines and utilising the key words biliary tract carcinoma; cholangiocarcinoma; management; surgery; chemotherapy; radiotherapy; photodynamic therapy; and radiofrequency ablation, in various combinations, was employed. RESULTS: Data on neo-adjuvant and adjuvant techniques remain limited, and much of the literature concerns palliation of inoperable disease. The only opportunity for long-term survival remains surgical resection with negative pathological margins or liver transplantation, both of which remain possible in only a minority of selected patients. Neo-adjuvant and adjuvant techniques currently provide only limited success in improving survival. CONCLUSIONS: The development of novel strategies and treatment techniques is crucial. However, the shortage of randomised controlled trials is compounded by the low feasibility of conducting adequately powered trials in liver surgery, due to the large sample sizes that are required.