Nutritional care pathways in cancer patients with malignant bowel obstruction: A retrospective multi-centre study.

INTRODUCTION: Variation in access to parenteral nutrition (PN) in patients with intestinal failure secondary to malignant bowel obstruction (MBO) exists due to differing practice, beliefs and resource access. We aimed to examine differences in nutritional care pathways and outcomes, by referral to nutrition team for PN in patients with MBO. METHODS: This is a retrospective cohort study of MBO adults admitted to eight UK hospitals within a year and 1 year follow-up. Demographic, nutritional and medical data were analysed by comparing patients referred (R) or not referred (NR) for PN. Differences between groups were tested by Kruskal-Wallis, Chi-Squared tests and multi-level regression and survival using Cox regression. RESULTS: 232 patients with 347 MBO admissions [median 66yr, (IQR: 55-74yrs), 67 % female], 79/232 patients were referred for PN (R group). Underlying primary malignancies of gynaecological and gastrointestinal origin predominated (71 %) and 78 % with metastases. Those in the NR group were found to be older, weigh more on admission, and more likely to be treated conservatively compared to those in the R group. For 123 (35 %) admissions, patients were referred to a nutrition team, and for 204 (59 %) admissions, patients were reviewed by a dietician. Multi-disciplinary team discussion and dietetic contact were more likely to occur in the R group-123/347 admissions (R vs NR group: 27 % vs. 7 %, P = 0.001; 95 % vs 39 %, P < 0.0001). Median admission weight loss was 8 % (IQR: 0 to 14). 43/123 R group admissions received inpatient PN only, with 32 patients discharged or already established on home parenteral nutrition. Overall survival was 150 days (126-232) with no difference between R/NR groups. CONCLUSION: In this multi-centre study evaluating nutritional care management of patients with malignant bowel obstruction, only 1 in 3 admissions resulted in a referral to the nutrition team for PN, and just over half were reviewed by a dietician. Further prospective research is required to evaluate possible consequences of these differential care pathways on clinical outcomes and quality of life.

Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab.

Background: Sequential drug treatment with biological agents in ulcerative colitis (UC) is becoming increasingly complex. There are few studies comparing head-to-head outcomes in second-line treatments. The study assesses whether using anti-tumour necrosis factor (anti-TNF)-α therapy following the α4ß7 integrin blocker vedolizumab (VDZ) or VDZ after an anti-TNF has more favourable clinical outcomes in UC in a real-world outpatient setting. Methods: Patients with UC who were exposed to first-line anti-TNF (adalimumab or infliximab) or VDZ who subsequently switched to the alternate class between May 2013 and August 2020 were identified by reviewing patient databases at 10 hospitals. Data were collected retrospectively using patient records. Baseline demographics, disease activity indices, biochemical markers, endoscopic Mayo score, colectomy rates, treatment persistence and urgent hospital utilisation composite endpoint (UHUC) rates were examined over a 52-week period. Results: Second-line week 52 treatment persistence was higher in the VDZ group (71/81, 89%) versus the anti-TNF group (15/34, 44%; p=0.0001), as were week 52 colectomy-free survival (VDZ: 77/80, 96%, vs anti-TNF: 26/32, 81%; p=0.009), week 52 UHUC survival (VDZ: 68/84, 81%, vs anti-TNF: 20/34, 59%; p=0.002) and week 52 corticosteroid-free clinical remission (CFCR) rates (VDZ: 22/34, 65%, vs anti-TNF: 4/20, 20%; p=0.001). Conclusion: Compared with second-line anti TNF usage, the VDZ second-line cohort had significantly higher 52-week treatment persistence, UHUC survival, higher colectomy-free survival rates and higher week 52 CFCR. These data suggest that VDZ is an effective biologic in UC as a second-line therapy after anti-TNF exposure. It highlights the effect of biological order on clinically important outcomes.

Gastrointestinal consequences of cancer treatment: evaluation of 10 years' experience at a tertiary UK centre.

OBJECTIVE: Up to 90% of patients treated for pelvic cancers experience chronic gastrointestinal (GI) symptoms. This study characterises this patient cohort at a single centre, addressing a paucity of publications reporting 'real-world' experiences. METHOD: Outpatient referrals, from oncology to the gastroenterology and nutrition services, at a tertiary London hospital from 2006 to 2016, were retrospectively identified. Patient characteristics, reported symptoms, investigations, diagnoses, response to therapeutics and follow-up were recorded. RESULTS: Of 269 patients referred, 81% were within the latter 5 years. A total of 260 patients had diagnoses of pelvic cancers (prostatic (52%), cervical (19%) and endometrial (19%)). Among 247 treated with radiotherapy, the median time from radiotherapy to symptom onset was 8 months. Common symptoms were rectal bleeding (51%), diarrhoea (32%), faecal urgency (19%) and pain (19%). Patients underwent a median of three investigations including lower GI endoscopy (86%), thyroid function tests (33%) and glucose hydrogen breath test (30%). Diagnoses included radiation proctopathy (39%), colonic polyps (16%), pelvic floor dysfunction (12%), bile acid malabsorption (BAM) (8%), small intestinal bacterial overgrowth (SIBO) (8%), vitamin D deficiency (7%) and iron deficiency (7%). Among 164 discharged patients, the time to discharge was 7 months, after a median of two appointments. CONCLUSIONS: This unique patient group reports a complex mix of symptoms and requires specialist review and consideration of often uninvestigated diagnoses (pelvic dysfunction, BAM, SIBO and nutritional deficiencies). Such patients are often overlooked, compared with those suffering many other chronic GI disorders. Further reports from non-dedicated centres treating patients with pelvic radiation disease will aid in understanding of secondary GI diagnoses and variation in practice.

Home Parenteral Nutrition in Patients with Advanced Cancer: A Systematic Review and Meta-Analysis.

The use of home parenteral nutrition (HPN) in patients with incurable cancer remains controversial with significant variation worldwide. We aimed to systematically evaluate the literature from 1960 to 2018 examining the use of HPN in advanced cancer patients for all intestinal failure indications and assess the potential benefits/burdens of HPN in this cohort of patients. The primary end point was survival and secondary end points were quality of life and nutritional/performance status. Meta-analysis was performed with a random effects model, where suitable. Of 493 studies retrieved, 22 met the quality inclusion criteria. Studies were mainly conducted in Western countries (Italy, USA, Canada, Germany), including a total of 3564 patients (mean age 57.8 years). Mean duration for HPN was 5.0 mo. Mean overall survival was 7.3 mo. Patients with improved performance status survived for longer on HPN. Quality of life was sparsely reported though there was no observed negative impact of PN. HPN-related complications were reported in eight studies only and were mainly catheter-related blood stream infections. In conclusion, HPN is used for several indications in advanced cancer, though there is significant heterogeneity of results. Disparities in geographical distribution of the studies may reflect variation in accessing HPN.

Clinical and Nutritional Care Pathways of Patients with Malignant Bowel Obstruction: A Retrospective Analysis in a Tertiary UK Center.

We describe a retrospective cohort study of patients with malignant bowel obstruction to examine their nutritional care pathways between 1.1.16 and 31.12.16 with readmissions until 31.12.17. Data were analyzed by comparing patients who were referred (R) and not referred (NR) for PN. We identified 72 patients with 117 MBO admissions (mean ± SD age:63.1 ± 13.1yrs, 79% female). 24/72 patients were in R group. Predominant primary malignancies were gynaecological and lower-gastrointestinal cancers (76%). 83% patients had metastases (61% sub-diaphragmatically). All patients were at high-risk of malnutrition and baseline mean weight loss was 7%. Discussion of PN at multidisciplinary team meeting (MDT) (22% vs.5%, P = 0.02) and dietetic contact (94% vs. 41%, P < 0.0001) were more likely to occur in the R group. In 13/69 MBO admissions in NR group, reasons for non-referral were unclear. Median baseline and follow-up weight was similar (55-55.8 kg). Overall survival was 4.7 (1.4-15.2)months, with no differences by referral groups. We compared a sub-sample of patients who 'may have' required PN (n = 10) vs. those discharged on home PN (n = 10) and found greater survival in the HPN group (323vs.91 day, P < 0.01). Our findings highlight disparity in care pathways suggesting that nutritional care should be integrated into clinical management discussion(s) at MDT to ensure equal access to nutritional services.

Nutritional Status and Quality of Life in Hospitalised Cancer Patients Who Develop Intestinal Failure and Require Parenteral Nutrition: An Observational Study.

(1) Background: Malnutrition in cancer patients impacts quality of life (QoL) and performance status (PS). When oral/enteral nutrition is not possible and patients develop intestinal failure, parenteral nutrition (PN) is indicated. Our aim was to assess nutritional status, QoL, and PS in hospitalised cancer patients recently initiated on PN for intestinal failure. (2) Methods: The design was a cross-sectional observational study. The following information was captured: demographic, anthropometric, biochemical and medical information, as well as nutritional screening tool (NST), patient-generated subjective global assessment (PG-SGA), functional assessment of cancer therapy-general (FACT-G), and Karnofsky PS (KPS) data. (3) Results: Among 85 PN referrals, 30 oncology patients (56.2 years, 56.7% male) were identified. Mean weight (60.3 ± 16.6 kg) corresponded to normal body mass index values (21.0 ± 5.1 kg/m2). However, weight loss was significant in patients with gastrointestinal tumours (p < 0.01). A high malnutrition risk was present in 53.3-56.7% of patients, depending on the screening tool. Patients had impaired QoL (FACT-G: 26.6 ± 9.8) but PS indicated above average capability with independent daily activities (KPS: 60 ± 10). (4) Conclusions: Future research should assess the impact of impaired NS and QoL on clinical outcomes such as survival, with a view to encompassing nutritional and QoL assessment in the management pathway of this patient group.

Serum Scoring and Quantitative Magnetic Resonance Imaging in Intestinal Failure-Associated Liver Disease: A Feasibility Study.

(1) Background: Intestinal failure-associated liver disease (IFALD) in adults is characterized by steatosis with variable progression to fibrosis/cirrhosis. Reference standard liver biopsy is not feasible for all patients, but non-invasive serological and quantitative MRI markers for diagnosis/monitoring have not been previously validated. Here, we examine the potential of serum scores and feasibility of quantitative MRI used in non-IFALD liver diseases for the diagnosis of IFALD steatosis; (2) Methods: Clinical and biochemical parameters were used to calculate serum scores in patients on home parenteral nutrition (HPN) with/without IFALD steatosis. A sub-group underwent multiparameter quantitative MRI measurements of liver fat fraction, iron content, tissue T1, liver blood flow and small bowel motility; (3) Results: Compared to non-IFALD (n = 12), patients with IFALD steatosis (n = 8) demonstrated serum score elevations in Enhanced Liver Fibrosis (p = 0.032), Aspartate transaminase-to-Platelet Ratio Index (p < 0.001), Fibrosis-4 Index (p = 0.010), Forns Index (p = 0.001), Gamma-glutamyl transferase-to-Platelet Ratio Index (p = 0.002) and Fibrosis Index (p = 0.001). Quantitative MRI scanning was feasible in all 10 sub-group patients. Median liver fat fraction was higher in IFALD steatosis patients (10.9% vs 2.1%, p = 0.032); other parameter differences were non-significant; (4) Conclusion: Serum scores used for non-IFALD liver diseases may be useful in IFALD steatosis. Multiparameter MRI is feasible in patients on HPN.

Adipose tissue imaging as nutritional predictors in patients undergoing enterocutaneous fistula repair.

OBJECTIVES: The management of enterocutaneous fistulae (ECF) is complex, challenging, and often associated with metabolic, septic, and nutritional complications. Radiographic quantification of body composition such as fat or lean body mass distribution is a potentially valuable preoperative assessment tool to optimize nutritional status. The aim of this study was to investigate the correlation between total adipose tissue (fat) area (TFA), assessed by computed tomography and magnetic resonance imaging radiology tests, with body weight, body mass index (BMI), various biochemical parameters, need for nutritional support, and survival in patients undergoing ECF repair. METHODS: Biochemical and anthropometric parameters at the time of ECF surgery were retrospectively collected for adult patients undergoing ECF repair at University College London Hospital, UK. Visceral and subcutaneous adiposity was measured at the level of the third lumbar vertebra (Image J) at computed tomography or magnetic resonance imaging. Statistical analysis included descriptives, univariate and multivariate analysis between TFA and various parameters, and their influence on postoperative survival. RESULTS: A complete set of data was available for 85 patients (51 women, 56.9 ± 14.5 y of age) who underwent ECF repair. ECF originated mainly as a surgical complication (86%) while 14% were undergoing a second ECF repair. Median BMI was 22.8 kg/m2 and mean TFA was 361 ± 174.9 cm2, with a higher visceral fat content in men than in women (183.8 ± 99.2 versus 99 ± 59.7 cm2, P < 0.001). BMI, body weight, and creatinine were significantly positively correlated with TFA (ρ = 0.77, 0.73, and 0.50, respectively, P < 0.001); no correlation was noted between TFA and preoperative albumin levels. Patients in the low TFA group had a higher use of parenteral nutrition (P = 0.049). Hospital length of stay was longer in patients receiving artificial nutrition support (70 versus 22 d, P < 0.001). A TFA cutoff point of 290 cm2 discriminated patients who required artificial nutrition versus no nutritional support with moderate sensitivity (75%) but poor specificity (45%). At multivariate analysis, only >60 y of age (hazard ratio [HR], 2.69, P < 0.02) and use of parenteral nutrition (HR, 3.90, P < 0.02) were associated with worse overall survival. CONCLUSION: Abdominal adiposity was strongly correlated with anthropometric parameters at the time of surgery. Earlier identification of patients requiring artificial nutrition at standard preoperative imaging might allow integration of nutritional optimization into initial clinical management plans reducing length of stay and improving clinical outcomes.

When is parenteral nutrition indicated in the hospitalized, acutely ill patient?

PURPOSE OF REVIEW: The current review discusses current practices regarding appropriate indications for parenteral nutrition in acutely ill hospitalized patients. We address-specific indications for parenteral nutrition in the perioperative period, and in inflammatory bowel disease, oncology, hepatobiliary, critical care and end-stage renal disease patients. RECENT FINDINGS: Acutely ill hospitalized patients can develop intestinal failure requiring parenteral nutrition. Recent studies have provided insight into the main indications. The most common indications for inpatient parenteral nutrition include postsurgical complications, including prolonged ileus, sepsis, fistula and leaks, and bowel obstruction, predominantly malignant. Severe or complicated inflammatory bowel disease and cancer treatment-related mucosal enteropathies (mucositis, enterocolitis, gut graft-versus-host disease) are the next commonest indications. Less frequent indications are primary motility disorders and inability to secure enteral access for enteral nutrition. Gastrointestinal failure of the intensive care patient is a separate entity resulting from multiple mechanisms, including an enteropathy and dysmotility. SUMMARY: Despite the wider availability of nutrition support teams, use of parenteral nutrition is not without risk. The risks and benefits of parenteral nutrition in the acute setting need to be carefully considered even when it is indicated.

Enteral Nutrition in Adult Crohn's Disease: Toward a Paradigm Shift.

Medical and surgical treatments for Crohn's disease are associated with toxic effects. Medical therapy aims for mucosal healing and is achievable with biologics, immunosuppressive therapy, and specialised enteral nutrition, but not with corticosteroids. Sustained remission remains a therapeutic challenge. Enteral nutrition, containing macro- and micro-nutrients, is nutritionally complete, and is provided in powder or liquid form. Enteral nutrition is a low-risk and minimally invasive therapy. It is well-established and recommended as first line induction therapy in paediatric Crohn's disease with remission rates of up to 80%. Other than in Japan, enteral nutrition is not routinely used in the adult population among Western countries, mainly due to unpalatable formulations which lead to poor compliance. This study aims to offer a comprehensive review of available enteral nutrition formulations and the literature supporting the use and mechanisms of action of enteral nutrition in adult Crohn's disease patients, in order to support clinicians in real world decision-making when offering/accepting treatment. The mechanisms of actions of enteral feed, including their impact on the gut microbiome, were explored. Barriers to the use of enteral nutrition, such as compliance and the route of administration, were considered. All available enteral preparations have been comprehensively described as a practical guide for clinical use. Likewise, guidelines are reported and discussed.

Needs-based quality of life in adults dependent on home parenteral nutrition.

BACKGROUND & AIMS: Home parenteral nutrition (HPN) provides life sustaining treatment for people with chronic intestinal failure. Individuals may require HPN for months or years and are dependent on regular intravenous infusions, usually 12-14 h overnight between 1 and 7 days each week. This regime can have adverse impact on the life of people dependent on the treatment. The aim of this study was to establish mean values for the Parenteral Nutrition Impact Questionnaire (PNIQ) and to determine the effect of disease, frequency of infusions per week and patient characteristics on quality of life of patients fed HPN. METHOD: The PNIQ was distributed to patients across nine UK HPN clinics. Data were analysed using linear regression, with PNIQ score as the dependent variable and potential confounders as independent variables. Unadjusted and adjusted models are presented. Higher PNIQ scores reflect poorer quality of life. RESULTS: Completed questionnaires were received from 466 people dependent on HPN. Mean PNIQ score was 11.04 (SD 5.79). A higher PNIQ score (effect size 0.52, CI 0.184 to 0.853) was recorded in those dependent on a higher frequency of HPN infusions per week. Respondents with cancer had a similar mean PNIQ score to those with inflammatory bowel disease (mean 10.82, SD 6.00 versus 11.04, SD 5.91). Those with surgical complications reported a poorer QoL (effect size 3.03, CI 0.642 to 5.418) and those with severe gastro-intestinal dysmotility reported a better QoL (effect size -3.03, CI -5.593 to -0.468), compared to other disease states. CONCLUSIONS: This large cohort study of quality of life in chronic intestinal failure demonstrates that HPN impacts individuals differently depending on their underlying disease. Furthermore, since the number of HPN infusions required per week is inversely related to an individual's needs-based quality of life, therapies that reduce PN burden should lead to an improvement in QoL.

Current Practices in Ileal Pouch Surveillance for Patients With Ulcerative Colitis: A Multinational, Retrospective Cohort Study.

BACKGROUND AND AIMS: There are no universally accepted guidelines regarding surveillance of ulcerative colitis [UC] patients after restorative proctocolectomy and ileal pouch-anal anastomosis [IPAA]. There also exists a lack of validated quality assurance standards for performing pouchoscopy. To better understand IPAA surveillance practices in the face of this clinical equipoise, we carried out a retrospective cohort study at five inflammatory bowel disease [IBD] referral centres. METHODS: Records of patients who underwent IPAA for UC or IBD unclassified [IBDU] were reviewed, and patients with <1-year follow-up after restoration of intestinal continuity were excluded. Criteria for determining the risk of pouch dysplasia formation were collected as well as the use of pouchoscopy, biopsies, and completeness of reports. RESULTS: We included 272 patients. Median duration of pouch follow-up was 10.5 [3.3-23.6] years; 95/272 [35%] had never undergone pouchoscopy for any indication; 191/272 [70%] had never undergone pouchoscopy with surveillance as the specific indication; and 3/26 [12%] high-risk patients had never undergone pouchoscopy. Two cases of adenocarcinoma were identified, occurring in the rectal cuff of low-risk patients. Patients under the care of surgeons appeared more likely to undergo surveillance, but rates of incomplete reporting were higher among surgeons [78%] than gastroenterologists [54%, p = 0.002]. CONCLUSIONS: We observed wide variation in surveillance of UC/IBDU-IPAA patients. In addition, the rate of neoplasia formation among 'low-risk' patients was higher than may have been expected. We therefore concur with previous recommendations that pouchoscopy be performed at 1 year postoperatively, to refine risk-stratification based on clinical factors alone. Reports should document findings in all regions of the pouch and biopsies should be taken.

The Microbiome and Radiation Induced-Bowel Injury: Evidence for Potential Mechanistic Role in Disease Pathogenesis.

Radiotherapy has played a major role in both the curative and palliative treatment of cancer patients for decades. However, its toxic effect to the surrounding normal healthy tissue remains a major drawback. In cases of intra-abdominal and/or pelvic malignancy, healthy bowel is inevitably included in the radiation field, causing undesirable consequences that subsequently manifest as radiation-induced bowel injury, which is associated with significant morbidity and mortality. The pathophysiology of radiation-induced bowel injury is poorly understood, although we now know that it derives from a complex interplay of epithelial injury and alterations in the enteric immune, nervous, and vascular systems in genetically predisposed individuals. Furthermore, evidence supporting a pivotal role for the gut microbiota in the development of radiation-induced bowel injury has been growing. In this review, we aim to appraise our current understanding of radiation-induced bowel injury and the role of the microbiome in its pathogenesis as well as prevention and treatment. Greater understanding of the relationship between the disease mechanism of radiation-induced bowel injury and gut microbiome might shed light on potential future prevention and treatment strategies through the modification of a patient's gut microbiome.

Performance Status, Prognostic Scoring, and Parenteral Nutrition Requirements Predict Survival in Patients with Advanced Cancer Receiving Home Parenteral Nutrition.

We describe a cohort of Home Parenteral Nutrition (HPN) patients with advanced cancer in order to identify factors affecting prognosis. Demographic, anthropometric, biochemical and medical factors, Karnofsky Performance Status (KPS), Glasgow Prognostic Score (GPS), and PN requirements were recorded. Univariate and multivariate analyses were performed including Kaplan-Meier curves, Cox Regression, and correlation analyses. In total, 107 HPN patients (68 women, 39 men, mean age 57 yr) with advanced cancer were identified. The main indications for HPN were bowel obstruction (74.3%) and high output ostomies (14.3%). Cancer cachexia was present in 87.1% of patients. The hazard ratio (HR) for upper gastrointestinal and "other" cancers vs. gynaecological malignancy was 1.75 (p = 0.077) and 2.11 (p = 0.05), respectively. KPS score, GPS, PN volume, and PN potassium levels significantly predicted survival (HRKPS ≥50 vs <50 = 0.47; HRGPS = 2 vs. GPS = 0 = 3.19). In multivariate analysis, KPS and GPS remained significant predictors (p < 0.05), whilst PN volume reached borderline significance (p = 0.094). Survival was not significantly affected by the presence of metastatic disease, previous or concurrent surgery, chemo-radiotherapy, or indication for HPN (p > 0.05). Most patients passed away in their homes or hospice (77.9%). Performance status, prognostic scoring, and PN requirements may predict survival in patients with advanced cancer receiving HPN.

Incidence and Severity of Prepouch Ileitis: A Distinct Disease Entity or a Manifestation of Refractory Pouchitis?

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is the operation of choice for patients with treatment-refractory ulcerative colitis. However, after this intervention, up to 50% of patients develop pouchitis. Moreover, a subgroup will also develop inflammation in the afferent ileum proximal to the pouch, a condition named prepouch ileitis (PI). METHODS: Data on 546 patients who underwent ileal pouch-anal anastomosis for ulcerative colitis were retrospectively collected from 3 tertiary inflammatory bowel disease referral centers in the Netherlands, Belgium, and England. PI was considered present if there was endoscopic and histological inflammation in the afferent limb proximal to the pouch. Crohn's disease was excluded by reviewing the histology of colectomy resection specimens. RESULTS: PI was present in 33/546 (6%) patients and all of these had concurrent pouchitis. One hundred forty-four (26%) patients had pouchitis without PI and 369 (68%) patients did not have inflammatory pouch disease. Of the 33 patients with PI, 6 (18%) received no specific treatment, 9 (27%) responded to antibiotics, and 18 (54%) required escalation in therapy to steroids/immunomodulators or anti-tumor necrosis factor agents. Potent immunosuppressive treatment was required more frequently in patients with PI than those with pouchitis alone. CONCLUSIONS: PI is less common and more treatment refractory than pouchitis alone. Once PI is diagnosed, clinicians should be aware that response to antibiotic therapy is less likely than in pouchitis alone. Immunomodulatory therapy and escalation to anti-tumor necrosis factor agents should be considered early in cases of nonresponse. The suggestion that PI represents misdiagnosed Crohn's disease could not be substantiated in our cohort.

Shotgun cholanomics of ileal fluid.

In this study we have developed a rapid method for the shotgun analysis of bile acids in intestinal fluid. The method is semi-quantitative, and requires little sample preparation. Bile salts might contribute to the pathogenesis of Crohn's disease. In a pilot study we demonstrate the method by analysing the bile acid content of ileal fluid from seven Crohn's disease patients and three healthy controls. The dominant bile acids observed were di and/or trihydroxycholanoates, di- and/or trihydroxycholanoylglycines, di- and/or tri-hydroxycholanoyltaurines, monosulphated dihydroxycholanoates and monosulphated dihydroxycholanoylglycine. The method can be similarly applied to samples derived from other parts of the intestine.

Lipidomic profiling in Crohn's disease: abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition.

Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition.

Defective tumor necrosis factor release from Crohn's disease macrophages in response to Toll-like receptor activation: relationship to phenotype and genome-wide association susceptibility loci.

BACKGROUND: Recent work provides evidence of a failure of acute inflammation in Crohn's disease (CD), and suggests that the primary defect operates at the level of the macrophage and cytokine release. Here we extend the characterization of the innate immune defect in CD by investigating the macrophage response to Toll-like receptor (TLR) agonists and assess potential links between genome-wide association study (GWAS) susceptibility loci, disease phenotype, and therapeutic regimens on tumor necrosis factor α (TNF) release. METHODS: Peripheral blood-derived macrophages were cultured from control subjects and patients with CD, stimulated with TLR ligands, and the release of TNF measured. Genomic DNA was purified from blood and genotyped for 34 single nucleotide polymorphisms (SNPs) identified as being associated with CD by GWAS. RESULTS: All stimuli resulted in a reduction (32%-48%) in TNF release from macrophages derived from CD patients (n = 28-101) compared to those from healthy control (HC) subjects. All phenotypes demonstrated impaired TNF release, with the greatest defect in patients with colonic disease. There was no detectable relationship between the level of TNF released and the presence of GWAS susceptibility loci in CD patients. Reduced TNF levels were not influenced by age, gender, or use of aminosalicylate (5-ASA) medication. CONCLUSIONS: This study supports the hypothesis of defective proinflammatory cytokine secretion and an innate immunodeficiency in CD. Abnormal TNF secretion is evident downstream of multiple TLRs, affects all disease phenotypes, and is unrelated to 34 polymorphisms associated with CD by GWAS.

G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction.

Glucose-6-phosphatase, an enzyme localized in the endoplasmic reticulum (ER), catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate. In humans, there are three differentially expressed glucose-6-phosphatase catabolic genes (G6PC1-3). Recently, it has been shown that mutations in the G6PC3 gene result in a syndrome associating congenital neutropenia and various organ malformations. The enzymatic function of G6PC3 is dependent on G6P transport into the ER, mediated by G6P translocase (G6PT). Mutations in the gene encoding G6PT result in glycogen storage disease type-1b (GSD-1b). Interestingly, GSD-1b patients exhibit a similar neutrophil dysfunction to that observed in G6PC3-deficient patients. To better understand the causes of neutrophil dysfunction in both diseases, we have studied the neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase of patients with G6PC3 and G6PT syndromes. Unexpectedly, sodium dodecyl sulfate-polyacrylamide gel electrophoresis experiments indicated hypo-glycosylation of gp91(phox), the electron-transporting component of the NADPH oxidase, in all of these patients. Rigorous mass spectrometric glycomic profiling showed that most of the complex-type antennae which characterize the neutrophil N-glycome of healthy individuals were severely truncated in the patients' neutrophils. A comparable truncation of the core 2 antenna of the O-glycans was also observed. This aberrant neutrophil glycosylation is predicted to have profound effects on the neutrophil function and merit designation of both syndromes as a new class of congenital disorders of glycosylation.

Survival following Treatment of Aortoesophageal Fistula with Dual Esophageal and Aortic Intervention.

Aortoesophageal fistulas are a rare but commonly fatal complication of esophageal cancer. Reports of successfully managed cases are few, with high mortality and morbidity usually resulting from failure to control the initial massive haemodynamic insult. We report the case of a 47-year-old Caucasian man with recently diagnosed advanced esophageal cancer who suffered an episode of massive haematemesis. Emergency gastroscopy revealed an arterial bleeding point in the proximal esophagus. A self-expanding metal esophageal stent was placed to achieve initial partial haemostasis. CT angiography confirmed an aortoesophageal fistula. An endoluminal stent device was thus inserted within the thoracic aorta stabilising the bleeding point. The patient subsequently made an uneventful recovery and was discharged on long-term antibiotics for palliative care. He survived for 2 months at home before dying of disseminated malignancy. The successful use of esophageal stenting as a means of achieving haemostasis, allowing time for endovascular intervention, is as yet a relatively unexplored area of management of this rare condition.