Inhibition of TLR7 and TLR9 Reduces Human Cholangiocarcinoma Cell Proliferation and Tumor Development.

BACKGROUND: Toll-like receptors (TLRs) are key players in innate immunity and modulation of TLR signaling has been demonstrated to profoundly affect proliferation and growth in different types of cancer. However, the role of TLRs in human intrahepatic cholangiocarcinoma (ICC) pathogenesis remains largely unexplored. AIMS: We set out to determine if TLRs play any role in ICCs which could potentially make them useful treatment targets. METHODS: Tissue microarrays containing samples from 9 human ICCs and normal livers were examined immunohistochemically for TLR4, TLR7, and TLR9 expression. Proliferation of human ICC cell line HuCCT1 was measured by MTS assay following treatment with CpG-ODN (TLR9 agonist), imiquimod (TLR7 agonist), chloroquine (TLR7 and TLR9 inhibitor) and IRS-954 (TLR7 and TLR9 antagonist). The in vivo effects of CQ and IRS-954 on tumor development were also examined in a NOD-SCID mouse xenograft model of human ICC. RESULTS: TLR4 was expressed in all normal human bile duct epithelium but absent in the majority (60%) of ICCs. TLR7 and TLR9 were expressed in 80% of human ICCs. However, TLR7 was absent in all cases of normal human bile duct epithelium and only one was TLR9 positive. HuCCT1 cell proliferation in vitro significantly increased following IMQ or CpG-ODN treatment (P < 0.03 and P < 0.002, respectively) but decreased with CQ (P < 0.02). In the mouse xenograft model there was significant reduction in size of tumors from CQ and IRS-954 treated mice compared to untreated controls. CONCLUSION: TLR7 and TLR9 should be further explored for their potential as actionable targets in the treatment of ICC.

Effect of intermittent or continuous feeding and amino acid concentration on urea-to-creatinine ratio in critical illness.

BACKGROUND: We sought to determine whether peaks in essential amino acid (EAA) concentration associated with intermittent feeding may provide anabolic advantages when compared with continuous feeding regimens in critical care. METHODS: We performed a secondary analysis of data from a multicenter trial of UK intensive care patients randomly assigned to intermittent or continuous feeding. A linear mixed-effects model was developed to assess differences in urea-creatinine ratio (raised values of which can be a marker of muscle wasting) between arms. To investigate metabolic phenotypes, we performed k-means urea-to-creatinine ratio trajectory clustering. Amino acid concentrations were also modeled against urea-to-creatinine ratio from day 1 to day 7. The main outcome measure was serum urea-to-creatinine ratio (millimole per millimole) from day 0 to the end of the 10-day study period. RESULTS: Urea-to-creatinine ratio trajectory differed between feeding regimens (coefficient -.245; P = .002). Patients receiving intermittent feeding demonstrated a flatter urea-to-creatinine ratio trajectory. With k-means analysis, the cluster with the largest proportion of continuously fed patients demonstrated the steepest rise in urea-to-creatinine ratio. Neither protein intake per se nor serum concentrations of EAA concentrations were correlated with urea-to-creatinine ratio (coefficient = .088 [P = .506] and coefficient <.001 [P = .122], respectively). CONCLUSION: Intermittent feeding can mitigate the rise in urea-to-creatinine ratio otherwise seen in those continuously fed, suggesting that catabolism may have been, to some degree, prevented.

Gut microbiota and metabolic aspects of cancer cachexia.

Cancer cachexia is a metabolic syndrome characterized by unintended weight loss and muscle wasting. It has a strong negative impact on survival. Its underlying mechanisms involve systemic inflammation and insulin resistance, which are known to be influenced by the gut microbiota. Preclinical studies support a role for the gut microbiota in cancer cachexia by demonstrating that cachectic mice display: 1) various gut microbiota composition changes; 2) increased gut permeability and translocation of pro-inflammatory microbial compounds; 3) muscle atrophy-related processes linked to gut microbiota properties; 4) positive effects of microbiota-modulating interventions. Data on the relationships between gut microbiota, insulin resistance, and hepatic/adipose tissue metabolism in cachexia models are lacking. Nevertheless, the available data and existing evidence for the impact of gut microbiota on metabolic aberrations in human obesity urge for exploration of its role in human cancer cachexia. We provide practical recommendations and discuss the challenges for such future clinical studies.

Fast Track Program in Conversion Bariatric Surgery, as Safe as in Primary Bariatric Surgery?

OBJECTIVES: Evaluate the safety of fast track (FT) surgery program in patients undergoing primary and revisional bariatric surgery (conversion from one procedure to another); identify limiting factors for early discharge and predictive factors for readmission. METHODS: This is a retrospective review of 730 consecutive morbidly obese patients who underwent bariatric surgery between January 2016 and December 2017. Fast track protocol was applied on all patients. Target discharge was after one-night stay. The primary end point is length of stay. The secondary end point is frequency of hospital contact after discharge, readmissions and reinterventions within 30 days. RESULTS: Primary procedures (n = 633) were banded Roux-en-Y gastric bypass (BRYGB, 79.3%), sleeve gastrectomy (10.7%), gastric band (4.7%) and others (5.3%). Mean age (± SD) was 44.32 ± 11.26 years, and mean BMI (± SD) was 43.58 ± 6.12 kg/m2. Conversion procedures (n = 97) were gastric band to BRYGB (40.2%), or to adjustable BRYGB (39.2%), Mason to BRYGB (11.3%), sleeve to BRYGB (4.1%) and others (5.2%). Mean age (± SD) was 47.22 ± 9.1 years, and mean BMI (± SD) was 37.9 ± 7.27 kg/m2. Mean LOS in primary patients was 1.3 ± 0.99, and that in conversion patients was 1.5 ± 1.4. Successful discharge at one night or less was achieved in 650 cases (573 primary and 77 conversion). After one-night discharge, incidence of contact to the hospital, readmission and reintervention was 23.9%, 5.9% and 1.9%, in the primary group and 31.2%, 13% and 5.2% in the conversion group. CONCLUSION: One-night discharge in FT managed conversion procedures is safe, compared to primary procedures. It is associated with higher readmission rates; however, the postdischarge hospital contacts and surgical complications were not statistically significant different.

Effect of wheat bran derived prebiotic supplementation on gastrointestinal transit, gut microbiota, and metabolic health: a randomized controlled trial in healthy adults with a slow gut transit.

Acute intake of the wheat bran extract Arabinoxylan-Oligosaccharide (AXOS) modulates the gut microbiota, improves stool characteristics and postprandial glycemia in healthy humans. Yet, little is known on how long-term AXOS intake influences gastrointestinal (GI) functioning, gut microbiota, and metabolic health. In this randomized, placebo-controlled, double-blind study, we evaluated the effects of AXOS intake on GI function and metabolic health in adults with slow GI transit without constipation. Forty-eight normoglycemic adults were included with whole-gut transit time (WGTT) of >35 h receiving either 15 g/day AXOS or placebo (maltodextrin) for 12-wks. The primary outcome was WGTT, and secondary outcomes included stool parameters, gut permeability, short-chain fatty acids (SCFA), microbiota composition, energy expenditure, substrate oxidation, glucose, insulin, lipids, gut hormones, and adipose tissue (AT) function. WGTT was unchanged, but stool consistency softened after AXOS. 12-wks of AXOS intake significantly changed the microbiota by increasing Bifidobacterium and decreasing microbial alpha-diversity. With a good classification accuracy, overall microbiota composition classified responders with decreased WGTT after AXOS. The incretin hormone Glucagon-like protein 1 was reduced after AXOS compared to placebo. Energy expenditure, plasma metabolites, AT parameters, SCFA, and gut permeability were unchanged. In conclusion, intake of wheat bran extract increases fecal Bifidobacterium and softens stool consistency without major effects on energy metabolism in healthy humans with a slow GI transit. We show that overall gut microbiota classified responders with decreased WGTT after AXOS highlighting that GI transit and change thereof were associated with gut microbiota independent of Bifidobacterium. NCT02491125.

Effect of Intermittent or Continuous Feed on Muscle Wasting in Critical Illness: A Phase 2 Clinical Trial.

BACKGROUND: Acute skeletal muscle wasting in critical illness is associated with excess morbidity and mortality. Continuous feeding may suppress muscle protein synthesis as a result of the muscle-full effect, unlike intermittent feeding, which may ameliorate it. RESEARCH QUESTION: Does intermittent enteral feed decrease muscle wasting compared with continuous feed in critically ill patients? STUDY DESIGN AND METHODS: In a phase 2 interventional single-blinded randomized controlled trial, 121 mechanically ventilated adult patients with multiorgan failure were recruited following prospective informed consultee assent. They were randomized to the intervention group (intermittent enteral feeding from six 4-hourly feeds per 24 h, n = 62) or control group (standard continuous enteral feeding, n = 59). The primary outcome was 10-day loss of rectus femoris muscle cross-sectional area determined by ultrasound. Secondary outcomes included nutritional target achievements, plasma amino acid concentrations, glycemic control, and physical function milestones. RESULTS: Muscle loss was similar between arms (-1.1% [95% CI, -6.1% to -4.0%]; P = .676). More intermittently fed patients received 80% or more of target protein (OR, 1.52 [1.16-1.99]; P < .001) and energy (OR, 1.59 [1.21-2.08]; P = .001). Plasma branched-chain amino acid concentrations before and after feeds were similar between arms on trial day 1 (71 µM [44-98 µM]; P = .547) and trial day 10 (239 µM [33-444 µM]; P = .178). During the 10-day intervention period the coefficient of variation for glucose concentrations was higher with intermittent feed (17.84 [18.6-20.4]) vs continuous feed (12.98 [14.0-15.7]; P < .001). However, days with reported hypoglycemia and insulin usage were similar in both groups. Safety profiles, gastric intolerance, physical function milestones, and discharge destinations did not differ between groups. INTERPRETATION: Intermittent feeding in early critical illness is not shown to preserve muscle mass in this trial despite resulting in a greater achievement of nutritional targets than continuous feeding. However, it is feasible and safe. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02358512; URL: www.clinicaltrials.gov.

Liver resection surgery versus thermal ablation for colorectal LiVer MetAstases (LAVA): study protocol for a randomised controlled trial.

BACKGROUND: Although surgical resection has been considered the only curative option for colorectal liver metastases (CLM), thermal ablation has recently been suggested as an alternative curative treatment. A prospective randomised trial is required to define the efficacy of resection vs ablation for the treatment of colorectal liver metastases. METHODS: Design and setting: This is a multicentre, open, randomised controlled non-inferiority trial design with internal pilot and will be performed in tertiary liver centres in UK and The Netherlands. PARTICIPANTS: Eligible patients will be those with colorectal liver metastases at high surgical risk because of their age, co-morbidities or tumour burden and who would be suitable for liver resection or thermal ablation. INTERVENTION: Thermal ablation as per local policy. CONTROL: Surgical liver resection performed as per centre protocol. Co-interventions: Further chemotherapy will be offered to patients as per current practice. Outcomes Pilot study: Same as main study and in addition patients and clinicians' acceptability of the trial to assist in optimisation of recruitment. PRIMARY OUTCOME: Disease-free survival (DFS) at two years post randomisation. SECONDARY OUTCOMES: Overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, DFS measured from end of intervention. FOLLOW-UP: 24 months from randomisation; five-year follow-up for overall survival. SAMPLE SIZE: 330 patients to demonstrate non-inferiority of thermal ablation. DISCUSSION: This trial will determine the effectiveness and cost-effectiveness of thermal ablation vs surgical resection for high-risk people with colorectal liver metastases, and guide the optimal treatment for these patients. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN52040363 . Registered on 9 March 2016.

Management of acute intestinal failure: A position paper from the European Society for Clinical Nutrition and Metabolism (ESPEN) Special Interest Group.

Intestinal failure (IF) is the consequence of a reduction of gut function below the minimum necessary for the absorption of nutrients from the gastrointestinal tract. Types I and II comprise acute intestinal failure (AIF). Although its prevalence is relatively low, type II AIF is serious and requires specialist multidisciplinary care, often for prolonged periods before its resolution. The key aspects are: sepsis control, fluid and electrolyte resuscitation, optimization of nutritional status, wound care, appropriate surgery and active rehabilitation. The ESPEN Acute Intestinal Failure Special Interest Group (AIF SIG) has devised this position paper to provide a state-of-the-art overview of the management of type II AIF and to point out areas for future research.