Longitudinal associations of plasma metabolites with persistent fatigue among colorectal cancer survivors up to 2 years after treatment.

The underlying biological mechanisms causing persistent fatigue complaints after colorectal cancer treatment need further investigation. We investigated longitudinal associations of circulating concentrations of 138 metabolites with total fatigue and subdomains of fatigue between 6 weeks and 2 years after colorectal cancer treatment. Among stage I-III colorectal cancer survivors (n = 252), blood samples were obtained at 6 weeks, and 6, 12 and 24 months posttreatment. Total fatigue and fatigue subdomains were measured using a validated questionnaire. Tandem mass spectrometry was applied to measure metabolite concentrations (BIOCRATES AbsoluteIDQp180 kit). Confounder-adjusted longitudinal associations were analyzed using linear mixed models, with false discovery rate (FDR) correction. We assessed interindividual (between-participant differences) and intraindividual longitudinal associations (within-participant changes over time). In the overall longitudinal analysis, statistically significant associations were observed for 12, 32, 17 and three metabolites with total fatigue and the subscales "fatigue severity," "reduced motivation" and "reduced activity," respectively. Specifically, higher concentrations of several amino acids, lysophosphatidylcholines, diacylphosphatidylcholines, acyl-alkylphosphatidylcholines and sphingomyelins were associated with less fatigue, while higher concentrations of acylcarnitines were associated with more fatigue. For "fatigue severity," associations appeared mainly driven by intraindividual associations, while for "reduced motivation" stronger interindividual associations were found. We observed longitudinal associations of several metabolites with total fatigue and fatigue subscales, and that intraindividual changes in metabolites over time were associated with fatigue severity. These findings point toward inflammation and an impaired energy metabolism due to mitochondrial dysfunction as underlying mechanisms. Mechanistic studies are necessary to determine whether these metabolites could be targets for intervention.

Control Crohn Safe with episodic adalimumab monotherapy as first-line treatment study (CoCroS): study protocol for a randomised controlled trial.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease with a heterogeneous clinical presentation, relapse rate and treatment response. At present, no markers are available to adequately predict disease course at diagnosis. To prevent overtreatment of patients with a relative mild disease course, a step-up approach starting with corticosteroids is usually applied. Timely introduction of potentially disease modifying drugs and tight control of mucosal inflammation are crucial to prevent disease-related complications in patients with a complex disease course. We hypothesise that episodic treatment with adalimumab monotherapy in combination with close monitoring after drug discontinuation improves long-term outcome and reduces drug-related side effects, while preventing overtreatment. METHODS AND ANALYSIS: In this pragmatic multicentre randomised controlled trial, newly diagnosed CD patients or CD patients with a flare, naïve to thiopurines and biologicals, will be included and randomised 1:1 to open-label episodic (ie, 24 weeks) adalimumab monotherapy or step-up care starting with corticosteroids. The primary outcome is the number of yearly quarters of corticosteroid free clinical (Monitor Inflammatory Bowel Disease At Home score ≤3) and biochemical (C reactive protein within normal range and faecal calprotectin ≤200 µg/g) remission at week 96. Secondary outcomes are total healthcare costs, cumulative corticosteroid dose, proportion of patients with endoscopic remission at week 24, corticosteroid-free clinical remission, time to remission and patient-reported outcome measures on quality of life, (work) disability and treatment adherence. Safety outcomes are drug-related and disease-related adverse events and disease progression on MRI-enterography at week 96. ETHICS AND DISSEMINATION: This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 21 August 2019 (METC18-076) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT03917303.

Longitudinal associations of physical activity with plasma metabolites among colorectal cancer survivors up to 2 years after treatment.

We investigated longitudinal associations of moderate-to-vigorous physical activity (MVPA) and light-intensity physical activity (LPA) with plasma concentrations of 138 metabolites after colorectal cancer (CRC) treatment. Self-reported physical activity data and blood samples were obtained at 6 weeks, and 6, 12 and 24 months post-treatment in stage I-III CRC survivors (n = 252). Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQp180 kit). Linear mixed models were used to evaluate confounder-adjusted longitudinal associations. Inter-individual (between-participant differences) and intra-individual associations (within-participant changes over time) were assessed as percentage difference in metabolite concentration per 5 h/week of MVPA or LPA. At 6 weeks post-treatment, participants reported a median of 6.5 h/week of MVPA (interquartile range:2.3,13.5) and 7.5 h/week of LPA (2.0,15.8). Inter-individual associations were observed with more MVPA being related (FDR-adjusted q-value < 0.05) to higher concentrations of arginine, citrulline and histidine, eight lysophosphatidylcholines, nine diacylphosphatidylcholines, 13 acyl-alkylphosphatidylcholines, two sphingomyelins, and acylcarnitine C10:1. No intra-individual associations were found. LPA was not associated with any metabolite. More MVPA was associated with higher concentrations of several lipids and three amino acids, which have been linked to anti-inflammatory processes and improved metabolic health. Mechanistic studies are needed to investigate whether these metabolites may affect prognosis.

Web-Based Educational Intervention for Patients With Uninvestigated Dyspepsia Referred for Upper Gastrointestinal Tract Endoscopy: A Randomized Clinical Trial.

Importance: Diagnostic yield of upper gastrointestinal (GI) tract endoscopy for uninvestigated dyspepsia is low, and its clinical implications are limited. There is an unmet need for better strategies to reduce the volume of upper GI tract endoscopic procedures for dyspepsia. Objective: To study the effectiveness of a web-based educational intervention as a tool to reduce upper GI tract endoscopy in uninvestigated dyspepsia. Design, Setting, and Participants: This open-label, multicenter, randomized clinical trial enrolled participants between November 1, 2017, and March 31, 2019, with follow-up 52 weeks after randomization, at 4 teaching hospitals in the Netherlands. Participants included patients with uninvestigated dyspeptic symptoms who were referred for upper GI tract endoscopy by their general health care clinician without prior consultation of a gastroenterologist. A total of 119 patients, aged 18 to 69 years, were included. Patients were excluded if any of the following red flag symptoms were present: (indirect) signs of upper GI tract hemorrhage (hematemesis, melena, hematochezia, or anemia), unintentional weight loss of 5% or higher of normal body weight during a period of 6 to 12 months, persistent vomiting, dysphagia, or jaundice. Interventions: Patients were randomly assigned (1:1) to education (intervention) or upper GI tract endoscopy (control). Education consisted of a self-managed web-based educational intervention, containing information on gastric function, dyspepsia, and upper GI tract endoscopy. Main Outcomes and Measures: Difference in the proportion of upper GI tract endoscopy procedures between those who received access to the web-based educational intervention and those who did not at 12 weeks and 52 weeks after randomization, analyzed in the intention-to-treat population. Secondary outcomes included quality of life (Nepean Dyspepsia Index) and symptom severity (Patient Assessment of Gastrointestinal Disorders Symptom Severity Index) measured at baseline and 12 weeks. Results: Of 119 patients included (median age, 48 years [interquartile range, 37-56 years]; 48 men [40%]), 62 were randomized to web-based education (intervention) and 57 to upper GI tract endoscopy (control). Significantly fewer patients compared with controls underwent upper GI tract endoscopy after using the web-based educational intervention: 24 (39%) vs 47 (82%) (relative risk, 0.46; 95% CI, 0.33-0.64; P < .001). Symptom severity and quality of life improved equivalently in both groups. One additional patient in the intervention group required upper GI tract endoscopy during follow-up. Conclusions and Relevance: Findings of this study indicate that web-based patient education is an effective tool to decrease the need for upper GI tract endoscopy in uninvestigated dyspepsia. Trial Registration: ClinicalTrials.gov Identifier: NCT03205319.

Is dietary supplement use longitudinally associated with fatigue in stage I-III colorectal cancer survivors?

BACKGROUND & AIMS: Supplement use among colorectal cancer (CRC) survivors is common, yet evidence supporting its beneficial health effects is mostly lacking and cancer-specific lifestyle guidelines advise against the use of supplements. We aimed to describe the use of supplements by CRC survivors from diagnosis to 2 years post-treatment and investigate how overall supplement use is longitudinally associated with fatigue. METHODS: In a prospective cohort study of stage I-III CRC survivors (n = 325), information on supplement use was collected during repeated home visits at diagnosis and at 6 weeks, 6, 12, and 24 months post-treatment. Fatigue was assessed using the Checklist Individual Strength (score range 20-140) at all post-treatment time points. Linear mixed-models were applied to analyze longitudinal associations of overall supplement use with fatigue, adjusted for sex, age, comorbidities, chemotherapy, and physical activity. RESULTS: At all time points, about 40% of participants used supplements. Multivitamins/multiminerals were the most frequently used supplements at all time points. Of participants with at least two available measurements, 28% were consistent users, 45% consistent nonusers, and 27% inconsistent users (i.e. reported both use and nonuse). Reported fatigue levels declined significantly after treatment. Overall, no statistically significant differences in fatigue score over time were observed between supplement users and nonusers. Likewise, no intra-individual associations of supplement use and fatigue were found. However, in inter-individual analyses, supplement users reported to experience more fatigue compared to nonusers (ß 7.0, 95% CI 0.3; 13.7). CONCLUSIONS: No overall association between supplement use and fatigue was found. Results of the current study do therefore not imply that supplement use alleviates complaints of fatigue among CRC survivors. However, increased levels of fatigue may be a reason for supplement use among CRC survivors.

The added clinical value of performing CT colonography in patients with obstructing colorectal carcinoma.

BACKGROUND: A small percentage of incomplete optical colonoscopies (OCs) are the result of an obstructing tumor. According to current guidelines, CT colonography (CTC) is performed to prevent missing a synchronous tumor. The aim of this study was to evaluate how frequently a synchronous tumor was found on CTC and how often this led to a change in the surgical plan. METHODS: In this retrospective study, a total of 267 patients underwent CTC after an incomplete OC as a result of an obstructing colorectal carcinoma (CRC). Among them, 210 patients undergoing surgery met the inclusion criteria and were included in the analysis. The OC report, CTC report and surgical report of these patients were retrospectively evaluated for the presence of synchronous tumors using surgery and post-operative colonoscopy as the gold standard. RESULTS: Six of the 210 patients (2.9%) showed signs of a synchronous CRC proximal to the obstructing tumor on CTC. In three of these patients, a synchronous CRC was confirmed during surgery. All these tumors caused a change in the surgical plan. Three out of the six tumors found on CTC were found to be large, non-malignant polyps. All these polyps were located in the same segment as the obstructing tumor and therefore did not alter the surgical plan. CONCLUSION: In patients with obstructing CRC, the frequency of synchronous CRCs proximal to this lesion is low. Performing a CTC leads to a change in surgical plan based on the presence of these synchronous tumors in 1.4% of the cases. CTC should be employed as a one-stop shop in patients with an obstructing CRC.

Prospective multicenter validation of the Glasgow Blatchford bleeding score in the management of patients with upper gastrointestinal hemorrhage presenting at an emergency department.

BACKGROUND/AIMS: The Glasgow Blatchford Bleeding Score (GBS) has been developed to assess the need for treatment in patients with acute upper gastrointestinal hemorrhage (UGIH) presenting at emergency departments (EDs). We aimed (a) to determine the validity of the GBS and Rockall scoring systems for prediction of need for treatment and (b) to identify the optimal cut-off value of the GBS. METHODS: We carried out a population-based, prospective multicenter study of 520 consecutive patients presenting with acute UGIH at EDs of three hospitals. The accuracy of GBS and Rockall scores in predicting the need for treatment (i.e. endoscopic, surgical, or radiological intervention and blood transfusion) was analyzed using receiver operating characteristic curves. RESULTS: Receiver operating characteristic curve analysis showed that the GBS had a good discriminative ability to determine the need for treatment in patients with acute UGIH (area under the curve: 0.88; 95% confidence interval: 0.85-0.91). The GBS was superior to both the clinical Rockall and the full Rockall score in predicting the need for treatment (area under the curve: 0.86 vs. 0.70 vs. 0.77). At a cut-off value of up to 2, the GBS had the optimal combination of sensitivity (99.4%) and specificity (42.4%). CONCLUSION: The GBS is superior compared with both Rockall scores in predicting the need for treatment in patients with suspected acute UGIH presenting at EDs in the Netherlands. Patients with a GBS of 2 or less form a subgroup of low-risk patients. These low-risk patients are eligible for outpatient management, which might reduce hospital admissions and healthcare costs.

[Transfusions in the acutely bleeding patient: the borders between too little too late and too much too early]. / Transfusie bij de acuut bloedende patiënt: de grens tussen 'te weinig te laat' en 'te veel te vroeg'.

A restrictive regime regarding the initiation of blood transfusions was found to be safe in a Spanish study that included 921 patients with upper gastrointestinal bleeding. Survival after 6 weeks was higher (95 vs. 91%) in the restrictive group (Hb 4.3 mmol/l) than in the liberal group (Hb 5.6 mmol/l). The restrictive regimen was found favourable in patients with cirrhosis (class Child-Pugh A and B). In the Netherlands, guidelines prescribe the use of the 4-5-6 rule for initiating blood transfusions, depending on comorbidity (according to ASA classification) for patients who are haemodynamically stable and an aggressive regime when unstable. Starting blood transfusions can be lifesaving and must not be withheld in those who are haemodynamically unstable, but when stable, nuance is needed. In conclusion, the right balance needs to be found between too little too late and too much too early.

Predictive validity of the Glasgow Blatchford Bleeding Score in an unselected emergency department population in continental Europe.

BACKGROUND AND AIM: Glasgow Blatchford Bleeding Score stratifies patients presenting with acute upper gastrointestinal haemorrhage at the emergency department according to the likelihood of the need for treatment. The objective of this study was to validate the Glasgow Blatchford Bleeding Score for use in an emergency department in the Netherlands. Furthermore, we assessed its clinical usefulness for safe discharge of low-risk acute upper gastrointestinal haemorrhage patients and compared its test validity to that of other scoring systems. METHODS: This multicentre historic cohort study was conducted in two hospitals in the Netherlands. All 478 patients presenting with a suspicion of acute upper gastrointestinal haemorrhage at our emergency departments during a 1-year period were included. For each patient we calculated Glasgow Blatchford Bleeding Score and other commonly used scores. Test validity was assessed using the receiver operated characteristics curve analysis; calibration plots were used to assess the probability of the need for treatment of different levels of the scores. RESULTS: Glasgow Blatchford Bleeding Score had a good discriminative ability in predicting the need for treatment, receiver operated characteristics curve analysis showed an area under the curve of 0.879. Counting a score of 2 or less as low risk (negative), 104 patients (21.7%) were classified as low-risk, with a negative predictive value of 98.1%. These results were superior to those of the other scoring systems. CONCLUSION: Patients presenting at an emergency department in continental Europe with acute upper gastrointestinal haemorrhage and a Glasgow Blatchford Bleeding Score of 2 or less can be safely discharged. The Glasgow Blatchford Bleeding Score performed better than the other commonly used scoring systems.