Iron deficiency, immunology and colorectal cancer

This is an accepted manuscript of an article published by OUP in Nutrition Reviews on 17/7/2020, available online at: https://doi.org/10.1093/nutrit/nuaa040 The accepted version of the publication may differ from the final published version.Excessive gut luminal iron contributes to the initiation and progression of colorectal cancer. However, emerging evidence suggests that reduced iron intake and low systemic iron levels are also associated with the pathogenesis of colorectal cancer. This is important because patients with colorectal cancer often present with iron deficiency. Iron is necessary for appropriate immunological functions; hence, iron deficiency may hinder cancer immunosurveillance and potentially modify the tumor immune microenvironment, both of which may assist cancer development. This is supported by studies showing that patients with colorectal cancer with iron deficiency have inferior outcomes and reduced response to therapy. Here, we provide an overview of the immunological consequences of iron deficiency and suggest ensuring adequate iron therapy to limit these outcomes.Published onlin

Bile acids and the microbiome: Making sense of this dynamic relationship in their role and management in Crohn's disease

© 2022 The Authors. Published by Hindawi. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1155/2022/8416578Background. Bile acids help maintain the physiological balance of the gut microbiome and the integrity of the intestinal epithelial barrier. Similarly, intestinal bacteria play a major role in bile acid metabolism as they are involved in crucial biotransformation steps in the enterohepatic circulation pathway. Understanding the relationship between bile acid signalling and the gut microbiome in Crohn's disease can help target new and innovative treatment strategies. Aims. This review summarises the relationship between bile acids and the microbiome in Crohn's disease and discusses potential novel therapeutic options. Methods. We performed a literature review on bile acid signalling, its effect on the gut microbiome, and therapeutic applications in Crohn's disease. Results. Current research suggests that there is a strong interplay between the dysregulated microbiota, bile acid metabolism, and the mucosal immune system that can result in a changed immunological function, triggering the inflammatory response in Crohn's disease. Recent studies have demonstrated an association with altering the enterohepatic circulation and activating the farnesoid X receptor signalling pathway with the use of probiotics and faecal microbial transplantation, respectively. Bile acid sequestrants have been shown to have anti-inflammatory, cytoprotective, and anti-apoptotic properties with the potential to alter the intestinal microbial composition, suggesting a possible role in inducing and maintaining Crohn's disease. Conclusions. Active Crohn's disease has been correlated with changes in bacterial concentrations, which may be associated with changes in bile acid modification. Further research should focus on targeting these areas for future therapeutic options.The research department of MJB received project funding from Bowel and Cancer Research for part of this work and from an unrestricted grant from Tillotts Pharma for part of this work.Published versio

Influence of iron on the gut microbiota in colorectal cancer

© 2020 The Authors. Published by MDPI. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.3390/nu12092512Perturbations of the colonic microbiota can contribute to the initiation and progression of colorectal cancer, leading to an increase in pathogenic bacteria at the expense of protective bacteria. This can contribute to disease through increasing carcinogenic metabolite/toxin production, inducing inflammation, and activating oncogenic signaling. To limit disease progression, external factors that may influence the colonic microbiota need to be considered in patients with colorectal cancer. One major factor that can influence the colonic microbiota is iron. Iron is an essential micronutrient that is required by both prokaryotes and eukaryotes for cellular function. Most pathogenic bacteria have heightened iron acquisition mechanisms and therefore tend to outcompete protective bacteria for free iron. Colorectal cancer patients often present with anemia due to iron deficiency, and thus they require iron therapy. Depending upon the route of administration, iron therapy has the potential to contribute to a procarciongenic microbiota. Orally administered iron is the common treatment for anemia in these patients but can lead to an increased gut iron concentration. This suggests the need to reassess the route of iron therapy in these patients. Currently, this has only been assessed in murine studies, with human trials being necessary to unravel the potential microbial outcomes of iron therapy.Published onlin

Data Resource Profile: The Virtual Cardio-Oncology Research Initiative (VICORI) linking national English cancer registration and cardiovascular audits

Background: Cancer and cardiovascular disease (CVD) are the most common causes of morbidity and mortality worldwide. Improvements in treatment strategies for both CVD and cancer have resulted in significant improvements in survival and, as a result, there is an increasing population of patients who now live with both conditions.1–3 It is well known that cancer and its treatment increase the risk of CVD.4–6 Yet a detailed understanding of the underlying relationship between these two conditions and their respective treatments, including both positive and negative modulation of risk, is lacking. This is partly because few cohorts have been large enough to conduct detailed investigations. To address this, the Virtual Cardio-Oncology Research Initiative (VICORI) has linked national cardiac and cancer registries to create a resource of a larger scale and with longer follow-up than typical investigator-led studies

Multiwavelength characterization of faint ultra steep spectrum radio sources: a search for high-redshift radio galaxies

Context. Ultra steep spectrum (USS) radio sources are one of the efficient tracers of powerful high-z radio galaxies (HzRGs). In contrast to searches for powerful HzRGs from radio surveys of moderate depths, fainter USS samples derived from deeper radio surveys can be useful in finding HzRGs at even higher redshifts and in unveiling a population of obscured weaker radio-loud AGN at moderate redshifts. Aims. Using our 325 MHz GMRT observations (5σ ∼ 800 μJy) and 1.4 GHz VLA observations (5σ ∼ 80−100 μJy) available in two subfields (VLA-VIMOS VLT Deep Survey (VLA-VVDS) and Subaru X-ray Deep Field (SXDF)) of the XMM-LSS field, we derive a large sample of 160 faint USS radio sources and characterize their nature. Methods. The optical and IR counterparts of our USS sample sources are searched using existing deep surveys, at respective wavelengths. We attempt to unveil the nature of our faint USS sources using diagnostic techniques based on mid-IR colors, flux ratios of radio to mid-IR, and radio luminosities. Results. Redshift estimates are available for 86/116 (∼74%) USS sources in the VLA-VVDS field and for 39/44 (∼87%) USS sources in the SXDF fields with median values (zmedian) ∼1.18 and ∼1.57, respectively, which are higher than estimates for non-USS radio sources (zmedian non−USS ∼ 0.99 and ∼0.96), in the two subfields. The MIR color–color diagnostic and radio luminosities are consistent with most of our USS sample sources at higher redshifts (z > 0.5) being AGN. The flux ratio of radio to mid-IR (S 1.4 GHz/S 3.6 μm) versus redshift diagnostic plot suggests that more than half of our USS sample sources distributed over z ∼ 0.5 to 3.8 are likely to be hosted in obscured environments. A significant fraction (∼26% in the VLA-VVDS and ∼13% in the SXDF) of our USS sources without redshift estimates mostly remain unidentified in the existing optical, IR surveys, and exhibit high radio to mid-IR flux ratio limits similar to HzRGs, and so, can be considered as potential HzRG candidates. Conclusions. Our study shows that the criterion of ultra steep spectral index remains a reasonably efficient method to select high-z sources even at sub-mJy flux densities. In addition to powerful HzRG candidates, our faint USS sample also contains populations of weaker radio-loud AGNs potentially hosted in obscured environments

Early mortality from colorectal cancer in England: a retrospective observational study of the factors associated with death in the first year after diagnosis

Background: The United Kingdom performs poorly in international comparisons of colorectal cancer survival with much of the deficit owing to high numbers of deaths close to the time of diagnosis. This retrospective cohort study investigates the patient, tumour and treatment characteristics of those who die in the first year after diagnosis of their disease. Methods: Patients diagnosed with colon (n=65,733) or rectal (n=26,123) cancer in England between 2006 and 2008 were identified in the National Cancer Data Repository. Multivariable logistic regression was used to investigate the odds of death within 1 month, 1-3 months and 3-12 months after diagnosis. Results: In all, 11.5% of colon and 5.4% of rectal cancer patients died within a month of diagnosis: this proportion decreased significantly over the study period. For both cancer sites, older age, stage at diagnosis, deprivation and emergency presentation were associated with early death. Individuals who died shortly after diagnosis were also more likely to have missing data about important prognostic factors such as disease stage and treatment. Conclusion: Using routinely collected data, at no inconvenience to patients, we have identified some important areas relating to early deaths from colorectal cancer, which merit further research

Iron therapy for preoperative anaemia

Preoperative anaemia is common and occurs in 5% to 76% of patients preoperatively. It is associated with an increased risk of perioperative allogeneic blood transfusion, longer hospital stay, and increased morbidity and mortality. Iron deficiency is one of the most common causes of anaemia. Oral and intravenous iron therapy can be used to treat anaemia. Parenteral iron preparations have been shown to be more effective in conditions such as inflammatory bowel disease, chronic heart failure and postpartum haemorrhage due to rapid correction of iron stores. A limited number of studies has investigated iron therapy for the treatment of preoperative anaemia. The aim of this Cochrane Review is to summarise the evidence for iron supplementation, both enteral and parenteral, for the management of preoperative anaemia. Objectives To evaluate the effects of preoperative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. Search methods We ran the search on 30 July 2018. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic and Embase (Ovid), CINAHL Plus (EBSCO), PubMed, and clinical trials registries, and we screened reference lists. We ran a top‐up search on 28 November 2019; one study is now awaiting classification. Selection criteria We included all randomised controlled trials (RCTs) that compared preoperative iron monotherapy to placebo, no treatment, standard care or another form of iron therapy for anaemic adults undergoing surgery. We defined anaemia as haemoglobin values less than 13 g/dL for males and 12 g/dL for non‐pregnant females. Data collection and analysis Two review authors collected data and a third review author checked all collected data. Data were collected on the proportion of patients who receive a blood transfusion, the amount of blood transfused per patient (units), quality of life, ferritin levels and haemoglobin levels, measured as continuous variables at the following predetermined time points: pretreatment (baseline), preoperatively but postintervention, and postoperatively. We performed statistical analysis using the Cochrane software, Review Manager 5. We summarised outcome data in tables and forest plots. We used the GRADE approach to describe the quality of the body of evidence. Main results Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required ‐ as calculated by our information size calculation ‐ to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta‐analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate‐quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI ‐0.07 to 1.34; 2 studies, 83 participants; low‐quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low‐quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low‐quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low‐quality evidence). Not all studies measured quality of life, short‐term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. Authors' conclusions The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well‐designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.Published onlin

Development of a core information set for colorectal cancer surgery: a consensus study

Objective ‘Core information sets’ (CISs) represent baseline information, agreed by patients and professionals, to stimulate individualised patient-centred discussions. This study developed a CIS for use before colorectal cancer (CRC) surgery. Design Three phase consensus study: (1) Systematic literature reviews and patient interviews to identify potential information of importance to patients, (2) UK national Delphi survey of patients and professionals to rate the importance of the information, (3) international consensus meeting to agree on the final CIS. Setting UK CRC centres. Participants Purposive sampling was conducted to ensure CRC centre representation based upon geographical region and caseload volume. Responses were received from 63/81 (78%) centres (90 professionals). Adult patients who had undergone CRC surgery were eligible, and purposive sampling was conducted to ensure representation based on age, sex and cancer location (rectum, left and right colon). Responses were received from 97/267 (35%) patients with a wide age range (29–87), equal sex ratio and cancer location. Attendees of the international Tripartite Colorectal Conference were eligible for the consensus meeting. Outcomes Phase 1: Information of potential importance to patients was extracted verbatim and operationalised into a Delphi questionnaire. Phase 2: Patients and professionals rated the importance information on a 9-point Likert scale, and resurveyed following group feedback. Information rated of low importance were discarded using predefined criteria. Phase 3: A modified nominal group technique was used to gain final consensus in separate consensus meetings with patients and professionals. Results Data sources identified 1216 pieces of information that informed a 98-item questionnaire. Analysis led to 50 and 23 information domains being retained after the first and second surveys, respectively. The final CIS included 11 concepts including specific surgical complications, short and long-term survival, disease recurrence, stoma and quality of life issues. Conclusions This study has established a CIS for professionals to discuss with patients before CRC surgery

Synthesis and summary of patient-reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery

AIM: Patient-reported outcome (PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum 'core' outcome set to be measured in all trials. METHOD: All PROMs were identified from a systematic review of prospective CRC surgical studies. The type and frequency of PROMs in each study were summarized, and the number of items documented. All items were extracted and independently categorized by content by two researchers into 'health domains', and discrepancies were discussed with a patient and expert. Domain popularity and the distribution of items were summarized. RESULTS: Fifty-eight different PROMs were identified from the 104 included studies. There were 23 generic, four cancer-specific, 11 disease-specific and 16 symptom-specific questionnaires, and three ad hoc measures. The most frequently used PROM was the EORTC QLQ-C30 (50 studies), and most PROMs (n = 40, 69%) were used in only one study. Detailed examination of the 50 available measures identified 917 items, which were categorized into 51 domains. The domains comprising the most items were 'anxiety' (n = 85, 9.2%), 'fatigue' (n = 67, 7.3%) and 'physical function' (n = 63, 6.9%). No domains were included in all PROMs. CONCLUSION: There is major heterogeneity of PRO measurement and a wide variation in content assessed in the PROMs available for CRC. A core outcome set will improve PRO outcome measurement and reporting in CRC trials