IBD-related mental health disorders: where do we go from here?

Inflammatory bowel disease is a complex and debilitating disease which is known to cause mental burden for patients. Even though few studies look at mental health disease in this cohort of patients, there is growing evidence of a correlation between disease activity and prevalence of mental health conditions such as anxiety, depression and post-traumatic stress disorder. In this literature review, the relationship between inflammatory bowel disease and mental health disorders is explored, with an emphasis on recognition, screening and therapeutic options and special considerations for these complex comorbidities. The relationship between medical and psychological disease is not often considered and less well understood and there is a need for further research in these fields. Patients would have much to gain both medically and psychologically from a multidisciplinary approach to this chronic disease association.

Meta-analysis: The efficacy of therapeutic drug monitoring of anti-TNF-therapy in inflammatory bowel disease.

BACKGROUND AND AIMS: This systematic review and meta-analysis aimed to determine whether the use of therapeutic drug monitoring (TDM) in inflammatory bowel disease (IBD) patients on anti-tumour necrosis factor (anti-TNF) therapy results in improved rates of clinical and endoscopic remission, surgery, corticosteroid-free remission and hospitalisation. METHODS: MEDLINE, EMBASE, EMBASE classic, PubMed, Cochrane central databases register of controlled trials and Cochrane Specialised Trials Register were searched between 01 Janurary 1946 and 08 April 2022. Randomised controlled trials (RCTs) and prospective and retrospective observational studies were included, comparing TDM to standard of care (SOC) or reactive vs proactive TDM. Results were reported as pooled relative risks (RR) with 95% confidence intervals (95% CI). RESULTS: Twenty-six studies, including 9 RCTs, were included. Compared to SOC, proactive TDM was associated with a significantly decreased risk of treatment failure (RR 0.64, 95% CI 0.48-0.85 p<0.01), and a non-significant decrease in need for surgery (RR 0.51, 95% CI 0.25-1.02) and hospitalisation (RR 0.64, 95% CI 0.40-1.00). Furthermore compared to SOC, Proactive TDM was associated with higher rates of endoscopic remission (RR 1.19, 95% CI 0.93-1.53) and clinical remission (RR 1.07, 95% CI 0.97-1.18). Compared to reactive TDM, proactive TDM was associated with significant decreased risk of treatment failure (RR 0.46, 95% CI 0.21 = 0.98, p = 0.04) and significant reduction in hospitalisation (RR 0.33, 95% CI 0.21-0.54, p < 0.01). CONCLUSIONS: Compared to SOC, proactive TDM was associated with significant benefit in reducing treatment failure. Compared to reactive TDM, proactive TDM led to a significant reduction in hospitalisation and treatment failure. More studies with larger RCTs and standardised assays are needed to substantiate these results and validate the cost-effectiveness of TDM.

Women in gastroenterology: the UK trainee experience.

Introduction: Compared with other medical specialties, there are lower numbers of female trainees and lower rates of flexible working in gastroenterology. This study aims to examine the experience of male and female trainees to understand specialty demographics and the experience of training. Methods: Gastroenterology training data were obtained from the British Society of Gastroenterology (BSG) trainee surveys from 2014, 2018 and 2020, and from the Royal College of Physicians Medical Workforce unit between 2011 and 2019. Data on endoscopy measures from 2011 to 2021 were obtained from the Joint Advisory Group (JAG) on gastrointestinal endoscopy, including the JAG Endoscopy training system and the National Endoscopy Database. Data were segregated and compared by gender. Results: The percentage of female gastroenterology trainees remains at around 40%, largely unchanged over the previous decade. From the BSG trainee survey, 29.5% of women have flexible working patterns compared with 2.6% of men (p<0.001), which is lower than other medical specialties. Less than half of female trainees felt confident about their job prospects once they qualify. A greater proportion of male than female trainees achieved provisional colonoscopy certification during training (55% vs 45%, p=0.005) and female trainees took longer to certify than male trainees (63 months vs 56 months, p=0.004). The total length of training time from primary medical qualification to consultancy was the same for men and women. Conclusion: Changes must be addressed from a national and institutional level to address equitable access to national training programmes and equality of outcome for male and female trainees.

The impact of treatment with bile acid sequestrants on quality of life in patients with bile acid diarrhoea.

BACKGROUND: Bile acid diarrhoea (BAD) can be severely debilitating and negatively affect patients' quality of life (QoL). We carried out a multi-centre prospective study exploring QoL outcomes in patients with BAD after treatment with colesevelam. METHODS: Patients with or without a positive 23-seleno-25-homotaurocholic acid (SeHCAT) scan were recruited and categorised into four groups: SeHCAT negative control group (CG), idiopathic BAD, post-cholecystectomy (PC) and post-terminal ileal resection for Crohn's disease (CD). Patients with a positive SeHCAT were treated with colesevelam and dosing was titrated to symptomatic response. Patients were reviewed at 4- and 8-weekly intervals and QoL was evaluated by EQ-5D-3L, SF-36, IBDQ-32 at each visit (where relevant). Patients with a negative SeHCAT (CG cohort) completed one set of questionnaires before being discharged from the study. RESULTS: 47 patients (BAD = 24, PC = 12, CD = 11) completed paired QoL questionnaires before and after treatment and 30 CG patients completed a baseline questionnaire. There was a significant improvement in IBDQ-32 mean scores before and after treatment in CD patients [134.6 (95%CI 112.5-156.6) and 158.4 (136.1-180.6), respectively (p = 0.007). Following treatment, BAD patients had significantly improved mean SF-36 scores in the "Role limitation due to physical health" dimension (p = 0.02) and in the overall mental component summary (p = 0.03). Prior to starting treatment, BAD patients had the lowest scores in the 'activity' dimension of the EQ-5D-3L (p = 0.04), which improved significantly after treatment (p = 0.002). Overall, the BAD and CD cohort showed improved mean scores with treatment in all components of the SF-36 and EQ-5D-3L, while the PC cohort showed a general decline in mean scores after treatment. 55% of patients clinically responded to treatment of which 41.7%, 58.3% and 81.8% responded from the BAD, PC and CD groups respectively. Correlations between those deemed as responders with improvements on the SF-36 and EQ-5D dimensions were not statistically significant. CONCLUSION: Our results demonstrate improved QoL in the BAD and CD cohort with treatment. Further larger studies are recommended specifically investigating the PC cohort and whether patients may improve with newer treatments such as FXR agonists. Trial registration Ethical approval REC Ref: 16/LO/1325.

A single faecal bile acid stool test demonstrates potential efficacy in replacing SeHCAT testing for bile acid diarrhoea in selected patients.

This study examines the validity of measuring faecal bile acids (FBA) in a single stool sample as a diagnostic tool for bile acid diarrhoea (BAD) by direct comparison to the 75selenium-homotaurocholic acid (SeHCAT) scan. A prospective observational study was undertaken. Patients with chronic diarrhoea (> 6 weeks) being investigated for potential BAD with SeHCAT scan provided stool samples for measurement of FBA, using an enzyme-linked immunosorbent assay. Patients were characterised into four groups: SeHCAT negative control group, post-cholecystectomy, idiopathic BAD and post-operative terminal ileal resected Crohn's disease. Stool samples were collected at baseline and 8-weeks post treatment to determine whether FBA measurement could be used to monitor therapeutic response. 113 patients had a stool sample to directly compare with their SeHCAT result. FBA concentrations (µmol/g) and interquartile ranges in patients in the control group (2.8; 1.6-4.2), BAD (3.6; 1.9-7.2) and post-cholecystectomy cohort 3.8 (2.3-6.8) were similar, but all were significantly lower (p < 0.001) compared to the Crohn's disease cohort (11.8; 10.1-16.2). FBA concentrations in patients with SeHCAT retention of < 15% (4.95; 2.6-10.5) and < 5% (9.9; 4.8-15.4) were significantly higher than those with a SeHCAT retention > 15% (2.6; 1.6-4.2); (p < 0.001 and p < 0.0001, respectively). The sensitivity and specificity using FBA cut-off of 1.6 µmol/g (using ≤ 15% SeHCAT retention as diagnostic of BAD) were 90% and 25% respectively. A single random stool sample may have potential use in diagnosing severe BAD or BAD in Crohn's patients. Larger studies are now needed to confirm the potential efficacy of this test to accurately diagnose BAD in the absence of SeHCAT testing.

Bile Acids and the Microbiome: Making Sense of This Dynamic Relationship in Their Role and Management in Crohn's Disease.

Background: 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.

A review of the therapeutic management of Crohn's disease.

Crohn's disease is a chronic inflammatory, relapsing-remitting, and progressive gastrointestinal disorder with an often-negative impact on the physical, emotional, and psychological well-being. Over the past two decades, the medical compendium for the treatment of Crohn's disease has increased significantly, enabling treatment beyond symptoms. Indeed, early and timely use of effective medical therapy has been reflected by improved outcomes with reduction in surgery and ability to achieve clinical and endoscopic remission, reduce corticosteroid dependance, and prevent long-term complications in more patients. In this review, we discuss the key milestones in the medical management of Crohn's disease.

Iron deficiency anaemia: pathophysiology, assessment, practical management.

The WHO has recognised iron deficiency anaemia (IDA) as the most common nutritional deficiency in the world, with 30% of the population being affected with this condition. Although the most common causes of IDA are gastrointestinal bleeding and menstruation in women, decreased dietary iron and decreased iron absorption are also culpable causes. Patients with IDA should be treated with the aim of replenishing iron stores and returning the haemoglobin to a normal level. This has shown to improve quality of life, morbidity, prognosis in chronic disease and outcomes in pregnancy. Iron deficiency occurs in many chronic inflammatory conditions, including congestive cardiac failure, chronic kidney disease and inflammatory bowel disease. This article will provide an updated overview on diagnosis and management of IDA in patients with chronic conditions, preoperative and in pregnancy. We will discuss the benefits and limitations of oral versus intravenous iron replacement in each cohort, with an overview on cost analysis between the different iron formulations currently on the market.

Differences in the On- and Off-Tumor Microbiota between Right- and Left-Sided Colorectal Cancer.

This study aims to determine differences in the on- and off-tumor microbiota between patients with right- and left-sided colorectal cancer. Microbiome profiling of tumor and tumor-adjacent biopsies from patients with right-sided (n = 17) and left-sided (n = 7) colorectal adenocarcinoma was performed using 16S ribosomal RNA sequencing. Off-tumor alpha and beta diversity were significantly different between right- and left-sided colorectal cancer patients. However, no differences in on-tumor diversity were observed between tumor locations. Comparing the off-tumor microbiota showed the right colon to be enriched with species of the Lachnoclostridium, Selenomonas, and Ruminococcus genera. Whereas the left colon is enriched with Epsilonbacteraeota phylum, Campylobacteria class, and Pasteurellales and Campylobacterales orders, in contrast, the on-tumor microbiota showed relatively fewer differences in bacterial taxonomy between tumor sites, with left tumors being enriched with Methylophilaceae and Vadin BE97 families and Alloprevotella, Intestinibacter, Romboutsia, and Ruminococcus 2 genera. Patients with left-sided colorectal cancer had large taxonomic differences between their paired on- and off-tumor microbiota, while patients with right-sided colorectal cancer showed relatively fewer taxonomic differences. Collectively, this suggests that the right and left colon show distinctive bacterial populations; however, the presence of a colonic tumor leads to a more consistent microbiota between locations.

Oral and Intravenous Iron Therapy Differentially Alter the On- and Off-Tumor Microbiota in Anemic Colorectal Cancer Patients.

Iron deficiency anemia is a common complication of colorectal cancer and may require iron therapy. Oral iron can increase the iron available to gut bacteria and may alter the colonic microbiota. We performed an intervention study to compare oral and intravenous iron therapy on the colonic tumor-associated (on-tumor) and paired non-tumor-associated adjacent (off-tumor) microbiota. Anemic patients with colorectal adenocarcinoma received either oral ferrous sulphate (n = 16) or intravenous ferric carboxymaltose (n = 24). On- and off-tumor biopsies were obtained post-surgery and microbial profiling was performed using 16S ribosomal RNA analysis. Off-tumor α- and ß-diversity were significantly different between iron treatment groups. No differences in on-tumor diversity were observed. Off-tumor microbiota of oral iron-treated patients showed higher abundances of the orders Clostridiales, Cytophagales, and Anaeroplasmatales compared to intravenous iron-treated patients. The on-tumor microbiota was enriched with the orders Lactobacillales and Alteromonadales in the oral and intravenous iron groups, respectively. The on- and off-tumor microbiota associated with intravenous iron-treated patients infers increased abundances of enzymes involved in iron sequestration and anti-inflammatory/oncogenic metabolite production, compared to oral iron-treated patients. Collectively, this suggests that intravenous iron may be a more appropriate therapy to limit adverse microbial outcomes compared to oral iron.

Iron Therapy in Inflammatory Bowel Disease.

The most common complication seen in inflammatory bowel disease (IBD) patients is iron deficiency anaemia (IDA). Symptoms such as chronic fatigue can be as debilitating to IBD patients as pathological symptoms of abdominal pain and diarrhoea. Recognising and correcting anaemia may be as important as managing IBD symptoms and improving overall quality of life. Thus, iron replacement should be commenced the moment IDA is identified. Although intravenous iron is now considered standard treatment for IBD patients in Europe, oral iron still appears to be the preferred option. Advantages of oral iron include greater availability, lower costs and ease of applicability. However, its multitude of side effects, impact on the microbiome and further exacerbating IBD activity can have consequences on patient compliance. The newer oral iron formulations show promising safety and efficacy data with a good side effect profile. Intravenous iron formulations bypass the gastrointestinal tract absorption thereby leading to less side effects. Multiple studies have shown its superiority compared to oral formulations although its risk for hypersensitivity reactions continue to lead to clinician hesitancy in prescribing this formulation. This article provides an updated review on diagnosis and management of IDA in IBD patients, discussing the newer oral and intravenous formulations.

Influence of Iron on the Gut Microbiota in Colorectal Cancer.

Perturbations 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.

Small Molecule Inhibitors Targeting Gαi2 Protein Attenuate Migration of Cancer Cells.

Heterotrimeric G-proteins are ubiquitously expressed in several cancers, and they transduce signals from activated G-protein coupled receptors. These proteins have numerous biological functions, and they are becoming interesting target molecules in cancer therapy. Previously, we have shown that heterotrimeric G-protein subunit alphai2 (Gαi2) has an essential role in the migration and invasion of prostate cancer cells. Using a structure-based approach, we have synthesized optimized small molecule inhibitors that are able to prevent specifically the activation of the Gαi2 subunit, keeping the protein in its inactive GDP-bound state. We observed that two of the compounds (13 and 14) at 10 µΜ significantly inhibited the migratory behavior of the PC3 and DU145 prostate cancer cell lines. Additionally, compound 14 at 10 µΜ blocked the activation of Gαi2 in oxytocin-stimulated prostate cancer PC3 cells, and inhibited the migratory capability of DU145 cells overexpressing the constitutively active form of Gαi2, under basal and EGF-stimulated conditions. We also observed that the knockdown or inhibition of Gαi2 negatively regulated migration of renal and ovarian cancer cell lines. Our results suggest that small molecule inhibitors of Gαi2 have potential as leads for discovering novel anti-metastatic agents for attenuating the capability of cancer cells to spread and invade to distant sites.

An International Phase 2 Study of Pazopanib in Progressive and Metastatic Thyroglobulin Antibody Negative Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease <6 months preceding enrollment was required. With a sample size of 68 (assuming 23 attaining partial response [PR]), there would be 90% chance of detecting a difference of >30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6-50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: -86.8%; interquartile range [IQR]: -90.7% to -70.9%) compared with the 28 who did not (median: -69.0%; IQR: -78.1% to -27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (-23.5% [CI: -55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

An interesting cause of chronic abdominal pain in a child.

We encountered an eight-year-old boy who was subsequently diagnosed with a retroperitoneal ganglioneuroma. In view of the rarity of this tumour and its presentation, we are prompted to report this case.

Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer.

Context: Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal. Objective: To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival. Design: MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999. Patients: Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT. Main Outcome Measure: Overall survival (OS) and progression-free survival determined by Kaplan-Meier method. Results: Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy. Conclusion: MMT appears to convey longer survival in ATC among patients with stage IVA/B disease.

No Exit: Identifying Avoidable Terminal Oncology Intensive Care Unit Hospitalizations.

PURPOSE: Terminal oncology intensive care unit (ICU) hospitalizations are associated with high costs and inferior quality of care. This study identifies and characterizes potentially avoidable terminal admissions of oncology patients to ICUs. METHODS: This was a retrospective case series of patients cared for in an academic medical center's ambulatory oncology practice who died in an ICU during July 1, 2012 to June 30, 2013. An oncologist, intensivist, and hospitalist reviewed each patient's electronic health record from 3 months preceding terminal hospitalization until death. The primary outcome was the proportion of terminal ICU hospitalizations identified as potentially avoidable by two or more reviewers. Univariate and multivariate analysis were performed to identify characteristics associated with avoidable terminal ICU hospitalizations. RESULTS: Seventy-two patients met inclusion criteria. The majority had solid tumor malignancies (71%), poor performance status (51%), and multiple encounters with the health care system. Despite high-intensity health care utilization, only 25% had documented advance directives. During a 4-day median ICU length of stay, 81% were intubated and 39% had cardiopulmonary resuscitation. Forty-seven percent of these hospitalizations were identified as potentially avoidable. Avoidable hospitalizations were associated with factors including: worse performance status before admission (median 2 v 1; P = .01), worse Charlson comorbidity score (median 8.5 v 7.0, P = .04), reason for hospitalization (P = .006), and number of prior hospitalizations (median 2 v 1; P = .05). CONCLUSION: Given the high frequency of avoidable terminal ICU hospitalizations, health care leaders should develop strategies to prospectively identify patients at high risk and formulate interventions to improve end-of-life care.