Prospective, randomised, parallel-group, open-label study to evaluate the effectiveness and safety of IMU-838, in combination with oseltamivir, in adults with COVID-19: the IONIC trial protocol.

BACKGROUND: Globally, there is a scarcity of effective treatments for SARS-CoV-2 infections (causing COVID-19). Repurposing existing medications may offer the best hope for treating patients with COVID-19 to curb the pandemic. IMU-838 is a dihydroorotate dehydrogenase inhibitor, which is an effective mechanism for antiviral effects against respiratory viruses. When used synergistically with oseltamivir, therapeutic effects have been observed against influenza and SARS-CoV-2 in rodents. The IMU-838 and Oseltamivir in the Treatment of COVID-19 (IONIC) trial is a randomised controlled trial that will investigate whether time to clinical improvement in patients with COVID-19 is improved following a 14-day course of IMU-838+oseltamivir versus oseltamivir alone. METHODS: IONIC trial is an open-label study in which participants will be randomised 1:1 in two parallel arms: the intervention arm (IMU-838+oseltamivir) and the control arm (oseltamivir only). The primary outcome is time to clinical improvement; defined as the time from randomisation to a two-point improvement on WHO ordinal scale; discharge from hospital, or death (whichever occurs first). The study is sponsored by the University Hospitals Coventry and Warwickshire NHS Trust and funded by LifeArc. DISCUSSION: The IONIC protocol describes an overarching trial design to provide reliable evidence on the effectiveness of IMU-838 (vidofludimus calcium) when delivered in combination with an antiviral therapy (oseltamivir) (IONIC intervention) for confirmed or suspected COVID-19 infection in adult patients receiving usual standard of care. ETHICS AND DISSEMINATION: This study has been independently reviewed and approved by Wales Research Ethics Committee. In addition, required regulatory approvals were received from Medicines and Healthcare products Regulatory Agency. TRIAL REGISTRATION NUMBER: EudraCT 2020-001805-21, ISRCTN53038326, NCT04516915.

Fibrotic Phenotype of Peritumour Mesenteric Adipose Tissue in Human Colon Cancer: A Potential Hallmark of Metastatic Properties.

The impact of tumour associated stroma on cancer metastasis is an emerging field. However, cancer associated genes in peritumoral adipose tissue (pAT) in human colon cancer have not been explored. The aim of this study was to identify differentially expressed genes (DEGs) associated with cancer pathways in mesenteric pAT compared with adjacent adipose tissue. In total, nine patients with colon cancer pathological stage T2/T4 were employed in this study. DEGs were identified in 6 patients employing Nanostring PanCancer Pathway Panel and pathway enrichment analyses were performed. Differential expression of the 5 most up-regulated and 2 down regulated genes was validated with qRT-PCR. Results showed collagen type I alpha 1 chain (COL1A1) p = 0.007; secreted frizzled related protein (SFRP2) p = 0.057; fibroblast growth factor 7 (FGF7) not significant (ns); phospholipase A2, group IIA (PLA2G2A) ns; nerve growth factor receptor (NGFR) ns; lymphoid enhancer binding factor 1 (LEF1) p = 0.03; cadherin 1, Type 1, E-cadherin (epithelial) (CDH1) 0.09. Results have highlighted down-regulation of the Wingless/Integrated (Wnt) pathway in mesenteric pAT compared to distal adipose tissue. Highly upregulated genes in mesenteric pAT were involved in extracellular matrix (ECM)-receptor interactions and focal adhesion. Highly down regulated genes were involved in the cell cycle. Immunohistochemistry revealed differential distribution of COL1A1 showing maximum levels in tumour tissue and gradually decreasing in distant adipose tissue. COL1A1 and down regulation of Wnt pathway may have a role in local invasion and distant metastasis. COL1A1 may represent a stromal prognostic biomarker and therapeutic target in colon cancer.

C-reactive protein and albumin association with mortality of hospitalised SARS-CoV-2 patients: A tertiary hospital experience.

OBJECTIVE: The objective was to study hospitalised COVID-19 patients' mortality and intensive care unit (ICU) admission with covariates of interest (age, gender, ethnicity, clinical presentation, comorbidities and admission laboratory findings). METHODS: Logistic regression analyses were performed for patients admitted to University Hospital, University Hospitals Coventry and Warwickshire NHS Trust, between 24 January 2020 - 13 April 2020. RESULTS: There were 321 patients hospitalised. Median age was 73 years and 189 (59%) were male. Ethnicity was divided between Caucasian (77%), and black, Asian, and minority ethnic (BAME) groups (23%). Commonest symptoms were dyspnoea (62.9%), fever (59.1%) and cough (56%). Gastrointestinal symptoms amounted to 11.8%.Forty-four patients (13.7%) received ICU care. ICU male to female ratio was 3:1 (p=0.027; odds ratio (OR) 2.3; 95% confidence interval (CI) 1.1-4.9), BAME (p=0.008; OR 2.5; 95% CI 1.3-4.9), age >65 years (p=0.026; OR 0.28; 95% CI 0.09-0.93), heart disease (p=0.009; OR 0.2; 95% CI 0.1-0.6) and elevated C-reactive protein (CRP; p<0.001; OR 1.004; 95% CI 1.002-1.008) were associated with ICU admission.One-hundred and four patients (32.4%) died. Age >65 years (p=0.011; OR 5; 95% CI 1.6-21.9), neutrophils (p=0.047), neutrophil:lymphocyte ratio (NLR; p=0.028), CRP (p<0.001) and albumin (p=0.002) were associated with mortality. When analysis adjusted for age, CRP (p<0.001; OR 1.006; 95% CI 1.004-1.008) and albumin (p=0.005; OR 0.94; 95% CI 0.90-0.98) remained associated with mortality. CONCLUSIONS: COVID-19 has high mortality. BAME and male patients were associated with ICU admission. High CRP and low albumin (after correcting for age) were associated with mortality.

Systematic review with meta-analysis of over 90 000 patients. Does fast-track review diagnose colorectal cancer earlier?

BACKGROUND: National UK data on colorectal cancer (CRC) stage at diagnosis is incomplete. Site-specific fast-track (2-week wait) cancer data are not collected directly by NHS England. Policy making based on these data alone can lead to inaccuracy. AIMS: To review available data on key outcomes (cancer conversion rate and stage at diagnosis) for the UK's lower gastrointestinal 2-week wait pathway. METHODS: A comprehensive literature search was conducted between 2000 and 2017. Primary outcomes were cancer conversion rate and cancer stage at diagnosis. Results were expressed as proportions with 95% CIs. A random effects model was used for meta-analysis; heterogeneity was assessed by I2 . RESULTS: Of 95 papers reviewed, 49 were included in analysis with a total study population of 93,655. Cancer conversion rate was 7.7% (95% CI: 6.9-8.5). The proportion presenting at Dukes A = 11.2% (95% CI 7.4-15.6), B = 36.7% (95% CI 30.8-42.8), C = 35.7% (95% CI: 30.8-40.8) and D = 11.1% (95% CI 7.3-15.5). No colonic pathology was diagnosed in 54.6% (95% CI: 46.2-62.8). CONCLUSIONS: Only 7.7% of patients referred by the 2-week wait pathway were found to have CRC. No beneficial effect on stage at diagnosis was found compared to non-2-week wait referral pathways. Over half of patients had no colonic pathology and detection of adenomas was very low. These results should prompt a reconsideration of the benefits of the 2-week wait pathway in CRC diagnosis and outcomes, with more focus on strategies to improve patient selection.

Role of tissue microenvironment resident adipocytes in colon cancer.

Colorectal cancer (CRC) is a multifactorial disease characterized by several genetic and epigenetic alterations occurring in epithelial cells. It is increasingly recognized that tumour progression is also regulated by tumour microenvironment (TME). The bidirectional cross-talk between tumour resident adipocytes and cancer cells within TME has been proposed as active contributor to carcinogenesis. Tumour resident adipocytes exhibit an activated phenotype characterized by increased secretion of pro-tumorigenic factors (angiogenic/inflammatory/immune) which contribute to cancer cell proliferation, invasion, neoangiogenesis, evasion of immune surveillance and therapy resistance. Furthermore, adipocytes represent a fuel rich source for increasing energy demand of rapidly proliferating tumour cells. Interestingly, a relationship between obesity and molecular variants in CRC has recently been identified. Whether adipose tissue promotes cancer progression in subsets of molecular phenotypes or whether local tissue adipocytes are involved in inactivation of tumour suppressor genes and/or activation of oncogenes still needs to be explored. This editorial highlights the major findings related to cross-talk between adipocytes and colon cancer cells and how local paracrine interactions may promote cancer progression. Furthermore, we provide future strategies in studying colonic TME which could provide insights in bidirectional cross-talk mechanisms between adipocytes and colonic epithelial cells. This could enable to decipher critical signalling pathways of both early colonic carcinogenesis and cancer progression.

The effect of the 2-week wait referral system on the detection of and mortality from colorectal cancer: protocol of a systematic review and meta-analysis.

BACKGROUND: Colorectal cancer represents the fourth most common cancer in England and Wales; survival is high for early stage disease but declines sharply with advanced stage. UK figures suggest that cancer survival rates are lower than those of other Western European countries. Current 5-year survival is around 50 %. A rapid access strategy was introduced through the Department of Health in 2000. This 2-week wait (TWW) referral pathway was devised to streamline referral for suspected cancer, allow diagnosis at an earlier stage, reduce cancer survival inequality and reduce cancer-related mortality. However, only around half of patients with colorectal cancer have symptoms that fit the TWW criteria plus there is a fourfold difference in referral rates across England and Wales. High-quality evidence of TWW outcome measures for colorectal cancer is lacking. This systematic review will collate and evaluate the latest evidence on colorectal cancer detection rate, stage at diagnosis and mortality. METHODS: English-language publications from 2000 reporting outcomes on the TWW referral system for suspected colorectal cancer will be eligible for inclusion. Cochrane, EMBASE, MEDLINE via PubMed, NHS Evidence, Trip and the British Library Catalogue databases will be searched. Two paired reviewers will independently screen all titles/abstracts and full text for eligibility, then extract data and assess for bias using standardised formats. They will hand review reference lists of eligible articles. Disagreement will be resolved via third party adjudication. Summary effect measures for post-referral diagnosis and mortality rates will be calculated and expressed as relative risk, hazard rate ratio or risk difference with corresponding 95 % confidence intervals. Where possible summary effect measures will be pooled, heterogeneity and its extent for pooled estimates will be assessed via visual inspection of forest plots and explored via sub-group analysis. DISCUSSION: In this systematic review, we aim to summarise the relevant evidence on cancer detection rate, cancer stage at diagnosis and disease-related mortality rates for patients with suspected colorectal cancer investigated through the TWW referral system in England and Wales. We will highlight gaps in the evidence and provide a better understanding of whether it is meeting its desired effect. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016037368.

Improving detection of celiac disease patients: a prospective study in iron-deficient blood donors without anemia in north Italy.

OBJECTIVE: To evaluate the prevalence of celiac disease in asymptomatic iron-deficient blood donors without anemia. MATERIAL AND METHODS: Between the period February 2004 and January 2006, iron-deficient male donors with serum ferritin less than 30 ng/ml and female donors with serum ferritin less than 10 ng/ml were screened for immunoglobulin A (IgA) and IgG antitissue transglutaminase antibodies and donors with positive antibody titers were referred for endoscopy with multiple biopsies of the second/third part of duodenum. The frequency of celiac disease in iron-deficient blood donors without anemia and the predictive value of ferritin levels were analyzed. RESULTS: Of the 1679 blood donors, 579 (34.4%) were identified as iron deficient and screened for celiac disease. 290 (50%) were men (mean age: 39 years; range: 19-65) and 289 (50%) were women (mean age: 37 years; range: 19-63). Thirteen donors (2.2%) were positive for serum IgA antitissue transglutaminase antibodies, of whom six were men (2.0%) and seven were women (2.4%). 10 donors of 13 (1.7%) at histology presented alterations in the mucosal architecture according to the modified Marsh classification (Marsh I-III). Low ferritin level was not predictive for celiac disease (median serum ferritin level in celiac donors 14.7 ng/ml and in nonceliac donors 15.8 ng/ml, Wilcoxon test: P not significant). The prevalence of celiac disease among iron-deficient blood donors without anemia was 1.7%. CONCLUSION: The prevalence of celiac disease in our population of asymptomatic iron-deficient blood donors without anemia was 1.7%. We suggest screening for celiac disease in iron-deficient individuals without anemia to increase diagnosis of asymptomatic celiac disease.

The versatile role of gliadin peptides in celiac disease.

The link between the gluten component of wheat and celiac disease (CD) was discovered in 1952 by a team of physicians from Birmingham, England. Villous atrophy was described by John W. Paulley in 1954. During the 1960s, other features of CD were elucidated; its hereditary nature was recognized in 1965, and in 1966, dermatitis herpetiformis was linked to gluten sensitivity. Following the discovery of a link between gluten and CD, it was demonstrated that gliadin, one of the two principal protein groups comprising gluten, plays a critical role in CD. It has since become clear that the different and crucial roles of gliadin in CD result from its ability to activate multiple signaling pathways that modulate CD pathology. Most of these pathways involve the host innate and adaptive immune responses, but some pathways are activated when gliadin interacts with the intestinal cellular compartment. This review covers the current knowledge of the role of gliadin peptides in CD disorders that are characterized by intraepithelial T-cells infiltration (IEL), production of autoantibodies, endosomal trafficking, alteration of intestinal barrier function and intestinal cell proliferation. In addition, it examines the ability of these characteristics to determine the main clinicopathological features of gluten sensitivity for the purpose of identifying new strategies, other than maintaining a gluten-free diet, to improve the management of CD patients in the future.

Acute severe colitis: infliximab and/or cyclosporine?

Acute severe ulcerative colitis is a serious condition that requires early hospitalization, with intensive monitoring and treatment. Despite the recent progress in the medical approach of Inflammatory Bowel Diseases acute severe ulcerative colitis remains a clinical challenge, with a mortality rate of nearly 1%. As of today, I.V. corticosteroids remain the 1(st)-line therapy for this complication. For non-responders (up to one-third of patients) possible options are surgery - whose timing is a critical point in the overall management of the disease - or rescue therapy with 2(nd)- line agents such as Cyclosporine and Infliximab. Here we will review the published studies dealing with the use of these medications in acute severe ulcerative colitis.