Rare and severe adverse events in children with inflammatory bowel disease: analysis of data from the PIBD-SETQuality Safety Registry.

BACKGROUND: Rare and severe adverse events can occur in children with inflammatory bowel disease (IBD), and the relationship with disease or drug treatment is often uncertain. We aimed to establish a method of reporting adverse events of interest in children with IBD, allowing for estimates of incidence rates with comparison between different regions, and, if possible, to compare with published data on rates of adverse events in children overall. METHODS: For this analysis, we used data from the Paediatric Inflammatory Bowel Disease Network for Safety, Efficacy and Treatment and Quality improvement of care (PIBD-SETQuality) Safety Registry, which collects data on multiple rare and severe adverse events in children younger than 19 years with IBD. Overall, the registry collected data on ten prespecified rare and severe adverse events in children with IBD, as established by a panel of paediatric IBD experts, via reports from paediatric gastroenterologists at participating hospitals between Nov 1, 2016, and March 31, 2023. Reporting physicians, who could only be paediatric gastroenterologists or IBD nurses reporting on behalf of paediatric gastroenterologists, were recruited through invitations sent to both national and international IBD networks and at conferences. Once per month, participating paediatric gastroenterologists received an email with an anonymous and unique link to an online survey asking them to report whether any of ten rare and severe adverse events had occurred in a patient in their paediatric-IBD population in the previous month. Prevalent or retrospective rare and severe adverse events were excluded, as were events occurring in children with an unconfirmed diagnosis of IBD or for whom inflammatory colitis was part of a monogenic immunodeficiency disorder. Duplicates and events that did not meet the definitions and criteria were excluded. Physicians could also report other, non-categorised adverse events if they considered them rare and severe. In case of no response, up to two reminders were sent for each per-month survey. Annual denominator data surveys were sent to obtain the total number of person-years for the estimation of incidence rates, which were calculated via Poisson regression models. FINDINGS: Responses were gathered from 220 paediatric gastroenterologists from 167 centres. 121 centres were in Europe, 23 centres were in North America, 17 centres were in Asia, and six centres were in Oceania. Combined, the total population with paediatric IBD consisted of an estimated 30 193 children with 114 528 person-years of follow-up. 451 adverse events were initially reported. After excluding and reorganising adverse events, 402 were eligible; 261 (65%) were categorised and 141 (35%) were non-categorised. The most frequently reported adverse events were venous-thromboembolic events (n=66), renal failure (n=43), opportunistic infections (n=42), and cancer (n=33). Haemophagocytic lymphohistiocytosis (n=4) and liver failure (n=3) were the least frequently reported adverse events. Incidence rates per 10 000 person-years were 5·50 (95% CI 4·25-6·97) for venous-thromboembolic events, 3·75 (2·74-4·99) for renal failure, 3·67 (2·67-4·89) for opportunistic infection, and 2·88 (2·01-3·98) for cancer. Of 66 venous-thromboembolic events, 31 (47%) involved cerebral venous sinus thrombosis at an incidence rate of 2·71 (95% CI 1·86-3·77). INTERPRETATION: The PIBD-SETQuality Safety Registry enabled us to identify incidence rates of rare and severe adverse events in children with IBD. Our findings can guide physicians and enhance awareness of the incidence of adverse events in children with IBD that are considered to be rare. FUNDING: EU Horizon 2020 Research and Innovation Programme.

Accuracy of an artificial intelligence as a medical device as part of a UK-based skin cancer teledermatology service.

Introduction: An artificial intelligence as a medical device (AIaMD), built on convolutional neural networks, has demonstrated high sensitivity for melanoma. To be of clinical value, it needs to safely reduce referral rates. The primary objective of this study was to demonstrate that the AIaMD had a higher rate of correctly classifying lesions that did not need to be referred for biopsy or urgent face-to-face dermatologist review, compared to teledermatology standard of care (SoC), while achieving the same sensitivity to detect malignancy. Secondary endpoints included the sensitivity, specificity, positive and negative predictive values, and number needed to biopsy to identify one case of melanoma or squamous cell carcinoma (SCC) by both the AIaMD and SoC. Methods: This prospective, single-centre, single-arm, masked, non-inferiority, adaptive, group sequential design trial recruited patients referred to a teledermatology cancer pathway (clinicaltrials.gov NCT04123678). Additional dermoscopic images of each suspicious lesion were taken using a smartphone with a dermoscopic lens attachment. The images were assessed independently by a consultant dermatologist and the AIaMD. The outputs were compared with the final histological or clinical diagnosis. Results: A total of 700 patients with 867 lesions were recruited, of which 622 participants with 789 lesions were included in the per-protocol (PP) population. In total, 63.3% of PP participants were female; 89.0% identified as white, and the median age was 51 (range 18-95); and all Fitzpatrick skin types were represented including 25/622 (4.0%) type IV-VI skin. A total of 67 malignant lesions were identified, including 8 diagnosed as melanoma. The AIaMD sensitivity was set at 91 and 92.5%, to match the literature-defined clinician sensitivity (91.46%) as closely as possible. In both settings, the AIaMD identified had a significantly higher rate of identifying lesions that did not need a biopsy or urgent referral compared to SoC (p-value = 0.001) with comparable sensitivity for skin cancer. Discussion: The AIaMD identified significantly more lesions that did not need to be referred for biopsy or urgent face-to-face dermatologist review, compared to teledermatologists. This has the potential to reduce the burden of unnecessary referrals when used as part of a teledermatology service.

Role of HBsAg levels in guiding hepatitis B virus prophylaxis in pregnancy: Insights from a multi-ethnic cohort.

Pregnant mothers with chronic hepatitis B infection (CHB) need peri-partum antiviral prophylaxis (PAP) to reduce the risk of mother-to-child-transmission. Currently, PAP is recommended in those with high viral load (VL) that is, HBV DNA >200,000 IU/mL. Quantitative hepatitis B surface antigen (qHBsAg) >10,000 IU/mL, a cut-off derived primarily from hepatitis B e-antigen (HBeAg) positive antenatal cohorts in Chinese populations, is advocated as a surrogate marker of VL for guiding PAP. We investigated the utility of qHBsAg to predict high-VL in a multi-ethnic urban cohort with CHB. A consecutive cohort of women with CHB was identified from Barts Health NHS Trust databases in the United Kingdom. We included women with paired HBV DNA and qHBsAg during pregnancy. Women already on antiviral at conception were excluded. A total of 769 pregnancies in 678 CHB pregnant mothers (median age 31 years-old, 8.6% HBeAg+) were included. At median gestational age of 15.3 weeks, HBV DNA was 336 (IQR 44-2998) IU/mL, with 65 (8.5%) being high-VL. Serum qHBsAg was most useful in Black/Black-British/Caribbean/African (AUROC 0.946) with 100% sensitivity and 80.6% specificity to predict high-VL; but it performed less well for other ethnicities: Asian (AUROC 0.877), White (AUROC 0.797) and mixed ethnicities (AUROC 0.742). In conclusion, for settings where healthcare resources are not limited, HBV DNA remains the optimal marker to identify highly viraemic pregnancies for guiding PAP. For resource-limited settings where the prevailing cost is treatment, serum qHBsAg can be used in Black/Black British/Caribbean/African sub-cohorts, but not for other ethnicities.

Patient perspectives of artificial intelligence as a medical device in a skin cancer pathway.

The use of artificial intelligence as a medical device (AIaMD) in healthcare systems is increasing rapidly. In dermatology, this has been accelerated in response to increasing skin cancer referral rates, workforce shortages and backlog generated by the COVID-19 pandemic. Evidence regarding patient perspectives of AIaMD is currently lacking in the literature. Patient acceptability is fundamental if this novel technology is to be effectively integrated into care pathways and patients must be confident that it is implemented safely, legally, and ethically. A prospective, single-center, single-arm, masked, non-inferiority, adaptive, group sequential design trial, recruited patients referred to a teledermatology cancer pathway. AIaMD assessment of dermoscopic images were compared with clinical or histological diagnosis, to assess performance (NCT04123678). Participants completed an online questionnaire to evaluate their views regarding use of AIaMD in the skin cancer pathway. Two hundred and sixty eight responses were received between February 2020 and August 2021. The majority of respondents were female (57.5%), ranged in age between 18 and 93 years old, Fitzpatrick type I-II skin (81.3%) and all 6 skin types were represented. Overall, there was a positive sentiment regarding potential use of AIaMD in skin cancer pathways. The majority of respondents felt confident in computers being used to help doctors diagnose and formulate management plans (median = 70; interquartile range (IQR) = 50-95) and as a support tool for general practitioners when assessing skin lesions (median = 85; IQR = 65-100). Respondents were comfortable having their photographs taken with a mobile phone device (median = 95; IQR = 70-100), which is similar to other studies assessing patient acceptability of teledermatology services. To the best of our knowledge, this is the first comprehensive study evaluating patient perspectives of AIaMD in skin cancer pathways in the UK. Patient involvement is essential for the development and implementation of new technologies. Continued end-user feedback will allow refinement of services to ensure patient acceptability. This study demonstrates patient acceptability of the use of AIaMD in both primary and secondary care settings.

HepFREEPak: protocol for a multi-centre, prospective observational study examining efficacy and impact of current therapies for the treatment of hepatitis C in Pakistan and reporting resistance to antiviral drugs: study protocol.

BACKGROUND: Pakistan has one of the highest burdens of Hepatitis C virus (HCV) infection globally. To achieve the World Health Organization's goals for HCV elimination, there is a need for substantial scale-up in testing, treatment, and a reduction in new infections. Data on the population impact of scaling up treatment is not available in Pakistan, nor is there reliable data on the incidence of infection/reinfection. This project will fill this gap by providing important empirical data on the incidence of infection (primary and reinfection) in Pakistan. Then, by using this data in epidemic models, the study will determine whether response rates achieved with affordable therapies (sofosbuvir plus daclatasvir) will be sufficient to eliminate HCV in Pakistan. METHODS: This prospective multi-centre cohort study will screen 25,000 individuals for HCV antibody (Ab) and RNA (if Ab-positive) at various centers in Pakistan- Karachi (Sindh) and Punjab, providing estimates of the disease prevalence. HCV positive patients will be treated with sofosbuvir and daclatasvir for 12-weeks, (extended to 24-weeks in those with cirrhosis) and the proportion responding to this first-line treatment estimated. Patients who test HCV Ab negative will be recalled 12 months later to test for new HCV infections, providing estimates of the incidence rate. Patients diagnosed with HCV (~ 4,000) will be treated and tested for Sustained Virological Response (SVR). Questionnaires to assess risk factors, productivity, health care usage and quality of life will be completed at both the initial screening and at 12-month follow-up, allowing mathematical modelling and economic analysis to assess the current treatment strategies. Viral resistance will be analysed and patients who have successfully completed treatment will be retested 12 months later to estimate the rate of re-infection. CONCLUSION: The HepFREEPak study will provide evidence on the efficacy of available and widely used treatment options in Pakistan. It will also provide data on the incidence rate of primary infections and re-infections. Data on incidence risk factors will allow us to model and incorporate heterogeneity of risk and how that affects screening and treatment strategies. These data will identify any gaps in current test-and-treat programs to achieve HCV elimination in Pakistan. STUDY REGISTRATION: This study was registered on clinicaltrials.gov (NCT04943588) on June 29, 2021.

Improved clinical outcomes with early anti-tumour necrosis factor alpha therapy in children with newly diagnosed Crohn's disease: real world data from the international prospective PIBD-SETQuality inception cohort study.

BACKGROUND & AIMS: Treatment guidelines for paediatric Crohn's disease (CD) suggest early use of anti-tumour necrosis factor alpha (anti-TNF) in high-risk individuals. The aim is to evaluate the effect of early anti-TNF in a real-world cohort. METHODS: Children with newly-diagnosed CD were prospectively recruited at 28 participating sites of the international observational PIBD-SETQuality study. Outcomes were compared at 3 months, 1 and 2 years between patients receiving early anti-TNF (<90 days after diagnosis) and those not receiving early anti-TNF. Outcomes included sustained steroid-free remission (SSFR) without treatment intensification (specified as SSFR*) and sustained steroid-free mild/inactive disease without treatment intensification (specified as SSFMI*). Penalised logistic regression model-based standardisation was applied to estimate the relative risks (RR) of early therapy on outcomes. RRs were estimated for high-risk and low-risk patients based on presence of predictors of poor outcome (POPOs) and disease activity at diagnosis. RESULTS: In total, 331 children (median age 13.9 years [IQR 12.2 - 15.3]) were enrolled, with 135 (41%) receiving early anti-TNF. At 1 year, patients on early anti-TNF had higher rates of SSFR* (30% vs. 14%, p<0.001) and SSFMI* (69% vs. 33%, p<0.001), with RRs of 2.95 (95%CI 1.63-5.36) and 4.67 (95%CI 2.46-8.87) respectively. At 1 year, the RRs for SSFMI* were higher, and statistically significant in high-risk patients, i.e. those with moderate/severe disease compared to mild/inactive disease at diagnosis (5.50 [95%CI 2.51-12.05]) vs. 2.91 [95%CI 0.92-9.11]), and those with any POPO compared to no POPO (5.05 [95%CI 2.45-10.43] vs. 3.41 [95%CI 0.54-21.7]). CONCLUSION: In this cohort of children with newly-diagnosed CD, early anti-TNF demonstrated superior effectiveness in high-risk patients.

Effectiveness of an image analyzing AI-based Digital Health Technology to identify Non-Melanoma Skin Cancer and other skin lesions: results of the DERM-003 study.

Introduction: Identification of skin cancer by an Artificial Intelligence (AI)-based Digital Health Technology could help improve the triage and management of suspicious skin lesions. Methods: The DERM-003 study (NCT04116983) was a prospective, multi-center, single-arm, masked study that aimed to demonstrate the effectiveness of an AI as a Medical Device (AIaMD) to identify Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma (BCC), pre-malignant and benign lesions from dermoscopic images of suspicious skin lesions. Suspicious skin lesions that were suitable for photography were photographed with 3 smartphone cameras (iPhone 6S, iPhone 11, Samsung 10) with a DL1 dermoscopic lens attachment. Dermatologists provided clinical diagnoses and histopathology results were obtained for biopsied lesions. Each image was assessed by the AIaMD and the output compared to the ground truth diagnosis. Results: 572 patients (49.5% female, mean age 68.5 years, 96.9% Fitzpatrick skin types I-III) were recruited from 4 UK NHS Trusts, providing images of 611 suspicious lesions. 395 (64.6%) lesions were biopsied; 47 (11%) were diagnosed as SCC and 184 (44%) as BCC. The AIaMD AUROC on images taken by iPhone 6S was 0.88 (95% CI: 0.83-0.93) for SCC and 0.87 (95% CI: 0.84-0.91) for BCC. For Samsung 10 the AUROCs were 0.85 (95% CI: 0.79-0.90) and 0.87 (95% CI, 0.83-0.90), and for the iPhone 11 they were 0.88 (95% CI, 0.84-0.93) and 0.89 (95% CI, 0.86-0.92) for SCC and BCC, respectively. Using pre-determined diagnostic thresholds on images taken on the iPhone 6S the AIaMD achieved a sensitivity and specificity of 98% (95% CI, 88-100%) and 38% (95% CI, 33-44%) for SCC; and 94% (95% CI, 90-97%) and 28% (95 CI, 21-35%) for BCC. All 16 lesions diagnosed as melanoma in the study were correctly classified by the AIaMD. Discussion: The AIaMD has the potential to support the timely diagnosis of malignant and premalignant skin lesions.

Validation of predictive models for disease outcomes in paediatric ulcerative colitis: A multicentre prospective inception cohort.

BACKGROUND: Several studies have proposed models to predict disease outcomes in paediatric ulcerative colitis (UC), notably PROTECT, Schechter and PIBD-ahead, but none has been validated by external cohorts AIM: To explore these models in a prospective multicentre inception cohort METHODS: Children newly diagnosed with UC in 17 centres were followed at disease onset and 3 and 12 months thereafter, as well as at last visit. Outcomes included steroid-free remission (SFR) and acute severe colitis (ASC). RESULTS: Of the 223 included children, 74 (34%), 97 (43%) and 52 (23%) presented with mild, moderate and severe disease, respectively. SFR rate was 35% at 3 months and 47% at 12 months (62% of those with mild disease at diagnosis vs. 41% in moderate-severe disease; p = 0.01). Thirty-six (16%) children developed ASC during the first month after diagnosis, and 53 (24%) during the first year. The AUC of the PROTECT model for predicting SFR at 3 and 12 months was 0.78 [95% CI 0.65-0.92] and 0.57 [95% CI 0.47-0.66], respectively. The sensitivity/specificity/PPV/NPV of Schechter's criteria to predict sustained SFR at 12 months was 50%/60%/35%/74%. ASC was predicted only by the PUCAI score at diagnosis and at 3 months. CONCLUSIONS: The PROTECT model had a good predictive utility for SFR at 3 months, but not at 12 months. The other predictive models did not achieve sufficient accuracy, which was far from that reported in the original studies. This highlights the necessity for external validation of any prediction model prior to its implementation into clinical practice.

Corrigendum: TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human.

[This corrects the article DOI: 10.3389/fnmol.2021.757646.].

High Impact of Pediatric Inflammatory Bowel Disease on Caregivers' Work Productivity and Daily Activities: An International Prospective Study.

OBJECTIVES: To evaluate the longitudinal evolution of work productivity loss and activity impairment in caregivers of children with inflammatory bowel disease (IBD). We also evaluated the associations between these impairments, IBD-related factors, and caregivers' health-related quality of life (HRQOL) and estimated the indirect costs related to work absenteeism. STUDY DESIGN: Since January 2017, children with newly diagnosed IBD were enrolled prospectively in the Pediatric Inflammatory Bowel Disease Network for Safety, Efficacy, Treatment and Quality improvement of care study. The impact of pediatric-onset IBD on caregivers' socioeconomic functioning (work and daily activities) and HRQOL was assessed using the Work Productivity and Activity Impairment for caregivers questionnaire and the European Quality of Life Five Dimension Five Level questionnaire, at diagnosis and 3 and 12 months of age. Generalized estimating equation models were applied to evaluate outcomes longitudinally, adjusted for IBD type, disease activity, and child's age at diagnosis. RESULTS: Up to July 2021, 491 children with IBD were eligible for analysis of caregivers' Work Productivity and Activity Impairment questionnaire. At diagnosis, the mean caregivers' employment rate was 78.4%; the adjusted mean work productivity loss was 44.6% (95% CI, 40.2%-49.0%), and the adjusted mean activity impairment was 34.3% (95% CI, 30.8%-37.7%). Work productivity loss and activity impairment significantly decreased over time and were associated with disease activity, but not with IBD type or child's age. Caregivers' HRQOL was associated with both impairments. Costs related to work absenteeism were at least €6272 ($7276) per patient during the first year after diagnosis. CONCLUSIONS: Caregivers of children with IBD experience significant impairments in work and daily activities, especially at diagnosis. The impact decreases thereafter and is associated with disease activity and caregivers' HRQOL. Work absenteeism results in high indirect costs.

The Incidence and Characteristics of Venous Thromboembolisms in Paediatric-Onset Inflammatory Bowel Disease: A Prospective International Cohort Study Based on the PIBD-SETQuality Safety Registry.

BACKGROUND AND AIMS: Guidelines regarding thromboprophylaxis for venous thromboembolisms [VTEs] in children with inflammatory bowel disease [IBD] are based on limited paediatric evidence. We aimed to prospectively assess the incidence of VTEs in paediatric-onset IBD [PIBD], characterize PIBD patients with a VTE and identify potential IBD-related risk factors. METHODS: From October 2016 to September 2020, paediatric gastroenterologists prospectively replied to the international Safety Registry, monthly indicating whether they had observed a VTE case in a patient <19 years with IBD. IBD details [type, Paris classification, clinical and biochemical disease activity, treatment] and VTE details [type, location, treatment, outcome] were collected. To estimate VTE incidence, participants annually reported the number of PIBD patients, data source and catchment area of their centre. A systematic literature review and meta-analysis was performed to calculate the VTE incidence in the general paediatric population. RESULTS: Participation of 129 PIBD centres resulted in coverage of 24 802 PIBD patients. Twenty cases of VTE were identified [30% Crohn's disease]. The incidence of VTEs was 3.72 (95% confidence interval [CI] 2.27-5.74) per 10 000 person-years, 14-fold higher than in the general paediatric population (0.27 [95% CI 0.18-0.38], p < 0.001). Cerebral sinus venous thrombosis was most frequently reported [50%]. All but one patient had active IBD, 45% were using steroids and 45% were hospitalized. No patient received thromboprophylaxis, whereas according to current PIBD guidelines, this was recommended in 4/20 patients. CONCLUSION: There is an increased risk of VTEs in the PIBD population compared to the general paediatric population. Awareness of VTE occurrence and prevention should be extended to all PIBD patients with active disease, especially those hospitalized.

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human.

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning.

Socioeconomic Factors Associated With Liver-Related Mortality From 1985 to 2015 in 36 Developed Countries.

BACKGROUND & AIMS: There is increasing disparity in liver-related mortality worldwide. Although there are many biologic and lifestyle risk factors for liver-related mortality, the effects of inequalities in social and economic determinants of health have received little attention. We investigated changes in liver-related mortality from 1985 through 2015 in 36 countries, using 4 international health and economic databases, and searched for socioeconomic factors that might influence these trends. METHODS: We collected information on sex- and country-specific liver-related mortality from countries with designated high-usability data from the World Health Organization mortality database. We obtained data on alcohol consumption per capita, the percentage of adults with a body mass index greater than 30 kg/m2, health expenditure per capita, gross domestic product per capita, Gini index, national unemployment estimates, and diabetes prevalence from the World Health Organization global health observatory data repository, the World Bank database, and the International Diabetes Federation. We examined changes in mortality using Joinpoint regression analysis. Univariate analysis and a mixed-effects linear model were used to identify factors associated with liver-related mortality. RESULTS: From 1985 to 2015, the mean liver-related deaths per 100,000 persons increased in men from 23.8 to 26.1, and in women from 9.7 to 11.9. Increased liver-related mortality was associated with male sex, a high level of alcohol consumption, obesity, and indicators of national wealth and government health expenditure gross domestic product or government expenditure on health. CONCLUSIONS: In addition to established risk factors for liver mortality, this study identified addressable economic factors associated with liver-related mortality trends. Health care professionals and policy makers may wish to consider these factors to reduce liver-related mortality.

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study.

INTRODUCTION: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors. METHODS AND ANALYSIS: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up. ETHICS AND DISSEMINATION: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications. TRIAL REGISTRATION NUMBER: NCT03571373.

Correlation Between Bevacizumab Exposure and Survival in Patients with Metastatic Colorectal Cancer.

BACKGROUND: Bevacizumab treatment is subject to large interpatient variability in efficacy, which may partly be explained by differences in complex bevacizumab pharmacokinetic characteristics that influence bevacizumab exposure. Exposure-response relationships have been identified for other monoclonal antibodies. We aimed to identify possible exposure-survival relationships in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: Patients with mCRC who started first-line bevacizumab-based chemotherapy between July 2012 and July 2014, and from whom serial blood samples and survival were prospectively collected, were included. Follow-up was carried out until July 2018. Total bevacizumab trough concentrations were measured from cycle 2 to cycle 30 of treatment. The receiver operating characteristic (ROC) curve analysis and Cox analysis were used to identify the relationship between concentrations and overall survival (OS). In addition, OS was compared between different trough concentration groups. RESULTS: One hundred fifty-seven blood samples from 46 patients were evaluable for analyses. ROC analysis showed a clear separation in survival based on trough levels (area under the curve = 0.739, p = .009). Cox regression also showed a strong positive correlation between trough levels and survival (p = .0004). Three distinct groups of exposure were identified: low (median trough concentration [Ctm ] ≤41.9 mg/L); medium (Ctm 43-87.2 mg/L) with median OS of 12.8 and 36 months, respectively (p = .0003); and high (Ctm ≥7.9 mg/L), where the majority of patients were still alive 60 months after the initiation of treatment. CONCLUSION: This study shows that survival was proportional to the magnitude of exposure in patients with mCRC. Further clinical research should focus on clarifying these exposure-outcome relationships in order to optimize dosing. IMPLICATIONS FOR PRACTICE: Bevacizumab-based chemotherapy is standard first-line treatment in metastatic colorectal cancer. Moreover, bevacizumab presents complicated pharmacokinetics, and in many cases, clinical outcomes can be highly variable, with some patients responding remarkably well and others not. This study's results show that patients who experienced longer overall survival also had significantly higher exposure to bevacizumab. Therefore, bevacizumab trough concentrations could be used both as a predictive biomarker and as a tool for treatment monitoring and optimization. Finally, the development of validated, rapid, and sensitive assays for bevacizumab concentration measurements in combination with these results may lead to a therapeutic drug monitoring-guided approach in bevacizumab treatment with better clinical outcomes.

VEGF-A and ICAM-1 Gene Polymorphisms as Predictors of Clinical Outcome to First-Line Bevacizumab-Based Treatment in Metastatic Colorectal Cancer.

Bevacizumab is used to treat metastatic colorectal cancer (mCRC). However, there are still no available predictors of clinical outcomes. We investigated selected single nucleotide polymorphisms (SNPs) in the genes involved in VEGF-dependent and -independent angiogenesis pathways and other major intracellular signaling pathways involved in the pathogenesis of mCRC as an attempt to find predictors of clinical outcome. Forty-six patients treated with first-line bevacizumab-based chemotherapy were included in this study with a 5 year follow up. Genomic DNA was isolated from whole blood for the analysis of VEGF-A (rs2010963, 1570360, rs699947), ICAM-1 (rs5498, rs1799969) SNPs and from tumor tissue for the detection of genomic variants in KRAS, NRAS, BRAF genes. PCR and next generation sequencing were used for the analysis. The endpoints of the study were progression-free survival (PFS) and overall survival (OS). The VEGF-A rs699947 A/A allele was associated with increased PFS (p = 0.006) and OS (p = 0.043). The ICAM-1 rs1799969 G/A allele was associated with prolonged OS (p = 0.036). Finally, BRAF wild type was associated with increased OS (p = 0.027). We identified VEGF-A and ICAM-1 variants in angiogenesis and other major intracellular signaling pathways, such as BRAF, that can predict clinical outcome upon bevacizumab administration. These identified biomarkers could be used to select patients with mCRC who may achieve long-term responses and benefit from bevacizumab-based therapies.

The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis.

BACKGROUND: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. AIM: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. METHODS: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation. RESULTS: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. CONCLUSION: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.

Non-invasive markers of liver fibrosis in fatty liver disease are unreliable in people of South Asian descent.

OBJECTIVE: Liver biopsy is the most accurate method for determining stage and grade of injury in non-alcoholic fatty liver disease (NAFLD). Given risks and limitations of biopsy, non-invasive tests such as NAFLD fibrosis score, aspartate transaminase (AST) to platelet ratio index, Fib-4, AST/alanine transaminase ratio and BARD are used. Prevalence and severity of NAFLD and metabolic syndrome vary by ethnicity, yet tests have been developed in largely white populations. We tested our hypothesis that non-invasive tests that include metabolic parameters are less accurate in South Asian compared with white patients. DESIGN: Retrospective cross-sectional. SETTING: Specialist liver centre. PATIENTS: Patients with histologically confirmed NAFLD. INTERVENTIONS: Scores calculated using clinical data taken within 1 week and compared with histology (Kleiner). MAIN OUTCOME MEASURES: Diagnostic test characteristics. RESULTS: 175 patients were identified. South Asians (n=90) were younger, had lower body mass index and lower proportion of obesity compared with white patients (n=79), with comparable rates of diabetes and liver injury. Tests are less sensitive at detecting advanced fibrosis in South Asian compared with white patients. Relative risk of correct diagnosis in white patients compared with South Asians is 1.86 (95% CI 1.4 to 2.6). In binary logistic regression models, ethnicity and platelet count predicted accuracy. Transient elastography was equally and highly accurate in both ethnicities. CONCLUSIONS: Blood test-based non-invasive scores are less accurate in South Asian patients, irrespective of metabolic parameters. Ethnicity should be considered when devising risk-stratification algorithms for NAFLD.

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) has a bidirectional association with metabolic syndrome. It affects up to 30% of the general population, 70% of individuals with diabetes and 90% with obesity. The main histological hallmark of progressive NAFLD is fibrosis. There is a bidirectional epidemiological link between periodontitis and metabolic syndrome. NAFLD, periodontitis and diabetes share common risk factors, are characterised by inflammation and associated with changes in commensal bacteria. Therefore we tested the hypothesis that periodontitis is associated with NAFLD and with significant fibrosis in two study groups. METHODS: We analyzed data from a population-based survey and a patient-based study. NHANES III participants with abdominal ultrasound and sociodemographic, clinical, and oral examination data were extracted and appropriate weighting applied. In a separate patient-based study, consenting patients with biopsy-proved NAFLD (or with liver indices too mild to justify biopsy) underwent dental examination. Basic Periodontal Examination score was recorded. RESULTS: In NHANES, periodontitis was significantly associated with steatosis in 8172 adults even after adjusting for sociodemographic factors. However, associations were fully explained after accounting for features of metabolic syndrome. In the patient-based study, periodontitis was significantly more common in patients with biopsy-proven NASH and any fibrosis (F0-F4) than without NASH (p = 0.009). Periodontitis was more common in patients with NASH and significant fibrosis (F2-4) than mild or no fibrosis (F0-1, p = 0.04). CONCLUSIONS: Complementary evidence from an epidemiological survey and a clinical study show that NAFLD is associated with periodontitis and that the association is stronger with significant liver fibrosis.