Development and validation of a faecal immunochemical test-based model in the work-up of patients with iron deficiency anaemia.

Objective: In patients with iron deficiency anaemia (IDA), the diagnostic yield of gastroscopy and colonoscopy (bidirectional endoscopy) in detecting neoplastic lesions is low. This study aimed to develop and validate a faecal immunochemical test (FIT)-based model to optimise the work-up of patients with IDA. Methods: Outpatients with IDA were enrolled in a prospective, multicentre study from April 2016 to October 2019. One FIT was performed before bidirectional endoscopy. Significant gastrointestinal lesions were recorded and a combined model developed with variables that were independently associated with significant colorectal lesions in the multivariate analysis. The model cut-off was selected to provide a sensitivity of at least 95% for colorectal cancer (CRC) detection, and its performance was compared to different FIT cut-offs. The data set was randomly split into two groups (developed and validation cohorts). An online calculator was developed for clinical application. Results: The development and validation cohorts included 373 and 160 patients, respectively. The developed model included FIT value, age, and sex. In the development and validation cohorts, a model cut-off of 0.1375 provided a negative predictive value of 98.1 and 96.7% for CRC and 90.7 and 88.3% for significant colorectal lesions, respectively. This combined model reduced the rate of missed significant colorectal lesions compared to FIT alone and could have avoided more than one-fourth of colonoscopies. Conclusion: The FIT-based combined model developed in this study may serve as a useful diagnostic tool to triage IDA patients for early endoscopic referral, resulting in considerable reduction of unnecessary colonoscopies.

Psoriasis induced by antiTNF therapy in inflammatory bowel disease: Therapeutic management and evolution of both diseases in a nationwide cohort study.

BACKGROUND: some patients with inflammatory bowel disease (IBD) treated with antiTNF develop drug-induced psoriasis (antiTNF-IP). Several therapeutic strategies are possible. AIMS: to assess the management of antiTNF-IP in IBD, and its impact in both diseases. METHODS: patients with antiTNF-IP from ENEIDA registry were included. Therapeutic strategy was classified as continuing the same antiTNF, stopping antiTNF, switch to another antiTNF or swap to a non-antiTNF biologic. IP severity and IBD activity were assessed at baseline and 16, 32 and 54 weeks. RESULTS: 234 patients were included. At baseline, antiTNF-IP was moderate-severe in 60 % of them, and IBD was in remission in 80 %. Therapeutic strategy was associated to antiTNF-IP severity (p < 0.001). AntiTNF-IP improved at week 54 with all strategies, but continuing with the same antiTNF showed the worst results (p = 0.042). Among patients with IBD in remission, relapse was higher in those who stopped antiTNF (p = 0.025). In multivariate analysis, stopping antiTNF, trunk and palms and soles location were associated with antiTNF-IP remission; female sex and previous surgery in Crohn´s disease with IBD relapse. CONCLUSION: skin lesions severity and IBD activity seem to determine antiTNF-IP management. Continuing antiTNF in mild antiTNF-IP, and swap to ustekinumab or switch to another antiTNF in moderate-severe cases, are suitable strategies.

Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).

BACKGROUND: Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection. METHODS AND FINDINGS: This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up. CONCLUSIONS: In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02567045).

Serum Levels of Lipoprotein Lipase Are Increased in Patients with Inflammatory Bowel Disease.

Disruption of the lipid profile is commonly found in patients with inflammatory bowel disease (IBD). Lipoprotein lipase (LPL) is a key molecule involved in triglyceride metabolism that plays a significant role in the progression of atherosclerosis. In this study, our aim was to study whether serum LPL levels are different in IBD patients and controls and whether IBD features are related to LPL. This was a cross-sectional study that encompassed 405 individuals; 197 IBD patients with a median disease duration of 12 years and 208 age- and sex-matched controls. LPL levels and a complete lipid profile were assessed in all individuals. A multivariable analysis was performed to determine whether LPL serum levels were altered in IBD and to study their relationship with IBD characteristics. After the fully multivariable analysis, including cardiovascular risk factors and the changes in lipid profile that the disease causes itself, patients with IBD showed significantly higher levels of circulating LPL (beta coefficient 196 (95% confidence interval from 113 to 259) ng/mL, p < 0.001). LPL serum levels did not differ between Crohn's disease and ulcerative colitis. However, serum C-reactive protein levels, disease duration, and the presence of an ileocolonic Crohn's disease phenotype were found to be significantly and independently positively related to LPL. In contrast, LPL was not associated with subclinical carotid atherosclerosis. In conclusion, serum LPL levels were independently upregulated in patients with IBD. Inflammatory markers, disease duration and disease phenotype were responsible for this upregulation.

Efficacy, Efficiency, and Acceptability of Telemedicine for Inflammatory Bowel Disease Patients' Follow-Up Care during the COVID-19 Pandemic.

BACKGROUND: During the COVID-19 pandemic, ambulatory clinic visits were replaced by the implementation of telehealth modalities in most inflammatory bowel disease (IBD) units. AIMS: The aim of this study was to assess the efficacy, efficiency, patient satisfaction, and acceptability of using telephone consultation in an IBD unit. METHODS: A prospective cohort study was performed in IBD patients who underwent telephone consultation during COVID-19 lockdown (between 16th March and 13th April 2020). To assess the efficacy of this telephone consultation (lockdown visit), nonscheduled visits, emergency consultation, hospital admission, and surgery from lockdown visit to the next scheduled consultation (post-lockdown) were checked. To evaluate efficiency, the time between lockdown visit and post-lockdown consultation was compared with previous consultation (pre-lockdown), and the total number of visits 12 months before and after lockdown visit was checked. A telephone survey was designed to rate perception for a telephone consultation. RESULTS: Out of a total of 274 patients, 220 patients (52.2% male; mean age 49 ± 16 years; Crohn's disease, n = 126; ulcerative colitis, n = 83; indeterminate colitis, n = 11) were included. Only one patient was consulted at the emergency department, 11 patients needed to rearrange the visit, and none patient underwent surgery before the scheduled post-lockdown visit. The interval to post-lockdown visit compared to pre-lockdown visit increased in 37.7% of patients. The satisfaction survey (n = 185) revealed that 94.6% perceived it was effective. However, 44.4% of patients rather prefer on-site consultation for follow-up. CONCLUSIONS: Telemedicine during the COVID-19 pandemic was shown to be effective and efficient to care for IBD patients. In addition, telephone consultation is well accepted by patients in non-extended follow-up periods.

Definition of a therapeutic range for predicting long-term infliximab response in patients with inflammatory bowel disease.

INTRODUCTION: Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD. METHODS: This single-centre retrospective study (2017-2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined. RESULTS: Multivariate analysis determined that IFX concentrations>7µg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7µg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3µg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044). CONCLUSIONS AND RELEVANCE: The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance.

Differentially Deregulated MicroRNAs as Novel Biomarkers for Neoplastic Progression in Ulcerative Colitis.

INTRODUCTION: Colorectal cancer (CRC) is a potentially life-threatening complication of long-standing ulcerative colitis (UC). MicroRNAs (miRNA) are epigenetic regulators that have been involved in the development of UC-associated CRC. However, their role as potential mucosal biomarkers of neoplastic progression has not been adequately studied. METHODS: In this study, we analyzed the expression of 96 preselected miRNAs in human formalin-fixed and paraffin-embedded tissue of 52 case biopsies (20 normal mucosa, 20 dysplasia, and 12 UC-associated CRCs) and 50 control biopsies (10 normal mucosa, 21 sporadic adenomas, and 19 sporadic CRCs) by using Custom TaqMan Array Cards. For validation of deregulated miRNAs, we performed individual quantitative real-time polymerase chain reaction in an independent cohort of 50 cases (13 normal mucosa, 25 dysplasia, and 12 UC-associated CRCs) and 46 controls (7 normal mucosa, 19 sporadic adenomas, and 20 sporadic CRCs). RESULTS: Sixty-four miRNAs were found to be differentially deregulated in the UC-associated CRC sequence. Eight of these miRNAs were chosen for further validation. We confirmed miR-31, -106a, and -135b to be significantly deregulated between normal mucosa and dysplasia, as well as across the UC-associated CRC sequence (all P < 0.01). Notably, these miRNAs also confirmed to have a significant differential expression compared with sporadic CRC (all P < 0.05). DISCUSSION: UC-associated and sporadic CRCs have distinct miRNA expression patterns, and some miRNAs indicate early neoplastic progression.

Mutational signature profiling classifies subtypes of clinically different mismatch-repair-deficient tumours with a differential immunogenic response potential.

BACKGROUND: Mismatch repair (MMR) deficiency is the hallmark of tumours from Lynch syndrome (LS), sporadic MLH1 hypermethylated and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterisation to identify novel features that can impact tumour behaviour and clinical management. METHODS: We tested 105 MMR-deficient colorectal cancer tumours (25 LS, 35 LLS and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load. RESULTS: Fifty-three percent of tumours showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumours. Thirty-one percent of tumours showed weaker features of MMR deficiency, 62% lost MSH2/MSH6 expression and included 60% of LS and 44% of LLS tumours. Remarkably, 9% of all tumours lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumours that show the strongest contribution of MMR-deficient tumours. CONCLUSIONS: Next-generation sequencing approaches allow for a granular molecular characterisation of MMR-deficient tumours, which can be essential to properly diagnose and treat patients with these tumours in the setting of personalised medicine.

Quality of Colonoscopy Is Associated With Adenoma Detection and Postcolonoscopy Colorectal Cancer Prevention in Lynch Syndrome.

BACKGROUND & AIMS: Colonoscopy reduces colorectal cancer (CRC) incidence and mortality in Lynch syndrome (LS) carriers. However, a high incidence of postcolonoscopy CRC (PCCRC) has been reported. Colonoscopy is highly dependent on endoscopist skill and is subject to quality variability. We aimed to evaluate the impact of key colonoscopy quality indicators on adenoma detection and prevention of PCCRC in LS. METHODS: We conducted a multicenter study focused on LS carriers without previous CRC undergoing colonoscopy surveillance (n = 893). Incident colorectal neoplasia during surveillance and quality indicators of all colonoscopies were analyzed. We performed an emulated target trial comparing the results from the first and second surveillance colonoscopies to assess the effect of colonoscopy quality indicators on adenoma detection and PCCRC incidence. Risk analyses were conducted using a multivariable logistic regression model. RESULTS: The 10-year cumulative incidence of adenoma and PCCRC was 60.6% (95% CI, 55.5%-65.2%) and 7.9% (95% CI, 5.2%-10.6%), respectively. Adequate bowel preparation (odds ratio [OR], 2.07; 95% CI, 1.06-4.3), complete colonoscopies (20% vs 0%; P = .01), and pan-chromoendoscopy use (OR, 2.14; 95% CI, 1.15-3.95) were associated with significant improvement in adenoma detection. PCCRC risk was significantly lower when colonoscopies were performed during a time interval of less than every 3 years (OR, 0.35; 95% CI, 0.14-0.97). We observed a consistent but not significant reduction in PCCRC risk for a previous complete examination (OR, 0.16; 95% CI, 0.03-1.28), adequate bowel preparation (OR, 0.64; 95% CI, 0.17-3.24), or previous use of high-definition colonoscopy (OR, 0.37; 95% CI, 0.02-2.33). CONCLUSIONS: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals of less than 3 years are associated with a reduction of PCCRC incidence. In LS, high-quality colonoscopy surveillance is of utmost importance for CRC prevention.

Re-induction With Intravenous Ustekinumab in Patients With Crohn's Disease and a Loss of Response to This Therapy.

BACKGROUND: A significant percentage of patients treated with ustekinumab may lose response. Our aim was to evaluate the short-term efficacy and safety of intravenous re-induction with ustekinumab in patients with Crohn's disease who have lost the response to the treatment. METHODS: This is a retrospective, observational, multicenter study. Treatment efficacy was measured at week 8 and 16; clinical remission was defined when the Harvey-Bradshaw Index was ≤4 points, and clinical response was defined as a decrease of ≥3 points in the index compared with the baseline. Adverse events and treatment decisions after re-induction were also collected. RESULTS: Fifty-three patients from 13 centers were included. Forty-nine percent had previously failed to respond to 2 biological treatments, and 24.5% had failed to respond to 3. The average exposure time to ustekinumab before re-induction was 17.7 ± 12.8 months. In 56.6% of patients, the administration interval had been shortened to every 4 to 6 weeks before re-induction. At week 8 and 16 after re-induction, 49.0% (n = 26) and 43.3% (n = 23), respectively, were in remission, whereas 64.1% (n = 34) and 52.8% (n = 28) had a clinical response. Patients who achieved remission at week 16 had lower C-reactive protein levels than those who did not respond (2.8 ± 1.6 vs 12.5 ± 9.5 mg/dL; P = 0.001). No serious adverse events related to re-induction were observed. CONCLUSION: Intravenous re-induction with ustekinumab is an effective and safe strategy that recovers the response in approximately half of the patients with refractory Crohn's disease who experience a loss of response. Re-induction can be attempted before switching out of the therapy class.

Adherence to subcutaneous biologic treatment for inflammatory bowel disease.

BACKGROUND: Nonadherence to medication is common in patients with inflammatory bowel disease (IBD) and can result in disease complications, therapy escalation, and the need for corticosteroids. The aim of this study was to assess the adherence to self-administered subcutaneous biologic medications prescribed for IBD and to identify the risk factors for nonadherence. METHODS: A retrospective cohort study on IBD patients initiated on subcutaneous biologic therapy between January 2016 and July 2019 was performed. Medical records were retrospectively reviewed for collection of demographic and IBD data. Medication possession ratios (mMPRs) during the first 12 months of treatment and at the end of the follow-up period (global, 42 months) were calculated. Nonadherence was defined as an mMPR of <90%. Multiple regression analysis was performed to assess the risk factors for nonadherence to therapy. RESULTS: A total of 154 patients (84 male and 70 female; mean age at biologic treatment initiation, 36±14 years; Crohn's disease, n=118; ulcerative colitis, n=31; indeterminate colitis, n=5) were included; 121 received adalimumab (ADA) and 33 received ustekinumab (UST); 63% were naive to anti-TNF therapy, while 16.9% previously received more than two biologic treatments. Mean time from IBD diagnosis to subcutaneous biological agent use was 16±10 months. Mean duration of subcutaneous agent use was 17.6 (SD, 11.0) and 17.08 (SD, 6.8) months for ADA and UST, respectively. Global nonadherence (mMPR≤90%) rate was 6.6% for all patients receiving subcutaneous treatment, 6.3% for ADA, and 6.5% for UST. Nonadherence during the first 12 months of treatment (n=98) was 6.1% for all patients, 2.7% for ADA, and 16% for UST. In the multivariate analysis, UST use was independently associated with higher nonadherence only within the first 12 months (OR, 6.7; 95% CI, 1.1-39.5). CONCLUSIONS: High global adherence to self-administered subcutaneous biologic treatment was shown in our study, with higher rates of adherence to ADA than to UST within the first 12 months.

Safety and effectiveness of vedolizumab in paediatric patients with inflammatory bowel disease: an observational multicentre Spanish study.

Vedolizumab is a humanised monoclonal antibody that binds to integrin α4ß7 expressed in T-cells, inhibiting its binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is specifically expressed in the small intestine and colon, playing a fundamental role in T-cell migration to the gastrointestinal tract. Vedolizumab has been shown to be effective in treating adults with inflammatory bowel disease; however, efficacy data for paediatric use are scarce. The objective of the present study was to assess the effectiveness and safety of vedolizumab for inducing and maintaining clinical remission in children with inflammatory bowel disease. We conducted a retrospective multicentre study of patients younger than 18 years with inflammatory bowel disease refractory to anti-tumour necrosis factor alpha (anti-TNF-α) drugs, who underwent treatment with vedolizumab. Clinical remission was defined as a score < 10 points in the activity indices. We included 42 patients, 22 of whom were male (52.3%), with a median age of 13.1 years (IQR 10.2-14.2) at the start of treatment. Of the 42 patients, 14 (33.3%) had Crohn's disease (CD) and 28 (66.7%) had ulcerative colitis (UC). At the start of treatment with vedolizumab, the Paediatric Crohn's Disease Activity Index was 36 (IQR 24-40) and the Paediatric Ulcerative Colitis Activity Index was 47 (IQR 25-65). All of them had received prior treatment with anti-TNF and 3 patients ustekinumab. At week 14, 69% of the patients responded to the treatment (57.1% of those with CD and 75% of those with UC; p=0.238), and 52.4% achieved remission (35.7% with CD and 60.7% with UC; p=0.126). At 30 weeks, the response rate was 66.7% (46.2% and 78.3% for CD and UC, respectively; p=0.049), and 52.8% achieved remission (30.8% and 65.2% for CD and UC, respectively; p=0.047). Among the patients with remission at week 14, 80% of the patients with CD and 84.5% of those with UC maintained the remission at 52 weeks. Adverse effects were uncommon and mild. Three patients (7.1%) presented headaches, 1 presented alopecia, 1 presented anaemia and 1 presented dermatitis.Conclusion: The results show that treatment with vedolizumab is a safe and effective option for achieving clinical remission in paediatric patients with inflammatory bowel disease with primary failure or loss of response to other treatments, especially in UC. What is Known: • Vedolizumab is effective in inducing and maintaining remission in adult patients with inflammatory bowel disease. • Most studies and clinical trials have been performed on adult populations, and there is currently no indication for paediatric populations. What is New: • Children with inflammatory bowel disease refractory to anti-TNF presented higher clinical remission rates than those published for adults. • There are few publications of this magnitude on paediatric populations treated with vedolizumab and with long-term follow-up (52 weeks).

Polypropylene and polyvinylidene fluoride transobturator slings for the treatment of female stress urinary incontinence: 1-Year outcomes from a multicentre randomized trial.

AIMS: To compare the effectiveness and safety of polypropylene (PP) and polyvinylidene fluoride (PVDF) transobturator tapes (TOT) for the treatment of female stress urinary incontinence (SUI). METHODS: This is a multicentre randomized trial. Women with SUI or stress-predominant mixed urinary incontinence and scheduled for a TOT procedure were randomized to PP or PVDF slings. The primary outcome was 1-year cure or improvement rate using composite criteria. Complications were also compared. Relationships with outcomes were analyzed using multivariable logistic regressions models. RESULTS: From April 2016 to January 2018 285 participants were randomized. PP and PVDF slings showed similar high cure or improvement rate (91.0% vs. 95.6%, p = .138). Improvement in validated questionnaires was also similar. PVDF slings were associated with a lower rate of de novo urgency incontinence (adjusted odds ratio = 0.35; 95% confidence interval = 0.15-0.80). We found no statistical differences in complications rates, although a higher incidence of long-term pain events were observed in the PP group. The study is underpowered to find differences in specific complications owing to the low number of events. CONCLUSION: PP and PVDF TOTs are equally effective, although PVDF is associated with fewer cases of de novo urgency incontinence. Further studies are needed to give robust conclusions on safety profiles.

Risk of Cancer in Family Members of Patients with Lynch-Like Syndrome.

Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56-2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67-4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44-2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26-5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

Usefulness of magnetic resonance enterography in the clinical decision-making process for patients with inflammatory bowel disease.

OBJECTIVE: To evaluate the impact of magnetic resonance enterography (MRE) diagnosis on clinical decision-making regarding treatment choice and maintenance of treatment over time in patients with inflammatory bowel disease (IBD). METHODS: A cohort of patients who underwent MRE for IBD assessment between 2011 and 2014 was analyzed. From clinical records, we retrospectively retrieved their demographic data and clinical data on their IBD at the time of MRE, the results of MRE and the patient's clinical course. Medical management decisions made during the three months following MRE and at the 15-month follow-up were assessed. RESULTS: In total, 474 MREs were reviewed. In the first three-month period, MRE results led to changes in the medical management of 266 patients (56.1%). Of those, maintenance therapy was altered in 140 patients (68.3%) (90.7% step-up and 9.3% top-down strategy), 65 (24.4%) were prescribed a course of steroids and 61 (22.9%) underwent surgery. MRE confirmed a CD diagnosis in 14/41 patients (34.1%) previously diagnosed with indeterminate colitis or ulcerative colitis and in 4/18 patients (22.2%) with suspected IBD. At the 15-month follow-up, treatment remained unchanged in 289 patients (65.8%). CONCLUSIONS: These results suggest that MRE is a diagnostic tool that provides valid information for the clinical-decision making process for patients with CD.

Metallodrugs are unique: opportunities and challenges of discovery and development.

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

Clinical and Pathological Characterization of Lynch-Like Syndrome.

BACKGROUND & AIMS: Lynch syndrome is characterized by DNA mismatch repair (MMR) deficiency. Some patients with suspected Lynch syndrome have DNA MMR deficiencies but no detectable mutations in genes that encode MMR proteins-this is called Lynch-like syndrome (LLS). There is no consensus on management of patients with LLS. We collected data from a large series of patients with LLS to identify clinical and pathology features. METHODS: We collected data from a nationwide-registry of patients with colorectal cancer (CRC) in Spain. We identified patients whose colorectal tumors had loss of MSH2, MSH6, PMS2, or MLH1 (based on immunohistochemistry), without the mutation encoding V600E in BRAF (detected by real-time PCR), and/or no methylation at MLH1 (determined by methylation-specific multiplex ligation-dependent probe amplification), and no pathogenic mutations in MMR genes, BRAF, or EPCAM (determined by DNA sequencing). These patients were considered to have LLS. We collected data on demographic, clinical, and pathology features and family history of neoplasms. The χ2 test was used to analyze the association between qualitative variables, followed by the Fisher exact test and the Student t test or the Mann-Whitney test for quantitative variables. RESULTS: We identified 160 patients with LLS; their mean age at diagnosis of CRC was 55 years and 66 patients were female (41%). The Amsterdam I and II criteria for Lynch syndrome were fulfilled by 11% of cases and the revised Bethesda guideline criteria by 65% of cases. Of the patients with LLS, 24% were identified in universal screening. There were no proportional differences in sex, indication for colonoscopy, immunohistochemistry, pathology findings, or personal history of CRC or other Lynch syndrome-related tumors between patients who met the Amsterdam and/or Bethesda criteria for Lynch syndrome and patients identified in universal screening for Lynch syndrome, without a family history of CRC. CONCLUSIONS: Patients with LLS have homogeneous clinical, demographic, and pathology characteristics, regardless of family history of CRC.

Redesigning the Coumarin Scaffold into Small Bright Fluorophores with Far-Red to Near-Infrared Emission and Large Stokes Shifts Useful for Cell Imaging.

Among the palette of previously described fluorescent organic molecules, coumarins are ideal candidates for developing cellular and molecular imaging tools due to their high cell permeability and minimal perturbation of living systems. However, blue-to-cyan fluorescence emission is usually difficult in in vivo applications due to the inherent toxicity and poor tissue penetration of short visible light wavelengths. Here, we introduce a new family of coumarin-based fluorophores, nicknamed COUPY, with promising photophysical properties, including emission in the far-red/near-infrared (NIR) region, large Stokes shifts, high photostability, and excellent brightness. COUPY fluorophores were efficiently synthesized in only three linear synthetic steps from commercially available precursors, with the N-alkylation of a pyridine moiety being the key step at the end of the synthetic route, as it allows for the tuning of the photophysical properties of the resulting dye. Owing to their low molecular weights, COUPY dyes show excellent cell permeability and accumulate selectively in nucleoli and/or mitochondria of HeLa cells, as their far-red/NIR fluorescence emission is easily detected at a concentration as low as 0.5 µM after an incubation of only 20 min. We anticipate that these coumarin scaffolds will open a way to the development of novel coumarin-based far-red to NIR emitting fluorophores with potential applications for organelle imaging and biomolecule labeling.

Early Colonoscopy Improves the Outcome of Patients With Symptomatic Colorectal Cancer.

BACKGROUND: Long waiting times from early symptoms to diagnosis and treatment may influence the staging and prognosis of patients with colorectal cancer. We analyzed the effect of colonoscopy timing on the outcome of these patients. OBJECTIVE: This study aimed to compare the outcome (tumoral staging and long-term survival) of patients with suspected colorectal cancer according to diagnostic colonoscopy timing. DESIGN: This study is an analysis of a prospectively maintained database. SETTINGS: The study was conducted at the Open Access Endoscopy Service of the tertiary public healthcare center Hospital Universitario de Canarias, in the Spanish island of Tenerife. PATIENTS: Consecutive patients diagnosed of colorectal cancer between February 2008 and October 2010, fulfilling 1 or more National Institute for Health and Clinical Excellence criteria, were assigned to early colonoscopy (<30 days from referral) or to standard-schedule colonoscopy at the discretion of the referring physician. Tumor staging (TNM classification) at diagnosis and long-term survival after treatment were compared in both strategies. MAIN OUTCOME MEASURES: The primary outcomes measured were the stage at presentation and overall survival, as determined by prompt or standard referral. RESULTS: Overall, 257 patients with colorectal cancer were diagnosed (101 at early colonoscopy and 156 at standard-schedule colonoscopy). TNM stages I and II were found in 52 (54.2%) and 60 (41.7%) patients in the early colonoscopy group and standard-schedule colonoscopy group. Stage IV was confirmed in 13 patients (13.5%) diagnosed in the early colonoscopy group and in 40 (28%) detected in the standard-schedule colonoscopy group. Survival rates at 12 and 60 months after treatment were significantly higher in the early colonoscopy group compared with the standard-schedule colonoscopy group (p < 0.001). LIMITATIONS: Controlled randomization of early versus standard-referral colonoscopy, size and scope of analysis, the time interval from symptom onset to first physician assessment, and the different locations of colorectal cancer between groups were limitations of the study. CONCLUSIONS: Colonoscopy within 30 days from referral improves outcome in patients with symptomatic colorectal cancer. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.

Rate of detection of advanced neoplasms in proximal colon by simulated sigmoidoscopy vs fecal immunochemical tests.

BACKGROUND & AIMS: We compared the ability of biennial fecal immunochemical testing (FIT) and one-time sigmoidoscopy to detect colon side-specific advanced neoplasms in a population-based, multicenter, nationwide, randomized controlled trial. METHODS: We identified asymptomatic men and women, 50-69 years old, through community health registries and randomly assigned them to groups that received a single colonoscopy examination or biennial FIT. Sigmoidoscopy yield was simulated from results obtained from the colonoscopy group, according to the criteria proposed in the UK Flexible Sigmoidoscopy Trial for colonoscopy referral. Patients who underwent FIT and were found to have ≥75 ng hemoglobin/mL were referred for colonoscopy. Data were analyzed from 5059 subjects in the colonoscopy group and 10,507 in the FIT group. The main outcome was rate of detection of any advanced neoplasm proximal to the splenic flexure. RESULTS: Advanced neoplasms were detected in 317 subjects (6.3%) in the sigmoidoscopy simulation group compared with 288 (2.7%) in the FIT group (odds ratio for sigmoidoscopy, 2.29; 95% confidence interval, 1.93-2.70; P = .0001). Sigmoidoscopy also detected advanced distal neoplasia in a higher percentage of patients than FIT (odds ratio, 2.61; 95% confidence interval, 2.20-3.10; P = .0001). The methods did not differ significantly in identifying patients with advanced proximal neoplasms (odds ratio, 1.17; 95% confidence interval, 0.78-1.76; P = .44). This was probably due to the lower performance of both strategies in detecting patients with proximal lesions (sigmoidoscopy detected these in 19.1% of patients and FIT in 14.9% of patients) vs distal ones (sigmoidoscopy detected these in 86.8% of patients and FIT in 33.5% of patients). Sigmoidoscopy, but not FIT, detected proximal lesions in lower percentages of women (especially those 50-59 years old) than men. CONCLUSIONS: Sigmoidoscopy and FIT have similar limitations in detecting advanced proximal neoplasms, which depend on patients' characteristics; sigmoidoscopy underperforms for women 50-59 years old. Screening strategies should be designed on the basis of target population to increase effectiveness and cost-effectiveness. ClinicalTrials.gov number: NCT00906997.