Publications by authors named "Luis Bujanda"

271 Publications

Germline and Somatic Whole-Exome Sequencing Identifies New Candidate Genes Involved in Familial Predisposition to Serrated Polyposis Syndrome.

Cancers (Basel) 2021 Feb 23;13(4). Epub 2021 Feb 23.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, Spain.

The serrated polyposis syndrome (SPS) is the most common and yet underdiagnosed colorectal polyposis syndrome. It is characterized by multiple and/or large colonic serrated polyps and a higher associated risk for colorectal cancer (CRC). The main objective of this study was to identify new candidate genes involved in the germline predisposition to SPS/CRC. Thirty-nine SPS patients from 16 families (≥2 patients per family) were recruited without alterations in well-known hereditary CRC genes, and germline and somatic whole-exome sequencing were performed. Germline rare variants with plausible pathogenicity, located in genes involved in cancer development, senescence and epigenetic regulation were selected. Somatic mutational profiling and signature analysis was pursued in one sample per family, when possible. After data filtering, , , , , , , , , , , , , and were highlighted as the more promising candidate genes for SPS germline predisposition with potentially pathogenic variants shared within families. Somatic analysis characterized mutational profiles in advanced serrated polyps/tumors, revealing a high proportion of hypermutated samples, with a prevalence of clock-like mutational signatures in most samples and the presence of DNA mismatch repair-defective signatures in some cases. In conclusion, we identified new candidate genes to be involved in familial SPS. Further functional studies and replication in additional cohorts are required to confirm the selected candidates.
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http://dx.doi.org/10.3390/cancers13040929DOI Listing
February 2021

Clinical correlates of anti-SARS-CoV-2 antibody profiles in Spanish COVID-19 patients from a high incidence region.

Sci Rep 2021 02 23;11(1):4363. Epub 2021 Feb 23.

Institute of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany.

Laboratory testing for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consists of two pillars: the detection of viral RNA via rt-PCR as the diagnostic gold standard in acute cases, and the detection of antibodies against SARS-CoV-2. However, concerning the latter, questions remain about their diagnostic and prognostic value and it is not clear whether all patients develop detectable antibodies. We examined sera from 347 Spanish COVID-19 patients, collected during the peak of the epidemic outbreak in Spain, for the presence of IgA and IgG antibodies against SARS-CoV-2 and evaluated possible associations with age, sex and disease severity (as measured by duration of hospitalization, kind of respiratory support, treatment in ICU and death). The presence and to some degree the levels of anti-SARS-CoV-2 antibodies depended mainly on the amount of time between onset of symptoms and the collection of serum. A subgroup of patients did not develop antibodies at the time of sample collection. Compared to the patients that did, no differences were found. The presence and level of antibodies was not associated with age, sex, duration of hospitalization, treatment in the ICU or death. The case-fatality rate increased exponentially with older age. Neither the presence, nor the levels of anti-SARS-CoV-2 antibodies served as prognostic markers in our cohort. This is discussed as a possible consequence of the timing of the sample collection. Age is the most important risk factor for an adverse outcome in our cohort. Some patients appear not to develop antibodies within a reasonable time frame. It is unclear, however, why that is, as these patients differ in no respect examined by us from those who developed antibodies.
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http://dx.doi.org/10.1038/s41598-021-83969-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902674PMC
February 2021

Identification of New Genes Involved in Germline Predisposition to Early-Onset Gastric Cancer.

Int J Mol Sci 2021 Jan 28;22(3). Epub 2021 Jan 28.

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036 Barcelona, Spain.

The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, , , and seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
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http://dx.doi.org/10.3390/ijms22031310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866206PMC
January 2021

Room for Improvement in the Treatment of Helicobacter pylori Infection: Lessons from the European Registry on H. pylori Management (Hp-EuReg).

J Clin Gastroenterol 2021 Jan 5;Publish Ahead of Print. Epub 2021 Jan 5.

Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) Digestive Service, HM Sanchinarro, Madrid Digestive Unit, Agencia Sanitaria Costa del Sol, Marbella, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Málaga Digestive Unit, Hospital de Valme, Sevilla Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). Universidad del País Vasco (UPV/EHU), Donostia Hospital de Tomelloso, Ciudad Real, Tomelloso Gastroenterology Unit, Hospital Universitario Central de Asturias, Oviedo Hospital General Universitario de Valencia, Valencia Hospital San Pedro de Alcántara, Cáceres Hospital Río Hortega Hospital Clínico Universitario, Valladolid, Spain Department of Surgical and Clinical Sciences, University of Bologna, Bologna Gastronterology Area, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy Gastroenterology Unit, AM DC Rogaska, Rogaska Slatina DC Bled Slovenj Gradec General Hospital, Slovenj Gradec, Slovenia Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania Department of Pancreatobiliary and Upper GI Diseases, Moscow Clinical Scientific Center, and A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow Gastrocentre Perm, Perm Kazan State Medical University, Kazan, Russia Laboratoire de Bactériologie, Hôpital Pellegrin, Bordeaux Cedex, France Trinity College Dublin, Faculty of Health Sciences, Trinity College Dublin, Dublin/IE, Faculty of Health Sciences, Dublin, Ireland.

Background: Managing Helicobacter pylori infection requires constant decision making, and each decision is open to possible errors.

Aim: The aim was to evaluate common mistakes in the eradication of H. pylori, based on the "European Registry on Helicobacter pylori management".

Methods: European Registry on Helicobacter pylori management is an international multicentre prospective noninterventional registry evaluating the decisions and outcomes of H. pylori management by European gastroenterologists in routine clinical practice.

Results: Countries recruiting more than 1000 patients were included (26,340 patients). The most common mistakes (percentages) were: (1) To use the standard triple therapy where it is ineffective (46%). (2) To prescribe eradication therapy for only 7 to 10 days (69%). (3) To use a low dose of proton pump inhibitors (48%). (4) In patients allergic to penicillin, to prescribe always a triple therapy with clarithromycin and metronidazole (38%). (5) To repeat certain antibiotics after eradication failure (>15%). (6) Failing to consider the importance of compliance with treatment (2%). (7) Not to check the eradication success (6%). Time-trend analyses showed progressive greater compliance with current clinical guidelines.

Conclusion: The management of H. pylori infection by some European gastroenterologists is heterogeneous, frequently suboptimal and discrepant with current recommendations. Clinical practice is constantly adapting to updated recommendations, although this shift is delayed and slow.
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http://dx.doi.org/10.1097/MCG.0000000000001482DOI Listing
January 2021

European Registry on Management: Effectiveness of First and Second-Line Treatment in Spain.

Antibiotics (Basel) 2020 Dec 25;10(1). Epub 2020 Dec 25.

Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 28006 Madrid, Spain.

The management of infection has to rely on previous local effectiveness due to the geographical variability of antibiotic resistance. The aim of this study was to evaluate the effectiveness of first and second-line treatment in Spain, where the empirical prescription is recommended. A multicentre prospective non-interventional registry of the clinical practice of European gastroenterologists concerning infection (Hp-EuReg) was developed, including patients from 2013 until June 2019. Effectiveness was evaluated descriptively and through a multivariate analysis concerning age, gender, presence of ulcer, proton-pump inhibitor (PPI) dose, therapy duration and compliance. Overall, 53 Spanish hospitals were included, and 10,267 patients received a first-line therapy. The best results were obtained with the 10-day bismuth single-capsule therapy (95% cure rate by intention-to-treat) and with both the 14-day bismuth-clarithromycin quadruple (PPI-bismuth-clarithromycin-amoxicillin, 91%) and the 14-day non-bismuth quadruple concomitant (PPI-clarithromycin-amoxicillin-metronidazole, 92%) therapies. Second-line therapies were prescribed to 2448 patients, with most-effective therapies being the triple quinolone (PPI-amoxicillin-levofloxacin/moxifloxacin) and the bismuth-levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-amoxicillin) prescribed for 14 days (92%, 89% and 90% effectiveness, respectively), and the bismuth single-capsule (10 days, 88.5%). Compliance, longer duration and higher acid inhibition were associated with higher effectiveness. "Optimized" therapies achieve over 90% success in Spain.
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http://dx.doi.org/10.3390/antibiotics10010013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823881PMC
December 2020

RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease.

Gut 2020 Dec 24. Epub 2020 Dec 24.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal

Objective: Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.

Design: RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or -deficient () mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.

Results: RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in mice. Furthermore, 3 deficiency hampered tumourigenesis. Intriguingly, mice displayed increased body weight gain, while lipidomics showed that deletion of shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.

Conclusion: Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
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http://dx.doi.org/10.1136/gutjnl-2020-321767DOI Listing
December 2020

Predictive Value of Carcinoembryonic Antigen in Symptomatic Patients without Colorectal Cancer: A Post-Hoc Analysis within the COLONPREDICT Cohort.

Diagnostics (Basel) 2020 Dec 2;10(12). Epub 2020 Dec 2.

Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 32005 Ourense, Spain.

We aimed to assess the risk of cancer in patients with abdominal symptoms after a complete colonoscopy without colorectal cancer (CRC), according to the carcinoembryonic antigen (CEA) concentration, as well as its diagnostic accuracy. For this purpose, we performed a post-hoc analysis within a cohort of 1431 patients from the COLONPREDICT study, prospectively designed to assess the fecal immunochemical test accuracy in detecting CRC. Over 36.5 ± 8.4 months, cancer was detected in 115 (8%) patients. Patients with CEA values higher than 3 ng/mL revealed an increased risk of cancer (HR 2.0, 95% CI 1.3-3.1), CRC (HR 4.4, 95% CI 1.1-17.7) and non-gastrointestinal cancer (HR 1.7, 95% CI 1.0-2.8). A new malignancy was detected in 51 (3.6%) patients during the first year and three variables were independently associated: anemia (OR 2.8, 95% CI 1.3-5.8), rectal bleeding (OR 0.3, 95% CI 0.1-0.7) and CEA level >3 ng/mL (OR 3.4, 95% CI 1.7-7.1). However, CEA was increased only in 31.8% (95% CI, 16.4-52.7%) and 50% (95% CI, 25.4-74.6%) of patients with and without anemia, respectively, who would be diagnosed with cancer during the first year of follow-up. On the basis of this information, CEA should not be used to assist in the triage of patients presenting with lower bowel symptoms who have recently been ruled out a CRC.
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http://dx.doi.org/10.3390/diagnostics10121036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770570PMC
December 2020

Pathogenesis of Cholangiocarcinoma.

Annu Rev Pathol 2021 01 2;16:433-463. Epub 2020 Dec 2.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), 20014 San Sebastian, Spain; email:

Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.
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http://dx.doi.org/10.1146/annurev-pathol-030220-020455DOI Listing
January 2021

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

Clin Gastroenterol Hepatol 2020 Nov 3. Epub 2020 Nov 3.

Department of Gastroenterology, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Electronic address:

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 surgical 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.
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http://dx.doi.org/10.1016/j.cgh.2020.11.002DOI Listing
November 2020

Comparative Effects of Pterostilbene and Its Parent Compound Resveratrol on Oxidative Stress and Inflammation in Steatohepatitis Induced by High-Fat High-Fructose Feeding.

Antioxidants (Basel) 2020 Oct 24;9(11). Epub 2020 Oct 24.

Nutrition and Obesity group, Department of Nutrition and Food Science, Faculty of Pharmacy, University of the Basque Country (UPV/EHU), Lucio Lascaray Research Centre, 01006 Vitoria-Gasteiz, Spain.

Different studies have revealed that oxidative stress and inflammation are crucial in NAFLD (Non-alcoholic fatty liver disease). The aim of this study is to analyze whether pterostilbene and resveratrol are able to either avoid or delay the progression of non-alcoholic liver steatosis towards steatohepatitis. This has been performed by examining their effects on oxidative stress, inflammation, fibrosis and pre-carcinogenic stages. Rats were distributed into five experimental groups and were fed with either a standard diet or a high-fat high-fructose diet, supplemented or not with pterostilbene (15 or 30 mg/kg/d) or resveratrol (30 mg/kg/d), for 8 weeks. Liver histological analysis was carried out by haematoxylin-eosin staining. Serum and hepatic oxidative stress-related parameters were assessed using spectrophotometry, and the expression of genes related to inflammation, fibrosis and cancer by qRT-PCR. The dietary model used in this study led to the development of steatohepatitis, where rats displayed oxidative stress, inflammation and ballooning, although not fibrosis. It also modified the expression of hepatocarcinoma-related genes. The results show, for the first time, that pterostilbene was able to partially prevent these alterations, with the exception of changes in hepatocarcinoma-related genes, mainly at 30 mg/kg/d. Pterostilbene was more effective than its parent compound resveratrol, probably due to its high bioavailability and higher anti-oxidant and anti-inflammatory activities, attributable to its different chemical structure.
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http://dx.doi.org/10.3390/antiox9111042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690896PMC
October 2020

Surgery and emergency gastrointestinal endoscopy during the Covid-19 pandemic.

Gastroenterol Hepatol 2020 Sep 16. Epub 2020 Sep 16.

Department of Surgery, Hospital Universitary Donostia, Instituto Biodonostia, Spain.

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http://dx.doi.org/10.1016/j.gastrohep.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494326PMC
September 2020

European Registry on management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients.

Gut 2021 01 21;70(1):40-54. Epub 2020 Sep 21.

Gastroenterolgy Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Spain

Objective: The best approach for management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.

Design: International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed.

Results: 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%).

Conclusion: Management of infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.
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http://dx.doi.org/10.1136/gutjnl-2020-321372DOI Listing
January 2021

Antitumor Necrosis Factor Agents to Treat Endoscopic Postoperative Recurrence of Crohn's Disease: A Nationwide Study With Propensity-Matched Score Analysis.

Clin Transl Gastroenterol 2020 Aug;11(8):e00218

Gastroentorology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

Introduction: Patients with Crohn's disease experiencing endoscopic postoperative recurrence (POR) may benefit from antitumor necrosis factor (TNF) agents but scarce data on this are available. Our aim was to assess the efficacy of anti-TNF in improving mucosal lesions in patients with endoscopic POR.

Methods: Multicenter, retrospective, study of patients with Crohn's disease who underwent therapy with anti-TNF agents for endoscopic POR (Rutgeerts score > i1). Treatment outcomes were assessed by the findings in the last ileocolonoscopy performed after anti-TNF therapy was initiated. Endoscopic improvement and remission were defined as any reduction in the baseline Rutgeerts score and by a Rutgeerts score < i2, respectively.

Results: A total of 179 patients were included, 83 were treated with infliximab and 96 with adalimumab. Median time on anti-TNF therapy at the last endoscopic assessment was 31 months (interquartile range, 13-54). Endoscopic improvement was observed in 61%, including 42% who achieved endoscopic remission. Concomitant use of thiopurines and treatment with infliximab were associated with endoscopic improvement (odds ratio [OR] 2.15, 95% confidence interval [CI] 1.04-4.46; P = 0.03, and OR 2.34, 95% CI 1.18-4.62; P < 0.01, respectively) and endoscopic remission (OR 3.16, 95% CI 1.65-6.05; P < 0.01, and OR 2.01, 95% CI 1.05-3.88; P = 0.04, respectively) in the multivariable logistic regression analysis. These results were confirmed in a propensity-matched score analysis.

Discussion: In patients with endoscopic POR, anti-TNF agents improve mucosal lesions in almost two-thirds of the patients. In this setting, concomitant use of thiopurines and use of infliximab seem to be more effective in improving mucosal lesions.
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http://dx.doi.org/10.14309/ctg.0000000000000218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431219PMC
August 2020

Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models.

J Hepatol 2021 Feb 17;74(2):394-406. Epub 2020 Sep 17.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital -, University of the Basque Country (UPV/EHU), San Sebastian, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, "Instituto de Salud Carlos III"), Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain. Electronic address:

Background & Aims: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting.

Methods: Levels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry.

Results: Most SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis.

Conclusions: Cystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy.

Lay Summary: Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients.
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http://dx.doi.org/10.1016/j.jhep.2020.09.010DOI Listing
February 2021

TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms.

Gut 2020 Sep 9. Epub 2020 Sep 9.

Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain

Objective: Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis.

Design: TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and mice, and studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted.

Results: expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, animals developed more and larger tumours in fibrosis-associated HCC models. livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth through attenuated Wnt ligand secretion.

Conclusion: TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.
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http://dx.doi.org/10.1136/gutjnl-2019-319227DOI Listing
September 2020

Colorectal Cancer Survival in 50- to 69-Year-Olds after Introducing the Faecal Immunochemical Test.

Cancers (Basel) 2020 Aug 25;12(9). Epub 2020 Aug 25.

Gastroenterology Department, Osakidetza, Hospital Universitario Donostia, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), University of the Basque Country (UPV/EHU), 20014 San Sebastián, Spain.

Population screening has improved early diagnosis of colorectal cancer (CRC). Nonetheless, most cases are diagnosed in symptomatic patients. Faecal immunochemical testing has been recommended for assessing patients with lower gastrointestinal symptoms, but whether it improves patient survival is unknown. Our objective was to compare CRC survival in 50- to 69-year-olds between asymptomatic screen-detected patients and symptomatic patients by route to diagnosis.

Methods: We identified all cases of CRC diagnosed in 50-to 69-year-olds between 2009 and 2016, in Donostialdea (Gipuzkoa, Spain). Three groups were created: 1-screen-detected CRC; 2-CRC detected in symptomatic patients after a positive faecal immunochemical test(FIT); and 3-CRC detected in symptomatic patients without a FIT or after a negative result. We analysed survival using the Kaplan-Meier method and log-rank tests.

Results: Of 930 patients diagnosed with CRC, 433 cases were detected through screening and 497 in symptomatic patients, 7.9% after a positive FIT and 45.5% by other means. The 3-year CRC survival was significantly lower in group 3 (69.5%) than groups 1 (93%; = 0.007) or 2 (87.5%; = 0.02). The risk of death was lower in groups 1 (HR 0.42, 95% CI 0.30-0.58) and 2 (HR 0.51; 95% CI 0.29-0.87).

Conclusion: Half of CRC cases in 50- to 69-year-olds are diagnosed outside screening. Use of the FIT as a diagnostic strategy in symptomatic patients may improve survival.
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http://dx.doi.org/10.3390/cancers12092412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565457PMC
August 2020

Food groups, diet quality and colorectal cancer risk in the Basque Country.

World J Gastroenterol 2020 Jul;26(28):4108-4125

Department of Pharmacy and Food Sciences, Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz 01006, Spain.

Background: The results obtained to date concerning food groups, diet quality and colorectal cancer (CRC) risk vary according to criteria used and the study populations.

Aim: To study the relationships between food groups, diet quality and CRC risk, in an adult population of the Basque Country (North of Spain).

Methods: This observational study included 308 patients diagnosed with CRC and 308 age- and sex-matched subjects as controls. During recruitment, dietary, anthropometric, lifestyle, socioeconomic, demographic and health status information was collected. Adherence to the dietary recommendations was evaluated utilizing the Healthy Eating Index for the Spanish Diet and the MedDietScore. Conditional logistic regressions were used to evaluate the associations of food group intakes, diet quality scores, categorized in tertiles, with CRC risk.

Results: The adjusted models for potential confounding factors showed a direct association between milk and dairy products consumption, in particular high-fat cheeses [odds ratio (OR) third tertile first tertile = 1.87, 95% confidence intervals (CI): 1.11-3.16], and CRC risk. While the consumption of fiber-containing foods, especially whole grains (OR third tertile first tertile = 0.62, 95%CI: 0.39-0.98), and fatty fish (OR third tertile first tertile = 0.53, 95%CI: 0.27-0.99) was associated with a lower risk for CRC. Moreover, higher MD adherence was associated with a reduced CRC risk in adjusted models (OR third tertile first tertile = 0.40, 95%CI: 0.20-0.80).

Conclusion: Direct associations were found for high-fat cheese, whereas an inverse relation was reported for fiber-containing foods and fatty fish, as well as adherence to a Mediterranean dietary pattern.
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http://dx.doi.org/10.3748/wjg.v26.i28.4108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403796PMC
July 2020

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

Cancers (Basel) 2020 Aug 9;12(8). Epub 2020 Aug 9.

Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria ISABIAL, 03010 Alicante, Spain.

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 wild type; and/or no 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; < 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; < 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.
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http://dx.doi.org/10.3390/cancers12082225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466118PMC
August 2020

Gene-Diet Interactions in Colorectal Cancer: Survey Design, Instruments, Participants and Descriptive Data of a Case-Control Study in the Basque Country.

Nutrients 2020 Aug 7;12(8). Epub 2020 Aug 7.

Department of Pharmacy and Food Sciences. Faculty of Pharmacy, University of the Basque Country UPV/EHU, 01006 Vitoria-Gasteiz, Spain.

Epidemiologic studies have revealed inconsistent evidence of gene-diet interaction in relation to colorectal cancer (CRC). The aim of this study was to analyze them in a sample of cases and controls from the population-based bowel cancer screening program of the Osakidetza/Basque Health Service. This study analyzed dietetic, genetic, demographic, socioeconomic factors and lifestyles. In the present manuscript, the survey design, sampling, instruments, measurements and related quality management were presented. Moreover, we analyze differences between cases and controls in some data, especially those related to diet. The participants were 308 cases and 308 age- and sex-matched subjects as controls. Cases were more likely than controls to have overweight/obesity (67.5% vs. 58.1%, < 0.05), a lower intake of vitamin B (0.86 ± 0.23 vs. 0.92 ± 0.23 mg/1000 kcal, < 0.01) and calcium:phosphorus ratio (0.62 ± 0.12 vs. 0.65 ± 0.13, < 0.01). A higher proportion of cases than controls did not meet the Nutritional Objectives for saturated fatty acids (85.7% vs. 67.5%, < 0.001) or cholesterol (35.4% vs. 25.0%, < 0.01). In conclusion, the present study provides valuable data for analyzing the complexity of gene-diet interaction in relation to CRC. The results presented here suggest that overweight/obesity and a high intake of certain dietary components, especially saturated fatty acids and cholesterol, are more frequent in cases than in controls.
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http://dx.doi.org/10.3390/nu12082362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468855PMC
August 2020

Optimal diagnostic accuracy of quantitative faecal immunochemical test positivity thresholds for colorectal cancer detection in primary health care: A community-based cohort study.

United European Gastroenterol J 2020 Aug 10:2050640620949714. Epub 2020 Aug 10.

Gastroenterology Department, Complexo Hospitalario Universitario de Ourense, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Ourense, Spain.

Background: Optimizing colonoscopy resources is challenging, and information regarding performing diagnostic quantitative faecal immunochemical test (FIT) in daily clinical practice in primary health care is still limited. This study aimed to assess the sensitivity, specificity, positive predictive value and negative predictive value of varying FIT positivity thresholds on colorectal cancer (CRC) detection in primary health care.

Methods: A retrospective cohort study of 38,675 asymptomatic and symptomatic patients with a FIT (OC-Sensor™) performed between 2012 and 2016 in a primary health-care setting, using a clinical laboratory database of two Spanish areas linked with the National Health System's Hospital Discharge Records Database. The primary outcome was 2-year CRC incidence.

Results: The mean age of the participants was 63.2 years; 17,792 (46.0%) were male. CRC prevalence was 1.7% (650/38,675). The percentage of patients with a FIT result above the threshold was 20.7% and 14.6% for 10 µg Hb/g faeces and 20 µg Hb/g faeces thresholds, respectively. Sensitivity was 90.5% (95% confidence interval 88.0-92.5%) at a 10 µg Hb/g faeces threshold, and this decreased by 3.1% when a 20 µg Hb/g faeces threshold was used. The negative predictive value for CRC was at least 99.2% in any subgroup analysed. At a 20 µg Hb/g faeces threshold, less than one additional CRC would be missed per 1000 patients investigated, while approximately 1.3 times more colonoscopy examinations were needed to identify an incidence of CRC using the lowest threshold for any situation analysed.

Conclusions: In primary health care, a quantitative FIT threshold should be tailored to colonoscopy capacity and CRC prevalence in specific populations.
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http://dx.doi.org/10.1177/2050640620949714DOI Listing
August 2020

Extraintestinal Manifestations in Patients with Inflammatory Bowel Disease: Study Based on the ENEIDA Registry.

Dig Dis Sci 2020 Jul 15. Epub 2020 Jul 15.

Department of Gastroenterology of Hospital Universitario de Fuenlabrada, Madrid, Spain.

Background: Patients with inflammatory bowel disease (IBD) may present extraintestinal manifestations (EIMs) that affect the joints, skin, eyes, and hepatobiliary area, among others.

Aims: Our aim was to analyse the prevalence and characteristics of EIMs in patients with IBD and to identify the possible risk factors associated with the development of EIMs in the largest series published to date.

Methods: Observational, cross-sectional study including patients from the Spanish ENEIDA registry promoted by GETECCU. We retrospectively identified all cases of EIMs in the ENEIDA registry until January 2018.

Results: The study included 31,077 patients, 5779 of whom had at least one EIM (global prevalence 19%; 95% CI 18.2-19.0). Among the different types of EIMs, rheumatic manifestations had a prevalence of 13% (95% CI 12.9-13.7; 63% of EIMs), with a prevalence of 5% (95% CI 4.7-5.2) for mucocutaneous manifestations, 2.1% (95% CI 1.9-2.2) for ocular manifestations, and 0.7% (95% CI 0.6-0.8) for hepatobiliary manifestations. The multivariable analysis showed that the type of IBD (Crohn's disease, p < 0.001), gender (female, p < 0.001), the need for an immunomodulator (p < 0.001) or biologic drugs (p < 0.001), a previous family history of IBD (p < 0.001), and an extensive location of IBD (p < 0.001) were risk factors for the presence of EIMs.

Conclusions: One-fifth of patients with IBD may have associated EIMs, with rheumatic manifestations as the most frequent (> 60% of EIMs). Female patients with severe Crohn's disease represent the group with the highest risk of developing EIMs. These patients should therefore be specially monitored and referred to the corresponding specialist when suggestive symptoms appear.
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http://dx.doi.org/10.1007/s10620-020-06424-xDOI Listing
July 2020

Bismuth quadruple regimen with tetracycline or doxycycline versus three-in-one single capsule as third-line rescue therapy for Helicobacter pylori infection: Spanish data of the European Helicobacter pylori Registry (Hp-EuReg).

Helicobacter 2020 Oct 13;25(5):e12722. Epub 2020 Jul 13.

Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.

Background: Different bismuth quadruple therapies containing proton-pump inhibitors, bismuth salts, metronidazole, and a tetracycline have been recommended as third-line Helicobacter pylori eradication treatment after failure with clarithromycin and levofloxacin.

Aim: To evaluate the efficacy and safety of third-line treatments with bismuth, metronidazole, and either tetracycline or doxycycline.

Methods: Sub-study with Spanish data of the "European Registry on H pylori Management" (Hp-EuReg), international multicenter prospective non-interventional Registry of the routine clinical practice of gastroenterologists. After previous failure with clarithromycin- and levofloxacin-containing therapies, patients receiving a third-line regimen with 10/14-day bismuth salts, metronidazole, and either tetracycline (BQT-Tet) or doxycycline (BQT-Dox), or single capsule (BQT-three-in-one) were included. Data were registered at AEG-REDCap database. Univariate and multivariate analyses were performed.

Results: Four-hundred and fifty-four patients have been treated so far: 85 with BQT-Tet, 94 with BQT-Dox, and 275 with BQT-three-in-one. Average age was 53 years, 68% were women. Overall modified intention-to-treat and per-protocol eradication rates were 81% (BQT-Dox: 65%, BQT-Tet: 76%, BQT-three-in-one: 88%) and 82% (BQT-Dox: 66%, BQT-Tet: 77%, BQT-three-in-one: 88%), respectively. By logistic regression, higher eradication rates were associated with compliance (OR = 2.96; 95% CI = 1.01-8.84) and no prior metronidazole use (OR = 1.96; 95% CI = 1.15-3.33); BQT-three-in-one was superior to BQT-Dox (OR = 4.46; 95% CI = 2.51-8.27), and BQT-Tet was marginally superior to BQT-Dox (OR = 1.67; 95% CI = 0.85-3.29).

Conclusion: Third-line H pylori eradication with bismuth quadruple treatment (after failure with clarithromycin and levofloxacin) offers acceptable efficacy and safety. Highest efficacy was found in compliant patients and those taking 10-day BQT-three-in-one or 14-day BQT-Tet. Doxycycline seems to be less effective and therefore should not be recommended.
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http://dx.doi.org/10.1111/hel.12722DOI Listing
October 2020

Impact of the faecal immunochemical test on colorectal cancer survival.

BMC Cancer 2020 Jul 1;20(1):616. Epub 2020 Jul 1.

BIOEF: the Basque Foundation for Health Innovation and Research, Department of Gastroenterology, Biodonostia Institute, Avda Paseo Beguiristain s/n 20014, San Sebastián, Spain.

Background: There is already evidence that the faecal immunochemical test (FIT) is a useful tool for the diagnosis of colorectal cancer (CRC) that helps to identify symptomatic patients requiring early colonoscopy. Although the recommendation to use FIT is widely accepted, there are no data concerning whether this strategy improves patient survival.The objective was to assess whether the survival is higher if CRC patients have been first diagnosed by FIT (as compared with the rest of patients with CRC).

Methods: We identified all cases of CRC diagnosed between 2009 and 2016 in Donostialdea (Spain), excluding all the CRC detected in population screening. We focused on symptomatic patients. One thousand five hundred twenty-seven cases of CRC were divided into two groups based on the route to diagnosis: group 1: individuals who tested positive in a FIT during the year before diagnosis, and group 2: others.Survival was assessed by Kaplan-Meier estimation, and with the log-rank test. A Cox regression model was used to adjust for differences between groups due to other variables associated with survival.

Results: One thousand nine hundred sixty-seven cases of invasive CRC were identified, of which 22.4% were detected in population screening. Of the 1527 cases diagnosed in symptomatic patients, 317 patients had undergone a FIT in the year before the diagnosis of CRC. In 279 cases(18.3%), the result had been positive and this was the first step towards their CRC diagnosis (group 1). Group 2 was composed of the 1248 cases of CRC (81.7%). Considering these cases, 1210 patients with CRC did not undergo any FIT while 38 patients presented a negative result in the year before the diagnosis. The rate of early-stage disease (stage I or II) was higher in group 1 (51.3% vs 45.5% in group 2) (p = 0.04). Furthermore, the 3-year survival was longer in group 1 (72% vs 59% in group 2) (HR 1.50; 95% CI 1.22-1.84).The variables independently associated with worse survival were: group 2, age > 70 years and stage at the moment of diagnosis.

Conclusions: The use of FIT as a diagnostic strategy in symptomatic patients may improve survival in CRC. Nonetheless,FIT is still not widely used in our region.
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http://dx.doi.org/10.1186/s12885-020-07074-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328266PMC
July 2020

Linkage to care strategy for the micro-elimination of hepatitis C among parenteral drug users on methadone replacement therapy in Gipuzkoa.

Rev Esp Enferm Dig 2020 Jul;112(7):545-549

Aparato Digestivo, Hospital Universitario Donostia.

Introduction: parenteral drug users (PDUs) are a population with a high prevalence of infection with the hepatitis C virus (HCV) and significant difficulties to access to treatment. Opioid replacement therapy programs regularly monitor these individuals.

Objective: to effectively treat this population using a directly observed therapy (DOT) and bringing resources closer to the methadone dispensing center in Gipuzkoa (Bitarte).

Methods: all methadone users that were positive for anti-HCV antibodies were included in the study. Using a simplified circuit, a hepatologist visits the center with a Fibroscan® device and requests treatment following assessment. Treatment is dispensed at the addict center, under the supervision of a psychiatrist and nursing staff. Prevalence, population characteristics and circuit effectiveness were assessed.

Results: Bitarte monitors 660 individuals. Of these, 73.6 % were positive for antibodies against HCV. The prevalence of viremic infection is 62.5 %. The predominant genotype was 1a, followed by 3. A total of 38.5 % had advanced fibrosis (F3 and F4) and 38 % of users admitted to active heroin use. In all, 82.07 % (174/212) of the population received treatment and 97 % had sustained viral response (SVR) after 12 weeks. No re-infections were recorded.

Conclusions: the prevalence of viremic HCV infection among PDUs under treatment with methadone is 62 %. The linkage to care strategy was effective and > 80 % of the population with an active infection have been treated so far.
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http://dx.doi.org/10.17235/reed.2020.7194/2020DOI Listing
July 2020

Genomewide Association Study of Severe Covid-19 with Respiratory Failure.

Authors:
David Ellinghaus Frauke Degenhardt Luis Bujanda Maria Buti Agustín Albillos Pietro Invernizzi Javier Fernández Daniele Prati Guido Baselli Rosanna Asselta Marit M Grimsrud Chiara Milani Fátima Aziz Jan Kässens Sandra May Mareike Wendorff Lars Wienbrandt Florian Uellendahl-Werth Tenghao Zheng Xiaoli Yi Raúl de Pablo Adolfo G Chercoles Adriana Palom Alba-Estela Garcia-Fernandez Francisco Rodriguez-Frias Alberto Zanella Alessandra Bandera Alessandro Protti Alessio Aghemo Ana Lleo Andrea Biondi Andrea Caballero-Garralda Andrea Gori Anja Tanck Anna Carreras Nolla Anna Latiano Anna Ludovica Fracanzani Anna Peschuck Antonio Julià Antonio Pesenti Antonio Voza David Jiménez Beatriz Mateos Beatriz Nafria Jimenez Carmen Quereda Cinzia Paccapelo Christoph Gassner Claudio Angelini Cristina Cea Aurora Solier David Pestaña Eduardo Muñiz-Diaz Elena Sandoval Elvezia M Paraboschi Enrique Navas Félix García Sánchez Ferruccio Ceriotti Filippo Martinelli-Boneschi Flora Peyvandi Francesco Blasi Luis Téllez Albert Blanco-Grau Georg Hemmrich-Stanisak Giacomo Grasselli Giorgio Costantino Giulia Cardamone Giuseppe Foti Serena Aneli Hayato Kurihara Hesham ElAbd Ilaria My Iván Galván-Femenia Javier Martín Jeanette Erdmann Jose Ferrusquía-Acosta Koldo Garcia-Etxebarria Laura Izquierdo-Sanchez Laura R Bettini Lauro Sumoy Leonardo Terranova Leticia Moreira Luigi Santoro Luigia Scudeller Francisco Mesonero Luisa Roade Malte C Rühlemann Marco Schaefer Maria Carrabba Mar Riveiro-Barciela Maria E Figuera Basso Maria G Valsecchi María Hernandez-Tejero Marialbert Acosta-Herrera Mariella D'Angiò Marina Baldini Marina Cazzaniga Martin Schulzky Maurizio Cecconi Michael Wittig Michele Ciccarelli Miguel Rodríguez-Gandía Monica Bocciolone Monica Miozzo Nicola Montano Nicole Braun Nicoletta Sacchi Nilda Martínez Onur Özer Orazio Palmieri Paola Faverio Paoletta Preatoni Paolo Bonfanti Paolo Omodei Paolo Tentorio Pedro Castro Pedro M Rodrigues Aaron Blandino Ortiz Rafael de Cid Ricard Ferrer Roberta Gualtierotti Rosa Nieto Siegfried Goerg Salvatore Badalamenti Sara Marsal Giuseppe Matullo Serena Pelusi Simonas Juzenas Stefano Aliberti Valter Monzani Victor Moreno Tanja Wesse Tobias L Lenz Tomas Pumarola Valeria Rimoldi Silvano Bosari Wolfgang Albrecht Wolfgang Peter Manuel Romero-Gómez Mauro D'Amato Stefano Duga Jesus M Banales Johannes R Hov Trine Folseraas Luca Valenti Andre Franke Tom H Karlsen

N Engl J Med 2020 10 17;383(16):1522-1534. Epub 2020 Jun 17.

From the Institute of Clinical Molecular Biology, Christian-Albrechts-University (D.E., F.D., J.K., S. May, M. Wendorff, L.W., F.U.-W., X.Y., A.T., A. Peschuck, C.G., G.H.-S., H.E.A., M.C.R., M.E.F.B., M. Schulzky, M. Wittig, N.B., S.J., T.W., W.A., M. D'Amato, A.F.), and University Hospital Schleswig-Holstein, Campus Kiel (N.B., A.F.), Kiel, the Institute for Cardiogenetics, University of Lübeck, Lübeck (J.E.), the German Research Center for Cardiovascular Research, partner site Hamburg-Lübeck-Kiel (J.E.), the University Heart Center Lübeck (J.E.), and the Institute of Transfusion Medicine, University Hospital Schleswig-Holstein (S.G.), Lübeck, Stefan-Morsch-Stiftung, Birkenfeld (M. Schaefer, W.P.), and the Research Group for Evolutionary Immunogenomics, Max Planck Institute for Evolutionary Biology, Plön (O.O., T.L.L.) - all in Germany; Novo Nordisk Foundation Center for Protein Research, Disease Systems Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (D.E.); the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute-Donostia University Hospital-University of the Basque Country (L.B., K.G.-E., L.I.-S., P.M.R., J.M.B.), Osakidetza Basque Health Service, Donostialdea Integrated Health Organization, Clinical Biochemistry Department (A.G.C., B.N.J.), and the Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute (M. D'Amato), San Sebastian, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III (L.B., M. Buti, A. Albillos, A. Palom, F.R.-F., B.M., L. Téllez, K.G.-E., L.I.-S., F.M., L.R., M.R.-B., M. Rodríguez-Gandía, P.M.R., M. Romero-Gómez, J.M.B.), the Departments of Gastroenterology (A. Albillos, B.M., L. Téllez, F.M., M. Rodríguez-Gandía), Intensive Care (R.P., A.B.O.), Respiratory Diseases (D.J., A.S., R.N.), Infectious Diseases (C.Q., E.N.), and Anesthesiology (D. Pestaña, N. Martínez), Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria, University of Alcalá, and Histocompatibilidad y Biologia Molecular, Centro de Transfusion de Madrid (F.G.S.), Madrid, the Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus (M. Buti, A. Palom, L.R., M.R.-B.), Hospital Clinic, University of Barcelona, and the August Pi i Sunyer Biomedical Research Institute (J.F., F.A., E.S., J.F.-A., L.M., M.H.-T., P.C.), the European Foundation for the Study of Chronic Liver Failure (J.F.), Vall d'Hebron Institut de Recerca (A. Palom, F.R.-F., A.J., S. Marsal), and the Departments of Biochemistry (A.-E.G.-F., F.R.-F., A.C.-G., C.C., A.B.-G.), Intensive Care (R.F.), and Microbiology (T.P.), University Hospital Vall d'Hebron, the Immunohematology Department, Banc de Sang i Teixits, Autonomous University of Barcelona (E.M.-D.), Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Consortium for Biomedical Research in Epidemiology and Public Health and University of Barcelona, l'Hospitalet (V. Moreno), and Autonoma University of Barcelona (T.P.), Barcelona, Universitat Autònoma de Barcelona, Bellatera (M. Buti, F.R.-F., M.R.-B.), GenomesForLife-GCAT Lab Group, Germans Trias i Pujol Research Institute (A.C.N., I.G.-F., R.C.), and High Content Genomics and Bioinformatics Unit, Germans Trias i Pujol Research Institute (L. Sumoy), Badalona, Institute of Parasitology and Biomedicine Lopez-Neyra, Granada (J.M., M.A.-H.), the Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville (M. Romero-Gómez), and Ikerbasque, Basque Foundation for Science, Bilbao (M. D'Amato, J.M.B.) - all in Spain; the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca (P.I., C.M.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (D. Prati, G.B., A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, C.P., F.C., F.M.-B., F.P., F.B., G.G., G. Costantino, L. Terranova, L. Santoro, L. Scudeller, M. Carrabba, M. Baldini, M.M., N. Montano, R.G., S.P., S. Aliberti, V. Monzani, S. Bosari, L.V.), the Department of Biomedical Sciences, Humanitas University (R.A., A. Protti, A. Aghemo, A. Lleo, E.M.P., G. Cardamone, M. Cecconi, V.R., S.D.), Humanitas Clinical and Research Center, IRCCS (R.A., A. Protti, A. Aghemo, A. Lleo, A.V., C.A., E.M.P., H.K., I.M., M. Cecconi, M. Ciccarelli, M. Bocciolone, P.P., P.O., P.T., S. Badalamenti, S.D.), University of Milan (A.Z., A. Bandera, A.G., A.L.F., A. Pesenti, F.M.-B., F.P., F.B., G.G., G. Costantino, M.M., N. Montano, R.G., S.P., S. Aliberti, S. Bosari, L.V.), and the Center of Bioinformatics, Biostatistics, and Bioimaging (M.G.V.) and the Phase 1 Research Center (M. Cazzaniga), School of Medicine and Surgery, and the Departments of Emergency, Anesthesia, and Intensive Care (G.F.), Pneumologia (P.F.), and Infectious Diseases (P.B.); University of Milano-Bicocca, Milan, the European Reference Network on Hepatological Diseases (P.I., C.M.) and the Infectious Diseases Unit (P.B.), San Gerardo Hospital, Monza, the Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo (A. Biondi, L.R.B., M. D'Angiò), the Gastroenterology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (A. Latiano, O.P.), the Department of Medical Sciences, Università degli Studi di Torino, Turin (S. Aneli, G.M.), and the Italian Bone Marrow Donor Registry, E.O. Ospedali Galliera, Genoa (N.S.) - all in Italy; the Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, and the Research Institute for Internal Medicine, Division of Surgery, Inflammatory Diseases, and Transplantation, Oslo University Hospital Rikshospitalet and University of Oslo (M.M.G., J.R.H., T.F., T.H.K.), and the Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery, and Transplantation, Oslo University Hospital Rikshospitalet (J.R.H., T.F., T.H.K.), Oslo; the School of Biological Sciences, Monash University, Clayton, VIC, Australia (T.Z., M. D'Amato); Private University in the Principality of Liechtenstein (C.G.); the Institute of Biotechnology, Vilnius University, Vilnius, Lithuania (S.J.); and the Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm (M. D'Amato).

Background: There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19.

Methods: We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels.

Results: We detected cross-replicating associations with rs11385942 at locus 3p21.31 and with rs657152 at locus 9q34.2, which were significant at the genomewide level (P<5×10) in the meta-analysis of the two case-control panels (odds ratio, 1.77; 95% confidence interval [CI], 1.48 to 2.11; P = 1.15×10; and odds ratio, 1.32; 95% CI, 1.20 to 1.47; P = 4.95×10, respectively). At locus 3p21.31, the association signal spanned the genes , , , , and . The association signal at locus 9q34.2 coincided with the blood group locus; in this cohort, a blood-group-specific analysis showed a higher risk in blood group A than in other blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P = 1.48×10) and a protective effect in blood group O as compared with other blood groups (odds ratio, 0.65; 95% CI, 0.53 to 0.79; P = 1.06×10).

Conclusions: We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system. (Funded by Stein Erik Hagen and others.).
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http://dx.doi.org/10.1056/NEJMoa2020283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315890PMC
October 2020

The utility of flow cytometry in the diagnostic work up of malignant effusions due to nonhematopoietic neoplasms.

Cytometry B Clin Cytom 2020 11 7;98(6):504-515. Epub 2020 Jun 7.

School of Medicine, University of the Basque Country (UPV-EHU), San Sebastián, País Vasco, Spain.

Malignant pleural effusion and peritoneal carcinomatosis are frequent causes of effusion. Cytological evaluation (PAP-stained slides followed by immunocytochemistry, IHC, if applicable) is currently the gold standard for the diagnosis of malignant effusions, but its sensitivity varies between 40 and 80%, being a time-consuming technique. Although flow cytometry (FC) is not routinely used in the diagnosis or follow-up of nonhematopoietic neoplasms, it has the advantage of being rapidly applicable to fresh samples, potentially decreasing the time for the diagnosis. The main objective of this study was to assess the utility of FC as a confirmatory tool in the diagnosis of neoplastic effusions, based on the expression of EpCAM antibody in tumor cells versus the cytological evaluation. In this work 1,535 serous fluids were collected, of which 101 (68 pleural, 33 ascites) were selected through a screening algorithm and sent to the FC and cytological evaluation. Seventy-three of these samples (46 pleural, 27 ascites) were considered malignant as determined by clinical, cytological and radiological criteria. According to our data, 75% (55/73) of these samples were positive by Cytology/IHC and 74% (54/73) by FC. We noticed that, although the sensitivity, specificity, and area under the curve were similar, the turn-around time was shorter when using FC. Moreover, these results clearly improved by combining both techniques. We conclude that FC provides information about malignant effusions faster than immunohistochemical staining, and we believe that performing both techniques in parallel would improve diagnostic performance.
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http://dx.doi.org/10.1002/cyto.b.21886DOI Listing
November 2020

A Novel Serum Metabolomic Profile for the Differential Diagnosis of Distal Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma.

Cancers (Basel) 2020 May 31;12(6). Epub 2020 May 31.

Experimental Hepatology and Drug Targeting (HEVEFARM) Group, University of Salamanca, Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain.

The diagnosis of adenocarcinomas located in the pancreas head, i.e., distal cholangiocarcinoma (dCCA) and pancreatic ductal adenocarcinoma (PDAC), constitutes a clinical challenge because they share many symptoms, are not easily distinguishable using imaging techniques and accurate biomarkers are not available. Searching for biomarkers with potential usefulness in the differential diagnosis of these tumors, we have determined serum metabolomic profiles in healthy controls and patients with dCCA, PDAC or benign pancreatic diseases (BPD). Ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) analysis was performed in serum samples from dCCA ( = 34), PDAC ( = 38), BPD ( = 42) and control ( = 25) individuals, divided into discovery and validation cohorts. This approach permitted 484 metabolites to be determined, mainly lipids and amino acids. The analysis of the results led to the proposal of a logistic regression model able to discriminate patients with dCCA and PDAC (AUC value of 0.888) based on the combination of serum levels of nine metabolites (acylcarnitine AC(16:0), ceramide Cer(d18:1/24:0), phosphatidylcholines PC(20:0/0:0) and PC(O-16:0/20:3), lysophosphatidylcholines PC(20:0/0:0) and PC(0:0/20:0), lysophosphatidylethanolamine PE(P-18:2/0:0), and sphingomyelins SM(d18:2/22:0) and SM(d18:2/23:0)) and CA 19-9. In conclusion, we propose a novel specific panel of serum metabolites that can help in the differential diagnosis of dCCA and PDAC. Further validation of their clinical usefulness in prospective studies is required.
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http://dx.doi.org/10.3390/cancers12061433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352809PMC
May 2020

Modeling Personalized Adjuvant TreaTment in EaRly stage coloN cancer (PATTERN).

Eur J Health Econ 2020 Sep 26;21(7):1059-1073. Epub 2020 May 26.

Department of Epidemiology and Biostatistics, Amsterdam UMC, VU University, MF F-wing, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

Aim: To develop a decision model for the population-level evaluation of strategies to improve the selection of stage II colon cancer (CC) patients who benefit from adjuvant chemotherapy.

Methods: A Markov cohort model with a one-month cycle length and a lifelong time horizon was developed. Five health states were included; diagnosis, 90-day mortality, death other causes, recurrence and CC death. Data from the Netherlands Cancer Registry were used to parameterize the model. Transition probabilities were estimated using parametric survival models including relevant clinical and pathological covariates. Subsequently, biomarker status was implemented using external data. Treatment effect was incorporated using pooled trial data. Model development, data sources used, parameter estimation, and internal and external validation are described in detail. To illustrate the use of the model, three example strategies were evaluated in which allocation of treatment was based on (A) 100% adherence to the Dutch guidelines, (B) observed adherence to guideline recommendations and (C) a biomarker-driven strategy.

Results: Overall, the model showed good internal and external validity. Age, tumor growth, tumor sidedness, evaluated lymph nodes, and biomarker status were included as covariates. For the example strategies, the model predicted 83, 87 and 77 CC deaths after 5 years in a cohort of 1000 patients for strategies A, B and C, respectively.

Conclusion: This model can be used to evaluate strategies for the allocation of adjuvant chemotherapy in stage II CC patients. In future studies, the model will be used to estimate population-level long-term health gain and cost-effectiveness of biomarker-based selection strategies.
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http://dx.doi.org/10.1007/s10198-020-01199-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423797PMC
September 2020

Resumption of activity in gastroenterology departments. Recommendations by SEPD, AEEH, GETECCU and AEG.

Gastroenterol Hepatol 2020 Jun - Jul;43(6):332-347. Epub 2020 Apr 25.

Vicepresidente de la AEEH. Jefe del Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro Majadahonda. Instituto de Investigación Biomédica IDIPHIM. Universidad Autónoma de Madrid, Majadahonda, Madrid, España.

The set of measures proposed by SEPD, AEEH, GETECCU and AEG are aimed to help departments in their resumption of usual activity. We have prepared a number of practical recommendations regarding patient management and the stepwise resumption of healthcare activity. These recommendations are based on the sparse, changing evidence available, and will be updated in the future according to daily needs and the availability of expendable materials to suit them; in each department they will be implemented depending upon the cumulative incidence of SARS-CoV-2 infection in each region, and the burden the pandemic has represented for each hospital. The general objectives of these recommendations include: (a)To protect our patients against the risks of infection with SARS-CoV-2 and to provide them with high-quality care. (b)To protect all healthcare professionals against the risks of infection with SARS-CoV-2. (c)To resume normal functioning of our departments in a setting of ongoing risk for infection with SARS-CoV-2.
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http://dx.doi.org/10.1016/j.gastrohep.2020.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183290PMC
June 2020

Colonic mucosal Schwann cell hamartoma.

J Dig Dis 2020 Aug 11;21(8):475-477. Epub 2020 Jun 11.

Department of Gastroenterology, University Hospital Donostia, San Sebastián, Spain.

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http://dx.doi.org/10.1111/1751-2980.12874DOI Listing
August 2020