Co Treatment With Biologic Agents and Immunotherapy in the Setting of irAEs of Difficult Management

Adverse drugs reaction; Immune check-point inhibitors therapy; Immunosuppression therapyReacción adversa a medicamentos; Terapia con inhibidores del punto de control inmunitario; Terapia inmunosupresoraReaccions adverses als fàrmacs; Teràpia amb inhibidors del punt de control immune; Teràpia d'immunosupressióIn recent years, immunotherapy has become an important pillar of cancer treatment, with high response rates regardless of tumor histology or baseline mutations, sometime in patients without any alternative of treatment. Moreover, these treatments are moving from later line therapies to front-line therapies in the metastasic setting. However, immune activation associated with immune check-point inhibitors (ICI) is not selective and a large variety of immune-related adverse events, with an increasing frequency, have been associated with anti-PD1, anti-PD-1/L-1 and anti-CTLA-4 agents. In clinical trials, and sometimes also in real life practice, patients who develop severe toxicities on ICI-based therapies are usually not allowed to resume ICI once their disease progresses, because of the chance of developing severe irAEs on rechallenge with immunotherapies. Moreover, patients with irAEs suffer important side effects due to the high dose corticosteroids that are used to treat them. Therapy with ICI is sometimes the only alternative for certain patients, and for this reason co treatment with classic (DMARDS) or biologic immunosuppression therapy and ICI must be considered. Co-treatment with this type of immunosuppressant drugs, apart from allowing the maintenance of ICI therapy, drive to a lesser use of corticosteroids, with an improvement of the safety and quality of life of the patients. Such a tailored scheme of treatment is mostly an expert opinion based on recommendation and currently there is scarce evidence supporting it. Herein we present comprehensive, current recommendations and real-world data on the use of co-treatment with ICI and DMARDS and biologic immunosuppression

Sucrosomial Iron Supplementation for the Treatment of Iron Deficiency Anemia in Inflammatory Bowel Disease Patients Refractory to Oral Iron Treatment

Malaltia inflamatòria intestinal; Deficiència de ferro; Suplementació de ferroEnfermedad inflamatoria intestinal; Deficiencia de hierro; Suplementación con hierroInflammatory bowel disease; Iron deficiency; Iron supplementationIron deficiency anemia (IDA) is a common manifestation of Inflammatory Bowel Disease (IBD). Oral iron supplements are the treatment of choice, but are not always well tolerated. Sucrosomial® iron (SI) may represent an alternative. This prospective study assessed the tolerability and effectiveness of SI, and quality of life (QoL) of IDA-IBD patients who were intolerant to oral iron salts. The study included 52 individuals treated with 1 capsule/day for 12 weeks. Tolerability was assessed through a gastrointestinal symptom severity questionnaire. Hemoglobin (Hb) levels and clinical symptoms of IDA were analyzed. QoL was assessed using IBDQ-9 and EuroQoL questionnaires. The percentage of patients with excellent/good health increased from 42.9% to 94.3%. Mean Hb concentration significantly increased at all follow-up visits (p < 0.05). Almost all participants (96.9%) were adherent to the study medication. Patients’ QoL improved (IBDQ-9: from 60.9 to 65.5). Patients also improved in mobility (71.8% to 78.1%), usual activities (51.3% to 68.7%), pain/discomfort (41.0% to 53.1%), and extreme depression/anxiety problems (7.7% to 3.2%); they worsened in self-care (100% to 90.6%), but perceived an enhancement in their global health [EQ-VAS score: 61.9 (±26.1) to 66.9 (±20.3)]. SI was well tolerated and improved IDA symptoms, IBD activity, and patients’ QoL. In conclusion, SI should be considered in IDA–IBD patients.The authors of this manuscript received financial support from ZAMBON S.A.U. for the writing of the manuscript. The sponsor had no role in the design or conduct of the study, data collection and analysis, or preparation of the manuscript

Colonic bacterial diversity and dysbiosis in active microscopic colitis as compared to chronic diarrhoea and healthy controls: effect of polyethylene glycol after bowel lavage for colonoscopy

Faecal microbiome; Microscopic colitis; Polyethylene glycolMicrobioma fecal; Colitis microscópica; PolietilenglicolMicrobioma fecal; Colitis microscòpica; PolietilenglicolBackground Most microbiota studies in microscopic colitis patients are performed after diagnostic colonoscopy without considering the potential effect of colonic lavage. Patients may achieve clinical remission after colonoscopy and it is unknown whether lavage-induced changes play a role. Aim To assess the effect of polyethylene glycol (PEG) colonic lavage on clinical remission rate, microbial diversity, microbial dysbiosis index and specific microbial changes in patients with active microscopic colitis as compared to other diarrhoeal diseases and healthy controls. Methods Fifty-five consecutive patients presenting chronic watery diarrhoea and 12 healthy controls were included. Faecal samples were collected three days before and 30 days after PEG in patients and controls for microbiome analysis. Results Clinical remission was observed in 53% of microscopic colitis patients, and in 32% of non-microscopic colitis patients (p = 0.16). Considering patients with persisting diarrhoea after colonoscopy, 71% of non-microscopic colitis patients had bile acid diarrhoea. Baseline Shannon Index was lower in diarrhoea groups than in healthy controls (p = 0.0025); there were no differences between microscopic colitis, bile-acid diarrhoea and functional diarrhoea. The microbial dysbiosis index was significantly higher in microscopic colitis than in bile acid diarrhoea plus functional diarrhoea (p = 0.0095), but no bacterial species showed a significantly different relative abundance among the diarrheal groups. Conclusions Dysbiosis is a feature in active microscopic colitis, but loss of microbial diversity was similar in all diarrheal groups, suggesting that faecal microbial changes are not due to microscopic colitis itself but associated with stool form. A considerable number of microscopic colitis patients achieved clinical remission after colonoscopy, but we were unable to demonstrate related PEG-induced changes in faecal microbiome

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Crohn’s disease; Effectiveness; UstekinumabEnfermedad de Crohn; Eficacia; UstekinumabMalaltia de Crohn; Efectivitat; UstekinumabBackground Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.This work was supported by Janssen-Cilag Spain. This sponsor had a partial role in study design, analysis, and interpretation of data. Medical writing and editorial assistance for the preparation of this article was funded by Janssen-Cilag Spain. This assistance was provided by the following individuals, who are either employees of Springer Healthcare Communications (S.H.C.), or were contracted by S.H.C. to undertake editorial work in connection with the preparation of the article: Eliana Mesa, MD, Sheridan Henness, PhD, Fernando Sánchez Barbero, PhD

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Malaltia de Crohn; Factors predictius; UstekinumabEnfermedad de Crohn; Factores predictivos; UstekinumabCrohn’s disease; Predictive factors; UstekinumabUstekinumab has shown efficacy in Crohn’s Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients’ data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index ≤ 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission.This work was supported by Janssen-Cilag Spain. This sponsor had a partial role in study design, analysis, and interpretation of data

Using Interpretable Machine Learning to Identify Baseline Predictive Factors of Remission and Drug Durability in Crohn’s Disease Patients on Ustekinumab

Ustekinumab has shown efficacy in Crohn's Disease (CD) patients. To identify patient profiles of those who benefit the most from this treatment would help to position this drug in the therapeutic paradigm of CD and generate hypotheses for future trials. The objective of this analysis was to determine whether baseline patient characteristics are predictive of remission and the drug durability of ustekinumab, and whether its positioning with respect to prior use of biologics has a significant effect after correcting for disease severity and phenotype at baseline using interpretable machine learning. Patients' data from SUSTAIN, a retrospective multicenter single-arm cohort study, were used. Disease phenotype, baseline laboratory data, and prior treatment characteristics were documented. Clinical remission was defined as the Harvey Bradshaw Index <= 4 and was tracked longitudinally. Drug durability was defined as the time until a patient discontinued treatment. A total of 439 participants from 60 centers were included and a total of 20 baseline covariates considered. Less exposure to previous biologics had a positive effect on remission, even after controlling for baseline disease severity using a non-linear, additive, multivariable model. Additionally, age, body mass index, and fecal calprotectin at baseline were found to be statistically significant as independent negative risk factors for both remission and drug survival, with further risk factors identified for remission

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study

Background Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Results A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

Introduction: We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Methods: Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. Discussion: This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain.The study was partially funded by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT- 2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the The Catalan Government DURSI grant 2009SGR1489

Multidisciplinary Assessment of Nature-Based Strategies to Address Groundwater Overexploitation and Drought Risk in Medina Del Campo Groundwater Body

[EN] Five decades of intensive groundwater exploitation have brought important economic, social and environmental changes in Medina del Campo Groundwater Body (MCGWB). Declining piezometric levels have worsened water quality, increased the costs of water supply and abstraction, and drained connected wetlands and rivers. This chapter presents the different methods and tools developed to assess the impacts and effectiveness for adaptation to droughts of the selected NAS strategies in biophysical, economic and social terms. It follows the methodologies presented in Chaps. 4, 5 and 6. It also summarizes the approaches for integrating all these assessments, as well as the main conclusions and lessons learnt. Important progress has been achieved on understanding and modelling the aquifer-system dynamics and functioning. First, geological and geophysical data analysis, debugging and integration have provided a basis for constructing a set of geological models of the MCGWB. Second, water balance components need to be updated through a deeper analysis of the recharge and groundwater abstractions (pumping). Third, a trend analysis of critical groundwater-related ecosystem services (GRES) and piezometric levels points at groundwater abstraction reductions as the most effective measure for a widespread recovery of the groundwater levels and storage. Fifth, the proposed managed artificial recharge would have limited effects on the recovery of the surface water bodies and no effect on the groundwater bodies. Sixth, the environmental reconstruction from a sedimentary record of the main wetland bed (Lagunas Reales) provides a reference knowledge base to understand the system response to human and climate changes. Finally, different barriers for design and implementation of NAS strategies have been identified and evaluated. Particularly, the lack of effective interaction mechanisms among the different actors involved/interested in the process could play a key role in the future.Peer reviewe

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality