Publications by authors named "Juan Diaz-Martin"

55 Publications

A Novel Gene Fusion in Solitary Fibrous Tumor: A Case Report.

Int J Mol Sci 2021 Jul 13;22(14). Epub 2021 Jul 13.

Fundacion Jimenez Diaz University Hospital Health Research Institute (IIS/FJD), 28015 Madrid, Spain.

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion , resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of mapping to 19p13.2 and mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for in solitary fibrous tumor opens intriguing new hypotheses to refine the role of in the sarcomatogenesis of this entity.
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http://dx.doi.org/10.3390/ijms22147514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305824PMC
July 2021

[Satisfaction in telephone consultations during confinement due to COVID-19].

An Pediatr (Barc) 2021 Jun 1. Epub 2021 Jun 1.

Hospital Universitario Central de Asturias, Oviedo, Asturias, España.

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http://dx.doi.org/10.1016/j.anpedi.2021.05.012DOI Listing
June 2021

Characterizing the Invasive Tumor Front of Aggressive Uterine Adenocarcinoma and Leiomyosarcoma.

Front Cell Dev Biol 2021 3;9:670185. Epub 2021 Jun 3.

Cancer CIBER (CIBERONC), Madrid, Spain.

The invasive tumor front (the tumor-host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and cell adhesion-related methylation signatures. Although no evident overall differences in immune response were detected at the gene expression and methylation level, impaired antimicrobial humoral response might be involved in uterine leiomyosarcoma spread. Similarities found at the invasive tumor front of uterine adenocarcinomas and leiomyosarcomas could facilitate the use of common biomarkers and therapies. Furthermore, molecular and architectural characterization of the invasive front of uterine malignancies may provide additional prognostic information beyond established prognostic factors.
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http://dx.doi.org/10.3389/fcell.2021.670185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209546PMC
June 2021

Study of adherence to the gluten-free diet in coeliac patients.

An Pediatr (Engl Ed) 2021 Jun 19;94(6):377-384. Epub 2021 May 19.

Servicio de Gastroenterología-Hepatología y Nutrición, Hospital Universitario Central de Asturias, Oviedo, Spain.

Introduction: The following of a strict gluten-free diet (GFD) is essential in the control of coeliac disease. The aim of this study was to determine the adherence to a GFD in coeliac patients and to evaluate the factors that could influence this adherence.

Material And Methods: A descriptive observational study was carried out, in which gluten immunogenic peptides (GIP) were determined in faeces using a semi-quantitative method, and the Coeliac Dietary Adherence Test was completed. Sociodemographic and clinical details were collected, and an ad hoc questionnaire was prepared.

Results: Of the 80 patients included, 92.5% were adherent according to the GIP and 86.3% according to Coeliac Dietary Adherence Test (acceptable agreement; Kappa: 0.31, P = .004). The large majority (83.3%) of patients with positive GIP gave negative anti-transglutaminase antibodies in the latest determination. Current age and time of onset were significantly associated with adherence. Those with a positive GIP had a mean age of 5 years more (P = .0001) and were 52 months more on a GFD (P = .025). One quarter of those surveyed considered the diet difficult to follow. Just under two-thirds (60%) considered that the variability in the eating site was an important factor in leading to infringements, with children's parties being the main area where they occurred (66.7%). The lack of variety (61.4%) and the increased cost (98.6%) of gluten-free foods is highlighted.

Conclusions: The adherence to the GFD is generally good. The analysis of GIP helps to detect non-adherent patients that would pass unnoticed in other circumstances. Measures must be established in order to maintain good long-term adherence, taking into account the risk factors and difficulties detected.
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http://dx.doi.org/10.1016/j.anpede.2020.06.012DOI Listing
June 2021

[Analysis of health-related quality life in celiac patients].

Nutr Hosp 2021 Jul;38(4):715-721

Área de Gestión Clínica de Pediatría. Hospital Universitario Central de Asturias.

Introduction: Introduction: treatment of celiac disease is gluten-free diet for life. This can impact the quality of life (QoL) of patients. Objectives:the aim of this study was to evaluate the QoL and the factors with an impact on QoL in a sample of children with celiac disease. Methods and materials: a descriptive observational study. QoL was evaluated using the Celiac Disease Dux Questionnaire (CDDUX). Adherence to gluten-free diet was assessed with the Celiac Dietary Adherence Test (CDAT) and the presence of gluten immunogenic peptides (GIP) in the stools. Sociodemographic and clinical data were collected, and an ad-hoc survey was developed. Results: eighty patients were included. Median CDDUX score was 44.04 points (QoL: "neutral"). Subscale scores included: "communication", 58.3 points ("neutral"); "having CD", 25 points ("Bad"); and "diet", 41.6 points ("neutral"). QoL was worse among patients with celiac relatives (the result of the survey was "bad" vs. "neutral" with p = 0.02) and among those who found unsatisfactory the somatosensory characteristics and the price of gluten-free food (the result of the survey was "bad" vs. "neutral" with p = 0.02). Those who found unsatisfactory the texture of these food reported a worse QoL ("bad" vs. "neutral", p = 0.009). Those who reported eating outside the home as a transgression inducer reported a "bad" QoL; those who did not, reported a "neutral" QoL (p = 0.03). Conclusions: celiac patients report a "neutral" QoL. A poorer QoL was related to having celiac relatives, finding gluten-free food unsatisfactory, and considering eating outside the home as an inducer factor for transgressions.
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http://dx.doi.org/10.20960/nh.03538DOI Listing
July 2021

Gluten-Free Diet: Nutritional Strategies to Improve Eating Habits in Children with Celiac Disease: A Prospective, Single-arm Intervention Study.

Nutrients 2021 Mar 28;13(4). Epub 2021 Mar 28.

Pediatric Gastroenterology and Nutrition University Hospital Universitario Central de Asturias, Oviedo, Asturias. Av. Roma, s/n, 33011 Oviedo, Asturias, Spain.

Background: Elimination of gluten-containing cereals and consumption of ultra-processed gluten-free foods might cause an unbalanced diet, deficient in fiber and rich in sugar and fat, circumstances that may predispose celiac children to chronic constipation.

Aim: to evaluate if counseling with a registered dietitian (RD) was capable of improving eating and bowel habits in a celiac pediatric population.

Methods: Dietetic, lipid profile and stool modifications were analyzed, comparing baseline assessments with those twelve months after receiving heathy eating and nutrition education sessions. At both time points, 3-day food records, a bowel habit record and a lipid panel were conducted. Calculated relative intake of macro- and micro-nutrients were compared with current recommendations by the European Food Safety Authority (EFSA). Student's paired -test, McNemar test, Mandasky test and Pearson correlation tests were used.

Results: Seventy-two subjects (58.3% girls) with a mean (standard deviation (SD)) age of 10.2 (3.4) years were included. Baseline diets were imbalanced in macronutrient composition. Significant improvements were observed in their compliance with dietary reference values (DRVs), where 50% of the subjects met fat requirements after the education and 67% and 49% with those of carbohydrates and fiber, respectively ( < 0.001). Celiac children decreased red meat and ultra-processed foods consumption ( < 0.001) and increased fruits and vegetables intake ( < 0.001), leading to a reduction in saturated fat ( < 0.001) and sugar intake ( < 0.001). Furthermore, 92% of the patients achieved a normal bowel habit, including absence of hard stools in 80% of children constipated at baseline ( < 0.001).

Conclusions: RD-led nutrition education is able to improve eating patterns in children with celiac disease (CD).
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http://dx.doi.org/10.3390/nu13041108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065720PMC
March 2021

Faecal calprotectin in children with multisystem inflammatory syndrome: A pilot case-control study.

Acta Paediatr 2021 Jul 30;110(7):2246-2248. Epub 2021 Mar 30.

Pediatric Gastroenterology and Nutrition, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.

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http://dx.doi.org/10.1111/apa.15856DOI Listing
July 2021

Sarcoma classification by DNA methylation profiling.

Nat Commun 2021 01 21;12(1):498. Epub 2021 Jan 21.

Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
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http://dx.doi.org/10.1038/s41467-020-20603-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819999PMC
January 2021

Management of small intestinal bacterial overgrowth by pediatric gastroenterologists in Spain.

Rev Esp Enferm Dig 2021 Jun;113(6):436-441

Pediatric Gastroenterology and Nutrition Unit, Hospital Regional Universitario de Malaga, España.

Background: small intestinal bacterial overgrowth (SIBO) is a heterogeneous condition with nonspecific symptoms. This study aimed to report its management by pediatric gastroenterologists in Spain.

Methods: a descriptive study was performed by means of a survey sent to 184 active members of the Spanish Society of Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP).

Results: one hundred and forty-eight responses (80.4 %) were received. Forty-four patients had no predisposing condition, 31.1 % used antibiotics followed by probiotics, 33.1 % antibiotherapy concomitant with probiotics, 24.3 % only antibiotics and 10.8 % only probiotics. The diagnosis was established via clinical parameters in 73.8 % of participants and the therapeutic response was checked only by clinical data in 90 %.

Conclusions: there is high variability in the management of SIBO among pediatric population in Spain.
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http://dx.doi.org/10.17235/reed.2020.7582/2020DOI Listing
June 2021

Molecular Approaches to Diagnosis in Ewing Sarcoma: Targeted RNA Sequencing.

Methods Mol Biol 2021 ;2226:105-116

Department of Pathology, Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Seville, Spain.

Molecular testing of pathognomonic gene fusions is mandatory for small round cell tumor diagnosis, including Ewing sarcoma which is indeed defined by a variety of chimeric genes. Reference laboratories are increasingly implementing NGS-based techniques to overcome several limitations of conventional singleplex determinations. We have been early adopters of a targeted-RNA sequencing method based on Anchored multiplex PCR, which allows assessing several fusion transcripts simultaneously with previous knowledge of only one partner gene. Here we describe in detail our protocol and tips for nucleic acid extraction, library preparation, sequencing, and reporting of gene fusions.
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http://dx.doi.org/10.1007/978-1-0716-1020-6_8DOI Listing
April 2021

Spanish Pediatric Inflammatory Bowel Disease Diagnostic Delay Registry: SPIDER Study From Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica.

Front Pediatr 2020 15;8:584278. Epub 2020 Oct 15.

Unit for the Comprehensive Care of Paediatric Inflammatory Bowel Disease, Hospital Sant Joan de Deu, Barcelona, Spain.

Diagnostic delay (DD) is especially relevant in children with inflammatory bowel disease, leading to potential complications. We examined the intervals and factors for DD in the pediatric population of Spain. We conducted a multicentric prospective study, including 149 pediatric inflammatory bowel disease patients, obtaining clinical, anthropometric, and biochemical data. Time to diagnosis (TD) was divided into several intervals to identify those where the DD was longer and find the variables that prolonged those intervals. Missed opportunities for diagnosis (MODs) were also identified. Overall TD was 4.4 months (interquartile range [IQR] 2.6-10.4), being significantly higher in Crohn's disease (CD) than in ulcerative colitis (UC) (6.3 [IQR 3.3-12.3] vs. 3 [IQR 1.6-5.6] months, p = 0.0001). Time from the visit to the first physician until referral to a pediatric gastroenterologist was the main contributor to TD (2.4 months [IQR 1.03-7.17] in CD vs. 0.83 months [IQR 0.30-2.50] in UC, p = 0.0001). One hundred and ten patients (78.3%) visited more than one physician (29.9% to 4 or more), and 16.3% visited the same physician more than six times before being assessed by the pediatric gastroenterologist. The number of MODs was significantly higher in CD than that in UC patients: 4 MODs (IQR 2-7) vs. 2 MODs ([IQR 1-5], p = 0.003). Referral by pediatricians from hospital care allowed earlier IBD diagnosis (odds ratio 3.2 [95% confidence interval 1.1-8.9], p = 0.025). TD and DD were significantly higher in CD than those in UC. IBD patients (especially those with CD) undergo a large number of medical visits until the final diagnosis.
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http://dx.doi.org/10.3389/fped.2020.584278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593447PMC
October 2020

COVID-19 Gastrointestinal Manifestations Are Independent Predictors of PICU Admission in Hospitalized Pediatric Patients.

Pediatr Infect Dis J 2020 12;39(12):e459-e462

Pediatric Gastroenterology and Nutrition, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Spain.

Multicenter study conducted in 15 hospitals including 101 COVID-19 pediatric inpatients aiming to describe associated gastrointestinal (GI) manifestations. GI symptoms were present in 57% and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had higher risk of pediatric intensive care unit admission. GI symptoms are predictive of severity in COVID-19 children admitted to hospitals.
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http://dx.doi.org/10.1097/INF.0000000000002935DOI Listing
December 2020

[Study of adherence to the gluten-free diet in coeliac patients].

An Pediatr (Barc) 2021 Jun 20;94(6):377-384. Epub 2020 Aug 20.

Servicio de Gastroenterología-Hepatología y Nutrición, Hospital Universitario Central de Asturias, Oviedo, España.

Introduction: The following of a strict gluten-free diet (GFD) is essential in the control of coeliac disease. The aim of this study was to determine the adherence to a GFD in coeliac patients and to evaluate the factors that could influence this adherence.

Material And Methods: A descriptive observational study was carried out, in which gluten immunogenic peptides (GIP) were determined in faeces using a semi-quantitative method, and the Coeliac Dietary Adherence Test was completed. Sociodemographic and clinical details were collected, and an ad hoc questionnaire was prepared.

Results: Of the 80 patients included, 92.5% were adherent according to the GIP and 86.3% according to Coeliac Dietary Adherence Test (acceptable agreement; Kappa: 0.31, P=.004). The large majority (83.3%) of patients with positive GIP gave negative anti-transglutaminase antibodies in the latest determination. Current age and time of onset were significantly associated with adherence. Those with a positive GIP had a mean age of 5 years more (P=.0001) and were 52 months more on a GFD (P=.025). One quarter of those surveyed considered the diet difficult to follow. Just under two-thirds (60%) considered that the variability in the eating site was an important factor in leading to infringements, with children's parties being the main area where they occurred (66.7%). The lack of variety (61.4%) and the increased cost (98.6%) of gluten-free foods is highlighted.

Conclusions: The adherence to the GFD is generally good. The analysis of GIP helps to detect non-adherent patients that would pass unnoticed in other circumstances. Measures must be established in order to maintain good long-term adherence, taking into account the risk factors and difficulties detected.
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http://dx.doi.org/10.1016/j.anpedi.2020.06.017DOI Listing
June 2021

Assessment of Two Nutritional Screening Tools in Hospitalized Children.

Nutrients 2020 Apr 26;12(5). Epub 2020 Apr 26.

Pediatric Gastroenterology and Nutrition, Hospital Universitario Central de Asturias, University of Oviedo, 33011 Oviedo, Asturias, Spain.

Aim: to evaluate validity and concordance of Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) and Screening Tool for Risk On Nutritional status and Growth (STRONGkids) screening tools for assessment of nutritional risk in pediatric inpatients.

Methods: Prospective longitudinal observational multicenter study in children aged 1 month or older admitted as inpatients. Weight, height, cause of admission, demographic data, length of stay, and nutritional interventions were recorded. STAMP and STRONGkids were applied within the first 72 h of admission. Anthropometric measurements were recorded again 12-18 months after admission.

Results: Eighty-one patients with median age of 4.1 years completed the study. Agreement between tools was moderate (κ = 0.47). STAMP had a greater tendency to classify patients as high risk (12.3% vs. 2.5%). Both tools showed very weak correlation with height for age. All undernourished patients at the beginning and the end of the study were classified as medium or high risk by STAMP and STRONGkids (100% sensitivity), although specificity was below 50% in all cases. There were no differences in length of stay based on nutritional risk with any of the tools.

Conclusions: STAMP and STRONGkids demonstrated moderate agreement, with high sensitivity but low specificity for the diagnosis of undernutrition. Further studies are required to analyze cost-effectiveness of these tools and nutritional interventions derived from them.
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http://dx.doi.org/10.3390/nu12051221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281986PMC
April 2020

Breakthrough Technologies Reshape the Ewing Sarcoma Molecular Landscape.

Cells 2020 03 26;9(4). Epub 2020 Mar 26.

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, 41013 Seville, Spain.

Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma.
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http://dx.doi.org/10.3390/cells9040804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226764PMC
March 2020

Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2020 03 14;21(3):456-466. Epub 2020 Feb 14.

Cancer Medicine Department, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Istituto Nazionale Tumori, Milan, Italy.

Background: Solitary fibrous tumour is an ultra-rare sarcoma, which encompasses different clinicopathological subgroups. The dedifferentiated subgroup shows an aggressive course with resistance to pazopanib, whereas in the malignant subgroup, pazopanib shows higher activity than in previous studies with chemotherapy. We designed a trial to test pazopanib activity in two different cohorts of solitary fibrous tumour: the malignant-dedifferentiated cohort, which was previously published, and the typical cohort, which is presented here.

Methods: In this single-arm, phase 2 trial, adult patients (aged ≥18 years) diagnosed with confirmed metastatic or unresectable typical solitary fibrous tumour of any location, who had progressed in the previous 6 months (by Choi criteria or Response Evaluation Criteria in Solid Tumors [RECIST]) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were enrolled at 11 tertiary hospitals in Italy, France, and Spain. Patients received pazopanib 800 mg once daily, taken orally, until progression, unacceptable toxicity, withdrawal of consent, non-compliance, or a delay in pazopanib administration of longer than 3 weeks. The primary endpoint was proportion of patients achieving an overall response measured by Choi criteria in patients who received at least 1 month of treatment with at least one radiological assessment. All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered in ClinicalTrials.gov, NCT02066285, and with the European Clinical Trials Database, EudraCT 2013-005456-15.

Findings: From June 26, 2014, to Dec 13, 2018, of 40 patients who were assessed, 34 patients were enrolled and 31 patients were included in the response analysis. Median follow-up was 18 months (IQR 14-34), and 18 (58%) of 31 patients had a partial response, 12 (39%) had stable disease, and one (3%) showed progressive disease according to Choi criteria and central review. The proportion of overall response based on Choi criteria was 58% (95% CI 34-69). There were no deaths caused by toxicity, and the most frequent adverse events were diarrhoea (18 [53%] of 34 patients), fatigue (17 [50%]), and hypertension (17 [50%]).

Interpretation: To our knowledge, this is the first prospective trial of pazopanib for advanced typical solitary fibrous tumour. The manageable toxicity and activity shown by pazopanib in this cohort suggest that this drug could be considered as first-line treatment for advanced typical solitary fibrous tumour.

Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(19)30826-5DOI Listing
March 2020

Hippo pathway effectors YAP1/TAZ induce an EWS-FLI1-opposing gene signature and associate with disease progression in Ewing sarcoma.

J Pathol 2020 04 4;250(4):374-386. Epub 2020 Feb 4.

Department of Pathology, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, CSIC-Universidad de Sevilla, Seville, Spain.

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1 and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of the Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro-tumorigenic isoform RASSF1C, which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5379DOI Listing
April 2020

DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.

J Cancer Res Clin Oncol 2019 May 20;145(5):1273-1281. Epub 2019 Mar 20.

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.

Purpose: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1-ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS.

Methods: We collected five cases matching the group of URCS with EWSR1-NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1-ETS fusions and one EwS with FUS-ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas.

Results: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1-NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1-NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively.

Conclusion: In summary, URCS with EWSR1-NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS.
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http://dx.doi.org/10.1007/s00432-019-02895-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607515PMC
May 2019

[Effect of healthy eating before intervention with a low FODMAP diet in pediatric patients with irritable bowel syndrome].

Nutr Hosp 2019 Apr;36(2):275-281

Hospital Universitario de Asturias.

Introduction: Background: a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) may be effective in the treatment of pediatric patients with irritable bowel syndrome (IBS). Its complexity and side effects make it a secondary therapeutic alternative. Objective: to demonstrate that nutritional education, aimed at optimizing the diet of children with IBS, is able to improve gastrointestinal symptoms of children without following a diet low in FODMAP. Methods: prospective intervention study. Changes in gastrointestinal symptoms were analyzed by means of the Pediatric Quality of Life Inventory™ Gastrointestinal Symptoms (PedsQL™ GI Symptoms), after receiving nutritional education based on a healthy diet. Likewise, anthropometric changes and dietary habits were analyzed. Results: twenty-one patients were included (12 girls) with a mean age of 10.6 years (5-14 years). A diet with excess intake of simple sugars, saturated fats and salt along with fiber deficit was observed. After the intervention, an increase in 8.07 points was observed in the inventory (95% CI: 13.42 a -2.73, p = 0.005). Additionally, significant weight loss was observed in overweight and obese patients (decrease in body mass index [BMI]; Z-score 0.62 SD, p = 0.001). Significant changes in dietary habits were observed: increased consumption of complex carbohydrates, fruits and vegetables and reduction of simple sugars. Conclusions: healthy eating is effective to improve gastrointestinal symptoms in pediatric patients with IBS, without requiring the exclusion of FODMAP.
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http://dx.doi.org/10.20960/nh.2234DOI Listing
April 2019

[Non-IgE-mediated cow's milk allergy: Consensus document of the Spanish Society of Paediatric Gastroenterology, Hepatology, and Nutrition (SEGHNP), the Spanish Association of Paediatric Primary Care (AEPAP), the Spanish Society of Extra-hospital Paediatrics and Primary Health Care (SEPEAP), and the Spanish Society of Paediatric ClinicaL Immunology, Allergy, and Asthma (SEICAP)].

An Pediatr (Engl Ed) 2019 Mar 19;90(3):193.e1-193.e11. Epub 2019 Jan 19.

Sección de Gastroenterología, Hepatología y Nutrición Pediátrica, Hospital Universitario La Fe, Valencia, España.

Non-IgE-mediated cow's milk allergy is a frequent disorder in paediatrics. As patients might be seen by professionals from different specialties and levels of expertise, a great variability in diagnostic procedures and disease monitoring is commonly observed. Therefore, four scientific societies involved in its management have developed a consensus document providing specific recommendations related to its prevention, diagnosis, treatment and follow up.
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http://dx.doi.org/10.1016/j.anpedi.2018.11.007DOI Listing
March 2019

Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial.

Lancet Oncol 2019 01 18;20(1):134-144. Epub 2018 Dec 18.

Department of Medical Oncology, University Hospital of Canarias, Tenerife, Spain.

Background: A solitary fibrous tumour is a rare soft-tissue tumour with three clinicopathological variants: typical, malignant, and dedifferentiated. Preclinical experiments and retrospective studies have shown different sensitivities of solitary fibrous tumour to chemotherapy and antiangiogenics. We therefore designed a trial to assess the activity of pazopanib in a cohort of patients with malignant or dedifferentiated solitary fibrous tumour. The clinical and translational results are presented here.

Methods: In this single-arm, phase 2 trial, adult patients (aged ≥ 18 years) with histologically confirmed metastatic or unresectable malignant or dedifferentiated solitary fibrous tumour at any location, who had progressed (by RECIST and Choi criteria) in the previous 6 months and had an ECOG performance status of 0-2, were enrolled at 16 third-level hospitals with expertise in sarcoma care in Spain, Italy, and France. Patients received pazopanib 800 mg once daily, taken orally without food, at least 1 h before or 2 h after a meal, until progression or intolerance. The primary endpoint of the study was overall response measured by Choi criteria in the subset of the intention-to-treat population (patients who received at least 1 month of treatment with at least one radiological assessment). All patients who received at least one dose of the study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02066285, and with the European Clinical Trials Database, EudraCT number 2013-005456-15.

Findings: From June 26, 2014, to Nov 24, 2016, of 40 patients assessed, 36 were enrolled (34 with malignant solitary fibrous tumour and two with dedifferentiated solitary fibrous tumour). Median follow-up was 27 months (IQR 16-31). Based on central radiology review, 18 (51%) of 35 evaluable patients had partial responses, nine (26%) had stable disease, and eight (23%) had progressive disease according to Choi criteria. Further enrolment of patients with dedifferentiated solitary fibrous tumour was stopped after detection of early and fast progressions in a planned interim analysis. 51% (95% CI 34-69) of 35 patients achieved an overall response according to Choi criteria. Ten (29%) of 35 patients died. There were no deaths related to adverse events and the most frequent grade 3 or higher adverse events were hypertension (11 [31%] of 36 patients), neutropenia (four [11%]), increased concentrations of alanine aminotransferase (four [11%]), and increased concentrations of bilirubin (three [8%]).

Interpretation: To our knowledge, this is the first trial of pazopanib for treatment of malignant solitary fibrous tumour showing activity in this patient group. The manageable toxicity profile and the activity shown by pazopanib suggests that this drug could be an option for systemic treatment of advanced malignant solitary fibrous tumour, and provides a benchmark for future trials.

Funding: Spanish Group for Research on Sarcomas (GEIS), Italian Sarcoma Group (ISG), French Sarcoma Group (FSG), GlaxoSmithKline, and Novartis.
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http://dx.doi.org/10.1016/S1470-2045(18)30676-4DOI Listing
January 2019

What's in a name? Molecular subclassification of sarcomas creates fresh challenges.

J Pathol 2019 Apr 16;247(4):409-412. Epub 2019 Jan 16.

Department of Pathology, Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain.

This commentary addresses the issue of the classification of sarcomas in the article written by Watson and colleagues published recently in this journal. The article delves into the molecular characterization and distinct phenotypes of some recently described entities (e.g. BCOR-rearranged sarcomas, CIC-fused sarcomas) and describes new groups with common characteristics. This commentary focuses on several questions raised in the article, such as what makes a group of sarcomas become a clinical entity, which should be the main driver of sarcoma classification, how the classification of small round cell sarcomas is expected to evolve and how high-throughput techniques could be applied to sarcoma diagnosis in the short term. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5206DOI Listing
April 2019

Preclinical Efficacy of Endoglin-Targeting Antibody-Drug Conjugates for the Treatment of Ewing Sarcoma.

Clin Cancer Res 2019 04 12;25(7):2228-2240. Epub 2018 Nov 12.

Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain.

Purpose: Endoglin (ENG; CD105) is a coreceptor of the TGFβ family that is highly expressed in proliferating endothelial cells. Often coopted by cancer cells, ENG can lead to neo-angiogenesis and vasculogenic mimicry in aggressive malignancies. It exists both as a transmembrane cell surface protein, where it primarily interacts with TGFβ, and as a soluble matricellular protein (sENG) when cleaved by matrix metalloproteinase 14 (MMP14). High ENG expression has been associated with poor prognosis in Ewing sarcoma, an aggressive bone cancer that primarily occurs in adolescents and young adults. However, the therapeutic value of ENG targeting has not been fully explored in this disease.

Experimental Design: We characterized the expression pattern of transmembrane ENG, sENG, and MMP14 in preclinical and clinical samples. Subsequently, the antineoplastic potential of two novel ENG-targeting monoclonal antibody-drug conjugates (ADC), OMTX503 and OMTX703, which differed only by their drug payload (nigrin-b A chain and cytolysin, respectively), was assessed in cell lines and preclinical animal models of Ewing sarcoma.

Results: Both ADCs suppressed cell proliferation in proportion to the endogenous levels of ENG observed . Moreover, the ADCs significantly delayed tumor growth in Ewing sarcoma cell line-derived xenografts and patient-derived xenografts in a dose-dependent manner.

Conclusions: Taken together, these studies demonstrate potent preclinical activity of first-in-class anti-ENG ADCs as a nascent strategy to eradicate Ewing sarcoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445738PMC
April 2019

Study on the nutritional status and feeding habits in school-children in Madrid City (Spain) during the economic crisis.

Nutr Hosp 2018 Oct 5;35(5):1054-1058. Epub 2018 Oct 5.

Clínica Universidad de Navarra.

Introduction: the recent economic and financial crisis has affected most Western countries, especially families of low socioeconomic classes. We speculate that worsening of socioeconomic condition associated with the crisis would increase obesity, mainly in disadvantaged families.

Material And Methods: cross-sectional study of the 290,111 children aged three to 12 years old attending public school during the term 2014-2015 in Madrid City, by means of a stratified weighted sample randomly chosen, taking into account age (grade), city district and schools. The questionnaire included weight and height (auto-reported), dietary report (weekly frequency of intake), as well as socioeconomic variables.

Results: 1,208 questionnaires were evaluated from 64 classes. Half of participants were boys; 42% were younger than five years old, 35% werebetween six and eight years old, and 23% older than eight. Undernutrition was present in 5.0%, and excess of weight (overweight + obesity) in 36.7%. Undernutrition was higher in children under the age of six (9.1%). No relationship was found between undernutrition and the characteristics of the families but was slightly higher in families where both parents were unemployed. Excess of weight was higher in children of non-Spaniard parents (44% vs 32%, p < 0.0001), as well as in those families with economic problems (41% vs 31%, p = 0.0005). Only for meat, grains and dairy, the weekly intake was close to the recommendations.

Conclusions: children from lower income households were at a higher risk of being overweight compared with their peers. Participation in a school-based food aid program may reduce food insecurity for children and their families.
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http://dx.doi.org/10.20960/nh.1824DOI Listing
October 2018

[Cow's milk protein allergy with skin lesions. Is it always necessary to refer to a dermatologist?]

An Pediatr (Engl Ed) 2018 Oct 30;89(4):261-262. Epub 2018 Jun 30.

Sección de Gastroenterología, Hepatología y Nutrición Pediátrica, Área de Gestión Clínica de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.

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http://dx.doi.org/10.1016/j.anpedi.2018.05.010DOI Listing
October 2018

[Attitudes towards cow's milk protein allergy management by spanish gastroenterologist].

An Pediatr (Engl Ed) 2018 Oct 10;89(4):222-229. Epub 2018 Jan 10.

Unidad de Gastroenterología, Hepatología y Nutrición Pediátrica, Área de Gestión Clínica de Pediatría, Hospital Universitario Central de Asturias, Oviedo, España.

Introduction: Food allergy is an increasing health problem in the developed world. Cow's milk protein is the main cause of food allergy in infants. Without an appropriate diagnostic workup, there is a high risk of both over- and underdiagnosis and therefore, over and undertreatment. The objective of our study was to analyze the variability in cow's milk protein allergy (CMPA) management by pediatric gastroenterologists in Spain.

Methods: A fifty item questionnaire, including open and closed items in a Likert's scale from 0 to 5, was drafted and distributed through the Spanish Society for Pediatric Gastroenterology, Hepatology and Nutrition (SEGHNP) e-mail list.

Results: Seventy-three questionnaires were received back out of 321. Only 3 of the items achieved concordance greater than 90%. Thirty-three percent considered oral challenge to be necessary for the diagnosis of CMPA under any circumstance. Twenty-five percent considered that symptom improvement after cow's milk removal was enough for the diagnosis. Oral challenge was performed at home by 83.5% in non-IgE mediated cases. Extensively hydrolyzed casein formulas were the treatment of choice for 69.9%. Soy formulas were the last option. Almost all respondents were aware of the existence of clinical guidelines on CMPA, being European Society of Pediatric Gastroenterology, Hepatology and Nutrition guidelines the most followed (64.4%). Twenty-three percent considered that their knowledge about allergy was inadequate.

Conclusions: Although CMPA is a prevalent condition that pediatric gastroenterologists have been treating for decades, we found a huge variability on its management. There is potential for improvement in this field among pediatric gastroenterologist in the future.
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http://dx.doi.org/10.1016/j.anpedi.2017.10.015DOI Listing
October 2018

[2016: Inflammatory bowel disease epidemic in Asturias].

An Pediatr (Engl Ed) 2018 Sep 13;89(3):183-184. Epub 2017 Dec 13.

Sección de Gastroenterología, Hepatología y Nutrición Pediátrica, Área de Gestión Clínica de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.

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http://dx.doi.org/10.1016/j.anpedi.2017.11.008DOI Listing
September 2018

[Excess weight in patients with cystic fibrosis: is it always beneficial?]

Nutr Hosp 2017 06 5;34(3):578-583. Epub 2017 Jun 5.

HOSPITAL CARMEN Y SEVERO OCHOA.

Introduction: The primary objective of this study was to find out the prevalence of overweight and obese status, as well as their association to pulmonary function, total cholesterol and vitamin D in patients with cystic fibrosis (CF).

Materials And Methods: This is a multicenter descriptive and cross-sectional study. Twelve Spanish hospitals participated. 451 patients with CF were included. Adults were classified according to body mass index (BMI) and children were classified according to BMI percentiles (WHO tables). Pearson's correlation, Anova, Student's t-test and multiple linear regression were conducted.

Results: Mean age was 12.3 (range 4-57) years old, 51% were male and 18% had pancreatic sufficiency. Participants were classified in five nutritional status categories: 12% were malnourished; 57%, at nutritional risk; 24%, normally nourished; 6%, overweight; and 1%, obese. Pulmonary function in overweight or obese patients (91 ± 19%) was better than in malnourished patients (77 ± 24%) (p = 0.017). However, no difference was observed between those at nutritional risk (86 ± 19%) or normally nourished (90 ± 22%) groups. Overweight and obese patients had higher levels of total cholesterol (p = 0.0049), a greater proportion of hypercholesterolemia (p = 0.001), as well as lower levels of 25 OH vitamin D (p = 0.058).

Conclusions: Prevalence of overweight and obese was 6 and 1%. Excess weight status does not offer any benefit in pulmonary function in comparison to normally nourished patients.
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http://dx.doi.org/10.20960/nh.620DOI Listing
June 2017

[Splenic granulomas in a girl with Crohn's disease].

An Pediatr (Engl Ed) 2018 Feb 11;88(2):113-115. Epub 2017 Jun 11.

Área de Gestión Clínica de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, España.

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http://dx.doi.org/10.1016/j.anpedi.2017.05.001DOI Listing
February 2018

[Childhood obesity: Prevention or treatment?]

An Pediatr (Barc) 2017 Apr 24;86(4):173-175. Epub 2017 Jan 24.

Sección de Gastroenterología y Nutrición, Área de Gestión Clínica de Pediatría, Hospital Universitario Central de Asturias, Oviedo, Asturias, España. Electronic address:

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http://dx.doi.org/10.1016/j.anpedi.2016.12.004DOI Listing
April 2017
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