Publications by authors named "Antonia Perelló"

28 Publications

  • Page 1 of 1

Palbociclib and Trastuzumab in HER2-Positive Advanced Breast Cancer: Results from the Phase II SOLTI-1303 PATRICIA Trial.

Clin Cancer Res 2020 Nov 16;26(22):5820-5829. Epub 2020 Sep 16.

SOLTI Breast Cancer Research Group, Barcelona, Spain.

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer.

Patients And Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes.

Results: Seventy-one patients were recruited ( = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1-2 and 3-4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3-4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; = 0.003).

Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0844DOI Listing
November 2020

Efficacy of proton pump inhibitor therapy for eosinophilic oesophagitis in 630 patients: results from the EoE connect registry.

Aliment Pharmacol Ther 2020 09 17;52(5):798-807. Epub 2020 Jul 17.

Tomelloso, Spain.

Background: Proton pump inhibitors (PPIs) are the most commonly used first-line therapy for patients with eosinophilic oesophagitis (EoE). However, many aspects related to PPIs in EoE are still unknown.

Aims: To assess the effectiveness of PPI therapy for EoE in real-world practice.

Methods: This cross-sectional study collected data on PPI efficacy from the multicentre EoE CONNECT database. Clinical remission was defined as a decrease of ≥50% in dysphagia symptom score; histological remission was defined as a peak eosinophil count below 15 eosinophils per high-power field. Factors associated with effectiveness of PPI therapy were identified by binary logistic regression multivariate analyses.

Results: Overall, 630 patients (76 children) received PPI as initial therapy (n = 600) or after failure to respond to other therapies (n = 30). PPI therapy achieved eosinophil density below 15 eosinophils per high-power field in 48.8% and a decreased symptom score in 71.0% of patients. More EoE patients with an inflammatory rather than stricturing phenotype accomplished clinico-histological remission after PPI therapy (OR 3.7; 95% CI, 1.4-9.5); as well as those who prolonged treatment length from 8 to 12 weeks (OR 2.7; 95% CI, 1.3-5.3). After achieving clinico-histological remission of EoE, PPI dosage reduction was effectively maintained in 69.9% of patients, but tended to be less effective among those with a stricturing phenotype.

Conclusions: Inflammatory EoE phenotype and treatment duration up to 12 weeks correlated with greater chance for inducing remission of EoE. A stricturing phenotype decreased response rates to PPI therapy both initially and in the long term.
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http://dx.doi.org/10.1111/apt.15957DOI Listing
September 2020

Efficacy of Therapy for Eosinophilic Esophagitis in Real-World Practice.

Clin Gastroenterol Hepatol 2020 Dec 25;18(13):2903-2911.e4. Epub 2020 Jan 25.

Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain; Instituto de Investigación Sanitaria Princesa, Madrid, Spain; Centro de Investigacion Biomedica en Red Enfermedades Hepáticas y Digestivas, Madrid, Spain. Electronic address:

Background & Aims: Topical steroids, proton pump inhibitors (PPIs), and dietary interventions are recommended first- and second-line therapies for eosinophilic esophagitis (EoE). We investigated differences in their effectiveness in a real-world, clinical practice cohort of patients with EoE.

Methods: We collected data on the efficacy of different therapies for EoE (ability to induce clinical and histologic remission) from the multicenter EoE CONNECT database-a database of patients with a confirmed diagnosis of EoE in Europe that began in 2016. We obtained data from 589 patients, treated at 11 centers, on sex, age, time of diagnosis, starting date of any therapy, response to therapy, treatment end dates, alternative treatments, and findings from endoscopy. The baseline endoscopy was used for diagnosis of EoE; second endoscopy was performed to evaluate response to first-line therapies. After changes in treatment, generally because lack of efficacy, a last endoscopy was performed. The time elapsed between endoscopies depended on the criteria of attending physicians. Clinical remission was defined by a decrease of more than 50% in Dysphagia Symptom Score; improvement in symptoms by less than 50% from baseline was considered as clinical response. Histologic remission was defined as a peak eosinophil count below 5 eosinophils/hpf. A peak eosinophil count between 5 and 14 eosinophils/hpf was considered histologic response. We identified factors associated with therapy selection and effectiveness using χ2 and multinomial logistic regression analyses RESULTS: PPIs were the first-line treatment for 76.4% of patients, followed by topical steroids (for 10.5%) and elimination diets (for 7.8%). Topical steroids were most effective in inducing clinical and histologic remission or response (in 67.7% of patients), followed by empiric elimination diets (in 52.0%), and PPIs (in 50.2%). Among the 344 patients who switched to a second-line therapy, dietary interventions were selected for 47.1% of patients, followed by PPIs (for 29.1%) and topical steroids (for 18.6%). Clinical and histologic remission or response was achieved by 80.7% of patients treated with topical steroids, 69.2% of patients given PPIs, and 41.7% of patients on empiric elimination diets. Multivariate analyses found the stricturing phenotype of EoE to be associated with selection of topical steroids over PPIs as the first-line therapy; lack of fibrotic features at initial endoscopy was associated with selection of elimination diets over topical steroids as a second-line therapy. The recruiting center was significantly associated with therapy choice; second-line treatment with topical steroids or PPIs were the only variables associated with clinical and histologic remission.

Conclusions: In an analysis of data from a large cohort of patients with EoE in Europe, we found topical steroids to be the most effective at inducing clinical and histologic remission, but PPIs to be the most frequently prescribed. Treatment approaches vary with institution and presence of fibrosis or strictures.
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http://dx.doi.org/10.1016/j.cgh.2020.01.024DOI Listing
December 2020

Fulvestrant Plus Vistusertib vs Fulvestrant Plus Everolimus vs Fulvestrant Alone for Women With Hormone Receptor-Positive Metastatic Breast Cancer: The MANTA Phase 2 Randomized Clinical Trial.

JAMA Oncol 2019 Aug 29. Epub 2019 Aug 29.

Vall d'Hebron Institute of Oncology, SOLTI Breast Cancer Research Group, Vall d'Hebron University Hospital, Barcelona, Spain.

Importance: Randomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.

Objective: To evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.

Design, Setting, And Participants: The MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.

Interventions: Fulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS).

Results: Among the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).

Conclusions And Relevance: The combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.

Trial Registration: ClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.
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http://dx.doi.org/10.1001/jamaoncol.2019.2526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865233PMC
August 2019

Clinical response to linaclotide at week 4 predicts sustained response in irritable bowel syndrome with constipation and improvements in digestive and extra-digestive symptoms.

Therap Adv Gastroenterol 2019 5;12:1756284819857358. Epub 2019 Aug 5.

Servicio de Aparato Digestivo, Hospital Clínico San Carlos, Universidad Complutense, Instituto de Investigación Sanitaria San Carlos (IdISSC), 28040 Madrid, Spain.

Background: Linaclotide is approved for the treatment of moderate-to-severe irritable bowel syndrome (IBS) with constipation (IBS-C) in adults. This study aimed to assess factors predictive of a clinical response and improvements in non-IBS symptoms with linaclotide treatment in a Spanish patient population.

Methods: In this open-label phase IIIb study, patients with moderate-to-severe IBS-C received linaclotide 290 μg once daily for 12 weeks. The primary endpoint was clinical response at week 12, defined as >30% reduction in IBS symptom severity score (IBS-SSS) or IBS-SSS <75 plus self-reported response of feeling 'better' or 'much better' the baseline. Digestive nonintestinal and extra-digestive symptom scores were assessed. Baseline characteristics and week 4 clinical response were assessed as predictors of week 12 clinical response.

Results: A total of 96 patients were eligible; 91 were female and the mean age was 47.4 years. Mean (SD) baseline IBS-SSS was 371 (72.5). In the intention-to-treat and per-protocol populations, 22.9% and 31.7% were clinical responders at week 4, respectively, and 25.0% and 36.7% were clinical responders at week 12. Digestive nonintestinal and extra-digestive symptom scores were significantly improved at weeks 4 and 12. Baseline characteristic was not associated with week 12 clinical response; however, clinical response at week 4 was predictive of response at week 12 (OR: 6.5; 95%IC: 2.1-19.8). The most common adverse event was diarrhea inclusive of loose or watery stools (35.4%).

Conclusions: Linaclotide improves IBS-C symptoms, including digestive nonintestinal and extra-digestive symptoms. A clinical response at week 4 may predict response at week 12.
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http://dx.doi.org/10.1177/1756284819857358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683318PMC
August 2019

Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication.

Ther Adv Med Oncol 2019 10;11:1758835919833867. Epub 2019 May 10.

SOLTI, Barcelona, Spain.

Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the 'First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications'. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.
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http://dx.doi.org/10.1177/1758835919833867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535716PMC
May 2019

A retrospective and prospective 12-month observational study of the socioeconomic burden of moderate to severe irritable bowel syndrome with constipation in Spain.

Gastroenterol Hepatol 2019 Mar 3;42(3):141-149. Epub 2019 Jan 3.

University of Leuven, Leuven, Belgium.

Introduction: The socioeconomic burden of irritable bowel syndrome with constipation (IBS-C) has never been formally assessed in Spain.

Patients And Methods: This 12-month (6-month retrospective and prospective periods) observational, multicentre study assessed the burden of moderate-to-severe IBS-C in Spain. Patients were included if they had been diagnosed with IBS-C (Rome III criteria) within the last 5 years and had moderate-to-severe IBS-C (IBS Symptom Severity Scale score [IBS-SSS] ≥175) at inclusion. The primary objective was to assess the direct cost to the Spanish healthcare system (HS).

Results: A total of 112 patients were included, 64 (57%) of which had severe IBS-C at inclusion. At baseline, 89 (80%) patients reported abdominal pain and distention. Patient quality of life (QoL), measured by the IBS-C QoL and EQ-5D instruments, was found to be impaired with a mean score of 59 and 57 (0-100, worst-best), respectively. Over the 6-month prospective period the mean IBS-C severity, measured using the IBS-SSS showed some improvement (315-234 [0-500, best-worst]). During the year, 89 (80%) patients used prescription drugs for IBS-C, with laxatives being the most frequently prescribed (n=70; 63%). The direct cost to the HS was €1067, and to the patient was €568 per year. The total direct cost for moderate-to-severe IBS-C was €1635.

Discussion: The majority of patients reported continuous IBS-C symptoms despite that 80% were taking medication to treat their IBS-C. Overall healthcare resource use and direct costs were asymmetric, with a small group of patients consuming the majority of resources.
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http://dx.doi.org/10.1016/j.gastrohep.2018.10.008DOI Listing
March 2019

Helicobacter pylori infection does not protect against eosinophilic esophagitis: results from a large multicenter case-control study.

Am J Gastroenterol 2018 07 15;113(7):972-979. Epub 2018 Mar 15.

Department of Gastroenterology, Hospital Universitario San Pedro de Alcantara, Caceres, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain. Department of Pediatrics, Pediatric Gastroenterology Unit, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain. Department of Surgery, Division of Gastroenterology, Oncology and Gastroenterology, University of Padua, Padua, Italy. Gastroenterology and Endoscopy Unit, Università degli Studi di Milano, Milan, Italy. Department of Gastroenterology, Consorci Sanitari Terrassa, Barcelona, Spain. Department of Allergy, Hospital Universitario Gregorio Marañon, Madrid, Spain. Department of Gastroenterology, Hospital Universitario Miguel Servet, Zaragoza, Spain. Department of Gastroenterology, Hospital de Viladecans, Barcelona, Spain. Department of Gastroenterology, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain. Department of Gastroenterology, Hospital Clinico Universitario, Valladolid, Spain. Clinical Analysis and Pediatrics, Hospital Universitario Río Hortega, Valladolid, Spain. Department of Pediatrics, Hospital Universitario San Pedro de Alcantara, Caceres, Spain. Department of Gastroenterology, Hospital Quirón, Marbella, Spain. Departement of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), and CIBEREHD, Madrid, Spain. Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, and CIBEREHD, Ciudad Real, Spain.

Objectives: Rising trends in eosinophilic esophagitis (EoE) have been repeatedly linked to declining Helicobacter pylori (H. pylori) infection, mostly in retrospective studies. We aimed to prospectively evaluate this inverse association.

Methods: Prospective case-control study conducted in 23 centers. Children and adults naïve to eradication therapy for H. pylori were included. Cases were EoE patients, whereas controls were defined by esophageal symptoms and <5 eos/HPF on esophageal biopsies. H. pylori status was diagnosed by non-invasive (excluding serology) or invasive testing off proton pump inhibitor (PPI) therapy for 2 weeks. Atopy was defined by the presence of IgE-mediated conditions diagnosed by an allergist.

Results: 808 individuals, including 404 cases and 404 controls (170 children) were enrolled. Overall H. pylori prevalence was 38% (45% children vs. 37% adults, p 0.009) and was not different between cases and controls (37% vs. 40%, p 0.3; odds ratio (OR) 0.97; 95% confidence interval (CI) 0.73-1.30), neither in children (42% vs. 46%, p 0.1) nor in adults (36% vs. 38%, p 0.4). Atopy (OR 0.85; 95%CI 0.75-0.98) and allergic rhinitis (OR 0.81; 95%CI 0.68-0.98) showed a borderline inverse association with H. pylori infection in EoE patients. This trend was not confirmed for asthma or food allergy.

Conclusions: H. pylori infection was not inversely associated with EoE, neither in children nor in adults. A borderline inverse association was confirmed for atopy and allergic rhinitis, but not asthma of food allergy. Our findings question a true protective role of H. pylori infection against allergic disorders, including EoE.
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http://dx.doi.org/10.1038/s41395-018-0035-6DOI Listing
July 2018

Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials.

J Clin Oncol 2017 Sep 27;35(27):3113-3122. Epub 2017 Jun 27.

Poornima Saha and Gini F. Fleming, The University of Chicago Medical Center, Chicago, IL; Meredith M. Regan, Weixiu Luo, Harold J. Burstein, and Richard D. Gelber, Dana-Farber Cancer Institute; Meredith M. Regan, Harold J. Burstein, and Richard D. Gelber, Harvard Medical School; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard T.H. Chan School of Public Health, Boston, MA; Olivia Pagani, Institute of Oncology of Southern Switzerland, Lugano Viganello; Karin Ribi and Jürg Bernhard, International Breast Cancer Study Group Coordinating Center; Jürg Bernhard, Bern University Hospital, Inselspital, Bern, Switzerland; Prudence A. Francis, Peter MacCallum Cancer Center; St Vincent's Hospital; University of Melbourne, Melbourne; Josephine Stewart, Austin and Heidelberg Repatriation Medical Center, Heidelberg, Victoria; Prudence A. Francis, Josephine Stewart, and Michelle Nottage, University of Newcastle, Newcastle; Alan S. Coates, University of Sydney, Sydney, New South Wales; Michelle Nottage, Royal Brisbane Hospital, Brisbane, Queensland, Australia; Barbara A. Walley, University of Calgary; National Cancer Institute of Canada, Calgary, Alberta, Canada; Henry L. Gómez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Vani Parmar, Tata Memorial Centre, Mumbai, India; Roberto Torres, Instituto Nacional del Cancer, Santiago de Chile, Chile; Meritxell Bellet, Vall d'Hebron Institute of Oncology; Vall d'Hebron University Hospital; Universitat Autònoma de Barcelona, Barcelona; Antonia Perelló, Hospital Universitari Son Espases, Palma de Mallorca, Spain; Faysal Dane, Marmara University Hospital, Istanbul, Turkey; Antonio Moreira, Instituto Português de Oncologia Francisco Gentil - Centro de Lisboa, Lisbon, Portugal; Daniel Vorobiof, Sandton Oncology Centre, Johannesburg, South Africa; and Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy.

Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.
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http://dx.doi.org/10.1200/JCO.2016.72.0946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597253PMC
September 2017

Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial.

J Clin Oncol 2016 05 28;34(14):1601-10. Epub 2016 Mar 28.

Karin Ribi, Aron Goldhirsch, and Jürg Bernhard, International Breast Cancer Study Group Coordinating Center; Jürg Bernhard, Bern University Hospital, Inselspital, Bern; Thomas Ruhstaller, Breast Center St Gallen, Swiss Group for Clinical Cancer Research, and International Breast Cancer Study Group, St Gallen, Switzerland; Weixiu Luo, Karen N. Price, Richard D. Gelber, and Meredith M. Regan, International Breast Cancer Study Group Statistical Center; Weixiu Luo, Harold J. Burstein, Richard D. Gelber, and Meredith M. Regan, Dana-Farber Cancer Institute; Harold J. Burstein, Alliance for Clinical Trials in Oncology; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber and Meredith M. Regan, Harvard Medical School, Boston, MA; Gini F. Fleming, The University of Chicago Medical Center and Alliance for Clinical Trials in Oncology, Chicago, IL; Prudence A. Francis, International Breast Cancer Study Group, Peter MacCallum Cancer Center, St Vincent's Hospital, University of Melbourne, Melbourne, Victoria; Australia and New Zealand Breast Cancer Trials Group, University of Newcastle, Newcastle; Alan S. Coates, International Breast Cancer Study Group and University of Sydney, Sydney, New South Wales, Australia; Eva Ciruelos, University Hospital 12 de Octubre and SOLTI Group, Madrid; Meritxell Bellet, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, and SOLTI Group, Universitat Autònoma de Barcelona, Barcelona; Ana Lluch, Hospital Clinico Universitario de Valencia, Incliva Biomedical Research Institute, University of Valencia and SOLTI Group, Valencia; Antonia Perelló, Hospital Universitari Son Espases and SOLTI Group, Palma de Mallorca, Spain; Lorenzo Pavesi, Salvatore Maugeri Foundation and International Breast Cancer Study Group, Pavia; Marilena Visini, Ospedale Civile di Lecco and International Breast Cancer Study Group, Lecco; Carlo Tondini, Ospedale Papa Giovanni XXIII and International Brea

Purpose: The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes.

Patients And Methods: The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor-positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall.

Results: Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period.

Conclusion: Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.
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http://dx.doi.org/10.1200/JCO.2015.64.8675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872319PMC
May 2016

Factors Associated with the Selection of First-line Bevacizumab plus Chemotherapy and Clinical Response in HER2-negative Metastatic Breast Cancer: ONCOSUR AVALOX Study.

Anticancer Res 2015 Dec;35(12):6941-50

Hospital 12 de Octubre, ONCOSUR, Madrid, Spain.

Aim: To evaluate factors associated with the selection of first-line bevacizumab plus chemotherapy and clinical response in HER2-negative metastatic breast cancer (MBC) in clinical practice in Spain.

Patients And Methods: All consecutive adult female patients with HER2-negative MBC who had received first-line bevacizumab plus chemotherapy for at least 3 months were enrolled in the present study.

Results: A total of 292 evaluable patients were included; 25% had triple-negative breast cancer (TNBC) and 75% had hormone receptor-positive breast cancer (HRPBC). Nearly 40% of patients had ≥3 metastatic sites, mainly located in the bone (48%) and liver (40%). Bevacizumab was mostly combined with paclitaxel (67.1%). ER-positive tumors were only identified as an independent factor associated with the choice of treatment (odds ratio (OR): 0.538; p=0.02). The overall response rate (ORR) was 63.7% (TNBC: 57.5%; HRPBC: 65.9%). Patients aged 36-50 years (OR: 3.03; p=0.028) and those with metastases at sites other than the bone (OR: 0.38; p=0.001) and ≥3 metastatic sites (OR: 1.41; p=0.018) were more likely to achieve objective responses.

Conclusion: First-line bevacizumab plus chemotherapy, mainly paclitaxel, is an effective and well-tolerated treatment option for HER2-negative MBC, particularly in more aggressive disease.
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December 2015

Transcultural adaptation and validation of the "Adult Eosinophilic Esophagitis Quality of Life Questionnaire" into Spanish.

Rev Esp Enferm Dig 2014 Jun;106(6):386-94

Background: The "Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) Questionnaire" was developed in English as a valid, reliable, and disease-specific health-related QoL measure.This research aims to adapt and validate this questionnaire for Spanish-speaking patients.

Patients And Methods: A multicenter, observational, prospective study was conducted at 8 Spanish hospitals. The cultural adaptation of the original EoE-QoL-A questionnaire was undertaken through a standardized 3-phase procedure: 1. Translation; 2. Retrotranslation; and 3. Pilot study. Patients completed the Hospital Anxiety and Depression Scale (HADS), the Short Form (SF)-12, the Brief Illness Perception Questionnaire (BIPQ), and the adapted EoE-QoL-A, with a retest 3 months later.Statistical analysis included construct validity, internal consistency, criterion validity, and reproducibility.

Results: One hundred and seventy adult EoE patients (73.5 % male; aged 33.5 ± 11.4-y) were included in the study.With regard to internal validity, all Cronbach alpha values were > 0.75. A significant correlation between items assessed in the SF-12, BIPQ and EoE-QoL-A questionnaires (p < 0.001) was observed. Correlations with the HADS were stronger for anxiety than for depression levels. Anxiety related to disease diagnosis and choking were the most affected dimensions; less affected were the dimensions related to eating, social, and emotional development. Intraclass correlation coefficients between the test and retest assessments were acceptable for all questionnaires, with the highest values (0.73-0.84) calculated for the EoE-QoL-A Spanish version.

Conclusion: The Spanish version of the EoE-QoL-A is a reliable, valid, and responsive questionnaire. Diagnosis and choking anxiety were the most affected dimensions in the health-related QoL in adult EoE patients.
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June 2014

Bone turnover markers as predictive indicators of outcome in patients with breast cancer and bone metastases treated with bisphosphonates: results from a 2-year multicentre observational study (ZOMAR study).

Bone 2014 Nov 7;68:32-40. Epub 2014 Aug 7.

Medicine Department, Universitat Autònoma de Barcelona, Barcelona, Spain; Medical Oncology Department, Hospital del Mar, Passeig Marítim de la Barceloneta, 25-29, 08003 Barcelona, Spain. Electronic address:

Background: We evaluated the evolution and predictive value of bone turnover markers (BTMs) and circulating tumor cells (CTCs) with respect to mortality, disease progression (DP) and skeletal-related events (SREs), in patients with bone metastatic breast cancer (BmBCa). The correlation between BTMs and CTCs was also studied.

Methods: In a 2-year observational, multicenter study, the levels of three BTMs (N- and C-terminal telopeptides of collagen I [NTX and αα-CTX], and bone-specific alkaline phosphatase [BSAP]) and CTCs were analyzed every three months. Patients received zoledronic acid (4mg every 28days) from the baseline visit.

Results: 234 patients were analyzed. The levels of the BTMs were increased at baseline and significantly decreased after 3months (P<0.05). In the Cox regression univariate analyses significant hazard ratios (HRs) for death were found for pathological BSAP values at baseline (5.03 [95% CI: 1.214-20.839; P=0.0259]) and at 3months (3.41 [95% CI: 1.367-8.498; P=0.0085]). HRs >2 were found for increased baseline and 3-month levels of NTX and CTC (P<0.05). Only increased baseline BSAP levels were associated with DP (HR=2.25 [95% CI: 1.391-3.626; P=0.0009]). No biomarker was associated with SREs. In the multivariate analysis, pathologic levels at 3months of NTX and BSAP were significantly associated with mortality (HRs=3.59 [95% CI: 1.375-9.382; P=0.0091] and 3.25 [95% CI: 1.293-8.189; P=0.0120], respectively). CTC and BSAP were correlated during all study timepoints (P<0.05).

Conclusions: Baseline levels of NTX, BSAP and CTCs, and changes after treatment initiation with bisphosphonates, may be useful for the prognostic assessment of patients with BmBCa. BSAP showed the strongest prognostic value.
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http://dx.doi.org/10.1016/j.bone.2014.07.036DOI Listing
November 2014

[Poorly differentiated neuroendocrine carcinoma of the colon with liver metastases].

Gastroenterol Hepatol 2012 Apr 22;35(4):251-3. Epub 2012 Mar 22.

Servicio de Aparato Digestivo, Hospital de Viladecans, Barcelona, España.

Neuroendocrine tumors of the gastrointestinal tract are highly infrequent. We report the case of a 57-year-old woman who presented with toxic syndrome, vomiting and a 3-month history diarrhea, with a final diagnosis of poorly-differentiated neuroendocrine tumor. Based on this case, we review the clinical characteristics, diagnostic procedures, prognostic factors and therapeutic possibilities in this type of tumor. Neuroendocrine tumors should be considered in the diagnosis of colonic tumors with hyperechoic liver metastases.
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http://dx.doi.org/10.1016/j.gastrohep.2012.01.013DOI Listing
April 2012

[Recurrent abdominal pain in a patient with irritable bowel syndrome].

Gastroenterol Hepatol 2011 Jun-Jul;34(6):438-40. Epub 2011 Apr 9.

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http://dx.doi.org/10.1016/j.gastrohep.2011.01.008DOI Listing
November 2011

[Prolonged fever and jaundice in a patient with alcoholic liver disease].

Gastroenterol Hepatol 2010 Oct 3;33(8):574-7. Epub 2010 Aug 3.

Servei de Gastroenterologia i Aparell Digestiu, Hospital de Viladecans, Barcelona, España.

We report the case of a 40-year-old man with underlying alcoholic liver disease who presented with prolonged fever, jaundice and liver failure associated with Coxiella burnetii infection. After diagnosis and appropriate antibiotic treatment, the patient made a complete recovery. We describe aspects of this case and provide a practical review of the literature on the topic. We also discuss the importance of this infection and the need for its inclusion in the differential diagnosis of this clinical picture.
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http://dx.doi.org/10.1016/j.gastrohep.2010.05.006DOI Listing
October 2010

Pathogenic mechanisms of postinfectious functional gastrointestinal disorders: results 3 years after gastroenteritis.

Scand J Gastroenterol 2009 ;44(10):1173-85

Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain.

Objective: Functional gastrointestinal disorders (FGID) may appear after acute gastroenteritis. The aim of this study was to evaluate the possible mechanisms (inflammation, visceral hypersensitivity, psychological and immunogenetic factors) related to the development of postinfectious (PI) FGID 3 years after a Salmonella outbreak.

Material And Methods: Biopsies of the antrum, and right- and left colon from 16 PI-FGID patients, 8 PI control patients, and 18 healthy controls (H-controls) were processed for immunohistochemistry, cytokines, and mast-cell electron microscopy. DNA was typed for cytokine gene polymorphisms. Visceral sensitivity (satiety test and rectal barostat) and psychological factors (SCL-90 and vital events) were assessed.

Results: The number of mast cells and T lymphocytes was similar among the groups in all locations. Mast cells within 5 microm of nerve fibers of both PI groups were increased compared to H-controls: (stomach: 5.6+/-1.2 versus 6.6+/-1.5 versus 2.5+/-1.1; right colon: 9.7+/-1.3 versus 8.0+/-1.3 versus 4.1+/-1.7; left colon: 8.9+/-0.9 versus 8.5+/-1.8 versus 2.2+/-2.0 per field) (p<0.05). No differences in the production of IL-1beta, IL-1ra, IL-6, and IL-10 or in their genotypes were found. PI-FGID patients showed a lower pain threshold to rectal distention (29+/-2 versus 37+/- 2 mmHg; p<0.05). Scores for anxiety (0.63+/-0.11 versus 0.28+/-0.14) and somatization (1.01+/-0.15 versus 0.45+/-0.15) were higher in PI-FGID patients than in PI controls (p<0.05). The number of stressful life events was not significantly different between both PI groups.

Conclusions: Three years after salmonellosis, PI-FGID patients showed no evidence of inflammation in the gastric or colonic mucosa, but visceral sensitivity and anxiety/somatization levels were increased. The close anatomical mast cell-nerve fibers relation does not seem to be related to the FGID but to the infection itself.
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http://dx.doi.org/10.1080/00365520903171276DOI Listing
March 2010

[Irritable bowel syndrome and inflammatory bowel disease: Is there a connection?].

Gastroenterol Hepatol 2009 May 12;32(5):364-72. Epub 2009 May 12.

Instituto de Trastornos Funcionales y Motores Digestivos, Servicio de Aparato Digestivo, Centro Médico Teknon, Barcelona, España.

Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders and is that with the greatest socioeconomic impact worldwide. Diagnosis of IBS is based on clinical criteria that have been modified over time, the Rome II criteria being those that are currently followed. Some of the symptoms of IBS are similar to those in patients with inflammatory bowel disease (IBD), which can hamper or delay diagnosis. The use of inflammatory markers in stools (such as calprotectin) may help to distinguish between these two entities. A possible connection between IBS and IBD could be based on five points: (i) both disorders have similar symptoms; (ii) symptoms often overlap in the same patients; (iii) IBS and IBD have a common familial aggregation; (iv) some predisposing factors, such as a history of acute gastroenteritis, play a role in both disorders, and (v) importantly, signs of microinflammation are found in the bowels of patients with IBS. With regard to this latter point, an increase in inflammatory cells has been found in the intestinal mucosa of patients with IBS and, more specifically, mastocytes have been found to be increased in the jejunum and colon while CD3 and CD25 intraepithelial lymphocytes have be observed to be increased in the colon. Moreover, activated mastocytes are increased near to nerve endings in patients with IBS and this finding has been correlated with the intensity of both intestinal symptoms (abdominal pain) and psychological symptoms (depression and fatigue). A good model of microinflammation is post-infectious IBS, since the timing of the onset of the infectious process is known. In patients with post-infectious IBS, an increase in intraepithelial lymphocytes and enterochromaffin cells is initially found, which is reduced over time; consequently, although the symptoms of IBS persist, after 3 years no differences are detected in the number of inflammatory cells between IBS patients and controls. Among the various factors that can favor the development of IBS in these patients, two host-dependent mechanisms are most closely implicated in the physiopathology of IBS: polymorphism of the genes codifying pro- or anti-inflammatory cytokines and psychological factors such as anxiety, depression, somatization and neuroticism at the time of the acute infection. In view of all of the above, the similarities between IBS and IBD are probably more than mere coincidence and may reflect distinct manifestations of a broad spectrum of inflammation in the colon.
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http://dx.doi.org/10.1016/j.gastrohep.2008.12.007DOI Listing
May 2009

[Functional and motor gastrointestinal disorders].

Gastroenterol Hepatol 2008 Oct;31 Suppl 4:3-17

Servicio de Aparato Digestive, Instituto de Trastornos Funcionales y Motores Digestivos, Centro Medico Teknon, Barcelona, España.

Functional gastrointestinal (GI) and motility disorders generate a large volume of consultations in gastroenterology and primary care offices. The present article summarizes the most interesting studies presented in the annual meeting of the American Gastroenterological Association 2008. For all functional GI disorders, studies were presented that evaluated the applicability of diagnostic criteria in clinical practice and new data were presented on physiopathology (for example, mediation by neuromodulators such as serotonin, microinflammation, alterations in intestinal microbiota, and psychological factors). More specifically, the therapeutic results of new prokinetic agents in functional dyspepsia, such as acotiamide, were presented. This agent has been demonstrated to have good efficacy in symptom control, especially in patients with postprandial distress syndrome. In irritable bowel syndrome, data were presented on several drugs that act through diverse mechanisms of action and have been shown to be more effective than placebo in symptom control. These drugs include antiinflammatory agents such as mesalazine, antibiotics such as rifaximin, probiotics with distinct bacterial strains, and prokinetic agents such as lubiprostone. Highly promising results have been obtained in the treatment of constipation with prokinetics such as prucalopride and with novel laxatives such as linaclotide, as well as with techniques that continue to be shown to be effective such as anorectal biofeedback, which is also highly useful in patients with fecal incontinence. Another disorder that is less frequent but highly difficult to treat is gastroparesis. For several years, treatment in the most severe cases has consisted of implantation of a gastric pacemaker. Although the results are far from perfect, new data were presented that allow better patient selection to achieve greater symptom control. The list of new advances, both in knowledge of the physiopathology of these disorders and on their treatments, is extensive. Consequently, 2008 has been a good year in terms of the useful information gathered for physicians interested in functional GI and motor disorders.
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October 2008

GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study.

Eur J Haematol 2008 Feb 20;80(2):127-32. Epub 2007 Nov 20.

Service of Hematology, Hospital Vall d'Hebron, Barcelona, Spain.

Objectives: The prognosis of old or immunocompromised patients with refractory or relapsing diffuse large-cell lymphoma (DLCL) is very poor as the current standard of salvage therapy with autologous stem cell transplantation (ASCT) is not feasible for most of them. New active regimens with an acceptable toxicity profile are needed. We aim to report the results of a phase II trial of the GEMOX-R regimen in DLCL.

Methods: A total of 32 patients received GEMOX-R regimen in 2-wk intervals if feasible or every 3 wk for a planned six to eight courses.

Results: Median age of the population was 69 yr. Forty-one percent of the patients were primary refractory and 59% after relapsing. At GEMOX-R, 75% of patients had a stage III-IV and an adjusted International Prognostic Index > 1 was observed in 69%. The response rate was 43% with 34% complete response. Neutropenia and thrombopenia grade III-IV were observed in 43% of the patients and neurotoxicity grade III-IV in 7% of cases. Median follow-up for alive patients was 13 months and the median survival was 9.1 months. At 12 months, the overall survival and progression-free survival were 41% and 29%, respectively.

Conclusions: GEMOX-R is a new salvage regimen for DLCL with high activity and relatively safe toxicity profile, which can be offered to elderly patients not candidates of ASCT consolidation. The high efficacy of the regimen in this unfavorable population and also in immunocompromised situations warrant further investigation of this regimen in all salvage situations of this type of lymphomas.
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http://dx.doi.org/10.1111/j.1600-0609.2007.00996.xDOI Listing
February 2008

Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis outbreak: one-year follow-up cohort study.

Gastroenterology 2005 Jul;129(1):98-104

Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain.

Background & Aims: It has been reported that some patients develop functional digestive disorders, particularly irritable bowel syndrome (IBS), after acute gastroenteritis (AGE). However, the presence of dyspepsia has not been specifically addressed. We prospectively evaluated development of dyspepsia and IBS during a 1-year follow-up in a cohort of adult patients affected by a Salmonella enteritidis AGE outbreak.

Methods: Questionnaires were sent to 1878 potential participants at baseline and 3, 6, and 12 months; 677 had experienced a Salmonella enteritidis AGE on June 23, 2002, and 1201 had not (randomly selected controls, matched for village of residence, age, and sex). At 12 months, 271 patients and 335 controls returned the questionnaires. Data permitted the establishment of dyspepsia and IBS diagnosis by Rome II criteria.

Results: Before the AGE outbreak, the prevalence of dyspepsia was similar in cases and controls (2.5% vs 3.8%); the prevalence of IBS was also similar (2.9% vs 2.3%). At 3, 6, and 12 months, the prevalence of both dyspepsia and IBS had increased significantly in exposed compared with unexposed subjects. Overlap between dyspepsia and IBS was frequent. At 1 year, the relative risk for development of dyspepsia was 5.2 (95% confidence interval, 2.7-9.8) and for IBS was 7.8 (95% confidence interval, 3.1-19.7). Prolonged abdominal pain and vomiting during AGE were positive predictors of dyspepsia. No predictive factors for IBS were found.

Conclusions: Salmonella gastroenteritis is a significant risk factor not only for IBS but also for dyspepsia; at 1 year of follow-up, 1 in 7 and 1 in 10 subjects developed dyspepsia or IBS, respectively.
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http://dx.doi.org/10.1053/j.gastro.2005.04.012DOI Listing
July 2005

Prevalence of functional gastrointestinal disorders in women who report domestic violence to the police.

Clin Gastroenterol Hepatol 2005 May;3(5):436-41

Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain

Background & Aims: Retrospective studies found an association between past sexual, physical, or psychological abuse and functional gastrointestinal disorders (FGIDs). However, there are no studies evaluating such an association concurrently with the ongoing abuse. Our aim was to investigate the prevalence of the main FGIDs, functional dyspepsia and irritable bowel syndrome, in 70 women reporting a situation of domestic violence to the police and to evaluate the level of psychological distress and its relationship with the presence of FGID.

Methods: Through an interview between a social worker and the woman reporting abuse, digestive symptoms, psychological status, and type of abuse were recorded. These data were matched against police records. Functional dyspepsia and irritable bowel syndrome were diagnosed according to Rome II criteria.

Results: Seventy-one percent of the women had an FGID: 67% functional dyspepsia, 47% irritable bowel syndrome, and 43% both. In two thirds of the cases, FGID onset occurred simultaneously with or soon after abuse onset. Only 34% of the women had sought medical attention for FGID symptoms. No differences were found between women with or without FGID regarding age and type or duration of abuse; psychological distress tended to be more severe in the group of women with FGIDs.

Conclusions: Most women who suffer domestic violence (reported to the police) have functional dyspepsia and/or irritable bowel syndrome and also have elevated psychological distress. This has important implications, not only for comprehensive health care of women in a situation of abuse, but also for medical treatment of women with FGIDs.
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http://dx.doi.org/10.1016/s1542-3565(04)00776-1DOI Listing
May 2005

A novel thymidine phosphorylase mutation in a Spanish MNGIE patient.

J Neurol Sci 2005 Jan 12;228(1):35-9. Epub 2004 Nov 12.

Department of Neurology, Hospital Universitari Vall d' Hebron, Barcelona, Spain.

A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE.
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http://dx.doi.org/10.1016/j.jns.2004.09.034DOI Listing
January 2005

[Primary intestinal lymphangiectasia: effectiveness of treatment with slow-release octreotide].

Med Clin (Barc) 2004 Sep;123(8):319

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http://dx.doi.org/10.1016/s0025-7753(04)74503-0DOI Listing
September 2004

Left ventricular hypertrophy in rats with biliary cirrhosis.

Hepatology 2003 Sep;38(3):589-98

Servicio de Cardiología, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Portal hypertension induces neuroendocrine activation and a hyperkinetic circulation state. This study investigated the consequences of portal hypertension on heart structure and function. Intrahepatic portal hypertension was induced in male Sprague-Dawley rats by chronic bile duct ligation (CBDL). Six weeks later, CBDL rats showed higher plasma angiotensin-II and endothelin-1 (P <.01), 56% reduction in peripheral resistance and 73% reduction in pulmonary resistance (P <.01), 87% increase in cardiac index and 30% increase in heart weight (P <.01), and increased myocardial nitric oxide (NO) synthesis. In CBDL rats, macroscopic analysis demonstrated a 30% (P <.01) increase in cross-sectional area of the left ventricular (LV) wall without changes in the LV cavity or in the right ventricle (RV). Histomorphometric analysis revealed increased cell width (12%, P <.01) of cardiomyocytes from the LV of CBDL rats, but no differences in myocardial collagen content. Myocytes isolated from the LV were wider (12%) and longer (8%) than right ventricular myocytes (P <.01) in CBDL rats but not in controls. CBDL rats showed an increased expression of ANF and CK-B genes (P <.01). Isolated perfused CBDL hearts showed pressure/end-diastolic pressure curves and response to isoproterenol identical to sham hearts, although generated wall tension was reduced because of the increased wall thickness. Coronary resistance was markedly reduced. This reduction was abolished by inhibition of NO synthesis with N-nitro-L-arginine. Expression of eNOS was increased in CBDL hearts. In conclusion, portal hypertension associated to biliary cirrhosis induces marked LV hypertrophy and increased myocardial NO synthesis without detectable fibrosis or functional impairment. This observation could be relevant to patients with cirrhosis.
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http://dx.doi.org/10.1053/jhep.2003.50369DOI Listing
September 2003

Total effective vascular compliance in patients with cirrhosis. Effects of propranolol.

J Hepatol 2002 Mar;36(3):356-61

Liver Unit, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain.

Background: Total effective vascular compliance (TEVC), may be increased in cirrhosis. However, its significance is unclear.

Aims: To investigate TEVC in patients with cirrhosis, and the effects of propranolol.

Methods: Seven patients without liver disease and 44 cirrhotic patients were studied before and after double-blind administration of propranolol (n=33) or placebo (n=11).

Measurements: TEVC (right atrial pressure response to rapid central volume expansion), hepatic venous pressure gradient (HVPG) and systemic hemodynamics.

Results: TEVC (ml x mmHg(-1) x kg(-1)) was increased in cirrhotics (1.67 +/- 0.66 versus 1.33 +/- 0.32 in controls; P<0.05). TEVC was not modified by placebo, but was markedly reduced by propranolol (from 1.74 +/- 0.75 to 1.33 +/- 0.56; P<0.01). Propranolol decreased HVPG >10% in 20 patients ('responders': -20 +/- 9%) but <10% in 13 'non-responders'. TEVC was normalized by propranolol in HVPG 'responders' (from 1.76 +/- 0.88 to 1.21 +/- 0.51; P<0.01), but not in 'non-responders' (1.69 +/- 0.48 to 1.52 +/- 0.59; NS). Reduction of TEVC in responders was accompanied by increased free hepatic vein pressure (+21 +/- 20%, P=0.05; approximately 60% of the fall in HVPG), which was not observed in non-responders (+3 +/- 11%, NS).

Conclusions: TEVC is increased in cirrhosis. This abnormality is corrected by propranolol in patients exhibiting a >10% fall in HVPG, suggesting that changes in vascular compliance may influence the portal pressure response to propranolol.
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http://dx.doi.org/10.1016/s0168-8278(01)00300-2DOI Listing
March 2002

TIPS is a useful long-term derivative therapy for patients with Budd-Chiari syndrome uncontrolled by medical therapy.

Hepatology 2002 Jan;35(1):132-9

Hepatic Hemodynamic Laboratory, Liver Unit, Institut de Malalties Digestives, University of Barcelona, Barcelona, Catalunya, Spain.

Patients with Budd-Chiari syndrome (BCS) may require treatment with portal decompressive surgery or liver transplantation. Transjugular intrahepatic portosystemic shunt (TIPS) represents a new treatment alternative, but its long-term effect on BCS outcome has not been evaluated. Twenty-one patients with BCS consecutively admitted to our unit were evaluated. The mean follow-up was 4 +/- 3 years. Seven patients had nonprogressive forms and were successfully controlled with medical therapy; 1 case, with a short-length hepatic vein stenosis was successfully treated by angioplasty. All 8 patients are alive and asymptomatic. The remaining 13 patients, had a TIPS because of clinical deterioration (in one of them, because early TIPS thrombosis a successful side-to-side portacaval shunt [SSPCS] was performed) followed by an improvement in clinical condition. However, a patient with fulminant liver failure before TIPS insertion, died 4 months later and another patient with cirrhosis at diagnosis had liver transplantation 2 years later. The remaining 11 patients are alive and free of ascites. In 3 of these patients TIPS is patent after 3, 6, and 12 months. The remaining 8 patients developed late TIPS dysfunction. In two of these cases, after angioplasty and restenting, TIPS is patent after a follow-up of 9 and 80 months. In 5 other patients, recurring TIPS occlusion was not further corrected because no signs of portal hypertension were present. In conclusion, in patients with BCS uncontrolled with medical therapy, TIPS is a highly effective technique that is associated with long-term survival.
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http://dx.doi.org/10.1053/jhep.2002.30274DOI Listing
January 2002