Publications by authors named "Sergio Peralta"

29 Publications

  • Page 1 of 1

A phase II randomized, multicenter, open-label trial of continuing adjuvant temozolomide beyond 6 cycles in patients with glioblastoma (GEINO 14-01).

Neuro Oncol 2020 12;22(12):1851-1861

Pathology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.

Background: Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for 6 cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized trial investigating whether extending adjuvant temozolomide for more than 6 cycles improved outcome.

Methods: Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after 6 cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of 12 cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and safety (Clinicaltrials.gov NCT02209948).

Results: From August 2014 to November 2018, 166 patients were screened, 7 of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001).

Conclusions: Continuing temozolomide after 6 adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS.

Key Points: 1. Extending adjuvant temozolomide to 12 cycles did not improve 6-month PFS.2. Extending adjuvant temozolomide did not improve PFS or OS in any patient subset.3. Extending adjuvant temozolomide was linked to increased toxicities.
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http://dx.doi.org/10.1093/neuonc/noaa107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746946PMC
December 2020

Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis.

Lancet Respir Med 2018 10 9;6(10):771-781. Epub 2018 Aug 9.

Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Spain; Centro de Investigación Biomédica en Red de Cancer, Madrid, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona, Spain; Institucio Catalana de Recerca i Estudis Avançats, Barcelona, Spain. Electronic address:

Background: Anti-programmed death-1 (PD-1) treatment for advanced non-small-cell lung cancer (NSCLC) has improved the survival of patients. However, a substantial percentage of patients do not respond to this treatment. We examined the use of DNA methylation profiles to determine the efficacy of anti-PD-1 treatment in patients recruited with current stage IV NSCLC.

Methods: In this multicentre study, we recruited adult patients from 15 hospitals in France, Spain, and Italy who had histologically proven stage IV NSCLC and had been exposed to PD-1 blockade during the course of the disease. The study structure comprised a discovery cohort to assess the correlation between epigenetic features and clinical benefit with PD-1 blockade and two validation cohorts to assess the validity of our assumptions. We first established an epigenomic profile based on a microarray DNA methylation signature (EPIMMUNE) in a discovery set of tumour samples from patients treated with nivolumab or pembrolizumab. The EPIMMUNE signature was validated in an independent set of patients. A derived DNA methylation marker was validated by a single-methylation assay in a validation cohort of patients. The main study outcomes were progression-free survival and overall survival. We used the Kaplan-Meier method to estimate progression-free and overall survival, and calculated the differences between the groups with the log-rank test. We constructed a multivariate Cox model to identify the variables independently associated with progression-free and overall survival.

Findings: Between June 23, 2014, and May 18, 2017, we obtained samples from 142 patients: 34 in the discovery cohort, 47 in the EPIMMUNE validation cohort, and 61 in the derived methylation marker cohort (the T-cell differentiation factor forkhead box P1 [FOXP1]). The EPIMMUNE signature in patients with stage IV NSCLC treated with anti-PD-1 agents was associated with improved progression-free survival (hazard ratio [HR] 0·010, 95% CI 3·29 × 10-0·0282; p=0·0067) and overall survival (0·080, 0·017-0·373; p=0·0012). The EPIMMUNE-positive signature was not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load. EPIMMUNE-negative tumours were enriched in tumour-associated macrophages and neutrophils, cancer-associated fibroblasts, and senescent endothelial cells. The EPIMMUNE-positive signature was associated with improved progression-free survival in the EPIMMUNE validation cohort (0·330, 0·149-0·727; p=0·0064). The unmethylated status of FOXP1 was associated with improved progression-free survival (0·415, 0·209-0·802; p=0·0063) and overall survival (0·409, 0·220-0·780; p=0·0094) in the FOXP1 validation cohort. The EPIMMUNE signature and unmethylated FOXP1 were not associated with clinical benefit in lung tumours that did not receive immunotherapy.

Interpretation: Our study shows that the epigenetic milieu of NSCLC tumours indicates which patients are most likely to benefit from nivolumab or pembrolizumab treatments. The methylation status of FOXP1 could be associated with validated predictive biomarkers such as PD-L1 staining and mutational load to better select patients who will experience clinical benefit with PD-1 blockade, and its predictive value should be evaluated in prospective studies.

Funding: "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.
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http://dx.doi.org/10.1016/S2213-2600(18)30284-4DOI Listing
October 2018

Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor-Like Molecule 1A+Interleukin-23+ Monocytes Are Expanded in Patients With Ankylosing Spondylitis and Modulate Innate Lymphoid Cell 3 Immune Functions.

Arthritis Rheumatol 2018 12;70(12):2003-2013

Krembil Research Institute, University of Toronto, and University Health Network, Toronto, Ontario, Canada.

Objective: Gut-derived innate lymphoid cell 3 (ILC3) has been shown to participate in the pathogenesis of ankylosing spondylitis (AS). CX CR1+ mononuclear phagocytes (MNPs) have been demonstrated to modulate ILC3 function in the gut. This study was undertaken to investigate the role of proinflammatory CX CR1+CD59+ MNPs in modulating ILC3 function in AS patients.

Methods: MNP subsets in the blood of AS patients and controls were analyzed by flow cytometry. The presence of CX CR1+CD59+ cells in tissue was confirmed by confocal microscopy. Expression of the proinflammatory chemokines CX CL1 and CCL2 and decoy receptor 6 (DcR-6) was analyzed. Peripheral CX CR1+CD59+ cells were cocultured with ILC3, and changes in their frequency were evaluated by flow cytometry. Transcriptome analysis of circulating CX CR1+ monocytes was also performed.

Results: DcR-6 deficiency and CCL2 overexpression were observed in inflamed tissues from AS patients. In the gut, the proinflammatory CX CR1+CD59+ MNP population was expanded, correlated with the presence of bacteria, and produced high levels of tumor necrosis factor-like molecule 1A (TL1A) and interleukin-23 (IL-23). MNPs positive for CD11b, CD11c, and major histocompatibility complex class II, predominantly expressing CX CR1, were also expanded in the small intestines of treatment-naive SKG relative to BALB/c mice. The frequency of gut-derived CX CR1+CD59+CCR9+TL1A+IL-23+ MNPs was significantly higher in the peripheral blood and synovial fluid of AS patients than controls. CCR9+CX CR1+CD59+ monocytes were also expanded in AS synovial and bone marrow samples. Transcriptome analysis of isolated CX CR1+CD59+ monocytes demonstrated a specific proinflammatory profile in AS. Isolated proinflammatory CX CR1+CD59+ MNPs from AS patients induced the expansion and activation of ILC3.

Conclusion: Proinflammatory CX CR1+CD59+TL1A+IL-23+ MNPs are expanded in AS patients and display a specific proinflammatory transcriptome profile. Given the ability of these cells to support ILC3 expansion, they may promote a sustained proinflammatory status in AS.
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http://dx.doi.org/10.1002/art.40582DOI Listing
December 2018

Randomized Phase III Trial of Erlotinib versus Docetaxel in Patients with Advanced Squamous Cell Non-Small Cell Lung Cancer Failing First-Line Platinum-Based Doublet Chemotherapy Stratified by VeriStrat Good versus VeriStrat Poor. The European Thoracic Oncology Platform (ETOP) EMPHASIS-lung Trial.

J Thorac Oncol 2017 04 23;12(4):752-762. Epub 2016 Dec 23.

Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.

Introduction: Docetaxel and erlotinib are registered second-line treatments for wild-type EGFR NSCLC. Previous studies suggested a predictive value of the VeriStrat test in second-line therapy of NSCLC, classifying patients as either VeriStrat good or VeriStrat poor. EMPHASIS-lung aimed at exploring this predictive effect in patients with squamous cell NSCLC. The trial closed prematurely because of low accrual and results from other trials. Our analysis includes an exploratory combined analysis with results from the PROSE trial.

Methods: EMPHASIS-lung was a randomized phase III multicenter trial exploring the differential effect of second-line erlotinib versus docetaxel on progression-free survival (PFS) in VeriStrat good versus VeriStrat poor patients with squamous cell NSCLC.

Results: A total of 80 patients were randomized, with 72.5% categorized as VeriStrat good. Patient characteristics were balanced between VeriStrat status and treatment groups. The median PFS times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 4.1 and 1.6 months, respectively, versus 1.9 and 2.1 months, respectively, in the VeriStrat poor cohort. The median overall survival (OS) times with docetaxel and erlotinib treatment in the VeriStrat good cohort were 7.8 and 8.4 months, respectively, and 4.4 and 5.2 months, respectively, in the VeriStrat poor cohort. An additional exploratory analysis was performed; in it, 47 patients from the squamous cell subgroup of PROSE were included in a combined analysis, contributing with 45 PFS and 41 OS events.

Conclusions: The final analysis of EMPHASIS-lung did not show a differential effect on PFS for erlotinib versus docetaxel stratified by VeriStrat status. Similarly, in the combined analysis, no significant treatment by VeriStrat status interaction was observed (interaction p = 0.24 for PFS and 0.45 for OS, stratified by study).
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http://dx.doi.org/10.1016/j.jtho.2016.12.017DOI Listing
April 2017

Mechanisms, applications, and perspectives of antiviral RNA silencing in plants.

Rev Mex Fitopatol 2016 May-Sep;34(3). Epub 2016 Sep 2.

Department of Biology, Kuztown University of Pennsylvania, Kuztown, PA 19530 USA.

Viral diseases of plants cause important economic losses due to reduction in crop quality and quantity to the point of threatening food security in some countries. Given the reduced availability of natural sources, genetic resistance to viruses has been successfully engineered for some plant-virus combinations. A sound understanding of the basic mechanisms governing plant-virus interactions, including antiviral RNA silencing, is the foundation to design better management strategies and biotechnological approaches to engineer and implement antiviral resistance in plants. In this review, we present current molecular models to explain antiviral RNA silencing and its application in basic plant research, biotechnology and genetic engineering.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586037PMC
http://dx.doi.org/10.18781/R.MEX.FIT.1606-8DOI Listing
September 2016

Effects of Eradicating Hepatitis C Virus Infection in Patients With Cirrhosis Differ With Stage of Portal Hypertension.

Gastroenterology 2016 07 1;151(1):130-139.e2. Epub 2016 Apr 1.

Sezione di Gastroenterologia e Epatologia, Dipartimento Biomedico di Medicina Interna e Specialistica, University of Palermo, Italy.

Background & Aims: Clearance of hepatitis C virus (HCV) via antiviral treatment changes the course of liver disease. We evaluated the benefit of sustained virologic response (SVR) in patients with HCV and cirrhosis without (stage 1) and with (stage 2) esophageal varices (EV).

Methods: We performed a prospective cohort study of 444 patients with HCV and compensated cirrhosis (218 with stage 1 and 226 with stage 2 disease) treated with peg-interferon and ribavirin from June 2001 through December 2009 at the University of Palermo, Italy and followed for a median of 7.6 years (range, 1-12.6 years). We used Cox regression analysis to identify variables associated with appearance or progression of EVs, development of hepatocellular carcinoma (HCC), liver decompensation, and overall survival.

Results: In the intention-to-treat analysis, 67 patients with stage 1 disease (30.7%) and 41 patients with stage 2 disease (18.1%) achieved an SVR (P = .003). Patients with stage 1 disease and an SVR were less likely to develop EVs than stage 1 patients without an SVR (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.11-0.48; P < .001). However, SVR did not affect whether patients with stage 2 disease developed further EVs (HR, 1.58; 95% CI, 0.33-1.03; P = .07, by log-rank test). An SVR was associated with lower risk for HCC (HR, 0.25; 95% CI, 0.12-0.55; P < .001). Patients with stage 2 disease, regardless of SVR, were at greater risk than patients with stage 1 disease for liver decompensation (HR, 2.82; 95% CI, 1.73-4.59; P < .001) or death (HR, 1.77; 95% CI, 1.12-2.80; P = .015). A lower proportion of patients with stage 1 disease and an SVR died from HCC (2.9%), compared with those without an SVR (11.9%) (P = .03) or developed liver decompensation (none vs 7.1% without an SVR; P = .009). A lower proportion of patients with stage 2 disease and an SVR died from causes secondary to HCC (2.0%) compared with those without an SVR (18.4%) (P = .003). Death from causes secondary to liver decompensation did not differ significantly between patients with stage 2 disease with or without an SVR (12.1% vs 25.4%; P = .15).

Conclusions: In a prospective study of 444 patients with HCV and compensated cirrhosis, HCV eradication reduced risk for liver decompensation, HCC, and death, regardless of whether the patients had EVs.
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http://dx.doi.org/10.1053/j.gastro.2016.03.036DOI Listing
July 2016

Interleukin-9 Overexpression and Th9 Polarization Characterize the Inflamed Gut, the Synovial Tissue, and the Peripheral Blood of Patients With Psoriatic Arthritis.

Arthritis Rheumatol 2016 08;68(8):1922-31

Università degli Studi di Palermo, Palermo, Italy.

Objective: To investigate the expression and tissue distribution of Th9-related cytokines in patients with psoriatic arthritis (PsA).

Methods: Quantitative gene expression analysis of Th1, Th17, and Th9 cytokines was performed in intestinal biopsy samples obtained from patients with PsA, HLA-B27-positive patients with ankylosing spondylitis (AS), patients with Crohn's disease (CD), and healthy controls. Expression and tissue distribution of interleukin-23 (IL-23), IL-17, IL-22, IL-9, and IL-9 receptor (IL-9R) were evaluated by immunohistochemistry and confocal microscopy. Flow cytometry was used to study the frequency of Th9 cells among peripheral blood, lamina propria, and synovial fluid mononuclear cells. The functional relevance of IL-9R expression on epithelial cells was assessed in functional in vitro studies. Th9 cells in synovial tissue from patients with PsA were also studied.

Results: Subclinical gut inflammation in PsA patients was characterized by a clear Th17 and Th22, but not Th1, polarized immune response. Unlike AS and CD, a strong and significant up-regulation of IL-9 was observed in PsA gut, especially among infiltrating mononuclear cells, high endothelial venules, and Paneth cells. IL-9-positive mononuclear cells were demonstrated to be in large part Th9 cells. IL-9 overexpression was accompanied by significant Paneth cell hyperplasia. Paneth cells strongly overexpressed IL-9R, and stimulation of epithelial cells, isolated from PsA patients, with IL-9 resulted in overexpression of α-defensin 5 and IL-23p19. Peripheral and synovial expansion of α4β7+ Th9 cells was also observed in patients with PsA. Increased expression of IL-9 and IL-9R was also found in synovial tissue.

Conclusion: Strong IL-9/Th9 polarization seems to be the predominant immunologic signature in patients in PsA.
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http://dx.doi.org/10.1002/art.39649DOI Listing
August 2016

Transition of gastroenterological patients from paediatric to adult care: A position statement by the Italian Societies of Gastroenterology.

Dig Liver Dis 2015 Sep 14;47(9):734-40. Epub 2015 Apr 14.

Paediatric Department, Maggiore Hospital Crema, Italy. Electronic address:

In 2013, four Italian Gastroenterological Societies (the Italian Society of Paediatric Gastroenterology, Hepatology and Nutrition, the Italian Society of Hospital Gastroenterologists and Endoscopists, the Italian Society of Endoscopy, and the Italian Society of Gastroenterology) formed a joint panel of experts with the aim of preparing an official statement on transition medicine in Gastroenterology. The transition of adolescents from paediatric to adult care is a crucial moment in managing chronic diseases such as celiac disease, inflammatory bowel disease, liver disease and liver transplantation. Improved medical treatment and availability of new drugs and surgical techniques have improved the prognosis of many paediatric disorders, prolonging survival, thus making the transition to adulthood possible and necessary. An inappropriate transition or the incomplete transmission of data from the paediatrician to the adult Gastroenterologist can dramatically decrease compliance to treatment and prognosis of a young patient, particularly in the case of severe disorders. For these reasons, the Italian gastroenterological societies decided to develop an official shared transition protocol. The resulting document discusses the factors influencing the transition process and highlights the main points to accomplish to optimize compliance and prognosis of gastroenterological patients during the difficult transition from childhood to adolescence and adulthood.
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http://dx.doi.org/10.1016/j.dld.2015.04.002DOI Listing
September 2015

Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis.

Ann Rheum Dis 2015 Sep 22;74(9):1739-47. Epub 2015 Apr 22.

Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università degli Studi di Palermo, Palermo, Italy.

Background: The aim of the study was to better characterise the immunological origin and the behaviour of interleukin (IL)-23-responsive innate lymphoid cells (ILCs) in the gut, synovial fluid (SF) and bone marrow (BM) of patients with ankylosing spondylitis (AS).

Methods: ILC1, ILC2 and ILC3 cells were determined and characterised by confocal microscopy and flow cytometry in ileal and BM biopsies, in peripheral blood (PB) and SF mononuclear cells obtained from patients with AS and controls. Mucosal vascular addressin cell adhesion molecule 1 (MADCAM-1), IL-7, IL-15 and aggregates of lymphoid tissue inducer cells (LTi) were evaluated by immunohistochemistry. The in vitro ability of epithelial cells in driving the differentiation of ILC3 and the effect of tumour necrosis factor inhibitors (TNFi) on the frequency of ILC3 and the expression of MADCAM1 were also assessed.

Results: ILC3 characterised as Lyn(-)RORc(-)Tbet(+) NKp44(+) cells were significantly expanded in the gut, SF and BM of patients with AS compared with controls, produced high levels of IL-17 and IL-22 and expressed α4β7. MADcAM1 was overexpressed in BM and ileal high endothelial venules. IL-7 was significantly increased in AS gut, especially in the context of Paneth cells, and accompanied by the presence of aggregates of c-kit/IL-7R(+) cells (LTi). In in vitro experiments, epithelial cells from patients with AS actively induced differentiation of ILC3 from LTi. TNFi efficacy was accompanied by a significant decrease in the percentage of intestinal and circulating ILC3 and in the expression of MADCAM1.

Conclusions: Gut-derived IL-17(+) and IL-22(+)ILC3 are expanded in the peripheral blood, SF and inflamed BM of patients with AS, suggesting the presence of an active homing axis between the gut and the inflamed sacroiliac joints.
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http://dx.doi.org/10.1136/annrheumdis-2014-206323DOI Listing
September 2015

Liver Function Test Abnormalities in Patients with Inflammatory Bowel Diseases: A Hospital-based Survey.

Clin Med Insights Gastroenterol 2014 17;7:25-31. Epub 2014 Jun 17.

Gastroenterology and Hepatology Section, Dipartimento Biomedico di Medicina Interna e Specialistica, Università di Palermo, Palermo, Italy.

Background And Aims: Inflammatory bowel diseases (IBD) are frequently associated with altered liver function tests (LFTs). The causal relationship between abnormal LFTs and IBD is unclear. The aim of our study was to evaluate the prevalence and etiology of LFTs abnormalities and their association with clinical variables in a cohort of IBD patients followed up in a single center.

Materials And Methods: A retrospective review was undertaken of all consecutive IBD in- and outpatients routinely followed up at a single referral center. Clinical and demographic parameters were recorded. Subjects were excluded if they had a previous diagnosis of chronic liver disease. LFT abnormality was defined as an increase in aspartate aminotransferase, (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), or total bilirubin.

Results: A cohort of 335 patients (179 males, mean age 46.0 ± 15.6 years) was analyzed. Abnormal LFTs were detected in 70 patients (20.9%). In most cases, the alterations were mild and spontaneously returned to normal values in about 60% of patients. Patients with abnormal LFTs were less frequently on treatment with aminosalicylates (22.8 vs. 36.6%, P = 0.04). The most frequent cause for transient abnormal LFTs was drug-induced cholestasis (34.1%), whereas fatty liver was the most frequent cause of persistent liver damage (65.4%). A cholestatic pattern was found in 60.0% of patients and was mainly related to older age, longer duration of disease, and hypertension.

Conclusions: The prevalence of LFT abnormalities is relatively high in IBD patients, but the development of severe liver injury is exceptional. Moreover, most alterations of LFTs are mild and spontaneously return to normal values. Drug-induced hepatotoxicity and fatty liver are the most relevant causes of abnormal LFTs in patients with IBD.
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http://dx.doi.org/10.4137/CGast.S13125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069044PMC
June 2014

Fecal calprotectin in clinical practice: a noninvasive screening tool for patients with chronic diarrhea.

J Clin Gastroenterol 2012 Jul;46(6):504-8

Sezione e U.O.C. di Gastroenterologia, Di.Bi.M.I.S, Università di Palermo, Palermo, Italy.

Background: Surrogate markers of colorectal inflammation are increasingly being recognized as important in differentiating organic from functional intestinal disorders. Fecal calprotectin (FC) can be easily measured in the stool, being released by leukocytes in inflammatory conditions.

Aim: We evaluated FC as an index of inflammation in consecutive outpatients referred for colonoscopy for chronic, nonbloody diarrhea.

Methods: Stool specimens of 346 outpatients with chronic, nonbloody diarrhea, referred for colonoscopy, were measured for FC levels. The proportion of patients correctly diagnosed with the test and the relationship with endoscopic and histologic findings were measured.

Results: Abnormal endoscopic findings were detected in 104 patients (30.1%). Histologic findings included 142 patients (41.0%) with inflammation and 204 (59.0%) without inflammation. Fecal excretion of calprotectin significantly correlated with the finding of inflammation at endoscopy and histology (P<0.0001). When 150 mcg/g of stool was used as the upper reference limit, FC showed 75.4% sensitivity and 88.3% specificity, with 81.7% positive and 83.7% negative predictive values for histologic inflammation.

Conclusions: In outpatients referred for colonoscopy a measurement of FC is accurate to identify those with histologic inflammation. Assay of FC may be a reliable and noninvasive screening tool to identify inflammatory causes of chronic, nonbloody diarrhea.
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http://dx.doi.org/10.1097/MCG.0b013e318248f289DOI Listing
July 2012

Interleukin-22 and interleukin-22-producing NKp44+ natural killer cells in subclinical gut inflammation in ankylosing spondylitis.

Arthritis Rheum 2012 Jun 27;64(6):1869-78. Epub 2011 Dec 27.

Università di Palermo, Palermo, Italy.

Objective: The intestinal inflammation observed in patients with ankylosing spondylitis (AS) is characterized by an overexpression of interleukin-23 (IL-23). IL-23 is known to regulate IL-22 production through lamina propria NKp44+ natural killer (NK) cells, which are thought to be involved in protective mucosal mechanisms. This study was undertaken to evaluate the frequency of NKp44+ NK cells and the expression of IL-22 in the ileum of AS patients.

Methods: Tissue NKp44+ NK cells, NKp46+ NK cells, and IL-22-producing cells were analyzed by flow cytometry. Quantitative gene expression analysis of IL-22, IL-23, IL-17, STAT-3, and mucin 1 (MUC-1) was performed by reverse transcriptase-polymerase chain reaction on ileal samples from 15 patients with AS, 15 patients with Crohn's disease (CD), and 15 healthy controls. NKp44, pSTAT-3, and IL-22 expression was analyzed by immunohistochemistry.

Results: The frequency of NKp44+ but not NKp46+ NK cells was increased in the inflamed ileum of AS patients compared to CD patients and controls. The frequency of NKp46+ NK cells was significantly increased only in CD patients. Among CD4+ lymphocytes and NKp44+ NK cell subsets, the latter were the major source of IL-22 on lamina propria mononuclear cells from AS patients. Significant up-regulation of IL-22, IL-23p19, MUC-1, and STAT-3 transcripts in the terminal ileum of patients with AS was observed. Immunohistochemical analysis confirmed the increased IL-22 and pSTAT-3 expression in inflamed mucosa from AS and CD patients.

Conclusion: Our findings indicate that overexpression of IL-22, together with an increased number of IL-22-producing NKp44+ NK cells, occurs in the gut of AS patients, where it appears to play a tissue-protective role.
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http://dx.doi.org/10.1002/art.34355DOI Listing
June 2012

A Th1 but not a Th17 response is present in the gastrointestinal involvement of Behçet's disease.

Clin Exp Rheumatol 2010 Jul-Aug;28(4 Suppl 60):S27-30. Epub 2010 Sep 23.

Dipartimento Biomedico di Medicina Interna e Specialistica, Palermo University School of Medicine, Palermo, Italy.

Objectives: Behçet's disease has been historically classified as a Th1 disease. The recently described IL-17/IL-23 pathway seems to play an important role in many inflammatory diseases and in the intestinal abnormalities of AS and CD. The aim of the present study was to evaluate the IL-17/IL-23 axis in parallel with Th1 and IL-27 response in the intestine of patients with BD and gastrointestinal abnormalities.

Methods: Quantitative TaqMan reverse transcriptase-polymerase chain reaction (RT-PCR) was utilised for all determinations on ileal biopsy specimens obtained from BD, AS and CD patients. The serum levels of Th1 and Th17 cytokines were evaluated by enzyme-linked immunosorbent assay.

Results: A Th1 but not a Th17 response is present in the gastrointestinal involvement of Behçet's disease.

Conclusions: Although BD shares clinical manifestations with both CD and AS, the immunologic abnormalities seen in the intestine are quite different, indicating that other immune mechanisms should be taken into account.
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January 2011

Expansion of intestinal CD4+CD25(high) Treg cells in patients with ankylosing spondylitis: a putative role for interleukin-10 in preventing intestinal Th17 response.

Arthritis Rheum 2010 Dec;62(12):3625-34

University of Palermo, Palermo, Italy.

Objective: Subclinical gut inflammation has been demonstrated in patients with ankylosing spondylitis (AS). This study was undertaken to determine the frequency of regulatory CD4+CD25(high) T cells (Treg cells) and to evaluate Treg cell-related cytokines (interleukin-2 [IL-2], transforming growth factor β [TGFβ], and IL-10) and transcription factors (FoxP3 and STAT-5) in the ileum of patients with AS.

Methods: Quantitative gene expression analysis, by reverse transcriptase-polymerase chain reaction, of Treg-related cytokines (IL-2, TGFβ, and IL-10) and transcription factors (STAT-5 and FoxP3) was performed on ileal biopsy specimens from 18 patients with AS, 15 patients with active Crohn's disease (CD), and 15 healthy subjects. Tissue and circulating Treg cells were also analyzed by flow cytometry.

Results: A significant up-regulation of IL-2, TGFβ, FoxP3, STAT-5, and IL-10 transcripts in the terminal ileum of AS patients displaying chronic ileal inflammation was observed. Flow cytometric analysis of Treg cells showed significant peripheral expansion in both patients with AS and chronic inflammation and patients with CD (mean ± SD 1.08 ± 0.4% and 1.05 ± 0.3%, respectively) as compared with healthy subjects (0.25 ± 0.12%) (P < 0.05). Interestingly, a 5-fold increase in the proportion of Treg cells was observed in the gut of patients with AS (5 ± 3%) as compared with healthy subjects (1.2 ± 0.4%) (P < 0.001), with 70-80% of these cells also producing IL-10. In vitro studies showed that blocking IL-10 was sufficient to induce Th17 polarization on lamina propria mononuclear cells isolated from AS patients.

Conclusion: Our findings provide the first evidence that an active Treg cell response, mainly dominated by IL-10 production, occurs in the gut of AS patients and is probably responsible for the absence of a clear Th17 polarization in the ileum of AS patients.
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http://dx.doi.org/10.1002/art.27699DOI Listing
December 2010

Over-expression of paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation.

Rheumatology (Oxford) 2010 Nov 5;49(11):2076-83. Epub 2010 Aug 5.

Dipartimento Biomedico di Medicina Interna e Specialistica, Divisione di Reumatologia, Università di Palermo, Palermo, Italy.

Objectives: Subclinical gut inflammation has been demonstrated in patients with AS. Altered expression of paneth cell (PC) anti-microbial peptides have been reported in the inflamed ileum of patients with Crohn's disease (CD). Here, we investigated the expression of PC-derived peptides in subclinical gut inflammation in AS.

Methods: Multiple adjacent mucosal biopsies from terminal ileum were obtained from 25 patients with AS, 30 CD and 15 healthy controls (HCs). Expression of human α-defensin 5 (HD-5), phospholipase A2 (PLA2), lysozyme and SOX-9 molecules was assessed by quantitative Taqman RT-PCR on mucosal samples. Immunohistochemistry with anti-human HD-5 antibody and genotyping of relevant NOD2 mutations was also performed.

Results: HD-5, PLA2 and lysozyme transcript levels were strongly increased in AS and CD with similar degrees of intestinal inflammation when compared with normal controls. Immunohistochemical evaluation showed a normal number of PCs in both AS patients with chronic gut inflammation and CD patients with less-inflamed ileal samples. Conversely, CD patients with higher degree of gut inflammation had a reduced number of PCs and low expression levels of HD-5.

Conclusion: In this study, we provide evidence that over-expression of PC-derived anti-microbial peptides occurs in the ileum of AS patients with subclinical gut inflammation, likely representing an important early alteration of the mucosal innate immune component and intestinal host defence in AS.
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http://dx.doi.org/10.1093/rheumatology/keq239DOI Listing
November 2010

Oesophagogastroduodenoscopy in patients with cirrhosis: Extending the range of detection beyond portal hypertension.

Dig Liver Dis 2011 Jan 14;43(1):48-53. Epub 2010 May 14.

Di.Bi.M.I.S., University of Palermo, Italy.

Background: Oesophagogastroduodenoscopy is currently recommended for the screening of varices in cirrhosis. In addition to the assessment of varices, oesophagogastroduodenoscopy can detect conditions that, while unrelated to portal hypertension, may require treatment.

Aims: We evaluated in a large cohort of cirrhotic patients the prevalence of upper digestive findings other than oesophagogastric varices, the associations between upper gastrointestinal findings, portal hypertension and features of cirrhosis, and the incidence of new lesions in the course of a surveillance program.

Methods: Analysis of the records of 611 consecutive cirrhotic patients undergoing oesophagogastroduodenoscopy for screening and surveillance.

Results: 232 patients (38%) presented endoscopic lesions not related to portal hypertension: peptic diseases (n=193), proliferative diseases (n=27) and vascular diseases (n=12). In the screening group, 127 patients (39.4%) had pathologic lesions. At multivariate analysis, an association was found between peptic diseases and the absence of portal hypertensive gastropathy (RR 3.3; 95% CI 2.2-4.8); vascular diseases were associated with endoscopic signs of portal hypertension (p=0.01). During surveillance, 9/55 patients (16.3%) in the group without previous pathologic findings developed new lesions.

Conclusions: Oesophagogastroduodenoscopy in patients with cirrhosis undergoing endoscopy for screening diagnosed pathologic lesions unrelated to portal hypertension requiring a change in management in 39.4% of asymptomatic subjects.
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http://dx.doi.org/10.1016/j.dld.2010.04.004DOI Listing
January 2011

Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms: experience with Rifaximin.

World J Gastroenterol 2009 Jun;15(21):2628-31

Operative Unit of Gastroenterology and Hepatology, Di.Bi.M.I.S, Piazza delle Cliniche 2, Palermo 90127, Italy.

Aim: To estimate the prevalence of small intestinal bacterial overgrowth (SIBO) in our geographical area (Western Sicily, Italy) by means of an observational study, and to gather information on the use of locally active, non-absorbable antibiotics for treatment of SIBO.

Methods: Our survey included 115 patients fulfilling the Rome II criteria for diagnosis of irritable bowel syndrome (IBS); a total of 97 patients accepted to perform a breath test with lactulose (BTLact), and those who had a positive test, received Rifaximin (Normix, Alfa Wassermann) 1200 mg/d for 7 d; 3 wk after the end of treatment, the BTLact was repeated.

Results: Based on the BTLact results, SIBO was present in about 56% of IBS patients, and it was responsible for some IBS-related symptoms, such as abdominal bloating and discomfort, and diarrhoea. 1-wk treatment with Rifaximin turned the BTLact to negative in about 50% of patients and significantly reduced the symptoms, especially in those patients with an alternated constipation/diarrhoea-variant IBS.

Conclusion: SIBO should be always suspected in patients with IBS, and a differential diagnosis is done by means of a "breath test". Rifaximin may represent a valid approach to the treatment of SIBO.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2691494PMC
http://dx.doi.org/10.3748/wjg.15.2628DOI Listing
June 2009

Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis.

Arthritis Rheum 2009 Apr;60(4):955-65

University of Palermo, Palermo, Italy.

Objective: Subclinical gut inflammation is common in spondylarthritis, but the immunologic abnormalities underlying this process are undefined. Perturbation of the interleukin-23 (IL-23)/Th17 axis has emerged as a fundamental trigger of chronic inflammation. This study was undertaken to investigate the expression and tissue distribution of IL-23/Th17-related molecules in Crohn's disease (CD) and in subclinical gut inflammation in ankylosing spondylitis (AS).

Methods: Quantitative gene expression analysis of Th1/Th2 and IL-23/Th17 responses was performed in intestinal biopsy samples obtained from 12 patients with CD, 15 patients with AS, and 13 controls. IL-23 tissue distribution and identification of IL-23-producing cells were evaluated by immunohistochemistry.

Results: We demonstrated a strong and significant up-regulation of IL-23p19 transcripts in the terminal ileum in patients with AS and patients with CD. IL-23 was abundantly produced by infiltrating monocyte-like cells in inflamed mucosa from AS and CD patients. Notably, we also identified Paneth cells as a major source of IL-23 in patients with AS, patients with CD, and normal controls. Unlike CD, in AS patients, IL-23 was not associated with up-regulation of IL-17 and the IL-17-inducing cytokines IL-6 and IL-1beta. Finally, while the Th1-related cytokines interferon-gamma, IL-12p35, and IL-27p28 were overexpressed only in CD patients, IL-4, IL-5, and STAT-6 were also significantly increased in AS patients.

Conclusion: Our findings indicate that overexpression of IL-23, but not IL-17, is a pivotal feature of subclinical gut inflammation in AS. Identification of resident Paneth cells as a pivotal source of IL-23 in physiologic and pathologic conditions strongly suggests that IL-23 is a master regulator of gut mucosal immunity, providing a pathophysiologic significance to the reported association between IL-23 receptor polymorphisms and intestinal inflammation.
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http://dx.doi.org/10.1002/art.24389DOI Listing
April 2009

Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis.

Hepatology 2009 Jan;49(1):195-203

Cattedra & Unità Operativa di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy.

Unlabelled: Indirect methods to predict the presence of esophageal varices (EV) in patients with cirrhosis are not sensitive enough to be used as a surrogate for endoscopy. We tested the effectiveness of liver stiffness measurement (LSM) by transient elastography and the presence of insulin resistance (IR), a marker associated with fibrosis progression, in the noninvasive prediction of portal hypertension. One hundred four consecutive patients with newly diagnosed Child A hepatitis C virus (HCV) cirrhosis underwent upper gastrointestinal endoscopy to search for EV. Clinical, anthropometric, biochemical, ultrasonographic, and metabolic features, including IR by the homeostasis model assessment (HOMA), and LSM by transient elastography, were recorded at the time of endoscopy. EVs were detected in 63 of 104 patients (60%). In 10 patients (16%), the EVs were medium-large (>or=F2). By multivariate analysis, the presence of EVs was independently associated with a low platelet count/spleen diameter ratio (OR, 0.998; 95% CI, 0.996-0.999) and a high HOMA-IR score (OR, 1.296; 95%CI, 1.018-1.649), not with LSM (OR, 1.009; 95%CI, 0.951-1.070). It is noteworthy that nine of ten patients with medium-large EVs had a platelet/spleen ratio of less than 792 or an HOMA-IR of greater than 3.5. The independent association between low platelet count/spleen diameter ratio (OR, 0.998; 95%CI, 0.996-1.000), high HOMA-IR score (OR, 1.373; 95%CI, 1.014-1.859) and presence of EV was confirmed in the subgroup of 77 nondiabetic subjects.

Conclusions: In patients with Child A HCV cirrhosis, two simple, easy-to-get tests, namely the platelet/spleen ratio and insulin resistance measured by HOMA-IR, regardless of the presence of diabetes, significantly predict the presence of EV, outweighing the contribution given by transient elastography.
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http://dx.doi.org/10.1002/hep.22655DOI Listing
January 2009

Update on novel strategies to optimize cetuximab therapy in patients with metastatic colorectal cancer.

Clin Colorectal Cancer 2008 Sep;7(5):300-8

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radiation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy.
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http://dx.doi.org/10.3816/CCC.2008.n.039DOI Listing
September 2008

Oxaliplatin-based chemotherapy in the management of colorectal cancer.

Expert Rev Anticancer Ther 2008 Aug;8(8):1223-36

Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Oxaliplatin is the only third-generation platinum derivative compound that has found a place in the routine treatment of colorectal cancer (CRC). The appearance of oxaliplatin, as well as irinotecan, in the CRC treatment armamentarium has offered new standards for adjuvant treatment and greater hopes in metastatic disease. Moreover, the combination of oxaliplatin-based chemotherapy with new targeted drugs has improved response rates and survival of these patients. Despite these new approaches, the prognosis of CRC remains poor and a better understanding of the molecular pathways is needed to optimize the use of these new approaches. In this review, the authors examine the development of oxaliplatin as well as the main trials that have positioned oxaliplatin as a key drug in the treatment of CRC.
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http://dx.doi.org/10.1586/14737140.8.8.1223DOI Listing
August 2008

A phase II pharmacodynamic study of erlotinib in patients with advanced non-small cell lung cancer previously treated with platinum-based chemotherapy.

Clin Cancer Res 2008 Jun;14(12):3867-74

Medical Oncology Service and Pathology Service, Vall d'Hebron University Hospital, Barcelona, Spain.

Purpose: To examine potential markers of clinical benefit and the effects of erlotinib on the epidermal growth factor receptor (EGFR) signaling pathway in advanced non-small cell lung cancer patients refractory to platinum-based chemotherapy.

Experimental Design: Patients were given erlotinib (150 mg/d). Tumor biopsies were done immediately before treatment and in a subgroup of patients after 6 weeks' treatment.

Results: Of 73 evaluable patients, 7 (10%) had partial response and 28 (38%) had stable disease. In 53 patients with baseline tumor samples, no relationship was observed between pretreatment levels of EGFR, phosphorylated (p)-EGFR, p-AKT, p-mitogen-activated protein kinase (MAPK), or p27 and clinical benefit (i.e., response, or stable disease >/=12 weeks). Tumors from 15 of 57 patients had high EGFR gene copy number, assessed using fluorescence in situ hybridization (FISH positive), 10 of whom had clinical benefit, compared with 5 of 42 FISH-negative patients. FISH-positive patients had longer median progression-free [137 versus 43 days, P = 0.002; hazard ratio (HR), 0.37] and overall (226 versus 106 days, P = 0.267; HR, 0.70) survival than FISH-negative patients. In paired biopsy samples from 14 patients, p-EGFR (P = 0.002), p-MAPK (P = 0.001), and Ki-67 (P = 0.025) levels were significantly reduced after 6 weeks' treatment. Apoptosis was significantly increased in patients with clinical benefit (P = 0.029), and may be a marker of clinical benefit.

Conclusion: In this study, EGFR FISH-positive status was associated with improved outcome after erlotinib therapy. Erlotinib led to reduced levels of p-EGFR, p-MAPK, and Ki-67, and stimulated apoptosis in tumor samples from patients with clinical benefit.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-5186DOI Listing
June 2008

A rare case of malignant solitary fibrous tumor of the spinal cord.

Spine (Phila Pa 1976) 2008 May;33(12):E397-9

Vall d'Hebron University Hospital, Department of Medical Oncology, Barcelona, Spain.

Study Design: Case report.

Objective: We present a case of an ambulatory patient with a solitary fibrous tumor of the spinal cord.

Summary Of Background Data: Solitary fibrous tumor (SFT) is an uncommon mesenchymal tumor of the pleural cavity, increasingly recognized at numerous extrathoracic sites, including, among others, prostate, kidney, and thyroid. The spinal cord is an extremely rare localization of SFTs with only 17 cases reported in the literature since 1996. Although SFTs are usually indolent neoplasms that are cured with complete surgical resection, malignant transformation has been described within histologically benign SFTs. However, no cases of malignant dissemination have been described in this localization.

Methods: Discussion of the patient's clinical and radiologic history with a review of the relevant background literature.

Results: We report the first case of spinal cord SFT with visceral dissemination years after the primary diagnosis, despite benign histologic features of the primary tumor.

Conclusion: This finding may indicate that long-term follow-up might be necessary in these patients. In addition, metastatic radical surgery of SFTs should be considered to achieve long-term survival since there are no currently available effective systemic therapies.
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http://dx.doi.org/10.1097/BRS.0b013e31817343dcDOI Listing
May 2008

Successful treatment of pulmonary metastatic salivary ductal carcinoma with trastuzumab-based therapy.

Head Neck 2008 May;30(5):680-3

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Salivary ductal carcinoma (SDC) is an uncommon malignant tumor of the salivary glands. Although there is no known standard of care for the treatment of advanced disease, the vast majority of patients with SDC may be offered palliative systemic therapy. We report a case of epidermal growth factor receptor 2 (HER2)-positive metastatic submandibular SDC with a complete and durable clinical response to treatment with trastuzumab in combination with chemotherapy.

Methods And Results: A 62-year-old man was diagnosed with SDC of the left submandibular gland with extensive cervical lymph node involvement. The lesion was completely resected, and the patient underwent postoperative radiotherapy. After 6 months, multiple pulmonary metastatic lesions were detected. A complete response was reached with trastuzumab-based combination therapy, and no evidence of disease progression has been observed after 14 months of initiation of systemic therapy.

Conclusion: Trastuzumab-based combination therapies should be considered for advanced SDC.
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http://dx.doi.org/10.1002/hed.20714DOI Listing
May 2008

Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial.

J Hepatol 2007 Oct 27;47(4):484-91. Epub 2007 Jun 27.

Cattedra di Gastroenterologia and Unità Operativa Complessa di Gastroenterologia ed Epatologia, Di.Bi.M.I.S, Piazza delle Cliniche 2, 90127 Palermo, Italy.

Background/aims: Risks and benefits of antiviral therapy in HCV cirrhosis with portal hypertension are poorly known.

Methods: We performed a randomized controlled trial in 102 HCV patients with compensated cirrhosis and portal hypertension: 51 received 1 microg/kg/week of Pegylated-interferon alpha-2b and 51 Pegylated-interferon plus 800 mg/day of ribavirin up to 52 weeks.

Results: By intention-to-treat analysis, five patients on monotherapy and eleven on combination therapy achieved a sustained virological response (9.8% vs. 21.6%, p=0.06). The response was more frequent for genotypes 2 or 3 than genotype 1 (66.6% vs. 11.3%, p=0.001). Genotype 1, who had low viral load at start of therapy, were HCV-RNA negative at 4 weeks, and were adherent to the scheduled therapy had a higher probability of sustained virological response. Patients with sustained virological response had less disease events compared to nonresponders (6.2% vs. 38.3%, p=0.03 by log rank test) during follow-up.

Conclusions: In HCV cirrhosis with portal hypertension Peg-interferon plus ribavirin is a feasible treatment. Although the rate of viral eradication is modest, tailoring by genotype and early viral response allows to keep patients on treatment who are more likely to have viral eradication. Patients with viral eradication have fewer disease complications during follow-up.
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http://dx.doi.org/10.1016/j.jhep.2007.04.020DOI Listing
October 2007

Hepatic pneumatosis as a complication of an abdominal desmoid tumor.

J Clin Oncol 2007 Mar;25(7):897-8

Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.

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http://dx.doi.org/10.1200/JCO.2006.09.6537DOI Listing
March 2007

[Diagnosis of Krabbe's leukodystrophy by transmission electron microscopy. Case report].

Cir Cir 2006 Nov-Dec;74(6):477-81

Departomento de Morfología Celular y Molecular, Torre de Investigación, Instituto Nacional de Rehabilitación, México, DF.

Krabbe's leukodystrophy is a rare hereditary disease in Mexico. For that reason we report the case of an 11-year-old child. Ultrastructural studies of sural nerve biopsy specimen are described. Myelin sheaths were uniformly thin for the fiber diameters. Cytoplasm of Schwann cells exhibited a moderate dilatation with non-membrane masses with partly curvilinear, needle-shaped structures of variable length. The inclusions often had electron-dense or electron-lucent halos. These inclusions ultrastructurally represented Krabbe's leukodystrophy, and this method aids in the diagnosis in cases that are not available for genetic studies or special laboratory techniques. In this patient, diagnosis of Krabbe's disease was delayed and established several years after the initial symptoms. Electron microscopic examination of a sural nerve provided evidence for a diagnosis of Krabbe's leukodystrophy.
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July 2007