Publications by authors named "Xavier Farré"

30 Publications

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Computer extracted gland features from H&E predicts prostate cancer recurrence comparably to a genomic companion diagnostic test: a large multi-site study.

NPJ Precis Oncol 2021 May 3;5(1):35. Epub 2021 May 3.

Department of Urology, Case Western Reserve University, Cleveland, OH, USA.

Existing tools for post-radical prostatectomy (RP) prostate cancer biochemical recurrence (BCR) prognosis rely on human pathologist-derived parameters such as tumor grade, with the resulting inter-reviewer variability. Genomic companion diagnostic tests such as Decipher tend to be tissue destructive, expensive, and not routinely available in most centers. We present a tissue non-destructive method for automated BCR prognosis, termed "Histotyping", that employs computational image analysis of morphologic patterns of prostate tissue from a single, routinely acquired hematoxylin and eosin slide. Patients from two institutions (n = 214) were used to train Histotyping for identifying high-risk patients based on six features of glandular morphology extracted from RP specimens. Histotyping was validated for post-RP BCR prognosis on a separate set of n = 675 patients from five institutions and compared against Decipher on n = 167 patients. Histotyping was prognostic of BCR in the validation set (p < 0.001, univariable hazard ratio [HR] = 2.83, 95% confidence interval [CI]: 2.03-3.93, concordance index [c-index] = 0.68, median years-to-BCR: 1.7). Histotyping was also prognostic in clinically stratified subsets, such as patients with Gleason grade group 3 (HR = 4.09) and negative surgical margins (HR = 3.26). Histotyping was prognostic independent of grade group, margin status, pathological stage, and preoperative prostate-specific antigen (PSA) (multivariable p < 0.001, HR = 2.09, 95% CI: 1.40-3.10, n = 648). The combination of Histotyping, grade group, and preoperative PSA outperformed Decipher (c-index = 0.75 vs. 0.70, n = 167). These results suggest that a prognostic classifier for prostate cancer based on digital images could serve as an alternative or complement to molecular-based companion diagnostic tests.
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http://dx.doi.org/10.1038/s41698-021-00174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093226PMC
May 2021

Computationally Derived Cribriform Area Index from Prostate Cancer Hematoxylin and Eosin Images Is Associated with Biochemical Recurrence Following Radical Prostatectomy and Is Most Prognostic in Gleason Grade Group 2.

Eur Urol Focus 2021 Apr 30. Epub 2021 Apr 30.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, Cleveland, OH, USA. Electronic address:

Background: The presence of invasive cribriform adenocarcinoma (ICC), an expanse of cells containing punched-out lumina uninterrupted by stroma, in radical prostatectomy (RP) specimens has been associated with biochemical recurrence (BCR). However, ICC identification has only moderate inter-reviewer agreement.

Objective: To investigate quantitative machine-based assessment of the extent and prognostic utility of ICC, especially within individual Gleason grade groups.

Design, Setting, And Participants: A machine learning approach was developed for ICC segmentation using 70 RP patients and validated in a cohort of 749 patients from four sites whose median year of surgery was 2007 and with median follow-up of 28 mo. ICC was segmented on one representative hematoxylin and eosin RP slide per patient and the fraction of tumor area composed of ICC, the cribriform area index (CAI), was measured.

Outcome Measurements And Statistical Analysis: The association between CAI and BCR was measured in terms of the concordance index (c index) and hazard ratio (HR).

Results And Limitations: CAI was correlated with BCR (c index 0.62) in the validation set of 411 patients with ICC morphology, especially those with Gleason grade group 2 cancer (n = 192; c index 0.66), and was less prognostic when patients without ICC were included (c index 0.54). A doubling of CAI in the group with ICC morphology was prognostic after controlling for Gleason grade, surgical margin positivity, preoperative prostate-specific antigen level, pathological T stage, and age (HR 1.19, 95% confidence interval 1.03-1.38; p = 0.018).

Conclusions: Automated image analysis and machine learning could provide an objective, quantitative, reproducible, and high-throughput method of quantifying ICC area. The performance of CAI for grade group 2 cancer suggests that for patients with little Gleason 4 pattern, the ICC fraction has a strong prognostic role.

Patient Summary: Machine-based measurement of a specific cell pattern (cribriform; sieve-like, with lots of spaces) in images of prostate specimens could improve risk stratification for patients with prostate cancer. In the future, this could help in expanding the criteria for active surveillance.
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http://dx.doi.org/10.1016/j.euf.2021.04.016DOI Listing
April 2021

T1 and T2 MR fingerprinting measurements of prostate cancer and prostatitis correlate with deep learning-derived estimates of epithelium, lumen, and stromal composition on corresponding whole mount histopathology.

Eur Radiol 2021 Mar 2;31(3):1336-1346. Epub 2020 Sep 2.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USA.

Objectives: To explore the associations between T1 and T2 magnetic resonance fingerprinting (MRF) measurements and corresponding tissue compartment ratios (TCRs) on whole mount histopathology of prostate cancer (PCa) and prostatitis.

Materials And Methods: A retrospective, IRB-approved, HIPAA-compliant cohort consisting of 14 PCa patients who underwent 3 T multiparametric MRI along with T1 and T2 MRF maps prior to radical prostatectomy was used. Correspondences between whole mount specimens and MRI and MRF were manually established. Prostatitis, PCa, and normal peripheral zone (PZ) regions of interest (ROIs) on pathology were segmented for TCRs of epithelium, lumen, and stroma using two U-net deep learning models. Corresponding ROIs were mapped to T2-weighted MRI (T2w), apparent diffusion coefficient (ADC), and T1 and T2 MRF maps. Their correlations with TCRs were computed using Pearson's correlation coefficient (R). Statistically significant differences in means were assessed using one-way ANOVA.

Results: Statistically significant differences (p < 0.01) in means of TCRs and T1 and T2 MRF were observed between PCa, prostatitis, and normal PZ. A negative correlation was observed between T1 and T2 MRF and epithelium (R = - 0.38, - 0.44, p < 0.05) of PCa. T1 MRF was correlated in opposite directions with stroma of PCa and prostatitis (R = 0.35, - 0.44, p < 0.05). T2 MRF was positively correlated with lumen of PCa and prostatitis (R = 0.57, 0.46, p < 0.01). Mean T2 MRF showed significant differences (p < 0.01) between PCa and prostatitis across both transition zone (TZ) and PZ, while mean T1 MRF was significant (p = 0.02) in TZ.

Conclusion: Significant associations between MRF (T1 in the TZ and T2 in the PZ) and tissue compartments on corresponding histopathology were observed.

Key Points: • Mean T2 MRF measurements and ADC within cancerous regions of interest dropped with increasing ISUP prognostic groups (IPG). • Mean T1 and T2 MRF measurements were significantly different (p < 0.001) across IPGs, prostatitis, and normal peripheral zone (NPZ). • T2 MRF showed stronger correlations in the peripheral zone, while T1 MRF showed stronger correlations in the transition zone with histopathology for prostate cancer.
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http://dx.doi.org/10.1007/s00330-020-07214-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882016PMC
March 2021

The shared genetic architecture of schizophrenia, bipolar disorder and lifespan.

Hum Genet 2021 Mar 9;140(3):441-455. Epub 2020 Aug 9.

Biomedical Network Research Centre on Mental Health (CIBERSAM), Hospital Universitari Institut Pere Mata, IISPV Universitat Rovira i Virgili, Reus, Spain.

Psychiatric disorders such as Schizophrenia (SCZ) and Bipolar Disorder (BD) represent an evolutionary paradox, as they exhibit strong negative effects on fitness, such as decreased fecundity and early mortality, yet they persist at a worldwide prevalence of approximately 1%. Molecular mechanisms affecting lifespan, which may be widely common among complex diseases with fitness effects, can be studied by the integrated analysis of data from genome-wide association studies (GWAS) of human longevity together with any disease of interest. Here, we report the first of such studies, focusing on the genetic overlap-pleiotropy-between two psychiatric disorders with shortened lifespan, SCZ and BD, and human parental lifespan (PLS) as a surrogate of life expectancy. Our results are twofold: first, we demonstrate extensive polygenic overlap between SCZ and PLS and to a lesser extent between BD and PLS. Second, we identified novel loci shared between PLS and SCZ (n = 39), and BD (n = 8). Whereas most of the identified SCZ (66%) and BD (62%) pleiotropic risk alleles were associated with reduced lifespan, we also detected some antagonistic protective alleles associated to shorter lifespans. In fact, top-associated SNPs with SCZ seems to explain longevity variance explained (LVE) better than many other life-threatening diseases, including Type 2 diabetes and most cancers, probably due to a high overlap with smoking-related pathways. Overall, our study provides evidence of a genetic burden driven through premature mortality among people with SCZ, which can have profound implications for understanding, and potentially treating, the mortality gap associated with this psychiatric disorder.
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http://dx.doi.org/10.1007/s00439-020-02213-8DOI Listing
March 2021

Artificial intelligence assistance significantly improves Gleason grading of prostate biopsies by pathologists.

Mod Pathol 2021 03 5;34(3):660-671. Epub 2020 Aug 5.

Department of Pathology, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohen's kappa, 0.799 vs. 0.872; p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohen's kappa, 0.733 vs. 0.786; p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.
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http://dx.doi.org/10.1038/s41379-020-0640-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897578PMC
March 2021

Copy number variants and fixed duplications among 198 rhesus macaques (Macaca mulatta).

PLoS Genet 2020 05 11;16(5):e1008742. Epub 2020 May 11.

Institut de Biologia Evolutiva (CSIC-Universitat Pompeu Fabra), Parc de Recerca Biomèdica de Barcelona, Barcelona, Catalonia, Spain.

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes.
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http://dx.doi.org/10.1371/journal.pgen.1008742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241854PMC
May 2020

POLR3A-related spastic ataxia: new mutations and a look into the phenotype.

J Neurol 2020 Feb 21;267(2):324-330. Epub 2019 Oct 21.

Neurogenetics Laboratory, Functional and Translational Neurogenetics Unit, Department of Neuroscience, Germans Trias i Pujol Research Institute (IGTP), Universitat Autònoma de Barcelona-Can Ruti Campus, Badalona, Barcelona, Spain.

Adolescent-onset spastic ataxia is a proposed novel phenotype in compound heterozygous carriers of an intronic mutation (c.1909 + 22G > A) in the POLR3A gene. Here, we present ten new cases of POLR3A-related spastic ataxia and discuss the genetic, clinical and imaging findings. Patients belonged to six pedigrees with hereditary spastic paraplegia or cerebellar ataxia of unknown origin. All affected subjects presented with compound heterozygous variants, comprising c.1909 + 22G > A in combination in each pedigree with one of the following novel mutations (Thr596Met, Tyr665LeufsTer11, Glu198Ter, c.646-687_1185 + 844del). The new mutations segregated with the phenotype in all families. The phenotype combined variable cerebellar ataxia, gait and lower limb spasticity, involvement of central sensory tracts and in some cases also intention tremor. The reportedly characteristic hyperintensity along the superior cerebellar peduncle on MRI was observed in ~ 80% of the cases. Our study extends the clinical and molecular phenotype further supporting the pathogenic role of the c.1909 + 22G4A intronic mutation and identifying four novel causative mutations in POLR3A-related spastic ataxia. Certain characteristic MRI features may be useful to guide genetic diagnosis.
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http://dx.doi.org/10.1007/s00415-019-09574-9DOI Listing
February 2020

Genome-phenome explorer (GePhEx): a tool for the visualization and interpretation of phenotypic relationships supported by genetic evidence.

Bioinformatics 2020 02;36(3):890-896

Department of Experimental and Health Sciences, Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia 08003, Spain.

Motivation: Association studies based on SNP arrays and Next Generation Sequencing technologies have enabled the discovery of thousands of genetic loci related to human diseases. Nevertheless, their biological interpretation is still elusive, and their medical applications limited. Recently, various tools have been developed to help bridging the gap between genomes and phenomes. To our knowledge, however none of these tools allows users to retrieve the phenotype-wide list of genetic variants that may be linked to a given disease or to visually explore the joint genetic architecture of different pathologies.

Results: We present the Genome-Phenome Explorer (GePhEx), a web-tool easing the visual exploration of phenotypic relationships supported by genetic evidences. GePhEx is primarily based on the thorough analysis of linkage disequilibrium between disease-associated variants and also considers relationships based on genes, pathways or drug-targets, leveraging on publicly available variant-disease associations to detect potential relationships between diseases. We demonstrate that GePhEx does retrieve well-known relationships as well as novel ones, and that, thus, it might help shedding light on the patho-physiological mechanisms underlying complex diseases. To this end, we investigate the potential relationship between schizophrenia and lung cancer, first detected using GePhEx and provide further evidence supporting a functional link between them.

Availability And Implementation: GePhEx is available at: https://gephex.ega-archive.org/.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btz622DOI Listing
February 2020

Reply to: Retesting the influences of mutation accumulation and antagonistic pleiotropy on human senescence and disease.

Nat Ecol Evol 2019 07 24;3(7):994-995. Epub 2019 Jun 24.

Institute of Evolutionary Biology (UPF-CSIC), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.

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http://dx.doi.org/10.1038/s41559-019-0926-yDOI Listing
July 2019

FaST-LMM for Two-Way Epistasis Tests on High-Performance Clusters.

J Comput Biol 2018 08 18;25(8):862-870. Epub 2018 Jul 18.

2 Department of Experimental and Health Sciences, Pompeu Fabra University , Barcelona, Spain .

We introduce a version of the epistasis test in FaST-LMM for clusters of multithreaded processors. This new software maintains the sensitivity of the original FaST-LMM while delivering acceleration that is close to linear on 12-16 nodes of two recent platforms, with respect to improved implementation of FaST-LMM presented in an earlier work. This efficiency is attained through several enhancements on the original single-node version of FaST-LMM, together with the development of a message passing interface (MPI)-based version that ensures a balanced distribution of the workload as well as a multigraphics processing unit (GPU) module that can exploit the presence of multiple GPUs per node.
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http://dx.doi.org/10.1089/cmb.2018.0087DOI Listing
August 2018

Biological Processes Modulating Longevity across Primates: A Phylogenetic Genome-Phenome Analysis.

Mol Biol Evol 2018 08;35(8):1990-2004

Institute of Evolutionary Biology (UPF-CSIC), Universitat Pompeu Fabra, Barcelona, Catalonia, Spain.

Aging is a complex process affecting different species and individuals in different ways. Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity. Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity. Here, we examine the relationship between genomic variation and maximum lifespan across primate species. We used two different approaches. First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage. Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms. The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders. We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging. A second approach was focused on changes in rates of protein evolution across the primate phylogeny. Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits. These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes. Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.
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http://dx.doi.org/10.1093/molbev/msy105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063263PMC
August 2018

In reply to Egevad et al.: 'Utility of Pathology Imagebase for standardisation of prostate cancer grading'.

Histopathology 2018 08 30;73(2):360-361. Epub 2018 May 30.

Self-employed pathologist, Lleida, Catalonia, Spain.

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http://dx.doi.org/10.1111/his.13636DOI Listing
August 2018

Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples.

PLoS One 2017 27;12(6):e0179446. Epub 2017 Jun 27.

Institute of Evolutionary Biology (UPF-CSIC), Departament de Ciències Experimentals i la Salut, Universitat Pompeu Fabra, PRBB, Barcelona, Catalonia, Spain.

Epstein-Barr virus (EBV), human herpes virus 4, has been classically associated with infectious mononucleosis, multiple sclerosis and several types of cancers. Many of these diseases show marked geographical differences in prevalence, which points to underlying genetic and/or environmental factors. Those factors may include a different susceptibility to EBV infection and viral copy number among human populations. Since EBV is commonly used to transform B-cells into lymphoblastoid cell lines (LCLs) we hypothesize that differences in EBV copy number among individual LCLs may reflect differential susceptibility to EBV infection. To test this hypothesis, we retrieved whole-genome sequenced EBV-mapping reads from 1,753 LCL samples derived from 19 populations worldwide that were sequenced within the context of the 1000 Genomes Project. An in silico methodology was developed to estimate the number of EBV copy number in LCLs and validated these estimations by real-time PCR. After experimentally confirming that EBV relative copy number remains stable over cell passages, we performed a genome wide association analysis (GWAS) to try detecting genetic variants of the host that may be associated with EBV copy number. Our GWAS has yielded several genomic regions suggestively associated with the number of EBV genomes per cell in LCLs, unraveling promising candidate genes such as CAND1, a known inhibitor of EBV replication. While this GWAS does not unequivocally establish the degree to which genetic makeup of individuals determine viral levels within their derived LCLs, for which a larger sample size will be needed, it potentially highlighted human genes affecting EBV-related processes, which constitute interesting candidates to follow up in the context of EBV related pathologies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487016PMC
September 2017

Combining Multiple Hypothesis Testing with Machine Learning Increases the Statistical Power of Genome-wide Association Studies.

Sci Rep 2016 11 28;6:36671. Epub 2016 Nov 28.

Machine Learning Group, Technische Universität Berlin, Berlin, 10587, Germany.

The standard approach to the analysis of genome-wide association studies (GWAS) is based on testing each position in the genome individually for statistical significance of its association with the phenotype under investigation. To improve the analysis of GWAS, we propose a combination of machine learning and statistical testing that takes correlation structures within the set of SNPs under investigation in a mathematically well-controlled manner into account. The novel two-step algorithm, COMBI, first trains a support vector machine to determine a subset of candidate SNPs and then performs hypothesis tests for these SNPs together with an adequate threshold correction. Applying COMBI to data from a WTCCC study (2007) and measuring performance as replication by independent GWAS published within the 2008-2015 period, we show that our method outperforms ordinary raw p-value thresholding as well as other state-of-the-art methods. COMBI presents higher power and precision than the examined alternatives while yielding fewer false (i.e. non-replicated) and more true (i.e. replicated) discoveries when its results are validated on later GWAS studies. More than 80% of the discoveries made by COMBI upon WTCCC data have been validated by independent studies. Implementations of the COMBI method are available as a part of the GWASpi toolbox 2.0.
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http://dx.doi.org/10.1038/srep36671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125008PMC
November 2016

Pharmacogenomic study in patients with multiple sclerosis: Responders and nonresponders to IFN-β.

Neurol Neuroimmunol Neuroinflamm 2015 Oct 24;2(5):e154. Epub 2015 Sep 24.

Servei de Neurologia-Neuroimmunologia (M.F.B., S.M., J.R., X.M., M.C.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Institute of Evolutionary Biology (UPF-CSIC) (C.M.-S., X.F., A.N.), PRBB, Barcelona, Spain; National Institute for Bioinformatics (C.M.-S., X.F., A.N.), Universitat Pompeu Fabra, Barcelona, Spain; Servicio de Neurología (L.L., O.F.), Instituto de Neurociencias Clínicas, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain; Department of Neurology (U.K.Z.), University of Rostock, Rostock, Germany; Department of Neurology (J.K.), Multiple Sclerosis Centre Amsterdam, Vrije University Medical Centre, Amsterdam, the Netherlands; Pole des neurosciences et INSERM U1043 (D.B.), Université de Toulouse III, Hopital Purpan, Toulouse, France; Neuroinmunología (J.A.G.-M., A.J.S.), Hospital Universitario Puerta de Hierro, Madrid, Spain; Servicio de Neurología (E.U., R.A.-L.), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain; Department of Neurology and Immunology (L.M.V., J.C.A.-C.), Hospital Ramón y Cajal, IRYCIS, Madrid, Spain; Department of Neurology (J.L.-S.), John Hunter Hospital, Newcastle, Australia; Hunter Medical Research Institute (J.L.-S.), University Newcastle, Australia; University Newcastle (J.L.-S.), Callaghan Campus, Australia; Neurogenomiks Group (K.V.), Universidad del País Vasco (UPV/EHU), Leioa, Spain; IKERBASQUE (K.V.), Basque Foundation for Science, Bilbao, Spain; Achucarro Basque Center for Neuroscience (K.V.), Zamudio, Spain; Servicio de Neurología (A.R.-A.), Hospital de Basurto, Bilbao, Spain; Clinic of Neurology (J.S.D.), Clinical Centre of Serbia (CCS), Faculty of Medicine, University of Belgrade, Serbia; Laboratory of Genetics of Neurological Complex Disorders and Department of Neuro-rehabilitation (F.M.B

Objectives: We aimed to investigate the association between polymorphisms located in type I interferon (IFN)-induced genes, genes belonging to the toll-like receptor (TLR) pathway, and genes encoding neurotransmitter receptors and the response to IFN-β treatment in patients with multiple sclerosis (MS).

Methods: In a first or screening phase of the study, 384 polymorphisms were genotyped in 830 patients with MS classified into IFN-β responders (n = 416) and nonresponders (n = 414) according to clinical criteria. In a second or validation phase, the most significant polymorphisms associated with IFN-β response were genotyped in an independent validation cohort of 555 patients with MS (281 IFN-β responders and 274 nonresponders).

Results: Seven single nucleotide polymorphisms (SNPs) were selected from the screening phase for further validation: rs832032 (GABRR3; p = 0.0006), rs6597 (STUB1; p = 0.019), rs3747517 (IFIH1; p = 0.010), rs2277302 (PELI3; p = 0.017), rs10958713 (IKBKB; p = 0.003), rs2834202 (IFNAR1; p = 0.030), and rs4422395 (CXCL1; p = 0.017). None of these SNPs were significantly associated with IFN-β response when genotyped in an independent cohort of patients. Combined analysis of these SNPs in all patients with MS (N = 1,385) revealed 2 polymorphisms associated with IFN-β response: rs2277302 (PELI3; p = 0.008) and rs832032 (GABRR3; p = 0.006).

Conclusions: These findings do not support an association between polymorphisms located in genes related to the type I IFN or TLR pathways or genes encoding neurotransmitter receptors and the clinical response to IFN-β. Nevertheless, additional genetic and functional studies of PELI3 and GABRR3 are warranted.
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http://dx.doi.org/10.1212/NXI.0000000000000154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582905PMC
October 2015

The Long-HER study: clinical and molecular analysis of patients with HER2+ advanced breast cancer who become long-term survivors with trastuzumab-based therapy.

PLoS One 2014 20;9(10):e109611. Epub 2014 Oct 20.

Medical Oncology Department, Hospital La Paz, Madrid, Spain.

Background: Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.

Methods: Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.

Results: 103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.

Conclusions: Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109611PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203741PMC
July 2015

Expression of Ep-CAM, but not of E48, associates with nodal involvement in advanced squamous cell carcinomas of the larynx.

Histopathology 2013 May 12;62(6):954-61. Epub 2013 Apr 12.

Hospital Universitari Sant Joan de Reus, Reus, Spain.

Aims: To evaluate epithelial cell adhesion molecule (Ep-CAM) and E48 expression, and their relationship with histological differentiation and nodal metastasis, in laryngeal squamous cell carcinomas (SCC).

Methods And Results: The expression of Ep-CAM and E48 was investigated using immunohistochemistry in a series of 66 SCC (stages 3 and 4) and their adjacent non-neoplastic epithelia. Ep-CAM expression increased with the progression from normal squamous epithelium to SCC. It was detected in 96% of carcinomas and high levels of Ep-CAM expression (50% or more positive cells) were associated with poorer differentiation (P = 0.003) and the presence of lymph node metastases (P = 0.001). E48 expression was characteristically strong and diffuse in non-neoplastic squamous epithelium, and decreased with progression to SCC. Poorly differentiated (grade 4) tumours had lower proportions of E48-positive cells than well- to moderately- differentiated cases (P < 0.001).

Conclusions: Expression of both Ep-CAM and E48 correlated with cell differentiation, although in inverse fashion. In particular, the association between high levels of Ep-CAM expression and high frequency of nodal metastases suggests that Ep-CAM plays a role in the development of lymph node metastases in SCC of the larynx.
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http://dx.doi.org/10.1111/his.12108DOI Listing
May 2013

A working group classification of focal prostate atrophy lesions.

Am J Surg Pathol 2006 Oct;30(10):1281-91

Johns Hopkins University School of Medicine, USA.

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.
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http://dx.doi.org/10.1097/01.pas.0000213289.50660.beDOI Listing
October 2006

Power Doppler sonography of invasive breast carcinoma: does tumor vascularization contribute to prediction of axillary status?

Radiology 2005 Feb 15;234(2):374-80. Epub 2004 Dec 15.

Department of Radiology, Hospital Clínic and University of Barcelona Medical School, Villarroel 170, 08036 Barcelona, Spain.

Purpose: To prospectively compare unenhanced power Doppler sonographic findings of arterial vascularization of invasive breast carcinoma with histopathologic and immunohistochemical parameters and to determine whether tumor arterial vascularization contributes to prediction of axillary node status.

Materials And Methods: Ethics committee approval and informed consent were obtained. A total of 97 invasive breast carcinomas were prospectively studied with unenhanced power Doppler sonography before surgery. Lumpectomy or mastectomy with full axillary nodal dissection was performed. Sonographic tumor size and number of tumor arteries were correlated with axillary nodal status by means of logistic regression analysis. Tumor microvascularization was immunohistochemically assessed in a subset of 55 carcinomas. Sonographic variables were correlated with tumor arteries with a diameter larger than 300 mum and with the density and area of microvascularization. The kappa statistic and Bland-Altman agreement limits were used to measure agreement between techniques.

Results: Good agreement of sonographic and histologic findings regarding number of tumor arteries (kappa= 0.66, P < .001) and tumor size (P = .012) was observed. Multivariate analysis showed an independent relationship between probability of axillary metastasis, number of tumor arteries (P = .016), and sonographic tumor size (P = .035). A predictive model of axillary status was developed. The receiver operating characteristic curve was used to determine 0.2324 as the score to classify axillary nodal status. This score indicated high sensitivity (96.1%), low specificity (53.0%), and high negative predictive value (96.1%).

Conclusion: The number of arteries in invasive breast carcinoma detected with unenhanced power Doppler sonography and sonographic tumor size are independent predictors of axillary nodal status; these variables could contribute to reliable prediction of absence of axillary involvement on the basis of a mathematic model.
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http://dx.doi.org/10.1148/radiol.2342031252DOI Listing
February 2005

Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors.

Int J Cancer 2004 Dec;112(6):959-66

Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain.

Deoxynucleoside analogs are used in the treatment of a variety of solid tumors. Their transport across the plasma membrane may determine their cytotoxicity and thus nucleoside transporter (NT) expression patterns may be of clinical relevance. Lack of appropriate antibodies for use in paraffin-embedded biopsies has been a bottleneck to undertake high-throughput analysis of NT expression in solid tumors. Here we report the characterization of 2 new antibodies raised against the low-affinity equilibrative NTs, hENT1 and hENT2, suitable for that purpose. These 2 antisera, along with a previously characterized antibody that specifically recognizes the high-affinity Na-dependent concentrative NT, hCNT1, have been used to analyze, using a tissue array approach, NT expression in gynecologic cancers (90 ovarian, 80 endometrial and 118 uterine cervix carcinomas). Human CNT1 was not detected in 33% and 39% of the ovarian and uterine cervix carcinomas, respectively, whereas hENT1 and hENT2 expression was significantly retained in a high percentage of tumors (91% and 96% for hENT1, 84% and 98% for hENT2, in ovarian and cervix carcinomas, respectively). Only a few endometrial carcinomas (15%) were found to be negative for hCNT1, but they all retained hENT1 and hENT2 expression. In ovarian cancer, the loss of all 3 NT proteins was a more common event in the clear cell histologic subtype than in the serous, mucinous and endometrioid histotypes. In uterine cervix tumors, the loss of expression of hCNT1 was significantly associated with the adenocarcinoma subtype. In summary, hCNT1 was by far the isoform whose expression was most frequently reduced or lost in the 3 types of gynecologic tumors analyzed. Moreover, NT expression is related to the type of gynecologic tumor and its specific subtype, hCNT1 protein loss being highly correlated with poor prognosis histotypes. Since hCNT1, hENT1 and hENT2 recognize fluoropyrimidines as substrates, but with different affinities, this study anticipates high variability in drug uptake efficiency in solid tumors.
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http://dx.doi.org/10.1002/ijc.20524DOI Listing
December 2004

Particulate silicone for vocal fold augmentation: morphometric evaluation in a rabbit model.

Ann Otol Rhinol Laryngol 2004 Mar;113(3 Pt 1):234-41

Department of Otorhinolaryngology, Hospital Clínic, Barcelona, University of Barcelona, Barcelona, Spain.

To study the augmentation of the paralyzed vocal fold in response to the injection of particulate plastics in a rabbit model, we performed a prospective, experimental, and controlled study in 45 New Zealand rabbits with surgical vocal fold paralysis. We compared a control group (acute unilateral recurrent nerve section) with a group that underwent polytetrafluoroethylene (PTFE) injection and with another group that underwent polydimethylsiloxane (PDMS) injection. Equal volumes of implant material were injected. The animals were killed either 6 weeks or 6 months after intervention and compared by histomorphology using a digital measuring system. The injection sites showed a substantial foreign body giant cell reaction against the PDMS and PTFE, surrounded by a light, fibrous stroma. No differences in the frequency of displacement or disaggregation of implants were observed. No extrusion to the laryngeal lumen, signs of migration outside the larynx, or malignant changes were seen. No differences were found in the length of the vocal fold between the PDMS group and the PTFE group. The vocal fold was thicker in the PDMS group than in the PTFE group, but a statistically significant difference was found only for the anterior and middle thirds at 6 weeks. In the PDMS sample, the thicknesses were similar in the 6-week and 6-month subgroups. The group with injection of PDMS yielded histologic images compatible with greater and more stable medialization than did the group with injection of PTFE.
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http://dx.doi.org/10.1177/000348940411300313DOI Listing
March 2004

Low p27 expression predicts biochemical relapse after radical prostatectomy in patients with clinically localised prostate cancer.

Anticancer Res 2003 Nov-Dec;23(6D):5101-6

Departments of Urology and Kidney Transplant, Hospital Clinic, Institut d'Investigacio Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Objective: To assess the prognostic value of p27 protein expression in clinically localised prostate cancer with respect to biochemical recurrence after radical prostatectomy.

Patients And Methods: Fifty-two patients (median age 63 years) with prostate cancer were treated by radical prostatectomy in an 18-month period. Data recorded: preoperative PSA level, histopathological Gleason grade, pathological stage and status of surgical margins. p27 expression was evaluated in this group of tumors by immunohistochemistry (positivity was defined as > or = 30% positive cells). Biochemical relapse (BR) was defined by a serum PSA level > or = 0.3 ng/ml.

Results: Twenty-two out of 47 patients (47%) with available follow-up showed a low p27 protein expression. p27 expression did not correlate with pathological stage, Gleason score, serum PSA levels or the status of the surgical margins. Patients presented with BR during the follow-up (risk of BR (RBR) at 36 months: 40%). Patients with low p27 expression showed a higher RBR than the others (RBR 36-month 59% vs. 18%, respectively; p = 0.02). In a multivariate analysis, only p27 along with stage maintained the predictive value for biochemical relapse.

Conclusion: p27 expression is a promising prognostic factor in prostate cancer, since it has proved to be a predictor of biochemical relapse.
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April 2004

Polydimethylsiloxane versus polytetrafluoroethylene for vocal fold medialization: histologic evaluation in a rabbit model.

J Biomed Mater Res B Appl Biomater 2003 Oct;67(1):666-74

Department of Otorhinolaryngology, Hospital Clínic of Barcelona, Spain.

The objective is to study the tissue reaction of the paralyzed vocal cord in response to the injection of particulate plastics in a rabbit model. Forty-five New Zealand rabbits with surgical vocal-fold paralysis were used in the study. Histologic reactions of the larynx and the regional lymph nodes were analyzed by a single blinded pathologist at 6 weeks and 6 months after a vocal-cord injection of Teflon or of silicone elastomer. Macroscopic studies of the liver, lungs, spleen, kidney, and brain were performed. The histological study showed a greater proportion of chronic granulomatous inflammation in animals injected with silicone than in those injected with Teflon. The immunohistochemical study showed a higher degree of phagocytosis of Teflon particles than of the silicone particles. The silicone group presented a more severe fibrous reaction than the Teflon group, but the difference was not significant. No migration particles were found. It is concluded that silicone, having a greater viscosity than Teflon because of the size of its particles, induces more fibrosis and a larger proportion of foreign giant cells in the host. Due to this histological reaction, silicone particles present greater anchorage and stability.
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http://dx.doi.org/10.1002/jbm.b.10061DOI Listing
October 2003

Autologous elastic cartilage for laryngoplasty: histologic evaluation in a rabbit model.

Ann Otol Rhinol Laryngol 2003 Aug;112(8):734-9

Department of Otorhinolaryngology, Hospital Clinic of Barcelona, Barcelona, Spain.

A wide range of materials have been used to achieve medialization of the paralyzed vocal fold. Recently, medialization techniques using autologous cartilage have been described, but little information is available on cartilage integration and viability in this situation. In this prospective, experimental, controlled study, right vocal fold paralysis was surgically induced in 30 New Zealand rabbits. An autologous auricular cartilage transplant was inserted in the vocal fold in 15 animals. In the control group, only the laryngeal nerve was sectioned. Each group was divided into two groups with follow-ups of 6 weeks and 6 months, respectively. Histologic studies revealed no inflammatory reaction against the cartilage transplants. There were no differences in the transplant surfaces in the 6-week and 6-month groups. The results show tissue integration and a low level of initial transplant resorption that stabilizes with time. Autologous auricular cartilage appears to be an appropriate material for type I thyroplasty procedures because of the low absorption rate.
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http://dx.doi.org/10.1177/000348940311200815DOI Listing
August 2003

PTOV-1, a novel protein overexpressed in prostate cancer, shuttles between the cytoplasm and the nucleus and promotes entry into the S phase of the cell division cycle.

Am J Pathol 2003 Mar;162(3):897-905

Unitat de Recerca Biomèdica, Hospital Vall d'Hebrón, Barcelona, Spain.

PTOV1 was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer. The PTOV1 protein consists of two novel protein domains arranged in tandem, without significant similarities to known protein motifs. By immunohistochemical analysis, we have found that PTOV1 is overexpressed in 71% of 38 prostate carcinomas and in 80% of samples with prostate intraepithelial neoplasia. High levels of PTOV1 in tumors correlated significantly with proliferative index, as assessed by Ki67 immunoreactivity, and associated with a nuclear localization of the protein, suggesting a functional relationship between PTOV1 overexpression, proliferative status, and nuclear localization. In quiescent cultured prostate tumor cells, PTOV1 localized to the cytoplasm, being excluded from nuclei. After serum stimulation, PTOV1 partially translocated to the nucleus at the beginning of the S phase. At the end of mitosis, PTOV1 exited the nucleus. Transient transfection of chimeric green fluorescent protein-PTOV1 forced the entry of cells into the S phase of the cell cycle, as shown by double fluorescent imaging for green fluorescent protein and for Ki67, and also by flow cytometry. This was accompanied by greatly increased levels of cyclin D1 protein in the transfected cells. These observations suggest that overexpression of PTOV1 can contribute to the proliferative status of prostate tumor cells and thus to their biological behavior.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868092PMC
http://dx.doi.org/10.1016/S0002-9440(10)63885-0DOI Listing
March 2003

Alterations of cell cycle-regulatory genes in prostate cancer.

Pathobiology 2002 ;70(1):1-10

Department of Anatomical Pathology, Hospital Clínic, University of Barcelona, Barcelona, Spain.

Deregulated proliferation is one of the main events in neoplastic transformation, and this has prompted increased attention being given to the understanding of the mechanisms involved in cell cycle regulation and its alterations. The 'retinoblastoma pathway', a key effector controlling G1-S phase transition, includes several oncogenes and tumour suppressor genes which display a wide range of abnormalities with potential usefulness as markers of evolution or treatment response in prostate cancer. Among these, the existence of p53 mutations seems to predict resistance to radiotherapy or systemic treatment, and p16 overexpression or p27 downregulation seems to serve as markers of poor evolution. The well-established existence of a critical hormonal role in prostate carcinogenesis coupled with the relationship of androgenic activity and regulation of several cell cycle modulators forces cell cycle control in the prostate to be envisioned as a highly complex steroid-influenced system, which will undoubtedly have critical implications in the future management of prostate cancer patients.
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http://dx.doi.org/10.1159/000065998DOI Listing
April 2003