J Feliu

Hospital Universitario La Paz, Madrid, Madrid, Spain

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Publications (174)563.94 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Altered glycosylation is considered a universal cancer hallmark. Mucin-type core 2 1,6-N-acetylglucosaminyltransferase enzyme (C2GnT-M), encoded by the GCNT3 gene, has been reported to be altered in tumours and to possess tumour suppressor properties. In this work, we aimed to determine the possible role of GCNT3 gene expression as prognostic marker in colon cancer. We investigated the differential expression of GCNT3 gene among tumour samples from stage II colon cancer patients by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Univariate and Multivariate Cox regression analyses were used to determine the correlation between GCNT3 expression and disease-free survival. The risk of relapse in GCNT3 low-expressing cancer patients was significantly higher than that in GCNT3 high-expressing patients in both training (Hazard Ratio (HR) 4.26, p=0.002) and validation (HR 3.06, p=0.024) series of patients, and this association was independent of clinical factors. Additionally, qRT-PCR was used to explore the modulation of GCNT3 expression by different antitumour drugs. Three chemotherapeutic agents with different mechanism of action (5-fluorouracil, bortezomib and paclitaxel) significantly induced GCNT3 expression in several cancer cells, being observed the correlation between antitumour action and GCNT3 modulation, whereas this gene was not modulated in cells that do not respond to treatment. Overall, these results indicate that low GCNT3 expression is a promising prognostic biomarker for colon cancer that could be used to identify early-stage colon cancer patients at high risk of relapse. Additionally, our results suggest that this enzyme might also constitute a biomarker to monitor tumour response to chemotherapy in cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 11/2014; · 4.12 Impact Factor
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    ABSTRACT: Treatment of metastatic colorectal cancer (mCRC) is generally based on genetic testing performed in primary tumor biopsies, but whether the genomic status of primary tumors is identical to that of metastases is not well known. We compared the gene expression profiles of formalin-fixed paraffin-embedded (FFPE) biopsies of colorectal primary tumors and matched liver metastases.
    10/2014;
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    ABSTRACT: Colorectal cancer is one of the most common tumors worldwide and at least 50 % of patients with this disease develop metastases. In this setting, additional treatment options are needed for patients presenting disease progression after exhausting all standard therapies. Regorafenib is an orally administered multikinase inhibitor which has been shown to provide survival benefits to patients with metastatic colorectal cancer (mCRC). Although most adverse events (AEs) associated with regorafenib may resolve within the first 8 weeks of treatment, some of them may require dose reduction or treatment interruption. Overall, while remaining aware of the safety profile of regorafenib and how to manage the most common toxicities related to its use, this drug should be considered a new standard of care for patients with pretreated mCRC. This review addresses practical aspects of its use, such as dosing, patient monitoring, and management of the most common regorafenib-related AEs.
    09/2014;
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    ABSTRACT: Author Summary BACKGROUND: The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma.
    The Oncologist 09/2014; · 4.10 Impact Factor
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    ABSTRACT: Colorectal liver metastases (CLM) have significant molecular heterogeneity, which contributes to the risk of recurrence following surgery. Most of the traditional scores intended to predict recurrence is based on clinicopathological variables and it is unclear whether incorporating molecular biomarkers might improve our assessment of the risk of recurrence. Our aim was to determine if molecular biomarkers might be associated with the risk of recurrence after surgery of CLM.
    07/2014;
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    ABSTRACT: Identifying molecular markers for tumour recurrence is critical in successfully selecting colon cancer (CC) patients who are more likely to benefit from adjuvant chemotherapy (CT). We investigated the effect of single nucleotide polymorphisms (SNPs) within genes involved in oxaliplatin and fluoropyrimidines metabolism, DNA repair mechanisms, drug transport or angiogenesis pathways on outcome for patients with stage II-III CC treated with adjuvant CT. Genomic DNA was extracted from formalin-fixed-paraffin-embedded samples of 202 stage II-III CC patients receiving oxaliplatin-based adjuvant CT from January-2004 to December-2009. Genotyping was performed for 67 SNPs in 32 genes using the MassARRAY (SEQUENOM) technology. Our results were validated in an independent cohort of 177 patients treated with the same CT regimens. The combination of the selectin E (SELE) rs3917412 G>A G/G and the methylentetrahydrofolate reductase (MTHFR) rs1801133 T/T genotypes was associated with a significantly increased risk for recurrence in both the training (RR= 4.103; 95% CI, 1.803-9.334; p=0.001) and the validation cohorts (RR= 3.567; 95% CI, 1.253-10.151; p=0.017) in the multiple regression analysis considering the stage, lymphovascular invasion and bowel perforation as covariates. The combined analysis of these polymorphisms was also significantly associated with overall survival (OS) in both cohorts (RR= 3.388; 95% CI, 0.988-11.623; p=0.052 and RR= 3.929; 95% CI, 1.144-13.485; p=0.020, respectively). Our findings suggest that the SELE rs3917412 and MTHFR rs1801133 SNPs could serve as pharmacogenetic predictors of tumour recurrence in early-stage CC patients treated with oxaliplatin-based adjuvant CT, thus allowing personalized selection of treatment to optimize clinical outcomes.
    Molecular Cancer Therapeutics 06/2014; · 5.60 Impact Factor
  • Angela Lamarca, Jaime Feliu
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is known for its poor prognosis. Most of the patients are diagnosed with advanced stages, when no curative treatment is available. Currently, despite extensive clinical research on PDA, the median overall survival remains short. Diagnosis delay and primary chemo-resistance due to its intrinsic biological nature may explain the challenges to improve our results. Our knowledge about the molecular biology of PDA has exponentially increased during the last decades and its use for the development of biomarkers could help to reach better results in the clinical setting. These biomarkers could be the clue for the improvement in PDA clinical research by earlier detection strategies with diagnostic biomarkers, and by an individualization of treatment approach with prognostic and predictive biomarkers. This review summarizes the current knowledge about the molecular biology of PDA and the status of the most important prognostic and predictive biomarkers.
    World Journal of Gastroenterology 06/2014; 20(24):7819-7829. · 2.55 Impact Factor
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    ABSTRACT: Background:Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC.Methods:Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP).Results:The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%).Conclusions:Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.British Journal of Cancer advance online publication, 19 June 2014; doi:10.1038/bjc.2014.346 www.bjcancer.com.
    British journal of cancer. 06/2014;
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    ABSTRACT: Studies have recently suggested that metabolic syndrome and its components increase the risk of colorectal cancer. Both diseases are increasing in most countries, and the genetic association between them has not been fully elucidated. The objective of this study was to assess the association between genetic risk factors of metabolic syndrome or related conditions (obesity, hyperlipidaemia, diabetes mellitus type 2) and clinical outcome in stage II colorectal cancer patients. Expression levels of several genes related to metabolic syndrome and associated alterations were analysed by real-time qPCR in two equivalent but independent sets of stage II colorectal cancer patients. Using logistic regression models and cross-validation analysis with all tumour samples, we developed a metabolic syndrome-related gene expression profile to predict clinical outcome in stage II colorectal cancer patients. The results showed that a gene expression profile constituted by genes previously related to metabolic syndrome was significantly associated with clinical outcome of stage II colorectal cancer patients. This metabolic profile was able to identify patients with a low risk and high risk of relapse. Its predictive value was validated using an independent set of stage II colorectal cancer patients. The identification of a set of genes related to metabolic syndrome that predict survival in intermediate-stage colorectal cancer patients allows delineation of a high-risk group that may benefit from adjuvant therapy and avoid the toxic and unnecessary chemotherapy in patients classified as low risk. Our results also confirm the linkage between metabolic disorder and colorectal cancer and suggest the potential for cancer prevention and/or treatment by targeting these genes.
    Molecular oncology. 06/2014;
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    ABSTRACT: Chemotherapy can induce cognitive impairment in cancer patients. The main goal of this longitudinal study was to determine the incidence, characteristics, and duration of cognitive dysfunction in patients treated with adjuvant chemotherapy for colon cancer. We assessed cognitive function, quality of life, anxiety and depression, fatigue, and hemoglobin levels in colon cancer patients at three assessment points: pre-chemotherapy (n = 81), post-chemotherapy (n = 73), and after 6-month follow-up (n = 54). All patients were treated with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) for 6 months. Thirty patients (37 %) had cognitive impairment in the pre-chemotherapy evaluation, mainly in processing speed and psychomotor executive function (Trail Making Test A and B). At the end of treatment, the main domain affected was the verbal memory, with an acute decline detected in 56 % of patients. Fifty-four percent of the patients improved their dysfunction after 6 months of follow-up, whereas 18 (33 %) of them showed worsening in at least one test. Cognitive impairment was most common in older patients and in those with less years of education. Quality of life, anxiety, depression, fatigue, and hemoglobin did not influence the results of the cognitive tests. Adjuvant FOLFOX4 in patients with colon cancer can have a negative effect on verbal memory. This deterioration is usually mild and transient.
    Supportive Care in Cancer 02/2014; · 2.09 Impact Factor
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    ABSTRACT: Sorafenib, an oral inhibitor of B-raf, VEGFR2, and PDGFR2-beta, acts against pancreatic cancer in preclinical models. Due to the radio-sensitization activity of both sorafenib and gemcitabine, we designed a multicenter, phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy. Patients with biopsy-proven, unresectable pancreatic adenocarcinoma (based on vascular invasion detected by computed tomography) were treated with gemcitabine (300 mg/m2 i.v. weekly ×5 weeks) concurrently with radiation therapy (45 Gy in 25 fractions) and sorafenib (escalated doses in a 3+3 design, from 200 to 800 mg/day). Radiation portals included the primary tumor but not the regional lymph nodes. Patients with planning target volumes (PTV) over 500 cc were excluded. Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression. Twelve patients were included. Three patients received 200 mg/day, 6 received 400 mg/day, and 3 received 800 mg/day; PTVs ranged from 105 to 500 cc. No dose-limiting toxicities occurred. The most common grade 2 toxicities were fatigue, neutropenia, nausea, and raised serum transaminases. Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy. There were no treatment-related deaths. The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma. A dose of 800 mg/day is recommended for phase II evaluation. EudraCT 2007-003211-31 ClinicalTrials.gov 00789763.
    PLoS ONE 01/2014; 9(1):e82209. · 3.53 Impact Factor
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    ABSTRACT: Oxaliplatin-based chemotherapy (CT), widely used as adjuvant therapy for stage III and selected high-risk stage II colon cancer (CC) patients, is often associated with cumulative peripheral neuropathy. Our aim is to identify single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, DNA repair mechanisms, cell cycle control, detoxification or excretion pathways to predict severe (grade 2-3) oxaliplatin-induced peripheral neuropathy (OXPN) among CC patients treated with oxaliplatin and fluoropyrimidine-based adjuvant CT. Genomic DNA was extracted from formalin-fixed-paraffin-embedded peritumoral samples from 206 high-risk stage II and stage III CC patients receiving oxaliplatin-based adjuvant CT from January 2004 to December 2009. Genotyping was carried out for 34 SNPs in 15 genes using MassARRAY (SEQUENOM) technology. A total of 181 stage II-III CC patients treated with the same CT regimens were enrolled as a validation set. The rs2230641 cyclin H (CCNH) rs2230641 C/C [odd ratio (OR) = 5.03, 95% confidence interval (CI) 1.061-2.41, P = 0.042] and the ATP-binding cassette subfamily G, member 2 (ABCG2) rs3114018 A/A genotypes (OR = 2.67; 95% CI 0.95-4.41; P = 0.059) were associated with a higher risk of severe OXPN. In addition, patients harboring the combination of CCNH C/C and/or the ABCG2 rs3114018 A/A genotypes had a higher risk of grade 2-3 OXPN than those with the CCNH any T and ABCG2 any C genotypes (37.73% versus 19.42%; OR = 2.46; 95% CI 1.19-5.07; P = 0.014) in the logistic regression analysis using age, gender, adjuvant CT regimen and cumulative dose of oxaliplatin as covariates. The ability to predict severe OXPN of this combined analysis was independently validated in the second cohort (58% versus 33.33%; OR = 2.99; 95% CI 1.45-6.13; P = 0.002). Our results suggest that SNPs in CCNH and ABCG2 can modulate the development of severe OXPN among stage II-III CC patients who received oxaliplatin-based CT, thus enabling the individualization of adjuvant treatment.
    Annals of Oncology 12/2013; · 7.38 Impact Factor
  • Cancer 11/2013; · 5.20 Impact Factor
  • Raquel Molina, Jaime Feliu
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    ABSTRACT: Because of improvements in diagnosis and treatment, cancer survival has increased in recent decades. Cancer survivors may experience problems when returning to their normal lives, particularly with returning to work. In the past few decades, a number of studies examining the work-return process of cancer survivors have been conducted in a select group of countries, but comparable studies are lacking in other countries, including Spain. To review the research literature on cancer and work in Spain and the design and methodology of the interventions studied. A systematic literature review was performed on return to work and employment in Spanish cancer survivors with the databases PubMed, Medline and Spanish database IME.RESULTS: Eight studies were reviewed and analyzed. The studies had a mean sample size of 115 participants. Two of the studies predominantly focused on mixed cancer populations; 3 of the studies focused on breast cancer patients, 1 study focused on head and neck cancer patients, 1 study focused on colorectal cancer patients and 1 study focused on patients with lymphoma. Further research in Spain and other countries is necessary, and efforts should be made to support the re-employment of cancer patients.
    Work 09/2013; · 0.52 Impact Factor
  • Colorectal Cancer. 08/2013; 2(4):279-283.
  • Medicina Clínica. 07/2013; 114(13):506–510.
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    J Feliu, E Espinosa
    Clinical and Translational Oncology 06/2013; · 1.28 Impact Factor
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    ABSTRACT: OBJECTIVE: Hypomethylation of LINE-1 elements has emerged as a distinguishing feature in human cancers. Limited evidence indicates that some LINE-1 elements encode an additional internal antisense promoter, and increased hypomethylation of this region may lead to inadvertent activation of evolutionarily methylation-silenced downstream genes. However, the significance of this fundamental epigenetic mechanism in colorectal cancer (CRC) has not been investigated previously. DESIGN: We analysed tissue specimens from 77 CRC patients with matched sets of normal colonic mucosa, primary CRC tissues (PC), and liver metastasis tissues (LM). LINE-1 methylation levels were determined by quantitative bisulfite pyrosequencing. MET, RAB3IP and CHRM3 protein expression was determined by western blotting and IHC. MET proto-oncogene transcription and 5-hydroxymethylcytosine (5-hmc) were evaluated by quantitative real-time-PCR. RESULTS: Global LINE-1 methylation levels in LM were significantly lower compared with the matched PC (PC=66.2% vs LM=63.8%; p<0.001). More importantly, we observed that specific LINE-1 sequences residing within the intronic regions of multiple proto-oncogenes, MET (p<0.001), RAB3IP (p=0.05) and CHRM3 (p=0.01), were significantly hypomethylated in LM tissues compared with corresponding matched PC. Furthermore, reduced methylation of specific LINE-1 elements within the MET gene inversely correlated with induction of MET expression in CRC metastases (R=-0.44; p<0.0001). Finally, increased 5-hmc content was associated with LINE-1 hypomethylation. CONCLUSIONS: Our results provide novel evidence that hypomethylation of specific LINE-1 elements permits inadvertent activation of methylation-silenced MET, RAB3IP and CHRM3 proto-oncogenes in CRC metastasis. Moreover, since 5-hmc content inversely correlated with LINE-1 hypomethylation in neoplastic tissues, our results provide important mechanistic insights into the fundamental processes underlying global DNA hypomethylation in human CRC.
    Gut 05/2013; · 10.73 Impact Factor
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    ABSTRACT: Angiogenesis is a universal requirement for the growth of solid tumours beyond the limits of oxygen diffusion from the existing vasculature. The expression and function of proangiogenic and antiangiogenic factors are altered in solid malignancies to drive net neoangiogenesis. Vascular endothelial growth factor (VEGF) has been confirmed in several clinical trials as an important therapeutic target in colorectal cancer (CRC) treatment. However, given that the efficacy of antiangiogenic agents appears to be limited to a subset of patients, the identification of who will obtain the greater benefit from this therapy or suffer from specific toxicities and when or for how long they should be administered in the treatment algorithm are major open questions for clinicians and challenges for present and future research. Current evidence indicates some predictive value for particular circulating measures, such as an increase in VEGF, a decrease in vascular endothelial growth factor receptor 2 (VEGFR-2) or circulating endothelial cells, tissue biomarkers, microvessel density, KRAS and BRAF gene mutations or polymorphisms affecting components of the VEGF pathway. Many questions relating to these and other surrogate biomarkers, however, remain unanswered and their clinical usefulness has yet to be proven. This review will focus on the present status of knowledge and future perspectives for developing molecular tools to foresee and monitor antiangiogenic therapy activity in CRC patients.
    Cancer Treatment Reviews 03/2013; · 6.02 Impact Factor
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    ABSTRACT: Tumors of the biliary tract (gallbladder tumors, cholangiocarcinomas and ampullary carcinomas) are low incidence tumors with poor prognosis. The five-year overall survival is 50% for stage I, 30% stage II, 10% stage III and 0% stage IV. Treatment is based on surgery for potentially resectable tumors. Chemotherapy and chemo-radiotherapy is the treatment of choice when surgery is not amenable, however it has not achieved encouraging results. These patients use to have very few symptoms, which is the reason for the delay in diagnosis and the poor prognosis. They frequently develop biliary obstruction: obstructive jaundice, right upper quadrant pain and weight loss. Ampullary carcinomas are frequently related to steatorrhea due to malabsorption. The most effective chemotherapy drugs used in monotherapy are 5FU (response rate 20%) and gemcitabine (response rate of 13%–60%), so they have been selected for further development in multiple phase II clinical trials to explore their efficacy and safety in combination with other agents. In a phase III clinical trial, combination of gemcitabine and cisplatin has been selected as the schedule of choice. Target therapies are also being developed in this malignancy. The present work reviews the most current knowledge of the pathogenesis, diagnosis and natural history of biliary tract tumors. Further, review of surgery, current adjuvant treatment and therapies for unresectable and advanced disease is provided. The most recent understanding for target therapies and molecular biology is also summarized.
    The Chinese-German Journal of Clinical Oncology 02/2013; 12(2).

Publication Stats

1k Citations
563.94 Total Impact Points

Institutions

  • 1987–2014
    • Hospital Universitario La Paz
      • Servicio de Oncología
      Madrid, Madrid, Spain
  • 2009–2013
    • University of Alcalá
      • Faculty of Medicine and Health Sciences
      Cómpluto, Madrid, Spain
  • 2012
    • Instituto Valenciano de Oncologia
      Valenza, Valencia, Spain
    • Complutense University of Madrid
      • Facultad de Psicología
      Madrid, Madrid, Spain
  • 2011
    • Hospital Universitario Infanta Sofía
      Madrid, Madrid, Spain
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2008–2011
    • Hospital Universitario de Getafe
      Madrid, Madrid, Spain
    • MD Anderson Cancer Center Madrid
      Madrid, Madrid, Spain
  • 1988–2007
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain
  • 2005
    • Sociedad Española de Oncología Médica
      Madrid, Madrid, Spain