J R Germà

Institut Català d'Oncologia, Barcino, Catalonia, Spain

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Publications (60)208.39 Total impact

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    ABSTRACT: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups.
    Annals of Oncology 09/2014; · 7.38 Impact Factor
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    ABSTRACT: BACKGROUND: The malignant potential of tumour cells may be influenced by the molecular nature of KRAS mutations being codon 13 mutations less aggressive than codon 12 ones. Their metabolic profile is also different, with an increased anaerobic glycolytic metabolism in cells harbouring codon 12 KRAS mutations compared with cells containing codon 13 mutations. We hypothesized that this distinct metabolic behaviour could be associated with different HIF-1alpha expression and a distinct angiogenic profile. METHODS: Codon13 KRAS mutation (ASP13) or codon12 KRAS mutation (CYS12) NIH3T3 transfectants were analyzed in vitro and in vivo. Expression of HIF-1alpha, and VEGF-A was studied at RNA and protein levels. Regulation of VEGF-A promoter activity was assessed by means of luciferase assays using different plasmid constructs. Vascular network was assessed in tumors growing after subcutaneous inoculation. Non parametric statistics were used for analysis of results. RESULTS: Our results show that in normoxic conditions ASP13 transfectants exhibited less HIF-1alpha protein levels and activity than CYS12. In contrast, codon 13 transfectants exhibited higher VEGF-A mRNA and protein levels and enhanced VEGF-A promoter activity. These differences were due to a differential activation of Sp1/AP2 transcription elements of the VEGF-A promoter associated with increased ERKs signalling in ASP13 transfectants. Subcutaneous CYS12 tumours expressed less VEGF-A and showed a higher microvessel density (MVD) than ASP13 tumours. In contrast, prominent vessels were only observed in the latter. CONCLUSION: Subtle changes in the molecular nature of KRAS oncogene activating mutations occurring in tumour cells have a major impact on the vascular strategy devised providing with new insights on the role of KRAS mutations on angiogenesis.
    BMC Cancer 03/2013; 13(1):125. · 3.33 Impact Factor
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    International Journal of Cancer 01/2013; 2013 Jan 7. doi: 10.1002/ijc.28009. [Epub ahead of print]. · 6.20 Impact Factor
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    ABSTRACT: In this work we have analyzed the expression of different members of the ErbB family in human samples of germ-cell testicular tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. In order to confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signalling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of GCT patients. © 2012 Wiley Periodicals, Inc.
    International Journal of Cancer 01/2013; · 6.20 Impact Factor
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    ABSTRACT: Aim:  Adjuvant 5-flourouracil based chemotherapy has demonstrated benefit in stage III colon cancer (CC) but still remains controversial in stage II. The aim of this study was to analyse the prognostic impact of clinico-pathological factors that may help guide treatment decisions in stage II CC. Method:  Between 1996 and 2006 data from patients diagnosed with colorectal cancer at Hospital Universitari Bellvitge (HUB) and its referral comprehensive cancer center, Institut Català d'Oncologia (ICO)/ L'Hospitalet, were prospectively included in a database. We identified 432 patients with stage II CC operated at HUB. 5-year relapse free survival (RFS) and colon cancer specific survival (CCSS) were determined. Results:  5-year RFS and CCSS were 83% and 88%, respectively. Lymphovascular or perineural invasion was associated with RFS (HR of 1.84; 95% CI, 1.01-3.35). Gender (women HR of 0.48; 95% CI, 0.23-1) and lymphovascular or perineural invasion (HR 3.51; 95% CI, 1.86-6.64), along with pT4 (HR 2.79; 95% CI, 1.44-5.41) influenced CCSS. In multivariate analysis pT4 and lymphovascular or perineural invasion remained significantly associated with CCSS. We performed a risk index with those factors with prognostic impact. Patients with pT4 tumours and lymphovascular or perineural invasion had a 5-year CCSS of 61%, versus the 93% (HR 5.87; 95 CI, 2.46-13.97) of those without any of these factors. Conclusion:  pT4 and lymphatic, venous, or perineural invasion are confirmed as significant prognostic factors in stage II CC and should be taken into account in the clinical validation process of new molecular prognostic factors. © 2012 The Authors Colorectal Disease © 2012 The Association of Coloproctology of Great Britain and Ireland.
    Colorectal Disease 09/2012; · 2.08 Impact Factor
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    Annals of Oncology 02/2010; 21(2):195-8. · 7.38 Impact Factor
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    ABSTRACT: : In recurrent ovarian cancer, CA-125 could be the only objective response criteria. This study analyzes response patterns regarding CA-125 in responders versus nonresponders and determines whether a specific cutoff value for CA-125 could predict clinical response, compared with response evaluation criteria in solid tumors, in patients receiving pegylated liposomal doxorubicin (PLD). : Sixty-eight patients were identified, 78% were platinum resistant. Relative changes in CA-125 values were calculated, and response was defined as higher than 50% reduction in CA-125 from baseline. Receiver operating characteristic (ROC) curves were constructed based on CA-125 value after the first cycle of PLD to evaluate the most precise cutoff point for the decision model predicting response. : Fifty-three patients were assessable for response: 16 patients responded and 37 did not; the median increase of CA-125 was 0.20 (-63; 312) and 52 (-29; 620), respectively. Our ROC curve generated a cutoff value with a sensitivity of 35% (positive test, the proportion of patients who will not respond) and a predictive positive value of 80%. According to the predictive positive value, 20% of the responder patients will be identified as nonresponders; P = 0.025. : Our ROC analysis did not demonstrate any reliable CA-125 cutoff on response. Discontinuation of the therapy before cycle 3 may exclude some patients who will benefit from PLD.
    International Journal of Gynecological Cancer 01/2010; 20(1):87-91. · 1.94 Impact Factor
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    ABSTRACT: Germ cell tumors (GCT) of the testis are highly curable, but those patients who are refractory to cisplatin (CDDP)-based combination chemotherapy have a poor prognosis. Therefore, identifying new alternatives for treatment remains a priority. Several studies support an important role for angiogenesis in GCTs, suggesting that antiangiogenic treatment might be a good alternative. Sunitinib is an oral multitarget tyrosine kinase receptor inhibitor with antiangiogenic and antitumor activities. In the present study, we evaluated the effect of sunitinib, CDDP, or the combination of both drugs using an orthotopic model of human testicular GCT. Mice were implanted with four different testicular tumors: a yolk sac, two choriocarcinomas, and a CDDP-resistant choriocarcinoma variant induced in mice by continuous exposure to CDDP. Mice were treated with vehicle, CDDP, sunitinib, or the combination of both drugs and their effects on tumors were analyzed. We observed a significant inhibition in tumor growth accompanied by longer survival after sunitinib treatment. Combination therapy with CDDP significantly enhanced these effects. Sunitinib induced apoptosis, reduced tumor cell proliferation and tumor vasculature, and inhibited vascular endothelial growth factor receptor 1, 2, and 3 and platelet-derived growth factor receptor alpha phosphorylation without affecting phosphorylation of other tyrosine kinase receptors. More importantly, tumor growth inhibition induced by sunitinib was also observed in the induced CDDP-resistant choriocarcinoma model. Taken together, these results suggest that sunitinib might be a new alternative for treatment of CDDP-refractory patients.
    Clinical Cancer Research 06/2009; 15(10):3384-95. · 7.84 Impact Factor
  • Journal of Management & Marketing in Healthcare. 04/2009; 2(2):174-183.
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    ABSTRACT: To provide an outpatient facility to improve the management of chemotherapy toxicity in cancer patients. We set up an oncology acute toxicity unit (OATU) to improve toxicity management. A telephone helpline was the initial contact which filters out inappropriate non-toxicity-related events. Patients were provided an information booklet describing the possible side effects of the chemotherapy and the helpline telephone number. A specialist nurse received the calls and consulted the doctor if necessary. Depending on requirements, the patient's problem was resolved by telephone, or a consultation visit at the OATU was arranged. Between February 1999 and August 2001, 1126 patients made 2007 contacts with the OATU. The most common tumours were breast (26%), colorectal (20%) and lung (20%). The telephone helpline was used in 87% of contacts and 37% were considered inappropriate. Of the 1263 appropriate contacts, the most frequent chemotherapy schedules that had been administered were 5FU-leucovorin (11.2%) and CMF (10.4%). The most frequent side effects were fever (35.5%), diarrhoea (18.5%), mucositis (16.2%) and emesis (13%). The problem was resolved by telephone in 48% of cases and 52% required attendance in the OATU, of which 40% required hospital admission, i.e., 21.1% of the initial appropriate helpline contacts. The most frequent reason was Grade 3-4 neutropenic fever (56.5%). The OATU enables prompt and efficient access of patients to medical oncology facilities in the event of toxicity due to chemotherapy. Unnecessary emergency room use is avoided while oncology outpatient and hospitalisation facilities are optimised.
    Clinical and Translational Oncology 12/2008; 9(12):784-8. · 1.28 Impact Factor
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    ABSTRACT: Gemcitabine shows a marked antitumor effect as a result of its cytotoxic action toward proliferative cells. In this article, we aim to investigate the potential antitumor and antiangiogenic effect of gemcitabine following a metronomic schedule that involves the regular administration of cytotoxic drugs at doses lower than standard treatment. In vitro results showed that human endothelial cells are more sensitive to gemcitabine (IC(50) 3 nmol/L) than pancreatic tumor cells (IC(50) 20 nmol/L). For in vivo studies, we used an orthotopic implantation model of human pancreatic carcinoma in nude mice. Gemcitabine was administered i.p. following a low-dose schedule (1 mg/kg/d for a month) and compared with the conventional schedule (100 mg/kg days 0, 3, 6, and 9 postimplantation). Metronomic treatment effect on established tumor was equivalent to standard administration. The measure of CD31 endothelial marked area allowed us to show an in vivo antiangiogenic effect of this drug that was further enhanced by using metronomic administration. This effect correlated with an induction of thrombospondin-1, a natural inhibitor of angiogenesis. Our results allow us to hypothesize that, in addition to a direct antiproliferative or cytotoxic antiendothelial cell effect, a secondary effect involving thrombospondin-1 induction might provide an explanation for the specificity of the effects of metronomic gemcitabine treatment.
    Molecular Cancer Therapeutics 04/2008; 7(3):638-47. · 5.60 Impact Factor
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    ABSTRACT: To assess the impact on the medicines budget of the introduction of new treatments in colorectal cancer, as monoclonal antibodies cetuximab and bevacizumab and oxaliplatin in the adjuvant setting, for the Catalan health public system in 2006. In advanced stages of the disease, the medicines budget impact of the introduction of cetuximab and bevacizumab in relation to the standard treatment (FOLFIRI and FOLFOX regimes) was evaluated. In adjuvant treatment stage II-III, the medicines budget impact of the utilization of FOLFOX regime compared to the combination of fluorouracil and folinic acid was evaluated. The medicines budget impact of the new therapies is evaluated at 27.9 million euros and 18.3 million euros in advanced stages of the disease and the adjuvant setting, respectively. In the adjuvant setting, the impact assessed depends on the number of new cases estimated. The impact on the health budget in Catalonia will be of great magnitude, and it could be higher considering these drugs are just only an example. Health policy should take this impact into account when future costs of health care are assessed in the public sector.
    Medicina Clínica 07/2007; 129(4):134-6. · 1.25 Impact Factor
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    ABSTRACT: The aim of this study was to analyze the prognostic value of TP53 mutations in a consecutive series of patients with hepatic metastases (HMs) from colorectal cancer undergoing surgical resection. Ninety-one patients with liver metastases from colorectal carcinoma were included. Mutational analysis of TP53, exons 4-10, was performed by single-strand conformation polymorphism and sequencing. P53 and P21 protein immunostaining was assessed. Multivariate Cox models were adjusted for gender, number of metastasis, resection margin, presence of TP53 mutations and chemotherapy treatment. Forty-six of 91 (50.05%) metastases showed mutations in TP53, observed mainly in exons 5-8, although 14.3% (n = 13) were located in exons 9 and 10. Forty percent (n = 22) were protein-truncating mutations. TP53 status associated with multiple (> or =3) metastases (65.6%, P = 0.033), advanced primary tumor Dukes' stage (P = 0.011) and younger age (<57 years old, P = 0.03). Presence of mutation associated with poor prognosis in univariate (P = 0.017) and multivariate Cox model [hazard ratio (HR) = 1.80, 95% confidence interval (CI) = 1.07-3.06, P = 0.028]. Prognostic value was maintained in patients undergoing radical resection (R0 series, n = 79, P = 0.014). Mutation associated with a worse outcome in chemotherapy-treated patients (HR = 2.54, 95% CI = 1.12-5.75, P = 0.026). The combination of > or =3 metastases and TP53 mutation identified a subset of patients with very poor prognosis (P = 0.009). P53 and P21 protein immunostaining did not show correlation with survival. TP53 mutational status seems to be an important prognostic factor in patients undergoing surgical resection of colorectal cancer HMs.
    Carcinogenesis 06/2007; 28(6):1241-6. · 5.64 Impact Factor
  • B Laquente, F Viñals, J R Germà
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    ABSTRACT: Conventional cytotoxic anticancer chemotherapeutic drugs were developed with the intent of treating cancer by direct killing or inhibition of growth of cycling tumour cells. Recently, however, there has been considerable interest in the notion of exploiting such drugs as angiogenesis inhibitors. The rationale is based on the fact that virtually all classes of cancer chemotherapeutic drugs are designed to damage DNA or disrupt microtubules of dividing cells, and endothelial cell division takes place during new blood vessel formation, including tumour angiogenesis. The results of recent experimental studies have suggested that frequent administration of certain cytotoxic agents at low doses, known as "metronomic chemotherapy", increases the putative antiangiogenic activity of certain drugs. Metronomic chemotherapy refers to the chronic administration of comparatively low doses of cytotoxic drugs at close, regular intervals, with no prolonged drug-free interruptions. The advantage of this strategy is lower toxicity and risk of emergence of drug-resistant tumour cells than conventional administration. This review describes the possible antiangiogenesis basis of this therapeutic strategy, the experimental studies published and the recent clinical studies that explore this less toxic schedule.
    Clinical and Translational Oncology 03/2007; 9(2):93-8. · 1.28 Impact Factor
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    ABSTRACT: Background and objective To assess the impact on the medicines budget of the introduction of new treatments in colorectal cancer, as monoclonal antibodies cetuximab and bevacizumab and oxaliplatin in the adjuvant setting, for the Catalan health public system in 2006. Method In advanced stages of the disease, the medicines budget impact of the introduction of cetuximab and bevacizumab in relation to the standard treatment (FOLFIRI and FOLFOX regimes) was evaluated. In adjuvant treatment stage II-III, the medicines budget impact of the utilization of FOLFOX regime compared to the combination of fluorouracil and folinic acid was evaluated. Results The medicines budget impact of the new therapies is evaluated at 27.9 million euros and 18.3 million euros in advanced stages of the disease and the adjuvant setting, respectively. In the adjuvant setting, the impact assessed depends on the number of new cases estimated. Conclusions The impact on the health budget in Catalonia will be of great magnitude, and it could be higher considering these drugs are just only an example. Health policy should take this impact into account when future costs of health care are assessed in the public sector.
    Medicina Clinica - MED CLIN. 01/2007; 129(4):134-136.
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    ABSTRACT: We previously described Ad-Delta24RGD as an enhanced-infectivity oncolytic adenovirus that targets tumors with an impaired RB pathway. The common alteration of this pathway in cancer eliminates the interaction of pRB with E2F and releases free E2F to activate E2F-responsive promoters, including the E2F-1 promoter. To improve the selectivity towards RB pathway-defective tumors and reduce the toxicity of Ad-Delta24RGD we aimed to control E1A-Delta24 expression under the E2F-1 promoter. A polyA signal was inserted upstream of the E2F-1 promoter to stop transcription initiated at the adenovirus ITR and packaging signal. The human myotonic dystropy locus insulator (DM-1) was also located between the E1a enhancers and the E2F-1 promoter to further insulate the promoter. The Ad-Delta24RGD derivative containing these insulation sequences expressed less E1a-Delta24 in normal cells and resulted less toxic while maintaining the potent oncolytic activity of the parental virus. These results demonstrate that the human DM-1 inslulator can function in an adenovirus context to maintain heterologous promoter selectivity. The new oncolytic adenovirus presented here may represent a valuable therapeutic option for a broad range of tumors with a deregulated E2F/pRB pathway.
    Cancer Gene Therapy 08/2006; 13(7):696-705. · 2.95 Impact Factor
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    ABSTRACT: The purpose of this study was to analyze the value of germline and tumor thymidylate synthase (TS) genotyping as a prognostic marker in a series of colorectal cancer patients receiving adjuvant fluorouracil (FU) -based treatment. One hundred twenty-nine colorectal cancer patients homogeneously treated with FU plus levamisole or leucovorin in the adjuvant setting were included. TS enhancer region, 3R G > C single nucleotide polymorphism (SNP), and TS 1494del6 polymorphisms were assessed in both fresh-frozen normal mucosa and tumor. Mutational analyses of TS and allelic imbalances were studied in all primary tumors and in 18 additional metachronic metastases. TS protein immunostaining was assessed in an expanded series of 214 tumors. Multivariate Cox models were adjusted for stage, differentiation, and location. Tumor genotyping (frequency of allelic loss, 26%) showed that the 3R/3R genotype was associated with a better outcome (hazard ratio [HR] = 0.38; 95% CI, 0.16 to 0.93; P = .020 for the recessive model). 3R G > C SNP genotyping did not add prognostic information. Tumor TS 1494del6 allele (frequency of allelic loss, 36%) was protective (for each allele with the deletion, based on an additive model, HR = 0.42; 95% CI, 0.22 to 0.82; P = .0034). Both polymorphisms were in strong linkage disequilibrium (D' = 0.71, P < .001), and the 3R/-6 base pair (bp) haplotype showed a significant overall survival benefit compared with the most prevalent haplotype 2R/+6bp (HR = 0.42; 95% CI, 0.20 to 0.85; P = .017). No TS point mutation was detected in primary tumors or metastases. TS protein immunostaining was not associated with survival or any of the genotypes analyzed. Tumor TS 1494del6 genotype may be a prognostic factor in FU-based adjuvant treatment of colorectal cancer patients.
    Journal of Clinical Oncology 05/2006; 24(10):1603-11. · 18.04 Impact Factor
  • Jorge Aparicio, J R Germà
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    ABSTRACT: More than a half of patients with testicular cancer are diagnosed with clinical stage I disease. In this setting, definitive cure is the rule. However, there is no consensus on the optimal treatment choice. A literature review (1990-2005) was performed in order to identify the pros and the cons associated with each therapy, as well as their long-term outcomes. Several treatment alternatives yield similar efficacy results. Thus, therapy-related morbidity, economic costs, quality-of-life issues, and patient preferences should be considered. Refinement in the knowledge of predictive factors for relapse and amounting experience with both surveillance and adjuvant chemotherapy have led to consideration of risk-adapted treatment policies as an alternative to more traditional approaches (i.e., prophylactic irradiation for seminomas and retroperitoneal lymph node dissection for non-seminomas). In conclusion, with cure rates approaching 100%, close surveillance for low-risk patients and adjuvant chemotherapy for those at high risk of relapse seems the preferred option for clinical stage I testicular cancer, in both seminoma and non-seminoma cases.
    Medical Oncology 02/2006; 23(3):305-15. · 2.14 Impact Factor
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    ABSTRACT: The incidence of familial adenomatous polyposis (FAP) is approximately 7.4 per 100,000 inhabitants. APC gene mutations have been found in 60-70% of all FAP families, codons 1309 (20%) and 1061 (8%) being known hot-spots. We searched for mutations in the APC gene in a population-based registry of FAP from the Spanish Balearic Islands. Fifty-one members of 12 FAP families registered in the Balearic Islands Cancer Registry were studied; three of them were de novo cases. Mutations in the APC gene were analyzed by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing. Haplotype was established by combining intra- and extragenic markers. Mutations in the APC gene were detected in 10 out of 12 (83%) families analyzed. Six families shared the same mutation, a 5-bp deletion at codon 1061 (c.3221_3225delACAAA). Five of the families containing this mutation shared the same haplotype and originated in the same geographic area. The codon 1061 mutation in the APC gene is the most common one in the Balearic Islands. Although this codon is a hot-spot, the haplotype analysis of these families is consistent for the presence of a founder effect of the 5-bp deletion at codon 1061 in FAP families in the Spanish Balearic Islands.
    Cancer Genetics and Cytogenetics 05/2005; 158(1):70-4. · 1.93 Impact Factor
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    ABSTRACT: The purpose of the current study was to evaluate the expression levels of p53, p21 and pRB as predictors of for long-term organ preservation and survival in patients with bladder carcinoma who were treated with bladder-sparing intent using a combined-modality approach. Tumor samples from 82 consecutive patients with localized invasive bladder carcinoma treated on 3 different bladder-sparing studies were examined for p53, p21, and pRB expression by immunohistochemical methods. Treatment consisted of transurethral resection, platinum-based neoadjuvant chemotherapy, and, according to response, either radiotherapy or radical cystectomy. The median follow-up duration was 55 months. Positive immunoreactivity for p53, p21, and pRB was observed in 47%, 52%, and 67% of patients, respectively. Positive p53 immunoreactivity and positive p21 immunoreactivity were independent predictors of decreased survival with bladder preservation (P = 0.02 and P = 0.02, respectively) and disease-free survival (DFS; P = 0.005 and P = 0.009, respectively) in a multivariate analysis adjusting for clinical stage, ureteral obstruction, and age. Regarding overall survival (OS), p53 overexpression was associated with poor outcome (P = 0.03), whereas the association of poor outcome with p21 expression did not reach statistical significance (P = 0.07). No association between pRB immunoreactivity and outcome was found. When the combined expression of p53 and p21 was assessed, the positive expression of both markers was a strong and unfavorable prognostic factor for survival with bladder preservation (P = 0.006), DFS (P = 0.003), and OS (P = 0.02). Expression levels of p53 and p21, especially when simultaneously assessed, exhibit independent predictive value for long-term bladder preservation and survival in patients with bladder carcinoma treated with combined-modality therapy. These determinations could be useful in the selection of candidates for bladder-preserving treatment.
    Cancer 06/2004; 100(9):1859-67. · 5.20 Impact Factor

Publication Stats

772 Citations
208.39 Total Impact Points

Institutions

  • 2000–2014
    • Institut Català d'Oncologia
      Barcino, Catalonia, Spain
  • 2013
    • IDIBELL Bellvitge Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2003–2006
    • Hospital Universitari i Politècnic la Fe
      • Department of Medical Oncology
      Valenza, Valencia, Spain
  • 2001
    • Catalan Institute of Oncology
      Badalona, Catalonia, Spain
  • 1990
    • Universidad Autónoma de Madrid
      Madrid, Madrid, Spain