Publications (48)295.93 Total impact
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Article: Soluble FAS in the prediction of benefit from cetuximab and irinotecan for patients with advanced colorectal cancer.
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ABSTRACT: The FAS/FASL system, comprising membrane-bound (mFAS and mFASL) and soluble forms (sFAS and sFASL), has been related to apoptosis driven by chemotherapy administration. In vitro experiments show chemotherapy upregulating membrane-bound forms, leading to an increase of receptor availability (at 24-72 h) and favoring apoptosis. The regulatory effect of chemotherapy on sFAS in patients has never been explored prospectively in advanced colorectal cancer (ACRC). We performed a pharmacodynamic study to address sFAS/sFASL variation. A prospective phase II translational multicenter study was designed to evaluate progression-free rate (PFR) in patients with ACRC treated with irinotecan and cetuximab in third-line therapy. The effect of sFAS was studied in vitro in colorectal cancer cell lines. Our results showed that statistically significant changes were observed in sFAS at 24-72 h compared to baseline levels in the pharmacodynamic study. Of the 93 patients enrolled in the prospective study in third-line therapy with cetuximab-irinotecan, 85 were evaluated for sFAS/sFASL changes at 48 h. There was no difference in PFR at 4 months between patients with sFAS and sFASL changes. In vitro analysis showed that although LoVo cell lines were sensitive to oxaliplatin and fluorouracil due to modulation of sFAS and FAS, HT29 lines were not. In summary, chemotherapy regulates FAS soluble fractions in vitro and in vivo, but does not predict PFR in ACRC patients undergoing third-line therapy with the combination of cetuximab and irinotecan.Medical Oncology 03/2013; 30(1):428. · 2.14 Impact Factor -
Article: Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5'fluoruracil-based adjuvant chemotherapy.
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ABSTRACT: Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high-risk patients. This study was aimed to identify a gene-expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5'fluoruracil (5FU)-based adjuvant chemotherapy. Two-hundred and twenty-eight patients diagnosed with Stages II-III colon cancer and treated with surgical resection and 5FU-based adjuvant chemotherapy were included. RNA was extracted from formalin-fixed, paraffin-embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT-qPCR. A tumor recurrence predicting model, including clinico-pathological variables and gene-expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71-4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12-6.42; p = 0.03). Identification of a new gene-expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU-based chemotherapy, and its combination in a robust, easy-to-use and reliable algorithm may contribute to tailor treatment and surveillance strategies.International Journal of Cancer 07/2012; · 5.44 Impact Factor -
Article: A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer.
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ABSTRACT: The aim of this study was to compare TOMOX versus FOLFOX4 as first-line treatment of advanced colorectal cancer (CRC). 191 chemotherapy-naïve patients were randomized to receive TOMOX or FOLFOX4. Patients were evaluated every 3 months and chemotherapy was continued until disease progression or unacceptable toxicity. Overall response rate was the primary endpoint. 183 patients were included in the intent-to-treat analysis (92 TOMOX and 91 FOLFOX4). Overall response rate was 45.6 and 36.3 % (p = 0.003) for TOMOX and FOLFOX4, respectively. No statistically significant differences were observed in overall survival (15.6 and 17.2 months; p = 0.475); progression-free survival (7.7 and 8.7 months; p = 0.292), and response duration (6.4 and 7.6 months; p = 0.372) for TOMOX and FOLFOX4, respectively. Grades 3 and 4 neutropenia (p < 0.0001) and leukopenia (p = 0.028) were more common with the FOLFOX4 regimen, while hepatic disorders and asthenia were higher in TOMOX group (p = ns). There were two treatment-related deaths in the FOLFOX4 arm and one in the TOMOX arm. Quality of life analysis based on the SF-36 revealed differences between the two regimens for physical and mental composite scores after 6 weeks, and for body pain and emotional role functioning after 6 and 12 weeks; all of these favored the FOLFOX4 arm (p ≤ 0.05). TOMOX and FOLFOX4 seem to have similar efficacy and are well tolerated in the first-line treatment for advanced CRC with different profiles of toxicity. The convenient TOMOX regimen may offer an alternative to fluoropyrimidine-based regimens.Clinical and Translational Oncology 07/2012; 14(8):606-12. · 1.33 Impact Factor -
Article: Cisplatin plus weekly CPT-11/docetaxel in advanced esophagogastric cancer: a phase I study with pharmacogenetic assessment of XPD, XRCC3 and UGT1A1 polymorphisms
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ABSTRACT: PurposeA multicenter phase I trial to establish the recommended dose of CPT-11/docetaxel plus cisplatin in advanced esophagogastric cancer patients and to correlate the efficacy and toxicity with genetic polymorphisms in DNA repair genes (XPD and XRCC3) and the UGT1A1 gene. MethodsFour dose levels with a fixed dose of cisplatin (60mg/m2), day 1, and dose-escalation of CPT-11 (50–70mg/m2) and docetaxel (25–30mg/m2), days 1 and 8, every 3weeks were planned. Polymorphisms of XPD (Asp312Asn and Lys751Gln), XRCC3 (Thr241Met) and UGT1A1*28 were examined in baseline peripheral blood. ResultsTwenty-eight patients were included at three different dose levels. Dose-limiting toxicities were febrile neutropenia and diarrhea; the recommended dose was established at CPT-11 60mg/m2 and docetaxel 25mg/m2 plus cisplatin 60mg/m2. Objective response was observed in 13 patients (50%). Median time to progression was 6.6months, and median survival was 11.3months. Median time to progression was 9.7months for patients harboring the XRCC3 Met241Met genotype versus 8.4months for patients with Thr241Met and 3.1months for those with Thr241Thr (P=.04). ConclusionsCPT-11/docetaxel plus cisplatin is active in patients with advanced esophagogastric cancer. XRCC3 Met241Thr polymorphisms could be a useful marker to predict prognosis in patients treated with a cisplatin-based chemotherapy. However, these results are required to be confirmed with a great number of patients.Cancer Chemotherapy and Pharmacology 04/2012; 62(6):1075-1083. · 2.83 Impact Factor -
Article: Upregulation of Trefoil Factor 3 (TFF3) After Rectal Cancer Chemoradiotherapy Is an Adverse Prognostic Factor and a Potential Therapeutic Target.
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ABSTRACT: PURPOSE: Management of locally advanced rectal cancer (RC) consists of neoadjuvant chemoradiotherapy (CRT) with fluoropyrimidines, followed by total mesorectal excision. We sought to evaluate the expression of selected genes, some of which were derived from a previous undirected SAGE (serial analysis of gene expression)-based approach, before and after CRT, to identify mechanisms of resistance. METHODS: This retrospective cohort study included 129 consecutive patients. Quantitative polymerase chain reaction of 53 candidate genes was performed on the biopsy specimen before treatment and on the surgical specimen after CRT. A paired-samples t test was performed to determine genes that were significantly changed after CRT. The result was correlated with patients' disease-free survival. RESULTS: Twenty-two genes were significantly upregulated, and two were significantly downregulated. Several of the upregulated genes have roles in cell cycle control; these include CCNB1IP1, RCC1, EEF2, CDKN1, TFF3, and BCL2. The upregulation of TFF3 was associated with worse disease-free survival on multivariate analyses (hazard ratio, 2.64; P=.027). Patients whose surgical specimens immunohistochemically showed secretion of TFF3 into the lumen of the tumoral microglands had a higher risk of relapse (hazard ratio, 2.51; P=.014). In vitro experiments showed that DLD-1 cells stably transfected with TFF3 were significantly less sensitive to 5-fluorouracil and showed upregulation of genes involved in the transcriptional machinery and in resistance to apoptosis. CONCLUSION: Upregulation of TFF3 after CRT for RC is associated with a higher risk of relapse. The physiological role of TFF3 in restoring the mucosa during CRT could be interfering with treatment efficacy. Our results could reveal not only a novel RC prognostic marker but also a therapeutic target.International journal of radiation oncology, biology, physics 04/2012; · 4.59 Impact Factor -
Article: EUS and magnetic resonance imaging in the staging of rectal cancer: a prospective and comparative study.
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ABSTRACT: Accurate locoregional staging is crucial in rectal cancer for deciding patient management because the administration of neoadjuvant therapy depends on it. EUS and magnetic resonance imaging (MRI) are used indistinctly in the pretherapeutic workup of rectal cancer. To prospectively compare the performance of EUS and MRI in the locoregional staging of rectal cancer in a large series of patients. Prospective and comparative study. Tertiary center. Patients with histologically proven rectal cancer. EUS and MRI were performed in all patients by a different operator unaware of the results of the other procedure. Epidemiological, clinical, radiological, and echographic variables were evaluated. Pathological examination of the surgical specimen was used as the criterion standard. Ninety patients (54 men and 36 women with a mean age of 68 ± 12 years; range 33-87 years) constitute the final sample of this study. Most of the tumors were stages T2-T3 (85%; 95% CI, 77%-92%). Twenty of them (22%; 95% CI, 14%-32%) were stenotic and 24 (27%; 95% CI, 18%-37%) had polypoid morphology. The accuracy of T staging was very similar for EUS and MRI for stage T2 (76%; 95% CI, 65%-84% and 77%; 95% CI, 67%-85%, respectively; P = not significant) and stage T3 (76%; 95% CI, 65%-84% and 83%, 95% CI, 73%-90%, respectively; P = not significant). MRI was not able to visualize any T1 tumor, whereas EUS understaged all T4 tumors. The univariate analysis showed that the polypoid morphology of the tumor inversely correlated with T staging on MRI. The accuracy of MRI for N staging was higher than that of EUS, although the difference did not reach statistical significance (79%; 95% CI, 65%-88% and 65%; 95% CI, 51%-78%, respectively). When performing the univariate analysis to assess the reasons for this difference, the presence of a stenotic tumor was the only parameter significantly related to a poorer performance of EUS in N staging. The small number of early and locally advanced lesions. EUS and MRI have similar accuracy in the T and N staging in rectal cancer. The presence of stenosis and polypoid morphology is inversely associated with accuracy for either EUS or MRI.Gastrointestinal endoscopy 08/2011; 74(2):347-54. · 6.71 Impact Factor -
Article: Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study.
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ABSTRACT: To assess the activity and toxicity of the combination of gemcitabine plus dacarbazine (DTIC) in patients with advanced soft tissue sarcoma (STS) in a randomized, multicenter, phase II study using DTIC alone as a control arm. Patients with previously treated advanced STS were randomly assigned to receive either fixed-dose rate gemcitabine (10 mg/m2/min) at 1800 mg/m2 followed by DTIC at 500 mg/m2 every 2 weeks, or DTIC alone at 1200 mg/m2 every 3 weeks. The primary end point of the study was progression-free rate (PFR) at 3 months. From November 2005 to September 2008, 113 patients were included. PFR at 3 months was 56% for gemcitabine plus DTIC versus 37% for DTIC alone (P = .001). Median progression-free survival was 4.2 months versus 2 months (hazard ratio [HR], 0.58; 95% CI, 0.39 to 0.86; P = .005), and median overall survival was 16.8 months versus 8.2 months (HR, 0.56; 95% CI, 0.36 to 0.90; P = .014); both favored the arm of gemcitabine plus DTIC. Gemcitabine plus DTIC was also associated with a higher objective response or higher stable disease rate than was DTIC alone (49% v 25%; P = .009). Severe toxicities were uncommon, and treatment discontinuation for toxicity was rare. Granulocytopenia was the more common serious adverse event, but febrile neutropenia was uncommon. Asthenia, emesis, and stomatitis were the most frequent nonhematologic effects. The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.Journal of Clinical Oncology 06/2011; 29(18):2528-33. · 18.37 Impact Factor -
Article: Characterization of human pancreatic orthotopic tumor xenografts suitable for drug screening.
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ABSTRACT: Efforts to identify novel therapeutic options for human pancreatic ductal adenocarcinoma (PDAC) have failed to result in a clear improvement in patient survival to date. Pancreatic cancer requires efficient therapies that must be designed and assayed in preclinical models with improved predictor ability. Among the available preclinical models, the orthotopic approach fits with this expectation, but its use is still occasional. An in vivo platform of 11 orthotopic tumor xenografts has been generated by direct implantation of fresh surgical material. In addition, a frozen tumorgraft bank has been created, ensuring future model recovery and tumor tissue availability. Tissue microarray studies allow showing a high degree of original histology preservation and maintenance of protein expression patterns through passages. The models display stable growth kinetics and characteristic metastatic behavior. Moreover, the molecular diversity may facilitate the identification of tumor subtypes and comparison of drug responses that complement or confirm information obtained with other preclinical models. This panel represents a useful preclinical tool for testing new agents and treatment protocols and for further exploration of the biological basis of drug responses.Cellular oncology (Dordrecht). 06/2011; 34(6):511-21. -
Article: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
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ABSTRACT: The addition of cetuximab to irinotecan, fluorouracil, and leucovorin (FOLFIRI) as first-line treatment for metastatic colorectal cancer (mCRC) was shown to reduce the risk of disease progression and increase the chance of response in patients with KRAS wild-type disease. An updated survival analysis, including additional patients analyzed for tumor mutation status, was undertaken. Patients were randomly assigned to receive FOLFIRI with or without cetuximab. DNA was extracted from additional slide-mounted tumor samples previously used to assess epidermal growth factor receptor expression. Clinical outcome according to the tumor mutation status of KRAS and BRAF was assessed in the expanded patient series. The ascertainment rate of patients analyzed for tumor KRAS status was increased from 45% to 89%, with mutations detected in 37% of tumors. The addition of cetuximab to FOLFIRI in patients with KRAS wild-type disease resulted in significant improvements in overall survival (median, 23.5 v 20.0 months; hazard ratio [HR], 0.796; P = .0093), progression-free survival (median, 9.9 v 8.4 months; HR, 0.696; P = .0012), and response (rate 57.3% v 39.7%; odds ratio, 2.069; P < .001) compared with FOLFIRI alone. Significant interactions between KRAS status and treatment effect were noted for all key efficacy end points. KRAS mutation status was confirmed as a powerful predictive biomarker for the efficacy of cetuximab plus FOLFIRI. BRAF tumor mutation was a strong indicator of poor prognosis. The addition of cetuximab to FOLFIRI as first-line therapy improves survival in patients with KRAS wild-type mCRC. BRAF tumor mutation is an indicator of poor prognosis.Journal of Clinical Oncology 05/2011; 29(15):2011-9. · 18.37 Impact Factor -
Article: Design and Endpoints of Clinical and Translational Trials in Advanced Colorectal Cancer. A Proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD)
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ABSTRACT: Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations [1-6]. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.Reviews on Recent Clinical Trials 04/2011; 6(2):158-170. -
Article: A combined strategy of SAGE and quantitative PCR Provides a 13-gene signature that predicts preoperative chemoradiotherapy response and outcome in rectal cancer.
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ABSTRACT: Preoperative chemoradiotherapy (CRT) is the treatment of choice for rectal cancer (RC), but half of the patients do not respond, suffer unnecessary toxicities, and surgery delays. We aimed to develop a model that could predict a clinically meaningful response to CRT by using formalin-fixed paraffin-embedded (FFPE) biopsies. We first carried out an exploratory screening of candidate genes by using SAGE technology to evaluate dynamic changes in the RC transcriptome in selected refractory patients before and after CRT. Next, 53 genes (24 from SAGE and 29 from the literature) were analyzed by qPCR arrays in FFPE initial biopsies from 94 stage II/III RC patients who were preoperatively treated with CRT. Tumor response was defined by using Dworak's tumor regression grade (2-3-4 vs. 0-1). Multivariate Cox methods and stepwise algorithms were applied to generate an optimized predictor of response and outcome. In the training cohort (57 patients), a 13-gene signature predicted tumor response with 86% accuracy, 87% sensitivity, and 82% specificity. In a testing cohort (37 patients), the model correctly classified 6 of 7 nonresponders, with an overall accuracy of 76%. A signature-based score identified patients with a higher risk of relapse in univariate (3-year disease-free survival 64% vs. 90%, P = 0.001) and multivariate analysis (HR = 4.35 95% CI: 1.2-15.75, P = 0.02), in which it remained the only statistically significant prognostic factor. A basal 13-gene signature efficiently predicted CRT response and outcome. Multicentric validation by the GEMCAD collaborative group is currently ongoing. If confirmed, the predictor could be used to improve patient selection in RC studies.Clinical Cancer Research 04/2011; 17(12):4145-54. · 7.74 Impact Factor -
Article: Serum matrilysin correlates with poor survival independently of KRAS and BRAF status in refractory advanced colorectal cancer patients treated with irinotecan plus cetuximab.
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ABSTRACT: The purpose of the study was to prospectively explore the role of serum MMP-7 as a predictive and prognostic marker of anti-epidermal growth factor receptor (EGFR) therapy and irinotecan efficacy in third-line advanced colorectal cancer therapy. One hundred patients were recruited prospectively from six Spanish hospitals. Patients were treated with biweekly irinotecan 180 mg/m(2) and cetuximab 400 mg/m(2) (loading dose) and weekly cetuximab 250 mg/m(2) until progressive disease or unacceptable toxicity. Baseline MMP-7 was determined using a quantitative solid-phase sandwich ELISA. KRAS and BRAF mutational status were also assessed. The clinical endpoints examined were overall survival (OS), progression-free survival (PFS), and response rate. No association between serum MMP-7 and neither KRAS nor BRAF mutational status was found. The multivariate analysis revealed that MMP-7 predicts PFS both in wild-type (WT) KRAS patients (HR 1.03, 95% CI 1.00-1.06; p = 0.046) and in mutant KRAS patients (HR 1.18, 95% CI 1.01-1.35; p = 0.036). The presence of mutant BRAF was associated with shorter PFS (HR 8.49, 95% CI 2.88-25.0; p < 0.001) and worse OS (HR 3.55, 95% CI 1.39-9.09; p = 0.008) in the subset of WT KRAS patients. Serum MMP-7 is associated with PFS in colorectal patients treated with anti-EGFR therapy as third-line treatment independently of KRAS status.Tumor Biology 04/2011; 32(2):417-24. · 1.94 Impact Factor -
Article: [Malignancy predictive factors in pancreatic intraductal papillary mucinous neoplasm].
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ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is a premalignant lesion of the pancreas. Its natural history is not well known. We evaluated the characteristics and predictor factors of malignancy of IPMN. A retrospective analysis was performed in 88 patients diagnosed with IPMN between January 1997 and December 2008. The diagnosis was done by abdominal computed tomography (CT), pancreatic-magnetic resonance imaging (MRI) and/or endoscopic ultrasound (EUS). Gender, age, symptoms, origin, location, CA 19.9 serum levels, size of tumours and nodules by imaging techniques, type of surgery, malignancy and survival were evaluated. Nine pre-surgical variables were selected, and univariate and multivariate analysis to identify independent prognostic factors of malignancy were performed. The mean age was 64 years and 53% were men. 39% of tumours were incidental. 50% had their origin on the main pancreatic duct, 37% on collateral branchs and 13% were multifocal. 68% patients were operated: 42% had malignant neoplasms (32% carcinoma in situ and 68% invasive). Twelve patients died (1 benign, 1 in situ and 10 invasive). Univariate and multivariate analysis identified the symptoms and the tumour size (≥ 22 mm [median of our serie] and ≥ 30 mm [size accepted in literature]) as independent predictor factors of malignancy. Many IPMN are incidental findings. The presence of symptoms and size of the tumour are independent prognostic factors of malignancy and they should be considered to decide therapeutic actions.Medicina Clínica 03/2011; 137(14):631-6. · 1.38 Impact Factor -
Article: [Soft tissue sarcomas: clinical practice guidelines].
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ABSTRACT: Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.Medicina Clínica 03/2011; 136(9):408.e1-8. · 1.38 Impact Factor -
Article: Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).
[show abstract] [hide abstract]
ABSTRACT: Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.01/2011; 6(2):158-70. · 1.07 Impact Factor -
Article: Co-expression of matrix metalloproteinase-7 (MMP-7) and phosphorylated insulin growth factor receptor I (pIGF-1R) correlates with poor prognosis in patients with wild-type KRAS treated with cetuximab or panitumumab: a GEMCAD study.
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ABSTRACT: By transactivacion, phosphorylated insulin growth factor receptor I (IGF-1R) can activate epidermal growth factor receptor (EGFR). MMP-7, produced by colorectal cancer cells, also can activate IGF-1R by degrading IGFBP-3 and releasing IGF-I. A cohort of patients (pts) with advanced colorectal cancer (CRC), under second- or third-line treatment with cetuximab or panitumumab, was tested using immunohistochemistry for expression of the activated form of IGF-1R (p-IGF-1R) and MMP-7. KRAS and BRAF mutation status was determined by sequencing and allelic discrimination analysis, respectively. Analyses were performed in primary CRC tumor samples or metastases, and the association of immunohistochemistry findings, mutational results, and treatment outcomes was investigated in both univariate and multivariate analyses. Expression of activated IGF-1R and MMP-7 was observed in 51 and 49% of pts, respectively. Co-expression of MMP-7 and pIGF-1R (double positivity, DP) was observed in 28 pts (25%). There was no association between KRAS or BRAF mutational status and DP (p=0.52). Pts with DP responded more poorly to first-line chemotherapy (p=0.005) and to anti-EGFR treatment (p=0.01) than non-DP pts. In wild type (WT) KRAS pts, those with DP have poorer PFS (2.7 months vs. 3.5m, p=0.036; HR 1.98, 95% CI 1.05-3.75) and OS (6.4 months vs. 8.6 m, p=0.010; HR 2.33, 95%CI 1.23-4.43) in the adjusted multivariate analysis. Our study suggests that concomitant expression of MMP-7 and activation of p-IGF-1R (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR.Cancer biology & therapy 01/2011; 11(2):177-83. · 2.64 Impact Factor -
Article: Potential usefulness of an EPA-enriched nutritional supplement on chemotherapy tolerability in cancer patients without overt malnutrition.
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ABSTRACT: To assess the effect of an intervention with an Eicosapentaenoic Acid-enriched oral nutritional supplement on chemotherapy tolerability in patients with advanced colorectal cancer. Thirteen patients diagnosed with stage IV colorectal cancer were included. Patients in the experimental group received 2 packs of supplement per day during 12 weeks plus dietary counseling. The control group only received dietary counseling. Patients were assessed for nutritional status, dietary intake, health related quality of life (HRQOL) and chemotherapy compliance. Only patients in the supplemented group significantly increased their weight after the intervention. They also had better scores in important domains of HRQOL, compared to controls. Although not statistically significant, the supplemented group did not experience interruptions in their chemotherapy treatment compared to the control group, with more interruptions due to toxicity. The present study, although limited by sample size, points out towards a positive effect of the intervention on chemotherapy tolerability.Nutricion hospitalaria: organo oficial de la Sociedad Espanola de Nutricion Parenteral y Enteral 10/2010; 25(5):736-40. · 1.12 Impact Factor -
Article: [Incidence and characteristics of pancreatic cystic neoplasms].
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ABSTRACT: Cystic neoplasms (CN) of the pancreas represent 10% of cystic lesions and 1% of pancreatic tumors. Mucinous cystic neoplasm (MCN), serous cystadenoma (SC) and intraductal papillary mucinous neoplasm (IPMN) are cystic neoplasms and represent more than 90% of these types of lesion. Few series have been published on these lesions, especially in Spain. To evaluate the incidence, characteristics and survival of patients with cystic neoplasms attended in our hospital in the last 12 years. A retrospective analysis was carried out in all patients diagnosed with CN between January 1997 and December 2008. Diagnosis was made by abdominal computed tomography, pancreatic-magnetic resonance imaging and/or endoscopic ultrasonography. Sex, age, year of diagnosis, symptoms, tumoral location and size, type of surgery, pathology, and survival were evaluated. A total of 117 patients were analyzed. The mean age was 63±14 years and 56% were women. Eighty-eight patients had IPMN, 21 had SC and eight had MCN. Fifty-six per cent were diagnosed in the last 4 years, 42.7% were diagnosed as an incidental finding and 19% had a history of acute pancreatitis. The most frequent location was the pancreatic head (53%). The mean imaging size was 32mm. Surgical resection was performed in 69.2% of the patients. Twenty-three percent of the tumors were malignant, 30% were carcinoma in situ and 70% were invasive. Thirteen percent of the patients died; of these 93.3% had invasive carcinoma. Five-year survival was 94.7% in SC, 76% in IPMN and 60% in MCN. CN were mainly identified as incidental findings, although acute pancreatitis is another possible cause. The most frequent tumor in our environment is IPMN. Surgical treatment of IPMN and MCN, at the right moment, may be useful to prevent the development of pancreatic carcinoma.Gastroenterología y Hepatología 10/2010; 33(8):563-8. · 0.73 Impact Factor -
Article: Imatinib plus low-dose doxorubicin in patients with advanced gastrointestinal stromal tumors refractory to high-dose imatinib: a phase I-II study by the Spanish Group for Research on Sarcomas.
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ABSTRACT: In KIT-expressing Ewing sarcoma cell lines, the addition of doxorubicin to imatinib increases apoptosis, compared with imatinib or doxorubicin alone. On the basis of these in vitro data, the authors conducted a phase 1-2 trial of doxorubicin with imatinib in patients with gastrointestinal sarcoma tumors refractory to high-dose imatinib therapy. Patients with metastatic gastrointestinal sarcoma tumor resistant to imatinib at 400 mg by mouth (p.o.) twice a day were eligible for this multicenter study, and received imatinib (400 mg p.o. every day [q.d.]) concomitantly with doxorubicin 15-20 mg/m2/weekly for 4 cycles (monthly cycles), followed by imatinib (400 mg p.o. q.d.) maintenance in nonprogressive patients. Spiral computed tomography and positron emission tomography with F18-fluorodeoxyglucose were done basally and after 2 months of therapy to evaluate response. An in vitro study assessed the effect of combining imatinib and doxorubicin. Twenty-six patients with progressive gastrointestinal sarcoma tumor were entered in the study. Treatment was well tolerated. Three (14%) of 22 evaluable patients had partial responses per Response Evaluation Criteria in Solid Tumors, and 8 (36%) had clinical benefit (partial response or stable disease for >or=6 months). Median progression-free survival (PFS) was 100 days (95% confidence interval [CI], 62-138), and median survival was 390 days (95% CI, 264-516). Interestingly, PFS was 211 days (95% CI, 52-370) in patients with wild type (WT) KIT and 82 days (95% CI, 53-111) in non-WT patients (10 mutant, 6 not assessed). A synergistic effect on cell line proliferation and apoptosis was found with imatinib and doxorubicin combination. Low-dose chemobiotherapy combination showed promising activity in heavily pretreated gastrointestinal sarcoma tumor patients, especially in those with WT-KIT genotype.Cancer 08/2010; 116(15):3692-701. · 4.77 Impact Factor -
Article: [Recommendations for diagnosis, staging and treatment of pancreatic cancer (Part I). Grupo Español de Consenso en Cáncer de Páncreas].
Medicina Clínica 03/2010; 134(14):643-55. · 1.38 Impact Factor
Top co-authors
Top Journals
Institutions
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2004–2013
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Hospital Clínic de Barcelona
Barcelona, Catalonia, Spain
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2011
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Catalan Institute of Oncology
Badalona, Catalonia, Spain -
Hospital Universitario Miguel Servet
Zaragoza, Aragon, Spain
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2009
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Institut d’Investigacions Biomèdiques August Pi i Sunyer
Barcelona, Catalonia, Spain
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2007–2008
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University of Barcelona
Barcelona, Catalonia, Spain
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2005
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Hospital Son Dureta
Palma, Balearic Islands, Spain -
Institut Català de Nanotecnologia
Barcelona, Catalonia, Spain
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