Pere Gascón

IDIBAPS August Pi i Sunyer Biomedical Research Institute, Barcino, Catalonia, Spain

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Publications (118)426.27 Total impact

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    ABSTRACT: The crucial role of tumor associated fibroblasts (TAFs) in cancer progression is now clear in non-small cell lung cancer (NSCLC). However, therapies against TAFs are limited due to a lack of understanding in the subtype-specific mechanisms underlying their accumulation. Here the mechanical (i.e., matrix rigidity) and soluble mitogenic cues that drive the accumulation of TAFs from major NSCLC subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SQC) were dissected. Fibroblasts were cultured on substrata engineered to exhibit normal- or tumor-like stiffnesses at different serum concentrations, and critical regulatory processes were elucidated. In control fibroblasts from non-malignant tissue, matrix stiffening alone increased fibroblast accumulation, and this mechanical effect was dominant or comparable to that of soluble growth factors up to 0.5% serum. The stimulatory cues of matrix rigidity were driven by beta1 integrin mechano-sensing through FAK (pY397), and were associated with a posttranscriptionally driven rise in beta1 integrin expression. The latter mechano-regulatory circuit was also observed in TAFs but in a subtype-specific fashion, since SQC-TAFs exhibited higher FAK (pY397), beta1 expression and ERK1/2 (pT202/Y204) than ADC-TAFs. Moreover, matrix stiffening induced a larger TAF accumulation in SQC- (> 50%) compared to ADC-TAFs (10-20%). In contrast, SQC-TAFs were largely serum desensitized, whereas ADC-TAFs responded to high serum concentration only. These findings provide the first evidence of subtype-specific regulation of NSCLC-TAF accumulation. Furthermore, these data support that therapies aiming to restore normal lung elasticity and/or beta1 integrin-dependent mechano-regulation may be effective against SQC-TAFs, whereas inhibiting stromal growth factor signaling may be effective against ADC-TAFs. Implications: This study reveals distinct mechanisms underlying the abnormal accumulation of tumor supporting fibroblasts in two major subtypes of lung cancer, which will assist the development of personalized therapies against these cells.
    Molecular cancer research : MCR. 10/2014;
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    ABSTRACT: Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer (PC) participating in a phase-II neoadjuvant docetaxel (D) and androgen deprivation (AD) trial to identify mediators of resistance. Transcriptional level of 93 genes from a D-resistant PC cell lines microarray study was analyzed by Taqman low-density arrays in tumors from patients with high-risk localized PC (36 surgically treated, 28 with neoadjuvant D+AD). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and P65 were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and D-resistant CRPC cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after D-exposure. Reversion of EMT phenotype was investigated as a D-resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P<0.05), including genes related to androgen receptor, NFKB transcription factor, and EMT. Increased EMT markers expression correlated with radiological relapse. D-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted D-resistance and reduced CD44 expression in DU-145R and PC-3R. Before D-exposure, a selected CD44+ subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic D-resistance; ZEB1/CD44+ subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early PC.
    Molecular Cancer Therapeutics 03/2014; · 5.60 Impact Factor
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    ABSTRACT: The purpose of this prospective cohort study was to assess the feasibility of outpatient treatment in patients with cancer and objectively confirmed pulmonary embolism (PE), and to compare the performance of the different prognostic scales available in this setting. Patients were selected for outpatient management according to a set of exclusion criteria. Outcomes at 30 and 90 days of follow-up included thromboembolic recurrences, major bleeding, and all-cause death. The performance of 4 prognostic scales (Pulmonary Embolism Severity Index, Geneva Prognostic Score, POMPE-C, and Registro Informatizado de Enfermedad Tromboembólica [RIETE registry]) was evaluated. Of 138 patients, 62 (45%) were managed as outpatients. Incidental PE constituted 47% of the sample. Most patients treated at home had an incidentally detected PE (89%). The rate of recurrence and major bleeding events was similar in both groups. Mortality rates were higher for patients admitted to the hospital compared with outpatients at 30 days (18% vs 3%; P=.06) and 90 days (34% vs 10%; P=.001) of follow-up. None of the patients selected for home treatment required further admission because of PE complications. None of the prognostic models developed for symptomatic PE was significantly associated with 30-day mortality. Improved survival outcomes were observed in incidentally detected PEs compared with acute symptomatic events (overall mortality rates, 3.2% vs 18.4%; P=.006). A large proportion of patients with cancer and PE may be safely treated as outpatients, especially those with incidental PE. Cancer-specific prognostic scales including incidental PE should be developed for the optimal management of PE in this setting.
    Journal of the National Comprehensive Cancer Network: JNCCN 03/2014; 12(3):365-73. · 5.11 Impact Factor
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    ABSTRACT: The objective of the present study was to describe the prevalence and management of anaemia and iron deficiency (ID) in treatment-naïve patients with solid tumours in Spain and the incidence of anaemia over 4 months of cancer treatment in clinical practice. Multicentre, prospective and observational study in newly diagnosed cancer patients. Data on anaemia and iron parameters and its management were collected prior to the initiation of chemotherapy, at each cycle of chemotherapy and after 4 months of treatment. The main outcomes of the study were the prevalence of anaemia at baseline, its incidence during cancer treatment and the prevalence of absolute ID (AID) and functional ID (FID) prior to chemotherapy initiation. A total of 295 patients were included in the study. Anaemia was present at diagnosis in 38.6 % of patients and was treated only in 32.5 % of those. A total of 106 patients (60.2 %) without anaemia at baseline developed anaemia during cancer treatment. Serum ferritin and transferrin saturation data were available for 151 of the patients (51.2 %) included in the study. The overall prevalence of ID was 59 %: 48 patients (31.8 %) presented with AID and 41 patients (27.2 %) presented with FID before starting anti-cancer therapy. Thirty-three of 44 non-anaemic iron-deficient patients did not receive any type of iron supplementation before initiating cancer therapy. Iron parameters are not commonly measured in newly diagnosed cancer patients. A correct evaluation and early management of ID could reduce the incidence of treatment-related anaemia in cancer patients.
    Clinical and Translational Oncology 01/2014; · 1.28 Impact Factor
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    ABSTRACT: Cancer therapy exerts a strong selection pressure that shapes tumor evolution, yet our knowledge of how tumors change during treatment is limited. Here, we report the analysis of cellular heterogeneity for genetic and phenotypic features and their spatial distribution in breast tumors pre- and post-neoadjuvant chemotherapy. We found that intratumor genetic diversity was tumor-subtype specific, and it did not change during treatment in tumors with partial or no response. However, lower pretreatment genetic diversity was significantly associated with pathologic complete response. In contrast, phenotypic diversity was different between pre- and posttreatment samples. We also observed significant changes in the spatial distribution of cells with distinct genetic and phenotypic features. We used these experimental data to develop a stochastic computational model to infer tumor growth patterns and evolutionary dynamics. Our results highlight the importance of integrated analysis of genotypes and phenotypes of single cells in intact tissues to predict tumor evolution.
    Cell Reports 01/2014; · 7.21 Impact Factor
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    ABSTRACT: Demographic, personal, clinical, and behavioral factors predicting chemotherapy-induced nausea and vomiting (CINV) have been assessed in the past, but inconsistencies exist in the literature, studies have methodological shortcomings, and many risk factors have been examined in cross-sectional studies and univariate analyses. To evaluate the predictive power of personal and treatment-related characteristics in the development of CINV, using a large and prospectively evaluated sample of a heterogeneous group of cancer patients receiving routine chemotherapy. This was a multicountry, multisite prospective study over three cycles of chemotherapy. Adult patients from eight European countries about to receive highly and moderately emetogenic chemotherapy were recruited. Clinicians completed a case report form at or before the initial chemotherapy treatment, recording patient demographic and baseline clinical characteristics. Participants completed a daily patient diary for six days per chemotherapy cycle describing their CINV experience. Baseline patient data also included a history of nausea/vomiting (yes/no), patient expectation of nausea (0-100 mm visual analogue scale [VAS]), prechemotherapy anxiety (0-100 mm VAS), and prechemotherapy nausea (0-100 mm VAS) measured during the 24-hour period before chemotherapy initiation. There were 991 evaluable patients with complete Cycle 1 data, 888 for Cycle 2 data, and 769 for Cycle 3 data. A complex picture of predictor variables was shown, with different contribution of variables to the acute, delayed, and overall phases of CINV. Key predictor variables included the use of antiemetics inconsistent with international guidelines, younger age, prechemotherapy nausea, and no CINV complete response in an earlier cycle (all at P < 0.05). Anxiety, history of nausea/vomiting, and expectations of nausea were important predictors for some phases and cycles but not consistently across the CINV pathway. The results of this study provide clarity for the relative contribution of a set of characteristics in the development of CINV. Following evidence-based clinical antiemetic guidelines is of paramount importance, alongside treating patients with increased risk for CINV more aggressively, which both could lead to more optimal CINV management. These data can assist clinicians in making decisions about the antiemetic management of their patients.
    Journal of pain and symptom management 09/2013; · 2.42 Impact Factor
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    ABSTRACT: Cancer anorexia-cachexia syndrome (CACS) is a complex metabolic syndrome, different from malnutrition and sarcopenia, which is very common in cancer patients. Treatment for CACS is based on nutritional support and CACS pathophysiology-modulating drugs. The most commonly used are megestrol acetate (MA) and corticosteroids. The efficacy of MA has been confirmed by multiple clinical trials and meta-analyses. Glucocorticoids are also effective but should only be used for short periods and in selected cases. Future strategies should include intensified research into potentially effective drugs (ω-3 fatty acids, thalidomide, cannabinoids, ghrelin, bortezomib, and COX-2 inhibitors), combined treatment and new drugs (anti-IL-6 monoclonal antibodies, melanocortin, β-2 antagonists, and androgen receptor-modulating analogues). We propose a review based on the literature on the pathophysiology of CACS, the diagnostic criteria and treatment, and future strategies.
    Critical reviews in oncology/hematology 08/2013; · 5.27 Impact Factor
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    ABSTRACT: Biosimilars are similar, but non-identical, versions of existing biological drugs for which patents have expired. Despite the rigorous approval process for biosimilars, concerns have been expressed about the efficacy and safety of these products in clinical practice. Biosimilars of filgrastim, based on the originator product Neupogen®, have been available since 2008 and are now in widespread clinical use in Europe and elsewhere. Three biosimilar G-CSFs have been approved based on a combination of physicochemical and biological protein characterisation, pharmacokinetic and pharmacodynamic assessment in healthy volunteers and efficacy and safety data in patients with cancer. To assess whether biosimilars are effective in the real-world clinical practice setting, a pooled analysis of five post-approval studies of biosimilar G-CSF (Zarzio®) that included 1,302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia was conducted. A total of 36 % of patients had a febrile neutropenia risk of >20 %, while 39.6 % had a risk of 10-20 % based on chemotherapy regimen. The occurrence of severe or febrile neutropenia was within the range of that observed in previous studies of originator G-CSF. In addition, the safety profile of Zarzio® was consistent with that reported for originator G-CSF and the known safety profile of G-CSF. Initial concerns about the use of biosimilars, at least with regard to biosimilar G-CSFs, appear to be unfounded. Adoption of cost-effective biosimilars should help reduce healthcare costs and improve patient access to biological treatments.
    Supportive Care in Cancer 08/2013; · 2.09 Impact Factor
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    ABSTRACT: The PERFORM Questionnaire is a 12-item scale developed for assessing fatigue in cancer patients in the clinical practice. It has advantages over other tools in that it is short and includes beliefs and attitudes of patients about fatigue. It was psychometrically validated in cancer patients with and without anemia. We evaluated the usefulness of the PERFORM scale to measure fatigue in a large study focusing exclusively on anemic patients. This was an observational, multicenter, prospective, 3-month study in cancer patients with hemoglobin (Hb)≤11 g/dl. Fatigue was assessed using the PERFORM questionnaire. The overall score ranges from 12 (no fatigue) to 60 (maximum fatigue). We included 667 patients: 54.1 % women, mean age 60 (standard deviation, 12) years. A highly significant, but mild correlation was observed between low baseline Hb and high patient perception of fatigue (r with PERFORM score=-0.215, p < 0.0001). Of the patients, 65.8 % improved Hb level during follow-up (increase of ≥1 g/dL and/or achieving >11 g/dL), which translated into a significant improvement in the PERFORM score [mean (95 % confidence interval (CI)] change, -1.2 (-0.04 to -2.4), whereas more fatigue was observed in patients without improvement in Hb [change (95 % CI) in PERFORM, +3.3 (1.5 to 5)]. In a multivariate linear regression analysis, the independent factors associated to fatigue at 3 months were a low Hb level, a low Karnofsky index, active chemotherapy, cancer treatment with palliative intention, and transfusion need in the last 3 months. Minimal increases or decreases in Hb of ≥1 g/dL were associated with meaningful changes in patient-perceived fatigue as measured with the PERFORM questionnaire. In addition to anemia severity, other factors such as active chemotherapy and advanced disease contribute to perception of fatigue by cancer patients.
    Supportive Care in Cancer 06/2013; · 2.09 Impact Factor
  • Cancer Research 01/2013; · 8.65 Impact Factor
  • PERE GASCÓN
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    ABSTRACT: SUMMARY Erythropoiesis-stimulating agents (ESAs) are widely used in oncology to correct the anemia associated with chemotherapy, although only 50–70% of patients show an optimal response, mostly because of functional iron deficiency (FID). As intravenous (IV) iron can overcome this FID, it has become an important adjunct to obtaining and maintaining adequate hemoglobin levels in patients with cancer receiving chemotherapy. In fact, six out of seven published randomized, controlled trials performed in cancer patients have demonstrated that IV iron given concomitantly to ESAs induces a faster and much more robust response than with ESAs alone. The possibility that giving only IV iron can also produce adequate hemoglobin responses requires further studies. However, there still exists some reluctance among many oncologists to use IV iron because of the poor safety profile observed in the past with the old iron preparations, in particular high-molecular-weight iron dextran. As the efficacy and safety of the new iron preparations have been proven, the use of IV iron should be considered in the management of anemia secondary to chemotherapy treatments.
    Transfusion Alternatives in Transfusion Medicine 12/2012; 12(3‐4).
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    ABSTRACT: BACKGROUND: Previous work showed that the NF-κB survival pathway is activated by docetaxel (D) and contributes to D resistance in prostate cancer. In this study we aimed to investigate the dynamics of the relationship between NF-κB and IL-6 in the shift from D-naive castration-resistant prostate cancer (CRPC) to D-resistance in patients and cell lines. METHODS: CRPC tumor samples were tested for NF-κB/p65 and IL-6 by immunohistochemistry. CRPC patients treated with D were also tested for serum IL-6 (ELISA). Two D-resistant cell lines, PC-3R and DU-145R, derived from the CRPC cells PC-3 and DU-145, respectively, were tested for NF-κB activation (EMSA), NF-κB-related genes expression (RT-PCR), NF-κB inhibition (p65 siRNA) and IL-6 and IL-8 soluble levels (ELISA). RESULTS: In CRPC patients treated with D (n = 72), pre-treatment IL-6 level correlated with nuclear NF-κB/p65 tumor staining and response to D, and was an independent prognostic factor for overall survival. However, IL-6 level changes under treatment did not correlate with clinical outcome. In PC-3 and DU-145 parental CRPC cells, as well as in D-resistant counterparts, D treatment induced NF-κB activation. In fact, NF-κB inhibition was sufficient to re-sensitize DU-145R cells to D. Despite enhanced NF-κB activity, IL-6 secretion in D-resistant cell lines was reduced and not induced by D treatment. The same occurred with IL-8 cytokine. CONCLUSIONS: These preclinical and clinical results support a role of NF-κB and IL-6 in the resistance to D in CRPC, and support the investigation of targeted therapies to enhance the antitumor activity of D in this patient population. Prostate © 2012 Wiley Periodicals, Inc.
    The Prostate 10/2012; · 3.84 Impact Factor
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    ABSTRACT: Neutropenia induced by chemotherapy (CT) is an infection risk factor associated to greater morbidity/mortality and dose-limiting toxicity that on many occasions requires a reduction of the dose of cytostatics or a delay in the administration of treatment. This may have a negative effect on the patient's quality of life and even diminish the efficacy of the treatment, especially when the intention is to cure or prolong survival. Management of treatment or prophylaxis of grade 3-4 neutropenia and febrile neutropenia with myeloid growth factors (CSF) varies very much in clinical practice, both in the time of starting treatment and the types of patients it is given to. The need to generalise and facilitate practice based on clinical evidence has led the Spanish Society of Medical Oncology (SEOM) to prepare clinical practice guidelines on the use of myeloid growth factors.
    Clinical and Translational Oncology 07/2012; 14(7):491-8. · 1.28 Impact Factor
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    ABSTRACT: Chronic diseases reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency (ID) and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of ID, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents (ESAs). Clinical trial reports were identified in PubMed and abstracts at relevant major congresses. Reported prevalence of ID in cancer patients ranges from 32 to 60% and most iron-deficient patients are also anaemic. Randomised clinical trials have shown superior efficacy of i.v. iron over oral or no iron in reducing blood transfusions, increasing haemoglobin, and improving quality of life in ESA-treated anaemic cancer patients. Furthermore, i.v. iron without additional ESA should be evaluated as potential treatment in patients with chemotherapy-induced anaemia. At recommended doses, i.v. iron is well tolerated, particularly compared with oral iron. No serious drug-related adverse effects were seen during long-term use in renal disease and no effect on tumour growth has been observed in trials with anaemic cancer patients. Reliable diagnosis and treatment of ID are recommended key steps in modern cancer patient management to minimise impact on quality of life and performance status.
    Annals of Oncology 05/2012; 23(8):1954-62. · 7.38 Impact Factor
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    ABSTRACT: While guidelines for preventing chemotherapy-induced nausea and vomiting (CINV) are widely available, clinical uptake of guidelines remains low. Our objective was to evaluate the effect of guideline-consistent CINV prophylaxis (GCCP) on patient outcomes. This prospective, observational multicenter study enrolled chemotherapy-naive adults initiating single-day highly or moderately emetogenic chemotherapy (HEC or MEC) for cancer. Patients completed 6-day daily diaries beginning with cycle 1 for up to three chemotherapy cycles. The primary study end point, complete response (no emesis and no use of rescue therapy) during 120 h after cycle 1 chemotherapy, was compared between GCCP and guideline-inconsistent CINV prophylaxis (GICP) cohorts using multivariate logistic regression, adjusting for potential confounding factors. In cycle 1 (N=991), use of GCCP was 55% and 46% during acute and delayed phases, respectively, and 29 % for the overall study period (acute plus delayed phases). Complete response was recorded by 172/287 (59.9%) and 357/704 (50.7%) patients in GCCP and GICP cohorts, respectively (P=0.008). The adjusted odds ratio for complete response was 1.43 (95% confidence interval 1.04-1.97; P=0.027) for patients receiving GCCP versus GICP. GCCP reduces the incidence of CINV after single-day HEC and MEC.
    Annals of Oncology 03/2012; 23(8):1986-92. · 7.38 Impact Factor
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    Pere Gascon
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    ABSTRACT: Biopharmaceuticals were copies of endogenous human proteins developed in the mid-1990s that were characterized by complex three-dimensional, high-molecular weight compounds. What made them unique was that contrary to classical chemotherapeutical drugs, they were manufactured by living cells. One of these biopharmaceuticals was granulocyte-colony stimulating factor (G-CSF). Once their patent expired, generic versions appeared in pharmacies. They are now called biosimilars. There are several biosimilar G-CSFs approved in Europe: Biograstim®/Filgrastim ratiopharm/Ratiograstim®/Tevagrastim® (XM02); Zarzio® and Nivestim®. All these new products are manufactured in facilities with state-of-the-art technology. All products have passed the regulatory requirements for approval, mainly phase I and phase III, with the consequent PD/PK evaluations and studies on efficacy and safety. However, there are still some concerns regarding their long-term evaluation, in particular, the limited experience at the time of approval of these products in terms of efficacy, safety and immunogenicity. For this reason, pharmacovigilance should be rigorous. A lot of work remains to be done in terms of clarification with regard to substituting a biosimilar G-CSF for the innovator product and, finally, information must be provided to physicians, pharmacists and patients to allow for proper decision-making. Ultimately, only clinical trials and effective post-marketing pharmacovigilance will provide definitive evidence that a biosimilar is comparable to the originator-reference product in terms of efficacy and safety.
    Targeted Oncology 03/2012; 7 Suppl 1:S29-34. · 3.46 Impact Factor
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    ABSTRACT: Background: Lung cancer (LC) is the most frequent solid tumor diagnosed worldwide and is one of the most common tumors in series of patients with cancer-related venous thromboembolism (VTE). The aim of this study was to analyze the clinical characteristics and outcome of VTE in patients with LC compared to patients with other types of cancer (OC). Patients and Methods: A prospective observational study enrolling consecutive cancer patients with newly diagnosed VTE was performed from May 2006 to April 2009 in our Department of Medical Oncology. All patients were uniformly treated and followed according to the American College of Chest Physicians guidelines.Results: A total of 340 cancer patients were enrolled with LC being the most frequent primary tumor in 89 (26%) patients (69 male; mean age 62 ± 11 years). VTE was diagnosed earlier in patients with LC after the initial cancer diagnosis, with a median of 4 months (95% CI 2.79- 5.20) compared to 7 months (95% CI 4.40-9.59) in patients with OC (p<0.0001). The VTE presented as pulmonary embolism in a higher proportion of patients with LC (51% vs 28%, p=0.005) although there were no differences in VTE-related outcomes due to the acute thrombotic event. After a mean follow-up of 14 ± 13 months no significant differences were found in venous re-thrombosis, major-bleeding or causes of death in patients with LC and OC. Conclusion: VTE in patients with LC occurs earlier after cancer diagnosis although no differences in VTE-related outcomes were observed compared to patients with OC.
    Advances in Cancer: Research & Treatment. 01/2012;
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    ABSTRACT: Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels < 10 g/dL (US) or ≤ 10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥ 10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan-Meier percentage (95% CI) of patients achieving Hb ≥ 10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥ 1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a ≥ 1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≤ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis.
    Medical Oncology 11/2011; 29(3):2291-9. · 2.14 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) play an important role in carcinogenesis through the regulation of their target genes. miRNA-related single nucleotide polymorphisms (miR-SNPs) can affect miRNA biogenesis and target sites and can alter microRNA expression and functions. We examined 11 miR-SNPs, including 5 in microRNA genes, 3 in microRNA binding sites and 3 in microRNA-processing machinery components, and evaluated time to recurrence (TTR) according to miR-SNP genotypes in 175 surgically resected non-small-cell lung cancer (NSCLC) patients. Significant differences in TTR were found according to KRT81 rs3660 (median TTR: 20.3 months for the CC genotype versus 86.8 months for the CG or GG genotype; P = 0.003) and XPO5 rs11077 (median TTR: 24.7 months for the AA genotype versus 73.1 months for the AC or CC genotypes; P = 0.029). Moreover, when patients were divided according to stage, these differences were maintained for stage I patients (P = 0.002 for KRT81 rs3660; P<0.001 for XPO5 rs11077). When patients were divided into sub-groups according to histology, the effect of the KRT81 rs3660 genotype on TTR was significant in patients with squamous cell carcinoma (P = 0.004) but not in those with adenocarcinoma. In the multivariate analyses, the KRT81 rs3660 CC genotype (OR = 1.8; P = 0.023) and the XPO5 rs11077 AA genotype (OR = 1.77; P = 0.026) emerged as independent variables influencing TTR. Immunohistochemical analyses in 80 lung specimens showed that 95% of squamous cell carcinomas were positive for KRT81, compared to only 19% of adenocarcinomas (P<0.0001). In conclusion, miR-SNPs are a novel class of SNPs that can add useful prognostic information on the clinical outcome of resected NSCLC patients and may be a potential key tool for selecting high-risk stage I patients. Moreover, KRT81 has emerged as a promising immunohistochemical marker for the identification of squamous cell lung carcinoma.
    PLoS ONE 07/2011; 6(7):e22509. · 3.53 Impact Factor
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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.

Publication Stats

2k Citations
426.27 Total Impact Points

Institutions

  • 2005–2014
    • IDIBAPS August Pi i Sunyer Biomedical Research Institute
      Barcino, Catalonia, Spain
  • 2001–2014
    • Hospital Clínic de Barcelona
      Barcino, Catalonia, Spain
  • 2004–2013
    • University of Barcelona
      • Department of Medicine
      Barcino, Catalonia, Spain
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Fundació Clínic per a la Recerca Biomèdica
      Barcino, Catalonia, Spain
  • 2011
    • Hospital Universitario Miguel Servet
      Caesaraugusta, Aragon, Spain
  • 2010
    • IMIM Hospital del Mar Medical Research Institute
      • Cancer Research Programme
      Barcelona, Catalonia, Spain
  • 2009
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2007
    • London Health Sciences Centre
      London, Ontario, Canada
  • 2006
    • Uppsala University Hospital
      • Department of Internal Medicine
      Uppsala, Uppsala, Sweden