Publications by authors named "Tania Fleitas"

18 Publications

  • Page 1 of 1

Neoadjuvant Chemotherapy in Locally Advanced Rectal Cancer.

Cancers (Basel) 2020 Dec 3;12(12). Epub 2020 Dec 3.

Department of Medical Oncology, Hospital Clínico Universitario de Valencia, INCLIVA Biomedical Research Institute, University of Valencia, Avda. Blasco Ibañez 17, 46010 Valencia, Spain.

Most clinical practice guidelines recommend a selective approach for rectal cancer after clinical staging. In low-risk patients, upfront surgery may be an appropriate option. However, in patients with MRI-defined high-risk features such as extramural vascular invasion, multiple nodal involvement or T4 and/or tumors close to or invading the mesorectal fascia, a more intensive preoperative approach is recommended, which may include neoadjuvant or preoperative chemotherapy. The potential benefits include better compliance than postoperative chemotherapy, a higher pathological complete remission rate, which facilitates a non-surgical approach, and earlier treatment of micrometastatic disease with improved disease-free survival compared to standard preoperative chemoradiation or short-course radiation. Two recently reported phase III randomized trials, RAPIDO and PRODIGE 23, show that adding neoadjuvant chemotherapy to either standard short-course radiation or standard long-course chemoradiation in locally advanced rectal cancer patients reduces the risk of metastasis and significantly prolongs disease-related treatment failure and disease-free survival. This review discusses these potentially practice-changing trials and how they may affect our current understanding of treating locally advanced rectal cancers.
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http://dx.doi.org/10.3390/cancers12123611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761666PMC
December 2020

Precision Medicine to Treat Advanced Gastroesophageal Adenocarcinoma: A Work in Progress.

J Clin Med 2020 Sep 22;9(9). Epub 2020 Sep 22.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Blasco Ibañez 17, 46010 Valencia, Spain.

Gastroesophageal adenocarcinoma (GEA) represents a heterogeneous disease and, when diagnosed as locally advanced or metastatic, it is characterized by poor prognosis. During the last few years, several molecular classifications have been proposed to try to personalize treatment for those patients diagnosed with advanced disease. Nevertheless, despite the great effort, precision medicine is still far from being a reality. The improvement in the molecular analysis due to the application of high throughput technologies based on DNA and RNA sequencing has opened a novel scenario leading to the personalization of treatment. The possibility to target epidermal growth factor receptor (HER)2, Claudine, Fibroblast Growth Factor Receptors (FGFR), and other alterations with a molecular matched therapy could significantly improve clinical outcomes over advanced gastric cancer patients. On the other hand, the development of immunotherapy could also represent a promising strategy in a selected population. In this review, we sought to describe the novel pathways implicated in GEA progression and the results of the molecular matched therapies.
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http://dx.doi.org/10.3390/jcm9093049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564841PMC
September 2020

Detection of postoperative plasma circulating tumour DNA and lack of CDX2 expression as markers of recurrence in patients with localised colon cancer.

ESMO Open 2020 09;5(5):e000847

Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain. Electronic address:

Background: Colon cancer (CC) is a heterogeneous disease. Novel prognostic factors beyond pathological staging are required to accurately identify patients at higher risk of relapse. Integrating these new biological factors, such as plasma circulating tumour DNA (ctDNA), CDX2 staining, inflammation-associated cytokines and transcriptomic consensus molecular subtypes (CMS) classification, into a multimodal approach may improve our accuracy in determining risk of recurrence.

Methods: One hundred and fifty patients consecutively diagnosed with localised CC were prospectively enrolled in our study. ctDNA was tracked to detect minimal residual disease by droplet digital PCR. CDX2 expression was analysed by immunostaining. Plasma levels of cytokines potentially involved in disease progression were measured using ELISAs. A 96 custom gene panel for nCounter assay was used to classify CC into colorectal cancer assigner and CMS.

Results: Most patients were classified into CMS4 (37%) and CMS2 (28%), followed by CMS1 (20%) and CMS3 (15%) groups. CDX2-negative tumours were enriched in CMS1 and CMS4 subtypes. In univariable analysis, prognosis was influenced by primary tumour location, stage, vascular and perineural invasion together with high interleukin-6 plasma levels at baseline, tumours belonging to CMS 1 vs CMS2 +CMS3, ctDNA presence in plasma and CDX2 loss. However, only positive ctDNA in plasma samples (HR 13.64; p=0.002) and lack of CDX2 expression (HR 23.12; p=0.001) were found to be independent prognostic factors for disease-free survival in the multivariable model.

Conclusions: ctDNA detection after surgery and lack of CDX2 expression identified patients at very high risk of recurrence in localised CC.
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http://dx.doi.org/10.1136/esmoopen-2020-000847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513635PMC
September 2020

Personalized Medicine: Recent Progress in Cancer Therapy.

Cancers (Basel) 2020 Apr 19;12(4). Epub 2020 Apr 19.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain.

Translational research has revolutionized how we develop new treatments for cancer patients. The change from an organ-centric concept guiding treatment choice towards deep molecular analysis, driving a personalized approach, is one of the most important advances of modern oncology. Several tools such as next generation sequencing and RNA sequencing have greatly improved the capacity to detect predictive and prognostic molecular alterations. Detection of gene mutations, amplifications, and fusions has therefore altered the history of several diseases in both a localized and metastatic setting. This shift in perspective, in which attention is focused on the specific molecular alterations of the tumor, has opened the door to personalized treatment. This situation is reflected in the increasing number of basket trials selecting specific molecular targets. Nonetheless, some weaknesses need to be addressed. The complexity of cancer cells enriched with concomitant molecular alterations complicates identification of the driver. Moreover, tumor heterogeneity could be responsible for the lack of benefit when targeted agents are used. In light of this, there is growing interest in the role of multidisciplinary committees or molecular tumor boards to try to enhance selection. The aim of this review is to critically analyze the evolution of cancer treatment towards a precision approach, underlining some recent successes and unexpected failures.
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http://dx.doi.org/10.3390/cancers12041009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226371PMC
April 2020

In the literature: December 2018.

ESMO Open 2018 28;3(7):e000468. Epub 2018 Nov 28.

Department of Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, CIBERONC, Valencia, Spain.

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http://dx.doi.org/10.1136/esmoopen-2018-000468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6267463PMC
November 2018

NRF2 through RPS6 Activation Is Related to Anti-HER2 Drug Resistance in -Amplified Gastric Cancer.

Clin Cancer Res 2019 03 30;25(5):1639-1649. Epub 2018 Nov 30.

Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.

Purpose: Despite the clinical advantage of the combination of trastuzumab and platinum-based chemotherapy in -amplified tumors, resistance will eventually develop. The identification of molecular mechanisms related to primary and acquired resistance is needed.

Experimental Design: We generated lapatinib- and trastuzumab-resistant clones deriving from two different -amplified gastric cancer cell lines. Molecular changes such as protein expression and gene-expression profile were evaluated to detect alterations that could be related to resistance. Functional studies were corroborated . The translational relevance of our findings was verified in a patient cohort.

Results: We found RPS6 activation and NRF2 to be related to anti-HER2 drug resistance. RPS6 or NRF2 inhibition with siRNA reduced viability and resistance to anti-HER2 drugs. In knockdown cells for RPS6, a decrease of NRF2 expression was demonstrated, suggesting a potential link between these two proteins. The use of a PI3K/TORC1/TORC2 inhibitor, tested and , inhibited pRPS6 and NRF2 expression and caused cell and tumor growth reduction, in anti-HER2-resistant models. In a cohort of -amplified patients treated with trastuzumab and chemotherapy, a high level of NRF2 at baseline corresponds with worse progression-free survival.

Conclusions: NRF2 through the PI3K/AKT/mTOR/RPS6 pathway could be a potential effector of resistance to anti-HER2 drugs in our models. RPS6 inhibition decreases NRF2 expression and restores sensitivity in -amplified gastric cancer and . High NRF2 expression in gastric cancer patients predicts resistance to treatment. RPS6 and NRF2 inhibition could prevent resistance to anti-HER2 drugs.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2421DOI Listing
March 2019

Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity.

Clin Cancer Res 2017 Sep 9;23(18):5406-5415. Epub 2017 Jun 9.

Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany.

This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas. The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of mRNA and mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib. Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor and mRNA levels were associated with a numerically higher disease control rate but not ORR. The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher mRNA expression levels. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0812DOI Listing
September 2017

Epigenetic changes in localized gastric cancer: the role of RUNX3 in tumor progression and the immune microenvironment.

Oncotarget 2016 Sep;7(39):63424-63436

Medical Oncology, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain.

Gastric cancer (GC) pathogenesis involves genetic, epigenetic and environmental factors. Epigenetic alterations, such as DNA methylation are considered pivotal in the inactivation of tumor-related genes. We assessed a methylation panel of 5 genes to study their association to GC progression and microsatellite instability (MSI), and studied the role of RUNX3 in GC pathogenesis and the tumor immune microenvironment.The methylation status of 47 promoter-CpG islands was studied through MALDI-TOF mass spectrometry analysis in 35 Microsatellite stable (MSS) GC, 26 MSI, and 18 cancer-free samples (CFS), and 6 MSS GC and 4 MSI GC cell lines. We also studied RUNX3 expression by immunohistochemistry (IHC) in 40 samples, and validated differences in methylation levels between tumor, normal, and immune tissue in 14 additional samples.Unsupervised hierarchical clustering of methylation levels revealed no distinct subgroups between MSI and MSS samples or cell lines. CFSs clustered together showing higher levels of RUNX3 methylation compared to GC samples. RUNX3 showed protein silencing in cancer and normal mucosa, compared to inflammatory peritumoural infiltrate in almost all cases, showing a non-lymphocytic predominant pattern and being correlated with epigenetic silencing.Our results show aberrant promoter's methylation in APC, CDH1, CDKN2A, MLH1 and RUNX3 associated with GC, as well as a non-lymphocytic predominant infiltrate with high expression of RUNX3. Deep study of RUNX3 inflammation signaling could help in understanding inflammation and immune activation in the tumor microenvironment.
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http://dx.doi.org/10.18632/oncotarget.11520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325374PMC
September 2016

MassARRAY determination of somatic oncogenic mutations in solid tumors: Moving forward to personalized medicine.

Cancer Treat Rev 2016 Sep 29;49:57-64. Epub 2016 Jul 29.

Department of Hematology and Medical Oncology, Biomedical Research Institute-INCLIVA, University of Valencia, Av. Blasco Ibañez 17, 46010 Valencia, Spain. Electronic address:

This article will review the impact of the recently developed MassARRAY technology on our understanding of cancer biology and treatment. Analysis of somatic mutations is a useful tool in selecting personalized therapy, and for predicting the outcome of many solid tumors. Here, we review the literature on the application of MassARRAY technology (Sequenom Hamburg, Germany) to determine the mutation profile of solid tumors from patients. We summarize the use of commercially available panels of mutations - such as OncoCarta™ or other combinations - and their concordance with results obtained by using other technologies, such as next generation sequencing.
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http://dx.doi.org/10.1016/j.ctrv.2016.07.007DOI Listing
September 2016

Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.

Oncotarget 2016 May;7(22):32925-32

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors.
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http://dx.doi.org/10.18632/oncotarget.9076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078063PMC
May 2016

Determination of somatic oncogenic mutations linked to target-based therapies using MassARRAY technology.

Oncotarget 2016 Apr;7(16):22543-55

Hematology and Medical Oncology Unit, Biomedical Research Institute INCLIVA, Valencia, Spain.

Somatic mutation analysis represents a useful tool in selecting personalized therapy. The aim of our study was to determine the presence of common genetic events affecting actionable oncogenes using a MassARRAY technology in patients with advanced solid tumors who were potential candidates for target-based therapies. The analysis of 238 mutations across 19 oncogenes was performed in 197 formalin-fixed paraffin-embedded samples of different tumors using the OncoCarta Panel v1.0 (Sequenom Hamburg, Germany). Of the 197 specimens, 97 (49.2%) presented at least one mutation. Forty-nine different oncogenic mutations in 16 genes were detected. Mutations in KRAS and PIK3CA were detected in 40/97 (41.2%) and 30/97 (30.9%) patients respectively. Thirty-one patients (32.0%) had mutations in two genes, 20 of them (64.5%) initially diagnosed with colorectal cancer. The co-occurrence of mutation involved mainly KRAS, PIK3CA, KIT and RET. Mutation profiles were validated using a customized panel and the Junior Next-Generation Sequencing technology (GS-Junior 454, Roche). Twenty-eight patients participated in early clinical trials or received specific treatments according to the molecular characterization (28.0%). MassARRAY technology is a rapid and effective method for identifying key cancer-driving mutations across a large number of samples, which allows for a more appropriate selection for personalized therapies.
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http://dx.doi.org/10.18632/oncotarget.8002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008380PMC
April 2016

Phase II trial of irinotecan and metronomic temozolomide in patients with recurrent glioblastoma.

Anticancer Drugs 2016 Feb;27(2):133-7

aDepartment of Medical Oncology bResearch Center, Hospital Universitari i Politècnic La Fe cDepartment of Hematology and Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia dDepartment of Medical Oncology, Institut Català d'Oncologia, Badalona eDepartment of Medical Oncology, Hospital Clínico Universitario San Carlos fDepartment of Medical Oncology, Hospital Universitario Ramón y Cajal gDepartment of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid hDepartment of Medical Oncology, Hospital Regional Universitario Carlos Haya, Málaga iDepartment of Medical Oncology, Hospital Sant Pau jDepartment of Medical Oncology, Institut Català d'Oncologia-IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain.

This phase II study was conducted to determine the efficacy and safety of metronomic temozolomide (TMZ) in combination with irinotecan in glioblastoma (GB) at first relapse. Patients with GB at first relapse received TMZ 50 mg/m/2day divided into three doses, except for a single 100 mg/m2 dose, administered between 3 and 6 h before every irinotecan infusion. Irinotecan was given intravenously at the previously established dose of 100 mg/m2 on days 8 and 22 of 28-day cycles. Treatment was given for a maximum of nine cycles or until progression or unacceptable toxicity occurred. Vascular endothelial growth factor and its soluble receptor 1, thrombospondin-1, microparticles, and microparticle-dependent procoagulant activity were measured in blood before treatment. The primary objective was 6-month progression-free survival (PFS). Twenty-seven evaluable patients were enrolled. Six-month PFS was 20.8%. Median PFS was 11.6 weeks (95% confidence interval: 7.5-15.7). Stable disease was the best response for nine (37.5%) patients, with a median duration of 11.2 weeks (4.2-35.85 weeks). No differences in PFS or response were observed among patients who relapsed during or after completion of adjuvant TMZ. Grade 3/4 adverse events included lymphopenia (15%), fatigue, diarrhea and febrile neutropenia (3.7% each), lymphopenia, neutropenia, and nausea/vomiting (11.1% each). One patient died from pneumonia and one patient died from pulmonary thromboembolism. Pretreatment levels of angiogenesis biomarkers, microparticles, and microparticle-related procoagulant activity were elevated in patients compared with healthy volunteers. This regimen is feasible, but failed to improve the results obtained with other second-line therapies in recurrent GB.
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http://dx.doi.org/10.1097/CAD.0000000000000314DOI Listing
February 2016

Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer.

Oncotarget 2015 Sep;6(29):26935-45

Hematology and Medical Oncology Unit, Biomedical Research Institute INCLIVA, University of Valencia, 46010, Valencia, Spain.

Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.
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http://dx.doi.org/10.18632/oncotarget.4775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694964PMC
September 2015

Circulating endothelial cells and procoagulant microparticles in patients with glioblastoma: prognostic value.

PLoS One 2013 29;8(7):e69034. Epub 2013 Jul 29.

Servicio de Oncología Médica, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Aim: Circulating endothelial cells and microparticles are prognostic factors in cancer. However, their prognostic and predictive value in patients with glioblastoma is unclear. The objective of this study was to investigate the potential prognostic value of circulating endothelial cells and microparticles in patients with newly diagnosed glioblastoma treated with standard radiotherapy and concomitant temozolomide. In addition, we have analyzed the methylation status of the MGMT promoter.

Methods: Peripheral blood samples were obtained before and at the end of the concomitant treatment. Blood samples from healthy volunteers were also obtained as controls. Endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Microparticles were quantified by flow cytometry. Microparticle-mediated procoagulant activity was measured by endogen thrombin generation and by phospholipid-dependent clotting time. Methylation status of MGMT promoter was determined by multiplex ligation-dependent probe amplification.

Results: Pretreatment levels of circulating endothelial cells and microparticles were higher in patients than in controls (p<0.001). After treatment, levels of microparticles and thrombin generation decreased, and phospholipid-dependent clotting time increased significantly. A high pretreatment endothelial cell count, corresponding to the 99(th) percentile in controls, was associated with poor overall survival. MGMT promoter methylation was present in 27% of tumor samples and was associated to a higher overall survival (66 weeks vs 30 weeks, p<0.004).

Conclusion: Levels of circulating endothelial cells may have prognostic value in patients with glioblastoma.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069034PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726739PMC
February 2014

Circulating endothelial cells and microparticles as prognostic markers in advanced non-small cell lung cancer.

PLoS One 2012 15;7(10):e47365. Epub 2012 Oct 15.

Department of Medical Oncology, Hospital Universitario y Politécnico La Fe Valencia, Valencia, Spain.

Background: Circulating endothelial cells and microparticles have prognostic value in cancer, and might be predictors of response to chemotherapy and antiangiogenic treatments. We have investigated the prognostic value of circulating endothelial cells and microparticles in patients treated for advanced non-small cell lung cancer.

Methodology/principal Findings: Peripheral blood samples were obtained from 60 patients before first line, platinum-based chemotherapy +/- bevacizumab, and after the third cycle of treatment. Blood samples from 60 healthy volunteers were also obtained as controls. Circulating endothelial cells were measured by an immunomagnetic technique and immunofluorescence microscopy. Phosphatidylserine-positive microparticles were evaluated by flow cytometry. Microparticle-mediated procoagulant activity was measured by the endogen thrombin generation assay.

Results: pre- and posttreatment levels of markers were higher in patients than in controls (p<0.0001). Elevated levels of microparticles were associated with longer survival. Elevated pretreatment levels of circulating endothelial cells were associated with shorter survival.

Conclusions/significance: Circulating levels of microparticles and circulating endothelial cells correlate with prognosis, and could be useful as prognostic markers in patients with advanced non-small cell lung cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0047365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471832PMC
July 2013

Circulating endothelial and endothelial progenitor cells in non-small-cell lung cancer.

Clin Transl Oncol 2010 Aug;12(8):521-5

Medical Oncology Department, La Fe University Hospital, Valencia, Spain.

New treatments have recently been introduced for treating non-small-cell lung cancer. Chemotherapeutic agents, such as pemetrexed, and targeted therapies, such as bevacizumab, erlotinib or gefitinib, have extended treatment options for selected histological subgroups. Antiangiogenic treatments, either associated with conventional chemotherapeutic drugs or given alone as maintenance therapy, constitute an active clinical research field. However, not all lung cancer patients benefit from antiangiogenic compounds. Moreover, tumour response assessment is often difficult when using these drugs, since targeted therapies generally do not cause rapid and measurable tumour shrinkage but, rather, long stabilisations and slight density changes on imaging tests. The finding of clinical or biological factors that might identify patients who will better benefit from these treatments, as well as identifying surrogate markers of tumour response and prognosis, is an issue of great interest. In that sense, different research lines have investigated the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) pathways. Circulating endothelial (CECs) and endothelial progenitor cells (CEPCs) are of prognostic value in different types of cancers, and relevant data are published about their potential usefulness as predictors of response to chemotherapy and antiangiogenic treatments. In this review, we discuss the data available on the role of CECs and CEPCs as prognostic factors and as surrogate markers of treatment response in non-small-cell lung cancer.
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http://dx.doi.org/10.1007/s12094-010-0549-xDOI Listing
August 2010

Circulating markers of angiogenesis, inflammation, and coagulation in patients with glioblastoma.

J Neurooncol 2011 Mar 6;102(1):35-41. Epub 2010 Jul 6.

Servicio de Oncología Médica, Hospital Universitario La Fe, Avda. Campanar 21, 46009 Valencia, Spain.

Inflammation, angiogenesis, and coagulation are linked to the development of cancer. In glioblastoma, microvascular proliferation is a hallmark, and lymphocytic infiltration is a common finding. Thromboses are frequent in patients with glioblastoma. The objective of this study was to assess presurgical levels of circulating markers of inflammation, angiogenesis, and coagulation in a prospective series of patients with glioblastoma, and to explore their correlations and possible associations with clinical findings. Angiogenesis markers included were vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor-receptor 1 (sVEGFR-1), and thrombospondin-1 (TSP-1). Inflammatory markers included were C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and sialic acid (SA). Coagulation markers included were fibrinogen (Fg), endogen thrombin generation (ETG), prothrombin fragments 1 + 2 (F1 + 2), and tissue factor (TF). Forty-seven patients and 60 healthy subjects were included in the study. Signs of tumor necrosis in presurgical MRI were associated with shorter survival (P < 0.01). All inflammation markers, F1 + 2, ETG, VEGF and sVEGFR-1, were significantly elevated in glioblastoma patients. Correlations were found between ETG and Fg (r = 0.44, P < 0.01). Sialic acid correlated with Fg (r = 0.63, P < 0,001); CPR correlated with SA (r = 0.60, P < 0.001), Fg (r = 0.76, P < 0.001), TNFα (r = 0.56, P < 0.001), and IL-6 (r = 0.65, P < 0.001); and IL-6 also correlated positively with TNFα (r = 0.40, P < 0.02) and Fg (r = 0.45, P < 0.01). Vascular endothelial growth factor inversely correlated with sVEGFR-1 (r = -0.35, P < 0.02). No associations were found between marker levels and survival or progression-free survival.
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http://dx.doi.org/10.1007/s11060-010-0290-xDOI Listing
March 2011

Paraneoplastic hyperinsulinism and secondary hypoglycaemia in a patient with advanced colon cancer: a rare association.

World J Gastroenterol 2008 Mar;14(12):1952-4

Medical Oncology Unit, University Hospital La Fe, Avenida Campanar 19-21, Valencia 46009, Spain.

We review the case of a 74-year-old patient with advanced colon cancer who suffered recurrent bouts of hypoglycemia. A state of inappropriate, non-suppressed hyperinsulinism in the presence of severe hypoglycemia was diagnosed. We finally discuss the known mechanisms behind fasting hypoglycemia in patients with advanced cancer, the diagnosis, and possible treatments of this rare paraneoplastic endocrine complication.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2700411PMC
http://dx.doi.org/10.3748/wjg.14.1952DOI Listing
March 2008
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