[18F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: Usefulness of different quantitative methods of tumor proliferation | Revista Española de Medicina Nuclear e Imagen Molecular

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Conventional planar images after 2h(A), show two hot spots in the right cervical area that were considered as sentinel nodes. The 3-dimensional reconstruction of the SPECT/CT (B) gives important information of the precise localization of the sentinel nodes (levels II and III). In this case the portable gamma camera (D,E) was used successfully for a precise skin marking of the two sentinel nodes." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Borbón-Arce, O.R. Brouwer, N.S. van den Berg, H. Mathéron, W.M.C. Klop, A.J.M. Balm, F.W.B. van Leeuwen, R.A. Valdés-Olmos" "autores" => array:8 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Borbón-Arce" ] 1 => array:2 [ "nombre" => "O.R." "apellidos" => "Brouwer" ] 2 => array:2 [ "nombre" => "N.S." "apellidos" => "van den Berg" ] 3 => array:2 [ "nombre" => "H." "apellidos" => "Mathéron" ] 4 => array:2 [ "nombre" => "W.M.C." "apellidos" => "Klop" ] 5 => array:2 [ "nombre" => "A.J.M." "apellidos" => "Balm" ] 6 => array:2 [ "nombre" => "F.W.B." "apellidos" => "van Leeuwen" ] 7 => array:2 [ "nombre" => "R.A." "apellidos" => "Valdés-Olmos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2253654X14000195?idApp=UINPBA00004N" "url" => "/2253654X/0000003300000005/v1_201408270842/S2253654X14000195/v1_201408270842/en/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Original" "titulo" => "[18F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: Usefulness of different quantitative methods of tumor proliferation" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "280" "paginaFinal" => "285" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "J.M. Marti-Climent, I. Dominguez-Prado, M.J. Garcia-Velloso, V. Boni, I. Peñuelas, I. Toledo, J.A. Richter" "autores" => array:7 [ 0 => array:4 [ "nombre" => "J.M." "apellidos" => "Marti-Climent" "email" => array:1 [ 0 => "jmmartic@uanv.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "I." "apellidos" => "Dominguez-Prado" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "M.J." "apellidos" => "Garcia-Velloso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "V." "apellidos" => "Boni" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 4 => array:3 [ "nombre" => "I." "apellidos" => "Peñuelas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "I." 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"apellidos" => "Richter" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Nuclear, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Departamento de Oncología Médica, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "[18F]fluortimidina-PET en pacientes con carcinoma de mama localmente avanzado en tratamiento con bevacizumab: utilidad de diferentes métodos de cuantificación de la proliferación celular" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1162 "Ancho" => 2176 "Tamanyo" => 78986 ] ] "descripcion" => array:1 [ "en" => "[18F]FLT PET scan in the breast tumor before (A) and after (B) a single infusion of bevacizumab. A decrease of the PET parameters was observed: SUV40 from 4.57 to 3.33, SUV50 from 4.35 to 3.52, Ki_LV from 0.109 to 0.078 and Ki_DA from 0.128 to 0.098." ] ] ] "textoCompleto" => "IntroductionBreast cancer is the most frequent neoplasm in women and the most frequent cause of death in women between 35 and 55 years of age. Five-year overall survival is estimated to be 65%, with large disparities between stages. At the time of the diagnosis up to 20% of breast cancer patients present a locally advanced breast cancer (LABC) without distant metastases.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The current standard of care for LABC is preoperative systemic therapy (PST). In general, 60–90% of patients achieve clinical response to PST.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> Complete pathologic remissions (pCR) are, however, noted in only 3–30% of patients in most breast cancer trials.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> These patients have improved survival compared with patients achieving a less than pCR. An ideal setting for preoperative chemotherapy would be to give the most sensitive and effective chemotherapy drug regimen to the patient to increase the fraction of pCR achieved. In the last years, special attention was directed on the identification of molecular profiles and predictive biomarkers associated with pCR.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> PST offers the ability to discern treatment effect in vivo and ultimately may allow the identification of useful biomarkers for individualization of treatment based on clinical, pathologic, image-guided, or molecular assessment of the tumor during initial treatment.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The monoclonal antibody to the vascular endothelial growth factor (VEGF) bevacizumab (Avastin, Genetech) is routinely used in different tumor types,<a class="elsevierStyleCrossRefs" href="#bib0030">6–10</a> including metastatic breast cancer, based on results from the E2100 phase III study conducted in 722 patients.<a class="elsevierStyleCrossRef" href="#bib0040">8</a> This study showed that bevacizumab substantially improves the progression-free-survival, but not overall survival, of metastatic breast cancer when compared with single-agent paclitaxel. Currently, its role in the preoperative setting together with the identification of predictive biomarkers has become an important field of research. Wedam et al.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> showed that bevacizumab alone followed by bevacizumab with doxorubicin/docetaxel in patients with inflammatory breast cancer resulted in a 70% clinical response.Currently no validated biomarkers exist for appropriate selection of patients with cancer for antiangiogenic therapy; however, a number of systemic, circulating, tissue and imaging biomarkers are emerging. PET is a non-invasive imaging modality that offers the possibility to visualize in vivo different metabolic cellular processes and tumor biology. Recently, García García-Esquinas et al.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> have demonstrated that SUVmax percentage changes (ΔSUVmax) in PET-CT could accurately predict pCR to neoadjuvant chemotherapy (NAC) of breast cancer patients. Forty-three women with stage II–III breast cancer were included in their study. FDG PET-CT was performed at baseline and after NAC, and ΔSUVmax were compared with pathologic findings at surgery. They obtained an accuracy of 90.7% to predict tumor response. 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) has been evaluated for detecting and staging different tumor types.<a class="elsevierStyleCrossRefs" href="#bib0065">13–15</a> [18F]FLT kinetics has been investigated during treatment of recurrent high-grade brain tumors with bevacizumab and irinotecan.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> High correlation was found between [18F]FLT uptake in tumor (SUV) and influx rate constant (Ki), indicating that [18F]FLT PET is a potential useful imaging biomarker for therapy monitoring with prognostic value. Thus, imaging tumor proliferation with [18F]-FLT PET could offer a new approach to assessing tumor growth kinetics. The ability of [18F]FLT imaging to provide an early measure of treatment response has been demonstrated in several preclinical and clinical studies with a variety of tumor types.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> The PET data have also been correlated with biological factors. García Vicente et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> correlated biological parameters and semiquantitative metabolic parameters in 36 women with locally advanced breast cancer.This study was included in a multicenter, prospective, phase II clinical trial, designed to identify biomarkers of response to bevacizumab therapy in the preoperative setting in patients with untreated LABC. A dose of bevacizumab alone (15mg/kg) was administered in cycle 1, and bevacizumab in combination with adriamicine and docetaxel were administered for cycle 2 through cycle 5. After PST all patients underwent surgery. We sought to determine whether tumor sampling techniques can be replaced with non-invasive imaging methods to assess tumor changes following neoadjuvant bevacizumab treatment. The status of biomarkers and tumor imaging profiles before treatment, together with changes after treatment, may allow prediction of sensitivity or resistance to anti-VEGF agents and provide an opportunity to understand their mechanism of action.The objectives of the present report were to evaluate different quantitative methods to monitor tumor proliferative changes using [18F]FLT-PET in patients with LABC, studied before and after a single infusion of bevacizumab, and to study if changes observed in [18F]FLT before and after the antiangiogenesis therapy correlates with those observed in the immunohistochemical biomarker of proliferation Ki67.Material and methodsPatient selectionThirty women with newly diagnosed, biopsy-proven, untreated LABC were enrolled [mean age: 50±10 years (35–69 years)]. Patients were required to be at least 18 year old, be cancer-free for the previous 5 years, not be pregnant or breastfeeding, and able to give informed consent and to lie still for the duration of the study.This study, as a part of a clinical trial, was conducted under protocols approved by the institutional review board/independent Ethics Committee, Human Subjects Division and Radiation Safety Committee at each study center and patients signed informed consent at the hospital before enrollment.[18F]FLT synthesis[18F]FLT was automatically synthesized and prepared for human use in our institution. Syntheses and quality control strictly followed the Standard Operational Procedures (SOPs) and were subject to inspection. The labeling yield, radiochemical purity, and specific radioactivity of [18F]FLT were checked and recorded after each production.All reagents were obtained with the highest purity available and were used without further purification. The precursor 3-N-Boc-5′-O-dimethoxytrityl-3′-O-nosyl-thymidine was purchased from ABX Advanced Biomedical Compounds (Germany).The synthesis process was based on other previously published methods<a class="elsevierStyleCrossRef" href="#bib0090">18</a> and developed by our team using Eckert & Ziegler “Modular Lab System”. Briefly, [18F]fluoride was obtained by irradiation of H218O, concentrated by azeotropic distillation and 25mg of the Boc precursor in 1mL of acetonitrile were added to the dried [18F]fluoride residue. The nucleophilic substitution reaction was carried out at 110°C, the reaction mixture hydrolized with 1N HCl, neutralized and injected into the semi-preparative HPLC system (C18 column). Using H2O/EtOH (92/8) as mobile phase, [18F]FLT eluted at around min 19. The product fraction was filtered into a sterile multidose vial through two 0.22μm sterile filters. The final yield of the synthesis was usually 15% (uncorrected) with a radiochemical purity >97%.PET scan and reconstructionEach patient was scheduled to have two PET evaluations. Baseline [18F]FLT scans were scheduled preceding the commencement of treatment. Patients continued in the study irrespective of whether [18F]FLT tumor uptake was identified on the baseline scan to explore whether lesions initially undetectable by [18F]FLT might become visible during treatment. On-treatment [18F]FLT PET scans were performed 14 days after a single bevacizumab dose (15mg/kg), in order to capture information regarding initial DNA damage to cells and early response to treatment.The PET scans were carried out in an ECAT EXACT HR+ scanner (CTI-Siemens, Knoxville, USA). The patient was placed with the tumor centered in the field of view (15.2cm).<a class="elsevierStyleCrossRef" href="#bib0095">19</a> A 5min transmission study with three 68Ge sources was conducted in order to perform the attenuation correction. Simultaneously with a bolus injection of 385±56MBq (10.4±1.5mCi) [18F]FLT, a dynamic acquisition started in 2D mode with a total duration of 60min, with a sequence 6×5s, 6×10s, 3×20s, 5×30s, 5×60s, 8×150s, 6×300s.The reconstruction was performed as 128×128 matrices using ordered-subset expectation maximization (OSEM) with two iterations and 8 subsets followed by a postsmoothing of the reconstructed image using a 5mm FWHM Gaussian filter. Corrections were applied to account for scattered photons, random events and photon attenuation. Each frame of the dynamic study had 63 axial slices.Other proceduresWithin 24h after the completion of the PET studies, before and after treatment with bevacizumab, an ultrasound-guided biopsy of the tumor was performed. The Ki67 index of cell proliferation in these biopsies was determined.[18F]FLT quantificationFor the quantification of [18F]FLT PET studies, Patlak graphical analysis<a class="elsevierStyleCrossRef" href="#bib0100">20</a> was carried out with an input function obtained from the image (image derived input function, IDIF).<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a> Two input functions were obtained using spherical volumes of interest (VOI) (15mm diameter) drawn on the left ventricle (LV) and on the descending aorta (DA) in the early image 25–50s after administration of [18F]FLT as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a. These volumes were applied to the dynamic study to obtain, from the mean value functions, the input curves for the kinetic model (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>The input functions were corrected for the presence of metabolites. For this purpose we used the metabolite fractions according to the Schiepers formula<a class="elsevierStyleCrossRef" href="#bib0115">23</a>:<elsevierMultimedia ident="eq0005"></elsevierMultimedia>Patlak analysis was performed using the PMOD 3.0 software (PMOD Technologies Ltd., Adliswil, Switzerland) in the time interval between 10 and 60min after injection, determining the influx constant (Ki). Two constants were obtained, considering the input function from the left ventricle (Ki_LV) and the curve from the descending aorta (Ki_DA).The dynamic study was used to obtain PET images equivalent to a static PET study at the end of the dynamic sequence, corresponding to the time intervals 40–60min and 50–60min, which corresponds to studies of 20 and 10min starting 40–50min after administration of the radiopharmaceutical. These images allowed quantifying the standardized uptake value (SUV) SUV40 and SUV50 respectively. SUV values were derived from the maximum uptake in the tumor.Changes in tumor proliferation before and after treatment were calculated according to the formula:<elsevierMultimedia ident="eq0010"></elsevierMultimedia>Statistical analysisWe analyzed the descriptive parameters, the correlation and the concordance between the quantitative variables PET (SUV and Ki constant), and PET parameters were also correlated with cell proliferation index Ki67. Statistical analysis was performed using SPSS software (version 15.0; IBM).ResultsThe statistical parameters of SUV values and Ki influx constant of both scans are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>, and the corresponding box plots are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>. The four parameters used to quantify cell proliferation showed a statistically significant reduction after treatment compared to baseline values. Mean decrease of SUV50, SUV40, Ki_LV and Ki_DA were 26%, 27%, 27% and 31% respectively, while the constant Ki67 felt 14 units. Statistically significant differences (p<0.05) between the influx constants Ki_LV and Ki_DA in the post-bevacizumab treatment PET scan were also observed. An example of the bevacizumab treatment effect in a patient is illustrated in <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>, where a decrease of the four PET quantitative parameters studied is presented.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>Changes in the SUV50 and Ki_DA PET parameters between basal state and after bevacizumab treatment showed a moderate correlation with changes in the Ki67 index (Pearson r=0.35 and 0.26, respectively). SUV50 changes were more accurate (p=0.06) than changes in Ki_DA (p=0.16). Changes in SUV40 and Ki_LV showed a weaker correlation with the Ki67 reduction than SUV50 and Ki_DA (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). The percentage of patients that had lower [18F]FLT uptake after the bevacizumab treatment was 97 and 93% according to SUV50 and SUV40 measurements respectively.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>The agreement within the two SUV measures and within the two influx constants were studied evaluating the interclass correlation coefficient (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). The accordance degree was almost perfect (ICC>0.81) in the 4 comparisons, showing the interchangeability of quantitative data between SUV40 and SUV50 and between Ki_LV and Ki_DA.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>The correlation between the SUV values in tumors with the corresponding Ki influx constant, obtained at baseline and after treatment, is illustrated in <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>. A stronger and significant correlation was found for Ki obtained with the input function from the left ventricle than the one obtained from the descending aorta (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>Discussion[18F]FLT is phosphorylated by thymidine kinase-1 (TK1) and trapped inside the cell. The application of [18F]FLT phosphorylation as a biomarker of cell proliferation is based in the assumption that cellular [18F]FLT trapping is a representation of TK1 activity, which reflects the DNA synthesis.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> [18F]FLT-PET has been shown to be useful in predicting breast cancer responses to therapy<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and it has been investigated during treatment of recurrent high-grade brain tumors with bevacizumab and irinotecan.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> In this study we have investigated the usefulness of different [18F]FLT-PET quantitative methods in patients with LABC, studied before and after a single infusion of bevacizumab, within a multicenter, prospective, phase II clinical trial.Van der Weerdt et al.<a class="elsevierStyleCrossRef" href="#bib0105">21</a> proposed the use of the ascending aorta as the structure of choice for defining IDIF and a large region of interest (ROI with 15mm diameter, approximately) to minimize the effects of statistical noise. They also found that ascending aorta and DA had lower interobserver variation when applied to myocardial metabolic rate of glucose determination, compared with the use of left ventricle. De Langen et al.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> used IDIF with ROIs in the ascending aorta and aortic arch, but in our study the VOI were not always possible to be correctly drawn because the scanner field of view was centered in the breast tumor. Our results showed that Ki changes after an infusion of bevacizumab evaluated using IDIF obtained from the DA had a slightly higher correlation with the Ki67 index change than with those Ki changes obtained using the LV.Ki and SUV obtained from the maximum values showed similar correlation with the proliferation index Ki67, although SUV obtained from a static acquisition required a shorter protocol and data analysis easier to be performed than needed for the influx constant evaluation. The latter was simplified using a modeled metabolic fraction<a class="elsevierStyleCrossRef" href="#bib0115">23</a> that allowed the use of image derived input functions, without the need of blood sampling and further analysis.Correlation between SUV values and the influx constant obtained with the LV derived input function were higher than those where the structure used was the DA. This is related to the higher dispersion of the Ki values obtained in the DA compared with those from the LV. These high correlation coefficients indicate that simple semiquantitative analysis (SUV) might be sufficient for clinical applications, as has been suggested by others.<a class="elsevierStyleCrossRef" href="#bib0070">14</a>In these 30 patients of this multicenter clinical trial, the interclass correlation coefficient showed the interchangeability within the standard uptake values obtained at the time interval 40–60 and 50–60min post-administration of [18F]FLT, and within the influx constant Ki obtained with the image derived input function using the LV and the DA as structures.In conclusion, [18F]FLT-PET is a non-invasive imaging technique that allowed the evaluation of tumor proliferation, by assessing the activity of the enzyme thymidine kinase. The [18F]FLT-PET quantification has demonstrated proliferative changes after a single dose of bevacizumab in patients with LABC. In our population, quantification of tumor proliferation through the SUV and the Patlak influx constant, with input function derived image, have shown similar results in the evaluation of bevacizumab therapy in patients with LABC previously untreated. Nevertheless, it is suggested to extend these quantitative methods to a longer series of patients, to corroborate our results.FundingThis study is part of a clinical trial funded by F. Hoffman-La Roche Ltd y Roche España.Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres364721" "titulo" => array:5 [ 0 => "Abstract" 1 => "Objectives" 2 => "Material and methods" 3 => "Results" 4 => "Conclusions" ] ] 1 => array:2 [ "identificador" => "xpalclavsec344341" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres364720" "titulo" => array:5 [ 0 => "Resumen" 1 => "Objetivos" 2 => "Material y métodos" 3 => "Resultados" 4 => "Conclusiones" ] ] 3 => array:2 [ "identificador" => "xpalclavsec344340" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Patient selection" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "[F]FLT synthesis" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "PET scan and reconstruction" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Other procedures" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "[F]FLT quantification" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack90862" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-12-13" "fechaAceptado" => "2014-01-24" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec344341" "palabras" => array:6 [ 0 => "FLT" 1 => "Fluorothymidine" 2 => "Breast cancer" 3 => "Bevacizumab" 4 => "PET" 5 => "Angiogenesis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec344340" "palabras" => array:6 [ 0 => "FLT" 1 => "Fluortimidina" 2 => "Cáncer de mama" 3 => "Bevacizumab" 4 => "PET" 5 => "Angiogénesis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "ObjectivesTo investigate quantitative methods of tumor proliferation using 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) PET in patients with breast cancer (BC), studied before and after one bevacizumab administration, and to correlate the [18F]FLT-PET uptake with the Ki67 index. Material and methodsThirty patients with newly diagnosed, untreated BC underwent a [18F]FLT-PET before and 14 days after bevacizumab treatment. A dynamic scan centered over the tumor began simultaneously with the injection of [18F]FLT (385±56MBq). Image derived input functions were obtained using regions of interest drawn on the left ventricle (LV) and descending aorta (DA). Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis (time interval 10–60min after injection). Maximum SUV values were derived for the intervals 40–60min (SUV40) and 50–60min (SUV50). PET parameters were correlated with the Ki67 index obtained staining tumor biopsies. Results[18F]FLT uptake parameters decreased significantly (p<0.001) after treatment: SUV50=3.09±1.21 vs 2.22±0.96; SUV40=3.00±1.18 vs 2.14±0.95, Ki_LV(10–3)=52[22–116] vs 38[13–80] and Ki_DA(10–3)=49[15–129] vs 33[11–98]. Consistency interclass correlation coefficients within SUV and within Ki were high. Changes of SUV50 and Ki_DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index (r-Pearson=0.35 and 0.26, p=0.06 and 0.16, respectively). Conclusions[18F]FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC. Quantification of tumor proliferation by means of SUV and Ki has shown similar results, but SUV50 obtained better results. A correlation between [18F]FLT changes and Ki67 index was observed." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "ObjetivosEvaluar métodos cuantitativos de proliferación celular en PET con 3′-[18F]fluoro-3′-desoxitimidina ([18F]FLT), antes y después de una dosis de bevacizumab en pacientes con carcinoma de mama (CM), y correlacionar la captación de [18F]FLT con el índice Ki67. Material y métodosSe incluyeron 30 mujeres con CM no tratado. Se realizó [18F]FLT-PET antes y 14 días después de una dosis de bevacizumab. La PET dinámica centrada en el tumor se inició simultáneamente con la infusión de [18F]FLT (385±56MBq). Se dibujaron regiones de interés en ventrículo izquierdo (VI) y aorta descendente (AD), obteniéndose funciones de entrada, que corregidas por metabolitos, se utilizaron para obtener la constante Ki de Patlak (intervalo: 10-60min). Se calcularon valores máximos del SUV en los intervalos 40-60min (SUV40) y 50-60min (SUV50). Los parámetros PET se correlacionaron con el Ki67, obtenido en biopsias tumorales teñidas. ResultadosLos parámetros de la captación de [18F]FLT disminuyeron significativamente (p<0,001) tras el tratamiento: SUV50=3,09±1,21 vs 2,22±0,96; SUV40=3,00±1,18 vs 2,14±0,95, Ki_VI(10-3)=52[22–116] vs 38[13–80] y Ki_AD(10-3)=49[15–129] vs 33[11–98]. Los coeficientes de correlación intraclase fueron elevados en los SUV y en los Ki. Los cambios de SUV50 y Ki_AD entre la PET basal y la PET tras bevacizumab se correlacionaron con los cambios en el Ki67 (r-Pearson=0,35 y 0,26, p=0,06 y 0,16, respectivamente). ConclusionesLa [18F]FLT-PET refleja los cambios en la proliferación celular tras una dosis de bevacizumab en pacientes con CM. La cuantificación de la proliferación por medio del SUV y la Ki arrojó resultados similares, si bien fueron mejores con el SUV50. Los cambios en [18F]FLT se correlacionaron con los cambios en el índice Ki67." ] ] "multimedia" => array:10 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1558 "Ancho" => 1308 "Tamanyo" => 112200 ] ] "descripcion" => array:1 [ "en" => "Patlak analysis: (A) example of volumes of interest in the left ventricle and descending aorta structures for image derived input function determination (B)." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1234 "Ancho" => 2505 "Tamanyo" => 97959 ] ] "descripcion" => array:1 [ "en" => "Box-plot of the quantitative parameters SUV and influx rate constant Ki (min−1) before and after an infusion of bevacizumab." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1162 "Ancho" => 2176 "Tamanyo" => 78986 ] ] "descripcion" => array:1 [ "en" => "[18F]FLT PET scan in the breast tumor before (A) and after (B) a single infusion of bevacizumab. A decrease of the PET parameters was observed: SUV40 from 4.57 to 3.33, SUV50 from 4.35 to 3.52, Ki_LV from 0.109 to 0.078 and Ki_DA from 0.128 to 0.098." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1756 "Ancho" => 2178 "Tamanyo" => 179487 ] ] "descripcion" => array:1 [ "en" => "Correlation between Ki67 change and PET change before and after a bevacizumab infusion (Spearman Rho)." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1358 "Ancho" => 1707 "Tamanyo" => 138887 ] ] "descripcion" => array:1 [ "en" => "Correlation between SUV values and the Patlak influx constant, pre and post the bevacizumab administration." ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Parameter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Post-treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">p value \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.09±1.21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.22±0.96 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3.00±1.18 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.14±0.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_LV (10−3min−1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">52 [22–116] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">38 [13–80] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_DA (10−3min−1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">49 [15–129] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 [11–98] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><0.001 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab547469.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Descriptive statistics, mean±standard deviation or median [range], for 18F-FLT quantitative parameters of basal and post treatment scans." ] ] 6 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">PET \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Compared parameters \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Coefficient \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.992 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Post-treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.992 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Basal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_LV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_DA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.933 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Post-treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_LV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_DA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.874 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab547468.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Interclass correlation coefficient within PET quantitative parameters." ] ] 7 => array:7 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Correlation \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Pre-treatment \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" style="border-bottom: 2px solid black">Post-treatment \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_LV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.877 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.898 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_DA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.694 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.781 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_LV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.868 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.859 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">SUV40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ki_DA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.684 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.766 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab547470.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Correlation between SUV measures and influx constant before and after a single bevacizumab infusion. All correlations (Spearman rho) were statistically significant (p<0.001)." ] ] 8 => array:5 [ "identificador" => "eq0005" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "Metabolite fraction=0.42[1−exp(−0.029t)]" "Fichero" => "si1.jpeg" "Tamanyo" => 2891 "Alto" => 15 "Ancho" => 316 ] ] 9 => array:5 [ "identificador" => "eq0010" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "%   change=[F18]FLT post-treatment−[F18]FLT pre-treatment[F18]FLT pre-treatment×100" "Fichero" => "si2.jpeg" "Tamanyo" => 6590 "Alto" => 59 "Ancho" => 436 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:24 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Cancer statistics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. 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[18F]fluorothymidine-positron emission tomography in patients with locally advanced breast cancer under bevacizumab treatment: Usefulness of different quantitative methods of tumor proliferation

[18F]fluortimidina-PET en pacientes con carcinoma de mama localmente avanzado en tratamiento con bevacizumab: utilidad de diferentes métodos de cuantificación de la proliferación celular

J.M. Marti-Climenta,

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jmmartic@uanv.es

Corresponding author.

, I. Dominguez-Pradoa, M.J. Garcia-Vellosoa, V. Bonib, I. Peñuelasa, I. Toledoc, J.A. Richtera

a Servicio de Medicina Nuclear, Clínica Universidad de Navarra, Pamplona, Spain

b Departamento de Oncología Médica, Clínica Universidad de Navarra, Pamplona, Spain

c Departamento de Medicina Preventiva y Salud Pública, Facultad de Medicina, Universidad de Navarra, Pamplona, Spain

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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT PET scan in the breast tumor before &#40;A&#41; and after &#40;B&#41; a single infusion of bevacizumab&#46; A decrease of the PET parameters was observed&#58; SUV40 from 4&#46;57 to 3&#46;33&#44; SUV50 from 4&#46;35 to 3&#46;52&#44; Ki&#95;LV from 0&#46;109 to 0&#46;078 and Ki&#95;DA from 0&#46;128 to 0&#46;098&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Breast cancer is the most frequent neoplasm in women and the most frequent cause of death in women between 35 and 55 years of age&#46; Five-year overall survival is estimated to be 65&#37;&#44; with large disparities between stages&#46; At the time of the diagnosis up to 20&#37; of breast cancer patients present a locally advanced breast cancer &#40;LABC&#41; without distant metastases&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The current standard of care for LABC is preoperative systemic therapy &#40;PST&#41;&#46; In general&#44; 60&#8211;90&#37; of patients achieve clinical response to PST&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Complete pathologic remissions &#40;pCR&#41; are&#44; however&#44; noted in only 3&#8211;30&#37; of patients in most breast cancer trials&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> These patients have improved survival compared with patients achieving a less than pCR&#46; An ideal setting for preoperative chemotherapy would be to give the most sensitive and effective chemotherapy drug regimen to the patient to increase the fraction of pCR achieved&#46; In the last years&#44; special attention was directed on the identification of molecular profiles and predictive biomarkers associated with pCR&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> PST offers the ability to discern treatment effect in vivo and ultimately may allow the identification of useful biomarkers for individualization of treatment based on clinical&#44; pathologic&#44; image-guided&#44; or molecular assessment of the tumor during initial treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The monoclonal antibody to the vascular endothelial growth factor &#40;VEGF&#41; bevacizumab &#40;<span class="elsevierStyleItalic">Avastin</span>&#44; Genetech&#41; is routinely used in different tumor types&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;10</span></a> including metastatic breast cancer&#44; based on results from the E2100 phase III study conducted in 722 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> This study showed that bevacizumab substantially improves the progression-free-survival&#44; but not overall survival&#44; of metastatic breast cancer when compared with single-agent paclitaxel&#46; Currently&#44; its role in the preoperative setting together with the identification of predictive biomarkers has become an important field of research&#46; Wedam et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> showed that bevacizumab alone followed by bevacizumab with doxorubicin&#47;docetaxel in patients with inflammatory breast cancer resulted in a 70&#37; clinical response&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Currently no validated biomarkers exist for appropriate selection of patients with cancer for antiangiogenic therapy&#59; however&#44; a number of systemic&#44; circulating&#44; tissue and imaging biomarkers are emerging&#46; PET is a non-invasive imaging modality that offers the possibility to visualize in vivo different metabolic cellular processes and tumor biology&#46; Recently&#44; Garc&#237;a Garc&#237;a-Esquinas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> have demonstrated that SUVmax percentage changes &#40;&#916;SUVmax&#41; in PET-CT could accurately predict pCR to neoadjuvant chemotherapy &#40;NAC&#41; of breast cancer patients&#46; Forty-three women with stage II&#8211;III breast cancer were included in their study&#46; FDG PET-CT was performed at baseline and after NAC&#44; and &#916;SUVmax were compared with pathologic findings at surgery&#46; They obtained an accuracy of 90&#46;7&#37; to predict tumor response&#46; 3&#8242;-&#91;<span class="elsevierStyleSup">18</span>F&#93;fluoro-3&#8242;-deoxythymidine &#40;&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT&#41; has been evaluated for detecting and staging different tumor types&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#8211;15</span></a> &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT kinetics has been investigated during treatment of recurrent high-grade brain tumors with bevacizumab and irinotecan&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> High correlation was found between &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT uptake in tumor &#40;SUV&#41; and influx rate constant &#40;Ki&#41;&#44; indicating that &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT PET is a potential useful imaging biomarker for therapy monitoring with prognostic value&#46; Thus&#44; imaging tumor proliferation with &#91;<span class="elsevierStyleSup">18</span>F&#93;-FLT PET could offer a new approach to assessing tumor growth kinetics&#46; The ability of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT imaging to provide an early measure of treatment response has been demonstrated in several preclinical and clinical studies with a variety of tumor types&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The PET data have also been correlated with biological factors&#46; Garc&#237;a Vicente et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> correlated biological parameters and semiquantitative metabolic parameters in 36 women with locally advanced breast cancer&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">This study was included in a multicenter&#44; prospective&#44; phase II clinical trial&#44; designed to identify biomarkers of response to bevacizumab therapy in the preoperative setting in patients with untreated LABC&#46; A dose of bevacizumab alone &#40;15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; was administered in cycle 1&#44; and bevacizumab in combination with adriamicine and docetaxel were administered for cycle 2 through cycle 5&#46; After PST all patients underwent surgery&#46; We sought to determine whether tumor sampling techniques can be replaced with non-invasive imaging methods to assess tumor changes following neoadjuvant bevacizumab treatment&#46; The status of biomarkers and tumor imaging profiles before treatment&#44; together with changes after treatment&#44; may allow prediction of sensitivity or resistance to anti-VEGF agents and provide an opportunity to understand their mechanism of action&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The objectives of the present report were to evaluate different quantitative methods to monitor tumor proliferative changes using &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET in patients with LABC&#44; studied before and after a single infusion of bevacizumab&#44; and to study if changes observed in &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT before and after the antiangiogenesis therapy correlates with those observed in the immunohistochemical biomarker of proliferation Ki67&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Patient selection</span><p id="par0025" class="elsevierStylePara elsevierViewall">Thirty women with newly diagnosed&#44; biopsy-proven&#44; untreated LABC were enrolled &#91;mean age&#58; 50<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10 years &#40;35&#8211;69 years&#41;&#93;&#46; Patients were required to be at least 18 year old&#44; be cancer-free for the previous 5 years&#44; not be pregnant or breastfeeding&#44; and able to give informed consent and to lie still for the duration of the study&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">This study&#44; as a part of a clinical trial&#44; was conducted under protocols approved by the institutional review board&#47;independent Ethics Committee&#44; Human Subjects Division and Radiation Safety Committee at each study center and patients signed informed consent at the hospital before enrollment&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT synthesis</span><p id="par0035" class="elsevierStylePara elsevierViewall">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT was automatically synthesized and prepared for human use in our institution&#46; Syntheses and quality control strictly followed the Standard Operational Procedures &#40;SOPs&#41; and were subject to inspection&#46; The labeling yield&#44; radiochemical purity&#44; and specific radioactivity of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT were checked and recorded after each production&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">All reagents were obtained with the highest purity available and were used without further purification&#46; The precursor 3-N-Boc-5&#8242;-O-dimethoxytrityl-3&#8242;-O-nosyl-thymidine was purchased from ABX Advanced Biomedical Compounds &#40;Germany&#41;&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The synthesis process was based on other previously published methods<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and developed by our team using Eckert &#38; Ziegler &#8220;Modular Lab System&#8221;&#46; Briefly&#44; &#91;<span class="elsevierStyleSup">18</span>F&#93;fluoride was obtained by irradiation of H<span class="elsevierStyleInf">2</span><span class="elsevierStyleSup">18</span>O&#44; concentrated by azeotropic distillation and 25<span class="elsevierStyleHsp" style=""></span>mg of the Boc precursor in 1<span class="elsevierStyleHsp" style=""></span>mL of acetonitrile were added to the dried &#91;<span class="elsevierStyleSup">18</span>F&#93;fluoride residue&#46; The nucleophilic substitution reaction was carried out at 110<span class="elsevierStyleHsp" style=""></span>&#176;C&#44; the reaction mixture hydrolized with 1<span class="elsevierStyleHsp" style=""></span>N HCl&#44; neutralized and injected into the semi-preparative HPLC system &#40;C18 column&#41;&#46; Using H<span class="elsevierStyleInf">2</span>O&#47;EtOH &#40;92&#47;8&#41; as mobile phase&#44; &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT eluted at around min 19&#46; The product fraction was filtered into a sterile multidose vial through two 0&#46;22<span class="elsevierStyleHsp" style=""></span>&#956;m sterile filters&#46; The final yield of the synthesis was usually 15&#37; &#40;uncorrected&#41; with a radiochemical purity &#62;97&#37;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PET scan and reconstruction</span><p id="par0050" class="elsevierStylePara elsevierViewall">Each patient was scheduled to have two PET evaluations&#46; Baseline &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT scans were scheduled preceding the commencement of treatment&#46; Patients continued in the study irrespective of whether &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT tumor uptake was identified on the baseline scan to explore whether lesions initially undetectable by &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT might become visible during treatment&#46; On-treatment &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT PET scans were performed 14 days after a single bevacizumab dose &#40;15<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41;&#44; in order to capture information regarding initial DNA damage to cells and early response to treatment&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">The PET scans were carried out in an ECAT EXACT HR&#43; scanner &#40;CTI-Siemens&#44; Knoxville&#44; USA&#41;&#46; The patient was placed with the tumor centered in the field of view &#40;15&#46;2<span class="elsevierStyleHsp" style=""></span>cm&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> A 5<span class="elsevierStyleHsp" style=""></span>min transmission study with three <span class="elsevierStyleSup">68</span>Ge sources was conducted in order to perform the attenuation correction&#46; Simultaneously with a bolus injection of 385<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>56<span class="elsevierStyleHsp" style=""></span>MBq &#40;10&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>mCi&#41; &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT&#44; a dynamic acquisition started in 2D mode with a total duration of 60<span class="elsevierStyleHsp" style=""></span>min&#44; with a sequence 6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>5<span class="elsevierStyleHsp" style=""></span>s&#44; 6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleHsp" style=""></span>s&#44; 3<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>s&#44; 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>s&#44; 5<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>60<span class="elsevierStyleHsp" style=""></span>s&#44; 8<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>s&#44; 6<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>s&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">The reconstruction was performed as 128<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>128 matrices using ordered-subset expectation maximization &#40;OSEM&#41; with two iterations and 8 subsets followed by a postsmoothing of the reconstructed image using a 5<span class="elsevierStyleHsp" style=""></span>mm FWHM Gaussian filter&#46; Corrections were applied to account for scattered photons&#44; random events and photon attenuation&#46; Each frame of the dynamic study had 63 axial slices&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Other procedures</span><p id="par0065" class="elsevierStylePara elsevierViewall">Within 24<span class="elsevierStyleHsp" style=""></span>h after the completion of the PET studies&#44; before and after treatment with bevacizumab&#44; an ultrasound-guided biopsy of the tumor was performed&#46; The Ki67 index of cell proliferation in these biopsies was determined&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT quantification</span><p id="par0070" class="elsevierStylePara elsevierViewall">For the quantification of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT PET studies&#44; Patlak graphical analysis<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> was carried out with an input function obtained from the image &#40;image derived input function&#44; IDIF&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> Two input functions were obtained using spherical volumes of interest &#40;VOI&#41; &#40;15<span class="elsevierStyleHsp" style=""></span>mm diameter&#41; drawn on the left ventricle &#40;LV&#41; and on the descending aorta &#40;DA&#41; in the early image 25&#8211;50<span class="elsevierStyleHsp" style=""></span>s after administration of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>a&#46; These volumes were applied to the dynamic study to obtain&#44; from the mean value functions&#44; the input curves for the kinetic model &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>b&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0075" class="elsevierStylePara elsevierViewall">The input functions were corrected for the presence of metabolites&#46; For this purpose we used the metabolite fractions according to the Schiepers formula<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a>&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><p id="par0080" class="elsevierStylePara elsevierViewall">Patlak analysis was performed using the PMOD 3&#46;0 software &#40;PMOD Technologies Ltd&#46;&#44; Adliswil&#44; Switzerland&#41; in the time interval between 10 and 60<span class="elsevierStyleHsp" style=""></span>min after injection&#44; determining the influx constant &#40;Ki&#41;&#46; Two constants were obtained&#44; considering the input function from the left ventricle &#40;Ki&#95;LV&#41; and the curve from the descending aorta &#40;Ki&#95;DA&#41;&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">The dynamic study was used to obtain PET images equivalent to a static PET study at the end of the dynamic sequence&#44; corresponding to the time intervals 40&#8211;60<span class="elsevierStyleHsp" style=""></span>min and 50&#8211;60<span class="elsevierStyleHsp" style=""></span>min&#44; which corresponds to studies of 20 and 10<span class="elsevierStyleHsp" style=""></span>min starting 40&#8211;50<span class="elsevierStyleHsp" style=""></span>min after administration of the radiopharmaceutical&#46; These images allowed quantifying the standardized uptake value &#40;SUV&#41; SUV40 and SUV50 respectively&#46; SUV values were derived from the maximum uptake in the tumor&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Changes in tumor proliferation before and after treatment were calculated according to the formula&#58;<elsevierMultimedia ident="eq0010"></elsevierMultimedia></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0095" class="elsevierStylePara elsevierViewall">We analyzed the descriptive parameters&#44; the correlation and the concordance between the quantitative variables PET &#40;SUV and Ki constant&#41;&#44; and PET parameters were also correlated with cell proliferation index Ki67&#46; Statistical analysis was performed using SPSS software &#40;version 15&#46;0&#59; IBM&#41;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0100" class="elsevierStylePara elsevierViewall">The statistical parameters of SUV values and Ki influx constant of both scans are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; and the corresponding box plots are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; The four parameters used to quantify cell proliferation showed a statistically significant reduction after treatment compared to baseline values&#46; Mean decrease of SUV50&#44; SUV40&#44; Ki&#95;LV and Ki&#95;DA were 26&#37;&#44; 27&#37;&#44; 27&#37; and 31&#37; respectively&#44; while the constant Ki67 felt 14 units&#46; Statistically significant differences &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; between the influx constants Ki&#95;LV and Ki&#95;DA in the post-bevacizumab treatment PET scan were also observed&#46; An example of the bevacizumab treatment effect in a patient is illustrated in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; where a decrease of the four PET quantitative parameters studied is presented&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0105" class="elsevierStylePara elsevierViewall">Changes in the SUV50 and Ki&#95;DA PET parameters between basal state and after bevacizumab treatment showed a moderate correlation with changes in the Ki67 index &#40;Pearson <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35 and 0&#46;26&#44; respectively&#41;&#46; SUV50 changes were more accurate &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06&#41; than changes in Ki&#95;DA &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;16&#41;&#46; Changes in SUV40 and Ki&#95;LV showed a weaker correlation with the Ki67 reduction than SUV50 and Ki&#95;DA &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; The percentage of patients that had lower &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT uptake after the bevacizumab treatment was 97 and 93&#37; according to SUV50 and SUV40 measurements respectively&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The agreement within the two SUV measures and within the two influx constants were studied evaluating the interclass correlation coefficient &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; The accordance degree was almost perfect &#40;ICC<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;81&#41; in the 4 comparisons&#44; showing the interchangeability of quantitative data between SUV40 and SUV50 and between Ki&#95;LV and Ki&#95;DA&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">The correlation between the SUV values in tumors with the corresponding Ki influx constant&#44; obtained at baseline and after treatment&#44; is illustrated in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>&#46; A stronger and significant correlation was found for Ki obtained with the input function from the left ventricle than the one obtained from the descending aorta &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0120" class="elsevierStylePara elsevierViewall">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT is phosphorylated by thymidine kinase-1 &#40;TK1&#41; and trapped inside the cell&#46; The application of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT phosphorylation as a biomarker of cell proliferation is based in the assumption that cellular &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT trapping is a representation of TK1 activity&#44; which reflects the DNA synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET has been shown to be useful in predicting breast cancer responses to therapy<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and it has been investigated during treatment of recurrent high-grade brain tumors with bevacizumab and irinotecan&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> In this study we have investigated the usefulness of different &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET quantitative methods in patients with LABC&#44; studied before and after a single infusion of bevacizumab&#44; within a multicenter&#44; prospective&#44; phase II clinical trial&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">Van der Weerdt et al&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> proposed the use of the ascending aorta as the structure of choice for defining IDIF and a large region of interest &#40;ROI with 15<span class="elsevierStyleHsp" style=""></span>mm diameter&#44; approximately&#41; to minimize the effects of statistical noise&#46; They also found that ascending aorta and DA had lower interobserver variation when applied to myocardial metabolic rate of glucose determination&#44; compared with the use of left ventricle&#46; De Langen et al&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> used IDIF with ROIs in the ascending aorta and aortic arch&#44; but in our study the VOI were not always possible to be correctly drawn because the scanner field of view was centered in the breast tumor&#46; Our results showed that Ki changes after an infusion of bevacizumab evaluated using IDIF obtained from the DA had a slightly higher correlation with the Ki67 index change than with those Ki changes obtained using the LV&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Ki and SUV obtained from the maximum values showed similar correlation with the proliferation index Ki67&#44; although SUV obtained from a static acquisition required a shorter protocol and data analysis easier to be performed than needed for the influx constant evaluation&#46; The latter was simplified using a modeled metabolic fraction<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> that allowed the use of image derived input functions&#44; without the need of blood sampling and further analysis&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">Correlation between SUV values and the influx constant obtained with the LV derived input function were higher than those where the structure used was the DA&#46; This is related to the higher dispersion of the Ki values obtained in the DA compared with those from the LV&#46; These high correlation coefficients indicate that simple semiquantitative analysis &#40;SUV&#41; might be sufficient for clinical applications&#44; as has been suggested by others&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In these 30 patients of this multicenter clinical trial&#44; the interclass correlation coefficient showed the interchangeability within the standard uptake values obtained at the time interval 40&#8211;60 and 50&#8211;60<span class="elsevierStyleHsp" style=""></span>min post-administration of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT&#44; and within the influx constant Ki obtained with the image derived input function using the LV and the DA as structures&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">In conclusion&#44; &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET is a non-invasive imaging technique that allowed the evaluation of tumor proliferation&#44; by assessing the activity of the enzyme thymidine kinase&#46; The &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET quantification has demonstrated proliferative changes after a single dose of bevacizumab in patients with LABC&#46; In our population&#44; quantification of tumor proliferation through the SUV and the Patlak influx constant&#44; with input function derived image&#44; have shown similar results in the evaluation of bevacizumab therapy in patients with LABC previously untreated&#46; Nevertheless&#44; it is suggested to extend these quantitative methods to a longer series of patients&#44; to corroborate our results&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Funding</span><p id="par0150" class="elsevierStylePara elsevierViewall">This study is part of a clinical trial funded by <span class="elsevierStyleGrantSponsor" id="gs0005">F&#46; Hoffman-La Roche Ltd y Roche Espa&#241;a</span>&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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    "fechaRecibido" => "2013-12-13"
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        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To investigate quantitative methods of tumor proliferation using 3&#8242;-&#91;<span class="elsevierStyleSup">18</span>F&#93;fluoro-3&#8242;-deoxythymidine &#40;&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT&#41; PET in patients with breast cancer &#40;BC&#41;&#44; studied before and after one bevacizumab administration&#44; and to correlate the &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET uptake with the Ki67 index&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Thirty patients with newly diagnosed&#44; untreated BC underwent a &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET before and 14 days after bevacizumab treatment&#46; A dynamic scan centered over the tumor began simultaneously with the injection of &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT &#40;385<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>56<span class="elsevierStyleHsp" style=""></span>MBq&#41;&#46; Image derived input functions were obtained using regions of interest drawn on the left ventricle &#40;LV&#41; and descending aorta &#40;DA&#41;&#46; Metabolite corrected blood curves were used as input functions to obtain the kinetic Ki constant using the Patlak graphical analysis &#40;time interval 10&#8211;60<span class="elsevierStyleHsp" style=""></span>min after injection&#41;&#46; Maximum SUV values were derived for the intervals 40&#8211;60<span class="elsevierStyleHsp" style=""></span>min &#40;SUV40&#41; and 50&#8211;60<span class="elsevierStyleHsp" style=""></span>min &#40;SUV50&#41;&#46; PET parameters were correlated with the Ki67 index obtained staining tumor biopsies&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT uptake parameters decreased significantly &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; after treatment&#58; SUV50<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;09<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;21 vs 2&#46;22<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;96&#59; SUV40<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;18 vs 2&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;95&#44; Ki&#95;LV&#40;10&#8211;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#91;22&#8211;116&#93; vs 38&#91;13&#8211;80&#93; and Ki&#95;DA&#40;10&#8211;3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>49&#91;15&#8211;129&#93; vs 33&#91;11&#8211;98&#93;&#46; Consistency interclass correlation coefficients within SUV and within Ki were high&#46; Changes of SUV50 and Ki&#95;DA between baseline PET and after one bevacizumab dose PET correlated with changes in Ki67 index &#40;<span class="elsevierStyleItalic">r</span>-Pearson<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35 and 0&#46;26&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;06 and 0&#46;16&#44; respectively&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET is useful to demonstrate proliferative changes after a dose of bevacizumab in patients with BC&#46; Quantification of tumor proliferation by means of SUV and Ki has shown similar results&#44; but SUV50 obtained better results&#46; A correlation between &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT changes and Ki67 index was observed&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Evaluar m&#233;todos cuantitativos de proliferaci&#243;n celular en PET con 3&#8242;-&#91;<span class="elsevierStyleSup">18</span>F&#93;fluoro-3&#8242;-desoxitimidina &#40;&#91;<span class="elsevierStyleSup">18</span>F&#93;FLT&#41;&#44; antes y despu&#233;s de una dosis de bevacizumab en pacientes con carcinoma de mama &#40;CM&#41;&#44; y correlacionar la captaci&#243;n de &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT con el &#237;ndice Ki67&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Material y m&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron 30 mujeres con CM no tratado&#46; Se realiz&#243; &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET antes y 14 d&#237;as despu&#233;s de una dosis de bevacizumab&#46; La PET din&#225;mica centrada en el tumor se inici&#243; simult&#225;neamente con la infusi&#243;n de &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT &#40;385<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>56<span class="elsevierStyleHsp" style=""></span>MBq&#41;&#46; Se dibujaron regiones de inter&#233;s en ventr&#237;culo izquierdo &#40;VI&#41; y aorta descendente &#40;AD&#41;&#44; obteni&#233;ndose funciones de entrada&#44; que corregidas por metabolitos&#44; se utilizaron para obtener la constante Ki de Patlak &#40;intervalo&#58; 10-60<span class="elsevierStyleHsp" style=""></span>min&#41;&#46; Se calcularon valores m&#225;ximos del SUV en los intervalos 40-60<span class="elsevierStyleHsp" style=""></span>min &#40;SUV40&#41; y 50-60<span class="elsevierStyleHsp" style=""></span>min &#40;SUV50&#41;&#46; Los par&#225;metros PET se correlacionaron con el Ki67&#44; obtenido en biopsias tumorales te&#241;idas&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Los par&#225;metros de la captaci&#243;n de &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT disminuyeron significativamente &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; tras el tratamiento&#58; SUV50<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;09<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;21 vs 2&#44;22<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;96&#59; SUV40<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#44;18 vs 2&#44;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#44;95&#44; Ki&#95;VI&#40;10-3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>52&#91;22&#8211;116&#93; vs 38&#91;13&#8211;80&#93; y Ki&#95;AD&#40;10-3&#41;<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>49&#91;15&#8211;129&#93; vs 33&#91;11&#8211;98&#93;&#46; Los coeficientes de correlaci&#243;n intraclase fueron elevados en los SUV y en los Ki&#46; Los cambios de SUV50 y Ki&#95;AD entre la PET basal y la PET tras bevacizumab se correlacionaron con los cambios en el Ki67 &#40;r-Pearson<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;35 y 0&#44;26&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;06 y 0&#44;16&#44; respectivamente&#41;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT-PET refleja los cambios en la proliferaci&#243;n celular tras una dosis de bevacizumab en pacientes con CM&#46; La cuantificaci&#243;n de la proliferaci&#243;n por medio del SUV y la Ki arroj&#243; resultados similares&#44; si bien fueron mejores con el SUV50&#46; Los cambios en &#91;<span class="elsevierStyleSup">18</span>F&#93;FLT se correlacionaron con los cambios en el &#237;ndice Ki67&#46;</p>"
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SUV40&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#46;00<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;18&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;14<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;95&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ki&#95;LV &#40;10<span class="elsevierStyleSup">&#8722;3</span><span class="elsevierStyleHsp" style=""></span>min<span class="elsevierStyleSup">&#8722;1</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">52 &#91;22&#8211;116&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38 &#91;13&#8211;80&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ki&#95;DA &#40;10<span class="elsevierStyleSup">&#8722;3</span><span class="elsevierStyleHsp" style=""></span>min<span class="elsevierStyleSup">&#8722;1</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">49 &#91;15&#8211;129&#93;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">33 &#91;11&#8211;98&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">&#60;0&#46;001&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => "xTab547469.png"
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          "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Descriptive statistics&#44; mean<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>standard deviation or median &#91;range&#93;&#44; for <span class="elsevierStyleSup">18</span>F-FLT quantitative parameters of basal and post treatment scans&#46;</p>"
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        "identificador" => "tbl0010"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">PET&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Compared parameters&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Coefficient&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SUV50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SUV40&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Post-treatment&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">SUV50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ki&#95;LV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">Ki&#95;DA&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Correlation&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Pre-treatment&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Post-treatment&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">SUV50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">Ki&#95;LV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;877&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;898&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">SUV50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ki&#95;DA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;694&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#46;781&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">SUV40&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ki&#95;LV&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;868&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;859&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;684&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">0&#46;766&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Correlation between SUV measures and influx constant before and after a single bevacizumab infusion&#46; All correlations &#40;Spearman rho&#41; were statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46;</p>"
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        "tipo" => "MULTIMEDIAFORMULA"
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        0 => array:2 [
          "identificador" => "bibs0005"
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            0 => array:3 [
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              "etiqueta" => "1"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Cancer statistics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Jemal"
                            1 => "R&#46; Siegel"
                            2 => "J&#46; Xu"
                            3 => "E&#46; Ward"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3322/caac.20073"
                      "Revista" => array:6 [
                        "tituloSerie" => "CA Cancer J Clin"
                        "fecha" => "2010"
                        "volumen" => "60"
                        "paginaInicial" => "277"
                        "paginaFinal" => "300"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20610543"
                            "web" => "Medline"
                          ]
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              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Preoperative chemotherapy in patients with operable breast cancer&#58; nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "N&#46; Wolmark"
                            1 => "J&#46; Wang"
                            2 => "E&#46; Mamounas"
                            3 => "J&#46; Bryant"
                            4 => "B&#46; Fisher"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Natl Cancer Inst Monogr"
                        "fecha" => "2001"
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Article information

ISSN: 2253654X
Original language: English

DOI:10.1016/j.remn.2014.01.007

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Year/Month	Html	Pdf	Total

2024 May	1	2	3
2023 March	4	6	10
2021 September	1	0	1
2020 March	2	2	4
2019 July	16	2	18
2018 February	3	0	3
2018 January	11	2	13
2017 December	8	0	8
2017 November	7	4	11
2017 October	8	5	13
2017 September	16	4	20
2017 August	12	3	15
2017 July	15	1	16
2017 June	21	8	29
2017 May	13	6	19
2017 April	21	8	29
2017 March	16	27	43
2017 February	9	2	11
2017 January	20	5	25
2016 December	24	3	27
2016 November	33	4	37
2016 October	36	6	42
2016 September	30	2	32
2016 August	16	3	19
2016 July	9	6	15
2016 May	1	2	3
2016 March	1	0	1
2016 January	11	2	13
2015 December	20	13	33
2015 November	16	6	22
2015 October	21	10	31
2015 September	21	8	29
2015 May	0	2	2
2015 March	28	1	29
2015 February	12	0	12
2015 January	24	0	24
2014 December	18	0	18
2014 November	11	1	12
2014 October	13	2	15
2014 September	0	1	1

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