Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging
Identifieur interne : 004712 ( Pmc/Curation ); précédent : 004711; suivant : 004713Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging
Auteurs : Kenneth M. Tichauer [États-Unis] ; Kimberley S. Samkoe [États-Unis] ; Jason R. Gunn [États-Unis] ; Stephen C. Kanick [États-Unis] ; P. Jack Hoopes [États-Unis] ; Richard J. Barth [États-Unis] ; Peter A. Kaufman [États-Unis] ; Tayyaba Hasan [États-Unis] ; Brian W. Pogue [États-Unis]Source :
- Nature medicine [ 1078-8956 ] ; 2014.
Abstract
Lymph node biopsy (LNB) is employed in many cancer surgeries to identify metastatic disease and stage the cancer, yet morbidity and diagnostic delays associated with LNB could be avoided if non-invasive imaging of nodal involvement was reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers has made conventional approaches ineffective clinically. A method of correcting for non-specific uptake with injection of a second untargeted tracer is presented, allowing tumor burden in lymph nodes to be quantified. The approach was confirmed in an athymic mouse model of metastatic human breast cancer targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. A significant correlation was observed between
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DOI: 10.1038/nm.3732
PubMed: 25344739
PubMed Central: 4224611
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Pogue</name><affiliation wicri:level="2"><nlm:aff id="A2">Department of Surgery, Geisel School of Medicine, Hanover, NH 03755</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Hampshire</region></placeName><wicri:cityArea>Department of Surgery, Geisel School of Medicine, Hanover</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="A3">Thayer School of Engineering, Dartmouth College, Hanover, NH 03755</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">New Hampshire</region></placeName><wicri:cityArea>Thayer School of Engineering, Dartmouth College, Hanover</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="A5">Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Wellman Center for Photomedicine, Massachusetts General Hospital, Boston</wicri:cityArea></affiliation></author></analytic><series><title level="j">Nature medicine</title><idno type="ISSN">1078-8956</idno><idno type="eISSN">1546-170X</idno><imprint><date when="2014">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Lymph node biopsy (LNB) is employed in many cancer surgeries to identify metastatic disease and stage the cancer, yet morbidity and diagnostic delays associated with LNB could be avoided if non-invasive imaging of nodal involvement was reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers has made conventional approaches ineffective clinically. A method of correcting for non-specific uptake with injection of a second untargeted tracer is presented, allowing tumor burden in lymph nodes to be quantified. The approach was confirmed in an athymic mouse model of metastatic human breast cancer targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. A significant correlation was observed between <italic>in vivo</italic> (dual-tracer) and <italic>ex vivo</italic> measures of tumor burden (<italic>r</italic> = 0.97, <italic>p</italic> < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional LNB).</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Chen, Sl" uniqKey="Chen S">SL Chen</name></author><author><name sortKey="Iddings, Dm" uniqKey="Iddings D">DM Iddings</name></author><author><name sortKey="Scheri, Rp" uniqKey="Scheri R">RP Scheri</name></author><author><name sortKey="Bilchik, Aj" uniqKey="Bilchik A">AJ Bilchik</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tobler, Ne" uniqKey="Tobler N">NE Tobler</name></author><author><name sortKey="Detmar, M" uniqKey="Detmar M">M Detmar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schrenk, P" uniqKey="Schrenk 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<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9502015</journal-id><journal-id journal-id-type="pubmed-jr-id">8791</journal-id><journal-id journal-id-type="nlm-ta">Nat Med</journal-id><journal-id journal-id-type="iso-abbrev">Nat. Med.</journal-id><journal-title-group><journal-title>Nature medicine</journal-title></journal-title-group><issn pub-type="ppub">1078-8956</issn><issn pub-type="epub">1546-170X</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25344739</article-id><article-id pub-id-type="pmc">4224611</article-id><article-id pub-id-type="doi">10.1038/nm.3732</article-id><article-id pub-id-type="manuscript">NIHMS611240</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Microscopic lymph node tumor burden quantified by macroscopic dual-tracer molecular imaging</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Tichauer</surname><given-names>Kenneth M.</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib><contrib contrib-type="author"><name><surname>Samkoe</surname><given-names>Kimberley S.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Gunn</surname><given-names>Jason R.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kanick</surname><given-names>Stephen C.</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Hoopes</surname><given-names>P. Jack</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Barth</surname><given-names>Richard J.</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Kaufman</surname><given-names>Peter A.</given-names></name><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Hasan</surname><given-names>Tayyaba</given-names></name><xref ref-type="aff" rid="A5">5</xref></contrib><contrib contrib-type="author"><name><surname>Pogue</surname><given-names>Brian W.</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="aff" rid="A5">5</xref><xref rid="FN1" ref-type="author-notes">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616</aff><aff id="A2"><label>2</label>Department of Surgery, Geisel School of Medicine, Hanover, NH 03755</aff><aff id="A3"><label>3</label>Thayer School of Engineering, Dartmouth College, Hanover, NH 03755</aff><aff id="A4"><label>4</label>Department of Medicine, Geisel School of Medicine, Lebanon, NH 03756</aff><aff id="A5"><label>5</label>Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114</aff><author-notes><corresp id="FN1"><label>*</label>Corresponding Author: Brian W. Pogue, Thayer School of Engineering, Dartmouth College, 14 Engineering Drive, Hanover, NH 03755, 1-603-646-3861, <email>brian.w.pogue@dartmouth.edu</email> or Kenneth M. Tichauer, Biomedical Engineering, Illinois Institute of Technology, Chicago, IL 60616, 1-312-567-3858, <email>ktichaue@iit.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>9</day><month>7</month><year>2014</year></pub-date><pub-date pub-type="epub"><day>26</day><month>10</month><year>2014</year></pub-date><pub-date pub-type="ppub"><month>11</month><year>2014</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>5</month><year>2015</year></pub-date><volume>20</volume><issue>11</issue><fpage>1348</fpage><lpage>1353</lpage><pmc-comment>elocation-id from pubmed: 10.1038/nm.3732</pmc-comment>
<permissions><license xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms"><license-p>Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:<ext-link ext-link-type="uri" xlink:href="http://www.nature.com/authors/editorial_policies/license.html#terms">http://www.nature.com/authors/editorial_policies/license.html#terms</ext-link></license-p></license></permissions><abstract><p id="P1">Lymph node biopsy (LNB) is employed in many cancer surgeries to identify metastatic disease and stage the cancer, yet morbidity and diagnostic delays associated with LNB could be avoided if non-invasive imaging of nodal involvement was reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers has made conventional approaches ineffective clinically. A method of correcting for non-specific uptake with injection of a second untargeted tracer is presented, allowing tumor burden in lymph nodes to be quantified. The approach was confirmed in an athymic mouse model of metastatic human breast cancer targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. A significant correlation was observed between <italic>in vivo</italic> (dual-tracer) and <italic>ex vivo</italic> measures of tumor burden (<italic>r</italic> = 0.97, <italic>p</italic> < 0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional LNB).</p></abstract><kwd-group><kwd>fluorescence</kwd><kwd>metastasis</kwd><kwd>surgical oncology</kwd><kwd>tracer kinetics</kwd><kwd>mouse xenograft</kwd><kwd>breast cancer</kwd></kwd-group></article-meta></front><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Animal model</title><p>A white-light image of a mouse positioned for axillary lymph node imaging is presented in (<bold>a</bold>) – (<italic>n</italic> = 1 of 22 mice imaged: 18 tumor bearing, 4 controls). A bioluminescence image demonstrating metastasis of cancer cells to the axillary lymph node using the MDA-MB-231-luc-D3H2LN cell line is demonstrated in (<bold>b</bold>). White light (left) and EGFR receptor concentration (right) images depicting typical regions of interest used for calculating the average EGFR concentration in a lymph node are presented in (<bold>c</bold>). Hemotoxylin and eosin stains of lymph node tissue from a healthy (left) and tumor-bearing mouse (right) are presented in (<bold>d</bold>) and (<bold>e</bold>) respectively. The white arrows are meant to locate a tumor cell cluster in (<bold>e</bold>). A standard curve relating quantitative PCR (qPCR) numbers to the number of tumor cells is presented in (<bold>f</bold>). The slope of this line was 257 tumor cells PCR#<sup>−1</sup>. Scale bars are 1 cm in (<bold>a</bold>)-(<bold>c</bold>), and 500 μm in (<bold>d</bold>) and (<bold>e</bold>).</p></caption><graphic xlink:href="nihms611240f1"></graphic></fig><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>Lymph node molecular concentration imaging (LN-MCI)</title><p>A table of images with 3 rows and 3 columns is presented. In each table-cell there are two images: the left image is a white light image of a mouse with 30%-threshold overlays of the 3-hour post-injection signal from targeted fluorescence (top row of images), the 3-hour post-injection signal from untargeted fluorescence (middle row), or the EGFR concentration map (bottom row). Fluorescence from the injection sites of on the forelegs of the mice was also removed in the overlay images. The image on the right of each cell of the table corresponds to the corresponding fluorescence of EGFR concentration image alone with no thresholds. Each column corresponds to images from a representative mouse from the study: the first column of images pertain to a control mouse (<italic>n</italic> = 1 of 4 in the imaging study), the middle column of images pertain to a tumor-bearing mouse with verified tumor burden in the right axillary lymph node, and the last column of images pertain to a tumor-bearing mouse with verified tumor burden in the left axillary lymph node, where the yellow arrows denote the side with confirmed tumor burden (<italic>n</italic> = 2 tumor-bearing mice of 18 included in the imaging study). The units of fluorescence are in percent of the dynamic range of the Pearl Imaging System (<italic>i.e.</italic>, a unit of 100 would be the level of saturation), and the units of the EGFR concentration maps are in nM. Scale bars are 1 cm.</p></caption><graphic xlink:href="nihms611240f2"></graphic></fig><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Dual-tracer compared to single tracer imaging</title><p>Ratiometric estimations of EGFR concentration [(targeted – untargeted)/untargeted] as a function of time after tracer injection are presented in (<bold>a</bold>) for lymph nodes with various levels of tumor burden determined by quantitative PCR (black = 727 cells, dark gray = 501 cells, gray = 323 cells, and light gray = 296 cells (<italic>n</italic> = 4 lymph nodes of 36 imaged); and dashed black = mean ± s.d. of 8 lymph nodes from 4 control mice). A correlation between the time to plateau of the curves in (<bold>a</bold>) and the average lymph flow rates for all tumor bearing lymph nodes is presented in (<bold>b</bold>). The dashed line represents the linear regression of the data. Average fluorescence signal measured from the uptake of the EGFR targeted tracer at 3 h post-injection in the axillary lymph nodes of control mice (<italic>n</italic> = 4; 8 nodes), nodes from tumor-bearing mice with less than 200 tumor cells detected by qPCR (<italic>n</italic> = 10; 20 nodes), nodes from tumor-bearing mice with greater than 200 tumor cells detected by qPCR (<italic>n</italic> = 8, 16 nodes), are presented in a boxplot format in (<bold>c</bold>). The units of fluorescence correspond to percentage of the dynamic range of the CCD camera used to detect the fluorescence in the Pearl Imaging System. The same boxplot format is used to compare the average EGFR concentrations measured <italic>in vivo</italic> in each lymph node using the single time point lymph node receptor imaging (LN-MCI) model in (<bold>e</bold>). *<italic>p</italic> < 0.001 compared to control and < 200 cell groups. <sup>#</sup><italic>p</italic> < 0.05 compared to the control group using a one-tailed t-test and Tamhane correction for multiple comparisons with unequal variance. Groups in the LN-MCI plots were non-normal by Shapiro-Wilk Test so Kruskal-Wallis nonparametric test was used to determine significance rather than one-way ANOVA. Logscale plots of (<bold>c</bold>) and (<bold>e</bold>) are presented in (<bold>d</bold>) and (<bold>f</bold>), respectively, to illuminate group differences. Errobars are s.d..</p></caption><graphic xlink:href="nihms611240f3"></graphic></fig><fig id="F4" orientation="portrait" position="float"><label>Figure 4</label><caption><title>Estimation of tumor burden</title><p>The correlation between dual-tracer imaging estimates of axillary lymph node tumor burden at 3 h post-tracer injection and qPCR tumor burden measures is presented in (<bold>a</bold>): <italic>n</italic> = 36 axillary lymph nodes from 18 mice. The blue circles represent data from lymph nodes with greater than 200 tumor cells detected by qPCR and the red exes represent those with less than 200 tumor cells detected. The plot in (<bold>b</bold>) is the same as in (<bold>a</bold>) but for lymph nodes with less than 1,000 cells to provide a clearer view of the correlation at lower tumor burden. Linear regression (dashed black lines) determined the correlation in (<bold>a</bold>) and (<bold>b</bold>) to be statistically significant (slope: 0.4 pM cell<sup>−1</sup> cm<sup>−2</sup><italic>r</italic> = 0.97, <italic>p</italic> < 0.01 in both plots).</p></caption><graphic xlink:href="nihms611240f4"></graphic></fig><fig id="F5" orientation="portrait" position="float"><label>Figure 5</label><caption><title>Modeling and simulations</title><p>The tracer kinetic compartment model for the targeted (right side) and the untargeted (left side) tracers is depicted in (<bold>a</bold>). C<sub>l</sub> represents the concentration of tracer in the upstream lymph vessels feeding the sentinel lymph node, C<sub>U</sub> represents the concentration of untargeted tracer in the lymph node, C<sub>f</sub> represents the concentration of unbound targeted tracer in the lymph node, C<sub>b</sub> represents the concentration of specifically bound targeted tracer in the lymph node, F<sub>l</sub> represents the lymph fluid flow rate, and k<sub>3</sub> and k<sub>4</sub> represent the rates of association and dissociation, respectively, of the targeted tracer with its receptor. Typical curves of average fluorescence at the site of injection for the targeted tracer (red curve) and the untargeted tracer (green curve) are plotted in (<bold>b</bold>). The results of a simulation study noise analysis are presented in the form of a histogram in (<bold>c</bold>), with applying the single-time-point receptor concentration estimate at 20, 60, 120, and 180 min after tracer injection for a lymph flow rate of 0.15 min<sup>−1</sup> and a simulated receptor concentration of 1 nM. The mean ± s.d. of the histograms plotted in (<bold>c</bold>) are depicted in (<bold>d</bold>) for over a range of theoretical lymph flow rates.</p></caption><graphic xlink:href="nihms611240f5"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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