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</div>
<div class="action-panel-control-wrap">
<label for="email-from" class="action-panel-label">
From:
</label>
<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="27702824">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://aacrjournals.org/clincancerres/article-lookup/doi/10.1158/1078-0432.CCR-16-0985"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=7898&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=27702824&amp;db=pubmed&amp;nlmid=9502500"
title="See full text options at Silverchair Information Systems"
data-ga-category="full_text"
data-ga-action="Silverchair Information Systems"
data-ga-label="27702824"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--aacrjournals.org-images-pubmed-clincanres_final.gif" alt="Silverchair Information Systems full text link"><span class="text">
Silverchair Information Systems
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/27702824/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=27702824&amp;db=pubmed&amp;nlmid=9502500"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="27702824"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/27702824/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/27702824/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="27702824" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F27702824%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="4WhoyHlOS3fRccZSSrdUh0LSwMPfybPplJ1tbxOasE2l6D5IvKQWL8hw4QxrrMnJ"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
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<h1 class="heading-title">
Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children&#x27;s Oncology Group
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Significance of TP53 Mutation in Wilms Tumors with Diffuse Anaplasia: A Report from the Children&#x27;s Oncology Group
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<span class="authors-list-item "><span class="full-name">Ariadne H A G Ooms</span><span class="citation-separator">&nbsp;et al.</span></span>
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Richard A Moore">Richard A Moore</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Canada&#x27;s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency (BCCA), Vancouver, British Columbia, Canada." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Marco A Marra">Marco A Marra</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Canada&#x27;s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency (BCCA), Vancouver, British Columbia, Canada." href="#short-view-affiliation-7" ref="linksrc=author_aff">
7
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada." href="#short-view-affiliation-8" ref="linksrc=author_aff">
8
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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11
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</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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13
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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13
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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14
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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14
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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15
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Northwestern Medicine Developmental Therapeutics Institute, Northwestern Memorial Hospital, Chicago, Illinois." href="#short-view-affiliation-16" ref="linksrc=author_aff">
16
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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2
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pathology, Reinier de Graaf Hospital, Delft, the Netherlands." href="#short-view-affiliation-17" ref="linksrc=author_aff">
17
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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18
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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18
</a><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Departments of Pathology and Pediatrics, Ohio State University College of Medicine, Columbus, Ohio." href="#short-view-affiliation-19" ref="linksrc=author_aff">
19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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data-ga-label="Elizabeth J Perlman">Elizabeth J Perlman</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children&#x27;s Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois. Eperlman@luriechildrens.org." href="#short-view-affiliation-20" ref="linksrc=author_aff">
20
</a></sup></span>
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<div class="affiliations">
<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children&#x27;s Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Princess Maxima Centre for Pediatric Oncology, Utrecht, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Department of Pathology, Pathan BV, Sint Franciscus Gasthuis, Rotterdam, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, Maryland.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Canada&#x27;s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency (BCCA), Vancouver, British Columbia, Canada.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.</li>
<li data-affiliation-id="short-view-affiliation-10"
id="short-view-affiliation-10"
><sup class="key">10</sup> Division of Pediatric Hematology/Oncology, Children&#x27;s National Medical Center, Washington, DC.</li>
<li data-affiliation-id="short-view-affiliation-11"
id="short-view-affiliation-11"
><sup class="key">11</sup> Department of Biostatistics, University of Florida, Gainesville, Florida.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> Division of Pediatric Oncology, Cincinnati Children&#x27;s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio.</li>
<li data-affiliation-id="short-view-affiliation-13"
id="short-view-affiliation-13"
><sup class="key">13</sup> Department of Pathology, St. Jude Children&#x27;s Research Hospital, Memphis, Tennessee.</li>
<li data-affiliation-id="short-view-affiliation-14"
id="short-view-affiliation-14"
><sup class="key">14</sup> Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.</li>
<li data-affiliation-id="short-view-affiliation-15"
id="short-view-affiliation-15"
><sup class="key">15</sup> Division of Hematology-Oncology and Transplantation, Ann and Robert H. Lurie Children&#x27;s Hospital of Chicago, Northwestern University&#x27;s Feinberg School of Medicine, Chicago, Illinois.</li>
<li data-affiliation-id="short-view-affiliation-16"
id="short-view-affiliation-16"
><sup class="key">16</sup> Northwestern Medicine Developmental Therapeutics Institute, Northwestern Memorial Hospital, Chicago, Illinois.</li>
<li data-affiliation-id="short-view-affiliation-17"
id="short-view-affiliation-17"
><sup class="key">17</sup> Department of Pathology, Reinier de Graaf Hospital, Delft, the Netherlands.</li>
<li data-affiliation-id="short-view-affiliation-18"
id="short-view-affiliation-18"
><sup class="key">18</sup> Department of Pathology and Laboratory Medicine, Nationwide Children&#x27;s Hospital, Ohio State University College of Medicine, Columbus, Ohio.</li>
<li data-affiliation-id="short-view-affiliation-19"
id="short-view-affiliation-19"
><sup class="key">19</sup> Departments of Pathology and Pediatrics, Ohio State University College of Medicine, Columbus, Ohio.</li>
<li data-affiliation-id="short-view-affiliation-20"
id="short-view-affiliation-20"
><sup class="key">20</sup> Department of Pathology and Laboratory Medicine, Ann and Robert H. Lurie Children&#x27;s Hospital of Chicago, Robert H. Lurie Cancer Center, Northwestern University, Chicago, Illinois. Eperlman@luriechildrens.org.</li>
</ul>
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<h2 class="title">
Abstract
</h2>
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id="eng-abstract">
<p>
<strong class="sub-title">
Purpose:
</strong>
To investigate the role and significance of TP53 mutation in diffusely anaplastic Wilms tumors (DAWTs).
</p>
<p>
<strong class="sub-title">
Experimental design:
</strong>
All DAWTs registered on National Wilms Tumor Study-5 (n = 118) with available samples were analyzed for TP53 mutations and copy loss. Integrative genomic analysis was performed on 39 selected DAWTs.
</p>
<p>
<strong class="sub-title">
Results:
</strong>
Following analysis of a single random sample, 57 DAWTs (48%) demonstrated TP53 mutations, 13 (11%) copy loss without mutation, and 48 (41%) lacked both [defined as TP53-wild-type (wt)]. Patients with stage III/IV TP53-wt DAWTs (but not those with stage I/II disease) had significantly lower relapse and death rates than those with TP53 abnormalities. In-depth analysis of a subset of 39 DAWTs showed seven (18%) to be TP53-wt: These demonstrated gene expression evidence of an active p53 pathway. Retrospective pathology review of TP53-wt DAWT revealed no or very low volume of anaplasia in six of seven tumors. When samples from TP53-wt tumors known to contain anaplasia histologically were available, abnormal p53 protein accumulation was observed by immunohistochemistry.
</p>
<p>
<strong class="sub-title">
Conclusions:
</strong>
These data support the key role of TP53 loss in the development of anaplasia in WT, and support its significant clinical impact in patients with residual anaplastic tumor following surgery. These data also suggest that most DAWTs will show evidence of TP53 mutation when samples selected for the presence of anaplasia are analyzed. This suggests that modifications of the current criteria to also consider volume of anaplasia and documentation of TP53 aberrations may better reflect the risk of relapse and death and enable optimization of therapeutic stratification. Clin Cancer Res; 22(22); 5582-91. ©2016 AACR.
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©2016 American Association for Cancer Research.
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors disclose no potential conflicts of interest</p>
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<h2 class="title">
Figures
</h2>
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id="article-image-0"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/5ad30d41540e/nihms815170f1.gif"
alt="Figure 1" />
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<strong class="figure-label">
<p> Figure 1. <i> TP53 </i> Mutations in DAWTs </p>
</strong>
<div class="figure-caption-contents"><p> Illustrated… </p></div>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 1. <i> TP53 </i> Mutations in DAWTs </p>
</strong>
<div class="figure-caption-contents"><p> Illustrated is the location of the <i> TP53 </i> mutations (n=61)… </p></div>
</div>
<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 1. <i>TP53</i> Mutations in DAWTs
</strong>
<div class="figure-caption-contents">Illustrated is the location of the <i>TP53</i> mutations (n=61) within the known p53 protein domains. The number of variants detected for each is provided in the parenthesis. TAD = Transcription-Activation Domain; DNABD = DNA binding domain; TM = Tetramerization Domain.</div>
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data-image-width="512"
data-image-height="843"
data-image-alt="Figure 2"
data-pmc-id="PMC5290091"
data-figure-id="F2">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-1"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/ad4da0556588/nihms815170f2.gif"
alt="Figure 2" />
</a>
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<p> Figure 2. Association between stage, <i> TP53 </i> status… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 2. Association between stage, <i> TP53 </i> status and Disease Free Survival </p>
</strong>
<div class="figure-caption-contents"><p> Kaplan-Meier curve of Disease… </p></div>
</div>
<figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 2. Association between stage, <i>TP53</i> status and Disease Free Survival
</strong>
<div class="figure-caption-contents">Kaplan-Meier curve of Disease Free Survival (DFS) (in years), comparing DAWTs with <i>TP53</i> mutation and/or copy loss and DAWTs without either. Numbers at risk are listed at the bottom of the graphs. All patients who relapsed or progressed also died.</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
itemprop="associatedMedia"
data-slide-index="2"
data-label-slug="figure-3">
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/01c4a3a4e2de/nihms815170f3.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-2"
role="button"
data-image-width="400"
data-image-height="850"
data-image-alt="Figure 3"
data-pmc-id="PMC5290091"
data-figure-id="F3">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-2"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/580dfd474d28/nihms815170f3.gif"
alt="Figure 3" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="400">
<meta itemprop="height" itemtype="http://schema.org/ImageObject" content="850">
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<div class="caption-wrap">
<strong class="figure-label">
<p> Figure 3. Comparison of Copy number variations… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 3. Comparison of Copy number variations and gene expression in DAWTs with and without… </p>
</strong>
</div>
<figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 3. Comparison of Copy number variations and gene expression in DAWTs with and without <i>TP53</i> abnormalities
</strong>
<div class="figure-caption-contents">A. Copy number variations (CNVs; defined as segments with ≥ 8 markers and log2 ratio ≥ +0.5 or ≤ 0.5) identified in DAWTs with <i>TP53</i> abnormalities (top panel) or without <i>TP53</i> abnormalities (bottom panel). Each row represents one DAWT. Segments in red represent CN loss and those in blue CN gain. The seven <i>TP53</i>-wt samples showed fewer copy number alterations in their genome when compared to the DAWTs carrying <i>TP53</i> mutations and/or copy loss, and are similar to those previously reported in FHWTs. The tumors with <i>TP53</i> abnormalities had recurrent loss of chromosomes 4q, 14q, 16q, 17p, and 22. B. Hierarchical analysis of genes differentially expressed in <i>TP53</i> mutant DAWT: Statistical Analysis for Microarray (SAM) comparing the seven <i>TP53</i>-wt tumors with the remaining 31 tumors identified 35 genes differentially expressed (SAM q&lt;0.10 and Students t-test BH corrected p value &lt; 0.05). Hierarchical analysis of these 35 genes shows all to be upregulated in the tumors lacking <i>TP53</i> mutation or 17p13 copy number loss (red is upregulation and blue indicates downregulation). These include several genes located on 17p, and other genes associated within apoptotic pathways known to be regulated by p53 (such as <i>BAX</i> and <i>CDKN1A</i>).</div>
</figcaption>
</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
itemprop="associatedMedia"
data-slide-index="3"
data-label-slug="figure-4">
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itemprop="contentUrl"
aria-describedby="figure-caption-3"
role="button"
data-image-width="430"
data-image-height="950"
data-image-alt="Figure 4"
data-pmc-id="PMC5290091"
data-figure-id="F4">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-3"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/2dbf9a62d0fe/nihms815170f4.gif"
alt="Figure 4" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="430">
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<strong class="figure-label">
<p> Figure 4. Abnormal protein accumulation by p53… </p>
</strong>
</div>
</div>
<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 4. Abnormal protein accumulation by p53 immunohistochemistry </p>
</strong>
<div class="figure-caption-contents"><p> Archival tissue blocks containing histologic evidence of… </p></div>
</div>
<figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 4. Abnormal protein accumulation by p53 immunohistochemistry
</strong>
<div class="figure-caption-contents">Archival tissue blocks containing histologic evidence of anaplasia were available for three of the seven DAWTs determined to be <i>TP53</i>-wt by the absence of <i>TP53</i> mutation and copy number loss in a single randomly selected frozen tumor sample (the remaining four cases did not have archival tissue within the biopathology center containing clear histologic evidence of anaplasia). (Original magnification 40X for all.) A) PAJMLZ: The block containing anaplasia shows diffuse abnormal p53 protein accumulation. B) PALEZT: The block contains anaplastic cells that were stromal that surrounded non-anaplastic blastemal cells. Immunohistochemistry shows nodules of blastemal cells that were largely negative for p53 protein, with anaplastic stromal cells containing marked accumulation of p53 protein. C) PAJNRH: The block had a microscopic focus of anaplasia, which shows intense abnormal nuclear p53 staining.</div>
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</figure>
<figure class="figure-item "
itemscope itemtype="http://schema.org/ImageObject"
itemprop="associatedMedia"
data-slide-index="4"
data-label-slug="figure-5">
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href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/b6b08da25e97/nihms815170f5.jpg"
itemprop="contentUrl"
aria-describedby="figure-caption-4"
role="button"
data-image-width="714"
data-image-height="342"
data-image-alt="Figure 5"
data-pmc-id="PMC5290091"
data-figure-id="F5">
<img class="figure-thumb" itemprop="thumbnail"
id="article-image-4"
src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3b00/5290091/6705ef426740/nihms815170f5.gif"
alt="Figure 5" />
</a>
<meta itemprop="width" itemtype="http://schema.org/ImageObject" content="714">
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<p> Figure 5. Tumor heterogeneity and sample selection… </p>
</strong>
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<div class="figure-caption-medium figure-caption-text" aria-hidden="true">
<strong class="figure-label">
<p> Figure 5. Tumor heterogeneity and sample selection in detecting <i> TP53 </i> abnormalities </p>
</strong>
<div class="figure-caption-contents"><p> The predominant underlying cause… </p></div>
</div>
<figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
<strong class="figure-label">
Figure 5. Tumor heterogeneity and sample selection in detecting <i>TP53</i> abnormalities
</strong>
<div class="figure-caption-contents">The predominant underlying cause of failure to detect <i>TP53</i> abnormalities is heterogeneity in tumors with a low volume of anaplasia. The diagnosis of DAWT is established by a pathologist after analyzing multiple representative slides taken from all regions of the tumor. In contrast, single randomly selected tissue samples are taken for banking or biologic studies without knowledge of the histology. In some cases anaplasia may be diffuse, but may still be due to a very small percentage of cells, making it difficult to detect <i>TP53</i> abnormalities. If there are scattered nodules of anaplasia, area(s) of anaplasia may not be selected; or there might be only a very small focus of anaplasia within the sample selected, insufficient for the detection of <i>TP53</i> abnormalities.</div>
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Howlader NNA, Krapcho M, Garshell J, Miller D, Altekruse SF, et al. In: SEER Cancer Statistics Review, 19752012. Cronin KA, editor. National Cancer Institute; 2014. posted to the SEER website, April 2015.
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Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumors: results from the First National Wilms Tumor Study. Cancer. 1978;41(5):193748. Epub 1978/05/01.
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Faria P, Beckwith JB, Mishra K, Zuppan C, Weeks DA, Breslow N, et al. Focal versus diffuse anaplasia in Wilms tumor--new definitions with prognostic significance: a report from the National Wilms Tumor Study Group. The American journal of surgical pathology. 1996;20(8):90920. Epub 1996/08/01.
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Dome JS, Cotton CA, Perlman EJ, Breslow NE, Kalapurakal JA, Ritchey ML, et al. Treatment of anaplastic histology Wilms tumor: results from the fifth National Wilms Tumor Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006;24(15):23528. doi: 10.1200/jco.2005.04.7852. Epub 2006/05/20.
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Pritchard-Jones K, Moroz V, Vujanic G, Powis M, Walker J, Messahel B, et al. Treatment and outcome of Wilms tumour patients: an analysis of all cases registered in the UKW3 trial. Annals of oncology : official journal of the European Society for Medical Oncology/ESMO. 2012;23(9):245763. doi: 10.1093/annonc/mds025. Epub 2012/03/15.
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