Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial
Identifieur interne : 000963 ( Pmc/Checkpoint ); précédent : 000962; suivant : 000964Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial
Auteurs : N. Raje ; S. Vadhan-Raj [États-Unis] ; W. Willenbacher [Autriche] ; E. Terpos [Grèce] ; V. Hungria [Brésil] ; A. Spencer [Australie] ; Y. Alexeeva [Russie] ; T. Facon [France] ; A K Stewart [États-Unis] ; A. Feng [États-Unis] ; A. Braun [États-Unis] ; A. Balakumaran [États-Unis] ; G D Roodman [États-Unis]Source :
- Blood Cancer Journal [ 2044-5385 ] ; 2016.
Abstract
In a phase 3 trial of denosumab vs zoledronic acid in patients (
Url:
DOI: 10.1038/bcj.2015.96
PubMed: 26745852
PubMed Central: 4742634
Affiliations:
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<author><name sortKey="Roodman, G D" sort="Roodman, G D" uniqKey="Roodman G" first="G D" last="Roodman">G D Roodman</name>
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, Indianapolis, IN,<country>USA</country>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea># see nlm:aff country strict</wicri:regionArea>
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<series><title level="j">Blood Cancer Journal</title>
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<imprint><date when="2016">2016</date>
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<front><div type="abstract" xml:lang="en"><p>In a phase 3 trial of denosumab vs zoledronic acid in patients (<italic>n</italic>
=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an <italic>ad hoc</italic>
overall survival analysis in the multiple myeloma subset of patients (<italic>n</italic>
=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13–4.50; <italic>P</italic>
=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90–3.84; <italic>P</italic>
=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80–2.15; <italic>P</italic>
=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.</p>
</div>
</front>
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<front><journal-meta><journal-id journal-id-type="nlm-ta">Blood Cancer J</journal-id>
<journal-id journal-id-type="iso-abbrev">Blood Cancer J</journal-id>
<journal-title-group><journal-title>Blood Cancer Journal</journal-title>
</journal-title-group>
<issn pub-type="epub">2044-5385</issn>
<publisher><publisher-name>Nature Publishing Group</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26745852</article-id>
<article-id pub-id-type="pmc">4742634</article-id>
<article-id pub-id-type="pii">bcj201596</article-id>
<article-id pub-id-type="doi">10.1038/bcj.2015.96</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Evaluating results from the multiple myeloma patient subset treated with denosumab or zoledronic acid in a randomized phase 3 trial</article-title>
<alt-title alt-title-type="running">Denosumab vs zoledronic acid in multiple myeloma</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Raje</surname>
<given-names>N</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Vadhan-Raj</surname>
<given-names>S</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Willenbacher</surname>
<given-names>W</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Terpos</surname>
<given-names>E</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Hungria</surname>
<given-names>V</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Spencer</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alexeeva</surname>
<given-names>Y</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Facon</surname>
<given-names>T</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Stewart</surname>
<given-names>A K</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Feng</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Braun</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Balakumaran</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Roodman</surname>
<given-names>G D</given-names>
</name>
<xref ref-type="aff" rid="aff11">11</xref>
</contrib>
<aff id="aff1"><label>1</label>
<institution>Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center</institution>
,<country>Boston</country>
, MA,<country>USA</country>
</aff>
<aff id="aff2"><label>2</label>
<institution>University of Texas, MD Anderson Cancer Center</institution>
, Houston, TX,<country>USA</country>
</aff>
<aff id="aff3"><label>3</label>
<institution>Internal Medicine V, Haematology and Oncology, Medical University of Innsbruck</institution>
, Innsbruck,<country>Austria</country>
</aff>
<aff id="aff4"><label>4</label>
<institution>Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine</institution>
, Athens,<country>Greece</country>
</aff>
<aff id="aff5"><label>5</label>
<institution>Irmandade da Santa Casa de Misericordia de Sao Paulo</institution>
, São Paulo,<country>Brazil</country>
</aff>
<aff id="aff6"><label>6</label>
<institution>The Alfred Hospital</institution>
, Melbourne, Victoria,<country>Australia</country>
</aff>
<aff id="aff7"><label>7</label>
<institution>City Hospital No. 31</institution>
, Saint Petersburg,<country>Russia</country>
</aff>
<aff id="aff8"><label>8</label>
<institution>Hôpital Claude Huriez</institution>
, Lille,<country>France</country>
</aff>
<aff id="aff9"><label>9</label>
<institution>Mayo Clinic</institution>
, Scottsdale, AZ,<country>USA</country>
</aff>
<aff id="aff10"><label>10</label>
<institution>Amgen Inc.</institution>
, Thousand Oaks, CA,<country>USA</country>
</aff>
<aff id="aff11"><label>11</label>
<institution>Indiana University School of Medicine</institution>
, Indianapolis, IN,<country>USA</country>
</aff>
</contrib-group>
<author-notes><corresp id="caf1"><label>*</label>
<institution>Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center</institution>
, Boston, MA 02114, <country>USA</country>
. E-mail: <email>nraje@partners.org</email>
</corresp>
</author-notes>
<pub-date pub-type="ppub"><month>01</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="epub"><day>08</day>
<month>01</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>1</day>
<month>1</month>
<year>2016</year>
</pub-date>
<volume>6</volume>
<issue>1</issue>
<fpage>e378</fpage>
<lpage></lpage>
<history><date date-type="received"><day>14</day>
<month>04</month>
<year>2015</year>
</date>
<date date-type="rev-recd"><day>18</day>
<month>08</month>
<year>2015</year>
</date>
<date date-type="accepted"><day>02</day>
<month>09</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>Copyright © 2016 Macmillan Publishers Limited</copyright-statement>
<copyright-year>2016</copyright-year>
<copyright-holder>Macmillan Publishers Limited</copyright-holder>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><pmc-comment>author-paid</pmc-comment>
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<abstract><p>In a phase 3 trial of denosumab vs zoledronic acid in patients (<italic>n</italic>
=1776) with bone metastases and solid tumors or multiple myeloma, denosumab was superior to zoledronic acid for the primary end point of prevention of skeletal-related events. There was no difference in overall survival between the two groups; however, an <italic>ad hoc</italic>
overall survival analysis in the multiple myeloma subset of patients (<italic>n</italic>
=180) favored zoledronic acid (hazard ratio (HR) 2.26; 95% confidence interval (CI) 1.13–4.50; <italic>P</italic>
=0.014). In the present analysis, we found imbalances between the groups with respect to baseline risk characteristics. HRs with two-sided 95% CIs were estimated using the Cox model. After adjustment in a covariate analysis, the CI crossed unity (HR 1.86; 95% CI 0.90–3.84; <italic>P</italic>
=0.0954). Furthermore, we found a higher rate of early withdrawals for the reasons of lost to follow-up and withdrawal of consent in the zoledronic acid group; after accounting for these, the HR was 1.31 (95% CI 0.80–2.15; <italic>P</italic>
=0.278). In conclusion, the survival results in multiple myeloma patients in this trial were confounded and will eventually be resolved by an ongoing phase 3 trial.</p>
</abstract>
</article-meta>
</front>
<floats-group><fig id="fig1"><label>Figure 1</label>
<caption><p>(<bold>a</bold>
) Overall survival analysis, multiple myeloma subset. (<bold>b</bold>
) Time to death, consent withdrawn or lost to follow-up. Q4W, every 4 weeks.</p>
</caption>
<graphic xlink:href="bcj201596f1"></graphic>
</fig>
<fig id="fig2"><label>Figure 2</label>
<caption><p>Overall survival rate: Myeloma IX study vs study 244 multiple myeloma subgroup.</p>
</caption>
<graphic xlink:href="bcj201596f2"></graphic>
</fig>
<table-wrap id="tbl1"><label>Table 1</label>
<caption><title>Baseline/on-study characteristics in the multiple myeloma subset of the phase 3 study</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Characteristic,</italic>
n <italic>(%)</italic>
</th>
<th align="center" valign="top" char="(" charoff="50"><italic>Zoledronic acid (</italic>
n=<italic>93)</italic>
</th>
<th align="center" valign="top" char="(" charoff="50"><italic>Denosumab (</italic>
n=<italic>87)</italic>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td colspan="3" align="left" valign="top" charoff="50"><italic>Sex</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Male</td>
<td align="char" valign="top" char="(" charoff="50">54 (58%)</td>
<td align="char" valign="top" char="(" charoff="50">57 (66%)</td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"><italic>Age, years</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Mean (s.d.)</td>
<td align="char" valign="top" char="(" charoff="50">63 (11)</td>
<td align="char" valign="top" char="(" charoff="50">62 (10)</td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"><italic>ECOG performance status at study entry</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 0</td>
<td align="char" valign="top" char="(" charoff="50">30 (32%)</td>
<td align="char" valign="top" char="(" charoff="50">21 (24%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 1</td>
<td align="char" valign="top" char="(" charoff="50">44 (47%)</td>
<td align="char" valign="top" char="(" charoff="50">50 (58%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> 2</td>
<td align="char" valign="top" char="(" charoff="50">18 (19%)</td>
<td align="char" valign="top" char="(" charoff="50">15 (17%)</td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"><italic>Creatinine clearance at baseline</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> ⩾30 ml/min to <40 ml/min</td>
<td align="char" valign="top" char="(" charoff="50">2 (2%)</td>
<td align="char" valign="top" char="(" charoff="50">9 (10%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> ⩾40 ml/min to ⩽60 ml/min</td>
<td align="char" valign="top" char="(" charoff="50">23 (25%)</td>
<td align="char" valign="top" char="(" charoff="50">2 (2%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> >60 ml/min</td>
<td align="char" valign="top" char="(" charoff="50">64 (69%)</td>
<td align="char" valign="top" char="(" charoff="50">76 (87%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Missing</td>
<td align="char" valign="top" char="(" charoff="50">4 (4%)</td>
<td align="char" valign="top" char="(" charoff="50">0 (0%)</td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"> </td>
</tr>
<tr><td colspan="3" align="left" valign="top" charoff="50"><italic>Primary ISS stage at diagnosis–multiple myeloma</italic>
</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> I</td>
<td align="char" valign="top" char="(" charoff="50">13 (14%)</td>
<td align="char" valign="top" char="(" charoff="50">9 (10%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> II</td>
<td align="char" valign="top" char="(" charoff="50">23 (25%)</td>
<td align="char" valign="top" char="(" charoff="50">28 (32%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> III</td>
<td align="char" valign="top" char="(" charoff="50">56 (60%)</td>
<td align="char" valign="top" char="(" charoff="50">49 (56%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50">Autologous stem cell transplant (before or on study), <italic>n</italic>
</td>
<td align="center" valign="top" char="(" charoff="50">93
23 (25%)</td>
<td align="center" valign="top" char="(" charoff="50">86
15 (17%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"><italic>Anti-myeloma treatments on study,</italic>
<xref ref-type="fn" rid="t1-fn2">a</xref>
n</td>
<td align="center" valign="top" char="(" charoff="50">92</td>
<td align="center" valign="top" char="(" charoff="50">86</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Melphalan</td>
<td align="char" valign="top" char="(" charoff="50">48 (52%)</td>
<td align="char" valign="top" char="(" charoff="50">34 (40%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Thalidomide</td>
<td align="char" valign="top" char="(" charoff="50">44 (48%)</td>
<td align="char" valign="top" char="(" charoff="50">32 (37%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Bortezomib</td>
<td align="char" valign="top" char="(" charoff="50">25 (27%)</td>
<td align="char" valign="top" char="(" charoff="50">28 (33%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Cyclophosphamide</td>
<td align="char" valign="top" char="(" charoff="50">19 (21%)</td>
<td align="char" valign="top" char="(" charoff="50">25 (29%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Lenalidomide</td>
<td align="char" valign="top" char="(" charoff="50">19 (21%)</td>
<td align="char" valign="top" char="(" charoff="50">16 (19%)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System.</p>
</fn>
<fn id="t1-fn2"><label>a</label>
<p>Further details on combination regimens were not collected.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl2"><label>Table 2</label>
<caption><title>Patient disposition</title>
</caption>
<table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col>
<col align="char" char="("></col>
<col align="char" char="("></col>
</colgroup>
<thead valign="bottom"><tr><th align="left" valign="top" charoff="50"><italic>Characteristic,</italic>
n <italic>(%)</italic>
</th>
<th align="center" valign="top" char="(" charoff="50"><italic>Zoledronic acid (</italic>
n=<italic>93)</italic>
</th>
<th align="center" valign="top" char="(" charoff="50"><italic>Denosumab (</italic>
n=<italic>87)</italic>
</th>
</tr>
</thead>
<tbody valign="top"><tr><td align="left" valign="top" charoff="50"><italic>Withdrew before primary data cutoff</italic>
</td>
<td align="char" valign="top" char="(" charoff="50">45 (48%)</td>
<td align="char" valign="top" char="(" charoff="50">48 (55%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Death</td>
<td align="char" valign="top" char="(" charoff="50">8 (9%)</td>
<td align="char" valign="top" char="(" charoff="50">19 (22%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Consent withdrawn</td>
<td align="char" valign="top" char="(" charoff="50">16 (17%)</td>
<td align="char" valign="top" char="(" charoff="50">11 (13%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Other</td>
<td align="char" valign="top" char="(" charoff="50">3 (3%)</td>
<td align="char" valign="top" char="(" charoff="50">6 (7%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Disease progression</td>
<td align="char" valign="top" char="(" charoff="50">1 (1%)</td>
<td align="char" valign="top" char="(" charoff="50">6 (7%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Subject request</td>
<td align="char" valign="top" char="(" charoff="50">6 (7%)</td>
<td align="char" valign="top" char="(" charoff="50">3 (3%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Adverse event</td>
<td align="char" valign="top" char="(" charoff="50">7 (8%)</td>
<td align="char" valign="top" char="(" charoff="50">2 (3%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Protocol deviation</td>
<td align="char" valign="top" char="(" charoff="50">0 (0%)</td>
<td align="char" valign="top" char="(" charoff="50">1 (1%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Noncompliance</td>
<td align="char" valign="top" char="(" charoff="50">2 (2%)</td>
<td align="char" valign="top" char="(" charoff="50">0 (0%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Ineligibility determined</td>
<td align="char" valign="top" char="(" charoff="50">1 (1%)</td>
<td align="char" valign="top" char="(" charoff="50">0 (0%)</td>
</tr>
<tr><td align="left" valign="top" charoff="50"> Lost to follow-up</td>
<td align="char" valign="top" char="(" charoff="50">1 (1%)</td>
<td align="char" valign="top" char="(" charoff="50">0 (0%)</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>Australie</li>
<li>Autriche</li>
<li>Brésil</li>
<li>France</li>
<li>Grèce</li>
<li>Russie</li>
<li>États-Unis</li>
</country>
</list>
<tree><noCountry><name sortKey="Raje, N" sort="Raje, N" uniqKey="Raje N" first="N" last="Raje">N. Raje</name>
</noCountry>
<country name="États-Unis"><noRegion><name sortKey="Vadhan Raj, S" sort="Vadhan Raj, S" uniqKey="Vadhan Raj S" first="S" last="Vadhan-Raj">S. Vadhan-Raj</name>
</noRegion>
<name sortKey="Balakumaran, A" sort="Balakumaran, A" uniqKey="Balakumaran A" first="A" last="Balakumaran">A. Balakumaran</name>
<name sortKey="Braun, A" sort="Braun, A" uniqKey="Braun A" first="A" last="Braun">A. Braun</name>
<name sortKey="Feng, A" sort="Feng, A" uniqKey="Feng A" first="A" last="Feng">A. Feng</name>
<name sortKey="Roodman, G D" sort="Roodman, G D" uniqKey="Roodman G" first="G D" last="Roodman">G D Roodman</name>
<name sortKey="Stewart, A K" sort="Stewart, A K" uniqKey="Stewart A" first="A K" last="Stewart">A K Stewart</name>
</country>
<country name="Autriche"><noRegion><name sortKey="Willenbacher, W" sort="Willenbacher, W" uniqKey="Willenbacher W" first="W" last="Willenbacher">W. Willenbacher</name>
</noRegion>
</country>
<country name="Grèce"><noRegion><name sortKey="Terpos, E" sort="Terpos, E" uniqKey="Terpos E" first="E" last="Terpos">E. Terpos</name>
</noRegion>
</country>
<country name="Brésil"><noRegion><name sortKey="Hungria, V" sort="Hungria, V" uniqKey="Hungria V" first="V" last="Hungria">V. Hungria</name>
</noRegion>
</country>
<country name="Australie"><noRegion><name sortKey="Spencer, A" sort="Spencer, A" uniqKey="Spencer A" first="A" last="Spencer">A. Spencer</name>
</noRegion>
</country>
<country name="Russie"><noRegion><name sortKey="Alexeeva, Y" sort="Alexeeva, Y" uniqKey="Alexeeva Y" first="Y" last="Alexeeva">Y. Alexeeva</name>
</noRegion>
</country>
<country name="France"><noRegion><name sortKey="Facon, T" sort="Facon, T" uniqKey="Facon T" first="T" last="Facon">T. Facon</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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