<?xml version="1.0" encoding="ISO-8859-1"?><cms:container xmlns:cms="http://edoc.hu-berlin.de/diml/module/cms"><cms:document><cms:meta><cms:entry id="front" part="front" ref="front" type="front"/><cms:entry type="title">
			Einfluß des operativen Traumas auf die  Entwicklung pulmonaler Metastasen bei  hämatogen zirkulierenden Tumorzellen  &#8211; Prävention und Immuntherapie
		</cms:entry><cms:entry type="author">Peer Wildbrett</cms:entry><cms:entry id="N1008E" part="N1008E" ref="N1008E" type="dedication">
				Widmung</cms:entry><cms:entry id="N10092" part="N1008E" ref="N10092" type="pagenumber">9</cms:entry><cms:entry id="N1009E" part="N1009E" ref="N1009E" type="preface">
				Vorwort</cms:entry><cms:entry id="N100A2" part="N1009E" ref="N100A2" type="pagenumber">10</cms:entry><cms:entry id="chapter1" part="chapter1" ref="chapter1" type="chapter">1.</cms:entry><cms:entry id="N100B8" part="chapter1" ref="N100B8" type="pagenumber">11</cms:entry><cms:entry id="N100BD" part="chapter1" ref="N100BD" type="section">1.1.</cms:entry><cms:entry id="N100C9" part="chapter1" ref="N100C9" type="section">1.2.</cms:entry><cms:entry id="N100D9" part="chapter1" ref="N100D9" type="subsection">1.2.1.</cms:entry><cms:entry id="N100E0" part="chapter1" ref="N100E0" type="pagenumber">12</cms:entry><cms:entry id="N100FF" part="chapter1" ref="N100FF" type="subsection">1.2.2.</cms:entry><cms:entry id="N10109" part="chapter1" ref="N10109" type="pagenumber">13</cms:entry><cms:entry id="N10114" part="chapter1" ref="N10114" type="mm">611#377</cms:entry><cms:entry id="N10122" part="chapter1" ref="N10122" type="section">1.3.</cms:entry><cms:entry id="N10126" part="chapter1" ref="N10126" type="pagenumber">14</cms:entry><cms:entry id="N10140" part="chapter1" ref="N10140" type="pagenumber">15</cms:entry><cms:entry id="N10147" part="chapter1" ref="N10147" type="mm">504#885</cms:entry><cms:entry id="N10152" part="chapter1" ref="N10152" type="pagenumber">16</cms:entry><cms:entry id="N10160" part="chapter1" ref="N10160" type="section">1.4.</cms:entry><cms:entry id="N10185" part="chapter1" ref="N10185" type="pagenumber">17</cms:entry><cms:entry id="N1018B" part="chapter1" ref="N1018B" type="section">1.5.</cms:entry><cms:entry id="N101A3" part="chapter1" ref="N101A3" type="subsection">1.5.1.</cms:entry><cms:entry id="N101AE" part="chapter1" ref="N101AE" type="pagenumber">18</cms:entry><cms:entry id="N101D2" part="chapter1" ref="N101D2" type="subsection">1.5.2.</cms:entry><cms:entry id="N101E9" part="chapter1" ref="N101E9" type="pagenumber">19</cms:entry><cms:entry id="N101F3" part="chapter1" ref="N101F3" type="subsection">1.5.3.</cms:entry><cms:entry id="N1020C" part="chapter1" ref="N1020C" type="pagenumber">20</cms:entry><cms:entry id="N10212" part="chapter1" ref="N10212" type="table"/><cms:entry id="N1022A" part="chapter1" ref="N1022A" type="mm">563#886</cms:entry><cms:entry id="N10236" part="chapter1" ref="N10236" type="section">1.6.</cms:entry><cms:entry id="N1023A" part="chapter1" ref="N1023A" type="pagenumber">21</cms:entry><cms:entry id="N1023F" part="chapter1" ref="N1023F" type="subsection">1.6.1.</cms:entry><cms:entry id="N10266" part="chapter1" ref="N10266" type="subsection">1.6.2.</cms:entry><cms:entry id="N10271" part="chapter1" ref="N10271" type="pagenumber">22</cms:entry><cms:entry id="_1116776062" part="chapter1" ref="_1116776062" type="link"/><cms:entry id="_1116776105" part="chapter1" ref="_1116776105" type="link"/><cms:entry id="_1117114958" part="chapter1" ref="_1117114958" type="link"/><cms:entry id="N10294" part="chapter1" ref="N10294" type="mm">544#374</cms:entry><cms:entry id="N1029F" part="chapter1" ref="N1029F" type="pagenumber">23</cms:entry><cms:entry id="_1116776549" part="chapter1" ref="_1116776549" type="link"/><cms:entry id="_1117115029" part="chapter1" ref="_1117115029" type="link"/><cms:entry id="N102B0" part="chapter1" ref="N102B0" type="mm">534#374</cms:entry><cms:entry id="N102BA" part="chapter1" ref="N102BA" type="subsection">1.6.3.</cms:entry><cms:entry id="N102D4" part="chapter1" ref="N102D4" type="pagenumber">24</cms:entry><cms:entry id="_1116776839" part="chapter1" ref="_1116776839" type="link"/><cms:entry id="_1116776898" part="chapter1" ref="_1116776898" type="link"/><cms:entry id="_1116777094" part="chapter1" ref="_1116777094" type="link"/><cms:entry id="N102EF" part="chapter1" ref="N102EF" type="mm">442#176</cms:entry><cms:entry id="N10327" part="chapter1" ref="N10327" type="pagenumber">25</cms:entry><cms:entry id="_1116777282" part="chapter1" ref="_1116777282" type="link"/><cms:entry id="_1116777497" part="chapter1" ref="_1116777497" type="link"/><cms:entry id="_1119022205" part="chapter1" ref="_1119022205" type="link"/><cms:entry id="N10337" part="chapter1" ref="N10337" type="mm">511#350</cms:entry><cms:entry ref="chapter2" type="chapter">2.</cms:entry><cms:entry ref="N1034E" type="pagenumber">26</cms:entry><cms:entry ref="N10353" type="section">2.1.</cms:entry><cms:entry ref="N10367" type="section">2.2.</cms:entry><cms:entry ref="N10375" type="pagenumber">27</cms:entry><cms:entry id="chapter3" part="chapter3" ref="chapter3" type="chapter">3.</cms:entry><cms:entry id="N10380" part="chapter3" ref="N10380" type="pagenumber">28</cms:entry><cms:entry id="N10385" part="chapter3" ref="N10385" type="section">3.1.</cms:entry><cms:entry id="N1038E" part="chapter3" ref="N1038E" type="section">3.2.</cms:entry><cms:entry id="N10397" part="chapter3" ref="N10397" type="section">3.3.</cms:entry><cms:entry id="N1039C" part="chapter3" ref="N1039C" type="subsection">3.3.1.</cms:entry><cms:entry id="N103A5" part="chapter3" ref="N103A5" type="subsection">3.3.2.</cms:entry><cms:entry id="N103A9" part="chapter3" ref="N103A9" type="pagenumber">29</cms:entry><cms:entry id="N103B3" part="chapter3" ref="N103B3" type="table"/><cms:entry id="N1043B" part="chapter3" ref="N1043B" type="mm">606#146</cms:entry><cms:entry id="N10446" part="chapter3" ref="N10446" type="section">3.4.</cms:entry><cms:entry id="N1044D" part="chapter3" ref="N1044D" type="pagenumber">30</cms:entry><cms:entry id="N10453" part="chapter3" ref="N10453" type="section">3.5.</cms:entry><cms:entry id="N1045C" part="chapter3" ref="N1045C" type="section">3.6.</cms:entry><cms:entry id="N10465" part="chapter3" ref="N10465" type="section">3.7.</cms:entry><cms:entry id="N1046E" part="chapter3" ref="N1046E" type="section">3.8.</cms:entry><cms:entry id="N10477" part="chapter3" ref="N10477" type="section">3.9.</cms:entry><cms:entry id="N1047B" part="chapter3" ref="N1047B" type="pagenumber">31</cms:entry><cms:entry id="N10484" part="chapter3" ref="N10484" type="section">3.10.</cms:entry><cms:entry id="N1048C" part="chapter3" ref="N1048C" type="subsection">3.10.1.</cms:entry><cms:entry id="N10495" part="chapter3" ref="N10495" type="subsection">3.10.2.</cms:entry><cms:entry id="N104A8" part="chapter3" ref="N104A8" type="pagenumber">32</cms:entry><cms:entry id="_1116779257" part="chapter3" ref="_1116779257" type="link"/><cms:entry id="_1116779376" part="chapter3" ref="_1116779376" type="link"/><cms:entry id="N104B5" part="chapter3" ref="N104B5" type="mm">602#407</cms:entry><cms:entry id="N104BF" part="chapter3" ref="N104BF" type="subsection">3.10.3.</cms:entry><cms:entry id="N104C6" part="chapter3" ref="N104C6" type="pagenumber">33</cms:entry><cms:entry id="N104CC" part="chapter3" ref="N104CC" type="subsection">3.10.4.</cms:entry><cms:entry id="N104D5" part="chapter3" ref="N104D5" type="subsection">3.10.5.</cms:entry><cms:entry id="N104DE" part="chapter3" ref="N104DE" type="subsection">3.10.6.</cms:entry><cms:entry id="N104E5" part="chapter3" ref="N104E5" type="pagenumber">34</cms:entry><cms:entry id="N104EB" part="chapter3" ref="N104EB" type="subsection">3.10.7.</cms:entry><cms:entry id="N104F5" part="chapter3" ref="N104F5" type="section">3.11.</cms:entry><cms:entry id="N10502" part="chapter3" ref="N10502" type="section">3.12.</cms:entry><cms:entry id="N1050B" part="chapter3" ref="N1050B" type="section">3.13.</cms:entry><cms:entry id="N1050F" part="chapter3" ref="N1050F" type="pagenumber">35</cms:entry><cms:entry id="N1051C" part="chapter3" ref="N1051C" type="section">3.14.</cms:entry><cms:entry id="chapter4" part="chapter4" ref="chapter4" type="chapter">4.</cms:entry><cms:entry id="N10530" part="chapter4" ref="N10530" type="pagenumber">36</cms:entry><cms:entry id="N10535" part="chapter4" ref="N10535" type="section">4.1.</cms:entry><cms:entry id="_1116779506" part="chapter4" ref="_1116779506" type="link"/><cms:entry id="_1116779594" part="chapter4" ref="_1116779594" type="link"/><cms:entry id="N10545" part="chapter4" ref="N10545" type="mm">401#271</cms:entry><cms:entry id="N10550" part="chapter4" ref="N10550" type="pagenumber">37</cms:entry><cms:entry id="N10554" part="chapter4" ref="N10554" type="mm">397#272</cms:entry><cms:entry id="N1055E" part="chapter4" ref="N1055E" type="section">4.2.</cms:entry><cms:entry id="N10568" part="chapter4" ref="N10568" type="mm">605#286</cms:entry><cms:entry id="N10572" part="chapter4" ref="N10572" type="section">4.3.</cms:entry><cms:entry id="N10576" part="chapter4" ref="N10576" type="pagenumber">38</cms:entry><cms:entry id="N1057B" part="chapter4" ref="N1057B" type="subsection">4.3.1.</cms:entry><cms:entry id="N10585" part="chapter4" ref="N10585" type="table"/><cms:entry id="N10612" part="chapter4" ref="N10612" type="subsection">4.3.2.</cms:entry><cms:entry id="N1061C" part="chapter4" ref="N1061C" type="table"/><cms:entry id="N1070B" part="chapter4" ref="N1070B" type="subsection">4.3.3.</cms:entry><cms:entry id="N1070F" part="chapter4" ref="N1070F" type="pagenumber">39</cms:entry><cms:entry id="N10719" part="chapter4" ref="N10719" type="table"/><cms:entry id="N107AF" part="chapter4" ref="N107AF" type="subsection">4.3.4.</cms:entry><cms:entry id="N107B9" part="chapter4" ref="N107B9" type="table"/><cms:entry id="N108F7" part="chapter4" ref="N108F7" type="pagenumber">40</cms:entry><cms:entry id="N108FB" part="chapter4" ref="N108FB" type="mm">587#470</cms:entry><cms:entry id="N10905" part="chapter4" ref="N10905" type="subsection">4.3.5.</cms:entry><cms:entry id="N1090F" part="chapter4" ref="N1090F" type="table"/><cms:entry id="N10996" part="chapter4" ref="N10996" type="subsection">4.3.6.</cms:entry><cms:entry id="N1099A" part="chapter4" ref="N1099A" type="pagenumber">41</cms:entry><cms:entry id="N109A4" part="chapter4" ref="N109A4" type="table"/><cms:entry id="N10ABA" part="chapter4" ref="N10ABA" type="section">4.4.</cms:entry><cms:entry id="N10ABF" part="chapter4" ref="N10ABF" type="subsection">4.4.1.</cms:entry><cms:entry id="N10AC9" part="chapter4" ref="N10AC9" type="table"/><cms:entry id="N10B7F" part="chapter4" ref="N10B7F" type="subsection">4.4.2.</cms:entry><cms:entry id="N10B83" part="chapter4" ref="N10B83" type="pagenumber">42</cms:entry><cms:entry id="N10B8D" part="chapter4" ref="N10B8D" type="table"/><cms:entry id="N10CCE" part="chapter4" ref="N10CCE" type="table"/><cms:entry id="N10CD5" part="chapter4" ref="N10CD5" type="pagenumber">43</cms:entry><cms:entry id="N10DD4" part="chapter4" ref="N10DD4" type="subsection">4.4.3.</cms:entry><cms:entry id="N10DDE" part="chapter4" ref="N10DDE" type="table"/><cms:entry id="N10EB0" part="chapter4" ref="N10EB0" type="subsection">4.4.4.</cms:entry><cms:entry id="N10EB4" part="chapter4" ref="N10EB4" type="pagenumber">44</cms:entry><cms:entry id="N10EBB" part="chapter4" ref="N10EBB" type="table"/><cms:entry id="N1107D" part="chapter4" ref="N1107D" type="pagenumber">45</cms:entry><cms:entry id="N11081" part="chapter4" ref="N11081" type="mm">603#489</cms:entry><cms:entry id="N1108B" part="chapter4" ref="N1108B" type="subsection">4.4.5.</cms:entry><cms:entry id="N11097" part="chapter4" ref="N11097" type="table"/><cms:entry id="N11136" part="chapter4" ref="N11136" type="subsection">4.4.6.</cms:entry><cms:entry id="N1113A" part="chapter4" ref="N1113A" type="pagenumber">46</cms:entry><cms:entry id="N11144" part="chapter4" ref="N11144" type="table"/><cms:entry id="N11250" part="chapter4" ref="N11250" type="pagenumber">47</cms:entry><cms:entry id="N11257" part="chapter4" ref="N11257" type="table"/><cms:entry id="N113B7" part="chapter4" ref="N113B7" type="table"/><cms:entry id="N114C7" part="chapter4" ref="N114C7" type="table"/><cms:entry id="N11587" part="chapter4" ref="N11587" type="table"/><cms:entry id="chapter5" part="chapter5" ref="chapter5" type="chapter">5.</cms:entry><cms:entry id="N115FC" part="chapter5" ref="N115FC" type="pagenumber">48</cms:entry><cms:entry id="N11601" part="chapter5" ref="N11601" type="section">5.1.</cms:entry><cms:entry id="N1160C" part="chapter5" ref="N1160C" type="subsection">5.1.1.</cms:entry><cms:entry id="N1162D" part="chapter5" ref="N1162D" type="pagenumber">49</cms:entry><cms:entry id="N11638" part="chapter5" ref="N11638" type="mm">604#334</cms:entry><cms:entry id="N1165C" part="chapter5" ref="N1165C" type="pagenumber">50</cms:entry><cms:entry id="N1167B" part="chapter5" ref="N1167B" type="mm">604#317</cms:entry><cms:entry id="N11688" part="chapter5" ref="N11688" type="pagenumber">51</cms:entry><cms:entry id="N1168B" part="chapter5" ref="N1168B" type="mm"/><cms:entry id="N116A5" part="chapter5" ref="N116A5" type="pagenumber">52</cms:entry><cms:entry id="N116AB" part="chapter5" ref="N116AB" type="subsection">5.1.2.</cms:entry><cms:entry id="N116D4" part="chapter5" ref="N116D4" type="pagenumber">53</cms:entry><cms:entry id="N116E6" part="chapter5" ref="N116E6" type="mm">586#406</cms:entry><cms:entry id="N11700" part="chapter5" ref="N11700" type="pagenumber">54</cms:entry><cms:entry id="N11709" part="chapter5" ref="N11709" type="subsection">5.1.3.</cms:entry><cms:entry id="N11722" part="chapter5" ref="N11722" type="pagenumber">55</cms:entry><cms:entry id="N11734" part="chapter5" ref="N11734" type="section">5.2.</cms:entry><cms:entry id="N11739" part="chapter5" ref="N11739" type="subsection">5.2.1.</cms:entry><cms:entry id="N1174A" part="chapter5" ref="N1174A" type="pagenumber">56</cms:entry><cms:entry id="N1175A" part="chapter5" ref="N1175A" type="subsection">5.2.2.</cms:entry><cms:entry id="N11763" part="chapter5" ref="N11763" type="subsection">5.2.3.</cms:entry><cms:entry id="N11777" part="chapter5" ref="N11777" type="pagenumber">57</cms:entry><cms:entry id="N11782" part="chapter5" ref="N11782" type="mm">570#441</cms:entry><cms:entry id="N1178D" part="chapter5" ref="N1178D" type="pagenumber">58</cms:entry><cms:entry id="N11798" part="chapter5" ref="N11798" type="mm">510#360</cms:entry><cms:entry id="N117A2" part="chapter5" ref="N117A2" type="subsection">5.2.4.</cms:entry><cms:entry id="N117A9" part="chapter5" ref="N117A9" type="pagenumber">59</cms:entry><cms:entry id="N117BB" part="chapter5" ref="N117BB" type="mm">510#389</cms:entry><cms:entry id="N117C6" part="chapter5" ref="N117C6" type="pagenumber">60</cms:entry><cms:entry id="chapter6" part="chapter6" ref="chapter6" type="chapter">6.</cms:entry><cms:entry id="N117D9" part="chapter6" ref="N117D9" type="pagenumber">61</cms:entry><cms:entry id="N117F5" part="chapter6" ref="N117F5" type="pagenumber">62</cms:entry><cms:entry ref="N11800" type="back"/><cms:entry id="N11802" part="N11802" ref="N11802" type="bibliography">
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				Danksagung</cms:entry><cms:entry id="N12405" part="N12401" ref="N12405" type="pagenumber">72</cms:entry><cms:entry id="N12411" part="N12411" ref="N12411" type="declaration">
				Eidestattliche Erklärung</cms:entry><cms:entry id="N12415" part="N12411" ref="N12415" type="pagenumber">73</cms:entry><cms:entry part="chapter2" type=":current"/><cms:entry type=":lang">de</cms:entry><cms:entry id=":contents" part="front" ref=":contents" type=":contents">Inhaltsverzeichnis</cms:entry><cms:entry type=":help"><url href="http://...">Hilfe</url></cms:entry></cms:meta><cms:content><chapter id="chapter2" label="2.">
			<head>
				<pagenumber id="N1034E" label="26" numbering="arabic" start="26"/>Herleitung der Aufgabenstellung</head>
			<section id="N10353" label="2.1.">
				<head>Entwicklung pulmonaler Metastasen nach operativem Trauma</head>
				<p>Bundesweit werden ca. 20% der abdominalchirurgischen Operationen laparoskopisch durchgeführt [<link ref="_bib85">58</link>]. Obwohl die Invasion in den Körper, verglichen mit konventioneller Technik, die gleiche ist, wird durch Anwendung laparoskopischer Verfahren das operative Trauma deutlich reduziert. Sämtliche Vorteile der Minimal Invasiven Chirurgie gegenüber konventionellen Operationen ergeben sich aus dieser Verringerung des Traumas. Weniger Trauma bedeutet für den Patienten geringere postoperative Schmerzen, weniger Einschränkung der Lungenfunktion, weniger Beeinflussung der gastrointestinalen Motilität und weniger Immundepression. Daraus ergeben sich frühe Mobilisation, rasche Nahrungsaufnahme, rascher Beginn der Darmtätigkeit und Stuhlentleerung, frühe Entlassung aus der Klinik und frühere Rückkehr zu normaler Belastung. Denkbare Vorteile sind geringere Raten an Thrombosen und Pneumonien, bedingt durch die kurze Liegezeit. In den nächsten Jahren ist mit einer Zunahme laparoskopischer Operationen von ungefähr 10% zu rechnen [<link ref="_bib85">58</link>]. Ein Teil dieser minimal invasiven Eingriffe wird auch die Tumorchirurgie betreffen. Es bleibt dabei abzuwarten, ob durch Reduktion des chirurgischen Traumas auch die onkologischen Langzeitergebnisse verbessert werden können. </p>
				<p>Hypothese 1: Eine mediane Laparotomie vom Xiphoid bis zur Symphyse führt bei hämatogen zirkulierenden malignen Zellen zu einer deutlich gesteigerten pulmonalen Metastasierung. Im Vergleich dazu bewirkt der Aufbau eines Pneumoperitoneums keine gesteigerte Anzahl pulmonaler Metastasen.</p>
			</section>
			<section id="N10367" label="2.2.">
				<head>Prävention pulmonaler Metastasen durch spezifische Immuntherapie</head>
				<p>Berechtigte Hoffnung, daß in den nächsten Jahren eine wirkungsvolle Therapieform maligner Erkrankungen zur Verfügung steht, basiert auf der Identifizierung neuer Tumorantigene. Sollte es möglich sein, das spezifische Immunsystem gegen diese Antigene zu aktivieren, d. h. T-Lymphozyten zu stimulieren und eine zelluläre Immunreaktion auszulösen, könnten die nach Resektion des Primärtumors im Körper verbliebenen Tumorzellen effektiv bekämpft werden. Prinzipiell kann das Immunsystem minimale Veränderungen wie Punktmutationen erkennen, wenn das mutierte Peptid auf einem der HLA-Moleküle der Tumorzelle präsentiert wird [<link ref="_bib20">33</link>]. Werden die Tumorzellen lysiert und intraperitoneal verabreicht, kommt es zur Phagozytose der Zelltrümmer durch Peritonealmakrophagen. Die Makrophagen präsentieren die Tumorantigene in Verbindung mit akzessorischen Molekülen auf ihrer Zelloberfläche und können somit eine antitumorale Immunantwort auslösen. Werden dem Patienten nach Resektion des Primärtumors autogene, lysierte, maligne Zellen verabreicht, könnten diese das Substrat für eine wirkungsvolle Therapie der sekundären Tumore sein. </p>
				<p>
					<pagenumber id="N10375" label="27" numbering="arabic" start="27"/>Hypothese 2: Die Induktion einer spezifischen Immunreaktion gegen hämatogen zirkulierende Tumorzellen durch Verabreichen autogener Tumorzellfragmente in Kombination mit einem Adjuvans bewirkt eine signifikant geringere Anzahl pulmonaler Metastasen nach Laparotomie.</p>
			</section>
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