Neuroendokrina Tunntarmstumörer (SI-NETs) är indolenta neoplasier med en årlig incidens kring 1 / 100,000 personer. De är ofta diagnocerade senare i sjukdomsförloppet, vilket begränsar behandlingens effektivitet. Syftet med denna avhandlingen är att undersöka pre-kliniska och kliniska aspekter av patienter med avancerad och / eller spridd sjukdom, med speciellt fokus på hantering av intra-abdominell fibros, rollen av lokoregional kirurgi och levertransplantation, samt ex vivo sensitivitet av cytotoxiska substanser på tumörprover. Dessutom undersöktes nya serum biomarkörer för diagnos och prognos av SI-NETs.
Bakgrunden i delarbete I var att serotonin och andra cytokiner, som utsöndras från SI-NET tumörceller kan orsaka fibros, vilket leder till karcinoid hjärtsjukdom och fibrotiska reaktioner intraabdominellt. Syftet med arbetet var att studera förekomsten, kliniska komplikationer och hantering av den fibrotiska reaktionen i buken. Trettiosex patienter identifierades med signifikanta radiologiska tecken och symtom på fibros.
Av dessa hade 20 patienter central mesenteriell fibros, som orsakade tarmischemi och 16 hade retroperitoneal fibros, som orsakade obstruktiv uropati med hydronefros. Palliativa ingrepp i form av stentinläggning i Vena mesenterica superior eller resektion av centrala mesenteriella metastaser och/eller perkutan nefrostomi och J-stent behandling var fördelaktiga hos majoriteten av patienterna. Slutsatsen från detta delarbetet var att tidig diagnos och minimalinvasiva åtgärder var effektiva för sjukdomspalliation.
I delabete II undersöktes rollen av lokoregional kirurgi vid diagnos hos asymtomatiska patienter med SI-NET och fjärrmetastaser. Data erhölls från vår Uppsala databas för SI-NET och det Nationella Patientregistret.
Trehundrasextiotre patienter med SI-NET utan lokala tumörrelaterade symptom vid diagnos uppdelades i två grupper, varav en grupp som opererades inom sex månader från diagnos och en kontrollgrupp, som antingen behandlades icke-kirurgiskt eller opererades senare i sjukdomsförloppet. ”Propensity score” matchning utfördes för att reducera risken för selektions-bias. De matchade grupperna visade ingen skillnad i total överlevnad, 30-dagars postoperativ mortalitet och morbiditet samt vårdtid vid sjukhus. Däremot visar studien att gruppen som opererades vid diagnos genomgick flera re-operationer pga tarmobstruktion. Slutsatsen är
att man generellt inte kan rekommendera lokoregional kirurgi i ett profylaktiskt syfte vid diagnos hos asymptomatiska SI-NET patienter vid stadium IV.
I delarbete III undersöktes rollen av levertransplantation (LTx) hos patienter med levermetastaserade SI-NET. Från Uppsaladatabasen för SI-NET identifierades 78 patienter, som uppfyllde befintliga LTx kriterier: <65 år, radikalt genomförd lokoregional kirurgi och avsaknad av extra-hepatisk sjukdom. Patienterna genomgick behandling enligt de kliniska protokollen vid vårt centrum, och under denna tidsperiod utfördes inte några LTx.
Resultaten i detta delarbete visar att de flesta unga patienter (<65 år) med SI-NET och levermetastaser har en lång överlevnad med standardiserad multimodal behandling, dvs utan LTx, och att de flesta överlevnadssiffror som rapporteras efter LTx för NET i andra centra inte överträffar dessa siffror.
I delarbete IV undersöktes nya diagnostiska och prognostiska biomarkörer vid SI-NET. Etthundrafyrtiofem biomarkörer i plasma hos 96 patienter med SI-NET och 23 friska kontrollpersoner undersöktes med metoderna PLA och PEA (proximity ligation assay och proximity extension assay, Olink bioscience). Nitton biomarkörer vid PLA och 17 vid PEA visade sig ha olika serumnivåer mellan patienter och friska kontroller. Tre markörer studerades vidare; DcR3, TFF3 och Midkine. Alla dessa proteiner uttrycktes i tumörvävnad enligt immunohistokemiskt analys. Resultatet visar att höga serum nivåer av DcR3 och TFF3 var associerat med en sämre överlevnad.
DcR3 är en markör för levermetastaser och TFF3 samt Midkine är nya diagnostiska biomarkörer vid SI-NET tidigt i sjukdomsförloppet.
SI-NET anses vara allmänt resistenta mot systemisk behandling förutom somatostatinanaloger och alfa-interferon. I delarbete V undersökte vi denna tumörtyp med hänsyn till sensitivitet ex vivo mot en panel av kemoterapeutiska och riktade medel med användning av ”fluorometric microculture cytotoxicity assay” (FMCA). Tumörceller från patientprover med njurcancer, kolorektal cancer, äggstockscancer och kronisk lymfocytär leukemi användes som jämförelse. SI-NET-proverna analyserades även i förhållande till kliniska-patologiska variabler (ålder vid diagnos, stadium, peritoneal carcinomatos, extra-abdominella metastaser och grad) samt befintliga biomarkörer, (serum-Chromogranin A och urin-5HIAA).
Resultaten av detta delarbetet visar att tumörceller från SI-NET uppvisar variabel men generellt intermediär sensitivitet ex vivo jämfört med andra tumördiagnoser. Kliniska-patologiska faktorer och befintliga biomarkörer var inte associerade till sensitivitet ex vivo och utmanade dessa kriterier för behandlingsbeslut i SI-NET. Den stora variationen i ex vivo sensitivitet
innebär att det sannolikt finns utrymme för individuellt anpassad behandling där fler faktorer inklusive ex vivo sensitiviteten vägs in.
Acknowledgements
I would like to express my sincere gratitude to the following people, who have helped and supported me along the way.
Professor Peter Stålberg, my main supervisor, for introducing me to both basic and clinical scientific research, for the highly educative conversations we had, and most importantly for his support and exceptional guidance throughout all parts of this thesis.
Professor Per Hellman, my co-supervisor, for his encouragement and kindness and for sharing his invaluable expertise with me.
Associate Professor Olov Norlén, my co-supervisor, for his rapid and insightful advice, outstanding statistical skills and also his positive spirit.
Professor Peter Nygren, my co-supervisor, for concise and detailed instructions, as well as excellent support in the final article in this thesis.
Katarina Edfeldt, my co-author, for valuable instructions and help in the laboratory in the fourth article in the thesis.
Andreas Karakatsanis, my co-author, for his valuable help, enthusiasm and stimulating conversations.
Birgitta Bondeson for her great technical assistance in tissue preparation and immunohistochemical staining in the laboratory.
My other co-authors: Eva Tiensuu Janson, Kjell Öberg, Staffan Welin, Heather C Stuart, Ola Hessman, Göran Åkerström, Gunnar Westin and Christopher Bäcklin for valuable contributions to the articles in this thesis.
Claes Juhlin and Kristiina Kask, former and present Head of the Department of Surgery, as well as Professor Olle Nilsson and Professor Per Hellman, former and current Chair of the Department of Surgical Sciences, for providing the means for clinical work and scientific research.
Ola Hessman, Head of the Endocrine Section and former clinical supervisor, for teaching me his surgical skills, sharing his deep knowledge in the field and supporting me.
My sister Argyro for artistic contributions in the front page and some of the figures in the thesis and also my little sister Despoina for her support.
My parents Markos and Euthalia for supporting every step in my life, for the principles they inspired in me and for their unconditional love.
My two sons Markos and Aristides, for bringing light and joy into my life.
My wife Julia, for her love and understanding. It is her patience and strength that have made this thesis possible.
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