Stage Ib-III

In patients with submucosal AC, the overall risk of lymph node metastases was 20% in sm2-3 and overall risk for recurrence 27%, results in accordance with previously published results (160, 173, 178, 187, 188, 242). With higher risks for metastasis and recurrence, radical surgery is recommended generally (9, 33, 248). A German group (189) reported favorable long-term survival after mucosal resection of submucosal esophageal AC, in a group with sm1 level infiltration, well to

moderate differentiation and no lymphovascular infiltration. If low risk patients can be reliably identified by pathologists, endoscopic ablation may be a viable alternative for patients, even for those in the superficial pT1b category, at high risk of not undergoing successful surgery.

MIE has been developed to decrease the rate of pulmonary complications after traditional OE (231, 232). In study IV, we compared the perioperative and oncologic results of OE and MIE following esophageal resection, for locally advanced esophageal AC after neoadjuvant chemotherapy. One-month mortality rates and also three-One-month mortality rates were both low, as compared to series from high volume centers (31, 42, 46, 170) and they did not differ from each other with any significance. The anastomotic leak rates and rates of respiratory complications did not differ and the overall rates of complications were similar. Statistical difference was seen in intraoperative bleeding and total hospital stay in favor of the minimally invasive approach. Less pulmonary complications, less operative bleeding, a shorter hospital time for MIE, and similar rates of anastomotic leaks between the OE and MIE approaches are reported in meta-analyses (43-45, 234) and a recent randomized trial (46). These results are in line with ours. In our study, the rate of R0 resections was the same and short-term (three-year) survival did not differ with any significance.

The number of retrieved lymph nodes was higher for open esophagectomy, but for MIE, the median of retrieved nodes was 20, a result similar to reports from meta-analyses (234, 235). The incidence of late complications did not differ between the OE and MIE approaches.

Overall, MIE appears to be comparable to traditional OE when comparing postoperative results and it achieves the same oncologic radicality with comparable short-term survival rates. Our series also includes the learning curve for a new, very demanding technique, and our results should be expected to be even better in future. Surgery and treatment for esophageal cancer overall, is complex and requires an experienced multidisciplinary team. Treatment options range from endoscopic therapies to different surgical resections. The surgical team should be able to handle all methods and tailor treatments to match their patients’ reserves.

10 CONCLUSIONS

1. In proximal gastric mucosa of patients with Barrett’s esophagus and esophageal adenocarcinoma, elevated oxidative stress, increased oxidative DNA damage and depleted antioxidative buffer concentrations can be measured.

2. In early esophageal adenocarcinoma, half of the patients were alive 10 year after the operation. Cancer recurrence was the most common cause of death during the 5-year follow-up, and after that, diseases related to aging.

3. The accuracy of FDG-PET-CT was not good enough to guide clinical decision-making, based on this modality alone. An over 67% decrease in the metabolic activity of the primary tumor was associated with a 4-fold decrease in the of risk death due to esophageal adenocarcinoma.

4. As compared to open esophagectomy, minimally invasive esophagectomy shortens overall stay in hospital and is associated with less blood loss during the operation. The rates of complications or re-operations do not differ with any significance. The oncologic results are also comparable, as the rates of complete resection and 3-year survival are similar.

11 YHTEENVETO (FINNISH SUMMARY)

Ruokatorven ja mahansuun adenokarsinooma on huonoennusteinen tauti, jonka ilmaantuvuus länsimaissa on ollut nousussa viime vuosikymmeninä. Sen patogeneesi liittyy gastroduodenaalisen refluksin aiheuttamaan krooniseen tulehdukseen ja oksidatiiviseen stressiin ruokatorven limakalvolla. Parantuminen on mahdollista potilailla, joille tehdään onnistunut radikaali leikkaus ja joiden syövän aste on varhainen. Paikallisesti edenneissä tapauksissa paraneminen on mahdollista osalla potilaista, joiden leikkausta edeltää onnistunut onkologinen esihoito. Ruokatorvikirurgiaan liittyy paljon komplikaatioita ja merkittävä leikkauskuolleisuuden riski. Siksi on keskeistä löytää menetelmiä, jotka auttava löytämään leikkauksesta hyötyvät potilaat sekä selvittää myös vähemmän invasiivisten menetelmien tulokset.

Tämän tutkimuksen tavoitteena oli 1) selvittää oksidatiivisen stressin merkitystä mahalaukun alkuosassa Barrett’n ruokatorven ja ruokatorven adenokarsinooman synnyssä, 2) arvioida varhaisvaiheen ruokatorven adenokarsinooman pitkäaikaisennusteta ja potilaiden kuolinsyitä, 3) arvioida kuinka 18F-fluorodeoksi-D-glukoosi-positroniemissiotomografia liitettynä tietokone-tomografiaan (FDG-PET-CT) ennustaa kirurgiaa edeltävän kemoterapian vastetta ruokatorven adenokarsinooman hoidossa ja 4) verrata mini-invasiivisen radikaalileikkauksen tuloksia avoimeen ruokatorven syövän leikkaukseen.

Ensimmäisessä osatyössä potilasaineisto koostui 43 tutkimus- ja 15 kontrollipotilaasta, joiden ruokatorven ja mahansuun limakalvoilta mittaukset tehtiin. Oksidatiivista stressiä määritettiin mittaamalla 8-isoprostaanipitoisuus. Antioksidanttikapasiteettia varten mitattiin glutationin hapettuneen ja pelkistyneen muodon pitoisuudet ja vaurioituneen DNA:n tunnistamiseksi mitattiin 8-OH-deoksiglukoosipitoisuus. Toisessa osatyössä varhaisvaiheen ruokatorven adenokarsinooman pitkäaikaisennusteen ja kuolinsyiden määrittämiseksi tutkittiin potilasarkiston ja kuolinsyyrekisterin tiedot 85:lta potilaalta joilta oli kirurgisesti hoidettu limakalvoon tai sen alaiseen kerrokseen rajoittuva tauti. Kolmannessa osatyössä arvioitiin kirurgiaa edeltävän kemoterapiana annetun esihoidon tehoa tekemällä FDG-PET-CT kuvaus ennen ja jälkeen kemoterapian 66 potilaalle joille sen jälkeen tehtiin radikaali leikkaus. Tutkimuksessa arvioitiin kasvaimen aineenvaihdunnan aktiivisuuden muutoksen yhteyttä tuumorikudoksen katoon sekä potilaan ennusteeseen. Neljäs osatyö koostui leikkaustulosten vertailusta mini-invasiivisesti ja avoimesti tehtyjen leikkausten välillä. Vertailussa oli 75 mini-invasiivisesti ja 79 avoimesti leikattua potilasta, jotka sairastivat

paikallisesti levinnyttä ruokatorven adenokarsinoomaa. Tutkimuksessa verrattiin leikkauksen jälkeistä kuolleisuutta, komplikaatioita, leikkauksen onkologista radikaliteettia sekä ennustetta.

Tutkimusten tulokset olivat seuraavat: 1) Mahalaukun alkuosan 8-isoprostaani sekä 8-OHdG pitoisuudet olivat korkeammalla tutkimus- kuin kontrolliryhmässä, ja ero oli tilastollisesti merkitsevä. Antioksidattikapasiteetti (glutationipitoisuus) oli merkitsevästi matalampi tutkimus-, kuin kontrolliryhmässä. 2) Ruokatorven varhaisvaiheen adenokarsinoomaa sairastavien potilaiden alle viiden vuoden kuolleisuus johtui taudin uusimisesta, kun taas pitkäaikaisennuste riippui ikääntymiseen liittyvistä kuolinsyistä. Viiden vuoden seurannan jälkeen 80 % potilaista oli tautivapaita, eikä uusia residiivejä tullut tämän jälkeen. 3) Paikallisesti edenneen ruokatorvisyövän täyttä häviämistä leikkauspreparaatista ennusti parhaiten 67 % lasku tuumorin FDG-PET-CT kuvauksen osoittamassa aktiivisuudessa esihoidon jälkeen(sensitiivisyys 79 % ja spesifisyys 75 %).

PET-aktiivisuuden lasku jatkuvana muuttujana, oli monimuuttujamallissa yhteydessä potilaiden kokonaisennusteeseen itsenäisenäkin ennustetekijänä. 4) Mini-invasiivinen ja avoin tekniikka olivat yhteneväisiä tuloksiltaan kolmen kuukauden kuolleisuuden, komplikaatioiden kokonaismäärän ja kolmen vuoden elossaololukujen suhteen. Mini-invasiivisen tekniikan käyttöön liittyi vähäisempi verenvuoto leikkauksen aikana sekä lyhyempi sairaalahoitoaika. Tutkimustemme johtopäätökset olivat seuraavat: 1) Barrett- ja ruokatorven adenokarsinoomapotilaiden mahalaukun alkuosan oksidatiivinen stressi on lisääntynyt, koska 8-isoprostaanitaso on kohonnut ja antioksidanttikapasiteetti vähentynyt verrattuna terveisiin verrokkeihin. Myös hapettumisen vaurioittamaa DNA:ta voidaan todeta merkitsevästi enemmän kuin verrokeilla. Näin ollen mahalaukun alkuosan oksidatiivisella stressillä voi olla osuutensa Barrettin ruokatorven ja ruokatorven adenokarsinooman kehittymisessä. 2) Ruokatorven adenokarsinooman varhaisasteen tautikohtainen ennuste oli hyvä, mutta taudin uusiminen oli silti yleisin kuolinsyy. Riski oli korkein potilailla, joilla oli paikallisten imusolmukkeiden metastaaseja ja tuumori kasvoi limakalvonalaiseen kerrokseen. Näinollen kirurgisen hoidon tulee edelleen olla ensisijainen menetelmä, varsinkin limakalvon alaiseen kerrokseen kasvavilla syövillä, ja endoskooppisia hoitomenetelmiä harkita valikoidusti. 3) FDG-PET-CT:n tarkkuus ei ollut riittävää ohjaamaan hoitopäätöksiä muutoin, kuin metastasoinnin ja tautiprogression poissulkemisen osalta. Kuitenkin PET-aktiivisuuden lasku oli yhteydessä potilaan parempaan ennusteeseen ja tämä tieto on hyödyksi pohdittaessa leikkauspäätöstä rajatapauksissa leikkauskelpoisuuden suhteen. 4) Mini-invasiivinen tekniikka osoittautui yhtä hyväksi kuin avotekniikka myös paikallisesti edenneen syövän hoidossa ja näyttää

lyhentävän hoitoaikaa. Se on kuitenkin teknisesti vaativampi ja edellyttää riittävää potilasmäärää ja kokemusta jotta etu avokirurgiaan nähden saavutetaan.

12 ACKNOWLEDGEMENTS

This study was carried out in the Department of General Thoracic and Esophageal Surgery of Helsinki University Hospital between 2009 and 2015. I wish to express my gratitude to all the people who made this work possible:

To Professor Ari Harjula for providing me the opportunity to perform this work.

To my supervisor Professor h.c. Jarmo Salo for his inspiring attitude, mentoring and guidance in both clinical and scientific work and for showing me, in the first hand, what high quality thoracic- and esophageal surgery is about.

To my supervisor Docent Jari Räsänen for mentorship, co-authoring, guidance, for teaching me the secrets of interventional endoscopy and minimally invasive thoracic- and esophageal surgery and helping me develop as a surgeon.

Docent Markku Luostarinen and Docent Juha Saarnio for their constructive criticism and enhancement of this thesis

Docent Eero Sihvo for co-authoring, guidance, training me in the ways of thoracic surgery and for being a surgeon role model.

Docent Niku Oksala for his friendship and absurd humor, for co-authoring, performing statistical analysis, and introducing me to the scientific work and life of pirañas.

Yvonne Sundström for her skillful secretarial work on my articles and this thesis, without her contribution none of this would ever have been published.

Merja Räsänen and Anja Laukkanen for their co-work and help with sample collection Donald Smart and Carol-Ann Pelli for author-editing of the language.

Docent Markku Ahotupa for biochemical analysis.

Professor Heikki Helin and Professor Ari Ristimäki for histopathologic analysis.

Docent Lauri Karhumäki and Docent Jukka Kemppainen for analysis of Positron Emission Tomography.

Docent Riikka Huuhtanen and Kaisa Nelskylä Ph.D. for co-authoring.

Docent Perttu Arkkila and Docent Urpo Nieminen for providing me control material.

Professor Ines Gockel and Professor Tuomo Rantanen for co-operation and providing me patients for our study.

All my colleagues and other co-workers at Helsinki University Hospital Heart and Lung Center for friendship, co-operation and help during these years both in clinical and research work. Especially I would like to thank Professor Kalervo Werkkala, Docent Ulla-Stina Salminen and Docent Peter Raivio. Also special thanks to Tarja Peräkylä Ph.D., Ilkka Ilonen Ph.D., Saana Andersson, Anne Juuti Ph.D., Jussi Ropponen, Antti Nykänen Ph.D., and Hanni Alho Ph.D.

My colleagues in Mikkeli Central Hospital of Etelä-Savo for teaching me the principles of general surgery. Many thanks for unforgettable morning meetings, endless self-ironic humor, marathon running, and “bloody” floor-ball sessions. Special thanks to Professor Hannu Paajanen, Tapani Liukkonen Ph.D., Niilo Härkönen, Seppo Ojala, Antti Virkkunen, Risto Hämäläinen, and all other specialists during the time in Mikkeli. Also special thanks to Sami Miilunpohja, Mikko Skutnabb, Jouni Huttunen, Lea Kyhälä and all other “Yrjös of Marski”.

My colleagues at the Department of Gastrointestinal Surgery, especially Professor Reijo Haapiainen and Docent Esko Kemppainen.

My friends and colleagues from my studying years in Kuopio, especially Juuso Kallinen Ph.D., Juha Rinne, Raine Tiihonen Ph.D., Pasi Pöyhönen, Aki Kotipelto, Juhana Aura Ph.D. for a great time, support and friendship.

My mother Marja, father Markku and brother Antti. Thank you for my upbringing, your encouragement, love, caring and support.

Most of all, my lovely wife Sinikka and my dear children Ilja and Seela. Thank you for your support and patience during my endless hours spent with this project. Now, it is finally done.

This thesis was financially supported by the Research Foundation (EVO) of Helsinki University Hospital.

Juha Kauppi Helsinki, May 2015

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