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«Univerza v Ljubljani Fakulteta za elektrotehniko Marija Marčan Načrtovanje zdravljenja globoko ležečih čvrstih tumorjev s terapijami na osnovi ...»

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Univerza v Ljubljani

Fakulteta za elektrotehniko

Marija Marčan

Načrtovanje zdravljenja globoko ležečih čvrstih tumorjev s

terapijami na osnovi elektroporacije


Mentor: prof. dr. Damijan Miklavčič

Ljubljana, 2015

University of Ljubljana

Faculty of Electrical Engineering

Marija Marčan

Pre-treatment planning for electroporation-based treatments of

deep-seated solid tumors


Mentor: prof. Damijan Miklavčič, Ph. D.

(University of Ljubljana, Slovenia) Ljubljana, 2015 Univerza v Ljubljani Fakulteta za elektrotehniko IZJAVA Spodaj podpisani/-a, ____________________, z vpisno številko _________ s svojim

podpisom izjavljam, da sem avtor/-ica zaključnega dela z naslovom:

S svojim podpisom potrjujem:

da je predloženo zaključno delo rezultat mojega samostojnega raziskovalnega dela in da so vsa dela in mnenja drugih avtorjev skladno s fakultetnimi navodili citirana in navedena v seznamu virov, ki je sestavni del predloženega zaključnega dela, da je elektronska oblika zaključnega dela identična predloženi tiskani obliki istega dela, da na Univerzo v Ljubljani neodplačno, neizključno, prostorsko in časovno neomejeno prenašam pravici shranitve avtorskega dela v elektronski obliki in reproduciranja ter pravico omogočanja javnega dostopa do avtorskega dela na svetovnem spletu preko Repozitorija Univerze v Ljubljani (RUL).

V Ljubljani, Podpis avtorja/-ice:

avtorja/ ice:


PREFACE The present PhD thesis is a result of medical image segmentation algorithm development, phantoms research and numerical modeling carried out during the PhD study period at the Laboratory of Biocybernetics, Faculty of Electrical Engineering, University of Ljubljana. The results of the performed work have been published (or are in press) in the following

international journals:



MARCAN Marija, PAVLIHA Denis, MAROLT MUSIC Maja, FUCKAN Igor, MAGJAREVIC Ratko, MIKLAVCIC Damijan Radiology and Oncology 48(3): 267-281, 2014.



MARČAN Marija, KOS Bor, MIKLAVČIČ Damijan PLoS ONE: 10(5): e0125591, 2015.


MARČAN Marija, PAVLIHA Denis, KOS Bor, FORJANIČ Tadeja, MIKLAVČIČ Damijan Biomedical Engineering Online: in press, 2015.



MARČAN Marija, MIKLAVČIČ Damijan IEEE Transactions on Medical Imaging: submitted, 2015.

–  –  –

Being able to conduct this research was a true privilege, for which I am sincerely grateful to my mentor, prof. dr. Damijan Miklavčič. Thank you for making me feel like a part of the team from the very beginning, never doubting my capabilities and helping me navigate through all the rough waters of the research business.

I owe another big thank you to my MSc mentor, prof. dr. Ratko Magjarević, who had opened my path to Ljubljana in the first place.

An important factor in making this experience a privilege were the members of the Laboratory of Biocybernetics: you were my family away from home and made working with you a fun and happy experience. I am especially thankful to: Denis - for collaboration and expressing the need for an exchange student five years ago; Bor - for endless patience in teaching me numerical modeling tricks; Matej - for all discussions and thesis printing; Andraž

- for being a great neighbor; Barbara - for being a true friend and keeping me sane. And to Lea.

Parts of research in this thesis would also not have been possible without the help of colleagues from the Institute of Oncology in Ljubljana, namely prof. dr. Gregor Serša who provided support in clinical matters, dr. Maja Mušič who contoured the vessels and dr. Robert Hudej, who provided prostate images - thank you all. I would also like to thank dr. Uroš Mitrović for the early discussions and advice that helped me kick start my work.

Boštjan - thank you for being right (most of the time) - especially regarding the 'you can do it' part. Your advice and support have truly carried me through the finish line.

Na kraju svega, ali nikako ne najmanje važno: dragi moji tata, mama i seka - hvala vam što ste uvijek uz mene i što nikada, nikada niste odustali, pogotovo kad je bilo najteže. Bez vas mi ovo ne bi uspjelo.

This research has been supported by Slovenian Research Agency under a Junior Research grant.

–  –  –







Rezultati in razprava




Basic principles of electroporation

Applications of electroporation in medicine

Electrochemotherapy (ECT)

Irreversible electroporation (IRE)

Parameters for effective electroporation of tissues

Treatment planning for electroporation of deep-seated tumors

Web-based tool for treatment planning

Segmentation of medical images

–  –  –



Paper 1

Paper 2

Paper 3

Paper 4


Segmentation of hepatic vessels from MRI images

Influence of vessels on the outcome of electroporation-based treatments

Editing and validation of results of the automatic segmentation

Segmentation algorithm improvement based on database of validated segmented images




–  –  –

Electroporation is a name for a phenomenon which occurs when a living cell is exposed to a sufficiently high electric field. In such a case changes occur in the cell membrane which increase its permeability. When the electric field is within well-established values, the process of electroporation is reversible and the cell membrane returns to its normal state after a period of time. The process of reversible electroporation enables molecules which normally lack membrane transport mechanisms to enter the cell. Such are some chemotherapeutic drugs for which membrane has low cellular permeability, but which have an intracellular target. Application of electroporation in combination with such chemotherapeutic drugs is successfully used to treat tumors. This tumor treating procedure has been named electrochemotherapy. Another electroporation-based treatment that is applicable in treating solid tumors relies on the process of irreversible electroporation. This procedure has been named Irreversible Electroporation and is used to destroy tumor tissue without the use of drug.

The prerequisite for a successful electroporation-based treatment is that the whole tumor is covered with a sufficiently high electric field. The electric field distribution depends on the position of electrodes relative to the tumor and the voltage applied per electrode pair. To ensure a complete coverage of a deep-seated solid tumor with sufficiently high electric field it is necessary to generate a numerical model of the electric field distribution prior to the

electroporation-based procedure.

The numerical modeling procedure for electroporation-based treatment planning takes into account patient geometry obtained from medical images. The task of segmentation of medical images remains an open research topic which continues to yield new and improved methods. When applying medical image segmentation methods one must first define the

–  –  –

purpose of segmentation. The choice of segmentation procedure and possible parameter optimization is performed with respect to the type of tissue to be extracted and imaging modality.

This doctoral thesis presents an image segmentation framework which is intended to be used in pre-treatment planning for electroporation-based treatments of deep-seated solid tumors.

The main goal of the framework is to minimize user interaction while maintaining the necessary level of robustness and accuracy in order to produce reliable treatment plans. In order to achieve this framework is designed in a form of a cycle which consists of three phases. In the first, segmentation phase, algorithms for automatic segmentation are run in order to give an initial segmentation of structures of interest. Namely, a new algorithm for automatic segmentation of hepatic vessels from MRI images was developed. The accuracy of the developed algorithm was assessed with respect to recent advances in medical image segmentation validation and having in mind the purpose of the segmentation. A part of the validation process included a sensitivity study to assess the impact of segmentation accuracy on treatment outcome and define the level of accuracy needed to ensure reliable pretreatment planning for electroporation-based treatments.

In the second, validation phase, the users are provided with a web-based tool which enables them to validate the segmentation result of the first phase and perform corrections if necessary. The validation tool was designed so that it minimizes user interaction. Enabling the users to review, correct and validate the segmentation is a necessary step to ensure a correct segmentation while keeping the method robust regarding different image sources. The data gathered from segmentations which were validated by users provides a useful database of segmented cases. Such database can be further exploited to iteratively improve

segmentation algorithms.

In the third, evolution phase, the validated segmentations from the second phase are used in order to improve the results of automatic segmentation algorithms from the first phase. The main idea of this phase is to explore how can existing images’ meta-information such as imaging machine, protocol, coil type etc. along with information about rater variability be utilized in order to improve the results of automatic segmentation. This idea was implemented and tested in existing multi-atlas segmentation methods of prostate from MRI.





Izpostavitev biološke celice dovolj visokemu električnemu polju povzroči povečano prepustnost celične membrane. To povečanje prepustnosti membrane omogoča prenos molekul, ki slabo ali pa sploh ne prehajajo skozi celično membrano. Opisani učinek električnega polja na celico imenujemo elektroporacija (Neumann et al. 1982; Kotnik et al.

2012). Elektroporacija se deli na reverzibilno in ireverzibilno. Reverzibilnost/ireverzibilnost elektroporacije je v korelaciji z amplitudo pulzov, njihovim trajanjem ter številom. V primeru reverzibilne elektroporacije se celična membrana po določenem času vrne nazaj v normalno stanje. V primeru ireverzibilne elektroporacije pa prihaja do celične smrti zaradi trajne porušitve strukture celične membrane ali zaradi izgube znotrajceličnih komponent (Davalos et al. 2005; Sano et al. 2010).


V klinični praksi se elektroporacija danes uporablja kot del več različnih metod zdravljenja raka. Najpomembnejše izmed teh metod so elektrokemoterapija (Marty et al. 2006; Miklavčič et al. 2012), elektrogenska terapija (Heller & Heller 2010), cepljenje z DNA (Zhang et al. 2004) in atermična ablacija z ireverzibilno elektroporacijo (IRE) (Rubinsky et al. 2007; Garcia et al.

2011). Od teh se le elektrokemoterapija in IRE uporabljata za zdravljenje globlje ležečih čvrstih tumorjev (Edhemovic et al. 2014; Scheffer et al. 2014).



Elektrokemoterapija je metoda, ki združuje klasično kemoterapijo z reverzibilno elektroporacijo (Mir et al. 1991). Prednost elektrokemoterapije v primerjavi s klasično kemoterapijo je povečanje citotoksičnosti kemoterapevtikov, kot sta bleomicin in cisplatin, do katere pride zaradi povečane prepustnosti celične membrane po elektroporaciji (Serša et al.

1995; Mir et al. 2006).

Pri elektrokemoterapiji se pacientu najprej injicira citostatik, bodisi intravenozno ali neposredno v tumor. Potem se na območje tumorja preko elektrod dovedejo ustrezni električni pulzi z generatorjem pulzov posebej zasnovanim za ta namen (Reberšek et al.

2014). V primeru kožnih in podkožnih tumorjev se uporabljajo elektrode s fiksno geometrijo.

Običajno gre za ploščate ali za polje majhnih igelnih elektrod, odvisno od vrste tumorja (Miklavcic et al. 2006). Čeprav obstajajo primeri, ko se igelne elektrode s fiksno geometrijo lahko uporabijo tudi za elektrokemoterapijo globlje ležečih tumorjev, je položaj in velikost globokih tumorjev običajno takšen, da zahteva uporabo več posameznih, dolgih igelnih elektrod. V primeru uporabe dolgih igelnih elektrod položaj elektrod variira glede na posameznega bolnika in geometrijo tumorja.


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