In recent years laparoscopic liver surgery established itself into today’s standard of care regarding surgical liver treatment. It was a long way for minimally invasive liver resection to develop and popularize as it was accompanied by initial reservations and concerns. Some of these already had been clarified while other questions still remain and require further investigation in the complex field of laparoscopic liver surgery. Initial concerns with respect to oncological inferiority and technical inapplicability in contrast to open surgery treatment could have been disproved within the framework of retrospective studies. In contribution to that, the aim of the study was to compare the surgical results and postoperative outcomes of consecutive laparoscopic liver resections (LLR) and open liver resections (OLR) at the high-volume liver tumor center of Leipzig university hospital. Since common classification systems for open liver surgery cannot be applied for LLR, the introduction of specific difficulty scoring systems for LLR helps to assess and classify the complexity of minimal invasive liver resection. With an increase in experience, modification of hybrid surgery and the application of novel visualization techniques such as indocyanine green (ICG) staining or hyperspectral imaging (HSI), more challenging procedures were accomplished, that initially would have been contraindicated for the laparoscopic approach (e.g. perihilar cholangiocarcinoma (pCCA) requiring biliary reconstruction). During the years 2018 and 2019 42% of all liver resections were approached laparoscopically at the Leipzig University hospital. A retrospective data analysis of n=231 patients undergoing LLR or OLR for the years 2018 and 2019 was performed and previously determined variables were collected. As a primary outcome measure, the short-term surgical and postoperative outcome of patients receiving LLR (=LLR group) compared to the patient cohort being treated by open resection (=OLR group) was evaluated. All liver resections were executed or assisted by the same two surgeons. Prior to surgery, every case was reviewed in a multidisciplinary tumor-board meeting and primarily assessed for possible minimal invasive approach. Analysis for patient demographics, pathologic diagnosis, radiologic findings and peri- and intraoperative surgical data was carried out. For LLRs intraoperatively, ICG counter perfusion staining was used in anatomic liver resection and direct ICG tumor staining was employed for tumor demarcation. With respect to classification, the extent of OLR was graded according to the Brisbane 2000 terminology in minor and major resections, whereas LLRs were categorized by means of difficulty (in accordance with Ban et al. and Di Fabio et al.). For measurement of surgical complication and assessment of morbidity, the Clavien-Dindo classification was applied. OLR was performed in n=124 (57%) and LLR in n=93 (43%). From all minimally invasive treated patients, 79% were operated totally laparoscopic and 16% were laparoscopic-hand-assisted due to infeasible lesions in the posterosuperior segments 7, 8 and 4a. In 5 cases a conversion to open surgery was necessary because of inaccessibility, tumor infiltration or morbid obesity. 28% of patients had previous upper abdominal surgery, whereof 36% in the OLR group and 19% in the LLR group. Regarding patient demographics, the mean age was significantly higher in OLR and the sex ratio was in favor of men for both groups. Malignant tumor lesions comprised 77%, while 24% were benign lesions. In both groups this larger number of malignant oncologic operation remained valid. The most common benign indications comprised focal nodular hyperplasia (FNH) and liver adenomas. It was shown that patients with CCA and Colorectal liver metastases (CRLM) were predominantly treated by open surgery, while patients with HCC diagnosis received LLR to a greater extent. Concerning the type of liver resection, non-anatomical resections were the most frequent in the cohort with 47%, thereof 55% LLR and 40% OLR. Followed second most by anatomic right and left hemihepatectomies and third most by left lateral resections, which were predominantly performed in laparoscopic technique. On the other hand, extended resections and trisectionectomies were predominantly operated by OLR. Radical lymphadenectomy was performed to a greater extent during OLR. Results showed that the mean operative time was longer for OLR (341 minutes in median) compared to LLR (273 minutes in median). Also the mean length of hospital stay was shorter for LLR patients, as well as abdominal drains were placed to lesser extent in LLR compared to OLR. In regard to R0-resection, R0-rates were higher in LLR with 98% vs. 86% in OLR. Thereby being highest for CRLM resections, followed by HCC and CCA. Putting all liver resections into classification systems, it was found that of all open procedures, 52% had major and 48% underwent minor resection according to Brisbane 2000. From the LLR group, in accordance with Di Fabio et al. 39% were classified as laparoscopic major hepatectomies, comprising 44% laparoscopic traditional major hepatectomies (LTMH) and 56% laparoscopic posterosuperior major hepatectomies (LPMH), which were technically challenging. The difficulty index stated by Ban et al. was classified as low for 8% of all performed LLRs, intermediate for 45% and of high difficulty in even 47%. Relating to morbidity (=Clavien-Dindo 3b or greater), patients with LLR had significantly lower morbidity compared to OLR. The same applies for in-hospital mortality. Our data show that despite the high number of complex and high-difficulty-classified liver resections that were performed, morbidity and mortality rates were low. As mentioned before, R0 resection rate in the LLR group was better than in the OLR group, however, this was not a case matched study, so a direct comparison is not valid. But still the study could demonstrate that the high number of LLRs being performed at the Leipzig University hospital, did not impair R0-resection rates. With an overall hospital mortality rate of 5.9% in the cohort, good results were achieved. Particularly the low rate of 1% in the LLR group speaks for itself and confirms that the development of a minimal invasive liver resection program should be on the right track. The majority of patients in the LLR and OLR group received an oncologic resection, what also resembles the global attitude that minimally invasive techniques are not reserved for selected tumor entities. Still it should be emphasized, the indication for a liver resection should not be loosened just due to minimal invasive accessibility, especially in benign liver lesions. Nevertheless, in the study the majority of benign lesions was operated by LLR. A few patients diagnosed with CCA received LLR. Thereof predominantly iCCA cases were indicated for a minimal invasive approach without biliary duct reconstruction and satisfying short-term outcomes over OLR could be obtained. However, only one case of pCCA which required Roux-Y bile duct reconstruction was treated with LLR in the study group, so if laparoscopic surgery is capable to replace the open approach in terms of treatment strategies for pCCA remains questionable. Patients with CRLM represent the centerpiece of our study population, still only 13% received LLR. The main reason of applying OLR was the high tumor load requiring future liver remnant augmentation strategies. As liver resection is confirmed to be the approach of choice for patients with HCC in cirrhosis, it is not surprising that HCC diagnosis accounted for the major part of LLRS in our collective.:Vorbemerkung und Bibliographie, 3 Abkürzungsverzeichnis, 4 Einführung, 5 - 1. Development of minimal invasive liver surgery, 5 - 2. Prior concerns of LLR, 6 - 3. Benefits of laparoscopic surgery, 6 3.1 General advantages of minimal invasive surgery, 6 3.2 Specific benefits of applying LLR, 7 - 4. Indications for LLR, 7 4.1 Benign liver lesions, 8 4.2 Malignant liver lesions, 8 4.3 Liver transplantation, 9 - 5. Technical supplement, 9 5.1 Hybrid and hand-assisted techniques, 10 - 6. Classification systems, 11 6.1 Difficulty scoring, 11 6.2 Clavien-Dindo Classification ,12 - 7. Limitations of LLR, 12 - 8. Aim of the study, 13 Publikation, 14 Zusammenfassung, 26 Literaturverzeichnis, 30 Darstellung des eignen Beitrags, 34 Selbstständigkeitserklärung, 35

Ziel der vorliegenden Arbeit ist die retrospektive Beurteilung der Sicherheit und Effektivität der Leberteilresektion bei der Behandlung von Lebermetastasen des kolorektalen Karzinoms sowie der Re-Resektion bei Patienten mit Rezidivlebermetastasen. Weiterhin soll das operative Vorgehen bei synchronen Lebermetastasen hinsichtlich simultaner Resektionsverfahren und zweizeitigen Vorgehens untersucht werden. Insgesamt wurden die Ergebnisse von 660 Patienten ausgewertet, die zwischen 1988 und 2004 mit 685 Leberteilresektionen behandelt wurden. Unter diesen waren 75 Patienten, die eine Re-Resektion erhielten sowie 202 Patienten, bei denen die Lebermetastasen synchron auftraten. Neben der Analyse der postoperativen Letalität und postoperativen Komplikationen sollen prognostische Faktoren für das Langzeitüberleben und das Auftreten von Tumorrezidiven nach Leberteilresektion identifiziert werden. Da sich die Studienpopulation aus einem Zeitraum von über 15 Jahren rekrutiert, sollen außerdem verschiedene Zeitabschnitte vergleichend analysiert werden. Die Leberteilresektion ist derzeit die einzige potentiell kurative Therapie bei kolorektalen Lebermetastasen. Als prognostisch günstige Parameter in der multivariaten Analyse zeigten sich die Radikalität des Eingriffes, die Anzahl der Metastasen, vorhandene ligamentäre Lymph-knotenmetastasen sowie das Jahr der Resektion. Auch bei Rezidiven kolorektaler Lebermetastasen ist das chirurgische Vorgehen derzeit die einzige kurative Intervention. Re-Resektionen weisen ein vergleichbares operatives Risiko und vergleichbare Langzeitüberlebensraten auf wie Erstresektionen. Als einziger prognostischer Parameter für das Langzeitüberleben erwies sich in der multivariaten Analyse die Radikalität des Eingriffes. Bei synchronen Lebermetastasen sind die wichtigsten Kriterien, um eine simultane Resektion durchzuführen, die Berücksichtigung des Alters sowie des Resektionsausmaßes. Simultane Resektionen sind bei synchronen kolorektalen Lebermetastasen dann so sicher und effizient durchführbar wie Resektionen im zweizeitigen Vorgehen.

Le cancer colorectal est un enjeu majeur de Santé publique. Près de la moitié des patients porteurs d’un cancer colorectal va développer des métastases hépatiques. La chirurgie est le seul traitement potentiellement curatif. Tout doit donc être mis en oeuvre pour que ces patients accèdent à un geste chirurgical. Le volume de foie restant après hépatectomie est un des principaux facteurs limitant en chirurgie hépatique. Des techniques innovantes ont été développées dans l’optique d’une épargne parenchymateuse : l’utilisation conjointe des techniques de destruction focalisée et la chirurgie hépatique en deux temps. La chirurgie hépatique en deux temps est efficace d’un point de vue carcinologique, mais reste une procédure complexe techniquement avec une morbidité non négligeable, notamment à cause des adhérences péri-hépatiques post-opératoires. Ces adhérences sont systématiques après chirurgie hépatique mais peuvent être prévenues par l’utilisation de membranes antiadhérences après la première hépatectomie. Dans cette indication, l’étude de phase II multicentrique, présentée dans ce travail, retrouvait une diminution de l’incidence et de la sévérité de ces adhérences après utilisation de seprafilm®, ce qui facilitait la seconde hépatectomie. Les techniques de destruction focalisée peuvent dans certains cas se substituer à la chirurgie en cas de métastases résécables. Elles permettent également d’augmenter le nombre de patients candidats à une prise en charge à visée curative, lorsqu’elles sont associées à la chirurgie, en cas de métastases non résécables. Ces techniques présentent néanmoins plusieurs inconvénients qui limitent leur utilisation. Les ultrasons focalisés de haute intensité (HIFU) sont une technique récente, non ionisante, de destruction focalisée dont les avantages théoriques sont particulièrement adaptés au traitement des tumeurs hépatiques. La technologie HIFU actuelle repose sur un dispositif de traitement extra-corporel, dont la limite principale est la faible taille des ablations, qui doivent être juxtaposées pour traiter des tumeurs de quelques centimètres, ce qui nécessite des temps de traitement de plusieurs dizaines de minutes. Le développement d’une sonde HIFU per-opératoire, à géométrie torique, a permis d’obtenir des ablations d’environ 7 cm3 en 40 secondes sur un modèle porcin. Nous avons pu montrer, lors de l’étude de phase I-IIa présentée dans ce travail, que ces résultats étaient reproduits chez l’homme sur foie sain destiné à être réséqué. Les résultats positifs de ces deux études prospectives nous ont permis d’envisager une étude de phase III sur la prévention des adhérences péri-hépatiques, la poursuite de l’étude HIFU en ciblant cette fois les métastases hépatiques, et la réalisation d’une étude de phase II sur la résection hépatique assistée par HIFU comme aide à l’hémostase / Colorectal cancer is a major health problem. Almost half of patients will develop liver metastasis. Surgery is the only potentially curative treatment. Everything possible must be done for these patients to perform liver surgery. Remnant liver volume after hepatectomy is the main limit of liver surgery. Innovative techniques have been developed to spare liver parenchyma: concomitant use of focal destruction and two-stage hepatectomy. Two-stage hepatectomy is oncologically effective but is a challenging procedure with high morbidity, in part because of peri-hepatic adhesions. These adhesions occur systematically after liver surgery but can be prevented by the use of anti-adhesion membranes at the end of the first hepatectomy. In this indication, the multicentre phase II study presented herein, showed a decrease in extent and severity of adhesions with use of seprafilm®. It facilitated the dissection and so the second hepatectomy. Techniques involving focal destruction can replace surgery in selected cases of resectable metastases. They also increase the number of patients candidates to curative liver-directed therapy in unresectable metastases. These techniques have however several disadvantages, which limit their use. High intensity focused ultrasound (HIFU) is a recent, non-ionizing, technology of focal destruction. Theoretical advantages make HIFU a promising technique for focal ablation of liver tumours. Current technology is based on extra-corporeal treatment. The main limit is that elementary ablations are small and must be juxtaposed to treat supra-centimetric tumours, resulting in long-time treatment. A new and powerful HIFU device enabling destruction of larger liver volumes (7 cm3 in 40 seconds) has been developed based on toroidal transducers. We showed, in a phase I-IIa study presented herein, that preclinical results could be reproduced on healthy liver of patients undergoing hepatectomy. Positive results of these two prospective studies have allowed to design a phase III trial on prevention of peri-hepatic adhesions, to continue the evaluation of HIFU by targeting liver metastases and by assisting liver resection, in a phase II study, as a sealing device

Les ultrasons focalisés de haute intensité (HIFU) permettent la destruction de tissus biologiques par élévation de la température. Cette technique reconnue est utilisée actuellement dans le monde médical afin de traiter certaines masses tumorales. Le projet décrit dans ce document détaille la mise au point et l'utilisation de deux systèmes thérapeutiques indépendants, ayant pour objectif principal le traitement peropératoire puis extracorporel des tumeurs hépatiques. Dans un premier temps, un système chirurgical existant, destiné au traitement des métastases hépatiques et en cours d'évaluation clinique, a été utilisé. La mise en place d'une modalité de traitement par focalisation électronique a permis d'augmenter le volume de coagulation initial et ainsi faciliter la procédure opératoire. Basée sur les conclusions de cette première étude, une seconde version de sonde peropératoire a été modélisée puis développée. La géométrie du transducteur utilisé a permis une modification de la forme des lésions produites. Les performances de cette sonde de traitement ont été évaluées numériquement puis validées lors d'expérience in vitro et in vivo. L'efficacité, la simplicité et la reproductibilité des traitements réalisés sur le foie ont conduit à une possible application du dispositif aux cancers du pancréas. Après étude numérique et évaluation de la faisabilité in vitro, une validation sur modèle animal a été entreprise. L'ensemble des résultats obtenus au cours de ces différents traitements peropératoires a permis d'envisager la faisabilité d'un dispositif de traitement par voie extracorporelle. Une étude théorique a donné lieu à la réalisation d'un prototype expérimental. Après calibrations et étalonnages, des résultats in vitro préliminaires ont été obtenus / High intensity focused ultrasound (HIFU) allows the destruction of biological tissue by temperature increase. This technique is commonly used in the medical world for treating certain types of tumor masses. The project described in this document details the development and use of two independent therapy systems, with the main objective to treat intraoperatively and extracorporeally liver tumors. As a first step, an existing surgical system, intended to treat liver metastases and under clinical evaluation, was used. The establishment of a treatment modality based on electronic focusing has contributed to increase the coagulation volume and thus simplify the operative procedure. Based upon the findings of this first study, a second version of intraoperative probe was modeled and developed. The geometry of this new transducer allowed to change the shape of produced ablations. The performance of this probe were evaluated numerically and then validated with in vitro and in vivo studies. The effectiveness, simplicity and reproducibility of the treatments performed in the liver led to a possible application of the device to pancreatic cancer. After numerical study and in vitro feasibility assessment, animal model validation was also undertaken. All the results obtained during the peroperative treatments was used to study the feasibility of an extracorporeal treatment. A theoretical study has led to the development of an experimental prototype. After calibration, preliminary in vitro results were obtained

Lors du diagnostic de cancer colorectal, près d’un quart des patients ont des métastases hépatiques dites synchrones. Lorsque la tumeur primitive est asymptomatique, la stratégie chirurgicale (chirurgie première de la tumeur primitive versus chirurgie première des métastases hépatiques) reste débattue. Les recommandations actuelles ne reposent que sur des accords d’experts qui elles-mêmes sont basées sur des études cliniques rétrospectives. L’étude du microenvironnement tumoral a pris ces dernières années une place majeure dans la recherche sur le cancer. Elle a permis de changer de paradigme avec une nouvelle conception du processus métastatique : une tumeur primitive peut agir sur le microenvironnement du futur site métastatique pour créer une "niche pré-métastatique". Cette niche pré-métastatique permettrait secondairement la croissance des cellules tumorales via une angiogénèse tumorale et la formation de métastases. Par une triple approche à la fois fondamentale, translationnelle et clinique, nous avons obtenu des données qui suggèrent qu’une chirurgie première de la tumeur colique ou rectale permet de moduler l’angiogénèse au sein du microenvironnement hépatique. Cette stratégie chirurgicale permettrait également d’améliorer le pronostic oncologique des malades et l’efficacité des anti-angiogéniques. / At the time of the diagnosis of colorectal cancer, nearly 25% of patients have synchronous liver metastases. When this tumor is asymptomatic, the question of surgical strategy (primary tumor first versus liver-first strategy) remains debated. Current recommendations are based on agreements of experts which are by themselves based on retrospective clinical studies. The study of the tumor microenvironment has taken in recent years a major place in the field of cancer research. It leads to new paradigm with a new conception of the metastatic process. It may be possible that the microenvironment of the metastatic sites can be modulated by the primary tumor to promote the formation of the pre-“metastatic niche”. This leads to promote the growth of cancer cells and increase the metastatic potential of primary tumor. By a multidisciplinary research including fundamental, translational and clinical approaches, we have shown that primary tumor first strategy could modulate tumor angiogenesis and liver metastatic process. It is associated with improved survival of patients and efficacy of the anti-angiogenic therapy.

Relevance of tumor infiltrating lymphocytes as a prognostic factors in patients with portal vein embolisation (PVE) and patients with PVE and administration of autologous stem cells Background: low future liver remnant volume (FLRV) is the cause of why 75% of patients with colorectal liver metastases (CLM) are primarily inoperable. Portal vein embolisation (PVE) helps to increase FLRV and so increase the operability. But PVE fails in almost 40 % of patients. Usage of stem cells (SCs) could be the way how to support the effect of PVE. Currently, there are studies of interactions of the immune system and malignancies. We do not know about papers focused on relations of the immune system and CLM in patients treated by PVE. There were not described interactions of ABC transporters and CLM at patients after PVE was performed too. Aims: the aim of this dissertation was to verify the effect of PVE and intraportal administration of SCs on the growth of FLRV and progression of the CLM. Other aims were to evaluate the tumor infiltrating lymphocytes, ABCC10 and ABCC11 transportes in patients treated by surgery for CLM after PVE and their clinical relevances. Methods: intraportal administration of SCs after PVE and their effect was explored in a group of 63 patients (43 patients with PVE alone, 20 in the group PVE with...

Thermoablationsverfahren werden in der klinischen Routine zur Therapie bei Patienten mit primären Lebertumoren und Lebermetastasen eingesetzt, bei denen von einer Operation abgesehen wird. Die laserinduzierte Thermotherapie (LITT) ist ein minimal invasives radiologisches Verfahren zur perkutanen Tumorablation. Mit der Magnetresonanztomographie (MRT) am Hochfeldtomographen (1.5 Tesla) steht eine radiologische Methode mit der Option einer präzisen Prozesskontrolle der Thermoablation und einer suffizienten Erfolgskontrolle zur Verfügung. Ziel dieser Arbeit war es, im Tierexperiment die Anwendung der LITT zur Ablation von Pankreasgewebe zu erproben, das Potenzial der MRT für die Prozesskontrolle der LITT am Pankreas zu bestimmen und neue MRT-Sequenzen mit neuen Kontrastmitteln für die Optimierung der Erfolgskontrolle zu erforschen. Die LITT am Pankreas im Rahmen einer Pilotstudie an 15 Läuferschweinen war perkutan komplikationsarm durchführbar, generalisierte Pankreatitiden oder Blutungen traten nicht auf. Die qualitative Prozessbeobachtung mittels thermosensitiver Sequenzen zeigte eine hohe Übereinstimmung zwischen magnetresonanztomographisch dokumentierten Thermoeffekten und histopathologisch verifizierten thermisch induzierten Nekrosen. Die Untersuchung und invasive Kalibrierung verschiedener Messmethoden in vivo zur quantitativen MRT-Thermometrie ergab Vorteile für den Einsatz der Protonenresonanzfrequenz-Methode. Zur Optimierung der Erfolgskontrolle nach LITT von Lebergewebe im Tierexperiment sowie klinisch bei Lebermetastasen wurden die MRT-Kontrastmittel Gadomesoporphyrin, Eisenoxid und Gadobutrol erprobt. Mittels Spätaufnahmen 6 - 18 h post injectionem wurden mit Gadobutrol thermisch induzierte Nekrosen präzise visualisiert. / Thermoablation of primary liver tumors and liver metastases is widely used in patients without surgical options. The laser-induced thermotherapy (LITT) is a minimal invasive radiologic procedure for percutaneous tumor ablation. With high field magnetic resonance imaging at 1.5, monitoring of thermoablation and visualization of thermal induced ablation zones can be performed precisely. Aim of this work was to investigate the feasibility of MR-guided LITT of pancreatic tissue and to optimise the contrast between thermal induced lesions, residual tumor and normal tissue after LITT procedure. MR-guided LITT was feasible in 15 female pigs, generalized pancreatitis or bleeding did not occur. MR monitoring by thermosensitive sequences precisely visualized thermal induced ablation zones verified by histopathologic examination. Best results of MR thermometry (thermo-mapping) were obtained by proton resonance frequency method. Gadolinum- mesoporphyrine, superparamagnetic iron oxides (SPIO) and gadobutrol were used to optimise ablation control. Late enhanced imaging 6 - 18 hours after injection of gadobutrol precisely visualized thermal induced necrosis. In conclusion, percutaneous MR guided LITT of pancreatic tissue of female pigs was feasible and monitoring of thermoablation could be performed accurately. In contrast to other imaging methods, MR using new contrast agents enables accurate visualization of thermal induced necrosis.

Die Dissertation handelt über die Ergebnisse der Laserinduzierten Thermotherapie bei Lebertumoren aus Februar 2000 mit einem Follow up bis Februar 2002. Dabei wurden 43 Patienten mit 89 Läsionen therapiert. Betrachtet wurden Komplikationen, Liegezeiten, metastasenfreie Intervalle, Stichkanalmetastasen, Auswertungen der bildmorphologischen Ablationskontrollen und die Analyse der klinischen Verläufe. Dabei wurden die Patienten in drei Altersgruppen eingeteilt, so dass man die Ergebnisse auf das Alter beziehen konnte. Zu den Primärtumoren zählten zu 70 Prozent das Kolorektale Karzinom, zu 10 Prozent das HCC und zu 20 Prozent andere Tumoren. Liegezeit und Komplikationen waren in allen Altersklassen gleich. Die komplette Ablationsrate betrug 80 Prozent. Die Liegezeit betrug weniger als 3 Tage im Durchschnitt. Komplikationen, die zur Verlängerung der Liegezeit führten, waren intrathorakale Blutungen, subkapsuläre Hämatome und Fistelbildungen. Es wurde ein durchschnittlich sechsmonatiges metastasenfreies Intervall festgestellt. / The dissertation acts about the results of the Laser-Induced Thermotherapy of manignant liver tumors from February 2000 in follow up to February 2002. 43 patients with 89 lesions became to treat in this case. Were considered complications, time to stay in bed, metastasis-free interval, metastasis from prick in the duct, evaluations of the picture-morphological controls and the analyses of the clinical progresses. The patients were divided into 3 age-groups in this case so that one could get the results on the age. To the primary tumors counted in 70 percent the colorectal cancer, to 10 percent the HCC and to 20 percent other tumors. The time to stay in bed and complications were identical in all age-groups. The complete ablation was 80 percent. The time to stay in bed was on average little as 3 days. Complications which led to the prolongation of the time to stay in bed were pleural effusions, subcapsular hematoma and fistulae. It was found on the average an metastases-free interval for 6 month.