Recent studies from our laboratory on the aromatic amine carcinogen, 4-aminobiphenyl (ABP) have shown a significantly lower prevalence of ABP-induced liver tumors in male mice lacking the N-acetyltransferases, and a dramatically lower prevalence in females than in males, but no association of tumor prevalence with strain or sex differences in levels of acute ABP-induced DNA damage. This thesis aimed to investigate the possible involvement of acute cytotoxic effects of ABP in the development of a tumor-promoting inflammatory environment. We found that wild-type male mice showed higher acute hepatotoxicity to ABP, as well as, a possible trend towards higher serum levels of the pro-inflammatory cytokine interleukin 6. This correspondence between acute ABP cytotoxicity and inflammatory response with ultimate tumor growth is consistent with a model whereby ABP not only initiates cells by damaging DNA but also promotes tumor growth in a gender-selective fashion that may be governed by gonadal hormone influences.

The hepatitis C virus (HCV) was characterised in 1989. HCV was transmitted through transfusion of blood/blood products, but injection drug use is now the most common route of transmission. The infection is usually asymptomatic but becomes chronic in about 75%, and in 20 years 15-25% develops liver cirrhosis, with a risk for liver failure and liver cancer. HCV has also been associated with lymphoproliferative disorders. The aim of this thesis was to study morbidity and mortality in a national, population-based cohort of HCV-infected individuals. The study population consisted of all persons with a diagnosed HCV-infection recorded in the national surveillance database. This file was linked to other national registers to obtain information of emigration, deaths, cancers, and inpatient care. All personal identifiers were removed before analysis. In Paper I the standardized incidence ratios (SIR) for Hodgkin’s and non-Hodgkin’s lymphoma (NHL), multiple myeloma, acute and chronic lymphatic leukaemia, and thyroid cancer were studied. In the HCV-cohort (n: 27,150) there was a doubled risk for NHL and multiple myeloma in patients infected for more than 15 years, compared with the general population (age-, sex- and calendar-year specific incidence rates). The results strengthened these earlier controversial associations. The SIR and also the absolute risk for primary liver cancer were estimated in Paper II. In the HCV-cohort (n: 36,126) the individuals infected for more than 25 years had a more than 40 times increased risk for liver cancer compared with the general population. The absolute risk of primary liver cancer was 7% within 40 years of HCV-infection. Mortality and cause of death were studied in Paper III. The standardized mortality ratio (SMR) demonstrated a 5.8 times excess mortality in the HCV-cohort (n: 34,235) compared with the general population, and a 35.5 times excess mortality from liver disease. Deaths from illicit drugs and external reasons were common in young adults. Paper IV presents a study of inpatient care. The HCV-cohort (n: 43,000) was compared with a matched reference population (n: 215,000). Cox regression was used to estimate the likelihood, a hazard ratio, for admission to hospital, and frequencies and rates to estimate the total burden. In the HCV-cohort inpatient care was high and about 50% was psychiatric, often drug-related care. The likelihood for liver-related admissions was very high, and serious liver complications increased in the 2000s, indicating that HCV-associated liver disease will increase the next decade. In the 2000s, about 1000 individuals per year were treated with HCV-combination therapy. To conclude, the risk for NHL and multiple myeloma was doubled, and liver- and drug-related morbidity and mortality was very high in the HCV-cohort. Serious liver complications increased in the 2000s and will probably increase the coming decade.

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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

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First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction pathways such as mitogen-activated protein extracellular kinase (MEK)/ extracellular signal-regulated kinase (ERK), phosphotidyl-inositol-3-kinase (PI3K)/Akt/mTOR, NF-κB and Wnt/β-catenin pathway. In addition, studies show that AEG-1 not only alters global gene and protein expression profiles, it also modulates fundamental intracellular processes, such as transcription, translation and RNA interference in cancer cells most likely by functioning as a scaffold protein. The mechanisms by which AEG-1 is overexpressed in cancer have been studied extensively and it is clear that multiple layers of regulation including genomic amplification, transcriptional, posttranscriptional, and posttranslational controls are involved however; the mechanism by which AEG 1 itself induces its oncogenic effects is still poorly understood. Just as questions remain about the exact role of AEG-1 in carcinogenesis, very little is known about the role of AEG-1 in regulating normal physiological functions in the liver. With the help of the Massey Cancer Center Transgenic/Knockout Mouse Core, our lab has successfully created a germline-AEG-1 knockout mouse (AEG-1-/-) as a model to interrogate AEG-1 function in vivo. Here I present the insights gained from efforts to analyze this novel AEG-1-/- mouse model. Aspects of the physiological functions of AEG-1 will be covered in chapter two wherein details of the characterization of the AEG-1-/- mouse are described including the role of AEG-1 in lipid metabolism. Chapter three discusses novel discoveries about the specific role of AEG-1 in mediating hepatocarcinogenesis by modulating NF-κB, a critical inflammatory pathway. First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction pathways such as mitogen-activated protein extracellular kinase (MEK)/ extracellular signal-regulated kinase (ERK), phosphotidyl-inositol-3-kinase (PI3K)/Akt/mTOR, NF-κB and Wnt/β-catenin pathway. In addition, studies show that AEG-1 not only alters global gene and protein expression profiles, it also modulates fundamental intracellular processes, such as transcription, translation and RNA interference in cancer cells most likely by functioning as a scaffold protein. The mechanisms by which AEG-1 is overexpressed in cancer have been studied extensively and it is clear that multiple layers of regulation including genomic amplification, transcriptional, posttranscriptional, and posttranslational controls are involved however; the mechanism by which AEG 1 itself induces its oncogenic effects is still poorly understood. Just as questions remain about the exact role of AEG-1 in carcinogenesis, very little is known about the role of AEG-1 in regulating normal physiological functions in the liver. With the help of the Massey Cancer Center Transgenic/Knockout Mouse Core, our lab has successfully created a germline-AEG-1 knockout mouse (AEG-1-/-) as a model to interrogate AEG-1 function in vivo. Here I present the insights gained from efforts to analyze this novel AEG-1-/- mouse model. Aspects of the physiological functions of AEG-1 will be covered in chapter two wherein details of the characterization of the AEG-1-/- mouse are described including the role of AEG-1 in lipid metabolism. Chapter three discusses novel discoveries about the specific role of AEG-1 in mediating hepatocarcinogenesis by modulating NF-κB, a critical inflammatory pathway.