In this thesis Prognoslic factors of early recurrence of colorectal liver metastases after surgical therapy the autor characterizes the epidemidemiology, diagnostics and treatment of colorectal liver metastases (CLM) in relation to biological activity of tumour and the possibilities of determination. Contemporary the author introduces to problematics of tumour markers, which determine CLM and to clinical prognostic factors of CLM.

BACKGROUND: The gold standard treatment for colorectal cancer liver metastases (CRCLM) is surgical resection. Unfortunately, the majority of patients with colorectal hepatic metastases are not candidates for resection. In recent years, several alternatives have emerged for patients whom are not resection candidates including modern systemic chemotherapy, targeted biologic treatments, regional therapies and local tumor ablation options. Microwave ablation (MWA) therapy is one such treatment alternative, based on thermal tissue ablation. This modality in concert with the most recent published literature on its use for patients with CRCLM will be reviewed in this paper. LITERATURE REVIEW FINDINGS: A structured review of the literature on ablative technologies was performed. In recent years, there has been an evolution from radiofrequency ablation (RFA) to microwave ablation therapy for the treatment of CRCLM. RFA has several limitations to its use and MWA theoretically avoids such limitations making it the currently preferable treatment option. There are limited publications comparing the use of RFA to MWA and limited publications on the use of microwave ablation for CRCLM. This paper will focus on the most recent data on MWA for CRCLM. This data can then be compared to the already published data on RFA. PROPOSED METHODS: Given the relative novel status for MWA as a treatment option for CRCLM, a potential disadvantage for its use is the perceived lack of knowledge across the medical professional spectrum. In an effort to expand the knowledge of MWA, the proposed outcomes for this study include creating a curriculum to be offered as a CME course focused for Primary Care Providers (PCPs) to provide a basis of clinical familiarity for its use. This effort will familiarize providers who may have patients diagnosed with CRCLM and also allow them to initiate the conversation about this therapy with their patients who may be candidates for this treatment. CONCLUSIONS: MWA therapy is a safe and effective treatment modality for CRCLM. Due to this new development in treating liver lesions originating from colorectal cancer, it’s imperative for providers to become familiar with these new technologies especially considering the high incidence of CRCLM. Therefore, a curriculum for PCPs will allow for a better understanding of this new technology and foster better provider-patient relationships.

In this thesis Prognoslic factors of early recurrence of colorectal liver metastases after surgical therapy the autor characterizes the epidemidemiology, diagnostics and treatment of colorectal liver metastases (CLM) in relation to biological activity of tumour and the possibilities of determination. Contemporary the author introduces to problematics of tumour markers, which determine CLM and to clinical prognostic factors of CLM.

Background: Surgical treatment of colorectal liver metastases (CLRM) depends on resectability that is currently based on the CT scan. With the PET/CT scan, a more accurate pre-operative assessment of resectability may be possible. Methods: A Cochrane-based diagnostic test systematic review and a systematic review of cost-effectiveness studies on PET scans were conducted. Lastly, a diagnostic decision analysis model was created to assess the cost-effectiveness of the technology. Results: PET/CT scans was equally sensitive for hepatic metastases and more sensitive for extra-hepatic metastases compared to CT scans. A cost-savings of PET scans for CRLM is identified; with decision modelling demonstrating a cost-savings with the addition of PET/CT scans to the current clinical algorithm. Conclusion: There is cautious support for the addition of PET/CT scans to the pre-operative assessment in CRLM. Unnecessary surgery may be prevented, thus decreasing wait times. Future endeavours include finding, evaluating and validating methodology for appropriate effectiveness measures. / Health Technology Assessement

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京都大学 / 新制・課程博士 / 博士(医学) / 甲第23074号 / 医博第4701号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 増永 慎一郎, 教授 川口 義弥 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12889号 / 論医博第2089号 / 新制||医||1007(附属図書館) / 31643 / (主査)教授 福山 秀直, 教授 千葉 勉, 教授 平岡 眞寛 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Radiological imaging already has a key role in the detection and management of patients with metastatic colorectal cancer (mCRC). With the evolution of personalised medicine there is a need for non-invasive imaging biomarkers that can detect early tumour response to targeted therapies. Translation from bench to bedside requires a multicentre approach that follows an agreed development roadmap to ensure that the proposed biomarker is precise (reproducible/ repeatable) and accurate in its characterisation of a meaningful physiological, pathological or post treatment response. The following thesis (organized in the alternative format with experimental studies written as individual complete manuscripts) investigates methods to improve precision and accuracy of the Apparent Diffusion Coefficient (ADC), a proposed quantitative imaging biomarker with a potential role in characterisation of post treatment responses in mCRC. The first objective was to establish baseline multicentre reproducibility (n=20) for ADC. A change in ADC greater than 21.1% was required to determine a post treatment response. Using a statistical error model, the dominating factors that influenced reproducibility were motion artefact and tumour volume. In the second study these factors were addressed using a single centre cohort with pre and post treatment data. Correcting for errors due to motion and tumour volume improved sensitivity from 30.3% to 1.7%, so a post treatment response was detected in 6/12 tumours compared to 0/12 using the baseline approach. In the third study, motion correction was implemented and the statistical error model was applied successfully to a multicentre cohort of 15 patients (1.9% sensitivity). The results of this thesis highlights that with careful consideration and correction of factors that negatively influence sensitivity, ADC is a potential imaging biomarker for use in post treatment response for patients with mCRC.

Laser thermal ablation (LTA) is an in situ ablative technique that induces heat destruction of liver tumours. Despite increasing clinical use of LTA, reports of long-term outcomes and limitation of treatment in specific cohorts of patients with liver tumours are lacking. In addition, the mechanisms of action of therapy have not been fully elucidated. This study highlights the long-term clinical results and limitations of LTA in the treatment of a cohort of patients with unresectable colorectal liver metastases and examines the mechanisms of action of thermal ablative injury in a murine model.

Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality. About 50 % of patients with CRC will develop subsequent liver metastases (CLM). The survival for untreated CLM is only a few months and liver resection provides the only chance for a lasting cure. It is therefore essential to detect CLM early, enabling successful surgical resection and achieving a long-term cure. There are no optimal tumour markers for CRC or CLM. The best marker available is Carcinoembryonic Antigen (CEA), a marker found elevated in about 50-60% of patients with CLM, but also in many other conditions. The main focus of cancer research has been on the malignant cancer cell. However, a tumour consists of more than cancer cells. A major part of all solid tumours is made up by the stroma. The tumour stroma is defined as the non-malignant cells of a tumour such as fibroblasts, the cells of the vascular and immune systems as well as the extracellular matrix (ECM). The basement membrane (BM) is a specialized form of the ECM in which type IV collagen is the major protein component. All epithelial cells need a contact to the BM and the definition of an invasive cancer is the degradation of the BM and the spread of cancer cells beyond this structure. Different metastatic growth patterns of CLM have previously been described, namely the desmoplastic, pushing and replacement type of CLM. These differ in their stromal reaction in the border, which separates the tumour from the normal liver. In this thesis the tumour stroma of CRC and CLM is studied with a special emphasis on stromal collagens. The aim is to investigate whether stromal collagens/ circulating type IV collagen can be used as tumour markers for CRC and CLM, and to compare this to the conventional marker CEA. The circulating type IV collagen level is also measured in liver metastases from other primary tumours than CRC. Furthermore, the differences between the stroma of a primary CRC that metastasizes to the liver when compared to a CRC that never spreads are analysed. Additionally, the metastatic growth pattern of CLM is studied in relation to the primary tumour, stromal components and survival. We also sought out to find whether CRC cell lines possess the trait to produce ECM proteins endogenously, and in response to a normal liver stroma in a novel organotypic model for CLM. Methods: Expression patterns of type I, III and IV collagen were studied by immunofluorescence (IF), chemical staining and immunohistochemistry (IHC) in normal colorectal tissue, normal liver, CRC, CLM, benign liver lesions and in liver metastases of other origin than CRC. Circulating plasma levels of type IV collagen were analysed in healthy controls, patients with CRC (T stage I-III) and in patients with CLM. Samples were analysed at the time of diagnosis, during and after oncological and surgical treatment and at the time of relapsing or progressive disease. Additionally, circulating levels were analysed in patients with benign liver lesions and in liver metastases of other origin than CRC. The metastatic growth pattern of CLM was classified according to earlier descriptions. CRC cell lines were studied regarding their production of type IV collagen. The growth, invasiveness and stromal production in CRC cell lines were also investigated in a new organotypic model for CLM using human liver specimens. Results: Circulating type IV collagen levels are increased in patients with CLM and other epithelial-derived liver metastases, and is found normal in patients with primary CRC (stage I-III), with liver metastases from tumours of non-epithelial origin, benign liver lesions and in healthy controls. The type IV collagen levels in patients with CLM reflect the tumour burden in the liver, decreases in response to therapy and is found increased in progressive or relapsing disease. The combination of circulating type IV collagen and CEA increased the sensitivity and specificity for detecting CLM. Livermetastatic CRC displayed an increased stromal production when compared to non-metastatic CRC, with an increased type IV collagen expression in the direct vicinity of the CRC cells. The earlier described growth patterns of CLM were verified, with the pushing type of CLM associated with a short survival and poor outcome. Furthermore, CRC cell lines possess the trait of endogenously producing type IV collagen. The novel organotypic liver model revealed that CRC cell lines grown in the context of normal liver stroma, devoid of other cells, does not elicit a desmoplastic reaction. Conclusion: Circulating type IV collagen is a promising tumour marker for CLM, where the levels reflect the hepatic tumour burden and can detect disease relapse after liver surgery. The combination of the tumour markers CEA and type IV collagen is superior to CEA alone. The stromal composition of primary CRC predicts the risk of subsequent CLM and the metastatic growth pattern of CLM is related to survival.