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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.

Monitoring tumor growth dynamics is crucial for understanding cancer. To establish an in vitro method for the continuous assessment of patient-specific tumor growth, tumor organoids were generated from patients with intrahepatic CCA (iCCA). Organoid growth was monitored for 48 h by label-free live brightfield imaging. Growth kinetics were calculated and validated by MTS assay as well as immunohistochemistry of Ki67 to determine proliferation rates. We exposed iCCA organoids (iCCAOs) and non-tumor intrahepatic cholangiocyte organoids (ICOs) to sub-therapeutic concentrations of sorafenib. Monitoring the expansion rate of iCCAOs and ICOs revealed that iCCAO growth was inhibited by sorafenib in a time- and dose-dependent fashion, while ICOs were unaffected. Quantification of the proliferation marker Ki67 confirmed inhibition of iCCAO growth by roughly 50% after 48 h of treatment with 4 M sorafenib. We established a robust analysis pipeline combining brightfield microscopy and a straightforward image processing approach for the labelfree growth monitoring of patient-derived iCCAOs. Combined with bioanalytical validation, this approach is suitable for a fast and efficient high-throughput drug screening in tumor organoids to develop patient-specific systemic treatment options.

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