Heme oxygenase (HO) breaks down the pro-oxidant heme into carbon monoxide, iron and the antioxidant biliverdin. The isoform HO-1 plays an effective role to counteract oxidative damage and to control inflammation. Prolonged cellular damage due to chronic inflammation is one of the reasons leading to the development of tumours. The aim of this work was to investigate HO-1 expression and localization along the different stages of chemically induced hepatocarcinogenesis (HCC) and the occurring morphological changes. To provoke sustained oxidative stress and chronic inflammation, CF1 mice received dietary p-dimethylaminoazobenzene (DAB, 0.5%, w/w) during a whole period of 14 months. HO-1 expression increased along the experimental trial in morphologically normal hepatocytes in DAB-treated animals. HO-1 expression diminished in altered hepatic foci (AHF) and oval cells and early preneoplastic lesions. Otherwise, marked HO-1 overexpression was detected in Kupffer cells and macrophages surrounding necrotic and nodular areas. Adenomas showed decreased HO-1 immunostaining. In hepatocellular carcinomas, an inverse relationship was found between the immunohistochemical expression of HO-1 and the degree of tumour differentiation, being negative in poorly differentiated tumours. In our experimental model, down modulation of HO-1 expression correlated with malignancy progression. Thus, our data point to activation of HO-1 as a potential therapeutic tool.

PS and C-P score were the main prognostic factors for OS, followed by early-onset diarrhoea and bNLR. We identified four risk groups for OS depending on these parameters. This prognostic model could be useful for patient stratification, but an external validation is needed.

Cancer of unknown primary site (CUP) is defined as a heterogeneous group of tumors that appear as metastases, and of which standard diagnostic work-up fails to identify the origin. It is considered a separate entity with a specific biology, and nowadays molecular characteristics and the determination of actionable mutations may be important in a significant group of patients. In this guide, we summarize the diagnostic, therapeutic, and possible new developments in molecular medicine that may help us in the management of this unique disease entity.

Female and elderly patients have a higher grade 3-4 toxicity rate when treated with combination CT with oxaliplatin or irinotecan. Prognostic classifications such as Köhne's can help differentiate subgroups of patients who benefit little with the use of combination CT.

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