Introduction Sinusoidal Obstruction Syndrome (SOS) is associated with Oxaliplatin based chemotherapy in patients with colorectal liver metastases (CRLM) and is a cause of concern when undertaking major liver resection. The pathogenesis of SOS is poorly understood however a variety of candidate genes have been identified which may play a role in activating various molecular pathways involved. The aim of this study was to validate these gene expression changes in an independent cohort of patients.
Methods Patients undergoing liver resection for CRLM, were identified for inclusion and appropriate informed consent obtained. Full clinical information was recorded for each patient including pre-operative chemotherapy use. A biopsy of the non-tumour bearing liver was obtained, prior to parenchymal transection, and stored in RNAlater. Histopathology was reviewed to identify those with SOS. Hepatic gene expression was compared in chemotherapy naive patients (controls) with no evidence of underlying liver disease (n=10) and those who received pre-operative Oxaliplatin either with (n=13) or without (n=9) evidence of SOS by qRT-PCR. Mann–Whitney U test was used to assess statistical significance.
Results The interval between cessation of chemotherapy and surgery was similar for all patient groups (p=0.45). In contrast to previous studies we were unable to identify changes in extracellular matrix remodelling genes (MMP2, MMP9, TIMP1, TGFβ) thought to be involved in SOS. However there was up regulation of angiogenesis related VEGF-C (1.6-fold, p<0.05) along with the hypoxia induced HIF1α (1.98-fold; p<0.01) in those with SOS. It is suggested that SOS is associated with a pro-thrombotic tendency and in keeping with this there was a non-significant trend towards increased expression of vWF (2.5-fold; p=0.06). We also confirmed up-regulation of CCL20 in those with SOS (3.8-fold; p<0.05) which is chemotactic for colorectal cancer cells.
Conclusion We were able to confirm up-regulation of genes involved in angiogenesis, hypoxia and thrombogenesis in patients with SOS. It is likely that changes in extracellular matrix re-modelling genes occur early in the development of SOS and but have returned to baseline levels if there is a reasonable duration between stopping chemotherapy and surgical resection. Increased expression of CCL20 may account for the recently reported poorer disease specific survival in patients with SOS.
Competing interests None declared.
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