[Influence of neoadjuvant chemotherapy on liver integrity and ischemic tolerance]. / Der Einfluss neoadjuvanter Chemotherapie auf Leberintegrität und Ischämietoleranz.

The increasing interest in neoadjuvant chemotherapy of liver metastasis after colorectal carcinoma prior to resection has focussed surgical concerns to the influence of oncological chemotherapy on hepatic tolerance to intraoperative ischaemia. The present study was thus undertaken in order to produce first experimental data on liver function and morphology after neoadjuvant chemotherapy and subsequent ischaemic challenge in a rat model. Male Wistar rats were randomised to receive an intraperitoneal chemotherapy (CH) or placebo (PL) according to the same protocol. Afterwards the animals were subjected to 30 min of total hepatic ischaemia induced by Pringle's manoeuvre and subsequent reperfusion for 1 h or 24 h. Serum activities of hepatic enzymes showed no differences between CH and PL at any time. Bile flow, however, was found to be significantly reduced in CH. In contrast, post-ischaemic up-regulation of PUMA and cleavage of caspase3 was found to be more prominent in PL than in CH, while the antiapoptotic chaperone GRP78 revealed a higher expression in the latter. It is concluded that chemotherapy did not affect ischaemic tolerance of the liver in our model, but promoted a kind of preconditioning, that is likely to counteract cellular induction of apoptosis upon ischaemic challenge.

Endoplasmic and vascular surface activation during organ preservation: refining upon the benefits of machine perfusion.

The endoplasmic reticulum (ER) represents a subcellular target reactive to various cytosolic impairments. The involvement of ER-stress in organ preservation was investigated, comparing machine preservation, cold storage (CS) and a novel concept of only temporary perfusion after procurement. Rat livers were retrieved 30 min after cardiac arrest and preserved for 18 h by CS, oxygenated machine perfusion for 18 h (18 h MP) or for 2 h with subsequent CS for 16 h (2 h MP + 16 h CS). Upon reperfusion, 18 h MP significantly improved enzyme leakage (ALT, LDH) and promoted a 2-fold increase of metabolic recovery compared to CS. However, vascular stress, evaluated by endothelin-release, was significantly elevated after 18 h MP. Interestingly, better viability was obtained using the short-term perfusion protocol (2 h MP + 16 h CS), which further reduced enzyme leakage, maintained energetic recovery and mitigated endothelin-release compared to 18 h MP. Caspase 12-mRNA was upregulated in the 18 h MP-group but unchanged after CS or 2 h MP + 16 h CS. Activation/cleavage of caspase 12 protein was significantly enhanced after 18 h MP and very low in the 2 h MP + 16 h CS-group. Correspondingly, electron microscopy showed ultrastructural alterations of ER after CS and especially after 18 h MP but not after 2 h MP + 16 h CS. At this time mitochondrial appearance was unaffected in all groups, suggesting the ER to be an early subcellular target of preservation injury. In our model, ER and vascular endothelium were best protected by only temporary machine perfusion, which also maintained overall graft viability.