It is still controversial whether associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) or traditional staged hepatectomy such as portal vein embolization (PVE) and 2-staged hepatectomy (TSH) is better. The aim of this study was to compare these 3 available strategies in extended hepatectomy. Trials were identified by searching MEDLINE, PubMed, the Cochrane Library, and Embase and additional articles were identified by hand searching. Comparative clinical studies reporting volumetric changes, mortality, morbidity, and feasibility of the second stage about ALPPS versus PVE or ALPPS versus TSH were included. Nine studies involving 557 patients met the inclusion criteria. Five studies reported on comparison of ALPPS and PVE, and the other 4 reported about ALPPS and TSH. In the comparison of ALPPS versus traditional staged hepatectomy (PVE and TSH), ALPPS was associated with a greater increase in the future liver remnant (FLR) (RR: 4.87; 95%CI, 3.41–6.33) and more frequent completion of stage 2 resection (RR: 1.32; 95%CI, 1.21–1.44). Compared with the traditional staged hepatectomy, ALPPS had a trend toward higher morbidity (RR: 1.19, 95%CI, 0.96–1.47) and mortality (RR: 2.11, 95%CI, 1.02–4.33) after stage 2 resection. ALPPS is associated with greater future liver remnant hypertrophy and a higher rate of completion of stage 2, but this may be at the price of greater morbidity and mortality.

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo . Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.

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