Mechanisms of drug resistance in HCC.

HCC comprises ∼80% of primary liver cancer. HCC is the only major cancer for which death rates have not improved over the last 10 years. Most patients are diagnosed with advanced disease when surgical and locoregional treatments are not feasible or effective. Sorafenib, a multikinase inhibitor targeting cell growth and angiogenesis, was approved for advanced unresectable HCC in 2007. Since then, other multikinase inhibitors have been approved. Lenvatinib was found to be noninferior to sorafenib as a first-line agent. Regorafenib, cabozantinib, and ramucirumab were shown to prolong survival as second-line agents. Advances in immunotherapy for HCC have also added hope for patients, but their efficacy remains limited. A large proportion of patients with advanced HCC gain no long-term benefit from systemic therapy due to primary and acquired drug resistance, which, combined with its rising incidence, keeps HCC a highly fatal disease. This review summarizes mechanisms of primary and acquired resistance to therapy and includes methods for bypassing resistance. It addresses recent advancements in immunotherapy, provides new perspectives on the linkage between drug resistance and molecular etiology of HCC, and evaluates the role of the microbiome in drug resistance. It also discusses alterations in signaling pathways, dysregulation of apoptosis, modulations in the tumor microenvironment, involvement of cancer stem cells, changes in drug metabolism/transport, tumor hypoxia, DNA repair, and the role of microRNAs in drug resistance. Understanding the interplay among these factors will provide guidance on the development of new therapeutic strategies capable of improving patient outcomes.

Low vs Standard-Dose Indocyanine Green in the Identification of Biliary Anatomy Using Near-Infrared Fluorescence Imaging: A Multicenter Randomized Controlled Trial.

BACKGROUND: Near-infrared fluorescence imaging using intravenous indocyanine green (ICG) facilitates intraoperative identification of biliary anatomy. We hypothesize that a much lower dose of ICG than the standard decreases hepatic and background fluorescence and improves bile duct visualization. STUDY DESIGN: In this multicenter randomized controlled trial, 55 adult patients undergoing laparoscopic cholecystectomy were randomized to low-dose (0.05 mg) or standard-dose (2.5 mg) ICG preoperatively on the day of surgery. A quantitative assessment was performed on recorded videos from the operation using ImageJ software to quantify the fluorescence intensity of the bile duct, liver, and surrounding/background fat. Operating surgeons blinded to ICG dose provided a qualitative assessment of various aspects of the visualization of the extrahepatic biliary tree comparing near-infrared fluorescence to standard visible light imaging using a scale of 1 to 5 (1, unsatisfactory; 5, excellent). Quantitative and qualitative scores were compared between the groups to determine any significant differences between the doses. RESULTS: The bile duct-to-liver and bile duct-to-background fat fluorescence intensity ratios were significantly higher for the low-dose group compared with the standard-dose group (3.6 vs 0.68, p < 0.0001; and 7.5 vs 3.3, p < 0.0001, respectively). Low-dose ICG had a slightly higher (ie better) mean score on the qualitative assessment compared to the standard dose, although the differences were not statistically significant. CONCLUSIONS: Low-dose ICG leads to quantitative improvement of biliary visualization using near-infrared fluorescence imaging by minimizing liver fluorescence; this further facilitates routine use during hepatobiliary operations.