Cutaneous toxicities of targeted therapies in the treatment of hepatocellular carcinoma

Liver cancer accounts for 4.7%of all newly diagnosed cancers and 8.2%of cancer deaths annu-ally.Hepatocellular carcinoma(HCC)accounts for the majority of primary liver cancers.There are 2 curative strategies in HCC:resection and transplant.Unfortunately,50%of patients who undergo resection will relapse in 2 years and many patients on transplant lists become ineligible for transplant due to disease progression.The majority of patients still require systemic therapies.Tyrosine kinase inhibitors have successfully extended the overall survival in patients with hepa-tocellular carcinoma.However,these treatments have been noted to cause severe side effects in-cluding liver toxicity,hypertension,gastrointestinal toxicity and cutaneous adverse effects.This article will focus on the adverse skin reactions seen during the treatment of hepatocellular carci-noma by various tyrosine kinase inhibitors.The focus will be symptomatology,management,and whether the development of cutaneous toxicities can be prognostic.

DNA damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysiology of HFS are relatively widely reported,how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied.Additionally,prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce.In our study,we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS.Mechanistically,DNA damage,as the primary cytotoxic cause,in keratinocytes induces cell cycle arrest,activates the cGAS-STING signaling pathway,and subsequently mediates cellular senescence,ultimately fueling a robust secondary inflammatory response that results in HFS.More importantly,the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence.These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.