This is an important practical consideration as we attempt to improve the quality of studies in HCC and minimize risk. None of the studies mandated that an upper endoscopy be performed in order to screen for the presence of varices,

although two studies did introduce this after the occurrence of a serious hemorrhage. The risk of variceal hemorrhage in Ulixertinib patients with cirrhosis is difficult to quantify but has been reported to be as high as 40%.11 In the context of HCC the short- to medium-term risk is particularly important to assess given that in the SHARP study the median duration of sorafenib treatment was 5.3 months and the median overall survival for these patients was 10.7 months. The presence of even small varices is a marker of increased bleeding risk as shown by one prospective Kinase Inhibitor Library in vitro study where (12) the 2-year risk of bleeding was found to be significantly higher in patients with small varices at enrollment compared to those who did not have any varices (12% versus 2%). Several factors have been employed to predict

the risk of variceal hemorrhage, including the size and location of varices (gastric fundus varices of higher risk13), their physical appearance, and variceal pressure as measured by endoscopic gauge.14 The North Italian Endoscopic Club (NIEC) study established a prognostic index—depending on size, presence

of red wale marks, and Child class—which quantified 1-year bleeding risk, a relevant timepoint for a patient with a diagnosis of advanced HCC.15 According to that study there are “high risk” small varices (those that occur in Child C patients or have red wale marks) that may have the same risk of bleeding than a Child A patient 上海皓元医药股份有限公司 with large varices (and prophylaxis is recommended in these patients). Limiting eligibility in HCC studies to Childs A patients—as recommended by the American Association for the Study of Liver Diseases (AASLD)16—would mitigate some of this risk, but—also consistent with current AASLD guidelines17—Child A patients should undergo screening endoscopy unless they have had one in the last 2-3 years (with no varices demonstrated) or last 1-2 years (if small varices had been identified. Five of the studies we reviewed—including both the SHARP and AP studies—were confined to patients with Childs-Pugh grade A cirrhosis. Perhaps the most specific indicator of risk for variceal bleeding is the prior occurrence of a hemorrhagic event with the risk of a subsequent bleeding episode estimated to be 17%-40%,18 but also, in older analyses, as high as 70%.19 Seven of the studies in our analysis excluded patients with a history of active bleeding, although the duration of this was variable, ranging from 30 days to 1 year.