Yttrium-90 Radioembolization for Unresectable Combined Hepatocellular-Cholangiocarcinoma.

PURPOSE: Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare mixed cell type primary liver cancer with limited data to guide management. Transarterial radioembolization with yttrium-90 microspheres (RE) is an emerging treatment option for both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This study explored the safety and efficacy of RE for unresectable cHCC-CC. METHODS: Patients with histopathologically confirmed cHCC-CC treated with RE were retrospectively evaluated. Clinical and biochemical toxicities were assessed using the Common Toxicity Criteria for Adverse Events v4.03. Radiological response was analyzed using the Response Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST criteria. Survival times were calculated and prognostic variables identified. RESULTS: Ten patients (median age 59 years; six men, four women) with unresectable cHCC-CC underwent 14 RE treatments with resin (n = 6 patients) or glass (n = 4 patients) microspheres. Clinical toxicities were limited to grade 1-2 fatigue, anorexia, nausea, or abdominal pain. No significant biochemical toxicities were observed. Median overall survivals from the first RE treatment and from initial diagnosis were 10.2 and 17.7 months, respectively. Six of seven patients with elevated tumor biomarker levels before RE showed decreased levels after treatment (median decrease of 72%, range 13-80%). Best hepatic radiological response was 60% partial response and 40% stable disease by modified RECIST, and 100% stable disease by RECIST v1.1. Poor performance status and the presence of macrovascular invasion were identified as predictors of reduced survival after RE. CONCLUSION: RE appears to be a safe and promising treatment option for patients with unresectable cHCC-CC. LEVEL OF EVIDENCE: Level 4.

Regulation of Pax3 by proteasomal degradation of monoubiquitinated protein in skeletal muscle progenitors.

Pax3 and Pax7 play distinct but overlapping roles in developmental and postnatal myogenesis. The mechanisms involved in the differential regulation of these highly homologous proteins are unknown. We present evidence that Pax3, but not Pax7, is regulated by ubiquitination and proteasomal degradation during adult muscle stem cell activation. Intriguingly, only monoubiquitinated forms of Pax3 could be detected. Mutation of two specific lysine residues in the C-terminal region of Pax3 reduced the extent of its monoubiquitination and susceptibility to proteasomal degradation, whereas introduction of a key lysine into the C-terminal region of Pax7 rendered that protein susceptible to monoubiquitination and proteasomal degradation. Monoubiquitinated Pax3 was shuttled to the intrinsic proteasomal protein S5a by interacting specifically with the ubiquitin-binding protein Rad23B. Functionally, sustained expression of Pax3 proteins inhibited myogenic differentiation, demonstrating that Pax3 degradation is an essential step for the progression of the myogenic program. These results reveal an important mechanism of Pax3 regulation in muscle progenitors and an unrecognized role of protein monoubiquitination in mediating proteasomal degradation.