Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Objective: Patients with radioactive iodine-refractory differentiated thyroid cancer(RAIR-DTC) are often diagnosed with delay and constrained to limited treatment options. The correlation between RAI refractoriness and the underlying genetic characteristics has not been extensively studied.Methods: Adult patients with distant metastatic DTC were enrolled and assigned to undergo next-generation sequencing of a customized 26-gene panel(Thyro Lead). Patients were classified into RAIR-DTC or non-RAIR groups to determine the differences in clinicopathological and molecular characteristics. Molecular risk stratification(MRS) was constructed based on the association between molecular alterations identified and RAI refractoriness, and the results were classified as high, intermediate or low MRS.Results: A total of 220 patients with distant metastases were included, 63.2% of whom were identified as RAIRDTC. Genetic alterations were identified in 90% of all the patients, with BRAF(59.7% vs. 17.3%), TERT promoter(43.9% vs. 7.4%), and TP53 mutations(11.5% vs. 3.7%) being more prevalent in the RAIR-DTC group than in the non-RAIR group, except for RET fusions(15.8% vs. 39.5%), which had the opposite pattern. BRAF and TERT promoter are independent predictors of RAIR-DTC, accounting for 67.6% of patients with RAIR-DTC. MRS was strongly associated with RAI refractoriness(P<0.001), with an odds ratio(OR) of high to low MRS of 7.52 [95%confidence interval(95% CI), 3.96-14.28;P<0.001] and an OR of intermediate to low MRS of 3.20(95% CI,1.01-10.14;P=0.041).Conclusions: Molecular alterations were associated with RAI refractoriness, with BRAF and TERT promoter mutations being the predominant contributors, followed by TP53 and DICER1 mutations. MRS might serve as a valuable tool for both prognosticating clinical outcomes and directing precision-based therapeutic interventions.

Glutamine synthetase-negative hepatocellular carcinoma has better prognosis and response to sorafenib treatment after hepatectomy

Background:Glutamine synthetase(GS)and arginase 1(Arg1)are widely used pathological markers that discriminate hepatocellular carcinoma(HCC)from intrahepatic cholangiocarcinoma;however,their clinical significance in HCC remains unclear.Methods:We retrospectively analyzed 431 HCC patients:251 received hepatectomy alone,and the other 180 received sorafenib as adjuvant treatment after hepatectomy.Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining.mRNA sequencing and immunostaining to detect progenitor markers(cytokeratin 19[CK19]and epithelial cell adhesion molecule[EpCAM])and mutant TP53 were also conducted.Results:Up to 72.4%(312/431)of HCC tumors were GS positive(GS+).Of the patients receiving hepatectomy alone,GS negative(GS-)patients had significantly better overall survival(OS)and recurrence-free survival(RFS)than GS+patients;negative expression of Arg1,which is exclusively expressed in GS-hepatocytes in the healthy liver,had a negative effect on prognosis.Of the patients with a high risk of recurrence who received additional sorafenib treatment,GS-patients tended to have better RFS than GS+patients,regardless of the expression status of Arg1.GS+HCC tumors exhibit many features of the established proliferation molecular stratification subtype,including poor differentiation,high alpha-fetoprotein levels,increased progenitor tumor cells,TP53 mutation,and upregulation of multiple tumor-related signaling pathways.Conclusions:GS-HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy.Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.