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IMPORTANCEPatients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) have a poor prognosis and limited treatment options.OBJECTIVE To assess the efficacy and safety of apatinib, a highly selective vascular endothelial growth factor (VEGFR-2) inhibitor, in patients with progressive locally advanced or metastatic RAIR-DTC. DESIGN, SETTING, AND PARTICIPANTSThis randomized, double-blind, placebo-controlled, phase 3 trial (Efficacy of Apatinib in Radioactive Iodine-refractory Differentiated Thyroid Cancer [REALITY]) was conducted in 92 patients with progressive locally advanced or metastatic RAIR-DTC between February 17, 2017, and March 2, 2020, at 21 sites within China, and the data cutoff date for this analysis was March 25, 2020.INTERVENTIONS Patients were randomly assigned (1:1) to apatinib, 500 mg/d, or placebo. Patients who developed progression while receiving placebo were allowed to cross over to apatinib. MAIN OUTCOMES AND MEASURESThe primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response, time to objective response, and safety. Intention-to-treat analyses were performed to evaluate efficacy. RESULTSOf the 92 patients included in the trial, 56 were women (60.9%); mean (SD) age at baseline was 55.7 (10.6) years. Patients were randomized to the apatinib (n = 46) or placebo (n = 46) group. The median follow-up duration was 18.1 (IQR, 12.7-22.2) months. The median PFS was 22.2 (95% CI, 10.91-not reached) months for apatinib vs 4.5 (95% CI, 1.94-9.17) months for placebo (hazard ratio, 0.26; 95% CI, 0.14-0.47; P < .001). The confirmed ORR was 54.3% (95% CI, 39.0%-69.1%) and the DCR was 95.7% (95% CI, 85.2%-99.5%) in the apatinib group vs an ORR of 2.2% (95% CI, 0.1%-11.5%) and DCR of 58.7% (95% CI, 43.2%-73.0%) in the placebo group. The median overall survival was not reached for apatinib (95% CI, 26.25-not reached) and was 29.9 months (95% CI, 18.96-not reached) for placebo (hazard ratio, 0.42; 95% CI, 0.18-0.97; P = .04). The most common grade 3 or higher-level treatment-related adverse events in the apatinib group were hypertension (16 [34.8%]), hand-foot syndrome (8 [17.4%]), proteinuria (7 [15.2%]), and diarrhea (7 [15.2%])-none of which occurred in the placebo group. CONCLUSIONS AND RELEVANCEThe REALITY trial met its primary end point of PFS at the prespecified interim analysis. Apatinib showed significant clinical benefits in both prolonged PFS and overall survival with a manageable safety profile in patients with progressive locally advanced or metastatic RAIR-DTC.

Accumulating evidence suggests that cancer-associated stromal fibroblasts (CAFs) contribute to tumor growth by actively communicating with cancer cells. Our aim was to identify the signaling pathways that are involved in tumor-stromal cell interactions in human papillary thyroid carcinoma (PTC). Immunohistochemical analyses were performed with 127 archived formalin-fixed and paraffin-embedded thyroid tissue samples that included 70 cases of PTC, 35 cases of nodular goiter (NG), and 22 cases of normal thyroid tissues. The results showed that the expression levels of Notch1, transforming growth factor β (TGF-β1), and p-Smad3 in PTC cells and α-smooth muscle actin (α-SMA) in the stroma of PTC were all significantly higher than in NG and normal thyroid tissues. Further analysis showed that in PTC, higher expression levels of Notch1 and TGF-β1 were closely related with lymph node metastasis (P < 0.05), whereas for α-SMA and p-Smad3, the percent expression increased significantly with advanced tumor stages (P < 0.05). Correlation analysis revealed that TGF-β1 expression increased with increased Notch1 and p-Smad3 levels in PTC cells (P < 0.05). Moreover, a significant correlation was found between higher TGF-β1 expression in PTC cells and increased α-SMA levels in the fibroblasts surrounding the cancer cells (P < 0.05). We identified TGF-β1 as an important factor from PTC cells that act in a paracrine manner to influence the activation of stromal fibroblasts. These data suggest that the activation of Notch and TGF-β/Smad3 pathways in cancer cells influence tumor growth. Moreover, cancer cell-derived-TGF-β ligands also affect stromal cells in a paracrine fashion and enhance tumor growth.

It remains controversial whether radical radiotherapy in patients with esophageal squamous cell carcinoma (ESCC) still requires elective nodal irradiation (ENI), or only involved-field irradiation (IFI). In this study, a meta-analysis was conducted to compare ENI and IFI in the treatment of ESCC, in order to provide guidance for clinical practice. Literature on the use of ENI and IFI in the treatment of ESCC was retrieved, and the last access date was 31 December 2017. A meta-analysis was performed to evaluate the relative advantages and disadvantages of using ENI and IFI. Ten studies, involving a total of 1348 patients, were included in this analysis; of these, 605 patients underwent radiotherapy only, and 743 underwent radiochemotherapy. There was no significant difference in the 1-, 2- or 3-year local control rates between ENI and IFI, or in the 1-, 2- or 3-year overall survival rates. However, the incidences of ≥Grade 3 acute esophagitis and pneumonia were significantly lower in the IFI group. There were no differences in the rates of ≥Grade 3 myelosuppression or of out-field recurrence or metastasis between these two groups. Thus, neither local control rates nor overall survival rates differed significantly between the ENI and IFI groups, but in the latter group, incidences of severe radiation esophagitis and pneumonia were significantly lower. IFI was not associated with an increase in out-field recurrence or metastasis.

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) is a novel nuclear protein which is overexpressed in various cancers but not yet examined in esophageal squamous cell carcinoma (ESCC). The correlation between UHRF1 and the radioresistance in ESCC is still unclear. In the present study, the expression of UHRF1 was examined by immunohistochemistry in specimens of ESCC patients treated with radiotherapy. The results showed that UHRF1 was significantly overexpressed in ESCC specimens. Overexpression of UHRF1 correlated significantly with advanced T-stage, positive lymph node metastasis and poor differentiation. In addition, UHRF1 was associated with radiotherapy response, in which overexpression of UHRF1 was observed more frequently in the radioresistant group than in the effective group. At the molecular level, inhibition of UHRF1 by lentivirus-mediated shRNA targeting UHRF1 increased the radiosensitivity and apoptosis, while decreased radiation-induced G2/M phase arrest in TE-1 cells. Moreover, inhibition of UHRF1 resulted in higher residual γH2AX expression after irradiation, but not initial γH2AX. Further study showed that inhibition of UHRF1 down-regulated the endogenous expressions of DNA repair protein Ku70 and Ku80 in TE-1 cells, and significantly inhibited the increase of these proteins after irradiation. Above all, our data suggested that UHRF1 might play an important role in radioresistance of ESCC, and inhibition of UHRF1 can increase the radiosensitivity of TE-1 cells by altering cell cycle progression, enhancing apoptosis, and decreasing DNA damage repair capacity.