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Seong-Jang Kim, Sang-Woo Lee, Kyoungjune Pak, and Sung-Ryul Shim

We aimed to explore the role of the diagnostic accuracy of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for the detection of recurrent and/or metastatic diseases in differentiated thyroid cancer (DTC) patients with progressively and/or persistently elevated TgAb levels and negative radioactive iodine whole-body scan (RI-WBS) through a systematic review and meta-analysis. The MEDLINE, EMBASE and Cochrane Library database, from the earliest available date of indexing through June 30, 2017, were searched for studies evaluating the diagnostic performance of F-18 FDG PET/CT for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated TgAb levels and negative RI-WBS. We determined the sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR−). Across 9 studies (515 patients), the pooled sensitivity for F-18 FDG PET/CT was 0.84 (95% CI; 0.77–0.89) a pooled specificity of 0.78 (95% CI; 0.67–0.86). Likelihood ratio (LR) syntheses gave an overall positive likelihood ratio (LR+) of 3.8 (95% CI; 2.5–5.7) and negative likelihood ratio (LR−) of 0.21 (95% CI; 0.14–0.30). The pooled diagnostic odds ratio (DOR) was 18 (95% CI; 10–34). The area (AUC) under the hierarchical summary receiver-operating characteristic (HCROC) curve was 0.88 (95% CI: 0.85–0.90). F-18 FDG PET or PET/CT demonstrated moderate sensitivity and specificity for the detection of recurrent and/or metastatic diseases in DTC patients with progressively and/or persistently elevated TgAb levels and negative RI-WBS.

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Rodrigo A Toledo, Yuejuan Qin, Subramanya Srikantan, Nicole Paes Morales, Qun Li, Yilun Deng, Sang-Woo Kim, Maria Adelaide A Pereira, Sergio P A Toledo, Xiaoping Su, Ricardo C T Aguiar, and Patricia L M Dahia

Pheochromocytomas and paragangliomas are highly vascular tumors of the autonomic nervous system. Germline mutations, including those in hypoxia-related genes, occur in one third of the cases, but somatic mutations are infrequent in these tumors. Using exome sequencing of six paired constitutive and tumor DNA from sporadic pheochromocytomas and paragangliomas, we identified a somatic mutation in the HIF2A (EPAS1) gene. Screening of an additional 239 pheochromocytomas/paragangliomas uncovered three other HIF2A variants in sporadic (4/167, 2.3%) but not in hereditary tumors or controls. Three of the mutations involved proline 531, one of the two residues that controls HIF2α stability by hydroxylation. The fourth mutation, on Ser71, was adjacent to the DNA binding domain. No mutations were detected in the homologous regions of the HIF1A gene in 132 tumors. Mutant HIF2A tumors had increased expression of HIF2 α target genes, suggesting an activating effect of the mutations. Ectopically expressed HIF2 α mutants in HEK293, renal cell carcinoma 786-0, or rat pheochromocytoma PC12 cell lines showed increased stability, resistance to VHL-mediated degradation, target induction, and reduced chromaffin cell differentiation. Furthermore, mice injected with cells expressing mutant HIF2A developed tumors, and those with Pro531Thr and Pro531Ser mutations had shorter latency than tumors from mice with wild-type HIF2A. Our results support a direct oncogenic role for HIF2A in human neoplasia and strengthen the link between hypoxic pathways and pheochromocytomas and paragangliomas.