BACKGROUND. Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (¹³¹I-refractory) PTC. METHODS. PTC samples from 106 pediatric patients (age range: 4.3–19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983–March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison. RESULTS. We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAF^V600E in 41 patients, TERT^C228T in 2 patients [1 of whom had a coexisting BRAF^V600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAF^V600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive ¹³¹I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored ¹²⁵I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received ¹³¹I therapy combined with selpercatinib, resulting in a tumor response. In vitro ¹²⁵I uptake and ¹³¹I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity. CONCLUSIONS. In pediatric patients with fusion oncogene PTC who have ¹³¹I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC. FUNDING. The Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830). TRIAL REGISTRATION. Two patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

OBJECTIVE: Diabetes is associated with atherogenic risk factors. Hypertension has a major influence on cardiovascular disease in diabetic patients. Ambulatory blood pressure monitoring (ABPM) is useful for identifying nocturnal hypertension. Carotid intima-media thickness (cIMT) is a good measure for identifying subclinical atherosclerosis. This study aimed to evaluate whether nocturnal hypertension affects atherosclerosis in children and adolescents with type 1 diabetes and to investigate the relationship between atherogenic risk factors and cIMT. RESEARCH DESIGN AND METHODS: ABPM and cIMT were measured in 82 diabetic children and adolescents. We reviewed the hemoglobin A1c levels, 24-h urine microalbumin excretion, lipid profiles, and duration of diabetes. Nocturnal hypertension was defined as hypertension observed only at night. RESULTS: Forty-three (52%) subjects were hypertensive, and 30 subjects were classified as having nocturnal hypertension. cIMT was higher in the nocturnal hypertensive group than in the normotensive group (0.44 ± 0.03 vs. 0.42 ± 0.04 mm, P = 0.026). Among children and adolescents with nonhypertensive blood pressure levels in clinic blood pressure monitoring, cIMT and daytime blood pressure were higher in the nocturnal hypertensive group. All ABPM parameters were significantly related to cIMT in multiple linear regression analysis. CONCLUSIONS: This study showed significantly increased cIMT and daytime blood pressure in diabetic children and adolescents with nocturnal hypertension. ABPM may be a useful method for detecting the macrovascular complications of type 1 diabetes. Longitudinal studies are needed to find the causes of nocturnal hypertension and to evaluate the effect of nocturnal hypertension on atherosclerosis in type 1 diabetes.

Prenatal and postnatal exposure to bisphenol A (BPA) may affect early brain development. Rodent studies suggest that prenatal and postnatal neurodevelopmental toxicity from BPA exposure may manifest as social deficits in offspring. We investigated the association between prenatal and postnatal exposure to BPA and social impairments in a sample of 4-year-old children. We recruited second-trimester pregnant women between 2008 and 2011, and measured their creatinine-adjusted prenatal urine BPA levels. In 2014-2015, a subset of 4-year-old children born to these women underwent neurobehavioral assessment and physical examination. We collected urine and blood from the children and assessed social impairments, including deficits in social interaction, social communication, and other behavior patterns using the Korean version of the Social Communication Questionnaire (K-SCQ) (n = 304). We examined social impairments associated with prenatal exposure at mid-term pregnancy and postnatal exposure to BPA at 4 years of age, using linear and piecewise linear regression models. The relationship between prenatal BPA exposure and social communication was non-linear and statistically significant at or above the flexion point for BPA levels of 3.0 μg/g creatinine in girls (58.4%, 95% confidence interval [CI], 6.5% to 135.8%). Each 2-fold increase in postnatal BPA exposure was significantly associated with an 11.8% (95% CI, 0.6% to 24.3%) increase in impairment in social communication in 4-year old girls, as indicated by the linear regression model. Prenatal and postnatal BPA exposure is associated with social impairment at 4 years of age, particularly in girls.

Background: Pediatric thyroid cancer has characteristics that are distinct from adulthood thyroid cancer. Due to its very low prevalence, little is known about the genetic characteristics of pediatric follicular thyroid cancer (FTC). Methods: We investigated genetic alterations in tumor tissues from 15 patients aged <20 years (median: 14.3 years; range: 2.4 − 19.0 years) using multifaceted approaches. Whole-exome sequencing, targeted next-generation sequencing using a cancer gene panel, and Sanger sequencing of the major exons of the H/K/N-RAS and DICER1 genes and the promoter region of the TERT gene were performed. Normal tissues or blood of patients with DICER1- or PTEN -positive tumors was also evaluated to determine whether the variant is germ line. Results: The median tumor size was 3.1 cm (range: 0.6 − 6.4 cm). Four patients exhibited angioinvasion and one extensive capsular invasion; none showed evidence of disease over a median of 8.1 years. Eight patients (53.3%) had DICER1 variants, including four with DICER1 syndrome (three patients were <10 years of age). One patient had a germ line PTEN frameshift variant with the diagnosis of PTEN hamartoma tumor syndrome. One patient had a PAX8/PPARγ rearrangement, and two patients had no genetic driver alteration other than multiple loss of heterozygosity with or without copy number alterations in their tumors. No RAS or TERT variants were found. Nodular hyperplasia and follicular adenoma (FA) coexisted in DICER1 variant-positive FTCs more frequently than variant-negative FTCs ( p = 0.026). All DICER1 variant-positive FTCs had a somatic missense variant at metal binding sites (six at codon p.E1813 and two at codon p.D1709) within the RNase IIIb domain; seven had other missense, nonsense, or frameshift variants in the DICER1 gene. Six coexisting FAs of two patients with DICER1 syndrome (three of each) had additional somatic variants at metal binding sites within the RNase IIIb domain (codon p.E1705, p.D1709, p.D1810, or p.E1813), different from each other and from the indexed FTC tumor. Conclusions: Pediatric FTCs have distinct genomic alterations and pathogenesis compared with adults, particularly those characterized by DICER1 variants. The DICER1 variant should be considered in pediatric FTCs, especially in cases <10 years of age. In all DICER1 variant-positive FTCs and FAs, recurrent hotspot variants were found at metal binding sites within the RNase IIIb domain, suggesting they impact tumorigenesis.

Kim HY, et al. J Korean Med Sci. 2017 Oct;32(10):1633-1641. https://doi.org/10.3346/jkms.2017.32.10.1633