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Context The underlying genetic cause of nonmedullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management. Objective Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date. Methods Nationwide retrospective cohort study in tertiary referral centers. In total, 97 patients diagnosed with pediatric NMTC between 1970 and 2020 were included in this study. Patients underwent germline whole genome sequencing. The main outcome measures were mutation detection yield in (1) clinically relevant tumor predisposition genes and (2) genes previously associated with NMTC. Results In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic variant in a well-known tumor predisposition gene: APC (n = 1), BRCA2 (n = 2), CHEK2 (n = 4), DICER1 (n = 4), HOXB13 (n = 1), and MITF (n = 1). In addition, 1 patient was diagnosed with Pendred syndrome (SLC26A4) and 9 variants of high interest were found in other NMTC candidate susceptibility genes. Conclusion The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal/family history and histology led us to recommend genetic counseling for all patients with childhood NMTC. The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and presymptomatic genetic testing of at risk family members. [ABSTRACT FROM AUTHOR]

Aim: Tumor markers often remain elevated after intended curative resection of medullary thyroid carcinoma (MTC). The aim of this study was to determine the expression of αvβ3, a promising theranostics target, in MTC and its metastases. Materials & methods: Avβ3 expression was analyzed in 104 patients using a tissue microarray and correlated with clinicopathological variables and survival. Results: Cytoplasmic αvβ3 positivity was seen in 70 patients and was associated with lymph node metastases at time of initial surgery. Membranous positivity was considered positive in 30 patients and was associated with sporadic MTC. Conclusion: Avβ3 was expressed in the cytoplasm of 67% of MTC patients. Membranous expression, which is presumably most relevant for the theranostic use of αvβ3, was seen in 29%. Article highlights After intended curative resection of medullary thyroid carcinoma (MTC), calcitonin levels often remain elevated indicating remnant disease or metastasis. There is a demand for new imaging and therapeutic options for patients with MTC. Avβ3, an integrin expressed in many tumors, is a promising target for nuclear imaging and treatment using radiolabeled arginine-glycine-aspartic acid (RGD). Cytoplasmic and membranous αvβ3 expression was analyzed using a tissue microarray including primary tumors and lymph node metastases of 104 and 27 patients, respectively. Cytoplasmic expression was considered positive in 67% of patients and was associated with lymph node metastases at the time of initial surgery. Membranous expression, which is thought to be most relevant for the theranostic use of αvβ, was seen in 29% of patients and was associated with sporadic MTC. Survival analysis showed no prognostic value of αvβ3. The correlation of immunohistochemical αvβ3 expression and uptake of radiolabeled RGD should be further assessed in patients with membranous αvβ3 expression. [ABSTRACT FROM AUTHOR]

Purpose: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. Methods: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. Results: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). Conclusion: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost–benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques. [ABSTRACT FROM AUTHOR]

Introduction: Women with a current diagnosis or past history of Graves' disease (GD) are at risk of developing fetal thyrotoxicosis (FT) during pregnancy when they are inadequately treated, or because of placental passage of TSH receptor antibodies (TRAb). It is known that FT induced by high maternal thyroid hormone concentrations may result in infant (central) hypothyroidism. Case Presentation: In a euthyroid woman with a history of GD treated with radioactive iodide (I131), persistently high levels of maternal TRAb resulted in recurrent FT during two separate pregnancies, followed by neonatal hyperthyroidism and infant central hypothyroidism. Discussion: This case demonstrates the novel insight that FT due to high fetal thyroid hormone concentrations stimulated by high maternal TRAb levels might also result in (central) hypothyroidism, requiring long-term evaluation of the hypothalamus-pituitary-thyroid axis in these children. [ABSTRACT FROM AUTHOR]

Background: An accurate preoperative workup of cytologically indeterminate thyroid nodules (ITN) may rule out malignancy and avoid diagnostic surgery for benign nodules. This study assessed the performance of molecular diagnostics (MD) and 2-[18F]fluoro-2-deoxy-d-glucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in ITN, including their combined use, and explored whether molecular alterations drive the differences in [18F]FDG uptake among benign nodules. Methods: Adult, euthyroid patients with a Bethesda III or IV thyroid nodule were prospectively included in this multicenter study. They all underwent MD and an [18F]FDG-PET/CT scan of the neck. MD was performed using custom next-generation sequencing panels for somatic mutations, gene fusions, and copy number alterations and loss of heterozygosity. Sensitivity, specificity, negative and positive predictive value (NPV, PPV), and benign call rate (BCR) were assessed for MD and [18F]FDG-PET/CT separately and for a combined approach using both techniques. Results: In 115 of the 132 (87%) included patients, MD yielded a diagnostic result on cytology. Sensitivity, specificity, NPV, PPV, and BCR were 80%, 69%, 91%, 48%, and 57% for MD, and 93%, 41%, 95%, 36%, and 32% for [18F]FDG-PET/CT, respectively. When combined, sensitivity and specificity were 95% and 44% for a double-negative test (i.e., negative MD plus negative [18F]FDG-PET/CT) and 68% and 86% for a double-positive test, respectively. Concordance was 63% (82/130) between MD and [18F]FDG-PET/CT. There were more MD-positive nodules among the [18F]FDG-positive benign nodules (25/59, 42%, including 11 (44%) isolated RAS mutations) than among the [18F]FDG-negative benign nodules (7/30, 19%, p = 0.02). In oncocytic ITN, the BCR of [18F]FDG-PET/CT was mere 3% and MD was the superior technique. Conclusions: MD and [18F]FDG-PET/CT are both accurate rule-out tests when unresected nodules that remain unchanged on ultrasound follow-up are considered benign. It may vary worldwide which test is considered most suitable, depending on local availability of diagnostics, expertise, and cost-effectiveness considerations. Although complementary, the benefits of their combined use may be confined when therapeutic consequences are considered, and should therefore not routinely be recommended. In nononcocytic ITN, sequential testing may be considered in case of a first-step MD negative test to confirm that withholding diagnostic surgery is oncologically safe. In oncocytic ITN, after further validation studies, MD might be considered. Clinical Trial Registration: This trial is registered with ClinicalTrials.gov: NCT02208544 (August 5, 2014), https://clinicaltrials.gov/ct2/show/NCT02208544. [ABSTRACT FROM AUTHOR]

Background The impact of multifocality and bilaterality on recurrence in patients with low-risk papillary thyroid cancer (PTC) is relevant when considering patients for a de-escalated treatment strategy: hemithyroidectomy instead of total thyroidectomy followed with or without radioactive iodine. This study aims to analyze contralateral tumor probability in patients treated for low-risk PTC and assess multifocality and bilaterality as possible predictors for recurrence. Methods Patients with low-risk PTC treated with total thyroidectomy followed with or without radioactive iodine in the Netherlands between 2005 and 2015 were included in this study. Patients were identified from the Netherlands Comprehensive Cancer Organization (IKNL) and linked with the nationwide network and registry of Pathology in the Netherlands (PALGA). Contralateral tumor probability and recurrence were assessed. Results Of 791 included patients, 41.8% (331 of 791) had multifocal disease, with 68.9% (228 of 331) of those patients having bilateral disease. The contralateral tumor probability after hemithyroidectomy was 24.6% (150 of 610) for patients with unifocal disease and 43.1% (78 of 181) for patients with multifocal disease. We found a higher trend of recurrence in patients with bilateral disease, regardless of multifocality: in patients with contralateral disease after precompletion diagnosed unifocal disease 7.3% (11 of 150) had recurrent disease, and patients without contralateral disease after precompletion diagnosed multifocal disease 1.9% (2 per 103) had recurrence. Cox regression analysis showed that bilaterality (hazard ratio = 3.621, 95% confidence interval = 1.548 to 8.471) was the sole statistically significant risk factor for recurrence. Conclusion Low recurrence rates are found in patients with either multifocal or bilateral disease with low-risk PTC. Bilaterality should be taken into account when considering these patients for de-escalated treatment strategy. [ABSTRACT FROM AUTHOR]

Context: Imaging plays an important role in the characterization of adrenal tumors, but findings might be inconclusive. The clinical question is whether 18F fluodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is of diagnostic value in this setting. Objective: This meta-analysis was aimed at the diagnostic value of 18F-FDG PET/CT in differentiating benign from malignant adrenal tumors discovered either as adrenal incidentaloma or during staging or follow-up of oncologic patients. Data sources: PubMed, EMBASE, Web of Science, and Cochrane Library were searched to select articles between 2000 and 2021. Study selection: We included studies describing the diagnostic value of 18F-FDG PET/CT in adult patients with an adrenal tumor. Exclusion criteria were 10 or fewer participants, insufficient data on histopathology, clinical follow-up, or PET results. After screening of title and abstract by 2 independent reviewers, 79 studies were retrieved, of which 17 studies met the selection criteria. Data extraction: Data extraction using a protocol and quality assessment according to QUADAS-2 was performed independently by at least 2 authors. Data synthesis: A bivariate random-effects model was applied using R (version 3.6.2.). Pooled sensitivity and specificity of 18F-FDG PET/CT for identifying malignant adrenal tumors was 87.3% (95% CI, 82.5%-90.9%) and 84.7% (95% CI, 79.3%-88.9%), respectively. The pooled diagnostic odds ratio was 9.20 (95% CI, 5.27-16.08; P < .01). Major sources of heterogeneity (I², 57.1% [95% CI, 27.5%-74.6%]) were in population characteristics, reference standard, and interpretation criteria of imaging results. Conclusions: 18F-FDG PET/CT had good diagnostic accuracy for characterization of adrenal tumors. The literature, however, is limited, in particular regarding adrenal incidentalomas. Large prospective studies in well-defined patient populations with application of validated cutoff values are needed. [ABSTRACT FROM AUTHOR]