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BACKGROUND: Fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) imaging is recommended in patients with metastatic pheochromocytoma (PC) and paraganglioma (PGL). There are no data on whether routine preoperative (18)F-FDG PET/CT in all patients with PC/PGL impacts surgical management. OBJECTIVE: The aim of this study was to determine whether routine preoperative (18)F-FDG PET/CT imaging affects the surgical management of patients with PC/PGLs. METHODS: We analyzed clinical, biochemical, genetic, and anatomic imaging data in 93 consecutive patients with PC/PGL who collectively underwent a total of 100 operations and who had preoperative (18)F-FDG PET/CT imaging. RESULTS: Of 100 operations, preoperative (18)F-FDG PET/CT showed additional lesions compared to anatomic imaging in 15 cases. These patients were more likely to undergo an open surgical approach (P < 0.05). Presence of genetic mutation, redo operations, sex, age, or tumor size had no significant association with finding additional lesions on (18)F-FDG PET/CT. CONCLUSIONS: Additional lesions detected on preoperative (18)F-FDG-PET/CT imaging have an impact on the surgical approach in patients with PC/PGLs. Therefore, surgeons should routinely obtain (18)F-FDG-PET/CT imaging in patients with PC/PGL to allow for a more precise surgical intervention.

Background: Thyroid ultrasound (US), fine needle aspiration biopsy (FNAB), and molecular testing have been widely used to stratify the risk of malignancy in thyroid nodules. The goal of this study was to investigate a novel diagnostic approach for cytologically indeterminate thyroid nodules (ITN) based upon a combination of US features and genetic alterations.Methods: We performed a pilot cohort study of patients with ITN (Bethesda III/IV), who underwent surgical treatment. Based on standardized sonographic patterns established by the American Thyroid Association (ATA), each ITN received an US score (XUS), ranging between 0 and 0.9 according to its risk of thyroid cancer (TC). DNA and RNA were extracted from pathologic material, available for all patients, and subjected to Oncomine™ Comprehensive Assay v2 (OCAv2) next-generation sequencing. Each genetic alteration was annotated based on its strength of association with TC and its sum served as the genomic classifier score (XGC). The total risk score (TRS) was the sum of XUS and XGC. ROC curves were generated to assess the diagnostic accuracy of XUS, XGC, and TRS.Results: The study cohort consisted of 50 patients (39 females and 11 males), aged 47.5 ± 14.8 years. Three patients were excluded due to molecular testing failure. Among the remaining 47 patients, 28 (59.6%) were diagnosed with TC. BRAFV600E was the most common mutation in papillary TC, PAX8-PPARG fusion was present in NIFTP, pathogenic variants of SLX4, ATM, and NRAS were found in Hürthle cell TC and RET mutations in medullary TC. The diagnostic accuracy of XGC and TRS was significantly higher compared with XUS (88 vs. 62.5%, p < 0.001; 85.2 vs. 62.5%, p < 0.001, respectively). However, this increased accuracy was due to significantly better sensitivity (80.7 vs. 34.6%, p < 0.001; 84.6 vs. 34.6%, p < 0.001, respectively) without improved specificity (94.7 vs. 90%, p = 0.55; 85.7 vs. 90%, p = 0.63, respectively).Conclusion: Molecular testing might not be necessary in ITN with high-risk US pattern (XUS = 0.9), as specificity of TC diagnosis based on Xus alone is sufficient and not improved with molecular testing. OCAv2 is useful in guiding the management of ITN with low-to-intermediate risk US features (XUS < 0.9), as it increases the accuracy of TC diagnosis.

Background Approximately 10% of patients with primary hyperparathyroidism (PHPT) have hereditary disease. Hereditary PHPT may be syndromic (MEN1, 2, and 4 and hyperparathyroidism-jaw tumor syndrome) or non-syndromic (familial isolated PHPT). There are limited data on the probability of testing positive for genetic mutation based on clinical presentation. The aim of this study was to determine potential associations between clinical and biochemical features and mutation in susceptibility genes for PHPT in patients with a family history of PHPT. Study Design A retrospective analysis of 657 patients who had an initial parathyroidectomy for PHPT at a tertiary referral center. Logistic regression analyses were performed in 205 patients with a family history of PHPT to identify factors associated with a positive genetic test. Results Of 657 patients, 205 (31.2%) had a family history of PHPT. Of those 205 patients, 123 (60%) had a germline mutation detected (91 MEN1 , 14 CDC73 , and 18 GCM2 ). In univariate analysis, younger age (45 years and younger), male sex, multigland disease, and parathyroid carcinoma were associated with positive germline mutation; biochemical cure after an initial parathyroidectomy was less frequent in patients with familial PHPT (96.2% vs 89.2%; p = 0.005). In multivariable analysis, age 45 years and younger, male sex, and multigland disease were independent factors associated with positive genetic testing. Conclusions In addition to a family history of PHPT, male sex, age 45 years and younger, and presence of multigland disease, should prompt physicians to offer the opportunity for genetic counseling and testing, as it could influence the management of patients with PHPT.

Background Our knowledge of the susceptibility genes for pheochromocytomas/paragangliomas has increased; however, data on its impact on surgical decision-making has not been described. The aim of this study was to determine the effect of routine preoperative genetic testing on the operative intervention in patients with pheochromocytomas/paragangliomas. Methods One-hundred-eight patients diagnosed with pheochromocytomas/paragangliomas who underwent 118 operations had preoperative genetic testing for 9 known pheochromocytoma/paraganglioma susceptibility genes. A retrospective analysis of a prospective database was performed to evaluate clinical factors associated with the surgical approach selected and the outcome of the surgical intervention. Results In 51 patients (47%), a germline mutation was detected and one-third had no family history of pheochromocytoma/paraganglioma. In 77 operations (65%), it was the first operative intervention for the disease site (60 laparoscopic, 17 open), and 41 (35%) were reoperative interventions (36 open, 5 laparoscopic). For initial operations, variables associated with whether an open or laparoscopic approach was used were tumor size (P = .009) and presence of germline mutation (P = .042). Sixty-eight adrenal operations were performed (54 total, 14 cortical-sparing). Variables significantly associated with a cortical-sparing adrenalectomy being performed were the presence of germline mutation (P = .006) and tumor size (P = .013). Conclusion Preoperative knowledge of the germline mutation status affects the surgical approach and extent of adrenalectomy.

SummaryObjective Valproic acid (VA) is a histone deacetylase (HDAC) inhibitor that has antiproliferative effects on several types of cancer, including thyroid cancer. In addition, VA has been reported to upregulate the sodium-iodine symporter in thyroid cancer cells and increases radioiodine uptake in preclinical studies. The aim of this study was to assess the antiproliferative effects of VA and to evaluate if VA can increase the radioiodine uptake in patients with advanced, radioiodine-negative thyroid cancer. Design An open-label Simon two-stage phase II trial. Patients and Measurements Valproic acid was administered orally, and doses were adjusted to maintain serum trough levels between 50 and 100 mg/l for 10 weeks, followed by injections of recombinant human thyroid-stimulating hormone and a radioiodine uptake scan. Anatomical imaging studies were performed at week 16 to assess tumour response and radioiodine therapy in patients with increased radioiodine uptake. Results Thirteen patients with a median age of 66 years (50–78 years) were enrolled and evaluated. Seven patients had papillary thyroid cancer (PTC), two had follicular variant PTC, two had follicular thyroid cancer, and two had Hurthle cell carcinoma. None of the 10 patients who completed the 10-week treatment had increased radioiodine uptake at their tumour sites. Three patients were taken off the study prior to the 10-week radioiodine uptake scan: one with grade-3 hepatic toxicity, one with disease progression and one for noncompliance. Four of 13 patients had decreased stimulated serum thyroglobulin with VA treatment. None of the patients had complete or partial responses based on Response Evaluation Criteria in Solid Tumors (RECIST), and six patients had disease progression. Conclusions Valproic acid does not increase radioiodine uptake and does not have anticancer activity in patients with advanced, radioiodine-negative thyroid cancer of follicular cell origin.

PURPOSE: It has been proposed that rebound hyperglycemia after resection of insulinoma indicates a biochemical cure. However, there is scant objective data in the literature on the rate and need for intervention in hyperglycemia in patients undergoing resection of insulinoma. The goal of our study was to evaluate the rate of postoperative hyperglycemia, any predisposing factors, and the need for intervention in a prospective cohort study of all patients undergoing routine glucose monitoring. METHODS: A retrospective analysis of 33 patients who had an insulinoma resected and who underwent routine postoperative monitoring of blood glucose (every hour for the first six hours then every four hours for the first 24 h) was performed. Hyperglycemia was defined as glucose greater than 180 mg/dL (10 mmol/l). RESULTS: Twelve patients (36%) developed hyperglycemia within 24 h (range 1–16 h). In patients with hyperglycemia, the mean maximum plasma glucose level was 221.5 mg/dL (range 97–325 mg/dL) (12.3 mmol/l), and four (33%) patients were treated with insulin. There was no significant difference in age, gender, body mass index (BMI), tumor size, biochemical profile, or surgical approach and extent of pancreatectomy between patients who developed hyperglycemia and those who did not. Pre-excision and post-excision intraoperative insulin levels were evaluated in 14 of 33 patients. The percentage decrease of the intraoperative insulin levels was not significantly different between patients who developed hyperglycemia and those who did not. All patients with postoperative hyperglycemia had normalization of their glucose levels, and none were discharged on anti-hyperglycemic agents. CONCLUSIONS: Hyperglycemia is common after insulinoma resection, and a subset of patients require transient treatment with insulin.

Aim: The study's aim was to determine the utility of 68-Gallium DOTATATE positron emission tomography (PET)-CT scanning in patients with carcinoid-like symptoms and negative anatomical imaging. Methods: Retrospective analysis of 22 of 196 patients with carcinoid-like symptoms and no evidence of primary neuroendocrine tumor (NET) based on anatomical imaging and endoscopy who underwent 68-Gallium DOTATATE PET-CT as part of a prospective clinical trial. Results: Of the biochemically positive patients (n = 11), 18% (n = 2) had additional evidence of NETs based on 68-Gallium DOTATATE PET-CT. Of the patients identified by 68-Gallium DOTATATE PET-CT, 50% (n = 1) had a treatment change and 100% showed symptom improvement. Of the biochemically negative patients (n = 11), 68-Gallium DOTATATE PET-CT identified NETs in 64% (n = 7). Change in management occurred in 71% patients, and 57% of patients showed symptom improvement. Conclusion: 68-Gallium DOTATATE PET-CT imaging is useful in detecting NETs in symptomatic patients with negative anatomical imaging and changes the treatments in these patients.

Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism.We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism.Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P .001).GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.

Although a family history of thyroid cancer is one of the main risk factors for thyroid cancer, the benefit of screening individuals with a family history of thyroid cancer is not known.A prospective cohort study was performed with yearly screening using neck ultrasound and fine-needle aspiration biopsy of thyroid nodule(s)0.5 cm in at-risk individuals whose relatives were diagnosed with familial non-medullary thyroid cancer (FNMTC). The eligibility criteria were the presence of thyroid cancer in two or more first-degree relatives and being older than seven years of age. Twenty-five kindred were enrolled in the study (12 families with two members affected, and 13 with three or more members affected at enrollment).Thyroid cancer was detected by screening in 4.6% (2/43) of at-risk individuals from families with two members affected, and in 22.7% (15/66) of at-risk members from families with three or more patients affected (p = 0.01). FNMTC detected by screening was characterized by a smaller tumor size (0.7 ± 0.5 cm vs. 1.5 ± 1.1 cm; p = 0.006), a lower rate of central neck lymph node metastases (17.6% vs. 51.1%; p = 0.02), less extensive surgery (hemithyroidectomy 23.5% vs. 0%; p = 0.002), and a lower rate of radioactive iodine therapy (23.5% vs. 79%; p 0.001) compared to those affected at enrollment.Screening of at-risk family members resulted in earlier detection of low-risk FNMTC and was associated with a less aggressive initial treatment. Screening with thyroid ultrasound should be considered in kindred with three or more family members affected by FNMTC. Since active screening might be associated with the risk of overtreatment, it should be implemented with caution, specifically in elderly individuals.

Context: Phosphaturic mesenchymal tumors (PMTs) are small, typically difficult to localize, and express somatostatin receptors. Recent work suggests imaging studies using 68Gallium (68Ga)-conjugated somatostatin peptide analogues, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)TATE, which enables somatostatin receptor imaging with positron emission tomography (PET), may be useful at identifying these tumors. Objective: Our objective was to evaluate the use of 68Ga-DOTATATE PET/computed tomography (CT) for tumor localization in tumor-induced osteomalacia (TIO). Design: This was a single-center prospective study of patients with TIO. Setting: The study was conducted at the National Institutes of Health Clinical Center between February 2014 and February 2015. Subjects: Eleven subjects (six females, five males) with TIO were included. Intervention: Subjects underwent 68Ga-DOTATATE PET/CT in addition to 111In-pentetreotide single-photon emission CT (Octreoscan- SPECT/CT) and fluorodeoxy...