Estimated Effect of Parathyroidectomy on Long-Term Kidney Function in Adults With Primary Hyperparathyroidism.

BACKGROUND: Multidisciplinary guidelines recommend parathyroidectomy to slow the progression of chronic kidney disease in patients with primary hyperparathyroidism (PHPT) and an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. Limited data address the effect of parathyroidectomy on long-term kidney function. OBJECTIVE: To compare the incidence of a sustained decline in eGFR of at least 50% among patients with PHPT treated with parathyroidectomy versus nonoperative management. DESIGN: Target trial emulation was done using observational data from adults with PHPT, using an extended Cox model with time-varying inverse probability weighting. SETTING: Veterans Health Administration. PATIENTS: Patients with a new biochemical diagnosis of PHPT in 2000 to 2019. MEASUREMENTS: Sustained decline of at least 50% from pretreatment eGFR. RESULTS: Among 43 697 patients with PHPT (mean age, 66.8 years), 2928 (6.7%) had a decline of at least 50% in eGFR over a median follow-up of 4.9 years. The weighted cumulative incidence of eGFR decline was 5.1% at 5 years and 10.8% at 10 years in patients managed with parathyroidectomy, compared with 5.1% and 12.0%, respectively, in those managed nonoperatively. The adjusted hazard of eGFR decline did not differ between parathyroidectomy and nonoperative management (hazard ratio [HR], 0.98 [95% CI, 0.82 to 1.16]). Subgroup analyses found no heterogeneity of treatment effect based on pretreatment kidney function. Parathyroidectomy was associated with a reduced hazard of the primary outcome among patients younger than 60 years (HR, 0.75 [CI, 0.59 to 0.93]) that was not evident among those aged 60 years or older (HR, 1.08 [CI, 0.87 to 1.34]). LIMITATION: Analyses were done in a predominantly male cohort using observational data. CONCLUSION: Parathyroidectomy had no effect on long-term kidney function in older adults with PHPT. Potential benefits related to kidney function should not be the primary consideration for PHPT treatment decisions. PRIMARY FUNDING SOURCE: National Institute on Aging.

Evidence of the Role of Inflammation and the Hormonal Environment in the Pathogenesis of Adrenal Myelolipomas in Congenital Adrenal Hyperplasia.

Adrenal myelolipomas (AML) are composed of mature adipose and hematopoietic components. They represent approximately 3 percent of adrenal tumors and are commonly found in patients with congenital adrenal hyperplasia (CAH). CAH provides a unique environment to explore AML pathogenesis. We aimed to evaluate the role of the immune system and hormones that accumulate in poorly controlled CAH in the development of AML. When compared to normal adrenal tissue, CAH-affected adrenal tissue and myelolipomas showed an increased expression of inflammatory cells (CD68, IL2Rbeta), stem cells (CD117) B cells (IRF4), and adipogenic markers (aP2/FABP4, AdipoQ, PPARγ, Leptin, CideA), and immunostaining showed nodular lymphocytic accumulation. Immunohistochemistry staining revealed a higher density of inflammatory cells (CD20, CD3, CD68) in CAH compared to non-CAH myelolipomas. In vitro RNA-sequencing studies using NCI-H295R adrenocortical cells with exogenous exposure to ACTH, testosterone, and 17-hydroxyprogesterone hormones, showed the differential expression of genes involved in cell cycle progression, phosphorylation, and tumorigenesis. Migration of B-lymphocytes was initiated after the hormonal treatment of adrenocortical cells using the Boyden chamber chemotaxis assay, indicating a possible hormonal influence on triggering inflammation and the development of myelolipomas. These findings demonstrate the important role of inflammation and the hormonal milieu in the development of AML in CAH.

Adverse Cardiovascular Outcomes Among Older Adults With Primary Hyperparathyroidism Treated With Parathyroidectomy Versus Nonoperative Management.

OBJECTIVE: The authors sought to compare the incidence of adverse cardiovascular (CV) events in older adults with primary hyperparathyroidism (PHPT) treated with parathyroidectomy versus nonoperative management. BACKGROUND: PHPT is a common endocrine disorder that is associated with increased CV mortality, but it is not known whether parathyroidectomy reduces the incidence of adverse CV events. METHODS: The authors conducted a population-based, longitudinal cohort study of Medicare beneficiaries diagnosed with PHPT (2006-2017). Multivariable, inverse probability weighted Cox proportional hazards regression was used to determine the associations of parathyroidectomy with major adverse cardiovascular events (MACEs), CV disease-related hospitalization, and CV hospitalization-associated mortality. RESULTS: The authors identified 210,206 beneficiaries diagnosed with PHPT from 2006 to 2017. Among 63,136 (30.0%) treated with parathyroidectomy and 147,070 (70.0%) managed nonoperatively within 1 year of diagnosis, the unadjusted incidence of MACE was 10.0% [mean follow-up 59.1 (SD 35.6) months] and 11.5% [mean follow-up 54.1 (SD 34.0) months], respectively. In multivariable analysis, parathyroidectomy was associated with a lower incidence of MACE [hazard ratio (HR): 0.92; 95% confidence interval (95% CI): 0.90-0.94], CV disease-related hospitalization (HR: 0.89; 95% CI: 0.87-0.91), and CV hospitalization-associated mortality (HR: 0.76; 95% CI: 0.71-0.81) compared to nonoperative management. At 10 years, parathyroidectomy was associated with adjusted absolute risk reduction for MACE of 1.7% (95% CI: 1.3%-2.1%), for CV disease-related hospitalization of 2.5% (95% CI: 2.1%-2.9%), and for CV hospitalization-associated mortality of 1.4% (95% CI: 1.2%-1.6%). CONCLUSIONS: In this large, population-based cohort study, parathyroidectomy was associated with a lower long-term incidence of adverse CV outcomes when compared with nonoperative management for older adults with PHPT, which is relevant to surgical decision making for patients with a long life expectancy.

Increased Risk of Complications Associated With Concurrent Parathyroidectomy in Patients Undergoing Total Thyroidectomy.

INTRODUCTION: We sought to investigate the association of concurrent parathyroidectomy (PTX) with risks of total thyroidectomy (TTX) through analysis of Collaborative Endocrine Surgery Quality Improvement Program data. TTXis a common operation with complications including recurrent laryngeal nerve injury, neck hematoma, and hypoparathyroidism. A subset of patients undergoing thyroidectomy undergoes planned concurrent PTX for treatment of primary hyperparathyroidism. There are limited data on the risk profile of TTX with concurrent PTX (TTX + PTX). METHODS: We queried the Collaborative Endocrine Surgery Quality Improvement Program database for patients who underwent TTX or TTX + PTX from January 2014 through April 2020. Multivariable logistic regression was performed to predict hypoparathyroidism, vocal cord dysfunction, neck hematoma, and postoperative emergency department visit. Covariates included patient demographics, patient body mass index, indication for surgery, central neck dissection, anticoagulation use, and surgeon volume. RESULTS: Thirteen thousand six hundred forty seven patients underwent TTX and 654 patients underwent TTX + PTX. Unadjusted rates of hypoparathyroidism were higher in TTX + PTX patients at 30 d (9.6% versus 7.4%, P = 0.04) and 6 mo (7.9% versus 3.1%, P < 0.001). On multivariable regression, TTX + PTX was associated with an increased risk of hypoparathyroidism at 30 d (odds ratio [OR] 2.09, 95% confidence interval [CI] 1.57-2.79) and 6 mo (OR 4.63, 95% CI 3.06-7.00) and an increased risk of postoperative emergency department visit (OR 1.66, 95% CI 1.20-2.31). TTX + PTX was not associated with recurrent laryngeal nerve injury or neck hematoma. CONCLUSIONS: Concurrent PTX in patients undergoing TTX is associated with increased risk of immediate and long-term hypoparathyroidism, which should be considered in informed consent discussions and operative decision-making.

Integrated Single-cell and Plasma Proteomic Modeling to Predict Surgical Site Complications: A Prospective Cohort Study.

OBJECTIVE: The aim of this study was to determine whether single-cell and plasma proteomic elements of the host's immune response to surgery accurately identify patients who develop a surgical site complication (SSC) after major abdominal surgery. SUMMARY BACKGROUND DATA: SSCs may occur in up to 25% of patients undergoing bowel resection, resulting in significant morbidity and economic burden. However, the accurate prediction of SSCs remains clinically challenging. Leveraging high-content proteomic technologies to comprehensively profile patients' immune response to surgery is a promising approach to identify predictive biological factors of SSCs. METHODS: Forty-one patients undergoing non-cancer bowel resection were prospectively enrolled. Blood samples collected before surgery and on postoperative day one (POD1) were analyzed using a combination of single-cell mass cytometry and plasma proteomics. The primary outcome was the occurrence of an SSC, including surgical site infection, anastomotic leak, or wound dehiscence within 30 days of surgery. RESULTS: A multiomic model integrating the single-cell and plasma proteomic data collected on POD1 accurately differentiated patients with (n = 11) and without (n = 30) an SSC [area under the curve (AUC) = 0.86]. Model features included coregulated proinflammatory (eg, IL-6- and MyD88- signaling responses in myeloid cells) and immunosuppressive (eg, JAK/STAT signaling responses in M-MDSCs and Tregs) events preceding an SSC. Importantly, analysis of the immunological data obtained before surgery also yielded a model accurately predicting SSCs (AUC = 0.82). CONCLUSIONS: The multiomic analysis of patients' immune response after surgery and immune state before surgery revealed systemic immune signatures preceding the development of SSCs. Our results suggest that integrating immunological data in perioperative risk assessment paradigms is a plausible strategy to guide individualized clinical care.

Association of Parathyroidectomy With 5-Year Clinically Significant Kidney Stone Events in Patients With Primary Hyperparathyroidism.

OBJECTIVE: Patients with primary hyperparathyroidism (PHPT) are at increased risk of kidney stones. Guidelines recommend parathyroidectomy in patients with PHPT with a history of stone disease. This study aimed to compare the 5-year incidence of clinically significant kidney stone events in patients with PHPT treated with parathyroidectomy versus nonoperative management. METHODS: We performed a longitudinal cohort study of patients with PHPT in a national commercial insurance claims database (2006-2019). Propensity score inverse probability weighting-adjusted multivariable regression models were calculated. RESULTS: We identified 7623 patients aged ≥35 years old with continuous enrollment >1 year before and >5 years after PHPT diagnosis. A total of 2933 patients (38.5%) were treated with parathyroidectomy. The cohort had a mean age of 66.5 years, 5953 (78.1%) were female, and 5520 (72.4%) were White. Over 5 years, the unadjusted incidence of ≥1 kidney stone event was higher in patients who were managed with parathyroidectomy compared with those who were managed nonoperatively overall (5.4% vs 4.1%, respectively) and among those with a history of kidney stones at PHPT diagnosis (17.9% vs 16.4%, respectively). On multivariable analysis, parathyroidectomy was associated with no statistically significant difference in the odds of a 5-year kidney stone event among patients with a history of kidney stones (odds ratio, 1.03; 95% CI, 0.71-1.50) or those without a history of kidney stones (odds ratio, 1.16; 95% CI, 0.84-1.60). CONCLUSION: Based on this claim analysis, there was no difference in the odds of 5-year kidney stone events in patients with PHPT who were treated with parathyroidectomy versus nonoperative management. Time horizon for benefit should be considered when making treatment decisions for PHPT based on the risk of kidney stone events.

Comprehensive guidance on the diagnosis and management of primary mesenchymal tumours of the thyroid gland.

Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.

Executive Summary of the American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: The aim of this study was to develop evidence-based recommendations for safe, effective and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the United States. METHODS: The medical literature from January 1, 1985 to November 9, 2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches Laryngology Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSION: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults.

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate thyroidectomy. BACKGROUND: Surgical management of thyroid disease has evolved considerably over several decades leading to variability in rendered care. Over 100,000 thyroid operations are performed annually in the US. METHODS: The medical literature from 1/1/1985 to 11/9/2018 was reviewed by a panel of 19 experts in thyroid disorders representing multiple disciplines. The authors used the best available evidence to construct surgical management recommendations. Levels of evidence were determined using the American College of Physicians grading system, and management recommendations were discussed to consensus. Members of the American Association of Endocrine Surgeons reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines analyze the indications for thyroidectomy as well as its definitions, technique, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Fine Needle Aspiration Biopsy Diagnosis, Molecular Testing, Indications, Extent and Outcomes of Surgery, Preoperative Care, Initial Thyroidectomy, Perioperative Tissue Diagnosis, Nodal Dissection, Concurrent Parathyroidectomy, Hyperthyroid Conditions, Goiter, Adjuncts and Approaches to Thyroidectomy, Laryngology, Familial Thyroid Cancer, Postoperative Care and Complications, Cancer Management, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal surgical management of thyroid disease.

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

Contemporary Management of Anaplastic Thyroid Cancer.

OPINION STATEMENT: Anaplastic thyroid cancer (ATC) is a rare but very aggressive form of undifferentiated thyroid cancer. Due to its rapid rate of progression and invasive nature, ATC poses significant risks of morbidity and mortality. The cornerstone in the management of ATC remains a prompt diagnosis of the disease and timely management of complications depending on the stage of disease. Surgery continues to offer a higher chance of a cure, although not all patients are candidates for surgical management. Patients with advanced disease may be considered for palliative surgery to reduce morbidity and complications from advanced disease. With the advent of new molecular testing and improved methods of diagnosis, novel therapeutic targets have been identified. Systemic therapy (chemotherapy and radiation therapy) as well as novel immunotherapy have shown some promise in patients with targetable genetic mutations. Patients should therefore have molecular testing of their tumor-if it is unresectable-and be tested for mutations that are targetable. Mutation-targeted therapy may be effective and may result in a significant response to allow surgical intervention for exceptional responders. Overall, patients who receive all three modalities of therapy (surgery, chemotherapy, and radiation therapy) have the highest overall survival.

Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels.

BACKGROUND: Catecholamine excess in patients with pheochromocytomas or paragangliomas (PPGLs) can lead to hypertension, diabetes and hyperlipidemia. The aim was to investigate the prevalence of hyperlipidemia and the effect of surgical resection. METHODS: One hundred and thirty-two patients with PPGLs underwent an operation at the National Institutes of Health from 2009 to 2016, of which 54 patients met the inclusion criteria. Clinical demographics, BMI, genetic mutations, tumor size, perioperative catecholamine levels and perioperative lipid panels were retrospectively reviewed. Spearman correlation between catecholamines and lipid levels was evaluated. Paired Wilcoxon and paired t test were used to analyze differences in pre- and postoperative lipid levels. RESULTS: Preoperatively, 51 patients (94.4%) had elevated catecholamines, thirteen (24.1%) had elevated total cholesterol (TC) (>200 mg/dL), nine (16.6%) had elevated LDL (>130 mg/dL) and ten (18.5%) had elevated triglycerides (>150 mg/dL). Serum and urinary metanephrine levels were positively associated with TC (r = 0.2792, p = 0.0372 and r = 0.4146, p = 0.0031, respectively) and LDL levels (r = 0.2977, p = 0.0259 and r = 0.4434, p = 0.0014, respectively). Mean TC decreased from 176.4 to 166.3 mg/dL (p = 0.0064) and mean HDL decreased from 56.7 to 53.2 mg/dL (p = 0.0253) after PPGL resection (median 3.1 months (range 1.3-50.2) between lipid panels). Most patients with elevated TC (76.9%) had improvement with mean TC decreasing from 225 to 200.2 mg/dL (p = 0.0230). Of patients with elevated LDL, 66.7% had improvement with mean LDL decreasing from 149 to 131.1 mg/dL (p = 0.0313). CONCLUSIONS: The prevalence of hyperlipidemia in patients with PPGLs is 46%. Future prospective studies are needed to determine whether surgical resection improves TC and/or LDL levels.

Racial disparities in knowledge, attitudes and practices related to COVID-19 in the USA.

BACKGROUND: Recent reports indicate racial disparities in the rates of infection and mortality from the 2019 novel coronavirus (coronavirus disease 2019 [COVID-19]). The aim of this study was to determine whether disparities exist in the levels of knowledge, attitudes and practices (KAPs) related to COVID-19. METHODS: We analyzed data from 1216 adults in the March 2020 Kaiser Family Foundation 'Coronavirus Poll', to determine levels of KAPs across different groups. Univariate and multivariate regression analysis was used to identify predictors of KAPs. RESULTS: In contrast to White respondents, Non-White respondents were more likely to have low knowledge (58% versus 30%; P < 0.001) and low attitude scores (52% versus 27%; P < 0.001), but high practice scores (81% versus 59%; P < 0.001). By multivariate regression, White race (odds ratio [OR] 3.06; 95% confidence interval [CI]: 1.70-5.50), higher level of education (OR 1.80; 95% CI: 1.46-2.23) and higher income (OR 2.06; 95% CI: 1.58-2.70) were associated with high knowledge of COVID-19. Race, sex, education, income, health insurance status and political views were all associated with KAPs. CONCLUSIONS: Racial and socioeconomic disparity exists in the levels of KAPs related to COVID-19. More work is needed to identify educational tools that tailor to specific racial and socioeconomic groups.

Distinct genome-wide methylation patterns in sporadic and hereditary nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Aberrant methylation is a known cause of cancer initiation and/or progression. There are scant data on the genome-wide methylation pattern of nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) and sporadic and hereditary NFPanNETs. METHODS: Thirty-three tissue samples were analyzed: they included samples from sporadic (n = 9), von Hippel-Lindau (VHL)-related (n = 10), and multiple endocrine neoplasia type 1 (MEN1)-related NFPanNETs (n = 10) as well as normal islet cells (n = 4) for comparison. Genome-wide CpG methylation profiling was performed with the Infinium MethylationEPIC BeadChip assay and was analyzed with R-based tools. RESULTS: In unsupervised hierarchical clustering, sporadic and MEN1-related NFPanNETs clustered together, and the VHL group was in a separate cluster. MEN1-related NFPanNETs had a higher rate of hypermethylated CpG sites in comparison with sporadic and VHL-related tumor groups. Differentially methylated region analysis confirmed the higher rate of hypermethylation in MEN1-related tumors. Moreover, in an integrated analysis of gene expression data for the same tumor samples, downregulated gene expression was found in most genes that were hypermethylated. In a CpG island methylator phenotype analysis, 3 genes were identified and confirmed to have downregulated gene expression: secreted frizzle-related protein 5 (SFRP5) in sporadic NFPanNETs and cell division cycle-associated 7-like (CDCA7L) and RNA binding motif 47 (RBM47) in MEN1-related NFPanNETs. CONCLUSIONS: MEN1 NFPanNETs have a higher rate of geno me-wide hypermethylation than other NFPanNET subtypes. The similarity between the pathways enriched in a methylation analysis of known genes involved in NFPanNET tumorigenesis suggests a key role for aberrant methylation in the pathogenesis of NFPanNETs.

GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.

Preoperative 18F-FDG PET/CT in Pheochromocytomas and Paragangliomas Allows for Precision Surgery.

BACKGROUND: Fluorodeoxyglucose (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 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 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 F-FDG PET/CT imaging. RESULTS: Of 100 operations, preoperative 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 F-FDG PET/CT. CONCLUSIONS: Additional lesions detected on preoperative F-FDG-PET/CT imaging have an impact on the surgical approach in patients with PC/PGLs. Therefore, surgeons should routinely obtain F-FDG-PET/CT imaging in patients with PC/PGL to allow for a more precise surgical intervention.

Prognostic Utility of Total 68Ga-DOTATATE-Avid Tumor Volume in Patients With Neuroendocrine Tumors.

BACKGROUND & AIMS: Survival times vary among patients with neuroendocrine tumors (NETs) - even among those with the same site, stage, and grade of primary tumor. This makes it difficult to select treatment for patients with unresectable NETs because some patients can survive decades without treatment. 68Gallium-DOTATATE positron emission tomography with computed tomography (68Ga-DOTATATE PET/CT) is a sensitive imaging technique for detection of NETs. We investigated the prognostic accuracy of 68Ga-DOTATATE PET/CT-based analysis of tumor volume in patients with NETs. METHODS: We performed a prospective study of 184 patients with NETs (128 [69.6%] with metastases and 11 patients [6.0%] with locally advanced disease) at the National Institutes of Health Clinical Center (Bethesda, MD) from 2013 through 2017. All patients underwent 68Ga-DOTATATE PET/CT image analysis and total 68Ga-DOTATATE-Avid tumor volume (68Ga-DOTATATE TV) was determined. We also measured fasting serum chromogranin A, neuron-specific enolase, gastrin, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, and 24-hour urinary 5-hydroxyindoleacetic acid levels in all patients. Disease progression was defined as a new lesion or a growth of a known lesion during the interval between baseline 68Ga-DOTATATE PET/CT scan and follow-up imaging (14.0 ± 6.1 months; range, 1-35 months). The primary outcomes were progression-free survival (PFS) and disease-specific mortality during a median follow-up time of 18 months (range, 4-35 months). RESULTS: We found an inverse correlation between quartiles of 68Ga-DOTATATE TV and PFS (P = .001) and disease-specific survival (P = .002). A 68Ga-DOTATATE TV of 7.0 mL or more was associated with higher odds of disease progression (hazard ratio, 3.0; P = .04). A 68Ga-DOTATATE TV of 35.8 mL or more was associated with increased risk of disease-specific death (hazard ratio, 10.6) in multivariable analysis (P = .01), as well as in subgroup analysis of patients with pancreatic NETs. CONCLUSIONS: In a prospective study, we demonstrated the prognostic utility of 68Ga-DOTATATE TV in a large cohort of patients with NETs, in terms of PFS and disease-specific mortality.

Cumulative Radiation Exposures from CT Screening and Surveillance Strategies for von Hippel-Lindau-associated Solid Pancreatic Tumors.

Purpose To assess the potential ionizing radiation exposure from CT scans for both screening and surveillance of patients with von Hippel-Lindau (VHL) syndrome. Materials and Methods For this retrospective study, abdomen-pelvic (AP) and chest-abdomen-pelvic (CAP) CT scans were performed with either a three-phase (n = 1242) or a dual-energy virtual noncontrast protocol (VNC; n = 149) in 747 patients with VHL syndrome in the National Institutes of Health Clinical Center between 2009 and 2015 (mean age, 47.6 years ± 14.6 [standard deviation]; age range, 12-83 years; 320 women [42.8%]). CT scanning parameters for patients with pancreatic neuroendocrine tumors (PNETs; 124 patients and 381 scans) were compared between a tumor diameter-based surveillance protocol and a VHL genotype and tumor diameter-based algorithm (a tailored algorithm) developed by three VHL clinicians. Organ and lifetime radiation doses were estimated by two radiologists and five radiation scientists. Cumulative radiation doses were compared between the PNET surveillance algorithms by analyses of variance, and a two-tailed P value less than .05 indicated statistical significance. Results Median cumulative colon doses for annual CAP and AP CT scans from age 15 to 40 years ranged from 0.34 Gy (5th-95th percentiles, 0.18-0.75; dual-energy VNC CT) to 0.89 Gy (5th-95th percentiles, 0.42-1.0; three-phase CT). For the current PNET surveillance protocol, the cumulative effective radiation dose from age 40 to 65 years was 682 mSv (tumors < 1.2 cm) and 2125 mSv (tumors > 3 cm). The tailored algorithm could halve these doses for patients with initial tumor diameter less than 1.2 cm (P < .001). Conclusion CT screening of patients with von Hippel-Lindau syndrome can lead to substantial radiation exposures, even with dual-energy virtual noncontrast CT. A genome and tumor diameter-based algorithm for pancreatic neuroendocrine tumor surveillance may potentially reduce lifetime radiation exposure. © RSNA, 2018 Online supplemental material is available for this article.