Persistent Metastatic Thyroid Carcinoma.

The decision to biopsy small thyroid nodules (TNs) is controversial. Careful ultrasound (US) evaluation with shear wave elastography (SWE) of TN and cervical lymph nodes (LNs) may aid in the decision to biopsy and subsequently influence the extent of surgery. A 46-year-old female presented with TNs and hypothyroidism. Her target TN in the left lobe measured 4.8 mm × 4 mm × 4 mm. Fine needle aspiration biopsy of the left TN and a left neck level 6 LN was diagnostic for papillary thyroid carcinoma. In the left lateral neck posterior to the jugular vein, there was a LN with possible microcalcifications that could not be sampled due to vascular proximity. SWE examination showed high velocity suspicious for metastatic disease. In summary, risk stratification for small TNs and cervical LNs can be difficult. SWE can provide valuable information for assessing the risk for malignancy.

Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas.

Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal ß-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorphic, resulting in constitutive activation of cAMP and Ca(2+) signaling pathways involved in insulin secretion.

AN INDIVIDUALIZED APPROACH TO THE EVALUATION AND MANAGEMENT OF PRIMARY ALDOSTERONISM.

OBJECTIVE: With the increased emphasis on personalized and individualized medicine, the American Association of Clinical Endocrinologists Adrenal Scientific Committee has developed a series of articles to update members on personalized medicine as it applies to adrenal diseases. METHODS: We synthesized literature reviews, guidelines from professional societies, and personal experience. RESULTS: Since Conn described primary aldosteronism (PA) over 60 years ago, debate has raged about the prevalence of PA in the hypertensive population, the wisdom of broadly screening for PA, and prudent approaches to evaluate and manage these patients. Accumulated data from multiple centers around the globe have begun to crystallize the clinical characteristics about these patients, which allows for an individualized approach before the diagnosis of PA is even established. Evidence-based criteria for screening, improved and widely available clinical assays, and validated algorithms for evaluation empower all endocrinologists to address this complex disease in an effective manner. CONCLUSION: Breakthroughs in the pathogenesis and evolution of PA illustrate why our thinking about this disease must remain flexible: PA is not a rare and uniform condition, but rather a common syndrome with protean manifestations. ABBREVIATIONS: A/C = cortisol-corrected aldosterone concentration; ACE = angiotensin-converting enzyme; APA = aldosterone-producing adenoma; APCC = aldosterone-producing cell cluster; ARB = angiotensin receptor blocker; ARR = aldosterone-to-renin ratio; AVS = adrenal venous sampling; CT = computed tomography; ENaC = epithelial sodium channel; GRA = glucocorticoid remediable aldosteronism; IHA = idiopathic hyperaldosteronism; LI = lateralization ratio; MR = mineralocorticoid receptor; MRI = magnetic resonance imaging; PA = primary aldosteronism; PRA = plasma renin activity; SRA = surgical remediable aldosteronism.

Intracerebral hemorrhage with hypothyroidism.

BACKGROUND: Hypothyroidism is associated with increased ischemic stroke risk but paradoxically results in more favorable outcomes once a stroke occurs. Whether a similar pattern emerges in patients with primary intracerebral hemorrhage (ICH) is unknown. METHODS: A retrospective analysis of a prospective stroke center database was performed to analyze the clinical presentation and outcomes of hypothyroid patients with spontaneous ICH. Patients were classified into groups with no history of thyroid disease (n=491) versus those with hypothyroidism (n=72). Hypothyroid patients were further classified into patients receiving thyroid replacement on admission or those without replacement. The Glasgow Coma Scale, ICH score, and the National Institutes of Health Stroke Scale (NIHSS) were used to assess the initial severity. Outcome was assessed by admission to discharge change in the NIHSS and modified Barthel Index (mBI), in-hospital mortality, discharge disposition and mortality, and the mBI at 3 and 12 months. RESULTS: There were 563 patients in the analysis. Seventy-two patients had a history of hypothyroidism, and of these, 63% received thyroid hormone replacement. Patients receiving replacement had significantly lower NIHSS at presentation (median 4 [IQR 1, 11]) compared with either the control group (median 8 [IQR 3, 16]) or hypothyroid patients without replacement (median 9 [IQR 3.8, 15.5]; P=.004). There was no difference in in-hospital and 3-month mortality or functional outcomes at 3 and 12 months among the groups. CONCLUSIONS: This study suggests that the history of hypothyroidism does not affect clinical severity or outcome after ICH.

Precision Medicine with 3D Ultrasound.

Introduction: A 56-year-old woman was referred for thyroid nodules (TNs) found on a carotid ultrasonography (US). Her laboratories showed a normal thyroid stimulation hormone of 1.530 µIU/mL, normal thyroid hormone levels, and her thyroid antibodies were not elevated. Thyroid 2D US showed an isoechoic solid TN with regular margins measuring 12 × 8 × 10 mm (TR3) in the left thyroid lobe. 3D US demonstrated markedly irregular margins. The nodule volume was 0.52 cm3. Based on current American Thyroid Association and American College of Radiology-Thyroid Imaging, Reporting and Data System (ACR-TIRADS) guidelines, her nodule size would not fit the criteria for fine needle aspiration biopsy (FNAB).1,2 However, because of the irregular margins seen on 3D US, FNAB was offered along with repeat US after 6 months. After considering her options, she requested FNAB. She underwent effective US guided FNAB of the left TN and the cytopathology report indicated follicular neoplasm Bethesda category IV. Subsequently, she had follow-up US guided FNAB for molecular testing with the Afirma's gene sequencing classifier (GSC). The report showed GSC suspicious with an NRAS mutation, indicating a 50% malignancy risk. She elected to have left hemithyroidectomy. The final surgical pathology report demonstrated a 12-mm follicular carcinoma. Materials and Methods: In our thyroid clinic, we utilize conventional 2D US and 3D US to evaluate TN for possible FNAB. Laboratory measurements were performed at Labcorp. Informed consent was given by the patient. The 3D image acquisition follows 2D US examination. The first step in 3D US image acquisition is identifying the target nodule utilizing 2D US. Next, the 3D sweep of the target nodule produces a 3D volume data set and observation of 3D-rendered images generated simultaneously from longitudinal, transverse, and coronal views. A 2D US image displays a TN only on one plane in two dimensions, longitudinal or transverse. The saved 3D volume data set can be viewed and manipulated later. We can reconstruct new images from different angles after the study is completed. The 3D image acquisition direction (front to back versus up to down) will create a different display image and volume slice. The examiner can choose the direction of 3D acquisition before 3D sweep. A 2D US image or machine lacks these qualities. Discussion: This case illuminates recent advances in 3D US imaging and demonstrates that this technology may enhance the value of 2D US in diagnosing malignancy. This technology allows the user to create sequential cross-sectional images through the target nodule. The addition of coronal view to the existing 2D US has been an important contributing factor. Several recent publications have reported that 3D US can improve nodule selection criteria for FNAB.3-5 Our clinic has routinely utilized 3D US technology for the past 4 years. We have learned that this new technology can delineate TN borders more clearly. It not only enhances the observation of structures within but also those attached to the thyroid gland. The target nodule can be rotated and viewed from different angles. The margin irregularities of TNs can be viewed with 3D US in small and large nodules equally. We have found that the 3D US shows the irregular margins of malignant TNs to be more pronounced when compared with high-end 2D US systems. In our experience, the vast majority of benign TNs have regular margins on 3D US. Finally, the 3D volume measurement may provide additional information about the size of TNs for longitudinal follow-up of nodules with benign FNAB. The limitations or challenges of using 3D US in general practice include the cost of the ultrasound machine, lack of reimbursement, and the provider's learning curve. Adding 3D/4D technology to current 2D US does provide more detailed information; however, it requires additional time to complete a thyroid US study. 3D US technology might be more suitable for thyroid clinics or endocrine practices with high patient volumes. Conclusion: We conclude that 3D US can enhance observation of TN margin irregularities and potentially improve nodule selection for FNAB.No competing financial interests exist.Runtime of video: 2 hrs 25 mins 12 secs.

Daily Glucocorticoid Replacement Dose in Adrenal Insufficiency, a Mini Review.

The Endocrine Society Guidelines and recent reviews of adrenal insufficiency (AI) recommend a daily glucocorticoid replacement dose of 15 to 25 mg with a midpoint of 20 mg of hydrocortisone (HC) (alternatively 3 to 5 mg prednisolone) in divided doses in otherwise healthy individuals with AI. In contrast, a daily glucocorticoid replacement dose of 4.3 to 26 mg/d HC with a midpoint of 15 mg/d is predicted from current measurements of daily cortisol production rates and oral HC bioavailability. The higher HC doses recommended in the current guidelines may result in glucocorticoid overtreatment of some AI patients and associated long-term adverse outcomes. A titration method for determination of the individual patient's daily glucocorticoid replacement dose and the impact of lower doses are reviewed. Future related research questions are identified.

Resolution of manic symptoms following unilateral adrenalectomy in patient with primary bilateral macronodular adrenal hyperplasia.

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is often associated with symptoms of cortisol excess, which may include neuropsychological symptoms. We report a patient with PBMAH who presented with manic symptoms that resolved following unilateral adrenalectomy.

Metformin Decreases Serum Thyroglobulin Concentration in Nonmedullary Thyroid Carcinoma.

Context: The conventional treatment of nonmedullary thyroid carcinoma (NMTC) includes surgical resection, thyrotropin (TSH) suppression, and 131-iodine. Some patients develop persistent/recurrent metastatic disease requiring expensive alternative therapies, such as external radiation and multikinase inhibitors, which may have clinically significant side effects. Recent in vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional trials analyzing the effect of metformin have been performed in humans. Objective: We hypothesize that metformin administration will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC burden. Methods: This retrospective institutional review board-approved study included 10 patients with persistent/recurrent NMTC who had exhausted conventional therapies including total thyroidectomy and 131-iodine. Five had detectable disease on computed tomography imaging. All had biochemical evidence of NMTC with Tg > 2.0 ng/mL with nondetectable serum thyroglobulin antibody concentrations. Five elected to have metformin treatment at doses varying from 500 to 2000 mg/day for 2 to 5 months. The remaining 5 served as untreated controls. Statistical significance was determined by the Mann-Whitney test. Results: Tg decreased (mean decrease = 21.7 ± 8.4%) in all 5 patients receiving metformin and increased (mean increase = 16.6 ± 12.1%) in all 5 controls (P < .01). TSH did not change significantly in either group. Conclusion: In summary, metformin caused a TSH-independent Tg decrease in patients with persistent/recurrent NMTC. More extensive studies are required to determine if metformin slows NMTC progression.

Monthly triple-dose gadolinium administration: potential associations with leukopenia, hypophosphatemia, and bone marrow T1 hyperintensity.

OBJECTIVE: Monthly scanning with triple-dose gadopentetate dimeglumine has been shown to be associated with progressive increases in bone T1 hyperintensity, hypophosphatemia, and leukopenia. This study was performed to retrospectively investigate the potential associations among these phenomena. METHODS: This retrospective analysis involved patients who had received monthly triple-dose gadopentetate dimeglumine for up to 2 years as part of treatment for multiple sclerosis. Monthly magnetic resonance imaging scans of the brain (n = 67) were segmented to evaluate the signal intensity in the cranial marrow. Potential associations among the marrow T1 hyperintensity, serum phosphate concentration, and white blood cell count were examined. RESULTS: Patients in the no leukopenia group showed a statistically significant mean monthly increase in the bone marrow signal-to-noise ratio of 0.0430/month. Patients in the leukopenia group showed a mean monthly increase in the bone marrow signal-to-noise ratio of 0.0398/month, but this was not statistically significant. Patients in the hypophosphatemia group were significantly less likely to develop leukopenia than patients who had never developed hypophosphatemia. CONCLUSIONS: Although monthly administration of triple-dose gadopentetate dimeglumine over 13 months has been associated with progressive increases in leukopenia, hypophosphatemia, and T1 signal intensity of bone, this study showed an inverse relationship between leukopenia and hypophosphatemia.

A Retrospective Evaluation of the Diagnostic Performance of an Interdependent Pairwise MicroRNA Expression Analysis with a Mutation Panel in Indeterminate Thyroid Nodules.

Background: The addition of genetic analysis to the evaluation of thyroid nodule fine-needle aspiration biopsy samples improves diagnostic accuracy of cytologically indeterminate thyroid nodules (ITNs) with Bethesda III or IV cytopathology. We previously reported the performance of a multiplatform molecular test, referred to in this study as MPTXv1, that includes a mutation panel (ThyGeNEXT®) plus an algorithmic microRNA (miRNA) risk classifier (ThyraMIR®). Complex interactions of growth-promoting and -suppressing miRNAs affect the phenotype. We previously demonstrated that accounting for these interactions with pairwise miRNA expression analysis improves the diagnosis of medullary thyroid carcinoma. In this study, we assess the impact of pairwise miRNA expression analysis on risk stratification of ITNs. Methods: Pairwise expression analysis of 11 miRNAs was performed on a training cohort of histopathology-proven benign nodules (n = 50) to define the mean and standard deviation of each pairwise analysis and create a Benign/Malignant Profiler (MPTXv2), deviations from which predicted the malignancy risk. Clinical validation of MPTXv2 was assessed using a cohort of 178 ITN (Bethesda III and IV) samples from a multicentered, blinded retrospective study, previously evaluated by MPTXv1. Results: Compared with MPTXv1, MPTXv2 significantly improved the test performance. The receiver operating characteristic (ROC) areas under the curve (AUC) increased from 0.85 to 0.97 (p < 0.001), and the diagnostic accuracy at the positive threshold increased significantly (p < 0.05) from 83% [95% confidence interval (CI) = 76-88] to 93% [CI = 89-96]. The significant improvement in the ROC AUC and the diagnostic accuracy was due to a strong statistical trend for improvement in specificity at the positive threshold. At the positive threshold, the specificity for MPTXv1 was 90% [CI = 84-95] and improved to 98% [CI = 94-99] for MPTXv2. Using the MPTXv2, the Moderate-Risk cohort decreased from 50 samples (28% of the cohort) to 24 samples (13% of the cohort). This 52% decrease is statistically significant (p < 0.001) and clinically meaningful. Conclusion: As compared with MPTXv1, pairwise miRNA expression analysis used in MPTXv2 significantly improved the diagnostic accuracy of ITN risk stratification and reduced the size of the Moderate-Risk group. Prospective trials are indicated to confirm these findings in a clinical practice setting.

3-D Ultrasound and Thyroid Cancer Diagnosis: A Prospective Study.

This study tests the hypothesis that evaluation of thyroid nodule (TN) margin irregularities by three-dimensional ultrasound (3-D-US) distinguishes benign from malignant TNs with greater sensitivity and specificity than two-dimensional ultrasound (2-D-US). We prospectively evaluated 344 TNs using both 2-D-US and 3-D-US followed by fine needle aspiration biopsy. TNs were divided into four groups based on the 3-D-US appearance of the margins. Bi-variate and multi-variate analyses were used. Surgical pathology confirmed 44 thyroid cancers in 40 patients. For 2-D-US, irregular margins and micro-calcifications (p < 0.001) were found more frequently in malignant TNs. Irregular margins on 2-D-US had a sensitivity and specificity of 61.4% and 79.3%, respectively. Irregular margins on 3-D-US had a sensitivity and specificity of 86.4% and 83.3%, respectively. Sensitivity, specificity, positive and negative predictive values were higher for irregular margins on 3-D-US than micro-calcifications and irregular margins on 2-D-US. Evaluation of TN margins by 3-D-US distinguished benign from malignant TNs with greater sensitivity and specificity than 2-D-US.

Analytical and clinical validation of pairwise microRNA expression analysis to identify medullary thyroid cancer in thyroid fine-needle aspiration samples.

BACKGROUND: Medullary thyroid carcinoma (MTC) is an aggressive malignancy originating from the parafollicular C cells. Preoperatively, thyroid nodule fine-needle aspiration cytology (FNAC) and pathogenic gene mutations are definitive in approximately one-half of cases. MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded RNAs that regulate gene expression, a characteristic that confers the potential for identifying malignancy. In the current study, the authors hypothesized that differential pairwise (diff-pair) analysis of miRNA expression levels would reliably identify MTC in FNA samples. METHODS: The relative abundance of 10 different miRNAs in total nucleic acids was obtained from ThyraMIR test results. Diff-pair analysis was performed by subtracting the critical threshold value of one miRNA from the critical threshold values of other miRNAs. Next-generation sequencing with the ThyGeNEXT panel identified oncogenic gene alterations. The discovery cohort consisted of 30 formalin-fixed, paraffin-embedded benign and malignant thyroid neoplasms, including 4 cases of MTC. After analytical validation, clinical validation was performed using 3 distinct cohorts (total of 7557 specimens). RESULTS: In the discovery cohort, 9 diff-pairs were identified as having significant power using the Kruskal-Wallis test (P < .0001) to distinguish MTC samples from non-MTC samples. The assay correctly classified all MTC and non-MTC samples in the analytical validation study and in the 3 clinical validation cohorts. The overall test accuracy was 100% (95% confidence interval, 99%-100%). In indeterminate FNAC samples, the sensitivity of the diff-pair analysis was greater than that of the MTC-specific mutation analysis (100% vs 25%; P = .03). CONCLUSIONS: Pairwise miRNA expression analysis of ThyraMIR results were found to accurately predict MTC in thyroid FNA samples, including those with indeterminate FNAC findings.

Empiric Determination of the Daily Glucocorticoid Replacement Dose in Adrenal Insufficiency.

BACKGROUND: For the treatment of adrenal insufficiency (AI) in adults, the Endocrine Society's recommended daily glucocorticoid replacement dose (DGRD) is 15 to 25 mg hydrocortisone (HC), which is approximately 1.7 times the reported mean daily cortisol production rate. Prolonged glucocorticoid overtreatment causes multiple morbidities. HYPOTHESIS: We tested the hypotheses that the DGRD, empirically determined by individual patient titration, is lower than that of the Endocrine Society guidelines and tolerated without evidence of glucocorticoid under-replacement. METHODS: We empirically determined the DGRD in 25 otherwise healthy adults with AI by titrating the DGRD to the lowest dose tolerated as judged by body mass index, blood pressure, serum sodium concentration and AI symptoms. Patients received either HC or prednisone (PRED). The HC equivalent of PRED was assumed to be 4:1. RESULTS: The mean empirically determined DGRD, expressed as HC equivalent, was significantly less than the midpoint of the Endocrine Society's recommended DGRD (7.6 ± 3.5 mg/m2 vs 11.8 mg/m2; P < 0.001). The DGRD in the adrenalectomy group was not significantly different than the DGRD of those with other AI causes (7.9 ± 4.0 mg/m2 vs 7.3 ± 3.1 mg/m2; P = ns), demonstrating that the empirically determined DGRD was not biased by residual cortisol secretion. There was no evidence of glucocorticoid under-replacement as determined by measured biometrics and AI symptoms. CONCLUSIONS: We conclude that an empirically determined DGRD is significantly lower than that of the Endocrine Society guidelines and tolerated without evidence of glucocorticoid under-replacement.

Isolated DHEAS production by an adrenal neoplasm: Clinical, biochemical and pathologic characteristics.

Androgen-secreting adrenal neoplasms have a low incidence, usually secrete multiple hormones, and may present with hirsutism, acne, and alopecia. We report an exceedingly rare case of a purely dehydroepiandrosterone-sulfate (DHEA-S) secreting adrenal neoplasm found incidentally on cross sectional imaging. The clinical, biochemical, and pathologic findings of this neoplasm are described.

Precision Medicine with 3D Ultrasound.

Introduction: Currently, B-mode ultrasound (US) is the primary imaging modality in diagnosing thyroid nodules (TNs). B-mode is a two-dimensional US (2D US) imaging display. Recent studies suggest a role for strain and shear wave elastography for evaluating TN as well. Three-dimensional US (3D-US) has the potential to enhance the diagnostic accuracy and precision for thyroid cancer (TC) detection. Materials and Methods: An experienced ultrasonographer (G.A.) evaluated the patient using the following techniques: B-mode, strain and shear wave elastography, and 3D-US followed by fine needle aspiration biopsy (FNAB). Laboratory measurements were performed at LabCorp. Informed consent was obtained. Case: A 28-year-old woman referred for hypothyroidism. Her primary doctor initiated levothyroxine 50 mcg daily 6 months prior. At the time of her visit, her thyroid stimulating hormone (TSH) was 2.8 (0.45-4.5 uIU/mL) and both thyroid peroxidase and thyroglobulin antibodies were elevated, suggestive of Hashimoto's thyroiditis. Her thyroid US showed a heterogeneous gland with an isoechoic TN in the right lobe measuring 7.7 × 6.3 × 7 mm. Strain elastography showed diffuse and patchy tissue stiffness throughout the gland, suggestive of tissue fibrosis caused by Hashimoto's thyroiditis. This study did not distinguish target TN from the surrounding tissue. Shear wave elastography of the TN revealed moderately increased stiffness compared with surrounding tissue. The shear wave velocity (SWV) measurement for the TN was 3.1 m/s. 3D-US examination demonstrated an isoechoic TN with irregular margins, and the volume was 0.119 cm3. FNAB of the TN was performed. Cytopathology was diagnostic for papillary thyroid cancer (PTC), Bethesda Category VI. Subsequent total thyroidectomy confirmed a 7 mm PTC with positive surgical margins caused by thyroid capsule invasion and no clear-cut evidence of extra-thyroid extension. Discussion: This case showcases the recent technological advances in TN imaging. Our objective is to provide an improved approach to TN management. The American College of Radiology Thyroid Imaging Reporting and Data System stratifies the malignancy risk of TN primarily based on the size and B-mode US features. This model does not recommend FNAB for any TN <10 mm regardless of malignancy risk.1 This is our observation that with 3D-US the size cutoff of TN might not be an issue as with B-mode or elastography. Irregularities of the TN can be seen with 3D-US with small and large nodules equally. The finding of irregular margins on 3D-US and consulting with the patient lead us to perform FNAB. Recent publications in the journal of VideoEndocrinology showed utilizations of 3D-US in diagnosing parathyroid adenomas and TNs. 3D-US technology improves view of the target lesion by adding a third dimension, coronal view, to the transverse and longitudinal views of B-mode US.2,3 B-mode imaging provides excellent view of TNs. However, it has a low sensitivity for predicting TC.4 Prospective TN studies have demonstrated that adding elastography to B-mode imaging improves sensitivity of US technology for detecting TC.5-10 In a prospective study with 707 TN, we showed that a single cutoff analysis for predicting malignancy in TNs, a maximum SWV of 3.54 m/s had the best sensitivity. The mean SWV for benign nodules was 2.71 m/s. The mean SWV for malignant nodules was 3.96 m/s.6 In this particular case strain and shear wave were not as helpful. The discrepancy between the two systems has been described in cases with severe Hashimoto's thyroiditis associated with tissue fibrosis.6 In our experience, the presence of autoimmune thyroid disease increases the risk for malignancy. Recent publications reported an association between differentiated TC and autoimmune thyroid disease and/or TSH when all Bethesda classifications were included.11-13 Conclusion: 3D-US technology in conjunction with B-mode may improve diagnostic accuracy in detecting TC. No competing financial interests exist. Runtime of video: 2 mins 30 secs.

Number of aberrant crypt foci associated with adiposity and IGF1 bioavailability.

BACKGROUND: Dysregulation of the insulin-like growth factor (IGF) system, a common consequence of adiposity-induced insulin resistance, may be a key underlying mechanism linking excess body weight with colon cancer. Evidence has been derived from studies of cancer and polyps. Supporting data about aberrant crypt foci (ACF), putative pre-polyp changes, have been generated only from animal studies to date. METHODS: We randomly selected 26 patients with sex-specific elevated waist-hip-ratio (WHR) and 26 with normal values from a series of 150 patients seeking routine colonoscopy at the University of Connecticut Health Center. Cross-sectional analyses were performed of ACF number (<5, > or = 5) in relation to total IGF1, IGF-binding protein-3 (IGFBP3), insulin, body mass index (BMI), WHR and waist circumference (WC). Visualized ACF in the 20 cm of the distal colon were counted using advanced endoscopic imaging. RESULTS: Patients with > or = 5 ACF had higher BMI, WHR, and WC compared with patients with >5 ACF (p = 0.04, p = 0.03, and p = 0.01, respectively). IGFBP3 was reduced (p = 0.02) and IGF1:IGFBP3 molar ratio was greater (p = 0.03) in patients with > or = 5 ACF. We did not observe significant associations between ACF number and insulin or total IGF1. CONCLUSIONS: Our study provides the first report in humans of a possible association of ACF prevalence and IGF1 bioavailability as characterized by IGF1:IGFBP3 molar ratio and IGFBP3 level. More research is needed to determine whether this relationship is varied by ACF features (e.g., size, dysplasia, molecular changes), synchronous cancer and polyps, and is modified by colon cancer risk factors.

Diagnosis of Parathyroid Adenomas with New Ultrasound Imaging Modalities.

Ultrasound technology is becoming an integral part of diagnosing parathyroid adenomas. Careful ultrasound evaluation with b-mode, shear wave elastography, and three-dimensional (3D) of parathyroid adenomas may improve localization and outcome. Introduction: A 60-year-old woman was referred for the evaluation of hyperparathyroidism. This patient gave her informed consent. She had a history of hypothyroidism and thyroid nodules. She was being treated with levothyroxine 50 mcg daily. Routine testing revealed hypercalcemia. The serum calcium was 11.2 (nL range 8.7-10.2 mg/dL), creatinine was 0.69 (nL range 0.57-1.00 mg/dL), intact parathyroid hormone (PTH) was 70 (nL range 15-65 pg/mL), phosphorus was 2.7 (nL range 2.5-4.5 mg/dL), vitamin D was 38.7 (30-100 ng/mL), and 24 hours urine calcium was 362.9 (100-300 mg/24 hour). The neck ultrasound showed two lesions one superior/posterior and the other in the inferior/posterior aspect of the right thyroid lobe measuring 11.6 × 4.4 × 9.7 mm and 14.6 × 5.0 × 10.0 mm, respectively. Both lesions resembled parathyroid adenomas. Shear wave velocity (SWV) measurements for the superior and inferior lesions were 1.67 and 1.77 m/second, respectively. For the adjacent thyroid tissue SWV was 2.3 m/second, significantly higher. 3D ultrasound examination demonstrated a polar artery in both lesions. A sestamibi scan showed a probable right parathyroid adenoma and she was referred for surgery. She was found to have two right parathyroid adenomas in the superior and inferior poles corresponding with the ultrasound finding. Intraoperative PTH level decreased from 139.9 to 17 pg/mL postresection. Six weeks after surgery, her calcium and PTH were normal. Materials and Methods: This patient was evaluated in our clinic with ultrasound imaging, including b-mode, shear wave elastography (SWE), and 3D ultrasound. Discussion: Most patients with primary hyperparathyroidism have a single parathyroid adenoma. Other causes include glandular hyperplasia, multiple adenomas, and parathyroid carcinoma.1,2 This case shows two parathyroid adenomas in the neck posterior to the right thyroid lobe. The role of ultrasound in diagnosing parathyroid adenomas is becoming more prominent because of improved technology, low cost, and noninvasive nature. With this case we illustrate that SWE can be an added value to b-mode ultrasound in diagnosing parathyroid adenomas. Our previous publication in the Journal of European Radiology reported that SWV measurement of parathyroid adenomas may enhance other sonographic parameters to predict the diagnosis. In our view, parathyroid adenomas appear to have a more homogenous texture and lower tissue stiffness when compared with the thyroid gland.3 This case confirms our prior findings. It can be challenging to differentiate parathyroid adenomas from lymph nodes (LNs) and ectopic thyroid tissue at level 6, with b-mode ultrasound. A combination of 3D ultrasound images with 3D color Doppler (CD) might improve our ability to identify the polar artery and enhance differentiation from LN. 3D technology might improve the view by adding coronal view to current b-mode that comprises of transverse and longitudinal views. This is a preliminary report, and more studies need to be done. Conclusion: Combining multiple image modalities, including b-mode, shear wave elastography, and 3D technology, may improve our ability to identify parathyroid adenomas. Parathyroid adenomas have a lower SWV compared with thyroid tissue. 3D ultrasound technology may enhance view of polar artery when adding 3D CD. This challenging case illustrates the utility of these additional modalities. No competing financial interests exist. Runtime of video: 1 min, 52 secs.

Diagnosis of Thyroid Nodule with New Ultrasound Imaging Modalities.

Introduction: B-mode ultrasound (US) technology is an integral part of diagnosing and assessing risk stratification of thyroid nodules (TNs). The addition of shear wave elastography and three-dimensional (3D) US imaging may improve risk stratification for thyroid cancer (TC). Materials and Methods: The patient was evaluated in our clinic with US imaging including B-mode, shear wave elastography, 3D-US, and fine needle aspiration biopsy (FNAB). Laboratory measurements were performed at LabCorp. The patient gave informed consent. Case: A 20-year-old female referred for hypothyroidism who was on levothyroxine 25µg daily. Her thyroid-stimulating hormone (TSH) was 3.870 (0.45-4.5 µIU/mL). Thyroid peroxidase antibody and thyroglobulin antibody were elevated, suggestive of Hashimoto's thyroiditis. Her thyroid ultrasongraph showed a heterogeneous thyroid gland with a hypoechoic TN in the right lobe measuring 9.2 × 8.9 × 9 mm. Shear wave elastography examination was suggestive of a hard TN. The shear wave velocity (SWV) measurements for the target TN was 3.9 m/s. 3D-US examination demonstrated a hypoechoic TN with irregular margins and a volume of 0.322 cm3. FNAB of right TN was performed. The cytopathology was read as malignant (Bethesa Category VI), diagnostic for papillary thyroid cancer (PTC). She underwent total thyroidectomy. Surgical pathology report showed an 8 mm PTC in the right lobe and 2 mm PTC in the left lobe with a background of Hashimoto's thyroiditis. There were 3/10 positive lymph nodes (LNs) for metastases. The largest metastatic LN measured 5 mm at level 6. Discussion: This case illustrates recent advances in US technology. For decades, clinicians relied on B-mode US to assess the risk for TC. This case illustrates important challenges and advances in US technology. Current ACR-TIRADS guideline for TN management is based on B-mode US features and TN size.1 In our experience, including additional factors such as elastography, 3D-US, and laboratory evaluation helps to improve our diagnostic accuracy. In this case, her laboratory was suggestive of autoimmune thyroid disease. This information was helpful to put this patient in a higher risk category. Recent large studies reported an association between differentiated TC and autoimmune thyroid disease and/or TSH when all Bethesda classifications were included.2-4 Shear wave elastography examination showed that this TN had a high SWV, suggestive of a hard TN, which is suspicious for malignancy. Several recent publications have reported that elastography can assess the malignant potential of TN.5-10 In our prospective study, we reported that in a single cutoff analysis for predicting malignancy in TNs, a maximum SWV of 3.54 m/s had the best sensitivity. With greater SWV values, specificity increased but sensitivity decreased.6 3D-US technology enhances our ability to visualize the target lesion because of adding a new dimension, coronal view, to the existing B-mode that consists of transverse and longitudinal views. In this case, irregular margins of the TN are seen much better with 3D-US. This is a preliminary report, and more studies need to be done. Conclusion: Adding SWE and 3D-US technology to B-mode US may enhance our ability for risk stratification for TN before FNAB. 3D-US may improve our ability to visualize the margins of TN. No competing financial interests exist. Runtime of video: 2 mins 5 secs.

Adrenal vein sampling with and without cosyntropin stimulation for detection of surgically remediable aldosteronism.

CONTEXT AND OBJECTIVE: Bilateral adrenal vein sampling (AVS), the diagnostic standard for identifying surgically remediable aldosteronism (SRA), is commonly performed after cosyntropin stimulation (post-ACTHstim). The role of AVS without cosyntropin stimulation (pre-ACTHstim) has not been established. The selectivity index (SI), the adrenal vein (av) serum cortisol concentration divided by that in a peripheral vein, confirms av sampling. The minimally acceptable SI is controversial. The objectives of this study were to determine the role of pre-ACTHstim AVS and a predetermined SI. DESIGN: Using biochemical cure as the endpoint, we performed a retrospective head-to-head comparison of pre-ACTHstim AVS to post-ACTHstim AVS. The specificity of a predetermined minimum SI of 1.5 in pre-ACTHstim AVS was determined. PATIENTS: At a regional AVS referral centre, we analysed 32 patients who had undergone simultaneous bilateral AVS both pre- and post-ACTHstim and had returned for postadrenalectomy evaluation. MEASUREMENTS: Simultaneous bilateral AVS was performed with measurements of venous concentrations of aldosterone and cortisol. End points were postadrenalectomy plasma renin activity, serum aldosterone concentration, and number of antihypertensive medications. RESULTS: All 32 patients achieved a biochemical cure following adrenalectomy. The two AVS protocols were complementary. Notably, seven patients (22%; CI = 11-38) were found to have SRA by a lateralization index (LI) > 4 on the pre-ACTHstim AVS, but not on the post-ACTHstim AVS. SI pre-ACTHstim was divided into tertiles. Specificity was 100% in all. CONCLUSIONS: Simultaneous bilateral AVS performed both pre-ACTHstim and post-ACTHstim maximizes SRA identification. A SI of 1.5 pre-ACTHstim does not reduce specificity.

Shear wave elastography and Afirma™ gene expression classifier in thyroid nodules with indeterminate cytology: a comparison study.

PURPOSE: To compare shear wave elastography (SWE) and Afirma™ gene expression classifier (GEC) for diagnosis of malignancy in thyroid nodules (TNs) with Bethesda Classification (BC) III or IV indeterminate cytology. METHODS: This preliminary single-center prospective study was approved by the Institutional Review Board. We evaluated 151 consented patients with 151 indeterminate TNs (123 BC III, 28 BC IV) on fine-needle aspiration biopsy (FNAB). B-mode ultrasound, vascularity, and SWE were performed prior to FNAB. TN stiffness was measured as shear wave velocity (SWV) in meters per second (m/s). The stiffest area of the TN was selected for SWV measurement. GEC testing was performed with a second FNAB. Surgery was recommended for GEC-suspicious TNs, or GEC-benign TNs with two or more worrisome B-mode US features. RESULTS: Surgical pathology confirmed 31 malignant TNs. Among the GEC-suspicious group, 28 of 59 TNs were malignant. The SWV value of ≥3.59 m/s was the best cut-off for malignancy risk based on the receiver operating curve (ROC). Twenty-six malignant TNs had SWV ≥ 3.59 m/s. The sensitivity and specificity for SWV ≥ 3.59 m/s were 83.9 and 79.2%, respectively. Positive predictive value (PPV) was 51.0% and negative predictive value (NPV) was 95.0%. For the GEC-suspicious group, sensitivity, specificity, PPV, and NPV were 90.3, 74.2, 47.5, and 96.7%, respectively. In multivariate analysis, SWV and GEC-suspicious were significant predictors of malignancy, but B-mode features and vascularity were not. CONCLUSION: This preliminary study indicates that SWE and GEC are independent predictors of malignancy in TNs with BC III or IV.