Mitchell E. Tublin

Impact of Mutational Testing on the Diagnosis and Management of Patients with Cytologically Indeterminate Thyroid Nodules: A Prospective Analysis of 1056 FNA Samples

CONTEXT Thyroid nodules are common in adults, but only a small fraction of them is malignant. Fine-needle aspiration (FNA) cytology provides a definitive diagnosis of benign or malignant disease in many cases, whereas about 25% of nodules are indeterminate, hindering most appropriate management. OBJECTIVE The objective of the investigation was to study the clinical utility of molecular testing of thyroid FNA samples with indeterminate cytology. DESIGN Residual material from 1056 consecutive thyroid FNA samples with indeterminate cytology was used for prospective molecular analysis that included the assessment of cell adequacy by a newly developed PCR assay and testing for a panel of mutations consisted of BRAF V600E, NRAS codon 61, HRAS codon 61, and KRAS codons 12/13 point mutations and RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. RESULTS The collected material was adequate for molecular analysis in 967 samples (92%), which yielded 87 mutations including 19 BRAF, 62 RAS, 1 RET/PTC, and five PAX8/PPARγ. Four hundred seventy-nine patients who contributed 513 samples underwent surgery. In specific categories of indeterminate cytology, i.e. atypia of undetermined significance/follicular lesion of undetermined significance, follicular neoplasm/suspicious for a follicular neoplasm, and suspicious for malignant cells, the detection of any mutation conferred the risk of histologic malignancy of 88, 87, and 95%, respectively. The risk of cancer in mutation-negative nodules was 6, 14, and 28%, respectively. Of 6% of cancers in mutation-negative nodules with atypia of undetermined significance/follicular lesion of undetermined significance cytology, only 2.3% were invasive and 0.5% had extrathyroidal extension. CONCLUSION Molecular analysis for a panel of mutations has significant diagnostic value for all categories of indeterminate cytology and can be helpful for more effective clinical management of these patients.

Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay.

Fine‐needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next‐generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules.

Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism.

OBJECTIVE This article discusses the commonly used techniques for imaging the parathyroid glands and their role in the preoperative evaluation of patients with primary hyperparathyroidism. CONCLUSION The importance of sonography and sestamibi scintigraphy in the preoperative evaluation of patients with primary hyperthyroidism has increased with the adoption of minimally invasive parathyroidectomy techniques at most medical centers. When the results of these studies are concordant, the cure rates of minimally invasive surgery equal those of traditional bilateral neck exploration.

The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism

Importance Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades. Objective To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy. Evidence Review A multidisciplinary panel used PubMed to review the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Findings Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise. Conclusions and Relevance Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT.

Localization of Parathyroid Adenomas by Sonography and Technetium Tc 99m Sestamibi Single-Photon Emission Computed Tomography Before Minimally Invasive Parathyroidectomy Are Both Studies Really Needed?

Objective. The purpose of this study was to determine the utility of radiologist‐performed sonography as the principal modality for parathyroid localization before minimally invasive parathyroidectomy. Methods. Both sonography and technetium Tc 99m sestamibi single‐photon emission computed tomography (SPECT) are commonly performed during imaging evaluation of patients with primary hyperparathyroidism (HPTH). Sonographic examinations ordered during the study period were performed by 1 author (M.E.T.), and results were immediately reported. Findings of a subsequent Tc 99m sestamibi study were recorded blinded to the sonographic results. The sensitivity and specificity of sonography and Tc 99m sestamibi SPECT were assessed with the use of surgery and pathology reports as a reference standard. The 2007 global Medicare reimbursement rates were used to assess the costs of preoperative localization. Results. Parathyroidectomy was performed in 144 of 172 patients evaluated by both modalities. The sensitivity, specificity, and positive predictive value of sonography for identifying abnormal parathyroid glands were 74%, 96%, and 90%, respectively. Sonography correctly localized a single adenoma or suggested multiglandular disease in 112 of 144 patients (78%). The sensitivity, specificity, and positive predictive value of SPECT were 58%, 96%, and 89%. Technetium 99m sestamibi SPECT correctly predicted an adenoma or multiglandular disease in 88 of 144 patients (61%). Five patients with negative sonographic findings were shown to have uniglandular disease on Tc 99m sestamibi SPECT. Selective use of Tc 99m sestamibi SPECT (ie, when sonographic findings were negative or equivocal) would have decreased the cost of imaging by 53%. Conclusions. Radiologist‐performed sonography may potentially be used as a principal imaging modality for patients with HPTH. Selective use of Tc 99m sestamibi in cases with negative or equivocal sonographic findings can decrease the cost of imaging before parathyroid resection considerably.

Imaging the spectrum of biliary tract disease

An understanding of underlying biliary pathology and the corresponding subtle changes reflected at imaging can greatly improve imaging accuracy in evaluating the biliary tract. The optimal demonstration of biliary tract imaging findings requires attention to specific imaging and contrast techniques, regardless of the modality used.

Postoperative surveillance of differentiated thyroid carcinoma: rationale, techniques, and controversies.

Although differentiated thyroid cancer (DTC) is typically an indolent disease with a high rate of cure, recurrence is common (15%-30% of patients), even in early-stage disease. These high rates of recurrence have resulted in the widespread adoption of intensive posttherapy surveillance algorithms. Currently used strategies rely primarily on serial serum thyroglobulin measurements combined with cervical ultrasonography (US): US is utilized to search for recurrences within the thyroid bed or anterior cervical lymph nodes and as a guidance system for directed fine-needle aspiration biopsy of suspicious lesions. Positron emission tomography (PET) and coregistered computed tomography/fluorine 18 fluorodeoxyglucose PET are used primarily in the setting of non-iodine-avid tumors. Intensive surveillance has improved the ability to detect small-volume tumor recurrence with a sensitivity that surpasses current understanding of the clinical implications of detecting clinically occult residual or recurrent disease. Knowledge of currently used treatment and surveillance strategies is crucial for understanding the appropriate use of imaging studies, the clinical implications of imaging findings, and the appropriate use of US-guided tissue sampling in patients with DTC. Recent advances in the understanding of DTC tumor biology hold promise for improving the ability to predict tumor behavior and aggressiveness, thereby allowing more appropriate risk stratification, imaging surveillance, and treatment.

Ultrasound-Guided Fine-Needle Aspiration Versus Fine-Needle Capillary Sampling Biopsy of Thyroid Nodules Does Technique Matter?

Both fine‐needle aspiration (FNA) and fine‐needle capillary (FNC) sampling of palpable thyroid nodules have been advocated. The appropriate technique for biopsy of nonpalpable nodules now sampled under ultrasound guidance has not been assessed. The objective of this study was to determine cytologic adequacy rates of ultrasound‐guided FNA and FNC sampling.

Hepatic transplantation: postoperative complications

Advances in surgical techniques and immunosuppression have made orthotopic liver transplantation a first-line treatment for many patients with end-stage liver disease. The early detection and treatment of postoperative complications has contributed significantly to improved graft and patient survival with imaging playing a critical role in detection. Complications that can lead to graft failure or patient mortality include vascular abnormalities, biliary abnormalities, allograft rejection, and recurrent or post-transplant malignancy. Vascular abnormalities include stenosis and thrombosis of the hepatic artery, portal vein, and inferior vena cava, as well as hepatic artery pseudoaneurysm, arteriovenous fistula, and celiac stenosis. Biliary abnormalities include strictures, bile leak, obstruction, recurrent disease, and infection. While imaging is not used to diagnose allograft rejection, it plays an important role in identifying complications that can mimic rejection. Ultrasound is routinely performed as the initial imaging modality for the detection and follow-up of both early and delayed complications. Cholangiography and magnetic resonance cholangiopancreatography are used to characterize biliary complications and computed tomography is used to confirm abnormal findings on ultrasound or for the evaluation of postoperative collections. The purpose of this article is to describe and illustrate the imaging appearances and management of complications associated with liver transplantation.

Influence of Contrast Media on the Response of Rat Renal Arteries to Endothelin and Nitric Oxide: Influence of Contrast Media

RATIONALE AND OBJECTIVES Contrast media (CM) such as diatrizoate meglumine (DTZ) or iohexol can cause renal vasoconstriction in vivo, and this may initiate CM-induced nephropathy. Endothelin-1 (ET-1), a vasoconstrictor, and nitric oxide, a vasodilator, are key modulators of renal circulation. We tested the hypothesis that CM enhances arterial responses to ET-1, or diminishes responses to nitric oxide. METHODS A video dimension analyzer continuously recorded changes in diameter of isolated, pressurized rat interlobar renal arteries (200-400 microm diameter) superfused with combinations of CM, ET-1, nitric oxide, and other vasoactive agents. RESULTS Superfusion of arteries with 3.3% DTZ, but not with 3.3% iohexol, enhanced their sensitivity to ET-1 by approximately twofold, as assessed by shifts in concentration-response curves. Both DTZ and iohexol decreased the sensitivity of arteries to nitric oxide by approximately threefold. Neither DTZ nor iohexol affected arterial sensitivity to other vasoconstrictors (phenylephrine, potassium) or vasodilators (forskolin, diltiazem). CONCLUSIONS Diatrizoate meglumine and iohexol may induce or augment renal vasoconstriction in part by causing selective alterations in arterial sensitivity to ET-1 and to nitric oxide.