Repeat Fine Needle Aspiration Cytology Refines the Selection of Thyroid Nodules for Afirma Gene Expression Classifier Testing.

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

Thyroxine and treatment of hypothyroidism: seven decades of experience.

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations.

Massive pulmonary embolism presenting initially as acute psychosis.

This is a case of a 68-year-old man with Parkinson's disease who was admitted in the psychiatry floor for new-onset aggressive behaviour and hallucinations. On the third day of hospitalisation, he suddenly developed dyspnoea followed by an ECG showing atrial fibrillation with rapid ventricular response. A few seconds later, he went into cardiac arrest; he was resuscitated after multiple rounds of Advanced Cardiovascular Life Support. A transthoracic echo showed hypokinetic and enlarged right ventricle. A CT Chest showed a saddle embolus. Patient was provided with systemic thrombolysis, which led to an improvement in his haemodynamic status. Interestingly, his psychotic symptoms also improved. In this paper, we present and review how pulmonary embolism can be associated with acute psychosis.

BISPHOSPHONATES FOR THE TREATMENT OF CALCITRIOL-INDUCED HYPERCALCEMIA.

OBJECTIVE: Calcitriol excess is a less common cause of hypercalcemia than hyperparathyroidism. Hypercalcemia due to calcitriol excess is usually managed acutely with intravenous (IV) fluid administration and dietary calcium restriction. Steroids and ketoconazole are second-line agents. There is evidence supporting the role of bone resorption in the genesis of hypercalcemia in vitamin D intoxication and for a rapid response of hypercalcemia to treatment with bisphosphonates. We seek to demonstrate the utility of bisphosphonates in calcitriol-induced hypercalcemia (CIH). METHODS: We present the case of a patient with recurrent CIH from a follicular lymphoma who achieved normalization and subsequent stabilization of serum calcium levels following bisphosphonate administration. RESULTS: A 77-year-old woman with a history of non-small cell lung cancer was admitted with dry mouth, polyuria, weight loss, and fatigue. She was found to have a calcium level of 14.7 mg/dL (normal range is 8.5 to 10.2 mg/dL), 25-hydroxyvitamin D of 47 ng/mL (normal range is 30 to 60 ng/mL), 1,25-dihydroxyvitamin D of 89 pg/mL (normal range is 18 to 72 pg/mL), and parathyroid hormone of 19 pg/mL (normal range is 15 to 65 pg/mL), which recurred despite treatment with IV fluids and strict low-calcium diet. She received 5 mg of IV zoledronic acid and normocalcemia was maintained thereafter, without any diagnosis-specific treatment for >3 months. Positron emission tomography with computed tomography eventually showed new innumerable foci of increased uptake in the skeleton and lymph node biopsy revealed grade 3A follicular lymphoma. CONCLUSION: The first choice for CIH is treating the underlying cause. Bisphosphonates are, however, useful until a diagnosis is made, as they may be safer than steroids and can provide rapid relief even with a single treatment with minimal side effects.

An easy miss: aortic dissection in a 'healthy' male.

Aortic dissection is an uncommon cause of chest discomfort that can be rapidly fatal without early diagnosis and prompt treatment. In this report, we present a man with no risk factors who presented with chest discomfort not typical of a dissection, absent pulse and blood pressure differential and a normal chest radiograph. He eventually was diagnosed with an extensive Type-A aortic dissection. We discuss diagnostic clues, classification of aortic dissection and possible treatment options.