Nicole M. Iñiguez-Ariza

Bone biology, signaling pathways, and therapeutic targets for osteoporosis

Major advances have occurred recently in the treatment of osteoporosis in recent years. Most patients are currently treated with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Strontium ranelate and calcitonin have recently had their use restricted due to cardiovascular concerns and malignancy, respectively. The available agents have generally provided excellent options that effectively reduce fracture risk. New targets are being sought based on appreciation of the bone biology and signaling pathways involved in bone formation and resorption. These agents will directly target these signaling pathways, and further expand the options available for treatment of osteoporosis.

Malignant Pheochromocytoma and Paraganglioma: 272 Patients Over 55 Years

Context: Malignant pheochromocytoma (PHEO) and paraganglioma (PGL) are rare and knowledge of the natural history is limited. Objective: We aimed to describe baseline characteristics and outcomes of patients with malignant PHEO and PGL (PPGL) and to identify predictors of shorter survival. Design: Retrospective review of patients with malignant PPGL evaluated from 1960 to 2016. Setting: Referral center. Patients: The group comprised 272 patients. Main Outcome Measures: Baseline description, survival outcomes, and predictors of shorter survival were evaluated in patients with rapidly progressive (n = 29) and indolent disease (n = 188). Results: Malignant PPGL was diagnosed at a median age of 39 years (range, 7 to 83 years), with synchronous metastases in 96 (35%) patients. In 176 (65%) patients, metastases developed at a median of 5.5 years (range, 0.3 to 53.4 years) from the initial diagnosis. Median follow‐up was 8.2 years (range, 0.01 to 54.1 years). Median overall and disease‐specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex (P = 0.014), older age at the time of primary tumor (P = 0.0011), synchronous metastases (P < 0.0001), larger primary tumor size (P = 0.0039), elevated dopamine (P = 0.0195), and not undergoing primary tumor resection (P < 0.0001). There was no difference in the type of primary tumor or presence of SDHB mutation. Conclusions: The clinical course of patients with malignant PPGL is remarkably variable. Rapid disease progression is associated with male sex, older age at diagnosis, synchronous metastases, larger tumor size, elevated dopamine, and not undergoing resection of primary tumor. An individualized approach to patients with metastatic PPGL is warranted.

Salvage Lenvatinib Therapy in Metastatic Anaplastic Thyroid Cancer

BACKGROUND Historical anaplastic thyroid cancer (ATC) outcomes have been terrible, with a median survival of only five months and <20% one-year survival. Improved outcomes are now achieved with aggressive initial therapy in stages IVA and IVB disease, but patients with distant metastatic disease (stage IVC) still do poorly; improved therapies are sorely needed. Kinase inhibitors have emerged as promising agents in the therapy of advanced medullary and differentiated thyroid cancer, but there are limited data regarding the use of lenvatinib in ATC. The aim of this study was to delineate clinical outcomes in a series of patients with advanced ATC in response to lenvatinib therapy. METHODS A retrospective analysis was conducted involving all lenvatinib-treated Mayo Clinic ATC patients in 2015. RESULTS Of 28 distinct ATC patients seen in 2015, three (11%) with metastatic disease of ECOG performance status 2-3 were treated with lenvatinib. Two patients were male; age range at ATC diagnosis was 57-84 years. All three patients attained successful local control of their disease with surgery and/or combined chemoradiotherapy. Lenvatinib was offered as the second, third, or fourth line of therapy at the time of metastatic disease progression. Two patients incurred minor responses to therapy, with structural regression of distant metastatic tumor disease soon after starting lenvatinib treatment (at one to two months), while one patient achieved stable disease, but no Response Evaluation Criteria In Solid Tumors partial responses resulted. Overall survival after starting lenvatinib was two, six, and seven months. Fatigue and hypertension were prominent, and one patient developed pulmonary emboli while on lenvatinib. CONCLUSION This initial single-institution experience suggests that lenvatinib may have some disease-modifying activity in metastatic ATC that is otherwise refractory to cytotoxic chemotherapy. Unfortunately, observed benefits were transient, and toxicities were prominent. Clinical trials are required to ascertain better the utility of lenvatinib in the management of advanced ATC.

Ethanol Ablation for the Treatment of Cystic and Predominantly Cystic Thyroid Nodules

Objective: To determine the efficacy and safety of percutaneous ethanol injection (PEI) for the treatment of symptomatic cystic thyroid nodules. Patients and Methods: Retrospective analysis of patients with benign cystic thyroid nodules treated with PEI from February 1, 2000, through October 31, 2016. The main outcomes were efficacy, defined as symptom relief or reduction in nodule volume of 50% or more, and safety, defined as no or minor adverse events. Results: Twenty patients had PEI. Mean age at the time of PEI was 50 years, and 13 (65%) were women; all patients were euthyroid. Twelve patients (60%) had complex cystic thyroid nodules (>50% cystic component), with the rest being purely cystic. The median largest diameter of the thyroid cyst was 4.5 cm (interquartile range [IQR], 3.2‐5.3 cm; range, 2.3‐8.0 cm); the median volume pre‐PEI was 19.6 mL (IQR, 10.4‐48.5 mL; range, 2.8‐118.1 mL). The median amount of cystic fluid drained before PEI was 13.5 mL (IQR, 6.8‐32.3 mL), and the median amount of ethanol administered was 3 mL (IQR, 2‐5 mL; range, 0.5‐20 mL). After median follow‐up of 2 years, 17 of 19 patients (89%) were asymptomatic. Of 10 patients with available imaging on follow‐up, 7 (70%) had a 50% or greater reduction in nodule volume (median volume decrease, 75.64% [IQR, 41.40%‐91.99%]). Adverse effects occurred in 4 patients (20%) and were mild and temporary (slight pain, vagal reaction, and bleeding into the cyst). Conclusion: Percutaneous ethanol injection seems to be a safe and effective alternative to surgical resection for patients with purely or predominantly cystic thyroid nodules and compressive symptoms who decline surgery or are not good surgical candidates.

Impact of hypercortisolism on skeletal muscle mass and adipose tissue mass in patients with adrenal adenomas

Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality.

Systematic reviews of diagnostic tests in endocrinology: an audit of methods, reporting, and performance

BackgroundSystematic reviews provide clinicians and policymakers estimates of diagnostic test accuracy and their usefulness in clinical practice. We identified all available systematic reviews of diagnosis in endocrinology, summarized the diagnostic accuracy of the tests included, and assessed the credibility and clinical usefulness of the methods and reporting.MethodsWe searched Ovid MEDLINE, EMBASE, and Cochrane CENTRAL from inception to December 2015 for systematic reviews and meta-analyses reporting accuracy measures of diagnostic tests in endocrinology. Experienced reviewers independently screened for eligible studies and collected data. We summarized the results, methods, and reporting of the reviews. We performed subgroup analyses to categorize diagnostic tests as most useful based on their accuracy.ResultsWe identified 84 systematic reviews; half of the tests included were classified as helpful when positive, one-fourth as helpful when negative. Most authors adequately reported how studies were identified and selected and how their trustworthiness (risk of bias) was judged. Only one in three reviews, however, reported an overall judgment about trustworthiness and one in five reported using adequate meta-analytic methods. One in four reported contacting authors for further information and about half included only patients with diagnostic uncertainty.ConclusionUp to half of the diagnostic endocrine tests in which the likelihood ratio was calculated or provided are likely to be helpful in practice when positive as are one-quarter when negative. Most diagnostic systematic reviews in endocrine lack methodological rigor, protection against bias, and offer limited credibility. Substantial efforts, therefore, seem necessary to improve the quality of diagnostic systematic reviews in endocrinology.

Thyroid Cancer Treatment Choice: A Pilot Study of a Tool to Facilitate Conversations with Patients with Papillary Microcarcinomas Considering Treatment Options

BACKGROUND The 2015 American Thyroid Association guidelines recognize active surveillance as an alternative to immediate surgery in patients with papillary microcarcinomas (PMCs). As a way to incorporate active surveillance as one of the management options for patients with PMCs, we developed and tested a tool to support conversations between clinicians and patients with PMCs considering treatment options. METHODS Thyroid Cancer Treatment Choice was developed using an iterative process based on the principles of interaction, design, and participatory action research. To evaluate the impact of the tool on treatment choice, a prospective study was conducted in two thyroid cancer clinics in Seongnam-si and Seoul, South Korea. Both clinics had the expertise to offer active surveillance as well as immediate surgery. One clinic was trained in the use of the conversation aid, while the other clinic continued to care for patients without access to the conversation aid. RESULTS Between May 2016 and April 2017, 278 patients, mostly women (n = 220, 79%), were included in the study; 152 (53%) received care at the clinic using the conversation aid. Age, sex, and mean (±SD) tumor size (6.6 ± 1.6 mm and 6.5 ± 1.9 mm) distributions were similar across clinics. Overall, 233 (84%) patients opted for active surveillance and 53 (16%) for thyroid surgery. Patients in the conversation aid group were more likely to choose active surveillance than the patients seen in the usual care clinic (relative risk = 1.16 [confidence interval 1.04-1.29]). Of all patients opting for active surveillance, more patients in the conversation aid group had thyroid cancer nodules >5 mm than in the usual care group (81% vs. 67%; p = 0.013). CONCLUSIONS Thyroid Cancer Treatment Choice is an evidence-based tool that supports the presentation of treatment options for PMCs. Pilot testing suggests that this conversation tool increases acceptance of active surveillance, suggesting that this option is an acceptable and preferable alternative for informed patients. Further studies are warranted to confirm this finding.

Management of Low-Risk Papillary Thyroid Cancer

The incidence of thyroid cancer has increased, mainly due to the incidental finding of low-risk papillary thyroid cancers (PTC). These malignancies grow slowly, and are unlikely to cause morbidity and mortality. New understanding about the prognosis of tumor features has led to reclassification of many tumors within the low-risk thyroid category, and to the development of a new one “very low-risk tumors.” Alternative less aggressive approaches to therapy are now available including active surveillance and minimally invasive interventions. In this narrative review, we have summarized the available evidence for the management of low-risk PTC.

NECESSITY OF MULTIMODAL TREATMENT OF ACROMEGALY AND OUTCOMES

OBJECTIVE Uncontrolled acromegaly is associated with increased morbidity and mortality. Despite multimodal therapeutic options, adequate control can be challenging and lead to prolonged exposure to growth hormone excess. The aim of this study was to assess treatment patterns and outcomes in patients with acromegaly following surgery at a single institution. METHODS A retrospective analysis of response to treatment modalities for patients with a new diagnosis of acromegaly at the Mayo Clinic in Rochester, Minnesota, from 1995-2015. RESULTS A total of 245 patients with newly diagnosed acromegaly (mean age at diagnosis, 47 ± 14 years; mean follow-up, 5.5 ± 5 years) were evaluated. Primary surgical intervention was performed in 236 patients; 117 (54%) did not achieve remission. Among those with ≥3 months follow-up, 76/217 (35%) patients required three or more forms of treatment. Mean tumor size at diagnosis was 1.6 ± 0.8 cm (80% macroadenomas), and 35% (75/217) had cavernous sinus invasion on pre-operative imaging. The most common second-line treatment was radiation treatment (RT) (50%, 59/117). Among those with persistent disease following surgery, a normal insulin-like growth factor 1 (IGF-1) was achieved in 52% (61/117), with a median time to acromegaly control of 4.5 years. The rate of IGF-1 normalization was 2.1-fold higher in those who received RT compared to those who did not. CONCLUSION In patients with persistent acromegaly following surgery, multiple treatment modalities, including RT, may be required to achieve remission. Treatment outcome uncertainty and the need for multiple interventions add to the disease burden associated with persistent acromegaly. ABBREVIATIONS CI = confidence interval; GH = growth hormone; IGF-1 = insulin like growth factor-1; KM = Kaplan-Meier; RT = radiation treatment.

Effect of thyroid hormone suppression on control of advanced well-differentiated thyroid cancer

A 69 year old woman with long-standing diagnosis of radioactive iodine-refractory differentiated (papillary) thyroid cancer (DTC) was referred for consideration of initiation of kinase inhibitor therapy. She had been treated with 6 prior neck surgeries (initial thyroidectomy and consecutive central and lateral lymph node dissections over the years), but her disease progressed including in the thorax and yet remained asymptomatic. Supra-physiologic doses of levothyroxine were administered for the purpose of TSH suppression, since DTC is known to express the TSH receptor in the cell membrane and can respond to TSH stimulation with cell growth [1]. The current American Thyroid Association (ATA) guidelines [1] suggest that high-risk thyroid cancers patients, such as this case, should be maintained at a goal of TSH suppression of below 0.1 mU/L, as relapse free survival is lower compared to patients with non-suppressed TSH [2, 3]. When our patient was first seen, however, her TSH was suppressed to 0.2 mIU/L. The patient herein presented showed structural disease response (Fig. 1, representative metastasis circled in red, red arrows indicate the passage of time) attained 3 months after adjusting levothyroxine from 125 to 150 mcg per day, wherein her TSH decreased from 0.2 to 0.02 mU/L (her thyroglobulin level was not assessable due to high level of thyroglobulin antibodies). By RECIST 1.1 (response evaluation in solid tumors) criteria, a partial response was attained (RECIST measurements 66.3% baseline), confirmed upon later imaging 4 months thereafter. This case illustrates the exquisite sensitivity of some DTCs to aggressive TSH suppression, something that is sometimes neglected in the setting of newly approved and effective, but