Castro, M. Regina

Abstract Modern AI-based clinical decision support models owe their success in part to the very large number of predictors they use. Safe and robust decision support, especially for intervention planning, requires causal, not associative, relationships. Traditional methods of causal discovery, clinical trials and extracting biochemical pathways, are resource intensive and may not scale up to the number and complexity of relationships sufficient for precision treatment planning. Computational causal structure discovery (CSD) from electronic health records (EHR) data can represent a solution, however, current CSD methods fall short on EHR data. This paper presents a CSD method tailored to the EHR data. The application of the proposed methodology was demonstrated on type-2 diabetes mellitus. A large EHR dataset from Mayo Clinic was used as development cohort, and another large dataset from an independent health system, M Health Fairview, as external validation cohort. The proposed method achieved very high recall (.95) and substantially higher precision than the general-purpose methods (.84 versus .29, and .55). The causal relationships extracted from the development and external validation cohorts had a high (81%) overlap. Due to the adaptations to EHR data, the proposed method is more suitable for use in clinical decision support than the general-purpose methods.

Abstract Objective: Transgender and gender-diverse individuals are at risk of insufficient treatment of endocrine diseases due to a number of barriers to care. There are currently no data evaluating the prevalence of thyroid disease in this population, and it is unknown if gender-affirming hormone therapy affects treatment of thyroid disease in these individuals. Methods: Utilizing a registry of 676 patients over 18 years of age who were seen in our Transgender and Intersex Specialty Care Clinic from 2015-2019, we identified 554 individuals seeking medical therapy for gender dysphoria/incongruence. Of these, 56 patients were taking thyroid hormone or antithyroid medications or had a coded diagnosis of thyroid disease; 2 were excluded as they were receiving thyroid hormone as adjunctive therapy for refractory depression. 54 patients were therefore analyzed with respect to thyroid disease (TD+), and compared to those 498 patients without thyroid disease (TD-) with regard to average vital signs, demographics, and presence of common comorbidities. Results: Fifty percent of our TD+ patients were recorded female sex at birth, and 98% were Caucasian. TD+ patients were much more likely to have essential hypertension (OR 5.99), to use tobacco (OR 2.23), and to be overweight or obese (OR 2.16) than TD- patients. Due to the evolving natural history of disease, some TD+ patients belonged to multiple categories: 48 patients, 26 trans feminine and 21 trans masculine, had hypothyroidism, of whom 41 had overt hypothyroidism and 2 patients had subacute thyroiditis that progressed to the hypothyroid phase of illness. 5 patients (3 trans masculine and 2 trans feminine) demonstrated hyperthyroidism, 4 of whom had Graves’ Disease. 2 patients had multinodular goiter, both trans masculine. 2 patients had thyroid malignancies, both trans feminine, of whom one had proven follicular thyroid carcinoma and the other had unspecified thyroid malignancy. Among hypothyroid patients, there was a slight non-significant trend toward increased thyroid hormone requirements while receiving treatment with estradiol or testosterone. Conclusion: To our knowledge, this represents the first attempt to characterize the prevalence of various thyroid disease states in the gender diverse population. Our data corresponded to a prevalence of hypothyroidism of approximately 8.7%, which is higher than previously published estimates of 3-5% in the general population. Whether this represents actual increased prevalence or assessment bias is uncertain. It is important for all health professionals who care for gender diverse people to identify and appropriately treat thyroid disease, and to monitor thyroid function closely if gender-affirming hormone therapy is initiated.

Objective Our aim was to determine the radiologic and clinicopathologic characteristics of thyroid nodules with focal 68Ga-DOTATATE activity. Methods In this retrospective study of 1927 consecutive 68Ga-DOTATATE PET scans, 85 patients with incidental and nonincidental focal 68Ga-DOTATATE avid thyroid nodules were identified, of which 31 patients with 33 thyroid nodules underwent fine-needle aspiration (FNA) or surgery. These 33 nodules were reviewed for Krenning score and SUVmax of the thyroid nodule, contralateral thyroid lobe and left atrium. Results Cytology/histopathology included 58% (19/33) with benign findings, 18% (6/33) medullary thyroid carcinoma (MTC), 9% (3/33) atypia or follicular lesion of undetermined significance (AUS/FLUS), 9% (3/33) suspicious for follicular neoplasm and Hurthle cell adenoma (SFN/HCA) and 6% (2/33) nondiagnostic cytology. Median serum calcitonin was 1156 pg/mL (range, 460–1828) in MTC and was <5.0 pg/mL (<5.0–12.5) in patients with benign nodules. Nodules had Krenning score of 1, 2 and 3 in 46% (15/33), 27% (9/33) and 27% (9/33). The majority of MTC and AUS/FLUS nodules had a Krenning score of 3, and there was substantial intragroup variation in Krenning score among the benign nodules. The mean SUVmax for the entire cohort was 5.5 ± 2.9 (mean ± SD), and the range was 2.0–13.0. There was overlap in the nodule/contralateral thyroid SUVmax ratios between groups. The MTC and AUS/FLUS nodules tended to have a higher nodule/blood pool SUVmax ratio than the other pathologic groups. Conclusion There was considerable variation in radiologic characteristics among benign thyroid nodules. The ratio of thyroid nodule SUVmax/blood pool SUVmax may be useful to differentiate pathologic groups, but larger studies are needed to investigate this further. Given the potential for malignancy in thyroid nodules with focal 68Ga-DOTATATE activity, further evaluation with serum calcitonin and FNA may be considered. Video Abstract: http://links.lww.com/NMC/A186

Background: Medullary thyroid cancer (MTC) can be associated with significant morbidity and mortality in advanced cases. Hence, we aimed to identify factors at the time of MTC surgery that predict overall survival (OS), disease-specific survival (DSS), locoregional recurrence/persistence (LR), and distant metastases (DM). Methods: We performed a retrospective study of clinicopathologic, radiological, and laboratory data in MTC patients who underwent thyroidectomy at Mayo Clinic from January 1995 to December 2015. Results: We identified 163 patients (mean age 48.4 years, 48% males), 102 with sporadic MTC and 61 with hereditary disease ( n = 46 multiple endocrine neoplasia [MEN] 2A, n = 3 MEN 2B, n = 12 familial MTC) with a median follow-up time of 5.5 years. On univariate analysis, age >55 years, male sex, DM at the time of surgery (M1), lateral neck lymph node (LN) involvement (N1b), gross extrathyroidal extension (ETE), American Joint Committee on Cancer (AJCC) stage 3/4, tumor size (T) 3/4, tumor size, and postoperative calcitonin (Ctn) and carcinoembryonic antigen (CEA) were significant predictors of worse OS and DSS. On multivariable analysis, both gross ETE (hazard ratio [HR] 4.62, 6.58) and M1 (HR 5.11, 10.45) remained significant predictors of worse OS as well as DSS, while age >55 years (HR 3.21), male sex (HR 2.42), and postoperative Ctn (HR 1.002 for every 100 pg/mL increase) were significant only for worse OS. On univariate analysis, male sex, M1, N1b, gross ETE, stage 3/4, T 3/4, tumor size, number of LNs involved, and postoperative Ctn were significant predictors of LR and DM; age >55 years was additionally significant for DM. On multivariable analysis, gross ETE (HR 3.16, 5.93) and N1b (HR 4.31, 4.64) remained significant predictors of LR and DM; ratio of resected/involved LN (HR 10.91) was additionally predictive for LR and postoperative Ctn (HR 1.003 for every 100 pg/mL increase) for DM. Conclusions: Disease burden at initial surgery, especially gross ETE, lateral neck LN involvement, and DM, as well as the biochemical response to surgery appear to be more important than demographic factors in terms of MTC prognosis. These findings highlight the importance of rigorous perioperative assessment to better predict MTC outcomes.

Abstract Background Currently acceptable management options for patients with adult papillary thyroid microcarcinoma (APTM) range from immediate surgery, either unilateral lobectomy or bilateral lobar resection, to active surveillance (AS). An alternative minimally invasive approach, originally employed for eliminating neck nodal metastases, may be ultrasound-guided percutaneous ethanol ablation (EA). Here we present our experience of definitively treating with EA 15 patients with APTM. Patients and Methods During 2010 through 2017, the 15 cT1aN0M0 patients selected for EA were aged 36 to 86 years (median, 45 years). Tumor volumes (n = 17), assessed by sonography, ranged from 25 to 375 mm3 (median, 109 mm3). Fourteen of 15 patients had 2 ethanol injections on successive days; total volume injected ranged from 0.45 to 1.80 cc (median, 1.1 cc). All ablated patients were followed with sonography and underwent recalculation of tumor volume and reassessment of tumor perfusion at each follow-up visit. Results The ablated patients have now been followed for 10 to 100 months (median, 64 months). There were no complications and no ablated patient developed postprocedure recurrent laryngeal nerve dysfunction. All 17 ablated tumors shrank (median 93%) and Doppler flow eliminated. Median tumor volume reduction in 9 identifiable avascular foci was 82% (range, 26%-93%). After EA, 8 tumors (47%) disappeared on sonography after a median of 10 months. During follow-up no new PTM foci and no nodal metastases have been identified. Conclusions Definitive treatment of APTM by EA is effective, safe, and inexpensive. Our results suggest that, for APTM patients who do not wish neck surgery and are uncomfortable with AS, EA represents a well-tolerated and minimally invasive outpatient management option.

Background: Levothyroxine (LT4) is the mainstay of therapy for hypothyroidism. Yet, despite physician efforts at dose titration, some patients remain hypothyroid on LT4 doses in excess of weight-based calculations, a condition known as refractory hypothyroidism. The LT4 absorption test (LT4AT) has been proposed to have utility in these patients by enabling distinction of LT4 malabsorption from pseudomalabsorption, a condition of intentional nonadherence. Given its rare use in clinical practice, we reviewed our institution's experience with the LT4AT to assess its impact on management of refractory hypothyroidism. Methods: We reviewed the charts of 16 patients diagnosed with refractory hypothyroidism and who had completed the LT4AT between January 2015 to January 2019. The primary aim was to determine the utility of this test in distinguishing LT4 malabsorption from pseudomalabsorption. Secondary aims were to determine whether the results of this test impacted physicians' management decisions, as well as to report on clinical outcomes at follow-up. Our LT4AT is a six-hour test wherein patients receive a weight-based dose of LT4 followed by serial measurements of total thyroxine (TT4) and thyrotropin (TSH). Percentage absorption is calculated using the following formula, with normal absorption being ≥60%: Results: Percentage absorption was calculated in 13 of 16 patients due to lack of TT4 data for 3 patients. Absorption was impaired in one patient (% absorbed = 0), who had known causes of malabsorption. The remaining 12 patients had normal absorption by hour 4 of the test (% absorption 60–158) in conjunction with upward TT4 trends. Clinical follow-up ranged from 1 to 32 months (median 6.5 months), with 11 patients having follow-up data. Six of these had normal or suppressed TSH values at most recent follow-up, and four had improved but persistent TSH elevations. The one said patient with malabsorption improved with intravenous LT4. Conclusions: The LT4AT can provide valuable information for distinguishing malabsorption from pseudomalabsorption. Our findings support the combined use of calculated percentage absorptions with TT4 trends for at least a four-hour time frame when making determinations regarding absorption.