Search

Context Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. Objective (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. Methods (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. Results (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. Conclusion We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Thyroid nodules are common, usually asymptomatic, and often pose minimal risk to the affected patient. However, 10-15% prove malignant and serve as the rationale for diagnostic assessment. Safely identifying and treating a relevant thyroid cancer through a cost-effective process is the primary goal of the treating practitioner. Ultrasound is the principal means of initial nodule assessment and should be performed when any thyroid nodule is suspected. Fine-needle aspiration provides further cytological determination of benign or malignant disease and is generally applied to nodules larger than 1-2 cm in diameter, on the basis of holistic risk assessment. The Bethesda System for Reporting Thyroid Cytopathology provides standardised terminology, which enhances communication among health-care providers and patients. Benign cytology is highly accurate, whereas indeterminate cytology could benefit from further application of molecular testing. The ultimate goal of diagnostic assessment of thyroid nodules is to accurately identify malignancy while avoiding overtreatment. Low-risk thyroid nodules can be safely monitored in many patients with minimal diagnostic intervention.

In the past 30 years, there has been a substantial rise in the detection of thyroid nodules. Largely asymptomatic, thyroid nodules are most often incidental findings that typically pose minimal risk. Data supporting these findings show a rapid rise in the incidental detection of thyroid nodules and cancer, but minimal effect on mortality rates, despite treatment. These data imply that historical approaches to thyroid nodule and cancer care might at times include unnecessary or excessive care. To address this issue, the past decade has witnessed an increasingly conservative approach to nodule management, seeking to individualise care and provide the most focused intervention that leads to favourable outcomes. Benign nodules can be safely monitored with minimal, or long-interval follow-up imaging. Molecular testing should be considered for cytologically indeterminate nodules because of its ability to improve preoperative cancer risk determination and reduce unnecessary surgery. The treatment of biopsy-proven malignant nodules has become increasingly nuanced, since recommendations for near-total thyroidectomy are no longer routine. Hemithyroidectomy is now commonly considered when operative intervention is favoured. Some patients with small volume, isolated cancerous nodules are safely managed non-operatively with active monitoring. In summary, modern management strategies for thyroid nodular disease seek to incorporate the growing amount of available diagnostic and prognostic data, inclusive of demographic, radiological, pathological and molecular findings. Once obtained, an individualised management plan can be effectively formulated.

Supplementary Table S2. Clinical response and outcomes to everolimus in patients with advanced differentiated thyroid cancers by histologic subgroup

Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.

Comparison of minor allele frequencies between additional oncogenic mutations and BRAFV600E.

Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results: Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions: BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC. Clin Cancer Res; 23(9); 2367–73. ©2016 AACR.

Purpose:The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes.Experimental Design:We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations.Results:Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043).Conclusions:Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

Supplementary Figure 1 The most frequent phylogenetic tree based on sampling mutations according to their detection power (276/1000 samples). Supplementary Figure 2 Allelic copy number profiles generated by ABSOLUTE (see Methods).

Comparison of clinical and pathological features of thyroid cancer patients with BRAF mutations only versus BRAF plus additional mutations.

Context Predictive models of thyroid nodule cancer risk are presently based upon nodule composition, echogenicity, margins, and the presence of microcalcifications. Nodule shape has shown promise to be an additive factor helping determine the need for nodule biopsy. Objective We sought to determine if calculation of a nodule’s spherical shape independently associates with cancer risk. Methods This prospective cohort study, conducted at a single large academic healthcare system in the United States, included patients with 1 or 2 clinically relevant thyroid nodules (predominantly solid and over 1 cm) presenting for diagnostic evaluation. Thyroid ultrasound, cytological evaluation with fine-needle biopsy, and/or histopathological examination on occasion of thyroid surgery were performed. We calculated the nodule’s long to short ratio (spherical shape), and its association with tissue proven benign or malignant endpoints. Results The long to short nodule ratio was significantly lower in malignant compared to benign nodules indicating greater risk of malignancy in more spherical nodules (1.63 ± 0.38 for malignant nodules vs 1.74 ± 0.47 for benign, P 2.00, 14.6% cancer; ratio 1.51-2.00, 19.7%; ratio 1.00-1.50, 25.5%, P Conclusion The more a thyroid nodule is spherically shaped, as indicated by a long to short ratio approaching 1.0, the greater its risk of malignancy. This was independent of age, sex, and nodule size. Incorporating a nodule’s sphericity in the risk stratification systems may improve individualized clinical decision making.

The Association of American Medical College (AAMC) requires all students to demonstrate four core attributes: knowledge, skills, altruism and dutifulness. A formal service-learning curriculum may serve to explicitly foster altruism and dutifulness in the affective domain of Bloom's taxonomy as well as proactively improve student well-being.All Harvard Medical School students enrolled in the Principal Clinical Experience (PCE) programme in the 2018-2019 academic year at Brigham and Women's Hospital were excused from clerkship responsibilities and given the opportunity to participate in a half-day team-based community-service intervention at a not-for-profit organisation in Boston, MA. Following the service-learning initiative, we examined student compassion, civic responsibility, well-being and team cooperativeness using validated survey questions, supplemented by free-text feedback.Forty-five of the 55 PCE students (82%) attended the outing. Overall, 68% of students found the outing to be valuable and 23% somewhat valuable. On a scale of 0-20, students reported very high self-perception of compassion (mean = 19.9), civic responsibility (mean = 19.7) and team development and composition (mean = 19.1), after the event. Students reported lower perceptions of personal well-being (mean = 17.5), but emotional wellness was the most frequently mentioned theme in open response.Incorporation of a team-based service-learning activity contributes to the students' community understanding, empathy and class team building. Utilisation of a published framework in the development of this initiative likely contributed to its success. Given our findings, we plan further expansion of this service learning longitudinally through the 4-year curriculum to potentially strengthen the affective domain for students further.

Communities of practice foster knowledge sharing, scholarly collaboration, mentoring and professional identify formation. Easier access to technology overall and the desire to engage with peers during the pandemic have increased opportunities to engage in virtual global conversations.The Brigham Education Institute designed and implemented a series of six bimonthly, 1-hour 'Global Medical Education Cafés' between September 2020 and June 2021. They were offered on the Zoom platform and featured a core educational topic led by one or two discussants, followed by small group interactions surrounding specific questions or challenges. Discussants were selected based on their international reputation and recognition as health professions education scholars and leaders with expertise in specific areas. Each café was advertised through newsletters, social media, educational email lists and open to educators from any healthcare discipline or geographical region.Between 26 and 41 participants attended each session from 12 countries representing five continents. Content analysis of preliminary education evaluation data from chats and reflective narratives identified four key themes: (1) exciting interactive format; (2) sense of worldwide community; (3) safe space for conversations; and (4) strong moderators facilitating engaging peer conversations.The series leaders aimed to emphasise inclusive, non-hierarchical and cross-cultural conversations. Preliminary evaluation suggests that this goal was achieved; these will remain priorities in future series. Educators worldwide can organise similar events with minimal resources. A safe space for conversations and open-mindedness to learning from a variety of learning and societal cultures are likely essential elements for success.

Purpose: The extent to which routine genomic sequencing can identify relevant secondary genomic alterations among BRAFV600E-mutant papillary thyroid carcinoma (PTC) is unknown. Such markers would prove highly valuable for prognostic purposes. Experimental Design: We reviewed clinicopathologic data of 225 patients with BRAFV600E-mutant PTC and integrated them with genomic data derived from targeted next-generation sequencing (NGS) on tumor specimens. We defined patient subgroups based on bona fide secondary oncogenic events (separate from BRAFV600E) and compared their clinical features and outcomes with those without additional oncogenic alterations. Results: Additional oncogenic alterations were identified in 16% of tumors. Patients in the “BRAF+additional mutations” group were more likely to be at high American Thyroid Association (ATA) risk of recurrence (48.6% vs. 17.6%; P = 0.0009), had larger baseline tumor (2.7 vs. 1.9 cm; P = 0.0005) and more advanced stage at presentation (14.3% vs. 1.1% stage 4; P < 0.0001). Importantly, over a 65-month follow-up, disease-specific mortality (DSM) was increased when additional mutations were identified (13.8% vs. 1.4% in the BRAF-only group; P = 0.005). Separately, we identified a subcluster of patients harboring oncogenic mutations in key effectors of the PI3K/AKT/mTOR pathway, which were independently associated with DSM (OR = 47.9; 95% confidence interval, 3.5–1,246.5; P = 0.0043). Conclusions: Identification of additional PIK3/AKT/mTOR alterations in patients with BRAFV600E-mutant PTC provides important and actionable prognostic risk stratification. These data support genomic profiling of PTC tumors to inform prognosis and clinical strategy.

Context There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. Objective This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals. Methods This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes. Results Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals. Conclusion Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

Less aggressive treatment options, including hemithyroidectomy and active surveillance, have been accepted as treatment options for low-risk small, differentiated thyroid carcinoma (DTC). Multiple studies have shown a low rate of cancer growth and lymph node metastases and no evidence of distant metastases during active surveillance of low-risk small DTC. However, not all patients with low -risk small DTC are ideal or appropriate candidate for active surveillance. Patients with thyroid cancer adjacent to either the trachea or recurrent laryngeal nerve or those with evidence of extrathyroidal extension, a high-risk molecular profile, lymph node, or distant metastases are considered inappropriate candidates for active surveillance. In addition, there are other essential factors that clinicians should consider while recommending active surveillance, including patient financial and insurance status; availability of high-quality neck ultrasounds and experienced radiologists, endocrinologists, and surgeons; and patient preference, level of anxiety, and willingness to undergo prolonged surveillance and follow-up imaging.

BACKGROUND Strategies for integrating artificial intelligence (AI) into thyroid nodule management require additional development and testing. We developed a deep-learning AI model (ThyNet) to differentiate between malignant tumours and benign thyroid nodules and aimed to investigate how ThyNet could help radiologists improve diagnostic performance and avoid unnecessary fine needle aspiration. METHODS ThyNet was developed and trained on 18 049 images of 8339 patients (training set) from two hospitals (the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, and Sun Yat-sen University Cancer Center, Guangzhou, China) and tested on 4305 images of 2775 patients (total test set) from seven hospitals (the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China; the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; the Guangzhou Army General Hospital, Guangzhou, China; the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; the First Affiliated Hospital of Sun Yat-sen University; Sun Yat-sen University Cancer Center; and the First Affiliated Hospital of Guangxi Medical University, Nanning, China) in three stages. All nodules in the training and total test set were pathologically confirmed. The diagnostic performance of ThyNet was first compared with 12 radiologists (test set A); a ThyNet-assisted strategy, in which ThyNet assisted diagnoses made by radiologists, was developed to improve diagnostic performance of radiologists using images (test set B); the ThyNet assisted strategy was then tested in a real-world clinical setting (using images and videos; test set C). In a simulated scenario, the number of unnecessary fine needle aspirations avoided by ThyNet-assisted strategy was calculated. FINDINGS The area under the receiver operating characteristic curve (AUROC) for accurate diagnosis of ThyNet (0·922 [95% CI 0·910-0·934]) was significantly higher than that of the radiologists (0·839 [0·834-0·844]; p

Background: Insufficient or excessive iodine intake during gestation may compromise adaptive mechanisms in maternal thyroid function and lead to adverse pregnancy outcomes. In this context, we aime...

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-Analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-Analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb-And TgAb-positive women are needed to fully understand the spectrum of phenotypes.

Background Planar scintigraphy has long been indicated in patients receiving I-131 therapy for thyroid cancer to determine the anatomic location of metastases. We studied our experience upon implementing additional single-photon emission (SPECT)-CT scanning in these patients. Method We performed a retrospective study of consecutive adult patients with newly diagnosed thyroid cancer treated with I-131 between 2011 and 2017. Radiologic findings detected with planar scintigraphy alone vs those identified with SPECT-CT scanning were primary endpoints. Result In this study, 212 consecutive patients with thyroid cancer were analyzed in two separate cohorts (107 planar scintigraphy alone and 105 planar scintigraphy with SPECT-CT). The addition of SPECT-CT resulted in more findings, both thyroid-related and incidental. However, we identified only 3 of 21 cases in which SPECT-CT provided an unequivocal additional benefit by changing clinical management beyond planar scintigraphy alone. No difference in the detection of distant metastatic disease or outcome was identified between cohorts. Conclusion Synergistic SPECT-CT imaging in addition to planar nuclear scintigraphy adds limited clinical value to thyroid cancer patients harboring a low risk of distant metastases, while frequently identifying clinically insignificant findings. These data from a typical cohort of patients receiving standard thyroid cancer care provide insight into the routine use of SPECT-CT in such patients.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT(4) concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT(4) concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

PURPOSE The authors describe the implementation of the novel Longitudinal Clinical Experiences with Patients (LCEP) curriculum, designed to integrate continuity and longitudinal patient relationships into a traditional block clerkship (BC)-and present a mixed-methods analysis evaluating program effectiveness to assess its feasibility, value, and impact. METHOD This was a mixed-methods study of 54 Harvard Medical School students who participated in the LCEP during their core clerkship (third) year during the 2013-2014 academic year. Fifty-two students responded to an electronic survey about the patients they followed during the LCEP. Forty-two students completed confidential live interviews. Unique groups of 13-15 students were interviewed at three times during the year to assess students' perceptions of the LCEP over time. The data were analyzed using a content analysis framework. RESULTS On average, students followed 3.3 LCEP patients over the clerkship year. Ninety-four percent (n = 49/52) of students were able to follow two or more patients longitudinally. Most students met their longitudinal patient in the inpatient setting (71%, n = 37/52). Subsequent encounters were most often in the ambulatory setting. Students described scheduling logistics as key to the success or failure of the program. Many students described the challenges of competing priorities between their block clerkship responsibilities and longitudinal opportunities. Students found the LCEP deepened their understanding of the patient experience, the health care system, and disease progression. Over the course of an academic year, an increased proportion of students (60%) highlighted understanding the patient experience as a core value obtained through the LCEP. CONCLUSIONS The LCEP was feasible and proved successful in promoting longitudinal patient relationships within a traditional BC model. Prioritizing the depth of experience with a smaller number of patients may reduce the barriers described by students. The results suggest that such a hybrid program promotes patient-centeredness.

The 2015 American Thyroid Association (ATA) guidelines recommended that low-risk, differentiated thyroid cancers (DTC) between 1 and 4 cm may be treated with thyroid lobectomy alone. We sought to determine the effect of these guideline changes on the rate of completion thyroidectomy (CT) for low-risk DTC and factors influencing surgical decision-making. All patients from 2014 to 2018 who received an initial thyroid lobectomy at our institution with final pathology demonstrating DTC were included. Patients were divided into “pre” and “post” guideline cohorts (2014–2015 and 2016–2018, respectively). The rate of CT was compared between the two cohorts. Patient demographics and tumor characteristics were examined for association with CT. A total of 163 patients met study criteria: 63 patients in the 2014–2015 (“pre”) and 100 in the 2016–2018 (“post”) group. In the “pre” period, 41 (65.1%) patients received CT compared with 43 (43.0%) in the “post” period (p

Although prior studies have reported that patients with anaplastic thyroid carcinoma (ATC) with a focal anaplastic component may have a prolonged survival compared to other ATC patients, the outcome data are limited. We evaluated a cohort of ATC resected between 2003 and 2018. Tumor slides were reviewed to confirm the diagnosis and to identify cases with a minor ATC component (defined as comprising < 10% of the tumor). We evaluated the clinical outcome of these patients compared to that of all other cohort patients (characterized as having conventional ATC). Our cohort was composed of 24 cases of ATC that underwent resection, including 8 (33%) with a minor ATC component. Tumors with a minor ATC component were predominantly associated with papillary thyroid carcinoma. For patients with tumors with a minor ATC component, the 1-year and 2-year survival rates and median survival for patients who died of disease were 88%, 43%, and 17 months (range 6-73 months), respectively. In comparison, for patients with conventional ATC, the 1-year and 2-year survival rates and median survival for patients who died of disease were 56%, 44%, and 7 months (range 2-26 months), respectively. There was no difference in 1- and 2-year survival or overall survival by Kaplan-Meier analysis for patients with tumors with a minor ATC component and those with conventional ATC. In conclusion, the difference in overall survival between ATC groups in our cohort was not significant; however, this could be due to the small cohort size or due to characteristics of our group with a minor ATC component; that is, no tumors in this group were limited to the thyroid (stage IVA), resectability with negative margins was infrequent, and 38% of this group had distant metastases at diagnosis (stage IVC).

AIMS Hobnail variant of papillary thyroid carcinoma (PTC) is an aggressive PTC subtype characterised by a hobnail cytomorphology. However, some classic PTC have a 'hobnail-like' cytomorphology associated with thick, hyalinised, variably oedematous fibrovascular cores that appears to be a form of ischaemic/degenerative atypia. METHODS AND RESULTS We studied three cohorts to compare the histopathological characteristics and clinical outcome of 'hobnail-like' classic PTC and true hobnail variant of PTC: cohort 1, PTC consecutively resected between 2016 and 2017 (to assess frequency of 'hobnail-like' cytomorphology); cohort 2, 20 'hobnail-like' classic PTC resected between 2005 and 2007 (to assess clinical outcome); and cohort 3, seven true hobnail variant of PTC. A 'hobnail-like' cytomorphology was identified in 16% of consecutively resected PTC. Compared with true hobnail variant, 'hobnail-like' classic PTC occurred in younger patients (mean age 40 years versus 68 years, P

As the U.S. health care system changes and technology alters how doctors work and learn, medical schools and their faculty are compelled to modify their curricula and teaching methods. In this article, educational leaders and key faculty describe how the Pathways curriculum was conceived, designed, and implemented at Harvard Medical School. Faculty were committed to the principle that educators should focus on how students learn and their ability to apply what they learn in the evaluation and care of patients. Using the best evidence from the cognitive sciences about adult learning, they made major changes in the pedagogical approach employed in the classroom and clinic. The curriculum was built upon 4 foundational principles: to enhance critical thinking and provide developmentally appropriate content; to ensure both horizontal integration between courses and vertical integration between phases of the curriculum; to engage learners, foster curiosity, and reinforce the importance of student ownership and responsibility for their learning; and to support students' transformation to a professional dedicated to the care of their patients and to their obligations for lifelong, self-directed learning.The practice of medicine is rapidly evolving and will undoubtedly change in multiple ways over the career of a physician. By emphasizing personal responsibility, professionalism, and thinking skills over content transfer, the authors believe this curriculum will prepare students not only for the first day of practice but also for an uncertain future in the biological sciences, health and disease, and the nation's health care system, which they will encounter in the decades to come.

Background Medical educators struggle to incorporate socio-cultural topics into crowded curricula. The “continuum of learning” includes undergraduate and graduate medical education. Utilizing an exemplar socio-cultural topic, we studied the feasibility of achieving expert consensus among two groups of faculty (experts in medical education and experts in social determinants of health) on which aspects of the topic could be taught during undergraduate versus graduate medical education. Methods A modified Delphi method was used to generate expert consensus on which learning objectives of social determinants of health are best taught at each stage of medical education. Delphi respondents included experts in medical education or social determinants of health. A survey was created using nationally published criteria for social determinants of health learning objectives. Respondents were asked 1) which learning objectives were necessary for every physician (irrespective of specialty) to develop competence upon completion of medical training and 2) when the learning objective should be taught. Respondents were also asked an open-ended question on how they made the determination of when in the medical education continuum the learning objective should be taught. Results 26 out of 55 experts (13 social determinants of health and 13 education experts) responded to all 3 Delphi rounds. Experts evaluated a total of 49 learning objectives and were able to achieve consensus for at least one of the two research questions for 45 of 49 (92%) learning objectives. 50% more learning objectives reached consensus for inclusion in undergraduate (n = 21) versus graduate medical education (n = 14). Conclusions A modified Delphi technique demonstrated that experts could identify key learning objectives of social determinants of health needed by all physicians and allocate content along the undergraduate and graduate medical education continuum. This approach could serve as a model for similar socio-cultural content. Future work should employ a qualitative approach to capture principles utilized by experts when making these decisions.

Graves' disease (GD) is caused by the stimulation of thyrotropin receptors by autoantibodies. We compared the diagnostic accuracy of the thyroid-stimulating immunoglobulin (TSI) bioassay and thyrotropin-binding inhibitory immunoglobulin (TBII) assay in differentiating GD from other causes of thyrotoxicosis.We retrospectively evaluated 493 patients with thyrotoxicosis who were tested with the third-generation TSI and TBII assays simultaneously. Patients were classified according to the clinical, histopathologic, and imaging criteria into the following groups: positive reference group (PRG) (patients with GD), negative reference group (NRG) (patients without GD), and inconclusive group (patients without a definitive diagnosis).TSI and TBII assays were concordant in 88% of the cases and showed a strong positive correlation (rTSI and TBII assays showed similar performance in differentiating GD from other causes of thyrotoxicosis in a real-world sample of patients with active thyrotoxicosis. In combination, both tests showed little benefit compared with the TBII assay alone. Thyrotropin receptor antibody assay results should be carefully interpreted in patients with mild GD or longstanding disease.

Background The COVID-19 pandemic is unprecedented in terms of the extent and rapidity of the disruption forced upon formal clinical education, most notably the extensive transition of clinical skills learning to interactive video-based clinical education. Methods In a phenomenologic study, we used thematic analysis to explore the COVID-19 disruption to clinical training and understand processes relating to adaptation in a large academic medical center. We conducted semi-structured interviews with 14 clinical teachers and 16 trainees representing all levels of clinical learning. Interviews occurred within the initial three months of the crisis, and data were analyzed following a thematic analysis coding process. Results We constructed eight themes synthesizing our participants’ perceptions of the immediate unanticipated disruption, noting in the process their alignment with a change management framework. These included: urgency in adapting, with an obvious imperative for change; overcoming inconsistent involvement and support through the formation of self-organized frontline coalitions; attempts to develop strategy and vision via initially reactive but eventually consistent communication; empowering a volunteer army through co-creation and a flattened hierarchy; and efforts to sustain improvement and positive momentum with celebration of trial, error, and growth. The majority of participants found positive outcomes resulting from the tumultuous change process. Moreover, they were now more readily accepting of change, and tolerant of the ambiguous and iterative nature inherent in the education change process. Many anticipated that some innovation would, or would at least deserve to, continue post- crisis. Conclusions The COVID-19 pandemic afforded an opportunity to study the content and process of change during an active crisis. In this case of clinical education, our findings provide insight into the ways an academic medical system adapts to unanticipated circumstances. We found alignment with broader organizational change management models and that, compared with crisis management models (and their shorter term focus on resolving such crises), stakeholders self-organized in a reliable manner that carries the potential advantage of preserving such beneficial change.

Objective To investigate the concordance of serologic and sonographic evidence of Hashimoto’s thyroiditis with its gold standard histopathologic identification. Design We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto’s thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance. Results Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto’s thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto’s thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto’s thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto’s thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb. Conclusion Only moderate concordance exists between serological evidence of Hashimoto’s thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.

Thyroid nodules and thyroid cancer are common conditions and may be identified during pregnancy. The comprehensive evaluation of thyroid nodules during pregnancy includes a medical history, physical examination, ultrasound assessment, and (when indicated) an ultrasound-guided fine-needle aspiration biopsy. Most thyroid cancers detected during pregnancy will not grow nor pose significant risk during gestation, and thyroid surgery in pregnant women poses higher risks than in nonpregnant women. Through a balanced and informed approach to the clinical care of this unique population, outcomes can be optimized for both the mother and the fetus.

Background: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is used to interpret fine-needle aspiration (FNA) cytology of thyroid nodules in children and adults. Nodule management is guided by the implied malignancy risk of each cytological category, which has been derived from adult populations. Whether these implied risks are applicable to pediatric thyroid nodules remains uncertain. We compared malignancy rates between pediatric and adult thyroid nodules within each cytological category. Methods: We evaluated consecutive thyroid nodules ≥1 cm that underwent FNA at the Boston Children's Hospital and Brigham and Women's Hospital from 1998 to 2016. All cytology was interpreted by a single cytopathology group according to the BSRTC. Malignancy rates were compared between pediatric (

Background: Prior studies have reported mutations in mismatch repair (MMR) genes in a small subset of anaplastic thyroid carcinomas (ATC). The aim of this study was to identify MMR-protein-deficien...

Context The impact of Hashimoto thyroiditis (HT) on the risk of thyroid cancer and its accurate detection remains unclear. The presence of a chronic lymphocytic infiltration imparts a logical mechanism potentially altering neoplastic transformation, while also influencing the accuracy of diagnostic evaluation. Methods We performed a prospective, cohort analysis of 9851 consecutive patients with 21,397 nodules ≥1 cm who underwent nodule evaluation between 1995 and 2017. The definition of HT included (i) elevated thyroid peroxidase antibody (TPOAb) level and/or (ii) findings of diffuse heterogeneity on ultrasound, and/or (iii) the finding of diffuse lymphocytic thyroiditis on histopathology. The impact of HT on the distribution of cytology and, ultimately, on malignancy risk was determined. Results A total of 2651 patients (27%) were diagnosed with HT, and 3895 HT nodules and 10,168 non-HT nodules were biopsied. The prevalence of indeterminate and malignant cytology was higher in the HT vs non-HT group (indeterminate: 26.3% vs 21.8%, respectively, P < 0.001; malignant: 10.0% vs 6.4%, respectively, P < 0.001). Ultimately, the risk of any nodule proving malignant was significantly elevated in the setting of HT (relative risk, 1.6; 95% CI, 1.44 to 1.79; P < 0.001), and was maintained when patients with solitary or multiple nodules were analyzed separately (HT vs non-HT: 24.5% vs 16.3% solitary; 22.1% vs 15.4% multinodular; P < 0.01). Conclusion HT increases the risk of thyroid malignancy in any patient presenting for nodule evaluation. Diffuse sonographic heterogeneity and/or TPOAb positivity should be used for risk assessment at time of evaluation.

Background US of the thyroid bed in patients with thyroid cancer often depicts small lesions, but it is unclear whether US characteristics of lesions can help predict cancer recurrence. Purpose To determine whether size or US features of lesions in the thyroid bed after thyroidectomy in conjunction with clinical features can help predict thyroid cancer recurrence. Materials and Methods With use of a US reporting database, all patients imaged between July 2006 and June 2016 with an indication of post-thyroidectomy follow-up were retrospectively identified. Recorded data included patient demographic characteristics; date of thyroidectomy; thyroid cancer type; presence, size, and US characteristics of thyroid bed lesions; and results of fine-needle aspiration (FNA). Images were reviewed for lesions that underwent FNA. The Fisher exact test was used for analysis. Results A total of 1885 patients (mean age ± standard deviation, 48 years ± 15; 1493 female patients) underwent 5732 US examinations. Most patients (1541 of 1885 [82%]) had papillary cancer. Overall, 3163 thyroid bed lesions were reported in 5732 US examinations (40.4%). More than half of these lesions (1860 of 3163 [58.8%]) had a maximum measurement of 6 mm or greater. FNA was performed in 144 of the 3163 lesions (4.6%), of which 61 (42.4%) were malignant, 33 (22.9%) were benign, and 50 (34.7%) were nondiagnostic. Five nondiagnostic lesions eventually proved malignant. Only the presence of punctate echogenicities in the lesion (28 of 61 malignant lesions [45.9%]; three of 33 benign lesions [9%]; 12 of 50 nondiagnostic lesions [24%]; P < .001) or the history of positive lymph nodes at thyroidectomy (44 of 61 malignant lesions [72.1%]; 10 of 33 benign lesions [30%]; 19 of 50 nondiagnostic lesions [38%]; P < .001) were associated with malignancy. Of 3019 thyroid bed lesions that did not undergo FNA, three were malignant and 2248 showed no growth at follow-up US ranging from 6 months to 10 years and are presumed benign. Of the 1303 lesions smaller than 6 mm, only two (0.2%) were malignant. Conclusion Small lesions are commonly found in the thyroid bed after thyroidectomy, and most are likely to be benign. Lesions smaller than 6 mm with no punctate echogenicities had a minimal risk for malignancy. © RSNA, 2021 See also the editorial by Grant and Malhi in this issue.

Background: Similar to poorly differentiated thyroid carcinoma (PDTC), papillary thyroid carcinoma with high-grade features (PTC HGF) demonstrates increased mitotic activity and/or necrosis; howeve...

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birth weight but there are still important knowledge gaps regarding the impact of subclinical thyroid function test abnormalities on birth weight, in general or during the late second and third trimester of pregnancy, remains unknown. The aim of this study was to examine associations of maternal thyroid function with birth weight. METHODS: For this individual-participant data meta-analysis we searched Medline (Ovid), Embase.com, Web-of-Science, Cochrane CENTRAL and Google Scholar from inception to March 18(th) 2018, and published open invitations to join the Consortium on Thyroid and Pregnancy, to identify prospective cohort studies with data on maternal thyroid function during pregnancy and birth weight. We excluded participants with multiple pregnancies, in vitro fertilization, pre-existing thyroid disease or thyroid medication usage, miscarriages and stillbirth. Main outcomes were small for gestational age (SGA), large for gestational age (LGA) (defined by the lowest or highest 10(th) population-specific percentile of birth weight standardized to gestational age and sex, respectively) and birth weight. We analysed individual participant data using mixed-effects regression models adjusting for maternal age, body mass index, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex and gestational age at birth (the latter two only in case of birth weight continuously). The study protocol was pre-registered at the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42016043496. RESULTS: From 2,526 published reports, 36 cohorts met the inclusion criteria and were invited to participate of which 15 agreed and after addition of 5 unpublished datasets, a total of 20 cohorts were included. After exclusions, the study population comprised 48,145 mother-child pairs of whom 1,275 (3·1%) had subclinical hypothyroidism (increased TSH with normal FT4) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA compared to euthyroidism (11·8% vs. 10·0% respectively, adjusted risk difference 2·4% [95% CI, 0·4 to 4·8]; odds ratio (OR) 1·24 [95% CI 1·04 to 1.48], P=0·015) and lower mean birth weight (adjusted risk difference −38g [95% CI −61 to −15], P=0·001) with a higher effect estimate for measurement in the 3(rd) trimester compared with the 1(st) or 2(nd) trimester. Isolated hypothyroxinaemia was associated with a lower risk of SGA compared to euthyroidism (7·3% vs. 10·0%, adjusted risk difference −2·9 [95% CI, −4·5 to −0·9]; OR, 0·70 [95% CI 0·55 to 0·91], P=0·007) and higher mean birth weight (difference, 45g [95% CI 18 to 73], P=0·001). Each 1-SD higher maternal TSH concentration was associated with lower birth weight (−6g [−10 to −2], per SD, P=0·003), with higher effect estimates in TPOAb-positive than TPO-negative women (P for interaction=0·10). Each 1-SD higher FT4 concentration was associated with lower birth weight (−21g [95% CI −25 to −17] per SD, P