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Andrew G Gianoukakis,1 Natalia M Flores,2 Corey L Pelletier,3 Anna Forsythe,3 Gregory R Wolfe,2 Matthew H Taylor41Division of Endocrinology and Metabolism, Harbor-UCLA Medical Center, The University of California, Los Angeles, 2Health Outcomes Research, Kantar Health, Foster City, CA, 3Global Value and Access, Eisai, Inc., Woodcliff Lakes, NJ, 4Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USABackground: Patients with differentiated thyroid cancer (DTC) often respond well to treatment but some become refractory to radioactive iodine (RAI) treatment, and treatment options are limited. Despite the humanistic and economic burden RAI refractory disease imposes on patients, published research concerning treatment patterns and health care resource utilization is sparse.Methods: Data were collected from an online retrospective chart review study in the US and five European Union (EU) countries (France, Germany, Italy, Spain, and UK) with physicians recruited from an online panel. Physicians (N=211) provided demographics, disease history, treatment information, and health care resource utilization for one to four of their patients with radioactive iodine refractory differentiated thyroid cancer (RR-DTC).Results: The majority of the patients with RR-DTC (N=623) were female (56%), and their mean age was 58.2 years. In this sample, 63.2% had papillary thyroid cancer and 57.0% were in Stage IV when deemed RAI refractory. Patients with RR-DTC experienced regional recurrence in the thyroid bed/central neck area (25.3%) and had distant metastatic disease (53.6%). At the time data were collected, 50.7% were receiving systemic treatment. Of those, 78.5% were on first-line treatment and 62.7% were receiving multikinase inhibitors. Regional differences for prescribed treatments were observed; the US was more likely to have patients receiving multikinase inhibitors (79.2%) compared with UK (41.2%) and Italy (17.1%). Additional details regarding treatment patterns and resource utilization are discussed.Conclusion: The current study aimed to obtain a greater understanding of RR-DTC treatment globally. These results can assist in the development and implementation of treatment guidelines and ultimately enhance the care of patients with RR-DTC.Keywords: thyroid cancer, disease burden, therapy options, cost of illness

Purpose: Lenvatinib, a potent multikinase inhibitor, improves progression-free survival (PFS) in patients with radioiodine (RAI)-refractory differentiated thyroid cancer; however, most patients experience disease progression, warranting further therapy. We evaluated the efficacy and safety of lenvatinib plus pembrolizumab in these patients., Patients and Methods: We enrolled patients with progressive, RAI-refractory differentiated thyroid cancer who were either naïve to multikinase inhibitors (cohort 1) or who had progressed on lenvatinib (cohort 2). Patients received oral lenvatinib daily (cohort 1, 20 mg; cohort 2, dose at progression) and intravenous pembrolizumab (200 mg) every 21 days., Results: In cohorts 1 and 2, 30 and 27 patients were enrolled, respectively. Adverse events were consistent with those observed in other cancers. In cohort 1, the confirmed overall response rate was 65.5%. There were no complete responses (primary endpoint). The 12- and 18-month PFS were 72.0% and 58.0%, respectively, and the median PFS was 26.8 months. In cohort 2, the confirmed overall response rate was 16% (primary endpoint), and the median PFS was 10.0 months (95% confidence interval, 7.0-17.9 months). Tumor histology, driver mutations, and immune-related biomarkers, including PD-L1 expression, thyroid-specific antibody levels, and CD8+ T-cell tumor infiltrate, did not correlate with response to therapy. Increased baseline peripheral blood monocytes and neutrophil to lymphocyte ratio were associated with a worse PFS in cohort 1., Conclusions: Lenvatinib plus pembrolizumab may enhance the durability of lenvatinib monotherapy in lenvatinib-naïve patients. Furthermore, the addition of pembrolizumab may be a viable salvage therapy for patients who have progressed on lenvatinib., (©2024 American Association for Cancer Research.)

Background: The optimal timing for initiating multi-kinase inhibitors (MKIs) in patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC) remains unclear. Thus, we evaluated the real-world practice patterns and outcomes in asymptomatic patients with progressive RAI-R DTC (≥1 lesion ≥1 cm in diameter) in the USA (US population) and outside the USA (non-US population)., Methods: In this prospective, non-interventional, open-label study, eligible patients were chosen by treating physicians to receive MKI therapy (cohort 1) or undergo active surveillance (cohort 2) at study entry. Cohort 2 patients were allowed to transition to MKI therapy later. The primary endpoint was time to symptomatic progression (TTSP) from study entry. Data were compared descriptively. When endpoints were inestimable, 36-month rates were calculated., Results: Of the 647 patients, 478 underwent active surveillance (cohort 2) and 169 received MKI treatment (cohort 1). Patients underwent surveillance at a higher rate in the US (92.6%) vs the non-US (66.9%) populations. Half of US and non-US patients who qualified for MKI treatment had initial American Thyroid Association (ATA) low-to-intermediate-risk disease. In cohort 2, the 36-month TTSP rates from study entry were 65.6% and 66.5% in the US and non-US populations, respectively. Cohort 2 patients treated later demonstrated 36-month TTSP rates of 30.8% and 55.8% in the US and non-US populations, respectively., Conclusions: Active surveillance is a viable option for asymptomatic patients with progressive RAI-R DTC. However, early intervention with MKI therapy may be more suitable for others. Further research is needed to identify patients who are optimal for active surveillance., Registration: NCT02303444.

Background: In the phase 2 double-blind Study 211, a starting dose of lenvatinib 18 mg/day was compared with the approved starting dose of 24 mg/day in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). Predefined criteria for noninferiority for efficacy in the 18 mg arm were not met; safety was similar in both arms. Impact of lenvatinib treatment on health-related quality-of-life (HRQoL) was a secondary endpoint of Study 211., Methods: Patients with RR-DTC were randomly assigned to a blinded starting dose of lenvatinib 18 mg/day or 24 mg/day. HRQoL was assessed at baseline, every 8 weeks until Week 24, then every 16 weeks, and at the off-treatment visit, using the EQ-5D-3L and FACT-G instruments. Completion and compliance rates, mean change from baseline, and times to first and definitive deterioration were evaluated., Results: Baseline EQ-5D and FACT-G scores, and overall changes from baseline, were comparable between patients in the lenvatinib 18 mg/day (n = 77) and 24 mg/day arms (n = 75). For the 18 mg versus 24 mg arms, least squares mean differences were -0.42 (95% CI -4.88, 4.03) for EQ-5D-VAS and 0.47 (95% CI -3.45, 4.39) for FACT-G total. Time to first deterioration did not significantly favor either arm; EQ-5D-VAS HR [18 mg/24 mg] 0.93 (95% CI 0.61-1.40), EQ-5D-HUI HR [18 mg/24 mg] 0.68 (95% CI 0.44-1.05), FACT-G total HR [18 mg/24 mg] 0.73 (95% CI 0.48-1.12). Time to definitive deterioration did not significantly favor either arm, though EQ-5D-VAS showed a trend in favor of the 24 mg arm (HR [18 mg/24 mg] 1.72; 95% CI 0.99-3.01); EQ-5D-HUI HR [18 mg/24 mg] was 0.96 (95% CI 0.57-1.63), FACT-G total HR [18 mg/24 mg] was 0.72 (95% CI 0.43-1.21)., Conclusions: In Study 211, HRQoL for patients in the lenvatinib 18 mg/day arm was not statistically different from that of patients in the 24 mg/day arm. These data further support the use of the approved lenvatinib starting dose of 24 mg/day in patients with RR-DTC., Gov Number: NCT02702388., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Selumetinib can increase radioactive iodine (RAI) avidity in RAI-refractory tumors. We investigated whether selumetinib plus adjuvant RAI improves complete remission (CR) rates in patients with differentiated thyroid cancer (DTC) at high risk of primary treatment failure versus RAI alone., Methods: ASTRA (ClinicalTrials.gov identifier: NCT01843062) is an international, phase III, randomized, placebo-controlled, double-blind trial. Patients with DTC at high risk of primary treatment failure (primary tumor > 4 cm; gross extrathyroidal extension outside the thyroid gland [T4 disease]; or N1a/N1b disease with ≥ 1 metastatic lymph node(s) ≥ 1 cm or ≥ 5 lymph nodes [any size]) were randomly assigned 2:1 to selumetinib 75 mg orally twice daily or placebo for approximately 5 weeks (no stratification). On treatment days 29-31, recombinant human thyroid-stimulating hormone (0.9 mg)-stimulated RAI ( 131 I; 100 mCi/3.7 GBq) was administered, followed by 5 days of selumetinib/placebo. The primary end point (CR rate 18 months after RAI) was assessed in the intention-to-treat population., Results: Four hundred patients were enrolled (August 27, 2013-March 23, 2016) and 233 randomly assigned (selumetinib, n = 155 [67%]; placebo, n = 78 [33%]). No statistically significant difference in CR rate 18 months after RAI was observed (selumetinib n = 62 [40%]; placebo n = 30 [38%]; odds ratio 1.07 [95% CI, 0.61 to 1.87]; P = .8205). Treatment-related grade ≥ 3 adverse events were reported in 25/154 patients (16%) with selumetinib and none with placebo. The most common adverse event with selumetinib was dermatitis acneiform (n = 11 [7%]). No treatment-related deaths were reported., Conclusion: Postoperative pathologic risk stratification identified patients with DTC at high risk of primary treatment failure, although the addition of selumetinib to adjuvant RAI failed to improve the CR rate for these patients. Future strategies should focus on tumor genotype-tailored drug selection and maintaining drug dosing to optimize RAI efficacy., Competing Interests: Alan L. HoConsulting or Advisory Role: Bristol Myers Squibb, Eisai, Genzyme, Merck, Novartis, Sun Pharma, Eisai, Regeneron, TRM Oncology, Ayala Pharmaceuticals, AstraZeneca, Sanofi, CureVac, Prelude Therapeutics, Kura Oncology, McGivney Global Advisors, Rgenta, AffyImmune Therapeutics, Exelixis, Cellestia, InxmedSpeakers’ Bureau: Medscape, Omniprex America, NovartisResearch Funding: Lilly, Genentech/Roche (Inst), AstraZeneca, Allos Therapeutics, Astellas Pharma, Ayala Pharmaceuticals, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Elevar Therapeutics, Kolltan Pharmaceuticals, Kura Oncology, Merck, Novartis, PfizerTravel, Accommodations, Expenses: Janssen Oncology, Merck, Kura Oncology, Ignyta, Ayala Pharmaceuticals, Klusa Pharma Marek DedecjusHonoraria: Sanofi/Aventis, Bayer, Berlin-ChemieResearch Funding: AstraAzeneca/Merck, Exelixis Lori J. WirthConsulting or Advisory Role: Merck, Loxo, Blueprint Medicines, Eisai, Lilly, Bayer, ExelixisResearching Funding: Checkmate Pharmaceuticals (Inst), Lilly (Inst), Ayala Pharmaceuticals (Inst), Eisai (Inst)Expert Testimony: EisaiOther Relationship: PDS Biotechnology R. Michael TuttleResearch Funding: Elesta (Inst) Fernanda VaismanConsulting or Advisory Role: AstraZeneca/Merck, Ipsen, Lilly, Bayer HealthSpeaker’s Bureau: Bayer, AstraZeneca/Merck, Sanofi, United Medical Lars BastholtResearch Funding: Bristol Myers Squibb (Inst) Andrew G. GianoukakisConsulting or Advisory Role: Eisai, Exelixs Patrice RodienConsulting or Advisory Role: Eisai EuropeResearch Funding: Pfizer (Inst) Ralf PaschkeConsulting or Advisory Role: Bayer, EisaiResearching Funding: Bayer (Inst)Patents, Royalties, Other Intellectual Property: Licensing fee for a diagnostic testRossella EliseiConsulting or Advisory Role: EISAI, Genezyme, Loxo, Ipsen, Bayer, Lilly Karen SoEmployment: AstraZenecaStock and Other Ownership Interests: AstraZeneca Danielle CarrollEmployment: AstraZeneca/MedImmune, Azeria therapeutics (I)Leadership: Azeria therapeutics (I)Stock and Other Ownership Interests: AstraZeneca/MedImmune, Azeria Therapeutics (I)Honoraria: AstraZeneca (I)Consulting or Advisory Role: Azeria therapeutics (I)Research Funding: AstraZeneca (I)Patents, Royalties, Other Intellectual Property: Royalties from Active Motif (I), Compositions featuring an attenuated Newcastle disease virus and methods of use for treating neoplasia, Anti-cxc chemokine-2 binding molecules and uses thereof Tina HoveyEmployment: PhastarConsulting or Advisory Role: AstraZenecaResearch Funding: AstraZeneca James A. FaginHonoraria: Eisai EuropeConsulting or Advisory Role: Loxo OncologyPatents, Royalties, Other Intellectual Property: 3. MSK Ref. SK 2014-024-03 Title: Treatment of H-RAS-Driven Tumors. Application Number: 15/305,788. 3. Anti-TSHR Multispecific Antibodies and Uses Thereof, provisional patent.No other potential conflicts of interest were reported.

Background: Lenvatinib is a multikinase inhibitor approved to treat radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day. This study explored, in a double-blinded fashion, whether a starting dose of 18 mg/day would provide comparable efficacy with reduced toxicity., Methods: Patients with RR-DTC were randomized to lenvatinib 24 mg/day or 18 mg/day. The primary efficacy endpoint was objective response rate as of week 24 (ORRwk24); the odds ratio noninferiority margin was 0.4. The primary safety endpoint was frequency of grade ≥3 treatment-emergent adverse events (TEAEs) as of week 24. Tumors were assessed using RECIST v1.1. TEAEs were monitored and recorded., Results: The ORRwk24 was 57.3% (95% CI 46.1, 68.5) in the lenvatinib 24-mg arm and 40.3% (95% CI 29.3, 51.2) in the lenvatinib 18-mg arm, with an odds ratio (18/24 mg) of 0.50 (95% CI 0.26, 0.96). As of week 24, the rates of TEAEs grade ≥3 were 61.3% in the lenvatinib 24-mg arm and 57.1% in the lenvatinib 18-mg arm, a difference of -4.2% (95% CI -19.8, 11.4)., Conclusion: A starting dose of lenvatinib 18 mg/day did not demonstrate noninferiority compared to a starting dose of 24 mg/day as assessed by ORRwk24 in patients with RR-DTC. The results represent a clinically meaningful difference in ORRwk24. The safety profile was comparable, with no clinically relevant difference between arms. These results support the continued use of the approved starting dose of lenvatinib 24 mg/day in patients with RR-DTC and adjusting the dose as necessary., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Graves' disease (GD) has been associated with iron deficiency anemia (IDA). Atrophic gastritis leads to IDA and has been associated with autoimmune thyroid disease. This study prospectively determined the prevalence of atrophic gastritis markers and the relationship between these markers and markers of IDA in GD subjects., Methods: Newly diagnosed GD patients (90) and controls (41) were studied. Of the newly diagnosed GD patients, 65 were consecutively enrolled and identified with GD irrespective of anemia, 25 had GD and IDA. Thyroid function, hematologic indices, and atrophic gastritis markers [parietal-cell antibodies (PCab), Helicobacter pylori antibodies ( H. pylori ab), mean serum gastrin levels] were examined., Results: GD patients presenting with IDA were twice as likely (64% vs. 32%, P=0.049) to harbor PCabs when compared to all other GD subjects. Unselected GD subjects (n=65) had significantly higher PCab (37% vs. 7%, P<0.001) compared to controls. Gastrin levels were significantly elevated in all GD subjects compared to controls (105 vs. 39 pg/ml, P<0.0001). This difference was magnified in PCab+ subjects (202 vs. 64 pg/ml, P=0.003). In all GD subjects, PCabs were associated with increased gastrin levels (202 vs. 75 pg/ml, P=0.0004) and lower ferritin levels (52 vs. 95, P=0.05). In GD anemic subjects, PCabs were associated with lower mean corpuscular volume (75 vs. 81, P=0.001). Gastrin levels correlated inversely with ferritin levels in all GD subjects and positively with TIBC in GD anemic subjects., Conclusions: A significant subset of patients presenting with GD may suffer from IDA due to concurrent autoimmune atrophic gastritis., Competing Interests: None., (AJBR Copyright © 2021.)

Background: The prevalence and clinical significance of de novo detection of anti-thyroglobulin antibodies (TgAbs) during the follow-up of patients with differentiated thyroid cancer (DTC) is unknown. Methods: We utilized the National Thyroid Cancer Treatment Cooperative Study registry (1987-2012). Patients registered after 1996 ( n  = 3318) were analyzed. We identified 1545 subjects who had available TgAb status (TgAb cohort) between years 1996 and 2012, of whom 1325 were TgAb negative at first postoperative follow-up testing. From this initial TgAb-negative group, we excluded 513 patients: 423 patients who had less than 3 years of follow-up and/or fewer than three follow-up visits, 86 patients with persistent disease after initial treatment, and 4 patients with data entry errors. The remaining 812 patients were included for analysis, comprising the TgAb persistently negative group (defined as TgAb negative for at least 3 consecutive follow-up visits and at least 3 years of follow-up) ( n  = 772) and the de novo TgAb-positive group in whom TgAbs became detectable ( n  = 40). We then assessed whether de novo appearance of TgAb was associated with DTC structural recurrence by using the Kaplan-Meier method. Results: The de novo detection of TgAb occurred in 5% of DTC patients. Recurrence of DTC in the TgAb persistently negative group compared with the de novo TgAb-positive group did not differ significantly (9.6% vs. 15.0%, p  = 0.23). Baseline characteristics, histology, history of radiation exposure, staging, and median duration of follow-up were similar between the two groups. Interestingly, in all six patients who suffered a recurrence in the de novo TgAb-positive group, the TgAbs were negative at the time of recurrence detection and became positive at a median of 2.1 (0.7-8.7) years after the structural recurrence. Conclusions: Utilizing a large North American DTC registry, we found the prevalence of de novo TgAb detection to be 5% among initially TgAb-negative patients. We did not find a statistically significant association between de novo TgAb development and DTC structural recurrence. Larger prospective studies are required to confirm these findings and further assess the significance of de novo TgAb detection in the follow-up of DTC.

Purpose: To report a case of orbital fat expansion leading to globe prolapse in a Graves' disease patient undergoing high-dose glucocorticoid therapy. To evaluate the growth factor receptor specificities of plasma autoantibodies in Graves' disease patients who exhibited contrasting subtypes of thyroid-associated ophthalmopathy, i.e. orbital fat expansion-type vs . infiltrative., Methods: Sera from Graves' orbitopathy and control patients with or without Graves' disease were subjected to protein-A affinity chromatography to obtain immunoglobulin G. A (1/50 th to 1/1600 th ) range in dilutions of the protein-A eluate fraction was incubated for four days at 37 degrees C with bovine pulmonary artery endothelial cells to test for endothelial cell inhibition or stimulation. Growth stimulatory autoantibodies were co-incubated with specific neutralizing anti-insulin like growth factor 1 receptor antibodies or anti-basic fibroblast growth factor antibodies to assess autoantibody specificity in contrasting Graves' orbitopathy subtypes., Results: We observed increased mean endothelial cell growth promoting activity in the protein-A eluates of serum from eighteen patients with active Graves' disease (117 ± 28%, n = 18) compared to mean endothelial cell activity (89 ± 10%, n = 13, P = 0.003) in thirteen adults without Graves' disease. The protein-A eluate fraction in acute infiltrative-type Graves' orbitopathy contained a high titer (> 1:1000) of endothelial cell stimulatory activity which was significantly neutralized by specific monoclonal anti-human insulin-like growth factor 1 receptor antibodies. The protein-A eluate fraction in fat expansion-type Graves' orbitopathy contained endothelial cell inhibitory activity (at low titers) and stimulatory activity (at high titers), and the latter stimulatory activity was completely neutralized by specific anti-basic fibroblast growth factor antibodies., Conclusion: Graves' disease suffering globe prolapse secondary to marked orbital fat-expansion had coexisting plasma fibroblast growth factor-inhibitory and -stimulatory autoantibodies. The latter was completely neutralized by anti-basic fibroblast growth factor antibodies.

We present an updated analysis of lenvatinib in radioiodine-refractory differentiated thyroid cancer (RR-DTC) with new duration of response (DOR) data unavailable for the primary analysis. In this randomized, double-blind, multicenter, placebo-controlled phase 3 study, patients ≥18 years old with measurable, pathologically confirmed RR-DTC with independent radiologic confirmation of disease progression within the previous 13 months were randomized 2:1 to oral lenvatinib 24 mg/day or placebo. The main outcome measures for this analysis are DOR and progression-free survival (PFS). The median DOR for all lenvatinib responders (patients with complete or partial responses; objective response rate: 60.2%; 95% confidence interval (CI) 54.2-66.1) was 30.0 months (95% CI 18.4-36.7) and was generally similar across subgroups. DOR was shorter in patients with greater disease burden and with brain and liver metastases. Updated median PFS was longer in the overall lenvatinib group vs placebo (19.4 vs 3.7 months; hazard ratio (HR) 0.24; 99% CI 0.17-0.35; nominal P  < 0.0001). In lenvatinib responders, median PFS was 33.1 months (95% CI 27.8-44.6) vs 7.9 months (95% CI 5.8-10.7) in non-responders. The median DOR of 30.0 months seen with patients who achieved complete or partial responses with lenvatinib (60.2%) demonstrates that lenvatinib responders can have prolonged, durable and clinically meaningful responses. Prolonged PFS (33.1 months) was also observed in these lenvatinib responders., (© 2018 The authors.)

Context: Autoimmune thyroid disease is more common in women than in men. Fetal microchimerism has been implicated as a potential explanation for this disparity., Objective: The objective of this study was to evaluate the relationship between parity and thyroid autoimmunity in the US population., Design, Setting, Patients: The National Health and Nutrition Examination Survey was used to identify females with antithyroperoxidase (TPOAb) and antithyroglobulin antibody (TgAb) measurements and parity data. Subjects (n = 4864) were categorized as never pregnant (n = 909) or previously pregnant (n = 3955). The association of parity with thyroid autoantibodies was examined both qualitatively and quantitatively. Thyroid autoimmunity was defined as TPOAb and/or TgAb titers above the reference limits., Results: Previous pregnancy carried an odds ratio (OR) of 1.55 [95% confidence interval (CI): 1.26 to 1.91] for thyroid autoimmunity compared with never pregnant. Number of pregnancies was associated with thyroid autoimmunity: OR = 1.37 (95% CI: 1.02 to 1.84); 1.4 (95% CI: 1.08 to 1.81); 1.52 (95% CI: 1.18 to 1.96); and 1.73 (95% CI: 1.38 to 2.18) for 1, 2, 3, and ≥4 pregnancies, respectively. Because ever-pregnant women differed in several variables-age, race, smoking status, history of thyroid disease, and urinary iodine level-from never-pregnant women (P < 0.001), a multivariate regression analysis was performed, which showed no association of pregnancy with thyroid autoimmunity. The association was further examined utilizing an age-matched analysis, which confirmed the absence of an association between thyroid autoimmunity and parity., Conclusion: Although we initially observed a strong association between parity and thyroid autoimmunity, after controlling for age and other variables, we were unable to identify an association., (Copyright © 2017 Endocrine Society)

Background: The association between Graves' disease (GD) and thymic hyperplasia (TH) was first described in 1912 and has been reported numerous times thereafter. TH associated with GD presents as an incidental mediastinal mass on chest X-ray or computed tomography (CT). The pathogenesis of TH in the setting of GD is unclear but seems to involve a complex interplay of hormonal and immunological mechanisms., Summary: Here, the effect that thyroid hormones and autoimmunity have on thymic growth and size is reviewed. The authors' experience, along with a review of published case reports, reveals that general physicians may be unfamiliar with this association. This lack of familiarity may result in an aggressive management course, including surgical intervention, along with its associated risks and costs. The differential diagnosis and diagnostic workup of thymic enlargement associated with GD is discussed in light of the available clinical evidence., Conclusion: Recent literature confirms the generally benign nature of TH associated with GD, and supports a conservative approach for the diagnostic workup and initial management. Practical management recommendations for thymic enlargement associated with GD have been formulated and are presented here.

Background: We present a case of a cervical schwannoma, likely originating from the pharyngeal plexus of the vagal nerve. The lesion masqueraded as a thyroid nodule and magnetic resonance imaging (MRI) assisted in preoperative diagnosis. We review the radiographic characteristics of nerve sheath tumors on MRI as well as the diagnostic cytologic stains which can enhance the possibility of a correct preoperative diagnosis., Case: We describe a 60-year-old female with dysphagia and a neck mass consistent with a nodular goiter. The patient's history, diagnostic images, cytology, pathology, and surgical management are presented and analyzed. The preoperative diagnosis of a cervical schwannoma was suspected by the use of MRI which led to additional specialized cytologic stains., Conclusion: Pharyngeal wall schwannomas are important to consider in the differential diagnosis of thyroid nodules when fine needle aspiration cytology indicates cells of neural origin. Imaging by MRI can assist in identifying lesions of neural origin masquerading as thyroid nodules.

Purpose: In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study., Methods: Adverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables., Results: The most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months)., Conclusions: In the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.

Background: Lenvatinib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, fibroblast growth factor receptors 1 through 4, platelet-derived growth factor receptor α, RET, and KIT, showed clinical activity in a phase 2 study involving patients with differentiated thyroid cancer that was refractory to radioiodine (iodine-131)., Methods: In our phase 3, randomized, double-blind, multicenter study involving patients with progressive thyroid cancer that was refractory to iodine-131, we randomly assigned 261 patients to receive lenvatinib (at a daily dose of 24 mg per day in 28-day cycles) and 131 patients to receive placebo. At the time of disease progression, patients in the placebo group could receive open-label lenvatinib. The primary end point was progression-free survival. Secondary end points included the response rate, overall survival, and safety., Results: The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death, 0.21; 99% confidence interval, 0.14 to 0.31; P<0.001). A progression-free survival benefit associated with lenvatinib was observed in all prespecified subgroups. The response rate was 64.8% in the lenvatinib group (4 complete responses and 165 partial responses) and 1.5% in the placebo group (P<0.001). The median overall survival was not reached in either group. Treatment-related adverse effects of any grade, which occurred in more than 40% of patients in the lenvatinib group, were hypertension (in 67.8% of the patients), diarrhea (in 59.4%), fatigue or asthenia (in 59.0%), decreased appetite (in 50.2%), decreased weight (in 46.4%), and nausea (in 41.0%). Discontinuations of the study drug because of adverse effects occurred in 37 patients who received lenvatinib (14.2%) and 3 patients who received placebo (2.3%). In the lenvatinib group, 6 of 20 deaths that occurred during the treatment period were considered to be drug-related., Conclusions: Lenvatinib, as compared with placebo, was associated with significant improvements in progression-free survival and the response rate among patients with iodine-131-refractory thyroid cancer. Patients who received lenvatinib had more adverse effects. (Funded by Eisai; SELECT ClinicalTrials.gov number, NCT01321554.).

Purpose of Review: To provide an overview of the clinical utility of thyroglobulin antibody (TgAb) measurements in the management of differentiated thyroid cancer (DTC), taking into consideration the methodological concerns associated with these measurements., Recent Findings: In the past 1 to 2 years, clinical studies have added to our understanding of the limitations and pitfalls associated with TgAb assay methods, the association of autoimmune thyroid disease with DTC, the prognostic significance of TgAb positivity and the clinical utility of the trend of TgAb measurements as a surrogate tumor marker., Summary: TgAb trends appear to have clinical utility as a surrogate tumor marker in the surveillance of TgAb-positive DTC patients. The prognostic significance of TgAb status (positive/negative) as well as the nature and clinical significance of the association of autoimmune thyroid disease with DTC is less clear.

Background: The cribriform morular variant of papillary thyroid carcinoma (CMVPTC) is a rare subtype of papillary thyroid cancer that occurs most often in association with the familial adenomatous polyposis (FAP) syndrome., Patient Findings: A 18-year-old woman presented with recurrence of PTC in her neck. She had a prior diagnosis of FAP syndrome. Review of her original pathology slides reclassified the case as a CMVPTC. The tumor was examined for the four most common mutations found in PTC: BRAF, RET/PTC, RAS, and PAX/PPARγ., Summary: The molecular alterations associated with CMVPTC involve the WNT signaling pathway but are incompletely understood. When CMVPTC is associated with the FAP syndrome, a germline adenomatous polyposis coli (APC) gene mutation is almost always detected. For the initiation of oncogenesis however, one or more additional molecular alterations must occur, such as a new somatic mutation in the APC gene (biallelic inactivation), somatic mutations in the β-catenin (CTNNB1) gene, or gene-gene interaction (epistasis). To date, of the mutations commonly associated with PTC, only RET/PTC mutations have been reported in CMVPTC. We report a FAP-associated CMVPTC tumor with atypically aggressive features harboring a RAS mutation and review the molecular mechanisms associated with this interesting PTC subtype. The literature was reviewed using MEDLINE (included case presentations, original research, and reviews)., Conclusion: We report here the first RAS mutation detected in an FAP-associated CMVPTC tumor.

Context: Graves' disease (GD) is a systemic autoimmune syndrome comprising manifestations in thyroid and orbital connective tissue. The link between these two tissues in GD eludes our understanding. Patients with GD have increased frequency of circulating monocyte lineage cells known as fibrocytes. These fibrocytes infiltrate orbital connective tissues in thyroid-associated ophthalmopathy and express functional TSH receptor (TSHR)., Objective: The aim of the study was to identify and characterize CD34(+) fibrocytes in thyroid tissue., Design/setting/participants: Patients undergoing surgical thyroidectomy at two academic medical centers were recruited to the study., Main Outcome Measures: We performed immunohistochemistry, flow cytometry, real-time PCR, cytokine-specific ELISA, and cell differentiation., Results: CD34(+)ColI(+)CXCR4(+)TSHR(+) cells can be identified in situ in thyroid tissue from donors with GD, Hashimoto's thyroiditis, or in normal-appearing tissue. Thyroid fibroblasts cultivated from these glands express a CD34(-)ColI(+)CXCR4(+)TSHR(+) phenotype. TSHR levels are higher than those in orbital fibroblasts. When treated with TSH, thyroid fibroblasts generate IL-6 and IL-8. The induction of IL-6 can be blocked by dexamethasone, a chemical inhibitor of Akt/Pkb, and by knocking down Akt with a specific small interfering RNA. When treated with TGF-β or rosiglitazone, thyroid fibroblasts differentiate into myofibrocytes or adipocytes, respectively., Conclusions: ColI(+)CXCR4(+)TSHR(+) thyroid fibroblasts resemble orbital fibroblasts and circulating fibrocytes. CD34(+) fibrocytes appear to infiltrate both tissues in GD. Thyroid fibroblasts lose CD34 display in culture, unlike orbital fibroblasts and circulating fibrocytes. Fibrocytes and their fibroblast derivatives may participate in the pathogenesis of thyroid autoimmunity after TSHR activation. They could represent a therapeutic target for these diseases.

Background: The management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents an uncommon but significant clinical challenge associated with a high mortality rate. This article offers a literature review and discussion of the available management options in this setting., Summary: Treatment of severe thyrotoxicosis in patients unable to ingest medications by the oral route should focus on normalization of thyroid hormone levels utilizing conventional medical therapy for thyrotoxicosis, administered via non-oral routes. This includes thionamides, beta-blockers, iodine containing solutions, and glucocorticoids. When conventional medical therapy fails, plasmapheresis should be considered as a temporary therapeutic bridge until conventional therapies can be instituted effectively or emergent surgery performed., Conclusion: Although a rare scenario, the management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents a challenging clinical situation. Endocrinologists and critical care physicians should be apprised of the available treatment modalities which must be instituted swiftly in order to avoid a catastrophic outcome.

Our understanding of the molecular mechanisms responsible for follicular thyroid cell oncogenesis has been advanced significantly in recent years. Specific genetic alterations and the molecular pathways they affect have been associated with particular histologic subtypes of well-differentiated thyroid cancer and are now being evaluated for their utility as clinical tools with diagnostic, prognostic and even therapeutic relevance. This paper focuses on the most common and clinically relevant genetic alterations shown to be consistently associated with well-differentiated thyroid carcinoma. We review the impact of recent molecular and technological advances on thyroid cancer standard of care and the practice of clinical medicine., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

This has been an exciting year in thyroid research. In this article, we summarize the new developments in selected areas of thyroid research by reporting on key papers published during the period June 2009 to June 2010. We selected those papers that, in our opinion, have significant clinical or translational impact. Selection criteria were applied for inclusion of papers for the Year in Thyroid lecture at the 92nd Annual Meeting of The Endocrine Society in San Diego, June, 2010. Papers relating to translational and clinical discovery in thyroidology were reviewed. Papers were chosen if they provided new insight into the understanding of thyroid disease and advanced clinical science, or advanced the diagnosis of disease, or proposed new therapy, or provided new data on important clinical questions in thyroidology. Here we review and discuss these papers and show how they provide new insights into clinical thyroidology.

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms representing <5% of all pancreatic malignancies with an estimated incidence of 1-1.5 cases/100,000. PNETs are broadly classified as either functional or nonfunctional. Functional PNETs include insulinomas, gastrinomas, vasoactive intestinal peptideomas, glucagonomas, and somatostatinomas. The clinical manifestations associated with these tumors are the result of excessive hormonal secretion and action. The functional nature of these tumors makes pancreatic hormone testing critical not only for initial diagnosis but also for follow-up, because they are important tumor markers. Nonfunctional PNETs typically remain clinically silent until a substantial mass effect occurs. Although the majority of PNETs occur sporadically, it is important to recognize that these tumors may be associated with a variety of familial syndromes and in many cases genetic testing of PNET patients is warranted. This article familiarizes the reader with the clinical presentation and the biochemical, radiologic, and genetic testing indicated for diagnosis and follow-up of patients with PNET.

Purpose of Review: To weigh the clinical impact of new technological insights into heritable thyroid malignancies., Recent Findings: Medullary thyroid carcinoma and familial nonmedullary thyroid cancers represent the small minority of thyroid cancers that are inherited. New insights into the genetic alterations and molecular mechanisms implicated in these tumors are serving to refine the clinical tools available for their initial diagnosis as well as subsequent follow-up. In addition to an analysis of rearranged during transfection mutations and calcitonin profiles in medullary thyroid carcinoma, this review includes emphasis on familial nonmedullary thyroid cancer syndromes, including genetic findings in familial papillary thyroid cancer, familial adenomatous polyposis, Cowden syndrome, Carney complex, and Werner syndrome., Summary: Genetic mutational information is increasingly available on medullary and familial nonmedullary thyroid cancer and their associated syndromes. The clinical significance of this information for affected patients and their families continues to undergo evaluation.

Context: The pathogenic basis for Graves' disease (GD) continues to elude our understanding. Specifically why activating antibodies are generated against self-antigens remains uncertain as does the identity of the antigen(s) that provokes orbital involvement in GD, a process known as thyroid-associated ophthalmopathy (TAO)., Objective: The aim of the study was to determine whether CD34(+) fibrocytes are generated more frequently in GD, whether they infiltrate orbital connective tissues in TAO, and whether they express the thyrotropin receptor (TSHR)., Design/setting/participants: Generation of fibrocytes from peripheral blood mononuclear cells was examined in samples from 70 patients with GD and 25 healthy control subjects. Fibrocytes were characterized by flow cytometry. Orbital tissues and fibroblast culture strains were examined for their presence., Main Outcome Measures: The frequency of CD34(+) fibrocyte generation from peripheral blood cells, characterization of their phenotype, cytokine production, and their presence in affected orbital tissues were analyzed., Results: CD34(+)CXCR4(+)Col I(+) fibrocytes expressing IGF-I receptor are far more frequently generated from cultured peripheral blood mononuclear cells of donors with GD compared with healthy subjects. They express TSHR at high levels and TSH induces fibrocytes to produce IL-6 and TNF-alpha. Numerous CD34(+) fibrocytes were detected in orbital tissues in TAO but were absent in healthy orbits. Tissue-infiltrating fibrocytes express TSHR in situ and comprise a subpopulation of TAO-derived orbital fibroblasts., Conclusions: Our findings suggest that fibrocytes may participate in the pathogenesis of TAO because they express relevant autoantigens such as IGF-I receptor and functional TSHR and differentially accumulate in orbital tissue in TAO.

Background: Graves' disease (GD) is associated with hyperthyroidism. Thyrotoxicosis adversely affects multiple organ systems including haematopoiesis. Anaemia occurring specifically in GD has not been systematically studied previously., Objective: To define the prevalence and characteristics of the anaemia associated with GD., Design: Eighty-seven newly diagnosed patients with GD were recruited. Haematological indices, thyroid function and inflammatory parameters were examined at presentation and following successful treatment of hyperthyroidism., Setting: Tertiary care academic referral centre., Results: Thirty-three per cent of subjects presented with anaemia. The prevalence of anaemia not attributable to other causes (GD anaemia) was 22%. GD anaemia affected 41.6% (10/24) of men compared to 17.5% of women (11/63). Mean erythropoietin (EPO) levels (15.5 +/- 5.3 mIU/ml) were within normal reference limits but significantly higher (P = 0.004) than those of the non-anaemic controls. Hgb correlated inversely with EPO (P = 0.05) and CRP (P = 0.04) levels, a relationship that persisted after multivariate adjustment for TT3 or TT4. With antithyroid therapy for 16 +/- 6.3 weeks, Hgb levels normalized in 8 out of 9 subjects with GD anaemia (10.7 +/- 0.8 to 13.5 +/- 1.3 g/dl, P = 0.0001). After normalization of Hgb, mean MCV and TIBC were significantly increased, and median ferritin and mean EPO were significantly decreased., Conclusions: GD anaemia is common, resembles the anaemia of chronic disease, and is associated with markers of inflammation. It corrects promptly with return to the euthyroid state following treatment.

Graves' disease (GD) is an autoimmune process involving the thyroid and connective tissues in the orbit and pretibial skin. Activating anti-thyrotropin receptor Abs are responsible for hyperthyroidism in GD. However, neither these autoAbs nor the receptor they are directed against have been convincingly implicated in the connective tissue manifestations. Insulin-like growth factor-1 receptor (IGF-1R)-bearing fibroblasts overpopulate connective tissues in GD and when ligated with IgGs from these patients, express the T cell chemoattractants, IL-16, and RANTES. Disproportionately large fractions of peripheral blood T cells also express IGF-1R in patients with GD and may account, at least in part, for expansion of IGF-1R(+) memory T cells. We now report a similarly skewed B cell population exhibiting the IGF-1R(+) phenotype from the blood, orbit, and bone marrow of patients with GD. This expression profile exhibits durability in culture and is maintained or increased with CpG activation. Moreover, IGF-1R(+) B cells produce pathogenic Abs against the thyrotropin receptor. In lymphocytes from patients with GD, IGF-1 enhanced IgG production (p < 0.05) and increased B cell expansion (p < 0.02) in vitro while those from control donors failed to respond. These findings suggest a potentially important role for IGF-1R display by B lymphocytes in patients with GD in supporting their expansion and abnormal Ig production.

Thyroid-stimulating hormone receptor (TSHR) plays a central role in regulating thyroid function and is targeted by IgGs in Graves' disease (GD-IgG). Whether TSHR is involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the orbital manifestation of GD, remains uncertain. TSHR signaling overlaps with that of insulin-like grow factor 1 receptor (IGF-1R). GD-IgG can activate fibroblasts derived from donors with GD to synthesize T cell chemoattractants and hyaluronan, actions mediated through IGF-1R. In this study, we compare levels of IGF-1R and TSHR on the surfaces of TAO and control orbital fibroblasts and thyrocytes and explore the physical and functional relationship between the two receptors. TSHR levels are 11-fold higher on thyrocytes than on TAO or control fibroblasts. In contrast, IGF-1R levels are 3-fold higher on TAO vs control fibroblasts. In pull-down studies using fibroblasts, thyrocytes, and thyroid tissue, Abs directed specifically against either IGF-1Rbeta or TSHR bring both proteins out of solution. Moreover, IGF-1Rbeta and TSHR colocalize to the perinuclear and cytoplasmic compartments in fibroblasts and thyrocytes by confocal microscopy. Examination of orbital tissue from patients with TAO reveals similar colocalization to cell membranes. Treatment of primary thyrocytes with recombinant human TSH results in rapid ERK phosphorylation which can be blocked by an IGF-1R-blocking mAb. Our findings suggest that IGF-1R might mediate some TSH-provoked signaling. Furthermore, they indicate that TSHR levels on orbital fibroblasts are considerably lower than those on thyrocytes and that this receptor associates with IGF-1R in situ and together may comprise a functional complex in thyroid and orbital tissue.

Graves' disease, an autoimmune process associated with thyroid dysfunction, can also manifest as remodeling of orbital connective tissue. Affected tissues exhibit immune responses that appear to be orchestrated by resident cells and those recruited from the bone marrow through their expression and release of cytokines and surface display of cytokine receptors. Cytokines are small molecules produced by many types of cells, including those of the "professional" immune system. Aberrant cytokine expression appears to play an important role in the pathogenesis of many human diseases, including thyroid autoimmunity. The skewed pattern of cytokine expression in the thyroid, including the T helper cell bias, may condition the response to apoptotic signals and determine the characteristics of an autoimmune reaction. Furthermore, chemoattractant cytokines, including IL16, RANTES, and CXCL10, elaborated by resident cells in the thyroid and orbit may provoke mononuclear cell infiltration. Other cytokines may drive cell activation and tissue remodeling. Thus cytokines and the signaling pathways they activate represent attractive therapeutic targets. Interruption of these might alter the natural course of Graves' disease and its orbital manifestations.

Tissue remodeling associated with thyroid-associated ophthalmopathy (TAO) involves the complex interplay between resident cells (endothelium, vascular smooth muscle, extraocular muscle, and fibroblasts) and those recruited to the orbit, including members of the "professional" immune system. Inflammation early in the disease can later culminate in fibrosis and diminished extraocular muscle motility. TAO remains a poorly understood process, in large part because access to tissues early in the disease is limited and because no robust and complete animal models of Graves' disease have yet been devised. Remaining uncertainty as to the identity of a pathogenic autoantigen(s) that underlies lymphocyte trafficking to the orbit complicates matters. These limitations in our understanding of extrathyroidal Graves' disease have resulted in poorly served patients with severe TAO. Therapies have targeted symptoms rather than the underlying disease processes. Our laboratory group has focused over the last several years on defining the peculiarities of the human orbital fibroblasts as a strategy for shedding more light on the pathologies occurring in TAO. We have reasoned that unique properties of these cells might ultimately prove the basis for why the manifestations of Graves' disease occur in an anatomically selective manner. In this brief review we attempt to survey our findings. We believe that they might provide a "roadmap" for further discovery into the pathogenesis of TAO. Clearly, more questions remain than those thus far answered.

Thyroid-associated ophthalmopathy (TAO) is a common yet poorly understood component of Graves' disease involving inflammation, congestion and soft tissue remodelling of the orbit. Unlike most autoimmune disorders, TAO has variable severity but follows a predictable course and is usually self-limited. The objective of this study was to investigate the phenotypic profile of peripheral blood mononuclear cells in euthyroid patients with TAO. The study was a prospective, consecutive analysis of the peripheral blood mononuclear cell phenotype in patients with TAO and normal controls. We demonstrate that the fraction of T cells expressing CD69, CD25 or CXCR4 is significantly greater in patients with TAO compared to control donors. In addition, the fraction of CD19(+) CD25(+) B cells is significantly greater. We did not find differences between the two groups of subjects in monocytes expressing these markers. There is a phenotypic shift in peripheral blood lymphocytes associated with TAO that appears durable and persists beyond the hyperthyroid phase of Graves' disease. These changes may support the immune reaction provoking orbital disease development.

Graves' disease (GD), an autoimmune process involving thyroid and orbital tissue, is associated with lymphocyte abnormalities including expansion of memory T cells. Insulin-like growth factor receptor-1 (IGF-1R)-bearing fibroblasts overpopulate connective tissues in GD. IGF-1R on fibroblasts, when ligated with IgGs from these patients, results in the expression of the T cell chemoattractants, IL-16 and RANTES. We now report that a disproportionately large fraction of peripheral blood T cells express IGF-1R (CD3+IGF-R+). CD3+IGF-1R+ T cells comprise 48 +/- 4% (mean +/- SE; n = 33) in patients with GD compared with 15 +/- 3% (n = 21; p < 10(-8)) in controls. This increased population of IGF-1R+ T cells results, at least in part, from an expansion of CD45RO+ T cells expressing the receptor. In contrast, the fraction of CD45RA+IGF-1R+ T cells is similar in GD and controls. T cells harvested from affected orbital tissues in GD reflect similar differences in the proportion of IGF-1R+CD3+ and IGF-1R+CD4+CD3+ cells as those found in the peripheral circulation. GD-derived peripheral T cells express durable, constitutive IGF-1R expression in culture and receptor levels are further up-regulated following CD3 complex activation. IGF-1 enhanced GD-derived T cell incorporation of BrdU (p < 0.02) and inhibited Fas-mediated apoptosis (p < 0.02). These findings suggest a potential role for IGF-1R displayed by lymphocytes in supporting the expansion of memory T cells in GD.

Graves' disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune processes often associated with hyperthyroidism and hypothyroidism, respectively. Despite their diverging clinical presentations, immune activation drives both diseases and results in connective tissue accumulation of the nonsulfated glycosaminoglycan, hyaluronan. The hydrophilic property of hyaluronan contributes to the pathogenesis of thyroid-associated ophthalmopathy, dermopathy and hypothyroid myxedema. Whether hyaluronan accumulates in the thyroid and plays a role in goiter formation in GD and HT remains unknown. We report here that levels of hyaluronan are increased in thyroid tissue from individuals with both diseases compared with glands uninvolved with autoimmune disorders. The transcript encoding hyaluronan synthase (HAS)-3, one of three mammalian HAS isoforms, was detected in thyroid tissue. Isolated thyrocytes in primary culture express all three HAS isoforms when treated with IL-1beta. Thyrocytes and thyroid fibroblasts produce hyaluronan under basal culture conditions and IL-1beta enhances levels of this molecule in both cell types. On a per-cell basis, fibroblasts produce more hyaluronan than do thyrocytes under basal conditions and after cytokine treatment. Synthesis in thyrocytes can also be altered by increasing serum concentration in the medium and by modifying culture density. Our findings suggest that hyaluronan accumulation in thyroid tissue might derive from thyrocytes and fibroblasts. Moreover, this glycosaminoglycan becomes more abundant as a consequence of autoimmune disease. It may therefore contribute to increased thyroid volume in GD and HT. Coupled with the newly identified influence exerted by hyaluronan on immunocompetent cells, our findings represent potentially important insights into the pathogenesis of autoimmune thyroid diseases.

The thyroid target Ag for disease-inducing autoantibodies in Graves' disease is the receptor for thyroid-stimulating hormone (TSH), but little is known about the molecular basis of this pathogenic Ab response. We describe the characteristics of two high- affinity mAbs developed from an experimental murine model of hyperthyroid Graves' disease that exhibit potent thyroid-stimulating activity. Nanogram concentrations of the IgG mAbs KSAb1 and KSAb2 and their Fab induce full stimulation of the TSH receptor that is matched by the ligand TSH and, thus, act as full agonists for the receptor. However, KSAb1 and KSAb2 display differential activities in their ability to block TSH-mediated stimulation of the receptor, indicating subtle differences in their biological properties. In displacement studies, IgG and Fabs of KSAb1 and KSAb2 compete with Graves' disease autoantibodies as well as thyroid-blocking Abs present in some hypothyroid patients, indicating a close relationship between these autoimmune determinants on the receptor. In passive transfer studies, single injections of microgram quantities of KSAb1 or KSAb2 IgG led to rapid elevation of serum thyroxine and a hyperthyroid state that was maintained for a number of days. The thyroid glands showed evidence of cell necrosis, but there was no accompanying mononuclear cell infiltrate. In studying their receptor activation pathways, both KSAb1 and KSAb2 provoked phosphorylation of the intracellular ERK1/2 pathway in primary thyrocytes, indicating that multiple signaling pathways may participate in the pathogenesis of Graves' disease. In summary, our findings emphasize the similarities of the experimental mouse model in reproducing the human disorder and provide improved means for characterizing the molecular basis of this pathogenic response.

Mechanisms underlying lymphocyte infiltration of the thyroid gland and orbit in Graves' disease (GD) are poorly understood. The IGF-I receptor (IGF-IR) is a newly recognized self-antigen that, when activated in GD fibroblasts by IGF-I or GD-IgGs, provokes the expression of IL-16 and RANTES (regulated upon activation, normal T cell expressed and secreted)-dependent T lymphocyte chemoattraction and hyaluronan synthesis. IL-16 is a CD4(+)-specific ligand, and RANTES is a C-C chemokine. Here we report that IGF-I and GD-IgG could induce IL-16 and RANTES in cultured human thyrocytes in a time-dependent manner. Importantly, human TSH failed to induce either chemoattractant. This induction could be attenuated by dexamethasone. Rapamycin, a specific inhibitor of the FRAP/mammalian target of rapamycin/p70(s6k) pathway, prevented GD-IgG-provoked IL-16 synthesis. IH7, a monoclonal antibody directed at IGF-IR also blocked the induction of chemoattraction as well as RANTES mRNA synthesis. Our findings suggest that thyrocytes can be activated by GD-IgG and IGF-I to express powerful T-cell chemoattractants. These actions of GD-IgG appear to be mediated through pathways independent of the TSH receptor. Thus, in GD, thyrocytes may participate directly in lymphocyte recruitment through their expression of IL-16 and RANTES.

Mediators of lymphocyte infiltration in inflammatory thyroid disease have yet to be identified. Here we examine the ability of IL-1beta to enhance the production of chemoattractants by human thyrocytes. Primary cultures, when treated with the cytokine, release T lymphocyte chemotactic activity. The effect of IL-1beta is time dependent, and the chemoattraction activity can be partially attenuated by the addition of either anti-IL-16 or anti-regulated upon activation, normal T cell expressed, and secreted (RANTES) neutralizing antibodies. IL-16 is a CD4(+)-specific ligand, and RANTES is a C-C type chemokine that targets monocytes and lymphocytes. These chemoattractants could be detected by specific ELISAs in conditioned medium from IL-1beta treated thyrocytes. Northern analysis revealed that thyrocytes express high constitutive levels of IL-16 mRNA, which were invariant with regard to IL-1beta (10 ng/ml) or glucocorticoid treatment. RANTES mRNA was not detected in control cultures but was strongly induced by the cytokine. IL-16 but not RANTES expression was dependent on the activity of caspase-3. Pro-IL-16 protein could be detected in homogenates of thyroid tissue from patients with multinodular goiter and Graves' disease. Thus, human thyrocytes, through the expression of chemoattractants, may participate in the recruitment of lymphocytes to the thyroid in inflammatory states.

A 41-year-old white female underwent a positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) scan as part of staging follow-up for breast cancer. Focal FDG uptake was noted in the right neck. Further evaluation revealed only thyroid nodules and subclinical hyperthyroidism. A sodium pertechnetate thyroid scan showed two "hot" nodules in the right thyroid lobe corresponding to the focal uptake visualized on FDG-PET scan. Technetium-99m uptake was suppressed in the remaining thyroid gland. The patient underwent a subtotal thyroidectomy. Histopathologic evaluation revealed two hyperplastic nodules in each thyroid lobe. We review the literature with regard to FDG-PET imaging of normal and diseased thyroid tissue.

KAT-50, an established human thyrocyte cell line, expresses constitutively high levels of prostaglandin endoperoxide H synthase-2 (PGHS-2), the inflammatory cyclooxygenase. Here, we examine primary human thyrocytes. We find that they, too, express PGHS-2 mRNA and protein under control culture conditions. A substantial fraction of the basal prostaglandin E(2) (PGE(2)) produced by these cells can be inhibited by SC-58125 (5 microM), a PGHS-2-selective inhibitor. Interleukin (IL)-1beta (10 ng/ml) induces PGHS-2 expression and PGE(2) production in primary thyrocytes. The induction of PGHS-2 and PGE(2) synthesis by IL-1beta could be blocked by glucocorticoid treatment. Unlike KAT-50, most of the culture strains also express PGHS-1 protein. Our observations suggest that both cyclooxygenase isoforms may have functional roles in primary human thyroid epithelial cells, and PGHS-2 might predominate under basal and cytokine-activated culture conditions.

Objective: To compare the quality of ambulatory diabetes care provided by physicians in an endocrinology clinic with that in a primary-care clinic., Methods: We conducted a retrospective study of the medical records of patients with diabetes treated for 2 to 4 years in an endocrinology clinic and a primary-care clinic at an academic medical center. Adherence to American Diabetes Association (ADA) clinical practice recommendations and hemoglobin A(1c) (HbA(1c)) levels were assessed in randomly chosen patients-a total of 68 patients from the primary-care clinic and 105 patients from the endocrinology clinic, with total patient-years of follow-up of 241 and 370, respectively., Results: In six of seven areas assessed, the endocrinology clinic was significantly more compliant with ADA recommendations than was the primary-care clinic: queries about hypoglycemia (88% versus 20%); frequency of glycated hemoglobin determinations (3.3 versus 2.1 per patient/yr); yearly lipid panel (44% versus 25%); and yearly ophthalmologic (90% versus 50%), neurologic (56% versus 37%), and foot (88% versus 59%) examinations (all P<0.001). The rate of yearly proteinuria evaluations was similar in the two clinics (66% versus 65%). On assessment of all patients, the mean HbA(1c) level was significantly lower in the endocrinology clinic (8.29%) than in the primary-care clinic (8.73%) (P = 0.01)., Conclusion: Adherence to ADA clinical practice recommendations was significantly better in the endocrinology clinic than in the primary-care clinic. This finding and the significantly lower levels of HbA(1c) in patients in the endocrinology clinic setting would be expected to translate into improved long-term patient outcome.