Intensity-modulated radiation therapy and doxorubicin in thyroid cancer: A prospective phase 2 trial.

BACKGROUND: The use of external-beam radiotherapy for locally advanced nonanaplastic thyroid cancer remains controversial. This prospective study evaluated the efficacy and tolerability of intensity-modulated radiation therapy (IMRT) with or without concurrent chemotherapy in patients with locally advanced thyroid cancer. METHODS: The authors conducted a nonrandomized phase 2 trial of IMRT with or without concurrent doxorubicin in patients with gross residual or unresectable nonanaplastic thyroid carcinoma (ClinicalTrials.gov identifier NCT01882816). The primary end point was 2-year locoregional progression-free survival (PFS). Secondary end points included overall survival (OS), safety, patient-reported outcomes, and functional outcomes. RESULTS: Twenty-seven patients were enrolled: 12 (44.4%) with unresectable disease and 15 (55.6%) with gross residual disease. The median follow-up was 45.6 months (interquartile range, 42.0-51.6 months); the 2-year cumulative incidences of locoregional PFS and OS were 79.7% and 77.3%, respectively. The rate of grade 3 or higher acute and late toxicities was 33.4%. There were no significant functional differences 12 months after treatment (assessed objectively by the modified barium swallow study). Patient-reported quality of life in the experimental group was initially lower but returned to the baseline after 6 months and improved thereafter. In a post hoc analysis, concurrent chemotherapy with intensity-modulated radiation therapy (CC-IMRT) resulted in significantly less locoregional failure at 2 years (no failure vs 50%; P = .001), with higher rates of grade 2 or higher acute dermatitis, mucositis, and dysphagia but no difference in long-term toxicity, functionality, or patient-reported quality of life. CONCLUSIONS: In light of the excellent locoregional control rates achieved with CC-IMRT and its acceptable toxicity profile as confirmed by functional assessments and patient-reported outcomes, CC-IMRT may be preferred over IMRT alone.

Prolongation of tumour volume doubling time (midDT) is associated with improvement in disease-specific survival in patients with rapidly progressive radioactive iodine refractory differentiated thyroid cancer selected for molecular targeted therapy.

PURPOSE: To assess molecular targeted therapy (MTT)'s ability to affect tumour volume doubling time (TVDT) and disease-specific survival (DSS) in patients presenting with lung metastasis from radioactive iodine refractory progressive thyroid cancer. METHODS: In this retrospective study, we examined the clinical characteristics, average tumour volume doubling times of lung metastasis and disease-specific survival of patients with lung metastasis from differentiated thyroid cancer who were treated with MTT. RESULTS: The 5-year DSS from the distant metastasis (DM) diagnosis was 72% with median survival of 8 years (95% CI: 6.6-9.5). The median survival was 2.9 years after MTT start (95% CI: 2.1-3.6). On MTT, lung average tumour volume doubling time (midDT) was prolonged to midDT ≥3 years in 75% of patients with baseline midDT ≤1 year and 100% of patients with midDT 1-3 years. In patients with rapidly progressive thyroid cancer (midDT ≤1 year at baseline), the median survival was 4.5 years in those with MTT-achieved midDT ≥3 years (95% CI: 2.9-6.2), as opposed to 2.3 years (95% CI: 0.3-4.3) and 0.7 years (95% CI: 0.2-1.3) in those with MTT-achieved midDT of 1-3 years and MTT-achieved midDT ≤1 year, respectively (log rank P < 0.001). CONCLUSION: Lung midDT is a useful and important clinical marker of disease-specific survival for patients with progressive radioactive iodine refractory (RAIR) metastatic thyroid cancer. In patients with rapidly progressive metastatic RAIR thyroid cancer, molecular targeted therapy prolongs lung tumour volume doubling time and is associated with improved disease-specific survival.

Tumor volume doubling time of pulmonary metastases predicts overall survival and can guide the initiation of multikinase inhibitor therapy in patients with metastatic, follicular cell-derived thyroid carcinoma.

BACKGROUND: The current study was conducted to better characterize the association between overall survival (OS) from metastatic thyroid cancer and the rate of structural disease progression. METHODS: In this retrospective study, the average tumor volume doubling time (midDT) of 2 dominant lung metastases was used to group patients into 6 clinically relevant cohorts. OS was calculated from the time of metastasis diagnosis and from the time the pulmonary lesions crossed over the 1-cm diameter threshold. RESULTS: The tumor growth rate was remarkably constant in lung metastases from thyroid cancer over a median follow-up of 8.5 years (median correlation coefficient, 0.92; coefficient of determination, 0.85). Patients with a midDT ≤1 year were found to have worse OS compared with those with a higher midDT (log-rank P = .01). The 5-year OS rate from the 1-cm diameter time point was 20% for patients with a midDT ≤1 year (15 patients), 50% for patients with a midDT of 1 to 2 years (19 patients), 53% for patients with a midDT of 2 to 3 years (9 patients), 80% for patients with a midDT of 3 to 4 years (6 patients), and 80% for patients with a midDT of ≥4 years or who were negative (12 patients). Within the group of patients with a midDT ≤1 year, the 2-year OS rate from the 1-cm diameter point was 88% in the patients treated with multikinase inhibitors (8 patients) versus 43% in the nontreated group (7 patients) (P = .13). CONCLUSIONS: The midDT of lung metastases appears to be a good prognostic indicator of OS in patients with metastatic thyroid cancer. Unlike the thyroglobulin DT, the midDT alone can be used to predict eligibility for multikinase inhibitor therapy. Cancer 2017;123:2955-64. © 2017 American Cancer Society.

VARIABILITY IN THYROID CANCER MANAGEMENT AND PROGNOSIS AMONG HISPANIC VERSUS NON-HISPANIC PATIENTS : 17 YEARS DATA FROM UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AND UNIVERSITY HEALTH SYSTEM AT SAN ANTONIO.

Abstracts: Objective : Given the increase in the incidence of thyroid cancer in the United States, and it's potential public health implications, patient studies assessing ethnic, disparity and health care access are important. In this study, we retrospectively examined the variability in stage of thyroid cancer at presentation and final outcome among Hispanic vs non-Hispanic patients. METHOD: After obtaining IRB approval, we retrospectively reviewed the medical records of 220 adult patients with papillary thyroid carcinoma(PTC) who were treated at UT Health Science Center San Antonio between1996 and 2013. At disease presentation, patients were staged and risk stratified according to the 2009 American Thyroid Association (ATA) and TNM staging system. Clinical data obtained during the first 6-18 months was used to identify the initial response to therapy and clinical data from the last follow up visit was used to identify the "final" outcome. We examined the effect of insurance and ethnicity on initial response to therapy and final outcome using Chi-square test and one way ANOVA. RESULT: Our patient population's ATA risk at diagnosis, initial response to therapy and final outcome did not differ by ethnicity (P=0.5, 0.3 &0.4) and insurance coverage(P=0.7, 0.3 & 0.4) . CONCLUSION: Insurance coverage and ethnicity may not be independent factors since ethnic minority individuals are more likely to be uninsured.

Modeled nitrate levels in well water supplies and prevalence of abnormal thyroid conditions among the Old Order Amish in Pennsylvania.

BACKGROUND: Nitrate is a widespread contaminant of drinking water supplies, especially in agricultural areas. Nitrate intake from drinking water and dietary sources can interfere with the uptake of iodide by the thyroid, thus potentially impacting thyroid function. METHODS: We assessed the relation of estimated nitrate levels in well water supplies with thyroid health in a cohort of 2,543 Old Order Amish residing in Lancaster, Chester, and Lebanon counties in Pennsylvania for whom thyroid stimulating hormone (TSH) levels were measured during 1995-2008. Nitrate measurement data (1976-2006) for 3,613 wells in the study area were obtained from the U.S. Geological Survey and we used these data to estimate concentrations at study participants' residences using a standard linear mixed effects model that included hydrogeological covariates and kriging of the wells' residuals. Nitrate levels estimated by the model ranged from 0.35 mg/L to 16.4 mg/L N-NO3(-), with a median value of 6.5 mg/L, which was used as the cutpoint to define high and low nitrate exposure. In a validation analysis of the model, we calculated that the sensitivity of the model was 67% and the specificity was 93%. TSH levels were used to define the following outcomes: clinical hyperthyroidism (n = 10), clinical hypothyroidism (n = 56), subclinical hyperthyroidism (n = 25), and subclinical hypothyroidism (n = 228). RESULTS: In women, high nitrate exposure was significantly associated with subclinical hypothyroidism (OR = 1.60; 95% CI: 1.11-2.32). Nitrate was not associated with subclinical thyroid disease in men or with clinical thyroid disease in men or women. CONCLUSIONS: Although these data do not provide strong support for an association between nitrate in drinking water and thyroid health, our results do suggest that further exploration of this hypothesis is warranted using studies that incorporate individual measures of both dietary and drinking water nitrate intake.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Thyroid Cancer and Telemedicine During the COVID-19 Pandemic.

The COVID-19 pandemic has forced endocrinologists to utilize telemedicine to care for their patients. There is limited information on the experience of endocrinologists in managing patients with thyroid cancer virtually. We sent a 9-item questionnaire to endocrinologists and endocrine surgeons at our institution to better understand the barriers and benefits of caring for patients with thyroid cancer via telemedicine, as well as how we can incorporate telemedicine into our future care of patients with this malignancy. Among the 9 physicians who responded, the majority listed technological issues with the virtual platform as a challenge in caring for patients with thyroid cancer remotely. Additional barriers included difficulty in expressing empathy, decreased ability to coordinate care with the interdisciplinary team, and lack of the physical examination. Benefits included compliance with social distancing measures and convenience for patients with American Thyroid Association (ATA) low-risk thyroid cancer who presented for follow-up visits. Overall, physicians were satisfied or strongly satisfied with caring for patients with thyroid cancer remotely, especially low-risk patients on long-term follow-up. That said, they recommend that some patients be seen in person after the pandemic, including symptomatic patients and ATA high-risk patients. While the COVID-19 pandemic has allowed endocrinologists to manage patients with thyroid cancer remotely, the providers have faced challenges, some of which can be improved upon. Further studies will help determine how telemedicine affects patient outcomes, including satisfaction, disease progression, and survival, which will inform how we may incorporate this practice into our future care of patients with thyroid cancer.

Structural Doubling Time Predicts Overall Survival in Patients with Medullary Thyroid Cancer in Patients with Rapidly Progressive Metastatic Medullary Thyroid Cancer Treated with Molecular Targeted Therapies.

Purpose: To evaluate the impact of structural disease progression of metastatic lesions after initial surgery on overall survival (OS) of patients presenting with metastatic medullary thyroid cancer (MTC). We used tumor volume doubling time (TVDT) as a marker of structural disease progression and aimed to correlate the average structural tumor volume doubling time (midDT) with OS in MTC patients after initial surgery. Methods: In this retrospective study, we examined the clinical characteristics; average tumor volume doubling times of neck, lung, and liver metastasis; and disease-specific survival of patients with metastatic MTC. Results: Tumor growth is constant in MTC metastasis, irrespective of location of the metastasis. The median correlation coefficient (r) and the coefficient of determination (r2) were similar in lung metastasis (r = 0.91, r2 = 0.95) and liver metastasis (r = 0.88, r2 = 0.94), and comparable in neck metastasis (r = 0.73, r2 = 0.85). Patients with metastatic MTC with a midDT ≤1 year have a worse prognosis than those with higher midDT (p = 0.002). Those with midDT ≤1 year had a median OS of 11.1 years [confidence interval (CI) 7.4-14.8 years]. In contrast, patients with midDT 1-3 years had a median OS of 16.5 years [CI 10.3-22.6 years]. All patients with midDT ≥3 survived by the end of the follow-up period. Preliminary results suggest that measurement of midDT can predict response to molecular targeted therapies. Conclusions: In conclusion, TVDT is a strong predictor of OS in patients with recurrent or metastatic MTC, can be used as a marker of progression, and potentially can help select patients who may benefit from molecular targeted therapy.

Vemurafenib Redifferentiation of BRAF Mutant, RAI-Refractory Thyroid Cancers.

CONTEXT: BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI). OBJECTIVES: To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR). DESIGN: This was a pilot trial that enrolled from June 2014 to January 2016. SETTING: Academic cancer center. PATIENTS: Patients with RAIR, BRAF mutant thyroid cancer. INTERVENTION: Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation. MAIN OUTCOME MEASURE: The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I. RESULTS: Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048). CONCLUSIONS: Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.

AHNS Series: Do you know your guidelines? AHNS Endocrine Section Consensus Statement: State-of-the-art thyroid surgical recommendations in the era of noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

The newly introduced pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) will result in less bilateral thyroid surgery as well as deescalation in T4 suppressive and radioactive iodine treatment. Although, NIFTP is a nonmalignant lesion that has nuclear features of some papillary malignancies, the challenge for the surgeon is to identify a lesion as possibly NIFTP before the pathologic diagnosis. NIFTP, due to its reduction of overall rates of malignancy, will result in the initial surgical pendulum swinging toward lobectomy instead of initial total thyroidectomy. This American Head and Neck Society endocrine section consensus statement is intended to inform preoperative evaluation to attempt to identify those patients whose final pathology report may ultimately harbor NIFTP and can be offered a conservative surgical plan to assist in cost-effective, optimal management of patients with NIFTP.

Primary Thyroid Carcinoma with Low-Risk Histology and Distant Metastases: Clinicopathologic and Molecular Characteristics.

BACKGROUND: Distant metastases (DM) are a rare occurrence in well-differentiated thyroid carcinoma. The aim of this study was to analyze the clinical, pathologic, and molecular features of primary thyroid carcinoma with low-risk histology that develop DM. METHODS: A detailed clinicopathologic review and targeted next-generation sequencing were performed on a cohort of well-differentiated thyroid carcinoma lacking gross extrathyroidal extension, extensive vascular invasion, or significant lymph node metastases but exhibiting DM. RESULTS: Primary well-differentiated thyroid carcinoma with low-risk histologic features and DM was a rare occurrence, accounting for only 3% of metastatic non-anaplastic thyroid carcinoma. All 15 cases meeting the inclusion criteria harbored DM at presentation. The majority (11/15) of these tumors were follicular variant of papillary thyroid carcinoma (PTC), especially the encapsulated form (n = 8). The remaining patients harbored encapsulated Hürthle cell carcinoma (n = 2), encapsulated follicular carcinoma (n = 1), and an encapsulated papillary carcinoma classical variant (n = 1). Of the 12 encapsulated carcinomas, 10 had capsular invasion only and no vascular invasion. Ninety-two percent of the tumors exhibited extensive intra-tumoral fibrosis. Among the eight tumors that were subjected to next-generation sequencing analysis, a RAS mutation was the main driver (5/8), and TERT promoter mutation was highly prevalent (6/8). In four cases, TERT promoter mutations were associated with RAS or BRAF mutations. BRAF-mutated classical variant of papillary carcinoma also presented with DM but was less common (1/8). In 11/15 cases, the clinician was able to diagnose distant disease based on the clinical presentation. In 3/4 incidental cases that were genotyped, TERT promoter mutations were found. CONCLUSIONS: When DM occur in primary thyroid carcinoma with low-risk histology, they are almost always found at presentation. The majority are encapsulated follicular variant of PTC with capsular invasion only. TERT promoter mutations occur at a higher rate than that seen in PTC in general and may help explain the aggressive behavior of these histologically deceptive primary carcinomas.

Novel concepts for initiating multitargeted kinase inhibitors in radioactive iodine refractory differentiated thyroid cancer.

Multitargeted kinase inhibitors have been shown to improve progression-free survival in patients with structurally progressive, radioactive iodine refractory differentiated thyroid cancer. While the inclusion criteria for phase 3 clinical trials and clinical practice guidelines provide guidance with regard to the minimal requirements that need to be met prior to initiation of a multitargeted kinase inhibitor, a better way to integrate the rate of structural disease progression with the size of the metastatic foci to more precisely define the optimal time to recommend initiation of therapy for individual patients is needed. In this manuscript we describe how to use assessments of tumor size and growth rates (structural disease doubling times) to define the critical point in time when the volume and rate of progression of metastatic structural disease merits consideration for initiation of systemic therapy (the inflection point).

Patients with Multifocal Macroscopic Papillary Thyroid Carcinoma Have a Low Risk of Recurrence at Early Follow-Up after Total Thyroidectomy and Radioactive Iodine Treatment.

BACKGROUND: Multifocal thyroid cancer involvement is a common presentation in papillary thyroid cancer. The risk of recurrence of intrathyroidal multifocal papillary microcarcinoma (<1 cm) is documented to be low. However, the risk of recurrence of multifocal macroscopic thyroid cancer is not known. Prior studies have suggested that both the number of foci and the presence of nodal involvement at diagnosis are important predictors of recurrence in multifocal papillary thyroid carcinoma (PTC). OBJECTIVES: In this retrospective review of 99 patients presenting with multifocal macroscopic PTC (with 2 tumor foci >1 cm) without gross extrathyroidal extension, we examined the clinical outcomes of patients in the first 2 years after the initial therapy and at the end of the follow-up period (median: 5 years). RESULTS: Half of the patients presenting with multifocal macroscopic PTC had nodal involvement at diagnosis. Only 4 patients had a recurrence on long-term follow-up, all with classic or tall-cell variant PTC with bulky nodal involvement at diagnosis. The number of tumor foci did not influence the risk of recurrence in this cohort. The median time to recurrence in these 4 patients was 11 years, with all patients having a recurrence after 9 years of follow-up. None of patients developed distant metastasis or died from thyroid cancer. CONCLUSIONS: Patients presenting with multifocal macroscopic papillary thyroid cancer without bulky nodal involvement or gross extrathyroidal extension have a low risk of thyroid cancer recurrence.

Time Course and Predictors of Structural Disease Progression in Pulmonary Metastases Arising from Follicular Cell-Derived Thyroid Cancer.

BACKGROUND: With the advent of molecular targeted therapy for the management of radioactive iodine (RAI) refractory, progressive metastatic thyroid cancer, it becomes important to define the time course and risk factors for structural disease progression in follicular cell-derived thyroid cancer (FCDTC) patients. This will help in defining the optimal time to start these therapies and better define their impact on structural disease progression. OBJECTIVES: This retrospective review of 199 consecutive patients with FCDTC presenting with lung metastasis examined the progression-free survival (PFS) in thyroid cancer patients with lung metastasis treated with surgery and RAI, and who had not received molecular targeted therapy or chemotherapy. RESULTS: The median overall survival (OS) was 10.45 years, while the median PFS was 3.65 years. A strong correlation was found between OS and PFS. PFS is shorter in patients with RAI refractory disease, poorly differentiated/Hürthle cell histologies, male sex, fluorodeoxyglucose-avid metastatic foci, older age (>45 years), and pulmonary metastases >1 cm. At final follow-up (a median of 6.9 years from lung metastasis diagnosis), 68% of the patients had progressed and 46% had died. CONCLUSIONS: With the exception of younger patients with low disease burden, most patients presenting with lung metastasis from FCDTC (RAI avid and RAI refractory) using standard-of-care approaches will have disease progression on long-term follow-up. Additional studies are needed to identify novel therapies that would improve the PFS of such patients.

Clinicopathologic Features of Fatal Non-Anaplastic Follicular Cell-Derived Thyroid Carcinomas.

BACKGROUND: The vast majority of thyroid cancers, in particular the non-anaplastic follicular cell-derived thyroid carcinomas (non-ANA FCDC), are considered indolent tumors with very low mortality. Hence, it is crucial to analyze the subgroup of these patients who die of disease (DOD) in order to identify clinicopathologic features predictive of disease-specific mortality. METHODS: All non-ANA FCDC operated at a tertiary cancer center between 1985 and 2010 who were DOD were identified and submitted to a meticulous clinicopathologic analysis. RESULTS: Out of 3750 non-ANA FCDC, 58 (1.5%) DOD cases were identified. The DOD group was composed of 33 (57%) poorly differentiated carcinomas (PDTC), 14 (24%) tall-cell variant papillary thyroid carcinomas (TCVPTC), four (7%) Hürthle cell carcinomas, three (5%) papillary microcarcinomas, two (3%) classical variant PTC, and two (3%) follicular variant PTC. Twenty-seven (47%) patients presented with distant metastases (DM), 28 (48%) developed DM during follow-up, while the remaining three (5%) had locally advanced non-resectable recurrence. Gross extension beyond the thyroid (GET) was present in 36 (62%) and extensive vascular invasion (VI) in 21 (36%) of cases. All microcarcinomas had PDTC in their clinically apparent cervical lymph nodes at presentation. Encapsulated thyroid carcinomas were responsible for 17% of DOD cases, and all had extensive VI and/or DM at presentation. All patients had at least one of these high-risk features at diagnosis: DM at presentation, PDTC, GET, and/or extensive VI. The majority of patients died from DM (n = 51; 88%), three (5%) from locoregional disease, three (5%) from both, and one (2%) from unknown cause. CONCLUSIONS: PDTC and TCVPTC are responsible for the vast majority of deaths in differentiated thyroid carcinomas, while the few fatal classical, follicular variant PTC and microcarcinomas all harbor a PDTC component, DM, or GET. Encapsulated differentiated thyroid carcinoma with focal capsular and/or VI without DM at presentation does not seem to cause death. Lack of DM at presentation, PDTC, GET, and extensive VI identify thyroid carcinomas that are at almost no risk of DOD. The vast majority of patients die of DM rather than locoregional invasion, prompting the need for effective systemic treatment.

RAI thyroid bed uptake after total thyroidectomy: A novel SPECT-CT anatomic classification system.

OBJECTIVE: Recent, more selective use of radioactive iodine (RAI) has led to reevaluation of the clinical importance of achieving complete total thyroidectomy with minimal residual normal thyroid tissue. We utilize the improved localization by post-RAI remnant ablation, single photon emission computerized tomography-computed tomography (SPECT-CT) to define specific anatomic sites of residual RAI-uptake foci after total thyroidectomy for differentiated thyroid cancer (DTC) and to provide a novel classification system relating uptake to thyroid anatomy and preservation of adjacent neural structures. STUDY DESIGN: Retrospective. METHOD: Radioactive iodine-uptake foci in thyroid bed were localized by SPECT/CT imaging at the time of RAI remnant ablation in 141 DTC patients undergoing total thyroidectomy. RESULTS: Minimal residual RAI uptake (median 0.32% at 24 hours) in the thyroid bed was detected by diagnostic planar whole body scans in 93% and by posttherapy SPECT/CT imaging in 99% of subjects. Discrete RAI uptake foci were identified on the SPECT/CT imaging at Berry's ligament (87%), at superior thyroid poles (79%), in paratracheal-lobar regions (67%), in isthmus-region (54%), and in pyramidal lobe (46%). Despite the residual foci, the nonstimulated thyroglobulin (Tg) prior to remnant ablation (with a median thyroid-stimulating hormone of 0.36 m IU/L) was < 0.6 ng/mL in 53% and < 1 ng/mL in 73% of cases. CONCLUSION: After extracapsular total thyroidectomy, highly sensitive detection tools identify microscopic residual RAI avid foci in thyroid bed in the majority of patients. These foci can be classified as 1) neural-related and 2) capsule-related. These common residual foci have no relationship to postoperative Tg, suggesting that attempts at radical removal of thyroid tissue in these locations may not be warranted. LEVEL OF EVIDENCE: 4.

A genome-wide scan for autoimmune thyroiditis in the Old Order Amish: replication of genetic linkage on chromosome 5q11.2-q14.3.

Autoimmune thyroiditis (AITD) is a common disorder characterized by circulating antibodies to epitopes of thyroid tissue and hypothyroidism (Hashimoto's thyroiditis or AITD-hypothyroidism), although many subjects with AITD are euthyroid. Current evidence suggests that AITD is familial and polygenic. We studied AITD in a homogeneous founder Caucasian population, the Old Order Amish of Lancaster County, Pennsylvania. We found autoimmune thyroiditis, defined by the presence of circulating antimicrosomal antibodies, to be relatively common in the Amish, with a prevalence of 22.7%. The prevalence of AITD-hypothyroidism was 9.2%. We performed a genome-wide linkage analysis with 373 short tandem repeat markers in 445 subjects from 29 families. We observed suggestive evidence of linkage of AITD to a locus on chromosome 5q11.2-q14.3 (LOD, 2.30; P = 0.0006 at 94 cM; closest marker, D5S428), a region that was previously reported to be linked to AITD-hypothyroidism in a Japanese study. AITD-hypothyroidism showed a more modest linkage peak to the same region (LOD, 1.46; P = 0.005). Possible linkage (nominal P < 0.01) to autoimmune thyroiditis and/or AITD-hypothyroidism was also detected in five other regions. We conclude that a gene on chromosome 5q11.2-q14.3 is likely to contribute to susceptibility to AITD in the Amish.

Prevalence of diabetes mellitus in patients with newly evaluated papillary thyroid cancer.

BACKGROUND: This study investigates whether diabetes mellitus is a risk factor for the development of papillary thyroid cancer, using an age-, gender-, and race-matched analysis. METHODS: We retrospectively reviewed the charts of 1559 patients with newly evaluated thyroid cancer over a 4-year period at our institution and identified 1313 patients (84%) with papillary thyroid carcinoma. Characteristics of patients with diabetes versus those without diabetes were compared with a chi-square test for categorical variables and the Wilcoxon Rank Sum test for numeric variables. The prevalence of diabetes among patients with papillary thyroid carcinoma at our institution was compared (using an age-, gender-, and race-matched analysis) with that expected based on data from the continuous National Health and Nutrition Examination Survey (NHANES) from the same time period. RESULTS: For patients with papillary thyroid carcinoma, the median age was 47 years; 74% were female; 83% were white; and the prevalence of diabetes was 8%. Among those with diabetes, 92% had type 2 diabetes, and 24% were treated with insulin. Risk factors for diabetes included age and race. The prevalence of diabetes among patients with papillary thyroid carcinoma of all ages versus that among patients from NHANES of all ages was not significantly different (RR 1.07, CI 0.88 - 1.28). The prevalence of diabetes among patients with papillary thyroid cancer who were 44 years of age or younger versus that among patients from NHANES who were 44 years of age or younger, however, was significantly increased (RR 2.32, CI 1.37 - 3.66). There was no significant difference when subgroup analysis was performed by gender or race. CONCLUSIONS: We found an increased prevalence of diabetes in patients with papillary thyroid carcinoma who were 44 years of age or younger.

Higher administered activities of radioactive iodine are associated with less structural persistent response in older, but not younger, papillary thyroid cancer patients with lateral neck lymph node metastases.

BACKGROUND: While radioactive iodine (RAI) adjuvant therapy is commonly recommended for most papillary thyroid cancer patients presenting with large volume nodal involvement, it remains unclear if such therapy impacts the disease-specific recurrence rate and overall survival. In this study, we compared the risk of achieving a structural persistent response after low administered activity (100 mCi), intermediate administered activity (150 mCi), and high administered activity (>200 mCi) RAI adjuvant therapy in patients presenting with pathologic N1b disease. METHODS: This was a retrospective review of 181 papillary thyroid cancer patients with N1b disease treated with total thyroidectomy, neck dissection, and RAI remnant ablation. Dose-response relationships were determined between the administered activity of (131)I and the best response to initial therapy. RESULTS: Out of the 181 patients, only 39% achieved no clinical evidence of disease (NED) after initial therapy. Young patients (Stage I) had a statistically nonsignificant trend toward higher rates of NED with increasing dose (34% low activity, 36% intermediate activity, 46% high activity), but there was no evidence of dose-response effect with regard to the likelihood of having a structural persistent response to initial therapy or the likelihood of having persistent biochemical evidence of disease. However, analysis of the older patients (Stage IVa) did reveal a trend toward statistically significant dose-response relationships with increasing administered activities being associated with lower rates of structural persistent response (46% low activity, 23% intermediate activity, 17% high dose). Unfortunately, the lower rate of structural persistent response only modestly increased the likelihood that patients would be NED but was instead associated with a higher proportion of patients being classified as having biochemical persistent disease at 12-18 months. CONCLUSIONS: It appears that administering more than 100 mCi of RAI as adjuvant therapy in N1b disease is unlikely to improve the initial response to therapy. This is especially true for the younger (Stage I) patients. It is plausible that administered activities of 150-260 mCi may be associated with an improved response to initial therapy in older patients (Stage IVa) who are probably at highest risk of having poor outcomes, but the potential benefit from RAI should be balanced against potential adverse effects in those patients.