Shear wave elastography reveals a high prevalence of liver fibrosis in overweight or obese Hispanic youth.

Background: Obesity, prediabetes, and type 2 diabetes are risk factors for nonalcoholic fatty liver disease. Inflammation and hepatocellular damage associated with nonalcoholic fatty liver disease lead to progressive non-alcoholic steatohepatitis, fibrosis and cirrhosis. Current tests to identify fibrosis (liver biopsy) are invasive and not conducive to serial examination. For that reason, we used the newer technique of shear wave elastogrophy (SWE) to detect fibrosis in overweight or obese Hispanic youth and sought to determine if carbohydrate tolerance or insulin resistance were associated with fibrosis in this high risk population. Methods: A total of 67 Hispanic youth (8-18 years of age) with overweight or obesity who were referred for multidisciplinary evaluation were included. SWE was used to identify those with suspected fibrosis. Results of SWE were then compared with glycohemoglobin (A1c), insulin resistance (homeostatic model of insulin resistance), and biochemical parameters. Results: The prevalence of suspected fibrosis (SWE >5.10 kPa) in overweight or obese Hispanic youth was 62.7% (42/67). Patients with suspected fibrosis (SWE ≥5.10 kPa) had significantly higher levels of serum aspartate aminotransferase, alanine aminotransferase and the aminotransferase to platelet ratio index when compared to patients without significant fibrosis (SWE <5.01 kPa). However, there were no significant differences between the groups in body mass index, A1c, or homeostatic model of insulin resistance. Conclusions: SWE detected a high prevalence (62.7%) of suspected hepatic fibrosis in a group of high risk, overweight or obese Hispanic youth suggesting that SWE is a useful tool for surveillance and longitudinal studies.

Pediatric differentiated thyroid carcinoma: An update from the APSA Cancer Committee.

BACKGROUND: Differentiated thyroid carcinomas (DTCs) are rare in young children but represent almost 10% of all malignancies diagnosed in older adolescents. METHODS: This article reviews the recent literature describing surgical therapeutic approaches to pediatric DTC, associated complications, and long-term recurrence and survival outcomes. RESULTS: Similar to adult thyroid cancers, pediatric DTCs are more common in females and are associated with thyroid nodules, family history of thyroid cancer, radiation exposure, iodine deficiency, autoimmune thyroid disease, and genetic syndromes. Management of thyroid cancers in children involves ultrasound imaging, fine needle aspiration, and surgical resection with treatment decisions based on clinical and radiological features, cytology and risk assessment. CONCLUSIONS: Total thyroidectomy and compartment based resection of clinically involved lymph node basins form the cornerstone of treatment of DTC. There is an evolving literature regarding the use of molecular genetics to inform treatment strategies and the use of targeted therapies to treat iodine refractory and surgically unresectable progressive disease. TYPE OF STUDY: Summary review. LEVEL OF EVIDENCE: This is a review article of previously published Level 1-5 articles that includes expert opinion (Level 5).

FASpecT/CT, A New SPECT/CT Acquisition With Higher Sensitivity and Efficiency in Radioiodine Thyroid Cancer Imaging.

PURPOSE: This article demonstrates the use of a new SPECT/CT acquisition protocol in patients with differentiated thyroid cancer (DTC). METHODS: SPECT/CT scans (FASpecT/CT) with fewer angle acquisitions were retrospectively reviewed in 30 DTC patients treated with radioiodine at University Hospital, San Antonio, Tex, from July 2017 to March 2019. This FASpecT/CT of 12 versus 60 to 64 sampled views for convention SPECT was made possible by iterative reconstruction. RESULTS: The FASpecT/CT protocol was judged to increase lesion detection in patients with low count rates. Furthermore, in patients with higher count rates, this technique reduced the acquisition time. FASpecT/CT patient images are shown as case examples in 4 of the 30 patients reviewed. CONCLUSIONS: This FASpecT/CT acquisition in radioiodine-treated DTC offers the potential of higher sensitivity for metastatic lymph node detection in low count rates and a significant decrease in imaging time in high count rates. These advantages make SPECT/CT imaging more acceptable for patients who have difficulty with longer imaging times, to include the pediatric population.

Papillary thyroid carcinoma presenting as acute suppurative thyroiditis: A case report and review of the literature.

Acute suppurative thyroiditis is a rare, potentially life-threatening condition. We report the case of a 17-year-old male who initially presented with a thyroid abscess. Due to persistent symptoms and lack of evidence for underlying predisposing factors, he was followed closely and subsequently diagnosed with papillary thyroid cancer. He was successfully managed with surgery. His clinical course, radiological evaluation, and pathology reports are presented here along with a review of the literature. This case of papillary thyroid cancer highlights the need for close follow-up of patients presenting with a thyroid abscess, when other predisposing risk factors are not evident.

Evaluation and management of thyroid nodules in children.

PURPOSE OF REVIEW: The review is focused on new information about the presentation and management of thyroid nodules in children and adolescents. RECENT FINDINGS: Palpable thyroid nodules are uncommon in children but many children have nodules detected by radiologic imaging. How to evaluate them, when to suspect thyroid cancer, and how best to follow apparently benign nodules has become an area of great interest. The American Thyroid Association recently published treatment guidelines for children with thyroid nodules and cancers but much has been learned since that publication. SUMMARY: Personal and family history, ultrasound features, and fine needle aspiration cytology are used to determine the risk of cancer in thyroid nodules, which are then managed according to cancer risk.

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer.

BACKGROUND: Previous guidelines for the management of thyroid nodules and cancers were geared toward adults. Compared with thyroid neoplasms in adults, however, those in the pediatric population exhibit differences in pathophysiology, clinical presentation, and long-term outcomes. Furthermore, therapy that may be recommended for an adult may not be appropriate for a child who is at low risk for death but at higher risk for long-term harm from overly aggressive treatment. For these reasons, unique guidelines for children and adolescents with thyroid tumors are needed. METHODS: A task force commissioned by the American Thyroid Association (ATA) developed a series of clinically relevant questions pertaining to the management of children with thyroid nodules and differentiated thyroid cancer (DTC). Using an extensive literature search, primarily focused on studies that included subjects ≤18 years of age, the task force identified and reviewed relevant articles through April 2014. Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force. RESULTS: These inaugural guidelines provide recommendations for the evaluation and management of thyroid nodules in children and adolescents, including the role and interpretation of ultrasound, fine-needle aspiration cytology, and the management of benign nodules. Recommendations for the evaluation, treatment, and follow-up of children and adolescents with DTC are outlined and include preoperative staging, surgical management, postoperative staging, the role of radioactive iodine therapy, and goals for thyrotropin suppression. Management algorithms are proposed and separate recommendations for papillary and follicular thyroid cancers are provided. CONCLUSIONS: In response to our charge as an independent task force appointed by the ATA, we developed recommendations based on scientific evidence and expert opinion for the management of thyroid nodules and DTC in children and adolescents. In our opinion, these represent the current optimal care for children and adolescents with these conditions.

Ultrasound characteristics of the thyroid in children and adolescents with goiter: a single center experience.

INTRODUCTION: Autoimmune thyroiditis (AIT) is a common cause of goiter in children, and sonographic changes have been reported in more than one-third at presentation. The aim of this study was to evaluate the ultrasound (US) characteristics of the thyroid and the prevalence of thyroid nodules in children and adolescents presenting with goiter in the presence or absence of AIT. METHODS: A retrospective review was conducted of the US characteristics of 154 children and adolescents aged <18 years of age with goiter from July 2008 to December 2010. US characteristics were analyzed according to each patient's age, sex, thyrotropin (TSH) levels, and thyroid peroxidase antibody titer (TPOAb). Heterogeneity and nodule prevalence were compared between antibody-positive and -negative goiter. RESULTS: Heterogeneity was more common in TPOAb-positive (59/71, 83%) compared to TPOAb-negative goiter (24/46, 52%; p<0.001), but there was no correlation between the presence of heterogeneity and TPOAb titer within the antibody-positive group. Nodules were equally prevalent in children with (17%) and without (17.4%) TPOAb, and there was no correlation between the serum TSH level or TPOAb titer and the presence of nodules. Papillary thyroid cancer (PTC) was diagnosed in 3/71 with positive TPOAb compared to 1/46 with negative antibodies. Pseudonodules were identified in 11/71 antibody-positive and none of the antibody-negative patients. However, during follow-up, two of these were later identified as nodules and one was PTC. CONCLUSION: The majority of children and adolescents with goiter had positive TPOAb (71/117). Sonographic heterogeneity was more common among TPOAb-positive patients. However, thyroid nodules and PTC were equally common in both groups. Only 15% of the nodules and none of the PTC were palpable. These data support the utility of thyroid US to detect unsuspected thyroid nodules and PTC in children with goiter. Prospective follow-up studies of children with goiter are needed to formulate recommendations for evaluation with US and fine-needle aspiration.

Changes in body anthropometry and composition in obese adolescents in a lifestyle intervention program.

PURPOSE: Impact of lifestyle modification on obesity control during adolescence, a period of significant physical growth and development, is less quantitatively evaluated. Therefore, we investigated the impact of changes in reported energy intake and physical activity on anthropometrics and body composition in adolescents. METHODS: Participants were obese adolescents aged 11-18 years. All of them have a body mass index (BMI) ≥ 95th percentile specific for age and gender according to the 2000 CDC Growth Charts. The intervention consists of supervised physical activity, structured nutrition education and dietary modification, and behavioral support in 6 months. Hundred and forty-five obese adolescents completed the study. RESULTS: Compared to baseline, significant reductions in body weight (-1.4 kg, p < 0.001) and BMI (-0.1 kg/m(2), p < 0.001) were observed at 6 months. When compared to expected growth trajectories on the 2000 CDC Growth Charts, body weight and BMI were reduced by 3.6 kg and 1.5 kg/m(2), respectively, in boys and 5.6 kg and 1.9 kg/m(2) in girls. Age was inversely associated with changes in weight (ß = -1.48 kg, p < 0.01) and BMI (ß = -0.32 kg/m(2), p = 0.03). There was a dose-response relationship between reduction in energy intake and weight loss. A decrease of 100 kcal/day was significantly associated with reductions in body weight 0.30 kg, BMI 0.09 kg/m(2), and BMI Z score 0.01 (all p < 0.01). Physical activity was not significantly associated with changes in anthropometrics or body composition. CONCLUSIONS: Reduction in energy intake was a significant predictor of obesity reduction in these adolescents. A quantitative evaluation of adolescent weight loss programs should account for natural growth and development.

Update on the molecular signature of differentiated thyroid cancer: clinical implications and potential opportunities.

With the development and maturation of new technologies, there has been a steady incorporation of powerful new tools into the evaluation and management of thyroid nodules and thyroid cancer. An increasing number of reports on oncogene testing and molecular screening in fine-needle aspiration biopsy samples have been published. However, there remains a paucity of data and consensus on combining both conventional and molecular technologies to determine the diagnosis and/or prognosis of disease. All patients with differentiated thyroid cancer stand to benefit from the identification and incorporation of reliable molecular markers into clinical practice. Identification of reliable markers would allow for stratification of treatment, affording the medical and surgical teams an ability to individually tailor evaluation and treatment, applying aggressive therapy and monitoring only when clinically warranted. For the majority of patients with thyroid cancer, the incorporation of a validated, multifaceted molecular profiling system may not improve survival; however, there is great opportunity for these efforts to decrease the morbidity associated with our current approach.

Medullary thyroid cancer: management guidelines of the American Thyroid Association.

BACKGROUND: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians. METHODS: Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality. RESULTS: Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and handling of devascularized parathyroid glands), initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy), management of persistent or recurrent MTC (including the role of tumor marker doubling times, and treatment of patients with distant metastases and hormonally active metastases), long-term follow-up and management (including the frequency of follow-up and imaging), and directions for future research. CONCLUSIONS: One hundred twenty-two evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what we believe is current, rational, and optimal medical practice.

GABA receptor expression in benign and malignant thyroid tumors.

Neurotransmitter systems have recently been shown to be involved in multiple malignancies including breast, colon and prostate cancers. The role of neurotransmitters and neurotrophic factors has not yet been examined in thyroid cancer. To determine the possible involvement of neurotransmitter systems in thyroid carcinogenesis we characterized the patterns of gamma-aminobutyric acid (GABA) receptor expression in normal thyroid and thyroid tumors. We examined the expression patterns of the GABAergic system in 70 human thyroid tumor samples (13 follicular adenomas, 14 follicular carcinomas, 43 papillary carcinomas) and adjacent normal thyroid by immunohistochemistry. GABAergic system mRNA expression in thyroid cancer cell lines derived from primary (FTC133) and metastatic tumors (FTC236 and FTC238) was examined by real time PCR. Overall, GABA receptor expression is increased in tumors compared to normal thyroid tissue. Expression of GABAA receptor beta2 was detected in the vasculature of normal thyroid and thyroid tumors but not in thyroid cancer cells. GABAA alpha2 was detected in metastatic-derived but not in primary-tumor derived cell lines. Expression levels of GABAB R2 and GABA receptor associated protein (GABARAP) are increased in adenomas and thyroid cancer suggesting their role in early stages of thyroid tumorigenesis. This study represents the first demonstration of GABA receptor expression in human thyroid tissue and suggests that the GABAergic system is involved in thyroid carcinogenesis.

Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development.

Although treatment of children and adolescents who have disorders of growth and adolescent development with aromatase inhibitors is increasingly common, data for or against their use are extremely limited. Precocious puberty, short stature, and gynecomastia are conditions for which inhibition of the enzyme aromatase might prove beneficial to reduce clinical signs of estrogenization and/or estrogen-mediated skeletal maturation. In this report, we summarize the published data regarding the use of aromatase inhibitors in these conditions, and review known and potential benefits, safety concerns, and shortcomings of the available information.

Papillary and follicular thyroid cancers in children.

Benign and malignant neoplasms of the thyroid are uncommon during childhood, but they create diagnostic problems for the clinician to identify malignant legions that must be removed as well as medically important lesions that require treatment. Throughout the 20th century there was a rapid increase in the incidence of thyroid neoplasms which we now know were induced by ionizing radiation acquired from radiation therapy for benign medical conditions or from environmental sources such as nuclear testing and accidents [Cancer 1961;14:734-743]. Over recent decades, there have been major advances in our understanding of the molecular biology and clinical management of thyroid neoplasms. We hope that the reader of this chapter will find this information of benefit in the clinical management of children with thyroid neoplasms and will be encouraged to study remaining controversial issues. We have divided this chapter into two major sections, the first of which pertains to thyroid nodules and the second to well-differentiated thyroid cancers including papillary, follicular and other variants.

Thyroid cancer in children.

In 1996, the authors were asked to review the subject of thyroid cancer in children. Over the subsequent decade, much has been learned about the treatment and outcome of these uncommon tumors. We now recognize quantitative and perhaps qualitative differences in genetic mutations and growth factor expression patterns in childhood thyroid cancers compared with those of adults. We also know that thyroid cancers induce a robust immune response in children that might contribute to their longevity. Patients under 10 years of age probably represent a unique subset of children at particularly high risk for persistent or recurrent disease; the management of these patients is under evaluation. We remain limited in our knowledge of how to stratify children into low- and high-risk categories for appropriate long-term follow-up and in our knowledge of how to treat children who have detectable serum thyroglobulin but negative imaging studies. In this article, the authors update our understanding of thyroid cancers in children with special emphasis on how these data relate to the current guidelines for management of thyroid cancer developed by the American Thyroid Association Taskforce. The limited data regarding management of children who have detectable serum thyroglobulin but negative whole-body scans are also reviewed.

Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion.

Papillary thyroid carcinomas (PTCs) that invade into local structures are associated with a poor prognosis, but the mechanisms for PTC invasion are incompletely defined, limiting the development of new therapies. To characterize biological processes involved in PTC invasion, we analyzed the gene expression profiles of microscopically dissected intratumoral samples from central and invasive regions of seven widely invasive PTCs and normal thyroid tissue by oligonucleotide microarray and performed confirmatory expression and functional studies. In comparison with the central regions of primary PTCs, the invasive fronts overexpressed TGF beta, NFkappaB and integrin pathway members, and regulators of small G proteins and CDC42. Moreover, reduced levels of mRNAs encoding proteins involved in cell-cell adhesion and communication were identified, consistent with epithelial-to-mesenchymal transition (EMT). To confirm that aggressive PTCs were characterized by EMT, 34 additional PTCs were examined for expression of vimentin, a hallmark of EMT. Overexpression of vimentin was associated with PTC invasion and nodal metastasis. Functional, in vitro studies demonstrated that vimentin was required both for the development and maintenance of a mesenchymal morphology and invasiveness in thyroid cancer cells. We conclude that EMT is common in PTC invasion and that vimentin regulates thyroid cancer EMT in vitro.

Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive and highly lethal human cancers. Median survival after diagnosis is 4-6 months despite available radiotherapy and chemotherapy. Additional treatments are needed for ATC. Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulus, which is expressed by ATC. Previously, anti-VEGF antibody was used to block VEGF-dependent angiogenesis in ATC xenografts. This treatment induced partial (56%) but not complete tumor regression. Aplidin (APLD) is a marine derived antitumor agent currently in phase II clinical studies. Multiple activities of this compound have been described which likely contribute to its antiproliferative effect. Notably, APLD has been shown to have antiangiogenic properties which include: inhibition of VEGF secretion, reduction in the synthesis of the VEGF receptor (FLT-1), and blockade of matrix metalloproteinase production by endothelial cells. We hypothesized that Aplidin, with its broad spectrum of action and antiangiogenic properties, would be a potentially effective drug against ATC. METHODS: Thirty BALB/c nu/nu mice were injected with ATC cells (ARO-81, 1 x 10(6)) and allowed to implant for 3 weeks. Animals were randomized to receive daily intraperitoneal injections of vehicle, low dose (0.5 mg/kg/day), or high dose (1.0 mg/kg/day) APLD. After 3 days, the animals were killed and the tumors were removed, weighed, and divided for RNA and protein analyses. RESULTS: APLD significantly reduced ATC xenograft growth (low dose, 20% reduction, P = 0.01; high dose, 40% reduction, P < 0.001). This was associated with increased levels of apoptosis related proteins polyadenosylribose polymerase 85 (PARP-85, 75% increase, P = 0.024) and caspase 8 (greater than fivefold increase, P = 0.03). APLD treatment was further associated with lost or reduced expression of several genes that support angiogenesis to include: VEGF, hypoxia inducible factor 1(HIF-1), transforming growth factor-beta (TGFbeta), TGFbeta receptor 2 (TGFbetaR2), melanoma growth stimulating factor 1 (GRO1), cadherin, and vasostatin. CONCLUSIONS: This data supports the hypothesis that APLD may be an effective adjunctive therapy against ATC. The demonstrated molecular impact against angiogenic related genes specifically supports future strategies combining APLD with VEGF interacting agents.

Thyroid cancer and the immune system: a model for effective immune surveillance.

Differentiated thyroid cancers, including papillary and follicular variants, are a useful model with which to examine interactions between cancer and the immune system. Differentiated thyroid cancers are detected in only 20,000 individuals annually in the USA, but thyroid microcarcinomas (< 1 cm in diameter) are far more common. This suggests that the immune system might restrain the growth of these microcarcinomas. On the clinical level, patients with lymphocytes that infiltrate into papillary thyroid cancer have improved survival, supporting the notion that immune system activation might improve this. Together, these observations suggest that the growth and distant spread of thyroid carcinoma are suppressed by mechanisms of immune surveillance, possibly involving lymphocytes, macrophages and their secreted products. In this review, we examine the general hypothesis of immune surveillance and the data pertaining to the roles of lymphocytes, dendritic cells and cytokines in the immune response against thyroid cancers.

Thyroid cancers express CD-40 and CD-40 ligand: cancers that express CD-40 ligand may have a greater risk of recurrence in young patients.

The immune response might suppress thyroid cancer recurrence. Although the factors that control this are unknown, CD-40 and CD-40 ligand might be important. To test this, we stained 36 papillary (PTC) and four follicular (FTC) thyroid carcinomas for CD-40 (n = 37) and CD-40 ligand (n = 36) and graded staining from absent (grade 0) to intense (grade 3). Follicular cells of the majority of thyroid tumors expressed CD-40 (30/37, 81%) and CD-40 ligand (15/24, 69%). Cancers from young patients (< or =21 years of age) that expressed CD-40 contained more numerous lymphocytes/high-power field (36 +/- 11) than cancers that failed to express CD-40 (4 +/- 3, p = 0.01), but there was no correlation with clinical outcome. Among young patients, CD-40 ligand expression was more intense in multifocal (1.1 +/- 0.2 vs. 0.45 +/- 0.2, p = 0.037), aggressive (1.14 +/- 0.14 vs. 0.65 +/- 0.2, p = 0.05) and recurrent tumors (1.2 +/- 0.2 vs. 0.65 +/- 0.2, p = 0.05) and associated with reduced disease-free survival (p = 0.03). We conclude that the majority of thyroid cancers express CD-40 and CD-40 ligand. In patients < or =21 years of age, tumors with intense expression of CD-40 ligand are more often multifocal, aggressive, and recurrent.

Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults.

PURPOSE: The fluoropyrimidine carbamate (capecitabine) is converted to 5-fluorouracil (5-FU) by thymidine phosphorylase (TP) inside target tissues. 5-FU interferes with DNA synthesis by blocking thymidylate synthase (TS) but is inactivated by dihydropyrimidine dehydrogenase (DPD). Favorable enzyme profiles (high TP and low DPD) generate high intratumor levels of 5-FU that are effective against many tumors, especially those with low TS. Capecitabine has not been tested against thyroid cancers, and it is not known to what extent thyroid cancers express TP, TS or DPD. METHODS: To test this, we determined TP, TS and DPD in 19 thyroid cancers from young patients (14 papillary, 4 follicular, 1 medullary) by immunohistochemistry. After approval by the Human Use Committee, the intensity of TP, TS, and DPD staining was determined by two independent examiners and graded (absent=0 to intense=3) with >90% concordance. RESULTS: TS was detected in 7/19 cancers (37%), TP in 14/19 cancers (74%) and DPD in 14/19 cancers (74%). In six tumors, TP was more intense that DPD, suggesting capecitabine sensitivity. Only five tumors failed to express TP but four of these expressed DPD, suggesting capecitabine resistance. Overall, 6/19 tumors (32% of the total) had a favorable expression profile, and all of them were papillary cancers. CONCLUSIONS: We conclude that the majority of differentiated thyroid cancers (74%) express TP and low levels of TS (63% undetectable). The results support the hypothesis that capecitabine is activated in the majority of differentiated thyroid cancers and that 32% have favorable expression of all three enzymes (TP, TS, and DPD).