Heart rate informed artificial pancreas system enhances glycemic control during exercise in adolescents with T1D.

OBJECTIVE: To evaluate the safety and performance of using a heart rate (HR) monitor to inform an artificial pancreas (AP) system during exercise among adolescents with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized, cross-over trial, adolescents with T1D age 13 - 18 years were enrolled to receive on separate days either the unmodified UVa AP (stdAP) or an AP system connected to a portable HR monitor (AP-HR) that triggered an exercise algorithm for blood glucose (BG) control. During admissions participants underwent a structured exercise regimen. Hypoglycemic events and CGM tracings were compared between the two admissions, during exercise and for the full 24-hour period. RESULTS: Eighteen participants completed the trial. While number of hypoglycemic events during exercise and rest was not different between visits (0.39 AP-HR vs 0.50 stdAP), time below 70 mg dL -1 was lower on AP-HR compared to stdAP, 0.5±2.1% vs 7.4±12.5% (P = 0.028). Time with BG within 70-180 mg dL -1 was higher for the AP-HR admission vs stdAP during the exercise portion and overall (96% vs 87%, and 77% vs 74%), but these did not reach statistical significance (P = 0.075 and P = 0.366). CONCLUSIONS: Heart rate signals can safely and efficaciously be integrated in a wireless AP system to inform of physical activity. While exercise contributes to hypoglycemia among adolescents, even when using an AP system, informing the system of exercise via a HR monitor improved time <70 mg dL -1 . Nonetheless, it did not significantly reduce the total number of hypoglycemic events, which were low in both groups.

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.

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.

Psychological treatment improves hemoglobin A1c outcomes in adolescents with type 1 diabetes mellitus.

UNLABELLED: Adolescents diagnosed with Type 1 Diabetes Mellitus often exhibit reduced adherence to their medical regimen and poor glycemic control. A retrospective study examined longitudinal hemoglobin A1c (HgbA1c) outcomes for adolescent patients referred to the psychology service embedded within an endocrinology clinic. Three patient groups were examined: (1) TREATMENT: 59 adolescents referred who engaged in psychotherapy; (2) No TREATMENT: 40 adolescents referred yet failed to initiate psychotherapy; (3) CONTROL: 58 adolescents not referred for treatment and matched on demographics to the two treatment groups. Over 1 year, the TREATMENT group had a sustained decrease in HgbA1c while the No TREATMENT and CONTROL groups had an overall increase in HgbA1c. At study end, the TREATMENT group had HgbA1c values that were not significantly different from patients who were not considered in need of psychological treatment (CONTROL). Adolescents that utilized the pediatric psychology service saw decreased HgbA1c values over time.

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.

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.

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).

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.

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.

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.

Autoimmune thyroid diseases in children.

INTRODUCTION: Autoimmune thyroid diseases (AIT) are common in children and may present with a variety of signs and symptoms including: euthyroid goiter, hypothyroidism, or hyperthyroidism. The natural history of AIT may be different in children but in all age groups, there appear to be genetic risk factors and environmental triggers that initiate thyroid autoimmunity. Areas covered: In this review, we summarize recent studies that investigate the genetics and environmental triggers believed to be involved in thyroid autoimmunity. We also discuss the approach and controversies in the treatment of children with AIT. Expert commentary: Much has been learned about the major roles for genetics, cytokines, regulatory lymphocytes, and environmental triggers in CLT but controversies remain.

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 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.

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.

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.

Papillary thyroid carcinomas from young adults and children contain a mixture of lymphocytes.

The immune response appears to be important in preventing metastasis and recurrence of thyroid cancer. We previously showed that papillary thyroid carcinoma (PTC) from children and adolescents that contain the most numerous proliferating lymphocytes have the best prognosis. However, the types of lymphocytes involved are not yet known. To further define this, we examined 21 PTCs from patients 21 yr of age or younger (52% were 18-21 yr of age) for the presence of CD4+ (helper), CD8+ (killer), CD19+ (B cells), and CD56+ (natural killer) cells as well as proliferating lymphocytes (Ki-67+). Nearly half the PTCs contained CD4+ (9 of 21, 43%), CD8+ (8 of 21, 38%), or CD19+ (10 of 21, 48%) lymphocytes. Only one PTC (1 of 21, 5%) contained CD56+ lymphocytes, and none contained all four cell types. By dual staining, none of these lymphocytes were proliferating (Ki-67+). However, PTCs containing either CD8+ cells (n = 8) or a combination of CD4+, CD8+, and CD19+ cells (n = 5) contained more numerous proliferating lymphocytes than did PTCs containing any other combination (14.2-fold increase, P = 0.03 and 13.1-fold increase, P = 0.003, respectively). During follow-up, none of the PTCs containing either CD8+ lymphocytes or the combination of CD4+, CD8+, and CD19+ lymphocytes recurred. However, the cohort is too small and the follow-up inadequate to provide accurate information on the clinical impact of these immunological findings. We conclude that the immune response against PTC is important and also complex, involving more than one type of lymphocyte.

Intense expression of the b7-2 antigen presentation coactivator is an unfavorable prognostic indicator for differentiated thyroid carcinoma of children and adolescents.

Previous observations suggest that an immune response against thyroid carcinoma could be important for long-term survival. We recently found that infiltration of thyroid carcinoma by proliferating lymphocytes is associated with improved disease-free survival, but the factors that control lymphocytic infiltration and proliferation are largely unknown. We hypothesized that the antigen presentation coactivators (B7-1 and B7-2), which are important in other immune-mediated thyroid diseases, might be important in lymphocytic infiltration of thyroid carcinoma. To test this, we determined B7-1 and B7-2 expression by immunohistochemistry [absent (grade 0) to intense (grade 3)] in 27 papillary (PTC) and 8 follicular (FTC) thyroid carcinomas and 9 benign thyroid lesions. B7-1 and B7-2 were expressed by the majority of PTC and FTC (78% of PTC and 100% of FTC expressed B7-1; 88% of PTC and 88% of FTC expressed B7-2). B7-1 expression was more intense in PTC (1.4 +/- 0.2; P = 0.01) and FTC (2.6 +/- 0.2; P < 0.001) than in benign tumors (0.57 +/- 0.30) or presumably normal adjacent thyroid (0.07 +/- 0.07) and was more intense in carcinoma that contained lymphocytes (1.95 +/- 0.21) than in carcinoma that did not (1.08 +/- 0.26; P = 0.016). B7-2 expression was of similar intensity in benign and malignant tumors (PTC, 1.6 +/- 0.2; FTC, 2.1 +/- 0.4; benign, 1.86 +/- 0.4), but was more intense than in presumably normal adjacent thyroid (0.64 +/- 0.25; P

Evaluation of adult papillary thyroid carcinomas by comparative genomic hybridization and microsatellite instability analysis.

To clarify the mechanism of tumorigenesis in papillary thyroid carcinoma (PTC) and ascertain whether genomic changes correlate with histologic features, we conducted a comprehensive molecular evaluation of PTC using comparative genomic hybridization (CGH) and microsatellite instability (MSI) analysis in a set of 17 histologically well-characterized PTC specimens. To our knowledge, this is the first study that evaluates chromosomal and nucleotide instability in the same PTC tumor specimens. Four of 15 samples (27%) had aberrations detected by CGH. All four had a partial or complete gain of chromosome 20, and 3 of 4 had a partial or complete loss of chromosome 13. No MSI was detected in any of the PTC samples (n=16), and all samples examined by immunohistochemistry (n=9) expressed the DNA repair enzymes hmlh1 and hmsh2. All PTC samples with abnormal CGH had vascular invasion or invasion of the thyroid capsule, and there was a significant correlation between the presence of chromosomal aberrations and capsular/vascular invasion (P=0.026). We conclude that although chromosomal and microsatellite instability are uncommon in PTC, tumors with chromosomal aberrations are more likely to be associated with invasion.

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).

Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice.

BACKGROUND: Anaplastic thyroid cancer (ATC) does not respond well to any treatment and is one of the most aggressive of all human cancers. Based on the importance of angiogenesis in solid tumor growth, we hypothesized that angiogenic blockade might reduce the growth of ATC. METHODS: We tested the in vivo effect of vascular endothelial growth factor monoclonal antibody (VEGF-mAb) and thalidomide against ATC (ARO-81) xenografts in nude mice. Mice were injected subcutaneously with 1 x 10(6) ARO-81 cells, allowed to implant (1 week), and then given daily intraperitoneal injections of vehicle (control; n = 9), VEGF-mAb (200 microg/d; n = 9), or thalidomide (200 mg/kg per day; n = 9). Tumors were removed, sectioned, and stained for routine histology and immunohistochemistry. RESULTS: At 6 weeks, VEGF-mAb-treated tumors were smaller (1603 +/- 296 mm(3)) than either the thalidomide-treated (6007 +/- 1498 mm(3); p = 0.008) or the control groups (4040 +/- 831 mm(3); p = 0.014) and the VEGF-mAb-treated animals maintained greater weight (30.4 +/- 0.84 g at week 6 versus thalidomide-treated, 26.0 +/- 0.94 g, p = 0.003; and control, 25.8 +/- 0.78 g, p = 0.001 animals). Central necrosis was observed in 3 of 9 VEGF-mAb-treated confidence interval (33%; 95% [CI] = 0.12-0.65) but in none of the control or thalidomide-treated tumors (0/18 total; 95% CI = 0.0-0.30; p = 0.029). VEGF staining intensity for VEGF-mAb- (2.0 +/- 0.24; p = 0.012) and thalidomide- (2.1 +/- 0.05; p = 0.052) treated tumors was greater than control (0.89 +/- 0.31) as was p53 staining grade (VEGF-mAb [1.3 +/- 0.37; p = 0.012]; thalidomide [1.0 +/- 0.41; p = 0.05]; and controls [0.11 +/- 0.11]). CONCLUSION: We conclude that systemic VEGF-mAb significantly reduces growth of ATC xenografts and is associated with increased VEGF and p53 expression. Thalidomide has no effect on tumor growth, but is also associated with increased VEGF and p53 expression. These observations provide the first evidence that VEGF-mAb-induced angiogenesis blockade may be of use for the treatment of ATC.