Antineoplastic agents. 548. Synthesis of iodo- and diiodocombstatin phosphate prodrugs.

Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line. Of the diiodo series, 12a was also found to markedly inhibit growth of pediatric neuroblastoma, and monoiodocombstatin 9a strongly inhibited HUVEC growth. Overall, the strongest activity was found against the breast, CNS, leukemia, lung, and prostate cancer cell lines and the least activity against the pancreas and colon lines. Parallel biological investigations of tubulin interaction, antiangiogenesis, and antimicrobial effects were also conducted.

Protein synthesis inhibitors, in synergy with 5-azacytidine, restore sodium/iodide symporter gene expression in human thyroid adenoma cell line, KAK-1, suggesting trans-active transcriptional repressor.

CONTEXT: Therapy of thyroid carcinoma uses its radioiodine concentration ability for treatment. Dedifferentiated cells lose radioiodine uptake from human sodium-iodide symporter (hNIS) gene transcription failure consequent to genomic structure (chromatin compaction) and composition (CpG methylation). OBJECTIVE AND METHODS: We explored restoring hNIS expression in human thyroid carcinoma cells using thyroid adenoma and carcinoma cell lines: KAK-1, NPA87, BHT-101, and KAT-4B, with quantitative RT-PCR, chromatin immunoprecipitation, deoxyribonuclease I sensitivity assays, and luciferase reporter construct transfections containing hNIS promoter regions. RESULTS: Combined 5-azacytidine and sodium butyrate restores hNIS gene transcription in KAK-1 to levels approaching radioiodine-treatable tumors. Despite induction of H4 acetylation, there was no deoxyribonuclease I sensitivity enhancement in two regions of the hNIS gene promoter. Cycloheximide in cells transfected with luciferase reporter construct, 1.3 kb hNIS gene promoter, stimulated normalized luciferase expression, singly and synergistically with 5-azacytidine, in a dose-dependent, time course-dependent, cell type-specific, and promoter-specific fashion. Both anisomycin and emetine, but not puromycin, had similar effects. Cycloheximide also increased endogenous hNIS mRNA. Transfections with reporter constructs containing consecutive deletions of hNIS gene promoter sequences revealed responsible sequences at -427 to -131 bp. Deletion of 1.2 kb promoter region upstream of -131 bp enhanced basal luciferase reporter activity 3-fold above the activity of full length promoter construct, supporting inhibitory properties of this region. CONCLUSIONS: This suggests that trans-active protein factor(s) represses endogenous hNIS transcription in KAK-1 cells under basal conditions, accounting for loss of iodine uptake. Inhibition of this repressive activity increases endogenous hNIS transcription and presents a novel target to restore hNIS expression in dedifferentiated thyroid carcinoma.

Phase II trial of thalidomide for therapy of radioiodine-unresponsive and rapidly progressive thyroid carcinomas.

BACKGROUND: There are no known effective therapies for distantly metastatic, rapidly progressive thyroid carcinomas unresponsive to radioiodine. OBJECTIVE: Since thyroid carcinomas are hypervascular and thalidomide is antiangiogenic, we assessed thalidomide's tumoristatic effects and toxicity in a phase II trial. DESIGN: Thirty-six patients with follicular, papillary, insular, or medullary thyroid carcinomas and distant, radioiodine-unresponsive metastases (volumes increasing >or= 30% per year before entry) were accrued between July 2001 and December 2002. Daily thalidomide started at 200 mg, increasing over 6 weeks to 800 mg or maximum tolerated dose. Toxicities and responses were assessed at 8-week intervals with tumor volume assessments. MAIN OUTCOMES: Twenty-eight of 36 patients were evaluable, 5 with partial responses (PR: 18%; 95% confidence interval [95% CI]: 6-37%) and 9 patients with stable disease (SD: 32%; 95% CI: 12-42%) for overall 50% response (95% CI: 31-69%). Median PR duration was 4 months (range: 2-6 months), and SD duration was 6 months (range: 2-14 months). Median survival was 23.5 months for responders (PR + SD) and 11 months for nonresponders. Most frequent toxicity was fatigue (69% grade 1-2, 8% grade 3-4). Four patients had grade 3-4 infections (without neutropenia), one had pericardial effusion, and one had pulmonary embolus. CONCLUSIONS: Thalidomide confers therapeutic benefit in subsets of thyroid cancer patients with rapidly progressive, distantly metastatic disease.

Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro.

CONTEXT: The ubiquitin-proteasome pathway is a major pathway for degradation of intracellular proteins. Proteasome inhibitors constitute a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. The proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the Food and Drug Administration for the treatment of multiple myeloma and is being studied intensely in several other malignancies. Its mechanism of action is complex but appears to include the inhibition of inhibitory-kappaB degradation, which leads to inactivation of the transcriptional factor nuclear factor-kappaB (NF-kappaB). NF-kappaB has been implicated in the pathophysiology of the most aggressive forms of thyroid carcinoma, i.e. medullary and anaplastic. OBJECTIVE AND METHODS: We evaluated the effect of bortezomib on a panel of thyroid carcinoma cell lines, originating from papillary, follicular, anaplastic, and medullary carcinomas. RESULTS: Bortezomib induced apoptosis in medullary and anaplastic cell lines with IC(50) values well within the range of clinically achievable concentrations and much lower than respective IC(50) values for other solid malignancies. Bortezomib inhibited NF-kappaB activity; increased p53, p21, and jun expression; and induced caspase-dependent apoptosis. Sensitivity of thyroid carcinoma cells to bortezomib was partially decreased by overexpression of Bcl-2 or treatment with IGF-I, whereas the combination of bortezomib with chemotherapy (doxorubicin) was synergistic. CONCLUSIONS: These data provide both insights into the molecular mechanisms of antitumor activity of proteasome inhibitors and the rationale for future clinical trials of bortezomib, alone or in combination with conventional chemotherapy, to improve patient outcome in medullary and anaplastic thyroid carcinomas.

Outcomes of patients with differentiated thyroid carcinoma following initial therapy.

This analysis was performed to determine the effect of initial therapy on the outcomes of thyroid cancer patients. The study setting was a prospectively followed multi-institutional registry. Patients were stratified as low risk (stages I and II) or high risk (stages III and IV). Treatments employed included near-total thyroidectomy, administration of radioactive iodine, and thyroid hormone suppression therapy. Outcome measures were overall survival, disease-specific survival, and disease-free survival. Near-total thyroidectomy, radioactive iodine, and aggressive thyroid hormone suppression therapy were each independently associated with longer overall survival in high-risk patients. Near-total thyroidectomy followed by radioactive iodine therapy, and moderate thyroid hormone suppression therapy, both predicted improved overall survival in stage II patients. No treatment modality, including lack of radioactive iodine, was associated with altered survival in stage I patients. Based on our overall survival data, we confirm that near-total thyroidectomy is indicated in high-risk patients. We also conclude that radioactive iodine therapy is beneficial for stage II, III, and IV patients. Importantly, we show for the first time that superior outcomes are associated with aggressive thyroid hormone suppression therapy in high-risk patients, but are achieved with modest suppression in stage II patients. We were unable to show any impact, positive or negative, of specific therapies in stage I patients.

High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines.

The RAS-RAF-MEK-ERK-MAP kinase pathway mediates the cellular response to extracellular signals that regulate cell proliferation, differentiation, and apoptosis. Mutation of the RAS proto-oncogene occurs in various thyroid neoplasms such as papillary thyroid carcinomas (PTCs), follicular thyroid adenomas and carcinomas. A second genetic alteration frequently involved in PTC is RET/PTC rearrangements. Recent studies have shown that BRAF, which is a downstream signaling molecule of RET and RAS, is frequently mutated in melanomas. This study tests whether BRAF is also mutated in thyroid tumors and cell lines. We analyzed BRAF gene mutation at codon 599 in thyroid tumors using mutant-allele-specific PCR and in 10 thyroid tumor cell lines by DNA sequencing of the PCR-amplified exon 15. We found that BRAF was mutated in 8 of 10 thyroid tumor cell lines, including 2 of 2 papillary carcinoma cell lines, 4 of 5 anaplastic carcinoma cell lines, 1 of 2 follicular carcinoma cell lines, and 1 follicular adenoma cell line. BRAF mutation at codon 599 was detected in 21 of 56 PTC (38%) but not in 18 follicular adenomas and 6 goiters. BRAF mutation occurred in PTC at a significantly higher frequency in male patients than in female patients. To test whether BRAF mutation may cooperate with RET/PTC rearrangements in the oncogenesis of PTC, we tested whether BRAF-mutated PTCs were also positive for RET/PTC rearrangements. Immunohistochemical staining was conducted to evaluate RET/PTC rearrangements by using two different anti-RET antibodies. Surprisingly, we found that a large number of BRAF-mutated PTCs (8 of 21) also expressed RET, indicating that the RET proto-oncogene is rearranged in these BRAF-mutated PTCs. These observations suggest that mutated BRAF gene may cooperate with RET/PTC to induce the oncogenesis of PTC.

Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: a potential role in tumor metastasis.

PURPOSE: Heparanase-1 (HPR1) is an endoglycosidase that degrades the side chains of heparan sulfate proteoglycan (HSPG), a key component in cell surfaces, the extracellular matrix (ECM), and the basement membrane (BM). The purpose of this study was to evaluate HPR1 expression in thyroid neoplasms and its effect in degrading the HSPG substrates in the ECM and BM and to determine its role in thyroid tumor metastasis. EXPERIMENTAL DESIGN: HPR1 mRNA expression was analyzed by using in situ hybridization with a digoxigenin-labeled antisense RNA probe on paraffin-embedded tumor sections and reverse transcription-PCR (RT-PCR) in fresh tumor tissues. HPR1 protein expression was analyzed by using immunohistochemical staining with an anti-HPR1 rabbit antiserum and immunofluorescence (IF) with an anti-HPR1 monoclonal antibody. The effect of HPR1 expression in thyroid neoplasms was analyzed by examining the presence and integrity of the HSPG substrates in the ECM and BM using IF staining with a specific monoclonal antibody against heparan sulfate. The relationship of HPR1 expression in papillary thyroid carcinomas (PTCs) with various clinicopathological parameters was analyzed statistically. The role of HPR1 in thyroid tumor metastasis was further examined by comparing HPR1 levels in 10 thyroid tumor cell lines to their invasive and metastatic potential. RESULTS: In situ hybridization analysis of 81 tumor samples (62 papillary carcinomas and 19 follicular adenomas) revealed that HPR1 was expressed at a much higher frequency in PTCs than in follicular adenomas (P<0.05). RT-PCR analyses of fresh tumor tissues revealed that HPR1 mRNA could be detected in primary and metastatic thyroid papillary carcinomas. HPR1 expression was confirmed at the protein level by immunohistochemical staining and IF stainings. IF analysis of HSPG revealed that HS was deposited abundantly in the BM of normal thyroid follicles and benign follicular adenomas but was absent in most thyroid papillary carcinomas. A lack of heparan sulfate in PTCs inversely correlated with HPR1 expression. Clinicopathological data analyses revealed that PTCs with local and distant metastases scored HPR1 positive at a significantly higher frequency than nonmetastatic thyroid cancers (P=0.02). To further explore the role of HPR1 in tumor metastases, we characterized HPR1 expression in 10 thyroid tumor cell lines using RT-PCR and Western blot and measured HPR1 enzymatic activity using a novel ELISA. HPR1 was differentially expressed in different types of cell lines; overexpression of HPR1 in two tumor cell lines led to a dramatic increase of their invasive potential in vitro in an artificial BM. CONCLUSIONS: Our study suggests that HPR1 expressed in papillary carcinomas is functional and that HPR1 expression is associated with thyroid tumor malignancy and may significantly contribute to thyroid tumor metastases.

Radioiodine-remnant ablation in low-risk differentiated thyroid cancer: pros.

Differentiated thyroid carcinomas are typically treated with total thyroidectomy as initial therapy. Subsequent radioactive iodine (RAI) ablation destroys post-surgical thyroid remnants, can additionally provide adjuvant therapy of residual and metastatic thyroid cancers, and enhances the sensitivity and specificity of further diagnostic studies. There is current controversy regarding whether a large number of patients, broadly considered to have "low-risk" disease, should be provided RAI ablation. This is consequent to over-reliance on short-term studies, under-appreciation of the value of RAI remnant ablation, and inflation of the side effects of RAI therapy. A balanced assessment of all of these issues provides justification to utilize post-surgical radioiodine ablation, even in cases that are considered low risk on the basis of surgical findings.

Reversible cognitive, motor, and driving impairments in severe hypothyroidism.

BACKGROUND: Hypothyroidism has been associated with cognitive and motor impairments that are likely to constitute hazards in the operation of motor vehicles and a public safety risk. However, there is a paucity of data that would provide an evidence basis for recommendations to hypothyroid patients. The purpose of this study was to determine the specific neurological and psychological deficits consequent to hypothyroidism and whether they are of sufficient magnitude to impede the safe operation of motor vehicles. METHODS: Repeated measurements were obtained in euthyroid, hypothyroid, and euthyroid hormone replaced states of thyroid cancer outpatients, at an academic medical center, who underwent thyroid hormone withdrawal preparation for radioiodine scanning. Study design used a within-subjects longitudinal "A-B-A" with each subject tested at three visits in the same sequence: euthyroid, hypothyroid, and euthyroid for a total of 32 subjects. Data on clinical status and cognitive performance were collected using standard instruments, including ThyDQoL and ThySRQ measures, National Adult Reading Test, Boston Naming Test, Mini-Mental State Exam, Wechsler Adult Intelligence Test-Revised, Letter Fluency FAS, and Beck Depression Inventory. Fine-motor function was measured with an automated assessment panel, and driving performance on a commercial driving simulator. RESULTS: In severe hypothyroidism (median thyrotropin 83.2 mIU/L), fine-motor performance of hands and reaction times in emergency braking tests were slowed, as well as subjective slowing reported on structured clinical scales. Depression was present, typified by vegetative and mood alterations, but lacking reported guilt and lowered self-esteem seen in other types of depression. Cognitive impairment was characterized by declines on speeded executive tests. In contrast, episodic memory performance improved over time regardless of thyroid hormone status. Braking times increased in hypothyroidism by 8.5%, equivalent to reports of effects from a blood alcohol level of 0.082 g/100 mL (above the U.S. legal driving limit). CONCLUSIONS: Transient profound hypothyroidism is characterized by reversible depression, decreased fine-motor performance, slowed reaction times, and decreased processing speed. These data represent new empirical evidence that support the recommendation that complex activities requiring rapid responses, such as operating motor vehicles, should be avoided during hypothyroidism. This has broader implications regarding functional impairments and risk to public health.

Reassessing the NTCTCS Staging Systems for Differentiated Thyroid Cancer, Including Age at Diagnosis.

BACKGROUND: Thyroid cancer is unique for having age as a staging variable. Recently, the commonly used age cut-point of 45 years has been questioned. OBJECTIVE: This study assessed alternate staging systems on the outcome of overall survival, and compared these with current National Thyroid Cancer Treatment Cooperative Study (NTCTCS) staging systems for papillary and follicular thyroid cancer. METHODS: A total of 4721 patients with differentiated thyroid cancer were assessed. Five potential alternate staging systems were generated at age cut-points in five-year increments from 35 to 70 years, and tested for model discrimination (Harrell's C-statistic) and calibration (R(2)). The best five models for papillary and follicular cancer were further tested with bootstrap resampling and significance testing for discrimination. RESULTS: The best five alternate papillary cancer systems had age cut-points of 45-50 years, with the highest scoring model using 50 years. No significant difference in C-statistic was found between the best alternate and current NTCTCS systems (p = 0.200). The best five alternate follicular cancer systems had age cut-points of 50-55 years, with the highest scoring model using 50 years. All five best alternate staging systems performed better compared with the current system (p = 0.003-0.035). There was no significant difference in discrimination between the best alternate system (cut-point age 50 years) and the best system of cut-point age 45 years (p = 0.197). CONCLUSIONS: No alternate papillary cancer systems assessed were significantly better than the current system. New alternate staging systems for follicular cancer appear to be better than the current NTCTCS system, although they require external validation.

Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012.

CONTEXT: Initial treatments for patients with differentiated thyroid cancer are supported primarily by single-institution, retrospective studies, with limited follow-up and low event rates. We report updated analyses of long-term outcomes after treatment in patients with differentiated thyroid cancer. OBJECTIVE: The objective was to examine effects of initial therapies on outcomes. DESIGN/SETTING: This was a prospective multi-institutional registry. PATIENTS: A total of 4941 patients, median follow-up, 6 years, participated. INTERVENTION: Interventions included total/near-total thyroidectomy (T/NTT), postoperative radioiodine (RAI), and thyroid hormone suppression therapy (THST). MAIN OUTCOME MEASURE: Main outcome measures were overall survival (OS) and disease-free survival using product limit and proportional hazards analyses. RESULTS: Improved OS was noted in NTCTCS stage III patients who received RAI (risk ratio [RR], 0.66; P = .04) and stage IV patients who received both T/NTT and RAI (RR, 0.66 and 0.70; combined P = .049). In all stages, moderate THST (TSH maintained subnormal-normal) was associated with significantly improved OS (RR stages I-IV: 0.13, 0.09, 0.13, 0.33) and disease-free survival (RR stages I-III: 0.52, 0.40, 0.18); no additional survival benefit was achieved with more aggressive THST (TSH maintained undetectable-subnormal). This remained true, even when distant metastatic disease was diagnosed during follow-up. Lower initial stage and moderate THST were independent predictors of improved OS during follow-up years 1-3. CONCLUSIONS: We confirm previous findings that T/NTT followed by RAI is associated with benefit in high-risk patients, but not in low-risk patients. In contrast with earlier reports, moderate THST is associated with better outcomes across all stages, and aggressive THST may not be warranted even in patients diagnosed with distant metastatic disease during follow-up. Moderate THST continued at least 3 years after diagnosis may be indicated in high-risk patients.

Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin.

The skin is commonly affected in thyroid diseases, but the mechanism for this association is still unclear. As the skin expresses numerous neuroendocrine elements, we tested the additional cutaneous expression of mediators operating in the hypothalamic-pituitary-thyroid axis. We found significant expression of the thyroid-stimulating hormone receptor mRNA in cultured keratinocytes, epidermal melanocytes, and melanoma cells. The presence of thyroid-stimulating hormone receptor was confirmed by northern analyses and the thyroid-stimulating hormone receptor was found to be functionally active in cyclic adenosine monophosphate signal assays. Thyroid-stimulating hormone receptor expressing cells also expressed the sodium iodide symporter and thyroglobulin genes. We also found expression of deiodinases 2 and 3 (mainly deiodinase 2) in whole skin biopsy specimens, and in the majority of epidermal and dermal cells by reverse transcription-polymerase chain reaction followed by sequencing of the amplified gene segments. There was selective expression of the gene for thyroid-stimulating hormone beta; detection of the thyroid-releasing hormone gene was minimal and thyroid-releasing hormone receptor mRNA was not detected in most of the samples. Expression of functional thyroid-stimulating hormone receptor in the skin may have significant physiologic and pathologic consequences, particularly in autoimmune conditions associated with production of stimulating antibodies against the thyroid-stimulating hormone receptor. We conclude that the expanding list of neuroendocrine elements expressed in the skin supports a strong role for this system in cutaneous biology.

Imatinib mesylate (gleevec; STI571) monotherapy is ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro.

Imatinib mesylate is remarkably effective in treating chronic myeloid leukemia and metastatic gastrointestinal stromal tumors. Meanwhile, anaplastic thyroid carcinoma (ATC) remains a fatal malignancy for which there are currently no effective curative interventions. In chronic myeloid leukemia and gastrointestinal stromal tumors, imatinib inhibits the constitutive tyrosine kinase activity of BCR-ABL and c-KIT, respectively. Reports suggest that imatinib may also be effective against ABL and platelet-derived growth factor receptor kinase-dependent pathological conditions. These mechanisms provide a wide scope of possible clinical applications for the drug. Potentially, diseases instigated by constitutive kinase activity that can be inhibited with imatinib should be treatable with this drug. We evaluated the effects of imatinib on the viability, cycling, and tyrosine phosphorylation of ATC cells in vitro. Our data indicate that imatinib has negligible antineoplastic activity against ATC cell lines within established therapeutically useful concentrations. No constitutive kinase activity was detected in these cell lines that could be exploited as a therapeutic target by imatinib. We conclude that imatinib mesylate monotherapy would not be effective in ATC patients. Current preclinical data do not warrant future clinical studies of imatinib monotherapy for ATC.

Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors.

Anaplastic thyroid carcinoma (ATC) is a fatal malignancy the clinical outcome of which is unaltered by current therapeutic modalities. A recent phase 1 clinical trial of combretastatin A4 phosphate (CA4P) produced a long-lasting total remission in a patient with ATC. CA4P is a tubulin-binding agent derived from the African bush willow, Combretum caffrum, which possesses tumor vascular-targeting activity. In order to discriminate primary antineoplastic effects from tumor antivascular activity, we evaluated CA4P cytotoxicity in eight human ATC cell lines and compared it to paclitaxel, another tubulin-binding agent with significant clinical activity. CA4P displayed significant cytotoxicity against the ATC cell lines, comparable to that of paclitaxel, and these effects were longer lasting in two cell lines compared to the duration of paclitaxel. We further investigated the effects of CA4P on xenograft tumors from four ATC cell lines injected in athymic nude mice. Significantly lower tumor weights were observed in animals treated with CA4P compared to those treated with vehicle alone. Continuous monitoring of xenograft tumor volumes from one of the ATC cell lines also revealed a significantly lower rate of tumor growth in the CA4P-treated mice compared to those receiving vehicle alone. These results suggest that antitumoral effects of CA4P can be consequent to a combination of primary antineoplastic effects as well as the potential destruction of tumor vasculature.

Thyroglobulin: a specific serum marker for the management of thyroid carcinoma.

Thyroglobulin measurements in tissue and serum play an integral role in the evaluation of patients who have thyroid cancer. Immunohistochemical detection of thyroglobulin in surgical specimens is useful in the differential diagnosis of tumors of unknown origin; however, the most important application of thyroglobulin measurement in clinical practice is in the postsurgical management of differentiated thyroid cancer. Serum thyroglobulin is a highly specific and sensitive tumor marker for detecting persistent or recurrent thyroid cancer and for monitoring clinical status. The reappearance of circulating thyroglobulin after total thyroid ablation is pathognomonic for the presence of tumor. The measurement of thyroglobulin in serum is challenging, however, and several analytical problems limit assay performance. Thyroglobulin autoantibody interference is a particularly significant concern that requires all thyroglobulin samples to be screened for their presence. No immunoassay is totally free from interference by thyroglobulin autoantibodies. Measurement of thyroglobulin mRNA to detect circulating tumor cells may help to overcome some of the limitations of current protein-detection methods; serum thyroglobulin will continue to remain the "gold standard." The complex functional features of thyroid carcinomas make sole reliance upon any one diagnostic technique, including thyroglobulin assessments, potentially misleading. Thyroglobulin measurements are a critical component of a multifaceted diagnostic approach to this disease.

Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis.

BACKGROUND: Serum thyrotropin (TSH) concentration and thyroid autoimmunity may be of prognostic importance in differentiated thyroid cancer (DTC). Preoperative serum TSH level has been associated with higher DTC stage in cross-sectional studies; data are contradictory on the significance of thyroid autoimmunity at the time of diagnosis. OBJECTIVE: We sought to assess whether preoperative serum TSH and perioperative antithyroglobulin antibodies (TgAb) were associated with thyroid cancer stage and outcome in DTC patients followed by the National Thyroid Cancer Treatment Cooperative Study, a large multicenter thyroid cancer registry. METHODS: Patients registered after 1996 with available preoperative serum TSH (n=617; the TSH cohort) or perioperative TgAb status (n=1770; the TgAb cohort) were analyzed for tumor stage, persistent disease, recurrence, and overall survival (OS; median follow-up, 5.5 years). Parametric tests assessed log-transformed TSH, and categorical variables were tested with chi square. Disease-free survival (DFS) and OS was assessed with Cox models. RESULTS: Geometric mean serum TSH levels were higher in patients with higher-stage disease (Stage III/IV=1.48 vs. 1.02 mU/L for Stages I/II; p=0.006). The relationship persisted in those aged ≥45 years after adjusting for sex (p=0.01). Gross extrathyroidal extension (p=0.03) and presence of cervical lymph node metastases (p=0.003) were also significantly associated with higher serum TSH. Disease recurrence and all-cause mortality occurred in 37 and 38 TSH cohort patients respectively, which limited the power for survival analysis. Positive TgAb was associated with lower stage on univariate analysis (positive TgAb in 23.4% vs. 17.8% of Stage I/II vs. III/IV patients, respectively; p=0.01), although the relationship lost significance when adjusting for age and sex (p=0.34). Perioperative TgAb was not an independent predictor of DFS (hazard ratio=1.12 [95% confidence interval=0.74-1.69]) or OS (hazard ratio=0.98 [95% confidence interval=0.56-1.72]). CONCLUSIONS: Preoperative serum TSH level is associated with higher DTC stage, gross extrathyroidal extension, and neck node metastases. Perioperative TgAb is not an independent predictor of DTC prognosis. A larger cohort is required to assess whether preoperative serum TSH level predicts recurrence or mortality.

Quality of life impact of external beam radiotherapy for advanced thyroid carcinoma.

BACKGROUND: External beam radiotherapy (XRT) has an established role in the management of recurrent or advanced well-differentiated thyroid carcinoma (WDTC). The goal of this study was to investigate the impact of this additional intervention on the quality of life (QOL) compared with total thyroidectomy (TT), with or without adjuvant radioactive iodine (RAI). METHODS: A cross-sectional analysis using validated QOL instruments was performed. Patients receiving XRT between 1992 and 2008 for WDTC were identified and offered study participation. The Quality of Life Radiation Therapy Instrument and the Head and Neck Companion Module were administered retrospectively (N=13). For a comparison, patients previously treated with TT (N=11) alone as well as TT with postoperative RAI (N=11) for WDTC were also evaluated. RESULTS: Thirty-four patients were included in the analysis. The XRT group reported significant decreases in chewing, swallowing, and appetite, and significant increase in pain, compared with both the RAI group and the TT group. Significant differences were reported for questions with regard to peace of mind, feeling discouraged, saliva, taste, ability to eat regular food, and concerns for the appearance of the neck in both RAI and XRT groups compared with TT patients. Subscale analysis of head and neck specific questions demonstrated significant overall differences for both RAI and XRT groups compared with thyroidectomy alone, with no differences observed between RAI and XRT groups in a direct comparison. CONCLUSIONS: RAI therapy results in a measurable decrease in head and neck specific QOL measures compared with TT alone. The addition of XRT results in additional measurable morbidity secondary to pain and dysphagia.

American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare but highly lethal form of thyroid cancer. Rapid evaluation and establishment of treatment goals are imperative for optimum patient management and require a multidisciplinary team approach. Here we present guidelines for the management of ATC. The development of these guidelines was supported by the American Thyroid Association (ATA), which requested the authors, members the ATA Taskforce for ATC, to independently develop guidelines for ATC. METHODS: Relevant literature was reviewed, including serial PubMed searches supplemented with additional articles. The quality and strength of recommendations were adapted from the Clinical Guidelines Committee of the American College of Physicians, which in turn was developed by the Grading of Recommendations Assessment, Development and Evaluation workshop. RESULTS: The guidelines include the diagnosis, initial evaluation, establishment of treatment goals, approaches to locoregional disease (surgery, radiotherapy, systemic therapy, supportive care during active therapy), approaches to advanced/metastatic disease, palliative care options, surveillance and long-term monitoring, and ethical issues including end of life. The guidelines include 65 recommendations. CONCLUSIONS: These are the first comprehensive guidelines for ATC and provide recommendations for management of this extremely aggressive malignancy. Patients with stage IVA/IVB resectable disease have the best prognosis, particularly if a multimodal approach (surgery, radiation, systemic therapy) is used, and some stage IVB unresectable patients may respond to aggressive therapy. Patients with stage IVC disease should be considered for a clinical trial or hospice/palliative care, depending upon their preference.

Disparity between tissue and serum calcitonin and carcinoembryonic antigen in a patient with medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of parafollicular or C-cells of thyroid that comprises 5-10% of all thyroid cancers [1, 2]. The neoplastic cells secrete calcitonin, carcinoembryonic antigen (CEA), and chromogranin A. Typically, increased serum levels of these tumor markers permit them to be used for initial diagnosis and long-term disease status surveillance. This article reports a case of sporadic MTC (pT2N0M0) in a young patient with normal serum tumor markers. A 16-year-old woman presented with MTC without evidence for this to be a familial case due to the absence of germline mutations in the RET proto-oncogene and negative family history. Surprisingly, there were normal preoperative serum levels of calcitonin, CEA, and chromogranin A, despite the immunohistochemistry showing strong and diffuse positive staining for these markers. This disparity between serum levels and tumor expression of calcitonin and CEA in MTC is quite rare. The relevant features of this case are discussed in consideration of the published experiences. This case may represent an unique subgroup of MTC with abnormal secretory capacity that requires reliance upon radiological evaluation for evidence of recurrent or disseminated disease, without the diagnostic benefit of serum tumor markers.