Kinase Inhibitors in the Treatment of Thyroid Cancer: Institutional Experience.

Although most patients with thyroid cancer have a favorable clinical course, some patients develop a more aggressive type of cancer and exhibit more rapid disease progression with worse prognosis. Those patients usually exhibit mutations of proteins such as tyrosine kinase enzymes that play a significant role in regulation of tumor proliferation and spreading. Development of targeted therapies is based on the inhibition of mutated kinases which are involved in the MAPK signaling pathway. The aim of this study was to present the initial results of clinical experience with kinase inhibitors in patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and medullary thyroid cancer (MTC) who exhibited rapid disease progression. A total of 17 adult patients (11 women, mean age 53.3 years) managed for progressive, metastatic disease were included in the study. Twelve patients with DTC and PDTC were previously tested for BRAF mutations, of whom nine that had tumor tissue negative for the BRAF V600E mutation received sorafenib, while three patients with tumors harboring the BRAF V600E mutation were treated with vemurafenib. Patients with MTC were treated with sunitinib, vandetanib, and sorafenib. Two patients with tumors harboring the BRAF mutation treated with vemurafenib showed restoration of radioiodine uptake. Most of patients showed significant improvement in disease status but of limited duration until disease progression. Although there was an improvement in progression-free survival, future research has to achieve a greater and longer-lasting response, probably by utilizing combined targeted therapy.

The levels of 12 cytokines and growth factors in tears: hyperthyreosis vs euthyreosis.

PURPOSE: Simultaneous analyses of the contents and ratios of 12 cytokines and growth factors in single samples of human tears were performed, and the results were compared between a group of healthy subjects and a group of patients with Graves' hyperthyreosis (GH) without thyroid-associated orbitopathy (TAO). METHODS: Determinations and concentration measurements of interleukins (IL-2, IL4, IL-6, IL-8, IL-10, IL-1α, and IL-1ß) interferon (IFN-γ), tumor necrosis factor (TNF-α), monocyte chemoattractant protein (MCP-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) were performed with single tear samples from 21 patients with hyperthyreosis and 22 healthy subjects. The analyses were performed using a Randox microchip with an Evidence Biochip Array Analyzer. RESULTS: We found significant differences between the healthy donor group and the hyperthyreosis group in the levels of IL-6, IL-10, VEGF, IL-1α, and MCP-1. The concentration of IL-6 was considerably higher in the hyperthyreosis group, IL-10 was higher in the healthy donor group, and VEGF and MPC-1 were higher in the hyperthyreosis group. The IL-8 and IFN-γ levels were higher in the hyperthyreosis group. The ratios of all of the cytokines to anti-inflammatory IL-10 were significantly elevated in the hyperthyreosis group. CONCLUSION: There are clear differences in the levels of cytokines and growth factors in the tears of healthy subjects and patients with GH without TAO. Tear cytokine changes and related dysfunctional tear syndrome (DTS) could be an early sign of occult TAO in Graves' hyperthyreosis patients.

Efficacy of long-term ultrasonography in follow-up of patients with papillary thyroid carcinoma: a case of neck metastasis developed 19 years following primary treatment.

The cases of relapse in papillary thyroid cancer patients who were initially considered low-risk and for many years were without signs of the disease are extremely rare, but exist. This is supported by the clinical case of a patient who underwent a total thyroidectomy due to papillary thyroid cancer and 19 years later metastasis with extracapsular spreading in a presumed thyroid place was revealed. Due to such cases, the importance of long-term ultrasound monitoring is emphasized.

Platelet serotonin concentration and monoamine oxidase activity in hypothyroid patients.

BACKGROUND/AIM: The relationship between the hypothalamic-pituitary-thyroid (HPT) axis and the serotonergic (5-hydroxytryptamine, 5-HT) system is not clear. The aim of the study was to determine platelet biochemical markers (5-HT concentration and monoamine oxidase B, MAO-B, activity) in hypothyroid patients. METHODS: The study included 25 medication-free female hypothyroid patients in postoperative follow-up after total thyroidectomy due to papillary thyroid carcinoma, who had not been treated with synthetic thyroxine (T(4)) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T(4) and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively. RESULTS: Hypothyroid patients had significantly higher TSH, significantly lower T(4) levels and platelet 5-HT concentrations, and unchanged platelet MAO-B activity than healthy subjects. A positive correlation was found between the 5-HT concentration and platelet MAO-B activity, and between the platelet MAO-B activity and T(4) in control subjects. CONCLUSIONS: Reduced platelet 5-HT concentrations in hypothyroid patients suggests a complex interaction between the 5-HT system and HPT axis activity, which could be related to the frequent occurrence of depressive symptoms in hypothyroid patients. The determination of platelet 5-HT concentrations should be considered a diagnostic tool for the evaluation of depressive symptoms in hypothyroid patients during the hormone withdrawal procedure.

Thyroid remnant ablation in patients with papillary cancer: a comparison of low, moderate, and high activities of radioiodine.

OBJECTIVE: The consensus about optimal activities of I-131 for thyroid remnant ablation has not yet been achieved. The aim of this study was to compare ablation rates obtained with different I-131 activities. PATIENTS AND METHODS: The study included 466 patients divided into four groups according to I-131 activities given after total thyroidectomy for papillary thyroid cancer: group A [168 patients who received 888 MBq (24 mCi)], group B [125 patients who received 1480 MBq (40 mCi)], group C [65 patients who received 1850 MBq (50 mCi)], and group D [108 patients who received 4440 MBq (120 mCi)]. Ablation outcome was assessed by whole-body scan in hypothyroid state 6-9 months after ablation and finally 18-21 months after the treatment. RESULTS: The rate of successful ablation was similar in the group of patients who received 24 and 40 mCi (75 and 71.2%, respectively). The higher rate of ablation was achieved in the groups treated with 50 and 120 mCi of radioiodine (87.69 and 90.74%, respectively). The ablation rates at the first follow-up examinations (59.5, 67.2, 73.9, 80.6%) were lower than at second control study (75.0, 71.2, 87.7, 90.7%) in all groups. Time required for thyroid remnant ablation seems to be >or=18 months. CONCLUSION: Our study indicates that activity of 50 mCi seems to be optimal to achieve a successful ablation rate (approximately 90%). Low I-131 activities are acceptable for lower risk patients because of satisfactory ablation rate (>70%), lower expense, and minimal radiation burden to patients as well as lower radiation exposure to clinical staff. The ablative use of high activities seems neither justified nor optimized.

The value of 18F-DOPA PET/CT in patients with medullary thyroid carcinoma and increased calcitonin values.

AIM: The aim of this prospective observational study was to examine the benefit of a fluorine-18-L-dihydroxyphenylalanine (F-DOPA) PET/computed tomography (CT) scan in patients with medullary thyroid carcinoma (MTC) in terms of increased calcitonin levels. PATIENTS AND METHODS: Twenty-eight MTC patients after initial total thyreoidectomy with increasing follow-up calcitonin levels suggestive for active disease after negative conventional imaging findings (neck ultrasound or thorax, abdomen, pelvis multislice computed tomography as standard imaging) were scanned using F-DOPA PET/CT from November 2012 to April 2016. The mean calcitonin level was 108.5 (range: 6.7-290) pmol/l and the mean carcinoembryonic antigen level was 15.7 (range: 1.1-221.9) µg/l. The mean follow-up period was 19.7 months. RESULTS: F-DOPA PET/CT was positive in 16 out of 28 (57%) patients, mostly because of metabolically active neck and mediastinal lymph nodes metastases. Previously unknown bone metastases were found in six patients. A positive scan was reported in four patients (25% of positive scans) with a very low calcitonin value of less than 49.9 pmol/l. PET/CT findings led to a change of management and therapy in 16 out of 28 patients, with surgical procedure performed in eight patients, radiotherapy in five patients, and chemotherapy in two patients. CONCLUSION: F-DOPA PET/CT is a clinically useful modality in MTC whenever the calcitonin level is increased. There is a clear trend toward more positive scans with the higher calcitonin values, but patients with moderately elevated calcitonin values should also be taken into consideration for molecular imaging with F-DOPA PET/CT as the tumor burden in these patients is probably low, enabling further therapy to be individualized and consequently more efficient.

Urokinase plasminogen activator and its inhibitor type-1 as prognostic factors in differentiated thyroid carcinoma patients.

OBJECTIVE: To investigate the prognostic value of urokinase-type plasminogen activator (uPA) and its inhibitor, type-1 plasminogen activator inhibitor (PAI-1), in differentiated thyroid cancer. STUDY DESIGN: Prospective cohort study. SETTING: University hospital. SUBJECTS AND METHODS: Cytosolic concentrations of uPA and PAI-1 were determined in 105 patients with differentiated thyroid carcinoma and normal matched tissues using an enzyme-linked immunoassay (ELISA). RESULTS: Both uPA and PAI-1 concentrations were significantly higher in differentiated thyroid tumors (uPA = 0.509 ± 0.767 and PAI-1 = 6.337 ± 6.415 ng/mg) compared to normal tissues (uPA = 0.237 ± 0.051, P < .001; PAI-1 = 2.368 ± 0.418 ng/mg, P < .001). uPA and PAI-1 were significantly higher if extrathyroidal invasion (uPA, P = .015; PAI-1, P < .001) or distant metastasis (PAI-1 P < .001) was present, as well as in tumors whose size exceeded 1 cm in diameter (uPA, P = .002; PAI-1, P = .001). Survival analysis revealed the significant impact of both uPA and PAI-1 on progression-free survival (PFS) (82.22 vs 49.478 months for patients with low and high uPA, respectively, P < .001; 87.068 vs 44.964 months for patients with low and high PAI-1, respectively, P < .001). Univariate analysis showed that gender, tumor size, tumor grade, extrathyroid invasion, local lymph node involvement, distant metastasis, uPA, and PAI-1 were significant predictors of PFS. However, multivariate analysis identified only distant metastasis and tumor tissue uPA and PAI-1 as independent prognostic factors. CONCLUSION: These findings indicate that high uPA and PAI-1 levels represent independent unfavorable prognostic factors in patients with differentiated thyroid carcinoma.