Establishment and Characterization of Four Novel Thyroid Cancer Cell Lines and PDX Models Expressing the RET/PTC1 Rearrangement, BRAFV600E, or RASQ61R as Drivers.

Cancer cell lines are critical models to study tumor progression and response to therapy. In 2008, we showed that approximately 50% of thyroid cancer cell lines were redundant or not of thyroid cancer origin. We therefore generated new authenticated thyroid cancer cell lines and patient-derived xenograft (PDX) models using in vitro and feeder cell approaches, and characterized these models in vitro and in vivo. We developed four thyroid cancer cell lines, two derived from 2 different patients with papillary thyroid cancer (PTC) pleural effusions, CUTC5, and CUTC48; one derived from a patient with anaplastic thyroid cancer (ATC), CUTC60; and one derived from a patient with follicular thyroid cancer (FTC), CUTC61. One PDX model (CUTC60-PDX) was also developed. Short tandem repeat (STR) genotyping showed that each cell line and PDX is unique and match the original patient tissue. The CUTC5 and CUTC60 cells harbor the BRAF (V600E) mutation, the CUTC48 cell line expresses the RET/PTC1 rearrangement, and the CUTC61 cells have the HRAS (Q61R) mutation. Moderate to high levels of PAX8 and variable levels of NKX2-1 were detected in each cell line and PDX. The CUTC5 and CUTC60 cell lines form tumors in orthotopic and flank xenograft mouse models. IMPLICATIONS: We have developed the second RET/PTC1-expressing PTC-derived cell line in existence, which is a major advance in studying RET signaling. We have further linked all cell lines to the originating patients, providing a set of novel, authenticated thyroid cancer cell lines and PDX models to study advanced thyroid cancer.

A "safe and effective" protocol for management of post-thyroidectomy hypocalcemia.

BACKGROUND: This study evaluates the outcomes of a protocol to manage hypocalcemia after thyroidectomy (TTX). METHODS: A review of prospectively collected data was performed in 130 patients who underwent TTX after the introduction of a specific protocol. These patients were compared with a control group of 195 patients who underwent TTX the year prior when routine calcium supplementation was utilized and no specific protocol was used. RESULTS: Of the 120 patients in whom the protocol was followed, 44 (37%) patients were classified as high risk, 15 (13%) intermediate risk, and 61 (51%) low risk. The protocol had a sensitivity of 85% and a negative predictive value of 92% for predicting subsequent hypocalcemia. With the implementation of the protocol, there was significant reduction in temporary hypocalcemia events (P = .008) and intravenous calcium drip (P = .49). Also, calcium supplementation was significantly lower in the protocol group (P ≤ .001). CONCLUSIONS: This hypocalcemia protocol identifies patients who do not require additional supplementation and additional monitoring. At the same time, it identifies those who will benefit from supplementation after TTX.

Efficacy of localization studies and intraoperative parathormone monitoring in the surgical management of hyperfunctioning ectopic parathyroid glands.

BACKGROUND: Hyperfunctioning ectopic glands remain an operative challenge in patients with sporadic primary hyperparathyroidism. This study examines the incidence of ectopic glands and the utility of sestamibi scans (MIBI), surgeon-performed ultrasonography, and intraoperative parathormone monitoring in such patients undergoing parathyroidectomy. METHODS: We conducted a retrospective analysis of prospectively collected data from patients who underwent parathyroidectomy from 1980 to 2011 for sporadic primary hyperparathyroidism at a single institution. Demographics, localizing imaging studies, intraoperative parathyroid monitoring dynamics, and surgical outcome for patients with hyperfunctioning ectopic parathyroid glands were studied. RESULTS: Among 1,195 patients who underwent parathyroidectomy for sporadic primary hyperparathyroidism, 120 patients (10%) had hyperfunctioning ectopic glands, which were localized to the neck (n = 66) and mediastinum (n = 54). MIBI had a sensitivity of 85%, specificity of 97%, and positive predictive value (PPV) of 91% for ectopic glands in the neck, whereas in the mediastinum there was a sensitivity of 88%, specificity of 95%, and PPV of 86%. Surgeon-performed ultrasonography had a sensitivity of 81%, specificity of 98%, and PPV of 95% for neck ectopic glands. The overall accuracy of surgeon-performed ultrasonography, MIBI, and intraoperative parathyroid monitoring in the neck or mediastinum was 93%. Overall, operative success was 93% with a multiglandular disease rate of 5%. CONCLUSION: A high operative success rate for hyperfunctioning ectopic glands can be achieved using localization studies and intraoperative parathyroid monitoring. Nevertheless, surgeon judgment remains paramount in the operative direction of this patient population.

Reliability of fine-needle aspiration for thyroid nodules greater than or equal to 4 cm.

BACKGROUND: Fine-needle aspiration (FNA) is considered the diagnostic test of choice in the evaluation of thyroid nodules. Some practice recommendations, however, suggest surgical resection of larger thyroid nodules due to concerns of FNA unreliability in the diagnosis of thyroid malignancy. The purpose of this study was to determine the reliability of FNA in thyroid nodules ≥4 cm. METHODS: Retrospective review of prospectively collected data of 1068 consecutive patients who underwent FNA and thyroidectomy at a single tertiary medical center from 2003 to 2010 was performed. Patients were divided into two groups: those patients with a dominant thyroid nodule ≥4 cm (n = 212) and those patients with a dominant thyroid nodule <4 cm (n = 856). Sensitivity, specificity, and negative and positive predictive values were calculated for FNA results and final histopathology after thyroidectomy. RESULTS: Of 212 patients with lesions ≥4 cm, 35% had thyroid malignancy on final pathology. Conversely, 54% of 856 patients with dominant thyroid nodules <4 cm had a final diagnosis of thyroid cancer after thyroidectomy. FNA demonstrated similar test characteristics among patients with lesions ≥4 cm and <4 cm, with a specificity of 99% (CI: 96%-100%) and 98% (CI: 96%-99.0%), respectively, and a sensitivity of 35% (CI: 23%-49%) and 42% (CI: 37%-46%), respectively. The positive predictive value of FNA was 82% (CI: 75%-100%) for nodules ≥4 cm and 96% (CI: 92%-98%) for nodules <4 cm. Negative predictive value was significantly different, with a value of 82% (CI: 75%-87%) for lesions ≥4 cm and only 59% (CI: 55%-63%) for lesions <4 cm. CONCLUSIONS: The reliability of FNA as a diagnostic test is not affected by the size of thyroid nodules. Routine surgical resection for all thyroid nodules ≥4 cm should not be used as the only independent factor in determining need for surgical resection.

Number of lymph nodes removed during modified radical neck dissection for papillary thyroid cancer does not influence lateral neck recurrence.

BACKGROUND: This study examines the relationship between the number of lymph nodes removed during modified radical neck dissection and the incidence of disease recurrence. METHODS: A retrospective review of 117 patients with papillary thyroid cancer and lateral neck involvement (levels 2-5) who underwent modified radical neck dissection was performed. Data were analyzed for patient demographics, operative procedure, lymph node involvement, complications, radioactive iodine therapy, and disease recurrence. RESULTS: Of 117 patients who underwent modified radical neck dissection, the median follow-up of the entire study group was 25 months (range, 1-256 months). Recurrent disease was found in 8% of patients, with a median time to recurrence of 35 months. The median number of lymph nodes removed during modified radical neck dissection was similar in recurrent and nonrecurrent patients (P = .78). There was also no difference in the median number of positive lymph nodes removed (P = .14) between these 2 groups. On multivariate analysis, however, the number of positive lymph nodes (odds ratio, 1.16 [95% confidence interval, 1.01-1.34]) and tumor size (odds ratio, 1.60 [95% confidence interval, 1.03-2.49]) were independent predictors of recurrence of disease after modified radical neck dissection. CONCLUSION: Recurrence of papillary thyroid cancer after modified radical neck dissection is unrelated to the number of lymph nodes removed. This study suggests that attempts to maximize the number of lymph nodes removed during modified radical neck dissection for papillary thyroid cancer may not be necessary.