Subpopulations of cancer stem cells found in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer and while it has a generally good prognosis, tumor recurrence remains a major clinical challenge. Studying laboratory cell lines as well as clinical specimens indicate that PTC may follow the cancer stem cell (CSC) model. However, CSC characteristics relevant in PTC initiation and progression remain largely unknown. Here we studied a population of sphere-growing tumor cells isolated from primary cultures of clinical PTC. These sphere-growing cells consisted of aldehyde dehydrogenase positive (ALDH+) and ALDH negative (ALDH-) cell subpopulations and demonstrated a hierarchical pattern of cell division. Using combinations of selective depletion, specific inhibition and cell sorting, we found that both subpopulations of the sphere cells were able to self-renew and initiate xenograft tumors independently, and fulfilled the definition of CSC. Importantly, when the subpopulations functioned together, the cancer-initiation efficiency and the xenograft tumor progression were significantly enhanced compared to either subpopulation alone. These data revealed crucial roles of ALDH- CSC in PTC biology and suggested that CSC subpopulations function cooperatively to control PTC initiation and progression. Together, our study indicates that CSC subpopulations isolated from clinical specimens offer unprecedented opportunities for investigating PTC pathogenesis and developing effective therapies.

Surgery versus Imaging in Non-Localizing Primary Hyperparathyroidism: A Cost-Effectiveness Model.

OBJECTIVE: To determine whether advanced imaging is cost-effective compared to primary bilateral neck exploration in the management of non-localizing primary hyperparathyroidism. STUDY DESIGN: Cost-effectiveness analysis. METHODS: Cost-effectiveness analysis based on decision tree model and available Medicare financial data using data from 347 consecutive patients having parathyroidectomy for primary hyperparathyroidism with either 1) positive, concordant ultrasound and sestamibi or 2) negative sestamibi and negative ultrasound. RESULTS: Bilateral neck exploration (BNE) costs $9578 and has a success rate of 97.3%. Single photon emission computed tomography (SPECT) + minimally invasive parathyroidectomy (MIP) was modeled to have a total cost of $8197 with a success rate of 98.6%. SPECT/computed tomography (CT) + MIP was modeled to have a total cost of $8271 and a 98.9% success rate. Four-dimensional (4D)-CT + MIP was modeled to cost $8146 with a success rate of 99%. Incremental cost-effectiveness ratios (IECR) (as compared to BNE) were -536.1, -605.5, and -701.6 ($/percent cure rate) for SPECT, SPECT/CT, and 4D-CT respectively. One-way sensitivity analyses demonstrate the change in IECR and cut-off points (IECR = 0) for four major variables. CONCLUSIONS: In patients with non-localizing primary hyperparathyroidism, advanced imaging is associated with cost-savings compared to routine bilateral neck exploration. Increased cost-savings were predicted with increased imaging accuracy and decreased imaging costs. Increasing time for BNE or decreasing time for MIP were associated with increased cost savings. LEVEL OF EVIDENCE: III Laryngoscope, 2020.

Cancer stem cell self-renewal as a therapeutic target in human oral cancer.

Tumor recurrence following treatment remains a major clinical challenge in oral cavity cancer. Cancer stem cells (CSCs) have been isolated from human oral cancers and been considered as the driving force of tumor recurrence and metastasis. However, it still remains unclear whether targeting CSCs in oral cancer is a clinically relevant strategy to combat cancer recurrence and metastasis. Here, using clinical cancer specimens and patient-derived xenografts, we show that the self-renewal regulator BMI1 is highly expressed in CSCs of oral cavity squamous cell carcinoma. Inhibition of BMI1 decreases oral CSCs' self-renewal and tumor-initiating potential. Treatment of pre-established human oral cancer xenografts with a BMI1 inhibitor resulted in abrogation of tumor progression and reduced the frequency of CSCs in the xenografts. Remarkably, the BMI1 inhibitor has therapeutic effects in cisplatin-resistant tumors and can reduce metastases initiated by circulating CSCs. Mechanistically, BMI1-inhibition leads to oral CSC necroptotic cell death, which underlies the self-renewal impairment after inhibiting BMI1. Our data provide a pre-clinical proof-of-concept that targeting BMI1-related CSC self-renewal is a clinically relevant anti-cancer therapy in human oral cavity squamous cell carcinoma.