High Rates of Underlying Thyroid Cancer in Patients Undergoing Thyroidectomy for Hyperthyroidism.

BACKGROUND: The rate of thyroid cancer in patients with hyperthyroidism is reported to be rare, and patients with toxic thyroid nodules do not routinely undergo fine-needle aspiration (FNA) to evaluate for malignancy. However, higher rates of malignancy in hyperthyroid patients may exist than previously reported. This study examines the rate of malignancy in patients with hyperthyroidism who have undergone thyroidectomy. METHODS: A retrospective review of prospectively collected data of 138 patients with hyperthyroidism who underwent thyroidectomy at a single institution was performed. Patients were divided into three groups: Graves' disease (n = 80), toxic multinodular goiter (n = 46), and toxic solitary nodule (n = 12). Patients with previous thyroid surgery were excluded from the study. All patients had biochemical confirmation of hyperthyroidism with thyroid-stimulating hormone <0.1 mIU/L and clinical diagnosis by a referring physician. RESULTS: Of 138 patients, 22% (31/138) were found to have malignancy on final pathology. The breakdown of malignancy by hyperthyroid condition was as follows: 16% in Graves' disease, 24% in toxic multinodular goiter patients, and 50% in toxic solitary nodule patients. CONCLUSIONS: There is a clinically significant rate of malignancy seen in patients who undergo thyroidectomy for hyperthyroidism. Patients with distinct thyroid nodules in the presence of hyperthyroidism may have the highest rates of malignancy and should undergo appropriate workup with ultrasound and FNA to exclude underlying malignancy. In cases with suspicious ultrasound features and/or FNA cytopathology, surgical treatment should be considered as initial management.

Inverse Relationship of BMI to TSH and Risk of Papillary Thyroid Cancer in Surgical Patients.

BACKGROUND: Obesity and thyroid cancer has increased in recent decades. Thyroid malignancy is linked with elevated thyroid-stimulating hormone (TSH) levels, which may have a positive association with body mass index (BMI). This study examines obesity and TSH level effect on papillary thyroid cancer (PTC) risk in a surgical population. METHODS: A retrospective review of prospectively collected data for 991 patients who underwent thyroidectomy at a single institution was performed. Patients were stratified according to BMI into three groups: nonobese (18.5-29.9 kg/m2), obese (30-39.9 kg/m2), and morbidly obese (≥40 kg/m2). Further subdivisions into benign and malignant outcomes based on final pathology were compared with preoperative TSH levels. Subanalyses according to sex were also performed. RESULTS: Of 517 patients with PTC, rate of malignancy (ROM) decreased (55% versus 48% versus 41%, P < 0.05) as BMI increased with a concomitant decrease in average TSH levels (1.75 versus 1.69 versus 1.41 mU/L), respectively. According to sex, decreased ROM (53% versus 44% versus 42%, P < 0.05) and TSH (1.79 versus 1.70 versus 1.33 mU/L), respectively, with increased BMI was identified in women. However, decrease of ROM was not significant in men with increasing TSH levels as BMI increased. Male sex was associated with increased PTC risk (OR, 1.916; 95% CI, 1.331-2.759), whereas obesity with reduced PTC risk (OR, 0.736; 95% CI, 0.555-0.976). CONCLUSIONS: Higher BMI correlates with decreased PTC rates and lower TSH levels and suggests other factors may be involved in thyroid tumorigenesis. Obese patients with thyroid cancer should not be managed differently compared with nonobese patients.

FX11 inhibits aerobic glycolysis and growth of neuroblastoma cells.

BACKGROUND: The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. METHODS: We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression. Cell viability was measured with FX11 using a tetrazolium-based assay. Cell cycle analysis using propidium iodide with flow cytometry was performed to evaluate for growth arrest. Immunoblotting demonstrated PARP and Caspase 3 cleavage as evidence of apoptosis. RESULTS: LDHA is frequently expressed in both MYCN--amplified and MYCN-single copy cell lines. N-MYC and C-MYC protein levels did not correlate with LDHA protein expression. FX11 inhibits aerobic glycolysis and growth in three MYCN-amplified and one MYCN-single copy neuroblastoma cell lines. FX11 induces modest G1 cell cycle arrest with selective induction of apoptosis. CONCLUSION: Small molecule LDHA inhibition is capable of blocking aerobic glycolysis and growth of neuroblastoma cell lines in vitro and merits further in vivo evaluation of its preclinical efficacy in neuroblastomas.

Induced differentiation inhibits sphere formation in neuroblastoma.

Neuroblastoma arises from the neural crest, the precursor cells of the sympathoadrenal axis, and differentiation status is a key prognostic factor used for clinical risk group stratification and treatment strategies. Neuroblastoma tumor-initiating cells have been successfully isolated from patient tumor samples and bone marrow using sphere culture, which is well established to promote growth of neural crest stem cells. However, accurate quantification of sphere-forming frequency of commonly used neuroblastoma cell lines has not been reported. Here, we show that MYCN-amplified neuroblastoma cell lines form spheres more frequently than non-MYCN-amplified cell lines. We also show that sphere formation is directly sensitive to cellular differentiation status. 13-cis-retinoic acid is a clinically used differentiating agent that induces a neuronal phenotype in neuroblastoma cells. Induced differentiation nearly completely blocked sphere formation. Furthermore, sphere formation was specifically FGF-responsive and did not respond to increasing doses of EGF. Taken together, these data suggest that sphere formation is an accurate method of quantifying the stemness phenotype in neuroblastoma.