Preclinical characterization of tyrosine kinase inhibitor-based targeted therapies for neuroendocrine thyroid cancer.

Medullary thyroid carcinoma (MTC) is a slow growing neuroendocrine (NE) tumor for which few treatment options are available. Its incidence is rising and mortality rates have remained unchanged for decades. Increasing the repertoire of available treatments is thus crucial to manage MTC progression. Scarcity of patient samples and of relevant animal models are two challenges that have limited the development of effective non-surgical treatments. Here we use a clinically accurate mouse model of MTC to assess the effects and mode of action of the tyrosine kinase inhibitor (TKI) Vandetanib, one of only two drugs currently available to treat MTC. Effects on tumor progression, histopathology, and tumorigenic signaling were evaluated. Vandetanib blocked MTC growth through an anti-angiogenic mechanism. Furthermore, Vandetanib had an apparent anti-angiogenic effect in a patient MTC sample. Vandetanib displayed minimal anti-proliferative effects in vivo and in human and mouse MTC tumor-derived cells. Based on these results, we evaluated the second-generation TKI, Nintedanib, alone and in combination with the histone deacetylase (HDAC) inhibitor, Romidepsin, as potential alternative treatments to Vandetanib. Nintedanib showed an anti-angiogenic effect while Romidepsin decreased proliferation. Mechanistically, TKIs attenuated RET-, VEGFR2- and PI3K/AKT/FOXO signaling cascades. Nintedanib alone or in combination with Romidepsin, but not Vandetanib, inhibited mTOR signaling suggesting Nintedanib may have broader anti-cancer applicability. These findings validate the MTC mouse model as a clinically relevant platform for preclinical drug testing and reveal the modes of action and limitations of TKI therapies.

Association of Lymph Node Density With Survival of Patients With Papillary Thyroid Cancer.

Importance: Lymph node metastases are common in papillary thyroid cancer (PTC), yet the impact of nodal metastases on survival remains unclear. Lymph node density (LND) is the ratio between the number of positive lymph nodes excised and the total number of excised lymph nodes. Lymph node density has been suggested as a prognostic factor in many types of cancer. Objective: To evaluate the prognostic role of LND in PTC. Design, Setting, and Participants: This cohort study reviewed medical records of patients with PTC who were treated at the University of Texas MD Anderson Cancer Center between January 1, 2000, and December 31, 2015. Survival and recurrence outcomes were calculated by using the Kaplan-Meier method. Significant variables on univariate analysis were subjected to a Cox proportional hazards regression multivariate model. Main Outcomes and Measures: Primary study outcome was disease-specific survival (DSS); other measurements included overall survival (OS). Results: The study cohort included data for 2542 patients (1801 [71%] male; median age, 48 years [range, 18-97 years]) with a median follow-up of 55 months (range, 4-192 months). The 10-year disease-specific survival rate was 98% for patients with LND of 0.19 or less, compared with 90% for those with LND greater than 0.19 (effect size, 8%; 95% CI, 4%-15%). The 10-year overall survival was 87% for patients with LND of 0.19 or less, compared with 79% for patients with LND greater than 0.19 (effect size, 8%; 95% CI, 3%-15%). Multivariable analysis revealed that LND greater than 0.19 was independently associated with an adverse DSS (hazard ratio [HR], 4.11; 95% CI, 2.11-8.97) and OS (HR, 1.96; 95% CI, 1.24-4.11). Subgroup analysis of patients with 18 or more lymph nodes analyzed revealed that LND greater than 0.19 remained a significant marker for DSS (HR, 2.94; 95% CI, 1.36-9.81) and OS (HR, 2.26; 95% CI, 1.12-5.34). Incorporating LND into the current American Joint Committee on Cancer staging system successfully stratified risk groups compared with the traditional TNM staging system. Conclusions and Relevance: This single-institute study demonstrates the reproducibility of LND as a predictor of outcomes in PTC. Lymph node density can potentially assist in identifying patients with poorer survival who may benefit from more aggressive adjuvant therapy.

Differentiating Atypical Parathyroid Neoplasm from Parathyroid Cancer.

INTRODUCTION: The differentiation of benign parathyroid gland atypia and true parathyroid carcinoma (PC) can be challenging. In some instances, patients are classified as having 'atypical parathyroid neoplasms' (APNs), explicitly acknowledging that the distinction between benign and malignant disease appears impossible to determine. This 'grey area' diagnosis makes rendering an accurate prognosis difficult, and clouds clinical management and treatment planning. METHODS: We performed a retrospective chart review of all patients undergoing operation for primary hyperparathyroidism in our institution (2000-2014). Patients with a histopathological diagnosis of PC or APN were included. Demographics, clinical characteristics, and survival rates were analyzed, and analysis was conducted using SAS 9.4 (SAS Institute, Inc., Cary, NC, USA). RESULTS: Fifty-four patients were included in the study-31 (57.41 %) with PC and 23 (42.59 %) with APN. PC versus APN was associated with higher parathyroid hormone (PTH) (p = 0.005) and with males (p = 0.002). Five-year overall survival (OS) from diagnosis was 82.64 % [95 % confidence interval (CI) 59.82-93.17] for the PC group and 93.33 % (95 % CI 61.26-99.03) for the APN group, while the 5-year recurrence-free survival rate was 59.63 % (95 % CI 36.32-76.81) in the PC group and 90.91 % (95 % CI 50.81-98.67) in the APN group. CONCLUSION: PC and APN are distinct clinical entities with differences in tumor biology reflected in overall recurrence rates, disease-free survival, and OS. APNs present with a less accentuated biochemical profile and demonstrate an indolent clinical course compared with PCs. Efforts to improve categorization and staging of PC and APN are needed.