Papillary thyroid cancer organoids harboring BRAFV600E mutation reveal potentially beneficial effects of BRAF inhibitor-based combination therapies.

BACKGROUNDS: Papillary thyroid cancer (PTC), which is often driven by acquired somatic mutations in BRAF genes, is the most common pathologic type of thyroid cancer. PTC has an excellent prognosis after treatment with conventional therapies such as surgical resection, thyroid hormone therapy and adjuvant radioactive iodine therapy. Unfortunately, about 20% of patients develop regional recurrence or distant metastasis, making targeted therapeutics an important treatment option. Current in vitro PTC models are limited in representing the cellular and mutational characteristics of parental tumors. A clinically relevant tool that predicts the efficacy of therapy for individuals is urgently needed. METHODS: Surgically removed PTC tissue samples were dissociated, plated into Matrigel, and cultured to generate organoids. PTC organoids were subsequently subjected to histological analysis, DNA sequencing, and drug sensitivity assays, respectively. RESULTS: We established 9 patient-derived PTC organoid models, 5 of which harbor BRAFV600E mutation. These organoids have been cultured stably for more than 3 months and closely recapitulated the histological architectures as well as mutational landscapes of the respective primary tumors. Drug sensitivity assays of PTC organoid cultures demonstrated the intra- and inter-patient specific drug responses. BRAFV600E inhibitors, vemurafenib and dabrafenib monotherapy was mildly effective in treating BRAFV600E-mutant PTC organoids. Nevertheless, BRAF inhibitors in combination with MEK inhibitors, RTK inhibitors, or chemotherapeutic agents demonstrated improved efficacy compared to BRAF inhibition alone. CONCLUSIONS: These data indicate that patient-derived PTC organoids may be a powerful research tool to investigate tumor biology and drug responsiveness, thus being useful to validate or discover targeted drug combinations.

[Evaluation of radionuclide therapy for the residue after surgery in papillary thyroid carcinoma].

OBJECTIVE: To assess the efficacy of radioactive iodine (RAI) for the treatment of residual papillary thyroid cancer (PTC) after surgery. METHODS: A total of 20 patients diagnosed with PTC and underwent 2-6 courses of RAI therapy for residual PTC after surgery in other hospitals were included our study. Of these, 13 were in stage I, 3 in stage III and 4 in stage IV. All the cases were operated again due to the presence of suspicious residual tumors indicated by CT. Excision of thyroid tumor residue was performed in 5 cases and neck dissection in 15 cases (20 sides). The suspicious thyroid or neck residual tumors were examined pathologically after surgery. Response Evaluation Criteria in Solid Tumors (RECIST) was used to evaluate the efficacy of surgery treatment on residual tumor. T-test was used to identify variables associated to RAI and to calculate the propensity score to receive RAI after surgery. RESULTS: The patients aged 22-58 years, with a median age of 40 years. The mean times of surgeries received before RAI was 1.5 and the mean dose of applied RAI was 318 mCi (210-660 mCi). No significant difference in tumor size between pre-RAI and post-RAI was found (t = 1.177, P > 0.05). With postoperative pathological examination, the suspicious thyroid or neck residual tumors were confirmed as PTC or the cervical lymph metastasis of PTC. CONCLUSIONS: For the residue or metastasis of PTC after operation, reoperation should be a priority, while RAI therapy has no obvious therapeutic effect and it should be limited to selected cases such as those with distant metastasis or unsuitable for operation but with iodine uptake function, or taken as an adjuvant treatment after radical resection of cervical lesions.