Iodine-refractory Papillary Thyroid Cancer Research Articles

FAPI PET/CT provides higher uptake and better target to back ground in recurrent and metastatic tumors of patients with Iodine refractory papillary thyroid cancer compared with FDG PET CT.

The role of fibroblast activation protein inhibitor (FAPI) PET CT scan is not well documented in papillary thyroid cancer (PTC) patients. Patients with radioiodine refractory PTC and high thyroglobulin levels need PET/CT scan which is generally done by 18F FDG. In the current study, the diagnostic performance of 68Ga FAPI and FDG PET/CT scans were compared head to head in patients with radioiodine refractory PTC. Fourteen patients with negative whole body Iodine scans and high thyroglobulin levels underwent whole body PET scans with, respectively, 120-310 and 145-370 MBq 68Ga FAPI-46 and 18F FDG. SUVmax of the back ground in the blood pool and liver and the hottest, largest and average neck, mediastinum, lung and bone lesions were calculated and compared. Ten patients had at least one active (SUVmax>blood pool) lesion similarly in two scans. The liver and blood pool SUVmax values were 1.25(0.2) and 1.7(0.2) in FAPI and 2.65(0.2) and 2.0(0.2) in FDG PET images, respectively. The difference was significant (p=0.001). Standard SUV of the hottest lesion to liver was above 3 in all FAPI scans but in half of FDG scans. Target lesion number and intensity were similar between two PET studies but in a patient out of 5 pulmonary metastatic patients, pulmonary nodules were negative (SUVmax=0.9) in FDG while positive (SUVmax= 3.8) in FAPI images (i.e. 20% patient upstaged). FAPI accumulates in the recurrent and metastatic lesions of patients with Iodine refractory PTC at least as well as FDG with particular privileges as lower injected activity and lower back ground.

Association of extranodal extension and lymph node ratio with radioactive iodine-refractory papillary thyroid cancer

Objective: To investigate the related factors of radioiodine-refractory thyroid cancer (RAIR-DTC) and the increase of cumulative iodine treatment dose. Methods: The data of patients with papillary thyroid cancer who underwent surgery and iodine treatment for the first time in the Affiliated Cancer Hospital of Zhengzhou University from January 2015 to December 2017 were retrospectively analyzed. The related factors of RAIR-DTC and the increase of cumulative iodine treatment dose were explored. Results: A total of 650 patients were enrolled, including 217 males (33.4%) and 433 females (66.6%), aged 45 (34, 53) years. There were 123 patients (18.9%) over 55 years old, 171 patients (26.3%) with extranodal extension and 18 patients (2.8%) with distant metastasis. The median lymph node ratio was 0.22 (0.11, 0.33). Twenty patients (3.1%) had an accumulated iodine treatment dose>400 mCi and 19 patients (2.9%) had RAIR-DTC. Multivariate logistic regression analysis showed that extranodal extension (OR=19.833, 95%CI: 6.057-73.325, P<0.001) was related factors for the increase of cumulative iodine treatment dose. Age>55 years old (OR=3.322, 95%CI: 1.136-9.466, P=0.024), distant metastasis (OR=10.059, 95%CI: 2.508-38.888, P<0.001), extranodal extension (OR=5.278, 95%CI: 1.707-19.813, P=0.006) and lymph node ratio (OR=34.724, 95%CI: 2.749-384.575, P=0.004) were related factors for RAIR-DTC. Conclusions: Extranodal extension and lymph node ratio are related factors for RAIR-DTC. In clinical practice, more attention should be paid to the influence of different lymph node metastasis characteristics on the occurrence of RAIR-DTC and the cumulative therapeutic dose of iodine.

Pyruvate carboxylase promotes malignant transformation of papillary thyroid carcinoma and reduces iodine uptake

Previous studies have shown that pyruvate carboxylase (PC) plays a key role in the occurrence and progression of thyroid cancer (TC); however, the relationship between PC and iodine-refractory TC is unclear. Therefore, the present study aimed to investigate the molecular mechanism of PC in the malignant progression and loss of iodine uptake in papillary TC (PTC) and to explore the potential therapeutic effect of PC inhibitors in iodine-refractory PTC. PC increased cell proliferation, invasion, and metastasis, inhibited expression of the iodine metabolism-related genes TSHR, NIS, TPO, and TG, and decreased the iodine-uptake capacity by activating the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway in PTC cell lines. Furthermore, the PC inhibitor ZY-444 effectively inhibited the activation of PC, reduced the malignant invasiveness, and restored the expression of iodine metabolism-related genes and the iodine-uptake capacity in PTC cells. These findings suggest that PC activation is involved in the progression of iodine-refractory TC and that PC inhibitors may represent a potentially novel targeted therapy for iodine-refractory TC.

18F-FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY COMBINED WITH COMPUTED TOMOGRAPHY IN EVALUATION OF EFFECTIVENESS OF TARGETED THERAPY OF RADIOACTIVE IODINE-REFRACTORY DIFFERENTIATED THYROID CANCER (CLINICAL OBSERVATION)

N.N. Blokhin National Medical Research Oncology Center, Ministry of Health of Russia; 24 Kashirskoe Shosse, Moscow 115478, Russia Positron emission tomography (PET) with 18F-fluorodeoxyglucose is included in the algorithm of examination and monitoring in patients with radioactive iodine-refractory differentiated thyroid cancer. In assessing the effectiveness of targeted therapy, criteria based on the values of SUVmax (standardized uptake value) in metastases are used. The article shows the results of PET studies in a patient with radioactive iodine-refractory papillary thyroid cancer treated with sorafenib. The dynamics of tumor activity of metastases by different quantitative indicators were evaluated.

The effect of antagonizing RGD-binding integrin activity in papillary thyroid cancer cell lines.

Patients with papillary thyroid cancer (PTC) generally have good prognosis, but inoperable and radioactive iodine–refractory PTC still poses significant clinical challenges due to lack of effective treatment and higher mortality rates. Given the important role of integrins in multiple steps of tumor development, integrin-targeting therapy could be an effective strategy for PTC therapy. In this study, we investigated the antitumor effect of antagonizing Arg-Gly-Asp (RGD)-binding integrin activity in several PTC cell lines. Two RGD-binding integrin heterodimers αvβ3 and αvβ5 were first determined with fluorescence-activated cell sorting (FACS) and immunofluorescence assay. Cell proliferation and apoptosis were examined by Cell Counting Kit-8 assay and FACS, respectively. Cell migration and invasion were determined by transwell assays. All three PTC cell lines examined (BCPAP, K1, and TPC1) showed a moderate-to-high expression of αvβ3 and αvβ5 (P<0.05). Antagonizing the two heterodimers with the RGD-containing antagonist showed moderate inhibitory effect on cell viability of K1 and BCPAP cells, while the inhibitory effect was more significant in TPC1 cells. Similarly, the apoptotic effect induced by antagonizing αvβ3 and αvβ5 was much stronger in TPC1 cells than in BCPAP and K1 cells. Cell migration and invasion were significantly inhibited by αvβ3 and αvβ5 antagonism in all three PTC cell lines. Our results suggested that the demonstrated expression of RGD-binding integrin on PTC cells provides the possibility of integrin-targeting treatment in PTC. The strong apoptotic effect observed in TPC1 cells indicated that a subgroup of PTC patients may benefit from the cytotoxic effect of RGD-binding integrin antagonism, while the strong inhibitory effect on migration and invasion in all three PTC cells by antagonizing αvβ3 and αvβ5 showed there is an exciting possibility that targeting RGD-binding integrin may serve a potential therapeutic approach for metastatic PTC patients.

Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib.

To determine whether the selective BRAF inhibitor, dabrafenib, can stimulate radioiodine uptake in BRAF V600E-mutated unresectable or metastatic iodine-refractory papillary thyroid cancer (PTC). Ten patients with BRAF V600E-mutant iodine-refractory PTC were enrolled. Absence of radioiodine uptake on iodine-131 whole body scan obtained within 14 months of study entry was required. Each patient received dabrafenib (150 mg twice daily) for 25 days before thyrotropin α-stimulated iodine-131 whole body scan (4 mCi/148 MBq). Patients whose scan showed new sites of radioiodine uptake remained on dabrafenib for 17 more days, and then were treated with 150 mCi (5.5 GBq) iodine-131. The primary endpoint of the study was the percentage of patients with new radioiodine uptake after treatment with dabrafenib. Six of 10 patients (60%) demonstrated new radioiodine uptake on whole body scan after treatment with dabrafenib. All 6 were treated with 5.5 GBq iodine-131. Two patients had partial responses and 4 patients had stable disease on standard radiographic restaging at 3 months. Thyroglobulin decreased in 4 of 6 treated patients. One patient developed squamous cell carcinoma of the skin. There were no other significant adverse events attributed to dabrafenib. Dabrafenib can stimulate radioiodine uptake in patients with metastatic BRAF V600E-mutant iodine-refractory PTC, representing a potential new therapeutic approach for these patients.

Excellent long-term control in locoregionally recurrent radioactive iodine-refractory papillary thyroid cancer with the addition of external beam radiation therapy to maximal surgical resection.

e16035 Background: Locoregionally recurrent radioactive iodine (RAI) refractory papillary thyroid cancer represents a small percentage of papillary thyroid cancers but is an aggressive disease with significantly lower survival rates. This retrospective review is our experience with these cancers treated with maximal surgical resection followed by external beam radiotherapy. Methods: 26 patients treated from 2001-2011 were eligible for review. After obtaining IRB approval, medical records were reviewed for clinical outcome. All patients had histologically proven recurrences that were negative on I-131 scans. All patients were maximally resected. All patients received external radiotherapy to the thyroid bed, bilateral cervical lymph node levels II-IV, level VI, and superior mediastinal nodes. 15/26 patients received intensity modulated, 9/26 patients received 3-D conformal, and 2/26 patients received Tomotherapy radiation treatment. The mean dose was 5790 cGy (range 5280-6800 cGy). Results: All histologies were papillary thyroid cancer with 4/26 exhibiting tall cell features and 1/26 diffuse sclerosing features. All patients had locoregional relapse in the cervical nodes (16/26) or in the mediastinum (5/26) or both areas (5/26). The mean pre-treatment thyroglobulin was 5.2 (range &lt;0.1 to 599.1). The mean post-treatment thyroglobulin was 1.0 (range &lt;0.1-5.2). Median follow-up was 55 months (range 7-123 months). 0/26 patients failed locoregionally. 2/26 patients failed distantly (lungs). 20/26 patients (77%) of patients had undetectable thyroglobulin at last follow-up. 4/26 patients had detectable thyroglobulin (2.5-16.9), but had not recurred on imaging. 2/26 required PEG placement during treatment, but 0/26 patients were PEG-dependent on long-term follow-up. 1/26 patients experienced grade III osteoradionecrosis of the mandible. Conclusions: External beam radiotherapy provides excellent locoregional control for locoregionally recurrent radioactive iodine-refractory papillary thyroid cancers. Long-term grade III and IV toxicities are uncommon.