RESUMEN
Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [89Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [89Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89Zr (t1/2 = 78.4 h, ß+ = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [89Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [89Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (P < 0.0001) and FTC133 (P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (P < 0.0001) and TSHR+ FTC133 (P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [89Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference (P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [89Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.
Asunto(s)
Ratones Desnudos , Tomografía de Emisión de Positrones , Receptores de Tirotropina , Neoplasias de la Tiroides , Circonio , Animales , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Humanos , Ratones , Circonio/química , Tomografía de Emisión de Positrones/métodos , Línea Celular Tumoral , Femenino , Receptores de Tirotropina/metabolismo , Receptores de Tirotropina/genética , Radiofármacos/farmacocinética , Radiofármacos/química , Distribución Tisular , Masculino , Radioisótopos/químicaRESUMEN
BACKGROUND: Dexamethasone is a potent corticosteroid when administered alone or in combination alone has proven efficacious in preventing nausea and vomiting (PONV) perioperatively. However, the administration of even a single dose has been associated with hyperglycemia. This is the first study that evaluates the effect of two low-doses of dexamethasone (4 and 8 mg) on blood glucose concentrations among diabetics and nondiabetics in patients who have received spinal anesthesia. MATERIALS AND METHODS: After obtaining ethical clearance and patient consent, 180 American Society of Anesthesiologists 1-3 patients undergoing the elective infraumbilical surgeries under spinal anesthesia aged between 18 and 70 years were included in this study. Ninety diabetic patients were allotted to the diabetic group (DM), and ninety nondiabetic patients were allotted to the nondiabetic group (ND). Group DM was divided into three subgroups DM0, DM4, and DM8. Group ND was divided into three subgroups ND0, ND4, and ND8. The patients in groups DM0 and ND0 served as controls. The patients in groups DM4 and ND4 received 4 mg dexamethasone. The patients in groups DM8 and ND8 received 8 mg dexamethasone. The blood glucose concentrations were monitored at 0 (baseline), 1, 2, 3, 4, 5, 6, and 8 h after giving the drug. RESULTS: The baseline blood glucose values were higher in diabetics compared to nondiabetics (128.57 ± 22.26 vs 94.99 ± 12.82 mg/dL). There was a statistically significant increase in blood glucose concentrations in both diabetics and nondiabetics who received dexamethasone. The rise of blood glucose from baseline was similar in both diabetics and nondiabetics. CONCLUSION: The maximum rise in blood glucose was in the range of 40-45 mg/dl in the patients who received dexamethasone. The clinician should use his clinical judgment before administering dexamethasone for PONV prophylaxis/treatment.