ABSTRACT
CONTEXT: In low-risk differentiated thyroid cancer (DTC), postoperative (131)I remnant ablation should employ a minimum effective activity; reports increasingly suggest efficacy of low activities, e.g. 1110 MBq/30 mCi. OBJECTIVES, DESIGN, PATIENTS, AND INTERVENTIONS: We retrospectively studied the ablation capability and diagnostic utility of the Minidose protocol, two 740-MBq/20 mCi outpatient administrations, 6-18 months apart, plus related diagnostic procedures, in 160 consecutive (near-) totally thyroidectomized low-risk DTC (pT1/N0-Nx) patients. Successful ablation comprised negative 740-MBq whole-body scintigraphy with cervical uptake below 0.1%, negative stimulated thyroglobulin (STg) (<1 ng/ml, negative thyroglobulin antibodies), and negative Doppler ultrasonography (performed around Minidose 2). SETTING: The study took place at a referral center. RESULTS: Minidose imaging found unsuspected nodal or distant metastases in nine of 160 patients (5.6%). Ablation success rates after one (two) 740-MBq activity (activites) were 75.9% (90.2%) in 145 (132) evaluable imaging-negative patients. Compared with thyroid hormone withdrawal, recombinant human TSH stimulation was associated with higher urinary iodine excretion/creatinine, lower cervical uptake, and more frequent ablation success after the first 740 MBq; success rates no longer differed significantly after both administrations. Patients with STg below 10 ng/ml at Minidose 1 were oftener ablated at Minidose 2 (odds ratio=13.9, 95% confidence interval=2.5-76.4, P<0.003), attaining 92.0% final ablation success after recombinant human TSH preparation, suggesting that one 740-MBq activity should suffice in this subgroup. All 81 evaluable patients with prolonged follow-up (mean 41.8±21.9 months after Minidose 1) had no evidence of disease at the last visit. CONCLUSIONS: The Minidose outpatient ablation protocol is effective and diagnostically useful in low-risk DTC.
Subject(s)
Adenocarcinoma, Follicular/radiotherapy , Adenocarcinoma, Papillary/radiotherapy , Thyroid Neoplasms/radiotherapy , Adult , Aged , Aged, 80 and over , Ambulatory Care , Female , Follow-Up Studies , Humans , Male , Middle Aged , Postoperative Period , Retrospective Studies , Treatment OutcomeABSTRACT
From potent and selective inhibitors of GSK3beta displaying CYP1A2 inhibition and poor PK properties, mostly linked to metabolic instability and in vivo hydrolysis of the amide bond, we were able to obtain safe and orally available inhibitors with good half lives.
Subject(s)
Glycogen Synthase Kinase 3/antagonists & inhibitors , Glycogen Synthase Kinase 3/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/pharmacokinetics , Animals , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP1A2 Inhibitors , Glycogen Synthase Kinase 3 beta , Humans , Mice , Models, Molecular , Protein Kinase Inhibitors/chemistryABSTRACT
From an HTS hit, a series of potent and selective inhibitors of GSK3beta have been designed based on a Cdk2-homology model and with the help of several crystal structures of the compounds within Cdk2.
