18-fluorodeoxyglucose positron emission tomography in the early diagnostic workup of differentiated thyroid cancer patients with a negative post-therapeutic iodine scan and detectable thyroglobulin.

BACKGROUND: Surgery and high-dose radioactive iodine ((131)I) treatment are the cornerstones in the treatment of differentiated thyroid cancer. Patients without (131)I uptake on the post-therapeutic whole body scan (WBS), but with detectable thyroglobulin (Tg) during thyroxine withdrawal (Tg-off), are evaluated with an 18-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) for tumor localization within three months. The yield of (18)F-FDG-PET imaging and clinical usefulness of a Tg-off cutoff value to predict a positive scan were assessed. METHODS: From 2002 to 2011, 52 patients with a negative WBS and concurrent detectable Tg-off were evaluated. Thirty-five PET scans were performed during initial treatment, 17 after recurrent disease. Thirty-two patients were on substitution therapy, 17 were evaluated with endogenous thyrotropin elevation, and 3 after recombinant human thyrotropin stimulation. To determine the Tg-off cutoff value, a receiver operating characteristic curve was used. RESULTS: Nine (17%) (18)F-FDG-PET scans were true positive, 3 (6%) false positive, 36 (69%) true negative, and 4 (8%) false negative (sensitivity 69%, specificity 92%). In 13%, a true-positive scan resulted in a change in the clinical management. The area under the receiver operating characteristic curve is 0.82 [CI 0.64-0.99] (p<0.01), and the Tg-off cutoff value is 38.00 ng/mL (sensitivity 67%, specificity 95%). Ninety percent of (18)F-FDG-PET true-positive patients had a Tg-off >2.00 ng/mL. CONCLUSIONS: An (18)F-FDG-PET within three months after a negative WBS with detectable Tg-off showed additional tumor localization in 17% of the patients, leading to a change in clinical management in 13%. A clinically useful Tg-off cutoff value was not found, but 90% of positive (18)F-FDG-PET scans occurred in patients with a Tg-off >2.00 ng/mL.

Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene.

Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatigability, exercise intolerance and lactic acidosis in blood from early childhood. In muscle, subsarcolemmal mitochondrial proliferation and a severe complex I deficiency were observed. Exercise intolerance and complex I activity was improved by a supplement of riboflavin at high dosage. Homozygosity mapping revealed a candidate region on chromosome three containing six mitochondria-related genes. Four genes were screened for mutations and a homozygous substitution was identified in ACAD9 (c.1594 C>T), changing the highly conserved arginine-532 into tryptophan. This mutation was absent in 188 ethnically matched controls. Protein modelling suggested a functional effect due to the loss of a stabilizing hydrogen bond in an α-helix and a local flexibility change. To test whether the ACAD9 mutation caused the complex I deficiency, we transduced fibroblasts of patients with wild-type and mutant ACAD9. Wild-type, but not mutant, ACAD9 restored complex I activity. An unrelated patient with the same phenotype was compound heterozygous for c.380 G>A and c.1405 C>T, changing arginine-127 into glutamine and arginine-469 into tryptophan, respectively. These amino acids were highly conserved and the substitutions were not present in controls, making them very probably pathogenic. Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment.