Calcium-stimulated calcitonin test for the diagnosis of medullary thyroid cancer: results of a multicenter study and comparison between different assays.

BACKGROUND: A basal serum calcitonin (Ct) increase >100 pg/mL in patients with a thyroid nodule is consistent with the diagnosis of medullary thyroid cancer (MTC). In cases where the CT test have a slight to moderate increase, the calcium gluconate stimulation test is helpful to increase diagnostic accuracy. However, reliable cut-offs for calcium-stimulated Ct are still lacking. The aim of this study was to evaluate the sex-specific calcium-stimulated Ct cutoffs for the diagnosis of MTC in a multicenter series. A comparison between different Ct assays has been also performed. METHODS: 90 subjects undergone calcium-stimulated Ct for a suspected MTC in 5 Endocrine Units between 2010-2021 were retrospectively analyzed. Serum Ct concentrations were assessed by immunoradiometric (IRMA) or chemiluminescence (CLIA) assays. RESULTS: MTC was diagnosed in 37 (41.1%) and excluded in 53 (58.9%) patients. The best calcium-stimulated Ct cut-off to identify MTC was 611 pg/mL in males (AUC =0.90, 95% CI (0.76;1) and 445 pg/mL in females (AUC=0.79, 95% CI (0.66;0.91). Logistic regression analysis showed that both basal (OR 1.01, P=0.003) and peak Ct after stimulation (OR 1.07, P=0.007) were significantly associated with MTC, together with sex (OR=0.06, P<0.001). The "Ct assay" variable was also considered in the logistic regression model, but it was not significantly associated with MTC (OR=0.93, P=0.919). CONCLUSIONS: This study indicates that calcium test could be helpful to identify patients with early-stage MTC and those without MTC. A Ct value of 611 pg/mL in males and 445 pg/mL in females are proposed as the optimal Ct cut-offs at the stimulation test.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

Falsely elevated thyroglobulin and calcitonin due to rheumatoid factor in non-relapsing thyroid carcinoma: A case report.

RATIONALE: Thyroglobulin (Tg) is an accurate indicator of clinical outcome after total thyroidectomy in patients with differentiated thyroid carcinoma. Usually, Tg levels agree with whole body scan. However, in some patient, discordant results were found, often because of Tg immunoassay interference. Several reports indicated that 2-site immunoassay interference with heterophile antibodies (HAb) can lead to misinterpretation of the laboratory test result. PATIENT CONCERNS: We report a case of a 46-year-old woman referred to our endocrine clinic for markedly increased calcitonin (CT) without the associated clinical picture. The measurement was repeated with the same patient sample on a different analytical platform and the result was an undetectable CT level. The measurement of Tg was repeated on 3 different analytical platforms using chemiluminescence and electrochemiluminescence immunoassays and the results were different on each platform. HAb blocking tubes resulted in a different level of both CT and Tg, suggesting the presence of a heterophile substance in the serum sample. Further characterization showed reactivity to several animal species antibodies and an elevated level of the rheumatoid factor (RF). DIAGNOSES: She was diagnosed as papillary thyroid carcinoma. INTERVENTIONS: She had undergone thyroidectomy with lymph node dissection and radioactive therapy. OUTCOMES: She was found not to have recurrence despite a high serum Tg level. LESSONS: Our report illustrates a rare case of falsely elevated tumor markers levels due to assay interference caused by RF. This finding pointed out the importance of close communication between the clinician and laboratory staff in order to bring to light discordance between laboratory test results and clinical picture and avoid unnecessary diagnostic procedures and overtreatment.

Clinical outcome in differentiated thyroid carcinoma and microcarcinoma.

INTRODUCTION: Due to the frequent use of neck ultrasonography, the incidence of differentiated thyroid microcarcinoma (DTMC), defined as a lesion with greatest dimension ≤1 cm, is increasing worldwide. Although DTMC generally has a lower aggressivity and a better prognosis than differentiated thyroid carcinoma (DTC), some cases of clinically aggressive DTMC were found. The aim of this study is to compare the rate of recurrence in DTMC and DTC, during a 3-year follow-up. METHODS: Patients with differentiated thyroid carcinoma, who underwent total thyroidectomy and postoperative (131)I-RAI ablation, were stratified according to lesion diameter (DTC for diameter > 1 cm or DTMC ≤ 1 cm). After surgery, patients underwent a 3-year follow-up. Recurrent disease was defined on the basis of positive biochemical (Tg > 2 ng/ml under TSH-suppression or after rhTSH-stimulation) and/or imaging (US, WBS, CT, PET/CT) findings. RESULTS: 449 patients have been included in the final analysis. Linfoadenectomy rate and RAI ablative dose were significantly higher in DTC than in DTMC (32.7% vs. 22.4%, p = 0.018 and 112.3 ± 21 vs. 68.3 ± 24.1 mCi, p < 0.001). During the follow-up, 50 carcinoma recurrences occurred, more frequent in DTC than in DTMC (15.6% vs. 7.6%, p = 0.010). After adjustment for gender, age, rate of lymph node dissection and 131I dose of RAI treatment, the difference in the risk of recurrence was no longer significant among DTC and DTMC patients (HR: 1.585, 95% CI 0874-2877, p = 0.130). CONCLUSIONS: The prediction of disease severity cannot be based exclusively on lesion diameter. A more careful therapeutic approach and follow-up should be recommended in DTMC patients.