Radioimmunodetection of medullary thyroid carcinoma using indium-111 bivalent hapten and anti-CEA x anti-DTPA-indium bispecific antibody.

UNLABELLED: Pretargeting labeled bivalent hapten with bispecific antibodies has proven feasible in the clinic, and our earlier results have suggested the technique may be very sensitive for detecting small recurrences and metastases. Medullary thyroid carcinoma (MTC) is an example where this technique may be the most useful since local recurrences and isolated metastases are removed surgically when detected, and thyrocalcitonin provides a specific and sensitive tumor marker. In our current study, we evaluated pretargeted immunoscintigraphy in a larger number of MTC patients. METHODS: Anti-carcinoembryonic antigen (CEA) x anti-diethylenetriaminepentaacetic acid (DTPA) indium bispecific antibody and 111In-labeled bivalent DTPA hapten were administered sequentially (4-5 days apart) to 44 patients with elevated circulating calcitonin after resection of primary MTC. Immunoscintigraphy was performed 2, 5 and 24 hr after hapten injection and, when necessary, at longer time intervals. When available, a handheld gamma probe was used during surgery. RESULTS: Fifteen patients had known tumor sites before immunoscintigraphy. Tumors were imaged in 12 (80%) of these patients, including 3 with liver metastases. Five unknown tumor sites were detected. For the 29 patients with occult disease, immunoscintigraphy detected high-activity uptake sites in 21 patients (72%), including 5 in the liver. Twelve were confirmed by surgery, 1 by guided morphologic imaging and 1 by venous catheterization. There were 2 false-positive patients. The other 5 patients have not yet been confirmed. All detected liver metastases were high-activity uptake areas. Radioimmunoguided surgery was used in 14 patients. It was considered helpful by the surgeon in 12 patients, including 4 patients where it determined the resection of small, not palpable nor visible, tumor-involved lymph nodes. Surgical resection resulted in a significant decrease (8 patients) or normalization (1 patient) of circulating calcitonin and CEA. CONCLUSION: This technique affords high sensitivity and specificity for detecting small tumor lesions including liver metastases. Its use for immunoscintigraphy and guided surgery should improve the therapeutic management of recurrent MTC.

Prognostic factors for survival and for biochemical cure in medullary thyroid carcinoma: results in 899 patients. The GETC Study Group. Groupe d'étude des tumeurs à calcitonine.

BACKGROUND: Prognostic factors of sporadic or inherited medullary thyroid carcinoma (MTC) are still controversial and have been assessed in old and small series. A better knowledge of these factors would improve patient management. OBJECTIVE: To evaluate factors involved in the prognosis of MTC in a large series of cases, using uni- and multivariate analysis. DESIGN AND PATIENTS: Clinical, biological, surgical and epidemiological data on 899 MTC patients, diagnosed between 1952 and 1996, were collected by the French Calcitonin Tumors Study Group (GETC) with a standardized questionnaire, and processed in a national database. MEASUREMENTS: Survival and biochemical cure (i.e. normal basal post-operative serum calcitonin levels) were analysed with Kaplan and Meier and log-rank test statistical procedures. Data are presented as adjusted rather than observed survival, to consider only patients who died of MTC. Cox's forward-stepping proportional hazard model was used to analyse factors with a significant influence on survival by univariate analysis. RESULTS: Apart from the large proportion of familial forms (43%), the general characteristics of our population were similar to those in other studies: mean age at surgery = 43.4 years; sex ratio = 1 male/1.35 female; stage I = 20.8%; stage II = 21.2%; stage III = 46.5% and stage IV = 11.5%. 863 (96%) patients underwent surgery; 43% of operated patients were biochemically cured. Adjusted survival was 85.7 +/- 1.5% at 5 years and 78.4 +/- 2.1% at 10 years. Multivariate analysis showed that age and stage were independent predictive factors of survival. Gender, type of surgery, type of familial form were predictive only in univariate analysis. Biochemical cure predicts a survival rate of 97.7% at 10 years. Authentic recurrence, that is subsequent elevation of calcitonin (CT) after post-operative normalization, was found in 4.9%. In non-cured patients (57%), survival was still good: 80.2% (+/- 2.2%) and 70.3% (+/- 2.9%) at 5 and 10 years, respectively. Similarly, prediction of biochemical cure was solely dependent on stage. CONCLUSION: Survival of these medullary thyroid carcinoma patients appears better than expected even in non-cured patients. Considering the strong impact of stage, the necessity for pre-operative diagnosis of MTC is obvious.

[Value of the corticoliberine test in the etiologic diagnosis of Cushing's syndrome]. / Intérêt du test à la corticolibérine dans le diagnostic étiologique du syndrome de Cushing.

Several studies have demonstrated that the corticotropin-releasing factor test (CRF) is useful for the aetiological diagnosis of Cushing's syndrome: in Cushing's disease, as opposed to ectopic ACTH secretion syndrome, the hypothalamus-pituitary-adrenal (HPA) axis can still be stimulated by CRF. In the present study, we compared the CRF test with the reinforced dexamethasone suppression test in 18 patients: 11 with Cushing's disease, 6 with ectopic ACTH secretion and 1 with adrenal gland adenoma. We obtained 2 false-negative results with the CRF test and 1 false-positive result with the dexamethasone suppression test. Our study, together with published data, suggests that the CRF test is useful in the exploration of Cushing's syndromes of uncertain origin. However, the results obtained with this test must be compared with those of other methods used to explore the HPA axis and which are still necessary.

[Efficacy and long-term tolerance of ketoconazole in the treatment of Cushing's disease]. / Efficacité et tolérance à long terme du kétoconazole dans le traitement de la maladie de Cushing.

Successful short term treatment of patients with Cushing's disease by Ketoconazole without adverse effects is now well established. Little data are available about prolonged treatment of this disease with ketoconazole. We report herein our experience of ketoconazole therapy in four patients with Cushing's disease treated for 9 to 38 months. One patient rapidly developed adrenal hypofunction and required transient steroid therapy adjunction. In the other patients, cortisol overproduction was reduced to normal levels within two months and their urinary free cortisol remained within the normal range throughout the study. In two patients ketoconazole dose could be decreased but had to be increased after ten months of therapy in one patient. None of the patients had clinical or biochemical signs of drug toxicity. Thus, ketoconazole seems to be a useful drug for the prolonged metabolic control of Cushing's disease. However, in this circumstance, ketoconazole daily dose adaptation can be necessary in order to maintain normal urinary cortisol levels and the ability of ketoconazole to cure Cushing's disease still remains to be determined.

[Value of the CRF test in primary and secondary adrenal insufficiency]. / Intérêt du test au CRF dans l'insuffisance surrénalienne primitive et secondaire.

The ACTH and cortisol responses after CRF administration were studied in 21 patients with adrenal failure and compared with those obtained in 15 control subjects. In patients with Addison's disease, cortisol and ACTH responses were respectively abolished or excessive. In patients with secondary adrenal failure, a unique bolus injection of CRF allows the differentiation between pituitary or hypothalamic secretory defect. With regard to previous reports, the usefulness of CRF test in primary and secondary adrenal failure is stressed.