A high frequency (about 60%) of ret rearrangements in papillary thyroid carcinomas of children exposed to radioactive fallout in Belarus after the Chernobyl accident, has been reported by three recent studies Ito et al., 1994;Klugbauer et al., 1995). These studies suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In order to con®rm the postulated link between irradiation and the role of the ret protooncogene in thyroid tumorigenesis, we analysed for the presence of ret activating rearrangements using RT ± PCR, XL ± PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors (19 papillary carcinomas and 20 follicular adenomas), from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 spontaneous' tumors (20 papillary carcinomas and 19 follicular adenomas). Our data concerning the radiationassociated tumors, showed that: (1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; (2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1 instead of the RET/PTC3 and (3) all the tumors were negative for RET/PTC2. In the`spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15% : 3/20): 1 RET/PTC1, 1 RET/ PTC3 and 1 uncharacterized. In conclusion, our results con®rm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors appearing after therapeutic or accidental ionizing irradiation, and show, for the ®rst time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

Summary Circulating neuron-specific enolase (NSE) and chromogranin A (CgA) were measured in 128 patients with neuroendocrine tumours (NET) to compare their sensitivity and specificity, to investigate factors associated with elevated serum levels and to determine the usefulness of these markers in the follow-up of NET patients. NSE (Cispack NSE, Cis Bio Intemational, Gif-sur-Yvette, France; normal <12.5 gig h1), and chromogranin A (CgA-Riact, Cis Bio Intemational, normal <100 jig 1-') were measured in 128 patients without renal insufficiency.There were 99 patients with gastroenteropancreatic (GEP) NET, 19 with medullary thyroid carcinoma and ten with phaeochromocytoma. Fiftythree patients with non-NET were studied as controls. Serum NSE and CgA levels were elevated in 48 (38%) and 76 (59%) of the 128 NET patients respectively. In all groups of NET patients, CgA proved to be more sensitive than NSE. NSE and CgA had a specificity of 73°o and 68% respectively. Immunostaining for NSE was positive in three out of eight controls with elevated CgA levels, whereas immunostaining for CgA and synaptophysin was negative in all cases. Elevated CgA levels were significantly associated with two independent parameters, namely the presence of other secretions (P= 0.0001) and a heavy tumour burden (P= 0.001). Elevated NSE levels were exclusively associated with poor tumour differentiation (P= 0.01). Among six patients with NET followed for 11-37 months. CgA appeared to be a better marker of tumour evolution than NSE. We suggest that CgA ought to be the only general marker screened in NET patients.

The follow-up of patients with papillary and follicular thyroid carcinoma after thyroidectomy and radioiodine ablation is mainly based on serum thyroglobulin (Tg) level deter-mination. The positive predictive value (PPV) of serum Tg level after thyroid hormone withdrawal, measured during the first 6-12 months of follow-up (initial off L-T(4) Tg), was studied in 256 consecutive differentiated thyroid cancer patients. All underwent a total thyroidectomy and 3.7 GBq (131)I ablation; 37 patients had an elevated initial off L-T(4) Tg level. This study focuses on these 37 patients, 9 of whom had a clinical recurrence. The present data confirm that in this selected cohort of patients, 74-185 MBq (131)I-total body scan (TBS) has no clinical interest in the initial work-up and during the subsequent follow-up because it was negative in all patients, except in one with recurrent disease. The PPV of initial serum off L-T(4) Tg level above 5 ng/ml and 10 ng/ml was 42% and 53%, respectively; this PPV was only 50% at the time of recurrence or subsequent control. This relatively low PPV is related to the low recurrence rate in this series of patients, despite a prolonged follow-up, and to the subsequent decrease of serum Tg level in 14 of 37 (38%) patients in the absence of any further treatment. In contrast, the PPV of the increasing slope of serum Tg levels obtained after thyroid hormone withdrawal (83%) was excellent. In conclusion, we confirm that (131)I-TBS has a limited interest for the follow-up of thyroid cancer patients. Follow-up should rely on serum Tg level and prognostic parameters; however, initial serum Tg may be produced by thyroid tissues of various significance, an increase at two consecutive determinations indicating disease progression and a decrease being related to late effects of therapy. The best PPV is brought by the slope of serum Tg levels.