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Romiplostim (Rm) (AMG531, Nplate), a protein that binds to and stimulates the TPO receptor, has been shown to increase and maintain platelet counts in splenectomized and non-splenectomized adult patients with chronic immune thrombocytopenic purpura (ITP), and few adverse events have been reported.1, 2, 3, 4, 5 An overall response, defined as platelet count 50 000/μL for 4 weeks, was observed in 83% of patients, and 49% of these had a durable response.3 Interestingly, no antibodies against Rm or endogenous TPO were detected.2, 3 The study by Kuter et al.3 suggested that Rm could increase BM reticulin in some patients, though there was improvement upon withdrawal of the drug. The clinical significance of this finding remains unclear and warrants further study.6 In addition, discontinuation of Rm can cause a rapid decrease in platelet count in many patients. However, the safety and efficacy of long-term Rm treatment has been established in patients for up to 156 weeks of treatment.4 Altogether, these data have led to the approval of Rm for adult chronic ITP therapy in North America, Australia and Europe.

Resume La calcitonine (CT) et la thyroglobuline (Tgb) sont les principaux marqueurs de l'activite biologique de deux populations cellulaires de la glande thyroide, respectivement les cellules C et les cellules folliculaires. Malgre la specificite tissulaire de la Tgb, la diversite des pathologies fonctionnelles et tumorales du tissu folliculaire qui peuvent en modifier le taux circulant limite la valeur diagnostique et pronostique de son seul dosage. Celui-ci doit s'integrer parmi les elements indispensables a une demarche diagnostique fondee sur une confrontation des donnees clinique, biologique et morphologique. L'interet clinique du dosage de la CT est domine par les relations etroites entre sa production et le developpement d'une tumorisation des cellules C vers les cancers medullaires de la thyroide (CMT) : ces relations conferent au dosage de la CT circulante une indeniable valeur diagnostique et pronostique, appliquee au depistage des formes infra-cliniques de CMT hereditaire et au suivi evolutif des differentes formes de ce cancer. De plus, l'evaluation de son taux circulant et intratumoral s'integre parmi les moyens d'etudier l'expression du gene Calc I, gene produisant differents peptides recemment identifies : CCP I, CCP II associes a la procalcitonine, le CGRP I.

The diagnosis of medullary thyroid carcinoma by biochemical and genetic testing is possible in families with multiple endocrine neoplasia type 2. At an early stage total thyroidectomy usually cures the patient. As the clinical penetrance of the autosomal dominant, transmitted, multiple endocrine neoplasia type 2 gene is not complete, family screening is indicated for every new patient who presents with apparently sporadic medullary thyroid carcinoma. Problems related to a screening programme and early diagnosis have led the members of the European Community Concerted Action: Medullary Thyroid Carcinoma group to formulate a consensus on biochemical and genetic screening. For biochemical screening, measurement of basal and pentagastrin and/or calcium stimulated serum levels of calcitonin by radioimmunoassay are essential starting at the age of three and continuing annually until 35 years of age. Furthermore, annual screening for pheochromocytoma by measuring the urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination is indicated. Genetic screening using linked markers can be done with a 95% accuracy in informative families when DNA is available from at least two family members proven to be affected. Biochemical screening can thus be reserved for gene carriers, while those at low risk can be reassured. Combined biochemical and genetic screening for multiple endocrine neoplasia type 2 is important and effective for the cure of medullary thyroid carcinoma.

We have recently identified in medullary thyroid carcinoma the existence of a second calcitonin messenger, generated by a splicing between the 3' coding region of exon 4 and exon 5 of Calc I gene. It differs from the first one in its 3' coding sequence and codes for a calcitonin precursor which generates the same N terminal peptide, calcitonin and a specific 21 amino acid carboxy terminal peptide differing from Katacalcin by its 8 last amino acids. We searched for the expression of this new messenger in normal human thyroid tissue by Northern and by polymerase chain reaction techniques. This second calcitonin messenger was expressed in 4/4 normal thyroids and 4/5 medullary thyroid carcinoma tissue samples. The expression of this second messenger is apparently a common occurrence in C cells whether normal or tumoral.

Two genes code for calcitonin gene-related peptides (CGRPs). One expresses by tissue-specific alternate splicing calcitonin and CGRP I mRNAs, the other CGRP II mRNA. Calcitonin is the marker of sporadic or hereditary human medullary thyroid carcinoma (MTC). CGRP II expression is not well established in normal or tumoral thyroid. After amplification by polymerase chain reaction, CGRP I and II mRNAs were detected in six cases of MTC associated with other endocrine neoplasia (MEN IIa) and in two cases of isolated MTC. CGRP I was detected in all non-C cell tumoral thyroids (6 samples), CGRP II was barely detectable in three out of six cases. CGRP II could be a specific tumoral marker of MTC.

A new calcitonin (CT) immunoradiometric assay, using anti-11-7 and anti-24-32 CT fragment monoclonal antibodies was evaluated and compared to classical RIA. The sensitivity was 2.5 ng/L, the normal basal level (n = 83) was lower than 10 ng/L, the response to pentagastrin stimulation in control subjects was absent in nine and between 10-30 ng/L in nine others. (mean, 15.4). In patients with renal failure the basal level was increased between 10-52 ng/L. In patients with medullary thyroid carcinoma (MTC; n = 28), the basal level was between 189-28,900 ng/L. A pentagastrin test was performed as screening for familial MTC in eight patients with confirmed MTC at subsequent surgery; the calcitonin peak was equal or greater than 38 ng/L. Large differences exist between CT levels measured by RIA and immunoradiometric assay. The latter method provides a greater sensitivity to pentagastrin test and allows a better identification of microcarcinoma in hereditary cases of MTC.

The current work has been performed by the Cooperative French Group of Medullary Thyroid Carcinoma (GETC). A systematic evaluation of RIA somatostatin (SRIH) was performed in 34 medullary thyroid carcinomas (MTC) (25 inherited, seven sporadic). Plasma SRIH was measured by radioimmunoassay in parallel with calcitonin (CT) and carcinoembryonic antigen (CEA). Immunoassayable SRIH was tested in fresh tumoral tissue samples from the same 34 MTC and, for comparison, in 10 nontumoral thyroid extracts (less than 6 pmol/g wet). Although plasma SRIH was only slightly elevated in two of 20 cases, tumoral SRIH was elevated in 70.6% of our MTC (10 to 3973 pmol/g). The chromatography of two tumoral extracts showed that somatostatin 14 was the major molecular form. We found no correlation (P greater than 0.1) between tumoral SRIH and the following: (1) tumor size (r = 0.227); (2) epidemiologic form of MTC (r = 0.144); (3) plasma SRIH (r = 0.045), plasma CT (R = 0.095) or (4) plasma CEA (r = 0.032). Thus, in the authors' experience, SRIH appears as a major product of tumoral C-cell in human MTC, even when plasma SRIH is normal and SRIH immunohistochemical staining is scarce. Multiple hormonal production of these tumors may explain its presence but SRIH may act also as a regulator, since negative influence of SRIH on CT is demonstrated in normal as well in tumoral conditions.

Calcitonin (CT), a hypocalcemic and hypophosphatemic hormone, is produced by the C-cells of the thyroid gland. It is the main tumoral marker of medullary thyroid carcinoma (MTC). Hypersecretion of CT is also associated with other types of tumors. Thus, heterogeneity of ciculating CT can play an important role in the accurate determination of hormone levels in blood samples obtained from MTC patients. Further studies will be necessary to establish the predictive value of the several peptides coded by the calcitonin gene family. All of them specifically reflect the ways and the pattern of alternative splicing of the primary transcript of the Calc I gene. Such relations implicate further investigations concerning the relationship between calcitonin circulating levels, biosynthetic activity of C-cells and the expression of gene encoding for this hormone, in normal and neoplastic conditions.

A pentagastrin stimulation test using a calcitonin (CT) immunoradiometric assay was performed in 38 healthy subjects and in the following 50 patients: 25 subjects from families with at least 2 known cases of medullary thyroid carcinoma (MTC), 11 subjects from families with apparently sporadic MTC, 2 pheochromocytoma carriers, 1 primary hyperparathyroidism, 8 patients with thyroid nodules, and 3 others with various diseases. In healthy volunteers, basal CT values were always less than 10 ng/L; the response to pentagastrin was below 30 ng/L for 36, and for the remaining 2, the peaks reached 30 for 1 subject and 48 ng/L for the other. The pentagastrin-stimulated CT peak was above 30 ng/L in each of the patients presented here, and all were thyroidectomized. In screening the 25 relatives of patients with familial MTC, a CT peak level over 30 ng/L was constantly associated with C-cell disease (23 cases of MTC and 2 of C-cell hyperplasia). A response to pentagastrin above 100 ng/L was observed in 15 patients among the 23 with MTC. In 8 of the 10 patients with a peak CT level between 30-100 ng/L, pathological examination showed a MTC; the other 2 had C-cell hyperplasia and a negative linkage study analysis. In the 25 other patients in the study without familial MTC, the pentagastrin-stimulated CT level was over 100 ng/L in 11 of the 14 subjects with MTC. The abnormal CT response to pentagastrin, which has been used as a criterion for surgical treatment, is currently determined by an immunoradiometric assay. Our study confirms that subjects with a peak CT level above 100 ng/L should undergo surgery whatever the reason for the test. In the context of inherited MTC, our results suggest that for patients with a CT peak level between 30-100 ng/L, surgery may actually be postponed when their probability of being gene carriers is low. Recent progress with the characterization of specific mutations in affected individuals will make familial screening much easier in the next few months.

Summary OBJECTIVE We report clinical, biochemical, morphological and histological data of phaeochromocytoma in 40 French families and in apparently sporadic cases of multiple endocrine neoplasia (MEN) type 2 A (medullary thyroid carcinoma, phaeochromocytoma, with or without hyperparathyroidism). DESIGN This retrospective study was obtained from cases registered by the‘Groupe d'Etudes des Tumeurs a Calcitonine’ from 1968 to 1990. We analysed the cases having sufficiently precise data on phaeochromocytoma with Pigas Software. PATIENTS Characteristics of phaeochromocytoma In 100 patients with MEN 2 A were reviewed. Phaeochromocytoma was bilateral in 51 %. The disease was inherited in 94 patients from 40 families (40 probands, 54 relatives), and was apparently sporadic In six. RESULTS In this series, diagnostic circumstances were highly suggestive of phaeochromocytoma in 39.8% of the cases, whereas in 43.2%, diagnosis was made through systematic investigations of patients, either before (27.3%) or after (13.6%) thyroidectomy, or after discovery of hyperparathyroidism (2.3%). Fifteen per cent of patients were detected by family screening. Sudden death occurred in 8.9%, malignant phaeochromocytoma In 3%, and ectopic tissue in 4% of the cases. Urinary metanephrines appeared to be the most sensitive screening test. The extent of clinical symptoms was not associated with a particular hormonal pattern. Bilateral adrenalectomy was performed in 60% (in one step in 50%, in two steps in 10%). In these patients, bilateral histological lesions were observed in 92.5%. Simultaneous diagnosis for adrenal and thyroid disease was made in 73.4%, but phaeochromocytoma may be diagnosed before (9.6%) or after (17%) medullary thyroid carcinoma, with an interval greater than 2 years in 25 cases. CONCLUSION Owing to variable clinical symptoms of phaeochromocytoma in these 100 cases of MEN 2 A, systemic biological adrenal assay is required. The search for phaeochromocytoma in medullary thyroid carcinoma (and vice versa) has to be systematically performed, even in apparently sporadic cases. Screening for phaeochromocytoma must be repeated for years, owing to the frequency of bilateral adrenal disease.

The diagnosis of medullary thyroid carcinoma by biochemical and genetic testing is possible in families with multiple endocrine neoplasia type 2. At an early stage total thyroidectomy usually cures the patient. As the clinical penetrance of the autosomal dominant, transmitted, multiple endocrine neoplasia type 2 gene is not complete, family screening is indicated for every new patient who presents with apparently sporadic medullary thyroid carcinoma. Problems related to a screening programme and early diagnosis have led the members of the European Community Concerted Action: Medullary Thyroid Carcinoma group to formulate a consensus on biochemical and genetic screening. For biochemical screening, measurement of basal and pentagastrin and/or calcium stimulated serum levels of calcitonin by radioimmunoassay are essential starting at the age of three and continuing annually until 35 years of age. Furthermore, annual screening for pheochromocytoma by measuring the urinary excretion of catecholamines and for hyperparathyroidism by serum calcium determination is indicated. Genetic screening using linked markers can be done with a 95% accuracy in informative families when DNA is available from at least two family members proven to be affected. Biochemical screening can thus be reserved for gene carriers, while those at low risk can be reassured. Combined biochemical and genetic screening for multiple endocrine neoplasia type 2 is important and effective for the cure of medullary thyroid carcinoma.

We have recently identified in medullary thyroid carcinoma the existence of a second calcitonin messenger, generated by a splicing between the 3' coding region of exon 4 and exon 5 of Calc I gene. It differs from the first one in its 3' coding sequence and codes for a calcitonin precursor which generates the same N terminal peptide, calcitonin and a specific 21 amino acid carboxy terminal peptide differing from Katacalcin by its 8 last amino acids. We searched for the expression of this new messenger in normal human thyroid tissue by Northern and by polymerase chain reaction techniques. This second calcitonin messenger was expressed in 4/4 normal thyroids and 4/5 medullary thyroid carcinoma tissue samples. The expression of this second messenger is apparently a common occurrence in C cells whether normal or tumoral.

Pheochromocytoma is a frequent indicator of multiple endocrine neoplasia type 2A (MEN 2A); in the 35 French MEN 2A families in which a pheochromocytoma occurred first in some affected members, 30% of the patients had a pheochromocytoma as the first manifestation constituting 45% of all patients with pheochromocytomas. The finding of a pheochromocytoma is a strong indication for a search for medullary thyroid carcinoma and for initiating family screening.

Multiple endocrine neoplasia type 2 (MEN 2) is transmitted as an autosomal dominant trait, with 3 different forms. MEN 2a consists of medullary thyroid carcinoma, phaeochromocytoma(s) and hyperparathyroidism. In MEN 2b, parathyroid hyperplasia is absent, but a Marfan-like syndrome and neuromas of the mucosae are present. In some families, the only manifestation of MEN 2 is a medullary thyroid carcinoma. These 3 forms seem to related to one or several gene(s) located in the pericentromeric region of chromosome 10. The histological lesions of MEN 2a are multifocal, bilateral and associated with hyperplasia (which affects C-cells in the thyroid gland). Screening for familial medullary thyroid carcinoma is based upon plasma calcitonin levels measured before and after a pentagastrin stimulation test. The demonstration of DNA markers near the gene(s) of the disease in chromosome 10 pericentromeric region makes it possible to identify, with good probability, the subjects at risk for the disease. It is only by determining the responsible gene(s) that subjects carrying the hereditary anomaly will be identified directly, without marker assays.

Human medullary thyroid carcinomas from 19 patients were analyzed for their content in somatostatin (SRIF) receptors using receptor autoradiography with a SRIF-28 analogue and the SRIF octapeptide [Tyr3]-SMS 201-995 as iodinated radioligands. Four out of 19 cases were SRIF receptor positive with the SRIF octapeptide radioligand. These cases as well as four additional tumors were also positive with the SRIF-28 radioligand 125I-[Leu8, D-Trp22, Tyr25]-SRIF-28. High affinity binding sites pharmacologically specific for bioactive SRIF analogues, specifically located on tumor tissue, were identified. In some cases the SRIF receptors were distributed in a non-homogeneous pattern, with labelling occurring preferentially in highly differentiated tumor regions. Numerous cases were shown to have a high tumoral SRIF content measured by radioimmunoassay or immunohistochemical technique. However, there was no correlation between SRIF receptor status and tumor levels of endogenous SRIF. No correlation was seen between the clinical outcome or the survival of the patients and their tumoral SRIF receptor content. Whereas some medullary thyroid carcinomas seem to be a target for SRIF, the SRIF function in these tumors remains unclear. SRIF receptors in a group of medullary thyroid carcinomas may be useful morphological marker of these tumors and of potential interest for their in vivo localization.

We have previously shown that immunoassayable concentration of somatostatin (SRIH) was elevated in 70% of 34 consecutive medullary thyroid carcinoma (MTC) tissue samples. In the present study gastrin releasing peptide (GRP)-like immunoreactivity was measured in tissue extracts from these 34 MTC (25 inherited, 7 sporadic, 2 unclassified) and in 7 normal thyroid tissue. Plasma SRIH, calcitonin (CT) and carcinoembryonic antigen were assayed in all patients. Normal thyroid tissue contained less than 61 pmol GRP per g wet weight; in contrast GRP concentration was elevated (62-7800 pmol/g) in 32/34 tumor extracts. The distribution of tissue GRP values were similar in sporadic as well as in familial MTC. We found no significant correlation between tumor GRP concentration and plasma SRIH (r = -0.05), plasma CT (r = -0.24), or plasma carcinoembryonic antigen levels (r = -0.21). Tumor concentrations of immunoreactive GRP and SRIH were positively correlated when logarithmic transformation was used (P less than 0.01). Thus GRP, as well as SRIH, is a major product of tumoral C cells in human MTC when systematically evaluated in a large number of cases.

A geneological study made it possible to establish a link between two medullary thyroid carcinoma families from Normandy totalling 9 sick subjects, and a probable link with a third family. The study contributed to the diagnosis of multiple endocrine neoplasia type IIa, whereas the condition had been diagnosed for 6 years as familial medullary thyroid carcinoma, without phaechromocytoma. Group in these two families together increased the number of subjects tested, thereby facilitating genetic link analysis and enabling the link with markers of the disease on chromosome 10 to be asserted. The genetic study can now be used to detect individuals at risk, and with regular laboratory tests the diagnosis will be made at the "precancerous" stage. A genealogical study going back to the family-founding couple will increase the population which will benefit from screening in this region north of Rouen.

The current work has been performed by the Cooperative French Group of Medullary Thyroid Carcinoma (GETC). A systematic evaluation of RIA somatostatin (SRIH) was performed in 34 medullary thyroid carcinomas (MTC) (25 inherited, seven sporadic). Plasma SRIH was measured by radioimmunoassay in parallel with calcitonin (CT) and carcinoembryonic antigen (CEA). Immunoassayable SRIH was tested in fresh tumoral tissue samples from the same 34 MTC and, for comparison, in 10 nontumoral thyroid extracts (less than 6 pmol/g wet). Although plasma SRIH was only slightly elevated in two of 20 cases, tumoral SRIH was elevated in 70.6% of our MTC (10 to 3973 pmol/g). The chromatography of two tumoral extracts showed that somatostatin 14 was the major molecular form. We found no correlation (P greater than 0.1) between tumoral SRIH and the following: (1) tumor size (r = 0.227); (2) epidemiologic form of MTC (r = 0.144); (3) plasma SRIH (r = 0.045), plasma CT (R = 0.095) or (4) plasma CEA (r = 0.032). Thus, in the authors' experience, SRIH appears as a major product of tumoral C-cell in human MTC, even when plasma SRIH is normal and SRIH immunohistochemical staining is scarce. Multiple hormonal production of these tumors may explain its presence but SRIH may act also as a regulator, since negative influence of SRIH on CT is demonstrated in normal as well in tumoral conditions.

Medullary thyroid cancer (MTC) is either of the sporadic or familial type, whether it be isolated or constitute part of a type II multiple endocrine neoplasia. Progress in the knowledge of the disease has recently been obtained in the following ways: the IRMA assay of mature calcitonin, the disease marker, has permitted earlier diagnosis of familial cases and recurrence; the locus assignment of the gene on chromosome 10 now enables a valid discrimination in certain families of gene carriers; collaborative clinical, biological, pathological, therapeutic and epidemiological research on a nation-wide scale has had a beneficial effect on patients, with improvement in diagnosis of the familial forms, in disease prognosis, in cancer detection at an infraclinical stage, and in the regrouping and distribution of families in France.

Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal-dominant syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma and parathyroid hyperplasia. Recent reports have assigned the locus of MEN2A to the pericentromeric region of chromosome 10. Through the 'Groupe d'Etude des Tumeurs à Calcitonine', we have evaluated the ability to predict the carrier state using DNA probes. Our results suggest that the restriction fragment length polymorphism method can be used to identify individuals at risk within MEN2A families. They may then be followed by conventional endocrine methods for the onset of neoplastic changes, limiting the risk of subsequent metastatic disease. The method also permits the exclusion of further screening for family members at very low risk. Extension of the screening program can now be anticipated for other inherited forms of MTC, such as familial MTC without pheochromocytoma or other endocrinological tumor syndromes such as MEN1 for which the locus has also recently been mapped.

The authors report a case of laryngeal chemodectoma in a 53-year-old man who died from general dissemination and lymphatic and subcutaneous metastases. This functional neoplasm secreted calcitonin revealed by fluorescence and biochemical tests and perhaps adrenaline-like substances. Its cells looked like the light chief cells of the human carotid body; they contained secretory granules and lysosomal formations. Thirty similar cases had been previously reported. The superior laryngeal glomi and more occasionally the inferior ones were the seat of these tumours which occurred with an equal frequency in both sexes. A hoarseness was often the unique symptom noticed during the several months or years preceding the first examination of this slow growing neoplasm. Nevertheless among the chemodectomas of the head and the neck region those arising in the larynx had the highest incidence of malignant evolution. Five of the patients presented a general dissemination, two had lymphatic metastases and one a local recurrence. The ultra-structural features and sometimes the rarely detected functional activity of these chemodectomas are those of apudomas whose cells might originate from the cephalic portion of the neural crests.

Thirty-one patients were studied to evaluate the prognostic value of both calcitonin (CT) and CEA levels determined after the initial treatment in medullary thyroid carcinoma (MTC). Twenty-seven patients were evaluated three to nine months after initial treatment and four others afterwards. The CT and CEA levels were significantly higher and the survival rate lower in the eight patients with residual clinical disease as compared to the 19 patients in complete clinical remission. In patients in complete clinical remission, 11 had elevated CT level after treatment, and all had initial lymph node involvement. Five of these 11 relapsed and one died. None of the eight patients with normal CT levels after treatment relapsed. CEA levels were always abnormally high when patients relapsed. Fourteen patients in complete remission with high CT levels were followed for more than four years. Six had normal CEA levels and no relapse was observed. Eight of the 14 had pathological CEA levels and six of eight relapsed: five of these six patients presented CEA elevation from six to 36 months before the clinical relapse. In two of these six patients, a venous catheterization sampling method demonstrated infra clinical local recurrence. In two patients with liver metastases, the time course changes of CT and CEA levels were different and CEA appeared to be a more sensitive tumor marker than CT. These data are consistent with previous data concerning the values and limits of CT level for the management of MTC. Furthermore, this study demonstrates the prognostic significance of CEA determination in MTC. CEA appears to be a sensitive selective tumor marker capable of defining a high-risk subgroup.

An immunohistological study of five cases of medullary carcinoma of the thyroid was undertaken with monospecific antisera against CEA and NCA. CEA was present in different areas of the tumors: cell cytoplasm, cell membrane at its apical pole when the tumor had a pseudoglandular organization, deposits in the lumen of pseudoglands, and peri- and extra-cellular deposits. From these extra-cellular deposits, CEA could easily reach the circulation, thus causing rising serum levels up to high values. NCA was found in the same tumors and in the same localizations.

Les cellule C de la thyroide de rat ont ete localisees par un anticorps anticalcitonine humaine (immunofluorescence indirecte). L'inhibition de la reaction par la calcitonine humaine et ses fragments a ete etudie.

Seventeen patients with medullary thyroid carcinoma (MTC) underwent venous catheterization (VC) for sampling and serum calcitonin (CT) assay. The VC was performed either after an initial treatment in order to detect cervical recurrences and metastases (16 patients) or to prove abnormal CT thyroid secretion before any treatment (one patient). In 16 of the 32 tumoral localizations suspected by VC (50%), a tumoral focus was proven. For selective/peripheral CT gradient value superior to 2.50, 12 localizations of 12 (100%) were proven and for CT gradient value between 1.50 and 2.50, four localizations of 15 (26.6%) were proven. In six patients with exclusive cervical MTC secreting sites, treatment induced a total remission in two cases (12%) and improved in four cases (23%). The authors conclude that VC has a real value to localize MTC secreting sites. A total remission or an improvement can be obtained after treatment when VC detects exclusive cervical tumors.

Medullary thyroid carcinoma (MTC) is a particularly interesting model of gene expression in cancer. As a matter of fact, it is remarkable from many points of view: it occurs in two forms: (1) MTC only or part of a multiple endocrine neoplasia II (MEN II), and (2) it is sporadic or inherited and benefits from a specific and sensible marker, calcitonin; the gene responsible for the hereditary form is localized on chromosome 10. Taking into account clinical, biological, genealogical and epidemiological features of the disease as supporting one another, a French collective study has been initiated; preliminary analysis of data allows to conclude on the value of such national collaboration for early diagnosis, prognosis and estimation of the incidence of the disease.

Resume A l'occasion d'une enquete portant sur 26 membres d'une famille, 5 cas de neoplasie endocrinienne multiple de type II a ont ete decouverts. Cette etude, qui souligne l'interet du dosage de la thyrocalcitonine (TCT) basale et apres stimulation a la pentagastrine et de l'antigene carcino-embryonnaire (ACE) fournit en outre l'occasion d'insister sur certains aspects cliniques, soit inedits telles la decouverte d'un pheochromocytome a l'occasion d'un hemothorax accompagne de collapsus cardiovasculaire, soit particuliers, telle la faible malignite des cancers medullaires de la thyroide (CMT) observes dont la taille etait inferieure a 2 cm dans 4 observations sans metastases ganglionnaires ou viscerales meme aux âges de 87, 59 et 56 ans. D'autres aspects sont plus classiques tels le caractere toujours multifocal des CMT, leur latence, ainsi que celle des 2 cas de pheochromocytome et d'hyperparathyroidisme, la difficulte du diagnostic des pheochromocytome et le faible rendement de la tomoechographie, la transmission genetique de type autosomal dominant. Enfin la pluralite des secretions detectees au niveau des CMT (TCT, ACE, B endorphine, somatostatine) est soulignee, de meme que la decouverte des Ag HLA A2 — B15 chez 3 malades.

Fifty meta-iodobenzylguanidine (MIBG) scintiscans were performed in three groups of medullary thyroid cancer (MTC) patients. Group 1 (n = 11) included treated patients with normal calcitonin levels; Group 2 (n = 24) included patients with elevated calcitonin levels due to sporadic and isolated MTC; Group 3 (n = 15) included patients with elevated calcitonin levels due to familial MTC or multiple endocrine neoplasia Type IIA syndrome (MEN). In Group 1 three pheochromocytoma were depicted by MIBG scintiscan. In Group 2 MTC was seen in a small number of patients (3 of 24). In Group 3, besides adrenal hyperplasia and pheochromocytoma four patients, MIBG scintigraphy showed where MTC had localized and spread in almost half of patients (7 of 15). MIBG uptake occurred in patients with relatively high calcitonin level (greater than 0.6 nmol/l). These data indicate that in patients with familial MTC or MEN syndrome, MIBG scintiscan can be useful not only in detecting associated pheochromocytoma, but also in showing MTC.

Previous studies have shown that certain patients suffering from poorly differentiated follicular carcinoma (PDFC) of the thyroid had high levels of calcitonin (CT) and carcinoembryonic antigen (CEA) in the plasma. In this work, both CT and CEA were localized in tissue sections obtained at operation from patients suffering from PDFC. The results confirm the hypothesis that certain cases of PDFC are in fact CT-secreting tumors and represent another type of thyroid neoplasma. Patients suffering from PDFC should be screened using both CT and CEA assays.

This study is in favour of a real effect of SNS 201995 on calcitorin levels. This effect seems more effective in patients with less extensive medutary thyroid carcinoma (MTC). This suggests that SMS 201995 could be limited to the less aggressive form of MTC probably those in which the degree of undifferenciation is less marked

Un cancer trabeculaire de la thyroide, riche en mucopolysaccharides et depourvu de stroma amyloide, produit 1000 fois plus de calcitonine que le tissu thyroidien normal. Il semble s'agir d'une entite anatomopathologique nouvelle, correspondant a une tumeur differenciee secretant de la calcitonine.

The value of carcinoembryonic antigen (CEA) assay for diagnosis and follow-up in patients suffering from medullary carcinoma of the thyroid (MCT) was investigated in a large sample (106 cases). High levels of CEA were found in 84% of patients suffering from either the sporadic or the familial form of the disease. Levels of CEA and calcitonin (CT) are significantly and positively correlated. Removal of tumoral tissue is followed by a decrease in both CEA and CT levels. High levels of CEA were also observed in the parents of patients suffering from the familial form of MCT. These patients were operated on and MCT was confirmed histologically. The limitations of the use of CEA assay in the diagnosis of MCT are discussed.

Carcinoembryonic antigen (CEA) and calcitonin (CT) were extracted from medullary carcinoma of the thyroid (MCT) tissues, fractionated on Sephacryl S-200 and chromatographed on Concanavalin A. CEA purified from MCT is closely related to CEA extracted from colonic tumors. It has an equivalent molecular weight, is a glycoprotein and has a similar electrophoretic mobility in both SDS and basic polyacrylamide electrophoresis. A certain degree of heterogeneity is present in the form of a smaller molecular weight component. Large molecular forms of CT which are present in MCT tissues and which co-elute with the minor component of CEA on Sephacryl chromatography can be separated by Concanavalin A chromatography.

An immunohistochemical and electron microscopy study has allowed us to find in a human thyroid cancer, follicle differentiation associating in a characteristic architectural pattern C cells, ciliated cells and follicular cells. Ultrastructural features were similar to those described in the normal adult Mouse thyroid by Wetzel and Wollman [1] and interpreted by them as a second type of thyroid follicle of ultimobranchial origin. The discovery of these structures within metastatic lymph nodes excludes normal thyroid follicle contamination. The presence of these neoplastic structures lead us to make the hypothesis of a stem cell of ultimobranchial and endodermal origin common to all the cells described.

Chromatographic analysis of plasma, urine and tumour tissues extracted from medullary cancer patients demonstrates the existence of immunoreactive calcitonins with higher molecular weight than that of the monomer hormone.

Whilst investigating 26 members of the same family, we discovered 5 cases of multiple endocrine neoplasia type II a. The present report demonstrates the diagnostic value of basal plasma thyrocalcitonin (TCT) assays, before and after stimulation with pentagastrin, and of plasma carcinoembryonic antigen (CEA) assays. Some of the clinical features encountered were novel--e.g. in one patient the phaeochromocytoma was revealed by a haemothorax with cardiovascular collapse--and others were peculiar; thus, in 4 cases the medullary thyroid carcinoma (MTC) was less than 2 cm in diameter and without lymph node or visceral metastases, even in patients aged 87, 59 and 56. More classically, MTC, always multifocal, was clinically silent, as were the two cases of phaeochromocytoma and hyperparathyroidism. Phaeochromocytomas were difficult to diagnose. Ultrasonic tomography did not prove very helpful and the disease was transmitted as an autosomal dominant trait. Finally, MTC secreted a variety of substances (TCT, CEA, beta-endorphin, somatostatin), and HLA A2-B15 antigens were found in 3 patients.

The preoperative diagnosis of medullary thyroid carcinoma (MTC) can be made by measuring serum calcitonin levels (CT). If the patient has a thyroid nodule--sporadic or familial MTC--the serum CT will be raised but in the familial form of the disease, the diagnosis should be made at a much earlier, subclinical stage when surgery can be curative: this is possible when raised hormone levels are observed after stimulation tests. However, as this form of cancer sometimes presents late, repeated stimulation tests are necessary, with all the difficulties that it implies, in all patients with normal hormone levels in whom it is impossible to exclude tumoral heredity, whether they belong to a family with a case of sporadic MTC or to a healthy branch of a family affected by heredity.

The localization of intracellular calcitonin has been achieved by immunofluorescence in the cytoplasm of all cells forming the epithelium of the ultimobranchial body of eels, using a human antiserum against synthetic Salmon calcitonin I. The specificity of the reaction is demonstrated by inhibition with synthetic salmon calcitonin (S.C.T.); the fluorescence is not inhibited by synthetic human calcitonin (H.C.T.).

Radioimmunological assays of peptidic hormone levels is now an essential procedure for the diagnosis of polyadenomatosis. The diversity of pathological associations found in polyadenomatosis cannot be completely explained by the unitary theories that have been proposed. Neither the APUD system, nor the common embryonic origin, nor the reduction in calcitonin excretion can fully explain the clinical picture: a logical explanation has still to be discovered. In practice, ectopic secretions are frequent in type 2 polyadenomatosis (medullary cancer, pheochromocytoma, neurofibroma, Marfan's syndrome, hyperparathyroidism) contrary to what is observed in type 1 cases (pituitary, parathyroid, pancreas).

Seventeen patients with medullary thyroid carcinoma (MTC) underwent venous catheterization (VC) for sampling and serum calcitonin (CT) assay. The VC was performed either after an initial treatment in order to detect cervical recurrences and metastases (16 patients) or to prove abnormal CT thyroid secretion before any treatment (one patient). In 16 of the 32 tumoral localizations suspected by VC (50%), a tumoral focus was proven. For selective/peripheral CT gradient value superior to 2.50, 12 localizations of 12 (100%) were proven and for CT gradient value between 1.50 and 2.50, four localizations of 15 (26.6%) were proven. In six patients with exclusive cervical MTC secreting sites, treatment induced a total remission in two cases (12%) and improved in four cases (23%). The authors conclude that VC has a real value to localize MTC secreting sites. A total remission or an improvement can be obtained after treatment when VC detects exclusive cervical tumors.

Cross reaction studies using radioimmunoassays specific for human and porcine calcitonin showed that rabbit calcitonin is structurally more closely related to human than to porcine calcitonin.

Medullary thyroid carcinoma is a rare and sometimes hereditary disease. The tumour can be diagnosed and followed up by measuring the amounts of calcitonin it secretes. The prognosis of this cancer largely depends on an early diagnosis and treatment. From the clinical and laboratory (calcitonin assays) data recorded in our department, we have endeavoured to determine the influence of a national multidisciplinary co-operative group (GETC: French medullary study group) on the diagnosis and prognosis of this malignancy. We are able to show that the number of medullary thyroid carcinomas detected (principally in their familial forms) has increased by 141 per cent after the GETC was created. Calcitonin levels at the time of diagnosis are significantly lower (P less than 0.05) in familial cases, which reflects an early detection. The same applies to post-operative calcitonin levels (P less than 0.005), so that in the long run a better prognosis can be expected. It seems therefore that together with a better knowledge of this cancer and its detection, the setting up of a national multidisciplinary co-operative group results in a better clinical and therapeutic approach of these patients, and particularly of the familial cases of medullary thyroid carcinoma.

Medullary carcinoma tissue was incubated in vitro in Eagle's medium containing labeled cysteine or lysine. After extraction and purification by affinity chromatography using antibodies raised against synthetic human calcitonin (hCT), two major peaks of radioactivity were detected after SDS polyacrylamide gel electrophoresis. The estimated molecular weights were respectively 11 800 for the first peak and identical to that of hCT for the second. Chase experiments reduced drastically both peaks. In the incubation medium, a single labeled product was observed, comigrating with hCT. These results suggest that hCT is liberated prior to its secretion from a larger prohormone, 11 800 Mr (Apparent molecular weight).

Screening for medullary thyroid cancer (MTC) in France is based on a protocol that has been widely distributed nationally. A network of coordinators utilizing a common questionnaire provides for an effective national screening program. Calcitonin stimulation procedures are systematically used for all first-degree relatives of MTC patients. Pathological studies utilize special immunopathologic techniques. Genealogic information is obtained on all index cases, and blood specimens are collected for establishing permanent cell lines. The data collected are used not only to establish the diagnosis of the hereditary or sporadic form of the disease but also to expand the screening as appropriate. This common protocol has benefited patients and their families by improving early detection of cases, increasing the number of families available for follow-up, and improving the prognosis of this cancer. Studies on these families have contributed significantly to the localization of the multiple endocrine neoplasia type 2 gene.