Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features.

Familial pituitary adenoma is a rare syndrome which may present either as isolated lesions, or in association with other endocrine tumors, for example in the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The most frequently described forms of familial isolated pituitary adenoma (FIPA) are familial somatotropinomas or prolactinomas. Recently, some cases of familial isolated somatotropinoma have been associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The present report shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same family: somatotropinoma in the proband, giant prolactinoma in a brother, and gonadotroph cell macroadenoma in the father. A prospective survey also suggested the occurrence of a silent microadenoma in the proband's sister. Clinical screening was performed in the 3 affected members, the 4th suspected case, and 9 additional, asymptomatic relatives. They had no clinical evidence of associated endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2 affected members. In conclusion, these data suggest that familial pituitary adenomas can occur with a heterogeneous functional pattern that is distinguished from MEN-1 or CNC. The absence of mutation of the recently described AIP gene suggests the implication of other predisposing gene(s). Collaborative, multicentric studies are needed to further define the location of gene(s) involved in heterogeneous FIPA.

Hürthle cell thyroid carcinoma metastatic to the sigmoid colon.

Prognosis of differentiated thyroid cancer is favorable in the majority of cases. However, distant metastases occur in 10-15% of cases, predominantly in lungs and bones, especially in older patients exhibiting poorly differentiated forms or advanced stages. We report a case history of Hürthle cell thyroid carcinoma metastasized to the sigmoid colon. To the best of our knowledge, this location has never been described before. This case history illustrates the difficulties of diagnosis and treatment in patients whose metastases do not concentrate radioiodine. The interest of different imaging modalities, including fluoro-deoxy-glucose positron emission tomography scan and somatostatin receptor scintigraphy, is discussed.

[Role of hospital claims databases from care units for estimating thyroid cancer incidence in the Rhône-Alpes region of France]. / Place du Programme de médicalisation des systèmes d'information (PMSI) dans l'estimation de l'incidence du cancer de la thyroïde dans la région Rhône-Alpes.

BACKGROUND: Incidence measures are essentially based on the data collected by cancer registries. Hospital claims databases from care units (PMSI) can be used as a source of information for registries because they contain standard records of most cancer patients. Regarding thyroid cancer, we have evaluated the PMSI as a source of information for the Rhône-Alpes thyroid cancer registry and usefulness of PMSI as a tool for surveillance of thyroid cancer incidence. METHODS: Patients with incident thyroid cancer in 2002 were identified in the claims data of the Rhône-Alpes region using an algorithm based on DRG codes of thyroidectomy and on diagnosis codes of thyroid cancer in a principal or secondary position. The patients identified were compared to those in thyroid cancer registry of the Rhône-Alpes region regarding sex, age, ZIP code of residence, month of discharge and length of stay versus the diagnosis date. When the percentage of cases of claims data identified in the cancer registry and the percentage of cases of the cancer registry identified in claims data were obtained, the capture-recapture method was applied to estimate the number of missing cases and the total number of incident thyroid cancers in the region. RESULTS: 667 patients were identified in claims data while the cancer registry included 677 patients. 95.2% of patients identified in claims data were in the cancer registry and 82.3% of patients in the cancer registry were identified in claims data. Cases lacking in claims data mostly corresponded to micro-cancers which represented 41% of cases in the cancer registry. Regarding cancer above 1 cm, 92% of the cancer registry cases were identified in claims data. Sensitivity of combining information from cancer registry and claims data was 99.2%. Cases lacking in cancer registry, present in claims data base and considered as true cases after obtaining pathological confirmation represented 2% of the whole thyroid cancer population. CONCLUSION: Claims data obtained from anonymous regional or national bases can be helpful for checking the completeness of thyroid cancer registries and to provide a small amount of unknown cases. They can be considered an acceptable tool for surveillance of thyroid cancer incidence. The significance of the variations in incidence that could be observed from claims data remains to be evaluated in comparison with comparable data obtained from registries.

Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance.

BACKGROUND: Prolactinomas usually exhibit a benign course and can be safely and effectively managed by dopamine agonists (DA). However, some are locally invasive and may show resistance to DA therapy, and the management of such cases remains controversial. The aim of the present study was to determine whether histological features and markers of cell proliferation correlated to the clinical behaviour of prolactinomas and with DA resistance. METHOD: This retrospective study included 74 cases (36 men and 38 women) who had monohormonal prolactinomas removed by transsphenoidal surgery. The prolactinomas were categorized on the basis of tumour size (48 macroadenomas), invasion of the cavernous sinus (n = 31), and resistance to bromocriptine (BRC) therapy (n = 14). Group 1 consisted of non-invasive microprolactinomas (n = 24), group 2 of non-invasive macroprolactinomas (n = 19), group 3 of invasive non-BRC-resistant tumours (n = 19), and group 4 of invasive BRC-resistant tumours (n = 12). The later group included one case of carcinoma with bone and lung metastases. Seven additional parameters were studied, these being age, sex, basal prolactin (PRL) levels, the Ki-67 and PCNA labelling indices (LI), mitotic count, and cellular atypia. FINDINGS: Age and preoperative PRL levels did not correlate to the histological parameters studied. Tumour size and invasion were related to cellular atypia and the Ki-67 LI. BRC-resistant tumours were more frequently invasive (12/14) than BRC-responsive tumours (11/30; p = 0.002) and were more frequent in men than in women (33 versus 5%; p = 0.003). BRC-resistant tumours had a higher Ki-67 LI and mitotic count (4.2+/-2.0% and 4+/-1, respectively) than other tumours (0.7+/-0.2% and 1+/-0, respectively; p<0.05). The strongest correlations with tumoural staging were seen with male sex and high mitotic activity. Six out of the 12 invasive BRC-resistant macroprolactinomas, including the PRL secreting carcinoma, exhibited histological features of aggressiveness (a mitotic count >/=3 [i.e. in the fourth quartile] and/or a high Ki-67 LI and cellular atypia). CONCLUSIONS: In this surgical retrospective series, histological signs of aggressiveness are present in 50% of invasive and BRC-resistant prolactinomas, which are more frequent in men than in women. This fits with the behaviour of BRC-resistant prolactinomas, which can continue to grow despite DA treatment. These findings justify the long-term follow up of these tumours, and the use of surgery and/or radiotherapy if there is concern about the control of tumour growth.

Interest of Chromogranin A for diagnosis and follow-up of endocrine tumours.

OBJECTIVE: To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow-up in patients with gastroenteropancreatic endocrine tumours (GEP-ET) and multiple endocrine neoplasia type 1 (MEN-1). PATIENTS AND METHODS: CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP-ET, 34 MEN-1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant. RESULTS: Using a cut-off value of 130 micro g/l, established from a receiver-operating characteristic curve, the specificity of CgA was 98.4%, with a sensitivity of 62.9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0.003) and related to the extent of metastatic spreading (P < 0.001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN-1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow-up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0.001). CONCLUSION: Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN-1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow-up of GEP-ET tumours.

[Therapeutic strategies in somatotroph adenomas with extrasellar extension: role of the medical approach, a consensus study of the French Acromegaly Registry]. / Stratégies thérapeutiques dans les adénomes somatotropes avec extension extrasellaire. Place du traitement médical. Etude consensus du Répetoire français de l'Acromégalie.

UNLABELLED: From the first 198 patient files included into the French Acromegaly Registry, we analyzed 68 patients harboring a somatotroph adenoma with extrasellar extension, after exclusion of those treated by stereotactic or conventional radiotherapy. In these patients (including 37 women), aged 21-77 yr. (45.7 +/- 13.3), GH concentrations ranged from 2-260 microg/L (38.6 +/- 44.3), and IGF I from 86-967% of age-matched upper limit of normal (303 +/- 164). Maximal diameter of the adenoma at MRI was 11-36.5 mm (20.4 +/- 6.5), with cavernous sinus involvement in 68% of cases. Three subgroups were defined: 20 patients treated by long-acting somatostatin analogs only (group M), for a mean duration of 3 yr. (extremes 1-7 yr.), 48 patients initially treated by transsphenoidal surgery (group C), of whom 21 were secondarily treated by long-acting somatostatin analogs (group CM) for a mean duration of 1.2 yr. (extremes 0.2-2 yr.). All 3 groups were not statistically different in terms of tumor mass and initial levels of GH and IGF-1. Patients from group M were significantly older than those of the other groups (p<0.05). RESULTS: 46% of patients from group C after surgery vs. 45% of patients from group M had a mean GH below 2.5 microg/L. Biochemical remission (GH<2.5 microg/L and normal IGF1 normal) was obtained in 31% of cases in group C, vs. 25% in group M. In this group, a decrease of the largest tumor diameter was observed in 10 patients (71.5%), ranging from 10-25% in 7 (50%) and exceeded 50% in 3 (21.5%). In group CM, the biochemical remission rate (42%) and final GH or IGF1 values were not significantly different from group M. In conclusion, these data suggest that surgery or long-acting somatostatin analogs have a comparable efficacy in terms of remission rates in somatotroph macroadenomas with extrasellar extensions.

Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy.

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study.

HYPOTHESIS: Intra-arterial lipiodol labeled with iodine 131 ((131)I-lipiodol) can be safely used as adjuvant therapy following curative liver resection for hepatocellular carcinoma (HCC). DESIGN: Phase 2 pilot study. SETTING: Large teaching hospital. PATIENTS: Twenty-eight patients (24 men and 4 women; median age, 61.5 years; range, 33-75 years) were treated from January 1991 to June 1997. The liver was cirrhotic in 7 cases and noncirrhotic in 21 cases. An equal number of 14 patients underwent a major and a minor resection, all with clear margins. Median diameter of solitary tumors or the larger tumor when multiple tumors occurred was 5.5 cm (range, 2.5-29 cm). Tumor encapsulation was present in 12 cases and absent in 16 cases. After informed consent, patients who had no evidence of residual or recurrent tumor on computed tomographic (CT) scan and no sign of liver failure 2 to 3 months after curative resection for HCC were included in the trial. Complete follow-up was obtained (median, 51 months; range, 5-93 months). INTERVENTIONS: A 1110-MBq dose of (131)I-lipiodol was administered into the hepatic artery using the Seldinger technique. Patients were kept in a radio-protected room for 5 days. Postinjection radioactive whole scintiscan was performed at 5 days and an abdominal CT scan at 1 month after the injection. A second injection was performed in 16 patients 2 years later using the same protocol. MAIN OUTCOME MEASURE: Procedure safety. RESULTS: All patients experienced transient fever during the first 12 hours following injection. There were no noted adverse clinical effects or significant alteration in hepatic function due to the procedure or at immediate and late follow-up. The radioactive scan demonstrated an intense liver uptake, which was homogeneous in 19 cases and heterogeneous in 9. Mild detectable thyroid and lung uptake occurred in 50% of cases. No lipiodol liver fixation was observed on the 1-month CT scan. At the time of follow-up, 6 patients had died and 12 had developed recurrences, with 5 of the 6 deaths belonging to the recurrent group. Sixteen patients remained disease free. The median time to detected recurrence was 28 months (range, 12-62 months). Overall survival rates were 86% at 3 years and 65% at 5 years. CONCLUSIONS: This pilot study failed to demonstrate any clinically significant adverse effect of adjuvant therapy by intra-arterial (131)I-lipiodol after curative liver resection for HCC. Long-term survival compares favorably with those undergoing only surgery and suggests a benefit in lowering tumor recurrence. A randomized, multicenter, prospective trial comparing patients treated with intra-arterial (131)I-lipiodol with a nontreated control group seems appropriate.

Growth hormone-releasing hormone: past and present.

The discovery of hypothalamic hypophysiotropic factors confirmed the hypothesis of Green and Harris in the late 1940s. These hormones were isolated from their eutopic site of production (the hypothalamus) with the exception of growth hormone (GH)-releasing hormone (GHRH), which was isolated from an ectopic, tumoral site of production and found to be responsible for acromegaly. Following the isolation, characterization and synthesis of human GHRH, clinical studies were performed and are described below. Circulating levels of GHRH can be measured and provide the basis for the diagnosis of acromegaly related to the ectopic, tumoral production of GHRH. At present, GHRH is used as a test of GH secretion mainly as an adjunct to other agents which modify somatostatin status, or to GH-releasing peptides. Its therapeutic potential in children and the elderly is still under investigation. The role of GHRH in the pulsatile secretion of GH is described.

[131I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors.

Dosimetry and therapeutic application of [(131)I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [(131)I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy.MBq(-1). No intolerance or adverse effects were observed after the therapeutic doses (3.3-6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients.

[Symptomatic hypothalamo-hypophyseal metastasis revealing a small-cell bronchial carcinoma. Study of two cases]. / Métastase hypothalamo-hypophysaire symptomatique révélatrice d'un carcinome bronchique à petites cellules. Etude de deux cas.

Metastases are an uncommon cause of tumor in the sellar region. We report two cases of small cell lung cancer presenting with visual loss and hypopituitarism resulting from metastasis to the pituitary area.

GH deficiency in adults: an epidemiological approach.

OBJECTIVE: The prevalence of adult onset GH deficiency (GH-D) is poorly documented. Epidemiological data are now required to estimate the financial cost of GH treatment in adults. The aim of the present study was to estimate the prevalence of GH-D, from a cohort of 1652 adult patients with hypothalamo-pituitary diseases. DESIGN: The hormonal status of all patients presenting with pituitary diseaseand observed during the year 1994 in 15 endocrine units was retrospectively analyzed, irrespective of the date of disease onset, of the nature and date of pituitary investigations, and whether or not they included specific testing of the GH axis. Of the whole population of 1652 patients, a selected group (RG2) was chosen after exclusion of patients with active acromegaly (n=1414). RESULTS: GH stimulation tests had been performed in 549 patients of the RG2 group and a documented GH-D was found in 301. A relationship between the value of the GH peak and the number of pituitary deficits was evaluated. For instance, it was shown that 93% of patients with three deficits had GH-D. These results constituted the basis for estimating the number of GH-D in the group of untested patients. The number of GH-D deduced from the number of established GH-D (n=301) and from the number of GH-D hypothesized from other pituitary deficits (n=406) was 707 cases. Prevalence and annual incidence were calculated from data recorded in a referral center with a well-defined catchment area, Marseilles (Bouches du Rhône department). We projected a prevalence of 2638 for France and an annual incidence of 12 GH-D per million of the adult population.

Identification of thyroid hormone residues on serum thyroglobulin: a clue to the source of circulating thyroglobulin in thyroid diseases.

Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.

[Value of scintigraphic explorations by radiomarkers others than iodine radioisotope in differentiated thyroid cancer]. / Intérêt des explorations scintigraphiques par des radiotraceurs autres que l'iode radioactif dans le cancer thyroïdien différencié.

Radioiodine scintigraphy is the gold standard exploration for imaging metastases of differentiated thyroid cancer and enables the decision of therapy with 131 radioactive iodine to be made. However, other approaches may be of use for diagnosis when there is no visible uptake after the administration of 131I, while elevated thyroblobulin levels suggest the presence of metastatic tissue in one third of metastatic patients. In order to detect recurrences or metastases, in conjunction with conventional imaging techniques (cervical and hepatic ultrasonography, lung CT scan..), other scintigraphic explorations with various radiopharmaceutics may be used, although none of them has any specificity towards thyroid cancer. Tl201 and MIBI which are used as perfusion tracers for myocardial explorations, are also used for detection of various tumors and for metastatic thyroid cancer. The performances of both radiopharmaceutics in imaging metastases are differently evaluated between investigators with a sensitivity ranging from 45 to 94% while the specificity varies less (82-97%). 18-Fluoro-deoxyglucose is retained in malignant tissue depending on the grade of malignancy. It has been shown to accumulate in thyroid cancer and metastases. Its detection by whole body PETscan represents a limitation for use which will be modified by new techniques. 111In-octreotide which binds to somatostatin receptors located on tumor cell membranes is able to show thyroid cancer metastases in some instances. We report on the very preliminary results of these combined scintigraphic approaches, performed in a limited number of patients who had no radioiodine uptake and elevated Tg levels, in order to determine the most appropriate exploration in terms of performance and cost.

Somatostatin receptor imaging in somatotroph and non-functioning pituitary adenomas: correlation with hormonal and visual responses to octreotide.

OBJECTIVE: A multicentre study was undertaken to determine the value of somatostatin receptor (sst) scintigraphy in predicting hormonal and visual responses to octreotide treatment in GH-secreting and non-functioning pituitary adenomas. SUBJECTS AND METHODS: Somatostatin receptor scintigraphy was performed in 48 patients (19 acromegaly, 29 non-functioning pituitary adenomas with ophthalmological defects). Results were expressed as an uptake index of the pituitary area. A threshold for positivity was determined in 23 subjects considered as controls. Thirty-five patients were treated for 1 month with octreotide (300 micrograms daily). The therapeutic response was assessed on GH and IGF-I suppression or evolution of the ophthalmological defects. The relationships between the somatostatin receptor scintigraphy result, the therapeutic effect of octreotide and in vitro studies performed in 12 tumours were studied. RESULTS: From the results of control subjects the uptake index threshold for positivity was 2. In patients, somatostatin receptor scintigraphy was positive in 64% and there was no relationship between uptake index and tumour size. In GH tumours, somatostatin receptor scintigraphy was positive in 68%; uptake index was related to octreotide-induced GH and IGF I suppression. The positive predictive value was 100% and the negative predictive value was 50%. In vitro studies showed detectable binding sites for somatostatin with sst2 and sst5 expression in the 4 GH tumours studied although somatostatin receptor scintigraphy was negative in 2 cases. In non-functioning pituitary adenomas somatostatin receptor scintigraphy was positive in 62%. Based on visual effects, the positive predictive value was 61% and the negative predictive value was 100%. A wide distribution of somatostatin binding sites was found in 8 non-functioning pituitary adenomas with expression of sst2 only. CONCLUSION: In the conditions of the study, in patients with acromegaly, positive somatostatin receptor scintigraphy predicts a hormonal response but the value of somatostatin receptor scintigraphy is limited by its low negative predictive value. In patients with non-functioning pituitary adenomas, negative somatostatin receptor scintigraphy predicts that there will be no visual improvement during octreotide treatment.

Relationships between pathological diagnosis and clinical parameters in acromegaly.

From our series of 185 somatotropic adenomas with acromegaly, we found that sparsely granulated adenomas were more frequent (56%) than densely granulated ones. Immunocytochemistry detected growth hormone (GH) plurihormonal adenomas in 68% of patients. GH-alpha-subunit (alpha SU) and GH-alpha SU-prolactin (PRL) were more frequent (38%) than GH monohormonal adenomas (32%). The colocalization of GH and alpha SU in the same cell was obvious in many tumors. In contrast, colocalization of GH and PRL was demonstrated in only 25% of GH-PRL adenomas. The relationships between age, sex, tumor size, GH and PRL plasma levels, granularity, and percentage of GH-, alpha SU-, and PRL-immunoreactive cells were established in 105 acromegalic patients by three statistical methods, mainly by a principal component analysis. Correlations were found between the percentage of alpha SU- and GH-immunoreactive cells, and between densely granulated character and the percentage of GH-immunoreactive cells. Tumor size was not correlated with alpha SU, but was positively correlated with PRL plasma levels. Patients' age and percentage of GH-immunoreactive cells were inversely related to tumor size. Plurisecretion and sparsely granulated aspect are not related to age and tumor size.

Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and alpha-subunit-secreting tumors from acromegalic patients responsive to octreotide.

The functional study of SRIH receptors was performed in ectopic GHRH-secreting tumors from two patients with acromegaly; patient 1 presented with multiple endocrine neoplasia type 1 with GHRH- and insulin-secreting pancreatic tumors, and patient 2 presented with a multihormone-secreting carcinoid tumor (including GHRH and alpha-subunit secretion, as demonstrated by clinical and immunohistochemical studies). In both cases, plasma GH levels were responsive to octreotide. In patient 2, plasma GHRH and alpha-subunit levels were responsive to octreotide. In vitro perifusion studies of a tumor fragment from patient 1 also showed inhibition of GHRH secretion by SRIH. A high density of specific SRIH-binding sites was visualized by autoradiography in GHRH tumors from both patients. SRIH specific binding was much higher in the GHRH tumors (6.6-8.4 fmol/surface unit) than in the insulinoma (1.9 fmol/surface unit). The binding inhibition constant (IC50) was in the nanomolar range (0.9-3 nmol/L) in the GHRH tumors. SRIH-14 inhibited forskolin-stimulated adenylate cyclase in the GHRH tumors from both patients, but not in the insulinoma. The functional SRIH receptors negatively coupled to adenylate cyclase present in ectopic GHRH-secreting tumors mediate the inhibitory effect of octreotide on GHRH secretion and on previously underrecognized ectopic alpha-subunit secretion from carcinoid tumors.

Pharmacodynamics and relative bioavailability of cabergoline tablets vs solution in healthy volunteers.

The effect of formulation on the urinary pharmacokinetics, pharmacodynamics, and relative bioavailability of cabergoline was investigated. Twelve healthy female volunteers, aged 23-35 years, were treated, according to an open, randomized, crossover design, with cabergoline (1-mg single oral dose) both as tablets and as a solution. The two administrations were separated by a 4-week wash-out period. Cabergoline and prolactin were measured in urine and plasma, respectively, by specific radioimmunoassays. Blood samples were collected before and up to 30 days after dosing. Urine was collected before and up to 8 days after dosing. Cabergoline elimination half-lives calculated from urinary data were 68 and 63 h after administration of the tablets and the solution, respectively. Urinary excretion of unchanged cabergoline accounted, on average, for 1.92% (range, 0.14-3.26) and 1.80% (range, 0.67-3.09) of the dose after administration of the tablets and the aqueous solution, respectively. Relative bioavailability of tablets vs solution was 99% (geometric mean with the 90% confidence intervals of 68-144%). Prolactin levels in 10 out of 12 subjects fell below the detection limit of the assay (1.5 micrograms/L) after both treatments. The mean maximum prolactin decrease (ca. 70%) was achieved by 2 or 3 h after dosing; the effect persisted up to 9 days, being completely exhausted 23-28 days after dosing. The analysis of variance performed on the pharmacodynamic effects of the two cabergoline formulations indicated that the percent decreases of plasma prolactin levels were not significantly different for tablets and solution. These results indicate that the pharmacodynamics and relative bioavailability of cabergoline are not influenced by formulation, as tablets or solution.