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Oncocytomas are large cell tumors characterized by an abnormal proliferation of mitochondria. To investigate this phenomenon in thyroid oncocytomas, we determined gene expression profiles of 87 samples using microarrays of 6720 PCR products from cDNA clones. Samples included 29 thyroid oncocytomas and six papillary carcinomas, the remainder representing other thyroid pathologies or mitochondria-rich tumor samples, normal thyroid samples, and two thyroid cell lines. Hierarchical clustering and supervised analysis identified two specific oncocytic clusters and 163 distinctly regulated genes between oncocytoma and normal thyroid. Differential expression of five selected genes (APOD, BCL-2, COX, CTSB, and MAP2) was confirmed by immunohistochemistry. The two specific oncocytic clusters were rich in mitochondrial genes and revealed coordinated expression of nuclear and mitochondrial respiratory chain genes. We also observed the up-regulation of genes involved in mitochondrial biogenesis, such as nuclear respiratory factor 1 and the endothelial nitric oxide synthase. Several oxidative metabolism genes were overexpressed in oncocytomas, including those from the tricarboxylic acid cycle (MDH1) and cytosolic glycolysis (GAPD, ENO1, and GPI). On the contrary, the lactate dehydrogenase A gene, involved in anaerobic metabolism, was down-regulated. Our results suggest that, unlike a large number of solid tumors, thyroid oncocytomas produce energy through an aerobic pathway.

Objective: Although angiogenic proteins have been identified as positive modulators of myocardial revascularization following acute myocardial infarction, little if anything is known regarding the role that antiangiogenic proteins have in myocardial revascularization. We explored the temporospatial distribution of endothelial-monocyte activating polypeptide (EMAP) II to determine whether antiangiogenic proteins have a role in the repair of myocardial tissue following infarction., Methods: A rat model of myocardial infarction was utilized to examine EMAP II distribution (in situ hybridization) and protein expression (Western analysis) over a 6-week period., Results: At baseline, EMAP II protein and mRNA are minimally expressed with transcription products localizing predominately to the perivascular stroma region in the normal rat myocardium. Six hours following myocardial infarction, EMAP II changes its distribution from the perivascular stroma to an invading inflammatory cell population. This is associated with a 2-fold (P < 0.0009) increase in EMAP II protein and its transcription primarily localized to the infarct region. EMAP II protein expression remains elevated throughout the weeks following the infarction with transcription limited to the infarct region and a notable decrease in EMAP II transcription products noted in the viable vasculature surrounding the infarct zone. Six weeks following myocardial infarction, EMAP II protein is elevated above control, changes its location of transcription from the inflammatory cell population to that of the fibroblasts located in the relative avascular scar tissue, and has resumed its perivascular stromal distribution in the viable periinfarct tissue., Conclusions: Thus, the temporospatial distribution of this antiangiogenic protein suggests that negative vascular modulators may have a function in the revascularization process following acute myocardial infarction.

Thyroid oncocytomas are tumors characterized by dense mitochondrial accumulation, the cause of which is currently unknown. Members of the PGC-1 coactivator family have been identified as important mediators of mitochondrial biogenesis because of their ability to activate nuclear genes encoding mitochondrial proteins. We have investigated the influence of the PGC-1 related coactivator (PRC) on the high mitochondrial content observed in oncocytoma by quantifying the transcripts of PRC, the nuclear respiratory factor 1 (NRF-1) and the mitochondrial transcription factor A (TFAM), in 30 oncocytic tumors and corresponding normal tissues. The three genes studied were found to be significantly overexpressed in thyroid oncocytomas, concomitantly with an increase in cytochrome oxidase activity and mitochondrial DNA (mtDNA) content. However, no mtDNA variant in the D-loop region appeared to be involved in oncocytic development. We conclude that overexpression of the PRC pathway is responsible for mitochondrial proliferation in the context of thyroid oncocytoma.

A thoracic aortic aneurysm was diagnosed in a 6-month-old male Leonberg dog by use of radiography, transthoracic and transesophageal echocardiography, and magnetic resonance imaging. The aneurysm was associated with a twisted ascending aorta and dilatation of several other thoracic arteries (pulmonary trunk, brachiocephalic trunk, and left subclavian artery). Histologic examination of the aorta revealed cystic medial necrosis, with disruption of the elastic network, collagen fibers, and the muscle glycoprotein fibrillin-1. The dam and sire of the dog and 8 littermates were examined by use of transthoracic echocardiography. The sire and 1 male littermate also had an aneurysm of the ascending aorta. To the authors' knowledge, this is the first report of familial aortic aneurysm in dogs.

Pleomorphic carcinoma, firstly described in the lung, is exceptional in the digestive tract. This tumor is often associated with fever and peripheral blood leukocytosis. The histological feature is characterized by giant pleomorphic often multinucleated cells with dense neutrophil infiltration and frequent phagocytosis of neutrophils by the tumor cells. Expression of epithelial markers confirm the diagnosis. The prognosis is very poor. We hereby report one case of pleomorphic carcinoma unusually situated in the large intestine, emphasizing difficulties encountered in establishing diagnosis.

F-18 fluorodeoxyglucose (FDG) is typically administered intravenously for positron emission tomography. The authors present a case of oral administration of FDG for evaluation of a pulmonary nodule and review the limited literature on this subject. Oral administration of FDG is a useful alternative to intravenous administration in patients with difficult intravenous access when the alimentary tract is not involved in the clinical diagnosis.

Technetium-99m tetrofosmin has been used as a tumor-imaging agent in cases of lung cancer. The authors present a case showing a lung tumor that concentrated Tl-201 distinctly more than Tc-99m tetrofosmin during a dual-isotope cardiac examination. A brief review of the literature is provided and possible explanations for this difference in tracer uptake are discussed.

Objective: To improve the preoperative selection for operation of patients with solitary thyroid nodules., Design: Prospective cohort study., Setting: University hospital, France., Patients: 155 consecutive patients who presented with solitary thyroid nodules and were operated on., Interventions: Clinical examination, ultrasound examination, fine needle aspiration biopsy, followed by total thyroid lobectomy with frozen section and final histological examination., Main Outcome Measure: Correct prediction of thyroid carcinoma or benign adenoma., Results: A logistic regression analysis indicated that absence of rim (p < 0.002), solid and hypoechoic feature (p < 0.003) and malignant or suspicious fine needle aspiration biopsy results (p < 0.0001) were significantly associated with malignancy. Selection for operation by the logistic model would save 40 of 73 patients from operation and 40 of 59 from unnecessarily radical operation. It would detect a similar number of cancers as a strategy based solely on fine needle aspiration cytology., Conclusions: A combination of the available diagnostic methods provides substantial benefit in the preoperative selection of patients with an isolated thyroid nodule.

Endocervicosis of the urinary bladder is a rare non-neoplastic condition characterized by endocervical-type glands deeply situated in the urinary bladder wall of women of reproductive age. We compared the immunohistochemical phenotype of a case of endocervicosis in a 35-year-old woman with four normal uterine endocervices. We tested antibodies known as reactive in the uterus and not mentioned or negative in the urothelium (HBME-1, estrogen receptor (ER), progesterone receptors (PR), DF3, Chromogranin). The proliferative index was assessed with MIB-1 antibody. Endocervicosis glands displayed stronger expression of HBME-1, ER and PR than normal endocervices, while the urothelium was negative. There was no difference in DF3 expression. The number of Chromogranin-positive cells was higher in endocervicosis than in the endocervices. The proliferative index was higher in the endocervicosis glands (15%) than in the normal endocervices (mean 3%), but was within the normal range established for endocervical glands. Our results confirm the endocervical nature of endocervicosis and constitute further arguments for the mullerian origin hypothesis. The only modestly increased proliferative index, as compared to endocervical malignancies, is consistent with a benign diagnosis.

Unlabelled: 18F-FDG PET has been shown to effectively detect differentiated thyroid carcinoma (DTC) metastases with impaired iodine-trapping ability. This article evaluates the potential contribution of FDG PET in the follow-up of patients with differentiated thyroid carcinoma, elevated thyroglobulin (Tg) levels, and negative whole-body scan results obtained after high doses of (131)I., Methods: We prospectively assessed the ability of FDG to detect metastases in 37 DTC patients who had undergone total thyroidectomy and radioactive ablation and presented with persistent disease, as assessed from elevated Tg levels and negative results of whole-body scans performed after therapeutic doses of (131)I. Additional conventional imaging procedures were performed to detect residual disease, and the patients were divided into 2 groups: group 1, with positive conventional imaging findings (n = 10), and group 2, with negative conventional imaging findings (n = 27)., Results: FDG PET showed positive findings in 28 patients and accurately localized tumor sites in 89% of them. In group 1, FDG PET confirmed 17 of 18 previously known tumor sites and detected 11 additional sites. In group 2, FDG PET findings were positive in 19 of 27 patients with no previously detected metastases. PET was effective for both low- and high-stage tumors. The FDG data led to a change in the clinical management of 29 of 37 patients with further surgical resection in 23 patients, 14 of whom achieved disease-free status, and external radiation therapy in 4 patients., Conclusion: FDG PET is able to detect metastases undetected by (131)I posttherapy whole-body scanning in patients with elevated Tg levels. It should be proposed as a first-line investigation in patients with persistent disease but negative findings on (131)I whole-body scans after treatment.

Oxyphilic tumors (oncocytomas or Hürthle cell tumors) form a rare subgroup of thyroid tumors characterized by cells containing abundant mitochondria. The relationship between the mitochondrial proliferation and the pathogenesis of these tumors is unknown. We have assessed the expression of the mitochondrial ND2 and ND5 (subunits of the nicotinamide adenine dinucleotide dehydrogenase complex) genes and the nuclear UCP2 (uncoupling protein 2) gene in 22 oxyphilic thyroid tumors and matched controls. The consumption of oxygen in mitochondria from tumors was determined by polarography. ATP assays were used to explore the mitochondrial respiratory chain activity and the oxidative phosphorylation coupling in seven fresh thyroid tumors and controls. Adenosine triphosphate synthesis was significantly lower in all the tumors, compared with controls, suggesting that a coupling defect in oxidative phosphorylation may be a cause of mitochondrial hyperplasia in oxyphilic thyroid tumors.

Germline specific point mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) are associated with autosomal dominant human skeletal dysplasia and craniosynostosis syndromes. Mutations identical to the germinal activating mutations found in severe skeletal dysplasias have been identified in certain types of cancer: at low frequency in multiple myeloma and cervix carcinoma and at high frequency in bladder carcinoma. We analysed, by SSCP and sequencing, the prevalence of FGFR3 mutations in 116 primary tumours of various types (upper aerodigestive tract, oesophagus, stomach, lung and skin). The regions analysed encompassed all FGFR3 point mutations previously described in severe skeletal dysplasia and cancers. No mutations were detected in the tumour types examined, suggesting that FGFR3 mutations are restricted to a few tumour types, the evidence to date suggesting that they are very specific to bladder carcinomas.

The roles of the MYC, ERBB2, and CCND1 genes in thyroid carcinogenesis are poorly known. We used real-time quantitative polymerase chain reaction (PCR) assays based on fluorescent TaqMan methodology to quantify MYC, ERBB2, and CCND1 gene amplification and expression in 24 benign tumors (adenomas and goiter nodules) and 12 carcinomas (9 papillary, 2 follicular, and 1 anaplastic) of the thyroid. Real-time PCR is a recently developed method for nucleic acid quantification in homogeneous solutions, and has the potential to become a reference in terms of performance, accuracy, sensitivity, wide dynamic range, excellent interlaboratory agreement, and high throughput capacity, while avoiding the need for tedious post-PCR processing. Overexpression (>5 standard deviations above mean for normal thyroid tissues) of the ERBB2 and CCND1 genes was observed (3.2- to 5.2-fold and 3.8- to 8.4-fold, respectively) in 5 (14%) and 13 (36%) of 36 neoplastic thyroid RNA samples, respectively. Overexpression of the CCND1 gene was observed in both the benign and malignant thyroid tumors, whereas the ERBB2 gene was mainly overexpressed in malignant thyroid tumors. None of the neoplastic thyroid samples overexpressed MYC. No MYC, ERBB2, or CCND1 gene amplification was identified. These results suggest that the CCND1 gene plays an early role and the ERBB2 gene a later role in thyroid tumorigenesis.

Medullary carcinoma of the thyroid (MTC) is a rare tumour derived from thyroid C cells with serum calcitonin as a specific and sensitive marker. MTC is inherited in 25% of cases, with an autosomal dominant transmission, age-related penetrance and variable expressivity. MTC is an obligatory component of multiple endocrine neoplasia type 2 (MEN2), which comprises three well defined syndromes: MEN2A, which may be associated with pheochromocytoma and/or hyperparathyroidism; the much rarer MEN2B, which occurs early and is accompanied by developmental abnormalities; while in contrast, familial MTC (FMTC) is not associated with any endocrinopathy. The RET proto-oncogene is the causative gene of the MEN2 syndromes and mutations in this gene are found in >90% of inherited cases, allowing easier and more reliable family screening than pentagastrin stimulation tests. Nevertheless, the correlation between the genotype and the different clinical phenotypes is not perfect. The prognosis of MTC depends on its staging at presentation, and the early appearance of cervical lymph node metastases emphasizes the need for extensive surgery, although many patients still do not normalize calcitonin levels post-operatively, and they remain a challenge for the further management., (Copyright 2000 Harcourt Publishers Ltd.)

Aims: To study the clinical outcome of 82 cases of pancreatic neuroendocrine tumours classified according to the recent histological and prognostic classification of Capella., Methods and Results: Eighty-two surgical cases of pancreatic neuroendocrine tumours were examined histologically with immunohistochemical staining of paraffin sections using streptavidin-biotin complex and application of antibodies against chromogranin A and 10 hormonal peptides. Classification in four groups correlated with long follow-up and outcome of these cases. Histological examination showed 30 group I, four group II, 41 group III and seven group IV tumours. Twenty-one (70%) of group I tumours were insulinomas, whereas 25% of group III tumours were glucagonomas and 25% were unclassified. Most group IV tumours were unclassified, showing no immunohistochemical staining with any of the 10 hormonal peptides tested. Outcome was clearly correlated with tumour group. Among the 14 patients who died of the disease, four had group IV and 10 group III tumours. Thus, unclassified asymptomatic tumours without immunohistochemical staining had a poorer prognosis than asymptomatic tumours with staining., Conclusion: This study validates the Capella classification as easy to apply and useful in predicting clinical outcome.

Fifty-one in vivo characterized autonomous single adenomas have been studied for functional parameters in vitro, for gene and protein expression and for pathology, and have been systematically compared to the corresponding extratumoral quiescent tissue. The adenomas were characterized by a high level of iodide trapping that corresponds to a high level of Na+ /iodide symporter gene expression, a high thyroperoxidase mRNA and protein content, and a low H2O2 generation. This explains the iodide metabolism characteristics demonstrated before, ie, the main cause of the "hot" character of the adenomas is their increased iodide transport. The adenomas spontaneously secreted higher amounts of thyroid hormone than the quiescent tissue and in agreement with previous in vivo data, this secretion could be further enhanced by thyrotropin (TSH). Inositol uptake was also increased but there was no spontaneous increase of the generation of inositol phosphates and this metabolism could be further activated by TSH. These positive responses to TSH are in agreement with the properties of TSH-stimulated thyroid cells in vitro and in vivo. They are compatible with the characteristics of mutated TSH receptors whose constitutive activation accounts for the majority of autonomous thyroid adenomas in Europe. The number of cycling cells, as evaluated by MIB-1 immunolabeling was low but increased in comparison with the corresponding quiescent tissue or normal tissue. The cycling cells are observed mainly at the periphery; there was very little apoptosis. Both findings account for the slow growth of these established adenomas. On the other hand, by thyroperoxidase immunohistochemistry, the whole lesion appeared hyperfunctional, which demonstrates a dissociation of mitogenic and functional stimulations. Thyroglobulin, TSH receptor, and E-cadherin mRNA accumulations were not modified in a consistent way, which confirms the near-constitutive expression of the corresponding genes in normal differentiated tissue. On the contrary, early immediate genes expressions (c-myc, NGF1B, egr 1, genes of the fos and jun families) were decreased. This may be explained by the proliferative heterogeneity of the lesion and the previously described short, biphasic expression of these genes when induced by mitogenic agents. All the characteristics of the autonomous adenomas can therefore be explained by the effect of the known activating mutations of genes coding for proteins of the TSH cyclic adenosine monophosphate (cAMP) cascade, all cells being functionally activated while only those at the periphery multiply. The reason of this heterogeneity is unknown.

The aim of this study was to compare 64 genetically determined pheochromocytomas (PH) (49 MEN IIa, 3 MEN IIb, 6 Von Recklinghausen diseases, 1 von Hippel-Lindau disease, 5 familial pheochromocytomas) and 48 sporadic PH. Genetically determined PH were more often observed among men and more frequently bilateral and multicentric than sporadic PH. Sporadic tumors had more often adrenal capsular invasion, necrosis and pseudocysts. Genetically determined PH were more differentiated with an insular pattern, hyaline globules and a higher percentage of polyhedric cells. Sporadic tumors were less differentiated with more frequently a diffuse pattern and small cells. Adrenal medullar hyperplasia was significantly associated with genetically determined PH. Adrenal cortical hyperplasia was not associated with a particular type of PH. The PS100 and chromogranin immunodetection was equivalent in both groups.

Thirty-eight patients (25 women, 13 men; mean age, 57.8 [32 to 91]) showing one or more medullary thyroid microcarcinomas (ie, < 1 cm), with no prior MEN II or medullary thyroid carcinoma history in their family, were reviewed. Follow-up was available for 29 patients (mean, 53.6 months [1 to 147]). 21 patients (72.4%) are alive and free of disease, four patients (13.8%) died during follow-up without disease, 2 patients are alive with disease (local recurrence and persistent hypercalcitoninemia) after 80 and 99 months, respectively, and 2 patients died of disease after 24 and 46 months. Most tumors were incidental pathological findings (19 of 38) or were discovered by systematic blood calcitonin measurement for a nodular thyroid disease (15 of 38). Only the four patients who had an unfavorable outcome were symptomatic cases (palpable micro-MTC, diarrhea, cervical lymph node metastasis and pulmonary metastatic disease). The two patients with metastatic disease at diagnosis died during follow-up. In univariate analysis, a symptomatic medullary thyroid carcinoma was a strong predictor of an unfavourable outcome (p < .00008), as were the preoperative calcitonin level (P = .007) and an elevated postoperative calcitonin level (P = .004). Among 30 histopathological criteria, only the presence of amyloid correlated with an unfavorable outcome (P = .018).

This study demonstrates the involvement of a Bax-Bcl2-dependent apoptotic process in Graves-Basedow thyroid disease, a pathological condition known for its spontaneously oscillating evolution. A continuous series of 86 cases of surgically treated Graves' thyroid was evaluated for apoptotic cell content identified by histological criteria and confirmed by terminal desoxynucleotidyl transferase-mediated desoxyuridine triphosphate nick end-labeling (TUNEL). A significant correlation was found between tissue features of Graves' disease (epithelial hyperplasia, cellular hypertrophy, colloid content) and the amount of apoptotic cells. No correlation was found with lymphocytic infiltrates. Significantly, 11 cases (about 12% of the series) with high-level apoptosis displayed the typical features of active Graves' disease over all tissue sections. In contrast, cases with no detectable apoptosis exhibited regressive tissue features of Graves' disease. An intermediate group of cases was characterized by tissue heterogeneity with hyperactive foci, rich in apoptosis, alternating with regressive areas lacking apoptosis. In this group the participation of apoptosis to the remodeling of Graves' thyroid parenchyma, in a tight balance with cell proliferation, was best illustrated. Moreover, the thyroid follicle by accumulating apoptotic cells and bodies, allowed a tentative chronological ordering of apoptosis steps in correlation with Bax-Bcl2 tissue distribution and cellular pattern. Our observations suggest that the initiation of apoptosis corresponds to a loss of cellular cohesion, a drop in Bcl2 expression, and a delocalization of Bax from a putative Golgi storage location to a mitochondrial distribution.

The involvement of 5-HT1B receptors in the regulation of vigilance states was assessed by investigating the spontaneous sleep-waking cycles and the effects of 5-HT receptor ligands on sleep in knock-out (5-HT1B-/-) mice that do not express this receptor type. Both 5-HT1B-/- and wild-type 129/Sv mice exhibited a clear-cut diurnal sleep-wakefulness rhythm, but knock-out animals were characterized by higher amounts of paradoxical sleep and lower amounts of slow-wave sleep during the light phase and by a lack of paradoxical sleep rebound after deprivation. In wild-type mice, the 5-HT1B agonists CP 94253 (1-10 mg/kg, i.p.) and RU 24969 (0.25-2.0 mg/kg, i.p.) induced a dose-dependent reduction of paradoxical sleep during the 2-6 hr after injection, whereas the 5-HT1B/1D antagonist GR 127935 (0.1-1.0 mg/kg, i.p.) enhanced paradoxical sleep. In addition, pretreatment with GR 127935, but not with the 5-HT1A antagonist WAY 100635, prevented the effects of both 5-HT1B agonists. In contrast, none of the 5-HT1B receptor ligands, at the same doses as those used in wild-type mice, had any effect on sleep in 5-HT1B-/- mutants. Finally, the 5-HT1A agonist 8-OH-DPAT (0.2-1.2 mg/kg, s.c.) induced in both strains a reduction in the amount of paradoxical sleep. Altogether, these data indicate that 5-HT1B receptors participate in the regulation of paradoxical sleep in the mouse.

Although ultrasound (US)-guided fine needle aspiration biopsy (FNAB) is widely prescribed in nonpalpable thyroid nodules, the goal of this study was to define precisely the indications and limits of US-FNAB in a series of 450 nonpalpable nodules. Among 94 surgically controlled cases, 20 (8 infracentimetric and 12 centimetric or supracentimetric) carcinomas were diagnosed. The diagnosis of malignancy was successfully made by US-FNAB in 16 of 20 carcinomas, 3 were missed because of insufficient cytological material, and 1 was misdiagnosed. US-FNAB sensitivity and specificity were 94% and 63%, respectively. A logistic model indicated that nodule size (P < 0.6) was not associated with histological diagnosis, but that solid hypoechoic features were more likely to be malignant (P < 0.0003), with US sensitivity and specificity for malignancy of 80% and 70%, respectively. Logistic regression indicated that adequate cytological material significantly increased with nodule size (P < 0.0001). This result outlined the limits of US-FNAB in small nodules. Hence, indication of US-FNAB appears judicious in centimetric or supracentimetric nodules or in solid and hypoechoic ones. Such a management would allow the discovery of 15 of 20 carcinomas and would avoid 16% of unnecessary biopsies.

Clinical characteristics and prognosis of 80 patients (53 women and 27 men) with sporadic medullary thyroid carcinomas (MTC), less than 1 cm in size (micro-MTC), operated on between 1971 and 1996 are reported (73 total and 7 partial thyroidectomies). These patients, obtained from a national database of 899 patients with MTC, were compared with 357 cases of sporadic MTC greater than 1 cm and 149 subjects with familial MTC less than 1 cm (familial micro-MTC). Median age at surgery was 52.5 years, a distribution similar to larger sporadic MTC. Micro-MTC was identified due to elevated calcitonin (47.5%), clinically identified lymph node (10.0%), distant metastases (6.3%) or pathologic finding at surgery (36.2%). Diarrhea and/or flushing were observed in 6 patients including 4 with clinically identified lymph node. Among patients who had lymph node dissection at surgery (68.8%), lymph node involvement with tumor was observed in 30.9%, and was significantly more frequent in multifocal (7/11) than in unifocal micro-MTC (p < 0.03). All sporadic micro-MTC were unilateral. Survival rate was 93.9% +/- 4.4% (SE) at 10 years, greater than that observed in sporadic macro-MTC (p = 0.04). Normal postoperative basal calcitonin (CT) was obtained in 71.1% of micro-MTC patients versus 33.6% in sporadic macro-MTC (p < 0.01). Sporadic micro-MTC is much more frequent than expected, 15% of MTC in our series. Although specific survival rate and percentage of biological cure in micro-MTC are significantly better than for larger tumors, the frequency of lymph node involvement, however, justifies an aggressive surgical approach including total thyroidectomy and bilateral central lymph node dissection.

A group of 13 pathologists belonging to the French Calcitonin Tumor Study Group (GETC: Groupe d'Etude des Tumeurs à Calcitonine) examined the histological slides and medical records of 109 proband cases of medullary thyroid carcinoma (MTC) diagnosed on clinical features. The cases belonged to the various forms of the disease (80 sporadic and 29 familial MTC). The aim of the study was to detect histological predictors for survival by comparing morphological data from patients killed by the disease versus the others. Twenty-seven histological parameters were considered, including cellular heterogeneity, shape of the cells, and cytoplasmic characteristics. Other parameters such as sex, age, and phenotype of the disease were also studied. First, predictive parameters of interest on survival function were selected by univariate analysis (Mantel-Cox test). Then, the extracted parameters were tested in a multifactorial analysis using the Cox's forward stepping proportional hazard model. Five parameters were significantly associated with a lower survival function: presence of necrosis in the tumor (P = .001), squamous pattern (P = .002), age over 45 years (P = .004), presence of oxyphil cells in the tumor and absence of cells with intermediate cytoplasm (P = .025), less than 50% of calcitonin immunoreactive cells in the tumor (P = .04).

1. Our aim was to determine whether the cardiovascular neurones in the rostro-ventrolateral medulla (CV-RVLM neurones) were involved in the sympathoexcitation induced by stimulation of 5-HT3 receptors in the region of the nucleus tractus solitarii (NTS). Experiments were performed in pentobarbitone-anaesthetized rats, artificially ventilated and paralysed with pancuronium bromide. 2. Using extracellular recordings, different types of RVLM neurones were characterized: cardiovascular (CV), ventilation-related and baroreflex-insensitive (unidentified) neurones. The CV-RVLM cells were further subdivided into three populations according to their axonal conduction velocities: A (1.2 +/- 0.1 m s-1), B (2.5 +/- 0.2 m s-1) and C (6.8 +/- 1.1 m s-1). 3. Only the CV-RVLM neurones of the A and B categories were partially inhibited (-30 %) by a hypotensive dose (2.5 microg kg-1 i.v.) of clonidine. 4. Microinjections into the region of the commissural NTS of 1-(m-chlorophenyl)-biguanide (CPBG, 2 nmol), a selective 5-HT3 receptor agonist, elicited an increase in both lumbar sympathetic nerve discharge (SND) and arterial pressure. In addition, this treatment produced a marked excitation of CV-RVLM neurones of the A and B categories, without affecting those of the C type, as well as ventilation-related and unidentified RVLM cells. 5. The activity of the CV neurones in the caudo-ventrolateral part of the medulla oblongata (CV-CVLM) was not modified by 5-HT3 receptor stimulation in the NTS. 6. Prior intra-NTS microinjections of ondansetron (300 pmol, a selective 5-HT3 receptor antagonist) into the region of the commissural NTS prevented the excitation of A and B CV-RVLM neurones induced by CPBG. 7. Intracarotid administration of saline saturated with CO2 (chemoreceptor activation) elicited both an increase in the SND and an excitation of the clonidine-insensitive CV-RVLM neurones of the C type, without affecting A and B neurones. 8. In conclusion, the sympathoexcitation elicited following 5-HT3 receptor stimulation in the region of the commissural NTS of pentobarbitone-anaesthetized rats seems to result from the excitation of two different pools of clonidine-sensitive CV-RVLM neurones. These neurones are apparently not involved in the sympathetic component of the chemoreceptor reflex.

This review article illustrates the several histological and immunohistochemical patterns of thyroid insular carcinoma and their associated disease. Differential diagnosis are also discussed. Poorly differentiated thyroid carcinomas are overviewed. The interest of transgenic mice models is presented.

This article precises the technical conditions of fine-needle aspiration, elements of microscopical analyses which establish the diagnostic, complementary technics, specially immunocytochemistry that could enhance the performance. Limits and worrisome histologic changes following fine needle aspiration are also discussed. Fine needle aspiration results are discussed. The text is fully illustrated.

This article analyses in a large overview several of the actual problems encountered by pathologist in the management of MTC whatever the diagnostic circumstances. We insist on difficulties upon C cell hyperplasia and early detected disease. Unusual MTC cases are discussed. The need for large multidisciplinary group in studying such tumors is underlined with reference to the French GETC (Groupe d'Etude des Tumeurs à Calcitonine).

Mouse transgenic models that develop thyroid diseases were generated. All transgenes were driven by the thyroid specific promoter of the thyroglobulin gene. The tissue specificity of the promoter was investigated by using the bacterial chloramphenicol acetyltransferase gene as reporter. The expression of the adenosine A2a receptor resulted in the permanent activation of the cAMP cascade. As a consequence, transgenic mice developed severe hyperthyroidism and a large goiter, demonstrating in vivo the role of the cAMP cascade in the promotion of both function and proliferation of the thyroid cell. These mice constitute a model for autonomous hyperfunctional adenoma and non autoimmune familial hyperthyroidism, where mutant of thyrotropin receptors stimulate the cAMP cascade constitutively. The expression of a mutant of the alpha 1B adrenergic receptor resulted in the constitutive activation of both the cAMP and IP3-CA++ cascades, growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and development of malignancies. The expression of the SV40 large T antigen promoted the development of aggressive undifferentiated tumors mimicking the phenotype of human anaplastic carcinomas and embryonal tumors. In another transgenic model, the function of the retinoblastoma susceptibility gene product RB1 (and of related proteins) was inhibited by expressing the E7 oncoprotein of human papillomavirus type 16. The result was the development of a differentiated and normofunctional colloid goiter, with progressive development of differentiated malignant lesions. This model suggests the essential role of RB1 and related proteins in the negative control of proliferation that characterizes thyroid cells in the adult. Other transgenic models of thyroid diseases are discussed.

As a consequence of the Chernobyl nuclear power plant accident, a considerable increase of thyroid cancer among contaminated children has been reported in Ukraine, Belarus and Russia. A group of 29 children aged from 5 months to 10 years (mean 4.7 years) at the time of the accident, with a papillary thyroid cancer, have been examined at the Pitié-Salpêtrière hospital in Paris. The cancer was discovered by systematic ultrasonography in only 25% of cases. No reliable dosimetric estimation was achieved. The initial surgical treatment was performed in Ukraine. Cervical lymph node and pulmonary metastases were present in 24 and 11 cases respectively. A complementary surgical treatment was necessary for 9 children and one to four radioiodine treatments were given to 24 children. With a mean delay of 7 years after the cancer discovery, an apparent cure or a remission was obtained for 20 children, 6 children have cervical lymph node metastases requiring a surgical treatment and 3 have evolving lung metastases. The management of the great number of foreseeable cases of thyroid cancer requires an improved systematic screening, a large number of rooms dedicated to high activity radioiodine treatments, funds for disposable material and training missions.

MUC1 mucin is found in a variety of epithelial tissues and is overexpressed in several epithelial cancers. This molecule could modulate cellular adhesion and thereby influence tumor invasion and metastasis. Little is known of MUC1 gene expression in thyroid tissues. We investigated whether MUC1 mucin gene alteration and/or expression correlated with thyroid tumor progression by studying 21 fresh thyroid tissue specimens comprising 10 macrofollicular adenomas and 11 papillary carcinomas. Normal adjacent tissue from the same patients was also studied. To determine the integrity and expression of the MUC1 mucin gene, a complementary DNA (cDNA) probe was used for Southern blot analysis of DNA and Northern blot analysis of RNA. A detailed immunohistochemical analysis of MUC1 protein expression was performed with DF3 monoclonal antibody, and was compared with other tumor characteristics and clinical manifestations at diagnosis. Of the 14 tumors informative (heterozygous) with the pMUC10 polymorphic probe, 2 (14%) showed loss of heterozygosity (1 adenoma and 1 carcinoma). Overexpression of MUC1 RNA, compared with normal thyroid tissue, was observed in 6 of the 11 papillary carcinomas and in none of the 10 adenomas. Immunostaining of the corresponding formalin-fixed paraffin-embedded tissue sections detected MUC1 mucin protein at the apical domain of follicular cells. Most of the lining was thin in normal tissue and follicular adenomas, but the protein was more irregularly and less strongly expressed in adenomas. In carcinomas the epithelial mucin produced by the MUC1 gene was present irregularly as a thin and/or thick lining at the apical domain of tumor cells. In addition, 5 of the 6 samples with MUC1 mRNA overexpression showed intracytoplasmic staining. Moreover, intracytoplasmic MUC1 mucin staining was found in 75% of "high-risk" papillary thyroid carcinoma (PTC) (PTC with extrathyroid extension at initial diagnosis and/or lymph node involvement), and in only 28.5% of "low-risk" PTC (purely intrathyroidal carcinomas).

Rapid eye movement sleep can be elicited in the rat by microinjection of the cholinergic agonist carbachol into the oral pontine reticular nucleus. Intracerebroventricular administration, during the light period, of vasoactive intestinal peptide enhances rapid eye movement sleep in several species. Since this peptide is co-localized with acetylcholine in many neurons in the central nervous system, it was assumed that the oral pontine tegmentum could also be one target for vasoactive intestinal peptide to induce rapid eye movement sleep. This hypothesis was tested by recording the sleep-wakefulness cycle in freely-moving rats injected with vasoactive intestinal peptide or its fragments (1-12 and 10-28) directly into the oral pontine reticular nucleus. when administered into the posterior part of this nucleus, vasoactive intestinal peptide at 1 and 10 ng (in 0.1 microliter of saline), but not its fragments, induced a 2-fold enhancement of rapid eye movement sleep during 4 h, at the expense of wakefulness. At the dose of 10 ng, a significant increase in rapid eye movement sleep persisted for up to 8 h. Moreover, when the peptide was injected into the centre of the positive zone, rapid eye movement sleep was enhanced during three to eight consecutive days. These data provide the first evidence that rapid eye movement sleep can be elicited at both short- and long-term by a single intracerebral microinjection of vasoactive intestinal peptide. Peptidergic mechanisms, possibly in association with cholinergic mechanisms, within the caudal part of the oral pontine reticular nucleus may play a critical role in the long-term regulation of rapid eye movement sleep in rats.

This article describe the case of a 38-year-old woman with simultaneous involvement of the thyroid by Hashimoto's thyroiditis and Riedels's disease, associated with retroperitoneal fibrosis and lipidic endarteritis. According to a large review of the literature on the occurrence of this rare condition the difficulty in sharply defining the two thyroid processes is discussed. The chronology of the events is analyzed, and etiopathogenic hypotheses are listed with emphasis on the relationship between the vascular lesions and the onset of the fibrosing process.

We report a prospective quantitative image analysis study of C cells in 57 normal autopsy thyroid glands, serially sectioned and wholly embedded in paraffin; all slides were immunohistochemically stained for calcitonin. Computerized quantitative image analysis was performed on 47 cases to measure C cell surface area and parenchymatous surface area after immunoperoxidase staining for calcitonin. The method was time-effective, with a good reproducibility. C cells were mainly found in the middle third of each lobe. Important inter-individual variations were observed; the maximum C cell surface area in a section (Amax) ranged from 28 x 10(3) to 470 x 10(3) microns2 (mean, 167 x 10(3) microns2) among 42 adults. Of particular interest was the important difference observed between sexes; Amax was twice as high in men (mean, 201 x 10(3) microns2) as in women (mean, 91 x 10(3) microns2; P = 0.0009). Moreover, 14 (33%) adult subjects [2 women (15%) and 12 men (41%)] fulfilled C cell hyperplasia criteria, i.e. at least 3 fields at x 100 magnification containing more than 50 C cells, suggesting that a substantial part of the normal adult population could have C cell hyperplasia.

In a large review on the utility of fine needle aspiration biopsy of the thyroid in the diagnostic management of nodular thyroid disease, procedure, morphological diagnostic criteria and difficulties, complementary technics are overviewed. Relevant articles and series are reviewed to assess the results of fine needle aspiration biopsy. A question is highlighted: wether benign unoperated thyroid nodules diagnosed by fine needle aspiration biopsy are they an underestimate risk group.

Atheromatous aneurysmal degeneration of a venous bypass graft is a rare and late event after venous bypass grafting. We report the case of a 49-year-old man in whom a large aneurysm of a saphenous graft implanted 10 years earlier ruptured to the skin. Amputation was required. Graft degeneration can lead to complications which may be life or limb-threatening due to graft rupture, graft thrombosis or distal embolization. Close follow-up after arterial reconstruction using a vein graft is therefore highly warranted for early detection and correction of any abnormalities before onset of complications.

To evaluate the accuracy of fine-needle biopsy in the management of the solitary thyroid nodules, 320 biopsies without aspiration were performed in 212 patients, iteratively in 91 cases. Among the 212 initial biopsies, 93 smears were found presumably benign (43.9%), 6 malignant (2.8%), 49 benign implying cytologic control (23.1%), 24 suspicious with decision to operate (11.3%), 40 inadequate (18.9%). On 67 surgical indications (malignant or suspicious cytology, or clinical data), 59 operations were performed. The 11 diagnosed cancers (5.2% of the patients; 18.6% of the operations) correspond to six malignant and five suspicious cytologies at the first or second biopsy. On 145 cases without decision to operate, 125 were clinically surveyed, with sometimes another biopsy (mean survey: 27.6 months; range: 6-80 months), and it was never necessary to modify the initial expectancy attitude. Our results, rather similar to those related by most of the previous publications, confirm that the fine-needle biopsy is a reliable and effective means for the etiologic diagnosis of thyroid nodules and the indications for operative intervention. It spares many patients from a useless operation and is worthy to take a leading place in exploring these nodules.

This article reviews the pathology and classification of differentiated thyroid carcinomas. Diagnostic criteria are reviewed. Follicular and papillary carcinomas and their variants are described. New entities are detailed. Atypical adenomas and difficult follicular diseases are discussed. The need for a consensual terminology is assessed.

Since 1985, the French National Association ADICAP (Association for the promotion of computer use in Cytology and Anatomic Pathology) has been active in the creation a microscope workstation for developing a bank of digitized images to be used for diagnostic and educational purposes. In 1989 one of the authors (P. Dusserre) has created a first telepathology network using this workstation. Since then, 32 workstations have been set up in private and public Departments of Pathology. Two of them are located overseas, in the Martinique and Guadeloupe islands. In this paper, the authors describe this system, called Transpath, which is a multi-purpose and modulable workstation. 3-years experience and several accuracy tests have shown that the quality of transmitted images ensure a reliable diagnosis in more than 95% of cases. It has been decided to extend this service to other French overseas territories and to develop a group of experts. The images bank will also be developed and recorded on CD-ROM. The authors intend to participate in a future European project (PILOT project, i.e. Pathology International and Local Operational Telematics), with the purpose of establishing real intercommunication between European and other networks on a worldwide basis.

50 hepatic biopsies and 50 prostatic biopsies were submitted for diagnostic to an expert by the mean of static images previously digitalized by a consulting pathologist. Accuracy of diagnosis was obtained in 2 minutes with 4 images in 86% of cases. Additional data such as new images, several power fields, permitted accuracy of diagnosis in 98% of the cases. The experiences showed clearly that the quality of the transferred static images is sufficient to allow diagnoses. It pointed out the importance of the different actors involved in the consultation. It illustrates the possible use of this system as a training tool.

Since the first description by Wolfe et al of C-cell hyperplasia (CCH) in asymptomatic relatives of patients suffering from a medullary thyroid carcinoma (MTC), several investigators have described CCH associated with a chronic lymphocytic thyroiditis (CLT) not within the context of MTC or multiple endocrine neoplasia (MEN). We report the study of C-cell density in 112 cases of CLT on retrospective surgical material to determine the frequency of the association between CCH and CLT. The cases of CLT were compared with 19 normal thyroid glands obtained at necropsy. C cells, immunoreactive with a polyclonal anti-calcitonin (CT) antibody, were counted at high magnification (X400) and the number of low-power magnification (X100) microscopic fields (LPFs) containing at least 50 C cells per slide was assessed. Image analysis was performed to determine the C-cell density expressed in number of C cells/cm2. C-cell hyperplasia was defined by the following criteria: C-cell density > 40 cells/cm2 and the presence of at least three LPFs containing more than 50 C cells. Twenty percent of the cases of CLT showed a CCH thus defined, and four of them had an elevated serum CT level. Statistical analysis showed no clinical or biological correlation with the presence of CCH. However, the frequency of CCH was higher if a follicular cell carcinoma was associated with CLT. This study confirms a pathological association between CCH and CLT, provides new criteria for the definition of CCH on surgical pathology material, and reports four cases with an elevated serum CT level not within the context of MTC or MEN.

The 24-hour motor activity pattern was evaluated in 26 inpatients with major depression at treatment onset and after 4 weeks of antidepressant therapy. Clinical state, depression, and psychomotor retardation, as well as motor activity level and circadian rhythm, were simultaneously assessed. Treatment responders and nonresponders were also considered. Diurnal hypoactivity and reduced 24-hour rhythm amplitude were found at treatment onset. Activity level increased significantly on discharge. The rest-activity cycle for each depressed patient fit a cosine function of 24-hour periodicity. Data tended to show no phase shift but a large intragroup phase variability. Preliminary findings of a negative correlation between basic activity level and clinical improvement, and a trend toward responders having a lower activity level than nonresponders, suggest that activity could be used to predict therapeutic response.

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.