Skin and thigh muscle metastasis from papillary thyroid cancer.

A 44-year-old man with total thyroidectomy for papillary thyroid carcinoma (PTC) performed at the age of 38 years was referred for mediastinal metastases demonstrated on chest radiograph and high serum thyroglobulin (Tg 328 ng/ml). Computed tomography revealed mediastinal lymph node enlargement with left bronchial compression and reduction of bronchial diameter, as well as two metastases in the left lung. Bronchoscopic biopsy findings showed a poorly-differentiated PTC, while a whole body scan after 131-Iodine therapy demonstrated uptake in the right subclavicular region. External beam radiotherapy and chemotherapy yielded no benefit; the neoplasm was aggressive, diffuse and experienced fast growth, leading to the formation of metastases also at unusual sites, such as the skin and thigh muscle. The patient died from a brain metastasis. We report a rare case of PTC metastasis with a poorly-differentiated component in a young patient. Rapid and diffuse metastases also to unusual sites led to death eight years after the initial diagnosis and treatment.

Genetic mutations in thyroid carcinoma.

Thyroid carcinoma is the most common endocrine neoplasm and the seventh most frequent human malignancy. It can be distinguished into differentiated and undifferentiated. Differentiated tumors include those arising from thyrocytes, i.e. papillary and follicular carcinoma, while medullary carcinoma originates from parafollicular or C cells. Anaplastic carcinoma comprises undifferentiated tumors. The factors inducing thyroid carcinoma development are not fully understood despite some well-established associations, such as the one between ionizing radiation and papillary carcinoma and that between iodine deficiency and follicular carcinoma. Genetic investigations of differentiated thyroid tumors have documented mutation of genes involved in the regulation of MAP kinase pathway activation in papillary carcinoma, and of genes involved in the regulation of the PI3 kinase pathway in follicular carcinoma. Analysis of their clinical course and of positivity for mutations has demonstrated that prognosis is greatly affected by the type of mutated gene. Genetic investigations therefore have the potential to direct diagnosis, but especially to tailor therapy and follow-up to the individual patient and even the individual gene. Anaplastic carcinoma, a highly aggressive, undifferentiated form, can arise as such or else be the de-differentiated progression of a papillary or a follicular carcinoma. It displays a mutated tumor suppressor gene (p53), which is crucial in the regulation of cell apoptosis, in addition to the mutations found in papillary and follicular forms. Medullary carcinoma is a malignant neoplasm with an intermediate clinical course between differentiated and undifferentiated forms. It manifests more frequently as a sporadic neoplasm or as a familial MEN. The latter is a high-penetrance, autosomal dominant hereditary disorder. Identification of the gene responsible for medullary carcinoma has radically changed the diagnostic approach to the familial forms, enabling early neonatal diagnosis of mutation carriers and of the disease, and early surgical approach by prophylactic thyroidectomy. Genetic studies have significantly affected the endocrinologist's diagnostic approach, as in the case of medullary carcinoma; over the next few years they are expected to provide further information to tackle papillary and follicular thyroid carcinoma. This review addresses the main genetic mutations responsible for neoplastic transformation in thyroid disorders.

Fine analysis of the short arm of chromosome 1 in sporadic and familial pheochromocytoma.

OBJECTIVE: Despite the very recent discovery that about 25% of apparently sporadic forms of pheochromocytoma are actually due to germline mutations of RET, VHL, SDHB or SDHD genes, the genetic bases of the tumourigenesis of this type of cancer are still incompletely understood. Recent studies provided evidence that a new tumour suppressor gene, mapping on the short arm of chromosome 1, could be involved in early tumourigenesis of pheochromocytoma. DESIGN: We have performed a fine analysis of loss of heterozygosity (LOH) of this region. In particular, we have analysed 31 highly polymorphic microsatellites distributed at 3.8 Mege base (Mb) mean intervals along the short arm of the chromosome 1 in paired samples of DNA extracted from peripheral blood lymphocytes and tumour tissues. PATIENTS: The study was carried out on 38 patients with pheochromocytoma that had been grouped, by careful clinical and molecular investigation, in the following classes: 21 sporadic, five multiple endocrine neoplasia type 2 (MEN2), two type 1 neurofibromatosis (NF1), five von Hippel-Lindau (VHL), one somatic VHL mutated and four nonsyndromic familial cases. RESULTS: In 12/21 sporadic cases (57.1%), in 4/5 MEN2 (80%), 2/4 non-syndromic familial cases (50%), and in 2/2 NF1 (100%), the entire short arm was deleted, while in 6/21 sporadic (28.6%) and 1/5 MEN2 (20%) cases a partial deletion was detected. On the other hand, none of the five cases due to VHL mutation (either germline or somatic) had LOH at chromosome 1. In total, complete or partial deletion of 1p was detected in 27/38 (71%) of the cases. The most frequently deleted marker was D1S2890, which maps at 1p32.1. This region, which spans from 50 to 62 Mb from telomere, was therefore further investigated with markers located at a mean interval of 1.3 Mb in the subset of cases that showed a partial deletion of 1p. This analysis showed that a small region between 55.1 and 59.0 Mb was most frequently missing, which could therefore contain a novel pheochromocytoma locus. CONCLUSIONS: The results presented here confirm that the short arm of chromosome 1 harbours one or more genes responsible for the development of pheochromocytoma and suggest that one of them could map in a 3.9-Mb fragment between 1p32.3 and 1p32.1.

[Surgical treatment of differentiated thyroid carcinoma]. / Il trattamento chirurgico del carcinoma tiroideo differenziato.

Being the excellent prognosis, the extension of the thyroidectomy in the surgical management of differentiated thyroid carcinomas is still controversial: some authors recommend total thyroidectomy for all patients, others suggest a conservative approach, that guarantee the same good prognosis but is associated with fewer complications. Even the cervical lymph node dissection is discussed, both regarding to the indications and the extension. The authors reported a retrospective review of their experience of the last 10 years on 75 patients operated for differentiated thyroid cancer, 61 for papillary carcinoma and 14 for follicular carcinoma; 18 of them were men and 57 females, with a mean age of 48.2 years. We performed a total of 85 operations: 60 total thyroidectomy, 15 lobus-isthmusectomies and 10 completion thyroidectomy. Lymphadenectomy was performed in 17 patients with clinically or intraoperative evidence of enlarged lymph nodes. There was no surgical mortality. Permanent hypoparathyroidism occurred in 5 patients (5.8%) and permanent accidental laryngeal recurrent nerve injury, both monolateral, occurred in 2 cases (2.35%). The mean follow up was 53 months (4.5 years): 71 patients are still alive (94.7%), 68 of them disease free (90.6%) and 3 with recurrent disease (4%). Our results suggest that total thyroidectomy still represent the choice procedure for the treatment of differentiated carcinomas and that modified radical neck dissection is necessary in these patients with pre or intraoperative evidence of palpable lymph nodes. Some patients go well even undergoing more conservative surgery (lobectomy) but most problem is the impossibility to preoperatively identify these patients.

Ultrasonographic contrast agent: evaluation of time-intensity curves in the characterisation of solitary thyroid nodules.

PURPOSE: To evaluate whether the time-intensity curve can improve characterisation of solitary thyroid nodules. MATERIAL AND METHODS: From June to December 2000 we studied 61 patients (16 men and 45 women, mean age 46 years) with solitary thyroid nodules that were not associated with any important hormonal alteration and that showed poor tracer uptake at scintigraphy. We evaluated the Power Doppler vascular pattern before and after a 60" intravenous injection of 2.5 g of Levovist (diluted in 7 ml). The study lasted 5 minutes from the beginning of the infusion. Finally, the time-intensity curves were processed. All the nodules underwent fine needle aspiration biopsy (FNAB) and excision biopsy. RESULTS: Histology revealed 43 benign lesions and 18 malignant lesions. At contrast-enhanced Power Doppler 83.4% (15/18) of the malignant nodules were found to be hypervascularized, while 16.6% (3/18) were hypovascularized. Of the benign lesions, 90.7% (39/43) were hypervascularized, 9.3% (4/43) were hypovascularized. All the nodules, both hyper- and hypovascularized, displayed rapid and intense wash-in curves. By contrast, the wash-out curves were regular and monophasic in 40/43 (93%) benign lesions (36 hypervascularized and 4 hypovascularized lesions) and irregular and polyphasic in 16/18 (89%) malignant lesions (13 hypervascularized and 3 hypovascularized lesions); 3/43 (7%) benign nodules showed polyphasic wash-out and 2/18 malignant lesions (11%) showed monophasic wash-out. DISCUSSION AND CONCLUSIONS: Time-intensity curves, and particularly wash-out curves, provide useful information for the characterisation of solitary thyroid nodules. 93% of benign nodules (with regular vascularization) showed a monophasic pattern of the wash-out curve, while 89% of malignant nodules ("anarchical" vascularization) had polyphasic wash-out curves. This behaviour was observed in both hypervascularized and hypovascularized lesions. Our method proved to have a sensitivity of 88% and a specificity of 93%. The study of time-intensity curves could therefore enable us to differentiate between benign and malignant lesions and characterise hypovascularized malignant nodules which would not be observed without contrast agent.

Unusual clinical manifestation of pheochromocytoma in a MEN2A patient.

A case of unusual clinical manifestation of pheochromocytoma in a type 2A multiple endocrine neoplasia (MEN2A) patient is presented. A 27-year-old man affected by MEN2A syndrome, complaining of anxiety and depression, was admitted in our Division. Past medical history included a total thyroidectomy for medullary carcinoma in 1985, and left adrenalectomy for pheochromocytoma in 1994. Blood pressure was 130/ 85 mmHg without orthostatic hypotension and pulse rate was 72 beats/min. Laboratory data revealed thyroid hormones and carcinoembryonic antigen (CEA) in the normal range and high basal serum calcitonin levels (158 pg/ml). Plasma catecholamines and vanillylmandelic acid resulted in normal levels but epinephrine/norepinephrine ratio was elevated (0.65). The glucagon stimulation test showed positive clinical and biochemical response. Magnetic resonance imaging (MRI) and meta-iodobenzylguanidine (MIBG) scintiscan confirmed the presence of bilateral adrenal masses. Bilateral adrenalectomy by laparoscopic anterior approach was performed. Histology was consistent with adrenal pheochromocytomas. After surgical approach, psychiatric findings disappeared and did not recur at follow-up in spite of no medication for two years. In conclusion, bilateral pheochromocytoma is more frequent in MEN2A syndrome and probably understimated if the follow-up is not prolonged. In these cases clinical features are often aspecific and basal hormonal data may be normal in a great number of patients. Therefore long-term observation is justified in these patients. Pheochromocytoma was described as the "great mimic" for the numerous subjective manifestations. Differential diagnosis among typical features of neuropsychiatric disorders and pheochromocytoma must be considered.

Adrenal incidentaloma.

Incidentally discovered adrenal masses, or adrenal incidentalomas, have become a common clinical problem owing to wide application of radiologic imaging techniques. This definition encompasses a heterogeneous spectrum of pathologic entities, including primary adrenocortical and medullary tumors, benign or malignant lesions, hormonally active or inactive lesions, metastases, and infections. Once an adrenal mass is detected, the clinician needs to address two crucial questions: is the mass malignant, and is it hormonally active? This article provides an overview of the diagnostic clinical approach and management of the adrenal incidentaloma. Mass size is the most reliable variable to distinguish benign and malignant adrenal masses. Adrenalectomy should be recommended for masses greater than 4.0 cm because of the increased risk of malignancy. Adrenal scintigraphy has proved useful in discriminating between benign and malignant lesions. Finally, fine-needle aspiration biopsy is an important tool in the evaluation of oncological patients and it may be useful in establishing the presence of metastatic disease. The majority of adrenal incidentalomas are non-hypersecretory cortical adenomas but an endocrine evaluation can lead to the identification of a significant number of cases with subclinical Cushing's syndrome (5-15%), pheochromocytoma (1.5-13%) and aldosteronoma (0-7%). The first step of hormonal screening should include an overnight low dose dexamethasone suppression test, the measure of urinary catecholamines or metanephrines, serum potassium and, in hypertensive patients, upright plasma aldosterone/plasma renin activity ratio. Dehydroepiandrosterone sulfate measurement may show evidence of adrenal androgen excess.

[Comparison between the diagnostic accuracy in diagnosis of thyroid nodules with fine needle biopsy an intraoperative histological evaluation of frozen tissue]. / Raffronto dell'accuratezza diagnostica nella diagnosi dei noduli tiroidei fra biopsia con ago sottile e valutazione istologica intraoperatoria su tessuto congelato.

BACKGROUND: The aim of this study was to compare the diagnostic accuracy of fine needle biopsy (FNB) and intraoperative frozen-section biopsy (FS) regarding the surgical management of thyroid nodules. METHODS: A total of 812 patients with solitary nodule or dominant nodule in a multinodular goiter were evaluated. The patients underwent preoperative FNB and intraoperative FS diagnosis. RESULTS: The definitive histological diagnosis (HD) was: i) 222 malignant lesions (118 papillary, 67 follicular, 16 anaplastic and 8 medullary cancers); ii) 590 benign lesions. FNB accuracy was 90.6%, sensitivity 96.8% and specificity 87.1%. FS accuracy was 97.4%, sensitivity 91.3% and specificity 100%. False negative (FN) were 10 for FNB and 21 for FS. False positive (FP) were 74 for FNB and 0 for FS. FS was less sensitive for the diagnosis of papillary cancer (more FN) and more specific for the diagnosis of follicular thyroid cancers (no FP). CONCLUSIONS: In conclusion, FS is useful in patients undergoing surgery for a thyroid nodule having a "suspicious" cytology. It adds no information in patients with an FNB diagnosis of malignancy and is of limited use in those in whom an FNB benign lesion is diagnosed.

TGF-beta 1 immunohistochemistry in goiter: comparison of patients with recurrence or no recurrence.

The aim of this work was to establish whether the immunohistochemical pattern for TGF-beta 1 in goiters that recur after thyroid surgery is different when compared with goiters that do not recur postoperatively. Twelve goiters, surgically removed by partial resection between 1977 and 1982, were studied. Ten years after surgery, 6 patients had recurrence of goiter or thyroid nodules (group 1); the others did not have any recurrence (group 2). The presence and location of TGF-beta 1 were evaluated a posteriori by immunohistochemistry in histological samples of the tissue that was removed. In each goiter specimen, 50 randomly selected subcapsular follicles were studied to evaluate the percentage of follicles negative or positive for TGF-beta 1 and the protein's intrathyrocyte location. In the slides of group 1, the percentage of TGF-beta 1-positive follicles was statistically (p < 0.01) greater (93.1%) than in group 2 (71.4%). No difference in the location of TGF-beta 1 was found. The authors found a greater percentage of positive follicles for the TGF-beta 1 protein in group 1 patients. In conclusion, TGF-beta 1 production in goiter is variable, time dependent, and may be a marker of active cellular proliferation due to chronic exposure to a goitrogen stimulus. Thus, the more TGF-beta 1 found, the more the cell is stimulated and, therefore, the greater the risk of relapse.

TGF beta 1 immunostaining patterns and locations in adenoma which later recurred.

To investigate whether the immunohistochemical pattern of TGF beta 1 may be a marker of relapse for adenomatous pathology, 18 follicular adenomas, surgically removed by hemithyroidectomy between 1977 and 1982, were studied. The adenomas were divided into two groups according to the presence (group 1, N = 9) or absence (group 2, N = 9) of nodules recurring in the residual thyroid tissue. The presence and location of TGF beta 1 were evaluated a posteriori by immunohistochemistry in the removed adenoma. Fifty randomly selected subcapsular follicles were studied in each adenoma in order to evaluate the percentage of positive follicles and TGF beta 1 intra-thyrocyte location. In adenoma of group 1, the percentage of positive follicles for TGF beta 1 was lower (80%) than in adenoma of group 2 (84%); this was, however, not statistically significant. The location of TGF beta 1 was mainly at the cell base of the epithelial cells in the microfollicles of group 1, but was dominant at the cell apex in group 2 (p < 0.01). In conclusion, adenoma recurrence is independent of TGF beta 1 production; it may be due to an abnormal TGF beta 1 regulation in response to hyperplasiogenic stimuli.

[Evaluation of the role of repeat needle biopsy in the diagnosis and follow-up of thyroid nodules]. / Valutazione del ruolo della ripetizione dell'agoaspirato nella diagnosi e follow-up del nodulo tiroideo.

The goal of the present study was to determine in what percentage of cases was an initial benign cytological diagnosis modified to malignant or suspicion of malignancy by a second aspiration biopsy. The study group consisted of 708 patients, 98 males and 610 females, mean age 46.3 +/- 13.7; FNB was always repeated on the same nodule. The first FNB (cytology I), classified the nodule as: non-diagnostic (group I, 205 cases) or diagnostic (group II, 503 cases); these latter were classified as benign (471) or suspect (32). In 82 cases of group I the second examination after six months (cytology II) was still unable to arrive at a diagnosis; in the remaining 123 cases, it was able to classify 120 as benign and 3 as suspect (the latter being followed up by diagnostic surgery). In group II, cytology II modified the initial diagnosis from benign to suspect (8 cases) or non-diagnostic (7 cases). On the other hand, 29 cases had a change of their initial diagnosis from suspect to benign. The remaining cases of group II repeated a thyroid FNB after one year (cytology III) with a result of benign (486) or non-diagnostic (6). In the 14 cases followed up by diagnostic surgery, due to a second biopsy diagnosis of suspicion, histology showed the presence of Follicular Adenoma in 12 cases and Hashimoto's Thyroiditis in the remaining 2. Based on follow-up surgery, the suspicious lesions seen on the second biopsy turned out to be all non-malignant. However, it is important to underline the greater number of cases where the second examination gave a benign diagnosis when the first examination was judged suspicious. One can conclude that it may be useful to repeat FNB: 1) when the first exam resulted in an inadequate sample, as a second biopsy allows one to classify the nodule 60% of the time; 2) in all cases where there is an initial benign diagnosis, when non-surgical follow-up (clinical and/or echographic) is suspicious.

[Cytological diagnosis of thyroid nodules. Comparison of results obtained with guided echography with those from of a "blind" biopsy]. / Diagnosi citologica dei noduli tiroidei. Comparazione dei risultati ottenuti con guida ecografica rispetto a quelli ottenuti a "cielo coperto"

The goal of the study was to verify if echographic fine needle biopsy (US-FNB) improved the diagnostic accuracy of thyroid nodules with respect to a "blind" technique (B-FNB). The study group involved 6,693 patients who underwent aspiration biopsies (989 males and 5,704 females; mean age 46.3 +/- 13.7; range 5-88 years). Total biopsies were 7,952 as some patients underwent two or more biopsies in different nodules. 7,324 nodules with B-FNB and 628 nodules with US-FNB were studied; in this latter cases 136 nodules were not palpable. The diagnosis of malignancy was higher in US- FNB than B-FNB. However, non-diagnostic samples were more prevalent in US-FNB with respect to B-FNB. A histological diagnosis was available in 27 patients with US-FNB and 379 with B-FNB. In US-FNB, accuracy was 81.8%, sensitivity 86.6% and specificity 77.7%. In B-FNB, accuracy was 80.6%, sensitivity 85.1% and specificity 78.1%. These data show that US-FNB diagnostic accuracy was not better than B-FNB. The higher incidence of malignancy found in US-FNB was not dependent on better accuracy, sensitivity or specificity of the US-FNB technique with respect to the B-FNB examination. It is possible that the higher number of malignancies in patients studied with US-FNB was due to the fact that the US-FNB technique aspirated smaller nodules and particular areas of echographic suspicion, thus increasing the possibility of finding a malignancy. Based on our data, we feel that US-FNB results in a greater number of diagnostically inadequate samples. This may depend in part on the smaller size of the biopsied nodules (which are relatively more vascular than larger nodules) and in part on the greater difficulty in carrying-out this technique which directed towards particular echographic areas of suspicion resulting in greater biopsy blood contamination. The authors feel that US-FNB should be carried-out in all cases of non-palpable nodes found incidentally so as to rule out malignancy.

Enhanced expression of transforming growth factor beta1 in rat thyroid hyperplasia is thyrotropin induced and time dependent.

Forty-three 8-week-old male Wistar rats were studied to evaluate temporal changes of transforming growth factor beta1, (TGF-beta1) mRNA levels in thyroid tissue during pharmacologically induced goiter. Four rats were treated with purified bovine thyrotropin (TSH; Ambinon, 2 mU/day sc) for 7 days before being sacrificed. Thirty-one were treated with propylthiouracil (PTU), added to their drinking water at a concentration of 0.2 g%, and subsequently were sacrificed as follows: five after 1 week (PTU-1): five after 2 weeks (PTU-2); five after 4 weeks (PTU-4); five after 8 weeks (PTU-8); five after 12 weeks (PTU-12). In six rats, after 12 weeks of treatment. PTU was withdrawn for 2 months and subsequently started again in three rats which were sacrificed after 2 weeks (PTU-R); the remaining three rats were sacrificed without any further treatment (PTU-R control). Eight rats (control rats) were never treated and served as controls. After sacrifice, blood was drawn for determination of total thyroxine and the thyroid was excised and subdivided into two lobes. Northern analysis for TGF-beta1 was performed in one lobe. while histological and immunohistochemical studies were performed in the other lobe. Gene expression of TGF-beta1 was induced in TSH- and PTU-treated rats. In TSH-treated rats TGF-beta1 gene expression was less detectable than in PTU-treated rats, where it became evident after 2 weeks and remained through weeks 4-8. Gene expression of TGF-beta1 wits also seen in PTU-R rats, but not in the control and in the PTU-R control. Immunohistochemical analysis showed a different presence and location for the TGF-beta1 protein, which appears to be dependent on the time of exposure to mitogenic stimulus. In conclusion, TGF-beta1 is produced in response to both a direct (TSH by itself) and indirect (TSH induced by PTU-induced hypothyroidism) cellular proliferative stimulus and is not linked to an adaptative phenomenon secondary to hypothyroidism. The immunohistochemical location of TGF-beta1 within the thyrocytes is influenced by mitogen exposure time. A TGF-beta1 immunohistochemical evaluation may be important to define exposure time and activity of goitrogenic stimuli.

[Echo Doppler in the characterization of thyroid nodular disease]. / L'eco Doppler nella caratterizzazione della patologia nodulare tiroidea.

This study was aimed at investigating role and efficacy of color-Doppler US in the characterization of thyroid nodules. Eight-three consecutive patients with only one solid thyroid nodule, not smaller than 0.8 cm, were examined. They were submitted to scintigraphy and laboratory tests first and then to color-Doppler US, to fine-needle biopsy and/or to histologic examinations. Color-Doppler US examinations were performed with a 7.5 MHZ linear probe, 5-MHz Doppler frequency, PRF = 0.8 KHz, 40-50 degrees insonation angle, wall filters at the lowest level, 2-5 mm sample volume, color and Doppler gains set at 30-50% and asynchronous data collection. The final diagnosis, made at cytology and/or histology, showed 43 follicular hyperplasias, 19 follicular adenomas and 21 carcinomas. The following US variables were considered: nodule size, site, margins and the possible presence of the "halo sign" pattern, with a special attention paid to micro-/macrocalcifications, signs of invasion of surrounding anatomic structures and possible adenopathies. With color-Doppler US, we studied presence and distribution of nodular vascularization, peak (Vp) and middle (Vm) velocity, resistive index (RI) and Doppler spectrum morphology. In agreement with the current literature, 3 patterns of nodular vascularization were considered: not apparent, or type I (3/83), which was found only in follicular hyperplasia; peripheral, or type II (46/83) and finally, peri- and intranodular, or type III (31/83). Hyperplasias exhibited a type I pattern rarely and exclusively and, if vascularized, they always exhibited Vp < 50 cm/s, Vm < or = 40 cm/s and mostly (39/40 RI < or = 0.75; adenomas were always vascularized, with Vp > 50 cm/s and mostly (18/19) RI < or = 0.75; primary or secondary tumors were always vascularized, with an extremely variable distribution, and if Vp < 50 cm/s, their RI > 0.75, while if Vp < 50 cm/s, their RI was independent of the threshold value of 0.75. These preliminary conclusions seem to confirm that vascular patterns alone are not particularly helpful, compared with B-mode US results, in distinguishing among thyroid nodules. Nevertheless, Vp and RI may be of great usefulness in the characterization of solid nodules and in the selection of the patients to submit to fine-needle biopsy.

[Anti-microsomal, anti-thyroglobulin antibodies and thyroid stimulants in hyperthyroid subjects. Analysis of 315 patients followed-up for 3 years at a single medical center]. / Anticorpi anti micrsomi, anti tireoglobulina e tiroido stimolanti in soggetti ipertiroidei. Analisi di 315 pazienti seguiti per tre anni presso un unico centro medico.

The objective of the study was to evaluate the significance of the determination of antithyroid antibodies in hyperthyroid patients. Two-hundred-fifteen untreated Graves' hyperthyroid patients (active toxic diffuse goiter-TDG), 54 Plummer's hyperthyroid patients (focal hyperthyroidism) and 46 subjects with other forms of hyperthyroidism were studied. Serum levels of T4, T3, TSH, TSH receptor antibody (TRAb), microsomal antibody (TMAb), and thyroglobulin antibody (TGAb) were evaluated before starting treatment, at regular intervals during therapy, and during the follow-up period after therapy was withdrawn. The antibodies were positive in all patients with active and non-active TGD but positive in only two patients (3.7%) with focal hyperthyroidism. During the treatment interval, TRAb, TMAb and TGAb serum levels fell with a nadir in the 7th month of therapy. In particular, TRAb fell to normal levels in all patients who had basal levels less than 500 U/l (97.7% of the cases) while TMAb and TGAb remained positive. Relapses, following the completion of therapy, occurred in 20.4% after one year and in 33% after two years. Relapses were always linked to a new increase in TRAb. In conclusion, TRAb can be useful in the determination of early disease and in diagnosing remission. It did not appear useful as a prognostic indicator for relapse in individual patients.

Decreased expression of insulin-sensitive glucose transporter mRNA (GLUT-4) in adipose tissue of non-insulin-dependent diabetic and obese patients: evaluation by a simplified quantitative PCR assay.

Impaired cellular uptake and utilization of glucose is the hallmark of non-insulin-dependent-diabetes (NIDDM). We have developed a quantitative assay to probe the expression of glucose-transporter genes in tissues derived from patients with NIDDM. Using the polymerase chain reaction (PCR), we assessed levels of expression of the insulin responsive glucose transporter GLUT-4 in adipose tissue of patients with NIDDM and in obese patients. We report that expression of GLUT-4 is reduced in NIDDM and in obesity associated with hyperinsulinemia and insulin resistance. These results suggest that reduction of GLUT-4 levels in the adipose cell plays an important role in the pathogenesis of insulin resistance, an early feature of NIDDM.

Transforming growth factor-beta 1 is more expressed in thyroid follicular adenoma than in normal tissue.

It is well known that TSH is the main factor responsible for thyrocyte proliferation and growth. Recent studies have shown that other growth factors, including transforming growth factor-beta 1 (TGF-beta 1), have an important role in the control of thyrocyte proliferation and differentiation. The aim of the study was to evaluate the expression of the TGF-beta 1 gene in thyroid follicular adenoma (FA) by Northern analysis, and its protein localization by immunohistochemistry. Surgically removed thyroid tissue from 56 patients with thyroid FA was screened for the study. Normal thyroid tissue from 4 patients with papillary carcinoma was used as a control. Sixteen FA (8 with a "cold" and 8 with a "hot" scintiscan pattern) having homogeneous histological characteristics were subsequently selected. FA showed greater TGF-beta 1 gene expression than control tissue. There was not a statistically significant difference between "cold" and "hot" FA. Immunohistochemistry analysis showed that TGF-beta 1 was located in various histological structures of the adenomas (thyrocytes, endothelium, perinervium and connective tissue); on the other hand, perinodular and control tissue did not show appreciable TGF-beta 1 protein. Our data suggest that TGF-beta 1 may be involved in the pathogenesis of FA. The different TGF-beta 1 distribution in thyrocytes, endothelium, perinervium and connective tissue in FA suggests that TGF-beta 1 may be variably expressed during the natural history of FA. Since no significant difference in TGF-beta 1 gene expression between "hot" and "cold" adenomas was found, it appears that other factors are involved in their functional differentiation.

[Follow-up of a population of patients who underwent partial thyroidectomy for benign thyroid pathology]. / Follow-up di una popolazione di pazienti sottoposti a tiroidectomia parziale per patologia tiroidea benigna.

Natural history of partial thyroidectomy for thyroid disease has been studied in a population of 1196 consecutive cases surgically treated from 1977 to 1982. Follow-up analysis on this population (from six to eleven years) was carried out for appearance of recurrence. Generally, the recurrence incidence was small (only 9.9% of total population) but high frequency was observed for Graves' disease (46%) and lymphocytic chronic thyroiditis (21%). The substitutive/suppressive therapy administration did not influence recurrence of disease. Our results suggest that suppressive therapy does not modify the natural course of non cancerous thyroid pathology residual to partial thyroidectomy.

[Hypothalamic amenorrhea. Different patterns in the pulsatile secretion of LH during 24 hours and different responses to the stimulation test with GnRH]. / Amenorrea ipotalamica. Differente comportamento della secrezione pulsatile di LH nelle 24 ore e differenti risposte al test di stimolo con GNRH.

In 12 patients with hypothalamic amenorrhea and in 5 normal women, plasma gonadotropins (LH and FSH) were assayed before and 20, 30, 60, and 120 minutes after stimulation with 10 mcg GnRH i.v. and 24 hours after stimulation with 100 mcg GnRH i.v. In four patients and in controls the pulsatile secretion of LH was evaluated by blood sampling at 15 minute intervals for the 24-hour period. All patients showed different increases in LH after administration of 10 mcg and 100 mcg at 60 and 120 minutes. In two patients, with decreased LH pulse frequency, the gonadotropin increase is dose-dependent in respect to GnRH. In the other two, with normal LH pulse frequency, no difference was shown. In conclusion, this study suggests that the mechanism responsible for amenorrhea is due to reduced frequency of pulsatile GnRH secretion. However, in some patients LH pulse frequency was within the normal range. The double GnRH test (10 or 100 mcg) may be useful in distinguishing these different forms of amenorrhea.