The widened use of exogenous stimulation with recombinant human TSH to treat metastatic thyroid carcinoma in Italy.

Recently, in Italy, the reimbursement for the use of rhTSH in preparing patients for radiometabolic treatment of iodine-avid metastases from differentiated thyroid cancer has been made possible. Intramuscular administration of rhTSH increases the radioiodine uptake and thyroglobulin production by thyroid cells. In addition to the previous indications on the use of rhTSH (mainly: serum thyreoglobulin assay with or without 131I scintigraphy and ablation with 131I of remnants in low risk patients), the reimbursement is now allowed for the treatment with radioiodine of iodine-avid loco-regional and distant metastases, in subjects with inability to reach adequate TSH levels and/or severe clinical conditions which could be potentially worsened by other concurrent diseases (history of stroke or transient ischemic attack, severe cardiac disease, renal failure or major psychiatric disorders). The Italian Medicines Agency (AIFA) approved this use (and added this hormone in the special list of drugs regulated by the D.Lgs 648/96) on the basis of a series of scientific evidences, proposed by a "team of experts". In the present paper we illustrate the scientific background of the use of rhTSH (clinical usefulness, economic considerations, aspects related to a better quality of life) that allowed the modification of the reimbursement and how it was made possible in the Italian legislative context.

[Radiometabolic therapy for metastatic thyroid carcinoma: overview of the literature and rational bases for the use of recombinant human TSH]. / La terapia radiometabolica del carcinoma della tiroide metastatico: overview della letteratura e basi razionali all'utilizzo del TSH umano ricombinante.

The established treatment for differentiated thyroid carcinoma (DTC) is founded on total thyroidectomy and subsequent administration of radioiodine (131I) to ablate the thyroid remnant and to treat the metastatic disease. In the case of metastatic or recurrent disease, further cycles of 131I therapy are often necessary. The condition for maximizing the effectiveness of the treatment is to have an adequate stimulation from TSH, which must be >25-30 mIU/L. This elevation is achieved either discontinuing the hormone suppression therapy for an appropriate period, or administering recombinant human TSH (rhTSH). The latter has shown good clinical efficacy in patients with residual thyroid gland and is nowadays commonly employed since it is easy to use and allows to avoid the side effects of hypothyroidism. It thus represents a good alternative to thyroid hormone withdrawal for the remnant ablation, while is still open the question if its efficacy on the management of metastatic disease is superimposable to thyroid hormone withdrawal. To this purpose, a Panel of expert reviewed the literature, assessing the advantages and disadvantages for the patient, as well as the impact in terms of cost and benefit to the National Health Service. The work of the Panel concluded with a proposal for the use of rhTSH in selected patients with metastatic DTC, in which is considered the efficacy and safety of the product and is examined its use in terms of costs; this proposal was accepted by the Italian Drug Agency resulting in an update of the indications for rhTSH.

Sentinel lymph node and breast cancer staging: final results of the Turin Multicenter Study.

AIM OF THE STUDY: Validation of the sentinel node (SN) technique in breast cancer by means of lymphoscintigraphy. MATERIALS AND METHODS: From December 1996 to January 1999 102 T1-T2 breast carcinoma cases were recruited in Turin. 99mTc-human serum albumin colloids were injected subdermally the day before surgery (mean activity, 5.2 +/- 2.5 MBq). Scintigraphic imaging was performed after injection. After identification of the SN during surgery by a hand-held gamma probe, the SN was excised and sent for histologic examination. SN histology was compared with that of other axillary nodes. RESULTS: The SN detection rate was 86.3%; among 88 cases with an identified SN, 37 (42%) had axillary metastases; the SN was metastatic in 35 cases (sensitivity, 94.6%); in 51.3% of pN+ cases (19/37) the SN was the only metastatic site. In two of the 53 negative SNs, SN histology did not match with that of the remaining axilla (negative predictive value, 96.2%; staging accuracy, 97.7%). CONCLUSIONS: Our results agree with those reported in the literature; however, except in clinical trials and experienced structures axillary lymph node dissection should not be abandoned when mandatory for prognostic purposes, considering that at present SN biopsy alone is not completely accurate for axillary staging, especially in the absence of an adequate learning period.

Cortisol in human tissues at different stages of life.

Aim of the work was to measure the cortisol level in human tissues at different stages of life, by means of radioimmunoassay and by chromatography. Viable samples of 13 different tissues were obtained during surgical intervention from 30 to 70 years old patients of either sex. Mean tissue cortisol concentration was 78 +/- 35 ng/g, ranging from 20 +/- 10 ng/g in the thyroid to 124 +/- 76 ng/g in the kidney. Similar values were measured in the corresponding tissues from not decayed corpses, so that paired values could be mediated. However the pancreas, and corrupted autopsy tissues, gave nil or exceedingly high cortisol concentration values; in some cases, opposite extreme values were measured in different organs of the same body. Cortisol concentration was also measured in 11 sound different tissues of spontaneously aborted or stillbirth fetuses, between 16 and 36 weeks of gestation. Mean value was 63 +/- 27 ng/g, ranging from 30 +/- 25 ng/g in the liver to 104 +/- 52 ng/g in the lungs. Also in fetuses nil or exceedingly high cortisol values occurred in altered tissues. One hundred and fourteen samples of limbs and carcasses of 7 to 12 gestational weeks embryos, obtained from voluntary abortions, were also examined: 20% gave nil result, in the remaining mean cortisol concentration was 32 ng/g. In 33 samples of embryos' mixed viscera, RIA and chromatography gave unreliable exceedingly high values. The nil and the exceedingly high values measured in the altered autoptic tissue specimens were inconsistent with the cortisol blood level measured in the patients, as were those measured in embryonic tissues with the acknowledged blood and adrenals cortisol levels at that stage of life. Thus cortisol may be measured by RIA and by chromatography in sound tissues, while the values obtained in the pancreas, in corrupted tissues, and in embryonal viscera do not represent the hormonal milieu, but are likely artifacts due to impeachment of the diagnostic system.

Immunolike growth hormone substance in tissues from human embryos/fetuses and adults.

GH immunolike reactivity was measured by RIA and IRMA tests in the extracts of tissues from human fetuses (8-32 weeks) and adults. For some fetal tissues a comparison was made with the T4 values obtained in a previous study. Both hormones were already measurable in peripheral tissues at 8 weeks of gestation. The increase in GH was faster than for T4 and it reached the zenith at approximately 20 weeks; thereafter, the GH concentration declined until delivery. In contrast, T4 progressively increased until term. Thirteen tissues were studied both in fetuses and in adults: the GH concentration was about 10 times higher in fetal tissues, with the exception of the brain and the pancreas. The brain showed the lowest GH concentration throughout fetal life and adulthood, whereas the highest GH levels were recorded in adults' pancreas, but they resulted to be artifacts since the RIA values were not confirmed by the IRMA test. In both groups of subjects the highest GH concentrations were found in kidneys, liver and small intestine; the lowest, beyond the brain, in red muscle and cartilage. Thus, the pattern of the quantitative distribution of GH in fetal tissues is the same as in adults, suggesting a functional role of the hormone in the developing human during the prenatal period, in contrast with the concept that high tissue levels of GH are a mere reflection of high GH blood levels. Moreover, in all tissues examined no correlation was found between GH and T4 concentration.

Thyroid hormones in tissues from human embryos and fetuses.

This study was intended to quantify T3 and T4 in various human tissues at different stages of gestation as a contribute in the evaluation of the role of thyroid hormones in fetal development, particularly before the maturation of fetal thyroid function. Moreover, for a better comprehension of the influence of thyroid hormone status in tissues, the study was extended to adults. Embryonic specimens were obtained from voluntary abortions between 6 and 12 weeks of gestation, fetal and neonatal specimens from fetuses and neonates between 15 and 36 weeks of gestation after spontaneous abortion or stillbirth, and adult specimens from men (age range: 45-65 years) after death for cardiovascular diseases. Thyroid hormones were measured by the method of Gordon and coworkers. In embryos T3 and T4 were measured in limbs, carcasses, brain and liver: considering all values measured in the period 9-12 weeks, a mean concentration of 0.11 ng/g for T3 and 1.28 ng/g for T4 was obtained. In pooled limbs of 6-8 weeks T3 was barely measurable (0.01 ng/g). In the carcasses there was an increase in T3 and T4 concentrations of 40 and 20 times respectively from the 9th to the 12th week, when thyroid follicles organization takes place. In fetuses and adults T3 and T4 were measured in brain, heart, kidney, liver, lung, skeletal muscle and skin (mean concentrations: 0.86 ng/g for T3 and 7.44 ng/g for T4 in fetuses and neonates; 1.36 ng/g for T3 and 12.75 ng/g for T4 in adults). Hormones concentration increased with gestational age; the T3/T4 ratio increased until 22-24 weeks, when the prevalent increment in T4 occurs. T3 concentration up to 30 weeks was generally higher in tissues than in cord serum of the corresponding age. During the last month of gestation T3 increment was faster in serum. T4 level was always predominant in serum. In conclusion, T3 and T4 have been detected in the limbs of embryos before the onset of thyroid hormone secretion. Concentrations were 1/150 and 1/70, of the normal maternal blood values respectively. It is conceivable that these hormones are of maternal origin, and the question of whether such small quantities may play a role in fetal development is open.

[Metastasis of thyroid carcinoma. A rare case of secondary renal tumor]. / Metastasi da carcinoma tiroideo. Un raro caso di tumore secondario del rene.

Secondary tumours of the kidney are becoming an increasingly frequent pathology due to the accurate follow-up and longer survival of cancer patients. The paper reports a rare case of renal metastasis from a thyroid carcinoma, which started as a Hürthle cell adenoma and was transformed into a carcinoma with a follicular appearance after 26 years. The suspicion of a secondary site was based on the high serum levels of HTG (human thyroglobulin); metastasis was identified following scintigraphic tests using a dual marker (99mTC, 201TL) and renal scintigraphy with 123I Hippuran. The definitive diagnosis was obtained following histological tests; conservative surgery was performed to treat the metastasis (tumorectomy with removal of healthy pericapsular tissue).

Serum autoantibodies and thyroid lymphocytic infiltration in endemic goitre.

Patients with thyroid diseases from areas of endemic goitre in Northern Italy were examined for thyroid antibodies by passive haemoagglutination. Of 40 schoolboys with goitre only one had thyroid antibodies (AT) in the blood. Among 182 adults with grade 1-2 goitre, examined within an area of low endemia, the frequency of AT was 7%, not significantly different from that found in the 286 persons with thyroid 'O' living in the same area. Among 181 adults with grade 2-3 goitre, examined within an area of serious endemia, the frequency of AT was 16%; the percentage went up to 24% in 144 patients operated on for goitre. AT frequency was 36% in 87 patients with toxic goitre, more than 70% in 97 patients with Graves' disease and 17% in 60 patients with cancer of the thyroid. AT occurred three times more frequently in women than in men. Microsomal antibodies were more frequently detected than anti-thyroglobulin antibodies: the opposite was true in thyroid cancer. Lymphocytic infiltration (IL) of the gland was observed in 45% of the 464 simple goitres and in 52% of the 60 cancers of the thyroid: it was more frequent and intense in women. Among the 144 patients operated on for goitre the frequency and the titre of AT progressed in parallel with the intensity of the lymphocytic infiltration. Patients with a greater lymphocytic infiltration and higher AT had a higher TSH. Multinodular non-toxic goitre and autoimmune lymphocytic thyroiditis can be present in the same thyroid gland and the clinical expression will depend on which condition predominates.

Iodine content of human tissues after administration of iodine containing drugs or contrast media.

Total iodine contents were determined in 209 bioptic or autoptic specimens of various extrathyroidal tissues. Fifty-two of the 80 subjects examined had no previous exposure to excessive iodine, 24 were tested after administration of x-ray contrast media and 4 after treatment with various iodine containing drugs. Unexposed subjects had tissue iodine contents (mean +/- SD) ranging from 0.85 +/- 0.17 microgram/100 g in the brain and 9.78 +/- 2.75 microgram/100 g in the liver of adults. A significantly lower iodine concentration was found in the liver of newborns (2.79 +/- 1.00 microgram, p less than 0.001). Most of the other tissues had iodine concentrations of 2-4 microgram/100 g. Subjects with previous exposure to iodine containing drugs or x-ray contrast media showed increased iodine contents of various degree in all examined tissues, including adipose tissue, bone, brain, kidney, liver, lung, skeletal muscle, skin and spleen. Accumulation of iodine in adipose tissue was still demonstrable more than two years after cholecystography.

[Frequency of goiter and urinary iodine in the Peidmont school children. Data on iodine contents in some local food]. / Frequenza del gozzo e valori di ioduria negli scolari del Piemonte. Dati sul contenuto iodico di alcuni alimenti locali

The frequency of thyroid alterations was examined and dietary iodine intake was assessed via urinary iodine in 6-15 yr-old schoolchildren from 145 towns in Piedmont and the Aosta Valley. Local food iodine values were also determined in 56 towns. Alteration frequency and daily urinary elimination of iodine were inversely proportional, even within individual school populations. The endemic goitre urinary iodine threshold (around 40-50 mug I/g creatine) varied from area to area, with as much as double this value in some instances. Drinking water iodine was usually from 0 to 3 mug/l, with relatively low values in high localities. Much higher levels were noted in the presence of salsobromoiodic hot springs. Local Piedmontese foods contained less iodine than those bought in city markets.