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.

Diagnostics of neuroendocrine tumours.

Neuroendocrine tumours (NETs) are rare pathologies which origin from neuroectodermic and endodermic cells and that can produce peptides and amino acids. About 70% of NETs derive from gastroenterohepatic (GEP) system and the other 30% from the different sites through the body. They are distinguished into single and multiple localizations and also into sporadic, familial multiple endocrine-related forms and recurrent forms. Moreover, when they produce hormones they usually are symptomatic; yet, they are characterized by the synthesis and secretion in the blood stream of several tumor-specific markers or can express somatostatin receptors in their cellular surface. The diagnosis and follow-up of NETs rely on laboratory studies, histopathology and the combination of anatomical and functional imaging, with the latter being the main method for monitoring response to therapy. In recent years, nuclear medicine has contributed to the impressive development of the knowledge of NETs in terms of biology (receptor scintigraphy), pharmacology (development of new tracers) and therapy (radiometabolic therapy). Nuclear medicine procedures for diagnosis and treatment of NETs are based on the biological properties of these tumours: the expression of somatostatin receptors. Somatostatin receptor scintigraphy not only has a crucial role in diagnosis and staging of NETs, but also in assessing suitability for treatment with cold and radiolabelled somatostatin analogues, as well as in monitoring response to treatment and detecting recurrent disease. In conventional nuclear medicine, the two most important functional imaging modalities are ¹¹¹In-octrescan and ¹²³I-MIBG. Over the last 5 years, due to the development of new tracers, such as 68Ga labelled-DOTA-peptides PET and ¹8F-DOPA, PET has also been employed with significant benefits in the diagnosis and management of NETs.

Review. 18F-FDG PET in the diagnosis and follow-up of thyroid malignancy.

The diagnosis of carcinoma of the thyroid is usually made in the process of investigating a thyroid nodule with clinical examination, Technetium-99m scan, ultrasonography and fine-needle aspiration (FNA) cytology. The follow-up is mainly based on 123-iodine and 131-iodine scans and serum thyroglogulin measurement. The aim of the present review was to establish the role of 18F-FDG PET in the differential diagnosis of doubtful thyroid nodules and in the follow-up of patients with increased serum thyroglobulin levels and negative iodine-scan. It remains to be defined if metabolic imaging with PET could be a useful routine procedure in the management of thyroid tumours since the majority of them are well-differentiated and therefore have less avidity to 18F-FDG. In the present work we collected the specific literature derived from MEDLINE over the last 10 years to clarify the potential clinical value of 18F-FDG PET in thyroid malignancies. An emerging role for 18F-FDG PET is in the assessment of incidental finding of a thyroid nodule which, when showing high FDG uptake should be regarded as a possible malignancy that needs further assessment. Another well-documented role for 18F-FDG PET is in the investigation of cases of established well-differentiated thyroid carcinomas presenting with high thyroglobulin and negative iodine imaging. An increase of the 18F-FDG uptake in these tumours indicates a shift towards lesser differentiation (with more aggression and poor prognosis) and may benefit from alternative management. 18F-FDG PET can be considered a routine functional imaging method in detecting iodine-negative recurrent disease in thyroid cancer patients with elevated serum thyroglobulin levels during follow-up. 18F-FDG PET seems to be useful also in differential diagnosis of suspected thyroid nodules, especially using the semi-quantitative SUV analysis.

The role of 18F-FDG PET/CT in detecting metastatic deposits of recurrent medullary thyroid carcinoma: a prospective study.

AIM: To assess the diagnostic role of 18F-FDG PET/CT performed with a hybrid tomograph in the detection of tumoral deposits of recurrent medullary thyroid carcinoma (MTC). METHODS: Nineteen MTC patients with elevated serum calcitonin levels (58-1350 pg/ml) after first treatment were enrolled (11 F, 8 M, mean age 53.4 years, 14 sporadic MTC, 5 MEN-related MTC). All patients had previously undergone total thyroidectomy and lymphoadenectomy. When referred to us, they were studied with ultrasound (US), 18F-FDG PET/CT, (111)In-pentetreotide scan, and contrast-enhanced whole-body CT (c.e. CT). In 4 patients with equivocal abdominal findings at 18F-FDG PET/CT and/or at c.e. CT, laparoscopy was also performed. RESULTS: 18F-FGD PET/CT depicted metastases in 15 patients, 111In-pentetreotide in 8, c.e. CT in 11, US in 6. In 2 patients, liver micrometastases were detected at laparoscopy only. At a lesion-by-lesion analysis, 18F-FDG PET/CT visualized a total of 26 metastatic deposits, c.e. CT 18, 111In-pentetreotide 12, US 8. Final diagnosis was obtained by cytological or surgical findings. Four patients with evidence of limited metastatic spread to neck/upper mediastinum were re-operated, and in 2 of them serum calcitonin levels normalized. CONCLUSIONS: In our study, 18F-FDG PET/CT was the most sensitive imaging modality in detecting metastases in recurrent MTC patients with increased serum calcitonin levels. Moreover, 18F-FDG PET/CT was useful in some patients to plan a more accurate re-operation. From a diagnostic point of view, a multimodality imaging approach is recommended in recurrent MTC, especially based on the combination of c.e. CT and 18F-FDG PET/CT.

[PET/CT and thyroid carcinoma]. / La PET/CT nel carcinoma della tiroide.

In the present review we discuss the indications and clinical results of positron emission tomography (PET) in patients affected by differentiated thyroid cancer. It is well known that in this type of tumor the most used scintigraphy is based on 131-Iodine or 123-Iodine administration. However, a fraction of these tumors looses its capability to trap radioactive Iodine (this usually happens after multiple 131-Iodine treatments). This Iodine-negative- tumors are more frequently observed in the elderly and are characterized by a higher aggressiveness. Due to the poor clinical results of external radiotherapy and chemotherapy surgery remains the treatment of choice. Surgery can be performed with curative purposes also if the metastatic spread is visualized in an early phase. Among the various scintigraphic and radiologic techniques used, PET and PET-CT are reaching an even more important role in the early diagnosis of small tumoral deposits of thyroid cancer. The other issue we discuss in the present review is the potential value of PET and PET-CT in the differential diagnosis of suspected thyroid nodules.

[(111)In]Pentetreotide SPECT scintigraphy in neuroendocrine tumors: variability of reconstructing parameters related to patient characteristics and each body part.

AIM: Multi-headvariable-geometry gammacamera, allow us to carry out multi-dimensional scintigraphic single photon emission computed tomography (SPECT) studies, with the possibility of creating coronal, axial, sagittal, three-dimensional images like the last generation of multi-slice RMI or multislice CT scan. The aim of this paper is to weigh up the reconstruction parameters to apply in [(0111)In]Pentetreotide scintigraphy for evaluating neuroendocrine tumors and try to standardize them. METHODS: We have studied a group of 93 patients suffering from neuroendocrine tumors. Examination was carried out after administration of [111In] Pentetreotide with whole body and static acquisitions after 4 and 24 h, followed by SPECT acquisitions of head, thorax and abdomen after 24 h. RESULTS: The results obtained show that the Filtered Back Projection using Butterworth filter can produce images of greater resolution than the iterative reconstruction method. Moreover, the reconstruction parameters are easily standardizable for head and thorax while for the abdomen the choice of these parameters is more difficult. CONCLUSIONS: Our data show that filtered back projection with Butterworth filter is the best procedure to carry out a SPECT examination with [111In] Pentetreotide.

Accurate planning of minimally invasive surgery of parathyroid adenomas by means of [(99m)Tc]MIBI SPECT.

AIM: The aim of the study was to evaluate the clinical role or [(99m)Tc]MIBI SPECT in selecting primary hyperparathyroid (PHPT) patients for minimally invasive radioguided surgery (MIRS). METHODS: One hundred and forty-one consecutive PHPT patients were studied by a single-session [(99m)Tc]Percethnetate/[(99m)Tc]MIBI subtraction scintigraphy, followed by [(99m)Tc]MIBI SPECT in order to localize hyperfunctioning parathyroid adenoma (PA) and plan the surgical approach. RESULTS: A solitary PA was depicted at preoperative scintigraphy in 135 of 141 patients (95.7%), two or more PA in 5 patients, and was negative in 6 patients (4.3%). In 27 patients, the PA was located deep in the paraesophageal/paratracheal space. One hundred and twenty-four patients (in 18 of them the PA was located deeply in the neck) underwent successful MIRS using the low 37 MBq (1 mCi) [(99m)Tc]MIBI dose protocol. Intraoperative quick parathyroid hormone (QPTH) assay demonstrated a fall >50% in respect to the baseline value in all patients, confirming successful parathyroidectomy. After a follow-up of 6 to 37 months (median 18 months), no case of persistent/recurrent PHPT was recorded. When comparing the parathyroid to background (P/B) ratio measured at planar and SPECT preoperative scintigraphy with that measured intraoperatively with the gamma probe, a significant linear correlation was found between the SPECT and intraoperative gamma probe measurements (r = 0.91; P <0.01) while no correlation was found with planar scintigraphic data. CONCLUSIONS: Our data suggest that the P/B ratio calculated by means of [(99m)Tc]MIBI SPECT is more accurate in predicting the intraoperative measurements with the intraoperative gamma probe. Thus, a preoperative [(99m)Tc]MIBI SPECT acquisition should be recommended for a better selection of PHPT patients to offer MIRS.