Enio Martino, Furio Pacini, Paolo Vitti, and Luigi Bartalena
Percutaneous ethanol injection (PEI) has been proposed for the management of small hepatocellular carcinomas as an alternative modality of treatment devoid of the complications related to surgery in this kind of patient (1–4). Likewise, PEI has been used for liver and peritoneal metastases of abdominal tumors (1), offering the possibility to attack lesions unlikely to be controlled by surgery and/or chemotherapy. The mechanism of action of ethanol appears to be related to cellular dehydration followed by coagulative necrosis and vascular thrombosis and occlusion.
On the other hand, the use of PEI has also been proposed for non-malignant nodular lesions, such as parathyroid adenomas causing either primary (5, 6) or secondary (7) hyperparathyroidism. This modality of treatment appears to be particularly suitable for patients with chronic renal failure in whom the surgical risk of parathyroidectomy is high.
In 1990, Livraghi et al. (8) suggested that autonomous single thyroid nodules can be
Furio Pacini, Stefano Mariotti, Nunzio Formica, Rossella Elisei, Stefano Anelli, Enrico Capotorti, and Aldo Pinchera
Abstract. In the present investigation we studied serum anti-thyroglobulin and anti-thyroid microsomal autoantibodies, measured by hemagglutination technique, in 600 patients with thyroid cancer seen by us from 1975 to 1985 (mean follow-up 46 months). Positive thyroglobulin antibodies and/or microsomal antibodies were found in 138 (23%) patients (23.9% with papillary, 25% with follicular, 16.1% with anaplastic, and 4.1% with medullary thyroid carcinomas). The incidence of positive tests was similar in each decade of life (ranging between 21.9% and 27.9%), whereas in a normal sex-matched population with no evidence of thyroid disease, the frequency of positive tests was very low in young people and increased to 23% in people older than 60. In 64 patients with no evidence of residual or metastasic thyroid tissue after surgery and radioiodine, initially positive antibody titres became negative in 54.6%, decreased in 32.8%, did not change in 3.1%, and increased in 9.3%. On the contrary, antibody titres of patients with persistent disease became undetectable in 8.3%, decreased in 16.6%, remained unchanged in 25%, and increased in 50%. The clinical course of differentiated thyroid cancer was unaffected by the presence of thyroid antibodies and no difference was found in the death rate between antibody-positive and antibody-negative patients (11.5% and 13.6%, respectively). In conclusion, our data indicate that: 1) autoimmune phenomena are not an infrequent finding in thyroid cancer; 2) as in non-malignant thyroid diseases, positive-antibody tests are more frequently observed in females than in males; 3) at variance with normal controls, no age-dependent increase in serum anti-thyroid antibodies was found in thyroid cancer; 4) the presence of metastatic thyroid tissue seems to be necessary to perpetuate the autoantibody synthesis, and 5) anti-thyroid autoantibodies are not a protective or worsening factor in the tumour outcome.
Maria Grazia Castagna, Fabio Maino, Claudia Cipri, Valentina Belardini, Alexandra Theodoropoulou, Gabriele Cevenini, and Furio Pacini
After initial treatment, differentiated thyroid cancer (DTC) patients are stratified as low and high risk based on clinical/pathological features. Recently, a risk stratification based on additional clinical data accumulated during follow-up has been proposed.
To evaluate the predictive value of delayed risk stratification (DRS) obtained at the time of the first diagnostic control (8–12 months after initial treatment).
We reviewed 512 patients with DTC whose risk assessment was initially defined according to the American (ATA) and European Thyroid Association (ETA) guidelines. At the time of the first control, 8–12 months after initial treatment, patients were re-stratified according to their clinical status: DRS.
Using DRS, about 50% of ATA/ETA intermediate/high-risk patients moved to DRS low-risk category, while about 10% of ATA/ETA low-risk patients moved to DRS high-risk category. The ability of the DRS to predict the final outcome was superior to that of ATA and ETA. Positive and negative predictive values for both ATA (39.2 and 90.6% respectively) and ETA (38.4 and 91.3% respectively) were significantly lower than that observed with the DRS (72.8 and 96.3% respectively, P<0.05). The observed variance in predicting final outcome was 25.4% for ATA, 19.1% for ETA, and 62.1% for DRS.
Delaying the risk stratification of DTC patients at a time when the response to surgery and radioiodine ablation is evident allows to better define individual risk and to better modulate the subsequent follow-up.
Luca Chiovato, Giuseppe Canale, Doretta Maccherini, Valeria Falcone, Furio Pacini, and Aldo Pinchera
A patient with suppurative thyroiditis due to infection with Salmonella brandenburg is reported. Localization of the infection occurred to a pre-existing thyroid nodule after Salmonella bacteremia. S. brandenburg was isolated in pure culture from the fluid obtained by needle aspiration of the suppurated thyroid nodule. Surgical drainage followed by subtotal thyroidectomy was required to cure the disease. No evidence of pyriform sinus fistula was found. Suppurative thyroiditis due to Salmonella ubiquitous serotypes is an extremely rare condition, and infection to the thyroid produced by S. brandenburg is reported now for the first time. Indeed, the isolation rate of S. brandenburg from all human sources is low, and this microorganism is an uncommon agent of bacteremia.
Maria Grazia Castagna, Gabriele Cevenini, Alexandra Theodoropoulou, Fabio Maino, Silvia Memmo, Cipri Claudia, Valentina Belardini, Ernesto Brianzoni, and Furio Pacini
In differentiated thyroid cancer (DTC) patients at intermediate risk of recurrences, no evidences are provided regarding the optimal radioactive iodine (RAI) activity to be administered for post-surgical thyroid ablation.
This study aimed to evaluate the impact of RAI activities on the outcome of 225 DTC patients classified as intermediate risk, treated with low (1110–1850 MBq) or high RAI activities (≥3700 MBq).
Six to 18 months after ablation, remission was observed in 60.0% of patients treated with low and in 60.0% of those treated with high RAI activities, biochemical disease was found in 18.8% of patients treated with low and in 14.3% of patients treated with high RAI activities, metastatic disease was found in 21.2% of patients treated with low and in 25.7% of patients treated with high RAI activities (P=0.56). At the last follow-up (low activities, median 4.2 years; high activities, median 6.9 years), remission was observed in 76.5% of patients treated with low and in 72.1% of patients treated with high RAI activities, persistent disease was observed in 18.8% of patients treated with low and in 23.5% of patients treated with high RAI activities, recurrent disease was 2.4% in patients treated with low and 2.1% in patients treated with high RAI activities, deaths occurred in 2.4% of patients treated with low and in 2.1% of patients treated with high RAI activities (P=0.87).
Our study provides the first evidence that in DTC patients at intermediate risk, high RAI activities at ablation have no major advantage over low activities.
Furio Pacini, Martin Schlumberger, Henning Dralle, Rossella Elisei, Johannes W A Smit, and Wilmar Wiersinga
Group-author : the European Thyroid Cancer Taskforce
Chiara Colato, Caterina Vicentini, Silvia Cantara, Serena Pedron, Paolo Brazzarola, Ivo Marchetti, Giancarlo Di Coscio, Marco Chilosi, Matteo Brunelli, Furio Pacini, and Marco Ferdeghini
Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRA F WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes.
Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed.
We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break–apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR.
Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off.
FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.
Ferruccio Santini, Giulia Galli, Margherita Maffei, Paola Fierabracci, Caterina Pelosini, Alessandro Marsili, Monica Giannetti, Maria Grazia Castagna, Serenella Checchi, Eleonora Molinaro, Paolo Piaggi, Furio Pacini, Rossella Elisei, Paolo Vitti, and Aldo Pinchera
TSH-receptor (TSHR) has been found in a variety of cell types, including preadipocytes and adipocytes. In vitro, TSH-mediated preadipocyte and adipocyte responses include proliferation, differentiation, survival, and lipolysis.
To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo.
One hundred patients with differentiated thyroid cancer already treated by total thyroidectomy and 131I remnant ablation were enrolled. Mean (±s.e.m.) body mass index (BMI) was 26.9±0.6 kg/m2.
Patients received a standard dose of rhTSH for measurement of thyroglobulin in the follow-up of their disease. Blood samples were taken for the assay of TSH and leptin before the first administration of rhTSH (time 0), and 24 h (time 1), 48 h (time 2), 72 h (time 3), and 96 h (time 4) after the first administration of rhTSH.
Significant mean serum leptin increments, with respect to basal value, were 16, 13, 18, and 11% at times 1, 2, 3, and 4 respectively. Significant positive correlations of leptin–area under the curve with respect to basal leptin levels (r=0.43; P<0.0001) and BMI (r=0.32; P<0.005) were observed.
Acute rhTSH administration in hypothyroid subjects under l-thyroxine therapy produces a rise in serum leptin. This increase is proportional to the adipose mass suggesting that a functioning TSHR is expressed on the surface of adipocytes. The role that TSHR activation in adipocytes might play in physiological and pathological conditions remains a matter of investigation.
Furio Pacini, Martin Schlumberger, Clive Harmer, Gertrud G Berg, Ohad Cohen, Leonidas Duntas, François Jamar, Barbara Jarzab, Eduard Limbert, Peter Lind, Cristoph Reiners, Franco Sanchez Franco, Johannes Smit, and Wilmar Wiersinga
Objective: To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer.
Design and methods: A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries.
Results: There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a <2% recurrence rate after surgery alone, and that post-surgical radioiodine confers recurrence and cause-specific survival benefits in patients, strongly suspected of having persistent disease or known to have tumor in the neck or distant sites. In other patients, there is limited evidence that after complete thyroidectomy and adequate lymph node dissection performed by an expert surgeon, post-surgical radioiodine provides clear benefit. When there is any uncertainty about the completeness of surgery, evidence suggests that radioiodine can reduce recurrences and possibly mortality.
Conclusion: This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age <16 years, or with unfavorable histology.