Thyroid Diseases: Miccoli P

Rosato L, Miccoli P, Pinchera A, Lombardi G, Romano M, Avenia N, Bastagli A, Bellantone R, De Palma M, De Toma G, Gasparri G, Lampugnani R, Marini PL, Nasi PG, Pellizzo MR, Pezzullo L, Piccoli M, Testini M. · Dipartimento di Chirurgia - ASL TO/4, Ospedale di Ivrea, Italy. · G Chir. · Pubmed #19351456 No free full text.

Abstract: AIM: To review and to update the management protocols in thyroid surgery proposed two years ago by 1st Consensus Conference called on the topic by the Italian Association of Endocrine Surgery Units (UEC Club). METHOD: The 2nd Consensus Conference took place November 30, 2008 in Pisa within the framework of the 7th National Congress of the UEC Club. A selected board of endocrinologists and endocrine surgeons (chairmans: Paolo Miccoli and Aldo Pinchera; speaker: Lodovico Rosato) examined the individual chapters and submitted the consensus text for the approval of several experts. This plain and concise text provides the rationale of the thyroid patient management and wants to be the most complete possible tool for the physicians and other professionals in the field. CONCLUSIONS: The diagnostic, therapeutic and healthcare management protocols in thyroid surgery approved by the 2nd Consensus Conference are officially those proposed by the Italian Association of Endocrine Surgery Units (UEC Club) and are subject to review by two years.

Miccoli P, Ambrosini CE, Berti P. · Department of Surgery, University of Pisa, Pisa, Italy. · Minerva Endocrinol. · Pubmed #19209129 No free full text.

Abstract: Thyroid carcinoma can be divided in two main groups, differentiated, with a good prognosis and an average 10 years survival ranging from 70% to 95%, and undifferentiated which is lethal in few months. Differentiated thyroid carcinoma can be distinguished in those variants coming from follicular cells (papillary and follicular) and those from C cell (medullary carcinoma). Surgical approach represents the first step in the treatment of thyroid carcinoma. Minimally-invasive endoscopic technique can be applied only to a minority of case, the so called ''low risk'' carcinoma according to AGES and AMES criteria. During the last ten years many different endoscopic approaches have been proposed for the treatment of thyroid carcinoma and the minimally invasive videoassisted (MIVAT) by Prof Miccoli is undoubtly the one which resulted to be the most successful and spread all over the world. Through a 1.5 cm central skin incision 2 cm above the sternal notch MIVAT allows to perform a total thyroidectomy for low risk papillary carcinoma with a completeness similar to that of conventional thyroidectomy. Using the same central access it is also possible to perfom a prophylactic central neck dissection for RET gene positive carriers. A lateral neck minimally invasive videoassisted lymphadenectomy is under development for those patients with low risk papillary carcinoma and isolated lateral lymph node metastasis.

Antonelli A, Fallahi P, Ferrari SM, Carpi A, Berti P, Materazzi G, Minuto M, Guastalli M, Miccoli P. · Department of Internal Medicine, University of Pisa, School of Medicine, Via Roma, 67, I-56100 Pisa, Italy. · Biomed Pharmacother. · Pubmed #18725177 No free full text.

Abstract: Human papillary dedifferentiated thyroid cancer (HPDTC) represents a therapeutic dilemma. Targeted therapy (RET proto-oncogene or BRAF-targeting drugs) are promising treatments for HPDTC. Also PPARg agonists are another exciting field for redifferentiating therapy of HPDTC. However, even if many new approaches for the therapy of HPDTC are emerging, until now a significant clinical impact on survival by the use of these drugs is still lacking. In the future, the identification of patients who are likely to benefit from each therapeutic option will be important. In this view particular importance should be given to development of primary cells from the single patient by fine needle aspiration samples, as recently observed in anaplastic thyroid cancer. In fact, chemosensitivity tests in primary tumoral cells may help in detecting responsive patients and in preventing the administration of inactive drugs to those unresponsive.

Miccoli P, Minuto MN, Ugolini C, Pisano R, Fosso A, Berti P. · Department of Surgery, University of Pisa, Via Roma 63, 56126 Pisa, Italy. · World J Surg. · Pubmed #18305997 No free full text.

Abstract: BACKGROUND: A decade after nearly all surgical disciplines developed minimally invasive techniques, the first report of a single case of minimally invasive thyroidectomy was published. Minimally invasive video-assisted thyroidectomy (MIVAT) is now considered the most widely practiced and most easily reproducible minimally invasive procedure for thyroidectomy. The aim of this review was to analyze the treatment of benign thyroid diseases by MIVAT. METHODS: A systematic evidence-based literature review focusing on three questions was carried out. Additional data were obtained on the basis of our personal experience. (1) Are minimally invasive procedures indicated in the treatment of thyroid diseases? (2) Is MIVAT a safe technique and what are the demonstrated advantages? (3) Since different thyroid diseases may be treated by MIVAT, is it of any value in the treatment of benign thyroid diseases? RESULTS: MIVAT can be considered an appropriate treatment of some thyroid diseases; it represents a safe procedure with the same incidence of complications as traditional surgery, and also has advantages in terms of both cosmetic result and postoperative distress. CONCLUSIONS: In spite of an increasing trend toward performing more extensive procedures other than thyroidectomy alone during videoscopic procedures, the current literature seems to reaffirm that the main and safest indication for MIVAT is benign disease.

Miccoli P, Ambrosini CE, Materazzi G, Fregoli L, Fosso LA, Berti P. · Dipartimento di Chirurgia, Università degli Studi di Pisa, Pisa. · Minerva Chir. · Pubmed #17947945 No free full text.

Abstract: The onset of cervicoscopy dates back to the first endoscopic parathyroidectomy in 1996. This operation, along with its several variants, has become a valid option widespread in many important centres. Later on, endoscopic or video assisted thyroidectomy was introduced in spite of the limits imposed by the mass of the gland to remove. It is indicated for a minority of patients for this reason but both parathyroidectomy and thyroidectomy showed some important advantages with respect to conventional surgery, advantages demonstrated also in prospective studies. They are mainly represented by a better cosmetic outcome and a less distressful postoperative course. These approaches proved to be safe and feasible in any surgical background: their complication rate is the same as traditional open surgery in the neck. Very promising seems to be the videoscopic access to neck lymph nodes (central and lateral compartments) whereas other fields of application such as carotid artery surgery and spine surgery still remain object of experimental studies. As far as the lateral neck dissection is concerned the technique is going to be standardized in our centre as a variant of the well known video assisted approach adding a 5 mm trocar placed in the supraclavicular space. By consequence, cervicoscopy has to be considered an important surgical tool which can be further improved but which also has an excellent potentiality.

Miccoli P, Materazzi G, Antonelli A, Panicucci E, Frustaci G, Berti P. · Department of Surgery, University of Pisa, Pisa, Italy. · Langenbecks Arch Surg. · Pubmed #17131154 No free full text.

Abstract: INTRODUCTION: Malignant tumours of the thyroid are generally classified as either well-differentiated thyroid carcinoma, which is composed of papillary and follicular carcinoma, or undifferentiated/anaplastic thyroid carcinoma (ATC). ATC is not only the most lethal disease in the field of endocrine surgery but also one of the most aggressive tumours characterized by an almost invariable fatal outcome, which only very rarely exceeds a 1-year course. DISCUSSION: The impact of surgical resection in association with external beam radiation on ATC outcome has been extensively investigated also in studies based on multicentric database, and there is a general agreement on the significance of a complete resection of the tumour. It has been difficult up to now to collect data regarding chemotherapy adjuvant treatment. In spite of the lack of an extensive review about the results of this kind of treatment by itself or as part of a multimodal approach, it seems that among the several chemotherapy agents experienced, none proved to influence significantly ATC prognosis. Neither doxorubicin (the most commonly used) nor other drugs, such as cisplatin, bleomycin, fluorouracil or cyclophosphamide, showed any real efficacy in controlling the disease. CONCLUSION: The most recent development in this field seems to be represented by the possibility offered by PPARg agonists; even more promising might be the use of adenovirus-mediated p53 tumour suppressor gene therapy or BMP-7. All these new therapies need further confirmation coming from ongoing clinical trials such as those involving the use of vascular and growth factor-targeted agents.

Spinelli C, Bertocchini A, Donatini G, Miccoli P. · Department of General Surgery, University of Pisa, Pisa, Italy. · J Pediatr Surg. · Pubmed #15359382 No free full text.

Abstract: METHODS: From October 1998 to December 2002 in the Department of Surgery at the University of Pisa, 16 patients ages 18 years or younger (14 girls, 87.5%, and 2 boys, 12.5%; range, 11 to 18; mean age, 15 years, 8 months) underwent a surgical operation with video-assisted technique for thyroid pathology. These patients belong to a larger group of 270 patients treated with this technique. Surgical therapy with video-assisted technique was chosen; a lobectomy was used in 15 cases (90.0%) and a total thyroidectomy in 1 case (10%). RESULTS: Two patients (12.5%) underwent a second video-assisted operation to complete the thyroidectomy for a false-negative result at extemporal histologic examination during the first operation. The histologic examination found benign pathology in 14 cases (87.5%) and a malignant lesion (papillary type) in 2 cases (12.5%). No postoperative complications were observed. CONCLUSIONS: The results of the mini-invasive video-assisted technique for thyroidectomy in this preliminary experience seem to be equal to those of the traditional open surgical technique (200 surgical operations for thyroid pathology for the ages 18 years or younger). Elective indications of the mini-invasive video-assisted technique are the volume of the nodule and hystological type; this technique cannot be used in cases of voluminous goiter, medullary carcinomas and poorly differentiated carcinomas. The advantage that this technique offers, in addition to a better postoperation period, is an improved esthetic result, which is particularly important in young patients.

Miccoli P. · Department of Surgery, University of Pisa, Pisa, Italy. · Surg Endosc. · Pubmed #11961594 No free full text.

Abstract: During the past 4 years, some minimally invasive procedures for thyroid and parathyroid surgery have been described. All these techniques have been demonstrated as feasible and safe. Nevertheless, the surgeon should be well trained to obtain the best results with these approaches. Moreover, not all patients are eligible for minimally invasive procedures. At the moment, they can be proposed for most patients with sporadic primary hyperparathyroidism, but only for a minority of patients with thyroid nodules. The results from minimally invasive procedures are almost comparable with those of conventional surgery, but they have additional advantages in terms of cosmetic result and postoperative pain. Therefore, these procedures should be considered a valid option by surgeons dealing with neck endocrine surgery.

Bogazzi F, Miccoli P, Berti P, Cosci C, Brogioni S, Aghini-Lombardi F, Materazzi G, Bartalena L, Pinchera A, Braverman LE, Martino E. · Department of Endocrinology and Metabolism, University of Pisa, Cisanello Hospital, Via Paradisa 2, 56124 Pisa, Italy. · Surgery. · Pubmed #12490863 No free full text.

Abstract: BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) may develop either in apparently normal glands (type II AIT) or in the presence of thyroid abnormalities (type I AIT). Sometimes AIT is resistant to conventional treatment. Thyroidectomy was used in patients with AIT, but in patients who are thyrotoxic it may be hazardous. METHODS; Seven patients with AIT (6 type I and 1 type II, 5 men, 2 women, mean age 70 years [range, 60-82 years]) were prepared for total thyroidectomy with a short course of iopanoic acid (1 g/day orally for a mean of 13 days), an oral iodinated cholecystographic agent inhibiting 5'-deiodinase and causing a reduction in the peripheral conversion of thyroxine to triiodothyronine. Mean thyroid volume was 64 mL (range, 10-145 mL). RESULTS: Mean serum-free triiodothyronine levels decreased from 20 +/- 16.7 pmol/L to 6 +/- 2 pmol/L (P =.0004), whereas serum-free thyroxine values remained unchanged. Euthyroidism was rapidly (7-20 days) restored, allowing an uncomplicated total thyroidectomy in all patients and the ability to continue amiodarone therapy in 6 patients. None had increased surgical bleeding, recurrent nerve palsy, or hypoparathyroidism. No cardiovascular complications occurred. CONCLUSIONS: Iopanoic acid is an effective drug allowing rapid control of hyperthyroidism in AIT.

Miccoli P, Elisei R, Materazzi G, Capezzone M, Galleri D, Pacini F, Berti P, Pinchera A. · Department of Surgery, University of Pisa, S. Chiara Hospital, Via Roma 67, 56100 Pisa, Italy. · Surgery. · Pubmed #12490857 No free full text.

Abstract: BACKGROUND: The effectiveness of minimally invasive video-assisted thyroidectomy (MIVAT) in papillary thyroid carcinoma is still debated. Some are concerned about this procedure in patients with thyroid cancer. This prospective study aimed to demonstrate that near-total thyroidectomy can be performed by MIVAT with similar results compared with open thyroidectomy. METHODS: A total of 33 patients with a thyroid nodule proven to be a papillary thyroid carcinoma underwent a near-total thyroidectomy. They were randomly assigned to group A (n = 16) or group B (n = 17) who were treated either by MIVAT or conventional near-total thyroidectomy, respectively. Iodine-131 thyroid bed uptake and serum thyroglobulin were measured 1 month after operation. Data were analyzed by unpaired t test and Mann-Whitney statistic methods. RESULTS: . Mean iodine-131 uptake was 5.1 +/- 4.9% in group A and 4.6 +/- 6.7% in group B. Mean thyroglobulin serum levels were 5.3 +/- 5.8 ng/mL in group A and 7.6 +/- 21.7 ng/mL in group B. The differences were not statistically significant. CONCLUSIONS: The results of this study showed that the completeness obtained with MIVAT is similar to that obtained with open thyroidectomy, with the great advantage of a minimal neck wound. No conclusions can be drawn in terms of influence of MIVAT on the outcome of the patients with small papillary thyroid carcinoma.

Basolo F, Molinaro E, Agate L, Pinchera A, Pollina L, Chiappetta G, Monaco C, Santoro M, Fusco A, Miccoli P, Elisei R, Capezzone M, Pacini F. · Dipartimento di Oncologia, Universita di Pisa, Via Paradisa, 2, 56124 Pisa, Italy. · Eur J Endocrinol. · Pubmed #11720878 links to  free full text

Abstract: BACKGROUND: RET proto-oncogene rearrangements (RET/PTC) are causative events in the pathogenesis of a subset of papillary thyroid cancer (PTC). The prevalence of RET/PTC varies in different countries and according to specific clinical features: it is higher after radiation exposure and it is claimed to be higher in young patients. Conflicting results are reported regarding the prognostic role of RET/PTC activation. OBJECTIVE: To investigate the prognostic meaning of RET/PTC rearrangement on the long term outcome of PTC. METHODS: We have studied the expression of the RET encoded protein in 127 papillary thyroid carcinomas by immunohistochemistry using a polyclonal antibody against the tyrosine-kinase domain of the RET protein. These cases have been collected during 1970-1985, and have a mean (+/-S.D.) period of follow-up of 18.6+/-3.7 years (range 12-27 years). The results have been compared with the patients' outcome. RESULTS: The tyrosine-kinase domain of RET was expressed in 82 (64.6%) papillary carcinomas. Among them, RET was highly expressed in 65 (51.2%) cases and moderately expressed in 17 (13.4%). RET expression was absent in 45 (35.4%) cases. No correlation was found between RET expression and other parameters such as sex, age at diagnosis, tumor class and histological variant. Follow-up analysis showed no influence of RET expression on patients' outcome. By multivariate analysis, age (>45 years) and tumor class IV, but not sex and RET expression were adverse prognostic indicators of death. CONCLUSION: In conclusion, our analysis indicates that RET expression is frequently found in PTC, and has no influence on tumor outcome.

Miccoli P, Pinchera A, Materazzi G, Biagini A, Berti P, Faviana P, Molinaro E, Viola D, Elisei R. · Department of Surgery, University of Pisa, Via Roma 64, 56100 Pisa, Italy. · J Clin Endocrinol Metab. · Pubmed #19223525 No free full text.

Abstract: BACKGROUND: Minimally invasive video-assisted thyroidectomy (MIVAT) was introduced in the clinical practice to treat small benign thyroid nodules. This method has recently been demonstrated to produce the same completeness as a conventional thyroidectomy in patients with papillary thyroid cancer (PTC). The low number of treated cases and the limited follow-up of these patients represent the major limitations of these studies. OBJECTIVE: The aim of the study was to compare the outcome of two groups of PTC patients, one treated with MIVAT and the other with conventional thyroidectomy, after a median follow-up of 5 yr. STUDY GROUP: A total of 221 PTC patients were enrolled in this study according to the following criteria: 171 were treated with MIVAT (group A), and 50 were treated with conventional thyroidectomy (group B). RESULTS: The outcome and the cumulative (131)I activity administered to achieve curative status were compared. After a mean follow-up of 3.6 +/- 1.5 yr (range, 1-8 yr; median, 5 yr), no differences were found between group A and group B. A similar rate of permanent hypoparathyroidism and/or nerve cord palsy was found in both groups. CONCLUSION: We demonstrated that PTC patients operated on with MIVAT had a good outcome after 5 yr. This was similar to the outcome of patients treated with conventional thyroidectomy and the same degree of exposure to (131)I. These results, together with the evidence of a similar degree of completeness and rate of complications between the two surgical techniques, show that MIVAT is a valid option to treat low- and intermediate-risk PTC patients.

Miccoli P, Berti P, Ambrosini CE. · Department of Surgery, University of Pisa, Pisa, Italy. · ORL J Otorhinolaryngol Relat Spec. · Pubmed #18971591 No free full text.

Abstract: Minimally invasive video-assisted thyroidectomy (MIVAT) was introduced in our department in 1998. The procedure is based on a unique incision in the central neck, 2 cm above the sternal notch, using small conventional retractors and 2-mm reusable instruments. Hemostasis is achieved by using a Harmonic scalpel. 1,320 (1,136 female and 184 male, ratio 4:1) patients have undergone MIVAT since June 1998. Lobectomy was carried out in 421 patients, while 899 patients underwent total thyroidectomy. In 21 cases (RET oncogene mutation carriers), MIVAT was associated with central compartment lymph node clearance. Mean operative time of lobectomy was 32.3 min (range 20-120 min); for total thyroidectomy it was 44.1 min (range 30-130). Mean time for video-assisted central compartment lymphadenectomy was 57 min. Conversion to standard cervicotomy was required in 30 cases (2.2%); operative complications included transient unilateral recurrent nerve palsy in 35 cases (2.65%) and definitive unilateral recurrent nerve palsy in 15 cases (1.13%). Thirty-eight patients exhibited hypoparathyroidism, which corresponds to 4.2% of total thyroidectomies performed, but only 2 showed permanent hypoparathyroidism. MIVAT can be considered a safe operation offering significant cosmetic advantages and has possible new promising indications such as prophylactic thyroidectomy in RET gene mutation carriers.

Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F. · Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. · J Clin Endocrinol Metab. · Pubmed #18682506 No free full text.

Abstract: BACKGROUND: The BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF(V600E) mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAF(V600E) mutation in PTC patients with a long-term follow-up. METHODS: We studied 102 PTC patients with a median follow-up of 15 yr. The BRAF(V600E) mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAF(V600E) mutation, clinicopathological features, and outcome of PTC patients were evaluated. RESULTS: The BRAF(V600E) mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAF(V600E) mutation (P < 0.002). However, at multivariate analysis only the BRAF(V600E) mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAF(V600E)-mutated group (P = 0.015). CONCLUSIONS: In this study the BRAF(V600E) mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAF(V600E) mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.

Giusti L, Iacconi P, Ciregia F, Giannaccini G, Donatini GL, Basolo F, Miccoli P, Pinchera A, Lucacchini A. · Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, Pisa, Italy. · J Proteome Res. · Pubmed #18665625 No free full text.

Abstract: At present, the clinical and pathological analysis used in the diagnosis of papillary thyroid cancer (PTC) are insufficient to discern tumor behavior, and new diagnostic and prognostic markers need to be identified. In this study, we performed a comparative proteome analysis to examine the global changes of fine needle aspiration fluid (FNA) protein patterns of two variants of malignant PTC (classical variant PTC (cPTC) and tall cell variant PTC (TCV)) with respect to the controls. Changes in protein expression were identified using two-dimensional electrophoresis (2DE) and peptide mass fingerprinting via MALDI-TOF mass spectrometry (MS), as well as Western blot analysis. A statistical significant up-regulation of 17 protein spots in cPTC and/or TCV with respect to controls was demonstrated. These proteins included transthyretin precursor (TTR), ferritin light chain (FLC), proteasome activator complex subunit 1 and 2, alpha-1-antitrypsin precursor, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), lactate dehydrogenase chain B (LDH-B), apolipoprotein A1 precursor (Apo-A1), annexin A1, DJ-1 protein and cofilin-1. In addition, 12 protein spots were found exclusively in cPTC and three exclusively in TCV. These latter proteins (ferritin heavy chain (FHC), peroxiredoxin 1 (PRX1) and 6-phosphogluconate dehydrogenase (6-PDGH)) correspond to stress response proteins and, until now, had not been described in thyroid tumors. These findings illustrate the potential use of FNA proteomics to identify protein changes associated with thyroid cancer and to advance potential protein biomarkers in the diagnostic classification of the disease.

Spinelli C, Donatini G, Berti P, Materazzi G, Costanzo S, Miccoli P. · Department of General Surgery, University of Pisa, Pisa, Italy. · J Pediatr Surg. · Pubmed #18639679 No free full text.

Abstract: BACKGROUND: Minimally invasive video-assisted thyroidectomy (MIVAT) proved to be safe and effective in the treatment of both benign diseases and malignancies. We report our experience in thyroid surgery in pediatric patients. METHODS: From October 1998 to December 2005, 35 patients (27 females and 8 males) underwent MIVAT for thyroid disease. The mean age was 14.0 years (range, 8-18 years); mean ecographically estimated thyroid volume was 11.13 mL (range, 8-25 mL). RESULTS: A total thyroidectomy was performed in 22 patients, whereas lobectomy was performed in 13. Two patients of the latter group had a second lobectomy for a false-negative result at frozen section during the first operation. One patient underwent also a prophylactic central neck dissection for positive RET oncogene. The histologic examination found a papillary carcinoma in 11 patients, a microfollicular nodule in 7 patients, and multinodular goiter in 17 patients. The mean operative time was 54.1 minutes for thyroidectomy (range, 25-110 minutes) and 38.5 minutes for lobectomy (range, 20-65 minutes). All patients but one was discharged on the first postoperative day. One transient hypoparathyroidism was observed in the patient who underwent total thyroidectomy plus central neck lymphadenectomy. CONCLUSIONS: The MIVAT technique proved to be as safe and effective as conventional thyroidectomy with Kocher approach to treat patients with both benign and malignant diseases of the thyroid gland. The advantages of MIVAT are represented by a better and faster postoperative course and an improved aesthetic result, which is particularly important in this group of patients.

Antonelli A, Ferrari SM, Fallahi P, Berti P, Materazzi G, Marchetti I, Ugolini C, Basolo F, Miccoli P, Ferrannini E. · Department of Internal Medicine, School of Medicine, University of Pisa, Via Roma, 67, I-56100 Pisa, Italy. · Eur J Endocrinol. · Pubmed #18583391 No free full text.

Abstract: OBJECTIVE: Anaplastic thyroid cancer (ATC) is often unoperable and chemotherapy and radiotherapy are the main treatments. Until now 'primary ATC cell cultures' (ANA) have been developed from surgical biopsies. The possibility to obtain ANA from fine-needle aspiration (FNA-ANA) and to test their sensitivity to different drugs could increase the effectiveness of treatments and avoid unnecessary surgical procedures. DESIGN: To obtain FNA-ANA from six ATC patients before undergoing surgery and to evaluate the chemosensitivity of FNA-ANA to chemotherapeutic agents and thiazolidinediones (TZD). METHODS AND RESULTS: FNA-ANA from the six ATC patients were cultured in RPMI 1640 and propagated in DMEM. Chemosensitivity was evaluated by inhibiting the proliferation with increasing concentrations of five different chemotherapeutic agents (bleomycin, cisplatin, gemcitabine, etoposide, and carboplatin) or TZD (rosiglitazone). Chemotherapeutic agents significantly inhibited (P<0.0001) FNA-ANA proliferation, such as TZD (P<0.001); etoposide was the most effective in reducing cell growth. Another ANA culture for each patient was obtained from a biopsy specimen; the results for the chemosensitivity tests were similar to those obtained with FNA-ANA. The (V600E)BRAF mutation was observed in two ATC patients; the inhibition of proliferation by drugs was similar in tumors with or without (V600E)BRAF mutation. CONCLUSIONS: Our study demonstrates 1) the possibility to obtain FNA-ANA, and opens the way to the use of FNA-ANA to test the chemosensitivity to different drugs (chemotherapeutic agents or TZD; and possibly the radiosensitivity) in each patient, avoiding unnecessary surgical procedures and the administration of inactive chemotherapeutics; and 2) that etoposide is highly effective in reducing ATC cell growth in vitro.

Romei C, Ciampi R, Faviana P, Agate L, Molinaro E, Bottici V, Basolo F, Miccoli P, Pacini F, Pinchera A, Elisei R. · Departments of Endocrinology and Metabolism Oncology Surgery, University of Pisa, 56100 Pisa, Italy. · Endocr Relat Cancer. · Pubmed #18509003 links to  free full text

Abstract: A low sodium iodide symporter (NIS) expression has been shown in papillary thyroid carcinomas (PTCs) harboring the BRAFV600E mutation. In the present study, we analyzed the mRNA expression of thyroid differentiation genes, glucose transporter (GLUT)-1 and GLUT-3, in 78 PTCs according to the presence of BRAFV600E or RET/PTC rearrangements. We found BRAFV600E and RET/PTC rearrangements in 35.8 and 19.4% of PTCs respectively. The mRNA expression of NIS and thyroperoxidase (TPO) genes were significantly lower (P<0.0001 and P=0.004 respectively) in BRAFV600E-positive PTC with respect to non-mutated samples. In support of this result, immunohistochemistry showed that the percentage of NIS-positive cells was significantly lower (P=0.005) in BRAFV600E-mutated PTC (mean 53.5%) than in negative cases (mean 72.6%). In contrast, no difference either in NIS or in any other thyroid differentiation genes' mRNA expression was found in PTC with or without RET/PTC rearrangements. When GLUT-1 and GLUT-3 mRNA expression was considered, no correlation was found either in BRAFV600E- nor in RET/PTC-mutated cases. In conclusion, this study confirmed the presence of a genetic alteration of BRAF and/or RET oncogenes in 64% of PTC cases and revealed a significant correlation of BRAFV600E mutation with a lower expression of both NIS and TPO. This latter finding could indicate that an early dedifferentiation process is present at the molecular level in BRAFV600E-mutated PTC, thus suggesting that the previously demonstrated poor prognostic significance of BRAFV600E mutation could be related to the dedifferentiation process more than to a more advanced stage at diagnosis.

Miccoli P, Minuto MN, Ugolini C, Panicucci E, Massi M, Berti P, Basolo F. · Department of Surgery, University of Pisa, Pisa, Italy. · Otolaryngol Head Neck Surg. · Pubmed #18241716 No free full text.

Abstract: OBJECTIVE: To analyze aspects of a series of papillary thyroid carcinomas and evaluate the prognostic features specific to different age classes. STUDY DESIGN: Retrospective study. SUBJECTS AND METHODS: From 2000 to 2005, 2709 patients underwent a total thyroidectomy for papillary thyroid carcinoma in our department. Patients were divided into three groups: <18 years (G1), 19 to 45 years (G2), and >46 years (G3). Histologic and clinical features were statistically evaluated. RESULTS: Tumor size was larger in G1 when compared with both G2 and G3 (P < 0.0001). Infiltration of the thyroid capsule and node metastases were higher in G1 than both G2 and G3 (P < 0.0001). The Tall-cell variant was more represented in G2 and G3. CONCLUSION: In the pediatric population, papillary carcinoma is a more aggressive disease. Because pediatric cancers have a better prognosis than their adult counterparts, this does not influence patient outcome. Age can then be considered the most important factor in determining prognosis.

Antonelli A, Ferrari SM, Fallahi P, Berti P, Materazzi G, Barani L, Marchetti I, Ferrannini E, Miccoli P. · Department of Internal Medicine, University Hospital of Pisa, Pisa, Italy. · Clin Endocrinol (Oxf). · Pubmed #18194485 No free full text.

Abstract: OBJECTIVE: Anaplastic thyroid cancer (ATC) is often inoperable and chemotherapy and radiotherapy are the main treatments. Until now, 'primary ATC cell cultures' (ANA) have been developed from surgical biopsies. We investigated the possibility of obtaining ANA from fine-needle aspiration (FNA-ANA) and testing their sensitivity to chemotherapeutic agents, which could enable treatments to be more effective and avoid unnecessary surgical procedures. DESIGN AND PATIENTS: The aim of this study was to obtain FNA-ANA from three ATC patients and to evaluate the chemosensitivity of FNA-ANA to chemotherapeutic agents. MEASUREMENTS AND RESULTS: FNA-ANA from ATC patients were cultured in RPMI 1640 and propagated in Dulbecco's modified Eagle's medium (DMEM). Chemosensitivity was evaluated by inhibiting the proliferation (analysing the number of viable cells by the cleavage of tetrazolium salts), by increasing the concentration of four different chemotherapeutic agents: bleomycin, cisplatin, gemcitabine and etoposide. The chemotherapeutic agents significantly inhibited (> 50%) FNA-ANA proliferation. Another ANA for each patient was obtained from a surgical biopsy specimen; the results for the chemosensitivity tests were similar to those obtained using FNA-ANA. CONCLUSIONS: Our study demonstrates the possibility of obtaining FNA-ANA, and opens the way to the use of FNA-ANA as a means of testing the chemosensitivity to different chemotherapeutic agents (and possibly the radiosensitivity) in each patient, avoiding unnecessary surgical procedures and the administration of inactive chemotherapeutics.

Giusti L, Iacconi P, Ciregia F, Giannaccini G, Basolo F, Donatini G, Miccoli P, Lucacchini A. · Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology, University of Pisa, 56126 Pisa, Italy. · J Endocrinol Invest. · Pubmed #18075290 No free full text.

Abstract: The aim of this study was to determine the protein pattern of human thyroid fine needle aspiration fluid (FNA) using a proteomic approach. FNA proteins were separated using 2-dimensional gel electrophoresis (2DE), digested and then analyzed by peptide mass fingerprinting. For the first time, we provided an image of the protein components of the FNA, in which approximately 220 protein spots can be identified. The proteome analysis revealed a specific fingerprint of FNA with proteins appertaining to various functional systems. Our preliminary results of FNA protein pattern could be a starting point in studying the presence of potential markers implicated in thyroid diseases.

Miccoli P, Minuto MN, Paggini R, Rucci P, Oppo A, Donatini G, Golia F, Novelli L, Carlini M, Dell'Osso L. · Department of Surgery, University of Pisa, 56100 Pisa, Italy. · J Endocrinol Invest. · Pubmed #18075288 No free full text.

Abstract: INTRODUCTION: Existing trials investigated the impact of medical treatment of thyroid disorders on health-related quality of life (QOL) and psychiatric symptoms. The aim of this prospective study is to analyze the impact of thyroid surgery on QOL and severity of psychiatric symptoms. MATERIALS AND METHODS: Forty-seven patients undergoing thyroid surgery (TS) were assessed before thyroidectomy (T0) and 37 also after surgery, >or=6 months after euthyroidism was achieved (T1). QOL and psychiatric symptoms were evaluated at T0 and T1 using the Medical Outcomes Study Short Form Survey (SF-36) and the Symptom Checklist-90 (SCL-90-R). Scores at T0 were compared with those of patients undergoing surgery for non-thyroidal disease and the SF-36 scores were also compared with the normative Italian sample. Changes in QOL and psychiatric symptoms between T0 and T1 were also examined. RESULTS: Health-related QOL in TS patients before surgery was poorer than in the comparison group on the SF-36 mental component summary measure and social functioning. Mental health improved significantly after surgery but social functioning remained markedly impaired. A significant reduction in the severity of psychiatric symptoms was observed. DISCUSSION: Our results indicate that even long after euthyroidism is achieved after surgery, patients show a significant improvement of mental health and a reduction of psychiatric symptoms. Nevertheless, patients continue to have a poorer QOL compared to the Italian normative sample.

Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F, Miccoli P, Berti P, Pacini F, Pinchera A. · Department of Endocrinology, University of Pisa, Via Paradisa 2, 56124 Pisa, Italy. · J Clin Endocrinol Metab. · Pubmed #18073307 links to  free full text

Abstract: BACKGROUND: Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40-50% of MTCs. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been performed in small series with short-term follow ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTCs with a long follow up. METHODS: We studied 100 sporadic MTC patients with a 10.2 yr mean follow-up. RET gene exons 10-11 and 13-16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features, and outcome of MTC patients was evaluated. RESULTS: A somatic RET mutation was found in 43 of 100 (43%) sporadic MTCs. The most frequent mutation (34 of 43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (P=0.03), and in MTC with node and distant metastases (P<0.0001 and P=0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (P=0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (P=0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (P<0.0001 and P=0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (P=0.006). CONCLUSIONS: We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.

Miccoli P, Minuto MN, Ugolini C, Molinaro E, Basolo F, Berti P, Pinchera A, Elisei R. · Department of Surgery, University of Pisa, Via Roma 67, 56126 Pisa, Italy. · Endocr Relat Cancer. · Pubmed #18045961 links to  free full text

Abstract: Total thyroidectomy and central neck dissection are the procedures of choice in patients affected with medullary thyroid cancer. It is known that a medullary thyroid cancer with node metastases can be rarely cured, and therefore the utility of a modified radical neck dissection in the absence of suspicious node metastases still needs further evidence. The study aims to verify whether other epidemiological and pathological parameters could affect the prognosis of medullary thyroid cancer patients. We prospectively studied 70 medullary thyroid cancer patients consecutively operated on (from 2000 to 2004) at the same institution and analysed by the same pathologists. All patients underwent total thyroidectomy and central lymphadenectomy. In 27 cases, the ipsilateral (n=19) or bilateral (n=8) modified radical neck dissection was performed in the presence of suspicious lateral neck node metastases. After surgical treatment, basal and stimulated serum calcitonins (Cts) were measured in all patients. Follow-up ranged between 1 and 4 years. Patients were considered 'cured' when stimulated Ct was undetectable. Age, sex, tumour size, tumour capsule, multicentricity, nodes in the central neck and mean number of positive nodes were analysed in 'cured' and 'not-cured' patients. The presence of node metastases in the central compartment was significantly correlated with the outcome of the patients, being present in 9 and 72% of cured and not-cured patients respectively (P<0.000001). Tumour size was also significantly correlated with the outcome of the disease (P<0.00006). The presence of the tumour capsule correlated with better prognosis (P=0.0005) and absence of node metastases (P=0.0080). By multivariate analysis, the presence of node metastasis remained the most significant variable affecting the outcome of the disease (P=0.000014). Our results show that the outcome of encapsulated cancer is significantly better regardless of tumour size and node metastases. Although the early diagnosis and the extensive surgical treatment may favour the good outcome of medullary thyroid cancer, they do not always guarantee the definitive cure of the disease, being the capsular infiltration an independent bad prognostic factor.

Salvatore G, Nappi TC, Salerno P, Jiang Y, Garbi C, Ugolini C, Miccoli P, Basolo F, Castellone MD, Cirafici AM, Melillo RM, Fusco A, Bittner ML, Santoro M. · Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali, Universita' Parthenope, Naples, Italy. · Cancer Res. · Pubmed #17981789 links to  free full text

Abstract: Here, we show that the anaplastic thyroid carcinoma (ATC) features the up-regulation of a set of genes involved in the control of cell cycle progression and chromosome segregation. This phenotype differentiates ATC from normal tissue and from well-differentiated papillary thyroid carcinoma. Transcriptional promoters of the ATC up-regulated genes are characterized by a modular organization featuring binding sites for E2F and NF-Y transcription factors and cell cycle-dependent element (CDE)/cell cycle gene homology region (CHR) cis-regulatory elements. Two protein kinases involved in cell cycle regulation, namely, Polo-like kinase 1 (PLK1) and T cell tyrosine kinase (TTK), are part of the gene set that is up-regulated in ATC. Adoptive overexpression of p53, p21 (CIP1/WAF1), and E2F4 down-regulated transcription from the PLK1 and TTK promoters in ATC cells, suggesting that these genes might be under the negative control of tumor suppressors of the p53 and pRB families. ATC, but not normal thyroid, cells depended on PLK1 for survival. RNAi-mediated PLK1 knockdown caused cell cycle arrest associated with 4N DNA content and massive mitotic cell death. Thus, thyroid cell anaplastic transformation is accompanied by the overexpression of a cell proliferation/genetic instability-related gene cluster that includes PLK1 kinase, which is a potential molecular target for ATC treatment.