Minimally invasive video-assisted thyroidectomy: an analysis of results and a revision of indications.

BACKGROUND: The first report of minimally invasive video-assisted thyroidectomy (MIVAT) was published in 1999, and the indications were progressively implemented: from cytologically undetermined thyroid nodules to intermediate-risk differentiated thyroid cancers. The aim of this study was to review the entire series of patients who underwent a MIVAT, critically analyzing its indications and contraindications and trying to figure out how the indications might be extended. METHODS: From 1998 to 2009, a total of 1,946 patients (1,659 females, 287 males; mean age = 40.2 years) underwent MIVAT in our department. Inclusion criteria were benign thyroid nodules <35 mm, malignant nodules <20 mm, and an ultrasonographically estimated thyroid volume (ETV) <25 cc. The presence of suspicious or metastatic lymph nodes and the presence of severe thyroiditis were considered a contraindication for MIVAT. RESULTS: A total thyroidectomy was performed in 1,435 patients (72.3%). A total lobectomy was performed in 511 cases (26.3%), and a central neck node sampling was associated with total thyroidectomy in 104 cases. Final histology revealed benign disease in 979 cases (51.5%) and a malignancy was diagnosed in 915 cases (48.5%). Unexpected thyroiditis was found on final histology in 17.9% of the patients with benign disease and 30.9% of patients with malignancy. The incidence of thyroiditis was significantly different in these two populations (p < 0.0001). CONCLUSION: Our data confirm the validity of the traditional indications for MIVAT: low-risk differentiated thyroid cancer (DTC), cytologically undetermined nodules, and small-volume benign thyroid disease. The indications may be further and safely extended to those patients with associated thyroiditis and those with intermediate-risk DTC. MIVAT can be proposed on a much larger scale than it was at its onset and cannot be considered an option for only a limited number of patients.

Recombinant human TSH and ablation of post-surgical thyroid remnants in differentiated thyroid cancer: the effect of pre-treatment with furosemide and furosemide plus lithium.

BACKGROUND AND AIM: Recombinant human TSH (rhTSH) can be used for post-surgical radioiodine (I-131) thyroid remnants ablation in differentiated thyroid cancer (DTC) patients after surgery. Debate exists in literature about the optimal amount of I-131 that should be given for obtaining an effective ablation and about the role of iodine pool during treatment. Therefore, the aim of the present study was to assess whether I-131 ablation during rhTSH stimulus can be improved by reducing the circulating iodine pool and by increasing thyroid cell uptake and retention of I-131 obtained by administering furosemide and lithium. METHODS: A total of 201 consecutive DTC patients were entered in the study: they were treated by total thyroidectomy and I-131 therapy during rhTSH stimulus to ablate thyroid remnants. Patients were divided into two groups according to the TNM stage: group 1 included patients in stage I-II who were treated with a low 30-mCi I-131 dose, while group 2 included patients in stage III-IV who were treated by a high 100-mCi I-131 dose. Moreover, both groups were further subdivided into three subgroups. Subgroup (a) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-thyroxine (LT4). Subgroup (b) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day withdrawal of L-T4, and after furosemide administration (25 mg/day orally) during the 3 days before I-131. Subgroup (c) included 45 patients from group 1 and 22 from group 2: they were treated with I-131 under rhTSH stimulus, following a short 4-day L-T4 withdrawal, and after administration of furosemide (25 mg/day orally) during the 3 days prior I-131 and lithium (450 mg/day orally) during the 3 days following I-131. Another group (group 3) of 20 patients characterized by a very low-risk cancer (unifocal tumor <1.0 cm in diameter, without extra-capsular extension, N0) was treated with a 30-mCi I-131 dose under rhTSH stimulus without performing the short 4-day L-4 withdrawal: this group was taken as the control. Follow-up was performed by neck ultrasonography (US), and Tg measurement and I-131 WBS under rhTSH stimulus. RESULTS: Among the patients from group 1, those pre-treated with furosemide or with furosemide plus lithium showed a better outcome of ablation both in terms of undetectable Tg values (97.7% and 95.5 % vs. 79.5%, p < 0.05) and of WBS negativity (97.7% vs. 81.8%, p < 0.05) during the rhTSH stimulus. No similar findings were observed in group 2 patients. Moreover, in patients from group 3 (I-131 30 mCi, without L-T4 withdrawal), the outcome of ablation was significantly lower in comparison to patients from group 1 (I-131 30 mCi, with L-T4 withdrawal) in terms of undetectable Tg during the rhTSH stimulus (55.0%, p < 0.001). CONCLUSION: rhTSH is highly effective for post-surgical thyroid remnant ablation in low-risk cancer patients using the low 30-mCi dose protocol combined with the short 4-day withdrawal of L-T4. Moreover, in these patients the pre-treatment with furosemide seems to play an important role to further improve the outcome of ablation by reducing the iodine pool.

Standard versus video-assisted thyroidectomy: objective postoperative pain evaluation.

BACKGROUND: This prospective, randomized study was designed to objectively demonstrate that minimally invasive video-assisted thyroidectomy (MIVAT) improves postoperative pain compared with standard thyroidectomy, via the dosage of biochemical mediators measured before and after surgery. METHODS: Forty-nine patients undergoing total thyroidectomy were allotted to MIVAT (n = 23) or traditional thyroidectomy (OPEN) (n = 26) groups. At hospitalization (T0), interleukin (IL)-1, -2, -4, -6, -10, -3, tumor necrosis factor (TNF)-α, TGF-ß, and MCP-1 were measured. The basal pain tolerance also was evaluated by VAS. Blood samples for interleukin measurement and VAS evaluations were obtained from all patients in the recovery room (T1) and 24 h after surgery (T2). RESULTS: At T0, the MIVAT and the OPEN groups were not different in terms of basal pain tolerance and biochemical profile. At T1, VAS scores were significantly higher (p = 0.04), whereas TGF-ß (p = 0.03) and MCP-1 (p = 0.03) levels were significantly lower in the OPEN than in the MIVAT group. No significant difference was demonstrated for other interleukins. A significant inverse relationship between VAS and TGF-ß was demonstrated and confirmed through the correlation (p = 0.003) and regression (p = 0.003, p < 0.0001, R (2) = 0.172) coefficients; the stepwise regression also demonstrated that TGF was the most predictive factor of postoperative pain (p = 0.0038) through an inverse relationship. No statistically significant difference has been demonstrated at T2. CONCLUSIONS: TGF-ß serum levels immediately after surgery seem to correlate with pain evaluation, confirming that reduced postoperative distress is an objective outcome of MIVAT. This result confirms the results of studies based only on subjective pain evaluations.

1513A>C polymorphism in the P2X7 receptor gene in patients with papillary thyroid cancer: correlation with histological variants and clinical parameters.

INTRODUCTION: The modulation of the purinergic receptor P2X7 may be implicated in human carcinogenesis. The 1513A>C and 489C>T polymorphisms of P2X7R gene induce loss of function and gain of function, respectively. AIM: The aim of the study was to assess the frequency of both 1513A>C and 489C>T polymorphisms in patients with papillary thyroid carcinoma (PTC) and to evaluate the possible association with clinical and histological features. PATIENTS AND METHODS: P2X7R analysis was performed in lymphocytes from 121 PTC patients (100 women, 21 men; aged 43.4 +/- 13.6 yr), 100 matched healthy subjects, and 80 patients with nodular goiter. RESULTS: The minor allele frequency for 1513A>C polymorphism in PTC patients with the classical variant was similar to controls (0.21 and 0.20, respectively), whereas it resulted in a significant increase in patients with the follicular variant (0.36; P = 0.01 vs. classical variant, and P = 0.005 vs. controls). In detail, 13.6% of patients with PTC follicular variant were homozygous for the 1513C allele, compared to 2.6% of patients with the classical variant and 2% of controls. Moreover, a positive relationship between 1513A>C polymorphism and either cancer diameter (Rho = 0.22; P = 0.02) or TNM stage (Rho = 0.38; P < 0.001) was found. No significant difference in the genotype frequency of 489C>T polymorphism between PTC patients and healthy controls was observed (0.42 and 0.47, respectively). CONCLUSIONS: Our data show, for the first time, a strong association between 1513A>C polymorphism of P2X7R gene and the follicular variant of PTC. Further studies are needed to confirm the possible role of this polymorphism as a novel clinical marker of PTC follicular variant and its usefulness in selecting patients with different clinical outcome.

Thiazolidinediones and antiblastics in primary human anaplastic thyroid cancer cells.

OBJECTIVE: No study has evaluated the antiproliferative effects of thiazolidinediones and antiblastics in 'primary cultured human anaplastic thyroid cancer cells'. DESIGN: Primary anaplastic cells proliferation was evaluated after incubation with increasing concentrations of rosiglitazone or pioglitazone or antiblastics (bleomycin, cisplatin, gemcitabine) by a proliferation assay (WST-1-tetrazolium reaction) and cell counting. MEASUREMENTS AND RESULTS: A reduction of proliferation by thiazolidinediones at 1 h (from the start of tetrazolium reaction) [of 11% and 25%, with rosiglitazone, 10 or 20 (P = 0.0001) microM, respectively; of 7% and 17%, with pioglitazone, 10 or 20 (P = 0.0125) microM, respectively], and at 2 h [of 14% and 24%, with rosiglitazone, 10 (P = 0.0043) or 20 (P < 0.0001) microM, respectively; of 9% and 21%, with pioglitazone, 10 (P = 0.0397) or 20 (P = 0.0001) microM, respectively] was shown. No significant thiazolidinediones effect was observed in normal thyroid follicular cells. Bleomycin, cisplatin and gemcitabine significantly (P < 0.0001) inhibited (> 50%) anaplastic cells proliferation. Cell counting confirmed the above mentioned results. Inhibition of proliferation was similar in tumours with or without (V600E)BRAF mutation, both for thiazolidinediones and antiblastics. CONCLUSIONS: Thiazolidinediones exert an antiproliferative effect in primary cultured human anaplastic carcinoma cells in vitro, such as antiblastics.

Modified lateral neck lymphadenectomy: prospective randomized study comparing harmonic scalpel with clamp-and-tie technique.

OBJECTIVE: To compare the use of harmonic scalpel (HS) with clamp-and-tie technique to evaluate their comparative merits in modified lateral lymphadenectomy (LL). STUDY DESIGN: Prospective and randomized. SUBJECTS AND METHODS: Thirty-seven patients were recruited and divided into Group A (conventional; n = 20) and Group B (HS; n = 17). Thyroid volume, neck circumference, operative time, diameter of the tumor and lymph node, drainage volume, pain, and complications were compared. Operation consisted of thyroidectomy and LL. RESULTS: Groups were homogeneous for thyroid volume, diameter of thyroid nodule and lymph node, and neck circumference. Operative time was shorter in Group B than in Group A. The fluid collection in the vacuum between 24 and 48 hours and the increase of neck circumference were lower in Group B. Pain was significantly lower in Group B after 12 hours and decrease was faster in Group B. CONCLUSION: The use of HS during LL is as safe as conventional technique and may allow shorter operative time, lower lymphatic spillage, and faster decrease of pain.

Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study.

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.

Plasma and urine aldosterone to plasma renin activity ratio in the diagnosis of primary aldosteronism.

OBJECTIVE: To establish the best cut-off value of the aldosterone (ALD)/plasma renin activity (PRA) ratio when screening patients for primary aldosteronism. One hundred and six patients with primary aldosteronism and 100 essential hypertensive patients were investigated in rigorous standardized conditions. METHODS: The ALD/PRA cut-off values were calculated from both the plasma and urine ALD/PRA ratio and analyzed by receiver operating characteristic (ROC) curve. In patients with PRA below 0.2 ng/ml/h [our radioimmunoassay detection limit], values were calculated both with PRA levels set at 0.2 ng/ml/h ('adjusted') and with PRA levels detected ('unadjusted') in the assay. RESULTS: ROC analysis on the ALD/PRA ratio indicated that the best performance was obtained when the plasma ALD (ng/dl)/PRA ratio was used in comparison with that observed in the urine ALD (microg/day)/PRA ratio. In patients with primary aldosteronism, as a whole group, the cut-off value of 69 corresponded to the best compromise value between sensitivity (96%) and specificity (85%), with and without PRA adjustment. In patients with aldosterone-producing adenoma, the cut-off to obtain 100% sensitivity with high specificity (85%) proved to be 69, with and without PRA adjustment. In patients with bilateral adrenal hyperplasia, both with and without PRA adjustment, the best compromise between sensitivity (94%) and specificity (86%) was a cut-off value of 71. CONCLUSION: The best cut-off to identify patients with primary aldosteronism, corresponding to 69, was obtained by using the plasma ALD/PRA ratio. Adjustment of PRA to 0.2 ng/ml/h does not interfere with calculation of the plasma ALD/PRA ratio cut-off.

Primary cell cultures from anaplastic thyroid cancer obtained by fine-needle aspiration used for chemosensitivity tests.

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.

Dedifferentiated thyroid cancer: a therapeutic challenge.

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.

Papillary thyroid cancer: pathological parameters as prognostic factors in different classes of age.

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.

Clinically unpredictable prognostic factors in the outcome of medullary thyroid cancer.

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.

The heterogeneous distribution of BRAF mutation supports the independent clonal origin of distinct tumor foci in multifocal papillary thyroid carcinoma.

CONTEXT: Papillary thyroid carcinoma (PTC) is frequently multifocal. Independent PTC foci may occur either from intraglandular metastases from a single dominant tumor or as unrelated neoplastic clones. In rare cases, the simultaneous presence of PTC foci of different histopathological subtypes points to independent sites of tumor formation. OBJECTIVES: We examined the pattern of BRAF mutations in noncontiguous tumor foci and node metastases from 69 patients affected by multicentric PTC. These included 19 cases characterized by the simultaneous presence of different PTC histopathological variants. DESIGN: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples. RESULTS: Discordant patterns of BRAF mutation were found in about 40% of the multifocal PTCs. In node metastases, BRAF mutations were, in most but not all the cases, concordant with the dominant tumor. A discordant pattern of BRAF mutation was also found in about 50% of the cases in which multiple foci of different histopathological variants were present. CONCLUSIONS: The heterogeneous distribution of BRAF mutations suggests that discrete tumor foci in multifocal PTC may occur as independent tumors. This information has to be considered in the design of targeted therapeutic approaches with BRAF pathway inhibitors.

Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial.

CONTEXT: It is unclear whether patients with asymptomatic primary hyperparathyroidism (PHPT) do better with parathyroidectomy (PTx) as compared with conservative medical management. OBJECTIVE: The aim of the study was to evaluate the beneficial effect of PTx vs. conservative management in patients with mild asymptomatic PHPT. DESIGN: We conducted a prospective, randomized study. SETTING: The study took place at a referral center. PATIENTS: We studied 50 patients who did not meet any guidelines for parathyroid surgery as recommended by the National Institutes of Health Consensus Development Conference on Asymptomatic PHPT. INTERVENTION: Patients were randomly assigned to PTx or no PTx and were evaluated at 6 months and at 1 yr. MAIN OUTCOME MEASURES: We compared changes (percentage of basal) of lumbar spine bone mineral density (BMD) between the two groups at 1 yr. RESULTS: The change in BMD at lumbar spine was greater after PTx (+4.16 +/- 1.13 for PTx vs. -1.12 +/- 0.71 for no PTx; P = 0.0002). The change in BMD at the total hip was also significantly greater in the PTx group (+2.61 +/- 0.71 for PTx vs. -1.88 +/- 0.60 for no PTx; P = 0.0001). There was no difference in BMD after 1 yr between both groups at the one-third radius site. In comparison with those who did not undergo surgery, the PTx subjects, after 1 yr, showed significant differences in four quality of life measures as determined by the 36-item short form health survey scale: bodily pain (P = 0.001), general health (P = 0.008), vitality (P = 0.003), and mental health (P = 0.017). CONCLUSIONS: In patients with mild asymptomatic PHPT, successful PTx is followed by an improvement in BMD and quality of life. Most patients followed without surgery did not show evidence of progression.

Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma.

CONTEXT: Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation. OBJECTIVE: We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class. DESIGN: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples. RESULTS: In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600-1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600-3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P < 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P < 0.00000006), and absence of tumor capsule (P < 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation. CONCLUSIONS: Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.

Should parafibromin staining replace HRTP2 gene analysis as an additional tool for histologic diagnosis of parathyroid carcinoma?

OBJECTIVE: HRPT2 gene mutations are associated with parathyroid carcinomas, and absence of parafibromin immunoreactivity has been suggested as a diagnostic marker of malignancy. The aim of our study was to extend parafibromin studies in a series of benign and malignant parathyroid tumors and cross-validate the results of immunohistochemistry with those of HRPT2 analysis. DESIGN AND PATIENTS: We performed parafibromin and cyclin D1 immunostaining and HRPT2 gene analysis using loss of heterozygosity studies and sequencing analysis in parathyroid specimens from 11 patients with carcinoma (eleven primary tumors, one skin, and four lung metastases), 22 with sporadic adenomas, and 4 with atypical adenomas. RESULTS: Ten out of eleven parathyroid cancers were negative for parafibromin staining and showed HRPT2 gene abnormalities. The remaining sample was negative for immunostaining and genetic analyses. All but one sporadic adenomas showed parafibromin immunoreactivity and no HRPT2 gene abnormalities. The sample with negative immunostaining carried an HRPT2 mutation. Two atypical adenomas were positive and two negative with parafibromin staining. No HRPT2 abnormalities were found in these samples. Cyclin D1 expression was heterogeneous and there was no relationship between expression/expression level of cyclin D1 and parafibromin expression. CONCLUSIONS: We have shown that negative parafibromin staining is almost invariably associated with HRPT2 mutations and confirm that loss of parafibromin staining strongly predicts parathyroid malignancy. In clinical practice, these tests could be particularly useful in the subset of parathyroid tumors with equivocal histological examination. However, their diagnostic value in this setting remains to be proven.

Galectin-3 is highly expressed in nonencapsulated papillary thyroid carcinoma but weakly expressed in encapsulated type; comparison with Hector Battifora mesothelial cell 1 immunoreactivity.

The histologic diagnosis of the follicular variant of papillary thyroid carcinoma (FVPTC) may be troublesome, especially in its encapsulated form. We evaluated the expression of galectin-3 (gal-3) and Hector Battifora mesothelial cell (HBME-1) in 200 formalin-fixed thyroid tissues with diagnosis of classical variant of papillary thyroid carcinoma or FVPTC, encapsulated or with infiltrative growth, with or without lymph node metastasis. All cases of classical variant of papillary thyroid carcinoma were consistently positive for gal-3; similar results have been obtained by using HBME-1. Interestingly, the invasive type of FVPTC, with or without metastasis, was strongly positive for gal-3 (78.2% and 96%, respectively), whereas only 46.8% of encapsulated FVPTCs without metastasis showed immunostaining for this marker. In the latter group, the HBME-1 expression achieved a significantly higher percentage of positivity (87%). Surprisingly, gal-3 immunodetection showed negative results in 4 encapsulated FVPTCs, despite the strong immunoreactivity in corresponding metastasis. Our data suggest that gal-3 immunodetection alone is not able to support the diagnosis of encapsulated FVPTCs.

Combination of minimally invasive thyroid surgery and local anesthesia associated to iopanoic acid for patients with amiodarone-induced thyrotoxicosis and severe cardiac disorders: a pilot study.

BACKGROUND AND AIMS: Amiodarone-induced thyrotoxicosis is a life-threatening condition. A prompt control of thyrotoxicosis is obtained by thyroidectomy. Preparation with iopanoic acid proved to be very effective in reducing cardiovascular complications. Nevertheless, general anesthesia and extensive surgery may affect negatively patients also after adequate preparation. Safety and efficacy of minimally invasive video-assisted thyroidectomy performed under regional anesthesia (bilateral modified deep cervical block) in patients with amiodarone-induced thyrotoxicosis was evaluated. PATIENTS AND METHODS: Eight patients with amiodarone-induced thyrotoxicosis (three with type I and five with type II), mean age 66.2 years, were prepared with iopanoic acid. There were five men and three women. Three patients had dilatative cardiomyopathy, three had heart failure secondary to severe myocardial infarction, and two had refractory unstable rhythm disorders. RESULTS: Minimally invasive video-assisted thyroidectomy was performed under regional anesthesia. Mean operative time was 55.5 min. During surgery, lung and heart function remained well and no surgical complications occurred. After surgery, all patients remained on amiodarone therapy and two patients were subsequently removed from the checklist for heart transplantation. CONCLUSION: Minimally invasive video-assisted thyroidectomy under regional anesthesia can be proposed as resolution of amiodarone-induced thyrotoxicosis in high risk patients with severe cardiac disorders, after preparation with iopanoic acid.

Duodenal Crohn's disease.

The Authors report on an uncommon case of duodenal Crohn's disease in an adult man. The patient was admitted for a history of epigastric pain, recurrent vomiting, weight loss and low grade fever. He was evaluated with esophagogastroduodenoscopy and with radiological double-contrast technique. Then, due to these untreatable clinical manifestations, he underwents a surgical treatment.

Intensive post-operative follow-up of breast cancer patients with tumour markers: CEA, TPA or CA15.3 vs MCA and MCA-CA15.3 vs CEA-TPA-CA15.3 panel in the early detection of distant metastases.

BACKGROUND: In breast cancer current guidelines do not recommend the routine use of serum tumour markers. Differently, we observed that CEA-TPA-CA15.3 (carcinoembryonic (CEA) tissue polypeptide (TPA) and cancer associated 115D8/DF3 (CA15.3) antigens) panel permits early detection and treatment for most relapsing patients. As high sensitivity and specificity and different cut-off values have been reported for mucin-like carcinoma associated antigen (MCA), we compared MCA with the above mentioned tumour markers and MCA-CA15.3 with the CEA-TPA-CA15.3 panel. METHODS: In 289 breast cancer patients submitted to an intensive post-operative follow-up with tumour markers, we compared MCA (cut-off values, > or = 11 and > or = 15 U/mL) with CEA or CA15.3 or TPA for detection of relapse. In addition, we compared the MCA-CA15.3 and CEA-TPA-CA15.3 tumour marker panels. RESULTS: Distant metastases occurred 19 times in 18 (6.7%) of the 268 patients who were disease-free at the beginning of the study. MCA sensitivity with both cut-off values was higher than that of CEA or TPA or CA15.3 (68% vs 10%, 26%, 32% and 53% vs 16%, 42%, 32% respectively). With cut-off > or = 11 U/mL, MCA showed the lowest specificity (42%); with cut-off > or = 15 U/mL, MCA specificity was similar to TPA (73% vs 72%) and lower than that of CEA and CA15.3 (96% and 97% respectively). With > or = 15 U/mL MCA cut-off, MCA sensitivity increased from 53% to 58% after its association with CA15.3. Sensitivity of CEA-TPA-CA15.3 panel was 74% (14 of 19 recurrences). Eight of the 14 recurrences early detected with CEA-TPA-CA15.3 presented as a single lesion (oligometastatic disease) (5) or were confined to bony skeleton (3) (26% and 16% respectively of the 19 relapses). With > or = 11 U/mL MCA cut-off, MCA-CA15.3 association showed higher sensitivity but lower specificity, accuracy and positive predictive value than the CEA-TPA-CA15.3 panel. CONCLUSION: At both the evaluated cut-off values serum MCA sensitivity is higher than that of CEA, TPA or CA15.3 but its specificity is similar to or lower than that of TPA. Overall, CEA-TPA-CA15.3 panel is more accurate than MCA-CA15.3 association and can "early" detect a few relapsed patients with limited metastatic disease and more favourable prognosis. These findings further support the need for prospective randomised clinical trial to assess whether an intensive post-operative follow-up with an appropriate use of serum tumour markers can significantly improve clinical outcome of early detected relapsing patients.