CLM94, a novel cyclic amide with anti-VEGFR-2 and antiangiogenic properties, is active against primary anaplastic thyroid cancer in vitro and in vivo.

CONTEXT AND OBJECTIVE: We have studied the antitumor activity of a novel cyclic amide, CLM94, with anti-vascular endothelial growth factor (VEGF) receptor-2 and antiangiogenic activity in primary anaplastic thyroid cancer (ATC) cells in vitro and in vivo. DESIGN AND MAIN OUTCOME MEASURES: CLM94 was tested: 1) in two human cell lines (HMVEC-d, dermal microvascular endothelial cells; and 8305C, undifferentiated thyroid cancer) at 0.001-100 µm; 2) in ATC cells at the concentrations of 10, 30, and 50 µm; and 3) in an ATC cell line (AF) in CD nu/nu mice. RESULTS: CLM94 significantly inhibited VEGF receptor-2 and epidermal growth factor receptor phosphorylation in HMVEC-d and proliferation in HMVEC-d and 8305C cells. A significant reduction of proliferation with CLM94 in ATC cells (P < 0.01, ANOVA) and a slight but significant reduction of proliferation with CLM94 30 and 50 µm in normal thyroid follicular cells (P < 0.01, ANOVA) were shown. CLM94 increased the percentage of apoptotic ATC cells dose-dependently (P < 0.001, ANOVA) and inhibited migration (P < 0.01) and invasion (P < 0.001). AF cell line was injected sc in CD nu/nu mice, and tumor masses became detectable 25 d afterward. CLM94 (40 mg/kg · d) significantly inhibited tumor growth (starting 10 d after the beginning of treatment). CLM94 significantly decreased the VEGF-A gene expression in the AF cell line and the VEGF-A protein and microvessel density in AF tumor tissues. CONCLUSIONS: The antitumor and antiangiogenic activity of a new "cyclic amide" compound, CLM94, is very promising in ATC, opening the way to a future clinical evaluation.

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.

The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center.

BACKGROUND: Medullary thyroid carcinoma (MTC) is a calcitonin (CT)-producing C-cell tumor. In hereditary cases, a germline RET mutation is found in 98% of families. Because MTC is cured only if intrathyroidal, prophylactic thyroidectomy is recommended in the gene carrier (GC). AIMS: The aim was to determine whether thyroidectomy performed when stimulated CT becomes detectable is as safe as prophylactic thyroidectomy and to identify the serum CT cutoff able to distinguish intrathyroidal from extrathyroidal MTC. PATIENTS: Eighty-four GC were prospectively enrolled; 53 of the 84 underwent total thyroidectomy, one refused surgery, and 30 with normal basal and stimulated CT were under surveillance. The follow-up ranged from 2 to 18 yr. RESULTS: GC operated on for elevated stimulated CT included 27 GC with a positive peak CT at the screening and four cases who became positive after 4 yr. All of them had intrathyroidal MTC and no node metastases; all were cured after a mean follow-up of 7.5 yr. Among those operated on for detectable basal CT, intrathyroidal tumors were found when CT was below 60 pg/ml, whereas either node metastases or larger tumors were observed when CT was above 60 pg/ml. No correlation among serum CT, age, and type of RET mutation was observed. Thirty GC were still biochemically negative at the annual control. CONCLUSIONS: The time of thyroidectomy in GC with negative CT could be personalized and safely planned when stimulated CT becomes positive, independent of the type of RET mutation and patient's age. In this series, a basal CT below 60 pg/ml was always associated to an intrathyroidal localization of MTC.

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells.

AIMS: To demonstrate the antiproliferative and pro-apoptotic activity of the novel pyrazolopyrimidine derivative multiple tyrosine kinase inhibitor CLM3, alone and in combination with SN-38 (the active metabolite of irinotecan), on endothelial and tumor cells and to show its mechanism of action. METHODS: Proliferation and apoptotic assays were performed on microvascular endothelial (HMVEC-d) and lung (A549) and thyroid cancer (8305C, TT) cell lines exposed to CLM3 and to the simultaneous combination with SN38 for 72h. Cell-based phospho-VEGFR-2, phospho-EGFR and phospho-RET inhibition assays were performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Cyclin D1 gene expression was performed with real-time PCR and cyclin D1 intracellular concentrations were measured by ELISA. RESULTS: A strong effect on antiproliferative and pro-apoptotic activity was found with the CLM3 on endothelial and cancer cells, synergistically enhanced by SN38. Phospho-VEGFR-2, phospho-EGFR and phospho-RET levels significantly decreased after CLM3 treatments in activated endothelial and cancer cells; ERK1/2 and Akt phosphorylation were significantly inhibited by lower concentrations of the pyrazolopyrimidine drug in endothelial cells if compared to cancer cells. Moreover, CLM3 treatment greatly inhibited the expression of the cyclin D1 gene in endothelial and cancer cells, decreasing the cyclin D1 protein intracellular concentration. CONCLUSIONS: The pyrazolopyrimidine derivative CLM3 demonstrated a highly significant and promising antiproliferative and proapoptotic activity, alone and in combination with SN-38, for activated endothelial and cancer cells. These effects are mainly due to its inhibition of phosphorylation of VEGFR-2, EGFR and RET tyrosine kinases and their related signaling pathways.

Novel pyrazolopyrimidine derivatives as tyrosine kinase inhibitors with antitumoral activity in vitro and in vivo in papillary dedifferentiated thyroid cancer.

AIM: We have studied the antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3 and CLM29) in primary papillary dedifferentiated thyroid cancer (DePTC) cells. METHODS: The antiproliferative effect was tested in DePTC cells obtained at reoperation from patients with recurrence of the tumor. The concentrations of CLM3 and CLM29 used in the in vitro experiments were 1, 10, 30, and 50 µm. RESULTS: Proliferation assays in DePTC cells showed a significant reduction of proliferation by CLM3 and CLM29, which was by 12% with CLM3 (the most potent compound) 10 µm, 43% with CLM3 30 µm, and 60% with CLM3 50 µm. CLM3 and CLM29 increased the percentage of apoptotic cells in DePTC cells dose dependently (P < 0.001) and inhibited migration (P < 0.001). A DePTC cell line (AL) was injected sc in CD nu/nu mice, and tumor masses became detectable 10 d after xenotransplantation. CLM3 (40 mg/kg · die) significantly inhibited tumor growth and weight, and the therapeutic effect was significant starting on the 19th day after cell implantation (4 d after the beginning of treatment). The CLM3-treated group of animals did not show any appreciable toxicity. CLM3 and CLM29 increased thrombospondin-1 expression in the AL cell line. A significant reduction of microvessels and in the percentage of antivascular endothelial growth factor antibody immunoreactivity was observed in the CLM3 treated tumors, with a simultaneous increase of the percentage of necrosis. CONCLUSION: The antitumoral activity of two new pyrazolo[3,4-d]pyrimidine compounds (CLM3, CLM29) in vitro and CLM3 in vivo in DePTC has been shown, opening the way to a future clinical evaluation.

A proteomic approach to study parathyroid glands.

Parathyroid tumours are heterogeneous and in some cases the diagnosis may be difficult using histological features. In this study we used a two-dimensional electrophoresis (2D)/mass spectrometry (MS)-based approach to examine the global changes of parathyroid adenoma tissues protein profile compared to the parathyroid normal tissues. Validation of protein expression was performed by immunoblotting using specific antibodies. Ingenuity software was used to identify the biological processes to which these proteins belong and to construct a potential network. A total of 30 proteins were found to be differentially expressed, of which 22 resulted in being over-expressed. Proteins identified by 2D/MS/MS proteomics were classified into functional categories and a major change (≥ 2-fold) in terms of expression was found in proteins involved in response to biotic stimuli, cell organization and signal transduction. After Ingenuity analysis, 14-3-3 ζ/δ appears to be a key protein in the network of parathyroid adenoma, where it is linked to other proteins such as annexin A2, B box and SPRY domain-containing protein (BSPRY), p53 and epidermal growth factor receptor (EGFR). Our results suggest that the proteomic approach was able to differentiate the protein profiles of normal parathyroid and parathyroid adenoma and identify a panel of proteins which are differentially expressed. The functional role of these proteins in the network of intracellular pathways is discussed.

Intensive risk-adjusted follow-up with the CEA, TPA, CA19.9, and CA72.4 tumor marker panel and abdominal ultrasonography to diagnose operable colorectal cancer recurrences: effect on survival.

HYPOTHESIS: Intensive risk-adjusted follow-up leads to improved resectability of tumor recurrences and better overall survival among patients who have undergone surgery for colorectal cancer. DESIGN: Long-term observational single-center study. SETTING: University of Pisa, Pisa, Italy. PATIENTS: One hundred eight disease-free patients who had undergone surgery for colorectal cancer were submitted to long-term follow-up with the serum CEA, TPA, CA19.9, and CA72.4 tumor marker (TM) panel and abdominal ultrasonography. MAIN OUTCOME MEASURES: Sensitivities and specificities of TMs, abdominal ultrasonography, and abdominal and chest computed tomography (CT); the median survival among patients operated on and those not operated on and the cumulative 5-year overall survival among the entire group. RESULTS: Twenty-two patients with asymptomatic colorectal cancer recurred 32 times. The CEA, TPA, CA19.9, CA72.4, and TM panel sensitivities were 46.9%, 34.4%, 9.4%, 9.4%, and 81.0%, respectively, and the mean (SD) lead times before confirmation of recurrence were 4.3 (4.8), 4.1 (4.7), 8.3 (10.9), 5.0 (7.0), and 5.3 (5.8) months, respectively. Abdominal and chest CT sensitivities were 100.0%. Among 86 patients without recurrence, specificities of the TM panel and all panel markers were 100.0%, while specificities of abdominal ultrasonography, abdominal CT, and skeletal CT were 99.9%, 99.0%, and 100.0%, respectively. The median survival after first recurrence was 16 months (range, 3-48 months) for 8 patients with recurrence who did not undergo second-line surgery. Among 14 remaining patients who underwent metastasectomy, the median survival after first recurrence was 37 months (range, 12-187 months; P = .03). Among the entire group of 108 patients, the cumulative 5-year overall survival was 88.7%. CONCLUSIONS: Long-term intensive risk-adjusted monitoring using the CEA, TPA, CA19.9, and CA72.4 TM panel and abdominal ultrasonography allows early detection of most recurrences. Patients can then undergo radical metastasectomy, with potentially improved overall survival.

BRAF status of follicular variant of papillary thyroid carcinoma and its relationship to its clinical and cytological features.

BACKGROUND: The cytological discrimination between benign and malignant follicular-patterned lesions of the thyroid can represent a diagnostic challenge, even for experienced pathologists. To attempt to clarify this diagnostic problem, we analyzed the BRAF status of thyroid tumors in a group of patients with follicular variant of papillary thyroid carcinoma (FVPTC) and its correlation with cytomorphological features. METHODS: The BRAF status was evaluated in a total of 187 patients in whom FVPTC was consecutively diagnosed by histology between January 2006 and January 2009. Each case had a previous fine-needle aspiration diagnosis classified according to the British Thyroid Association Guidelines categorized as inadequate (Thy1) (n = 19), benign (Thy2) (n = 19), follicular lesion and follicular lesion with atypia (Thy3) (n = 109), suspicious of PTC (Thy4) (n = 29), or malignant (Thy5) (n = 11). The first 68 cases were selected for a morphological study by a quantitative analysis of four cytological features (grooves, intranuclear cytoplasmatic inclusions, number of cells per high power field (400 ×), and mean nuclear diameter) of the carcinomas. RESULTS: The BRAF status of each tumor was correlated with the cytological classes. 54.5% and 27.6% of Thy5 and Thy4, respectively, were BRAF-mutated, against 12.1% of follicular lesions and 9.3% of follicular lesion with atypia (Thy3). This comparison was statistically significative (p = 0.0017). Among the 68 cases selected for the cyto-morphological study, the BRAF status frequency was similar to that of the total case series. No significant differences were found correlating the cytological classes with the number of cells, the number of grooves, and the mean cell diameters. Only the number of intranuclear cytoplasmatic inclusions were associated (p < 0.05) with the Thy5 cytological class. CONCLUSIONS: BRAF is mutated in a low percentage of FVPTC, and most of these mutated cases are suspicious or positive on fine-needle aspiration. BRAF analysis is of limited value in the preoperative diagnosis of FVPTC.

Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases.

CONTEXT: Evaluation of the degree of neoplastic infiltration beyond the thyroid capsule remains a unique parameter that can be evaluated by histopathological examination to label a papillary thyroid carcinoma (PTC) of 20 mm or less in size as a pT1 or pT3 tumor. OBJECTIVE: We correlated the BRAF V600E mutation with both clinical-pathological features and the degree of neoplastic infiltration to redefine the reliability of the actual system of risk stratification in a large selected group of PTCs smaller than 20 mm. DESIGN: The presence of BRAF mutations was examined in 1060 PTCs less than 20 mm divided into four degrees of neoplastic infiltration: 1) totally encapsulated; 2) not encapsulated without thyroid capsule invasion; 3) thyroid capsule invasion; and 4) extrathyroidal extension. RESULTS: The overall frequency of the BRAF V600E mutation was 44.6%. In both univariate and multivariate analyses, BRAF mutations showed a strong association with PTC variants (classical and tall cell), tumor size (11-20 mm), multifocality, absence of tumor capsule, extrathyroidal extension, lymph node metastasis, higher American Joint Commission on Cancer stage, and younger patient age. In PTCs staged as pT1 with thyroid capsule invasion, the frequency of BRAF mutations was significantly higher than in pT1 tumors that did not invade the thyroid capsule (67.3 vs. 31.8%, respectively; P < 0.0001). No statistically significant difference in BRAF alterations was found between pT1 tumors with thyroid capsule invasion and pT3 tumors (67.3 and 67.5%, respectively). CONCLUSION: We suggest that evaluation of BRAF status would be useful even in pT1 tumors to improve risk stratification and patient management, although follow-up data are necessary to confirm our speculations.

Evaluation of a new ultrasonic device in thyroid surgery: comparative randomized study.

BACKGROUND: Conventional techniques for hemostasis during thyroidectomy rely on knot tying, clips, and electrocoagulation. Recently, the Harmonic FOCUS Shear (Ethicon Endo-Surgery, Inc, Cincinnati, OH) was developed for thyroidectomy. METHODS: Between December 2007 and March 2008, 62 consecutive patients (45 women, 17 men; mean age 50.9 years) undergoing thyroidectomy were randomized into 2 groups: group A, where the FOCUS was used, and group B, where electrocoagulation and clamp-and-tie technique were used. RESULTS: The 2 groups were similar in terms of age, sex ratio, indication for surgery, and thyroid volume. Operative time was significantly shorter in group A. Significantly fewer clips and ties were used, and postoperative pain and suction balloon amount were also significantly lower in the FOCUS group. The only postoperative complication was a patient with transient hypocalcemia in group B. CONCLUSIONS: FOCUS is a reliable and safe tool for thyroidectomy. Its utilization is associated with a shorter operative time, less blood loss, and less postoperative pain.

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.

Minimally invasive thyroidectomy in the treatment of well differentiated thyroid cancers: indications and limits.

PURPOSE OF REVIEW: To summarize recent papers in the literature with respect to minimally invasive thyroidectomy and discuss indications and limits of the endoscopic/video-assisted treatment of differentiated thyroid carcinoma. RECENT FINDINGS: During the 1990s, with the general tendency to develop minimally invasive operations, an endoscopic approach was applied to neck surgery for both parathyroidectomy and thyroidectomy. The most wide spread minimally invasive technique for thyroidectomy is minimally invasive video-assisted thyroidectomy (MIVAT). SUMMARY: Papillary carcinoma is the main indication for MIVAT, this cancer usually being found in normal glands of young women. In contrast, for locally invasive carcinomas, lymph node metastasis or both, the procedure must be immediately converted to the conventional technique. MIVAT also is not indicated for the treatment of medullary and anaplastic carcinomas. Recent prospective randomized studies clearly demonstrate that MIVAT allows the same clearance to be achieved at the thyroid bed level and the same outcome as with the conventional technique, when dealing with 'low-risk' papillary carcinoma. At the same time, patients can benefit from the main advantages of this minimally invasive technique: less postoperative pain, faster postoperative recovery and excellent cosmetic outcome.

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.

Dysregulation of secretion of CXC alpha-chemokine CXCL10 in papillary thyroid cancer: modulation by peroxisome proliferator-activated receptor-gamma agonists.

In papillary thyroid carcinomas (PTCs), oncogenes activate a transcriptional program including the upregulation of CXCL10 chemokine, which stimulates proliferation and invasion. Furthermore, peroxisome proliferator-activated receptor-gamma (PPARgamma) activators thiazolidinediones (TZDs) modulate CXCL10 secretion in normal thyroid follicular cells (TFC), and inhibit PTC growth. Until now, no study has evaluated the effect of cytokines on CXCL10 secretion in PTCs, nor the effect of PPARgamma activation. The combined effects of interferon gamma (IFNgamma) and tumor necrosis factor alpha (TNFalpha) stimulation on CXCL10 secretion in primary cells from PTCs and TFC were tested. Furthermore, the effect of PPARgamma activation by TZDs, on CXCL10 secretion and proliferation in these cell types was studied. In primary cultures of TFC and PTCs CXCL10 production was absent under basal conditions; a similar dose-dependent secretion of CXCL10 was induced by IFNgamma in both cell types. TNFalpha alone induced a slight but significant CXCL10 secretion only in PTCs. The stimulation with IFNgamma+TNFalpha induced a synergistic CXCL10 release in both cell types; however, a secretion more than ten times higher was induced in PTCs. Treatment of TFC with TZDs dose-dependently suppressed IFNgamma+TNFalpha-induced CXCL10 release, while TZDs stimulated CXCL10 secretion in PTCs. A significant antiproliferative effect by TZDs was observed only in PTCs. In conclusion, a dysregulation of CXCL10 secretion has been shown in PTCs. In fact, a CXCL10 secretion more than ten times higher has been induced by IFNgamma+TNFalpha in PTCs with respect to TFC. Moreover, TZDs inhibited CXCL10 secretion in TFC and stimulated it in PTCs. The effect of TZDs on CXCL10 was unrelated to the significant antiproliferative effect in PTCs.

Surgical treatment of low- and intermediate-risk papillary thyroid cancer with minimally invasive video-assisted thyroidectomy.

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.

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.

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.