Enrico De Antoni

Q-elastography in the presurgical diagnosis of thyroid nodules with indeterminate cytology.

Quantitative ultrasound (US) elastography (Q-USE), able to evaluate tissue stiffness has been indicated as a new diagnostic tool to differentiate benign from malignant thyroid lesions. Aim of this prospective study, conducted at the Department of Surgical Sciences, of the “Sapienza” University of Rome, was to evaluate the diagnostic accuracy of Q-USE, compared with US parameters, in thyroid nodules with indeterminate cytology (Thy3).The case study included 140 nodules from 140 consecutive patients. Patient’s thyroid nodules were evaluated by Q-USE, measuring the strain ratio (SR) of stiffness between nodular and surrounding normal thyroid tissue, and conventional US parameters prior fine-needle aspiration cytology. Those with Thy3 diagnosis were included in the study. Forty of the nodules analyzed harbored a malignant lesion. Q-USE demonstrated that malignant nodules have a significant higher stiffness with respect to benign one and an optimun SR cut-off value of 2.05 was individuated following ROC analysis. Univariate analysis showed that hypoechogenicity, irregular margins and SR >2.05 associated with malignancy, with an accuracy of 67.2%, 81,0% and 89.8%, respectively. Data were unaffected by nodule size or thyroiditis. These findings were confirmed in multivariate analysis demonstrating a significant association of the SR and the irregular margins with thyroid nodule’s malignancy. In conclusion, we demonstrated the diagnostic utility of Q-USE in the differential diagnosis of thyroid nodules with indeterminate cytology that, if confirmed, could be of major clinical utility in patients’ presurgical selection.

Prognostic Importance of Histologic Vascular Invasion in Papillary Thyroid Carcinoma

Objective:To conduct a retrospective study of 39 patients with papillary carcinoma of the thyroid with histologic vascular invasion (VI+) and 361 patients without any sign of vascular invasion (VI−). Summary Background Data:In the present study, we undertook a retrospective analysis of papillary carcinoma of the thyroid to assess whether histologically determined vascular invasion can be considered a predictive factor for prognosis. Methods:By means of a retrospective study, we evaluated the departments database of patients with papillary thyroid carcinoma who had undergone total thyroidectomy from January 1993 to December 1999. Results:Group I consisted of papillary carcinoma without any sign of vascular invasion (VI−) comprising 361 patients. Group II consisted of papillary carcinoma with vascular invasion (VI+) comprising 39 patients. At the time of diagnosis, we observed no metastases in patients with VI−, whereas a pulmonary metastasis was observed in 1 patient with VI+ (P = 0.0023). In 3.6% patients with VI− and in 20.5% patients with VI+, we observed recurrences in the regional lymph nodes (P < 0.001); we observed 6 (1.66%) distant metastases in patients with VI− and in the 12.8% patients with VI+ (P < 0.001). Three patients with VI+ (7.7%) and 2 patients with VI− (0.6%) died of tumor-related causes; these figures were found to be statistically significant (P < 0.001). Conclusions:In papillary carcinoma, it should be noted that histologic vascular invasion may be considered as a sign of an increased tendency toward hematogenic invasion and consequent increase in the relative percentage of metastases; ultimately, this means a poorer prognosis. In the presence of risk factors indicating a possible increase in biologic aggressiveness, adequate postoperative treatment and close follow up become essential.

Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues

Aurora-A kinase has recently been shown to be deregulated in thyroid cancer cells and tissues. Among the Aurora-A substrates identified, transforming acidic coiled-coil (TACC3), a member of the TACC family, plays an important role in cell cycle progression and alterations of its expression occur in different cancer tissues. In this study, we demonstrated the expression of the TACC3 gene in normal human thyroid cells (HTU5), and its modulation at both mRNA and protein levels during cell cycle. Its expression was found, with respect to HTU5 cells, unchanged in cells derived from a benign thyroid follicular tumor (HTU42), and significantly reduced in cell lines derived from follicular (FTC-133), papillary (B-CPAP), and anaplastic thyroid carcinomas (CAL-62 and 8305C). Moreover, in 16 differentiated thyroid cancer tissues, TACC3 mRNA levels were found, with respect to normal matched tissues, reduced by twofold in 56% of cases and increased by twofold in 44% of cases. In the same tissues, a correlation between the expression of the TACC3 and Aurora-A mRNAs was observed. TACC3 and Aurora-A interact in vivo in thyroid cells and both proteins localized onto the mitotic structure of thyroid cells. Finally, TACC3 localization on spindle microtubule was no more observed following the inhibition of Aurora kinase activity by VX-680. We propose that Aurora-A and TACC3 interaction is important to control the mitotic spindle organization required for proper chromosome segregation.

Comparison of Malignancy Rate in Thyroid Nodules with Cytology of Indeterminate Follicular or Indeterminate Hürthle Cell Neoplasm

BACKGROUND Thyroid nodules that are read on cytology as follicular or Hürthle cell neoplasms (FN and HN, respectively) and indeterminate for malignancy require surgery to differentiate benign from malignant nodules. We analyzed FN and HN with indeterminate cytology to determine if there were differences in the rate and types of thyroid malignancy and if the rate of thyroid malignancy was influenced by age or sex. METHODS We analyzed 463 nodules with an indeterminate cytological diagnosis of FN and 140 nodules with an indeterminate cytological diagnosis of HN. The histopathological diagnosis after thyroidectomy was the method for establishing the diagnosis and type of malignancy. RESULTS For the entire series of 603 patients there were 106 (17.6%) with thyroid cancer; 80 of these had a cytology reading of FN and 26 had HN. Extrathyroidal invasion in the grouped HN and FN patients who had papillary thyroid carcinoma (PTC) was more common in females than in males (62% vs. 25 %, p < 0.05). The rate of thyroid cancer was similar in FN (17.3%) and HN (18.6%). The rate of Hürthle cell thyroid cancer was significantly higher in HN than in FN (5.0% vs. 0.7%, p < 0.01) and the rate of the oncocytic variant of PTC was also significantly greater in HN compared to FN nodules (23.1% vs. 1.7%, p < 0.05). The rate of follicular thyroid carcinoma was almost identical in patients with HN and FN (19.2% vs. 18.8 %). CONCLUSIONS There is little difference in the rate of malignancy between thyroid nodules with a cytological reading of FN indeterminate for malignancy and HN indeterminate for malignancy but there is a difference in the types of thyroid cancers in these groups. Hürthle cell thyroid cancer and the oncocytic variant of PTC is more common in nodules with an HN indeterminate for malignancy cytology reading than in nodules with a FN indeterminate for malignancy cytology reading. Since Hürthle cell thyroid cancer and the oncocytic variant of PTC are more aggressive than other thyroid cancers, it is likely that patients with an HN indeterminate for malignancy cytology will, as a group, have more aggressive thyroid cancers than those with an FN indeterminate for malignancy cytology.

High Expression of the Urokinase Plasminogen Activator and Its Cognate Receptor Associates with Advanced Stages and Reduced Disease-Free Interval in Papillary Thyroid Carcinoma

CONTEXT The urokinase plasminogen activating system is implicated in neoplastic progression, and high tissue levels of urokinase plasminogen activating system components correlate with poor prognosis in various human cancers. OBJECTIVE The objective of the study was to investigate the prognostic relevance of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR), and the plasminogen activator inhibitor 1 (PAI-1) in human papillary thyroid cancer (PTC). DESIGN The expression of uPA, uPAR, and PAI-1 genes was analyzed in PTC and normal matched tissues by quantitative RT-PCR. The case study consisted of 99 patients (21 males and 78 females) affected by PTC including 77 classical, 15 follicular, four tall cell, and three oncocytic variants. Forty-one patients had lymph node metastases at the time of diagnosis. All the patients underwent thyroidectomy and radioiodine therapy followed by thyroid hormone replacement therapy. Follow-up data were available for 76 patients up to 64 months. RESULTS The uPA, uPAR, and PAI-1 mRNA levels were significantly higher in PTC compared with normal matched tissues by 9.63 ± 1,29-, 4.82 ± 0.45-, and 5.64 ± 0.71-fold, respectively. The increased expression of uPA and uPAR correlated statistically with advanced pT and N status. The uPA was also significantly associated with advanced tumor node metastasis stages. The Kaplan-Meier analysis showed a significant association of uPA and uPAR levels with reduced patient disease-free interval (DFI), and this association was stronger in stage I patients. CONCLUSION The study demonstrated that in PTC the increased gene expression of uPA and uPAR is associated with tumor invasiveness, advanced stages, and shorter DFI, suggesting their prognostic relevance. These observations warrant further investigation in larger patient populations with longer follow-up.

Cervical lymph node metastases from thyroid cancer: does thyroglobulin and calcitonin measurement in fine needle aspirates improve the diagnostic value of cytology?

BackgroundMeasurement of thyroglobulin (Tg) protein in the washout of the needle used for fine needle aspiration biopsy cytology (FNAB-C) has been shown to increase the sensitivity of FNAB-C in identifying cervical lymph node (CLN) metastasis from well-differentiated thyroid cancer (TC). In this study, we evaluated whether routine measurement of Tg protein (FNAB-Tgp), Tg mRNA (FNAB-Tgm) and calcitonin (CT) mRNA (FNAB-CTm) in the FNAB washout of CLN increases the accuracy of FNAB-C in the diagnosis of suspicious metastatic CLN.MethodsIn this prospective study 35 CLN from 28 patients were examined. Histology showed metastatic papillary TC (PTC) in 26 CLN, metastatic medullary TC (MTC) in 3 CLN, metastatic anaplastic TC (ATC) in 3 CLN and 3 metastatic CLN from extra-thyroidal cancers.ResultsThe overall accuracy of FNAB-C was 84.4%, reaching 95.7% when the analysis was restricted to PTC. Both FNAB-Tgp and FNAB-Tgm compared favorably with FNAB-C and shown diagnostic performances not statistically different from that of FNAB-C. However, FNAB-Tgp and FNAB-Tgm/FNAB-CTm were found useful in cases in which cytology results were inadequate or provided diagnosis inconsistent with patients clinical parameters.ConclusionsWe demonstrated that FNAB-C, Tg/CT mRNA and Tg protein determination in the fine-needle washout showed similar accuracy in the diagnosis of metastatic CLN from TC. The results of this study suggest that samples for Tg protein and Tg/CT mRNA measurements from CLN suspicious for metastatic TC should be collected, but their measurements should be restricted to cases in which FNAB-C provides uninformative or inconsistent diagnosis with respect to patients clinical parameters.

Analysis of clinical, ultrasound and colour flow‐Doppler characteristics in predicting malignancy in follicular thyroid neoplasms

Fine-needle aspiration cytology (FNAC) represents the main diagnostic tool in the evaluation of thyroid nodules because of its high sensitivity, specificity and accuracy. However, while FNAC is very reliable in detecting papillary thyroid carcinomas (PTC) and anaplastic thyroid carcinomas, follicular neoplasms (FN) represent the grey zone in which cytology cannot discriminate malignant from benign tumours. 1 Consequently, in presence of nodules cytologically classified as FN, thyroidectomy is usually required and the histological evaluation reveals that about 80% are benign lesions. Thus, identification of parameters associated with malignancy is needed. In this context, several studies have focused on clinical, ultrasonographic and cytological aspects, with controversial results. 2,3

EGFR Inhibition Abrogates Leiomyosarcoma Cell Chemoresistance through Inactivation of Survival Pathways and Impairment of CSC Potential

Background Tumor cells with stem-like phenotype and properties, known as cancer stem cells (CSC), have been identified in most solid tumors and are presumed to be responsible for driving tumor initiation, chemoresistance, relapse, or metastasis. A subpopulation of cells with increased stem-like potential has also been identified within sarcomas. These cells are endowed with increased tumorigenic potential, chemoresistance, expression of embryonic markers, and side population(SP) phenotype. Leiomyosarcomas (LMS) are soft tissue sarcomas presumably arising from undifferentiated cells of mesenchymal origin, the Mesenchymal Stem Cells (MSC). Frequent recurrence of LMS and chemoresistance of relapsed patients may likely result from the failure to target CSC. Therefore, therapeutic cues coming from the cancer stem cell (CSC) field may drastically improve patient outcome. Methodology/Principal Findings We expanded LMS stem-like cells from patient samples in vitro and examined the possibility to counteract LMS malignancy through a stem-like cell effective approach. LMS stem-like cells were in vitro expanded both as “tumor spheres” and as “monolayers” in Mesenchymal Stem Cell (MSC) conditions. LMS stem-like cells displayed MSC phenotype, higher SP fraction, and increased drug-extrusion, extended proliferation potential, self-renewal, and multiple differentiation ability. They were chemoresistant, highly tumorigenic, and faithfully reproduced the patient tumor in mice. Such cells displayed activation of EGFR/AKT/MAPK pathways, suggesting a possibility in overcoming their chemoresistance through EGFR blockade. IRESSA plus Vincristine treatment determined pathway inactivation, impairment of SP phenotype, high cytotoxicity in vitro and strong antitumor activity in stem-like cell-generated patient-like xenografts, targeting both stem-like and differentiated cells. Conclusions/Significance EGFR blockade combined with vincristine determines stem-like cell effective antitumor activity in vitro and in vivo against LMS, thus providing a potential therapy for LMS patients.

In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval

It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAFV600E mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease‐free interval (DFI).

Procollagen type 1 C-terminal extension peptide serum levels following parathyroidectomy in hyperparathyroid patients

Procollagen type 1 is mainly synthesized by osteoblasts and, after cleavage of the N- and C-terminal extension peptides, is utilized for collagen fibril deposition in the osteoid tissue. Serum levels of C-terminal extension peptide (Pcoll-1-C) of the procollagen molecule has been considered a useful marker for the evaluation of the rate of osteoblastic procollagen synthesis. To appraise whether in vivo parathyroid hormone (PTH) plays a suppressive role in the synthesis of procollagen type 1, a study has been carried out in 16 patients, 10 with severe secondary hyperparathyroidism of chronic renal failure and 6 with primary hyperparathyroidism. Following parathyroidectomy (PTX), in chronic renal failure patients a 94% fall in serum intact iPTH and a decline of serum calcium to hypocalcemic levels requiring calcitriol administration were observed. Serum Pcoll-1-C increased markedly with a peak after 7 days and a subsequent decline. Similar changes were observed for alkaline phosphatase and osteocalcin. In primary hyperparathyroidism, PTX was followed by an 88% drop in iPTH and mild hypocalcemia not requiring calcitriol administration. Also in this group serum Pcoll-1-C increased significantly with the same time course, unaccompanied by changes in alkaline phosphatase and osteocalcin. In 4 unsuccessfully neck-operated control patients no change in serum Pcoll-1-C levels was recorded during a period of 2 weeks postoperatively. In conclusion, acute withholding of parathyroid hypersecretion is accompanied by an abrupt and transitory increase of serum Pcoll-1-C, not dependent on calcitriol administration. Hypocalcemia following PTX may in part be due to uncoupling of bone formation and resorption.