36 results on '"Troncone, Giancarlo"'
Search Results
2. Surgical treatment of thyroid follicular neoplasms: results of a retrospective analysis of a large clinical series
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Conzo, Giovanni, Avenia, Nicola, Ansaldo, Gian Luca, Calò, Piergiorgio, De Palma, Maurizio, Dobrinja, Chiara, Docimo, Giovanni, Gambardella, Claudio, Grasso, Marica, Lombardi, Celestino Pio, Pelizzo, Maria Rosa, Pezzolla, Angela, Pezzullo, Luciano, Piccoli, Micaela, Rosato, Lodovico, Siciliano, Giuseppe, Spiezia, Stefano, Tartaglia, Ernesto, Tartaglia, Francesco, Testini, Mario, Troncone, Giancarlo, and Signoriello, Giuseppe
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- 2017
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3. Thyroid Carcinoma: Molecular Signature by Histotype-Specific Mutations and Gene Expression Patterns
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Malapelle, Umberto, Bellevicine, Claudio, Pustzai, Lajos, Troncone, Giancarlo, Russo, Antonio, editor, Iacobelli, Stefano, editor, and Iovanna, Juan, editor
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- 2012
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4. Type 2 Deiodinase Thr92Ala Polymorphism and Aging Are Associated with a Decreased Pituitary Sensitivity to Thyroid Hormone.
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Luongo, Cristina, De Stefano, Maria Angela, Ambrosio, Raffaele, Volpe, Fabio, Porcelli, Tommaso, Golia, Valeria, Bellevicine, Claudio, Troncone, Giancarlo, Masone, Stefania, Damiano, Vincenzo, Matano, Elide, Klain, Michele, Schlumberger, Martin, and Salvatore, Domenico
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THYROIDECTOMY ,THYROID hormones ,INSTITUTIONAL review boards ,AGING ,THYROID cancer - Abstract
Background: The DIO2 Thr92Ala polymorphism (rs225014), which occurs in about 15–30% of Caucasian people, determines a less efficient type 2 deiodinase (D2) enzyme. The aim of this study was to determine the impact of DIO2 Thr92Ala polymorphism on the serum thyrotropin (TSH) levels in thyroidectomized patients with hypothyroidism and to evaluate whether TSH levels and aging could be related, at pituitary level, to D2 activity. Methods: This prospective study was performed on 145 thyroid cancer patients, treated with total thyroidectomy, and undergoing radioiodine treatment after 3 weeks of levothyroxine (LT4) withdrawal. A mouse model has been used to determine D2 protein and mRNA levels in pituitary during aging. Results: Genetic analysis identified DIO2 Thr92Ala polymorphism in 56% of participants: 64/145 (44%) patients were homozygous wild type (WT) (Thr/Thr), 64 (44%) heterozygous (Thr/Ala), and 17 (12%) homozygous mutant (Ala/Ala). A significant negative relationship was observed between aging and the rise in serum TSH levels during LT4 withdrawal. However, this negative correlation found in WT was reduced in heterozygous and lost in mutant homozygous patients (Thr/Thr r = −0.45, p = 0.0002, 95% confidence interval [CI] −0.63 to −0.23; Ala/Thr r = −0.39, p = 0.0012, CI −0.60 to −0.67; and Ala/Ala r = −0.30, p = 0.2347; CI −0.70 to 0.20). Accordingly, when we compared the TSH measured in each patient to its theoretical value predicted from age, the TSH did not reach its putative target in 47% of WT patients, in 70% of Ala/Thr, and 76% of Ala/Ala carrying patients (p = 0.0036). This difference was lost in individuals older than 60 years, suggesting a decline of D2 associated with aging. The hypothesis that the pituitary D2 decreases with age was confirmed by the evidence that D2 mRNA and protein levels were lower in pituitary from old versus young mice. Conclusion: An age-related decline in TSH production in response to hypothyroidism was correlated with decreased D2 levels in pituitary. The presence of DIO2 homozygous Ala/Ala polymorphism was associated with a reduced level of TSH secretion in response to hypothyroidism, indicating a decreased pituitary sensitivity to serum thyroxine variation (Institutional Research Ethics board approval number no. 433/21). [ABSTRACT FROM AUTHOR]
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- 2023
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5. Thyroid Cancer and Fibroblasts.
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Avagliano, Angelica, Fiume, Giuseppe, Bellevicine, Claudio, Troncone, Giancarlo, Venuta, Alessandro, Acampora, Vittoria, De Lella, Sabrina, Ruocco, Maria Rosaria, Masone, Stefania, Velotti, Nunzio, Carotenuto, Pietro, Mallardo, Massimo, Caiazza, Carmen, Montagnani, Stefania, and Arcucci, Alessandro
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FIBROBLASTS ,THYROID gland tumors ,ENDOCRINE gland tumors ,METASTASIS ,CELL physiology ,CANCER ,DISEASE prevalence ,CELL lines ,DRUG resistance in cancer cells - Abstract
Simple Summary: Thyroid cancer is the most common solid tumor of the endocrine glands. The cancer cell contribution to thyroid cancer development and progression has been studied extensively, whereas the involvement of the tumor microenvironment, particularly of cancer-associated fibroblasts (CAFs), in thyroid cancer growth still must be largely analyzed. The tumor microenvironment, comprising molecules, blood and lymphatic tumor vessels and several non cancer stromal cells, such as CAFs, dramatically influences solid tumor growth and therapy resistance. In particular, investigations on CAF contribution to solid tumor growth and therapeutic resistance represent an important area of oncological research. Moreover, studies focused on the role of CAFs in thyroid cancer could lead to a better comprehension of mechanisms regulating cancer growth and to the development of new therapeutic strategies. Therefore, in this paper, we review the hallmarks of CAFs and their role on thyroid cancer. Thyroid cancer is the most common type of endocrine cancer, and its prevalence continue to rise. Non-metastatic thyroid cancer patients are successfully treated. However, looking for new therapeutic strategies is of great importance for metastatic thyroid cancers that still lead to death. With respect to this, the tumor microenvironment (TME), which plays a key role in tumor progression, should be considered as a new promising therapeutic target to hamper thyroid cancer progression. Indeed, thyroid tumors consist of cancer cells and a heterogeneous and ever-changing niche, represented by the TME, which contributes to establishing most of the features of cancer cells. The TME consists of extracellular matrix (ECM) molecules, soluble factors, metabolites, blood and lymphatic tumor vessels and several stromal cell types that, by interacting with each other and with tumor cells, affect TME remodeling, cancer growth and progression. Among the thyroid TME components, cancer-associated fibroblasts (CAFs) have gained more attention in the last years. Indeed, recent important evidence showed that thyroid CAFs strongly sustain thyroid cancer growth and progression by producing soluble factors and ECM proteins, which, in turn, deeply affect thyroid cancer cell behavior and aggressiveness. Hence, in this article, we describe the thyroid TME, focusing on the desmoplastic stromal reaction, which is a powerful indicator of thyroid cancer progression and an invasive growth pattern. In addition, we discuss the origins and features of the thyroid CAFs, their influence on thyroid cancer growth and progression, their role in remodeling the ECM and their immune-modulating functions. We finally debate therapeutic perspectives targeting CAFs. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Predictive molecular pathology in metastatic thyroid cancer: the role of RET fusions.
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Nacchio, Mariantonia, Pisapia, Pasquale, Pepe, Francesco, Russo, Gianluca, Vigliar, Elena, Porcelli, Tommaso, Luongo, Cristina, Iaccarino, Antonino, Pagni, Fabio, Salvatore, Domenico, Troncone, Giancarlo, Malapelle, Umberto, and Bellevicine, Claudio
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THYROID cancer ,MOLECULAR pathology ,METASTASIS ,GENE fusion ,PROTEIN-tyrosine kinase inhibitors ,THYROID gland ,NUCLEOTIDE sequencing - Abstract
Rearranged during transfection (RET) gene fusions are detected in 10–20% of thyroid cancer patients. Recently, RET fusion-positive metastatic thyroid cancers have attracted much attention owing to the FDA approval of two highly selective anti-RET tyrosine kinase inhibitors, namely, selpercatinib, and pralsetinib. This review summarizes the available evidence on the biological and predictive role of RET gene fusions in thyroid carcinoma patients and the latest screening assays currently used to detect these genomic alterations in histological and cytological specimens. Management of advanced thyroid carcinoma has significantly evolved over the last decade thanks to the approval of three multikinase inhibitors, i.e. sorafenib, lenvatinib, cabozantinib, and of two selective RET-tyrosine inhibitors, i.e. selpercatinib and pralsetinib. In this setting, the detection of RET-fusions in advanced thyroid cancer specimens through the use of next-generation sequencing has become a commonly used strategy in clinical practice to select the best treatment options. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Combination of Lenvatinib and Pembrolizumab as Salvage Treatment for Paucicellular Variant of Anaplastic Thyroid Cancer: A Case Report.
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Luongo, Cristina, Porcelli, Tommaso, Sessa, Francesca, De Stefano, Maria Angela, Scavuzzo, Francesco, Damiano, Vincenzo, Klain, Michele, Bellevicine, Claudio, Matano, Elide, Troncone, Giancarlo, Schlumberger, Martin, and Salvatore, Domenico
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ANAPLASTIC thyroid cancer ,PEMBROLIZUMAB ,THYROID cancer ,CANCER chemotherapy ,SALVAGE therapy ,CANCER invasiveness - Abstract
Anaplastic thyroid cancer (ATC) is a rare but aggressive thyroid cancer, responsible for about 50% of all thyroid cancer-related deaths. During the last two decades, the development of a multimodal personalized approach resulted in an increased survival. Here, we present an unusual case of a 54-year old woman with a paucicellular metastatic ATC, a rare variant of ATC, who was treated with a combination of surgery, radiation therapy and cytotoxic chemotherapy. More than two years later, when the disease was rapidly growing, a combination of lenvatinib and pembrolizumab induced a partial tumor response of lung metastasis that persisted over 18 months. Paucicellular ATC may initially show a less aggressive behavior compared to other histological ATC variants. However, over the time, its clinical course can rapidly progress like common ATC. The combination of lenvatinib and pembrolizumab was effective as a salvage therapy for a long period of time. [ABSTRACT FROM AUTHOR]
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- 2021
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8. Young investigator challenge: Can the Ion AmpliSeq Cancer Hotspot Panel v2 be used for next-generation sequencing of thyroid FNA samples?
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BELLEVICINE, CLAUDIO, SGARIGLIA, ROBERTA, MALAPELLE, UMBERTO, VIGLIAR, ELENA, NACCHIO, MARIANTONIA, CIANCIA, GIUSEPPE, Eszlinger, Markus, Paschke, Ralf, TRONCONE, GIANCARLO, Bellevicine, Claudio, Sgariglia, Roberta, Malapelle, Umberto, Vigliar, Elena, Nacchio, Mariantonia, Ciancia, Giuseppe, Eszlinger, Marku, Paschke, Ralf, and Troncone, Giancarlo
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postsequencing metric ,preanalytical factor ,thyroid fine-needle aspiration ,limited sample ,thyroid cancer ,next-generation sequencing ,Ion Torrent ,molecular diagnosi - Abstract
Fine-needle aspiration (FNA) cytology is accurate and cost-effective in the evaluation of thyroid nodules. Molecular techniques may contribute to risk stratification in indeterminate cases. Although next-generation sequencing (NGS) is a promising technique for the molecular testing of thyroid FNA specimens, thyroid-specific cancer gene panels are not commercially available. Conversely, the Ion AmpliSeq Cancer Hotspot Panel v2 (CHPv2), which includes the genes most frequently mutated in thyroid neoplasms, is commercially available and may represent an alternative to thyroid-specific panels. To the authors' knowledge to date, CHPv2 has performed well only on "ideal" cytological samples featuring abundant, high-quality DNA and satisfactory postsequencing metrics. The objective of the current study was to extend NGS to less-than-ideal samples, which represent a large percentage of routine clinical specimens.
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- 2016
9. Cytologically undetermined follicular lesions: surgical procedures and histological outcome in 472 cases
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Conzo G, Docimo G, Pizza A, Sciascia V, Napolitano S, Della Pietra C, Palazzo A, Signoriello G, Santini L., TRONCONE, GIANCARLO, BELLEVICINE, CLAUDIO, Conzo, G, Troncone, Giancarlo, Docimo, G, Pizza, A, Sciascia, V, Bellevicine, Claudio, Napolitano, S, Della Pietra, C, Palazzo, A, Signoriello, G, and Santini, L.
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"differentiated thyroid cancer" ,thyroid cancer ,cytology - Abstract
BACKGROUND: Fine needle cytology (FNC) of thyroid nodules is not always diagnostic. Most of FNCs undeterminated for malignancy belong to the cytological class of "follicular neoplasm/suspicious for follicular neoplasm" lesions (FN). In this group only 10-30% of cases are malignant and the most appropriate surgical management is still controversial. Here, this issue was addressed and the more reliable predictive criteria of malignancy were also evaluated. METHODS: We retrospectively evaluated 472 patients, surgically treated after a FN diagnosis in a tertiary care referral center. In patients affected by bilateral thyroid disease with a cytological diagnosis of FN, or when high-risk clinical features and familiarity for thyroid cancer were present, total thyroidectomy (TT) was performed. Conversely, hemithyroidectomy (HT) was preferred when the nodule was single and when the age was ≤ 45 years. Frozen section examination was not used, and if cancer was diagnosed by definitive pathology of the HT specimen, the remnant thyroid lobe was removed. Histological features, surgical complications, and long-term outcomes of the remnant lobe were reported. Clinical features predictivity was also evaluated. RESULTS: TT was performed in 154/472 pts (32.62%), while HT was carried out in 318/472 cases (67.37%). The overall malignancy rate (MR) was 18.85% (89/472 pts), respectively 16% (51/318pts) following HT, and 24.6% (38/154pts) following TT, with a statistically significant difference. Similarly, the rates of transient and definitive hypoparathyroidism and the mean hospital stay following TT were higher than after HT (and statistically significant). Age < 45years and female gender were more frequently associated to malignancy. The rate of complications following second surgery was comparable to that of primary HT. In the HT group incidence of unexpected contralateral papillary thyroid cancer (PTC) was 9.8% and, after 88.2 ± 30.42 months mean follow-up, completion surgery for benign pathology was carried out in 6.7% of cases. CONCLUSIONS: Our data show that histology following a cytological FN diagnosis is malignant only in a low percentage of cases (89/472, 18.85%). Following TT, a MR higher than in HT was observed. Even if some clinical features are cancer associated, malignancy cannot be reliably predicted before surgery. Thus, in solitary low-risk lesions, HT is still the standard of care. Its lower complication rates makes HT the safest procedure. In case of multiglandular disease TT may be recommended. Further investigation is warranted to achieve a better preoperative diagnostic accuracy in order to reduce the amount of surgical operations with diagnostic aim.
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- 2012
10. Potential involvement of neutrophils in human thyroid cancer.
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Galdiero, Maria Rosaria, Varricchi, Gilda, Loffredo, Stefania, Bellevicine, Claudio, Lansione, Tiziana, Ferrara, Anne Lise, Iannone, Raffaella, di Somma, Sarah, Borriello, Francesco, Clery, Eduardo, Triassi, Maria, Troncone, Giancarlo, and Marone, Gianni
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NEUTROPHILS ,THYROID cancer ,CANCER cells ,CELLULAR pathology ,MACROPHAGES - Abstract
Background: Neutrophil functions have long been regarded as limited to acute inflammation and the defense against microbes. The role(s) of neutrophils in cancer remain poorly understood. Neutrophils infiltrate tumors and are key effector cells in the orchestration of inflammatory responses. Thyroid cancer (TC) is the most recurrent endocrine malignant tumor and is responsible for 70% of deaths due to endocrine cancers. No studies are so far available on the role of neutrophils in TC. Objective: Our purpose was to study the involvement of tumor-associated neutrophils in TC. Methods: Highly purified human neutrophils (>99%) from healthy donors were stimulated in vitro with conditioned media derived from TC cell lines TPC1 and 8505c (TC-CMs). Neutrophil functions (e.g., chemotaxis, activation, plasticity, survival, gene expression, and protein release) were evaluated. Results: TC-derived soluble factors promoted neutrophil chemotaxis and survival. Neutrophil chemotaxis toward a TC-CM was mediated, at least in part, by CXCL8/IL-8, and survival was mediated by granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, each TC-CM induced morphological changes and activation of neutrophils (e.g., CD11b and CD66b upregulation and CD62L shedding) and modified neutrophils’ kinetic properties. Furthermore, each TC-CM induced production of reactive oxygen species, expression of proinflammatory and angiogenic mediators (CXCL8/IL-8, VEGF-A, and TNF-α), and a release of matrix metalloproteinase 9 (MMP-9). Moreover, in TC patients, tumor-associated neutrophils correlated with larger tumor size. Conclusions: TC cell lines produce soluble factors able to “educate” neutrophils toward an activated functional state. These data will advance the understanding of the molecular and cellular mechanisms of innate immunity in TC. [ABSTRACT FROM AUTHOR]
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- 2018
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11. Hashimoto's thyroiditis predicts outcome in intrathyroidal papillary thyroid cancer.
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Marotta, Vincenzo, Sciammarella, Concetta, Chiofalo, Maria Grazia, Gambardella, Claudio, Bellevicine, Claudio, Grasso, Marica, Conzo, Giovanni, Docimo, Giovanni, Botti, Gerardo, Losito, Simona, Troncone, Giancarlo, De Palma, Maurizio, Giacomelli, Laura, Pezzullo, Luciano, Colao, Annamaria, and Faggiano, Antongiulio
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AUTOIMMUNE thyroiditis ,THYROID cancer treatment ,THYROID cancer ,DISEASE remission ,PROGRESSION-free survival ,AUTOIMMUNE disease treatment ,PROGNOSIS - Abstract
Hashimoto's thyroiditis (HT) seems to have favourable prognostic impact on papillary thyroid cancer (PTC), but data were obtained analysing all disease stages. Given that HT-related microenvironment involves solely the thyroid, we aimed to assess the relationship between HT, as detected through pathological assessment and outcome in intrathyroidal PTC. This was a multicentre, retrospective, observational study including 301 PTC with no evidence of extrathyroidal disease. Primary study endpoint was the rate of clinical remission. Auxiliary endpoint was recurrence-free survival (RFS). HT was detected in 42.5% of the cohort and was associated to female gender, smaller tumour size, lower rate of aggressive PTC variants and less frequent post-surgery radio-iodine administration. HT showed relationship with significantly higher rate of clinical remission (P < 0.001, OR 4, 95% CI 1.78-8.94). PTCs with concomitant HT had significantly longer RFS, as compared with non-HT tumours (P=0.004). After adjustment for other parameters affecting disease outcome at univariate analysis (age at diagnosis, histology, tumour size and multifocality), prognostic effect of HT remained significant (P=0.006, OR 3.28, 95% CI 1.39-7.72). To verify whether HT could optimise the identification of PTCs with unfavourable outcome, we assessed the accuracy of 'non-HT statu's as negative prognostic marker, demonstrating poor capability of identifying patients not maintaining clinical remission until final follow-up (probability of no clinical remission in PTCs without HT: 21.05%, 95% CI 15.20-27.93). In conclusion, our data show that HT represents an independent prognostic parameter in intrathyroidal PTC, but cannot improve prognostic specificity. [ABSTRACT FROM AUTHOR]
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- 2017
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12. BAY 43-9006 Inhibition of Oncogenic RET Mutants.
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Carlomagno, Francesca, Anaganti, Suresh, Guida, Teresa, Salvatore, Giuliana, Troncone, Giancarlo, Wilhelm, Scott M., and Santoro, Massimo
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THYROID cancer ,ONCOGENIC viruses ,PROTEIN-tyrosine kinases ,PROTEIN kinases ,CANCER ,TUMORS - Abstract
Background: Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods: We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow cytometry. Growth of TT cell-derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results: BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC
50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts (n = 7) was reduced from 72.5 to 44 mm³ (difference = 28.5 mm³, 95% CI = 7 mm³ to 50 mm³), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm³ (difference = 320 mm³, 95% CI = 180 mm³ to 460 mm³; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions: BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study. [ABSTRACT FROM AUTHOR]- Published
- 2006
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13. Controversies in the surgical management of thyroid follicular neoplasms. Retrospective analysis of 721 patients.
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Conzo, Giovanni, Calò, Pietro Giorgio, Gambardella, Claudio, Tartaglia, Ernesto, Mauriello, Claudio, Della Pietra, Cristina, Medas, Fabio, Cruz, Rosa Santa, Podda, Francesco, Santini, Luigi, and Troncone, Giancarlo
- Abstract
The most appropriate surgical management of “follicular neoplasm/suspicious for follicular neoplasm” lesions, is still controversial. Analysing and comparing the experience of two units for endocrine surgery, we retrospectively evaluated 721 patients, surgically treated after a follicular neoplasm diagnosis. Total thyroidectomy was routinely performed in one Institution, while in the other one it was selectively carried out. The main criteria leading to hemythyroidectomy were a single nodule, the age ≤45 years, the absence of thyroiditis or clinical/intraoperative suspicion of malignancy. Total thyroidectomy was performed in 402/721 patients (55.7%), hemythyroidectomy in 319/721 cases (44.2%) and a completion thyroidectomy in 51/319 cases (15.9%). The overall malignancy rate was 24% (176/721 patients), respectively 16% (51/319 patients) following hemythyroidectomy, and 31% (125/402 patients) following total thyroidectomy. Definitive recurrent laryngeal nerve paralysis and permanent hypoparathyroidism were not reported in hemythyroidectomy patients in which lower mean hospitalization and costs were observed. Considering the low-risk of follicular neoplasm solitary lesions, hemythyroidectomy is still the safest standard of care with lower hospitalization and costs. In case of multiglandular disease or thyroiditis, that might be associated with a higher risk of cancer, total thyroidectomy should be recommended. Further investigation is warranted to achieve a better preoperative follicular neoplasm diagnostic accuracy in order to reduce the amount of unnecessary surgical operations with a diagnostic aim. [ABSTRACT FROM AUTHOR]
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- 2014
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14. Adherence to the Mediterranean Diet as a Modifiable Risk Factor for Thyroid Nodular Disease and Thyroid Cancer: Results From a Pilot Study
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Luigi Barrea, Giovanna Muscogiuri, Giulia de Alteriis, Tommaso Porcelli, Claudia Vetrani, Ludovica Verde, Sara Aprano, Francesco Fonderico, Giancarlo Troncone, Annamaria Colao, Silvia Savastano, Barrea, Luigi, Muscogiuri, Giovanna, de Alteriis, Giulia, Porcelli, Tommaso, Vetrani, Claudia, Verde, Ludovica, Aprano, Sara, Fonderico, Francesco, Troncone, Giancarlo, Colao, Annamaria, and Savastano, Silvia
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PREvención con DIeta MEDiterránea (PREDIMED) ,Tir ,Nutrition and Dietetics ,nutritionist ,FNA ,fine needle aspiration (FNA) ,Endocrinology, Diabetes and Metabolism ,thyroid cancer ,thyroid nodular disease ,Mediterranean diet (MD) ,Food Science - Abstract
Iodine deficiency is the most important established nutritional risk factor for the development of thyroid nodular disease. Nevertheless, to the best of our knowledge, to date no study focused on the association between the adherence to the Mediterranean diet (MD) and thyroid nodular disease. Adherence to the MD was evaluated using the PREvención con DIetaMEDiterránea (PREDIMED) questionnaire. Physical activity, smoking habits, and anthropometric parameters were studied. PREDIMED was used to evaluate the degree of adherence to the MD. Evaluation of fine needle aspiration cytology of thyroid lesions based on 2013 Italian thyroid cytology classification system. Cytology of thyroid nodules was carried out through sonography-guided fine-needle aspiration and patients were divided into 5 categories: TIR2, TIR3a, TIR3b, TIR4, and TIR5. The study population consisted of 794 subjects (554 females, 69.8%), aged 18–65 years, with BMIs ranging from 19.4 to 55.3 kg/m2. Thyroid nodular disease was present in 391 participants (49.2%), and the most frequent cytological categories was TIR2 (18.3 %), followed by a TIR4 (8.9 %). The presence of thyroid nodules was also significantly associated with the lowest adherence to the MD (OR 6.16, p < 0.001). Patients with TIR5 had the lower adherence to the MD (2.15 ± 1.12 score) compared to other TIRs (p < 0.001). The cytological category with high-risk of malignancy (TIR4/TIR5) was significantly associated with the lowest adherence to the MD (OR 137.55, p < 0.001) and PREDIMED score (OR = 0.33, p < 0.001, 95% IC = 0.26–0.41, R2 = 0.462). At multiple regression analysis, PREDIMED score was the main predictor of both the presence of nodules (p < 0.001) and the cytological category with high-risk of malignancy (p < 0.001). At ROC analysis PREDIMED score ≤ 5 and ≤ 4 (p = 0.001) were the values that predicted the presence of thyroid nodular disease and cytological category with high-risk of malignancy, respectively. In conclusion, our study demonstrated that the low adherence to the MD is associated with the presence of thyroid nodular disease and in particular with those at high-risk of malignancy.
- Published
- 2022
15. Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia.
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Bellelli, Roberto, Vitagliano, Donata, Federico, Giorgia, Marotta, Pina, Tamburrino, Anna, Salerno, Paolo, Paciello, Orlando, Papparella, Serenella, Knauf, Jeffrey A., Fagin, James A., Refetoff, Samuel, Troncone, Giancarlo, and Santoro, Massimo
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THYROID gland tumors , *ONCOGENES , *DOXYCYCLINE , *MITOGEN-activated protein kinases , *DNA damage , *BLOOD serum analysis , *DIAGNOSIS - Abstract
Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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16. Predictive molecular pathology in metastatic thyroid cancer: the role of RET fusions
- Author
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Mariantonia Nacchio, Pasquale Pisapia, Francesco Pepe, Gianluca Russo, Elena Vigliar, Tommaso Porcelli, Cristina Luongo, Antonino Iaccarino, Fabio Pagni, Domenico Salvatore, Giancarlo Troncone, Umberto Malapelle, Claudio Bellevicine, Nacchio, M, Pisapia, P, Pepe, F, Russo, G, Vigliar, E, Porcelli, T, Luongo, C, Iaccarino, A, Pagni, F, Salvatore, D, Troncone, G, Malapelle, U, Bellevicine, C, Nacchio, Mariantonia, Pisapia, Pasquale, Pepe, Francesco, Russo, Gianluca, Vigliar, Elena, Porcelli, Tommaso, Luongo, Cristina, Iaccarino, Antonino, Pagni, Fabio, Salvatore, Domenico, Troncone, Giancarlo, Malapelle, Umberto, and Bellevicine, Claudio
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molecular pathology ,Endocrinology, Diabetes and Metabolism ,pralsetinib ,RET fusion ,selpercatinib ,Thyroid cancer - Abstract
Background: Rearranged during transfection (RET) gene fusions are detected in 10–20% of thyroid cancer patients. Recently, RET fusion-positive metastatic thyroid cancers have attracted much attention owing to the FDA approval of two highly selective anti-RET tyrosine kinase inhibitors, namely, selpercatinib, and pralsetinib. Areas covered: This review summarizes the available evidence on the biological and predictive role of RET gene fusions in thyroid carcinoma patients and the latest screening assays currently used to detect these genomic alterations in histological and cytological specimens. Expert opinion: Management of advanced thyroid carcinoma has significantly evolved over the last decade thanks to the approval of three multikinase inhibitors, i.e. sorafenib, lenvatinib, cabozantinib, and of two selective RET-tyrosine inhibitors, i.e. selpercatinib and pralsetinib. In this setting, the detection of RET-fusions in advanced thyroid cancer specimens through the use of next-generation sequencing has become a commonly used strategy in clinical practice to select the best treatment options.
- Published
- 2022
17. The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias.
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Leone, Vincenza, Ferraro, Angelo, Schepis, Filippo, Federico, Antonella, Sepe, Romina, Arra, Claudio, Langella, Concetta, Palma, Giuseppe, De Lorenzo, Carlo, Troncone, Giancarlo, Masciullo, Valeria, Scambia, Giovanni, Fusco, Alfredo, and Pallante, Pierlorenzo
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THYROID cancer , *LABORATORY mice , *CADHERINS , *CARCINOGENESIS , *EMBRYOLOGY - Abstract
We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80 −/− mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80 −/− mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis. [ABSTRACT FROM AUTHOR]
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- 2015
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18. The loss of the CBX7 gene expression represents an adverse prognostic marker for survival of colon carcinoma patients
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Pallante, Pierlorenzo, Terracciano, Luigi, Carafa, Vincenza, Schneider, Sandra, Zlobec, Inti, Lugli, Alessandro, Bianco, Mimma, Ferraro, Angelo, Sacchetti, Silvana, Troncone, Giancarlo, Fusco, Alfredo, and Tornillo, Luigi
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COLON cancer patients , *GENE expression , *CANCER prognosis , *CANCER-related mortality , *THYROID cancer , *ANISOTROPY , *BIOMARKERS , *CANCER patients , *CELL physiology , *COLON tumors , *FLUORIMETRY , *EVALUATION of medical care , *POLYMERASE chain reaction , *PRESERVATION of organs, tissues, etc. , *PHENOTYPES , *DATA analysis , *DISEASE complications , *EVALUATION , *MORTALITY ,RECTUM tumors - Abstract
We have previously shown that CBX7 expression is associated with a more malignant phenotype in thyroid cancer. On this basis, we decided to investigate its possible prognostic value in colorectal cancer (CRC). CBX7 expression has been analysed by immunohistochemistry in tissue microarray (TMA) specimens obtained from a large series of sporadic CRC resections (n =1420). The CBX7 expression data have been correlated with several clinico-pathological parameters. CBX7 expression is reduced or absent in a significant number of CRC samples in comparison to the normal colonic mucosa and the loss of CBX7 expression correlates with a poor outcome of CRC (p <0.001). The block of CBX7 expression seems to occur at a transcriptional level since quantitative RT-PCR analysis showed a reduced CBX7-specific mRNA levels in CRC samples versus normal counterpart tissue (up to more than 50-fold). Finally, the restoration of CBX7 expression in two CRC cell lines reduces their proliferation rate suggesting a role of the loss of CBX7 expression in the progression step of colon carcinogenesis. Therefore, the data reported here indicate that the evaluation of CBX7 expression may represent a valid tool in the prognosis of colon cancer since a reduced survival of CRC patients is associated with the loss of CBX7 expression. [Copyright &y& Elsevier]
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- 2010
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19. Surgical treatment of thyroid follicular neoplasms: results of a retrospective analysis of a large clinical series
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Maria Rosa Pelizzo, Piergiorgio Calò, Giancarlo Troncone, Maurizio De Palma, Angela Pezzolla, Giovanni Conzo, Chiara Dobrinja, Giuseppe Signoriello, Marica Grasso, Giuseppe Siciliano, Gian Luca Ansaldo, Lodovico Rosato, Claudio Gambardella, Luciano Pezzullo, Mario Testini, Micaela Piccoli, Nicola Avenia, Celestino Pio Lombardi, Stefano Spiezia, Ernesto Tartaglia, Francesco Tartaglia, Giovanni Docimo, Conzo, Giovanni, Avenia, Nicola, Ansaldo, Gian Luca, Calò, Piergiorgio, De Palma, Maurizio, Dobrinja, Chiara, Docimo, Giovanni, Gambardella, Claudio, Grasso, Marica, Lombardi, Celestino Pio, Pelizzo, Maria Rosa, Pezzolla, Angela, Pezzullo, Luciano, Piccoli, Micaela, Rosato, Lodovico, Siciliano, Giuseppe, Spiezia, Stefano, Tartaglia, Ernesto, Tartaglia, Francesco, Testini, Mario, Troncone, Giancarlo, Signoriello, Giuseppe, Conzo, G., Avenia, N., Ansaldo, G. L., Calo, P., De Palma, M., Dobrinja, C., Docimo, G., Gambardella, C., Grasso, M., Lombardi, C. P., Pelizzo, M. R., Pezzolla, A., Pezzullo, L., Piccoli, M., Rosato, L., Siciliano, G., Spiezia, S., Tartaglia, E., Tartaglia, F., Testini, M., Troncone, G., Signoriello, G., and de Palma, Maurizio
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Male ,Fine needle cytology ,Follicular neoplasm ,Hemithyroidectomy ,Thyroid cancer ,Total thyroidectomy ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Thyroid Gland ,Thyroiditis ,Postoperative Complications ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Retrospective Studie ,Adenocarcinoma, Follicular ,Thyroid Neoplasm ,Adult ,Aged ,Female ,Humans ,Hypoparathyroidism ,Middle Aged ,Retrospective Studies ,Thyroid Neoplasms ,Thyroidectomy ,Treatment Outcome ,Thyroid ,Diabetes and Metabolism ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Human ,Thyroid nodules ,medicine.medical_specialty ,030209 endocrinology & metabolism ,Adenocarcinoma ,Malignancy ,03 medical and health sciences ,medicine ,business.industry ,Risk Factor ,Follicular ,medicine.disease ,Surgery ,Endocrine surgery ,Postoperative Complication ,business - Abstract
The most appropriate surgical management of "follicular neoplasm/suspicious for follicular neoplasm" lesions (FN), considering their low definitive malignancy rate and the limited predictive power of preoperative clinic-diagnostic factors, is still controversial. On behalf of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB), we collected and analyzed the experience of 26 endocrine centers by computerized questionnaire. 1379 patients, surgically treated after a FN diagnosis from January 2012 and December 2103, were evaluated. Histological features, surgical complications, and medium-term outcomes were reported. Total thyroidectomy (TT) was performed in 1055/1379 patients (76.5 %), while hemithyroidectomy (HT) was carried out in 324/1379 cases (23.5 %). Malignancy rate was higher in TT than in HT groups (36.4 vs. 26.2 %), whereas the rates of transient and definitive hypoparathyroidism following TT were higher than after HT. Consensual thyroiditis (16.8 vs. 9.9 %) and patient age (50.9 vs. 47.9 %) also differed between groups. A cytological FN diagnosis was associated to a not negligible malignancy rate (469/1379 patients; 34 %), that was higher in TT than in HT groups. However, a lower morbidity rate was observed in HT, which should be considered the standard of care in solitary lesions in absence of specific risk factors. Malignancy could not be preoperatively assessed and clinical decision-making is still controversial. Further efforts should be spent to more accurately preoperatively classify FN thyroid nodules. The most appropriate surgical management of “follicular neoplasm/suspicious for follicular neoplasm” lesions (FN), considering their low definitive malignancy rate and the limited predictive power of preoperative clinic-diagnostic factors, is still controversial. On behalf of the Italian Association of Endocrine Surgery Units (U.E.C. CLUB), we collected and analyzed the experience of 26 endocrine centers by computerized questionnaire. 1379 patients, surgically treated after a FN diagnosis from January 2012 and December 2103, were evaluated. Histological features, surgical complications, and medium-term outcomes were reported. Total thyroidectomy (TT) was performed in 1055/1379 patients (76.5 %), while hemithyroidectomy (HT) was carried out in 324/1379 cases (23.5 %). Malignancy rate was higher in TT than in HT groups (36.4 vs. 26.2 %), whereas the rates of transient and definitive hypoparathyroidism following TT were higher than after HT. Consensual thyroiditis (16.8 vs. 9.9 %) and patient age (50.9 vs. 47.9 %) also differed between groups. A cytological FN diagnosis was associated to a not negligible malignancy rate (469/1379 patients; 34 %), that was higher in TT than in HT groups. However, a lower morbidity rate was observed in HT, which should be considered the standard of care in solitary lesions in absence of specific risk factors. Malignancy could not be preoperatively assessed and clinical decision-making is still controversial. Further efforts should be spent to more accurately preoperatively classify FN thyroid nodules.
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- 2017
20. Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia
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Massimo Santoro, Anna Tamburrino, Samuel Refetoff, Giorgia Federico, Donata Vitagliano, Pina Marotta, Jeffrey A. Knauf, Orlando Paciello, James A. Fagin, Paolo Salerno, Serenella Papparella, Giancarlo Troncone, Roberto Bellelli, Bellelli, Roberto, Vitagliano, Donata, Federico, Giorgia, Marotta, Pina, Tamburrino, Anna, Salerno, Paolo, Paciello, Orlando, Papparella, Serenella, Knauf, Jeffrey A., Fagin, James A., Refetoff, Samuel, Troncone, Giancarlo, and Santoro, Massimo
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0301 basic medicine ,MAPK/ERK pathway ,Male ,endocrine system diseases ,Thyroid Gland ,Thyrotropin ,Apoptosis ,medicine.disease_cause ,Biochemistry ,Endocrinology ,Phosphorylation ,Thyroid cancer ,Cellular Senescence ,Thyroid ,Forkhead Transcription Factors ,medicine.anatomical_structure ,RET oncogene ,Female ,Senescence ,medicine.medical_specialty ,endocrine system ,DNA damage ,Mice, Transgenic ,Biology ,Article ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Thyroid Neoplasms ,Protein kinase B ,Molecular Biology ,Hyperplasia ,AKT ,Oncogene-induced senescence ,Oncogenes ,medicine.disease ,Enzyme Activation ,Disease Models, Animal ,Thyroxine ,030104 developmental biology ,Thyroid Epithelial Cells ,Cancer research ,Cattle ,Carcinogenesis ,Proto-Oncogene Proteins c-akt ,DNA Damage - Abstract
Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/ PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels.
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- 2015
21. UbcH10 expression on thyroid fine-needle aspirates
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Giancarlo Troncone, Maria Teresa Berlingieri, Antonino Iaccarino, Angelo Ferraro, Doriana Desiderio, Emiliano A. Palmieri, Pierlorenzo Pallante, Lucio Palombini, Eliana Guerriero, Alfredo Fusco, Guerriero, E., Ferraro, A., Desiderio, D., Pallante, P., Berlingieri, M. T., Iaccarino, Antonino, Palmieri, E., Palombini, Lucio, Fusco, Alfredo, and Troncone, Giancarlo
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Adult ,Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Adolescent ,Biopsy, Fine-Needle ,Thyroid Gland ,Malignancy ,thyroid ,Biopsy ,Biomarkers, Tumor ,Humans ,Medicine ,fine-needle aspiration ,RNA, Messenger ,Thyroid Neoplasms ,Thyroid cancer ,Aged ,Suspicious for Malignancy ,medicine.diagnostic_test ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,3-gene assay ,Thyroid ,Cancer ,Middle Aged ,UbcH10 ,medicine.disease ,Immunohistochemistry ,Ki-67 Antigen ,Fine-needle aspiration ,medicine.anatomical_structure ,Oncology ,Ki-67 ,Ubiquitin-Conjugating Enzymes ,biology.protein ,Female ,business - Abstract
BACKGROUND: Thyroid fine-needle aspiration (FNA) samples belonging to the follicular neoplasm/suspicious for malignancy classes are controversial. The authors identified UbcH10 as a marker useful in the diagnosis of several neoplasms, including thyroid cancer. Here, analysis of UbcH10 expression by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry was applied to FNAs. METHODS: A series of 84 follicular neoplasm/suspicious for malignancy FNAs with histological follow-up (30 malignant) was prospectively collected. UbcH10 immunostaining was performed on cell blocks and compared with that of the proliferation marker Ki-67. At the mRNA level, UbcH10 was compared with CCND2 and PCSK2 expression, these latter being the best performing components of the previously reported 3-gene assay; to determine the diagnostic accuracy, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each gene individually and in combination was evaluated. RESULTS: UbcH10 and Ki-67 shared a similar pattern; although UbcH10 expression was higher in malignant than in benign lesions (P < .001), staining was sporadic, and the cutoff value derived by the ROC analysis was too low (1.25%) for routine application. Conversely, UbcH10 expression assessment by quantitative RT-PCR was effective. UbcH10 mRNA levels associated with malignant histology were significantly higher than those associated with benign histology (P = .02). The AUC was 0.74 for UbcH10, 0.81 for CCDN2, 0.62 for PCSK2, and 0.84 for UbcH10 and CCND2 combination. CONCLUSIONS: UbcH10 quantitative RT-PCR analysis, rather than immunohistochemistry, is useful to increase the detection of malignancy in thyroid FNAs. UbcH10 may be added as a panel component in quantitative RT-PCR–based assays. Cancer (Cancer Cytopathol) 2010. © 2010 American Cancer Society.
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- 2010
22. Loss of p27 Expression Through RAS->BRAF->MAP Kinase-Dependent Pathway in Human Thyroid Carcinomas
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Massimo Santoro, Silvia De Gisi, Angela Persico, Donatella Malanga, Gennaro Chiappetta, Carmela De Marco, Maria Letizia Motti, Giancarlo Troncone, Daniela Califano, Giuseppe Viglietto, Simona Losito, Alfredo Fusco, Fernanda Fabiani, Motti, Ml, Marco, Cd, Califano, D, Gisi, Sd, Malanga, D, Troncone, Giancarlo, Persico, A, Losito, S, Fabiani, F, Santoro, Massimo, Fusco, Alfredo, and Viglietto, G.
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Proto-Oncogene Proteins B-raf ,endocrine system diseases ,MAP Kinase Signaling System ,thyroid ,Cell Line, Tumor ,medicine ,SKP2 ,Humans ,Thyroid Neoplasms ,Molecular Biology ,Thyroid cancer ,Thyroid hormone receptor ,biology ,Oncogene ,Cell growth ,Thyroid ,Cell Biology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Genes, ras ,medicine.anatomical_structure ,Mitogen-activated protein kinase ,biology.protein ,Cancer research ,cell cycle ,Mitogen-Activated Protein Kinases ,ra ,Cyclin-Dependent Kinase Inhibitor p27 ,braf ,Developmental Biology - Abstract
In the present study, we report that the RAS/BRAF/MAP kinase cascade plays a crucial role in the regulation of the Skp2/p27 pathway in thyroid cancer cells and that this is critical for cell proliferation. In vitro studies with cellular models of human thyroid carcinoma cells demonstrated that the adoptive expression of oncogenic RET/PTC1, Ha-RASV12 or BRAFV600E enhances Skp2 and reduces p27 protein expression in a MAP kinase-dependent manner; that RAS/BRAF/MAP kinase-dependent control of p27 expression in thyroid cancer cells occurs by regulating the stability of Skp2 and p27 protein; and that antisense oligonucleotides to p27 suppress growth arrest induced by MEK inhibitors. Finally, analysis of human thyroid carcinomas indicated that MAP kinase-positive thyroid tumors-as detected by immunostaining for p-ERK - presented high p27 degradative activity and low levels of p27 protein (n = 30; p < 0.05). In summary, our results indicate that constitutive signalling of the MAP kinase cascade contributes to the development of thyroid cancer promoted by activated RAS and BRAF oncogenes and that this occurs, at least in part, by compromising the inhibitory function of p27.
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- 2007
23. The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias
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Giancarlo Troncone, Romina Sepe, Alfredo Fusco, Pierlorenzo Pallante, Valeria Masciullo, Filippo Schepis, Concetta Langella, Giovanni Scambia, Antonella Federico, Angelo Ferraro, Vincenza Leone, Claudio Arra, Giuseppe Palma, Carlo De Lorenzo, Leone, Vincenza, Ferraro, Angelo, Schepis, Filippo, Federico, Antonella, Sepe, Romina, Arra, Claudio, Langella, Concetta, Palma, Giuseppe, De Lorenzo, Carlo, Troncone, Giancarlo, Masciullo, Valeria, Scambia, Giovanni, Fusco, Alfredo, and Pallante, Pierlorenzo
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Male ,Cancer Research ,Oncogene Proteins, Fusion ,endocrine system diseases ,Apoptosis ,Colorectal Neoplasm ,medicine.disease_cause ,Protein-Tyrosine Kinase ,Intercellular Signaling Peptides and Protein ,Knock-out mice ,Thyroid cancer ,Cells, Cultured ,Thyroid Neoplasm ,Ovarian Neoplasms ,Mice, Knockout ,Thyroid ,Extracellular Matrix Proteins ,Reverse Transcriptase Polymerase Chain Reaction ,Protein-Tyrosine Kinases ,Cl2/dro1/ccdc80 ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Knockout mouse ,Intercellular Signaling Peptides and Proteins ,Female ,Colorectal Neoplasms ,Breast Neoplasm ,Human ,Genetically modified mouse ,medicine.medical_specialty ,endocrine system ,Breast Neoplasms ,Ovary ,Mice, Transgenic ,Biology ,Thyroid carcinoma ,Internal medicine ,medicine ,Carcinoma ,Animals ,Humans ,Thyroid Neoplasms ,thyroid and ovarian neoplasias ,Glycoproteins ,Cell Proliferation ,cl2/dro1/ccdc80 ,Animal ,Ovarian Neoplasm ,Tumor Suppressor Proteins ,Apoptosi ,medicine.disease ,Embryo, Mammalian ,Carcinoma, Papillary ,Endocrinology ,Settore MED/40 - GINECOLOGIA E OSTETRICIA ,Cancer research ,Glycoprotein ,Carcinogenesis - Abstract
We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80 −/− mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80 −/− mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.
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- 2015
24. UbcH10 overexpression may represent a marker of anaplastic thyroid carcinomas
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P Pallante1, MT Berlingieri1, G Troncone2, M Kruhoffer3, TF Orntoft3, G Viglietto1, A Caleo2, I Migliaccio2, M Decaussin-Petrucci4, M Santoro1, L Palombini2, A Fusco, 1, 5, Pallante, Pierlorenzo, Berlingieri, M. T., Troncone, Giancarlo, K. R. U. H. O. F. F. E. R., . M., Orntoft, T. F., Viglietto, G., Caleo, A., Migliaccio, I., DECAUSSIN PETRUCCI, M., Santoro, Massimo, Palombini, Lucio, and Fusco, Alfredo
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endocrine system ,Cancer Research ,Pathology ,medicine.medical_specialty ,carcinomas ,endocrine system diseases ,Blotting, Western ,Mice, Transgenic ,Biology ,anaplastic ,thyroid ,Thyroid carcinoma ,Mice ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Carcinoma ,medicine ,Animals ,Humans ,Thyroid Neoplasms ,Anaplastic carcinoma ,Molecular Diagnostics ,Thyroid cancer ,Cell Proliferation ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Thyroid ,UbcH10 ,medicine.disease ,Rats ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,medicine.anatomical_structure ,Oncology ,Cell culture ,Ubiquitin-Conjugating Enzymes ,immunohistochemistry ,Cancer research ,Immunohistochemistry ,cell cycle - Abstract
The hybridisation of an Affymetrix HG_U95Av2 oligonucleotide array with RNAs extracted from six human thyroid carcinoma cell lines and a normal human thyroid primary cell culture led us to the identification of the UbcH10 gene that was upregulated by 150-fold in all of the carcinoma cell lines in comparison to the primary culture cells of human normal thyroid origin. Immunohistochemical studies performed on paraffin-embedded tissue sections showed abundant UbcH10 levels in thyroid anaplastic carcinoma samples, whereas no detectable UbcH10 expression was observed in normal thyroid tissues, in adenomas and goiters. Papillary and follicular carcinomas were only weakly positive. These results were further confirmed by RT–PCR and Western blot analyses. The block of UbcH10 protein synthesis induced by RNA interference significantly reduced the growth rate of thyroid carcinoma cell lines. Taken together, these results would indicate that UbcH10 overexpression is involved in thyroid cell proliferation, and may represent a marker of thyroid anaplastic carcinomas.
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- 2005
25. Aurora B Overexpression Associates with the Thyroid Carcinoma Undifferentiated Phenotype and Is Required for Thyroid Carcinoma Cell Proliferation
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Rosanna Sorrentino, Lucio Palombini, Giancarlo Troncone, Pierlorenzo Pallante, Daniela Spalletti-Cernia, Vassilios Bavetsias, Alfredo Fusco, Spiros Linardopoulos, Giuseppe Portella, Silvana Libertini, Paolo Laccetti, Paolo Chieffi, Sorrentino, R, Libertini, S, Pallante, Pl, Troncone, Giancarlo, Palombini, Lucio, Bavetsias, V, SPALLETTI CERNIA, D, Laccetti, Paolo, Linardopoulos, S, Chieffi, P, Fusco, Alfredo, Portella, Giuseppe, Sorrentino, R., Libertini, S., Pallante, P., Troncone, G., Palombini, L., Bavetsias, V., SPALLETTI CERNIA, D., Laccetti, P., Linardopoulos, S., Chieffi, Paolo, Fusco, A., and Portella, G.
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medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Transplantation, Heterologous ,Clinical Biochemistry ,Aurora inhibitor ,Aurora B kinase ,Mice, Nude ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Thyroid carcinoma ,Mice ,Endocrinology ,Aurora kinase ,Aurora Kinases ,Cell Line, Tumor ,Internal medicine ,medicine ,Animals ,Aurora Kinase B ,Humans ,Thyroid Neoplasms ,Thyroid cancer ,DNA Primers ,Base Sequence ,Reverse Transcriptase Polymerase Chain Reaction ,Carcinoma ,Biochemistry (medical) ,Thyroid ,Cell cycle ,medicine.disease ,Gene Expression Regulation, Neoplastic ,enzymes and coenzymes (carbohydrates) ,Phenotype ,medicine.anatomical_structure ,embryonic structures ,Cancer cell ,biological phenomena, cell phenomena, and immunity ,Cell Division - Abstract
Alterations in chromosome number (aneuploidy) are common in human neoplasias. Loss of mitotic regulation is believed to induce aneuploidy in cancer cells and act as a driving force during the malignant progression. The serine/theronine protein kinases of aurora family genes play a critical role in the regulation of key cell cycle processes. Aurora B mediates chromosome segregation by ensuring orientation of sister chromatids and overexpression of Aurora B in diploid human cells NHDF (normal human diploid fibroblast) induces multinuclearity. We analyzed Aurora B expression in human thyroid carcinomas. Cell lines originating from different histotypes showed an increase in Aurora B expression. Immunohistochemical analysis of archive samples showed a high expression of Aurora B in anaplastic thyroid carcinomas; conversely, Aurora B expression was not detectable in normal thyroid tissue. Real-time PCR analysis confirmed a strong expression of Aurora B in anaplastic thyroid carcinomas. The block of Aurora B expression induced by RNA interference or by using an inhibitor of Aurora kinase activity significantly reduced the growth of thyroid anaplastic carcinoma cells.
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- 2005
26. DNA methylation state of the galectin-3 gene represents a potential new marker of thyroid malignancy
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Simona Keller, Giancarlo Troncone, Tiziana Angrisano, Lorenzo Chiariotti, Francesca Lembo, Ermanno Florio, Mario Capasso, Raffaela Pero, Miriam Decaussin-Petrucci, Alfredo Fusco, Keller, Simona, Angrisano, Tiziana, Florio, E, Pero, Raffaela, Decaussin Petrucci, M, Troncone, Giancarlo, Capasso, Mario, Lembo, Francesca, Fusco, Alfredo, and Chiariotti, Lorenzo
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"epigenetics" ,endocrine system ,Cancer Research ,Pathology ,medicine.medical_specialty ,DNA methylation ,endocrine system diseases ,Thyroid ,human thyroid cancer ,Cancer ,Articles ,Methylation ,Biology ,medicine.disease ,Molecular medicine ,medicine.anatomical_structure ,Oncology ,CpG site ,galectin-3 ,tumor marker ,medicine ,thyroid cancer ,Thyroid cancer ,Tumor marker - Abstract
In order to supplement the cytopathological assessment of thyroid tumors, there is a need for new markers to correctly diagnose malignant thyroid lesions and avoid unnecessary and potentially harmful therapies for patients. The immunohistochemical expression of galectin-3 is currently considered to be the most accurate stand-alone marker for thyroid cancer diagnosis. The aim of this study was to establish whether the methylation state of the galectin-3 gene is a candidate molecular marker for thyroid malignancy. Thyroid specimens from 50 patients were analyzed, including 5 normal thyroid, 3 goiters, 39 papillary and 3 anaplastic thyroid carcinoma cases. High-resolution methylation analyses was performed to investigate the methylation state of a large genomic region (from −89 to +408) encompassing the galectin-3 transcriptional start site. Within this region, 5 CpG sites (nucleotide positions +134, +137, +142, +147 and +156) were observed to be differentially methylated among the samples and were further analyzed by the quantitative pyrosequencing technique. The hypomethylation of the +134, +137, +142, +147 and +156 CpG sites was observed to be markedly associated with cancer. Although the methylation degree of each single site was highly variable in non-neoplastic tissues, the average methylation state of the 5 CpG sites clearly distinguished cancer from the nonneoplastic thyroid tissues.
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- 2013
27. The tyrosine kinase inhibitor ZD6474 blocks proliferation of RET mutant medullary thyroid carcinoma cells
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Fortunato Ciardiello, Gennaro Chiappetta, Massimo Santoro, Giancarlo Troncone, Giampaolo Tortora, James A. Fagin, Valentina De Falco, Donata Vitagliano, Francesca Carlomagno, Anderson J. Ryan, Sabrina Coluzzi, Anna Tamburrino, Vitagliano, Donata, De Falco, V., Tamburrino, Anna, Coluzzi, S., Troncone, Giancarlo, Chiappetta, G., Ciardiello, F, Tortora, G., Fagin, J., Ryan, A. J., Carlomagno, Francesca, Santoro, Massimo, Vitagliano, D, DE FALCO, V, Tamburrino, A, Coluzzi, S, Troncone, G, Chiappetta, G, Ciardiello, Fortunato, Tortora, G, Fagin, Ja, Ryan, Aj, Carlomagno, F, and Santoro, M.
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MAPK/ERK pathway ,Cancer Research ,congenital, hereditary, and neonatal diseases and abnormalities ,endocrine system ,endocrine system diseases ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Vandetanib ,Tyrosine-kinase inhibitor ,Endocrinology ,Piperidines ,Cell Line, Tumor ,tyrosine kinase inhibitors ,medicine ,thyroid cancer ,Humans ,Thyroid Neoplasms ,Epidermal growth factor receptor ,Protein kinase A ,Protein Kinase Inhibitors ,neoplasms ,Cell Proliferation ,ret ,medullary thyroid carcinoma ,tyrosine kinase inhibitor ,biology ,Kinase ,Cell growth ,Proto-Oncogene Proteins c-ret ,tyrosine kinase ,Transforming Growth Factor alpha ,targeted therapy ,Vascular Endothelial Growth Factor Receptor-2 ,ErbB Receptors ,Oncology ,Carcinoma, Medullary ,Mutation ,Quinazolines ,Cancer research ,biology.protein ,cancer therapy ,Tyrosine kinase ,carcinoma midollare della tiroide ,Signal Transduction ,medicine.drug - Abstract
Oncogenic conversion of the RET tyrosine kinase is a frequent feature of medullary thyroid carcinoma (MTC). ZD6474 (vandetanib) is an ATP-competitive inhibitor of RET, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptors kinases. In this study, we have studied ZD6474 mechanism of action in TT and MZ-CRC-1 human MTC cell lines, carrying cysteine 634 to tryptophan (C634W) and methionine 918 to threonine (M918T) RET mutation respectively. ZD6474 blunted MTC cell proliferation and RET, Shc and p44/p42 mitogen-activated protein kinase (MAPK) phosphorylation. Single receptor knockdown by RNA interference showed that MTC cells depended on RET for proliferation. Adoptive expression of the ZD6474-resistant V804M RET mutant rescued proliferation of TT cells under ZD6474 treatment, showing that RET is a key ZD6474 target in these MTC cells. Upon RET inhibition, adoptive stimulation of EGFR partially rescued TT cell proliferation, MAPK signaling, and expression of cell-cycle-related genes. This suggests that simultaneous inhibition of RET and EGFR by ZD6474 may overcome the risk of MTC cells to escape from RET blockade through compensatory over-activation of EGFR.
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- 2011
28. The loss of the CBX7 gene expression represents an adverse prognostic marker for survival of colon carcinoma patients
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Giancarlo Troncone, Luigi Tornillo, Alfredo Fusco, Sandra Schneider, Inti Zlobec, Alessandro Lugli, Pierlorenzo Pallante, Vincenza Carafa, Silvana Sacchetti, Angelo Ferraro, Mimma Bianco, Luigi Terracciano, Pallante, Pierlorenzo, Terracciano, L., Carafa, V., Schneider, S., Zlobec, I., Lugli, A., Bianco, Mimma, Ferraro, Angelo, Sacchetti, Silvana, Troncone, Giancarlo, Fusco, Alfredo, and Tornillo, L.
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Adenoma ,Male ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Colorectal adenocarcinomas ,Kaplan-Meier Estimate ,Gastroenterology ,Colorectal adenocarcinoma ,FISH ,Internal medicine ,Cell Line, Tumor ,Gene expression ,Biomarkers, Tumor ,Medicine ,Humans ,Thyroid cancer ,In Situ Hybridization, Fluorescence ,Polycomb Repressive Complex 1 ,Tissue microarray ,medicine.diagnostic_test ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Cancer ,medicine.disease ,Prognosis ,Immunohistochemistry ,digestive system diseases ,Repressor Proteins ,Real-time polymerase chain reaction ,Oncology ,CBX7 ,Colonic Neoplasms ,Cancer research ,Female ,business ,Fluorescence in situ hybridization - Abstract
We have previously shown that CBX7 expression is associated with a more malignant phenotype in thyroid cancer. On this basis, we decided to investigate its possible prognostic value in colorectal cancer (CRC). CBX7 expression has been analysed by immunohistochemistry in tissue microarray (TMA) specimens obtained from a large series of sporadic CRC resections (n = 1420). The CBX7 expression data have been correlated with several clinico-pathological parameters. CBX7 expression is reduced or absent in a significant number of CRC samples in comparison to the normal colonic mucosa and the loss of CBX7 expression correlates with a poor outcome of CRC (p < 0.001). The block of CBX7 expression seems to occur at a transcriptional level since quantitative RT-PCR analysis showed a reduced CBX7-specific mRNA levels in CRC samples versus normal counterpart tissue (up to more than 50-fold). Finally, the restoration of CBX7 expression in two CRC cell lines reduces their proliferation rate suggesting a role of the loss of CBX7 expression in the progression step of colon carcinogenesis. Therefore, the data reported here indicate that the evaluation of CBX7 expression may represent a valid tool in the prognosis of colon cancer since a reduced survival of CRC patients is associated with the loss of CBX7 expression. © 2010 Elsevier Ltd. All rights reserved.
- Published
- 2010
29. Loss of the CBX7 gene expression correlates with a highly malignant phenotype in thyroid cancer
- Author
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Pierlorenzo Pallante, 1, 2 Antonella Federico, 2 Maria Teresa Berlingieri, 1 Mimma Bianco, 1 Angelo Ferraro, 2 Floriana Forzati, 1 Antonino Iaccarino, 3 Maria Russo, 3 Giovanna Maria Pierantoni, 1 Vincenza Leone, 2 Silvana Sacchetti, 2 Giancarlo Troncone, 2, 3 Massimo Santoro, Alfredo Fusco1, P., Pallante, A., Federico, Berlingieri, Mt, Bianco, M, Ferraro, A, Forzati, F, Iaccarino, A, Russo, M, Pierantoni, GIOVANNA MARIA, Leone, V, Sacchetti, S, Troncone, Giancarlo, Santoro, Massimo, and Fusco, Alfredo
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,carcinomas ,Chromosomes, Human, Pair 22 ,Blotting, Western ,Thyroid Gland ,Loss of Heterozygosity ,Mice, Nude ,Biology ,medicine.disease_cause ,Malignancy ,Adenoviridae ,thyroid ,Colony-Forming Units Assay ,Loss of heterozygosity ,Thyroid carcinoma ,Mice ,oncogene ,Cell Line, Tumor ,Adenocarcinoma, Follicular ,medicine ,Carcinoma ,Animals ,Humans ,RNA, Messenger ,RNA, Neoplasm ,Thyroid Neoplasms ,Thyroid cancer ,Cyclin-Dependent Kinase Inhibitor p16 ,Cell Proliferation ,Polycomb Repressive Complex 1 ,Reverse Transcriptase Polymerase Chain Reaction ,Thyroid ,cbx 7 ,medicine.disease ,Carcinoma, Papillary ,Rats ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,medicine.anatomical_structure ,Oncology ,CBX7 ,Adenocarcinoma ,Carcinogenesis - Abstract
Using gene expression profiling, we found that the CBX7 gene was drastically down-regulated in six thyroid carcinoma cell lines versus control cells. The aims of this study were to determine whether CBX7 is related to the thyroid cancer phenotype and to try to identify new tools for the diagnosis and prognosis of thyroid cancer. We thus evaluated CBX7 expression in various snap-frozen and paraffin-embedded thyroid carcinoma tissues of different degrees of malignancy by quantitative reverse transcription-PCR and immunohistochemistry, respectively. CBX7 expression progressively decreased with malignancy grade and neoplasia stage. Indeed, it decreased in an increasing percentage of cases going from benign adenomas to papillary (PTC), follicular, and anaplastic (ATC) thyroid carcinomas. This finding coincides with results obtained in rat and mouse models of thyroid carcinogenesis. CBX7 loss of heterozygosity occurred in 36.8% of PTC and in 68.7% of ATC. Restoration of CBX7 expression in thyroid cancer cells reduced growth rate, with a retention in the G1 phase of the cell cycle, suggesting that CBX7 can contribute to the proliferation of the transformed thyroid cells. In conclusion, loss of CBX7 expression correlates with a highly malignant phenotype in thyroid cancer patients. [Cancer Res 2008;68(16):6770–8]
- Published
- 2008
30. BRAF is a therapeutic target in aggressive thyroid carcinoma
- Author
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Scott Wilhelm, Giancarlo Troncone, Giuliana Salvatore, Valentina De Falco, Paolo Salerno, Tito Claudio Nappi, Massimo Santoro, Stefano Pepe, Francesca Carlomagno, Rosa Marina Melillo, G., Salvatore, V., De Falco, P., Salerno, T. C., Nappi, Pepe, Stefano, Troncone, Giancarlo, Carlomagno, Francesca, Melillo, ROSA MARINA, S. M., Wilhelm, and Santoro, Massimo
- Subjects
Sorafenib ,Male ,Niacinamide ,Proto-Oncogene Proteins B-raf ,Cancer Research ,endocrine system diseases ,Pyridines ,Cell ,Transplantation, Heterologous ,Thyroid Gland ,Mice, Nude ,BRAF ,Thyroid carcinoma ,multikinase inhibitor BAY 43-9006 ,phospho-mitogen-activated protein kinase inhibition ,Mice ,RNA interference ,medicine ,Carcinoma ,Animals ,Humans ,Thyroid Neoplasms ,RNA, Small Interfering ,neoplasms ,Thyroid cancer ,cell growth inhibition ,Cell Proliferation ,Gene knockdown ,Mice, Inbred BALB C ,business.industry ,Phenylurea Compounds ,Benzenesulfonates ,medicine.disease ,digestive system diseases ,Carcinoma, Papillary ,Transplantation ,medicine.anatomical_structure ,Oncology ,Mutation ,Cancer research ,Mitogen-Activated Protein Kinases ,business ,anaplastic thyroid carcinoma cell line ,V600E ,medicine.drug ,Signal Transduction - Abstract
Purpose: Oncogenic conversion of BRAF occurs in ∼44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In papillary thyroid carcinomas, this mutation is associated with an unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a potential therapeutic target for thyroid carcinoma. Experimental Design: We used RNA interference to evaluate the effect of BRAF knockdown in the human anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006 [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit RAF family kinases in a panel of six V600EBRAF-positive thyroid carcinoma cell lines and in nude mice bearing ARO cell xenografts. Statistical tests were two sided. Results: Knockdown of BRAF by small inhibitory duplex RNA, but not control small inhibitory duplex RNA, inhibited the mitogen-activated protein kinase signaling cascade and the growth of ARO and FRO cells (P < 0.0001). These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 μmol/L; P < 0.0001), whereas the compound had negligible effects in normal thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001) smaller in nude mice treated with BAY 43-9006 than in control mice. This inhibition was associated with suppression of phospho–mitogen-activated protein kinase levels. Conclusions: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the V600EBRAF mutation and, therefore, BRAF suppression might have therapeutic potential in V600EBRAF-positive thyroid cancer.
- Published
- 2006
31. Detection of BRAF mutation in thyroid papillary carcinomas by mutant allele-specific PCR amplification (MASA)
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Guido Pettinato, Maria Rosaria Sapio, Lucio Palombini, Guido Rossi, Gianfranco Fenzi, Giancarlo Troncone, Mario Vitale, D. Posca, Sapio, Mr, Posca, D, Troncone, Giancarlo, Pettinato, Guido, Palombini, Lucio, Rossi, Guido, Fenzi, Gianfranco, and Vitale, Mario
- Subjects
Adult ,Male ,Proto-Oncogene Proteins B-raf ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,law.invention ,Thyroid carcinoma ,Endocrinology ,law ,medicine ,Carcinoma ,Humans ,Point Mutation ,Thyroid Neoplasms ,Thyroid cancer ,Polymerase chain reaction ,Alleles ,Polymorphism, Single-Stranded Conformational ,Retrospective Studies ,Mutation ,Point mutation ,Thyroid ,Single-strand conformation polymorphism ,General Medicine ,DNA, Neoplasm ,Exons ,Sequence Analysis, DNA ,medicine.disease ,Carcinoma, Papillary ,medicine.anatomical_structure ,Cancer research ,Female - Abstract
Objective: The somatic point mutation in the BRAF gene, which results in a valine-to-glutamate substitution at residue 600 (BRAFV600E), is an ideal hallmark of papillary thyroid carcinoma (PTC). However, its prevalence is varyingly reported in different studies, and its expression in the follicular variant PTC is controversial, reducing its potential usefulness as diagnostic marker. Design and methods: We developed an assay based on mutant allele-specific PCR amplification (MASA) to detect BRAF mutation. We compared the sensitivity of MASA, single-strand conformation polymorphism (SSCP) and direct DNA sequencing of PCR products. Then, we used MASA 78 to analyze 78 archival thyroid tissues, including normal samples, follicular adenomas, follicular carcinomas and PTC. Results: The MASA assay proved to be a more sensitive method than SSCP and DNA sequencing of PCR products. BRAF mutation was found by MASA in 19/43 (44.2%) of PTC, including 14/31 (45.2%) classic forms and 5/12 (41.7%) follicular variants. No mutations of BRAF were detected in the normal thyroid tissues, nor in follicular adenomas or follicular carcinomas. No correlation was found between BRAF mutation and clinicopathologic features nor with recurrence during a postoperative follow-up period of 4–11 years. BRAFV600E significantly correlated with absence of node metastasis. Conclusions: BRAFV600E is present in PTC, both in the classic form and in follicular variant with similar prevalence. No correlation was found between BRAF mutation and aggressive clinical behavior. MASA-PCR proved to be a specific, sensitive and reliable method to detect BRAF T1799A in DNA extracted from different sources, including cytologic samples obtained either fresh or from archival glass slides. We propose this method as a useful tool to improve accuracy of preoperative diagnosis identifying PTC from biopsies with indeterminate cytologic findings.
- Published
- 2006
32. BAY 43-9006 inhibition of oncogenic RET mutants
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Giancarlo Troncone, Scott Wilhelm, Giuliana Salvatore, Massimo Santoro, Suresh Anaganti, Francesca Carlomagno, Teresa Guida, Carlomagno, Francesca, Anaganti, S, Guida, Teresa, Salvatore, G, Troncone, Giancarlo, Wilhelm, Sm, and Santoro, Massimo
- Subjects
Sorafenib ,Niacinamide ,Cancer Research ,medicine.medical_specialty ,endocrine system ,endocrine system diseases ,Pyridines ,Immunoblotting ,Transplantation, Heterologous ,Administration, Oral ,Mice, Nude ,Antineoplastic Agents ,Biology ,Transfection ,Drug Administration Schedule ,thyroid ,Inhibitory Concentration 50 ,Mice ,Internal medicine ,medicine ,Animals ,cancer ,Thyroid Neoplasms ,Kinase activity ,Tyrosine ,Enzyme Inhibitors ,Phosphorylation ,Thyroid cancer ,therapy ,Kinase ,Phenylurea Compounds ,Benzenesulfonates ,Cell Cycle ,Phosphotransferases ,Proto-Oncogene Proteins c-ret ,Fibroblasts ,medicine.disease ,Molecular biology ,Transplantation ,Endocrinology ,Oncology ,RET ,thyroid cancer ,Mutation ,NIH 3T3 Cells ,Tyrosine kinase ,medicine.drug - Abstract
Background : Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. Methods : We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fi broblasts by using immunocomplex kinase assays and immunoblotting with phospho-specifi c antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fi broblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and fl ow cytometry. Growth of TT cell – derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. Results : BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC 50 s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fi broblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC 50 = 110 nM, 95% confi dence interval [CI] = 88 to 133 nM) or RET V804M (IC 50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts ( n = 7) was reduced from 72.5 to 44 mm 3 (difference = 28.5 mm 3 , 95% CI = 7 mm 3 to 50 mm 3 ), whereas in vehicle-treated mice ( n = 7), mean tumor volume increased to 408 mm 3 (difference = 320 mm 3 , 95% CI = 180 mm 3 to 460 mm 3 ; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. Conclusions : BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study. [J Natl Cancer Inst 2006;98:326 – 34]
- Published
- 2006
33. Complex Regulation of the Cyclin-Dependent Kinase Inhibitor p27kip1 in Thyroid Cancer Cells by the PI3K/AKT Pathway
- Author
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Emiliano A. Palmieri, Giuseppe Viglietto, Maria Letizia Motti, Daniela Califano, Carmela De Marco, Ilenia Migliaccio, Lucio Palombini, Giancarlo Troncone, Luciano Pezzullo, Alfredo Fusco, Maria Letizia, Motti, Daniela, Califano, Troncone, Giancarlo, Carmela De, Marco, Ilenia, Migliaccio, Emiliano, Palmieri, Luciano, Pezzullo, Palombini, Lucio, Fusco, Alfredo, and Giuseppe, Viglietto
- Subjects
Tumor suppressor gene ,Biology ,medicine.disease ,medicine.disease_cause ,Pathology and Forensic Medicine ,Thyroid carcinoma ,medicine ,Cancer research ,biology.protein ,Phosphorylation ,PTEN ,Carcinogenesis ,Protein kinase B ,Thyroid cancer ,PI3K/AKT/mTOR pathway - Abstract
Functional inactivation of the tumor suppressor p27 kip1 in human cancer occurs either through loss of expression or through phosphorylation-dependent cytoplasmic sequestration. Here we demonstrate that dysregulation of the PI3K/AKT pathway is important in thyroid carcinogenesis and that p27 kip1 is a key target of the growth-regulatory activity exerted by this pathway in thyroid cancer cells. Using specific PI3K inhibitors (LY294002, wortmannin, and PTEN) and a dominant active AKT construct (myrAKT), we demonstrated that the PI3K/AKT pathway controlled thyroid cell proliferation by regulating the expression and subcellular localization of p27. Results obtained with phospho-specific antibodies and with transfection of nonphosphorylable p27 kip1 mutant constructs demonstrated that PI3K/AKT-dependent regulation of p27 kip1 mislocalization in thyroid cancer cells occurred via phosphorylation of p27 kip1 at T157 and T198 (but not at S10 or T187). Finally, we evaluated whether these results were applicable to human tumors. Analysis of 100 thyroid carcinomas indicated that p27 kip1 phosphorylation at T157/T198 and cytoplasmic mislocalization were preferentially associated with activation of the PI3K/AKT pathway. Thus the PI3/AKT pathway and its effector p27 kip1 play major roles in thyroid carcinogenesis.
- Published
- 2005
34. Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma
- Author
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Giancarlo Troncone, Massimo Santoro, Ilenia Migliaccio, Fulvio Basolo, Pinuccia Faviana, James A. Fagin, Riccardo Giannini, Giuliana Salvatore, Alessia Caleo, Lucio Palombini, Yuri E. Nikiforov, Salvatore, G, Giannini, R, Faviana, P, Caleo, A, Migliaccio, I, Fagin, Ja, Nikiforov, Ye, Troncone, Giancarlo, Palombini, Lucio, Basolo, F, and Santoro, Massimo
- Subjects
Adenoma ,Adult ,Male ,Proto-Oncogene Proteins B-raf ,endocrine system ,Pathology ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,endocrine system diseases ,kinase ,Endocrinology, Diabetes and Metabolism ,Biopsy, Fine-Needle ,Clinical Biochemistry ,Biochemistry ,BRAF ,Thyroid carcinoma ,Endocrinology ,Internal medicine ,Biopsy ,Biomarkers, Tumor ,Carcinoma ,medicine ,thyroid cancer ,Humans ,Point Mutation ,Thyroid Neoplasms ,neoplasms ,Thyroid cancer ,Retrospective Studies ,Gene Rearrangement ,Oncogene Proteins ,RET/PTC Rearrangement ,medicine.diagnostic_test ,business.industry ,Biochemistry (medical) ,Thyroid ,Gene rearrangement ,Protein-Tyrosine Kinases ,medicine.disease ,Carcinoma, Papillary ,digestive system diseases ,Fine-needle aspiration ,medicine.anatomical_structure ,Cancer research ,Female ,business - Abstract
Point mutations in BRAF are genetic hallmarks of papillary thyroid carcinoma (PTC). In this retrospective study, we examined thyroid aspirates and corresponding paraffin-embedded surgical samples for the presence of BRAF mutations. Altogether, we examined 96 cases, including 69 PTCs, 19 follicular adenomas, and eight nontoxic nodular goiters for BRAF; 60 of these samples were also examined for RET/PTC rearrangements. The results were correlated with the cytological diagnosis and the final histopathology. The BRAF mutation (V599E) was detected in 38% of the samples that were PTC on histopathology; RET/PTC was found in 18% of the PTC cases. In all the cases, the presence of the genetic alteration was confirmed in the surgically resected tumor. The identification of BRAF mutation and RET/PTC refined the diagnosis of PTC in five of 15 samples that were considered either indeterminate or insufficient at cytology. No mutation was found in aspirates of follicular adenomas and nontoxic nodular goiters. These results indicate that BRAF mutation and RET/PTC rearrangements are molecular markers of PTC that can be applied to FNA in adjunct to traditional cytology.
- Published
- 2004
35. Ultimobranchial Body Remnants (Solid Cell Nests) as a Pitfall in Thyroid Pathology
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Guido Pettinato, Giancarlo Troncone, Debora Arpaia, Claudio Bellevicine, Giuseppe Ciancia, Bernadette Biondi, Serena Ippolito, Bellevicine, Claudio, Ippolito, S, Arpaia, D, Ciancia, G, Pettinato, Guido, Troncone, Giancarlo, and Biondi, Bernadette
- Subjects
Male ,endocrine system ,medicine.medical_specialty ,Pathology ,Neoplasm, Residual ,Goiter ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Hashimoto Disease ,Ultimobranchial Body ,Biochemistry ,Diagnosis, Differential ,Endocrinology ,Internal medicine ,Ultimopharyngeal body ,medicine ,Animals ,Humans ,Euthyroid ,Thyroid Neoplasms ,Thyroid cancer ,Completion thyroidectomy ,Pathology, Clinical ,business.industry ,Thyroid disease ,Carcinoma ,Biochemistry (medical) ,Thyroid ,Middle Aged ,medicine.disease ,Carcinoma, Papillary ,medicine.anatomical_structure ,Research Design ,Thyroid Cancer, Papillary ,Thyroidectomy ,Histopathology ,business - Abstract
We report the history of a pitfall in thyroid histopathology of a 47-yr-old man with a euthyroid nodular goiter involving the right lobe. The ultrasound-guided fineneedle aspiration of the dominant (3 cm) nodule, showing benign-appearing follicular cells, colloid, and scattered Hurthle cells, was consistent with a benign hyperplastic nodule (1). Because the left lobe had not shown evidence of nodular disease, the patient was submitted to a right lobectomy. The pathologist described a heavy lymphoplasmacyticbackgroundwithoccasionalgerminalcenter formation, as observed in Hashimoto thyroiditis, and a microscopic ( 1cm) follicularproliferationofepithelial thyroidcellswhose nucleidisplayedmembrane irregularityandchromatinclearing with occasional grooves. Thus, a histological report of a follicular variant of papillary microcarcinoma was issued. The patient underwent a completion thyroidectomy at the Federico II UniversityofNaples.At thatoccasion, thecompletesetofslides from both surgeries was reviewed by expert pathologists in the field of thyroid disease.
- Published
- 2012
36. Quantitative assessment of oxyphilic cell lesions of the thyroid gland on fine needle aspiration samples
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Zeppa, P., Benincasa, G., Troncone, G., Zabatta, A., Franco Fulciniti, Vetrani, A., Palmieri, E. A., Palombini, L., Zeppa, P, Benincasa, G, Troncone, Giancarlo, Zabatta, A, Fulciniti, F, Vetrani, Antonio, Palmieri, Ea, and Palombini, L.
- Subjects
Oxyphil Cells ,Ploidies ,thyroid gland ,Biopsy, Needle ,fine needle aspiration ,Thyroiditis, Autoimmune ,DNA, Neoplasm ,Diagnosis, Differential ,oxyphilic cell lesions ,thyroid cancer ,Humans ,Densitometry ,Goiter, Nodular - Abstract
OBJECTIVE: To assess the possible contribution by a multiparametric quantitative approach to the cytologic diagnosis of oxyphilic cell (OC) thyroid lesions. STUDY DESIGN: Ten cases of chronic lymphocytic (Hashimoto) thyroiditis and 10 nodular goiters containing oxyphilic cells plus 20 cases of tumors subsequently classified as oxyphilic cell adenomas (10 cases) or oxyphilic cell well-differentiated carcinomas (10 cases) were evaluated. The study was performed on May-Grünwald-Giemsa-stained smears for planimetric measurements. The same smears were destained and Feulgen restained for densitometric measurements. The latter were performed using static cytometry equipment measuring 100 and 20-30 lymphocytes per case for the determination of integrated optical density (IOD). The following parameters were considered: nuclear area, perimeter, maximum diameter, form ELL, form PE, IOD, 5c exceeding rate (5cER) and visual classification of histograms as euploid, polyploid and aneuploid. RESULTS: Mean nuclear area of carcinomas was smaller than that of adenomas, goiter and thyroiditis. Nuclear area was larger in adenomas than in other benign lesions and carcinomas. All the other planimetric parameters were similar in the lesions examined. Four carcinomas and three adenomas were aneuploid, and all the rest were euploid. All the cases of thyroiditis and goiter were euploid or polyploid; four thyroiditis cases showed polyploid histograms and 5cER values > 1. CONCLUSION: Morphometric and densitometric procedures have a limited role in the discrimination of OC lesions, but small nuclear area values may be useful in distinguishing OC carcinoma from other lesions. The role of densitometry seems even more limited because aneuploid histograms may be found among adenomas and carcinomas. Further studies are needed to explain polyploidy and 5cER > 1 in Hashimoto thyroiditis.
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