Publications by authors named "Bernard Caillou"

43 Publications

DNA FISH Diagnostic Assay on Cytological Samples of Thyroid Follicular Neoplasms.

Cancers (Basel) 2020 Sep 6;12(9). Epub 2020 Sep 6.

Department of Endocrinology, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.

Although fine-needle aspiration cytology (FNAC) is helpful in determining whether thyroid nodules are benign or malignant, this distinction remains a cytological challenge in follicular neoplasms. Identification of genomic alterations in cytological specimens with direct and routine techniques would therefore have great clinical value. A series of 153 cases consisting of 72 and 81 histopathologically confirmed classic follicular adenomas (cFAs) and classic follicular thyroid carcinomas (cFTCs), respectively, was studied by means of different molecular techniques in three different cohorts of patients (pts). In the first cohort (training set) of 66 pts, three specific alterations characterized by array comparative genomic hybridization (aCGH) were exclusively found in half of cFTCs. These structural abnormalities corresponded to losses of 1p36.33-35.1 and 22q13.2-13.31, and gain of whole chromosome X. The second independent cohort (validation set) of 60 pts confirmed these data on touch preparations of frozen follicular neoplasms by triple DNA fluorescent in situ hybridization using selected commercially available probes. The third cohort, consisting of 27 archived cytological samples from an equal number of pts that had been obtained for preoperative FNAC and morphologically classified as and histologically verified to be follicular neoplasms, confirmed our previous findings and showed the feasibility of the DNA FISH (DNA fluorescent in situ hybridization) assay. All together, these data suggest that our triple DNA FISH diagnostic assay may detect 50% of cFTCs with a specificity higher than 98% and be useful as a low-cost adjunct to cytomorphology to help further classify follicular neoplasms on already routinely stained cytological specimens.
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http://dx.doi.org/10.3390/cancers12092529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564487PMC
September 2020

Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model, as analyzed by reverse phase protein array.

Thyroid 2014 Jan 24;24(1):43-51. Epub 2013 Dec 24.

1 Genetic Stability and Oncogenesis Research Unit, National Center for Scientific Research (CNRS UMR 8200), Gustave Roussy and University of Paris-Sud , Villejuif, France .

Background: Medullary thyroid carcinoma (MTC) is a rare tumor that is caused by activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA).

Methods: The human TT cell line was used to assess in vitro and in vivo activity of vandetanib. Protein extracts from TT cells or TT xenografted mice, treated by increasing concentrations of vandetanib for different periods of time, were probed with a set of 12 antibodies representing major signaling pathways, using RPPA. Results were validated using two distinct protein detection methods: Western immunoblotting and immunohistochemistry.

Results: Vandetanib displays antiproliferative and antiangiogenic activities and inhibits RET autophosphorylation. The MAPK and AKT pathways were the two major signaling pathways inhibited by vandetanib. Interestingly, phosphorylated levels of NFκB-p65 were significantly increased by vandetanib. Comparable results were obtained in both the in vitro and in vivo approaches, as well as for the protein detection methods. However, some discrepancies were observed between RPPA and Western immunoblotting, possibly due to lack of specificity of the primary antibodies used.

Conclusions: Overall, our results confirmed the interest of RPPA for screening global changes induced in signaling pathways by kinase inhibitors. MAPK and AKT were identified as the main pathways involved in vandetanib response in MTC models. Our results also suggest alternative routes for controlling the disease, and provide a rationale for the development of therapeutic combinations based on the comprehensive identification of molecular events induced by inhibitors.
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http://dx.doi.org/10.1089/thy.2013.0514DOI Listing
January 2014

Changes in signaling pathways induced by vandetanib in a human medullary thyroid carcinoma model, as analyzed by reverse phase protein array.

Thyroid 2013 Jul 3. Epub 2013 Jul 3.

Institut Gustave-Roussy, CNRS UMR8200, Villejuif, France ;

Background: Medullary thyroid carcinoma (MTC) is a rare tumor that is due to activating mutations in the proto-oncogene RET. Vandetanib, a tyrosine-kinase inhibitor, has been recently approved to treat adult patients with metastatic MTC. The aim of this study was to investigate changes in signaling pathways induced by vandetanib treatment in preclinical MTC models, using the reverse-phase protein array method (RPPA).

Methods: The human TT cell line was used to assess in vitro and in vivo activity of vandetanib. Protein extracts from TT cells or TT xenografted mice, treated by increasing concentrations of vandetanib for different periods of time, were probed with a set of 12 antibodies representing major signaling pathways, using RPPA. Results were validated using two distinct protein detection methods, western-immunoblotting and immunohistochemistry.

Results: Vandetanib displays antiproliferative and antiangiogenic activities and inhibits RET auto-phosphorylation. MAPK and AKT pathways were the two major signaling pathways inhibited by vandetanib. Interestingly, phosphorylated levels of NFκB-p65 were significantly increased by vandetanib. Comparable results were obtained in both the in vitro and in vivo approaches as well as for the protein detection methods, although some discrepancies were observed between RPPA and western-immunoblotting.

Conclusions: Results confirmed the reliability and the utility of RPPA for screening global changes induced in signaling pathways by kinase inhibitors. MAPK and AKT were identified as the main pathways involved in vandetanib response in MTC models. Our results also suggest alternative routes for controlling the disease and provide a rationale for the development of therapeutic combinations based on the comprehensive identification of molecular events induced by inhibitors.
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http://dx.doi.org/10.1089/thy.2012.0224DOI Listing
July 2013

Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1-specific CD8⁺ T lymphocyte emergence.

J Mol Med (Berl) 2013 Oct 7;91(10):1207-20. Epub 2013 Jun 7.

Institut National de la Santé et de la Recherche Médicale (INSERM U753), Institut Fédératif de Recherche 54 (IFR54), Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805, Villejuif, France.

Unlabelled: Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-γ) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag-specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-γ secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.

Key Message: GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naïve T lymphocyte activation.
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http://dx.doi.org/10.1007/s00109-013-1058-5DOI Listing
October 2013

Is (18)F-fluorodeoxyglucose-PET/CT useful for the presurgical characterization of thyroid nodules with indeterminate fine needle aspiration cytology?

Thyroid 2012 Feb 18;22(2):165-72. Epub 2012 Jan 18.

Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Villejuif, France.

Background: Thyroid nodules found incidentally on (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) have been shown to be malignant in 30%-50% of cases. The American Thyroid Association recommends performing fine needle aspiration cytology (FNAC) for thyroid nodules showing FDG uptake. On the other hand, the role of FDG-PET in characterizing thyroid nodules with indeterminate cytology before surgery is not clear. The goal of this study was to evaluate the role of FDG-PET/computed tomography (CT) in predicting malignancy of thyroid nodules with indeterminate FNAC and to correlate FDG uptake with pathological and ultrasonographic (US) features.

Methods: Between November 2006 and October 2009, 55 patients (42 women, mean age: 50 years) planned for surgery for 56 thyroid nodules with indeterminate FNAC were prospectively included and considered for analysis. All patients underwent presurgical FDG-PET/CT (Siemens Biograph, mean FDG injected activity: 165 MBq) and neck US. Pathology of the corresponding surgical specimen was the gold standard for statistical analysis.

Results: At pathology 34 nodules were benign, 10 were malignant (7 papillary and 3 follicular carcinomas), and 12 were tumors of uncertain malignant potential (TUMP). The median size of the thyroid nodules was 21 mm (range: 10-57). Sensitivity, specificity, positive (PPV), and negative predictive (NPV) values of FDG-PET in detecting cancer/TUMP were 77%, 62%, 57%, and 81%, respectively. In multivariate analysis, cellular atypia was the only factor predictive of FDG uptake (p<0.001). Hurthle cells and poorly differentiated components were independent predictive factors of high (≥5) SUV Max (p=0.02 and p=0.02). Sensitivity, specificity, PPV, and NPV of US in detecting cancer/TUMP were 82%, 47%, 50%, and 80%, respectively. In multivariate analysis, hypervascularization was correlated with malignancy/TUMP (p=0.007) and cystic features were correlated with benignity (p=0.03).

Conclusion: Adding FDG-PET findings to neck US provided no diagnostic benefit. The sensitivity and specificity of FDG-PET in the presurgical evaluation of indeterminate thyroid nodules are too low to recommend FDG-PET routinely.
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http://dx.doi.org/10.1089/thy.2011.0255DOI Listing
February 2012

Wnt/β-catenin signaling pathway is a direct enhancer of thyroid transcription factor-1 in human papillary thyroid carcinoma cells.

PLoS One 2011 21;6(7):e22280. Epub 2011 Jul 21.

UMR 8203 CNRS/Institut Gustave Roussy, Villejuif, France.

The Wnt/β-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. The follow-up of PTC patients is based on the monitoring of serum thyroglobulin levels which is regulated by the thyroid transcription factor 1 (TTF-1): a tissue-specific transcription factor essential for the differentiation of the thyroid. We investigated whether the Wnt/β-catenin pathway might regulate TTF-1 expression in a human PTC model and examined the molecular mechanisms underlying this regulation. Immunofluorescence analysis, real time RT-PCR and Western blot studies revealed that TTF-1 as well as the major Wnt pathway components are co-expressed in TPC-1 cells and human PTC tumours. Knocking-down the Wnt/β-catenin components by siRNAs inhibited both TTF-1 transcript and protein expression, while mimicking the activation of Wnt signaling by lithium chloride induced TTF-1 gene and protein expression. Functional promoter studies and ChIP analysis showed that the Wnt/β-catenin pathway exerts its effect by means of the binding of β-catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [-798, -792 bp] in TTF-1 promoter. In conclusion, we demonstrated that the Wnt/β-catenin pathway is a direct and forward driver of the TTF-1 expression. The localization of TCF-4 and TTF-1 in the same area of PTC tissues might be of clinical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141030PMC
December 2011

Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma.

PLoS One 2011 21;6(7):e22567. Epub 2011 Jul 21.

Department of Biopathology, Institut Gustave Roussy, Villejuif, France.

Background: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC.

Methodology/principal Findings: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells.

Conclusion: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022567PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3141071PMC
December 2011

Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models.

Clin Cancer Res 2011 Apr 15;17(7):2044-54. Epub 2011 Feb 15.

Unité CNRS UMR8200, Institut de Cancérologie Gustave Roussy and Univ Paris-Sud, Villejuif, France.

Purpose: Medullary thyroid carcinoma (MTC), an aggressive rare tumor due to activating mutations in the proto-oncogene RET, requires new therapeutic strategies. Sunitinib, a potent inhibitor of RET, VEGF receptor (VEGFR)-1, VEGFR-2, VEGFR-3, and platelet-derived growth factor receptor (PDGFR)α/β, has been reported as clinically effective in some patients with advanced MTC. In this study, we examine molecular mechanisms of action of sunitinib and identify candidate soluble biomarkers of response.

Experimental Design: Both in vitro and in vivo assays, using the human TT RET(C634W) MTC cell line, were done to assess the activity of sunitinib. Kinetic microarray studies were used to analyze molecular pathways modified by sunitinib and to identify candidate biomarkers that were subsequently investigated in the serum of patients.

Results: Sunitinib displayed antiproliferative and antiangiogenic activities and inhibited RET autophosphorylation and activation of downstream signaling pathways. We showed that sunitinib treatment induced major changes in the expression of genes involved in tissue invasion and metastasis including vimentin (VIM), urokinase plasminogen (PLAU), tenascin-C (TN-C), SPARC, and CD44. Analyzing downregulated genes, we identified those encoding secreted proteins and, among them, interleukin (IL)-8 was found to be modulated in the serum of xenografted mice under sunitinib treatment. Furthermore, we demonstrated that metastatic MTC patients presented increased serum levels of IL-8 and TGF-β2.

Conclusions: Experimental models confirm the clinical efficacy of sunitinib observed in a few studies. Molecular pathways revealed by genomic signatures underline the impact of sunitinib on tissue invasion. Selected soluble candidate biomarkers could be of value for monitoring sunitinib response in metastatic MTC patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-10-2041DOI Listing
April 2011

Gene expression signature discriminates sporadic from post-radiotherapy-induced thyroid tumors.

Endocr Relat Cancer 2011 Feb 19;18(1):193-206. Epub 2011 Jan 19.

CEA, DSV, IRCM, LCE, BP6, Fontenay-aux-Roses F-92265, France.

Both external and internal exposure to ionizing radiation are strong risk factors for the development of thyroid tumors. Until now, the diagnosis of radiation-induced thyroid tumors has been deduced from a network of arguments taken together with the individual history of radiation exposure. Neither the histological features nor the genetic alterations observed in these tumors have been shown to be specific fingerprints of an exposure to radiation. The aim of our work is to define ionizing radiation-related molecular specificities in a series of secondary thyroid tumors developed in the radiation field of patients treated by radiotherapy. To identify molecular markers that could represent a radiation-induction signature, we compared 25K microarray transcriptome profiles of a learning set of 28 thyroid tumors, which comprised 14 follicular thyroid adenomas (FTA) and 14 papillary thyroid carcinomas (PTC), either sporadic or consecutive to external radiotherapy in childhood. We identified a signature composed of 322 genes which discriminates radiation-induced tumors (FTA and PTC) from their sporadic counterparts. The robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 29 tumors (16 FTA and 13 PTC). After the histology code break by the clinicians, 26/29 tumors were well classified regarding tumor etiology, 1 was undetermined, and 2 were misclassified. Our results help shed light on radiation-induced thyroid carcinogenesis, since specific molecular pathways are deregulated in radiation-induced tumors.
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http://dx.doi.org/10.1677/ERC-10-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023880PMC
February 2011

Prognostic markers of survival after combined mitotane- and platinum-based chemotherapy in metastatic adrenocortical carcinoma.

Endocr Relat Cancer 2010 Sep 16;17(3):797-807. Epub 2010 Aug 16.

Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave-Roussy, Université Paris XI, 39 rue Camille Desmoulins, Villejuif Cedex, France.

To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level > or =14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.
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http://dx.doi.org/10.1677/ERC-09-0341DOI Listing
September 2010

[Anaplastic cancer of the thyroid: an example of epithelial-mesenchymal transition].

Ann Pathol 2009 Nov 8;29 Spec No 1:S67-8. Epub 2009 Oct 8.

Département d'anatomie-pathologique, institut Gustave-Roussy, rue Camille-Desmoulins, Villejuif cedex, France.

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http://dx.doi.org/10.1016/j.annpat.2009.07.036DOI Listing
November 2009

Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues.

Endocr Relat Cancer 2010 Mar 29;17(1):27-37. Epub 2010 Jan 29.

CNRS, FRE2939, Villejuif F-94805, France.

NADPH oxidase 4 (NOX4) belongs to the NOX family that generates reactive oxygen species (ROS). Function and tissue distribution of NOX4 have not yet been entirely clarified. To date, in the thyroid gland, only DUOX1/2 NOX systems have been described. NOX4 mRNA expression, as shown by real-time PCR, was present in normal thyroid tissue, regulated by TSH and significantly increased in differentiated cancer tissues. TSH increased the protein level of NOX4 in human thyroid primary culture and NOX4-dependent ROS generation. NOX4 immunostaining was detected in normal and pathologic thyroid tissues. In normal thyroid tissue, staining was heterogeneous and mostly found in activated columnar thyrocytes but absent in quiescent flat cells. Papillary and follicular thyroid carcinomas displayed more homogeneous staining. The p22(phox) protein that forms a heterodimeric enzyme complex with NOX4 displayed an identical cellular expression pattern and was also positively regulated by TSH. ROS may have various biological effects, depending on the site of production. Intracellular NOX4-p22(phox) localization suggests a role in cytoplasmic redox signaling, in contrast to the DUOX localization at the apical membrane that corresponds to an extracellular H(2)O(2) production. Increased NOX4-p22(phox) in cancer might be related to a higher proliferation rate and tumor progression but a role in the development of tumors has to be further studied and established in the future.
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http://dx.doi.org/10.1677/ERC-09-0175DOI Listing
March 2010

Aggressive inherited and sporadic medullary thyroid carcinomas display similar oncogenic pathways.

Endocr Relat Cancer 2009 Dec 12;16(4):1261-72. Epub 2009 Aug 12.

CNRS FRE 2939, Institut de Cancérologie Gustave-Roussy, Villejuif, France.

RET oncogene mutations are found in familial medullary thyroid carcinomas (MTC) and in one-third of sporadic cases. Oncogenic mechanisms involved in non-RET mutated sporadic MTC remain unclear. To study alterations associated with the development of both inherited and sporadic MTC, pangenomic DNA microarrays were used to analyze the transcriptome of 13 MTCs (four familial and nine sporadic). By using an ANOVA test, a list of 173 gene sequences with at least a twofold change expression was obtained. A subset of differentially expressed genes was controlled by real-time quantitative PCR and immunohistochemistry on a larger collection of MTCs. The expression pattern of those genes allowed us to distinguish two groups of sporadic tumors. The first group displays an expression profile similar to that expressed by inherited RET634 tumors. The second presents an expression profile close to that displayed by inherited RET918 tumors and includes tumors from patients with distant metastases. It is characterized by the overexpression of genes involved in proliferation and invasion (PTN, ESM1, and CEACAM6) or matrix remodeling (COL1A1, COL1A2, and FAP). Interestingly, RET918 tumors showed overexpression of the PTN gene, encoding pleiotrophin, a protein associated with metastasis. Using a MTC cell line, silencing of RET induced the inhibition of PTN gene expression. Overall, our results suggest that familial MTC and sporadic MTC could activate similar oncogenic pathways.
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http://dx.doi.org/10.1677/ERC-08-0289DOI Listing
December 2009

Expression of cell cycle biomarkers and telomere length in papillary thyroid carcinoma: a comparative study between radiation-associated and spontaneous cancers.

Am J Clin Oncol 2009 Feb;32(1):1-8

Laboratoire de Radiobiologie et Oncologie, DSV/DRR/Commissariat à l'Energie Atomique, Villejuif, France.

Objective: Radiation exposure during childhood is the only well-established risk factor for papillary thyroid carcinoma (PTC). To better define the biologic profile of radiation-induced and sporadic PTC, we compared in these two groups of PTC the expression of cell cycle regulatory proteins and telomere length.

Methods: Cell cycle markers (cyclin A, B1, D1, E, and Ki67) were evaluated on 100 PTC specimens (26 radiation-induced and 74 sporadic PTCs). The expression of cell cycle regulators was studied using immunohistochemistry; telomere length heterogeneity was studied using in situ hybridization in a subset of 16 formalin-fixed samples (8 radiation-induced and 8 sporadic PTCs).

Results: At multivariate analysis, only cytoplasmic cyclin E staining was overexpressed in sporadic cases (P = 0.006). The other cell cycle markers and telomere length did not differ significantly between sporadic PTC and radiation-induced PTC.

Conclusions: These markers cannot be used to differentiate radiation-induced from sporadic PTCs.
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http://dx.doi.org/10.1097/COC.0b013e3181783336DOI Listing
February 2009

Poorly differentiated follicular thyroid carcinoma: prognostic factors and relevance of histological classification.

Thyroid 2007 Jul;17(7):639-46

Nuclear Medicine and Endocrine Oncology, Commissariat à l'Energie Atomique LRC29V, Institut Gustave Roussy and University Paris Sud, Villejuif, France.

Objective: Poorly differentiated follicular thyroid carcinoma (PDFC) is a tumor of follicular cell origin with attributes intermediate between well-differentiated carcinomas and anaplastic carcinomas, but neither a clear histological description nor an established definition of prognostic indicators are available.

Design: This study correlates the clinical outcome and survival of 40 PDFC patients with histological architecture, cytological characteristics, and expression of various markers of cell proliferation and differentiation (cyclin A, cyclin B1, cyclin D1, cyclin E, Ki67, thyroperoxidase, galectin 3, dual oxidase [Duox], vascular endothelial growth factor, epidermal growth factor receptor, and p53).

Main Outcome: At 5 years, the overall survival rate was 63% and the metastasis-free survival rate was 57%. An older age at the time of diagnosis and a larger tumor size were associated with an increased risk of distant metastases and of cancer-related death. Polymorph architecture was associated with a reduced risk of metastases, whereas a high expression of Duox was associated with a reduced risk of death. In these patients with PDFC, no other histological features or expression of any other marker had a prognostic significance.

Conclusion: PDFC has a more aggressive behavior than well-differentiated carcinomas; prognosis is related to indicators that are also relevant in patients with well-differentiated carcinomas.
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http://dx.doi.org/10.1089/thy.2007.0029DOI Listing
July 2007

Ultrasound criteria of malignancy for cervical lymph nodes in patients followed up for differentiated thyroid cancer.

J Clin Endocrinol Metab 2007 Sep 3;92(9):3590-4. Epub 2007 Jul 3.

Department of Nuclear Medicine and Endocrine Oncology, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cedex, France.

Context: Neck ultrasonography (US) has become a keystone in the follow-up of patients with differentiated thyroid cancer.

Objective: The aim of this study was to determine specificity and sensitivity of ultrasound criteria of malignancy for cervical lymph nodes (LNs) in patients with differentiated thyroid cancer.

Design: We prospectively studied 19 patients referred to the Institut Gustave Roussy for neck LN dissection. All patients underwent a neck US within 4 d prior to surgery. Only LNs that were unequivocally matched between US and pathology were taken into account for the analysis.

Results: One hundred three LNs were detected on US, 578 LNs were surgically removed, and 56 LNs were analyzed (28 benign and 28 malignant). Sensitivity and specificity were 68 and 75% for the long axis (> or =1 cm), 61 and 96% for the short axis (>5 mm), 46 and 64% for the round shape (long to short axis ratio < 2), 100 and 29% for the loss of fatty hyperechoic hilum, 39 and 18% for hypoechogenicity, 11 and 100% for cystic appearance, 46 and 100% for hyperechoic punctuations, and 86 and 82% for peripheral vascularization.

Conclusion: Cystic appearance, hyperechoic punctuations, loss of hilum, and peripheral vascularization can be considered as major ultrasound criteria of LN malignancy. LNs with cystic appearance or hyperechoic punctuations are highly suspicious of malignancy. LNs with a hyperechoic hilum should be considered as benign. Peripheral vascularization has the best sensitivity-specificity compromise. Round shape, hypoechogenicity, and the loss of hilum taken as single criteria are not specific enough to suspect malignancy.
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http://dx.doi.org/10.1210/jc.2007-0444DOI Listing
September 2007

Functional characterization of human thyroid tissue with immunohistochemistry.

Thyroid 2007 Mar;17(3):203-11

Department of Pathology, Commissariat à l'Energie Atomique LRC29V, Institut Gustave Roussy, University Paris Sud, Villejuif Cedex, France.

Immunohistochemistry provides insights in the expression of functional proteins and of their localization in normal thyroid tissue and in thyroid diseases. In hyperfunctional thyroid tissues, staining for sodium/iodide symporter (NIS), pendrin, thyroid peroxidase (TPO), and thyroglobulin (Tg) is increased. In hypofunctioning thyroid tissues, NIS staining is markedly decreased; in benign hypofunctioning adenomas, the expression of the other functional proteins is unmodified or slightly decreased, whereas their expression is profoundly decreased or absent in differentiated thyroid carcinoma.
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http://dx.doi.org/10.1089/thy.2006.0174DOI Listing
March 2007

Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus.

J Clin Endocrinol Metab 2007 Jan 31;92(1):70-6. Epub 2006 Oct 31.

Faculty of Medicine René Descartes, Paris V, Site Necker, Institut National de la Santé et de la Recherche Médicale Equipe Mixte 0363, Pediatric Endocrine Unit, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Paris, France.

Context: Terminal differentiation of the human thyroid is characterized by the onset of follicle formation and thyroid hormone synthesis at 11 gestational weeks (GW).

Objective: This study aimed to investigate the ontogeny of thyroglobulin (Tg), thyroid peroxidase (TPO), sodium/iodide symporter (NIS), pendrin (PDS), dual oxidase 2 (DUOX2), thyroid-stimulating hormone receptor (TSHR), and thyroid transcription factor 1 (TITF1), forkhead box E1 (FOXE1), and paired box gene 8 (PAX8) in the developing human thyroid.

Design: Thyroid tissues from human embryos and fetuses (7-33 GW; n = 45) were analyzed by quantitative PCR to monitor mRNA expression for each gene and by immunohistochemistry to determine the cellular distribution of TITF1, TSHR, Tg, TPO, NIS, and the onset of T4 production. A broken line regression model was fitted for each gene to compare the loglinear increase in expression before and after the onset of T4 synthesis.

Results: TITF1, FOXE1, PAX8, TSHR, and DUOX2 were stably expressed from 7 to 33 GW. Tg, TPO, and PDS expression was detectable as early as 7 GW and was correlated with gestational age (all, P < 0.01), and the slope of the regression line was significantly different before and after the onset of T4 synthesis at 11 GW (all, P < 0.01). NIS expression appeared last and showed the highest fit by the broken line regression model of all genes (correlation age P < 0.0001, broken line regression P < 0.0001). Immunohistochemical studies detected TITF1, TSHR, and Tg in unpolarized thyrocytes before follicle formation. T(4) and NIS labeling were only found in developing follicles from 11 GW on.

Conclusion: These results imply a key role of NIS for the onset of human thyroid function.
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http://dx.doi.org/10.1210/jc.2006-1450DOI Listing
January 2007

Prognostic parameters of metastatic adrenocortical carcinoma.

J Clin Endocrinol Metab 2007 Jan 24;92(1):148-54. Epub 2006 Oct 24.

Service de Médecine Nucléaire et de Cancérologie Endocrinienne, Institut Gustave-Roussy, Université Paris XI, 94800 Villejuif, France.

Context: Prognostic parameters of metastatic adrenocortical carcinoma (ACC) are poorly characterized.

Objective: The objective of the study was to describe the clinical presentation of metastatic ACC and determine prognostic factors for survival.

Design: This was a retrospective cohort study (1988-2004).

Setting: The study was conducted in an institutional practice.

Patients: Participants included 124 consecutive patients with metastatic ACC, 70 from Gustave-Roussy Institute (main cohort) and 54 patients from the Cochin Hospital (validation cohort). Clinical data concerning all patients, histopathologic slides of primary tumors (44 in the main cohort and 40 in the validation cohort), and molecular biology data on 15 primary tumors (main cohort) were analyzed.

Intervention: There was no intervention.

Main Outcome: The main outcome was the specific survival after discovery of the first metastasis (Kaplan-Meier method). This included univariate analysis on the main cohort, confirmed on the validation cohort and then analyzed in a multivariate analysis.

Results: In the main cohort, overall median survival was 20 months. In univariate analysis, the presence of hepatic and bone metastases, the number of metastatic lesions and the number of tumoral organs at the time of the first metastasis, a high mitotic rate (>20 per 50 high-power field), and atypical mitoses in the primary tumor predicted survival (P = 0.05, 0.003, 0.046, 0.001, 0.01, and < 0.001, respectively). The number of tumoral organs and a high mitotic rate were confirmed on the validation cohort (P = 0.009 and 0.03, respectively). These two parameters were confirmed in multivariate analysis (P = 0.0058 and 0.049).

Conclusion: Metastatic ACC is a heterogeneous disease with poor outcome. The combination of the number of tumoral organs at the time of the first metastasis and the mitotic rate can predict different outcomes.
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http://dx.doi.org/10.1210/jc.2006-0706DOI Listing
January 2007

Ductal metaplasia in chronic lymphocytic thyroiditis as a manifestation of phylogenic regression to an exocrine structure.

Authors:
Bernard Caillou

Am J Surg Pathol 2006 Jun;30(6):774-81

Department of Pathology, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif Cedex, France.

From a morphologic and functional point of view the thyroid can be considered as both an exocrine and endocrine organ. Firstly, thyroglobulin is secreted at the apical pole of the thyrocyte. Secondly, after endocytosis thyroglobulin is lysed and T3 and T4 are secreted at the basal pole into the bloodstream. However, usually exocrine glands are constituted of 2 well separate components: an acinus/alveolar component and an exocrine duct component. Under particular conditions such as chronic injury the acinus/alveolar component is rapidly destroyed, whereas the ductal component seems to be far more resistant and can proliferate giving rise to a tubular network described as "ductulus reaction" or "ductal metaplasia." Normal exocrine ducts and metaplastic ducts exhibit common genetic and phenotypic features directly related to their tubular morphology. In this study, we describe in lymphocytic autoimmune thyroiditis the appearance of ductal-like structures which displayed the features of ductal metaplasia.
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http://dx.doi.org/10.1097/00000478-200606000-00016DOI Listing
June 2006

HEX, PAX-8 and TTF-1 gene expression in human thyroid tissues: a comparative analysis with other genes involved in iodide metabolism.

Clin Endocrinol (Oxf) 2006 Apr;64(4):398-404

Department of Clinical Biology, Institut Gustave-Roussy and Commissariat à l'Energie Atomique LRC 29V, Villejuif, France.

Objective: Benign and malignant thyroid tumours are characterized by alterations of the expression level of thyroid-specific genes involved in the iodide metabolism. Imbalance in the levels of transcription factors has been recognized as a critical molecular event in the development of neoplasm. The delineation of eventual correlations existing between the expression of transcription factors and of putative target genes in physiological and pathological conditions could be relevant to better understand tumorigenesis.

Patients And Methods: We examined the expression levels of transcription factors involved in thyroid development [thyroid transcription factor 1 (TTF-1), paired box gene 8 (PAX-8) and haematopoietically expressed homeobox (HEX)] in 101 thyroid tissues, including 14 normal thyroid tissues, 13 hyperfunctioning tissues, 27 benign adenomas and 47 follicular or papillary carcinomas. Then, we compared their expression levels with those of thyroid-specific genes involved in iodide metabolism.

Results: In benign tumours, PAX-8 and TTF-1 gene expression levels were not significantly different from the expression levels in normal tissues. However, a significant decrease was found in carcinomas. Interestingly, HEX gene expression was significantly decreased in both hyper- and hypofunctioning benign tissues and also in carcinomas. Expression levels of Pendred syndrome (PDS), natrium iodine symporter (NIS), thyroglobulin (Tg), thyroid peroxidase (TPO) and dual oxidase 1 or 2 (DUOX2) genes were significantly correlated with the expression of PAX-8 and with that of HEX. Expression level of TTF-1 was weakly correlated only with the expression levels of PDS and DUOX2.

Conclusion: Our findings suggest that alterations in the transcription factors PAX-8, TTF-1 and HEX gene expression, by acting individually or together, have a role in both thyroidal tumorigenesis and in the dedifferentiation process.
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http://dx.doi.org/10.1111/j.1365-2265.2006.02477.xDOI Listing
April 2006

Medullary thyroid carcinoma arises in the absence of prolactin signaling.

Cancer Res 2005 Sep;65(18):8497-503

Institut National de la Sante et de la Recherche Médicale U584, Faculté de Médecine Necker, Paris, France.

Prolactin, a pituitary hormone, exerts pleiotropic effects in various cells. These effects are mediated by a membrane receptor highly expressed in many tissues. To analyze prolactin effects on the thyroid gland, we first identified prolactin receptor (PRLR) mRNAs by in situ hybridization. To further evaluate the physiologic relevance of PRLR actions in the thyroid in vivo, we used PRLR knockout mice. Whereas the histologic structure of thyroid of PRLR-null mice was not disturbed, we show that T4 levels are lower in null animals (13.63 +/- 2.98 versus 10.78 +/- 2.25 pmol/L in null mice), confirming that prolactin participates in the control of thyroid metabolism. To further investigate thyroid effects in mice, we measured body temperature and thyroid-stimulating hormone in young and adult male and/or female PRLR-null mice and their normal siblings. Surprisingly, in null animals, we saw medullary thyroid carcinoma (MTC) arising from parafollicular C cells producing calcitonin. The incidence of these carcinomas attained 41% in PRLR-null mice, whereas this malignant tumor occurs sporadically or as a component of the familial cancer syndrome in humans. This finding suggests that PRLR-null mice could represent a valuable animal model for MTC, which could be compared with existing MTC models. These observations suggest a possible link between the appearance of this carcinoma and the absence of prolactin signaling.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-3937DOI Listing
September 2005

Prognostic factors for persistent or recurrent disease of papillary thyroid carcinoma with neck lymph node metastases and/or tumor extension beyond the thyroid capsule at initial diagnosis.

J Clin Endocrinol Metab 2005 Oct 19;90(10):5723-9. Epub 2005 Jul 19.

Department of Nuclear Medicine and Endocrine Tumors, Institut National de la Santé et de la Recherche Médicale U605, Institut Gustave Roussy, Rue Camille Desmoulins, 94805 Villejuif Cédex, France.

Context: Reliable prognostic factors are needed in papillary thyroid cancer patients to adapt initial therapy and follow-up schemes to the risks of persistent and recurrent disease. OBJECTIVE AND SETTINGS: To evaluate the respective prognostic impact of the extent of lymph node (LN) involvement and tumor extension beyond the thyroid capsule, we studied a group of 148 consecutive papillary thyroid cancer patients with LN metastases and/or extrathyroidal tumor extension. Initial treatment, performed at the Institut Gustave Roussy between 1987 and 1997, included in all patients a total thyroidectomy with central and ipsilateral en bloc neck dissection followed by radioactive iodine ablation.

Results: Uptake outside the thyroid bed, demonstrating persistent disease, was found on the postablation total body scan (TBS) in 22% of the patients. With a mean follow-up of 8 yr, eight patients (7%) with a normal postablation TBS experienced a recurrence. Ten-year disease-specific survival rate was 99% (confidence interval, 97-100%). Significant risk factors for persistent disease included the numbers of LN metastases (>10) and LN metastases with extracapsular extension (ECE-LN >3), tumor size (>4 cm), and LN metastases location (central). Significant risk factors for recurrent disease included the numbers of LN metastases (>10), ECE-LN (>3), and thyroglobulin level measured 6-12 months after initial treatment after T4 withdrawal.

Conclusion: We highlight an excellent survival rate and suggest risk classifications of persistent and recurrent disease based on the numbers of LN metastases and ECE-LN, LN metastases location, tumor size, and thyroglobulin level.
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http://dx.doi.org/10.1210/jc.2005-0285DOI Listing
October 2005

Radiation exposure and familial aggregation of cancers as risk factors for colorectal cancer after radioiodine treatment for thyroid carcinoma.

Int J Radiat Oncol Biol Phys 2005 Jul;62(4):1084-9

National Institute of Public Health and Medical Research, INSERM, Unit 605, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France.

Purpose: In thyroid cancer patients, radioiodine treatment has been shown to be associated with an increased risk of colon carcinoma. The aim of this study in thyroid cancer patients was to evaluate the role of familial factors in the risk of colorectal cancer and their potential interaction with radioiodine exposure.

Methods And Materials: We performed a case-control study on 15 colorectal cancer patients and 76 matched control subjects, nested in a cohort of 3708 thyroid cancer patients treated between 1933 and 1998. For each patient, the radiation dose delivered to the colon by radioiodine was estimated by use of standard tables. In those who received external radiation therapy, the average radiation doses delivered to the colon and rectum were estimated by use of DOS_Eg software. A complete familial history was obtained by face-to-face interviews, and a familial index was defined to evaluate the degree of familial aggregation.

Results: The risk of colorectal cancer increased with familial aggregation of colorectal cancer (p = 0.02). After adjustment for the radiation dose delivered to the colon and rectum, the risk of colorectal cancer was 2.8-fold higher (95% CI, 1.0-8.0) for patients with at least one relative affected by colorectal cancer than for patients without such a family history (p = 0.05). The radiation dose delivered to the colon and rectum by (131)I and external radiation therapy was associated with an increase of risk near the significance threshold (p = 0.1). No significant interaction was found between radiation dose and having an affected relative (p = 0.9).

Conclusions: The role of familial background in the risk of colorectal cancer following a differentiated thyroid carcinoma appears to increase with the radiation dose delivered to the colon and rectum. However, the study population was small and no interaction was found between these two factors.
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http://dx.doi.org/10.1016/j.ijrobp.2004.12.063DOI Listing
July 2005

Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations.

Am J Pathol 2005 Jul;167(1):223-31

Functional Genomic Unit, Institut Gustave-Roussy, Villejuif Cedex, France.

Follicular thyroid carcinomas (FTC) arise through oncogenic pathways distinct from those involved in the papillary histotype. Recently, a t(2;3)(q13;p25) rearrangement, which juxtaposes the thyroid transcription factor PAX8 to the peroxisome proliferator-activated receptor (PPAR) gamma1, was described in FTCs. In this report, we describe gene expression in 11 normal tissues, 4 adenomas, and 8 FTCs, with or without the PAX8-PPARgamma1 translocation, using custom 60-mer oligonucleotide microarrays. Results were confirmed by quantitative real-time polymerase chain reaction of 65 thyroid tissues and by immunohistochemistry. Statistical analysis revealed a pattern of 93 genes discriminating FTCs, with or without the translocation, that were morphologically undistinguishable. Although the expression of thyroid-specific genes was detectable, none appeared to be differentially regulated between tumors with or without the translocation. Differentially expressed genes included genes related to lipid/glucose/amino acid metabolism, tumorigenesis, and angiogenesis. Surprisingly, several PPARgamma target genes were up-regulated in PAX8-PPARgamma-positive FTCs such as angiopoietin-like 4 and aquaporin 7. Moreover many genes involved in PAX8-PPARgamma expression profile presented a putative PPARgamma-promoter site, compatible with a direct activity of the fusion product. These data identify several differentially expressed genes, such as FGD3, that may serve as potential targets of PPARgamma and as members of novel molecular pathways involved in the development of thyroid carcinomas.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1603430PMC
http://dx.doi.org/10.1016/s0002-9440(10)62967-7DOI Listing
July 2005

Neck recurrence from thyroid carcinoma: serum thyroglobulin and high-dose total body scan are not reliable criteria for cure after radioiodine treatment.

Clin Endocrinol (Oxf) 2005 Mar;62(3):376-9

Department of Nuclear Medicine and Endocrine Tumours, Institut Gustave Roussy, Villejuif Cédex, France.

Background: Local and regional recurrences occur in up to 20% of patients with papillary and follicular thyroid carcinoma. Diagnostic work-up and treatment modalities are still controversial, because nodal control is difficult to ascertain. We assessed the value of serum thyroglobulin (Tg) determination and of high-dose 131I total body scan (TBS) for ascertaining the absence of disease in patients who had already been treated with radioiodine and who subsequently underwent surgery.

Methods: Between 1990 and 2000, 105 patients who had been treated with radioiodine for lymph node recurrence with initial 131I uptake were included in a standardized protocol performed after withdrawal of thyroid hormone treatment: on day 1, serum Tg determination and administration of 3.7 GBq 131I; on day 4, 131I TBS; on day 5, surgery; on day 8, 131I TBS.

Results: In 25 patients the serum Tg obtained following thyroid hormone withdrawal was undetectable: for these patients, the 131I TBS showed uptake foci in 21 and pathology disclosed neoplastic foci in 19. In 32 patients the serum Tg ranged from 1 to 10 ng/ml: for these patients, the 131I TBS showed uptake foci in 26 and pathology disclosed neoplastic foci in 28. In 48 patients the serum Tg level was above 10 ng/ml: for these patients, the 131I TBS showed uptake foci in 38 and pathology disclosed neoplastic foci in 46. Thus, no uptake was found preoperatively in 20 patients, among whom pathology disclosed lymph node metastases in 16. However, both tests were negative in only two of the 93 patients in whom pathology disclosed neoplastic foci.

Conclusion: Serum Tg levels and 131I TBS cannot be considered as reliable indicators for the absence of disease in patients already treated with 131I. However, when both tests are negative, the risk of persistent disease is minimal.
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http://dx.doi.org/10.1111/j.1365-2265.2005.02228.xDOI Listing
March 2005

Morphological changes of follicular cell basal borders and basement membranes in benign and malignant nodular lesions of the thyroid gland: an ultrastructural study.

Ultrastruct Pathol 2004 Jul-Aug;28(4):199-207

Unit of Ultrastructural Pathology, Department of Human Pathology, University of Messina, Messina, Italy.

Microfollicular nodular lesions of the thyroid gland may represent a differential diagnosis problem. Firstly, nodular areas of follicular hyperplasia have to be distinguished from follicular adenomas. On the other hand, nodular microfollicular areas exhibiting large pale nuclei, occasionally found in hyperplastic nodules and follicular adenomas, must be discriminated from latent papillary carcinomas with predominant follicular architecture. The diagnosis of follicular carcinoma still requires the detection of vascular and/or capsular microinvasion. A more refined study was planned to search for additional descriptors useful for diagnosis The authors report the results of an ultrastructural investigation carried out on 220 thyroid nodular lesions and 50 specimens of macroscopically nonnodular glands. An infolding arrangements of the thyreocyte basal border (TBB) and follicular basement membrane (FBM) was demonstrated in 50/50 nonnodular thyroid tissue specimens and 53/67 (79.1%) hyperplastic nodular lesions (p<.005). A linear arrangement of the TBB and FBM was found in 85/121 (70.2%) follicular adenomas and in 32/32 differentiated carcinomas (p<.001). In the last group, 12/32 (37.5%) cases showed focal discontinuities of FBM. In conclusion, the benign thyroid nodules show a prevalently infolding arrangements of TBBs, whereas the majority of proliferative lesions display a linear morphology. In absence of an infiltrating pattern there is no morphological evidence of discriminating potentially malignant vs. benign lesions. The linear distribution of TBBs and FBMs places the case in a group of borderline lesions that involve a more careful postsurgery investigation.
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http://dx.doi.org/10.1080/019131290505130DOI Listing
March 2005

Dual oxidase2 is expressed all along the digestive tract.

Am J Physiol Gastrointest Liver Physiol 2005 May 9;288(5):G933-42. Epub 2004 Dec 9.

Unité 486 INSERM, Université Paris 11, Faculté de Pharmacie, 92296 Châtenay-Malabry Cedex, France.

The dual oxidase (Duox)2 flavoprotein is strongly expressed in the thyroid gland, where it plays a critical role in the synthesis of thyroid hormones by providing thyroperoxidase with H2O2. DUOX2 mRNA was recently detected by RT-PCR and in-situ hybridization experiments in other tissues, such as rat colon and rat and human epithelial cells from the salivary excretory ducts and rectal glands. We examined Duox2 expression at the protein level throughout the porcine digestive tract and in human colon. Western blot analysis identified Duox2 as the same two molecular species (M(r) 165 and 175 kDa) as detected in the thyroid. It was expressed in all the tissues tested, but the highest levels were found in the cecum and sigmoidal colon. Immunohistochemical studies showed that Duox2 protein is mainly present in these parts of the gut and located at the apical membrane of the enterocytes in the brush border, indicating that it is expressed only in highly differentiated cells. A Ca2+/NADPH-dependent H2O2-generating system was associated with Duox2 protein expression, which had the same biochemical characteristics as the NADPH oxidase in the thyroid. Indeed, treatment of the thyroid and cecum particulate fractions with phenylarsine oxide resulted in complete calcium desensitization of both enzymes. A marked increase in DUOX2 expression was also found during spontaneous differentiation of postconfluent Caco-2 cells. The discovery of Duox2 as a novel source of H2O2 in the digestive tract, particularly in the cecum and colon, makes it a new candidate mediator of physiopathological processes.
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http://dx.doi.org/10.1152/ajpgi.00198.2004DOI Listing
May 2005