Guy Andry

Molecular markers of head and neck squamous cell carcinoma: promising signs in need of prospective evaluation.

The aim of this article is to review recent developments in the biological understanding of head and neck squamous cell carcinomas.

Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Cell lines are crucial to elucidate mechanisms of tumorigenesis and serve as tools for cancer treatment screenings. Therefore, careful validation of whether these models have conserved properties of in vivo tumors is highly important. Thyrocyte-derived tumors are very interesting for cancer biology studies because from one cell type, at least five histologically characterized different benign and malignant tumor types can arise. To investigate whether thyroid tumor-derived cell lines are representative in vitro models, characteristics of eight of those cell lines were investigated with microarrays, differentiation markers, and karyotyping. Our results indicate that these cell lines derived from differentiated and undifferentiated tumor types have evolved in vitro into similar phenotypes with gene expression profiles the closest to in vivo undifferentiated tumors. Accordingly, the absence of expression of most thyrocyte-specific genes, the nonresponsiveness to thyrotropin, as well as their large number of chromosomal abnormalities, suggest that these cell lines have acquired characteristics of fully dedifferentiated cells. They represent the outcome of an adaptation and evolution in vitro, which questions the reliability of these cell lines as models for differentiated tumors. However, they may represent useful models for undifferentiated cancers, and by their comparison with differentiated cells, can help to define the genes involved in the differentiation/dedifferentiation process. The use of any cell line as a model for a cancer therefore requires prior careful and thorough validation for the investigated property.

ATP, bradykinin, TRH and TSH activate the Ca2+-phosphatidylinositol cascade of human thyrocytes in primary culture

We have recently shown that adenosine triphosphate (ATP), bradykinin and thyrotropin-releasing hormone (THR) increase the ([Ca2+]i) of human thyrocytes in primary culture. We show here that these agents also stimulate the generation of [3H]-inositol monophosphate (IP1), inositol bisphosphate (IP2) and inositol trisphosphate (IP3). The stimulation of IP3 generation followed two distinct kinetics: it was sustained when the cells were triggered with ATP and transient when the response was elicited by TRH or bradykinin. In addition, we have shown that under the appropriate experimental conditions, high thyroid-stimulating hormone (TSH) concentrations were also able to stimulate human thyrocyte IP1, IP2 and IP3 accumulation and to increase their [Ca2+]i. These data suggest that ATP, bradykinin, TRH and high TSH concentrations activate the Ca(2+)-phosphatidylinositol cascade of human thyrocytes. Since this cascade plays a crucial role in the control of protein iodination, ATP, TRH and bradykinin could be important regulators of thyroid hormone synthesis in human thyrocytes.

Association of duoxes with thyroid peroxidase and its regulation in thyrocytes.

CONTEXT Thyroid hormone synthesis requires H(2)O(2) produced by dual oxidases (Duoxes) and thyroperoxidase (TPO). Defects in this system lead to congenital hypothyroidism. H(2)O(2) damage to the thyrocytes may be a cause of cancer. OBJECTIVE The objective of the study was to investigate whether Duox and TPO, the H(2)O(2) producer and consumer, might constitute a complex in the plasma membrane of human thyroid cells, thus maximizing efficiency and minimizing leakage and damage. DESIGN The interaction between Duox and TPO was studied by coimmunoprecipitation and Western blotting of plasma membranes from incubated follicles prepared from freshly resected human thyroid tissue from patients undergoing thyroidectomy, and COS-7 cells transiently transfected with the entire Duoxes or truncated [amino (NH2) or carboxyl (COOH) terminal]. RESULTS The following results were reached: 1) Duox and TPO from membranes are coprecipitated, 2) this association is up-regulated through the Gq-phospholipase C-Ca(2+)-protein kinase C pathway and down-regulated through the Gs-cAMP-protein kinase A pathway, 3) H(2)O(2) increases the association of Duox1 and Duox2 to TPO in cells and in membranes, and 4) truncated NH(2)- or COOH-terminal Duox1 and Duox2 proteins show different binding abilities with TPO. CONCLUSION Coimmunoprecipitations show that Duox and TPO locate closely in the plasma membranes of human thyrocytes, and this association can be modulated by H(2)O(2), optimizing working efficiency and minimizing H(2)O(2) spillage. This association could represent one part of a postulated pluriprotein complex involved in iodination. This suggests that defects in this association could impair thyroid hormone synthesis and lead to thyroid insufficiency and cell damage.

Management of salivary gland tumors

Surgery after proper imaging (MRI or CT scan) is the main stay of treatment for salivary gland tumors. Although excision margins should be ≥5 mm for malignant tumors in cases of parotid gland carcinoma, the facial nerve should be preserved whenever it is not infiltrated. Adjuvant external radiation is indicated for malignant tumors with high-risk features such as close (or invaded) margins, perineural speed, lymphatic and/or vascular invasion, lymph-node involvement and high-grade histology. A Phase II trial testing adjuvant concomitant cisplatin plus radiation therapy versus adjuvant radiation therapy alone after surgery is currently under investigation for high-risk salivary gland cancer. For inoperable cancers, photons combined with proton boost seem to be a valuable option. Even if protons or carbon ions are promising, access to the latter is limited for usual treatment. For recurrent and/or metastatic cancer, polychemotherapy (cisplatin based) gives a 25% response rate in adenoid cystic carcinoma and should be used when the disease is overtly in progression. Targeted therapies with anti-EGF receptor molecules, antiangiogenic agents and tyrosine kinase inhibitors are ongoing, but more trials are needed to establish their efficacy, as is the use of bortezomib followed by doxorubicin. The products of fusion oncogenes, which have a pathogenic role in some adenoid cystic carcinoma and mucoepidermoid carcinomas, are of interest as potential therapeutic targets.

mRNA Expression in Papillary and Anaplastic Thyroid Carcinoma: Molecular Anatomy of a Killing Switch

Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. No effective treatment exists so far. ATC frequently derive from papillary thyroid carcinomas (PTC), which have a good prognosis. In this study, we analyzed the mRNA expression profiles of 59 thyroid tumors (11 ATC and 48 PTC) by microarrays. ATC and PTC showed largely overlapping mRNA expression profiles with most genes regulated in all ATC being also regulated in several PTC. 43% of the probes regulated in all the PTC are similarly regulated in all ATC. Many genes modulations observed in PTC are amplified in ATC. This illustrates the fact that ATC mostly derived from PTC. A molecular signature of aggressiveness composed of 9 genes clearly separates the two tumors. Moreover, this study demonstrates gene regulations corresponding to the ATC or PTC phenotypes like inflammatory reaction, epithelial to mesenchymal transition (EMT) and invasion, high proliferation rate, dedifferentiation, calcification and fibrosis processes, high glucose metabolism and glycolysis, lactate generation and chemoresistance. The main qualitative differences between the two tumor types bear on the much stronger EMT, dedifferentiation and glycolytic phenotypes showed by the ATC.

Acrylamide, an in vivo thyroid carcinogenic agent, induces DNA damage in rat thyroid cell lines and primary cultures

Chronic treatment of rats with acrylamide induces various tumors among which thyroid tumors are the most frequent. The aim of the present study was to develop an in vitro model of acrylamide action on thyroid cells to allow the investigation of the mechanism of this tumorigenic action. The first part of the study considered as targets, characteristics of thyroid metabolism, which could explain the thyroid specificity of acrylamide action: the cAMP mitogenic effect and the important H2O2 generation by thyroid cells. However, acrylamide did not modulate H2O2 or cAMP generation in the thyroid cell models studied. No effect on thyroid cell proliferation was observed in the rat thyroid cell line FRTL5. On the other hand, as shown by the comet assay, acrylamide induced DNA damage, as the positive control H2O2 in the PC Cl3 and FRTL5 rat thyroid cell lines, as well as in thyroid cell primary cultures. The absence of effect of acrylamide on H2AX histone phosphorylation suggests that this effect does not reflect the induction of DNA double strand breaks. DNA damage leads to the generation of mutations. It is proposed that such mutations could play a role in the carcinogenic effect of acrylamide. The mechanism of this effect can now be studied in this in vitro model.

Antimicrobial prophylaxis for major head and neck surgery in cancer patients.

A total of 113 patients were randomly allocated to receive either ticarcillin plus clavulanic acid (total dose, 20.8 g) or clindamycin (total dose, 2.4 g) plus amikacin (total dose, 1 g) as perioperative antimicrobial prophylaxis for major head and neck surgery. The two groups were similar in age, prior antineoplastic treatment (surgery, chemotherapy, and radiotherapy) or tracheostomy, and the various types of surgery including radical neck dissection. The wound infection rate was 10% in the group of patients receiving clindamycin plus amikacin and 36% in the group receiving ticarcillin plus clavulanic acid (P less than 0.05). Initiation of systemic antibiotic therapy within 15 days of surgery was necessary for 20 and 45% of these patients, respectively (P less than 0.05). The distribution of microorganisms causing wound infections was comparable in both groups, except for anaerobes, which were isolated predominantly from patients who had received ticarcillin plus clavulanic acid.

Métastases intrathyroïdiennes: série de 11 cas.

Introduction Un cancer non thyroidien donne rarement des metastases diagnostiquees dans la glande thyroide. Le but de cette etude retrospective a ete de definir la frequence du primitif, le diagnostic et le traitement de metastases intrathyroidiennes ainsi que leur pronostic. Methodes De janvier 1987 a juin 1999, 11 patients ont presente une metastase thyroidienne dont le primitif etait non thyroidien (un cancer pulmonaire dans 5 cas ; un hypernephrome dans 2 cas, un carcinome mammaire dans un cas ; un cancer cervico-facial dans un cas, un cancer oesophagien dans un cas et un leiomyosarcome dans un cas). L’âge median etait de 61 ans. 54,5 % des patients etait de sexe feminin. Les manifestations cliniques se resument principalement au diagnostic d’un nodule thyroidien sans dysthyroidie ou d’une dysphonie et/ou dysphagie. Resultats 10 patients ont eu une ponction a l’aiguille fine montrant un envahissement metastatique dans 9 cas. Le temps median entre la resection de la tumeur primitive et l’apparition de metastases thyroidiennes etait de 25 mois (extremes de 1 a 96 mois). Une thyroidectomie totale (9 cas) et une lobectomie thyroidienne (2 cas) ont ete realisees sans morbidite ou mortalite. Aucun patient n’a presente de recidive loco-regionale. La survie mediane apres traitement de metastases thyroidiennes etait de 10 mois (extremes de 1 a 29 mois). Une progression tumorale a ete la cause du deces dans une majorite de cas. Conclusion Dans le cas d’une metastase thyroidienne isolee, une resection chirurgicale doit etre proposee dans le but d’eviter la morbidite potentielle d’une recidive loco-regionale meme si le pronostic est sombre dans la majorite des cas. Abstract presente a Lyon, 6th European Congress of Endocrinology, 26-30 avril 2003.

Relation between estrogen receptor concentration and clinical and histological factors: their relative prognostic importance after radical mastectomy for primary breast cancer.

After modified radical mastectomy, 490 primary breast cancer patients were followed for a median of 75 months. Bloom grade was measured in 340 patients and ER status in 341. Follow-up of these patients has yielded the following results: (a) The value of traditional indices has been reaffirmed. (Coxs multivariate analysis identified, in order of decreasing importance, the number of invaded lymph nodes, the initial tumor size and the histological grade. Other variables were found to be of lesser importance and were correlated with the three main indices.) (b) The value of ER status disappeared after more than 3 years of follow-up. (c) ER positive patients fared better after recurrence. This was interpreted as being a consequence of their responsiveness to hormonal treatment.