New prognostic markers for tumors of the ampulla of Vater which could distinguish aggressive lesions would be highly useful. The aim of this study was to evaluate the abnormal expression of p53 protein in a series of 34 ampullomas with the monoclonal antibody DO7 directed against p53 protein. Mutations of exons 5 to 8 of p53 gene were also detected by PCR followed by denaturating gel electrophoresis and sequencing.

Acute promyelocytic leukaemia is a key model system in cancer biology. Its exquisite sensitivity to retinoic acid constitutes the first example of differentiation therapy. The PML/RAR alpha fusion protein generated by the t(34, 35) translocation is the molecular basis of transformation. PML/RAR alpha induces transformation most likely through a dominant negative interference with the function of nuclear receptors leading to a differentiation block. The fusion protein also delocalises PML and other nuclear body antigens and this alteration of nuclear protein traffic seems to play a role in growth control and apoptosis. The clinical response of this disease to retinoids and arsenic trioxide, both of which induce the degradation of the fusion protein, constitute the first example of a therapy directly targeted to a specific genetic lesion in a human cancer.

Disseminated neuroblastoma frequently show a very poor prognosis. N-myc gene amplification, 1p deletion and lack of CD44 gene expression, are all genetic factors associated with the disease's dissemination. Human neuroblastoma xenografts in nude mice has permitted to characterize, in disseminated neuroblasts, oncogenes overexpression, inactivation of tumor suppressor genes as well as detoxifying genes activation which contributes to increase cellular resistance to chemotherapy. These genetic abnormalities permit to propose a nosology of this very aggressive pediatric solid tumor. Hopefully, this genetic classification could be of great value for new therapeutic approaches.

Germline mutations in either the BRCA1 or the BRCA2 gene are responsible for the majority of hereditary breast cancers. The proposition that BRCA1 may play a role as a caretaker of the genome, was first put forward by the demonstration that, in mitotic and meiotic cells, BRCA1 can interact with Rad51, a major actor in repair and/or recombination processes. From there, a fair body of observations have converged to support the concept that BRCA1 and BRCA2 play a role in monitoring and/or repairing DNA lesions. The relaxation in this monitoring, due to mutations of either of these two genes, leaves unrepaired events and leads to the accumulation of mutations and ultimately to cancer. Understanding the precise biochemical function of BRCA1 and BRCA2 should provide basis for early diagnosis and prevention in women carrying a predisposition to breast cancer.

This article analyses in a large overview several of the actual problems encountered by pathologist in the management of MTC whatever the diagnostic circumstances. We insist on difficulties upon C cell hyperplasia and early detected disease. Unusual MTC cases are discussed. The need for large multidisciplinary group in studying such tumors is underlined with reference to the French GETC (Groupe d'Etude des Tumeurs à Calcitonine).

This review article illustrates the several histological and immunohistochemical patterns of thyroid insular carcinoma and their associated disease. Differential diagnosis are also discussed. Poorly differentiated thyroid carcinomas are overviewed. The interest of transgenic mice models is presented.

Mouse transgenic models that develop thyroid diseases were generated. All transgenes were driven by the thyroid specific promoter of the thyroglobulin gene. The tissue specificity of the promoter was investigated by using the bacterial chloramphenicol acetyltransferase gene as reporter. The expression of the adenosine A2a receptor resulted in the permanent activation of the cAMP cascade. As a consequence, transgenic mice developed severe hyperthyroidism and a large goiter, demonstrating in vivo the role of the cAMP cascade in the promotion of both function and proliferation of the thyroid cell. These mice constitute a model for autonomous hyperfunctional adenoma and non autoimmune familial hyperthyroidism, where mutant of thyrotropin receptors stimulate the cAMP cascade constitutively. The expression of a mutant of the alpha 1B adrenergic receptor resulted in the constitutive activation of both the cAMP and IP3-CA++ cascades, growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals, and development of malignancies. The expression of the SV40 large T antigen promoted the development of aggressive undifferentiated tumors mimicking the phenotype of human anaplastic carcinomas and embryonal tumors. In another transgenic model, the function of the retinoblastoma susceptibility gene product RB1 (and of related proteins) was inhibited by expressing the E7 oncoprotein of human papillomavirus type 16. The result was the development of a differentiated and normofunctional colloid goiter, with progressive development of differentiated malignant lesions. This model suggests the essential role of RB1 and related proteins in the negative control of proliferation that characterizes thyroid cells in the adult. Other transgenic models of thyroid diseases are discussed.

The RET proto-oncogene encodes a receptor tyrosine kinase which plays a crucial role during the embryonic development of the enteric nervous system and of the kidney. Cytogenetic analyses of papillary thyroid carcinoma (PTC), a neoplasm which originates from thyrocytes, have revealed that somatic rearrangements of the RET gene are involved in the etiology of a significant proportion of this tumour. Medullary thyroid carcinoma (MTC) which arises from neural-crest derived C-cells is the cardinal disease feature of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer syndrome. Recent studies have provided evidence that germline mutations of the RET gene are the underlying genetic events responsible for MEN 2. This review focuses on the role of RET mutations in the pathogenesis of PTC and MTC and summarizes our present knowledge on the consequences of these alterations on the RET tyrosine kinase function. We further describe a transgenic mouse model for hereditary MTC. Mice carrying a MEN 2A allele of RET under the control of the CGRP/calcitonin promoter develop bilateral and multifocal MTC, morphologically and biologically similar to human MTC.

Tumours of the thyroid follicular cell have been intensively studied as a model for investigating the molecular genetics of tumour development in epithelial cells. This review summarises the abnormalities of oncogenes and tumour suppressor genes which have been associated with the major sub-types of thyroid tumour. Although inevitably incomplete, the available data demonstrate well how successive genetic abnormalities drive clonal progression. Comparison of follicular and papillary tumours also reveals a fascinating correlation between genotype and pathological behaviour, consistent with a determining influence of the initiating oncogene on the "route" of tumour development. Finally, the emerging clinical implications are discussed.

The t (9;22) translocation is present in about 95 per cent of chronic myelogenous leukemia and in a significant subset of acute leukemias, mainly of the lymphoid subtype. This chromosomal rearrangement leads to the fusion of the bcr and c-abl genes and to the transcription of leukemia-specific bcr-abl mRNAs. The accurate identification of the t (9;22) translocation relies on cytogenetics (conventional or Fish) and molecular techniques. The detection of residual Ph positive cells following bone marrow transplant or interferon therapy is critical and has relevant therapeutic implications.

The association of human papillomaviruses (HPV), i.e., papillomavirus type 16, with cervical dysplasias and carcinomas is now well established. Additional agents such as sexual behaviour, immunity deficiency, sociodemographic factors, microbiological agents..., are however implicated in the multistage progression from viral infection to cancer. And inactivation of tumor suppressor gene products (p53, p105Rb), oncogene activation (c-myc, c-ras), aneuploidy, karyotypic abnormalities are key events in the tumor progression. Numerous aspects of the biology of human papillomavirus, i.e. natural history, epidemiology, nature and mechanisms of the immune response are under active investigation. Screening strategies of HPV infections (cytology, HPV DNA detection and HPV antibody detection) demonstrated their efficacy in many countries, while prophylaxy and treatment of these infections by vaccines are still under development.

Our aim was to test the therapeutic effects of adenovirus-mediated gene therapy in an animal brain tumor model which was obtained by stereotactic injection of 9L gliosarcoma cells into the caudate nucleus of rat brains. Seven days after the implantation of tumor cells, adenovirus vectors bearing the Escherichia coli beta-galactosidase gene (ADVbgal) or the herpes simplex virus thymidine kinase gene (ADVtk) were stereotactically injected into the tumor. Injection of the ADVbgal resulted in the expression of the marker gene in 11 animals. Transfer of the ADVtk was followed, 3 days later, by intraperitoneal injection of ganciclovir (GCV) for 10 days. A control group was treated with saline instead of GCV. We observed a significant regression of the tumors in the rats treated with ADVtk and GCV as compared with control animals. In four cases the tumor completely disappeared after treatment. These results demonstrate the potential efficacy of adenovirus-mediated transfer of the HSVtk gene following by GCV administration for the treatment of glioblastomas.

The aim of our study was to study therapeutic results after thyroidectomy in patients positive for predictive genetic analysis and with preoperative calcitonin (CT) response to pentagastlin (Pg) < 150 pg/ml.