Neurofibromatosis 1(NF1) is one of the most common genetic diseases. NF1 is an autosomal dominant genetic disorder and half of affected individuals have NF1 as the result of a new gene NF1 mutation. The offspring of an affected individual have a 50% risk of inheriting the altered NF1 gene. The disease manifestations are extremely variable, even within a family. NF1 is characterized by multiple cafe au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. Learning disabilities are frequent. Less common but potentially more serious manifestations include plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, vasculopathy, and osseous lesions.

The management of advanced stage ovarian cancer has been deeply modified over the last few years. In patients with massive peritoneal spread, the use of neoadjuvant chemotherapy, followed by interval surgery, reduces the morbidity of radical surgery with an improvement of the quality of life. Nevertheless, results of ongoing randomized studies should be waited before stating about the results on survival of such management compared to initial debulking surgery. Waiting such results, the standard treatment of advanced stage ovarian cancer in 2005 remains initial surgery, performed in order to obtain ideally a total resection of all macroscopic diseases, and followed by adjuvant chemotherapy. However, in patients with massive spread, interval debulking surgery is becoming an interesting option, and will perhaps become a standard management. But criteria to select patients between initial and interval debulking surgery should be clearly defined. Those different points will be studied in this paper.

We report an observation concerning a 48-year-old male who presented with a 5 cm tumour on his left leg, first noticed 18 months ago. The remainder of clinical examination was normal. Histological assessment revealed a tumoral infiltration of entire dermis and superficial hypodermis. This tumour consisted of monomorphous, ovoid or spindle cells, with clear cytoplasm and PAS+ granulations. There was strong immunoreactivity by tumoral cells only for vimentin. Ultrastructural studies revealed fibrohistiocytic-like tumoral cells, without epithelial, muscular, vascular or melanocytic differentiation. These results were consistent with the diagnosis of clear cell dermatofibroma. Cytogenetic evaluation and FISH analysis showed a deletion of p12. Clear cell dermatofibroma is a rare and recent variant of dermatofibroma, with a difficult histological evaluation and which must be differentiated from clear-cell sarcoma. This observation is the first case-report of this entity, to our knowledge, showing a cytogenetic abnormality.

The hereditary non-polyposis colon cancer (HNPCC) syndrome is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for other organs tumors. HNPCC syndrome is responsible for 5% of colorectal cancers.

Much progress has been made in treating human malignancies and there are now multiple treatment options with similar efficacy for nearly every type of cancer. However, the narrow therapeutic index of most chemotherapeutic agents and the severe consequences of undertreatment or overdosing have led to research molecular predictive factors of the toxicity and efficacy of cancer treatments. Genetic factors affecting drug metabolism and transport partly explain interindividual variability in drug response. Pharmacogenetic focuses on the molecular mechanisms involved in drug response, and its ultimate goal is the optimisation of the treatments, that combines the optimal efficacy and the minimal risk of severe side effects. Polymorphisms in genes encoding specific drug-metabolising enzymes can result in individuals in the general population being characterised as low, rapid or even ultra-rapid metabolisers. Phenotyping and genotyping tests are now available that determine or predict the metabolic status of an individual and, thus, enable the evaluation of risk of drug failure or toxicity. Some clinical applications of pharmacogenetics (5-FU, irinotecan, thiopurines) have already been developed in routine medicine resulting in significant improvement in patient treatment. The clinical validation of an increasing number of pharmacogenetic tests, as well as the development of new highly efficient technologies for genotyping (real-time PCR, DNA chips...) should further promote pharmacogenetics in clinical practice and lead to the development of a patient-tailored drug therapy.

Our work aims at defining in molecular terms the steps involved in the control of proliferation of normal thyroid cells and in the perversion of this process in thyroid tumors (hyperfunctioning autonomous adenomas, sporadic and post-Chernobyl papillary cancers). Our strategy has been to define such steps by gene expression analysis using different methodologies: we have first studied in vitro primary cultures of thyroid cells by differential screening, macroarray and differential PCR (CDNA AFLP-TP), and secondly thyroid tumors by microarray. The latter technology proved by far to be more powerful. We have implemented the biochemical and bioinformatical tools for this methodology and applied it to hyperfunctioning autonomous adenomas and to sporadic and post-Chernobyl papillary carcinomas. We are now investigating in depth genes whose regulation is altered in these tumors.

The introduction of imatinib mesylate (IM) has revolutionized the therapy of chronic myelogenous leukemia (CML) and changed dramatically the therapeutic strategies in this malignant disease. After the establishment of its success in patients refractory to standard treatments, IM has shown its superiority in terms of cytogenetic response in previously untreated patients and became the first line therapy in the majority of patients with CML. However, it is currently unknown if IM will have a curative potential in CML, a potential which has been shown only for allogeneic stem cell transplantation to date. The recent description of the development of resistance to IM and the discovery of the underlying Abl-kinase mutations as a principal mechanism of resistance prompted a major research effort to understand the pathophysiology of the resistance phenomenon and stimulated the implementation of new algorithms for the treatment.

Papillary thyroid carcinomas are characterized in 70% of cases by the presence of either a RET/PTC rearrangement, or an activating point mutation of RAS or BRAF genes that induce a constitutive activation of the MAP kinase pathway. Follicular carcinomas are characterized by the presence of a RAS mutation or of a PAX8-PPARgamma rearrangement. Inactivating mutations of the p53 gene are found only in anaplastic thyroid carcinomas.

To study the lymphoid clonality on Tunisian B-cell lymphomas cases by polymerase chain reaction (PCR)-based techniques using DNA from paraffin-embedded tissues.

Estimation of prevalence and incidence rates in a disease is crucial to estimate the risk of the natural evolution of the disease. We have reviewed published data on intracranial AVM and have noted that reported estimated risks were quite variable mainly due to the lack of population-based prospective data. Nonetheless, estimation of these parameters can be made from selected populations. We will note also that there is no published data confirming a genetic origin for the most frequent group of sporadic AVM.

New drugs aiming at the development of targeted therapies have been assayed in combination with ionizing radiation over the past few years. The rationale of this concept comes from the fact that the cytotoxic potential of targeted drugs is limited, thus requiring concomitant association with a cytotoxic agent for the eradication of tumor cells. Conversely a low level of cumulative toxicity is expected from targeted drugs. Most targeted drugs act through inhibition of post-translational modifications of proteins, such as dimerization of growth factor receptors, prenylation reactions, or phosphorylation of tyrosine or serine-threonine residues. Many systems involving the proteasome, neoangiogenesis promoters, TGF-beta, cyclooxygenase or the transcription factor NF-kappaB, are currently under investigation in hopes they will allow a control of cell proliferation, apoptosis, cell cycle progression, tumor angiogenesis and inflammation. A few drugs have demonstrated an antitumor potential in particular phenotypes. In most instances, however, radiation-drug interactions proved to be strictly additive in terms of cell growth inhibition or induced cell death. Strong potentiation of the response to radiotherapy is expected to require interaction with DNA repair mechanisms.

After the primary diagnosis of an adenocarcinoma, diagnosis of the origin of a second adenocarcinoma is a problem (primitive or metastatic). Although the clinical evolution or location sometimes makes it possible to determine the origin of the new lesion, in some cases the diagnosis cannot be confirmed. Although a pathological examination is essential for diagnosis, it may still be inconclusive, making management difficult. The use of molecular biology can help solve this problem. We report the case of a patient who presented with an ovarian adenocarcinoma of an undetermined origin one year after an adenocarcinoma of the colon. This clinical case illustrates the contribution of molecular biology in the diagnosis of the origin of an ovarian adenocarcinoma by characterizing allelic losses in 5 chromosome segments using microsatellite markers genotyping in the two lesions. The comparative analysis suggested the primitive origin of the ovarian lesion.

As their name implies, orphan diseases are rare, often poorly studied diseases. Patients with orphan diseases are often deprived of adequate diagnosis and treatment. To promote a comprehensive study of orphan pulmonary diseases, we established a network of pulmonologists, allowing us to collect and study several series of patients. Based on the examples of lymphangioleiomyomatosis and idiopathic eosinophilic pneumonia, we emphasize the value of a global approach to orphan diseases within the context of a medical specialty.

Telomeres are nucleoprotein complexes that cap the end of eukaryotic chromosomes. They are essential for the functions and the stability of the genomes. There is now compelling evidences that telomerase, the enzyme that adds telomeric DNA repeats to chromosome end, is an important player in oncogenesis. The absence of telomerase in somatic tissues is thought to promote genome instability at initial stages of oncogenesis, favoring the emergence of cancer-associated chromosomal abnormalities \; restablishment of telomerase activity is expected afterwards if long term cell cycling is to occur. In addition to telomerase, various factors control the structure and function of telomeres, suggesting that additional telomeric components play important roles during oncogenesis.

Since its discovery in murine thymoma in 1982, the p56lck (lymphocyte cellular kinase) has been shown to be a pivotal enzyme to both maturation of thymocytes and activation and proliferation of peripheral lymphocytes. The p56lck sequence appeared highly homologous to that of the oncogene p60c-src as did its exon-intron organisation. These data have suggested the lck gene originates from the ancestral src gene by the exon-shuffling mechanism. However, and in spite of this relationship with the p60src oncogene which is often implicated in human cancers, p56lck does not appear involved in lymphoproliferative diseases, either by overexpression or activating mutations. Nevertheless, its aberrant expression has been reported in some carcinomas (colon, lung and mammary). This unexpected expression of a lymphoid-specific protein in solid tumors remained enigmatic until recent studies. In this review, we report these data and explain the possible mechanisms which could lead to the p56lck ectopic expression. We also discuss of signalling pathways which could be affected by the abnormal presence of the p56lck in these tumoral epithelial cells. In particular, we indicate that p56lck could favor metastases by facilitating loss of cell adhesion.