The poor prognosis of pancreatic cancer has remained unchanged for many years, with a 5-year survival of less than 5 %. Current methods for diagnosing pancreatic cancer are inadequate at identifying small tumors that can be resected by surgery. Characterization of gene expression patterns in pancreatic cancer provided a list of genes that are specifically overexpressed in cancer cells. These genes are putative novel markers for the diagnosis and the prognosis of pancreatic cancer and for the development of targeted therapies. Gene expression analysis should lead to the discovery of molecular markers for early detection of pancreatic cancer that could benefit patients at high risk of developing pancreatic cancer.

There is emerging evidence from clinical and experimental data that familial breast cancers, including BRCA1 and BRCA2 related forms, could be in fact estrogen-sensitive. Interactions between BRCA1 gene expression and estrogens have been reported. On one hand, BRCA1 expression could be induced by estradiol in experimental models. On the other hand, recent studies indicate that BRCA 1 interacts with and regulates the activity of estrogen receptor ERalpha. Endogenous or exogenous estrogens, such as oral contraceptive, may also increase the risk of breast cancer in BRCA1 mutation carriers in clinical studies. Conversely, prophylactic oophorectomy and anti-estrogens may decrease the risk of familial breast cancer. Prospective studies are thus required to estimate the potential benefits of estrogen suppression therapies for prevention or adjuvant treatment of familial breast cancer. Oral contraception and hormonal replacement therapy after menopause should be used with caution in BRCA1 or BRCA2 mutation carriers.

The post-genomic era offers a huge challenge for scientists used to hand-made tailored approaches that can deal with deep insight into a small number of objects. Reciprocally, industry is used to undergo massively parallel approaches, dealing with large numbers but rather shallow insight. The complementation is obviously tantalizing, and Institut Curie and Hybrigenics (HGX) have signed an alliance in the field of cancer and signal transduction. A comparative proteomic approach was undertaken, where ortholog baits from Homo sapiens and flies were used to screen extremely complex two-hybrid cDNA libraries. New partners of "old" proteins have been identified, new networks have emerged, and unexpected connectors have been shown to link biological niches supposed to be independent.

More than 50% of the hereditary forms are associated with germ line mutation in either BRCA1 or BRCA2 genes (BReast CAncer 1/2). The BRCA1 protein is expressed ubiquitously and is likely to play a role in several fundamental processes, including the maintenance of genomic integrity. Paradoxically, BRCA1 appears as a gene essential for proliferation of embryonic cells that simultaneously carries tumor suppressor activity. The nature of the role of BRCA1 in DNA repair and maintenance of genome integrity remains enigmatic. BRCA1 may indeed be a sensor of "abnormal" DNA structures that undergo heterochromatinisation. This model finds some support in the recent report that BRCA1 participates in the maintenance of X-chromosome inactivation, a paradigm for facultative heterochromatinisation. Why are epithelial cells from mammary glands and ovaries the privileged targets for tumorigenesis in women carrying germline mutations in BRCA1? The inheritance of a single defective copy of BRCA1 by women confers a status of susceptibility for developing breast and/or ovarian cancer. The loss of the wild-type allele inherited from the unaffected parent (LOH), commonly observed in the primary breast and ovarian tumors in these susceptible women, represents the event that initiates the tumorigenesis process. This classical two hit model, which assumes that heterozygote cells are "normal" until the LOH occurs stochastically, remains enigmatic.

One example of the recent advances of scientific research on the human genome is the identification of two susceptibility genes to breast/ovarian cancer, BRCA1 and BRCA2, making possible the introduction in medical practices of genetic testing to detect patients with an increased risk of developing such cancers. In this context of diffusion, two surveys were carried out to appraise the activity profiles in 1998 and in 2001 of all the different participants in those new medical practices in France, physicians in charge of genetic counselling, medical centres where consultations take place and laboratories. Results show that over the period 1998-2001, few changes occurred, mainly the reduction of the average waiting time to get the result of a genetic test, the increase in the annual number of BRCA2 families identified to a level similar to the one of BRCA1 and the automation of the biological analyses without noting a considerable increase in the annual output of laboratories till 2001 however. This surprising moderate evolution must be connected to the existence of some particular external factors making the framework of the development of these new medical and biological practices and their future really uncertain. The diffusion of BRCA1/2 genetic testing has been carried out facing the traditional difficulties of any innovating activities, but also the uncertainties related to intellectual property rights on genes and the reimbursement of genetic counselling and biological testing. These uncertainties have certainly restrained the pace of change as many actors in this field have opted for a wait and see strategy bearing in mind the possible future constraints imposed to their future activity, especially if European patents on the BRCA1/2 genes are finally granted by the European patent office (EPO).

During the last decade, new insights in cellular and molecular biology have opened new avenues in cancer immunotherapy. Two distinct modalities have been developed: adoptive immunotherapy and anti-tumoral vaccination (active immunotherapy). We will first describe the main strategies of adoptive immunotherapy and then elaborate on the protocols of anti-tumoral vaccination against tumor associated antigens (TAA). In that context, we will pay peculiar attention on the pivotal role of dendritic cells (DC) as natural adjuvant.

Recent works aimed at clarifying the respective roles of p16INKa and p14ARF (both located on the same INK4a locus on chromosome 9p21 in man) in malignant transformation come to the conclusion that p16INK4a is the true tumor suppressor gene in man. In mouse, it is the p19ARF knockout that suppresses the barrier protecting cells from malignant transformation. This situation is in agreement with p19ARF- and p16-mediated senescence induced by oncogenic mutated ras (Ras*) in mouse and man respectively. Other results have shown that senescence in human diploid fibroblasts is associated with heterochromatin occurrence that maintains in repressed state E2F1-induced gens required for G1 to S phases transition. Since RB protein is responsible for this chromatin modification, cells with any impaired RB pathway cannot enter into senescence.

The polygenic and multifactor genetic basis of breast cancer confers to each tumour a different phenotype and clinical outcome. A therapeutic stake is to better determine this heterogeneity by using more reliable prognostic factors and to develop molecular therapies targeting the tumour cells selectively. The study of molecular alterations in breast cancer allowed considerable therapeutic progress by use of the hormonal receptors and the ERBB2 receptor. Today, new high-throughput technologies such as DNA microarrays allow measuring the activity of thousands of genes in a sample simultaneously. The awaited repercussions are multiple. Expression profiling of breast tumours allows the identification of new sub-groups of tumour in groups a priori identical, but with different outcome. This stratification should make it possible to better tailor the treatment and boost the discovery of new therapeutic targets

Sequencing the human genome brings new tools for the individualisation of cancer chemotherapy, firstly thanks to the identification of polymorphisms of genes involved in anticancer drug metabolism or activity (Pharmacogenetics), and secondly thanks to the determination of tumour gene expression profiles and their relationship to chemosensitivity and chemoresistance (Pharmacogenomics). A few functional polymorphisms have been known for a long time (thiopurine methyltransferase, glutathion S-transferases), but several new ones have been identified recently, at the level of the genes encoding drug targets (thymidylate synthase), at the level of DNA repair enzymes (XPD) or at the level of transport proteins (MDR1). On the other hand, the research of correlations between gene expression profiles and chemosensitivity has been performed on the in vitro models of the National Cancer Institute and may allow crucial improvements in the identification of patients who would best take advantage of a specific chemotherapy. Clinical trials, first on a retrospective basis, then on a prospective one, are implemented to validate this approach.

Between 1971 and 2002, 80 patients underwent surgery for insulinoma at the Department of General and Endocrine Surgery of the Lille University Hospitals. The present report deals with 13 patients with proven multiple endocrine neoplasia type I (MEN I) or supposed genetic-related insulinomas. This entity differs from spontaneous insulinoma by the presence of multiple foci in the pancreas. Enucleation is not advised in this setting due to the strong likelihood of persistence or recurrence. Various studies suggest different strategies for preoperative localization and surgical approach. We analyzed retrospectively the surgical strategy proposed by the A.F.C.E. and G.E.N.E.M. The purpose of this study was to validate the strategy, integrate the contribution of genotypic diagnosis, simplify preoperative imaging studies, and re-evaluate the value of intraoperative baseline secretin-stimulated insulin measurements. We recommend preoperative endoscopic ultrasonography of the pancreatic head only and routine left pancreatectomy with enucleation of cephalic tumors under intraoperative hormone monitoring. Preoperative invasive localization studies are proposed only if the endoscopic ultrasonography is negative for the pancreatic head. Intraoperative secretin stimulation test can be useful in difficult cases, especially with concurrent nesidioblastosis or in case of secondary surgery. All but one of the 13 patients achieved long-term cure with this strategy.

Sarcomatoïd carcinoma is a rare tumor of the esophagus, characterized macroscopically by a polypoid aspect and histologically by the association of spindle cell carcinoma with sarcomatous pleomorphic component. We report here a case of esophagus sarcomatoïd carcinoma. Diagnosis was based on immunohistochemical analysis of tIssue samples. Human papillomavirus (HVP) detection by PCR amplification of DNA extracted from tumoral tIssue was negative, ruling out the role of HPV infection in this tumor.

Cyfra 21-1 is a recognised marker for epidermoid lung and head and neck carcinomas oriented to the cytokeratin 19 that is expressed particularly in malignant epithelial cells. The aims of this study were to evaluate the importance of the use of this marker in nasopharyngeal carcinoma (NPC). Our prospective study interested 41 patients (33M/8F) with a mean age of 44 years (13 to 70) with 8 of them aged less than 30 years, presenting a nasopharyngeal carcinoma histologically confirmed from September 1999 to March 2000 and 45 healthy controls without evidence neoplasm. Undifferentiated forms represent 90.2% of cases and lesions are staged T2, T3 and T4 in 2.4%, 36.6% and 61% of cases, while N1, N2 and N3 represent 9.8%, 26.8% and 41.5% of cases. A blood sample was collected from each patient and control before any treatment, as well as controls to measure Cyfra 21-1 by immunoenzymatic assay, 2 groups of patients were selected after a period varying from 4 to 37 months with a median of 29 months: 27 patients with favourable evolution (without evidence of disease after initial treatment), 12 patients with non favourable evolution (1 death, 2 cases of loco-regional relapse and 9 patients with metastatic disease). 2 patients were lost to follow-up. The results showed that the mean serum Cyfra 21-1 values were significantly higher in patients with NPC than those in controls (p = 0.001). A significant correlation was found between the serum Cyfra 21-1 level before treatment and the clinical outcome of patients (p = 0.0009). Patients having a favourable evolution have the lowest level. Seric level of Cyfra 21-1 at diagnosis of NPC may play a predictive role to evaluate the risk of metastatic disease and prognosis.

The protein tyrosine phosphatase L1 (PTPL1), also known as FAP1, has two major types of remarkable structural domains, in addition to its catalytic unit: a FERM domain which is responsible for its localization at the apical pole of the cell plasma membrane and 5 PDZ domains suggestive of numerous possibilities of protein partners and consequently of a role as a cargo protein or an integrator between different signalling pathways. In fact, though it was initially suggested, in 1995, that this enzyme acts as an inhibitor of Fas death receptor several recent studies indicate that PTPL1 plays many other roles. It dephosphorylates Ephrin B (ligand of Eph, a receptor triggering angiogenesis and axonal guidance), it interacts with numerous proteins associated to cytoskeleton plasticity and it is implicated in cytokinesis. We have demonstrated that its expression is regulated by antiestrogens in mammary cancer and shown, with stable antisense transfectants, that PTPL1 plays a key role in the mediation of the inhibitory effects of these antagonists on growth factor signalling by impeding the IRS-I/PI3-K/Akt survival pathway. Altogether PTPL1 has to be regarded as a unique marker of mammary tumor response to antiestrogens and a potential therapeutic target to activate apoptotic stimuli in tumor cells.

Malignant adipose tissue tumors, also called liposarcomas, are the most common sarcoma of adult life. They may be hard to distinguish from benign adipose tissue tumors as well as from other types of sarcomas. Well-differentiated liposarcomas and myxoid liposarcomas are the two histological subtypes that have been best characterized at the genetic level. The defining genetic features of well-differentiated liposarcoma cells are supernumerary circular ("ring") and giant linear rod chromosomes. These rings and giant chromosomes contain amplification of the 12q14-15 region, including the MDM2 gene, associated with coamplification of various other chromosomal regions. In addition, they most often lack alpha-satellite centromeric sequences. The detection of MDM2 amplification is a valuable tool for the differential diagnosis between well-differentiated liposarcomas and lipomas. Dedifferentiated liposarcomas usually present with patterns of MDM2 amplification similar to those observed in well-differentiated liposarcomas. In addition, recent CGH-array studies suggest that co-amplification of MDM2 with the 6q23-25 region might be a specific feature. Myxoid and round-cell liposarcomas are characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. A rare variant translocation t(12;22) that fuses DDIT3 with EWS has also been described. The genetics of pleomorphic liposarcoma is still obscure. Pleomorphic liposarcomas show complex karyotypes with many numerical and structural chromosomal aberrations. To date, no specific molecular abnormality has been identified.

The HNPCC syndrome (hereditary non polyposis colon cancer) 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 small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure.

Cyclooxygenase-2 (Cox2) is an inductible isoenzyme of cyclooxygenase undetectable in normal colonic mucosa and overexpressed in 80% colonic tumor. Several works in vitro and in vivo showed that Cox2 plays a key role in the multistep process of colorectal tumorigenesis such apoptosis inhibition of cellular proliferation and angiogenesis induction. So that Cox2 represent a potential molecular target in colorectal management and specific Cox2 inhibitors may be useful as chemopreventive as well as therapeutic agent in humans. In animals study Cox2 inhibitors was shown to be effective and in humans Cox2 inhibitors are approved by the Food and Drug Administration as an adjunct to endoscopic surveillance and surgery in patients with Familial Adenomatous Polyposis (FAP). The purpose of this article is to review the relationship between Cox2/Cox2 inhibitors and differents signaling pathways of colorectal carcinogenesis and to precise their possible molecular mechanisms of action. This work although review clinicals data of their efficacy as chemopreventive agent as well as therapeutic in the differents group at risk for colorectal cancer.

Neuroblastoma and its benign counterpart, ganglioneuroma, are pediatric neuroblastic tumors arising in the sympathetic nervous system from neural-crest cells. Neuroblastoma, the most common extra-cranial solid tumour during childhood, is unique for its broad spectrum of clinical virulence from spontaneous remission to rapid and fatal progression despite intensive multimodality therapy. To a large extent, outcome could be predicted by the stage of disease and the age at diagnosis. However, a number of molecular events in neuroblastoma tumors, accounting for the variability of outcome and response to therapy, have been identified over the past decades. Among these, MYCN amplification is the most relevant prognostic factor and was the first genetic marker, in paediatric oncology, to be included in clinical strategies as a guide for therapeutic decision. This has allowed the most suitable intensity of therapy to be delivered according to a risk-stratified strategy, from observation to megadose chemotherapy with stem cell transplantation. Recent advances in understanding the biology and genetics of neuroblastoma will ultimately allow to select poor-risk patients for appropriate future biologically based therapies.