Cytogenetic studies of acute myeloid leukaemias reveal non-random chromosomal abnormalities in 50-70% of karyotypes. Some are correlated with morphological and immunological parameters and constitute a prognostic factor independent of the other factors of risk: favourable for acute leukaemias myeloid with translocations t(8;21), t(15;17) and inversion or translocation of the chromosome 16, inv(16)/t(16;16), poor with deletion of the long arm of chromosome 5 del(5q), rearrangement of the 11q23 region and complex karyotypes. The distribution of the anomalies depends on the age: 11q23 and t(8;21) more frequent for the child, del(5q) and complex anomalies more frequent for the adult. The karyotypes are essential for the diagnosis, the follow-up of the patients and the evaluation of the relapse. It plays a fundamental part in the detection of new genes and their partners implied in the leucemogenese. The knowledge of their function is essential to open new therapeutic ways.

The molecular analysis of chromosomal abnormalities associated with hematologic malignancies allowed the identification of genes involved in these rearrangements as well as of some recurrent mechanisms--gene deregulation, gene fusion--leading to the development of a tumoral process. PCR tools are now available, in addition to conventional and molecular cytogenetics, to detect and quantify these rearrangements, allowing a better follow-up for the patients.

Extraskeletal myxoid chondrosarcoma (EMC) is a phenotypically and genotypically distinct entity with a protracted course. A documented case of an extraskeletal myxoid chondrosarcoma characterized by a t(9; 17) (q22; q11) translocation with a neuroendocrine and neural differentiation is reported.

The role of a qualitatively and quantitatively altered nutrition for the development of cancer in human is largely recognized. While the human life expectancy is continuously expanding and the World Health Organization is predicting a dramatic rise in the number of patients that will get cancer and die from it in the next decades, it is useful to attempt to understand the real impact of nutrition at the level of the oncogenesis mechanisms. Oxidative stress, methylation deficit and imbalance in the ratio of omega-3 and omega-6 fatty acids represents situations directly linked to nutrition and which contribute to an increased risk for cancer development. The understanding of the mechanisms by which nutrition affects these processes should better stimulate health professionals to consider with more attention what their patients are eating.

We previously demonstrated a circadian rhythm in response to docetaxel chemotherapy in C3H/HeN mice bearing MA13/C mammary adenocarcinoma. We investigated the relation between this rhythm and the expression of BCL-2 in bone marrow and in tumor tissues. A circadian rhythm characterized BCL-2 expression in the bone marrow, which was hardly modified in tumor-bearing animals. BCL-2 acrophase coincided with the time of highest docetaxel tolerability and efficacy in this model. This suggests that BCL-2 protects the bone marrow from the drug toxicity, especially during the light phase.

p53 gene is a member of a multigene family that includes p53, p63 and p73. The association of p73 and p63 with cell transformation has been elusive as no genetic or epigenetic alteration of these genes has been uncovered yet. Recent work has shown clearly that p73 is an essential component of the signaling pathway that lead to apoptosis after DNA damage induced by cytotoxic agents use in cancer therapy. Furthermore, it has been established that a sub-category of mutant p53 is able to interact with p73 and inhibit its apoptotic activity. Such discovery will be important for a better understanding of the signaling pathway that lead to resistance to chemotherapy.

Head and neck cancer is believed to arise after accumulation of genetic alterations resulting at least partially from chronic exposure of the upper aerodigestive tract to tobacco carcinogens. Accumulation of somatic genetic events in genes implicated in cell growth and differentiation lead to cell transformation and to the acquisition of cancer phenotype. The most frequent alterations in head and neck cancer results from chromosomal instability with amplification and deletion of recurrent chromosome arms. Among the genes that drives head and neck carcinogenesis, TP53 mutations, p16 deletion or hypermethylation, amplification of cyclinD1 and overexpression of the epidermal growth factor receptor are of the most importance and will be discuss in this review. Correlation between genetic alterations and clinical parameters will be underlined. Indeed, the identification of molecular alterations linked to specific tumor parameters may be of help in the management of head and neck cancer patients or useful in the development of new therapeutic strategies. Finally, studies have shown that in some part, constitutional genetic background could also interfere with the development of head and neck cancer through the existence of polymorphisms in carcinogens metabolizing enzymes and/or DNA repair enzymes. Individuals with low carcinogens elimination or DNA repair capacities could therefore be at risk of head and neck cancer. In this review both aspects of head and neck carcinogenesis will be discuss and relation between fundamental research and clinical practice will be mentioned.

We report a case of nasal NK/T lymphoma occurring in a 42 year old man, after a 2 year history of nasal obstruction initially related to chronic sinusitis. A first superficial biopsy was not contributive. Twenty months later, a second nasal biopsy led to the diagnosis of nasal NK/T cell lymphoma in view of the presence of a pleomorphic lymphoid infiltrate associated with necrosis and angiocentric features. Extensive immunohistochemical studies performed on paraffin and frozen sections together with genotypic analysis supported the NK cell origin of the neoplastic cells. In addition, EBV infection was established by in situ hybridization which showed EBERs transcripts in the nuclei of virtually all neoplastic cells. The tumour rapidly progressed and the patient died six months after diagnosis.

The second part of this review on the pathology of soft tissue tumors focuses on malignant entities of recent description, including the following: soft tissue giant cell tumor, inflammatory myxohyaline tumor, inflammatory fibroblastic sarcoma, low grade fibromyxoid Evans sarcoma and its variant, the hyalinizing spindle cell tumor with giant rosettes, spindle cell liposarcoma, proximal type epithelioid sarcoma, sclerosing epithelioid fibrosarcoma. For each entity, the diagnostic criteria, the clinical presentation and the differential diagnosis are described. The role of immunohistochemistry and molecular pathology in the identification and delineation of these new entities is emphasized.

The fact that proteins such as Ras require farnesylation to induce malignant transformation prompted many investigators to design farnesyl transferase inhibitors (FTI) as novel anticancer drugs. FTIs inhibit the growth of ras transformed cells in vitro and induce tumor regression in ras dependent tumor in vivo. Moreover, FTIs inhibit tumor progression in human tumor xenograft models. Currently, FTIs are undergoing phase I and II trials in various cancer types. They show impressive antitumour efficacy and they lack toxicity. Despite these promising results, the development of such molecules in hindered by the absence of appropriate clinical endpoints and of surrogate biological markers. Indeed, it seems likely that Ras is not the critical target of FTIs and that inhibition of the farnesylation of proteins such as RhoB, might also contribute to the observed antitumour properties. Identification of targets that underlie their biological effect is essential in order to predict and evaluate their efficacy.

Oncogenes involved in the development of hematological malignancies were first discovered through the study of experimental leukemias induced in animals by retroviruses. The discovery that some of these genes were located at the breakpoints of chromosome rearrangements in human malignancies, such as the MYC gene in Burkitt's lymphoma and the ABL gene in chronic myeloid leukemia (CML) has suggested that chromosome abnormalities were causally implicated in the pathogenesis of human diseases. Numerous nonrandom somatically acquired chromosomal translocations or inversions have been identified in human leukemias. The molecular cloning of the genes located at the breakpoints of these rearrangements allowed to identify more than 100 new oncogenes, the products of which affect normal programs of cell proliferation, differentiation and survival. Chromosome translocations can lead to the deregulated expression of a normal gene product, but in most cases of leukemia, chromosome rearrangements result in the expression of a chimeric fusion protein. Oncogene products associated with acute leukemias are often transcription factors while tyrosine kinases and antiapoptotic proteins are more commonly activated or overexpressed in chronic leukemias and in lymphomas. Recent data indicated that gene rearrangements were not the sole gene alterations occurring in human leukemia since point mutations could also affect the function of transcription factors playing a key role in hematopoiesis such as C/EBP alpha, GATA1 and AML1. But the most exciting finding was the discovery of activating point mutations in tyrosine kinase receptors such as FLT3 and c-KIT in acute leukemia. Treatment of leukemia could therefore benefit from new therapeutic approaches targeting the function of specific oncogene products as already demonstrated for CML and acute promyelocytic leukemia.

Our vision of the cancer cell has dramatically changed since the discovery of proto-oncogenes, whose deregulation was proposed to mimic normal growth signalling. This notion, linking cancer to cell signalling pathways, has progressively led the way to the concept of the mutator phenotype, in which genetic instability plays an essential role in the onset of cancer. This then transformed cancer into a DNA repair disease. However, as foreseen decades ago by cytogeneticists, point mutations are not sufficient to give a full picture of the whole process. As a result, aneuploidy, rather than gene mutation, has been proposed as the explanation for the complex changes observed in cancer cells. The culprits were found among genes involved in the control of the cell division cycle, and work aimed at understanding the regulation of S phase and mitosis have yielded new insights into our understanding of cancer.

DNA methylation plays a pivotal role during development and carcinogenesis and is central to gene silencing. The recent characterization of the DNA methyltransferases--Dnmt- and their protein partners have helped to understand the molecular basis underlying methylation-mediated gene silencing and its involvement in cancer. These discoveries have important implications to the comprehension of transcriptional regulation but also to understand the molecular basis underlying tumorigenesis. Moreover, these studies open new ways towards an epigenetic therapy of cancer.

Some common human tumors are characterized by inactivating alterations of mismatch repair (MMR) genes that lead to an inability to recognize and repair errors that occur during DNA replication. These alterations are either inherited in the so-called hereditary non polyposis colorectal cancer (HNPCC) syndrome or can occur sporadically in 10-15% of colorectal, gastric, or endometrial tumors. Because of their repetitive nature, microsatellite sequences are particularly prone to mutation in tumors with MMR deficiency. Thousands of microsatellite alterations accumulate in MMR deficient cancers and these are referred to as MSI-H tumors (high level of microsatellite instability). MSI-H tumors have different clinicopathological features compared to cancers without this phenotype, and the repertoire of genetic events involved in their tumoral progression is also thought to be different. Many of the genetic alterations observed in MSI-H tumors affect nucleotide repeat tracks contained within genes thought to have a putative oncogenic function. These alterations are believed to play an important role during MSI-H carcinogenesis, since they can be either inactivating or activating events that are selected for in a recessive or dominant manner. We provide here an overview of the genetic changes that occur in MSI-H tumors and that appear to constitute a new genetic mutator pathway leading a normal cell to become malignant.

Melanoma frequency increases. Conventional antitumoral treatments fail. Gene therapy for metastatic melanoma is studied in 17 phase I-II clinical trials. ACTUALITES ET POINTS FORTS: Sixteen use cytokine genes. These studies are heterogenous as far as methodology is concerned. Gene therapy clinical tolerance is acceptable. Security is rarely discuted. In these studies overall response rate is 8%, with histological complete responses.

Breast and ovarian cancer occur more frequently in young women with BRCA 1 &2 mutations (respective cumulative risks from 37 to 85% and 10 to 20%), and raise specific gynaecologic problems as prophylactic surgery and hormonal treatments. Two medical files from 2 sisters with BRCA 1 mutation (exon 11) are presented and the authors discuss the therapeutic options chosen. BRCA 1 & 2 tumour suppressor genes seem to play a major role in the repair of cellular damages inducing by the estrogenic proliferative signal. The prophylactic mastectomy is effective for the breast cancer prevention but its acceptance is low. The oophorectomydecreases the ovarian risk (knowing the occurrence of peritoneal carcinomatosis in 1.8% of cases) and currently the breast cancer risk (RR = 0.47) by the hormonal privation: the hormone replacement therapy does not seem to increase the breast cancer risk in the small series published. The HRT is possible in women with BRCA mutation under medical supervision and if the doses of hormones are light. The first results concerning the chemoprevention by Tamoxifen are encouraging (RR = 0.38) in these patients, but more studies are needed. The oral contraception exerts an uncertain effect against ovarian cancer, but possibly enhances the breast cancer risk in this group of women (RR = 3.3). The management of women with BRCA mutation is varying according to their own priorities, which can change during their life.