The beginning of this century was marked, in our specialty as in other, by two revolutions: the routine use of molecular biology tools for a better prognosis of the disease (flt3 receptor duplication in AML, mutational profile of Ig genes in CLL, gene expression profile with ARN chips in aggressive lymphomas.), and the discovery of "intelligent" molecules, targeting the tumoral cell. In this category, the most appealing is the STI571 (Gleevec , Novartis), targeting the molecular abnormality of the cells expressing bcr-abl protein: CML, ALL Ph1(+). Other molecules targeting signal transduction proteins (ras farnesylation inhibitors for example) are already in clinical trials. The increasing therapeutic use of monoclonal antibodies is also to be cited, with a special mention concerning the rituximab, used in several B lymphoid pathologies, from lymphoma to autoimmune diseases. His very good tolerance permits his use in ambulatory patients, and his combination with chemotherapy or his linkage with radioactive elements render this molecule indispensable. The other side of these molecules is their incredibly high cost, explaining the uncontrolled expenses in 2001 of hospitals hosting hematology as well as oncology activities.

Authors have selected and presented radiofrequency tissue ablation for primary renal tumors and cellular therapy with dendritic cells or nonmyeloablative allogeneic transplantation as the main results in 2000-2001 on renal cell carcinoma. Furthermore other points are developed as hypertension increasing the risk of renal cell carcinoma, chromosomal events until renal cell carcinoma and prognosis of incidentally detected tumors.

The aim of this work was to quantify by flow cytometry the main adhesion receptors on CD34+ cells. These cells were isolated from bone marrow (BM) or mobilized peripheral blood (PB). The proportions of CD34+/CD49d+ and CD34+/CD49e+ are weaker on PB cells, without quantitative expression variation. This phenotypic variation may induce CD34+ cells exist from BM into circulation, promoting the mobilization. The homing to the BM implicate the CD62L receptor, which expression was found more frequently and stronger on PB cells than on BM. The CD11b, CD18 and CD54 receptors are implicated in CD34+ cells adhesion to BM micro-environment. No significant variation in CD34+/CD11b+ and CD34+/CD18+ cells frequency was noted. Moreover, CD54 receptor was more frequently expressed on PB cells. Quantitative analysis revealed that CD18 was more strongly expressed on BM than on PB cells. This quantitative variation could promote progenitor adhesion by interacting with stromal cells. Finally, quantitative expression of the main receptors on CD34+ cells provides an original option for studying CD34+ cells during the mobilization, the homing or the adhesion to BM micro-environment.

Ovarian carcinoma is the worst gynecologic cancer due to an advanced stage at diagnosis in two thirds of the cases. Advanced stages are usually characterized by a large tumor burden on the ovaries as well as metastatic disease in the peritoneal cavity. Early stages are more common in young women and the surgical treatment should comprise the tumor excision and a comprehensive abdominal staging to be sure that there is no extension beyond the ovaries--unilateral oophorectomy can preserve the fertility before childbearing. No treatment is needed after surgery in stage I without poor prognostic factors. Adjuvant chemotherapy should be applied postoperatively in the other cases. The best likelihood of prolonged survival is observed after optimal debulking surgery and chemotherapy in advanced stages. If possible surgery should be performed at first but in most advanced stage with large tumor volume in the upper abdomen according to clinical and CT-scan examination, the concept of chemosurgical debulking should be considered. Interval surgery underwent after three or four courses of front line chemotherapy but this strategy should be further evaluated by clinical trials. Currently paraplatin associated with paclitaxel is the most commonly used regimen due to its effectiveness and lower toxicity. In a near future progress can be expected with new protocols. Thank to aggressive surgery and chemotherapy many patients should be able to reach a complete remission of their disease but most of them will still die of recurrent disease. At this point, two questions should be answered: 1) how to manage the residual abdominal disease in order to prevent the recurrence. No consolidation treatment demonstrated any superiority but the French experience and trial with high dose chemotherapy supported by autologous stem cells transplantation showed recently positive results? 2) How to manage the recurrent disease with sometime indication for secondary surgical debulking and always chemotherapy? This is the field for testing new drugs or new strategies. A large number of patients should enter clinical trials in order to answer these questions and due to the very poor prognosis of this disease large attention should be given to the quality of life of theses patients.

A reliable model, usable in vitro and in vivo, is necessary for analysis of processes engaged during cell death, regeneration and differentiation. The peripheral olfactory system is an attractive model for studying these processes through its dynamic neurogenesis that occurs continually throughout the lifetime.

The hematopoietic system is the adult cellular model in which the biology of the stem cells is the best known and may be a model for numerous other tissues. This model is theoretically based on a hierarchy of cells, which begin on a stem cell that differentiates into mature cells through a large number of cellular stages including hematopoietic progenitors. Hematopoietic stem cells have three ain properties: (1) Self-renewal capacities. However, in transplantation experiments this property is limited and may be regulated by the stem cell niche. (2) Multipotentiality. Hematopoietic stem cells are capable of differentiation towards all myeloid and lymphoid lineages. However, recent experiments suggest that, like other somatic stem cells, hematopoietic stem cells are capable

The hematopoietic system is the adult cellular model in which the biology of the stem cells is the best known and may be a model for numerous other tissues. This model is theoretically based on a hierarchy of cells, which begin on a stem cell that differentiates into mature cells through a large number of cellular stages including hematopoietic progenitors. Hematopoietic stem cells have three main properties: (1) Self-renewal capacities. However, in transplantation experiments this property is limited and may be regulated by the stem cell niche. (2) Multipotentiality. Hematopoietic stem cells are capable of differentiation towards all myeloid and lymphoid lineages. However, recent experiments suggest that, like other somatic stem cells, hematopoietic stem cells are capable of differentiating towards non-hematopoietic lineages. The mechanisms of call commitment towards one cell lineage are beginning to be understood and involve competition between transcription factors. (3) Migration. Stem cells are able to travel through the blood. These migration capacities may be an important but underestimated role in the function of hematopoietic stem cells. Mobilization of stem cells by growth factors is now clinically used for hematopoietic transplantation in man. CXCR4 and its ligand, the SDF-1 chemokine, play an important role in stem cell chemotaxis and in their retention in the marrow.

Allogeneic transplantation of hematopoietic stem cells (HSC) is a curative treatment for hematological malignancies aiming to eradicate the malignant clone using the immunological conflict inherent to donor HSC installation in the recipient. The different possible sources of HSCs (bone marrow, blood, and cord blood) and better knowledge of HLA typing has led to the development of new transplantation techniques and modalities (transplantations after non-myeloablative conditioning, haploidentical transplantations, etc.), which should improve patient survival and extend allograft indications. HSC allografting is subject to immunological reactions stemming from the histocompatibility discrepancy between donor and recipient. For the most part, these are reactions of the graft against the host (graft-versus-host disease: GVHD) and graft rejection (host-versus-graft: HVG). This immunological conflict can also be responsible for recognizing and destroying the recipient's residual tumor cells, which carry specific tumor antigens and/or minor antigens of histocompatibility (graft-versus-leukemia effect, GVL or graft-versus-malignancy effect, GVM). The posttransplantation period can also be riddled with various complications such as veno-occlusive disease, endocrine complications, as well as complications arising from infections and secondary neoplasms because of a more or less substantial and durable immune deficiency. Acute and chronic leukemias are the major indications for HSC allogeneic transplantation, for which the results are variable and closely related to the patient status, the hematological disease, and the transplant procedure. Other hematological diseases are also indications for allogeneic transplantation but are rarer, for which allogeneic transplantation remains nevertheless the only curative treatment, despite an overly high level of toxicity. Improvement in the results of unrelated transplantations, use of peripheral HSC or cord blood cells, development of non-myeloablative conditioning regimens, and techniques of ex vivo manipulation of the graft have allowed HSC allogeneic transplantation indications to be extended. The antitumor efficacy of donor lymphocytes infusion for relapses after transplantation mirrors the GVL effect and is the first stage in a targeted cellular immunotherapy using sensitized lymphocytes or dendritic cells.

Economic evaluation of autologous peripheral blood stem cell (PBSC) transplantation certainly played a role in the very fast substitution from bone marrow to BC autograft. Economic evaluation is still ongoing about the optimization of the procedure by assessing the cost-effectiveness ratio of each new improvement of the technique. Among these improvements we present the administration of high dose CD34+ cells, the delayed administration of G-CSF and the outpatient management of post-graft follow-up. It is still very rare in the field of health economics to notice such an early and ongoing economic evaluation of an innovation.

This article summarizes the different clinical results of the IFM trials: high dose therapy supported with autologous stem cells improves survival, melphalan 200 mg/m2 is the best preparative regimen, unpurged peripheral blood stem cells are the recommended source of stem-cells to support high dose therapy, tandem transplants significantly improve survival. However, despite these encouraging results, long term survival needs inovative strategies evaluated with the current IFM 99 protocol.

Despite surgery, post-operative irradiation and adjuvant conventional chemotherapy, prognosis of high-grade gliomas remains poor. Carmustine (BCNU) has been shown to have limited activity at conventional dosage but is still the standard chemotherapy. Activity of chemotherapy is limited by the blood-brain barrier impermeability and high levels of expression of multidrug resistance proteins on tumor and/or endothelial cells. Despite high response rates, development of intra-arterial chemotherapy remains limited because of frequent acute brain toxicity related to drug administration. High-dose intravenous chemotherapy rescued by autologous hemopoietic stem cell transplantation is an alternative that might increase drug delivery through the blood-brain barrier and tumor control. Several phase I-II trials using high-dose BCNU were published. The maximum tolerated dose seems to be 800 mg/m2 and interstitial pneumonitis and hepatitis are dose-limiting toxicities. Few phase I-II trials of high-dose therapy were published using drug combinations. High response rates in patients with progressive tumor were observed and in adjuvant setting, encouraging results in terms of median survival time and long survivors were published. No phase III trial was reported to date. Future investigations should include randomized trials comparing high-dose and conventional-dose chemotherapy and development of new high-dose regimens that incorporate new drugs such as temozolomide.

Small cell lung cancer accounts for 20% of the primitive lung carcinomas. The pronostic is unfavourable, since two thirds of the patients present with extensive stage at diagnosis. The median survival without treatment is less than 3 months. Chemotherapy is the standard front line therapy. In selected patients, chest irradiation and so-called prophylactic cerebral irradiation are current options. Small cell lung cancer is a chemosensitive disease. Indeed, the response rate is around 80-95% of in limited disease patients of which 50-60% are complete responses. Despite these results, the median survival does not exceed 16 months. Early recurrences after initial response probably reflect various resistances mechanisms. Furthermore, small cell lung cancer is associated with a high fraction of dividing cells. It is a clinical model where the dose-response relationship concept is worth testing, and dose-intensity may be integrated into the therapeutic strategies. Therefore, many clinical trials have assessed these principles during the past 20 years. We present here the different methods of therapeutic intensification in small cell lung cancer: with or without hematopoïetic supports, using initial high dose of cytotoxic drugs, either at the beginning or at the end of induction treatment, or by increasing the dose-density.

Peripheral blood stem cells transplantation after high dose chemotherapy is increasingly used for the treatment of hematological malignancies and solid tumors. Autologous transplantation are now used as first line therapy. The use of hematopoïetic growth factors allowed to collect peripheral hematopoietic progenitors in quantity large enough for several autologous reinfusions. As for bone marrow, peripheral blood stem cells allow fast and long-term hematopoietic reconstitution. The fast regeneration is strictly correlated to the number of hematopoietic progenitors infused. Some questions are still opened anyway, notably about the tumoral contamination of the graft which has been clearly demonstrated. Even if residual tumor cells are clearly shown to participate to relapse, the interest of ex vivo purging is still matter of debate. Several techniques of positive selection are now available, selecting normal stem cells thanks to the CD34+ antigen. Negative selection is also available either using clinical purging or monoclonals antibodies against tumoral antigens. Endly, ex vivo expansion of hematopoietic stem cells is under investigation using medical progress in the field of growth factors. Therefore, improvement of mobilisation protocols, of technology for positive or negative selection, as well as the strategy for ex vivo expansion will be the tools for the development of the treatment of some hematological malignancies and solid tumors reducing the hematopoietic and extra hematopoietic toxicity.

We report four cases of non-synchronous antiphospholipid syndrome (APS) and malignant lymphoma, which highlight the complex relationship that seems to exist between these illnesses.

IMMUNOSUPPRESSIVE THERAPY: Intravenous immunoglobulins have demonstrated their value for highly immunized cross-match positive transplantation candidates. Graft rejection during the first two post-transplantation weeks can be avoided with CMPATH-1H, humanized anti-CD52 monoclonal antibody, which produces major and persistent T- and B-cell as well as monocyte depletion. FTY 720 is well tolerated and has demonstrated its efficacy in preventing acute rejection. Sirolimus would have an antiatheromatous effect. Attempts to minimize immunosuppression should be followed for several months. OTHER NEW DEVELOPMENTS: There has been considerable interest in Langerhans islet transplantation. Work also concerns follow-up techniques used to diagnosis rejection. FUNDAMENTAL SCIENCE: New advances in basic science that should have an impact on transplantation have been made in the area of lymphocyte activation, toll-like receptor structures, and germinal and stem cells, as well as in the areas of essay methods and gene therapy.

The general properties of chemokines and their receptors are described, and the perspectives raised for cellular therapy are discussed. Specific examples are provided in the cases of the CXC chemokine SDF1 and of chemokines ligands of CCR5.

This text describes, in an epistemological perspective, the development of the concept of cellular therapy applied to the treatment of type 1 diabetes. Emphasis is put on three recent papers describing the success of islet allograft in diabetic patients, the development of neo-islets from stem cells isolated from the pancreas of adult mice, and the effect of hepatic cell transfection with an adenovirus bearing the gene coding for PDX-1, a transcription factor involved in the maturation of islets of Langerhans. This text tries to delineate some factors which may be involved in the chances for these techniques to reach the real world of human therapeutics.

Articular cartilage has a very poor capacity for repair. In order to get a normal functional efficacy, the replaced tissue has to reproduce the structure, composition and physico-chemical properties of native cartilage tissue. The transplantation of cultured autologous chondrocytes into chondral defects is currently applicable only in the case of young sportive people with a limited lesion in an otherwise relatively normal joint. Recent experimental studies have shown that pluripotent mesenchymal cells from bone marrow could also repair experimental osteochondral defects. An advantage of this grafting procedure is that large areas of cartilage surface could be covered. Bone marrow cells are not so difficult to get, they have a high potency to divide and they can develop in vitro as chondrogenic, osteogenic or adipogenic cells. The present ways of research are: to characterize one or several growth factors capable to specifically induce the chondrogenic lineage; to determine nutrient and environmental conditions allowing the cultured chondrogenic cells to undergo a maturation process within the cell pellet; to elaborate three-dimensional synthetic, biodegradable polymeric scaffolds assessed with respect to chondrogenic cell adhesion, proliferation, maturation and cartilage matrix secretion; finally, to elaborate a mixed biomaterial composed of chondrogenic and osteogenic cells selectively distributed within polymeric scaffolds in order to get a better adherence of the implanted cells to the lesion sites.