Biomedical subjects

Serge Leyvraz

Publications and source records attributed to Serge Leyvraz.

25 records · Page 2Linked to original sources

PubMed2003

Long-term expansion of transplantable human fetal liver hematopoietic stem cells.

Hematopoietic stem cells (HSCs), with their dual ability for self-renewal and multilineage differentiation, constitute an essential component of hematopoietic transplantations. Human fetal liver (FL) represents a promising alternative HSC source, and we previously reported simple culture conditions allowing long-term expansion of FL hematopoietic progenitors. In the present study, we used the nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse xenotransplantation assay to confirm that human FL is rich in NOD/SCID-repopulating cells (SRCs) and to show that these culture conditions repeatedly maintained short- and long-term SRCs from various FL samples for at least 28 days. Quantitative limited dilution analysis in NOD/SCID mice demonstrated for the first time that a 10- to over a 100-fold net expansion of FL SRCs could be achieved after 28 days of culture. The efficiency of this culture system may lead to an increase in the use of FL as a source of HSCs for transplantation in adult patients, as previously demonstrated with umbilical cord blood under different culture conditions.

Adult↗

PubMed2003

Preoperative hyperfractionated accelerated radiotherapy (HART) and concomitant CPT-11 in locally advanced rectal carcinoma: a phase I study.

PURPOSE: Patients with locally advanced rectal carcinoma are at risk for both local recurrence and distant metastases. We demonstrated the efficacy of preoperative hyperfractionated accelerated radiotherapy (HART). In this Phase I trial, we aimed at introducing chemotherapy early in the treatment course with both intrinsic antitumor activity and a radiosensitizer effect. METHODS AND MATERIALS: Twenty-eight patients (19 males; median age 63, range 28-75) with advanced rectal carcinoma (cT3: 24; cT4: 4; cN+: 12; M1: 5) were enrolled, including 8 patients treated at the maximally tolerated dose. Escalating doses of CPT-11 (30-105 mg/m(2)/week) were given on Days 1, 8, and 15, and concomitant HART (41.6 Gy, 1.6 Gy bid x 13 days) started on Day 8. Surgery was to be performed within 1 week after the end of radiochemotherapy. RESULTS: Twenty-six patients completed all preoperative radiochemotherapy as scheduled; all patients underwent surgery. Dose-limiting toxicity was diarrhea Grade 3 occurring at dose level 6 (105 mg/m(2)). Hematotoxicity was mild, with only 1 patient experiencing Grade 3 neutropenia. Postoperative complications (30 days) occurred in 7 patients, with an anastomotic leak rate of 22%. CONCLUSIONS: The recommended Phase II dose of CPT-11 in this setting is 90 mg/m(2)/week. Further Phase II exploration at this dose is warranted.

Adolescent↗

PubMed2003

Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions.

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+ T-lymphocyte subsets, RA+CCR7-27+28+ and RA+CCR7-27+28-, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon gamma, and tumor necrosis factor alpha. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

Adult↗

PubMed2002

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide.

PURPOSE: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m(2)/d x 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy x 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m(2)/d x 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. RESULTS: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity. During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1- and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. CONCLUSION: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing.

Adult↗

PubMed2002

High-dose chemotherapy for solid tumors: results of the EBMT.

The European Group for Blood and Marrow Transplantation (EBMT), formerly known as European Group for Bone Marrow Transplantation, was established in 1974 in the Netherlands to share experiences, to promote research and clinical studies and to set up registries in the field of hematopoietic tissue transplantation. At the present time more 400 European and non-European centers are members of the EBMT group. In 1984 a new Working Party was created (Solid Tumors) with the aim to investigate the role of high-dose chemotherapy and stem cell support in the fields of adult and pediatric solid tumors. By January 2000 more than 14000 patients were registered, and at the present time this Registry is the world largest database on this subject. Several phase III randomized clinical trials have recently started on behalf of the Group in different diseases (breast carcinoma, small cell lung cancer, ovarian carcinoma, germ cell tumors and Ewing's family sarcoma). Hundreds of randomized patients will finally produce clearer information on this still experimental therapeutic modality. This paper will describe the EBMT Solid Tumors Working Party Registry updated results as well as the main ongoing studies.

Antineoplastic Agents↗

PubMed2002

Long-term ex vivo expansion of human fetal liver primitive haematopoietic progenitor cells in stroma-free cultures.

Successful expansion of haematopoietic cells in ex vivo cultures will have important applications in transplantation, gene therapy, immunotherapy and potentially also in the production of non-haematopoietic cell types. Haematopoietic stem cells (HSC), with their capacity to both self-renew and differentiate into all blood lineages, represent the ideal target for expansion protocols. However, human HSC are rare, poorly characterized phenotypically and genotypically, and difficult to test functionally. Defining optimal culture parameters for ex vivo expansion has been a major challenge. We devised a simple and reproducible stroma-free liquid culture system enabling long-term expansion of putative haematopoietic progenitors contained within frozen human fetal liver (FL) crude cell suspensions. Starting from a small number of total nucleated cells, a massive haematopoietic cell expansion, reaching > 1013-fold the input cell number after approximately 300 d of culture, was consistently achieved. Cells with a primitive phenotype were present throughout the culture and also underwent a continuous expansion. Moreover, the capacity for multilineage lymphomyeloid differentiation, as well as the recloning capacity of primitive myeloid progenitors, was maintained in culture. With its better proliferative potential as compared with adult sources, FL represents a promising alternative source of HSC and the culture system described here should be useful for clinical applications.

Antigens, CD34↗

PubMedDate not supplied

Pharmacokinetics of satraplatin (JM216), an oral platinum (IV) complex under daily oral administration for 5 or 14 days.

BACKGROUND: Satraplatin (JM216; bis-acetatoammine-dichlorocyclohexylamine platinum (IV)) is a platinum (Pt) complex developed in an attempt to circumvent tumour resistance and which can be administered by the oral route. The fate of platinum delivered by this oral formulation administered at various doses under the 5 or 14 days schedule, has been studied to a limited extent. PATIENTS AND METHODS: Total (Ptot) and ultrafilterable (PtUF) platinum were determined in 19 patients enrolled in phase I (PI) and II (PII) studies (PI, n = 14, advanced cancer; PII, n = 5, untreated small cell lung carcinoma). JM216 doses were 10 to 50 mg m-2 day-1 x 14 d (days) (dose escalation in PI) and 120 mg m-2 day-1 x 5d (fixed dose in PII), administered to fasted patients in a standardized way. Ptot and PtUF levels were determined by atomic absorption spectrometry on d1 and d14, followed over 28 days in PI; and on d1, followed over 5 days in PII. Pharmacokinetic parameters were derived by a noncompartmental approach. RESULTS: JM216 is rapidly absorbed with a Tmax obtained within 2.5-3 hours and 1-2 hours for Ptot and PtUF, respectively. The pharmacokinetics of JM216 was linear across the tested doses in PI, with the exposure of Ptot on d14 being better correlated with dose per BSA (Body surface area) (r = 0.91) than that of PtUF (r = 0.61). In PI, Cmax on d1 increased proportionally to the dose (r = 0.82 and r = 0.72 for Ptot and PtUF, respectively). Apparent clearances in PI were 1.1 +/- 0.5 L h-1 and 37.0 +/- 33 L h-1 for Ptot and PtUF, respectively. Prolonged terminal half-lives were observed after the last JM216 administration with mean values of 216 +/- 37 hours and 107 +/- 89 hours, for Ptot and PtUF respectively. The accumulation ratio (Cmaxd14/Cmaxd1) indicated a higher accumulation of Ptot (3.5 +/- 1.6) than of PtUF (1.8 +/- 1) under multiple dose regimen. The apparent volumes of distribution (terminal phase) were similar in the PI and PII studies: 326 +/- 112 L and 3094 +/- 1493 L, and 557 +/- 267 L and 4154 +/- 2147 L, for Ptot and PtUF, respectively. In PI, the nadir of thrombocytopenia was related both to the cumulated dose of JM216 (r = 0.81) and to the AUC of Ptot on d14 (r = 0.77), whereas the AUC of PtUF was not predictive (r = 0.48). The Cmax of Ptot and PtUF on d1 was related to neutropenia (r = 0.61 and r = 0.65, respectively) and to thrombocytopenia (r = 0.77 and r = 0.74, respectively). No relationships were found between leukocytes or neutrophils percent decrease and the AUCs or total, dose of JM216. CONCLUSION: JM216 is an orally bioavailable platinum-containing chemotherapeutic agent yielding predictable total levels of platinum which appears to accumulate in plasma after multiple administration over 14 days. These results should be set in relation to clinical efficacy and tolerance, to optimise the dose regimen of JM216 in further studies.

Administration, Oral↗