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Biomedical subjects

Jean-Yves Blay

Publications and source records attributed to Jean-Yves Blay.

51 records · Page 3Linked to original sources
PubMed2004

Coexpression of CD40 and CD40L on B lymphoma and carcinoma cells: an autocrine anti-apoptotic role.

To evaluate a possible autocrine role of CD40L, the expression and functional activity of CD40L on NHL and breast carcinoma cell lines were investigated. Using flow cytometry, CD40 was consistently detectable at the surface of all 5 NHL cell lines tested. CD40L expression was detectable at the surface of DAUDI (54%, MFI 47) and BJAB (12%, MFI 32) cell lines, and marginally on the RAJI cell line (7%, MFI 30), while 4 of 5 NHL cell lines (DAUDI, RAJI, BJAB, BL70) had detectable CD40L mRNA. CD40 was expressed on T47D and BT20 breast carcinoma cell lines while CD40L was detectable on T47D (93%, MFI 137) only. Both BT20 and T47D had detectable CD40 mRNA, while CD40L mRNA was detectable only in the T47D cell line. CD40, but not CD40L, was detectable on 6 renal, 1 prostatic and 1 colon carcinoma cell lines. CD40L expressed on tumor cells was functional, as shown by its capacity to decrease drug-induced apoptosis on CD40 expressing NHL and breast carcinoma cell lines, while irradiated CD40L negative cell line (BT20) had no effect. Blocking CD40L antibody abrogated the protective effect of irradiated CD40L positive T47D cell line against drug-induced apoptosis on BL70 cell line, confirming that CD40L is functional in the DAUDI and T47D cell lines. Importantly, blocking CD40L antibody increased drug-induced apoptosis in CD40L positive cell lines but had no effect on the CD40L negative cell lines. CD40L is expressed on CD40 positive B NHL and breast carcinoma cell lines and induces an autocrine antiapoptotic signal when cells are exposed to cytotoxic agents.

Antibodies, Blocking↗
PubMed2004

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

Animals↗
PubMed2004

[Organization and impact of the multidisciplinary committee in oncology].

Medical practices in oncology are expected to be more and more multidisciplinary, yet few articles studied how this may be concretely applied. This article is describing the functioning of a multidisciplinary specialized committee in a rare tumor. 219 medical cases during 26 meetings between 09/04/2003 and 14/02/2004 had been studied. Discussions had been observed, described and studied qualitatively and quantitatively. At the time of a national plan has been launched to impose obligatory the consultation of such committees before any treatment strategy, two lessons can be drawn from this case study. On the one hand, it shows that a multidisciplinary committee may be an organizational tool facilitating the emergence of collective decisions, since it may facilitate the formulation and the discussion of alternative options (72 cases out of 219). More generally, to take treatment decisions, members of the committee exchange arguments that deal mostly with clinical and psychological condition of the patient (50 cases out of 219), state-of-the-art knowledge (39 cases out of 219) and individual experience of the practitioners (33 cases out of 219). On the other hand, this article intends to underline that the creation of such committees cannot be considered as a sufficient condition to improve the quality of treatment decisions. Indeed, this case study shows that the quality of decisions does not only rely on the collective deliberation, but also on the individual and specific competencies of some members of the committee that other members admit.

Decision Making↗
PubMed2003

Summary statement on primary central nervous system lymphomas from the Eighth International Conference on Malignant Lymphoma, Lugano, Switzerland, June 12 to 15, 2002.

Under the sponsorship of the International Extranodal Lymphoma Study Group, a Multidisciplinary Workshop on primary CNS lymphoma (PCNSL) with over 50 participants from Europe, North America, Israel, and Australia was held as part of the Eighth International Conference on Malignant Lymphoma in Lugano, Switzerland (June 12 to 15, 2002). The main purposes of the Workshop were to exchange the latest scientific information, to analyze methodologic issues in the design of clinical trials, to reach a consensus on treatment recommendations and prognostic factors, to discuss clinical and molecular targets for future studies, and to establish an international collaborative group to conduct laboratory and clinical investigations in PCNSL. This article summarizes the contents of the Workshop, analyzes the current knowledge on the most relevant biologic and clinical issues in PCNSL, and focuses on fundamental challenges to be addressed in future studies.

Animals↗
PubMed2003

Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience.

PURPOSE: To identify survival predictors and to design a prognostic score useful for distinguishing risk groups in immunocompetent patients with primary CNS lymphomas (PCNSL). PATIENTS AND METHODS: The prognostic role of patient-, lymphoma-, and treatment-related variables was analyzed in a multicenter series of 378 PCNSL patients treated at 23 cancer centers from five different countries. RESULTS: Age more than 60 years, performance status (PS) more than 1, elevated lactate dehydrogenase (LDH) serum level, high CSF protein concentration, and involvement of deep regions of the brain (periventricular regions, basal ganglia, brainstem, and/or cerebellum) were significantly and independently associated with a worse survival. These five variables were used to design a prognostic score. Each variable was assigned a value of either 0, if favorable, or 1, if unfavorable. The values were then added together to arrive at a final score, which was tested in 105 assessable patients for which complete data of all five variables were available. The 2-year overall survival (OS) +/- SD was 80% +/- 8%, 48% +/- 7%, and 15% +/- 7% (P =.00001) for patients with zero to one, two to three, and four to five unfavorable features, respectively. The prognostic role of this score was confirmed by limiting analysis to assessable patients treated with high-dose methotrexate-based chemotherapy (2-year OS +/- SD: 85% +/- 8%, 57% +/- 8%, and 24% +/- 11%; P =.0004). CONCLUSION: Age, PS, LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies.

Adolescent↗
PubMed2003

Gastrointestinal stromal tumors: biology and treatment.

Scientific knowledge on gastrointestinal stromal tumors (GIST) has dramatically progressed over the last 10 years. During this period, this distinct disease entity was identified under various acronyms (GIST remaining the most commonly used), the molecular basis of disease transformation (i.e. activating c-KIT mutations) was identified in sporadic and familial cases, and finally GIST was identified as the sarcoma subtype most resistant to chemotherapy in both retrospective and prospective studies. Until 2000, surgery was the only reported efficient treatment modality in this disease, both in the localized and metastatic phase. In 2000, the first GIST patient received Glivec, and in the last 3 years, more than 2,000 patients were included in prospective trials evaluating this compound in advanced phases. Disease control is initially achieved in 80-90% of patients, with only 10-15% of patients dying in the first year following the occurrence of metastases, while the median overall survival was less than 12 months with previous treatment options. However, there still remain several questions regarding long-term outcome, tolerance, cure, dose of Glivec, and alternative treatment upon relapse of GIST in patients receiving Glivec. Additional follow-up is necessary. Glivec treatment of GIST is the first example of an efficient targeted treatment in a solid tumor.

Antineoplastic Agents↗
PubMed2003

[Clinical development of anti-angiogenic agents in 2002].

In 2002, new developments in anti-angiogenic strategies encompassed two main aspects. Firstly, essential improvements were made in the field of methodology : novel techniques permitted to measure directly on patients the biological effects induced by anti-angiogenic treatments in the course of clinical trials. Secondly, results of the first phase I trials of endostatin, one of the most awaited anti-angiogenic drugs, were published. These studies proved that endostatin was not toxic and that doses equivalent to the one effective in animals could safely be used in man, but efficacy results were not up to expectations. On the other hand, treatment targeting the VEGF pathway, and especially humanised anti-VEGF monoclonal antibody, had promising results. Further clinical trials are needed to gain clear insight into the precise role of those promising strategies for the management of solid tumours.

Angiogenesis Inhibitors↗
PubMed2003

[Gastro-intestinal stromal tumors: news and comments].

Gastrointestinal stromal tumors (GIST) are rare tumors occuring at all levels of the gastrointestinal tract, whose estimated incidence may be close to 2 new cases per 100 000 persons per year. GIST derive from the interstital cells of Cajal (ICC) responsible for the motility of the GI tract, or from a common precursor of ICC and of the smooth muscle cells of the digestive tract. GIST cells express the c-kit protoconcogene under an activated form, either mutated or constitutively activated, as well as the CD34 Ag. Mutations of the KIT gene is an early event in the process of transformation in these tumors. Until recently, GIST were not recognized as a distinct entity among soft tissue sarcoma. It is now clear that conventional chemotherapy is generally inactive in this tumor, surgery being the only efficient therapeutic modality even in patients with advanced disease. Rapidly accruing phase I, II and III trials in the USA and Europe (EORTC) have demonstrated since 2000 that imatinib mesylate (STI571) is an active agent in GIST with an initial response rate of 70 % and 10 % only of primary refractory tumors, yelding an improved overall survival as compared to historical series. Resistance are now being observed however. GIST has become the first model of a solid tumor treated efficiently by a treatment targetting the initial genetic alteration of the disease. Numerous question regarding the integration of this treatment with surgery and the long term outcome of these patients still remain to be answered however.

Age Factors↗
PubMed2003

[Anemia and chemotherapy].

Anemia is a real and frequent complication during the management of cancer patients. It is define as a decrease of the erythrocyte mass. The hemoglobin rate (which was an estimation of this erythrocyte mass) is the most often using criteria. The inferior threshold change with the sex and the age of the patients. This is 13 g/dl for the men and 11.5 g/dl for the women. This rate would be however decrease without any other associated pathology. This anemia is due to nutritional context of the patients and complications of the cancer pathology or his management (treatments). Anemia due to the chemotherapy toxicity is a real problem to investigate, to quantify, to prevent or to treat. The chemotherapy toxicity worsened previous anemia (inflammatory ethiology) which physiopathology is multifactoriel and depends on drugs, patients' characteristics, and sort of cancer. Anemia is also a therapeutic problem. Whatever is the severity of the anemia, impact on the quality of life with physical and social consequences is clear. In addition, anemia could relieve of specific treatment such as blood transfusion or preventive treatment with recombinant erythropoietin.

Age Factors↗
PubMedDate not supplied

Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.

BACKGROUND: Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. METHODS: 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. FINDINGS: At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). INTERPRETATION: If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

Aged↗
PubMedDate not supplied

ET-743: a novel agent with activity in soft tissue sarcomas.

Ecteinascidin-743 (ET-743) is a natural product derived from the marine tunicate Ectenascidia turbinate. ET-743 binds in the minor groove of DNA, blocks transcription factors activity, and traps protein from the nucleotide excision repair system, thus blocking cells in G2-M phase. ET-743 demonstrated cytotoxic activity at very low concentrations against sarcoma cell lines in pre-clinical studies. In several phase II clinical studies in patients with advanced sarcoma failing conventional doxorubicin- and ifosfamide-based chemotherapy, ET-743 delivered by continuous intravenous 24-hour infusion at a dose of 1,500 microg/m2 every 21 days yielded 8% overall response and 30%-40% stabilization rates for a clinical benefit rate close to 40%. Interestingly, long-term stabilizations over more than 3 years have been described. In vivo, ET-743 has a specific toxicity profile, the major toxicity of this product being hepatic, through biliary duct destruction, and hematologic. ET-743 has also been evaluated in first-line treatment for these patients. Finally, due to its original mode of action and the lack of cross-resistance with other chemotherapy agents, ET-743 was tested in a preclinical model in combination with other drugs. Synergy was reported in vitro with doxorubicin and cisplatin; phase I combination studies are in progress.

Antineoplastic Combined Chemotherapy Protocols↗