Melanoma: Lesimple T

Lesimple T, Voigt JJ, Bataillard A, Coindre JM, Culine S, Lortholary A, Merrouche Y, Ganem G, Kaminsky MC, Negrier S, Perol M, Bedossa P, Bertrand G, Bugat R, Fizazi K, Anonymous00330. · Oncologue médical, Centre Eugène Marquis, Rennes. · Bull Cancer. · Pubmed #14715428 links to  free full text

Abstract: CONTEXT: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. OBJECTIVES: To define Clinical Practice Guidelines (CPG) for the diagnosis of carcinomas of unknown primary site. METHODS: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers. RESULTS: The main recommendations for the diagnosis of carcinomas of unknown primary site are: 1) Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment. For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary. 2) An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies. This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. 3) A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later. 4) The clinician and pathologist should compare their opinions before and after the pathological diagnosis.

Quillien V, Lesimple T, Toujas L. · Centre régional de lutte contre le cancer de Rennes, rue de la Bataille Flandres-Dunkerque, CS 44229, 35042 Rennes, France. · Bull Cancer. · Pubmed #14609762 links to  free full text

Abstract: Cell vaccination therapy in melanoma has now an around 15-year experience. Initially, the treatment was based on the use of autologous or allogeneic inactivated tumor cells. Today, new means become available, such as synthetic peptide tumor antigens, preparations of dendritic cells of various sorts and transfer of genes into vaccinating cells. In the protocols that have been published and that utilize dendritic cells or macrophages, about 10% of the patients show objective tumor responses. Improving the treatments requires choices among the numerous options now proposed. Pre-clinical investigations are designed to select the cell products to be tested in phase I, then II, clinical protocols. Later on, only phase-III randomized trials will confirm or not the efficacy of this new therapeutic approach.

Bercovici N, Haicheur N, Massicard S, Vernel-Pauillac F, Adotevi O, Landais D, Gorin I, Robert C, Prince HM, Grob JJ, Leccia MT, Lesimple T, Wijdenes J, Bartholeyns J, Fridman WH, Salcedo M, Ferries E, Tartour E. · IDM, Hopital Européen Georges Pompidou, Unité d'Immunologie Biologique, EA 4054 Université Paris, France. · J Immunother. · Pubmed #18157017 No free full text.

Abstract: The primary goal of cancer vaccines is to induce CD8+ T cells specific for tumor-associated antigens (TAA) but the characterization of these cells has been difficult because of the low sensitivity of ex vivo assays. Here, we focused on TAA-specific CD8+ T-cell responses in melanoma patients after vaccination with autologous dendritic cells loaded with lysates derived from allogeneic tumor-cell lines (Lysate-DC). Out of 40 patients treated, 16 patients developed immune response to tumor-cell lysate and/or CD8+ T cells specific for differentiation and cancer-testis antigens. TAA-specific CD8+ T-cell responses were detected by interferon (IFN)-gamma enzyme-linked immunospot after in vitro sensitization and were, either transient during the treatment period or delayed, that is, observed after completion of all vaccinations. We could not correlate these immune responses to clinical data as none of the patients achieved an overall objective response according to Response Evaluation Criteria in Solid Tumors criteria. Three patients were reported as stable disease and 10 patients presented evidence of antitumor activity. We found that TAA-specific T cells characterized in 4 patients produced perforin ex vivo, but no IFN-gamma in enzyme-linked immunospot. Differential expression of IFN-gamma and perforin was also observed for viral-specific T cells. Altogether, our results show that Lysate-DC therapy elicited tumor-specific CD8+ T cells nonlimited to human leukocyte antigen-A2+ patients, with some T cells secreting perforin ex vivo and IFN-gamma only after restimulation. The differential expression of perforin and IFN-gamma by antitumor and antiviral CD8+ T cells supports that the sole use of IFN-gamma production to monitor T cells overlooks functional T-cell subpopulations triggered by vaccines.

Lesimple T, Neidhard EM, Vignard V, Lefeuvre C, Adamski H, Labarrière N, Carsin A, Monnier D, Collet B, Clapisson G, Birebent B, Philip I, Toujas L, Chokri M, Quillien V. · Centre Eugène Marquis, Rennes, France. · Clin Cancer Res. · Pubmed #17189411 links to  free full text

Abstract: PURPOSE: A phase I/II trial was conducted to evaluate clinical and immunologic responses after intralymphatic and intranodal injections of mature dendritic cells. EXPERIMENTAL DESIGN: Fourteen patients with a metastatic melanoma received matured dendritic cells, loaded with Melan-A/MART-1 and/or NA17-A peptides and keyhole limpet hemocyanin. The cells were matured overnight with Ribomunyl, a toll-like receptor ligand, and IFN-gamma, which ensured the production of high levels of interleukin-12p70. Dendritic cells were injected at monthly intervals, first into an afferent lymphatic and then twice intranodally. Immunologic responses were monitored by tetramer staining of circulating CD8(+) lymphocytes and delayed-type hypersensitivity tests. RESULTS: Dendritic cell vaccination induced delayed-type hypersensitivity reactivity toward NA17-A-pulsed, keyhole limpet hemocyanin-pulsed, and Melan-A-pulsed dendritic cells in 6 of 10, 4 of 11, and 3 of 9 patients, respectively. Four of the 12 patients analyzed by tetramer staining showed a significantly increased frequency of Melan-A-specific T cells, including one patient vaccinated only with NA17-A-pulsed dendritic cells. Furthermore, 2 of the 12 analyzed patients had a significant increase of NA17-A-specific T cells, including one immunized after an optional additional treatment course. No objective clinical response was observed. Two patients were stabilized at 4 and 10 months and three patients are still alive at 30, 39, and 48 months. CONCLUSIONS: Injections into the lymphatic system of mature peptide-loaded dendritic cells with potential TH1 polarization capacities did not result in marked clinical results, despite immunologic responses in some patients. This highlights the need to improve our understanding of dendritic cell physiology.

Quillien V, Moisan A, Carsin A, Lesimple T, Lefeuvre C, Adamski H, Bertho N, Devillers A, Leberre C, Toujas L. · Centre Régional de Lutte Contre le Cancer, Rennes, France. · Eur J Nucl Med Mol Imaging. · Pubmed #15924229 No free full text.

Abstract: PURPOSE: The purpose of this study was to investigate the biodistribution of mature dendritic cells (DCs) injected by various routes, during a cell therapy protocol. METHODS: In the context of a vaccine therapy protocol for melanoma, DCs matured with Ribomunyl and interferon-gamma were labelled with( 111)In-oxine and injected into eight patients along various routes: afferent lymphatic vessel (IL) (4 times), lymph node (IN) (5 times) and intradermally (ID) (6 times). RESULTS: Scintigraphic investigations showed that the IL route allowed localisation of 80% of injected radioactivity in eight to ten nodes. In three cases of IN injection, the entire radioactivity stagnated in the injected nodes, while in two cases, migration to adjacent nodes was observed. This migration was detected rapidly after injection, as with IL injections, suggesting that passive transport occurred along the physiological lymphatic pathways. In two of the six ID injections, 1-2% of injected radioactivity reached a proximal lymph node. Migration was detectable in the first hour, but increased considerably after 24 h, suggesting an active migration mechanism. In both of the aforementioned cases, DCs were strongly CCR7-positive, but this feature was not a sufficient condition for effective migration. In comparison with DCs matured with TNF-alpha, IL-1beta, IL-6 and PGE2, our DCs showed a weaker in vitro migratory response to CCL21, despite comparable CCR7 expression, and higher allostimulatory and TH1 polarisation capacities. CONCLUSION: The IL route allowed reproducible administration of specified numbers of DCs. The IN route sometimes yielded fairly similar results, but not reproducibly. Lastly, we showed that DCs matured without PGE2 that have in vitro TH1 polarisation capacities can migrate to lymph nodes after ID injection.

Smyth JF, Aamdal S, Awada A, Dittrich C, Caponigro F, Schöffski P, Gore M, Lesimple T, Djurasinovic N, Baron B, Ravic M, Fumoleau P, Punt CJ, Anonymous00024. · University of Edinburgh, Cancer Research Centre, Western General Hospital, Edinburgh, UK. · Ann Oncol. · Pubmed #15598954 links to  free full text

Abstract: E7070 is a synthetic chloro-indolyl sulphonamide that is being developed as an anti cancer agent. In this phase II study, 28 patients with metastatic melanoma received 700 mg/m(2) of E7070 as a 60-min infusion repeated every 3 weeks. Although therapy was well tolerated, with one patient receiving 14 courses of treatment, there were only minor responses on independent radiological review. E7070 does not warrant further development as a single agent for the treatment of metastatic melanoma.

Lesimple T, Moisan A, Carsin A, Ollivier I, Mousseau M, Meunier B, Leberre C, Collet B, Quillien V, Drenou B, Lefeuvre-Plesse C, Chevrant-Breton J, Toujas L. · Centre Régional de Lutte Contre le Cancer Eugène Marquis, rue de la Bataille Flandres-Dunkerque, CD 44229, 35042 Rennes, France. · Cancer Immunol Immunother. · Pubmed #12690521 No free full text.

Abstract: Patients' autologous macrophages (AM) were used as antigen-presenting cells (APC) in a vaccination protocol against malignant melanoma. AM were administered by various routes, including intralymphatic, since these cells did not express CCR7, a molecule required for APC migration to lymph nodes. Seven HLA-A2 patients with metastatic melanoma-two classified as M1 and five as M3-were included in the study. AM were produced from leukapheresis-separated mononuclear cells by 7-day culture with granulocyte-macrophage colony-stimulating factor. After separation by elutriation, AM were frozen in aliquots and subsequently thawed at monthly intervals, exposed to MAGE-3(271-279) peptide and injected subcutaneously into lymph nodes or into one peripheral lymph vessel. Intradermal tests were performed before and after treatment to determine peptide reactivity. No acute toxicity was observed following injection. One M1 patient had a 7-mm induration intradermal reaction response and was stabilized for 64 weeks. The M3 patients did not show any immunological or clinical response. In 11 patients, the biodistribution of 111In-labeled AM was investigated. There was no clear evidence that AM injected intradermally or subcutaneously left the site of injection. After injection into a lymph vessel of the foot region, scintigraphs showed five to ten popliteal and inguinocrural lymph nodes. This appeared to be the most efficient way to administer rapidly and safely large amounts of peptide-loaded APC into lymph nodes.

Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Nguyen BB, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre J, de Gislain C, Bensadoun JR, Clavel M. · Centre hospitalier Lyon-Sud, service de radiothérapie-oncologie, EA 643, 69495 cedex, Pierre-Bénite, France. · Cancer Radiother. · Pubmed #12648711 No free full text.

Abstract: PURPOSE: The main objective of this prospective multicenter randomised phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation versus fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma brain metastases. PATIENTS AND METHODS: Seventy-six patients (instead of the 106 planned patients; study was stopped after the interim analysis) were randomised receiving either fotemustine (arm A, n = 39) or fotemustine and whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg m(-2) on day 1, 8 and 15, followed by a 5-week rest period, then every 3 weeks in non-progressive patients. In arm B, a concomitant whole brain irradiation was performed at the total dose of 37.5 Gy (2.5 Gy/d(-1), days 1-5, 3 consecutive weeks). RESULTS: Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in brain response (arm A: 7.4%, B: 10.0%) or control rates (objective response plus stable disease) after seven weeks (arm A: 30%, B: 47%) and overall survival (arm A: 86d, B: 105d). However, there was a significant difference in favour of arm B for the time to brain progression (p = 0.028, Wilcoxon test). CONCLUSION: Fotemustine plus whole brain irradiation delayed the time to brain progression of melanoma cerebral metastases compared to fotemustine alone but without a significant improvement in terms of objective control or overall survival.

Mornex F, Thomas L, Mohr P, Hauschild A, Delaunay MM, Lesimple T, Tilgen W, Bui BN, Guillot B, Ulrich J, Bourdin S, Mousseau M, Cupissol D, Bonneterre ME, De Gislain C, Bensadoun RJ, Clavel M. · Centre Hospitalier Lyon Sud, Service de Radiothérapie-Oncologie, Pierre-Benite Cedex, France. · Melanoma Res. · Pubmed #12569292 No free full text.

Abstract: The main objective of this prospective multicentre randomized phase III study was to compare a combined regimen of fotemustine plus whole brain irradiation with fotemustine alone in terms of cerebral response and time to cerebral progression in patients with melanoma cerebral metastases. Seventy-six patients were randomized to receive either fotemustine (arm A, n = 39) or fotemustine plus whole brain irradiation (arm B, n = 37). Fotemustine was administered intravenously at 100 mg/m(2) on days 1, 8 and 15, followed by a 5 week rest period, then every 3 weeks in non-progressive patients. In arm B, concomitant whole brain irradiation was performed at a total dose of 37.5 Gy (2.5 Gy/day on days 1-5 for three consecutive weeks). Although patients who received fotemustine alone had worse prognostic factors, there was no significant difference in cerebral response (arm A, 7.4%, arm B, 10.0%) or control rates (objective responses plus stable disease) after 7 weeks (arm A, 30%; arm B, 47%) or in overall survival (arm A, 86 days; arm B, 105 days). However, there was a significant difference in favour of arm B for the time to cerebral progression (P = 0.028, Wilcoxon test). In conclusion, fotemustine plus whole brain irradiation delayed the time to cerebral progression of melanoma cerebral metastases compared with fotemustine alone but without a significant improvement in terms of objective control or overall survival.

Ravaud A, Bedane C, Geoffrois L, Lesimple T, Delaunay M. · Department of Medicine, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France. · Br J Cancer. · Pubmed #10468294 No free full text.

Abstract: To assess the feasibility and toxicity profile of high-dose interferon alpha-2b (IFN-alpha-2b) in the adjuvant treatment of patients with cutaneous malignant melanoma outside the reference ECOG 1684 clinical trial, we conducted a prospective follow-up in an identical population of patients (cutaneous melanoma, T4 and/or N1) treated by intravenous IFN-alpha-2b:20 MIU m(-2), 5 days a week for 4 weeks; and subcutaneous:10 MIU m(-2), 3 times a week for 11 months. Thirty-six consecutive patients were considered in four different institutions. The frequency and severity of side-effects related to IFN-alpha, as well as the percentage of the planned dose given to patients, were identical to those reported in the initial report by ECOG. Fifty per cent and 47% of patients had a grade 3/4 WHO toxicity in the induction and consolidation phase respectively. A dose modification was necessary for 47.2% and 55.8% of the patients in the induction and consolidation phase respectively. The schedule and dose of high-dose IFN-alpha-2b in the adjuvant treatment of cutaneous malignant melanoma, as reported by ECOG 1684, is feasible. The significant toxicity reported in ECOG 1684 was also seen in our patients. Nevertheless, this protocol will not be a 'standard' treatment until the publication of the ECOG 1690 trial.

Descheemaeker V, Garin E, Morcel K, Lesimple T, Burtin F, Levêque J. · Department of Obstetric Gynecology, CHU Anne de Bretagne, Rennes Cedex 2, France. · Surg Laparosc Endosc Percutan Tech. · Pubmed #18427341 No free full text.

Abstract: A 66-year-old woman was diagnosed with vaginal melanoma. Sentinel node mapping was performed using Tc sulfur colloid. Planar scintigraphic acquisitions detected 2 sentinel nodes in the right external iliac region, which were laparoscopically removed with an anterior vaginectomy. Sentinel node mapping is feasible in cases of vaginal melanoma.

Rivera JC, Lesimple T, Garin E, Laurent JF, Watier E, Hu W. · Service de chirurgie plastique, CHU de Rennes, France; Service de chirurgie plastique, CHU de Brest, 1, boulevard Tanguy-Prigent, 29200 Brest, France. · Ann Chir Plast Esthet. · Pubmed #17602816 No free full text.

Abstract: Malignant melanoma of soft parts (MMSP) (or "clear cell sarcoma") is a very rare tumour that shows up without primitive skin involvement (except in subcutaneous prolongations of deep tumours), mostly predominant in the extremities of young adults. Eight files of MMSP were studied retrospectively. The mean patient is a male of 35 years old affected in an extremity (four upper, three lower and one gluteal), according to classical descriptions. The importance of radical surgery in these cases has been extensively established. Confronted with these cases, the plastic surgeon must be aware of the specifics of this rare entity to ensure its proper inclusion in his clinical suspicion. Just in case.

Brouard M, Quillien V, Ollivier I, Lesimple T, Adamski H, Chevrant-Breton J. · Service de Dermatologie, Hôpital de Pontchaillou, CHU, 35033 Rennes. · Ann Dermatol Venereol. · Pubmed #10717564 No free full text.

Abstract: OBJECTIVE: We searched for a correlation between serum S100B protein and cutaneous malignant melanoma stage, according to the American Joint Committee on Cancer staging system, and between elevation of serum S100B protein and development of metastasis. PATIENTS AND METHODS: We conducted a prospective bicentric study for 20 months in 122 patients with malignant melanoma. LIA-mat(R) assay was used to determine serum S100B at each examination. The optimal cut-off value was determined from the ROC curve. RESULTS: The optimal cut-off value to discriminate patients with metastases from patients in remission was 0.09 microg/l. Sensitivity was 46 p. 100 in patients with stage III and 86 p. 100 in patients with stage IV disease. The positive predictive value for stage III/IV was 77 p. 100 and the negative predictive value was 89 p. 100. Serial measurements were made in 56 patients. The serum S100B protein level was elevated in 69 p. 100 of the patients disclosing disease progression (9/13). In 44 p. 100 of the patients (4/9), serum S100B protein level rose within a delay of 3 months before new metastases were detected. DISCUSSION: Our study confirms that serum S100B protein is a tumor marker for melanoma staging and follow-up. A rise in S100B protein precedes or reveals metastasis.

Lepelley-Dupont C, Meyer N, Lesimple T, Gueret P, Adamski H, Chevrant-Breton J. · No affiliation provided · J Eur Acad Dermatol Venereol. · Pubmed #19522900 No free full text.

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