Rôle du virus de l'herpès humain 8 dans l'étiologie de la maladie de Kaposi (analyse du réservoir viral in vivo et in vitro)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Prise en charge du sarcome de Kaposi post-transplantation rénale en Ile de France (analyse rétrospective de 89 patients)

Il s'agit d'une étude rétrospective observationnelle dont l'objectif était d'obtenir une vision globale et précise des caractéristiques, de la prise en charge et du pronostic de 89 patients ayant développé un sarcome de Kaposi post transplantation rénale entre 1990 et 2010 dans cinq centres d'Ile de France avec un suivi médian de 78 mois. Ces patients avaient développé un sarcome de Kaposi dans un délai médian de 18 mois après la transplantation rénale, étaient âgés de 54 ans en moyenne et présentaient au diagnostic, une maladie progressive dans 63% des cas, localisée à la peau et modérée dans 21 % des cas, localisée à la peau et sévère dans 17% des cas et il existait une atteinte viscérale chez 62% des malades. La sérologie HHV-8 était positive en pré-greffe chez 88% des patients suggérant une réactivation virale à l'origine de la maladie. Le traitement consistait pour la majorité des patients en une minimisation de l'irnmunosuppression suivi d'une intensification du traitement par inhibiteurs de mTOR et/ou chimiothérapie selon l'extension et l'évolution de la maladie entrainant une réponse dans 91 % des cas, sans qu'il y ait de facteurs prédictifs retrouvés. Le risque de rechute semblait associé au traitement par inhibiteurs de mTOR et à la présence d'une charge virale HHV-8 positive au diagnostic. La survie du greffon rénal de 85 et 75% à 5 et 10 ans et la survie globale de 86 et 71% à 5 et 10 ans tend à rejoindre les taux de survie de la population générale des greffés rénaux.This multicentric retrospective study aimed to obtain an overview of characteristics, management and prognosis of 89 patients with post renal transplant Kaposi's sarcoma which occurred between 1990 and 2010 in Ile de France with a median follow up of 78 months. The median time from graft to Kaposi's sarcoma was 18 months and their mean age a diagnostic was 54 years. At diagnosis, patients showed a progressive disease in 63%, isolated and moderate cutaneous lesions in 21 %, isolated and severe les ions in 17% and visceral involvement in 62%. 88% of recipients were seropositive for HHV-8 before graft suggesting that most cases of kaposi's sarcoma developed as a result of viral reactivation. The cornerstone in first line treatment was to taper down irnmunosuppressive regimens with intensified treatment (mTOR inhibitors and/or chemotherapy) in case of severe pathology leading to 91 % of response rate. There were no significant factors associated with treatment's response which. Risk of relapse might be associated with mTOR inhibitors treatment and positive HHV -8 viral load at diagnosis. Renal graft survival was 85 and 75% at 5 and 10 years and global survival was 86 and 71 % at 5 and 10 years which tend to reach survival rate of patients with renal graft.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Les Alternarioses cutanées (à propos de six cas)

Les alternarioses cutanées sont des infections fongiques rares, opportunistes et émergentes. Elles sont dues à des moisissures cosmopolites issues du sol, caractéristiques par la présence de mélanine dans leur paroi: les Alternaria.Six nouveaux cas d'alternariose cutanée, ont été colligés à l'hôpital Saint-Louis entre 1999 et 2005. Tous présentaient une immunodépression de plus de six mois liée à une transplantation rénale (deux cas), hépato-rénale (deux cas), ou à une corticothérapie générale pour une sarcoïdose (un cas) et pour un cancer prostatique métastatique (un cas). Le mode de contamination était lié à une effraction cutanée, favorisée très probablement par la fragilité cutanée cortico-induite. Le traumatisme était passé le plus souvent inaperçu (quatre cas sur six) Un granulome macrophagique s'était formé et se présentait sous la forme d'un nodule violacé, indolore. Les lésions étaient soit uniques (quatre cas) soit multiples (deux cas) ; toutes réparties sur les membres. Le traitement avait été chirurgical (trois cas); médical puis chirurgical (deux cas) ou exclusivement médical du fait d'un nombre important de lésions (un cas). L'itraconazole avait été proposé en première intention, à une posologie adaptée au terrain et en tenant compte des interactions médicamenteuses (risque d'augmentation des doses d'immunosuppresseurs, par inhibition de la voie des cytochromes P450). La réduction de l'immunosuppression avait été réalisée à chaque fois que cela avait été possible. Aucun patient n'a rechuté. Seul un patient s'est contaminé un an après lors d'un nouveau traumatisme. Il n'a jamais été rapporté de dissémination, ou de décès directement lié à ces moisissuresPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Rôle de la glycoprotéine EMMPRIN dans l'invasion et l'angiogenèse en général et dans le mélanome

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Targeted therapies in melanoma beyond BRAF : targeting NRAS-mutated and KIT-mutated melanoma

International audiencePurpose of review: Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma.Recent findings: In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma.Summary: Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit

EMMPRIN/CD147 up-regulates urokinase-type plasminogen activator: implications in oral tumor progression

Abstract Backgrounds An elevated level of EMMPRIN in cancer tissues have been correlated with tumor invasion in numerous cancers including oral cavity and larynx. Although EMMPRIN's effect has been generally attributed to its MMP inducing activity, we have previously demonstrated in breast cancer model that EMMPRIN can also enhance invasion by upregulating uPA. In this study, the role of EMMPRIN in regulating uPA and invasion was investigated in oral squamous cell carcinoma (OSCC) progression. Methods Precancerous and invasive oral tumoral tissues were used as well as the corresponding cell lines, DOK and SCC-9 respectively. The paracrine regulation of uPA by EMMPRIN was investigated by treating culture cells with EMMPRIN-enriched membrane vesicles. UPA expression was analyzed by qPCR and immunostaining and the consequence on the invasion capacity was studied using modified Boyden chamber assay, in the presence or absence of EMMPRIN blocking antibody, the uPA inhibitor amiloride or the MMP inhibitor marimastat. Results OSCC tumors were shown to express more EMMPRIN and uPA compared to dysplastic lesions. The corresponding cell models, SCC-9 and DOK cells, displayed similar expression pattern. In both cell types EMMPRIN upregulated the expression of uPA as well as that of MMP-2 and MMP-9. EMMPRIN treatment led to a significant increase in cell invasion both in the invasive SCC-9 and in the less invasive dysplastic DOK cells, in an MMP and uPA dependent manner. Conclusions Our results suggest that the upregulation of uPA contributes to EMMPRIN's effect in promoting oral tumor invasion.</p

EMMPRIN/CD147 up-regulates urokinase-type plasminogen activator: implications in oral tumor progression.

International audienceABSTRACT: Backgrounds An elevated level of EMMPRIN in cancer tissues have been correlated with tumor invasion in numerous cancers including oral cavity and larynx. Although EMMPRIN's effect has been generally attributed to its MMP inducing activity, we have previously demonstrated in breast cancer model that EMMPRIN can also enhance invasion by upregulating uPA. In this study, the role of EMMPRIN in regulating uPA and invasion was investigated in oral squamous cell carcinoma (OSCC) progression. METHODS: Precancerous and invasive oral tumoral tissues were used as well as the corresponding cell lines, DOK and SCC-9 respectively. The paracrine regulation of uPA by EMMPRIN was investigated by treating culture cells with EMMPRIN-enriched membrane vesicles. UPA expression was analyzed by qPCR and immunostaining and the consequence on the invasion capacity was studied using modified Boyden chamber assay, in the presence or absence of EMMPRIN blocking antibody, the uPA inhibitor amiloride or the MMP inhibitor marimastat. RESULTS: OSCC tumors were shown to express more EMMPRIN and uPA compared to dysplastic lesions. The corresponding cell models, SCC-9 and DOK cells, displayed similar expression pattern. In both cell types EMMPRIN upregulated the expression of uPA as well as that of MMP-2 and MMP-9. EMMPRIN treatment led to a significant increase in cell invasion both in the invasive SCC-9 and in the less invasive dysplastic DOK cells, in an MMP and uPA dependent manner. CONCLUSIONS: Our results suggest that the upregulation of uPA contributes to EMMPRIN's effect in promoting oral tumor invasion

Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction

More than 70% of human NRAS melanomas are resistant to MEK inhibitors highlighting the crucial need for efficient therapeutic strategies for these tumors. CD147, a membrane receptor, is overexpressed in most cancers including melanoma and is associated with poor prognosis. We show here that CD147i, a specific inhibitor of CD147/VEGFR-2 interaction represents a potential therapeutic strategy for NRAS melanoma cells. It significantly inhibited the malignant properties of NRAS melanomas ex vivo and in vivo. Importantly, NRAS patient’s-derived xenografts, which were resistant to MEKi, became sensitive when combined with CD147i leading to decreased proliferation ex vivo and tumor regression in vivo. Mechanistic studies revealed that CD147i effects were mediated through STAT3 pathway. These data bring a proof of concept on the impact of the inhibition of CD147/VEGFR-2 interaction on melanoma progression and represents a new therapeutic opportunity for NRAS melanoma when combined with MEKi.This work was supported by La Ligue Nationale contre le Cancer, the Institut National de la Santé et de la Recherche Médicale (INSERM) and La Société Française de Dermatologie. AL was supported by a PhD funding from La Ligue Nationale contre le Cancer and the Spanish Ministry of Science and Innovation (PID2019-110167RB-I00). We thank technological platform of the Institut Recherche Saint-Louis (IRSL) for confocal microscopy analyses and Dr Benoit Souquet for technical support

Fgf2 induces resistance to nilotinib through mapk pathway activation in kit mutated melanoma

KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma.SCOPUS: ar.jinfo:eu-repo/semantics/publishe