Exome sequencing identifies germline variants in DIS3 in familial multiple myeloma

[Excerpt] Multiple myeloma (MM) is the third most common hematological malignancy, after Non-Hodgkin Lymphoma and Leukemia. MM is generally preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS) [1], and epidemiological studies have identified older age, male gender, family history, and MGUS as risk factors for developing MM [2]. The somatic mutational landscape of sporadic MM has been increasingly investigated, aiming to identify recurrent genetic events involved in myelomagenesis. Whole exome and whole genome sequencing studies have shown that MM is a genetically heterogeneous disease that evolves through accumulation of both clonal and subclonal driver mutations [3] and identified recurrently somatically mutated genes, including KRAS, NRAS, FAM46C, TP53, DIS3, BRAF, TRAF3, CYLD, RB1 and PRDM1 [3,4,5]. Despite the fact that family-based studies have provided data consistent with an inherited genetic susceptibility to MM compatible with Mendelian transmission [6], the molecular basis of inherited MM predisposition is only partly understood. Genome-Wide Association (GWAS) studies have identified and validated 23 loci significantly associated with an increased risk of developing MM that explain ~16% of heritability [7] and only a subset of familial cases are thought to have a polygenic background [8]. Recent studies have identified rare germline variants predisposing to MM in KDM1A [9], ARID1A and USP45 [10], and the implementation of next-generation sequencing technology will allow the characterization of more such rare variants. [...]French National Cancer Institute (INCA) and the Fondation Française pour la Recherche contre le Myélome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myélome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myélome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organizatio

Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells

The efficacy of anti-tumor IgG reflects the balance between opposing signals mediated by activating and inhibitory Fcγ receptors (FcγRs) expressed by effector cells. Here, we show that human malignant melanoma cells express the inhibitory low-affinity Fcγ receptor FcγRIIB1 in 40% of tested metastases. When melanoma cells were grafted in nude mice, a profound inhibition of FcγRIIB1 tumor growth that required the intracytoplasmic region of the receptor was observed. IgG immune complexes (ICs) may be required for this inhibition, since sera from nude mice bearing tumors contained IgG that decreased the proliferation of FcγRIIB1-positive cells in vitro, and tumor development of FcγRIIB1-positive melanoma lines was not inhibited in antibody-defective severe combined immunodeficiency (SCID) mice. Passive immunization of SCID mice with anti–ganglioside G(D2) antibody resulted in significant inhibition of growth of FcγRIIB1-positive tumors in an intracytoplasmic-dependent manner. Altogether, these data suggest that human melanoma cells express biologically active inhibitory FcγRIIB1, which regulates their development upon direct interaction with anti-tumor antibodies. Therefore, FcγR expression on human tumors may be one component of the efficacy of antibody-mediated therapies, and FcγR-positive tumors could be the most sensitive candidates for such treatments

Clinical value of circulating endothelial cells and circulating tumor cells in metastatic breast cancer patients treated first line with bevacizumab and chemotherapy.

International audienceBACKGROUND: We investigated whether circulating tumor cells (CTCs) and circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy combined with bevacizumab in metastatic breast cancer patients. PATIENTS AND METHODS: In a French substudy of the MO19391 trial, CTC and CEC counts (CellSearch system) at baseline and changes after two cycles of treatment were correlated with time to progression (TtP). RESULTS: CTC and CEC levels were not correlated in the 67 patients included. At baseline, CTC positivity was a significant prognostic marker for TtP at a threshold of 3 CTC/7.5 ml (P /=45 years (P = 0.01), elevated lactate dehydrogenase (P < 0.01) and not with TtP at any threshold. Changes of CTC count during treatment were not a surrogate of TtP, with any of the model tested (threshold based or relative decrease in percent). However, increase in CEC count was associated with improved TtP, at the threshold of 20 CEC/4 ml (P < 0.01). CONCLUSION: Bevacizumab combined with first-line chemotherapy may modify the predictive value of CTC during treatment possibly due to impaired tumor cells intravasation through vessels endothelium. Variations in CEC levels appear to be a promising early surrogate marker of TtP under antiangiogenic treatment

: Cellules tumorales circulantes et cancer du sein

International audienceDue to recent technological progresses, Circulating Tumor Cells (CTC) are currently extensively studied in order to define their diagnostic, prognostic and predictive value. We review here the different detection techniques and their clinical results in breast cancer patients

Avis de l'Anses relatif à l’évaluation de la pertinence de l’application des avertissements etrecommandations exprimés dans les monographies de plantes médicinales de l’EMA aux compléments alimentaires contenant ces mêmes plantes

Citation suggérée : Anses. (2022). Évaluation de la pertinence de l’application des avertissements et recommandations exprimés dans les monographies de plantes médicinales de l’EMA auxcompléments alimentaires contenant ces mêmes plantes. (saisine 2019-SA-00155). Maisons-Alfort : Anses, 540 p.L’expertise est réalisée dans le cadre du décret n°2006-352 relatif aux complémentsalimentaires et de l’arrêté du 24 juin 2014, ci-après nommé arrêté « plantes », établissant laliste des plantes, autres que les champignons, les lichens et les algues, autorisées dans lescompléments alimentaires et les conditions de leur emploi.L’arrêté « plantes » prévoit des restrictions pour 73 plantes parmi les 540 plantes présentesdans son annexe I. Ces restrictions concernent le plus souvent des avertissements pour despopulations à risques, mais également des modes de préparation de l’extrait de plantes oul’indication de teneurs limites ou de valeurs d’exposition limites pour des substancespréoccupantes.En 2019, la Direction générale de la concurrence, de la consommation et de la répression desfraudes (DGCCRF) a publié une liste non réglementaire de 1011 plantes en précisant si laplante est susceptible de faire l’objet de restrictions sanitaires au regard des donnéesdisponibles, sans autres précisions. Les plantes de l’arrêté « plantes » sont reprises dans cettenouvelle liste.Dans le cadre de cette auto-saisine, le GT « Plantes » a recensé les plantes susceptiblesd’être utilisées dans les compléments alimentaires et bénéficiant d’une monographie del’Agence européenne des médicaments (European Medicines Agency), ci-après nommée« monographie EMA ». Certains avertissements et recommandations, proposés dans lesmonographies de ces plantes et utilisés dans le cadre du médicament, peuvent faire l’objetd’une extrapolation pour une utilisation de ces mêmes plantes dans les complémentsalimentaires. Après analyse des experts rapporteurs, cette extrapolation aura pour but decontribuer à l’encadrement de la sécurité d’utilisation de ces plantes dans les complémentsalimentaires, pour une exposition (plante ou substance) considérée comme équivalente