CSPG4 Expression in GIST Is Associated with Better Prognosis and Strong Cytotoxic Immune Response

The treatment of gastrointestinal stromal tumors (GIST) must be improved through the development of more reliable prognostic factors and of therapies able to overcome imatinib resistance. The immune system represents an attractive tool. CSPG4, a cell surface proteoglycan, emerged as a potential therapeutic target for immune therapy in different cancers, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in sarcomas. CSPG4 expression has never been studied in GIST. We analyzed CSPG4 mRNA expression data of 309 clinical GIST samples profiled using DNA microarrays and searched for correlations with clinicopathological and immune features. CSPG4 expression, higher in tumors than normal digestive tissues, was heterogeneous across tumors. High expression was associated with AFIP low-risk, gastric site, and localized stage, and independently with longer postoperative disease-free survival (DFS) in localized stage. The correlations between CSPG4 expression and immune signatures highlighted a higher anti-tumor immune response in “CSPG4-high” tumors, relying on both the adaptive and innate immune system, in which the boost of NK cells by CSPG4-CAR.CIKs might be instrumental, eventually combined with immune checkpoint inhibitors. In conclusion, high CSPG4 expression in GIST is associated with better DFS and offers an immune environment favorable to a vulnerability to CAR.CIKs

Activation of the ALTernative telomere maintenance mechanism in high-grade osteosarcomas

Pour s’immortaliser les cellules cancéreuses réactivent la télomérase, ou dans 10 à 15% des cas, utilisent un mécanisme alternatif, spécifique au cancer, appelé le ALT. Les ostéosarcomes de haut grade (OS) sont des tumeurs agressives connues pour utiliser le ALT à fréquence élevée. L’objectif de mes travaux de thèse était d’identifier les altérations génomiques et transcriptomiques associées au ALT dans ce type de cancer. Les caractéristiques du ALT (cercles C, corps PML et hétérogénéité de taille des télomères) ont été évaluées dans 22 OS pédiatriques naïfs de tout traitement. 73% des tumeurs étaient ALT-positives. Le ALT était associé à un plus mauvais pronostique chez les bons répondeurs à la chimiothérapie néoadjuvante. L'analyse supervisée des données génomique a identifié l’amplification de TOP3A, associée à sa surexpression, comme mutuellement exclusive de l'inactivation d'ATRX dans les tumeurs ALT. Nous avons montré la localisation de TOP3A au niveau des corps de la PML dans des lignées cellulaires ALT ATRX-positives et ATRX-négatives, et que le knock-down de TOP3A entraînait une augmentation des cercles C dans les lignées cellulaires ATRX-négatives, et une diminution dans les lignées cellulaires ATRX-positives associée à une augmentation des dommages à l’ADN aux télomères. L'effet de surexpression ectopique d'ATRX dans les cellules ATRX-négatives, qui a été précédemment décrit comme inhibant le ALT, pouvait également être contrecarré par la surexpression de TOP3A. Ces résultats valident l’amplification de TOP3A comme une nouvelle voie moléculaire associée au ALT dans les ostéosarcomes de haut grade.Cancer cells become immortalised through the activation of a telomere maintenance mechanism (TMM) – either telomerase or ALT. Osteosarcomas are highly aggressive tumours known for exhibiting a high frequency of ALT. This work aimed to identify genomic and transcriptomic alterations associated with ALT in osteosarcomas. ALT hallmarks (C-circles, ALT-associated PML bodies, and telomere length heterogeneity) were assessed in 22 paediatric, non-metastatic, high-grade osteosarcomas. 73% of the tumours were ALT-positive. ALT-positivity was associated with worse outcomes in good responders to neoadjuvant chemotherapy. Supervised genomic analysis identified TOP3A amplification, that was associated with TOP3A overexpression, as a mutual exclusive event with ATRX inactivation. We showed TOP3A localisation at PML bodies in both ATRX-positive and ATRX-negative ALT cells, and that TOP3A knock-down resulted in increased C-circle levels in ATRX-negative, and decreased levels in ATRX-positive cell lines associated with increased DNA damage at telomeres. The ATRX ectopic overexpression effect in ATRX-negative cells, that was previously described as repressing ALT, could also be counteracted by TOP3A overexpression. We identify TOP3A overexpression and ATRX inactivation as mutually exclusive ALT-associated features in osteosarcomas and validate their impact on ALT hallmarks. By identifying ALT as a potential predictive biomarker of neoadjuvant chemotherapy in osteosarcoma, our study suggests that ALT-positive and ALT-negative osteosarcomas may represent different entities with non-overlapping behaviour in terms of aggressiveness, therapeutic response, and progression

Homeopathy in cancer patients: What does the ``best'' evidence tell us?

Homeopathic medicines are used by many patients with cancer, usually alongside conventional treatment. A recent report by the European Academies' Science Advisory Council concluded that ``that there are no robust and reproducible evidence that homeopathy is effective''. This literature review aims to make the analysis of published controlled randomized trials involving homeopathic treatment in the field of oncology

Sacituzumab govitecan in triple-negative breast cancer

International audienc

Medical staff opposition to a deep and continuous palliative sedation request under Claeys-Leonetti law

Abstract Background For the year 2018, the French government plans a revision of bioethics laws, including certainly the recent Claeys-Leonetti law introducing the right to deep and continuous sedation at the request of palliative patients and prohibiting euthanasia for end-of-life patients. Because there is no published data on medical staff opposition to a deep and continuous palliative sedation request under Claeys-Leonetti law, we believe this report may give insight into physicians’ decision making, into the role of criteria for prudent practice, and thus contribute to the bioethical debate. Case presentation We report a 70-year-old patient with squamous cell carcinoma of the hypopharyngeal region, who categorically refused any treatment since one year and asked for deep and continuous palliative sedation until death after attempting suicide. The patient’s request was examined and denied by palliative multidisciplinary board, in accordance with by the French Oncology Coordination Centre guidelines. This situation did not fulfil the criteria requested by Claeys-Leonetti law. Conclusions As highlighted by the present case-report, patient’s expectation regarding palliative sedation can be ambivalent with properly so called euthanasia or assisted suicide. This ambivalent perception was part of the controversy surrounding the parliamentary debate, which is still relevant. This case report supports that deep and continuous sedation under Claeys-Leonetti law need to meet specific criteria defined by the law and documented in the medical files as a safeguard against inappropriate practice. In fact, one of the shortcomings of the current arrangements of Claeys-Leonetti law is a lack of objective medical-based criteria. So it is necessary that scientific peer-reviews papers be published quickly in order to deepen the bioethical debate on the end of life

RE: HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1

International audienc

The MonarchE trial: improving the clinical outcome in HR+/HER2− early breast cancer: recent results and next steps

International audienc

RE: NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis

International audienceNo abstract availabl

``Wnt/beta-Catenin in GIST''-Letter

In an article published on September, 2017, in Molecular Cancer Therapeutics, Zeng and colleagues showed that the WNT/beta-catenin oncogenic pathway was activated in a subset of human gastrointestinal stromal tumors (GIST) and that inhibiting its signaling alone or in combination with imatinib has antitumor efficacy in vitro and in vivo in imatinib-sensitive and resistant preclinical models. However, they concluded that ``more investigation is needed to correlate beta-catenin activation with clinicopathologic features in GIST clinical samples.'' Here, we examined the activation score of the beta-catenin pathway in 160 clinically annotated clinical samples of operated primary GISTs. We showed that the beta-catenin activation score, assessed as continuous variable, was heterogeneous across samples. Higher score was associated with certain prognostic clinicopathologic characteristics, including mutational status, tumor size, and AFIP classification, and even more importantly, with more postoperative relapses in uni-and multivariate analyses. Such unfavorable independent prognostic value of beta-catenin activation reinforces the potential therapeutic value of this new target in GIST and nicely complements Zeng's study. (C) 2018 AACR