Introducing mathematical modelling of kinetics into the therapeutic decision

Background Evolution of metastatic melanoma (MM) under B-RAF inhibitors (BRAFi) is unpredictable, but anticipation is crucial for therapeutic decision. Kinetics changes in metastatic growth are driven by molecular and immune events, and thus we hypothesized that they convey relevant information for decision making. Patients and methods We used a retrospective cohort of 37 MM patients treated by BRAFi only with at least 2 close CT-scans available before BRAFi, as a model to study kinetics of metastatic growth before, under and after BRAFi. All metastases (mets) were individually measured at each CT- scan. From these measurements, different measures of growth kinetics of each met and total tumor volume were computed at different time points. A historical cohort permitted to build a reference model for the expected spontaneous disease kinetics without BRAFi. All variables were included in Cox and multistate regression models for survival, to select best candidates for predicting overall survival. Results Before starting BRAFi, fast kinetics and moreover a wide range of kinetics (fast and slow growing mets in a same patient) were pejorative markers. At the first assessment after BRAFi introduction, high heterogeneity of kinetics predicted short survival, and added independent information over RECIST progression in multivariate analysis. Metastatic growth rates after BRAFi discontinuation was usually not faster than before BRAFi introduction, but they were often more heterogeneous than before. Conclusions Monitoring kinetics of different mets before and under BRAFi by repeated CT-scan provides information for predictive mathematical modelling. Disease kinetics deserves more interes

HVEM has a broader expression than PD-L1 in melanoma and constitutes a pejorative prognostic marker and potential treatment target for melanoma

HVEM est une molécule exprimée à la surface des mélanomes (M) qui pourrait contribuer à la croissance tumorale en se liant à BTLA, un co-récepteur inhibiteur exprimé par les lymphocytes T infiltrants les tumeurs (TILs). Nos objectifs étaient 1-d’explorer la valeur pronostique de l’expression d’HVEM par les M; 2-de confirmer l’existence d’une interaction HVEM/BTLA in vivo à l’interface mélanome-TILs; 3- de comprendre les mécanismes de régulation d’HVEM..Méthodes: L’expression d’HVEM a été analysée par immunohistochimie et corrélée à la survie globale des patients. Ces résultats ont été renforcés par l'étude de données transcriptomiques du TCGA. L’analyse de l’expression d’HVEM à la surface des cellules de M et de BTLA à la surface des TILs a été réalisée par cytométrie en flux et co-immunoflorescence afin de confirmer l’existence d’interactions HVEM-BTLA in vivo. Enfin, les mécanismes de régulation d’HVEM ont été explorés par des analyses bio-informatiques couplées à des techniques de siRNA.Résultats : Les patients ayant une expression élevée d’HVEM par leur M avaient une survie globale significativement plus réduite que ceux ayant une expression faible d’HVEM à la fois en immunohistochimie (p= 0,0124) et en transcriptomique (p=0,0282).D’un point de vue mécanistique: HVEM exprimé par les M interagissait avec BTLA exprimé par les TILs et l’expression d’HVEM n’était ni liée au statut mutationnel, ni induite par l’interféron gamma . Nous avons également montré que les gènes co-exprimés avec HVEM formaient une signature d’agressivité et que MITF contrôlait l’expression d’HVEM.Conclusion : HVEM ou BTLA pourraient être des cibles thérapeutiques de choix dans le M.Purpose: Upon engagement with HVEM, BTLA triggers inhibitory signals in T cells. Using melanoma, we correlated HVEM expression with clinical outcomes and confirmed the occurrence of HVEM-BTLA interaction inside melanoma. Moreover, we determined regulatory mechanisms accounting for the complementary pattern of expression we observed for HVEM and PD-L1.Experimental design: HVEM expression levels were analyzed by immunohistochemistry in melanoma metastases and correlated with overall survival (OS). Coincident expression of HVEM and its ligand BTLA was studied in tumor cells and tumor-infiltrated-lymphocytes (TILs) by flow cytometry and co-immunofluorescence. Candidate genes controlling HVEM expression on melanoma were defined by bioinformatics studies and validated by siRNA.Result: Patients with high HVEM expression on melanoma cells had a significantly poorer OS than those with a low expression as documented by immunohistochemistry (p=0.0124) and TCGA (p=0.0282). From a mechanistic point of view, we showed (1) that HVEM expressed at the surface of melanoma cells interacts with BTLA expressed by TILs, (2) that HVEM expression is neither linked to the melanoma mutational status nor inducible by IFN 3) that genes co-expressed with HVEM are associated with an aggressive gene signature, and (4) that MITF controls HVEM expression.Conclusion: In contrast to PD-L1, HVEM expression is constitutive and correlated with the expression of genes involved in aggressive features. Therefore, high HVEM expression on melanoma cells is a pejorative prognostic marker, substantiating the use of checkpoint inhibitors directed at HVEM and BTLA in the treatment of melanom

Safety and immunogenicity after 2 doses of the BNT162b2 COVID-19 vaccine in an early-phase oncology trial centre population

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Long-term treatment of cutaneous manifestations of tuberous sclerosis complex with topical 1% sirolimus cream: A prospective study of 25 patients

International audienceBACKGROUND:Data on long-term topical sirolimus treatment of the cutaneous manifestations of tuberous sclerosis complex are rare.OBJECTIVE:To evaluate the long-term benefit and tolerance of topical 1% sirolimus in tuberous sclerosis complex.METHODS:In this 18-month prospective single-center study, 1% sirolimus cream was applied daily to facial angiofibromas (FAs), fibrous cephalic plaques (FCPs), shagreen patches, hypomelanotic macules, and ungual fibromas. After complete clearance (CC) of FAs, we evaluated a maintenance protocol of 3 applications weekly.RESULTS:Twenty-five patients were enrolled. Fifty percent obtained CC of FAs within 9 months. Of 7 patients with CC (58%) who were following the maintenance protocol, 6 relapsed within 7 months and 1 was still responding at 1 year. Of 16 patients with FCPs, 7 (44%) remained stable at 12 months and 9 (56%) improved after 3 to 9 months of treatment. Only 1 of 5 patients treated for shagreen patches showed improvement at 12 months. Treatment was well tolerated with no serious adverse events.LIMITATIONS:The small number of patients was a limitation.CONCLUSIONS:Topical 1% sirolimus applied daily produced positive responses in treatment of FAs, FCPs, and facial hypomelanotic macules and was well tolerated. A 3-times-weekly maintenance protocol did not prevent FA relapses

Évolution du statut braf dans le melanome : mythe ou Réalité ?

International audienceKnowledge of the BRAF mutational status has become essential for melanoma therapeutic management. B-Raf inhibitors are associated with significant overall survival in patients with BRAFV600-mutated metastatic melanoma. Although the BRAF mutation appears to be an early and driver mutation, some authors hypothesized that its expression was not stable during melanoma progression, suggesting a molecular heterogeneity. This argument is often used to explain discrepancy in molecular status among patients with melanoma, discrepancies that we occasionally met during our practice. We retrospectively compared BRAF mutational status on matched melanoma samples (primary & metastatic lesions), thus 150 samples from 56 patients were analysed through immunohistochemistry anti-BRAF, PCR-HRM and Sanger sequencing, Next Generation Sequencing (NGS) and digital PCR. Seven cases presented an apparent tumor heterogeneity. The analysis of these discrepancies by a technique of increasing sensitivity made it possible to identify 1 false-negative result for the immunohistochemistry, 1 false-negative result for the NGS sequencing and 5 (3%) false-negative results by PCR-HRM SANGER. Our results are consistent with the most recent data, demonstrating the stability of the BRAF mutation during the course of melanoma. Immunohistochemistry shows excellent sensitivity for detecting the main BRAF mutation. In our study, the mutational heterogeneity was actually misleading, a result of imperfect sensitivity of some older molecular approaches.La connaissance du statut mutationnel du gène BRAF est devenue essentielle dans la prise en charge du mélanome. Les inhibiteurs de B-Raf sont à l’origine d’une nette amélioration de la survie globale chez les patients présentant un mélanome métastatique muté BRAF V600. Bien que la mutation BRAF soit considérée comme un événement précoce et conducteur (driver), certains travaux ont émis l’hypothèse qu’elle n’était pas stable lors de l’évolution d’un mélanome, impliquant une hétérogénéité moléculaire. Cet argument est souvent utilisé pour expliquer les discordances de statut moléculaire observées chez certains patients atteints de mélanome, discordances occasionnellement rencontrées au cours de notre pratique. Nous avons rétrospectivement comparé le statut mutationnel du gène BRAF sur plusieurs prélèvements appariés de mélanome (primitif & localisations secondaires), soit 150 prélèvements pour 56 patients, en utilisant l’immunohistochimie anti-BRAF, la PCR-HRM et séquençage Sanger, le séquençage massivement parallèle (NGS) et la PCR digitale. Sept cas présentaient une apparente hétérogénéité tumorale. L’analyse de ces discordances par une technique de sensibilité croissante a permis d’identifier 1 résultat faux-négatif pour l’immunohistochimie, 1 résultat faux-négatif pour le séquençage NGS et 5 (3 %) résultats faux-négatifs par technique PCR-HRM SANGER. Nos résultats sont cohérents avec les données les plus récentes, témoignant de la stabilité de la mutation BRAF au cours de l’évolution d’un mélanome. L’immunohistochimie présente une sensibilité excellente pour détecter la mutation majoritaire de BRAF. Dans notre étude, l’hétérogénéité mutationnelle était en réalité factice, conséquence d’une sensibilité imparfaite de certaines approches moléculaires plus anciennes

Macrophage activation syndrome: A new complication of checkpoint inhibitors

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Symmetrical Intertriginous and Flexural Exanthema due to Bortezomib (a Proteasome Inhibitor) Given for Myeloma

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Cross-cultural adaptation into French and validation of the SCAR-Q questionnaire

International audiencePurpose: Most questionnaires designed to evaluate patient-reported outcomes regarding scarring are available in English. The objective was to generate a validated French version of the SCAR-Q questionnaire.Methods: The SCAR-Q questionnaire (including Appearance, Symptom and Psychological impact scales) was translated into French using a translation-back-translation process in accordance with international guidelines (ISPOR and WHO). For validation, two hundred patients consulting in our tertiary center completed the questionnaire. We tested scale reliability (Cronbach's α), floor/ceiling effects and item redundancy (inter-item correlations). Structural validity was tested using confirmatory factor analysis (CFA) with the robust weighted least squares (WLSMV) estimator and Delta parameterization. Model fit was examined using the root mean square error of approximation (RMSEA), the comparative fit index (CFI) and the Tucker-Lewis index (TLI). Correlations between scales and scale repeatability were tested (Spearman coefficient, Intra-class-coefficient).Results: Four steps were required to obtain a translation consistent with the original version. Two hundred patients completed the questionnaire for validation. Internal consistency analysis found Cronbach's alphas > 0.7 for all scales (0.90 < α < 0.97). No floor or ceiling effect was found for all items (max = 85%). A ceiling effect was observed for all scales. Appearance and psychosocial impact scale items showed redundancy, with many inter-item correlations above 0.7. The CFA of the original structure displayed a reasonable fit, with RMSEA = 0.065, CFI = 0.974 and TLI = 0.972. Scales were positively correlated (0.45 < ρ < 0.65; p < 0.001). Test-retest intra-class correlation coefficients ranged from 0.94 to 0.99 for all scales.Conclusion: A French version of the SCAR-Q questionnaire is validated, ready for use

Surgery of small bowel melanoma metastases in the era of efficient medical therapies

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