BACKGROUND:Cemiplimab an anti-programmed cell death receptor-1 antibody, was approved by the FDA and EMA for patients with locally advanced cutaneous squamous cell carcinoma (laCSCC) ineligible for curative surgery/radiotherapy or with metastatic (m) CSCC. TOSCA study evaluated the real-world effectiveness and safety of cemiplimab compared to historical systemic therapies (HSTs). METHODS:TOSCA (NCT05302297) was a large French retrospective, multicenter study comparing patient with la/mCSCC treated with cemiplimab via the early access program (EAP, 2018-2019) or HST (2013-2018). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall response rate (ORR), and safety. Effectiveness analysis using inverse probability weighting included a trial-like cohort of only immunocompetent patients meeting the EAP criteria to emulate a randomized clinical trial; safety analysis included all real-life patients. FINDINGS:The study included 280 real-life patients (cemiplimab: n = 147; HST: n = 133). The primary effectiveness analysis included a trial-like cohort (cemiplimab: n = 129; HST: n = 70; median age: 81 and 78 years, respectively). Median follow-up was 20 and 10 months in the cemiplimab and HST arms, respectively; median OS was 21.2 and 9.8 months, respectively (HR 95% CI: 0.57 [0.45-0.73]; P < 0.0001); median PFS was 13.7 and 5.3 months, respectively (HR [95% CI]: 0.57 [0.43-0.76]; P = 0.0001). Adverse drug reactions occurred in 27% of cemiplimab patients and 33% of HST patients. INTERPRETATION:TOSCA demonstrated better survival and response outcomes for cemiplimab versus HST in la/mCSCC; emphasizing, the importance of this retrospective studie in the absence of standard comparative trials.

BACKGROUND:People living with HIV (PWH) have an increased risk of developing aggressive skin cancers, yet they have been largely excluded from immune checkpoint inhibitor (ICI) trials. Consequently, evidence on the safety and efficacy of ICIs in this population remains scarce, particularly for the nivolumab plus ipilimumab (NIVO+IPI) combination. METHODS:This multicentre, real-world study included PWH treated with ICIs for melanoma or non-melanoma skin cancers. The objective was to evaluate patient characteristics, treatment management, and clinical outcomes across the different skin cancer types. RESULTS:Among the 54 patients, 89% were male, and 92.6% had a suppressed HIV viral load. Melanoma was the most frequent tumour (35/54, 64.8%), followed by cutaneous squamous cell carcinoma (12/54, 22.2%), Kaposi sarcoma (4/54, 7.4%), basal cell carcinoma (2/54, 3.7%), and one Merkel cell carcinoma. Anti-PD-1/PD-L1 monotherapy was given as first-line treatment in 81.5% (44/54). Immune-related adverse events (irAEs) occurred in 42.6% (23/54), with a median onset of 43.5 days (IQR, 20.5-126). The maximum toxicity grade was 1/2 in 39% (21/54), grade ≥ 3 in 13% (7/54). Seventeen melanoma patients received NIVO+IPI. Among them, 64.7% (11/17) experienced irAEs, including grade ≥ 3 events in 30% (5/17). Objective response rates were 43% (9/21) in melanoma, 58% (7/12) in cSCC, and 75% (3/4) in Kaposi sarcoma. CONCLUSIONS:PWH treated with ICIs for skin cancer demonstrated favourable outcomes, with a notably reassuring safety profile of NIVO+IPI. These findings support managing well-controlled PWH similarly to the general population and highlight the importance of including this population across all settings of skin cancer trials.

The prognostic value of BRAF V600 mutation level on clinical outcomes in patients with BRAF V600-mutated metastatic melanoma treated with BRAF and MEK inhibitors remains uncertain. The association was retrospectively analysed between BRAF V600 mutation level (defined as the ratio of the quantification of the BRAF V600 allele to the percentage of tumoral cells in the sample analysed) and progression-free and overall survival (PFS and OS, respectively) and 3-month response rate in a cohort of 58 patients with metastatic melanoma who harboured BRAF V600E/K mutations and received dual targeted-therapy BRAF/MEK inhibitors. The BRAF mutation level cut-off determined by the area under the receiver operating characteristic curve after internal validation by bootstrap methods was 0.44. Risk of poor PFS and OS was associated with BRAF V600 mutation level > 0.44 on multivariate analysis (p = 0.02 and p = 0.02, respectively) after adjusting for major confounding factors (age, sex, lactate dehydrogenase level, brain metastasis, and treatment line). No association was found between BRAF mutation level and 3-month response rate. Our study shows that high BRAF V600 mutation level in melanoma tissue was associated with poor prognosis in patients with metastatic melanoma treated with BRAF and MEK inhibitors.

BACKGROUND:Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported. MATERIALS AND METHODS:By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. RESULTS:We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations. CONCLUSIONS:High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.

9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]

Les chirurgies micrographiques (CM) sont adaptées à l’exérèse des cancers cutanés qui ont une extension de proche en proche et dont l’extension infraclinique est imprévisible. Leur but est d’obtenir une visualisation histologique de la totalité des berges périphériques et leur intérêt principal est de garantir une exérèse complète donc de limiter le risque de récidive. La chirurgie de Mohs est la technique de référence. Elle consiste à prélever des strates successives de tissus qui sont examinées extemporanément après cryocongélation. Son efficacité en termes de diminution du risque de récidive et d’épargne tissulaire est démontrée dans le traitement de certains carcinomes basocellulaires. D’autres techniques avec examen histologique différé sur coupes paraffinées ont été développées. La chirurgie micrographique de Mohs avec inclusion en paraffine et les techniques d’histologie tridimensionnelle du « muffin » ou du « gâteau » permettent une analyse de la totalité des berges tumorales. Les techniques avec découpe en collerette permettent une analyse des berges latérales uniquement. Ces techniques sont plus faciles à mettre en œuvre y compris dans le cadre d’un exercice libéral et leur intérêt carcinologique a été rapporté dans plusieurs études non contrôlées. L’objectif de cet article est de faire une description pratique étapes par étapes des différentes techniques de CM et de rappeler leurs principales indications.

BACKGROUND:Clinical outcomes of advanced melanoma of unknown primary (MUP) in the era of novel therapies have been scarcely studied.OBJECTIVE:To investigate the efficacy and safety of systemic treatments in patients with advanced MUP compared to patients with stage-matched melanoma of known cutaneous primary (cMKP).METHODS:Based on the nationwide MelBase prospective database, this study included advanced melanoma patients treated from March 2013 to June 2021 with first-line immunotherapies, targeted therapies, or chemotherapy. Co-primary outcomes were progression-free survival and overall survival. Secondary outcome was treatment-related toxicities. Multivariate and propensity score analyses were performed.RESULTS:Of 1882 patients, 265 (14.1%) had advanced MUP. Patients with advanced MUP displayed more often unfavorable initial prognostic factors than those with cMKP. Progression-free and overall survival did not differ significantly between the groups (P = .73 and P = .93, respectively), as well as treatment-related toxicity rate and severity, regardless of treatment type.LIMITATIONS:No record of standard diagnostic criteria of MUP used in the participating centers.CONCLUSIONS:Although patients with MUP had less favorable baseline prognostic factors, they benefited from the novel therapies as much as those with cMKP. They should be managed according to similar strategies.

e21534 Background: Despite the approval of effective therapies in metastatic melanoma, durable benefit concerns only a fraction of patients and new therapeutic options are still needed. Next generation sequencing is now widely available to screen for targetable genomic alterations. Clinical impact of personalized medicine strategies in melanoma, outside classical targeting, have little been reported yet. Methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all metastatic melanoma patients, aged 18 and over, for whom a molecular testing has identified one, or more, actionable molecular alterations and who received molecularly matched therapy accordingly, between 2018 and 2022. We excluded patients with only BRAF, NRAS or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Response was evaluated using RECIST 1.1 criteria. Results: We included 26 patients, median age was 63 years [24-89] and sex ratio 2.7. They had been heavily pretreated (58% have received 3 or more previous lines of treatment); 77% had 3 or more metastatic sites; 58% elevated LDH levels; and 42% and 35% had brain and liver metastasis respectively; 69 % had an ECOG PS 0 or 1. Actionable molecular alterations affected MAP kinase pathway in 12/26 cases: 10 of them received trametinib for GNA11 mutations (n = 4), MAP2K1 mutations (n = 2), CBL mutation (n = 1), NF1 loss (n = 1), FYCO1-RAF1 fusion (n = 1) and KRAS amplification (n = 1) while tipifarnib was given for an HRAS mutation and sunitinib for a CBL mutation. Cell cycle pathway was targeted in 7/26 cases with abemaciclib for a CDKN2A/B mutation, palbociclib for CDKN2A deletion, ribociclib and binimetinib for concurrent loss of CDKN2A and NRAS mutations (n = 2) and siremaldin and ribociclib for CCND1 amplification and MDM2/ CDK4 amplification (n = 2). PIK3CA pathway was targeted with alpelisib (n = 1) and with sirolimus for 1 PTEN mutation. EGFR, ALK and MET mutations were targeted using afatinib, alectinib and cabozantanib respectively. BRCA spectrum ( ATM and BRCA1) was targeted with olaparib in 2 patients in combination with dabrafenib and trametinib for one patient who had relapsed under this therapy. 11/26 patients responded to this molecularly matched strategy with 4 partial responses and 7 stable diseases including 5 ≥ 6 months stable diseases, with a median follow-up of 8 months [1-54]. Among responders, median duration of response was 6.5 months [2.5-13] and 3 are still ongoing. Responding patients had GNA11 (n = 2), MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1 (n = 2), MDM2/ CDK4 and CDKN2A/NRAS (n = 2) alterations. Conclusions: High throughput sequencing followed by matched targeted therapy is a promising approach in metastatic melanoma patients refractory to approved treatments, underlying the importance of access to molecular testing and molecular tumor boards.

Samaran, Quentin MD*,†; Stoebner, Pierre-Emmanuel MD, PhD†,‡; Ovtchinnikoff, Bernadette MD†,‡ Author Information

Objective To quantify the risk of immune-related adverse events (irAEs) in patients with pre-existing autoimmune disease (pAID) treated by immune checkpoint inhibitors (ICIs) for stage III or IV melanoma. Methods Case-control study performed on a French multicentric prospective cohort of patients with melanoma, matched for irAE risk factors and oncological staging. Risk of irAE was assessed by logistic regression. Results 110 patients with pAID were included and matched with 330 controls, from March 2013 to October 2020. Over a median follow-up period of 7.2 months for cases and 6.9 months for controls, the ORs of developing all-grade and grade >= 3 irAEs among cases compared with controls were 1.91 (95% CI (1.56 to 2.27)) and 1.44 (95% CI (1.08 to 1.82)), respectively. Patients with pAID had an increased risk of multiple irAEs (OR 1.46, 95% CI (1.15 to 2.67)) and a shorter time to irAE onset. In contrast, there were no difference in irAE-related mortality nor in the rate of treatment discontinuation, and a landmark analysis revealed a better survival at 24 months among cases (p=0.02). Thirty per cent of cases experienced a pAID flare during follow-up, and baseline immunosuppression did not prevent irAE occurrence. Last, we report associations between the pAID clinical subsets and organ-specific irAEs. Conclusion In our study, patients with pAID were at greater risk of all-grade, severe and multiple irAEs, yet had a better 24-month survival than controls. Thus, patients with pAID should be eligible for ICI therapy but benefit from a close monitoring for irAE occurrence, especially during the first months of therapy.

Proteasomes are major non-lysosomal proteolytic complexes localized in the cytoplasm and in the nucleus of eukaryotic cells. Strikingly, high levels of extracellular proteasome have also been evidenced in the plasma (p-proteasome) of patients with specific diseases. Here, we examined the process by which proteasomes are secreted, as well as their structural and functional features once in the extracellular space. We demonstrate that assembled 20S core particles are secreted by cells within microvesicles budding from the plasma membrane. Part of the extracellular proteasome pool is also free of membranes in the supernatant of cultured cells, and likely originates from microvesicles leakage. We further demonstrate that this free proteasome released by cells (cc-proteasome for cell culture proteasome) possesses latent proteolytic activity and can degrade various extracellular proteins. Both standard (no immune-subunits) and intermediate (containing some immune-subunits) forms of 20S are observed. Moreover, we show that galectin-3, which displays a highly disordered N-terminal region, is efficiently cleaved by purified cc-proteasome, without SDS activation, likely after its binding to PSMA3 (α7) subunit through its intrinsically disordered region. As a consequence, galectin-3 is unable to induce red blood cells agglutination when preincubated with cc-proteasome. These results highlight potential novel physio- and pathologic functions for the extracellular proteasome.

9556 Background: Melanoma of unknown primary (MUP) account for 3% of all melanomas. Clinical outcome of advanced MUP in the era of novel therapies including immunotherapies (ICI) and targeted therapies (TT) have been only scarcely studied, whereas a possibly different biologic background might introduce changes in its management. Recent retrospective studies suggested that patients with advanced MUP could benefit at least as much from novel therapies as patients with known primary cutaneous melanoma (cMKP). Methods: Based on the nationwide MelBase prospective database (NCT02828202) this retrospective study included patients with advanced melanoma treated with first-line ICI, TT or CT. MUP was defined by upfront occurrence of (sub)cutaneous, nodal and/or visceral metastasis without any known prior or concomitant primary tumor. Patients with primary mucosal or ocular melanoma were excluded. Both progression-free survival (PFS) and overall survival (OS) were analyzed as co-primary variables in MUP vs cMKP, stratified by treatment subset (ICI vs TT vs CT vs whole cohort). Secondary variable was treatment-related toxicity. Multivariate analyses and propensity score analysis were performed. Objective: To investigate the efficacy and safety of systemic treatments (ICI, TT and chemotherapy (CT)) in patients with advanced MUP comparatively to stage-matched cMKP. Results: A total of 1882 patients were analyzed, including 265 (14.1%) MUP. Most patients were treated with first-line ICI. Median follow-up was 16 months. Patients in the MUP cohort more often displayed unfavorable initial prognostic factors (Table). PFS and OS did not significantly differ in MUP compared to MKP patients (p=0.73 and p=0.93 respectively). Stratification of cohorts by treatment type and application of propensity score did not lead to data modification. Treatment-related toxicity rate and severity did not differ between MUP and MKP, regardless of treatment type. Conclusions: Our results suggest that advanced MUP should be managed with similar strategies as advanced MKP. In our cohort, MUP patients benefited from novel therapies as much as MKP patients despite less favorable baseline prognostic factors. Exploratory studies investigating mutational burden and host immunity are needed to identify the underlying mechanisms. [Table: see text]

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated and wild-type patients. A multistate model was developed to describe treatment sequences, associated costs, and health outcomes over 10 years. Sequences, clinical outcomes, utility scores, and economic data were extracted from the prospective Melbase cohort, collecting individual data in 1518 patients since 2013, from their AM diagnosis until their death. To adjust the differences in patients' characteristics among sequences, weighting by inverse probability was used. In the BRAF-mutated population, the MONO-targeted therapies (TT)-anti-PD1 sequence was the less expensive, whereas the anti-PD1-BI-TT sequence had an incremental cost-effectiveness ratio (ICER) of 180,441 EUR/QALY. Regarding the BRAF wild-type population, the three sequences constituted the cost-effective frontier, with ICERs ranging from 116 to 806,000 EUR/QALY. For BRAF-mutated patients, the sequence anti-PD1-BI-TT appeared to be the most efficient one in BRAF-mutated AM patients until 2018. Regarding the BRAF wild-type population until 2018, the sequence starting with IPI+NIVO appeared inefficient compared to anti-PD1, considering the extra cost for the QALY gained.

PURPOSE:Mitogen-activating protein kinase inhibitors (MAPKis) are largely used in V600E/K BRAF-mutated metastatic melanomas, but data regarding effectiveness of targeted therapy in patients with rare BRAF mutations and molecular description of these infrequent mutations are scarce.PATIENTS AND METHODS:A multicenter study was conducted on patients with metastatic melanoma harboring a well-identified mutation of BRAF and enrolled from March 2013 to June 2021 in the French nationwide prospective cohort MelBase. The molecular BRAF mutation pattern, response to MAPKis when applicable, and survival data were analyzed.RESULTS:Of 856 selected patients, 51 (6%) harbored a non-V600E/K BRAF mutation involving codons V600 (24 of 51, 47%; V600G 27.4%, V600R 15.6%), K601 (6 of 51, 11.7%), and L597 (4 of 51, 7.8%). An objective response to MAPKis either BRAF inhibitor (BRAFi) alone or combined with MEK inhibitor was achieved in 56% (353 of 631) of V600E/K, 58% (11 of 19) of non-E/K V600, and 22% (2 of 9) of non-V600 BRAF-mutated patients, with a median progression-free survival of 7.7, 7.8, and 2.8 months, respectively. Overall, objective response rate was higher with BRAFi + MEK inhibitor combination than with BRAFi in monotherapy for each subset.CONCLUSION:Rare BRAF mutations are not anecdotal in the metastatic melanoma population. Although data interpretation must remain careful owing to the limited size of some subsets of patients, non-E/K V600 BRAF mutations seem to confer a high sensitivity to targeted therapy, whereas MAPKis seem less effective in patients with non-V600 BRAF mutations. However, this strategy may be used as an alternative option in the case of immunotherapy failure in the latter population.

Anti-PD1 agents are currently recommended as first-line treatment in advanced cutaneous squamous cell carcinoma (acSCC) by updated European guidelines. Although acSCC frequently affects elderly patients with multiple comorbidities, this subset of patients is often excluded of registration clinical trials. To assess anti-PD-1 efficacy and safety in elderly acSCC patients in real-life conditions and describe this specific population with oncogeriatric evaluation tools. A multicenter retrospective study including acSCC patients at least 70 years old treated with PD-1 inhibitors was conducted in French referral centers. The primary endpoint was the overall response rate (ORR). Secondary endpoints included safety data, time to response (TTR), duration of response (DOR), overall survival (OS), and progression-free survival (PFS). 63 patients were included. ORR was 57.1

L'épidémie COVID-19 a contraint enseignants et étudiants à s'adapter rapidement à des modes d'enseignements « distanciels ». Le format « visioconférence » s'est généralisé à tous les enseignements, de la formation initiale jusqu'aux congrès virtuels. Ces roues de secours, que nous pensions transitoires, ont modifié nos pratiques pendant plus d'un an : que faut-il en retenir pour notre enseignement ? Notre objectif était d'évaluer auprès des enseignants et des internes de dermatologie, leur expérience numérique au cours de l'épidémie. Entre le 10 et le 21/05/2021, une enquête par questionnaires, destinée aux enseignants et aux internes, a porté sur les thématiques suivantes: expériences en enseignement « visio »; aspects techniques; ressenti pédagogique. Les questionnaires ont été envoyés par un lien GoogleForm aux mailing-listes « enseignants » et « internes » du CEDEF; les réponses étaient anonymes. Les taux de participation étaient de 50 répondants/106 enseignants (47 %) et de 120 répondants/453 internes (26 %). La majorité des enseignants avait participé à de multiples enseignements en « visio » (cours DFASM 96%, congrès 84 %, réunion DES 70 %, cours DES 58 %, DU/DIU 56 %, EPU 60 %) et était autonome pour la "visio" (cours DFASM et DES 78 %, réunion DES 58 %, EPU 56 %). Le logiciel Zoom était utilisé par la majorité (90 %) des enseignants et des internes. La connexion restait problématique au CHU pour plus de 80 % des répondants. La « simplicité d'utilisation » était la qualité prioritaire d'un logiciel « visio ». Une majorité des enseignants estimait que les cours de DES (54 %) et les réunions de DES (52 %) pourraient être pérennisés en distanciel, tandis que les internes estimaient que les DU/DIU (56 %), les cours de DES (57 %), les réunions de DES (56 %) et les séminaires du CEDEF (61 %) pourraient être maintenues « en visio » après la pandémie. Seuls 3% des internes estimaient qu'aucun cours ne devrait être maintenu en "visio" contre 14% des enseignants (p = 0,03). Le format « hybride » des futurs congrès était plébiscité par la majorité (> 70 %) des répondants. L'expérience COVID a servi de catalyseur à un nouveau mode d'enseignement, pour lequel les enseignants ont acquis une expérience diversifiée et une certaine autonomie. Les enseignants sont plus réticents que les étudiants au maintien de formats « visio » en post-COVID, ces derniers privilégiant le format « visio » pour de nombreuses formes d'enseignements. Ainsi, la digitalisation de certains séminaires du CEDEF permet une accessibilité à un plus grand nombre et un suivi personnalisé du parcours de l'étudiant. Le présentiel reste privilégié pour les formations post-universitaires, les solutions « hybrides » permettant de combiner les avantages des deux formats.

Les léiomyosarcomes cutanés (cLMS) sont des tumeurs malignes de différenciation musculaire lisse et de topographie superficielle, dermique ou hypodermique. Du fait de leur rareté, le pronostic des cLMS est encore débattu. À ce jour, il n'existe aucune étude moléculaire somatique portant sur les cLMS. L'objectif principal de notre étude était de réaliser la plus grande collection française de données cliniques et histologiques de lcLMS et d'étudier les facteurs associés à la survie globale (SG) et sans récidive (SSR). L'objectif secondaire était d'analyser ces tumeurs sur le plan moléculaire. Il s'agit d'une étude rétrospective menée de janvier 2000 à juin 2019, multicentrique issue de 4 centres experts de dermatologie (Nice, Montpellier, Lyon, Nîmes). Les caractéristiques démographiques et clinico-histologiques et les données de survie ont été collectées. SG et SSR ont été analysées selon la méthode de Kaplan-Meier. Les analyses moléculaires suivantes ont été réalisées : analyse quantitative pan-génomique et séquençage de nouvelle génération ciblé à partir d'ADN et d'ARN extraits des tissus tumoraux. Un total de 79 cLMS ont été inclus, dont 57 (72 %) d'hommes ; l'âge médian au diagnostic était de 70 ans (57–79 ans). La durée médiane de suivi était de 39 mois. Les taux estimés de SG et SSP à 24 mois étaient respectivement de 92 % et 77 %. Parmi les facteurs pronostiques, un grade histopronostique intermédiaire ou élevé selon la FNCLCC (grade II-III) était significativement associé à la survenue de récidives locales ou métastatiques (HR 4,8 ; 95 %IC [1,6–14,6] ; p = 0,01). Les localisations des métastases étaient osseuses (n = 3), cutanées (n = 2), coliques (n = 1), lymphatiques (n = 1) et hépatiques (n = 1). En cas de récidive (n = 9/42), les marges de résection cliniques étaient significativement moins larges (1,06 vs 1,80 cm, p = 0,03). Onze cas ont été étudiés au niveau moléculaire avec identification de trois types de profils : sans aucune anomalie quantitative (n = 4), une seule anomalie quantitative (n = 3) et profils complexes avec plus de 10 anomalies quantitatives (n = 4). Les gènes les plus fréquemment altérés étaient RB1, TP53 et MYOCD. Deux cas présentaient des mutations ponctuelles du gène TP53. Le pronostic des cLMS est variable avec un risque non négligeable de récidive locale ou à distance qui est particulièrement associé à un grade histopronostique intermédiaire ou élevé (II-III). Nos résultats suggèrent que des marges de résection à 2 cm et un suivi à long terme doivent être recommandés dans ces situations. De plus, nous avons identifié un sous-groupe de cLMS avec profil moléculaire « agressif » dont l'association éventuelle avec une évolution plus péjorative nécessite une analyse prospective.

Cutaneous melanoma is the most lethal type of skin cancer. Early detection is crucial to improve the outcome of melanoma patients. The identification of noninvasive prognostic biomarkers for the follow-up of melanoma patients is still in demand for clinical use. We show here that exosomal melanotransferrin fulfills the biomarker characteristics required to meet this demand. Melanotransferrin is typically overexpressed in melanoma cells compared to other cell types - including cancer cells - and is efficiently sorted and secreted with nanovesicles, or so-called exosomes, due to its membrane-anchoring by a glycosylphosphatidylinositol. Melanotransferrin is exposed on the surface of exosomes and is accessible for antibody recognition. An ELISA was set up to quantify melanotransferrin after immobilization of nanovesicles through the exosomal constituent tetraspanins CD63. Melanotransferrin was detected using a low number of exosomes purified from melanoma cell line cultures, and melanotransferrin detection was abolished by phosphatidylinositol-specific phospholipase C treatment. This exosomal melanotransferrin ELISA was able to discriminate an equal number of assayed exosomes purified from two different melanoma cell lines (A-375 vs. SK-MEL-28). Moreover, plasma samples from patients with melanoma and noncancer disease were assayed using this ELISA and elevated levels of exosomal melanotransferrin were seen in the plasma of patients with melanoma. We propose that exosomal melanotransferrin should be assessed as a potential melanoma biomarker.

La chirurgie micrographique de Mohs (CMM) « classique » permet l'exérèse des cancers cutanés avec contrôle anatomopathologique extemporané de 100 % des berges tumorales. Elle est peu pratiquée en France en raison de difficultés logistiques qui pourraient être résolues en partie par une semi-automatisation de la lecture anatomopathologique. L'objectif de notre travail était d'élaborer un algorithme d'intelligence artificielle (IA) performant capable de localiser les foyers de carcinome basocellulaire (CBC) au sein de lames histologiques de CMM via un réseau neuronal convolutif (RNC). Les lames issues des procédures CMM réalisées dans notre centre entre 2016 et 2021 étaient incluses puis numérisées (grossissement x20). Les foyers de CBC étaient délimités manuellement via le logiciel Qupath. Les limites étaient systématiquement vérifiées par un anatomopathologiste compétent en CMM. Les images tissulaires de 71 lames issues de 49 patients étaient découpées en patchs de 256 × 256 pixels (200 × 200 μm). Le nombre de patchs était démultiplié (rotations, color augmentation). 106 567 patchs étaient obtenus; 7972 contenant du CBC formaient la classe « pathologique », 98595 formaient la classe « sain ». Ces patchs constituaient la base d'entraînement du RNC (Resnet-34). 10 lames issues de 10 patients différents formaient la base de test. 13 602 patchs tissulaires étaient automatiquement extraits puis classifiés par le RNC pré-entraîné. Premièrement, on déterminait un seuil de classification sain/pathologique pour que notre modèle soit cliniquement performant. Puis, la qualité de superposition des foyers de CBC prédits par le RNC et la vérité terrain était évaluée. Le principe de la métrique était que chaque foyer était considéré localisé si l'algorithme trouvait au moins un patch pathologique en son sein. L'AUC-ROC de notre algorithme était de 0,9787. Avec le seuil optimal cliniquement pertinent déterminé à 0,21, le RNC classait correctement 12945/13602 patchs (VP= 1171, FN = 293, FP = 364, VN = 11774) soit une Se de 0,80, une Sp de 0,97, une VPP de 0,76, une VPN de 0,98. Mais les patchs classés comme FN contenaient peu de CBC (7,4 % en moyenne), ils correspondaient majoritairement à des patchs en bordure de foyer tumoral. Pour les 10 lames de test, l'approche métrique permettait de localiser correctement 212/214 foyers, (FN = 2, FP = 67). Soit une Se de 0,99 et une VPP de 0,75. Les foyers FP avaient une taille moyenne de 1,4 patchs vs. 4,3 patchs pour les VP. Par sa bonne sensibilité, notre algorithme ouvre la voie de la CMM assistée par IA. Ses performances pourront être améliorées en augmentant la base d'apprentissage par un recrutement multicentrique, en intégrant plus de sous-types histologiques rares (sclérodermiformes) et avec les améliorations technologiques dont bénéficieront les RNC.