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The article presents a study of the characteristics of anti-PD1-induced psoriasis. Topics include 21 cases of inducted or exacerbated psoriasis in patients on anti-PD1 (programmed cell death protein 1) chemotherapy, risk of developing psoriasis with anti-PD1 with history of psoriasis, and use of topical treatments, steroids and vitamin D analogues.

Introduction Les Inhibiteurs de checkpoints (ICP) ont révolutionné le traitement de plusieurs cancers (mélanome, lymphomes, cancer pulmonaire). Cependant, les essais cliniques ayant conduit à leur utilisation en pratique clinique ont toujours exclu les patients greffés d’organe solide devant le risque de rejet. Néanmoins, les patients greffés ont un risque accru de développer un cancer à cause des traitements immunosuppresseurs et des infections à virus oncogènes. Il existe quelques cas cliniques d’utilisation des ICP chez les patients greffés rénaux avec un taux de rejet bas (4 patients sur 9) [1]. Devant le potentiel biais de publication des cas cliniques, nous avons recensé l’ensemble des patients greffés rénaux traités par ICP en France et en Belgique afin de d’évaluer les effets des ICP chez cette population. Patients/Matériels et méthodes Ont été inclus les patients greffés rénaux traité par ICP avec une survie du patient et/ou du greffon d’au moins 8 jours après le début du traitement. Les centres de transplantation rénale ont été contactés pour recenser les différents cas et le CRF a été rempli par le néphrologue et/ou l’oncologue référent. Observation/Résultats Nous avons identifié 7 patients en France et en Belgique. Ces patients ont été traité par un anticorps anti-CTLA4 (n = 1) ou anti-PD1/PD-L1 (n = 6) pour un mélanome (n = 4), un carcinome pulmonaire (n = 2) ou un carcinome à cellules de Merckel (n = 1). Après l’utilisation du ICP, 3 patients ont présenté un rejet, en moyenne 2 mois après la première utilisation. Tous ces rejets ont été traités par bolus de corticoïdes et arrêt de l’ICP, 2 patients ont finalement perdu leur greffon avec retour en dialyse. Tous les patients n’ayant pas fait de rejet (n = 4) avaient une corticothérapie au moment de l’utilisation du ICP contrairement aux autres. Finalement, la réponse oncologique est faible (n = 1) et 5 patients sont décédés de la progression tumorale. Discussion Notre série est la première concernant l’utilisation des ICP chez les greffés rénaux. Le taux de rejet est assez bas (43 %) avec un possible effet protecteur de la corticothérapie. En associant les observations de notre série avec les autres cas cliniques publiés, on observe qu’aucun patient traité par un anti-CTLA4 n’a présenté de rejet (n = 4) contrairement aux patients (58 %, n = 7/12) traité par un anti-PD1/PD-L (seul ou en association à un anti-CTLA4). Conclusion Des registres prospectifs et/ou des études cliniques sont nécessaires afin d’évaluer le rapport bénéfice/risque de l’utilisation des ICP chez ces patients. [ABSTRACT FROM AUTHOR]

Abstract Purpose Since 2011, significant progress was observed in metastatic melanoma (MM), with the commercialisation of seven immunotherapies or targeted therapies, which showed significant improvement in survival. In France, in 2004, the cost of MM was estimated at €1634 per patient; this cost has not been re-estimated since. This study provided an update on survival and cost in real-life clinical practice. Methods Clinical and economic data (treatments, hospitalisations, radiotherapy sessions, visits, imaging and biological exams) were extracted from the prospective MelBase cohort, collecting individual data in 955 patients in 26 hospitals, from diagnosis of metastatic disease until death. Survival was estimated by the Kaplan-Meier method. Costs were calculated from the health insurance perspective using French tariffs. For live patients, survival and costs were extrapolated using a multistate model, describing the 5-year course of the disease according to patient prognostic factors and number of treatment lines. Results Since the availability of new drugs, the mean survival time of MM patients has increased to 23.6 months (95% confidence interval [CI] :21.2;26.6), with 58% of patients receiving a second line of treatment. Mean management costs increased to €269,682 (95% CI:244,196;304,916) per patient. Drugs accounted for 80% of the total cost. Conclusion This study is the first that evaluated the impact of immunotherapies and targeted therapies both on survival and cost in real-life conditions. Alongside the introduction of breakthrough therapies in the first and subsequent lines, MM has been associated with a significant increase in survival but also in costs, raising the question of financial sustainability. Highlights • This study updates the survival and cost of advanced melanoma since the arrival of targeted therapies and immunotherapies. • Costs were calculated using individual data prospectively collected from the MelBase cohort in real-life conditions. • Mean survival time of patients with MM was estimated at 23.6 months, for a mean cost estimated at €269,682 per patient. [ABSTRACT FROM AUTHOR]

Background: Mycosis fungoides (MF) has usually an indolent course. However, some patients develop a more aggressive disease and few prognostic parameters have been identified. Isolated cases of pustular MF (pMF) suggest an unfavourable prognosis., Objectives: We aim to describe the clinico-pathological characteristics and prognostic value of pMF., Methods: We retrospectively collected data of all cases of MF with histological pustules diagnosed from 2009 to 2020. The outcomes and clinico-pathological characteristics of pMF at diagnosis (pMFD) were compared to those of a cohort of non-pustular MF (NpMF)., Results: 33 pMF (including 22 pMFD) and 86 NpMF cases were included. The median age at diagnosis of pMF was 61 years [IQR=50-75]. The median follow-up of pMFD was 32 months [IQR=14-49]. Clinically, 33% of pMF had pustules. Large-cell transformation (LCT) occurred in 17 cases. pMFD were at a significantly more advanced-stage and more showed LCT at diagnosis than NpMF (50% vs 7%, p<0.001 and 23% vs 0%, p<0.001, respectively). In multivariate Cox analysis, the presence of histological pustule at diagnostic was associated with shorter OS in all patients (HR=13.90, CI95%[2.43-79]; p=0.003), and in early-stage patients (HR=11.09, CI95%[1.56-78.82]; p=0.02). In multivariate Fine and Gray model analysis, pMFD was associated with a higher cumulative incidence of LCT (SHR=13.90, CI95% [2.43-79]; p=0.003) in all patients. Median OS after the occurrence of histological pustules during follow-up of all pMF patients was 37 months, with a five-year OS of 25% (CI95% [0.06-0.5])., Conclusion: pMF often follows an aggressive course, with a high risk of LCT and shorter survival, even for early-stage patients. Histological pustules at diagnostic of MF might represent an independent poor prognostic factor, to be confirmed by further studies. Because pustules are not always clinically identified, histological pustules should be mentioned in pathology reports of MF and prompt discussion of a closer follow-up., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The aim was to investigate the feasibility of a shortened dynamic whole-body (dWB) FDG-PET/CT protocol and Patlak imaging using a population-based input function (PBIF), instead of an image-derived input function (IDIF) across the 60-min post-injection period, and study its effect on the FDG influx rate (Ki) quantification in patients with metastatic melanoma (MM) undergoing immunotherapy., Methods: Thirty-seven patients were enrolled, including a PBIF modeling group (n = 17) and an independent validation cohort (n = 20) of MM from the ongoing prospective IMMUNOPET2 trial. All dWB-PET data were acquired on Vision 600 PET/CT systems. The PBIF was fitted using a Feng's 4-compartments model and scaled to the individual IDIF tail's section within the shortened acquisition time. The area under the curve (AUC) of PBIFs was compared to respective IDIFs AUC within 9 shortened time windows (TW) in terms of linear correlation (R 2 ) and Bland-Altman tests. Ki metrics calculated with PBIF vs IDIF on 8 organs with physiological tracer uptake, 44 tumoral lesions of MM and 11 immune-induced inflammatory sites of pseudo-progression disease were also compared (Mann-Whitney test)., Results: The mean ± SD relative AUC bias was calculated at 0.5 ± 3.8% (R 2  = 0.961, AUC PBIF  = 1.007 × AUC IDIF ). In terms of optimal use in routine practice and statistical results, the 5th-7th pass (R 2  = 0.999 for both Ki mean and Ki max) and 5th-8th pass (mean ± SD bias = - 4.9 ± 6.5% for Ki mean and - 4.8% ± 5.6% for Ki max) windows were selected. There was no significant difference in Ki values from PBIF 5&#95;7 vs IDIF 5&#95;7 for physiological uptakes (p > 0.05) as well as for tumor lesions (mean ± SD Ki IDIF 5&#95;7 3.07 ± 3.27 vs Ki PBIF 5&#95;7 2.86 ± 2.96 100ml/ml/min, p = 0.586) and for inflammatory sites (mean ± SD Ki IDIF 5&#95;7 1.13 ± 0.59 vs Ki PBIF 5&#95;7 1.13 ± 0.55 100ml/ml/min, p = 0.98)., Conclusion: Our study showed the feasibility of a shortened dWB-PET imaging protocol with a PBIF approach, allowing to reduce acquisition duration from 70 to 20 min with reasonable bias. These findings open perspectives for its clinical use in routine practice such as treatment response assessment in oncology., (© 2023. The Author(s).)

Background: The tumor mutational burden (TMB) is high in melanomas owing to UV-induced oncogenesis. While a high TMB is a predictive biomarker of response to PD-1 inhibitors, it may be associated with the rise of resistant clones to targeted therapy over time. We hypothesized that survivals may depend on both the sun-exposure profile of the site of primary melanoma and the type of systemic treatment., Patients and Methods: Patients were screened from MelBase, a multicenter biobank dedicated to the prospective follow-up of stage III/IV melanoma. All patients with a known cutaneous primary melanoma who received a 1st-line systemic treatment by immunotherapy or targeted therapy were included (2013-2019). Outcomes were progression-free survival (PFS) and overall survival (OS)., Results: 973 patients received either anti PD-1(n=466), anti CTLA-4(n=143), a combination of both (n=118), or targeted therapies (n=246). Patients' characteristics at treatment initiation were: male (62%), median age of 62, AJCC stage IV (84%). Median follow-up was 15.5 months. The primary melanoma was located on chronically sun-exposed skin in 202 patients (G1: head neck), on intermittently sun-exposed skin in 699 patients (G2: trunk, arms, legs), and on sun-protected areas in 72 patients (G3: palms, soles). Median PFS was significantly higher in G1 under anti PD-1 treatment (8.7 months vs 3.3 and 3.4 months for G2 and G3, respectively) (p=0.011). PFS did not significantly differ in other groups. Similarly, median OS was significantly higher in G1 receiving 1 st line anti PD-1 treatment (45.6 months vs 31.6 and 21.4 months for G2 and G3) (p=0.04), as opposed to 1 st line targeted therapy (19.5 months vs 16.3 and 21.1 months for G1, G2 and G3 respectively)., Conclusion: Our study confirms that immunotherapy with anti PD-1 is particularly recommended for melanomas originating from chronically sun-exposed areas, but this finding needs to be confirmed by further research., Competing Interests: SD reported receiving financial support from and is a consultant for BMS, Roche, and is employed by Sanofi with stock ownership. LM reported receiving financial support from and is a consultant for BMS, Amgen, Merck, Incyte, MSD, Roche, and Novartis. OD reported receiving financial support from and is a consultant for BMS, MSD, Pierre Fabre, Recordati, Genevrier, Kiowa Kirin, Leo Pharma, and Novartis. CA reported receiving financial support from Amgen, BMS, and Roche. J-PA reported receiving financial support from BMS and MSD. SD-R reported receiving financial support from BMS, Novartis and MSD. HM reported receiving financial support from BMS, Novartis, Pierre Fabre, Leo Pharma and MSD. CD reported receiving financial support from BMS, MSD, Pierre Fabre, and Novartis. JQ reported receiving financial support from BMS, Jansen Cilag. DL reported receiving financial support from BMS, MSD, Novartis, Leo Pharma, and Merck. EM reported receiving financial support from BMS, MSD, and Novartis. PS reported receiving financial support from BMS, MSD, Novartis, Roche, and Pierre Fabre. CL reported serving as a consultant for BMS and receiving financial support from BMS, MSD, Roche, Novartis, Amgen, Merck, Pierre Fabre, Pfizer, and Incyte. LB reported receiving financial support from Novartis, Pierre Fabre, Roche, BMS, MSD. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Russo, Dalle, Dereure, Mortier, Dalac-Rat, Dutriaux, Leccia, Legoupil, Montaudié, Maubec, De Quatrebarbes, Arnault, Brocard, Saïag, Dreno, Allayous, Oriano, Lefevre, Lebbé and Boussemart.)

Competing Interests: Conflicts of interest None disclosed.

Background: Lentigo maligna (LM) is a melanocytic proliferation occurring on photo-exposed skin that may progress to LM melanoma. Surgery is recommended as first-line treatment. Excision margins of 5-10 mm remain, without international consensus. Several studies have shown that imiquimod, an immunomodulator, induces LM regression. This study investigated the effect of imiquimod versus placebo in neoadjuvant settings., Patients and Methods: We performed a prospective, randomized, multicentre, phase III clinical study. Patients were randomly assigned in 1:1 ratio to receive imiquimod or placebo for 4 weeks, followed by LM excision 4 weeks after the last application of imiquimod or placebo. The primary endpoint was extra-lesional excision, with a 5 mm margin from the residual pigmentation after imiquimod or vehicle. Secondary endpoints included the gain on the surface removed between the two groups; number of revision surgeries to obtain extra-lesional excisions; relapse-free time; and number of complete remissions after treatment., Results: A total of 283 patients participated in this study; 247 patients, 121 patients in the placebo group and 126 in the imiquimod group, accounted for the modified ITT population. The first extralesional extirpation was performed in 116 (92%) imiquimod patients and in 102 (84%) placebo patients; the difference was not significant (p = 0.0743). Regarding the surface of LM, imiquimod reduced the LM surface (4.6-3.1 cm 2 ) significantly (p < 0.001) more compared to the placebo (3.9-4.1 cm 2 )., Conclusion: Imiquimod reduces the lentigo maligna surface after 1 month of treatment, without a higher risk of intralesional excision and with a positive aesthetic outcome., (© 2023 European Academy of Dermatology and Venereology.)

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., Competing Interests: Conflicts of interest Dr Dalle received research grants by BMS and MSD, travel costs covered by BMS, spouse working for Sanofi; Dr Dereure reported a Consulting or Advisory Role with Bristol-Myers Squibb, Genevrier, Kiowa Kirin, Leo Pharma, MSD, Novartis, Pierre Fabre, and Recordati, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Pierre Fabre, and Recordati; Dr Saiag has received outside of this study personal fees from Bristol-Myers Squibb, MSD, Merck-Serono, Pfizer, Roche-Genentech, Pierre Fabre, and Novartis; Dr Arnault consulting for NOVARTIS, Dr Lebbé reported honoraria from Amgen, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, reports a Consulting or Advisory Role with Amgen, Bristol-Myers Squibb, Merck Serono, MSD, Novartis, Roche, and Sanofi, is on the Speakers' Bureau for Amgen, Bristol-Myers Squibb, MSD, Novartis, and Roche, received Research Funding from Bristol-Myers Squibb, and Roche, reports travel, accommodations, and expenses from Bristol-Myers Squibb and MSD, and reports other relationship with Avantis Medical Systems; and Dr Montaudié reported a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, received Research Funding from Leo Pharma and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, and Pierre Fabre., (Copyright © 2022 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

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.

Background: Data regarding characteristics, safety and survival outcomes of patients aged 80 or older treated with immune checkpoint inhibitors (ICI) in routine oncology practice are limited., Materials and Methods: We retrospectively collected data of patients aged 80 and older with advanced non-small cell lung cancer (NSCLC) or melanoma treated with anti-PD1, anti-PD-L1 or anti-CTLA-4 regardless of the treatment line, in 14 institutions, between January 2014 and June 2017. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan Meier method. Toxicity was assessed according to CTCAE 5.0. Multivariate analyses were performed with the Cox model., Results: Eighty-two patients were included (36 with NSCLC, 45 with melanoma). Their median age was 82 years (range 80-93). Nivolumab and pembrolizumab were mainly used. In the NSCLC group, median PFS and OS were 2.3 months (95%CI 1.8-6.1) and 8.8 months (95%CI 5.5-18.1), respectively. In the melanoma group, median PFS and OS were 10.2 months (95%CI 4.5-20.0) and 24.5 months (95%CI 14.1-NR), respectively. The albumin level was found to be independently associated with a better OS in both groups. Grade 3-4 toxicities occurred in 15 patients (18.5%). One patient died from ICI-induced pulmonary toxicity., Conclusion: Our study findings suggest that treatment with ICI in elderly patients with NSCLC and melanoma has a risk-benefit ratio that supports its use. However, we report in this cohort that one in five patients has a grade 3-4 IRAEs leading to treatment discontinuation. Geriatric assessment prior to initiation of therapy and during therapy should be routine in patients aged 80 years and older.

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.

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., Competing Interests: Competing interests: DL: fees from Novartis, BMS et MSD. PS: consulting fees from Roche, Novartis, BMS, Pierre FABRE, MSD. FB-P: consulting fees from BMS and Sanofi. TL: consulting fees from MSD, BMS, Pierre Fabre, Novartis. J-JG : consulting fees from MSD, Roche, Novartis, Amgen, Pierre-Fabre, Sanofi, Philogen, Merck, Pfizer. CA: grants from Amgen, BMS, Roche. LM: grants from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre and consulting fees from BMS, Novartis, Roche, MSD, GSK, Pierre Fabre. CL: grants from BMS, MSD, Novartis, Sanofi, Pierre Fabre; consulting fees from BMS, MSD, Novartis, Amgen, Roche, Merck, Serono, Sanofi, Pierre Fabre and teaching fees from Roche, BMS, Novartis, Amgen, MSD., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the incidence of the abscopal response (AR) in patients with metastatic melanoma requiring palliative radiotherapy (RT). Patients and methods: Patients treated for metastatic melanoma between January 1998 and February 2020 in four oncology departments were screened. Patients with progression under immune checkpoint inhibitors or without ongoing systemic treatment, and requiring palliative RT were considered. The AR was defined as an objective response according to RECIST and/or iRECIST for at least one non-irradiated metastasis at distance (≥10 cm) from the irradiated lesion. Primary endpoint was the rate of AR. Secondary endpoints were overall survival (OS), progression-free survival (PFS), local control (LC) of the irradiated lesion, and toxicity as assessed by CTCAE v5. Results: Over the period considered, 118 patients were included and analyzed. Fifteen patients (12.7%) had an AR. With a median follow-up of 7.7 months (range, 0.2−242.2), median OS and PFS after RT were significantly longer in patients with an AR compared to those without: 28 vs. 6.6 months (p < 0.01) and not reached vs. 3.2 months, respectively. No grade ≥2 toxicity was reported. Patients who developed an AR were more likely to be treated with immunotherapy (93.3% vs. 55.9%, p = 0.02). In multivariate analysis, they had a higher number of irradiated metastases treated concomitantly (HR = 16.9, p < 0.01) and a higher rate of mild infections during RT (HR = 403.5, p < 0.01). Conclusions: AR in metastatic melanoma seems to be highly prognostic of overall survival, although it is a rare phenomenon. It may be promoted by multiple concomitant treatments with RT and immunotherapy and by acute inflammatory events such as infection.

Background: First-degree relatives (FDRs, defined as parents, children, and siblings) of melanoma patients are at a two-to-fivefold increased risk of developing melanoma themselves. FDRs are advised to perform self-skin examination (SSE) and annual medical total cutaneous examination (TCE) performed either by a dermatologist or a general practitioner, and to change their sun-related behavior. This advice is given orally to melanoma patients who are asked to relay the information to their FDRs., Objective: Our aim was to determine the impact of providing a tip sheet to melanoma patients intended to their first-degree relatives (FDRs) on early detection and sun-related behaviors in this group at increased risk of melanoma., Methods: A superiority, cluster-randomized trial was conducted at nine hospital centers. In the intervention group, dermatologists were asked to deliver to melanoma patients (index cases) the tip sheet and oral advice intended to their FDRs. The control group were asked to deliver the usual oral advice alone. The primary outcome was early detection of melanoma in FDRs with a medical TCE performed within one year after the first visit of the index case. Secondary outcomes were SSE and sun-related behaviors in FDRs., Results: A total of 48 index cases and 114 FDRS in the control group, 60 index cases and 166 FDRS in the intervention group were recruited. In the intervention group, 36.1% of FDRs performed a medical TCE as compared to 39.5% of FDRs in the control group (OR 0.9 [95% CI 0.5 to 1.5], p = 0.63). We did not find a between-group difference in SSE and sun-related behaviors., Conclusion: A tip sheet added to the usual oral advice did not increase medical TCE among FDRs of melanoma patients. Overall, the rate of TCE among FDRs was low. Research on other strategies is needed to increase melanoma detection in this population.

Background: Late-onset adverse events (AEs) of anti-programmed cell death 1 (anti-PD1) antibodies have not been systematically described., Objectives: The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered for at least 2 years in a real-life setting., Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow up of unresectable stage III or IV melanoma. The study included 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019. Median follow up was 41.7 months (range, 25.2-57.5 months). Fifty-three patients received nivolumab and 66 patients received pembrolizumab., Results: AEs occurred in 99 patients (83%) with a median time of 13.3 months (range, 0-53.9 months), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grades 1 or 2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations, of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first 2 years of treatment) and treatment duration (P = .02 and P = .03, respectively)., Conclusions: Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy. Late-onset AEs appear frequently and were mostly mild or moderate. Early-onset AEs and prolonged anti-PD1 treatment may increase the risk of late-onset AEs., Competing Interests: Conflicts of interest Dr Nardin has a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre. Dr. Dalle is an employee of Sanofi, has Stock and Other Ownership Interests in Sanofi, has a Consulting or Advisory Role with Bristol-Myers Squibb, received Research Funding from Bristol-Myers Squibb, and reports travel, accommodations, and expenses from Bristol-Myers Squibb and Pierre Fabre. Dr Leccia has No Relationships to Disclose. Dr Mortier received honoraria from Bristol-Myers Squibb and MSD Oncology, received Research Funding from MSD Oncology and Pierre Fabre, and received travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Roche/Genentech, and Roche/Genentech. Dr Dalac-Rat received honoraria from Bristol-Myers Squibb, MSD, and Novartis, reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, and Novartis, is on the Speakers' Bureau for Bristol-Myers Squibb, reports Research Funding from Bristol-Myers Squibb, MSD, and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb. Dr Dutriaux received honoraria from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre. Dr Legoupil received honoraria from Bristol-Myers Squibb and MSD, reports a Consulting or Advisory Role with Bristol-Myers Squibb and Pierre Fabre, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, MSD, and Pierre Fabre. Dr Montaudié reports a Consulting or Advisory Role with Bristol-Myers Squibb, MSD, Novartis, and Pierre Fabre, received Research Funding from Leo Pharma and Novartis, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, and Pierre Fabre. Dr Dereure reports a Consulting or Advisory Role with Bristol-Myers Squibb, Genevrier, Kiowa Kirin, Leo Pharma, MSD, Novartis, Pierre Fabre, and Recordati, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Pierre Fabre, and Recordati. Dr De Quatrebarbes is on the Speakers' Bureau for Bristol-Myers Squibb and Janssen-Cilag and reports travel, accommodations, and expenses from BMS and MSD Oncology. Dr Granel-Brocard has no relationships to disclose. Dr Le-Bouar has no relationships to disclose. Dr Charles has no relationships to disclose. Dr Brunet-Possenti reports a Consulting or Advisory Role with Bristol-Myers Squibb and Sanofi. Dr Dreno received honoraria from Bristol-Myers Squibb, Merck, Pierre Fabre, Roche, and Sanofi, reports a Consulting or Advisory Role with Bristol-Myers Squibb, Pierre Fabre, Roche, and Sanofi, and reports travel, accommodations, and expenses from Bristol-Myers Squibb, Pierre Fabre, and Roche. Dr Lefevre has no relationships to disclose. Dr Allayous reports travel, accommodations, and expenses from Amgen, Bristol-Myers Squibb, and Roche. Dr Lebbe reports honoraria from Amgen, Bristol-Myers Squibb, Incyte, MSD, Novartis, Pfizer, Pierre Fabre, and Roche, reports a Consulting or Advisory Role with Amgen, Bristol-Myers Squibb, Merck Serono, MSD, Novartis, Roche, and Sanofi, is on the Speakers' Bureau for Amgen, Bristol-Myers Squibb, MSD, Novartis, and Roche, received Research Funding from Bristol-Myers Squibb, and Roche, reports travel, accommodations, and expenses from Bristol-Myers Squibb and MSD, and reports other relationship with Avantis Medical Systems., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: The aim of this study was to evaluate prognostic factors in patients with non-metastatic Merkel cell carcinoma (MCC), with a particular focus on immunological markers such as TILs subtyping (CD3, CD8, CD68, FoxP3, PD-L1 and PD-1) and MCPyV., Methods: Patients treated for a non-metastatic MCC with oncologic surgical resection followed or not by adjuvant radiotherapy between 01/2007 and 12/2018 were analyzed. Local and regional control (LC, RC), distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated. Clinical variables analyzed included age, gender, performance status, comorbidity, tumor size, location and presentation type, extension, oncologic resection and adjuvant radiotherapy. Pathological variables analyzed included type of tumor-infiltrating lymphocytes, CD3, CD8, CD68, PD-L1 expression on immune cells and tumors cells, PD-1, FoxP3 and MCPyV, assessed with immunohistochemistry (IHC)., Results: 77 patients were included. After a median follow-up of 18 months (range 0.2-144), the 1-year LC, RC, DMFS and OS were 83%, 60%, 82% and 75%, respectively. In multivariate analysis, a percentage of PD-L1 expression by immune cells ≥ 1% was significantly correlated with improvement of RC (p = 0.012), DMFS (p = 0.003) and OS (p = 0.006). Adjuvant radiotherapy significantly improved DMFS (p = 0.021) and OS (0.041) rates. There was a correlation between the presence of MCPyV + and the expression of PD-L1 on IC (p = 0.05) and TC (p = 0.03)., Conclusion: PD-L1 expression by immune and tumor cells in non-metastatic MCC seems to significantly improve outcome in patients who did not received PD-1/PD-L1 inhibitors. Prospective studies are needed to confirm our hypothesis., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The French government imposed the first COVID-19 pandemic lockdown from March 17 until May 11, 2020. Only emergency cases and teledermatology (TD) were allowed in outpatient settings. A standardized questionnaire was developed to compare the satisfaction level of patients and their treating physicians. Our main question was whether the patients would perceive TD as a valid alternative for direct physical face-to-face consultation. Eighty-two patients and their 4 treating dermatologists from one dermatology department participated in the study (43 females, 39 males) with a mean age of 46.6 years (SD ±23.9). The reason for TD was a chronic disease in the majority (87.8%), and mainly as a follow-up (96.3%). Regarding satisfaction, almost all categories rated around 9 on a 0-10 verbal analogue scale. The same level of global satisfaction could be seen between the patients and the physicians as well as for the quality of the patient-physician relation and whether all questions could be addressed during the TC. Physicians showed significantly higher scores than patients only for the category of "length" of the consultation. Gender, age, as well as distance between the clinic and home of the patient were not influencing factors for satisfaction. Regarding the technical parameters, the evaluation was mostly comparable for patients and physicians, but overall lower than the relational satisfaction parameters, especially for image quality. Patients were significantly more motivated to continue the TD after the lockdown than their treating dermatologists. We see an interest for implementing TD in specialized centers with chronic patients coming from remote places for regular follow-ups. TD cannot replace in-person patient-physician interaction, but was helpful during the lockdown. As a result, TD might become part of dermatology training to prepare for future lockdown situations., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Background: Pruritus is a frequent adverse event during the use of immune checkpoint inhibitors (ICIs), with a frequency estimated to be between 11 and 47%. The underlying causes remain poorly understood. Objectives: The main goal was to search for putative causes of pruritus occurring in patients treated with ICIs for melanomas and cutaneous carcinomas. Other objectives were to assess the association between the occurrence of pruritus and survival and between the occurrence of pruritus and other adverse events. Methods: A monocentric retrospective descriptive study was performed using data for patients treated with ICIs (nivolumab, pembrolizumab, ipilimumab, and cemiplimab) between August 2010 and November 2019. Results: A total of 181 patients were included (mean age: 69 years). Pruritus was reported by 25 patients (13.8%). We were able to determine three subgroups of pruritus causes under ICI use: pruritus directly related to immunotherapy, pruritus indirectly related through other pruritus-inducing side effects and pruritus unrelated to ICIs. In 6/25 patients, no more specific cause of pruritus was found at the onset of pruritus or in their backgrounds, other than ICI use. Limitations: The study has some limitations due to unicentric and retrospective design. Conclusion: Pruritus was found in 25/181 patients in this series; only in 6/25 patients no potential cause other than ICI could be found, and pruritus was not associated with differences in survival., Competing Interests: DL: BMS, MSD, Novartis, Pierre Fabre. LM: BMS, Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Salinas, Nowak, Etienne, Legoupil, Fouchard, Brenaut and Misery.)

Purpose: To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs)., Patients and Methods: Patients, predominantly men, with their CSSCs' immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort's objective response rate at week 15 (ORR W15 ). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy-General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR W15 difference between PD-L1+ and PD-L1- patients, was assessed for ORR, disease control rate, and safety, but not survival., Results: Median age of all patients was 79 years. The primary cohort's ORR W15 was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR W15 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%; P = .02). Responders' W15 total FACT-G score had improved ( P = .025) compared with nonresponders., Conclusion: First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy.

Importance: Since 2011, many patients with metastatic melanoma have been treated with ipilimumab therapy and have developed severe immune-related adverse events (AEs). Because several immune therapies are now available to treat metastatic melanoma, a better knowledge of mechanisms and recurrence risks of immune-related AEs is needed before reintroduction of immunotherapies., Objectives: To evaluate the risk of a recurrence of immune toxic effects associated with anti-programmed cell death 1 antibody (anti-PD-1) therapy after discontinuation of ipilimumab monotherapy because of severe AEs., Design, Settings, and Participants: This cohort study conducted at 19 French melanoma referral centers included patients with metastatic melanoma who experienced severe immune-related AEs after ipilimumab therapy and then were treated with anti-PD-1 therapy between February 1, 2013, and December 31, 2016. The study cutoff was June 1, 2017. Statistical analysis was performed from June 1, 2016, to August 31, 2017., Exposures: Monotherapy with at least 1 cycle of ipilimumab that was associated with a grade 3 or 4 immune-related AE and subsequent treatment with at least 1 cycle of an anti-PD-1 (nivolumab or pembrolizumab) therapy., Main Outcomes and Measures: The primary outcome was the rate of immune-related AEs associated with anti-PD-1 therapy. Secondary outcomes were characteristics of ipilimumab-related and anti-PD-1 immune-related AEs and overall response rate and overall survival associated with anti-PD-1 therapy., Results: Of 56 patients with metastatic melanoma included in the study, all of whom experienced severe immune-related AEs after ipilimumab therapy (31 [55%] male; mean [SD] age, 64 [14.9] years), 20 (36%) experienced at least 1 immune-related AE associated with pembrolizumab (6 of 20 [30%]) or nivolumab (14 of 20 [70%]) therapy. A total of 12 patients (21%) experienced grade 3 or 4 immune-related AEs, and among these patients, 4 (33%) presented with the same immune-related AE as with ipilimumab therapy. Severe immune-related AEs were resolved with use of systemic corticosteroids (7 [58%]) and/or anti-tumor necrosis factor (1 [8%]), and no grade 5 toxic effects were reported. Five patients discontinued anti-PD-1 therapy because of immune-related AEs. The overall response rate was 43%, with a median overall survival of 21 months (interquartile range, 18 to ongoing)., Conclusions and Relevance: The findings suggest that anti-PD-1 therapy may be associated with reduced risk of toxic effects and improved survival among patients who have experienced severe toxic effects after ipilimumab therapy.

Background: Significant progress was recently observed in the treatment of metastatic melanoma (MM). With >50% of patients now reaching a second line of treatment and a significant improvement in the survival rate, an assessment of quality of life (QoL) during the whole course of the disease becomes necessary. The objective of this study was to describe the QoL of patients with MM in France, from their diagnosis of advanced disease to their death, in real life., Methods: QoL data were collected through MelBase, a prospective, French, multicentric cohort dedicated to the follow-up of adults with MM. QoL was assessed using the EuroQoL-5D questionnaire and the Functional Assessment of Cancer Treatment (FACT)-Melanoma questionnaire at the time of study inclusion, every 3 months, and at the time of each treatment change until death. To assess longitudinal changes from baseline to death, mixed-effect models for repeated-measures analyses were used to control for baseline covariates., Results: QoL was assessed in 1435 patients who were included in the study between 2013 and 2018. The median follow-up was 9.4 months, and 47% of patients died during follow-up. During first-line treatment, the model-based, mean utility score was 0.830 (95% CI, 0.818-0.843), the mean FACT-General score was 77.22 (95% CI, 76.23-78.22), and the mean FACT-Melanoma score was 129.46 (95% CI, 128.02-130.90). At the time of a change in treatment line, there was a decrease of -0.027 (95% CI, -0.03, -0.02) in the utility score, -1.82 (95% CI, -1.88, -1.76) in the FACT-General score, and -2.98 (95% CI, -3.05, -2.91) in the FACT-Melanoma score compared with first-line treatment., Conclusions: In the MelBase cohort, the QoL among patients with MM seems to be fairly stable over the whole disease course, although a small but significant decrease at time therapy is changed is observed., (© 2019 American Cancer Society.)

Predicting the response to PD-1/PD-L1 immune checkpoint blockade in patients with metastatic melanoma remains challenging. In this study, we have investigated for the relationships between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. We studied the formalin-fixed paraffin-embedded tumor samples of 36 patients with metastatic melanoma using PD-L1 immunohistochemistry (IHC) and PD-L1/chromosome 9 fluorescent in situ hybridization (FISH). PD-L1 IHC was positive in 3 patients (8.33%, with >5% stained tumor cells) and PD-L1 FISH test revealed 5 (13.8%) PD-L1 amplifications, 8 (22.2%) PD-L1 gains, and 2 (5.5%) PD-L1 losses. Among 14 responders and 13 nonresponders to anti-PD-1 immunotherapy, we concluded that there was no significant relationship between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. In our study, the determination of PD-L1 expression using IHC and PD-L1 copy number using FISH was insufficient to predict the response to PD-1/PD-L1 immune checkpoint blockade in patients with advanced melanomas.

Importance: The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable., Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma., Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017., Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (<12 months, 12-24 months, and >24 months)., Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment., Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

Background: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy., Patients and Methods: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias., Results: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively., Conclusion: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

NRAS and BRAF mutational status has become mandatory to treat patients with metastatic melanomas. Mutation-specific immunohistochemistry (IHC) can help analyze challenging tumor samples. We report our experience integrating NRASQ61R (SP174) and BRAFV600E (VE1) IHC in routine practice in a cancer molecular genetic platform. All samples screened for BRAF and NRAS mutations during the year 2014 were analyzed by IHC and pyrosequencing, with an independent analysis of the 2 methods. Cases with first-line discordant results benefited from a complementary second-round IHC and next-generation sequencing (NGS) with a final interpretation taking into account the results of pyrosequencing, IHC, NGS, and quantification of the tumor cells. We analyzed 111 consecutive formalin-fixed and paraffin-embedded melanoma samples from 101 patients. Twenty-two and 11 samples were concordant for BRAFV600E and NRASQ61R mutations, respectively. Second-round analyses of 9 discordant and 1 molecularly inconclusive samples allowed conclusion in 4 further mutated samples (2 BRAFV600E and 2 NRASQ61R). A sample remained NRASQ61R IHC negative but NRASQ61R mutated with molecular methods. Overall, BRAFV600 and NRASQ61 mutation frequencies were 31.7% and 30.7%, respectively. When compared to molecular results, the sensitivity and specificity of IHC were 100% for BRAFV600E IHC and 92.3% and 98.9% for NRASQ61R IHC, respectively. IHC interpretation required a more stringent cutoff for BRAFV600E IHC than NRASQ61R to minimize false results. We conclude that NRASQ61R and BRAFV600E IHC coupled with NGS allow detection of mutations in melanoma challenging samples., (Copyright © 2015 Elsevier Inc. All rights reserved.)