Publications by authors named "Florent Grange"

71 Publications

Response to Imatinib in a Patient with Double-mutant KIT Metastatic Penile Melanoma.

Acta Derm Venereol 2020 Dec 7. Epub 2020 Dec 7.

Department of Pathology, University Hospital of Reims, rue Koenig, FR-51100 Reims, France. E-mail:

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http://dx.doi.org/10.2340/00015555-3715DOI Listing
December 2020

Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas.

J Clin Oncol 2020 09 30;38(26):3051-3061. Epub 2020 Jul 30.

Assistance Publique-Hôpitaux de Paris, Hôpital Avicenne, Bobigny, France.

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). 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 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 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 for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1- patients (17%; = .02). Responders' W15 total FACT-G score had improved ( = .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.
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http://dx.doi.org/10.1200/JCO.19.03357DOI Listing
September 2020

Pembrolizumab Monotherapy for Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Arm Phase II Trial (KEYNOTE-629).

J Clin Oncol 2020 09 16;38(25):2916-2925. Epub 2020 Jul 16.

Royal Brisbane and Women's Hospital, Herston, QLD, Australia.

Purpose: Treatment options are limited for patients with recurrent and/or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC); mortality rates exceed 70% in patients with distant metastases. Here, we present the first interim analysis of the R/M cSCC cohort from the 2-cohort-locally advanced and R/M-phase II KEYNOTE-629 study.

Patients And Methods: Patients with R/M cSCC not amenable to surgery or radiation received pembrolizumab 200 mg every 3 weeks. The primary end point was objective response rate per RECIST v1.1. Secondary end points were duration of response, disease control rate, progression-free survival, overall survival, and safety.

Results: At data cutoff (April 8, 2019), median follow-up of 105 enrolled patients in the R/M cohort was 11.4 months (range, 0.4 to 16.3 months). Objective response rate was 34.3% (95% CI, 25.3% to 44.2%; 4 complete responses, 32 partial responses), and disease control rate was 52.4% (95% CI, 42.4% to 62.2%). Median duration of response was not reached (range, 2.7 to 13.1+ months; '+' refers to ongoing response at data cutoff). Median progression-free survival was 6.9 months (95% CI, 3.1 months to 8.5 months). Median overall survival was not reached (95% CI, 10.7 months to not reached). Treatment-related adverse events occurred in 66.7% of patients (n = 70), the most common of which were pruritus (n = 15; 14.3%), asthenia (n = 14; 13.3%), and fatigue (n = 13; 12.4%). Grade 3 to 5 treatment-related adverse events occurred in 5.7% (n = 6) of patients. One patient died of treatment-related cranial nerve neuropathy.

Conclusion: Pembrolizumab demonstrated effective antitumor activity; clinically meaningful, durable responses; and acceptable safety in primarily elderly patients with R/M cSCC, supporting its use in clinical practice. Pembrolizumab adverse events in this study were consistent with its established safety profile.
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http://dx.doi.org/10.1200/JCO.19.03054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460151PMC
September 2020

Association of Anti-Programmed Cell Death 1 Antibody Treatment With Risk of Recurrence of Toxic Effects After Immune-Related Adverse Events of Ipilimumab in Patients With Metastatic Melanoma.

JAMA Dermatol 2020 09;156(9):982-986

Department of Oncology, Comprehensive Cancer Center Eugène Marquis, Rennes, France.

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.
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http://dx.doi.org/10.1001/jamadermatol.2020.2149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364335PMC
September 2020

Early Phase of Primary Melanoma Growth from the Patient Point of view: A Prospective Cross Sectional Study on Melanoma over 1 mm in Thickness.

Acta Derm Venereol 2020 Jul 28;100(14):adv00222. Epub 2020 Jul 28.

Department of Dermatology and Skin Cancer, CHU Timone, APHM, Aix Marseille University, INSERM, CRCM, FR-13885 Marseille, France.

A Nodular Pink Lesion with an Uncommon Diagnosis: A QuizMost melanomas are diagnosed by the patients themselves or by their partners or relatives; they alone can describe its history. We designed a prospective cross-sectional study to describe patients' perception of morphology, growth pattern and kinetics of their primary melanoma over 1 mm in thickness before resection. Patients were interviewed with a questionnaire, a grid representing 9 possible scenarios of melanoma growth, and a set of 87 photographs of potential aspects of melanomas and precursors. Most patients were able to describe the growth of their melanoma and select pictures representative of its successive aspects before resection. Among 453 patients, 60% reported a preexisting lesion present for years. Growth pattern scenarios concurred with tumor kinetics but with no statistical difference between nodular and superficial spreading subtypes. These subjective patient-reported indicators about melanoma growth over time could dynamically complement its objective pathological analysis otherwise static at a single time point.
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http://dx.doi.org/10.2340/00015555-3591DOI Listing
July 2020

Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma.

J Immunother Cancer 2020 06;8(1)

Center for Immuno-Oncology, University Hospital of Siena, Instituto Toscano Tumori, Siena, Italy.

Background: We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.

Methods: This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.

Results: At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.

Conclusions: This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.

Trial Registration Number: NCT01515189.
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http://dx.doi.org/10.1136/jitc-2019-000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279645PMC
June 2020

Cutaneous Involvement in Waldenström's Macroglobulinaemia.

Acta Derm Venereol 2020 Aug 17;100(15):adv00225. Epub 2020 Aug 17.

Department of Oncodermatology, Robert Debré Hospital, avenue du Général Koenig, FR-51092 Reims Cedex, France. E-mail:

Cutaneous involvement in Waldenström's macroglobulinaemia (WM) has been poorly characterized. To describe this involvement, a retrospective study of 19 patients with WM and cutaneous involvement of tumour B cells was performed. Twelve patients (group 1) had lymphoplasmacytic, non-transformed cutaneous proliferation, while in 7 cases (group 2) cutaneous involvement corresponded to histological transformation. In group 1, skin involvement was inaugural in 6 cases. The lesions were infiltrated plaques (83%), papules (25%) and tumours (42%). Four patients had a similar clinical picture (purplish, bilateral and symmetrical infiltration on the face). MYD88 L265P mutation was detected in the skin biopsy in all 6 cases tested. The 3-year specific survival rate was 88%. In group 2, cutaneous transformation occurred during the follow-up of the WM (71%). Lesions presented as ulcerated tumours (86%) of the trunk (57%) and lower limbs (57%). The 3-year specific survival rate was 22%. Skin involvement in WM has distinctive characteristics (e.g. clinical, histological, immunohistochemical, MYD88 L265P mutation).
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http://dx.doi.org/10.2340/00015555-3535DOI Listing
August 2020

18FDG PET/CT in Primary Cutaneous Diffuse Large B-Cell Lymphoma Leg Type.

Clin Nucl Med 2020 May;45(5):403-404

Service de Dermatologie, CHU Robert Debré, Reims, France.

An 86-year-old woman was referred for a rare but aggressive subtype of primary cutaneous lymphoma of the right lower limb: diffuse large B-cell lymphoma leg type. Initial evaluation by whole-body F-FDG PET/CT showed intense hypermetabolic activity of multiple cutaneous and subcutaneous nodules of the distal third of the right leg. Follow-up evaluations by F-FDG PET/CT showed complete response after 4 and 8 cycles of appropriate rituximab combination with polychemotherapy. Although no specific recommendations are available, our case stresses the major role of F-FDG PET/CT for initial extension and treatment response evaluation in clinical practice of primary cutaneous diffuse large B-cell lymphoma leg type.
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http://dx.doi.org/10.1097/RLU.0000000000002995DOI Listing
May 2020

Congenital Hypogonadotropic Hypogonadism with Anosmia and Gorlin Features Caused by a PTCH1 Mutation Reveals a New Candidate Gene for Kallmann Syndrome.

Neuroendocrinology 2021 20;111(1-2):99-114. Epub 2020 Feb 20.

University Paris-Saclay, Le Kremlin-Bicêtre, France,

Background: Two loci (CHD7 and SOX10) underlying Kallmann syndrome (KS) were discovered through clinical and genetic analysis of CHARGE and Waardenburg syndromes, conditions that include congenital anosmia caused by olfactory bulb (CA/OBs) defects and congenital hypogonadotropic hypogonadism (CHH). We hypothesized that other candidate genes for KS could be discovered by analyzing rare syndromes presenting with these signs. Study Design, Size, Duration: We first investigated a family with Gorlin-Goltz syndrome (GGS) in which affected members exhibited clinical signs suggesting KS. Participants/Materials, Methods: Proband and family members underwent detailed clinical assessment. The proband received detailed neuroendocrine evaluation. Genetic analyses included sequencing the PTCH1 gene at diagnosis, followed by exome analyses of causative or candidate KS/CHH genes, in order to exclude contribution to the phenotypes of additional mutations. Exome analyses in additional 124 patients with KS/CHH probands with no additional GGS signs.

Results: The proband exhibited CA, absent OBs on magnetic resonance imaging, and had CHH with unilateral cryptorchidism, consistent with KS. Pulsatile Gonadotropin-releasing hormone (GnRH) therapy normalized serum gonadotropins and increased testosterone levels, supporting GnRH deficiency. Genetic studies revealed 3 affected family members harbor a novel mutation of PTCH1 (c.838G> T; p.Glu280*). This unreported nonsense deleterious mutation results in either a putative truncated Ptch1 protein or in an absence of translated Ptch1 protein related to nonsense mediated messenger RNA decay. This heterozygous mutation cosegregates in the pedigree with GGS and CA with OBs aplasia/hypoplasia and with CHH in the proband suggesting a genetic linkage and an autosomal dominant mode of inheritance. No pathogenic rare variants in other KS/CHH genes cosegregated with these phenotypes. In additional 124 KS/CHH patients, 3 additional heterozygous, rare missense variants were found and predicted in silico to be damaging: p.Ser1203Arg, p.Arg1192Ser, and p.Ile108Met.

Conclusion: This family suggests that the 2 main signs of KS can be included in GGS associated with PTCH1 mutations. Our data combined with mice models suggest that PTCH1 could be a novel candidate gene for KS/CHH and reinforce the role of the Hedgehog signaling pathway in pathophysiology of KS and GnRH neuron migration.
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http://dx.doi.org/10.1159/000506640DOI Listing
February 2020

Primary Cutaneous Gamma-Delta T-cell Lymphoma: Not an Aggressive Disease in All Cases.

Acta Derm Venereol 2020 Jan 23;100(1):adv00035. Epub 2020 Jan 23.

department of Dermatology, University of Montpellier, 34295 Montpellier, France.

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http://dx.doi.org/10.2340/00015555-3340DOI Listing
January 2020

Metastatic melanoma: pretreatment contrast-enhanced CT texture parameters as predictive biomarkers of survival in patients treated with pembrolizumab.

Eur Radiol 2019 Jun 15;29(6):3183-3191. Epub 2019 Jan 15.

Department of Radiology, Reims University Hospital, 45 rue Cognacq-jay, 51092, Reims, France.

Purpose: To determine whether texture analysis features on pretreatment contrast-enhanced computed tomography (CT) images can predict overall survival (OS) and progression-free survival (PFS) in patients with metastatic malignant melanoma (MM) treated with an anti-PD-1 monoclonal antibody, pembrolizumab.

Materials And Methods: This institutional-approved retrospective study included 31 patients with metastatic MM treated with pembrolizumab. Texture analysis of 74 metastatic lesions was performed on CT scanners obtained within 1 month before treatment. Mean gray-level, entropy, kurtosis, skewness, and standard deviation values were derived from the pixel distribution histogram before and after spatial filtration at different anatomic scales, ranging from fine to coarse. Lasso penalized Cox regression analyses were performed to identify independent predictors of OS and PFS.

Results: Median OS and PFS were 357 days (range 42-1355) and 99 days (range 35-1185), respectively. Skewness at coarse texture scale (SSF = 6; HR (CI 95%) = 6.017 (1.39, 26.056), p = 0.016), Response evaluation criteria in solid tumors (RECIST) conclusion (HR (CI 95%) = 3.41 (1.17, 9.89), p = 0.024), and body weight (HR (CI 95%) = 0.96 (0.92, 0.995), p = 0.026) were independent predictors of OS. Skewness at coarse texture scale (SSF = 6; HR (CI 95%) = 4.55 (1.46, 14.13), p = 0.0089) and RECIST conclusion (HR (CI 95%) = 10.63 (3.11, 36.29), p = 0.00016) were independent predictors of PFS. Skewness values above - 0.55 at coarse texture scale were significantly associated with both lower OS and lower PFS after administration of pembrolizumab.

Conclusion: Pretreatment CT texture analysis-derived tumor skewness may act as predictive biomarker of OS and PFS in patients with metastatic MM treated with pembrolizumab.

Key Points: • Pretreatment skewness at coarse texture scale in metastases from malignant melanoma was an independent predictor of overall survival and progression-free survival. • Skewness values above -0.55 at coarse texture scale were significantly associated with both lower OS and lower PFS after administration of pembrolizumab. • In patients with metastatic MM, texture analysis performed on pretreatment CT may act as a useful tool to select the best candidates for pembrolizumab therapy.
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http://dx.doi.org/10.1007/s00330-018-5933-xDOI Listing
June 2019

Prognostic factors and incidence of primary mucosal melanoma: a population-based study in France.

Eur J Dermatol 2018 Oct;28(5):654-660

Department of Dermatology.

Few population-based studies on the incidence and prognosis of primary mucosal melanoma (PMM) are available. The first objective was to evaluate disease-specific survival of PMM, overall and according to specific locations, and to identify prognostic factors. The second objective was to assess the global incidence of PMM compared to cutaneous melanoma and to specify the relative frequency of each affected location. A retrospective population-based study of incident PMM diagnosed between 2004 and 2014 was conducted, relying on the regional melanoma registry of the French Champagne-Ardenne region (1.34 million inhabitants). Thirty-nine cases were identified, including 17 head and neck (13 sinonasal and four oral), 12 vulvovaginal, six conjunctival, and four anorectal PMMs. Some 76.9% of cases were revealed by late symptoms. The median disease-specific survival time was 23.9 months and the five-year disease-specific survival rate was 31.8%. Univariate and multivariate analyses led to identification of primary tumour size and the presence of nodal or visceral macrometastases at diagnosis as adverse prognostic factors, while Breslow thickness and ulceration were unreported in 41% of cases and failed to display any prognostic value. Compared to other locations, conjunctival PMMs had a smaller tumour size and better prognosis. The annual incidence rate was 0.18/100,000 and the incidence ratio between PMM and cutaneous melanoma was 1/50. This population-based study confirms the rarity, delayed diagnosis, and severity of PMM, suggesting that improving prognosis will require specific, targeted therapies.
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http://dx.doi.org/10.1684/ejd.2018.3398DOI Listing
October 2018

Primary cutaneous acral CD8 T-cell lymphomas relapse more frequently in younger patients.

Br J Haematol 2019 05 23;185(3):598-601. Epub 2018 Oct 23.

Department of Pathology, University of Montréal, Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada.

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http://dx.doi.org/10.1111/bjh.15572DOI Listing
May 2019

Association of homogeneous inflamed gene signature with a better outcome in patients with metastatic melanoma treated with MAGE-A3 immunotherapeutic.

ESMO Open 2018 25;3(5):e000384. Epub 2018 Jul 25.

Celyad, Mont-Saint-Guibert, Belgium.

Purpose: This study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma.

Patients And Methods: In this open-label, multicentre, uncontrolled, Phase II study (ClinicalTrials.gov NCT00896480), patients received ≤24 doses of MAGE-A3 immunotherapeutic (4-cycle schedule). At screening, two skin lesions were biopsied for MAGE-A3 expression analysis and presence/absence of a previously identified gene signature (GS) associated with favourable clinical outcome. Clinical activity was assessed in terms of clinical response, time-to-treatment failure (TTF) and progression-free survival (PFS). Adverse events (AEs) and serious AEs (SAEs) were recorded. MAGE-A3-specific immune responses were assessed. Clinical activity and immunogenicity were analysed overall and separately in patients with 2/2 (GS+/+), 1/2 (GS+/-) or 0/2 (GS-/-) biopsies presenting GS.

Results: Of 49 screened patients, 32 had MAGE-A3-positive tumours; 24 (8 GS+/+, 8 GS+/-, 8 GS-/-) were treated. Two complete (GS+/+ patients) and two partial responses (one GS+/+, one GS+/-) were reported; of note, one of the two complete responses was unlikely to be related to the study treatment. Median TTF and PFS were 14.8 and 7.2 months for GS+/+, 2.3 and 2.8 months for GS+/- and 2.4 and 2.9 months for GS-/- patients. Three grade 3 AEs and two SAEs unrelated to treatment were reported. All patients were seropositive for MAGE-A3 antibodies on vaccination with no differences between the different GS profiles. MAGE-A3-specific CD4+ and CD8+ T cell immunogenicity was detected; 12/16 (75.0%) of patients presented CD4+ T cell responses.

Conclusion: Treatment with MAGE-A3 immunotherapeutic showed signs of clinical activity in GS+/+ patients. Treatment was well tolerated and immunogenic. No differences in immune responses according to GS status were observed.

Trial Registration Number: NCT00896480 (Results).
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http://dx.doi.org/10.1136/esmoopen-2018-000384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069918PMC
July 2018

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

Lancet Oncol 2018 07 13;19(7):916-929. Epub 2018 Jun 13.

UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

Background: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.

Methods: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445.

Findings: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.

Interpretation: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.

Funding: GlaxoSmithKline Biologicals SA.
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http://dx.doi.org/10.1016/S1470-2045(18)30254-7DOI Listing
July 2018

A Single-Arm Phase II Trial of Lenalidomide in Relapsing or Refractory Primary Cutaneous Large B-Cell Lymphoma, Leg Type.

J Invest Dermatol 2018 09 27;138(9):1982-1989. Epub 2018 Mar 27.

INSERM U1053, Bordeaux Research in Translational Oncology, Team 3 oncogenesis of cutaneous lymphomas, Université de Bordeaux, Bordeaux, France; Tumor Bank and Tumor Biology Laboratory, CHU Bordeaux, Pessac, France.

Although the combination of rituximab and polychemotherapy has improved prognosis of primary cutaneous diffuse large B-cell lymphoma, leg type, the advanced age of patients limits therapeutic options in relapsing/refractory cases. A multicenter, single-arm, phase II trial was conducted to assess the benefits and safety of lenalidomide in refractory/relapsing primary cutaneous diffuse large B-cell lymphoma, leg type. The primary endpoint was the 6-month overall response rate. Secondary endpoints were 12-month overall response rate, overall and specific survival, duration of response, progression-free survival, safety, and identification of prognostic factors. Among the 19 patients included, the 6-month overall response rate was 26.3% (90% confidence interval [CI] = 11-47.6), including four complete responses and one partial response. At 12 months, there were still two complete responses and one partial response. Median progression-free survival was 4 months. Median overall and specific survivals were 19.4 and 23.8 months, respectively. Reduced doses tended to be associated with higher 6-month overall response rate and progression-free survival. Absence of the MYD88 mutation was associated with a higher overall response under treatment (80.0% vs. 33.3%; P = 0.05). The most common grade 3 adverse events were hematologic. Two grade 5 adverse events occurred (sepsis and pulmonary embolism). Lenalidomide at reduced doses may allow prolonged responses in a few patients and represents a therapeutic option in relapsing/refractory primary cutaneous diffuse large B-cell lymphoma, leg type.
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http://dx.doi.org/10.1016/j.jid.2018.03.1516DOI Listing
September 2018

Safety and immunogenicity of MAGE-A3 cancer immunotherapeutic with dacarbazine in patients with MAGE-A3-positive metastatic cutaneous melanoma: an open phase I/II study with a first assessment of a predictive gene signature.

ESMO Open 2017 14;2(5):e000203. Epub 2017 Nov 14.

Oncology Franchise, Celyad, Mont-Saint-Guibert, Belgium.

Background: We assessed safety, immunogenicity and clinical activity of recombinant MAGE-A3 antigen combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) in association with dacarbazine in patients with metastatic melanoma.

Methods: In this open-label, phase I/II, uncontrolled multicentre trial conducted in Belgium and France, patients with MAGE-A3-positive melanoma received up to 24 doses of MAGE-A3 immunotherapeutic (four cycles) coadministered with eight doses of dacarbazine. Adverse events (AE) were recorded until 31 days postvaccination, and serious AEs (SAE), until 30 days following the last dose. MAGE-A3-specific antibodies were measured by ELISA. Clinical activity of MAGE-A3 immunotherapeutic was assessed in patients positive/negative for previously identified gene signature (GS) associated with clinical outcome.

Results: Forty-eight patients were enrolled and treated (32 GS+, 15 GS-, 1 unknown GS status); two patients completed the study. All patients reported AEs, the most common were 'general disorders and administration site conditions' (94%). Treatment-related AEs were reported by 85% of patients; the most common was pain at injection site (38%). Sixteen SAEs were reported by 21% of patients; two were considered as treatment related (neutropenia and thrombocytopenia; grade 4). Postdose 4, all patients were seropositive for MAGE-A3-specific antibodies, with a geometric mean titre of 2778.7 ELISA units (EU)/mL (95% CI 1638.3 to 4712.8). One complete and three partial responses were reported (only in GS+ patients). Median overall survival was 11.4 months for GS+ and 5.3 months for GS- patients.

Conclusion: Although this trial shows poor results compared with the new results with checkpoint inhibitors, it gives an interesting insight in rapidly developing fields like combinations of immunotherapy and chemotherapy, new generation vaccines and the use of gene profile as a predictive marker.

Trial Registration Number: NCT00849875.
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http://dx.doi.org/10.1136/esmoopen-2017-000203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687540PMC
November 2017

STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network.

J Invest Dermatol 2018 01 24;138(1):58-67. Epub 2017 Aug 24.

Service de Dermatologie, and CIC (Centre d'Investigations Cliniques), AP-HP, Hôpital Saint-Louis, Paris, France; INSERM, UMR-976, AP-HP, Hôpital Saint-Louis, Paris, France; Université Paris Diderot, Sorbonne Paris Cité, Paris, France.

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.
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http://dx.doi.org/10.1016/j.jid.2017.07.839DOI Listing
January 2018

Economic burden of advanced melanoma in France, Germany and the UK: a retrospective observational study (Melanoma Burden-of-Illness Study).

Melanoma Res 2017 12;27(6):607-618

aDepartment of Dermatology, Reims University Hospital, Reims bGSK France, Marly le Roi cedex, France cClinic of Dermatology, Elbekliniken Buxtehude, Buxtehude dGSK GmbH & Co KG, Munich, Germany eDepartment of Medical Oncology, Guy's and St Thomas's Hospitals NHS, Foundation Trust, Guy's Hospital, London fGSK UK, Middlesex gHealth Economics, RTI Health Solutions, The Pavilion, Towers Business Park, Manchester, UK hPatient-Centered Outcomes Assessment, RTI Health Solutions, Research Triangle Park, North Carolina iDepartment of Epidemiology, RTI Health Solutions, Waltham, Massachusetts, USA jGSK Vaccines, Rue de l'Institut, Rixensart, Belgium.

The aim of this study was to estimate the cost-of-illness associated with completely resected stage IIIB/IIIC melanoma with macroscopic lymph node involvement, overall and by disease phase, in France, Germany and the UK. This retrospective observational study included patients aged older than or equal to 18 years first diagnosed with stage IIIB/IIIC cutaneous melanoma between 1 January 2009 and 31 December 2011. Data were obtained from medical records and a patient survey. Direct costs, indirect costs and patient out-of-pocket expenses were estimated in euros (€) (and British pounds, £) by collecting resource use and multiplying by country-specific unit costs. National annual costs were estimated using national disease prevalence from the European cancer registry and other published data. Forty-nine centres provided data on 558 patients (58.2% aged <65 years, 53.6% stage IIIB disease at diagnosis). The mean follow-up duration was 27 months (France), 26 months (Germany) and 22 months (UK). The mean total direct cost per patient during follow-up was €23 582 in France, €32 058 in Germany and €37 970 (£31 123) in the UK. The largest cost drivers were melanoma drugs [mean €14 004, €21 269, €29 750 (£24 385), respectively] and hospitalization/emergency treatment [mean: €6634, €6950, €3449 (£2827), respectively]. The total mean indirect costs per patient were €129 (France), €4,441 (Germany) and €1712 (£1427) (UK). Estimates for annual national direct cost were €13.1 million (France), €30.2 million (Germany) and €27.8 (£22.8) million (UK). The economic burden of stage IIIB/IIIC melanoma with macroscopic lymph node involvement was substantial in all three countries. Total direct costs were the highest during the period with distant metastasis/terminal illness.
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http://dx.doi.org/10.1097/CMR.0000000000000372DOI Listing
December 2017

Treatment patterns and outcomes of Stage IIIB/IIIC melanoma in France, Germany and the UK: A retrospective and prospective observational study (MELABIS).

Int J Clin Pract 2017 May;71(5)

GSK, Rue de l'Institut, Rixensart, Belgium.

Aim: Real-world data on treatment patterns/outcomes in patients with advanced melanoma, while scarce, are useful for health technology assessments that govern patient access in many countries. We collected retrospective data on treatment patterns among patients in France, Germany and the UK with Stage IIIB/IIIC melanoma with macroscopic lymph node involvement, whose primary melanoma and regional lymph node metastases had been completely resected.

Methods: Patients ≥18 years were diagnosed between 1 January 2009 and 31 December 2011. Data were obtained from patients' medical records and a patient survey.

Results: Forty-nine centres provided data on 558 patients: 53.6% had Stage IIIB disease; 58.2% were of working age (<65 years), 22.5% reported a change in employment status due to melanoma, 8% were on long-term sick leave; and 35.1% were deceased over the study period. Overall median distant metastases-free survival was 23.4 months and median disease-free survival was 13.3 months. Hospitalisation frequency increased during distant metastatic/terminal disease phases. Adjuvant therapy was received by 7.0% (14/199) of patients in France, 2.6% (5/195) in the UK, and 33.5% (55/164) in Germany. Low-dose interferon was used more frequently than other regimens. High-dose interferon was associated with discontinuation in 28.6% and dose delay/reduction in 33.3% of patients.

Conclusions: Rapid disease progression combined with increased use of healthcare resources in later phases of disease result in a high burden-of-illness for patients and healthcare providers. The use of adjuvant interferon therapy varies considerably in this population in the countries studied, highlighting the need for improved treatments for melanoma.
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http://dx.doi.org/10.1111/ijcp.12946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697614PMC
May 2017

Ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with unresectable or metastatic melanoma: a randomised, double-blind, multicentre, phase 3 trial.

Lancet Oncol 2017 05 27;18(5):611-622. Epub 2017 Mar 27.

University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.

Background: A phase 2 trial suggested increased overall survival and increased incidence of treatment-related grade 3-4 adverse events with ipilimumab 10 mg/kg compared with ipilimumab 3 mg/kg in patients with advanced melanoma. We report a phase 3 trial comparing the benefit-risk profile of ipilimumab 10 mg/kg versus 3 mg/kg.

Methods: This randomised, double-blind, multicentre, phase 3 trial was done in 87 centres in 21 countries worldwide. Patients with untreated or previously treated unresectable stage III or IV melanoma, without previous treatment with BRAF inhibitors or immune checkpoint inhibitors, were randomly assigned (1:1) with an interactive voice response system by the permuted block method using block size 4 to ipilimumab 10 mg/kg or 3 mg/kg, administered by intravenous infusion for 90 min every 3 weeks for four doses. Patients were stratified by metastasis stage, previous treatment for metastatic melanoma, and Eastern Cooperative Oncology Group performance status. The patients, investigators, and site staff were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study treatment. This study is completed and was registered with ClinicalTrials.gov, number NCT01515189.

Findings: Between Feb 29, and July 9, 2012, 727 patients were enrolled and randomly assigned to ipilimumab 10 mg/kg (365 patients; 364 treated) or ipilimumab 3 mg/kg (362 patients; all treated). Median follow-up was 14·5 months (IQR 4·6-42·3) for the ipilimumab 10 mg/kg group and 11·2 months (4·9-29·4) for the ipilimumab 3 mg/kg group. Median overall survival was 15·7 months (95% CI 11·6-17·8) for ipilimumab 10 mg/kg compared with 11·5 months (9·9-13·3) for ipilimumab 3 mg/kg (hazard ratio 0·84, 95% CI 0·70-0·99; p=0·04). The most common grade 3-4 treatment-related adverse events were diarrhoea (37 [10%] of 364 patients in the 10 mg/kg group vs 21 [6%] of 362 patients in the 3 mg/kg group), colitis (19 [5%] vs nine [2%]), increased alanine aminotransferase (12 [3%] vs two [1%]), and hypophysitis (ten [3%] vs seven [2%]). Treatment-related serious adverse events were reported in 133 (37%) patients in the 10 mg/kg group and 66 (18%) patients in the 3 mg/kg group; four (1%) versus two (<1%) patients died from treatment-related adverse events.

Interpretation: In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg, but with increased treatment-related adverse events. Although the treatment landscape for advanced melanoma has changed since this study was initiated, the clinical use of ipilimumab in refractory patients with unmet medical needs could warrant further assessment.

Funding: Bristol-Myers Squibb.
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http://dx.doi.org/10.1016/S1470-2045(17)30231-0DOI Listing
May 2017

A case of arthritis under pembrolizumab.

Joint Bone Spine 2017 03 23;84(2):243-244. Epub 2016 Apr 23.

Dermatology department, Robert-Debré hospital, Reims university hospitals, 51092 Reims, France.

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http://dx.doi.org/10.1016/j.jbspin.2016.03.003DOI Listing
March 2017

Ethanolic Extract of Algerian Propolis and Galangin Decreased Murine Melanoma Tumor Progression in Mice

Anticancer Agents Med Chem 2016 ;16(9):1172-83

Laboratoire de Dermatologie, Unité de Formation et de Recherche de Médecine, 51 rue Cognacq-Jay, 51095 REIMS Cedex.

Melanoma is the more dangerous skin cancer, and metastatic melanoma still carries poor prognosis. Despite recent therapeutic advances, prolonged survival remains rare and research is still required. Propolis extracts from many countries have attracted a great deal of attention for their biological properties. We here investigated the ability of an ethanolic extract of Algerian propolis (EEP) to control melanoma tumour growth when given to mice bearing B16F1melanoma tumour either as preventive or as therapeutic treatment. EEP given after tumour occurrence increased mice survival (+30%) and reduced tumour growth (-75%). This was associated with a decrease of the Mitotic Index (-75%) and of Ki-67 (-50%) expression. When given either before or both before and after tumour occurrence, EEP reduced tumour growth but without prolonging mice life. Isolation of B16F1 melanoma cells from resected tumour showed that preventive and curative EEP treatments reduced invasiveness by 55% and 40% respectively compared to control. Galangin, one of the most abundant flavonoids in propolis, significantly reduced the number of melanoma cells in vitro and induced autophagy/apoptosis dose dependently. In conclusion, we showed that EEP reduced melanoma tumour progression/dissemination and could extend mice lifespan when used as therapeutic treatment. Then, EEP may help patients with melanoma when used as a complementary therapy to classical treatment for which autophagy is not contraindicated.
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http://dx.doi.org/10.2174/1871520616666160211124459DOI Listing
June 2017

Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF-CRAF Heterodimerization.

Cancer Res 2016 Mar 29;76(6):1476-84. Epub 2016 Jan 29.

Département de médecine oncologique, Gustave Roussy, Villejuif, France. INSERM, U981, Villejuif, France. Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicetre, France.

BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF-CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared with untreated patients. Our findings reveal that BRAF-CRAF complex formation is significantly associated with BRAFi treatment, and may therefore serve as a useful biomarker of BRAFi-induced cutaneous and extracutaneous tumor formation.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-2900-TDOI Listing
March 2016

Prevalence of hepatitis B and C and sensibility of a selective screening questionnaire in patients receiving chemotherapy for solid tumors.

BMC Cancer 2015 Dec 23;15:999. Epub 2015 Dec 23.

CHU Reims, Hôpital Robert Debré, Structure Interne d'Hépato-Gastro-Entérologie et Cancérologie Digestive, Avenue du Génénal Kœnig, Reims, F-51092, France.

Background: Reactivation of hepatitis B or C virus can occur in patients undergoing chemotherapy. Recommendations for selective or systematic hepatitis B virus testing prior chemotherapy for solid tumors differ. The primary aim was to determine the seroprevalence of hepatitis B or C in a low endemic country. The second objective was to assess the relevance of a questionnaire on hepatitis B/C risk factors to consider a selective screening.

Methods: Patients were prospectively tested for hepatitis B/C markers. HBs antigen positive patients and isolated anti-HBc positive patients with detectable viral load received antiviral preventive treatment. Patients or physicians completed the questionnaire on infection risk factors.

Results: Among the 450 patients included, 388 were tested for all serological markers and had gastrointestinal (63.7%), lung (31.2%) and skin (4.6%) cancers. The prevalence of subjects exposed to hepatitis B virus was 8.5% (33/388). One patient tested positive for HBs antigen and received preventive treatment. Prevalence of subjects exposed to hepatitis C was 1.3% (5/388). The questionnaire sensitivity was 45.5%, 100% and 50% for detecting carriers of hepatitis B, C and one or the other, respectively.

Conclusions: Seroprevalence of hepatitis B was low. Selective screening with the questionnaire was insufficiently sensitive. Systematic screening with serological tests prior to chemotherapy in patients with solid tumors is therefore relevant.
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http://dx.doi.org/10.1186/s12885-015-2033-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4688993PMC
December 2015

Frequency and Risk Factors for Associated Lymphomas in Patients With Lymphomatoid Papulosis.

Oncologist 2016 Jan 14;21(1):76-83. Epub 2015 Dec 14.

Department of Dermatology, Rouen University Hospital and INSERM U 519, Institute for Research and Innovation in Biomedicine, Rouen University, Rouen, Normandy, France.

Background: Lymphomatoid papulosis (LyP) is classified as an indolent cutaneous lymphoma, but outcome dramatically worsens if LyP is associated with lymphoma. The frequency of this association remains unclear in the literature. Here, we assess the frequency and risk factors of association between LyP and another lymphoma in an 11-year retrospective study conducted in 8 dermatology departments belonging to the French Study Group on Cutaneous Lymphoma (FSGCL).

Patients And Methods: Patients with LyP were identified and data extracted from the FSGCL registry between 1991 and 2006. Patients were followed up to January 2014. Age, sex, number of skin lesions, histologic subtype, and genotype were recorded at baseline. Risk factors were determined using univariate and multivariate analysis. Cumulative probability of association was calculated using the Kaplan-Meier method.

Results: We observed 52 cases of lymphomas (cutaneous, n = 38; systemic, n = 14) in 44 of 106 patients (41%). Lymphoma diagnosis was concomitant with or prior to LyP diagnosis in 31 cases and occurred during the course of LyP in 21 cases (cutaneous, n = 14; systemic, n = 7; median delay: 5 years; interquartile range: 1.5-7 years). In multivariate analysis, main prognostic factors for association between LyP and another lymphoma were older age (odds ratio [OR]: 1.05 per year; 95% confidence interval [CI]: 1.01-1.08; p = .011) and presence of a T-cell clone in LyP lesions (OR: 7.55; 95% CI: 2.18-26.18; p = .001).

Conclusion: Older age and presence of a T-cell clone in LyP lesions are risk factors for associated lymphomas in patients with LyP. These findings should help to identify patients who require close management in clinical practice.

Implications For Practice: The management of lymphomatoid papulosis (LyP) is that of an indolent cutaneous lymphoma, based on its excellent prognosis. However, this good prognosis is altered if LyP is associated with lymphoma. Furthermore, risk factors for and frequency of this association remain unclear in the literature. The results presented here demonstrate a high rate of association between LyP and other lymphomas (41%) as well as a long median delay of occurrence (5 years), which emphasizes the need for prolonged follow-up of patients with LyP. Moreover, two main risk factors (i.e., older age and presence of a T-cell clone in LyP lesions) are highlighted, which should help clinical practitioners to identify patients who require close management.
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http://dx.doi.org/10.1634/theoncologist.2015-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709209PMC
January 2016

Melanomas Associated With Blue Nevi or Mimicking Cellular Blue Nevi: Clinical, Pathologic, and Molecular Study of 11 Cases Displaying a High Frequency of GNA11 Mutations, BAP1 Expression Loss, and a Predilection for the Scalp.

Am J Surg Pathol 2016 Mar;40(3):368-77

*Department of Biopathology, Leon Berard Center, Lyon †Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, NSW, Australia ‡Department of Dermatology, Lyon Sud Hospital Center, Pierre-Benite, CRCL and CHU of Lyon, Lyon §Department of Dermatology, CHU Besançon, Besançon ∥Department of Medical Oncology, Eugene Marquis Center, Rennes ¶Department of Dermatology, Robert Debre´ University Hospital, Reims #Department of Dermatology, CHU of Dijon, Dijon **Department of Dermatology CHRU of Lille, Lille ††Department of Dermatology, Institut Gustave Roussy, Villejuif ‡‡Department of Dermatocancerology, Hotel Dieu, Nantes §§Department of Pathology, Lyon Sud Hospital Center, Pierre-Benite ∥∥Department of Pathology, CHU of Bordeaux, Hospital Haut-Leveque, Pessac, France.

Melanomas associated with blue nevi (MABN) or mimicking cellular blue nevi (MMCBN) represent exceptional variants of malignant cutaneous melanocytic tumors. Uveal and leptomeningeal melanomas frequently have somatic mutations of GNAQ or GNA11, which are believed to be early driver mutations. In uveal melanomas, monosomy 3, linked to the BAP1 gene, is an adverse prognostic factor. We have studied the clinical, histologic, BAP1 expression profile, and molecular data of 11 cases of MABN/MMCBN and 24 cellular blue nevi. Most of the cases of MABN/MMCBN occurred on the scalps of adult patients and presented as rapidly growing nodules, typically >1 cm, often arising at the site of a preexisting melanocytic lesion. The MABN/MMCBN were composed of dense nests of large dermal atypical melanocytes, in some cases lying adjacent to a blue nevus. Four patients developed metastatic disease, and 2 died from their disease. A GNA11 mutation was found in 8/11 cases and a GNAQ mutation in 1 case. Seven of 11 cases showed loss of nuclear BAP1 immunohistochemical (IHC) expression in the malignant component, sparing the adjacent nevus. Array comparative genomic hybridization revealed recurrent deletions of chromosomes 1p, 3p, 4q, 6q, 8p, 16q, and 17q and recurrent gains of chromosomes 6p, 8q, and 21q. The 24 cases of cellular blue nevi frequently occurred on the sacrum, had GNAQ mutations, and showed normal positive IHC staining for BAP1. These results underscore overlapping features in all blue-like malignant melanocytic tumors. Loss of BAP1 IHC expression was restricted to melanomas, including all metastatic cases.
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http://dx.doi.org/10.1097/PAS.0000000000000568DOI Listing
March 2016

Kawasaki disease in adults: Observations in France and literature review.

Autoimmun Rev 2016 Mar 26;15(3):242-9. Epub 2015 Nov 26.

Service de Médecine Interne, DHUi2B, Hôpital Saint Antoine, AP HP, Université Pierre et Marie Curie, France.

Objective: Kawasaki disease (KD) is a vasculitis that mostly occurs in young children and rarely in adults. We analyzed the characteristics of adult-onset KD (AKD) in France.

Methods: We collected retrospective and prospective data for patients with a diagnosis of KD occurring after the age of 18 years. Cases were obtained via various French medical networks and identified from the international literature.

Results: We included 43 patients of AKD at 26 institution from 1992 to 2015, with mean (SD) age 30 (11) years (range 18-68) and sex ratio (M/F) 1.2; 34 patients met the American Heart Association criteria and 9 were incomplete AKD. The median time to diagnosis was 13 days (interquartile range 8-21). The main symptoms were fever (100%), exanthema (98%), changes in the extremities (91%), conjunctivitis (77%), oral cavity changes (89%), cervical adenitis (55%) and cardiac abnormalities (45%). Overall, 35% of patients showed large-vessel vasculitis: coronary vasculitis (26%) and coronary aneurysm (19%). Treatment was mostly intravenous immunoglobulins (79%) and aspirin (81%). Four patients showed myocardial infarction due to coronary vasculitis, but none were treated with IVIg because of late diagnosis. After a median follow-up of 5 months (range 1-117), persistent aneurysm was noted in 9% of cases. Damage was significantly lower with early treatment than late or no treatment (p=0.01).

Conclusion: Given the high frequency of cardiac involvement and complications in this series of AKD, diagnosis and treatment should not be delayed, and early IVIg treatment seems to improve the outcome.
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http://dx.doi.org/10.1016/j.autrev.2015.11.010DOI Listing
March 2016