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PURPOSE Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation. METHODS An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy. RESULTS One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%). CONCLUSION Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.

International audience; BACKGROUND:MITF encodes an oncogenic lineage-specific transcription factor in which a germline mutation ( MITFE318K ) was identified in human patients predisposed to both nevus formation and, among other tumor types, melanoma. The molecular mechanisms underlying the oncogenic activity of MITF E318K remained uncharacterized.METHODS:Here, we compared the SUMOylation status of endogenous MITF by proximity ligation assay in melanocytes isolated from wild-type (n = 3) or E318K (n = 4) MITF donors. We also used a newly generated Mitf E318K knock-in (KI) mouse model to assess the role of Mitf E318K (n = 7 to 13 mice per group) in tumor development in vivo and performed transcriptomic analysis of the tumors to identify the molecular mechanisms. Finally, using immortalized or normal melanocytes (wild-type or E318K MITF, n = 2 per group), we assessed the role of MITF E318K on the induction of senescence mediated by BRAF V600E . All statistical tests were two-sided.RESULTS:We demonstrated a decrease in endogenous MITF SUMOylation in melanocytes from MITF E318K patients (mean of cells with hypoSUMOylated MITF, MITF E318K vs MITF WT , 94% vs 44%, difference = 50%, 95% CI = 21.8% to 67.2%, P = .004). The Mitf E318K mice were slightly hypopigmented (mean melanin content Mitf WT vs Mitf E318K/+ , 0.54 arbitrary units [AU] vs 0.36 AU, difference = -0.18, 95% CI = -0.36 to -0.007, P = .04). We provided genetic evidence that Mitf E318K enhances BRaf V600E -induced nevus formation in vivo (mean nevus number for Mitf E318K , BRaf V600E vs Mitf WT , BRaf V600E , 68 vs 44, difference = 24, 95% CI = 9.1 to 38.9, P = .006). Importantly, although Mitf E318K was not sufficient to cooperate with BRaf V600E alone in promoting metastatic melanoma, it accelerated tumor formation on a BRaf V600E , Pten-deficient background (median survival, Mitf E318K/+ = 42 days, 95% CI = 31 to 46 vs Mitf WT = 51 days, 95% CI = 50 to 55, P

SummaryBackground Dermatofibrosarcoma protuberans (DFSP) is a rare malignant cutaneous tumour of which diagnosis is often delayed because of the lack of early clinical clues. Objectives To describe the main dermoscopic features of DFSP. Methods We performed dermoscopic examination in 15 unselected, consecutive cases of biopsy-proven DFSP. Firstly, six dermoscopic features were identified collegially, then all cases were reviewed separately by six experienced dermoscopists. In a given lesion, features recognized only by all dermoscopists were taken into account. Results The median number of dermoscopic features was four per lesion. The following dermoscopic features were found: delicate pigmented network (87%), vessels (80%), structureless light brown areas (73%), shiny white streaks (67%), pink background coloration (67%) and structureless hypo- or depigmented areas (60%). When detected, vessels were of arborizing type in 11 of 12 cases, and presented as either unfocused only, or both unfocused and focused. Conclusions This first study of the dermoscopic spectrum of DFSP identifies six dermoscopic features (often associated in a multicomponent pattern) and a peculiar vascular pattern. Whether dermoscopy can help to identify suspected DFSP remains to be established by further studies.

Summary Background New primary melanomas arising in patients with stage IV melanoma and receiving BRAF inhibitors have recently been reported. This raises the question of the nature of the earliest cellular events identifiable within pre-existing moles. Objectives To use reflectance confocal microscopy (RCM) to investigate changing moles in patients using vemurafenib. Methods In the first part of the study 23 lesions were examined by RCM before excision (performed because of digital dermoscopy changes) and histopathological examination. In the second part, 10 randomly chosen lesions in two patients were examined before and after 3 months of vemurafenib treatment. Results The first step permitted the highlighting of an unusual RCM pattern identified in five lesions characterized by areas of marked atypia in otherwise nondysplastic lesions. In the second step, four initially nondysplastic lesions developed focal or multifocal areas of marked atypia under treatment, which were not always correlated with digital dermoscopy changes, but did correlate with histopathology. All four lesions were finally diagnosed as melanomas. Conclusions Although the clinical relevance of such findings remains questionable, RCM allowed us to observe, at the cellular level, the earliest events occurring within vemurafenib-induced changing moles. Moreover, repeated RCM examinations permitted to confirm that microscopic marked atypia that led to the histopathological diagnosis of melanoma appeared under treatment and were not pre-existing.

SummaryBackground Amelanotic nail tumours are difficult to diagnose. Dermoscopy is an accessible tool successfully used in diagnosis of amelanotic or melanotic skin tumours. We have previously shown the usefulness of dermoscopy in the preoperative diagnosis of onychomatricoma (OM). In this study, we completed this work by identifying additional intraoperative criteria to better establish the initial diagnosis of this tumour. Aims Evaluation of intraoperative dermoscopy in a small series of OM cases in order to define relevant diagnostic criteria. Methods In total, 10 patients with OM diagnosed in our centre were enrolled in the study. Six trained dermoscopists individually evaluated each criterion, then the data were compared and a consensus reached after discussion between the observers. For each criterion, we analysed its frequency and its interobserver accordance. We defined three architectural criteria (the ‘Sagrada Familia’ sign, digitations and the ‘mirror sign’), and three vascular criteria (sagittal vessels, dotted vessels and irregular vessels). Results The Sagrada Familia sign, digitations and mirror sign were found in 100%, 90% and 70% of the cases, respectively, with high interobserver agreement. The vascular criteria were less regularly observed: sagittal, dotted and irregular vessels were respectively found in 80%, 70% and 50% of the OM cases, and were more difficult to assess, as shown by the lower interobserver agreement rates. Conclusion Intraoperative dermoscopy of the nail matrix and bed offers useful information for the diagnosis and management of OM. Larger comparative studies should be performed to evaluate the true benefit of this approach.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are detected in a minority of dermatomyositis patients, who typically show little or no myositis, an increased risk of interstitial lung disease (ILD) [1-3], and a peculiar skin involvement [2].A 19-year-old Caucasian woman presented a nine-month history of painful digital ulcerations, peripheral arthralgia, progressive muscle weakness, dysphagia, and exertional dyspnoea. At baseline, the pulp and lateral aspects of her fingers showed [...]

Nature 480, 94–98 (2011); doi:10.1038/nature10539 In this Letter, one image was mistakenly duplicated during preparation of the artwork. In the original Fig. 3d, the left image illustrating migration of RCC4 cells transduced with empty adenovirus (EV) at 24 h is a duplicate of the middle image showing migration of RCC4 cells transduced with an adenovirus encoding Mi-WT.

Background Reflectance confocal microscopy (RCM)'s interest has been well established for the non-invasive diagnosis of skin cancers, especially melanocytic, and in the differential diagnosis between benign and malignant cutaneous lesions. However, its diagnostic interest in inflammatory skin diseases still needs to be demonstrated. Our purpose was to evaluate the correlation between RCM and conventional histopathology in a series of pustular eruptions of different pathogeny. Methods Reflectance confocal microscopy analysis was performed in eight consecutive unselected patients in whom the diagnoses of pustular psoriasis, bacterial sur-infection, herpes-type virus skin sur-infection, Sneddon-Wilkinson subcorneal putulosis and Hailey-Hailey disease have been made and images were compared to conventional histopathology. Results Neutrophils within the epidermis exhibited never reported earlier specific features, with either a shiny granular sludge or polylobated particules with a bright granular content. Moreover, some specific etiologies could be identified, such as acantholysis and herpes-type virus-infected keratinocytes. Conclusion Our studies show a good correlation between RCM and conventional histopathology in pustular eruptions. Reflectance confocal microscopy may play an important role in the differential diagnosis of pustular eruptions; as most of the pathologic clues are epidermal, narrow thickness of the field of imaging, its main technical limitation, is indeed of lesser importance.

Summary Background Although dermoscopy of the nail plate is helpful to discriminate between benign and malignant causes of nail pigmentations, there remain ambiguous cases in which a matricial biopsy is required. When a subungual melanoma is diagnosed histopathologically, a complementary surgical treatment is performed secondarily, the duration of postoperative disability being accordingly prolongated. Objectives The purpose of our study was to evaluate the feasibility of an intraoperative diagnosis by reflectance confocal microscopy (RCM). Patients and methods Our series included nine consecutive patients who underwent a matricial biopsy for an acquired melanonychia (one benign lentigo and eight melanomas). RCM examination was performed in vivo on the nail matrix after reclination of the nail plate, and/or ex vivo on the fresh tissue biopsy. RCM data were compared with histopathology. Results There was a good correlation between confocal and histopathological features. Seven melanoma cases were unequivocally diagnosed intraoperatively according to the confocal features, whereas the lentigo was correctly classified as a benign lesion according to RCM. The remaining lesion could not be unequivocally classified by RCM and corresponded histopathologically to an early melanoma that required immunostaining to be diagnosed. Conclusions Intraoperative RCM examination of the nail matrix is an efficient diagnostic approach of melanonychia striata that permits an extemporaneous diagnosis of malignancy and therefore a one-step surgical treatment of in situ or minimally invasive melanoma, reducing dramatically the duration of postoperative disability.

Summary Background Lentigo maligna melanoma (LMM) is the most common subtype of melanoma on the face. Its presentation may be quite subtle, particularly in early stages, and delayed diagnosis is common. Few dermoscopic studies have been performed and the main dermoscopic features of LMM were defined by Stolz and coworkers in 2000. Objectives To investigate classical as well as new dermoscopic features in a large series of LMM in a white-skinned population, in order to evaluate their diagnostic value. Methods One hundred and twenty-five consecutive histopathology-proven LMMs were analysed retrospectively based on medical records, clinical and dermoscopic photographs by three independent observers for the presence of 19 predefined criteria. Results At least one of the classical Stolz criteria was present in 87% of cases (hyperpigmented follicular opening, annular-granular pattern, pigmented rhomboidal structures, obliterated hair follicles). Three original criteria were also present at a relatively high frequency: increased density of the vascular network (58%), red rhomboidal structures (40%), target-like patterns (41%). Darkening at dermoscopic examination (when compared with naked-eye examination) was observed in 25% of lesions. Classical dermoscopic features of extrafacial melanoma (atypical pigment network, irregularly distributed globules, dots, streaks and pseudopods) and vertical growth phase-associated dermoscopic criteria (ulceration, blue papular areas and black structureless areas) were rarely seen. A large number of colours, pigmented rhomboidal structures, obliterated hair follicles and red rhomboidal structures were significantly more frequent in invasive LMMs. In contrast, in situ melanomas were more often associated with one or two colours and few distinctive dermoscopic features. Conclusions We present herein, in a large series of LMM, confirmation of the diagnostic value of the classical Stolz dermoscopic criteria and describe four additional original criteria, mainly vascular. A correlation between the presence of some dermoscopic features and thicker tumoral invasion has also been demonstrated.

Background The ‘dermoscopic island’ is a term that was recently proposed to design an area of a pigmented lesion with a uniform dermoscopic pattern different from the remainder of the lesion. The positive predictive value of this sign for the diagnosis of melanoma is about 50%. Objective The purpose of our study was to see if reflectance confocal microscopy (RCM) permitted to accurately distinguish between nevi and melanoma in such lesions. Methods Five lesions of five consecutive unselected patients, with a dermoscopic island but no feasible clear cut diagnosis on the basis of dermoscopy alone were examined by RCM before excision for histopathological evaluation. Results Two lesions corresponded to nevi, and three lesions were early melanomas arising on a benign naevus in one case, and on a dysplastic naevus in two cases. In all five cases, RCM permitted to make the correct diagnosis, with a very good correlation with conventional histopathology. Conclusion Reflectance confocal microscopy appears as a promising tool not only to enhance the early diagnosis of melanoma but also to avoid unnecessary excisions of lesions with a dermoscopic island.

Summary Background Infliximab, an antitumour necrosis factor-α chimeric monoclonal antibody, is effective for the treatment of severe psoriasis. While the induction of antinuclear antibodies (ANA) and antidouble-stranded-DNA antibodies (anti-dsDNA-ab) is frequently observed in patients with rheumatoid arthritis and Crohn disease receiving infliximab, the incidence of induced biological and clinical autoimmunity remains unknown in the context of psoriasis. Objectives To investigate biological and clinical signs of autoimmunity in 28 patients receiving infliximab for severe, recalcitrant forms of psoriasis, and the clinical response to treatment. Methods Twenty-eight patients, 15 men and 13 women (median age 39·4 years) with psoriasis refractory to three or more systemic treatments were included. Twenty presented with plaque-type psoriasis [median Psoriasis Area and Severity Index (PASI) score 25·9; range 7·2–48], five with psoriatic erythroderma (median PASI score 54; range 48–72) and three with generalized pustular psoriasis (GPP). Psoriatic arthritis was present in 13 patients (46·4%). Infliximab 5 mg kg−1 was given at week (W) 0, W2, W6 and every 8 weeks thereafter. Clinical data were assessed at baseline and before each infusion. Detection of ANA and of IgM and IgG anti-dsDNA-ab were performed at baseline and at W22 by immunofluorescence and enzyme-linked immunosorbent assay, respectively. Results The mean number of infliximab infusions was 5·5 (range 2–15). Among patients with plaque-type and erythrodermic psoriasis, 17 of 25 (68%) and three of five reached a PASI improvement of 75% or more, respectively, while rapid improvement of clinical and biological signs was observed in all three patients with GPP. The prevalence of positive detection of ANA raised from 12% at baseline to 72% at W22 (P = 0·0001), an increase which was also observed for IgM anti-dsDNA-ab (68% vs. 0%, P

9535 Background: Vismodegib is a Hedgehog Pathway inhibitor (HPI) indicated for treatment of inoperable locally advanced basal-cell carcinoma (laBCC). Previous studies showed an objective response (OR) rate of 67%, including 34% of complete response (CR). Discontinuation of vismodegib is very frequent, mostly due to intolerable side-effects. Long-term response and predictive factors of relapse after suspension of vismodegib have not yet been evaluated, but should play a crucial role in the management of laBCC patients. Methods: We conducted an observational retrospective study in 9 onco-dermatological French units. Medical charts of laBCC patients treated with vismodegib from March 2012 until June 2016 were reviewed and patients with CR who stopped treatment were selected. Relapse was diagnosed clinically and/or histologically. A survival analysis was conducted, and predictive factors, characterization and management of relapse were studied. Results: 119 laBCC patients achieved CR and stopped treatment. 21 were lost to follow-up and 6 died before relapse. Event-free survival median was 18.4 months (12.1 – 24.1) and cumulative incidence of relapse at 36 months was 59.04% (48.05 - 70.04), implying that more than 40% of patients do not relapse. Multiple BCC and BCC not localized on the head and neck were associated with a higher risk of relapse, independently of the existence of Gorlin syndrome (HR = 3.3 (IC95 = 1.6 - 6.7) and 2.01 (IC95 = 1.05 - 3.87) respectively). Total duration of treatment was not associated with relapse. 50% (n = 27) of patients who relapsed during follow-up were retreated with vismodegib, with an OR of 85.2% (n = 23). 42% (n = 24) were eligible to surgery only and other patients received local treatments. Conclusions: Long term responders after vismodegib treatment discontinuation are frequent independently of the time exposure to the drug before and after CR. Most patients who relapse are still responder to vismodegib rechallenge. Patients with multiple or laBCC not localized on the head and neck are more at risk of relapse after discontinuation. This study emphasizes the interest of treatment of laBCC with HPI.

Background: Vismodegib therapy achieves a breakthrough in patients with locally advanced basal cell carcinoma (BCC). Yet, long-term safety of hedgehog pathway inhibitors remains to be established, while drug resistance is becoming a new challenging issue. Case Report: We report the case of a 90-year-old male initially referred for a locally advanced BCC of the nose. He had been previously treated by topical 5-fluorouracil for an adjacent microinvasive squamous cell carcinoma (SCC), with complete clinical response. Afterwards, vismodegib was initiated to treat his BCC. At week 16, both tumor and tumor ulceration obviously progressed. Palliative rhinectomy was performed. Histological examination found a deeply invasive SCC. Conclusion: Although our case must be interpreted with caution, a role of vismodegib as a promoter of cutaneous SCC should be considered, consistently with recently published evidence. Physicians should perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors.

9562Background: A Hh pathway inhibitor, vismodegib (VISMO) is approved for the treatment of locally advanced (la BCC) and metastatic BCC (mBCC). While most patients respond to drug treatment, in th...

Background Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -naive patients with refractory cutaneous T-cell lymphoma (CTCL). Patients and methods Patients with CTCL subtypes mycosis fungoides and Sezary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20 mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir. Results Seventy-nine bexarotene-exposed and 60 bexarotene-naive patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -naive groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -naive groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-naive patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable. Conclusion Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -naive CTCL patients. ClinicalTrials.gov Identifier: NCT00425555 .

International audience

Background/Objectives Seborrheic keratoses are ubiquitous benign epithelial skin tumours. A number of unusual locations have already been reported. We report herein the case of a seborrheic keratosis of the nail bed with typical histological features. Methods/Results A 58-year-old man presented with a 1-year-history of longitudinal leukoxanthonychia of the right hallux. Surgical treatment was performed. The diagnosis of typical seborrheic keratosis of the nail bed was made on histological examination. Conclusion To our knowledge, this is the first report of a typical, histologically documented seborrheic keratosis of the nail bed. Therefore, this condition should be added to the differential diagnosis of acquired longitudinal leukoxanthonychia. However, surgical treatment remains necessary to rule out other causes, including squamous cell carcinoma.