Operational classification of cutaneous squamous cell carcinomas based on unsupervised clustering of real cases by experts.

BACKGROUND: There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision-making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas. OBJECTIVE: To generate a consensual and operational classification of cSCCs. METHOD: Unsupervised independent clustering of 248 cases of cSCCs considered difficult-to-treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K-mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners. RESULTS: Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy-to-treat cSCC was included, resulting in a six-group final classification: easy-to-treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases. CONCLUSION: Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials.

Treatment with a retinoic acid-inducible gene I (RIG-I) agonist as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors: results from two phase 1 studies.

BACKGROUND: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138). PATIENTS AND METHODS: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs. RESULTS: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines. CONCLUSIONS: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03065023 and NCT03739138.

Position statement on classification of basal cell carcinomas. Part 2: EADO proposal for new operational staging system adapted to basal cell carcinomas.

BACKGROUND: No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision-making, trials and guidelines. Unsupervised clustering of real cases of difficult-to-treat BCCs (DTT-BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT-BCCs based on five patterns of clinical situations. OBJECTIVE: Using this five patterns to generate an operational and comprehensive classification of BCCs. METHOD: Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. RESULTS: Sixty-two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT-BCCs, agreed on 90% of cases when classifying 199 DTT-BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT-BCCs were added a group representing the huge number of easy-to-treat BCCs, for which sub-classification has little interest, and a group of very rare metastatic cases, resulting in a four-stage and seven-substage staging system of BCCs. CONCLUSION: A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.

Position statement on classification of basal cell carcinomas. Part 1: unsupervised clustering of experts as a way to build an operational classification of advanced basal cell carcinoma based on pattern recognition.

BACKGROUND: No simple classification system has emerged for 'advanced basal cell carcinomas', and more generally for all difficult-to-treat BCCs (DTT-BCCs), due to the heterogeneity of situations, TNM inappropriateness to BCCs, and different approaches of different specialists. OBJECTIVE: To generate an operational classification, using the unconscious ability of experts to simplify the great heterogeneity of the clinical situations into a few relevant groups, which drive their treatment decisions. METHOD: Non-supervised independent and blinded clustering of real clinical cases of DTT-BCCs was used. Fourteen international experts from different specialties independently partitioned 199 patient cases considered 'difficult to treat' into as many clusters they want (≤10), choosing their own criteria for partitioning. Convergences and divergences between the individual partitions were analyzed using the similarity matrix, K-mean approach, and average silhouette method. RESULTS: There was a rather consensual clustering of cases, regardless of the specialty and nationality of the experts. Mathematical analysis showed that consensus between experts was best represented by a partition of DTT-BCCs into five clusters, easily recognized a posteriori as five clear-cut patterns of clinical situations. The concept of 'locally advanced' did not appear consistent between experts. CONCLUSION: Although convergence between experts was not granted, this experiment shows that clinicians dealing with BCCs all tend to work by a similar pattern recognition based on the overall analysis of the situation. This study thus provides the first consensual classification of DTT-BCCs. This experimental approach using mathematical analysis of independent and blinded clustering of cases by experts can probably be applied to many other situations in dermatology and oncology.

ESMO consensus conference recommendations on the management of locoregional melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee.

The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment for brain metastases. The expert panel was divided into five working groups to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of metastatic melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

[Five years' experience of cosmetic camouflage of disfiguring skin disorders: Patient satisfaction]. / Cinq ans d'expérience d'un atelier de maquillage médical correcteur des dermatoses affichantes : évaluation par la satisfaction des patients.

INTRODUCTION: Living with disfiguring disorders can impair the emotional well-being and relationships of patients as well as their social and professional life. Since 2010, courses in medical cosmetic correction for disfiguring diseases have been conducted at the dermatology department of the Timone University Hospital in Marseille and they form part of an educational program. The aim of this study was to assess the satisfaction of patients taking part in this program. PATIENTS AND METHODS: This is a retrospective study of 55 patients taking part in make-up sessions from January 2010 to December 2014 and subsequently completing a questionnaire. RESULTS: The median patient age was 46 years with most being women (n=49, 89 %). They presented pigmentary disorders (54.5 %), inflammatory diseases (27.3 %) and scars (18.2 %). 75 % of patients stated that they had improved their knowledge and 82 % remarked that the technique was personalized to their needs. The technique was considered as easy by 62 % and reproducible by 87 % of patients. 55 % of patients considered that cosmetic camouflage improved their quality of life and 56 % stated that it helped them accept the gaze of others. CONCLUSION: In our study skin camouflage appears easy to use and meets patient expectations.

Survival of melanoma patients treated with targeted therapy and immunotherapy after systematic upfront control of brain metastases by radiosurgery.

BACKGROUND: Targeted therapy (TT) and immunotherapies (ITs) have dramatically improved survival in metastatic melanoma (MM). However, their efficacy on brain metastasis (BM) remains limited and poorly documented. PATIENTS AND METHODS: Retrospective cohort of consecutive MM patients (pts) with BMs, all systematically upfront treated by Gamma-Knife (GK) at first BM and retreated in case of new BMs, from 2010 to 2015 at the time when ipilimumab BRAF ± MEK inhibitors and anti-PD1 were introduced in practice. Survival after 1st GK (OSGK1) according to prognostic factors and treatment. RESULTS: Among 179 consecutive pts treated by GK, 109 received IT and/or TT after the 1st GK. Median OSGK1 was 10.95 months and 1- and 2-year survival rates were 49.5% and 27.4%, respectively, versus a median overall survival (OS) of 2.29 months (p < .001) in those who did not receive IT or TT. In pts who initially had a single BM, median OS and 1- and 2-year survival rates were 14.46 months, 66.7% and 43.4%, respectively; in pts with 2-3 BMs: 8.85 months, 46.4% and 31%, respectively; in pts with >3 BMs: 7.25 months, 37.2% and 11.9%, respectively. Multivariate analysis for OSGK1 confirmed that IT and TT were significantly and highly protective. Best OSGK1 was observed in BRAF-wild-type pts receiving anti-PD1 or in BRAF-mutated pts receiving BRAF-inhibitors and anti-PD1 (12.26 and 14.82 months, respectively). CONCLUSION: In real-life MM pts with BMs, a strategy aiming at controlling BM with GK together with TT and/or TT seems to achieve unprecedented survival rates.

[Evaluation of practices in the management of scabies in children]. / Évaluation des pratiques dans la prise en charge de la gale chez les enfants.

BACKGROUND: Scabies has been on the rise in France in recent years and has posed therapeutic problems, mainly due to the withdrawal of benzyl benzoate. The objective of this study was to describe prescribing practices for scabies in children. METHODS: A national survey was conducted by means of a standardized questionnaire covering various clinical situations of scabies and the drugs used preferentially according to age, which was sent out between December 2014 and March 2015 to members of the clinical research group of the French Society of Paediatric Dermatology. RESULTS: Of the 38 experts contacted, 20 replied. For a typical case of scabies, 55% of the experts initially prescribed oral ivermectin for children aged 6 years, 15% prescribed ivermectin in children aged 2 years, and 5% in infants aged 3 months. Ivermectin was more widely prescribed after failure of prior treatment or recurrence of scabies, on skin lesions or impetigo, if precarious, especially for profuse hyperkeratotic scabies. A total of 35% of the experts reported no prescribing restrictions with regard to patient age or weight. Discrepancies were observed concerning the mode of administration and the time between consecutive doses. Esdepallethrin remained the preferred local treatment among the experts (38% of all topical prescriptions) except in asthmatic children, while permethrin was the least-prescribed topical agent. DISCUSSION: This study confirms the heterogeneity of our practices. Formal expert recommendations are awaited, particularly concerning the use of ivermectin in infants.

Predictors of long-term drug survival for infliximab in psoriasis.

BACKGROUND: Limited information is available regarding factors associated with long-term drug survival of infliximab for psoriasis in real life. OBJECTIVES: The main aim pf this study was to identify predictors of long-term (>12 months) drug survival among patients treated with infliximab for psoriasis in a real-world clinical setting. METHODS: Retrospectively collected data, relating to disease, patient characteristics and treatment procedures, in a multicentre observational cohort of patients with moderate-to-severe plaque psoriasis treated with infliximab at eight university hospitals, 120 of whom maintained a response to infliximab for more than 12 months, were compared with prospectively collected data in the same centres from 54 patients who experienced secondary loss of response within a 12-month period. RESULTS: Mean duration of drug survival of infliximab in patients with long-term drug survival was 41.12 months ± 20.64 SD vs. 8.5 months ± 2.43 SD in patients with a secondary loss of response. Multivariate analysis identified greater disease severity at treatment onset (PASI score >12) (OR = 5.18, 95% CI: 1.60-16.77, P = 0.006), high levels of initial psoriasis clearance (PASI-90 reduction or equivalent) (OR = 18.50, 95% CI: 4.56-74.45, P = 0.0001) and combination with methotrexate (OR = 13.15, 95% CI: 1.46-118.79, P = 0.022) as independent predictors of long-term drug survival and sustained efficacy of infliximab. CONCLUSION: Positive predictors for long-term drug survival of infliximab in real life were identified. Their impact on treatment management should be addressed in further prospective trials.

[Cutaneous adverse events of telaprevir/peginterferon/ribavirin therapy for chronic hepatitis C: A multicenter prospective cohort study]. / Effets secondaires cutanés de l'association télaprévir/peg-interféron/ribavirine pour le traitement de l'hépatite C chronique : étude prospective d'une cohorte multicentrique.

BACKGROUND: Telaprevir, sale of which was suspended, has been approved in combination with pegylated interferon and ribavirin (triple therapy) in the treatment of chronic hepatitis C virus (HCV). Skin eruptions and isolated cases of severe cutaneous adverse reactions (SCAR) have been reported. AIMS: Our aim was to assess the incidence of skin eruption and the clinical characteristics of mucocutaneous adverse events (AE), and to identify potential risk factors for telaprevir-associated skin eruption. PATIENTS AND METHODS: A prospective observational multicenter follow-up cohort study with monthly controls by a dermatologist and additional examinations in case of any undercurrent AE. RESULTS: Among the 48 enrolled patients, the incidence of skin eruption was 58.4%, consisting mainly of maculopapular and eczematous lesions and only one case of SCAR. Telaprevir was discontinued in 6% of patients due to severe rash, whereas peginterferon and ribavirin were continued. The median time to onset of rash following telaprevir initiation was 25 days (range: 3-79 days). The rash was preceded by skin dryness and associated with pruritus in 100% and 90% of patients, respectively. Of those presenting with skin eruption, 37.5% also complained of conjunctival or oral lesions, or of anorectal symptoms. Neither a past history of dermatological conditions nor sociodemographic or viral status was predictive factor for skin rash. CONCLUSIONS: Telaprevir-related dermatitis has a high incidence but is mostly of mild intensity. In most cases, tri-therapy was continued under close dermatological follow-up allowing rapid detection of rare instances of severe drug eruptions. Ribavirin and Interferon were thus continued even in the event of diffuse eruptions, enabling confirmation of the causative role of telaprevir in these eruptions.

[Therapeutic failure in scabies: An observational study]. / Gales en échec de traitement : étude observationnelle.

BACKGROUND: Several sources suggest an escalation of scabies in France. AIM: To describe a population of patients continuing to present with scabies despite multiple treatments in order to identify factors associated with persistence of infection. PATIENTS AND METHODS: A descriptive cross-sectional study in adults and children consulting for persistent scabies despite at least one previous treatment. A standardized questionnaire explored potential sources of treatment failure. RESULTS: Thirty-one patients were analyzed. Initial symptoms were noted to have started between two and 52 weeks earlier (mean: 19 weeks). The mean number of prior consultations with a general practitioner was 3.1 (0-10) and 1.7 with a dermatologist (0-7). The mean number of patients per household was 3.5 (1-9). At least one dose of oral ivermectin (maximum of 6 doses per household) was prescribed for 84 % of patients (29 % of whom were not fasted at the time). Further, 74 % of patients received at least one local application of esdepallethrin and piperonyl butoxide (maximum: 5 courses), four received benzyl benzoate and two received permethrin; however, 58 % did not reapply the substance after hand washing. All households bought the prescribed treatments despite the costs. Close contacts of patients were treated in 58 % of households. Decontamination of bedding and clothing was carried out properly in 90 % of households. DISCUSSION: Persistence of infection appears to be linked to: (1) insufficient treatment of close contacts; (2) absence of a second treatment between days 7 and 14; (3) insufficient efficacy of the available treatments, doubtless due to multiple factors (intrinsic resistance of Sarcoptes, failure to repeat treatment, poor explanation of methods for dosing and application, and oral intake of treatments). Access to non-reimbursed treatments was not identified as a problem and decontamination of bedding and clothing was correctly performed in most cases. CONCLUSION: Though certain fundamental aspects of scabies treatment must be better known, longer consultations and provision of efficacious treatments are also a priority.

On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases.

BACKGROUND: Both Gamma-Knife radiosurgery (GKRS) and BRAF inhibitors (BRAF-I) have been shown to be useful in melanoma patients with brain metastases (BMs), thus suggesting that it could be interesting to combine their respective advantages. However, cases of radiosensitization following conventional radiation therapy in BRAF-I treated patients have raised serious concerns about the real feasibility and risk/benefit ratio of this combination. PATIENTS AND METHODS: Review by two independent observers of brain magnetic resonance imaging (MRI) follow-up pictures, and volume and edema quantifications, and survival assessment in all patients who had been treated by GKRS and BRAF-I at a single institution. RESULTS: Among 53 GKRS carried out in 30 patients who ever received BRAF-I and GKRS, 33 GKRS were carried out in 24 patients while under BRAF-I treatment, from which only 4 with an interruption of BRAF-I. The 20 other GKRS were carried out in 15 patients (including 9 of the 24) before initiation of BRAF-I treatment. No case of radiation-induced necrosis and no scalp radiation dermatitis occurred. A >20% increase in volume was observed in 35 of the 263 BM treated by GKRS (13.3%), but only 3 clear-cut edemas and 3 hemorrhages were detected within 2 months after GKRS, and 4 edemas and 7 hemorrhages later. Neither the MRI features nor the incidence of the volume changes, hemorrhage and edema were deemed unexpected for melanoma BM treated by GKRS. Median survival from first GKRS under BRAF-I and first dose of BRAF-I were 24.8 and 48.8 weeks, respectively. CONCLUSION: This series does not show immediate radiotoxicity nor radiation recall, in melanoma patients with BRAF-I whose BMs are treated by GKRS. Interrupting BRAF-I for stereotactic radiosurgery (SRS) of BM seems useless, although it is still advised for other radiation therapies. The potential benefit of combining SRS and BRAF-I can be safely tested.

[Telangiectasia during amlodipine therapy]. / Télangiectasies au cours d'un traitement par amlodipine.

BACKGROUND: Calcium inhibitors are recommended as first-line treatment in hypertension. We report the development of telangiectasia on the trunk and upper limbs in a female patient on amlodipine (Amlor(®)) that subsided on treatment discontinuation. PATIENTS AND METHODS: A 63-year-old woman consulted for numerous asymptomatic stellate telangiectasias on her upper trunk and shoulders, with sparing of the face. No Darier's sign was seen and clinical examination was otherwise normal. The patient had been treated with amlodipine (Amlor(®)) and a combination of bisoprolol and hydrochlorothiazide (Lodoz(®)) for 5years for essential hypertension. Laboratory tests, which included serum tryptase assay, were normal. Histological analysis showed a normal epidermis with dilated superficial dermal capillaries and no inflammatory infiltrate or dermal elastosis. Amlodipine was discontinued and replaced with ramipril (an ACE inhibitor). The other treatments were changed over and the telangiectasias regressed spontaneously within several months, with no relapse being seen at one year of follow-up. COMMENTS: Reports of telangiectasia associated with calcium inhibitors most commonly involve the dihydropyridine family, of which amlodipine is a member. Inhibition of muscular contraction induced by this treatment results in vasodilatation, accounting for the associated antihypertensive properties, and this could play a role in telangiectasia formation. The literature contains reports of cases of photo-distributed telangiectasia, suggesting that as well as vasodilatation, calcium inhibitors may in certain cases cause abnormal sensitivity of blood vessels to ultraviolet radiation. The absence of facial lesions rules out the hypothesis of photo-induced lesions in our patient.