Nailfold dermoscopy predicts the absence of a capillaroscopy sclerodermic pattern: The multicentre, prospective VASCUL-R trial.

BACKGROUND: Nailfold capillaroscopy is recommended to diagnose primary or secondary Raynaud's phenomenon (RP). Capillaroscopy is normal in primary RP, which is the most frequent. Screening for RP capillary anomalies with nailfold dermoscopy has been promising. OBJECTIVE: To determine whether normal nailfold dermoscopy-based on the absence of five criteria that define a sclerodermic pattern-is able to predict normal capillaroscopy with good positive-predictive value (PPV). METHODS: Prospective, 2-phase (monocentre and multicentre) study on patients at first consultation for RP undergoing nailfold video capillaroscopy (NVC) and nailfold dermoscopy by two different 'blinded' trained observers, respectively, a vascular specialist and a dermatologist, not familiar with capillaroscopy. The five criteria noted were as follows: disorganization, megacapillaries, low capillary density, avascular areas and haemorrhages. RESULTS: Based on 105 patients, the dermoscopy PPV for a normal NVC was 100% (p = 0.015), with 37.9% sensitivity, when no criterion was observed. Excluding haemorrhages, the PPV remained 100% (p < 0.0001), with sensitivity rising to 73.7% and 100% specificity. CONCLUSION: Normal nailfold dermoscopy with the absence of four easy-to-observe criteria predicts normal NVC with an excellent PPV.

Asymmetric periflexural exanthem of childhood and influenza virus infection.

Asymmetric periflexural exanthem of childhood (APEC) is a self-limited disease characterized by unilateral exanthem. The etiology is unknown, but a viral agent is suspected. Most often there is no formal proof of an associated viral etiology, but several associations between APEC and some viruses have been described. We report a 2-year-old girl with APEC associated with influenza A. This case allows us to provide an additional argument on a probable viral etiology of APEC and a possible etiologic role of influenza A.

Iatrogenic cutaneous graft versus host disease.

A 65-year-old man with acute myeloid leukemia 6 was treated by bone marrow allograft, developed a systemic classic chronic graft versus host disease with hepatic, rheumatologic, ophthalmic, and muco-cutaneous involvement. He received systemic corticosteroid, ruxolitinib and extracorporeal photopheresis which resulted in complete remission. During follow-up the patient presented with viral cutaneous warts on his neck and submandibular area. After various subsequent topical treatments, he developed localized cutaneous GVHD without any general GVHD reactivation symptoms. To the best of our knowledge, there has been no description in the literature of a graft versus host disease developing after local immunomodulatory or cytotoxic treatments. Topical therapies are commonly used by dermatologists for superficial skin cancers and some viral skin lesions, in high risk populations such as organ transplant patients with regular follow-up.Practitioners should be made aware of a possible localized cutaneous GVHD reactivation induced by Koebner phenomenon after local therapy.

Acrodermatitis continua of Hallopeau response to optimized biological therapy.

Acrodermatitis continua of Hallopeau, first described in 1890, is an uncommon variant of pustular psoriasis. It presents as a sterile pustular eruption of the tips of fingers and toes. The condition has a chronic, relapsing course and is often resistant to many anti-psoriatic therapies. In the following case, we present our experience of etanercept use in a 61-year-old man. Although initial therapy with high-dose etanercept achieved a rapid, sustained response and remission, the lesions relapsed a few months into a lower, maintenance dosage. This result prompted the use a second biotherapeutic agent ustekinumab, which resulted in complete remission, but required a higher dosage than recommended with reduced dosing intervals.

Lower-limb Ulcers in Systemic Sclerosis: A Multicentre Retrospective Case-control Study.

Lower-limb ulcers in systemic sclerosis patients are rarely reported. The aim of this study was to describe the main causes and outcomes of lower-limb ulcers in systemic sclerosis patients and to assess factors associated with ischaemic causes (arterial disease and/or microvascular impairment). A retrospective, multicentre, case-control study was conducted in 2013 and 2014, including 45 systemic sclerosis patients presenting lower-limb ulcers between 2008 and 2013. The estimated prevalence of lower-limb ulcers among systemic sclerosis patients was 12.8%. Ulcers were related to venous insufficiency in 22 cases (49%), ischaemic causes in 21 (47%) and other causes in 2 (4%). Complete healing was observed in 60% of cases in a mean time of 10.3 months; 59% relapsed during a mean follow-up of 22 months. Ischaemic lower-limb ulcer outcomes were poor, with a 28.6% amputation rate. Logistic-regression multivariate analyses between ischaemic lower-limb ulcer cases and matched systemic sclerosis-controls identified past or concomitant digital ulcer and cutaneous sclerosis of the feet as independent risk factors associated with ischaemic lower-limb ulcers.

Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options.

Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.

Sentinel node status and immunosuppression: recurrence factors in localized Merkel cell carcinoma.

The prognostic value of the sentinel lymph node in Merkel cell carcinoma (MCC) has been examined previously in heterogeneous retrospective studies. The current retrospective study included a homogeneous population of patients with a localized MCC, all staged with sentinel lymph node biopsy. Factors associated with 3-year progression-free survival were analysed using logistic regression. The sentinel lymph node was positive in 32% of patients. The recurrence rate was 26.9%. In first analyses (n = 108), gender (p = 0.0115) and the presence of immunosuppression (p = 0.0494) were the only significant independent factors. In further analyses (n = 80), excluding patients treated with regional radiotherapy, sentinel lymph node status was the only significant prognostic factor (p = 0.0281). Immunosuppression and positive sentinel lymph node are associated with a worse prognosis in patients with MCC. Nodal irradiation impacts on the prognostic value of the sentinel lymph node status.

Generalized pruritus in dysmetabolic hyperferritinemia treated by phlebotomy.

This paper describes a case of pruritus caused by dysmetabolic hyperferritinemia treated by multiple phlebotomies. A 63-year-old man was followed for generalized pruritus, which was resistant to the usual treatments. He presented with metabolic syndrome. Physical examination showed only excoriations and lichenification on the skin. The serum ferritin was high at 1043 ng/ml, with transferrin saturation at 67%. The other biological investigations and genetic tests for hemochromatosis were negative. In spite of the dietary measures, the ferritin level was still high (853 ng/ml). Magnetic resonance imaging confirmed hepatic iron overload.The association of hyperferritinemia, hepatic iron overload, and metabolic syndrome led to the diagnosis of dysmetabolic hyperferritinemia. Phlebotomies are an unusual treatment, but because the pruritus and hyperferritinemia were still present, phlebotomy was initiated. After 19 months, the patient reported improvement of his pruritus and normalization of ferritin levels.

Clostridium difficile infection and immune checkpoint inhibitor-induced colitis in melanoma: 18 cases and a review of the literature.

Immunotherapy has become the standard of care for several types of cancer, such as melanoma. However, it can induce toxicity, including immune checkpoint inhibitor-induced colitis (CIC). CIC shares several clinical, histological, biological, and therapeutic features with inflammatory bowel disease (IBD). Clostridium difficile infection (CDI) can complicate the evolution of IBD. We aimed to characterize the association between CDI and CIC in patients treated with anti-CTLA-4 and anti-PD-1 for melanoma. Patients from nine centers treated with anti-CTLA-4 and anti-PD-1 for melanoma and presenting with CDI from 2010 to 2021 were included in this retrospective cohort. The primary endpoint was the occurrence of CIC. The secondary endpoints were findings allowing us to characterize CDI. Eighteen patients were included. Eleven were treated with anti-PD-1, four with anti-CTLA-4, and three with anti-PD-1 in combination with anti-CTLA-4. Among the 18 patients, six had isolated CDI and 12 had CIC and CDI. Among these 12 patients, eight had CIC complicated by CDI, three had concurrent CIC and CDI, and one had CDI followed by CIC. CDI was fulminant in three patients. Endoscopic and histological features did not specifically differentiate CDI from CIC. Nine of 11 patients required immunosuppressive therapy when CDI was associated with CIC. In nine cases, immunotherapy was discontinued due to digestive toxicity. CDI can be isolated or can complicate or reveal CIC. CDI in patients treated with immunotherapy shares many characteristics with CDI complicating IBD. Stool tests for Clostridium difficile should be carried out for all patients with diarrhea who are being treated with immunotherapy.

Elastic fiber alterations and calcifications in calcific uremic arteriolopathy.

Calcific uremic arteriolopathy (CUA) is a severely morbid disease, affecting mostly dialyzed end-stage renal disease (ESRD) patients, associated with calcium deposits in the skin. Calcifications have been identified in ESRD patients without CUA, indicating that their presence is not specific to the disease. The objective of this retrospective multicenter study was to compare elastic fiber structure and skin calcifications in ESRD patients with CUA to those without CUA using innovative structural techniques. Fourteen ESRD patients with CUA were compared to 12 ESRD patients without CUA. Analyses of elastic fiber structure and skin calcifications using multiphoton microscopy followed by machine-learning analysis and field-emission scanning electron microscopy coupled with energy dispersive X-ray were performed. Elastic fibers specifically appeared fragmented in CUA. Quantitative analyses of multiphoton images showed that they were significantly straighter in ESRD patients with CUA than without CUA. Interstitial and vascular calcifications were observed in both groups of ESRD patients, but vascular calcifications specifically appeared massive and circumferential in CUA. Unlike interstitial calcifications, massive circumferential vascular calcifications and elastic fibers straightening appeared specific to CUA. The origins of such specific elastic fiber's alteration are still to be explored and may involve relationships with ischemic vascular or inflammatory processes.

A randomized, controlled, double-blind prospective trial with a Lipido-Colloid Technology-Nano-OligoSaccharide Factor wound dressing in the local management of venous leg ulcers.

Venous leg ulcers (VLUs) are the most prevalent chronic wounds in western countries with a heavy socioeconomic impact. Compression therapy is the etiologic treatment of VLU but until now no wound dressing has been shown to be more effective than another. The aim of this study was to assess the efficacy of a new dressing in the management of VLU. Adult patients presenting a noninfected VLU and receiving effective compression therapy were enrolled in this randomized, controlled, double-blind trial. The VLUs were assessed every 2 weeks for 8 weeks. The primary study outcome was the relative Wound Area Reduction (WAR, in %), and the secondary objectives were absolute WAR, healing rate, and percentage of wounds with >40% surface area reduction. One hundred eighty-seven patients were randomly allocated to treatment groups. Median WAR was 58.3% in the Lipido-Colloid Technology-Nano-OligoSaccharide Factor (TLC-NOSF) dressing group (test group) and 31.6% in the TLC dressing group (control group) (difference: -26.7%; 95% confidence interval: -38.3 to -15.1%; p = 0.002). All other efficacy outcomes were also significant in favor of the TLC-NOSF dressing group. Clinical outcomes for patients treated with the new dressing are superior to those patients treated with the TLC dressing (without NOSF compound), suggesting a strong promotion of the VLU healing process.

Fibroblasts Influence Metastatic Melanoma Cell Sensitivity to Combined BRAF and MEK Inhibition.

The sensitivity of melanoma cells to targeted therapy compounds depends on the tumor microenvironment. Three-dimensional (3D) in vitro coculture systems better reflect the native structural architecture of tissues and are ideal for investigating cellular interactions modulating cell sensitivity to drugs. Metastatic melanoma (MM) cells (SK-MEL-28 BRAF V600E mutant and SK-MEL-2 BRAF wt) were cultured as a monolayer (2D) or cocultured on 3D dermal equivalents (with fibroblasts) and treated with a BRAFi (vemurafenib) combined with a MEK inhibitor (MEKi, cobimetinib). The drug combination efficiently inhibited 2D and 3D MM cell proliferation and survival regardless of their BRAF status. Two-dimensional and three-dimensional cancer-associated fibroblasts (CAFs), isolated from a cutaneous MM biopsy, were also sensitive to the targeted therapy. Conditioned media obtained from healthy dermal fibroblasts or CAFs modulated the MM cell's response differently to the treatment: while supernatants from healthy fibroblasts potentialized the efficiency of drugs on MM, those from CAFs tended to increase cell survival. Our data indicate that the secretory profiles of fibroblasts influence MM sensitivity to the combined vemurafenib and cobimetinib treatment and highlight the need for 3D in vitro cocultures representing the complex crosstalk between melanoma and CAFs during preclinical studies of drugs.

Autochthonous leprosy in Europe: a case report and literature review.

Leprosy is currently uncommon in Europe: the diagnosed cases are almost all imported from endemic areas. We report on an autochthonous case of borderline lepromatous leprosy in a 71-year-old Portuguese woman. The case was complicated by a reversal reaction and then by erythema nodosum leprosum. A literature review identified 18 reported cases of European autochthonous leprosy since 2000; all but one were observed in Mediterranean countries. Therefore, active clusters of leprosy persist in Europe, particularly in Spain, Greece, Portugal, and Italy.

Multidisciplinary team meetings in Oncology: first analysis of benefits and evaluation of activity in a Dermatology unit in France.

Improving Multi-Disciplinary Meetings (MDM) is one of the 70 clauses of the French Cancer Plan of 2003-2007. The French High Authority of Health (HAS) and the National Cancer Institute (INCa) have established guidelines to standardize MDM concerning cancer care. No objective assessment of cutaneous cancer (dermato-oncology) MDM has been published yet, despite the growing numbers in the incidence of skin cancers. This study aims to analyze two of our center's MDM concerns: its decisions and its compliance with HAS guidelines. A retrospective study of all skin tumors discussed in MDM held at Amiens University Hospital between 2006-2007 analyzed epidemiological data, MDM decisions (recommendations), and their compliance. 349 MDM conclusion reports concerning 228 patients were analyzed. The cases consisted of 132 melanomas, 27 basal cell carcinomas, 19 squamous cell carcinomas, 5 Merkel cell carcinomas, 8 sarcomas, 16 cutaneous lymphomas, and 21 other tumors. 45.7% of MDM had at least 3 different specialists present. Patients were present in 49.4% of discussions. 88% of the MDMs' recommendations were implemented. More than 94% of these decisions were according to the guidelines. MDM recommendations contributed to: making 13.6% of diagnoses, 74.7% of treatment decisions, 45.6% of investigations requested, and 48.2% of long-term follow-up decisions. Treatment recommendations were: surgery in 50.6% of patients, chemotherapy in 45.0% and radiotherapy in 12.5%. The MDM's therapeutic decisions tended to follow the specialty of the referring physician; e.g. patients were likely to have surgery when referred by a surgeon, etc (p < 0.0001). Dermato-oncology MDM at Amiens University Hospital comply with most of the guidelines, however, patient attendance at MDM, participation of different specialists and the formal function and structure, all have room for improvement.

Adjuvant therapy with pegylated interferon-alfa2b vs observation in stage II B/C patients with ulcerated primary: Results of the European Organisation for Research and Treatment of Cancer 18081 randomised trial.

BACKGROUND: Subgroup analyses of two large EORTC adjuvant interferon-alpha2b (IFNα-2b) vs observation randomised trials demonstrated that a treatment benefit was observed only in patients with an ulcerated melanoma without palpable nodes (hazard ratio [HR] for recurrence-free survival [RFS] was 0.69). This was confirmed by a meta-analysis of 15 adjuvant IFN trials (HR: 0.79). PATIENTS AND METHODS: In the EORTC 18081 trial, sentinel node-negative stage II patients with an ulcerated primary melanoma were 1:1 randomised between pegylated (PEG)-IFNα-2b at 3 µg/kg/week subcutaneously and observation, for 2 years, or until disease recurrence or unacceptable toxicity in spite of dose adjustments to maintain an Eastern Cooperative Oncology Group performance status of 0 or 1. Main end-point was RFS. Secondary end-points included distant metastasis-free survival (DMFS), overall survival, and safety (EudraCT Number: 2009-010273-20). RESULTS: Between February 2013 and January 2017, only 112 patients were randomised, 56 in each arm. The trial was stopped early for lack of recruitment. At a 3.4-year median follow-up, the estimated HR for the PEG-IFNα-2b group compared with the observation group regarding RFS was 0.66 (95% confidence interval [CI]: 0.32-1.37), and the 3-year RFS rate was 80.0% (95% CI: 65.7-88.8%) and 72.9% (95% CI: 58.3-83.0%), respectively. DMFS was prolonged: HR: 0.39 (95% CI: 0.15-0.97), and the 3-year DMFS rate was 90.6% (95% CI: 78.9-96.0%) vs 76.4% (95% CI: 62.1-85.9%). One patient in the PEG-IFNα-2b group died compared with 4 in the observation group. Fifty-four patients started PEG-IFNα-2b treatment, 16 (29%) completed 2 years of treatment, 2 (4%) stopped due to recurrence, 23 (43%) due to toxicity and 14 (25%) due to other reasons. CONCLUSIONS: The EORTC 18081 PEG-IFNα-2b randomised trial, observed a similar HR (0.69) for RFS as the previous EORTC trials (0.69). In countries without access to new drugs, adjuvant (PEG)-IFNα-2b treatment is an option for patients with ulcerated melanomas without palpable nodes.

Two cases of pneumonitis induced by targeted therapy.

Interstitial pneumonitis is a rare drug adverse effect. We report two cases of cobimetinib-induced and vemurafenib-induced reversible interstitial pneumonitis. Two patients presenting a BRAF-mutated metastatic melanoma were treated with cobimetinib and vemurafenib. After 3 months, they developed severe feverish dyspnea. Thoracic imaging showed a pattern of organizing pneumonia in one case and a pattern of hypersensitivity pneumonitis in the other case. Infectious and cardiogenic causes were eliminated. An improvement was noted after discontinuation of cobimetinib, vemurafenib, and introducing steroids. Treatment was switched to dabrafenib (a BRAF inhibitor) with no recurrence of drug pneumonitis. To the best of our knowledge, it appears that cases of targeted-therapy-induced pneumonitis are predominantly an MEK-inhibitor effect. We, therefore, propose a management strategy of discontinuing targeted therapy, introducing steroid treatment and switching to dabrafenib.

Subacute cutaneous lupus erythematosus induced by nivolumab: two case reports and a literature review.

Nivolumab is widely used to treat several late-stage malignancies such as melanoma and non-small-cell lung cancer by inhibiting the interaction between the programmed cell death protein-1 and its ligand. By stimulating an antitumor immune response, it also leads to immune adverse events. Here. we report two cases of subacute cutaneous lupus erythematosus (SCLE) induced by nivolumab. Case 1: a 72-year-old woman with a stage IV melanoma. Two months after nivolumab discontinuation because of autoimmune hepatitis, the patient was in complete remission and pruritic nummular erythematous plaques appeared on the back and arms. Case 2: a 43-year-old man put under nivolumab for a metastatic non-small-cell lung cancer. After two cycles, an annular erythematous eruption appeared on the hands, arms, and chest. The hypothesis of SCLE was confirmed by biopsies showing lymphoid perivascular inflammatory infiltrates, with scarce C3 deposits along the basal layer of the epidermis in patient 2. Both patients tested positive for antinuclear antibodies and anti-SSA antibodies. Lesions were regressive under topical corticosteroids and hydroxychloroquine for the first patient and oral prednisone for the second patient. No systemic involvement was observed. The occurrence of SCLE 2 months after nivolumab discontinuation is evidence that the drug effect is prolonged because of the maintenance of programmed cell death protein-1 reception saturation for months. A causal relationship between SCLE and nivolumab is suggested by (i) the occurrence of SCLE after at least two cycles, (ii) the regression of lesions following treatment with corticosteroids and hydroxychloroquine, and (iii) the fact that it appeared after remission in our first patient.

3D Coculture Models Underline Metastatic Melanoma Cell Sensitivity to Vemurafenib.

IMPACT STATEMENT: Three dimensional in vitro cell culture systems better reflect the native structural architecture of tissues and are attractive to investigate cancer cell sensitivity to drugs. We have developed and compared several metastatic melanoma (MM) models cultured as a monolayer (2D) and cocultured on three dimensional (3D) dermal equivalents with fibroblasts to better unravel factors modulating cell sensitivity to vemurafenib, a BRAF inhibitor. The heterotypic 3D melanoma model we have established summarizes paracrine signalization by stromal cells and type I collagen matrix, mimicking the natural microenvironment of cutaneous MM, and allows for the identification of potent sensitive melanoma cells to the drug. This model could be a powerful tool for predicting drug efficiency.