Relevance of body mass index as a predictor of systemic therapy outcomes in metastatic melanoma: analysis of the MelBase French cohort data☆.

BACKGROUND: The 'obesity paradox' suggests that higher body mass index (BMI) is associated with better survival values in metastatic melanoma patients, especially those receiving targeted and immune checkpoint inhibitor therapy. Higher BMI is also associated with higher incidences of treatment-related adverse events (TRAEs). This study assesses whether BMI is associated with survival outcomes and adverse events in metastatic melanoma patients with systemic therapy. PATIENTS AND METHODS: This multicentric retrospective study, conducted from 1 March 2013 to 29 April 2019, enrolled adults with unresectable stage III or IV melanoma from the French multicentric prospective cohort-MelBase (NCT02828202). Patients with first-line chemotherapy and targeted and immune therapy were included. Underweight people and those with metastatic mucosal or ocular melanoma were excluded. BMI was categorized using the World Health Organization criteria. Co-primary outcomes included the association between BMI and progression-free survival and overall survival, stratified by treatment type, sex, and age. Secondary endpoints were the association of BMI with overall response and TRAEs. Multivariate analyses were carried out. RESULTS: A total of 1214 patients were analyzed. Their median age was 66.0 years (range, 53-75). Male predominance was observed [n = 738 (61%)]. Most patients received immune checkpoint inhibitor therapy (63%), followed by targeted therapy (32%), and had stage M1c disease (60.5%). Obese patients represented 22% of the cohort. The median follow-up duration was 13.5 months (range, 6.0-27.5). In the pooled analysis, no positive or negative association between BMI and progression-free survival (P = 0.88)/overall survival (P = 0.25) was observed, regardless of treatment type, sex, and age. These results were nonsignificant in the univariate and multivariate analyses. The objective response rate, according to BMI category, did not differ significantly regardless of age. TRAEs were not associated with BMI. CONCLUSION: The observed lack of an association between BMI and survival demonstrates that BMI is not a valuable marker of systemic treatment-related outcomes in metastatic melanoma. Future approaches might focus on the whole-body distribution.

Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.

BACKGROUND: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

[What's new in dermatological research?] / Quoi de neuf en recherche dermatologique ?

This manuscript provides a selection of dermatological research manuscripts published from September 2016 to August 2017. It is not an exhaustive review but rather a selection of manuscripts susceptible to modify the dermatological practice or affording new pathophysiologic mechanisms and new therapeutic approaches. The following areas of interest are concerned: recognition of dermatological images by artificial intelligence, new concepts in atopic dermatitis, wound repair and hair growth cycle. New data concerning melanomagenesis, epidermolysis bullosa simplex and drug eruption are also highlighted.

Clinical and immunological features and outcome of anti-p200 pemphigoid.

BACKGROUND: Anti-p200 pemphigoid is a rare autoimmune blistering disease (AIBD) of the dermoepidermal junction, characterized by autoantibodies to laminin γ1. The clinical course of anti-p200 pemphigoid in patients remains poorly investigated. OBJECTIVES: We aimed to describe the clinical and immunological features and the course of a series of patients with anti-p200 pemphigoid. METHODS: We conducted a retrospective study by immunoblotting detection of sera on 200-kDa dermal protein extracts from the register of the French reference centre for AIBD. We recorded the clinical and immunological features and the course of patients. RESULTS: A total of 14 patients with a mean age 81·6 ± 6·5 years were included. Only one patient had an associated neurological condition and one had psoriasis. Twelve patients had atypical clinical presentation, including eczematous, urticarial, prurigo-like, dyshydrosis-like and rosette-like skin lesions. Eight patients (57%) had mucosal involvement. Immunoblot analysis of sera on dermal and epidermal extracts showed a 200-kDa band in 14 and 10 cases, respectively. All eight of the sera tested by enzyme-linked immunosorbent assay detected recombinant human laminin γ1. Disease control was obtained in six of nine patients treated with topical corticosteroids, and four of five patients who received systemic treatment. Seven patients relapsed (50%) and five patients (36%) died during the median follow-up time of 12·6 months. At the end of the study, only one of the nine living patients was in complete remission off therapy. CONCLUSIONS: Many patients with anti-p200 pemphigoid had heterogeneous clinical presentation and a more severe prognosis than previously suspected.

[Metastatic cervical fasciitis revealing invasive lobular breast carcinoma]. / Fasciite cervicale métastatique révélant un carcinome lobulaire infiltrant du sein.

BACKGROUND: We describe the case of a 71-year-old woman presenting cervical metastatic fasciitis with invasive lobular carcinoma (ILC) of the breast. PATIENTS AND METHODS: The patient consulted for a deep and painless skin infiltration of the neck associated with dysphagia and restricted cervical mobility. Skin and muscle biopsies were normal. Muscle fascia biopsy showed a linear infiltration of metastatic cells in "single file", revealing ILC of the right breast. DISCUSSION: ILCs have a particular metastatic pattern. They can permeate through tissue planes, infiltrate solid organs and spread on serous membranes in an insidious fashion. CONCLUSION: Our case shows that ILC can metastasise into muscular fascia, causing "fasciitis-like" symptoms. Dermatologists should be aware of this particular pattern of dissemination.

[Massive localized lymphedema]. / Lymphœdèmes massifs localisés.

BACKGROUND: Massive localized lymphedema (MLL) is a benign soft-tissue lesion that usually presents as a large and isolated mass in morbidly obese adults. PATIENTS AND METHODS: We report the case of a 39-year-old woman presenting obesity and multiple MLL. There was a large tumor in the left groin and two smaller lesions on the backs of the thighs. DISCUSSION: MLL is a benign tumor that must be removed wherever possible because such tumors may degenerate into angiosarcomas in 13% of cases. MLL is probably secondary to a prolonged obstruction of lymphatic vessels due to marked excess of adipose tissue.

Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin.

BACKGROUND: Deregulation of the proteasome pathway has been shown to be involved in the pathogenesis of several inflammatory disorders. To date limited information exists on proteasome and immunoproteasome expression and activity in psoriasis skin. OBJECTIVES: To investigate the potential role of proteasomes in the pathogenesis of psoriasis. METHODS: Thirty-six patients with psoriasis and 40 healthy subjects were included. The protein and mRNA expression levels and proteolytic activity of proteasome and immunoproteasome subunits were determined using immunohistochemistry, quantitative polymerase chain reaction and fluorogenic peptide substrate in lesional and nonlesional psoriasis skin. We additionally measured the plasmatic proteasome (p-proteasome) levels using enzyme-linked immunosorbent assay. RESULTS: We reveal an increased expression of proteasome and immunoproteasome subunits but stable mRNA levels in lesional psoriasis skin as compared with nonlesional psoriasis skin (n = 19), suggesting that proteasome and immunoproteasome expression is regulated post-transcriptionally. This proteasome overexpression was associated with a significant increase of the proteasomal chymotrypsin-like activity that was threefold higher in lesional skin than in nonlesional skin (n = 3). p-Proteasome levels were enhanced in patients with psoriasis (mean ± SEM 3960 ± 299 ng mL(-1) , range 1484-8987) when compared with controls (2535±187 ng mL(-1) , range 654-6446, P<0·001) and were significantly higher in psoriatic arthritis (4937±572 ng mL(-1) , range 2600-8987). In addition, they were correlated to the body surface area involved and appeared thus as a new biomarker of psoriasis severity. CONCLUSIONS: Altogether these results strongly suggest the involvement of the proteasome system in the pathogenesis of psoriasis and support the relevance of proteasome inhibitors in local or systemic treatment of psoriasis.

Management and outcome of metastatic melanoma during pregnancy.

BACKGROUND: Although metastatic melanoma occurrence during pregnancy challenges the physician in several ways, only a few studies have been published. OBJECTIVES: Our aim was to investigate therapeutic management together with maternal and fetal outcomes in pregnant women with advanced melanoma. METHODS: A French national retrospective study was conducted in 34 departments of Dermatology or Oncology. All patients with American Joint Committee on Cancer (AJCC) stage III/IV melanoma diagnosed during pregnancy were included. Data regarding melanoma history, pregnancy, treatment, delivery, maternal and infant outcomes were collected. RESULTS: Twenty-two women were included: 10 AJCC stage III and 12 stage IV. Abortion was performed in three patients. Therapeutic abstention during pregnancy was observed in three cases, 14 patients underwent surgery, four patients received chemotherapy and one patient was treated with brain radiotherapy alone. The median gestational age was 36 weeks amenorrhoea. Neither neonatal metastases nor deformities were observed. Placenta metastases were found in one case. Among 18 newborns, 17 are currently alive (median follow up, 17 months); one died of sudden infant death. The 2-year maternal survival rates were 56% (stage III) and 17% (stage IV). CONCLUSIONS: Faced with metastatic melanoma, a majority of women chose to continue with pregnancy, giving birth, based on our samples, to healthy, frequently premature infants. Except during the first trimester of pregnancy, conventional melanoma treatment was applied. No serious side effect was reported, except one case of miscarriage after surgery. Mortality rates do not suggest a worsened prognosis due to pregnancy but larger prospective controlled studies are necessary to assess this specific point.

[Necrotic arachnidism in the south of France: two clinical cases of loxoscelism]. / Envenimation nécrotique dans le Sud de la France : deux observations de loxoscélisme cutané

BACKGROUND: loxosceles spiders are found throughout the world and are responsible for numerous cases of envenomation in America and Southern Europe. We describe, to our knowledge for the first time in France, two clinical cases of cutaneous loxoscelism. CASE REPORT: two cases of skin necrosis arising after supposed spider bites were grouped together because of their similar clinical presentation: an initial painless bite and rapid development of an inflammatory and painful cutaneous lesion with a central hemorrhagic bulla surrounded by a perimeter of blanched skin (the "red, white, and blue" sign). The outcome in both cases was deep skin necrosis and chronic ulceration requiring surgical treatment. DISCUSSION: loxoscelism can result in dermonecrosis. Although our cases were not documented by capture of the spider, the diagnosis of cutaneous loxoscelism was supported by the characteristic appearance of the lesion, a typical clinical course, elimination of differential diagnoses, and the confirmed presence of Loxosceles rufescens in the region. CONCLUSION: loxoscelism can occur in the south of France and although rare, must be considered in this region as a possible cause of skin necrosis.

Solitary subungual keratoacanthoma arising in an MSH2 germline mutation carrier: confirmation of a relationship by immunohistochemical analysis.

BACKGROUND: Muir-Torre syndrome (MTS) is an autosomal dominant disorder characterized by the concurrent or sequential development of at least 1 sebaceous gland tumor or keratoacanthoma and 1 or more internal malignancies. It is actually considered as a variant of hereditary nonpolyposis colorectal cancer (HNPCC) as both MTS and HNPCC are more often associated with germline mutations in the DNA mismatch repair (MMR) gene. OBJECTIVE AND METHODS: We report the case of MTS diagnosed after the occurrence of a solitary subungual keratoacanthoma (SKA) in a man with a well-known family history of HNPCC and who is carrying a constitutional 1-7 deletion in the MSH2 MMR gene. RESULTS: The link between the germline mutation and the skin tumor was reinforced by immunohistochemical staining. MSH2 immunoreactivity was decreased in SKA tumoral cells when compared to normal adjacent epidermis and to 5 cases of sporadic KA used as controls. CONCLUSION: This observation indicates that a solitary SKA may be the first clinical manifestation of MTS and brings up the relevance for regular dermatological screening for MTS-associated skin lesions among gene carriers (and symptomatic individuals) for HNPCC syndrome.

[Photoaging of face]. / Photo-vieillissement du visage.

The environment, especially solar irradiation, plays a major role in skin aging. In humans, cutaneous areas frequently exposed to solar radiations are subject to premature skin ageing (heliodermatitis) which has specific clinical and histological features distinct from those observed in photoprotected skin. Most of the cellular and molecular mechanisms implicated in chronologic aging are observed in both ultraviolet exposed and photoprotected skin and can be stimulated in vitro and in vivo by repeated ultraviolet exposures. This article reviews the epidemiological, clinical and histological characteristics of photoaging and summarizes the recent findings acquired in this field.

[Intravascular B-cell lymphoma with febrile inflammatory lymphoedema of the lower limbs and lower back]. / Lymphome B intravasculaire à type de lymphoedème inflammatoire fébrile des membres inférieurs et des lombes.

BACKGROUND: Intravascular lymphomas are diffuse large-cell lymphomas belonging to a group of high-grade non-Hodgkin's lymphomas and are generally of phenotype B. They are rare and carry a severe prognosis. Clinical polymorphism is dominated by neurological and cutaneous involvement. PATIENTS AND METHODS: We report the case of an 80-year-old woman with cutaneous intravascular B-cell lymphoma as revealed by an isolated episode of febrile bilateral inflammatory lymphoedema. Following combined chemotherapy with rituximab and mini-CHOP (cyclophosphamide, adriamycin, oncovin and prednisone), complete remission was obtained rapidly, with no relapse at two years. DISCUSSION: Diagnosis of these tumours is rendered difficult by the clinical polymorphism and multifocal nature of lymphocytic proliferations. In the present case, diagnosis was based on histology results since presentation of the disease in the form of bilateral inflammatory oedema of the lower limbs is not sufficient to establish lymphoma. Combined rituximab and polychemotherapy comprising a CHOP regimen appears to yield the best results.

Update of survival and cost of metastatic melanoma with new drugs: Estimations from the MelBase cohort.

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

[Tumoral and pilotropic mycosis fongoides without mucin: evolution towards a pustulous erythroderma]. / Mycosis fongoïde tumoral et pilotrope sans mucine: évolution vers une érythrodermie pustuleuse.

INTRODUCTION: Pilotropic mycosis fongoides is a particular form of the disease, because of its clinical and histological aspects, its poor prognosis and its resistance to treatment. We report a case of pilotropic mycosis fongoides without mucinosis, immediately tumoral, the fatal progression of which was marked by the occurrence of pustular erythroderma. OBSERVATION: In 1998 a 69 year-old man presented with infiltrated erythro-squamatous plaques and nodules on the limbs associated with follicular lesions predominating on the cervical-cephalic area. Histological explorations revealed a pilotropic infiltrate with atypical CD4+ CD8 CD30 T-cells, without epidermotrophism or mucinosis. Study of genetic rearrangements found a clone lymphocyte T-cell in the skin. Diagnosis of pilotropic mycosis fongoides at the tumoral stage was made and, despite various treatments, the disease developed towards fatal pustular erythroderma. DISCUSSION: At the onset of its progression, pilotropic mycosis fongoides is sometimes difficult to distinguish from classical mycosis fongoides, during which follicular involvement is often seen. However it is important to differentiate these entities because of the poor prognosis of pilotropic mycosis fongoides. Development of tissue micro dissection techniques and lymphocyte T-cell clones from human skin would help to separate these cutaneous T-cell lymphoma sub-groups. Our case report is original because of the absence of dermal mucinosis combined with an immediately tumoral form and the progression towards generalized pustulosis. It also underlines the poor prognosis and resistance to treatment of pilotropic mycosis fongoides.

Transient protection by peripheral benzodiazepine receptors during the early events of ultraviolet light-induced apoptosis.

The peripheral benzodiazepine receptor (PBR) is a mitochondrial protein involved in the formation of mitochondrial permeability transition (PT) pores which play a critical role during the early events of apoptosis. PBRs are located in many tissues and are strongly expressed in the superficial layers of human epidermis. PBRs play a protective role against free radical damage and PBR ligands modulate apoptosis. To investigate the role of PBR during the early events of ultraviolet (UV)-mediated apoptosis we compared the effects of UVB on PBR-transfected Jurkat cells and their wild type counterparts devoid of any PBR expression. Results indicate that early after UVB exposure (up to 4 h), PBR-transfected cells were more resistant to apoptosis and exhibited a delayed mitochondrial transmembrane potential drop, a diminished superoxide anions production, and a reduced caspase-3 activation. Taken together these findings suggest that PBR may regulate early death signals leading to UV induced apoptosis.