Genetic landscape of indolent and aggressive Kaposi sarcomas.

BACKGROUND: Kaposi sarcoma (KS) is a rare skin tumour caused by herpesvirus 8 infection and characterized by either indolence or an aggressive course necessitating systemic therapies. The genetic basis of this difference remains unknown. OBJECTIVES: To explore the tumour mutational burden in indolent and aggressive KS. METHODS: We performed whole-exome sequencing on a cohort of 21 KS patients. We compared genetic landscape including tumor mutational burden between the two forms of indolent and agressive KS. RESULTS: Aggressive KS tumours had a significantly higher TMB and a larger cumulative number of deleterious mutations than indolent KS tumours. In addition, all aggressive tumours had at least three deleterious mutations, whereas most indolent tumours harboured only one or no predicted deleterious mutations. Deleterious mutations listed in the Cancer Gene Census were detected exclusively in patients with aggressive disease. An analysis of somatic copy-number alterations (SCNA) revealed a tendency towards higher number of alterations in aggressive KS. CONCLUSIONS: These data suggest that SCNA alterations and an increase in mutational burden promote aggressive KS and that it might be more appropriate to consider indolent KS as an opportunistic skin disease rather than a cancer.

[Rieger-Marchac flaps: Complications and patient satisfaction]. / Le lambeau de Rieger-Marchac : complications et satisfaction des patients.

PURPOSE: Like all surgical procedures, dorsal nasal flaps may be followed by both early and late complications. The aim of this study was to evaluate the surgical complications and cosmetic outcome of dorsal nasal flaps over a 7-year period in an academic dermatologic surgery unit. PATIENTS AND METHODS: Data were collected retrospectively for all patients undergoing dorsal nasal flap between 1 January 2006 and 31 December 2013. Early and late complications were recorded. Patients were contacted by phone to assess long-term outcomes. RESULTS: A total of 35 patients were included. Early complications included bleeding (n=2), local infection (n=2) and focal flap necrosis (n=1). Late complications comprised flap thickening (n=7), restriction of the medial canthus (n=2), opening of the labionasal angle (n=1), stitch granuloma (n=1) and telangiectasia on the flap (n=1). Regarding the aesthetic result, seven patients were very satisfied with the flap. Four patients underwent corrective surgery and one patient had laser treatment for telangiectasia on the flap. CONCLUSION: Two thirds of patients were satisfied with the aesthetic results and one third had late complications of the flap. Consequently, patients undergoing Rieger-Marchac procedures must be informed of the potential need for further corrective measures following nasal dorsal flap repair.

Anaplastic Kaposi's sarcoma: 5 cases of a rare and aggressive type of Kaposi's sarcoma.

BACKGROUND: Anaplastic Kaposi's sarcoma (KS) is a rare form of KS characterized clinically by the development of a tumour mass with unusual local aggressiveness and histologically by a specific architecture and cytological morphology. A very small number of limited series in endemic countries have established characteristics common to these anaplastic forms of KS. We present five patients with an anaplastic form in a context of KS ongoing for several years in a non-endemic country. MATERIALS AND METHODS: We collected 5 cases of anaplastic KS followed in our department over a period of 20years. We describe the main developmental, clinical, virological and histological features. RESULTS: The cases involved 4 men and 1 woman whose mean age at diagnosis of anaplastic KD was 70years, with an average time of 25years between initial diagnosis of KD and anaplastic transformation. Our patients were all treated with chemotherapy and/or radiotherapy (RT) prior to diagnosis of anaplastic transformation. All patients had a tumour mass of the lower limbs developing in classically indolent KS with associated chronic lymphoedema. Progression was very aggressive locally with deep invasion of the soft tissues as well as osteoarticular involvement, without visceral dissemination. At present, three patients are dead, one patient is showing partial response, and one patient is in locoregional progression. Diagnosis of the disease was based on histopathological findings. The tumour cells were undifferentiated, pseudo-cohesive, and chiefly organized in sheets. The mitotic count was high (27 mitoses per 10 fields at high magnification). Necrosis was constant. DISCUSSION: To our knowledge, this is the first series describing anaplastic Kaposi's sarcoma in a non-endemic country. The severity of the prognosis, despite the absence of visceral dissemination, is related to the local aggressiveness of anaplastic KS and to its resistance to radiotherapy and chemotherapy, with amputation being required in certain cases.

[Dermatologic surgery, hemophilia and Von Willebrand disease]. / Risques en dermatologie interventionnelle chez les patients hémophiles ou atteints de la maladie de Willebrand.

BACKGROUND: Von Willebrand disease (VWD) and hemophilia A and B are the most common types of hereditary coagulation-factor deficiencies. The frequency and type of complications of skin surgery in these patients are unknown. The increasing incidence of skin cancer prompted us to reflect upon this issue. While the incidence of skin cancer is increasing, the complications of skin surgery or ablative laser treatment remain unknown in this population. AIM: The aim of this study was to determine the frequency of bleeding complications during and after skin surgery in patients with a hereditary coagulation-factor deficiency (hemophilia or VWD). PATIENTS AND METHODS: We conducted a retrospective study in patients with hemophilia A or B or VWD undergoing skin surgery or ablative laser treatment at the Dermatology Department of the Cochin Hospital in Paris, France. RESULTS: Fourteen procedures were performed in 8 patients. Three episodes of bleeding occurred (n=3/14, 21.4%): one hematoma, one delayed bleed and one immediate bleed. None of these complications required surgical revision or resuscitation. DISCUSSION: The rate of hemorrhagic complications was higher than in the general population. However, these complications can be considered non-serious and the risk-benefit ratio remains favorable. Multidisciplinary management and coordination with the reference hemophilia center are mandatory in this population to establish a coagulation-factor (CF) substitution protocol suited to the disease characteristics and the surgical procedure.

Long-term sustained lesion clearance from Lmax with imiquimod 3.75%, a new field-directed treatment for actinic keratosis.

BACKGROUND: In patients with actinic keratosis (AK), subclinical and clinical lesions coexist across large areas of sun-exposed skin. The long-term efficacy of AK treatments depends on their ability to eradicate both types of lesions across the entire field. OBJECTIVE: To assess the long-term efficacy of imiquimod 3.75% using the reduction in lesions from Lmax (maximum lesion count during treatment), which assesses the ability to clear subclinical and clinical lesions. METHODS: Patients with 5-20 AK lesions on the full face or balding scalp from two 14-week, randomized, vehicle-controlled, double-blind studies of imiquimod 3.75% (daily for two 2-week treatment cycles separated by a 2-week treatment-free period) were eligible to enter a 12-month follow-up study if they had no AK lesions at Week 14. Lesion reduction from Lmax was calculated at 6 and 12 months during follow-up. RESULTS: The 42 patients in this long-term study had a median of nine baseline lesions and a median Lmax of 22 lesions. At 6 and 12 months of follow-up, the median absolute reduction in AK lesions from Lmax with imiquimod 3.75% was 21 and 19, respectively. The median percentage reduction in lesions from Lmax to 6 and 12 months was 100% and 97.2%, respectively. CONCLUSIONS: The ability of imiquimod 3.75% to eliminate clinical and subclinical lesions across an entire sun-exposed field translates into sustained long-term efficacy. Imiquimod 3.75% may therefore represent a first-choice treatment for patients with AK.

[Pregnancy-specific dermatoses]. / Dermatoses de la grossesse.

Pregnancy-specific dermatoses include polymorphic eruption of pregnancy, atopic eczema of pregnancy, and pemphigoid gestationis. Intrahepatic cholestasis of pregnancy and impetigo herpetiformis are not real pregnancy-specific dermatoses but they are important to know considering the fetal and maternal risks. Polymorphic eruption of pregnancy is a pruritic disease that usually occurs in primiparous women during the last trimester of pregnancy. Atopic eczema of pregnancy is still controversial as an entity covering conditions with eczematous lesions, prurigo, or folliculitis, and inconstantly associated with a personal history of atopy. Skin biopsy with direct immunofluorescence or search for serum anti-BPAg1 (180kD) NC16a antibodies is mandatory in pruritic dermatoses of pregnancy in order to rule out pemphigoid gestationis. Serum bile salts levels should be tested whenever a generalized pruritus develops during pregnancy in order to rule out intrahepatic cholestasis.

Effect of induced peritoneal endometriosis on oocyte and embryo quality in a mouse model.

PURPOSE: To assess the impact of peritoneal endometriosis on oocyte and embryo quality in a mouse model. METHODS: Peritoneal endometriosis was surgically induced in 33 B6CBA/F1 female mice (endometriosis group, N = 17) and sham-operated were used as control (sham group, N = 16). Mice were superovulated 4 weeks after surgery and mated or not, to collect E0.5-embryos or MII-oocytes. Evaluation of oocyte and zygote quality was done by immunofluorescence under spinning disk confocal microscopy. RESULTS: Endometriosis-like lesions were observed in all mice of endometriosis group. In both groups, a similar mean number of MII oocytes per mouse was observed in non-mated mice (30.2 vs 32.6), with a lower proportion of normal oocytes in the endometriosis group (61 vs 83 %, p < 0.0001). Abnormalities were incomplete extrusion or division of the first polar body and spindle abnormalities. The mean number of zygotes per mouse was lower in the endometriosis group (21 vs 35.5, p = 0.02) without difference in embryo quality. CONCLUSIONS: Our results support that induced peritoneal endometriosis in a mouse model is associated with a decrease in oocyte quality and embryo number. This experimental model allows further studies to understand mechanisms of endometriosis-associated infertility.

Efficacy of imiquimod 3.75% from Lmax according to the number of actinic keratosis lesions.

BACKGROUND: Imiquimod 3.75% reduces 92.2% of all actinic keratosis (AK) lesions, assumed to include both subclinical and clinical lesions, across a large sun-exposed field such as the full face or balding scalp. OBJECTIVE: To evaluate the efficacy of imiquimod 3.75% using the reduction in lesions from Lmax (the maximum lesion count during treatment) in subgroups of patients with low and high AK lesion counts. METHODS: Patients from two 14-week, placebo-controlled, double-blind studies were subgrouped according to whether they had ≤ 10 or >10 AK lesions at baseline. Treatment was applied to the full face or balding scalp during two 2-week treatment cycles separated by a 2-week treatment-free interval. RESULTS: Overall, 167 patients had ≤ 10 lesions and 152 patients had >10 AK lesions at baseline. With imiquimod 3.75%, the median percentage reduction in AK lesions from Lmax to end of study was similar in patients with ≤ 10 and >10 baseline lesions (91.5% and 93.0% respectively). The median absolute reduction in AK lesions from Lmax to end of study was 24.0 for patients with >10 baseline lesions and 10.0 for those with ≤ 10 baseline lesions. The median percentage and absolute reductions in lesions from Lmax were significantly greater with imiquimod 3.75% vs. placebo (P < 0.0001). CONCLUSIONS: Imiquimod 3.75% is effective regardless of disease severity as shown in this study by the reduction of over 90% of lesions from Lmax in patients with low or high AK lesion counts.

Pregnancy affects morphology of induced endometriotic lesions in a mouse model through alteration of proliferation and angiogenesis.

OBJECTIVE: Pregnancy is known to alleviate the symptoms of endometriosis and is also known to be a pro-angiogenic condition affecting blood and lymphatic vessels. However, angiogenesis actively participates in the development of endometriosis. The objective of our study was to study the impact of pregnancy on endometriotic tissue. Study design We performed a cross-sectional, control versus treatment study in a mouse model of endometriosis. Thirty-one female C57Bl6 mice were mated and became pregnant and 31 females were not mated and served as control. Intraperitoneal endometriotic lesions were surgically induced in C57Bl6 mice which were subsequently mated or not (group P: pregnant, group NP: non-pregnant). P and NP mice were sacrificed on day E15.5 of the pregnancy of P mice and lesions were harvested. Lesions were weighed and analyzed by histology, immunohistology, flow cytometry and real-time quantitative RT-PCR (qRT-PCR). RESULTS: Pregnancy reduced lesion weight, decreased the proportion of cystic component (0.02 vs. 0.4; p<0.001) and modified the architecture of peritoneal endometriotic lesions. Pregnancy also increased cell proliferation in both stromal and glandular tissue as shown by the increase in Ki 67-positive cells in the P group (glandular: 19 vs. 3.9%, p<0.001; stromal: 8.7 vs. 3.3%, p<0.01). Finally, pregnancy increased angiogenesis in endometriotic lesions as indicated by an increased microvessel density (CD-31 and LYVE-1 stainings: respectively 2.2 vs. 5.1%, p<0.01 and 0.4 vs. 0.9%, p<0.001), an increased number of LYVE1 positive cells evaluated by flow cytometry (18.9 vs. 4.6%, p<0.05) and a rise in VEGF-A, -R2 and -R3 RNA expression shown by qRT-PCR (p<0.001; p<0.01; p<0.05). CONCLUSION: These challenging results provide insight in understanding the pathophysiology of endometriosis and evoke a correlation between lesion architecture and symptomatology.

Evidence-based recommendations on the role of dermatologists in the diagnosis and management of psoriatic arthritis: systematic review and expert opinion.

BACKGROUND: Psoriatic arthritis (PsA) can develop at any time during the course of psoriasis. AIMS: The aims of these practical recommendations are to help dermatologists identify patients at risk of PsA, to diagnose PsA in collaboration with rheumatologists and to gain a better understanding of initial PsA management. MATERIALS AND METHODS: A scientific committee consisting of 10 dermatologists and a rheumatologist selected clinically relevant questions to be addressed by evidence-based recommendations using the DELPHI method. For each question, a systematic literature review was performed in Medline, Embase and the Cochrane Library databases. The levels of evidence of all selected and reviewed articles were appraised according to the Oxford levels of evidence. RESULTS: An expert board of 30 dermatologists reviewed and analysed the evidence and developed recommendations for the selected questions. Agreement among participants was assessed on a 10-point scale, and the potential impact of the recommendations on clinical practice was evaluated. Among the 6960 references identified, 190 relevant articles were included in the reviews. Three recommendations regarding risk factors for PsA and one regarding PsA prevalence were issued. The mean agreement score between participants varied from 7.8 to 9.6. Three recommendations on PsA screening tools that can be used by dermatologists were issued. The mean agreement score between participants varied from 7.7 to 9.4. Initial PsA treatment options according to published guidelines were critically appraised for axial and peripheral involvement and enthesitis/dactylitis. Three recommendations were issued. The mean agreement score between participants varied from 7.6 to 8.7. DISCUSSION: The systematic literature research and meta-analyses did not provide high-quality evidence to support recommendations regarding PsA screening. Conversely, PsA treatment options were supported by strong evidence. CONCLUSION: Cooperation between dermatologists and rheumatologists should be emphasized to better identify and manage PsA patients.

Treatment for palmoplantar pustular psoriasis: systematic literature review, evidence-based recommendations and expert opinion.

BACKGROUND: Palmoplantar pustular psoriasis (PPPP) is a variant of psoriasis whose the association with psoriatic arthritis (PsA) has been recently described. There is limited evidence regarding how to best reduce palmoplantar pustular psoriasis severity and to maintain remission once achieved. OBJECTIVE: The aim of this study was to elaborate evidence-based recommendations for PPPP treatment supported by a systematic literature review. METHODS: A systematic literature search was carried out in Embase, Medline and Cochrane Library databases from 1980 to February 2013 searching for any trial in patients with PPPP assessing therapeutic interventions not including a systemic biotherapy. The selection of articles was limited to human subjects and English or French languages. RESULTS: Among the 675 articles identified, 29 including one Cochrane review were analysed. The Cochrane review summarised 23 randomised controlled trials (RCTs) in chronic PPPP until February 2003, including 724 patients. The authors concluded that oral retinoid therapy (acitretin), photochemotherapy or combination of both, low dose of ciclosporin or topical corticosteroids under occlusion appeared to be helpful in relieving symptoms of PPPP. Since the publication of this review, 9 open studies on PPPP treatment have been published. Three new studies evaluated the benefits of PUVA on PPPP. They all showed a better efficacy of PUVA compared to UVB therapy. One open study concluded that a retinoid treatment with an arotinoid ethylesther showed a good efficacy. Five prospective studies (level of evidence of 3) assessed Laser Excimer UVB-NB (Excimer 308 nm) in PPPP. The combined analysis of these studies showed that 64% of patients experienced an improvement of 70% at the end of treatment. CONCLUSION: Phototherapy, ciclosporin and topical corticosteroids seem to be able to control PPPP. However, the standard of care for PPPP remains an issue and there is a strong need for reliable RCTs to better define treatment strategies for PPPP.

Is there a psoriasis skin phenotype associated with psoriatic arthritis? Systematic literature review.

Psoriatic arthritis (PsA) is associated with psoriasis with a prevalence varying from 5.94% to 23.9%. The aim of this study was to assess if some psoriatic skin features are associated with a higher risk of PsA. A systematic literature search was carried out from 1980 to January 2013, in the Embase and Pubmed databases, using a combination of keywords including (Psoriasis) AND (PsA). Of the 2746 articles retrieved, 25 references were selected. Meta-analysis was performed when possible. Mean age at psoriasis onset appeared to be similar among patients with skin disease alone and in those with PsA. There was no clinical type of psoriasis specifically associated with PsA, including pustular psoriasis of palms and soles. Nonetheless specific psoriasis localizations were significantly associated with an increased risk of developing PsA in one cohort study: scalp lesions [Hazard Ratio (HR) 3.89 (95% confidence interval (CI):2.18-6.94)] and intergluteal/perianal lesions [HR 2.35 (95%CI:1.32-4.19)]. A similar association was found in two cross-sectional studies. Nail involvement was significantly associated with PsA in the meta-analysis [Odds Ratio (OR) 2.92 (95% CI 2.34-3.64)], particularly onycholysis [OR 2.38 (95% CI 1.74-3.26)]. Moreover, nail psoriasis was also associated with distal interphalangeal joint arthritis. The extent of psoriasis appeared to be associated with PsA in one cohort study [≥3 sites: HR 2.24 (95% CI 1.23-4.08)], one case-control study [body surface area >75%: OR 2.52 (95% CI 1.33-4.75)] and three cross-sectional studies. The meta-analysis suggested a trend for an association between high PASI and PsA risk [mean difference 3.39 (95% CI 0.94-5.83)]. Therefore, psoriasis patients with such clinical features may require a particular attention for early and close detection of PsA during the course of the cutaneous disease.

Symptoms dermatologists should look for in daily practice to improve detection of psoriatic arthritis in psoriasis patients: an expert group consensus.

BACKGROUND: Up to 29% of patients with psoriasis seen by dermatologists have undiagnosed psoriatic arthritis (PsA). As early detection of PsA may be associated with improved joint and skin outcomes, it is essential for dermatologists to improve their ability to diagnose PsA. Skin and nail features of psoriasis associated with PsA are well known to dermatologists but they may feel less confortable assessing other symptoms and they rarely use PsA screening questionnaires. OBJECTIVE: To develop a limited list of clinical signs and symptoms that a dermatologist should be looking for in a psoriasis patient in addition to specific skin features and nail involvement, to improve PsA detection. METHODS: A systematic search was performed in Pubmed, Cochrane and Embase databases to identify clinical key symptoms associated with PsA. It yielded 27 studies in which we extracted a list of clinical signs and symptoms observed in PsA and submitted it to a panel of dermatology experts through a DELPHI selection process. The experts had to determine which minimal set of signs and symptoms dermatologists should look for in daily practice to improve detection of PsA in patients with psoriasis. RESULTS: The four items that received a score higher than 90% in the DELPHI process were finally selected. Those items were as follows: peripheral inflammatory pain (100%), axial inflammatory pain (95.3%), dactylitis (93%), buttock and sciatic pain (90.7%). The remaining items: distal interphalangeal joints (DIPs) involvement (83.7%), Talalgia (79.1%), swollen Achille's tendon (41.9%), costo-chondral involvement (32.6%), uveitis (7%), mouth ulcerations (2.3%), were not retained. CONCLUSION: We propose a set of four items to screen psoriasis patients for psoriatic arthritis for routine clinical use by dermatologists.

Treatment (biotherapy excluded) of psoriatic arthritis: an appraisal of methodological quality of international guidelines.

BACKGROUND: Some international guidelines have been published to provide the best care for patients with psoriatic arthritis (PsA) but little is known about their quality. OBJECTIVE: The primary aim of this study was to examine the quality of guidelines that concern treatment (biotherapy exluded) of PsA. The secondary aim was to review studies published since the publication of the most recent guideline. METHODS: A systematic literature search was carried out from 2007 to February 2013, in the Embase, Medline and Cochrane Library databases, in English and French using a combination of keywords including 'Arthritis, Psoriatic/therapy' NOT 'Biological Therapy' OR 'Antibodies, Monoclonal' OR 'Recombinant Fusion Proteins' OR 'tumour necrosis factor-alpha'. The AGREE instrument (Appraisal of Guidelines Research and Evaluation) was used by four reviewers to evaluate the quality of selected guidelines according to the proposed methodology. RESULTS: Of the 518 identified references, six guidelines and two studies were selected. There was considerable variation in the quality of clinical guidelines across the AGREE domains. The least well-addressed domains were 'applicability', 'stakeholder involvement', 'scope and purpose' and 'quality of development', whereas 'editorial independence' and 'clarity and presentation' were less problematic. CONCLUSION: Although guidelines development was of good quality, many of the studies that they included are of poorer quality. This work indicates that the current guidelines can be improved, particularly the stakeholder domain and the applicability domain. The prospective use of the AGREE instrument should improve the guideline quality. More controlled trials should be required but are unlikely to be conducted, given the lack of interest in studying old drugs.