Publications by authors named "Nicolas Dupin"

187 Publications

as an Opportunistic Pathogen: An Update of Its Virulence-Associated Factors.

Microorganisms 2021 Feb 2;9(2). Epub 2021 Feb 2.

NSERM Institut Cochin, INSERM U1016-CNRS UMR8104, Equipe de Biologie Cutanée, Université de Paris, 75014 Paris, France.

is a member of the skin microbiota found predominantly in regions rich in sebaceous glands. It is involved in maintaining healthy skin and has long been considered a commensal bacterium. Its involvement in various infections has led to its emergence as an opportunist pathogen. Interactions between and the human host, including the human skin microbiota, promote the selection of strains capable of producing several virulence factors that increase inflammatory capability. This pathogenic property may be related to many infectious mechanisms, such as an ability to form biofilms and the expression of putative virulence factors capable of triggering host immune responses or enabling to adapt to its environment. During the past decade, many studies have identified and characterized several putative virulence factors potentially involved in the pathogenicity of this bacterium. These virulence factors are involved in bacterial attachment to target cells, polysaccharide-based biofilm synthesis, molecular structures mediating inflammation, and the enzymatic degradation of host tissues. , like other skin-associated bacteria, can colonize various ecological niches other than skin. It produces several proteins or glycoproteins that could be considered to be active virulence factors, enabling the bacterium to adapt to the lipophilic environment of the pilosebaceous unit of the skin, but also to the various organs it colonizes. In this review, we summarize current knowledge concerning characterized virulence factors and their possible implication in the pathogenicity of .
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http://dx.doi.org/10.3390/microorganisms9020303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913060PMC
February 2021

Histopathologic Features of Chilblainlike Lesions Developing in the Setting of the Coronavirus Disease 2019 (COVID-19) Pandemic.

Arch Pathol Lab Med 2021 02;145(2):137-144

Department of Dermatology and Venereology (Matar, Dupin, Aractingi), Assistance Publique-Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France.

Context.—: During the coronavirus disease 2019 pandemic, several studies have described a distinctive cutaneous manifestation with a clinical picture resembling chilblains or chilblain lupus in young patients.

Objective.—: To report the histopathologic description of a series of chilblainlike lesions appearing in the context of the severe acute respiratory syndrome coronavirus 2 epidemic.

Design.—: The study included 13 patients with cutaneous acral lesions resembling chilblains occurring in the setting of suspected severe acute respiratory syndrome coronavirus 2 infection with available skin biopsy.

Results.—: Two main histopathologic patterns were observed: a chilblainlike histopathologic pattern (10 of 13 cases; 77%) and a thrombotic vasculopathy pattern (3 of 13 cases; 23%). The chilblainlike histopathologic pattern featured a superficial and deep perivascular infiltrate of lymphocytes of varying intensity. This infiltrate was sometimes peri-eccrine and alterations of eccrine glands were present in most cases. Vacuolar alteration of the basal layer of the epidermis was found in a majority of patients. Lichenoid interface dermatitis was rarely present. The thrombotic vasculopathy pattern featured an absent or mild inflammatory infiltrate, multiple intraluminal fibrin thrombi, and ischemic epidermal necrosis. In both patterns, no true vasculitis was observed. No patient tested positive for severe acute respiratory syndrome coronavirus 2 by polymerase chain reaction, possibly because these lesions may represent late cutaneous manifestations of the disease or are associated with an early effective immune response.

Conclusions.—: The relationship of chilblainlike lesions to severe acute respiratory syndrome coronavirus 2 requires further investigations. Histopathologic features mimic chilblains, chilblain lupus, and, less frequently, a thrombotic vasculopathy. Response to viral infection might trigger diverse mechanisms leading to the 2 histopathologic patterns described.
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http://dx.doi.org/10.5858/arpa.2020-0613-SADOI Listing
February 2021

Simultaneous quantification of dabrafenib, hydroxy-dabrafenib and trametinib in human plasma by liquid chromatography-tandem mass spectrometry.

J Pharm Biomed Anal 2021 Jan 27;193:113718. Epub 2020 Oct 27.

Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France; UMR8038 CNRS, U1268 INSERM, Faculty of Pharmacy, University of Paris, PRES Sorbonne Paris Cité, CARPEM, 75006 Paris, France.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of dabrafenib (DAB), its main metabolite hydroxy-dabrafenib (OHD) and trametinib (TRA) in human plasma has been developed and validated. After addition of internal standard (dabrafenib-d9), extraction was achieved after protein precipitation with acetonitrile containing 1 % (v/v) formic acid. Chromatographic separation was performed on an Accucore® C18 (2.1 × 50 mm; 2.6 μm) column using a gradient elution of water acidified with 0.1 % (v/v) formic acid (A) and acetonitrile containing 0.1 % (v/v) formic acid (B) at a flow rate of 500 μL/min. The calibration ranged from 10 to 2000 ng/mL for DAB and OHD and from 5 to 50 ng/mL for TRA. This method was validated with satisfactory results including good precision (intra- and inter-assay coefficient of variation from 2.0 %-14.9 %) and good accuracy (inter- and intra-day bias between -1.2 % and 10.9 %), as well as long term stability in unprocessed plasma at -20 °C. This newly proposed method is useful for clinical research purposes as well as therapeutic drug monitoring for patients with a Rapidly Accelerated Fibrosarcoma kinase B (BRAF)-mutated cancer.
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http://dx.doi.org/10.1016/j.jpba.2020.113718DOI Listing
January 2021

Trends and determinants of condomless sex in gonorrhoea patients diagnosed in France through the sentinel surveillance network ResIST, 2005-2014.

BMC Public Health 2020 Oct 28;20(1):1620. Epub 2020 Oct 28.

Santé Publique France (The French National Public Health Agency), Saint Maurice, France.

Background: Gonorrhoea is increasing in France since its resurgence in the late 1990's. Understanding trends of condomless sex is a requirement to tailor prevention toward most exposed individuals. This study aims to analyse trends and determinants of condomless penetrative sex (PS) in MSM and heterosexuals diagnosed with gonorrhoea in France.

Methods: A standardized self-administered questionnaire filled by 3453 patients was used to monitor condomless sex through the sentinel surveillance network ResIST between 2005 and 2014. Trends were used to describe consistent condom use for penetrative sex (PS). A logistic regression model analysed patients' characteristics associated with condomless PS.

Results: Between 2005 and 2014, condomless PS increased regardless of sexual orientation. Condomless PS was particularly common among HIV positive men who have sex with men (MSM (65%)). People living in metropolitan regions outside Paris area (adjusted odds-ratio (AOR) [95% CI] =1.33[1.12-1.58]) were more likely to engage in condomless PS. Conversely, MSM (AOR [95% CI] =0.21 [0.16-0.29]), HIV seronegative patients (AOR [95% CI] =0.68 [0.51-0.89]), patients diagnosed in hospital (AOR [95% CI] = 0.66 [0.45-0.97]) and multi-partners (≥ 10 partners, AOR [95% CI] = 0.54 [0.40-0.74]) were more likely to use condoms.

Conclusions: These findings highlight a decreasing use of condom in MSM and heterosexuals diagnosed with gonorrhoea. Prevention strategies should take in account drivers of condomless sex in a context of uncontrolled STI epidemics.
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http://dx.doi.org/10.1186/s12889-020-09703-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594409PMC
October 2020

Contribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis.

Nat Commun 2020 10 20;11(1):5067. Epub 2020 Oct 20.

Centre for Stem Cells and Regenerative Medicine, King's College London, Floor 28, Tower Wing, Guy's Hospital, Great Maze Pond, London, SE1 9RT, UK.

Although acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.
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http://dx.doi.org/10.1038/s41467-020-18784-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575575PMC
October 2020

Pyoderma Gangrenosum Revealing Myeloid Activation of Fanconi Anaemia: Two Case Reports.

Acta Derm Venereol 2020 Dec 1;100(19):adv00338. Epub 2020 Dec 1.

Department of Dermatology, Hôpital Cochin, Assistance Publique des Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France.

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http://dx.doi.org/10.2340/00015555-3671DOI Listing
December 2020

Histopathological features of Chilblain-like lesions developing in the setting of the COVID-19 pandemic.

Arch Pathol Lab Med 2020 Oct 9. Epub 2020 Oct 9.

Department of Pathology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France (Sohier, Laurent-Roussel) ; Department of Dermatology and Venereology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France (Matar, Dupin, Aractingi) ; Laboratory of Virology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France (Meritet) ; Université de Paris, Paris, France (Sohier, Dupin, Aractingi) ; Cutaneous Biology Lab, Institut Cochin, INSERM U1016, UMR8104 (Dupin, Aractingi).

Context: During the coronavirus disease 2019 pandemic, several studies have described a distinctive cutaneous manifestation with a clinical picture resembling chilblains or chilblain lupus in young patients.

Objective: To report the histopathological description of a series of chilblain-like lesions appearing in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic.

Design: The study included 13 patients with cutaneous acral lesions resembling chilblains occurring in the setting of suspected SARS-CoV-2 infection with available skin biopsy.

Results: Two main histopathological patterns were observed: a chilblain-like histopathological pattern (10 cases out of 13, 77%) and a thrombotic vasculopathy pattern (3 cases out of 13, 23% of cases). The chilblain-like histopathological pattern featured a superficial and deep perivascular infiltrate of lymphocytes of varying intensity. This infiltrate was sometimes peri-eccrine and alterations of eccrine glands were present in most cases. Vacuolar alteration of the basal layer of the epidermis was found in a majority of patients. Lichenoid interface dermatitis was rarely present. The thrombotic vasculopathy pattern featured an absent or mild inflammatory infiltrate, multiple intraluminal fibrin thrombi and ischemic epidermal necrosis. In both patterns, no true vasculitis was observed. No patient was tested positive for SARS-CoV-2 by polymerase chain reaction possibly due to the fact that these lesions may represent late cutaneous manifestations of the disease or are associated with an early effective immune response.

Conclusion: The relationship of chilblain-like lesions to SARS-CoV-2 requires further investigations. Histopathological features mimic chilblains, chilblain lupus and less frequently a thrombotic vasculopathy. Response to viral infection might trigger diverse mechanisms leading to the two histopathological patterns described.
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http://dx.doi.org/10.5858/arpa.2020-0613-SADOI Listing
October 2020

An Isolated Peculiar Gianotti-Crosti Rash in the Course of a COVID-19 Episode.

Acta Derm Venereol 2020 09 30;100(16):adv00276. Epub 2020 Sep 30.

Department of Dermatology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, AP-HP Centre-Université de Paris, Paris, France.

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http://dx.doi.org/10.2340/00015555-3641DOI Listing
September 2020

Surveillance of Antibiotic Resistance Genes in Treponema Pallidum Subspecies Pallidum from Patients with Early Syphilis in France.

Acta Derm Venereol 2020 Jul 28;100(14):adv00221. Epub 2020 Jul 28.

INSERM, Institut Cochin U1016-CNRS UMR8104, Université Sorbonne Paris Descartes, Groupe Hospitalier, Paris, France.

Benzathine penicillin G (BPG) is the reference treatment for early syphilis, but shortages have recently been reported, highlighting a need for the validation of alternative treatments. The aim of this study was to evaluate the genomic resistance of Treponema pallidum subspecies pallidum (TPA) to macrolides and doxycycline in France. Swabs from genital, anal, oral and cutaneous lesions were obtained from 146 patients with early syphilis in France. They were screened for mutations conferring resistance to macrolides and doxycycline by nested PCR and sequencing. Resistance to macrolides was detected in 85% of the isolates, but no point mutations conferring doxycycline resistance were detected. These findings confirm that, in France, resistance to macrolides is widespread. Moreover, we confirmed the absence of genomic resistance to doxycycline in the TPA strains. Therefore, doxycycline could be safely recommended as an alternative to BPG for the treatment of early syphilis.
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http://dx.doi.org/10.2340/00015555-3589DOI Listing
July 2020

Digitate Papulosquamous Eruption Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

JAMA Dermatol 2020 Jul;156(7):819-820

Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Division of Dermatology and Venereology, AP-HP Centre-Université de Paris, Paris, France.

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http://dx.doi.org/10.1001/jamadermatol.2020.1704DOI Listing
July 2020

Oral forms of secondary syphilis: An illustration of the pitfalls set by the great imitator.

J Am Acad Dermatol 2021 Feb 24;84(2):348-353. Epub 2020 Apr 24.

Service de Dermatologie, Hôpital Cochin, Assistance Publique des Hôpitaux, Paris, France; CeGIDD, Hôpital Hôtel Dieu, Assistance Publique des Hôpitaux, Paris, France; Centre National de Référence des infections sexuellement transmissibles, Laboratoire associé Syphilis, Paris, France; Institut Cochin, Inserm 1016, Université de Paris, Paris, France. Electronic address:

Introduction: Syphilis is reemerging in certain populations, such as in men who have sex with men in particular. Oral manifestations are not uncommon and can render diagnosis difficult, particularly if occurring in isolation.

Materials And Methods: We recovered clinical data for all patients receiving a diagnosis of secondary syphilis who were referred to the National Reference Center for Syphilis in Paris, France, from January 2000 to July 2019. We selected patients presenting oral symptoms only and analyzed their general characteristics, time to diagnosis, and clinical presentations.

Results: Secondary syphilis was diagnosed in 206 patients, 38 of whom (18%) presented oral manifestations, which were isolated in 14 patients (37%). The main oral manifestations were subacute erosive or ulcerative lesions (55%), mucous patches on the tongue (53%), and nodular (10%) and leukokeratotic lesions (5%). Mean time to diagnosis was 4.5 months, but was significantly longer for patients with isolated oral symptoms (8.8 vs 1.8 months; P = .02).

Conclusion: Oral presentations of secondary syphilis are frequent and challenging for diagnosis, even in patients with epidemiologic risk factors. Clinicians confronted with subacute oral lesions in such patients should bear in mind the possibility of this contagious, curable, and sometimes severe disease.
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http://dx.doi.org/10.1016/j.jaad.2020.04.089DOI Listing
February 2021

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma.

Cancers (Basel) 2020 Apr 9;12(4). Epub 2020 Apr 9.

Department of Pharmacokinetics and Pharmacochemistry, Cochin Hospital, AP-HP, CARPEM, 75014 Paris, France.

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure-response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances ( < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUC/AUC ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29-33.56); = 0.023 and 10.61 (2.34-48.15), = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11-9.50); = 0.032 and HR = 1.23 (1.35-10.39), = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUC/AUC deserves more investigation in a larger cohort of MM patients.
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http://dx.doi.org/10.3390/cancers12040931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226106PMC
April 2020

Clinical and pathological dermatological features of deficiency of adenosine deaminase 2: A multicenter, retrospective, observational study.

J Am Acad Dermatol 2020 Dec 10;83(6):1794-1798. Epub 2020 Apr 10.

Sorbonne Université, Faculté de Médecine, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Service de médecine interne, Centre de référence des maladies auto-inflammatoires et des amyloses d'origine inflammatoire (CEREMAIA), Paris, France.

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http://dx.doi.org/10.1016/j.jaad.2020.03.110DOI Listing
December 2020

Factors Associated With Short-term Relapse in Patients With Pemphigus Who Receive Rituximab as First-line Therapy: A Post Hoc Analysis of a Randomized Clinical Trial.

JAMA Dermatol 2020 05;156(5):545-552

Centre de référence des maladies bulleuses auto-immunes, Department of Dermatology, Rouen University Hospital, Normandie University, INSERM U1234, Rouen, France.

Importance: Rituximab and short-term corticosteroid therapy are the criterion standard treatments for patients with newly diagnosed moderate to severe pemphigus.

Objective: To examine factors associated with short-term relapse in patients with pemphigus treated with rituximab.

Design, Setting, And Participants: This post hoc analysis of a randomized clinical trial (Comparison Between Rituximab Treatment and Oral Corticosteroid Treatment in Patients With Pemphigus [RITUX 3]) conducted from January 1, 2010, to December 31, 2015, included patients from 20 dermatology departments of tertiary care centers in France from the RITUX 3 trial and 3 newly diagnosed patients treated according to the trial protocol. Data analysis was performed from February 1 to June 30, 2019.

Exposure: Patients randomly assigned to the rituximab group in the RITUX 3 trial and the 3 additional patients were treated with 1000 mg of intravenous rituximab on days 0 and 14 and 500 mg at months 12 and 18 combined with a short-term prednisone regimen.

Main Outcomes And Measures: Baseline (pretreatment) clinical and biological characteristics (Pemphigus Disease Area Index [PDAI] score, ranging from 0-250 points, with higher values indicating more severe disease) and changes in anti-desmoglein (DSG) 1 and anti-DSG3 values as measured by enzyme-linked immunosorbent assay during the 3 months after rituximab treatment were compared between patients with disease relapse and those who maintained clinical remission during the first 12 months after treatment. The positive and negative predictive values of these factors were calculated.

Results: Among 47 patients (mean [SD] age, 54.3 [17.0] years; 17 [36%] male and 30 [64%] female) included in the study, the mean (SD) baseline PDAI score for patients with relapsing disease was higher than that of the patients with nonrelapsing disease (54 [33] vs 28 [24]; P = .03). At month 3, 7 of 11 patients with relapsing disease (64%) vs 7 of 36 patients with nonrelapsing disease (19%) had persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher (P = .01). A PDAI score of 45 or higher defining severe pemphigus and/or persistent anti-DSG1 antibody values of 20 IU/mL or higher and/or anti-DSG3 antibody values of 130 IU/mL or higher at month 3 provided a positive predictive value of 50% (95% CI, 27%-73%) and a negative predictive value of 94% (95% CI, 73%-100%) for the occurrence of relapse after rituximab.

Conclusions And Relevance: The findings suggest that initial PDAI score and changes in anti-DSG antibody values after the initial cycle of rituximab might help differentiate a subgroup of patients with high risk of relapse who might benefit from maintenance rituximab infusion at month 6 from a subgroup of patients with low risk of relapse who do not need early maintenance therapy.

Trial Registration: NCT00784589.
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http://dx.doi.org/10.1001/jamadermatol.2020.0290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081151PMC
May 2020

Cetuximab is efficient and safe in patients with advanced cutaneous squamous cell carcinoma: a retrospective, multicentre study.

Oncotarget 2020 Jan 28;11(4):378-385. Epub 2020 Jan 28.

Medical Oncology Department, Antoine Lacassagne Center, Nice, France.

There is no standard of care for unresectable cutaneous squamous cell carcinoma (cSCC). Chemotherapy, alone or combined with radiotherapy, is commonly used mostly as palliative treatment; moreover, its poor safety profile limits its use most of the time, especially in elderly patients. Thus, alternative options are needed. Targeted molecular inhibitors, such as the epidermal growth factor receptor inhibitor cetuximab, seem promising, but data are limited. We retrospectively evaluated clinical outcomes of cetuximab as a single agent in this indication. The primary endpoint was the Disease Control Rate (DCR) at 6 weeks according to RECIST criteria. Secondary endpoints included DCR at 12 weeks, objective response rate (ORR) at 6 and 12 weeks, progression-free-survival (PFS), overall survival (OS), and safety profile. Fifty-eight patients received cetuximab as monotherapy. The median age was 83.2 (range, 47.4 to 96.1). The majority of patients was chemotherapy naïve. The median follow-up was 11.7 months (95% CI: 9.6-30.1). The DCR at 6 and 12 weeks was 87% and 70%, respectively. The ORR was 53% and 42%, respectively, at 6 and 12 weeks. The median PFS and OS were 9.7 months (95% CI: 4.8-43.4) and 17.5 months (95% CI: 9.4-43.1), respectively. Fifty-one patients (88%) experienced toxicity, and 67 adverse events related to cetuximab occurred. Most of them (84%) were grade 1 to 2. Our study shows that cetuximab is safe and efficient for the treatment of patients, even elderly ones, with advanced cSCC. These results indicate that cetuximab is a promising agent to test in new combinations, especially with immune checkpoint inhibitors such as anti-PD-1 agents.
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http://dx.doi.org/10.18632/oncotarget.27434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996917PMC
January 2020

Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study.

Melanoma Res 2020 06;30(3):317-320

Department of Dermatology, Hôpital Cochin, AP-HP.

Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dabrafenib and trametinib for BRAF-mutant advanced melanoma from January 2015 to March 2019. Patients presenting with histologically proven SLR were included. We also searched Medline database for all reported cases of SLR induced by targeted therapy. Of 63 patients on dabrafenib/trametinib combination, seven were diagnosed with a SLR. They all had specific cutaneous involvement, and one also displayed mediastinal and salivary glands involvement. None required systemic corticosteroids or dabrafenib/trametinib discontinuation. Three of them (43%) reached melanoma complete remission and are still on targeted therapy; and four patients progressed and died. A literature review yielded 22 additional cases of SLR induced by targeted therapy: the main affected organ was the skin, 11 patients (50%) had systemic involvement, five patients (23%) required systemic corticosteroids to reach partial or complete remission of SLR, 12 (55%) reached partial or complete response of melanoma while six (27%) progressed. BRAF and MEK inhibitors are potential triggers of SLR, although pathological mechanisms remain unclear. The mainstay of treatment is systemic or topical corticotherapy; targeted therapy discontinuation is usually not necessary.
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http://dx.doi.org/10.1097/CMR.0000000000000649DOI Listing
June 2020

Local Management of Anogenital Warts in Non-Immunocompromised Adults: A Network Meta-Analysis of Randomized Controlled Trials.

Dermatol Ther (Heidelb) 2020 Apr 6;10(2):249-262. Epub 2020 Feb 6.

EA 4537, Antilles-Guyane University, Martinique, France.

Introduction: No hierarchy of first-line treatments for anogenital warts (AGWs) is provided in international guidelines. This study aimed to determine the efficacy of topical treatments and ablative procedures for the management of AGWs.

Methods: Twelve electronic databases were systematically searched from inception to August 2018. All randomized controlled trials (RCTs) comparing immunocompetent adults with AGWs who received at least 1 provider-administered or patient-administered treatment in at least 1 parallel group were included. Risk of bias assessment followed the Cochrane Handbook. The study endpoint was complete lesion response after clearance and recurrence assessment. A network meta-analysis was performed.

Results: A network geometry was constructed based on 49 of the 70 RCTs included in our systematic review. All but 4 RCTs had a high risk of bias. The most efficacious treatments compared to placebo were surgery (RR 10.54; CI 95% 4.53-24.52), ablative therapy + imiquimod (RR 7.52; CI 95% 4.53-24.52), and electrosurgery (RR 7.10; CI 95% 3.47-14.53). SUCRA values confirmed the superiority of surgery (90.9%), ablative therapy + imiquimod (79.8%), and electrosurgery (77.1%). The most efficacious patient-administered treatments were podophyllotoxin 0.5% solution (63.5%) and podophyllotoxin 0.5% cream (62.2%).

Conclusions: With low-level evidence of most included RCTs, surgery and electrosurgery were superior to other treatments after clearance and recurrence assessment. Podophyllotoxin 0.5% was the most efficacious patient-administered treatment. Combined therapies should be evaluated in future RCTs in view of their identified effectiveness. The results of future RCTs should systematically include clinical type, number and location of AGWs, and sex of the patient, to refine therapeutic indications.

Protocol Registration: PROSPERO-CRD42015025827.
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http://dx.doi.org/10.1007/s13555-020-00357-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090115PMC
April 2020

Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up.

J Clin Endocrinol Metab 2020 03;105(3)

INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris.

Introduction: Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far.

Methods: This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation.

Results: The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype.

Conclusion: This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
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http://dx.doi.org/10.1210/clinem/dgaa002DOI Listing
March 2020

Update on oncogenesis and therapy for Kaposi sarcoma.

Authors:
Nicolas Dupin

Curr Opin Oncol 2020 03;32(2):122-128

Service de Dermatologie, Hôpital Cochin, APHP.CUP, Pavillon Tarnier, 89 rue d'Assas 75006 Paris, Institut Cochin, Inserm 1016, Université de Paris, Paris, France.

Purpose Of Review: This review is an update of the recent findings on pathophysiology of Kaposi sarcoma, the role of HHV-8 in Kaposi sarcoma pathogenesis and to summarize the recent advances in the treatment of Kaposi sarcoma and the role of immunity to control the disease.

Recent Findings: The causal agent of Kaposi sarcoma is HHV-8 and the mechanism by which HHV-8 drives the tumor development is unique. HHV-8 is not a classic oncogenic virus and the disease is an opportunistic tumor responding to immune restoration when it is possible.

Summary: Five epidemiologic types of Kaposi are recognized and HHV-8 is associated to all epidemiologic forms of Kaposi. HHV-8 is a virus favoring both angiogenesis and cellular proliferation, which are the two main histological features of Kaposi sarcoma. Although in many cases, treatment of Kaposi sarcoma is not necessary, specific chemotherapy, immunomodulation and immune stimulation are the tools for treating Kaposi sarcoma. Monochemotherapy has been shown to be as efficient as polychemotherapy and less toxic. Immune checkpoint inhibitors gave some promising results, which should be confirmed by prospective studies.
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http://dx.doi.org/10.1097/CCO.0000000000000601DOI Listing
March 2020

Mastocytosis onset in a patient with treated hairy cell leukemia: Just a coincidence?

Blood Cells Mol Dis 2020 03 29;81:102392. Epub 2019 Nov 29.

Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie Clinique, Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France.

Mastocytosis is a mast cell disease caused by functionally defective infiltrating mast cells and CD34+ mast cell precursors. The heterogeneous group of mast cell disorders is categorized into five variants in the updated 2017 World Health Organization (WHO) classification among those systemic mastocytosis with an associated neoplasm (SM-AHN). Except for myeloid neoplasia, lymphoproliferative disorders associated to SM-AHN are more scarce. Here, we report the second case ever described of associated mastocytosis and hairy-cell disease. A 38-year-old female patient without any specific medical history was diagnosed a hairy cell leukemia and BRAF mutation was found in hairy cells. Since purine-analogs were avoided to prevent prolonged myelosuppression, she was treated with vemurafenib and rituximab. Despite early discontinuation due to vemurafenib-induced agranulocytosis, a partial response was observed. Strikingly, bone marrow biopsy performed one month after vemurafenib discontinuation revealed a nodular infiltration by 30% tumoral mastocytes. Along with elevated tryptase level, KIT mutation on mastocytes and clinical exam, the patient was diagnosed with systemic mastocytosis with an associated hematological neoplasm (SM-AHN). No BRAF mutation was found on mastocytes. The physiopathology of this association is not known and might be only a coincidence or a common genetic driver mutation enhancing mast and hairy cells.
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http://dx.doi.org/10.1016/j.bcmd.2019.102392DOI Listing
March 2020

Local Management of Anogenital Warts in Non-immunocompromised Adults: A Systematic Review and Meta-analyses of Randomized Controlled Trials.

Dermatol Ther (Heidelb) 2019 Dec 13;9(4):761-774. Epub 2019 Oct 13.

EA 4537, Antilles University, Martinique, France.

Introduction: Several therapeutic options are available to manage anogenital warts (AGWs). However, no hierarchy of treatments is provided in the latest European and American recommendations. This study aimed to determine the efficacy and safety of local treatments for the management of AGWs.

Methods: A search was conducted through 12 databases from inception to August 2018. All randomized controlled trials (RCTs) in which at least one parallel treatment group composed of immunocompetent adults with AGWs received at least one provider-administered or patient-administered treatment were included. Risk of bias assessment and meta-analyses of aggregated study data were performed on the basis of the Cochrane Handbook, and quality of evidence evaluation followed the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Primary endpoints were complete clearance and recurrence at 3 months.

Results: Seventy RCTs (9931 patients) were included. All but four RCTs had a high risk of bias. CO laser was slightly more efficacious than cryotherapy [risk ratio (RR) 2.05; 95% confidence interval (CI) 1.61-2.62], with fewer recurrences at 3 months (RR 0.28; 95% CI 0.09-0.89). Electrosurgery was slightly more efficacious than cryotherapy. No differences in efficacy or side effects were found between cryotherapy and imiquimod or trichloroacetic acid. Podophyllotoxin gel was slightly more efficacious than podophyllotoxin cream. 5-Fluorouracil (5-FU) was slightly more efficacious and caused less erosion than CO laser (RR 1.37; 95% CI 1.11-1.70).

Conclusion: The vast majority of included RCTs had a low level of evidence, thereby preventing the establishment of a hierarchy of treatments. Nevertheless, our results provide an overview of the main AGW treatments available for general practitioners and specialists. While provider-administered treatments are superior, patient-administered treatments (e.g., imiquimod, podophyllotoxin) are useful solutions for compliant patients.

Protocol Registration: PROSPERO-CRD42015025827.
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http://dx.doi.org/10.1007/s13555-019-00328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828858PMC
December 2019

Directly Sequenced Genomes of Contemporary Strains of Syphilis Reveal Recombination-Driven Diversity in Genes Encoding Predicted Surface-Exposed Antigens.

Front Microbiol 2019 31;10:1691. Epub 2019 Jul 31.

Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.

Syphilis, caused by subsp. (TPA), remains an important public health problem with an increasing worldwide prevalence. Despite recent advances in cultivation, genetic variability of this pathogen during infection is poorly understood. Here, we present contemporary and geographically diverse complete treponemal genome sequences isolated directly from patients using a methyl-directed enrichment prior to sequencing. This approach reveals that approximately 50% of the genetic diversity found in TPA is driven by inter- and/or intra-strain recombination events, particularly in strains belonging to one of the defined genetic groups of syphilis treponemes: Nichols-like strains. Recombinant loci were found to encode putative outer-membrane proteins and the recombination variability was almost exclusively found in regions predicted to be at the host-pathogen interface. Genetic recombination has been considered to be a rare event in treponemes, yet our study unexpectedly showed that it occurs at a significant level and may have important impacts in the biology of this pathogen, especially as these events occur primarily in the outer membrane proteins. This study reveals the existence of strains with different repertoires of surface-exposed antigens circulating in the current human population, which should be taken into account during syphilis vaccine development.
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http://dx.doi.org/10.3389/fmicb.2019.01691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685089PMC
July 2019

Partial response in hairy cell leukemia with vemurafenib despite early discontinuation due to agranulocytosis.

Anticancer Drugs 2020 02;31(2):196-198

Centre Régional de Pharmacovigilance, Hôpitaux Universitaires Paris Centre, Assistance Publique Hôpitaux de Paris, Paris, France.

Vemurafenib is an oral BRAF kinase inhibitor approved since 2012 for the treatment of patients with unresectable or metastatic melanoma with BRAF mutations. Vemurafenib also demonstrated efficacy for patients with hairy cell leukemia genetically characterized by BRAF mutation. Here, we report the case of a 38-year-old female patient without any previous medical history who experienced agranulocytosis associated with erythrodermia after vemurafenib initiation for the treatment of hairy cell leukemia. Agranulocytosis was confirmed with bone marrow examination. Vemurafenib was considered the most probable drug responsible for this agranulocytosis and was thus stopped. We observed a full neutrophils recovery 10 days after vemurafenib cessation without any haematopoietic growth factors. A bone marrow biopsy performed 1 month after aplasia ending showed a good partial response with less than 5% of hairy cells remaining. To our knowledge, this is the first case ever described by vemurafenib-induced agranulocytosis. Thus, physicians should be warned about this risk given the growing number of patients treated with vemurafenib.
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http://dx.doi.org/10.1097/CAD.0000000000000821DOI Listing
February 2020

Local management of anogenital warts in immunocompetent adults: Systematic review and pooled analysis of randomized-controlled trial data.

J Am Acad Dermatol 2019 11 9;81(5):1203-1204. Epub 2019 Apr 9.

EA 4537, Antilles University, Martinique, France; DRCI, Martinique University Hospital, Fort-de-France, Martinique, France.

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http://dx.doi.org/10.1016/j.jaad.2019.04.008DOI Listing
November 2019

Methodologic gaps and risk of bias in randomized controlled trials of local anogenital wart treatments.

J Am Acad Dermatol 2019 11 4;81(5):1197-1198. Epub 2019 Apr 4.

EA 4537, Antilles University, Martinique, France; DRCI, Martinique University Hospital, Fort-de-France, Martinique, France.

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http://dx.doi.org/10.1016/j.jaad.2019.03.080DOI Listing
November 2019

Bacterial sexually transmitted infections in France: recent trends and patients' characteristics in 2016.

Euro Surveill 2019 Jan;24(5)

Santé publique France (the French national public health agency), Saint-Maurice, France.

Diagnoses of bacterial sexually transmitted infections (STI) have been increasing in France since their resurgence in the late 1990s. This article presents recent epidemiological trends until 2016 and the patients' characteristics. STI surveillance relies on sentinel networks: a clinician-based network RésIST (clinical, biological and behavioural data for early syphilis and gonorrhoea), the lymphogranuloma venereum (LGV) network (clinical, biological and behavioural data for rectal LGV, and the laboratory networks Rénachla and Rénago (demographic and biological data for chlamydial infections and gonorrhoea, respectively). Here we describe trends between 2014 and 2016, using data from diagnostic centres which participated regularly during the study period. The number of early syphilis, gonorrhoea and LGV diagnoses increased between 2014 and 2016, particularly in men who have sex with men. An increase in syphilis and gonorrhoea cases was also observed in heterosexuals. Nevertheless, we observed a drop in 2016 for syphilis and chlamydial infections after two decades of increases. Under-reporting and shortage of benzathine penicillin in 2016 may explain this latest evolution. Regular screening of patients and partners, followed by prompt treatment, remains essential to interrupt STI transmission in a context where human immunodeficiency virus (HIV) prevention has expanded towards biomedical prophylaxis.
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http://dx.doi.org/10.2807/1560-7917.ES.2019.24.5.1800038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6386212PMC
January 2019

Zika Virus Infection RIG-ged by Keratinocytes and Fibroblasts.

J Invest Dermatol 2019 02;139(2):281-282

Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Canada; Division of Dermatology, Women's College Hospital, Toronto, Canada. Electronic address:

Zika virus is an emergent virus targeting the skin. Ji-Ae et al. (2018) explore the interactions between Zika virus and skin cells. They showed that human keratinocytes play an important role in control of initial infection via the interaction with retinoic acid-inducible gene receptors.
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http://dx.doi.org/10.1016/j.jid.2018.09.003DOI Listing
February 2019