Publications by authors named "Nicolas Poulalhon"

21 Publications

  • Page 1 of 1

Diagnostic Concordance in Tertiary (Dermatologists-to-Experts) Teledermoscopy: A Final Diagnosis-Based Study on 290 Cases.

Dermatol Pract Concept 2020 Jul 29;10(3):e2020071. Epub 2020 Jun 29.

Service de Dermatologie, Centre Hospitalier Lyon Sud, France.

Background: Teledermoscopy (TDS) improves diagnostic accuracy and decreases the number of unnecessary consultations.

Objectives: To determine the diagnostic concordance in tertiary (dermatologist-to-experts) TDS with histopathology/follow-up-based diagnosis.

Methods: A descriptive retrospective cohort study including 290 requests.

Results: Perfect diagnostic concordance was found in 202 (69.7%) cases and partial agreement in 29 (10%). Disagreement was found in 59 (20.3%) cases. Perfect concordance on the benign/malignant nature of the lesion was found in 227 (78.3%) cases and disagreement in 63 (21.7%). In onychology, diagnostic concordance was perfect in 43 (76.8%) cases, partial in 7 (12.5%), and there was disagreement in 6 (10.7%). Final concordance on the benign/malignant nature of the lesion was perfect in 48 (85.7%) and there was disagreement in 8 (14.3%) nail cases. For pediatric requests, diagnostic concordance was perfect in 29 (65.9%) cases, partial in 5 (11.4%), and there was disagreement in 10 (22.7%). Final concordance on the benign/malignant nature of the lesion was observed in 34 (77.3%) cases, disagreement in 10 (22.7%).

Conclusions: This study confirms that tertiary TDS improves diagnostic accuracy of pigmented skin lesions. Moreover, it shows encouraging results in unusual conditions such as ungual and pediatric skin tumors. The main limitation was the retrospective nature and the "real-life" setting of our study that could have created a selection bias toward inclusion of the most difficult cases.
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http://dx.doi.org/10.5826/dpc.1003a71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319786PMC
July 2020

Lipofibromatosis-Like Neural Tumor: A Case Report and Review of the Literature.

Am J Dermatopathol 2020 Nov;42(11):881-884

Hospices Civils de Lyon, Hôpital Lyon Sud, Service d'anatomie et de cytologie pathologiques, Pierre Bénite, France.

Lipofibromatosis-like neural tumors (LPF-NT) are soft tissue tumors characterized by a lipofibromatosis-like pattern, CD34/PS100 positivity, and recurrent NTRK1 gene rearrangement. It occurs mainly in pediatric patients or young adults. We report here, the first case of LPF-NT in a middle-aged adult initially misdiagnosed as a myoepithelial tumor. LPF-NT may have a locally aggressive course but no recurrence was seen after complete surgeries, whereas metastatic diseases remain exceptional.
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http://dx.doi.org/10.1097/DAD.0000000000001734DOI Listing
November 2020

Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients.

J Clin Oncol 2019 12 14;37(34):3275-3282. Epub 2019 Oct 14.

Hôpital Saint-Louis, Paris, France.

Purpose: Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation.

Methods: An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy.

Results: One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%).

Conclusion: Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.
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http://dx.doi.org/10.1200/JCO.18.00794DOI Listing
December 2019

Deciphering the Role of Oncogenic MITFE318K in Senescence Delay and Melanoma Progression.

J Natl Cancer Inst 2017 08;109(8)

INSERM, U1065 (équipe 1), Equipe labélisée ARC 2016, C3M, Nice, France.

Background: MITF encodes an oncogenic lineage-specific transcription factor in which a germline mutation ( MITFE318K ) was identified in human patients predisposed to both nevus formation and, among other tumor types, melanoma. The molecular mechanisms underlying the oncogenic activity of MITF E318K remained uncharacterized.

Methods: Here, we compared the SUMOylation status of endogenous MITF by proximity ligation assay in melanocytes isolated from wild-type (n = 3) or E318K (n = 4) MITF donors. We also used a newly generated Mitf E318K knock-in (KI) mouse model to assess the role of Mitf E318K (n = 7 to 13 mice per group) in tumor development in vivo and performed transcriptomic analysis of the tumors to identify the molecular mechanisms. Finally, using immortalized or normal melanocytes (wild-type or E318K MITF, n = 2 per group), we assessed the role of MITF E318K on the induction of senescence mediated by BRAF V600E . All statistical tests were two-sided.

Results: We demonstrated a decrease in endogenous MITF SUMOylation in melanocytes from MITF E318K patients (mean of cells with hypoSUMOylated MITF, MITF E318K vs MITF WT , 94% vs 44%, difference = 50%, 95% CI = 21.8% to 67.2%, P  = .004). The Mitf E318K mice were slightly hypopigmented (mean melanin content Mitf WT vs Mitf E318K/+ , 0.54 arbitrary units [AU] vs 0.36 AU, difference = -0.18, 95% CI = -0.36 to -0.007, P  = .04). We provided genetic evidence that Mitf E318K enhances BRaf V600E -induced nevus formation in vivo (mean nevus number for Mitf E318K , BRaf V600E vs Mitf WT , BRaf V600E , 68 vs 44, difference = 24, 95% CI = 9.1 to 38.9, P  = .006). Importantly, although Mitf E318K was not sufficient to cooperate with BRaf V600E alone in promoting metastatic melanoma, it accelerated tumor formation on a BRaf V600E , Pten-deficient background (median survival, Mitf E318K/+  = 42 days, 95% CI = 31 to 46 vs Mitf WT  = 51 days, 95% CI = 50 to 55, P  < .001). Transcriptome analysis suggested a decrease in senescence in tumors from Mitf E318K mice. We confirmed this hypothesis by in vitro experiments, demonstrating that Mitf E318K impaired the ability of human melanocytes to undergo BRAF V600E -induced senescence.

Conclusions: We characterized the functions of melanoma-associated MITF E318K mutations. Our results demonstrate that MITF E318K reduces the program of senescence to potentially favor melanoma progression in vivo.
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http://dx.doi.org/10.1093/jnci/djw340DOI Listing
August 2017

Dermoscopic Evaluation of Melanocytic Nevi Changes With Combined Mitogen-Activated Protein Kinase Pathway Inhibitors Therapy for Melanoma.

JAMA Dermatol 2016 10;152(10):1162-1164

Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1001/jamadermatol.2016.2426DOI Listing
October 2016

Nasal septal perforation in the course of anti-MDA5 dermatomyositis.

Eur J Dermatol 2016 Jun;26(3):315-6

Department of Dermatology, Centre Hospitalier Lyon Sud, 69495 Pierre-Bénite cedex, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France.

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http://dx.doi.org/10.1684/ejd.2016.2764DOI Listing
June 2016

Blisters and Loss of Epidermis in Patients With Lupus Erythematosus: A Clinicopathological Study of 22 Patients.

Medicine (Baltimore) 2015 Nov;94(46):e2102

From the Faculté de Médecine, Université de Strasbourg; Clinique Dermatologique, Hôpitaux Universitaires de Strasbourg, Strasbourg (CM-D, DL); Faculté de Médecine, Université de Montpellier; Département de Dermatologie, Hôpital Saint Eloi, CHRU Montpellier, Montpellier (DB); Faculté de Médecine, Université Pierre-et-Marie-Curie Paris-VI, Service de Dermatologie Hôpital Tenon, Paris (CF); Faculté de Médecine, Université Claude Bernard Lyon 1, Service de Dermatologie, CHU Lyon Sud, Pierre-Bénite (NP, SD); and Service de Dermatologie-Médecine interne, CHU de Pointe-à-Pitre, Pointe-à-Pitre, Guadeloupe, (NC) France.

The nosology of bullous lesions or equivalents (vesicles, erosions, and crusts) in patients with lupus erythematosus (LE) is rarely addressed.The primary aim of this study was to draw up a precise phenotypic inventory of such skin lesions; the secondary objective was to assess a potential relationship between the different types of loss of epidermis and extracutaneous lupus manifestations.We conducted a retrospective multicenter study including 22 patients with definite LE and bullous lesions or equivalents. All biopsies were reviewed. Patients were recruited in the dermatology departments of 6 centers. Patients were included if they met the diagnosis of systemic LE according to American College of Rheumatology and/or Systemic Lupus International Collaborating Clinics criteria or diagnosis of cutaneous LE based on classic clinical criteria and/or histological ascertainment of LE. Patients were recruited through clinician's memory and photographic collections.Three clinico-pathological patterns could be individualized. First, toxic epidermal necrolysis (TEN)-like, sheet-like, skin detachment; sun-exposure, mild mucosal involvement, and dermal mucin deposition allow differential diagnosis with classical Lyell syndrome. Second, vesiculo-bullae and/or crusting occurring on typical lesions of subacute cutaneous lupus erythematosus or chronic cutaneous lupus erythematosus. Third, tense vesicles and/or blisters with an underlying neutrophilic dermatosis and a usual response to dapsone.A careful analysis of 22 LE patients with epidermal detachment reveals 2 main pathomechanisms: a classic LE interface dermatitis, which can be hyperacute and lead to TEN-like skin detachment; and a neutrophilic dermatosis, with tense vesicles and/or blisters, including classic bullous LE.
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http://dx.doi.org/10.1097/MD.0000000000002102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652835PMC
November 2015

Fast-growing cutaneous squamous cell carcinoma in a patient treated with vismodegib.

Dermatology 2015 24;230(2):101-4. Epub 2015 Jan 24.

Department of Dermatology, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Background: Vismodegib therapy achieves a breakthrough in patients with locally advanced basal cell carcinoma (BCC). Yet, long-term safety of hedgehog pathway inhibitors remains to be established, while drug resistance is becoming a new challenging issue.

Case Report: We report the case of a 90-year-old male initially referred for a locally advanced BCC of the nose. He had been previously treated by topical 5-fluorouracil for an adjacent microinvasive squamous cell carcinoma (SCC), with complete clinical response. Afterwards, vismodegib was initiated to treat his BCC. At week 16, both tumor and tumor ulceration obviously progressed. Palliative rhinectomy was performed. Histological examination found a deeply invasive SCC.

Conclusion: Although our case must be interpreted with caution, a role of vismodegib as a promoter of cutaneous SCC should be considered, consistently with recently published evidence. Physicians should perform new biopsies whenever in doubt about new and/or progressive skin lesions in patients receiving hedgehog pathway inhibitors.
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http://dx.doi.org/10.1159/000368350DOI Listing
December 2015

Acute renal failure associated with the new BRAF inhibitor vemurafenib: a case series of 8 patients.

Cancer 2014 Jul 15;120(14):2158-63. Epub 2014 Apr 15.

Service ICAR, Centre Hospitalier Universitaire (CHU) Pitié-Salpêtrière, Paris, France; Nephrology Department, CHU Pitié-Salpêtrière, Paris, France.

Background: Vemurafenib is a BRAF inhibitor that has become the cornerstone of metastatic or inoperable melanoma therapy since its approval in 2011 in the United States and 2012 in Europe. This targeted therapy has shown impressive results in terms of increased progression-free and overall survival as compared to dacarbazine. The safety profile did not include any renal manifestations at that time.

Methods: This report is the first case series of 8 patients who experienced significant to severe renal insufficiency under vemurafenib treatment.

Results: This case series shows that vemurafenib may induce potentially severe acute renal failure, including renal sequelae and persistent kidney disease in some cases.

Conclusions: Further studies are needed to investigate the effects of vemurafenib on the kidneys. Meanwhile, renal function should be closely monitored in treated patients for early detection of any renal dysfunction occurrence. Cancer 2014;120:2158-2163. © 2014 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.28709DOI Listing
July 2014

Melanoma patients under vemurafenib: prospective follow-up of melanocytic lesions by digital dermoscopy.

J Invest Dermatol 2014 May 7;134(5):1351-1358. Epub 2013 Nov 7.

Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France; Cancer Research Center of Lyon, Lyon, France. Electronic address:

Second primary melanomas (SPMs) induced by vemurafenib have been recently described. The aim of this study was to define the dermoscopical signs of melanoma in this context. Patients underwent a total body examination before receiving vemurafenib. Each single melanocytic lesion was registered before therapy by digital dermoscopy (DD), and then repeated monthly until therapy disruption. Forty-two patients were included, the mean duration of follow-up was 6.7 months, and a mean number of 51 lesions per patients were captured and followed. A total number of 2,155 lesions were recorded, of which 56.1% presented at least one change during the study. More common changes concerned the color of the lesions (up to 15%) and appearance or disappearance of globules (14.6%). Thirty-six of the melanocytic lesions were surgically excised, 21 were classified as a nevus, 1 was a lentigo, and 14 as a second new primary melanoma (occurring in 21% of our patients). DD allowed us to excise only 36/2,155 (1.6%) of the lesions and permitted us to detect 14 SPM in the 42 patients with a highly efficient malignant/benign ratio of 63.6%. Although vemurafenib is now tested in an adjuvant setting DD should be systematically used in order to accurately detect SPM and reduce the number of unnecessary excisions.
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http://dx.doi.org/10.1038/jid.2013.462DOI Listing
May 2014

Special locations dermoscopy: facial, acral, and nail.

Dermatol Clin 2013 Oct 23;31(4):615-24, ix. Epub 2013 Aug 23.

Department of Dermatology, Centre Hospitalier Lyon Sud, Université Claude Bernard Lyon 1, Piere Bénite Cedex 69495, France. Electronic address:

Although dermoscopy reflects the anatomy, skin anatomy is different on facial and acral skin as well as in the nail unit. Malignant patterns on acral sites include the parallel ridge pattern and irregular diffuse pigmentation, whose presence should lead to a biopsy. Malignant patterns on the face include features of follicular invasion (signet-ring images, annular granular images, and rhomboidal structures) and atypical vessels. Malignant patterns on the nail unit include the micro-Hutchinson sign and irregular longitudinal lines.
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http://dx.doi.org/10.1016/j.det.2013.06.006DOI Listing
October 2013

Panobinostat activity in both bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma: results of a phase II trial.

Eur J Cancer 2013 Jan 13;49(2):386-94. Epub 2012 Sep 13.

MD Anderson Cancer Center, Houston, TX, USA.

Background: Panobinostat is a potent, oral pan-deacetylase inhibitor (pan-DACi) that increases the acetylation of proteins involved in multiple oncogenic pathways. Here, panobinostat is studied in bexarotene-exposed and -naïve patients with refractory cutaneous T-cell lymphoma (CTCL).

Patients And Methods: Patients with CTCL subtypes mycosis fungoides and Sézary syndrome who received ⩾2 prior systemic therapy regimens received panobinostat (20mg) three times every week. The primary objective was overall response rate (ORR) as determined by a combined evaluation of skin disease and involvement of lymph node and viscera. Disease progression was defined as an unconfirmed, ⩾25% increase in modified Severity Weighted Assessment Tool (mSWAT) compared with nadir.

Results: Seventy-nine bexarotene-exposed and 60 bexarotene-naïve patients were enrolled. Reductions in baseline mSWAT scores were observed in 103 patients (74.1%). The ORR was 17.3% in all patients in the primary analysis (15.2% and 20.0% in the bexarotene-exposed and -naïve groups, respectively). The median progression-free survival was 4.2 and 3.7 months in the bexarotene-exposed and -naïve groups, respectively. The median duration of response was 5.6 months in the bexarotene-exposed patients and was not reached at data cutoff in the bexarotene-naïve patients. Additional responses were observed when less-stringent progression criteria were used. The most common adverse events were thrombocytopenia, diarrhoea, fatigue and nausea. Thrombocytopenia and neutropenia were the only grade 3/4 adverse events in >5% of patients and were manageable.

Conclusion: Despite a very conservative definition of disease progression, panobinostat demonstrated activity with a manageable safety profile in bexarotene-exposed and -naïve CTCL patients. ClinicalTrials.gov Identifier: NCT00425555.
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http://dx.doi.org/10.1016/j.ejca.2012.08.017DOI Listing
January 2013

Reflectance confocal microscopy characteristics of eight cases of pustular eruptions and histopathological correlations.

Skin Res Technol 2013 Feb 31;19(1):e444-52. Epub 2012 Aug 31.

Dermatology Department, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Background: Reflectance confocal microscopy (RCM)'s interest has been well established for the non-invasive diagnosis of skin cancers, especially melanocytic, and in the differential diagnosis between benign and malignant cutaneous lesions. However, its diagnostic interest in inflammatory skin diseases still needs to be demonstrated. Our purpose was to evaluate the correlation between RCM and conventional histopathology in a series of pustular eruptions of different pathogeny.

Methods: Reflectance confocal microscopy analysis was performed in eight consecutive unselected patients in whom the diagnoses of pustular psoriasis, bacterial sur-infection, herpes-type virus skin sur-infection, Sneddon-Wilkinson subcorneal putulosis and Hailey-Hailey disease have been made and images were compared to conventional histopathology.

Results: Neutrophils within the epidermis exhibited never reported earlier specific features, with either a shiny granular sludge or polylobated particules with a bright granular content. Moreover, some specific etiologies could be identified, such as acantholysis and herpes-type virus-infected keratinocytes.

Conclusion: Our studies show a good correlation between RCM and conventional histopathology in pustular eruptions. Reflectance confocal microscopy may play an important role in the differential diagnosis of pustular eruptions; as most of the pathologic clues are epidermal, narrow thickness of the field of imaging, its main technical limitation, is indeed of lesser importance.
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http://dx.doi.org/10.1111/j.1600-0846.2012.00662.xDOI Listing
February 2013

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma.

Authors:
Corine Bertolotto Fabienne Lesueur Sandy Giuliano Thomas Strub Mahaut de Lichy Karine Bille Philippe Dessen Benoit d'Hayer Hamida Mohamdi Audrey Remenieras Eve Maubec Arnaud de la Fouchardière Vincent Molinié Pierre Vabres Stéphane Dalle Nicolas Poulalhon Tanguy Martin-Denavit Luc Thomas Pascale Andry-Benzaquen Nicolas Dupin Françoise Boitier Annick Rossi Jean-Luc Perrot Bruno Labeille Caroline Robert Bernard Escudier Olivier Caron Laurence Brugières Simon Saule Betty Gardie Sophie Gad Stéphane Richard Jérôme Couturier Bin Tean Teh Paola Ghiorzo Lorenza Pastorino Susana Puig Celia Badenas Hakan Olsson Christian Ingvar Etienne Rouleau Rosette Lidereau Philippe Bahadoran Philippe Vielh Eve Corda Hélène Blanché Diana Zelenika Pilar Galan François Aubin Bertrand Bachollet Céline Becuwe Pascaline Berthet Yves Jean Bignon Valérie Bonadona Jean-Louis Bonafe Marie-Noëlle Bonnet-Dupeyron Fréderic Cambazard Jacqueline Chevrant-Breton Isabelle Coupier Sophie Dalac Liliane Demange Michel d'Incan Catherine Dugast Laurence Faivre Lynda Vincent-Fétita Marion Gauthier-Villars Brigitte Gilbert Florent Grange Jean-Jacques Grob Philippe Humbert Nicolas Janin Pascal Joly Delphine Kerob Christine Lasset Dominique Leroux Julien Levang Jean-Marc Limacher Cristina Livideanu Michel Longy Alain Lortholary Dominique Stoppa-Lyonnet Sandrine Mansard Ludovic Mansuy Karine Marrou Christine Matéus Christine Maugard Nicolas Meyer Catherine Nogues Pierre Souteyrand Laurence Venat-Bouvet Hélène Zattara Valérie Chaudru Gilbert M Lenoir Mark Lathrop Irwin Davidson Marie-Françoise Avril Florence Demenais Robert Ballotti Brigitte Bressac-de Paillerets

Nature 2011 Oct 19;480(7375):94-8. Epub 2011 Oct 19.

1] INSERM, U895 (équipe 1), Equipe labélisée Ligue Contre le Cancer, C3M, 06204 Nice, France [2] Université of Nice Sophia-Antipolis, UFR Médecine, 06204 Nice, France [3] Centre Hospitalier Universitaire de Nice, Service de Dermatologie, 06204 Nice, France [4].

So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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http://dx.doi.org/10.1038/nature10539DOI Listing
October 2011

Vemurafenib in melanoma with BRAF V600E mutation.

N Engl J Med 2011 10;365(15):1448-9; author reply 1450

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http://dx.doi.org/10.1056/NEJMc1108651DOI Listing
October 2011

Primary cutaneous marginal zone lymphoma as a complication of radiation therapy: Case report and review.

Dermatol Online J 2010 Dec 15;16(12). Epub 2010 Dec 15.

Service de dermatologie, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.

Background: The occurrence of primary cutaneous B-cell lymphoma at the site of radiation therapy is exceptional. We report herein the case of a primary cutaneous marginal zone lymphoma arising at the site of radiotherapy for breast cancer.

Methods/results: A seventy-year-old woman was diagnosed in 2005 with an invasive ductal carcinoma of the left breast, which was treated with surgery, adjuvant chemotherapy, and radiation therapy. Three years later she developed several cutaneous nodules on her left breast, followed by similar lesions on her back. Histologic, immunohistochemistry, and molecular findings were consistent with the diagnosis of cutaneous marginal zone lymphoma. Physical examination was otherwise negative, as well as mammography, total body CT, bone marrow biopsy, and Borrelia serology.

Conclusions: To our knowledge, this is the first published case of primary cutaneous marginal zone lymphoma occurring at the site of radiotherapy. Cutaneous surveillance is proposed from the first year after irradiation in order to detect new primary malignancies, including this rare cutaneous neoplasm.
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December 2010

Stevens-Johnson syndrome and toxic epidermal necrolysis induced by amifostine during head and neck radiotherapy.

Radiother Oncol 2008 May 6;87(2):300-3. Epub 2008 Mar 6.

Department of Dermatology, Université Paris XII, Créteil Cedex, France.

Amifostine is an organic thiophosphate prodrug used for cytoprotection against toxic effects of radiotherapy and chemotherapy. In a European prospective study of SJS/TEN, six patients were suspected to have SJS/TEN associated with amifostine. Our findings suggest that the risk of life-threatening cutaneous adverse reactions to amifostine could be significantly increased.
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http://dx.doi.org/10.1016/j.radonc.2008.01.021DOI Listing
May 2008

In vitro evidence for a direct antifibrotic role of the immunosuppressive drug mycophenolate mofetil.

J Pharmacol Exp Ther 2007 May 1;321(2):583-9. Epub 2007 Feb 1.

Institut National de la Santé et de la Recherche Médicale U697, Hôpital Saint-Louis, Pavillon Bazin, 1 Avenue Claude Vellefaux, 75010 Paris, France.

The immunosuppressive drug mycophenolate mofetil (MMF) is used to prevent organ rejection after transplantation and has shown some efficacy to prevent the fibrotic complications that occur during autoimmune diseases such as systemic sclerosis or during graft-versus-host disease (GVHD). We tested the hypothesis that MMF may exert direct effects on fibroblast extracellular matrix remodeling. Incubation of human lung fibroblast cultures with MMF led to dose- and time-dependent reduction in the synthesis and expression of type I collagen. Inhibition of COL1A1 and COL1A2 mRNA steady-state levels occurred at the level of transcription via repression of their promoters. In contrast, MMF significantly enhanced the expression and the synthesis of interstitial collagenase (matrix metalloproteinase-1). MMF was also found to diminish the capacity of fibroblast to contract mechanically unloaded collagen lattices and to reduce the synthesis of alpha-smooth muscle actin, a marker of the contractile myofibroblast phenotype. In addition, MMF diminished the fibroblasts motility. In conclusion, we provide novel mechanism by which MMF alters fibroblast functions important for wound healing and implicated in the development of tissue fibrosis, e.g., collagen production, extracellular matrix contraction, and cell migration. Such properties may contribute to the beneficial therapeutic effects of MMF against fibrotic lesions developing in systemic sclerosis or during GVHD.
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http://dx.doi.org/10.1124/jpet.106.117051DOI Listing
May 2007

Modulation of collagen and MMP-1 gene expression in fibroblasts by the immunosuppressive drug rapamycin. A direct role as an antifibrotic agent?

J Biol Chem 2006 Nov 16;281(44):33045-52. Epub 2006 Aug 16.

INSERM U697, Hôpital Saint-Louis, 75010 Paris, France.

We have examined whether rapamycin, an immunosuppressive drug, may exert part of its antifibrotic activity by directly targeting fibroblast extracellular matrix deposition. Incubation of human lung fibroblast (WI-26) cultures with rapamycin led to dose- and time-dependent reduction in the expression of types I and III collagens, both at the protein and mRNA levels. Rapamycin had no effect on collagen promoter activity but accelerated mRNA decay, indicating post-transcriptional control of collagen gene expression. In contrast, rapamycin significantly enhanced the expression of interstitial collagenase (MMP-1) at the protein and mRNA levels and transcriptionally. We determined that rapamycin efficiently activates AP-1-driven transcription by rapidly inducing c-jun/AP-1 phosphorylation with activation of the c-Jun N-terminal kinase (JNK) cascade, resulting in enhanced binding of AP-1.DNA complex formation and AP-1-dependent gene transactivation. Conversely, the JNK inhibitor SP600125 inhibited rapamycin-induced MMP-1 gene transactivation and AP-1/DNA interactions. A c-jun antisense expression vector efficiently prevented rapamycin-induced MMP-1 gene transcription. Pharmacological inhibition of either ERK or p38 MAPK pathways was without effect on rapamycin-induced MMP-1 gene expression. It thus appears that rapamycin may exert direct antifibrotic activities independent from its immunosuppressive action.
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http://dx.doi.org/10.1074/jbc.M606366200DOI Listing
November 2006