Publications by authors named "Laurent Parmentier"

18 Publications

  • Page 1 of 1

[Immunotherapy with immune checkpoint inhibitor and skin toxicity].

Rev Med Suisse 2020 May;16(695):1086-1091

Service d'oncologie, Centre hospitalier du Valais romand, Hôpital du Valais, Avenue du Grand-Champsec 86, 1950 Sion.

Dermatologic toxicities appear to be the most prevalent immunotherapy related adverse effects, both with anti-PD-1 and anti-CTLA-4 agents, as well as with the newly developed anti-PD-L1. They occur in more than one-third of the patients treated with immune check point inhibitors, regardless of the cancer being treated. They mainly manifest in the form of self-limiting maculopapular rashes and pruritus. Early recognition and management are essential in order to mitigate the severity of the lesions. A multidisciplinary team is crucial for optimal management.
View Article and Find Full Text PDF

Download full-text PDF

Source
May 2020

Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.

Nat Genet 2016 Apr 7;48(4):398-406. Epub 2016 Mar 7.

Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.

Basal cell carcinoma (BCC) of the skin is the most common malignant neoplasm in humans. BCC is primarily driven by the Sonic Hedgehog (Hh) pathway. However, its phenotypic variation remains unexplained. Our genetic profiling of 293 BCCs found the highest mutation rate in cancer (65 mutations/Mb). Eighty-five percent of the BCCs harbored mutations in Hh pathway genes (PTCH1, 73% or SMO, 20% (P = 6.6 × 10(-8)) and SUFU, 8%) and in TP53 (61%). However, 85% of the BCCs also harbored additional driver mutations in other cancer-related genes. We observed recurrent mutations in MYCN (30%), PPP6C (15%), STK19 (10%), LATS1 (8%), ERBB2 (4%), PIK3CA (2%), and NRAS, KRAS or HRAS (2%), and loss-of-function and deleterious missense mutations were present in PTPN14 (23%), RB1 (8%) and FBXW7 (5%). Consistent with the mutational profiles, N-Myc and Hippo-YAP pathway target genes were upregulated. Functional analysis of the mutations in MYCN, PTPN14 and LATS1 suggested their potential relevance in BCC tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3525DOI Listing
April 2016

Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus.

Am J Trop Med Hyg 2016 Apr 1;94(4):840-843. Epub 2016 Feb 1.

Leishmania parasites cause a broad range of disease, with cutaneous afflictions being, by far, the most prevalent. Variations in disease severity and symptomatic spectrum are mostly associated to parasite species. One risk factor for the severity and emergence of leishmaniasis is immunosuppression, usually arising by coinfection of the patient with human immunodeficiency virus (HIV). Interestingly, several species of Leishmania have been shown to bear an endogenous cytoplasmic dsRNA virus (LRV) of the Totiviridae family, and recently we correlated the presence of LRV1 within Leishmania parasites to an exacerbation murine leishmaniasis and with an elevated frequency of drug treatment failures in humans. This raises the possibility of further exacerbation of leishmaniasis in the presence of both viruses, and here we report a case of cutaneous leishmaniasis caused by Leishmania braziliensis bearing LRV1 with aggressive pathogenesis in an HIV patient. LRV1 was isolated and partially sequenced from skin and nasal lesions. Genetic identity of both sequences reinforced the assumption that nasal parasites originate from primary skin lesions. Surprisingly, combined antiretroviral therapy did not impact the devolution of Leishmania infection. The Leishmania infection was successfully treated through administration of liposomal amphotericin B.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4269/ajtmh.15-0803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824227PMC
April 2016

Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease.

Am J Hum Genet 2014 Jan;94(1):135-43

Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany. Electronic address:

Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4*), c.652C>T (p.Arg218*), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218*) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2013.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3882728PMC
January 2014

Acral purpura as leading clinical manifestation of dermatitis herpetiformis: report of two adult cases with a review of the literature.

Dermatology 2013 21;227(1):1-4. Epub 2013 Aug 21.

Shanghai Skin Disease Hospital, Shanghai, China.

Dermatitis herpetiformis (DH) is an autoimmune disease that clinically manifests as pruritic vesicles and papules. The diagnosis of DH is often challenging because of its wide spectrum of clinical presentations. We here report 2 patients with DH in whom finger petechiae represented the initial and leading manifestation of the disease, and the confirmed diagnosis critically relied on immunopathological studies. Therefore, besides the classic causes, clinicians should also consider DH in the differential diagnosis of acral purpura, even in patients only presenting with discrete acral petechial lesions. We also review the recent literature regarding the rare cases of petechiae in adult DH patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000347108DOI Listing
June 2014

Detection of Leishmania RNA virus in Leishmania parasites.

PLoS Negl Trop Dis 2013 10;7(1):e2006. Epub 2013 Jan 10.

Department of Biochemistry, University of Lausanne, Epalinges, Vaud, Switzerland.

Background: Patients suffering from cutaneous leishmaniasis (CL) caused by New World Leishmania (Viannia) species are at high risk of developing mucosal (ML) or disseminated cutaneous leishmaniasis (DCL). After the formation of a primary skin lesion at the site of the bite by a Leishmania-infected sand fly, the infection can disseminate to form secondary lesions. This metastatic phenotype causes significant morbidity and is often associated with a hyper-inflammatory immune response leading to the destruction of nasopharyngeal tissues in ML, and appearance of nodules or numerous ulcerated skin lesions in DCL. Recently, we connected this aggressive phenotype to the presence of Leishmania RNA virus (LRV) in strains of L. guyanensis, showing that LRV is responsible for elevated parasitaemia, destructive hyper-inflammation and an overall exacerbation of the disease. Further studies of this relationship and the distribution of LRVs in other Leishmania strains and species would benefit from improved methods of viral detection and quantitation, especially ones not dependent on prior knowledge of the viral sequence as LRVs show significant evolutionary divergence.

Methodology/principal Findings: This study reports various techniques, among which, the use of an anti-dsRNA monoclonal antibody (J2) stands out for its specific and quantitative recognition of dsRNA in a sequence-independent fashion. Applications of J2 include immunofluorescence, ELISA and dot blot: techniques complementing an arsenal of other detection tools, such as nucleic acid purification and quantitative real-time-PCR. We evaluate each method as well as demonstrate a successful LRV detection by the J2 antibody in several parasite strains, a freshly isolated patient sample and lesion biopsies of infected mice.

Conclusions/significance: We propose that refinements of these methods could be transferred to the field for use as a diagnostic tool in detecting the presence of LRV, and potentially assessing the LRV-related risk of complications in cutaneous leishmaniasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pntd.0002006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3542153PMC
June 2013

Unilesional follicular mycosis fungoides: report of two cases with progression to tumor stage and review of the literature.

J Cutan Pathol 2012 Sep 9;39(9):853-60. Epub 2012 Aug 9.

Kempf und Pfaltz, Histologische Diagnostik, Zurich, Switzerland.

Mycosis fungoides (MF) is the most common type of cutaneous lymphoma and has protean clinicopathological manifestations. Follicular or folliculotropic MF (FMF) is a rare variant, which histopathologically is characterized by pronounced folliculotropism of neoplastic T cells, with or without follicular mucinosis, and clinically by an impaired prognosis compared to classic MF. In contrast, unilesional MF is a very rare variant with an excellent prognosis, with a single case of large-cell transformation reported to date. The combination of folliculotropic and unilesional MF is very unusual, with only two cases reported to date. Here we report two patients with unilesional folliculotropic MF with progression to tumor stage in both patients. To the best of our knowledge, this is the first report on the disease evolution with large-cell transformation and progression of unilesional FMF. Complete remission was achieved by local radiation therapy in both patients. The differential diagnoses, classification and implications for the treatment of unilesional FMF as well as the pertinent literature are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1600-0560.2012.01965.xDOI Listing
September 2012

Facial basal cell carcinomas recurring after photodynamic therapy: a retrospective analysis of histological subtypes.

Dermatology 2012 29;224(4):346-51. Epub 2012 Jun 29.

Department of Dermatology, Inselspital, Berne University Hospital, Berne, Switzerland.

Background: Photodynamic therapy (PDT) is an established treatment for basal cell carcinomas (BCCs). Although recurrences are sometime observed, their histological patterns have never been specifically studied or compared with the one of the initial tumor.

Objective: To compare the histopathological aggressiveness of BCCs recurring after PDT with that of the primary tumors.

Methods: The study population included 12 patients with 16 post PDT recurrent BCCs. Outcome measures were proportion of histologically aggressive subtypes in BCC recurrences vs. primary tumor.

Results: 62.5% of recurrent BCCs displayed a transition from a non-aggressive to an aggressive subtype.

Conclusions: Post PDT recurrences appear to display an increased histological aggressiveness, although the latter may reflect the natural course of tumor progression. Despite the presence of potential biases, our study raises the possibility that PDT favors the selection of more aggressive tumor cells. Better systematic large-scale follow-up studies are required to assess the exact frequency and histological types of BCC recurrences after PDT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000339335DOI Listing
December 2012

Dermoscopy of Merkel cell carcinoma.

Dermatology 2012 6;224(2):140-4. Epub 2012 Apr 6.

Department of Dermatology, Claude Bernard University Lyon 1, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.

Introduction: Merkel cell carcinoma (MCC) is an aggressive cutaneous tumor whose clinical presentation, usually a pink nodule, is not specific. We aimed in this study to determine the dermoscopic criteria encountered in MCC.

Methods: From our image database we selected the patients diagnosed with MCC and scored the dermoscopic criteria shown by these tumors.

Results: Ten patients coming from three different academic hospitals were studied. Vascular structures were the more relevant dermoscopic features. In 8 out of 10 (80%) patients a polymorphic vascular pattern was seen, composed of milky-red clods/areas in association with one or more additional vascular structures.

Conclusion: Although an overlap existed between the dermoscopic features observed in MCC and amelanotic melanoma, the presence of a polymorphous vascular pattern may constitute an additional clinical clue to accurately diagnose this rare tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000337411DOI Listing
October 2012

Linear sclerodermic lupus erythematosus, a distinct variant of linear morphea and chronic cutaneous lupus erythematous.

Int J Dermatol 2011 Dec;50(12):1491-5

Department of Dermatology, University Hospital, Geneva, Switzerland.

Background: Overlap syndromes represent disorders that combine diagnostic criteria of two or more different connective tissue diseases.

Methods: We herein describe the case of a 34-year-old patient.

Results: Our patient developed a lesion on the scalp and forehead following Blaschko's line typical for linear morphea "en coup de sabre", while histopathological features were consistent with both chronic cutaneous lupus erythematosus and linear morphea, a cutaneous overlap syndrome previously described as linear sclerodermiform lupus erythematosus. The patient was given oral antimalarials in association with topical steroids and calcineurin inhibitors with good response.

Conclusions: Knowledge of this peculiar cutaneous overlap syndrome is warranted, since its management and prognosis is probably different from classical linear morphea.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-4632.2011.04936.xDOI Listing
December 2011

Specific nail alterations in cutaneous T-cell lymphoma: successful treatment with topical mechlorethamine.

Arch Dermatol 2010 Nov;146(11):1287-91

Department of Dermatology, Inselspital, Berne University Hospital, CH-3010-Bern, Switzerland.

Background: Cutaneous T-cell lymphoma can be associated with clinically significant nail alterations, the presentation of which can be protean and misleading. To date, only a few reports have demonstrated direct specific tumor infiltration of the nail bed, while little is known about the efficacy of topical treatments.

Observations: We describe the case of a 93-year-old man presenting with Sézary syndrome who developed clinically significant nail alterations. Light microscopy studies and T-cell receptor rearrangement analysis demonstrated the presence of a specific lymphocytic infiltrate within the nail bed. The patient was given repeated courses of topical mechlorethamine, leading to a sustained complete remission of both skin and nail alterations.

Conclusions: Specific nail involvement should be recognized and considered in all patients with cutaneous T-cell lymphomas. Topical mechlorethamine remains an attractive therapeutic option in cases of specific nail alterations, especially for situations in which systemic therapies are either not indicated or unlikely to be well tolerated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archdermatol.2010.325DOI Listing
November 2010

Evidence for a new fumarate hydratase gene mutation in a unilateral type 2 segmental leiomyomatosis.

Dermatology 2010 13;221(2):149-53. Epub 2010 Jul 13.

Department of Dermatology, Hôpitaux Universitaires de Genève, Genève, Switzerland.

Background: Multiple cutaneous and uterine leiomyomata syndrome (MCUL; MIM 150800) is a rare condition that sometimes predisposes to renal cancer. It is caused by deleterious mutations in the fumarate hydratase (FH) gene. In many patients, skin leiomyomas have been reported to develop according to a segmental type 1 or type 2 distribution. We report a patient showing multiple leiomyomas distributed according to a segmental type 2 distribution and covering several areas exclusively on the left side of his body.

Objective: To search for a specific mutation in the FH gene associated with this phenotype.

Methods: Genomic DNA from peripheral blood leucocytes of the proband was sequenced and screened for mutation of the FH gene.

Results: Heterozygosity for an as yet undescribed mutation c.695delG, leading to a truncated protein p.Gly232AspfsX24, was found.

Conclusion: We report a new mutation in the FH gene and discuss the unusual pattern of purely unilateral distribution in the present case.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000315068DOI Listing
December 2010

Delayed Nicolau's livedoid dermatitis after ultrasound-guided sclerotherapy.

Dermatol Surg 2010 4;36(1):155-8. Epub 2009 Nov 4.

Universitätsklinik für Dermatologie, Inselspital, Bern, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1524-4725.2009.01372.xDOI Listing
April 2010

Mucocutaneous lichen planus with esophageal involvement: successful treatment with an anti-CD20 monoclonal antibody.

Arch Dermatol 2008 Nov;144(11):1427-30

Service de Dermatologie, Hôpitaux Universitaires de Genève, Geneva, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archderm.144.11.1427DOI Listing
November 2008

Value of a novel Neisseria meningitidis--specific polymerase chain reaction assay in skin biopsy specimens as a diagnostic tool in chronic meningococcemia.

Arch Dermatol 2008 Jun;144(6):770-3

Polyclinique de Dermatologie et Vénéréologie, Hôpital Universitaire de Genève, Rue Micheli-du-Crest 24, 1211 Genève 14, Switzerland.

Background: Chronic meningococcemia (CM) is a diagnostic challenge. Skin lesions are frequent but in most cases nonspecific. Polymerase chain reaction (PCR)-based diagnosis has been validated in blood and cerebrospinal fluid for acute Neisseria meningitidis infection, in patients in whom routine microbiologic tests have failed to isolate the bacteria. In 2 patients with CM, we established the diagnosis by a newly developed PCR-based approach performed on skin biopsy specimens.

Observations: Two patients presented with fever together with systemic and cutaneous manifestations suggestive of CM. Although findings from blood cultures remained negative, we were able to identify N meningitidis in the skin lesions by a newly developed PCR assay. In 1 patient, an N meningitidis strain of the same serogroup was also isolated from a throat swab specimen. Both patients rapidly improved after appropriate antibiotherapy.

Conclusions: To our knowledge, we report the first cases of CM diagnosed by PCR testing on skin biopsy specimens. It is noteworthy that, although N meningitidis-specific PCR is highly sensitive in blood and cerebrospinal fluid in acute infections, our observations underscore the usefulness of PCR performed on skin lesions for the diagnosis of chronic N meningitidis infections. Whenever possible, this approach should be systematically employed in patients for whom N meningitidis infection cannot be confirmed by routine microbiologic investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archderm.144.6.770DOI Listing
June 2008

Inhibition of IkappaB kinase subunit 2 in cutaneous T-cell lymphoma down-regulates nuclear factor-kappaB constitutive activation, induces cell death, and potentiates the apoptotic response to antineoplastic chemotherapeutic agents.

Clin Cancer Res 2008 Feb;14(3):901-11

Unité Institut National de la Sante et de la Recherche Medicale U697 and Department of Dermatology 1, Hôpital Saint-Louis, AP-HP, Université Paris 7, Paris, France.

Purpose: A key molecular feature of cutaneous T-cell lymphomas (CTCL) is the constitutive activation of the nuclear factor-kappaB (NF-kappaB) transcription factor. We investigated in vitro the effects on CTCL survival and chemoresistance of a specific inhibition of IkappaB kinase subunit 2 (IKK2).

Experimental Design: Selective IKK2 inhibition was carried out by transfection of SeAx and MyLa CTCL lines with an inactive form of IKK2 and by exposing these lines and tumor cells from 10 patients with Sézary syndrome (SS) to AS602868, a new IKK2 inhibitor. The constitutive nuclear translocation of NF-kappaB was analyzed by electrophoretic mobility shift assay and confocal microscopy. Apoptosis was determined by Annexin V/propidium iodide-positive staining and mitochondrial transmembrane potential alterations as well as poly(ADP-ribose)polymerase cleavage. The expression of Bcl-2 family oncoproteins and survivin was studied by immunoblotting.

Results: Specific IKK2 inhibition resulting from transfection or from incubation with AS602868 allowed a down-regulation of NF-kappaB transcriptional activity. As shown by electrophoretic mobility shift assay and apoptosis assays, AS602868 down-regulated the nuclear translocation of NF-kappaB and induced a potent apoptotic response in CTCL lines and in tumor cells from patients with SS while preserving the viability of both peripheral blood lymphocytes from healthy donors and of nonmalignant T cells from SS patients. Moreover, CTCL death induction by conventional antineoplastic agents etoposide and vincristine was potentiated by AS602868. Finally, AS602868-induced apoptosis of CTCL cells was associated with an up-regulation of Bax dimers and a decrease of survivin.

Conclusion: These results indicate that IKK2 inhibition represents a promising strategy for the treatment of advanced stages of CTCL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-07-1419DOI Listing
February 2008

Pharmacogenetic and pharmacogenomic studies. Impact on drug discovery and drug development.

Therapie 2003 May-Jun;58(3):275-82

INSERM, Unité 367, Paris, France.

The topics discussed in this article are concerned with studying genomic polymorphism and identifying new therapeutic targets, the role of genetics in preclinical and clinical drug development, and cultural, regulatory and logistical aspects of the development of pharmacogenetics in France. The conclusions are that from a physiological, biochemical or genomic point of view, the study of human genetic polymorphism has obvious potential value for drug development, because it can help to identify new therapeutic targets, and to predict drug efficacy and tolerability more effectively. There are already several examples of the latter approach, which relies on studying the genetic variability of enzymes involved in drug metabolism, and that of the effector molecules of the pharmacological activity. Pharmacogenetics could eventually make it possible to personalize drug treatments, as methods for analysing genes are simplified and their cost reduced. To help attain this still far-off goal, certain recommendations have been proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2515/therapie:2003043DOI Listing
January 2004