Philippe Moguelet

Skin Toxicities Compromise Prolonged Pemetrexed Treatment

Introduction: Pemetrexed is approved to treat non-small cell lung cancer and has an overall favorable toxicity profile. A case of pemetrexed-induced cutaneous adverse events (CAE), i.e., periorbital edema with conjunctivitis and edema of the limbs, leading to severe fluid retention, was diagnosed in our unit. The aim of this study was to evaluate the incidence and risk factors for CAEs. Methods: Patients treated with pemetrexed were identified from a prospective cohort. To detect pemetrexed-associated CAEs, questionnaires were answered by patients and the referring oncologist. Results: Included were 107 patients treated with four cycles or more of pemetrexed. Pemetrexed-induced CAEs were observed in 37 of 107 (35%) total patients (TPs) and 25 of 47 (53%) alive patients (APs). Conjunctivitis was the most frequent CAE: 27 of 107 (25%) in TPs and 21 of 47 (44%) in APs. Periorbital edema occurred in 16 of 107 (15%) TPs and 14 of 47 (30%) APs. Limb edema was present in 14 of 107 (13%) TPs and 12 of 47 (25%) APs. Only two cases of CAE influenced pemetrexed treatment. No significant differences in age, body surface area, smoking status, and performance status were detected. Patients with CAE had more cycles of pemetrexed (7 versus 5.5; p = 0.028). In univariate and multivariate analyses, gender ratio was statistically different (p = 0.031): 48% (12/25) of women in the CAE group versus only 18% (4/18) in the control group. Conclusion: Pemetrexed induces frequent conjunctivitis, peripheral edema, and edema of the limbs. Female gender seems to be an independent risk for CAE. CAEs are frequently disabling and symptomatic treatment should be proposed.

Hydroxychloroquine-Induced Pigmentation in Patients With Systemic Lupus Erythematosus: A Case-Control Study

IMPORTANCEnHydroxychloroquine-induced pigmentation is not a rare adverse effect. Our data support the hypothesis that hydroxychloroquine-induced pigmentation is secondary to ecchymosis or bruising.nnnOBJECTIVEnTo describe the clinical features and outcome of hydroxychloroquine (HCQ)-induced pigmentation in patients with systemic lupus erythematosus (SLE).nnnDESIGN, SETTING, AND PARTICIPANTSnIn a case-control study conducted at a French referral center for SLE and antiphospholipid syndrome, 24 patients with SLE, with a diagnosis of HCQ-induced pigmentation, were compared with 517 SLE controls treated with HCQ.nnnMAIN OUTCOMES AND MEASURESnThe primary outcome was the clinical features of HCQ-induced pigmentation. Skin biopsies were performed on 5 patients, both in healthy skin and in the pigmented lesions. The statistical associations of HCQ-induced pigmentation with several variables were calculated using univariate and multivariate analyses.nnnRESULTSnAmong the 24 patients, skin pigmentation appeared after a median HCQ treatment duration of 6.1 years (range, 3 months-22 years). Twenty-two patients (92%) reported that the appearance of pigmented lesions was preceded by the occurrence of ecchymotic areas, which gave way to a localized blue-gray or brown pigmentation that persisted. Twenty-three patients (96%) had at least 1 condition predisposing them to easy bruising. Results from skin biopsies performed on 5 patients showed that the median concentration of iron was significantly higher in biopsy specimens of pigmented lesions compared with normal skin (4115 vs 413 nmol/g; Pu2009<u2009.001). Using multivariate logistic regression, we found that HCQ-induced pigmentation was independently associated with previous treatment with oral anticoagulants and/or antiplatelet agents and with higher blood HCQ concentration.nnnCONCLUSIONS AND RELEVANCEnHydroxychloroquine-induced pigmentation is not a rare adverse effect of HCQ. Our data support the hypothesis that HCQ-induced pigmentation is secondary to ecchymosis or bruising.

Spiny Follicular Hyperkeratosis Eruption: A New Cutaneous Adverse Effect of Sorafenib

TO THE EDITOR: Sorafenib is an inhibitor of angiogenesis approved by the European Medicines Agency and US Food and Drug Administration and widely used for the treatment of metastatic renal cell carcinoma and hepatocarcinoma. This oral multikinase inhibitor has a large spectrum of activity on various targets, including vascular endothelial growth factor (VEGF) receptor (VEGFR) 2 and VEGFR3, platelet-derived growth factor receptor, Fms-like tyrosine kinase 3, c-kit, and RAF-1 kinase pathway. Antitumoral activity has been also demonstrated in preclinical studies for various tumors including melanoma, non–small-cell lung cancer, and thyroid cancer. In two large pivotal trials and a daily practice report, cutaneous adverse events were frequently reported (70%) and comprised hand-foot skin reaction (30%), rash and desquamation (40%), subungual splinter hemorrhages (40%), alopecia (27%), slow beard growth, stomatitis and cheilitis, xerosis, hyperkeratosis of the nipples, and eruptive cysts. As observed in a phase I trial, dose interruption, dose reduction, and treatment discontinuation were mostly a result of dermatologic adverse effects. Physiopathology is unclear, and emerging toxicities are reported in clinical practice, such as eruptive nevus or keratoacanthomas and squamous cell carcinomas. Here, we report a new sorafenib-induced cutaneous adverse effect, highlighted by a multidisciplinary team around the patients’ treatment. Between March and November 2008, patients were prospectively included in a cohort with a multidisciplinary approach of toxicity induced by antiangiogenesis inhibitors in Cochin and Tenon Hospitals in France. All patients signed inform consent and were observed by a multidisciplinary team including oncologists, dermatologists, pathologists, and pharmacists in a hospitalized care unit (Centre d’Etudes et de Recours sur les Inhibiteurs de l’Angiogenèse). Past dermatologic history and drug interactions were assessed at first visit before intake of sorafenib. Clinical examinations and plasma concentration measurement of sorafenib were performed at baseline and every 2 weeks for 2 months and then once a month until the discontinuation of treatment. Dermatologic adverse events were reported and graded according to the National Cancer Institute Common Terminology Criteria of Adverse Events (version 3). The sorafenib plasma concentration was assayed by high-performance liquid chromatography and quantified by area under the curve with Bayesian pharmacokinetic modeling. Area under the concentration-time curve from 0 to 12 hours of sorafenib was calculated using a Bayesian estimator specifically developed in our institution for sorafenib. Beside the already known cutaneous adverse events, relevant or unusual dermatologic events were characterized with pictures and skin biopsy. Patients were treated for skin adverse events according to international guidelines. Forty-three patients (30 men and 13 women) with a median age of 61 years (range, 31 to 81 years) without past dermatologic history were treated with sorafenib for several cancers including hepatocarcinoma (n 12, 27%), metastatic cutaneous melanoma (n 11, 26%), renal carcinoma (n 6, 14%), thyroid carcinoma (n 7, 16%), neuroendocrine tumor (n 3, 7%), choroid melanoma (n 2, 5%), and fibrolamellar hepatocarcinoma (n 2, 5%). Previous oncologic treatments included cytotoxic chemotherapy (n 13, 30%) and the angiogenesis inhibitors sunitinib (n 8, 19%) and bevacizumab (n 1). Most patients had initial good performance status (Eastern Cooperative Oncology Group performance status of 0 to 1, n 32, 74%). The median time of sorafenib treatment was 171 days (range, 5 to 534 days). Patient demographics clinical and histopathologic characteristics are listed in Table 1. After sorafenib intake, nine patients (21%) experienced an asymptomatic white spiny follicular hyperkeratosis (SFH) located on the face, scalp, upper trunk, and, less frequently, upper arms, but always sparing the palms and soles. Each spiny lesion was approximately 0.5 to 1 mm in diameter and up to 5 mm high. Four of nine patients had pathology analysis. For two patients, a biopsy of a white spiny keratotic projection on the abdomen showed a spike-like orthoparakeratotic column filling the infundibulum and protruding above the surface; a sparse lymphocytic infiltrate was present in the adjacent dermis without lichenoid alteration (Fig 1). The surrounding epidermis was normal. The SFH appeared a median of 82 days (range, 9 to164 days) after treatment began and disappeared after a median of 98 days (range, 4 to 168 days). No patient required specific topical treatment or dose interruption. Four patients experienced treatment discontinuation for extradermatologic adverse effects with disappearance of the eruption after 5 to 7 days. A rechallenge with sorafenib for two of the patients was followed by reappearance of the SFH. The residual plasma concentration of sorafenib was assessed in eight patients, and three patients had a high level (area under the concentration-time curve 65 mg/L h). A comparison between patients with SFH and the main cohort revealed no statistical association of SFH with grade 2 or 3 hand-foot skin reaction (seven patients [77%] v 21 patients [61%], respectively; P .37) or alopecia (three patients [33%] v eight patients [23.5%], respectively; P .68). This type of eruption has been described under several names, including spiny follicular keratoderma, hyperkeratotic spicules, filiform hyperkeratosis, parakeratotic horns, and follicular hyperkeratosis. Facial hyperkeratotic spicule eruption was reported in association with monoclonal gammopathy and linked to cutaneous deposits of the monoclonal immunoglobulins and was also reported in association with viral particles in a patient with lymphoma. Filiform palmoplantar hyperkeratosis, which is clinically close to this pattern, was reported in familial and sporadic forms but rarely in association with malignant diseases (renal, breast, and rectal carcinomas and melanoma) and exceptionally with chronic renal failure, hypovitaminosis A, and Crohn’s disease. In the patients described here, palms and soles were spared by the eruption, corresponding to type IIb Zarour et al classification. JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E VOLUME 28 NUMBER 31 NOVEMBER 1 2010

Is Topical Monotherapy Effective for Localized Pyoderma Gangrenosum

In May 2008, a 32-year-old woman was seen with a painful infiltrated erythematous lesion 11 cm in diameter, studded with purulent necrotic pits, on the anterior right shin (Figure, A). It had started as an erythematous infiltrated lesion 3 months previously and had been stable for 1 month. Pyoderma gangrenosum was diagnosed based on the clinical appearance, negative findings on bacterial culture, and histologic examination of a skin biopsy specimen. No systemic underlying disease was found during investigations, including a colonoscopy. There is little evidence on the efficacy of PG treatment because there is only 1 randomized controlled trial to date comparing the effects of infliximab vs placebo. Systemic corticosteroids and cyclosporine are usually recommended as first-line treatments. Given the stability of this solitary lesion, we decided to consider the option of topical monotherapy for our patient. The objective of this article was to determine from the available evidence whether a topical agent would be an effective and safe treatment in this setting. Literature Search

Generalized interstitial granuloma annulare induced by pegylated interferon-alpha.

a Service de dermatologie, b Service d’anatomo-pathologie, c Service d’hépato-gastroentérologie, Hôpital Tenon, Paris , France an interstitial granuloma annulare (GA) that occurred during Peg-IFN therapy. A 52-year-old woman was seen for erythematous papules and plaques that developed 6 weeks after initiation of a combined PegIFN -ribavirine therapy for hepatitis C virus (HCV) infection. Her medical history was notable for an HCV infection treated in 2000 with IFN and ribavirine. At that time, no cutaneous eruption was reported and hypothyroidism was the only side effect. In 2003, because of a viral relapse, another treatment with ribavirine and Peg-IFN was initiated. Other treatments included atorvastatine for hypercholesterolemia and paroxetine for depression. Both drugs were given for more than 6 months. Physical examination revealed erythematous papules and plaques involving mainly extremities ( fig. 1 ). A skin biopsy ( fig. 2 ) showed typical features of interstitial GA: areas of necrobiosis of the superficial and mid dermis surrounded by numerous histiocytes and lymphocytes without true palisade. Antivirals were maintained and clobetasol ointment was applied. This slightly improved the skin lesions. Nevertheless, new flares developed at other skin sites throughout the whole antiviral

Ten-Year Experience of Cutaneous and/or Subcutaneous Infections Due to Coelomycetes in France

Background.u2003Coelomycetes are rarely but increasingly reported in association with human infections involving mostly skin and subcutaneous tissues, both in immunocompetent and immunocompromised patients. Coelomycetes constitute a heterogeneous group of filamentous fungi with distinct morphological characteristics in culture, namely an ability to produce asexual spores within fruit bodies. Methods.u2003We included all cases of proven primary cutaneous and/or subcutaneous infections due to coelomycetes received for identification at the French National Reference Center for Invasive Mycoses and Antifungals between 2005 and 2014. Eumycetoma, chromoblastomycosis, and disseminated infections were excluded. Results.u2003Eighteen cases were analyzed. The median age was 60.5 years. In all cases, patients originated from tropical or subtropical areas. An underlying immunodepression was present in 89% of cases. Cutaneous and/or subcutaneous lesions, mainly nodules, abscesses, or infiltrated plaques, were observed in distal body areas. Isolates of different genera of coelomycetes were identified: Medicopsis (6), Paraconiothyrium (3), Gloniopsis (3), Diaporthe (3), Peyronellaea (2), Lasiodiplodia (1). Lesion treatment consisted of complete (10) or partial (2) surgical excision and/or the use of systemic antifungal therapy, namely voriconazole (5) and posaconazole (4). Literature review yielded 48 additional cases of cutaneous and/or subcutaneous infections due to coelomycetes. Conclusions.u2003Infectious diseases physicians should suspect coelomycetes when observing cutaneous and/or subcutaneous infections in immunocompromised hosts from tropical areas; a sequence-based approach is crucial for strains identification but must be supported by consistent phenotypic features; surgical treatment should be favored for solitary, well limited lesions; new triazoles may be used in case of extensive lesions, especially in immunocompromised patients.

Contact dermatitis due to ultrasound gel: A case report and published work review.

Adverse skin reactions with ultrasound gel are rare and related mostly to allergic contact dermatitis or contact urticaria. We report an allergic contact dermatitis with Doppler ultrasound gel applied in a 67‐year‐old man. The patient developed atypical purpuric cutaneous presentation located on vascular axes. Semi‐open test with ultrasound gel and patch test with phenoxyethanol were followed by the same clinical purpuric eruption which strongly suggested the accountability of this later component as allergen. Based on this observation, we present a review of published work with a focus on clinical features and allergens involved in ultrasound gel cutaneous reaction.

Bullous pemphigoid after boiling water burn.

Bullous pemphigoid is the most frequent autoimmune blistering disease, usually affecting elderly patients. Most cases are idiopathic. We report a case of bullous pemphigoid developing four weeks after a boiling water burn, initially at the site of the burn, then elsewhere.

Efflorescence of facial molluscum contagiosum as a manifestation of immune reconstitution inflammatory syndrome in a patient with AIDS

Auteur(s) : Claude Bachmeyer1, Philippe Moguelet2, Francoise Baud3, Francois-Xavier Lescure4 1Service de medecine interne 2Service d’anatomo-pathologie 3Pharmacie 4Service des maladies infectieuses et tropicales, CHU Tenon (AP-HP), 4xa0rue de la Chine, 75020 Paris, France Molluscum contagiosum (MC) is a self-limited disease due to a DNA virus of the poxviridae family. It is a frequent condition in children and is reported in immunocompetent adults in the genital areas, suggesting sexual [...]

Purpuric papulonodular sarcoidosis mimicking granulomatous pigmented purpura

Auteur(s) : Claude BACHMEYER1 claude.bachmeyer@tnn.aphp.fr, Belen EGUIA2, Patrice CALLARD3, Philippe MOGUELET3 1 Service de medecine interne, 2 Service de dermatologie, 3 Service d’anatomie pathologique, CHU Tenon (AP-HP), 4, rue de la Chine, 75020 Paris, France A 86-year-old man with diabetes mellitus type 2, treated with gliclazide, was hospitalized in May 2009 for evaluation of fever, fatigue and weight loss of 10 kg over the last 6 months. On examination his temperature was 38xa0C. [...]