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Dive into the research topics where N. Kramkimel is active.

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Featured researches published by N. Kramkimel.


Joint Bone Spine | 2017

Pembrolizumab-induced polymyalgia rheumatica in two patients with metastatic melanoma.

Bethsabée Garel; N. Kramkimel; Anne-Priscille Trouvin; Camelia Frantz; Nicolas Dupin

Joint Bone Spine - In Press.Proof corrected by the author Available online since mardi 26 avril 2016


Dermatology | 2015

Sarcoidosis in Patients Treated with Vemurafenib for Metastatic Melanoma: A Paradoxical Autoimmune Activation

C. Lheure; N. Kramkimel; N. Franck; Sara Laurent-Roussel; A. Carlotti; Astrid Queant; François Goldwasser; Marie-Françoise Avril; Nicolas Dupin

Background: Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. Objectives: We describe 5 cases of sarcoidosis in patients treated with vemurafenib. Methods: Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. Results: Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. Conclusion: BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.


British Journal of Dermatology | 2017

Neutrophilic eccrine hidradenitis in 2 patients treated with BRAF inhibitors: a new cutaneous adverse event

F. Herms; N. Franck; N. Kramkimel; F. Fichel; L. Delaval; Sara Laurent-Roussel; A. Carlotti; M.-F. Avril

Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant haemopathy. It has polymorphous clinical features and the association of both clinical and histological features is necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after the initiation of treatment and were badly tolerated. Histological analyses confirmed the diagnosis of NEH. Symptoms disappeared a few days after the cessation of treatment and introduction of topical steroids. The replacement of one BRAFi with another is a therapeutic alternative as it is not necessarily associated with a relapse of NEH. NEH can be added to the spectrum of neutrophilic dermatoses induced by BRAFis. It occurs earlier (3–4 days) than previously described drug‐induced NEH (9–12 days) and may be an earlier stage of eccrine squamous syringometaplasia, which has already been reported in the context of BRAFi‐treated patients.


Melanoma Research | 2016

Age and clear eyes are associated with an increased risk of cutaneous squamous cell carcinomas in vemurafenib-treated melanoma patients.

Florian Herms; N. Kramkimel; Elodie Regnier-Rosencher; A. Carlotti; Johan Chanal; F. Boitier; S. Aractingi; Nicolas Dupin; Marie-Françoise Avril

Cutaneous squamous cell carcinoma (cSCC) is a frequent side-effect of vemurafenib treatment. The main aim of this study was to identify the clinical risk factors associated with the development of cSCC in melanoma patients treated with vemurafenib. We carried out a retrospective study, including 63 consecutive melanoma patients treated with vemurafenib for BRAF-mutant metastatic melanoma in an oncodermatological department. Clinical and follow-up data were collected and analysed, and a comparison of the subgroups who did and did not develop cSCC was performed. A total of 42.9% of patients (n=27) treated with vemurafenib developed one or more cSCC. Patients with cSCC were significantly older (P=0.01). Clear eyes were also associated with a higher risk of developing cSCC (odds ratio=3.50; 95% confidence interval: 1.08–12.43). Three patients developed cSCC more than 1 year after the initiation of treatment (12, 16 and 18 months, respectively). Clinicians should be vigilant in older patients undergoing vemurafenib therapy as well as patients with clear eyes as they seem to be at increased risk of developing cSCC, even late after the initiation of treatment.


Journal of the Endocrine Society | 2017

Polyendocrinopathy Resulting From Pembrolizumab in a Patient With a Malignant Melanoma

Anne-Cécile Paepegaey; C. Lheure; Carole Ratour; Gaëlle Lethielleux; Jérôme Clerc; Jérôme Bertherat; N. Kramkimel; Lionel Groussin

Introduction: Checkpoint inhibitors have significantly improved the prognosis of patients with advanced melanoma. These cancer immunotherapy drugs have specific endocrine autoimmune toxicity. We describe a case of an adrenal insufficiency secondary to pembrolizumab, an anti-programmed cell death-1 monoclonal antibody. Moreover, this case of polyendocrinopathy resulting from a pembrolizumab as the adrenal insufficiency occurred after a thyroiditis. Participant: A 55-year-old female was started on pembrolizumab immunotherapy for a metastatic choroidal melanoma. Five months after initiation, she suffered from thyrotoxicosis. A thyroiditis was diagnosed by iodine-123 thyroid scintigraphy and ultrasonography. Pembrolizumab therapy was maintained. Two weeks later, without any other treatment given, she patient developed hypothyroidism and levothyroxine substitution was started. Pembrolizumab proved to be ineffective and was stopped 9 months after initiation. One month following its discontinuation, the patient was hospitalized in the intensive care unit. Severe hyponatremia (115 mmol/L) associated with hyperkalemia (5.7 mmol/L) led to the early recognition and treatment of an acute adrenal insufficiency. Positive results for adrenal cortex and 21-hydroxylase antibodies were in favor of autoimmune toxicity. Conclusion: This case highlights the diversity of potential endocrine toxicity of checkpoint inhibitors. Because acute adrenal crisis may be associated with substantial morbidity and mortality, physicians must be aware of these rare adverse events to allow an early diagnosis.


Pharmacological Research | 2016

Plasma vemurafenib exposure and pre-treatment hepatocyte growth factor level are two factors contributing to the early peripheral lymphocytes depletion in BRAF-mutated melanoma patients.

Alicja Puszkiel; Melanie White-Koning; Nicolas Dupin; N. Kramkimel; Audrey Thomas-Schoemann; Gaëlle Noé; Nicolas Chapuis; Michel Vidal; François Goldwasser; Etienne Chatelut; Benoit Blanchet

The therapeutic response to vemurafenib, a BRAF serine-threonine kinase inhibitor, exhibits large variations between patients. Evaluation of factors predicting the clinical efficacy of vemurafenib may help to identify patients at high risk of non-response in the early phase of treatment. The aim of this study was to analyze the pharmacokinetics of vemurafenib by a population approach and to evaluate the relationship between plasma drug exposure and pre-treatment plasma hepatocyte growth factor (HGF) levels with clinical effects (progression-free survival (PFS), peripheral lymphocytes depletion) in patients with metastatic BRAFV600 mutated melanoma treated with single agent vemurafenib. Concentration-time data (n=332) obtained in 44 patients were analyzed using the NONMEM program. Pre-treatment plasma levels of HGF (n=36) were assayed by ELISA method. A Cox model was used to identify prognostic factors associated with progression-free survival (PFS), and a linear regression to identify factors contributing to the depletion of peripheral lymphocytes at day 15. Steady-state pharmacokinetics of vemurafenib was described by a one compartment model with first order absorption and first order elimination. None of the tested covariates explained the inter-patient variability in CL/F. A significant decrease in total lymphocytes count was observed within the first 15days (median ratio Day15/Day0=0.66, p<0.0001). Patients with Day15/Day0 ratio below 0.66 had longer PFS (14 vs 4 months, HR=0.41, CI95%=[0.15-0.77], p=0.0095). In the multivariate Cox model analysis, ECOG PS was the only parameter independently associated with PFS (grade 1 vs 0, HR=3.26, CI95%=[1.29-8.22], p=0.01 and grade ≥2 vs 0, HR=4.77, CI95%=[1.52-14.95], p=0.007). Plasma vemurafenib exposure (p=0.046) and pre-treatment HGF levels (p=0.003) were independently associated with the total lymphocyte ratio Day15/Day0. These findings show that plasma vemurafenib exposure and pre-treatment HGF levels are two factors contributing to the early peripheral lymphocytes depletion which itself is associated with PFS.


British Journal of Dermatology | 2017

BRAFV600 inhibitor discontinuation after complete response in advanced melanoma. A retrospective analysis of 16 patients

C. Vanhaecke; F. Deilhes; Johan Chanal; Elodie Regnier-Rosencher; F. Boitier; S. Boulinguez; M.-F. Avril; Sarah Guégan; Nicolas Dupin; S. Aractingi; N. Meyer; N. Kramkimel

BRAF inhibitors (BRAFi) improve progression-free survival and overall survival in patients with advanced melanoma (1,2), with 3 to 6% of patients experiencing complete remission (CR)(1,3). Nevertheless, this efficacy comes at a cost with 90% of patients experiencing at least one adverse event and 45% grade 3 or 4 adverse events (4). Management of long-term responders is not yet well delineated: safety argues for treatment continuation, because evolution after discontinuation is unknown. This article is protected by copyright. All rights reserved.


Journal of Lower Genital Tract Disease | 2016

Locally Advanced Unresectable Vaginal Melanoma: Response With Anti-Programmed Death Receptor 1.

Johan Chanal; N. Kramkimel; Sarah Guégan; Philippe Moguelet; Virginie Fourchotte; Marie-Françoise Avril

CASE REPORT Mucosal melanoma is rare. We report an impressive partial response to pembrolizumab, an anti–programmed death receptor 1 (PD-1) in a patient with locally advanced and unresectable vaginal mucosal melanoma after failure of imatinib and ipilimumab. A 72-year-old woman attended in July 2012 for a mucosal vaginal melanoma of the anterior vaginalwall, described as a large infiltration of 2.5 mm in Breslow thickness and an 8-mm thick polypoid lesion. She underwent full colpectomy with bilateral adnexectomy and pelvic lymph node dissection. Pathological report showed residual mucosal vaginal melanoma of 1.5 mm in thickness whose resection was incomplete laterally and without any lymph node involvement among 9 resected bilateral iliac lymph nodes. The tumor harbored neither BRAF nor NRASmutations. There was no mutation of the c-kit gene but amplification. Immunostaining was negative for PD-1 or PD-L1 (program death receptor ligand). An additional treatment was discussed. Interferon alpha was contraindicated because of the depressive mood of the patient, already treated by paroxetine. Imatinib was also considered but did not seem appropriate at that stage because of the absence of an evaluable target either clinically or radiologically. Finally, the surgeons were asked for an additional resection but judged that it was not appropriate. Therefore, a close followup both clinical every 3 months and by imaging every 6 months was proposed to the patient. Ten months later, new melanocytic lesions developed on the colpectomy scar. Progression was confirmed by a PET scan and by a biopsy. Surgical treatment consisted in resection of the entire residual vagina, resection of a 5-mm portion of distal urethra, and resection of a left inguinal lymph node and a right superficial lymph node dissection that provided 3 lymph nodes. Urethra and lymph nodes were disease free. Excision of the melanoma was again incomplete pathologically. Surgeons were asked to reoperate but were reluctant to perform a pelviectomy with colic derivation. Imatinib was not considered in the absence of any radiological target lesion. The situation was explained to the patient who refused a mutilating operation. Therefore, a follow-up without additional treatment was restarted. Six months later, pelvic magnetic resonance imaging (MRI) identified a recurrent nodule of the vaginal wall measuring 35 26 mm in diameters. Imatinib (400 mg daily) was initiated. Two months later, the treatment was stopped because of neutropenia


British Journal of Dermatology | 2016

First‐line treatment with paclitaxel for non‐HIV‐related Kaposi sarcoma: experience in 10 cases

D. Denis; E. Régnier-Rosencher; N. Kramkimel; A. Jafari; M.-F. Avril; Nicolas Dupin

DEAR EDITOR, Kaposi sarcoma (KS) is a rare angioproliferative neoplasm caused by infection with human herpesvirus 8. Four epidemiological forms of KS have been characterized: classic KS, endemic KS, iatrogenic KS and AIDS-related KS. In most cases, classic and endemic KS are indolent diseases, for which systemic treatment is unnecessary. However, aggressive forms may develop with visceral involvement or lymphoedema. Chemotherapy is justified for the treatment of these forms, although the age of the patients, many of whom are old, may limit treatment options. In a recent systematic review of the literature, the authors concluded that they could not recommend a particular strategy for patients with KS requiring systemic treatment. The treatment options for such patients include immunotherapy with interferon, or chemotherapy, often with single drugs such as vinblastine, vincristine, bleomycin or oral etoposide, with similar response rates. More aggressive forms of KS may require anthracyclines, either alone or with other drugs. Taxanes have been approved by the US Food and Drug Association as a second-line treatment for AIDS-related KS, following the publication of a limited number of prospective studies highlighting the good responses obtained in this setting. These microtubule-stabilizing agents interfere with KS by inhibiting Bcl-2 antiapoptotic activity. Taxanes have a low toxicity and are therefore suitable for use in the elderly. A few recent studies have reported these drugs to be effective against classic or endemic KS refractory to other types of chemotherapy, and a few individual case reports have suggested that they may also be effective as first-line treatment. We describe here our experience concerning the efficacy and toxicity of paclitaxel as a first-line treatment in aggressive non-HIV-related KS. From 2007 to 2014, 10 patients with non-HIV-related KS (six cases of classic KS and four of endemic KS) received paclitaxel as first-line treatment. The patient characteristics, response to treatment, tolerance and outcome are summarized in Table 1. There were nine men and one woman, and the mean age at KS diagnosis was 66 years. Patients were classified as having stage II–IV disease, according to the Krigel classification. One patient had visceral involvement, characterized by a symptomatic localization on the piriform recess; one patient had inguinal and parailiac lymph node involvement and the other eight patients were treated due to extensive cutaneous disease and the presence of a large lymphoedema. All had functional impairment. Two patients had received local radiotherapy before chemotherapy. None of the other patients had received any prior treatment. The patients underwent intravenous infusions of paclitaxel, at a dose of 80 mg m 2 (n = 2) or 100 mg m 2 (n = 8) every 2 weeks. Treatment was stopped if a stable response had been achieved by the first evaluation (after four to six cycles) or if a serious adverse event occurred. The mean number of taxane infusions per patient was 4 6 (range 1–6). In all of the patients, functional impairment and lymphoedema were found to have improved substantially after as few as two cycles. We report the response according to the AIDS Clinical Trials Group criteria. Treatment was stopped in one patient, during the second infusion, due to a severe systemic allergic reaction, which is a well-known dose-independent adverse event, justifying the administration of prophylactic premedication. Another patient presented an atrioventricular conduction disturbance during the third infusion. The treatment was stopped for safety reasons, and all the necessary cardiological examinations were carried out. The patient did not need a pacemaker. Four patients had episodes of paraesthesia, after the first or second course of treatment. The neuropathy persisted in one patient despite the interruption of the treatment after the third cycle. Treatment was continued in the other three patients without recurrence of paraesthesia. One patient complained of asthenia and myalgia, and two patients presented grade 2 alopecia. No haematological intolerance was observed, and thus no infection related to myelosuppression. The outcome of the patients after treatment was recorded and is shown in Table 1 and Figure 1. The median follow-up was 59 months. Progression was reported in five of the 10 patients, with a median time to progression of 14 months. However, two of these five patients were controlled with only local treatment. Three patients required further treatment by chemotherapy. Paclitaxel was reintroduced in two of them, with a favourable outcome: one did not require any other drug treatment, whereas the disease was controlled for 3 years in the other, who subsequently required other treatments. Finally, only two patients underwent other chemotherapy treatments: the patient who had received only one paclitaxel


Journal of The European Academy of Dermatology and Venereology | 2018

A fifth subtype of Kaposi's sarcoma, classic Kaposi's sarcoma in men who have sex with men: a cohort study in Paris

D. Denis; V. Seta; E. Régnier-Rosencher; N. Kramkimel; Johan Chanal; M.-F. Avril; Nicolas Dupin

Classic Kaposis sarcoma (CKS) occurs predominantly among elderly men and is associated with Kaposis sarcoma‐associated herpesvirus (KSHV). In low‐endemic countries, KSHV infects predominantly men having sex with men (MSM).

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Nicolas Dupin

Paris Descartes University

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M.-F. Avril

Paris Descartes University

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Johan Chanal

Paris Descartes University

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N. Franck

Paris Descartes University

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A. Carlotti

Paris Descartes University

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Benoit Blanchet

Paris Descartes University

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