Purpose
Dabrafenib plus trametinib combination has greatly improved survival in
BRAF
V600
mut
metastatic melanoma patients. However, data regarding the influence of pharmacokinetic markers in ...real-life patients are lacking. In this study, we aimed to explore dabrafenib and trametinib pharmacokinetic impact on progression-free survival (PFS), duration of response (DOR) or all grades treatment-related adverse events (ARAE) occurrence in routine care patients.
Methods
BRAF
V600
mut
metastatic melanoma patients initiating standard doses of dabrafenib 150 mg BID plus trametinib 2 mg QD were included. Clinical data were collected via the French biobank MelBase, prospectively enrolling unresectable stage III or IV melanoma. Clinical response evaluation, ARAE reporting and dabrafenib and trametinib plasma quantification were performed. Association of individual Bayesian-estimated pharmacokinetic markers (AUC
0–
τ
and
C
trough
) and baseline clinical variables with DOR, PFS, clinical response, and ARAE was then assessed.
Results
Fifty patients (comprising 4 AJCC stage IIIc and 46 stage IV) were included. Median PFS reached 11.4 months, and overall response rate 70%. Fifty percent of patients experienced ARAE (G3
n
= 10, G4
n
= 0). In univariate analysis, median dabrafenib
C
trough
within intermediate range was associated with a significantly higher PFS (HR 95% CI = 0.41 0.18; 0.91,
p
= 0.029) and DOR (HR 95% CI = 0.39 0.16; 0.94,
p
= 0.024), and association with DOR remained significant in multivariate analysis (HR 95% CI = 0.34 0.12; 0.95,
p
= 0.040). Trametinib pharmacokinetic markers were significantly higher in patients experiencing ARAE compared to patients without ARAE.
Conclusion
In this study, exposure-efficacy and tolerance analysis highlighted the interest of therapeutic drug monitoring to optimize therapeutic management in
BRAF
V600
mut
metastatic melanoma patients based on trough concentrations of dabrafenib and trametinib.
Mycoplasma genitalium (MG) infection accounts for 10-35% of non-gonococcal non-chlamydial (NGNC) urethritis. However, given that most people infected with MG do not develop symptoms and that ...antimicrobial resistance is increasing worldwide, there is no evidence of any benefits of screening asymptomatic individuals. We conducted this study to describe MG screening practices and outcomes at a French Sexually Transmitted Infections (STI) center in which MG testing was performed selectively and multiplex assays were not carried out i.e., simultaneous screening for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and MG.
A retrospective, observational, single-center study was conducted at the STI unit of Saint-Louis Hospital in Paris. The records of all patients undergoing MG testing from January 1st, 2017, to December 31st, 2018, were reviewed. The primary aim of the study was to describe and evaluate the proportion of MG-positive (MG+) patients among those tested. Secondary objectives were determination of the prevalence of MG+ status among symptomatic patients, risk factors associated with MG infection, and therapeutic modalities and efficacy.
Two hundred and forty-nine patients underwent MG testing, 28 (11%) of whom were positive (MG+). The prevalence of MG+ status among symptomatic NGNC patients was 12%. HIV-positive (HIV+) status was significantly associated with MG+ status in univariate and multivariate analyses (Odds Ratio=7.3, 95% Confidence Interval 1.3-41.7; P=0.02). Twenty-three patients (85%) received antibiotics. Eighteen (67%) received azithromycin for 5 days, but 7 had clinical resistance. No quinolone resistance was reported.
Despite unavailability of multiplex testing at our facility, which led to targeted-only screening for MG, its relatively high local prevalence is in keeping with what is generally observed at similar facilities across the world, where use of multiplex tests enables systematic screening for MG alongside NG and CT. This reinforces the current recommendations in Europe, France and the US against systematic MG testing or treatment in asymptomatic patients.
Summary
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.
What's already known about this topic?
Cutaneous adverse events are frequent with BRAF inhibitors, including cases of neutrophilic dermatoses.
Neutrophilic eccrine hidradenitis is a neutrophilic dermatosis occurring mostly in patients treated with chemotherapy for a malignant haemopathy.
What does this study add?
Neutrophilic eccrine hidradenitis can be added to the spectrum of neutrophilic dermatoses induced by BRAF inhibitors.
Replacing one BRAF inhibitor with another is a therapeutic option, as it is not necessarily associated with a relapse of the neutrophilic eccrine hidradenitis.
Linked Comment: Basu. Br J Dermatol 2017; 176:1443–1444
Actinic cheilitis: a systematic review of treatment options Trager, M.H.; Farmer, K.; Ulrich, C. ...
Journal of the European Academy of Dermatology and Venereology,
April 2021, 2021-Apr, 2021-04-00, 20210401, Volume:
35, Issue:
4
Journal Article
Peer reviewed
Actinic cheilitis is a premalignant condition that can progress to squamous cell carcinoma with a higher propensity for metastasis than cutaneous squamous cell carcinoma. Optimal treatment for ...actinic cheilitis has not been established, and evidence‐based estimates of clinical cure in the dermatology literature are limited. Here, we review and synthesize outcome data published for patients with actinic cheilitis after treatment with various modalities. A systematic review was conducted in MEDLINE, Embase and the Cochrane library for English, French and German‐language studies and references of included articles from inception to 20 January 2020. Studies were included if they reported on at least six patients with biopsy‐proven actinic cheilitis. After quality appraisal, results of studies with the strongest methodology criteria were synthesized. 18 studies of 411 patients (published 1985 to 2016) were included. The majority of the studies were case series. Carbon dioxide laser ablation and vermilionectomy were associated with the most favourable outcomes with fewest recurrences. Chemical peel and photodynamic therapy were associated with higher recurrence. Adverse effects generally resolved in the weeks following treatment and cosmetic outcomes were favourable overall. In conclusion, there is a lack of high‐quality comparative studies evaluating different treatment options for actinic cheilitis. The included publications used various outcome measures; however, the majority reported on the recently defined core outcome sets. These results suggest that both carbon dioxide laser ablation and vermilionectomy are effective treatments for actinic cheilitis. Prospective head‐to‐head studies are needed to compare these treatment modalities and to assess patient preferences.
