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1.
Clin Nucl Med ; 44(10): 806-807, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31306191

RESUMO

A 49-year-old patient with metastatic melanoma was treated with nivolumab (Opdivo). An early F-FDG PET/CT after 2 cycles showed a progressive metabolic disease. A 4-month optimal follow-up F-FDG PET/CT showed a complete metabolic response. The treatment was stopped after 22 cycles because of immunotherapy-related pneumonitis. After discontinuation of treatment, PET/CT examinations demonstrated a metabolic complete remission during 2 years. The metabolic pattern on early PET was suggestive of pseudoprogression, which is a rare phenomenon reflecting an activation of inflammatory cells within the tumor microenvironment causing lesions to increase in size and to accumulate FDG until a sufficient immune response is developed.


Assuntos
Fluordesoxiglucose F18 , Melanoma/tratamento farmacológico , Melanoma/patologia , Nivolumabe/efeitos adversos , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Feminino , Humanos , Melanoma/imunologia , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico
3.
Paediatr Drugs ; 21(3): 169-175, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31155692

RESUMO

BACKGROUND: Phase III clinical trials of biotherapies for childhood psoriasis are designed for a selected population, which can differ from real-life patients. OBJECTIVE: Our objective was to assess the proportion of children with psoriasis that received biotherapy in the biological treatments for pediatric psoriasis (BiPe) cohort that would be excluded from phase III clinical trials of these treatments. METHODS: Data concerning initiation of the first biotherapy from all patients included in the BiPe cohort were analyzed. Ineligibility was assessed after applying the exclusion criteria used in the principal phase III trials of etanercept, adalimumab, and ustekinumab for childhood psoriasis. RESULTS: Of the 134 patients included, 73 (54.5%) were ineligible for at least one randomized controlled trial based on one or more exclusion criteria. Amongst the 63 children treated with etanercept, 35 (55.5%) were ineligible: 22 because of the type of psoriasis, 12 because of concomitant treatment, and six because of psoriasis severity based on psoriasis assessment severity index (PASI) and physician global assessment (PGA) scores (PASI < 12 and PGA < 3). Amongst the 44 children treated with adalimumab, 32 (72.7%) were ineligible: 17 because of the clinical type of psoriasis, 12 because of psoriasis severity (PASI < 20 and PGA < 4), and seven because of concomitant treatment. Amongst the 27 children patients treated with ustekinumab, 12 (44.4%) were ineligible: eight because of psoriasis severity (PASI < 12 and PGA < 3), five because of the clinical type of psoriasis, and one because of concomitant treatment. Drug survival and the frequency of serious adverse events did not differ between eligible and ineligible patients. CONCLUSION: The majority of children treated with biotherapies in real-life practice differ from those in phase III trials, most commonly because of the clinical type of their psoriasis, the disease severity being lower than required and the use of prior or concomitant psoriasis treatment. Efficacy and safety results from phase III clinical trials in selected populations may not sufficiently reflect what is seen in real life, thus results from real-life cohort studies are necessary.


Assuntos
Terapia Biológica/métodos , Psoríase/tratamento farmacológico , Adolescente , Feminino , Humanos , Masculino , Resultado do Tratamento
4.
J Am Acad Dermatol ; 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31202870

RESUMO

BACKGROUND: Patients with epidermal nevi strongly demand cosmetic improvement. Laser treatment appears appealing and is frequently used in clinical practice. Nevertheless, large series with long-term follow-up are missing, preventing definitive conclusions about its real benefit. OBJECTIVE: To evaluate the long-term effectiveness and safety of lasers for epidermal nevi. METHODS: Bicentric, retrospective, cohort study, including all patients treated with a laser for an epidermal nevus with more than a one-year follow-up. RESULTS: Seventy patients were treated for different types of epidermal nevi, mostly with ablative lasers: 23 verrucous epidermal nevi, 16 nevi sebaceous, 26 Becker nevi, two inflammatory linear verrucous epidermal nevi, one smooth-muscle hamartoma, one rounded and velvety epidermal nevus, and one nevus lipomatosus superficialis. The follow-up period ranged between 12 and 127 months (median 37 months). Better results, fewer recurrences, and higher patient satisfaction were noted in treatments for verrucous epidermal nevi than for nevi sebaceous. Q-switched (QS) lasers failed to show any degree of improvement in almost all patients with Becker nevus. LIMITATIONS: The retrospective nature of the study. CONCLUSIONS: Ablative lasers can treat verrucous epidermal nevi with good long-term esthetic results, but they have limited long-term efficacy for nevus sebaceous. Q-switched lasers failed to improve Becker nevi.

5.
JAMA Dermatol ; 155(6): 673-678, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042256

RESUMO

Importance: The prognosis of advanced melanoma has been greatly improved by new therapeutic agents and clinicians rely on dynamic signals to drive their therapeutic choices. Although the kinetics of metastatic disease seem to be correlated with survival, progression of the localized disease is not predictable. Objective: To assess whether progression of metastatic disease is associated with the time to the first distant recurrence of melanoma. Design, Setting, and Participants: This study was conducted from March 1, 2013, to September 1, 2017, among 638 adults with unresectable stage III or IV melanoma within the French multicentric prospective cohort MelBase. Patients treated with first-line immunotherapies, targeted therapies, or chemotherapy were included. Patients with unknown primary or de novo metastatic melanoma were not included. Data were analyzed from March 1, 2013, to December 1, 2017. Main Outcomes and Measures: The date of primary excision and time to first distant recurrence, progression-free survival, and overall survival were collected. Cox proportional hazards regression models were planned to assess the association between time to first distant recurrence and progression-free survival or overall survival, which was evaluated in terms of hazard ratio (HR). Time to recurrence was analyzed both as a continuous and categorical variable (<12 months, 12-24 months, and >24 months). Results: A total of 638 patients (272 women and 366 men; median age, 64 years [interquartile range, 52-73 years]) were included in the study. The median time from primary excision to first distant recurrence was 25 months (interquartile range, 12-55 months). There was no evidence of association of the time to recurrence with progression-free survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.99-1.01) or after categorization (12-24 months: HR, 0.75; 95% CI, 0.56-1.02; >24 months: HR, 0.62; 95% CI; 0.47-1.01). There was no evidence of association of the time to recurrence with overall survival, both when analyzed as a continuous variable (HR, 0.99; 95% CI, 0.98-1.02) or after categorization (12-24 months: HR, 0.76; 95% CI, 0.54-1.07; >24 months: HR, 0.61; 95% CI, 0.54-1.03). Those results remained nonsignificant after stratification by treatment. Conclusions and Relevance: In the MelBase cohort, time to recurrence of metastatic melanoma appears not to be associated with progression-free survival or overall survival.

6.
Eur J Cancer ; 112: 38-46, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30909072

RESUMO

BACKGROUND: Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy. PATIENTS AND METHODS: Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias. RESULTS: Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4-0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively. CONCLUSION: This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.

7.
J Am Acad Dermatol ; 81(1): 143-151, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30825533

RESUMO

BACKGROUND: Dupilumab is the first biologic available to treat atopic dermatitis (AD). Its effectiveness and safety were demonstrated in clinical trials. OBJECTIVE: We sought to assess the effectiveness and safety of dupilumab in adults with AD in a real-life French multicenter retrospective cohort. METHODS: We included patients treated during March 2017-April 2018. Efficacy outcomes, including Scoring Atopic Dermatitis (SCORAD) and Eczema Area and Severity Index (EASI) scores, were collected at baseline and 3 months when available. Adverse events (AEs) were recorded at follow-up. RESULTS: We included 241 patients. The median ± interquartile range (IQR) follow-up time was 3.8 ± 3.7 months. A ≥75% improvement in SCORAD was achieved in 27 of 163 (16.6%) patients, and a ≥75% improvement in EASI was achieved in 40 of 82 (48.8%) patients. The median SCORAD and EASI scores at 3 months were significantly lower than those at baseline (SCORAD ± IQR, 25 ± 21 vs 56 ± 27.4, P < 10-9 and EASI ± IQR, 4.1 ± 6.8 vs 17.9 ± 15.4, P < 10-9, respectively). Conjunctivitis was reported in 84 of 241 (38.2%) patients. The proportion with eosinophilia (>500 cells/mm3) during follow-up (57%) was higher than that at baseline (33.7%) (n = 172, P < 10-6). Dupilumab was stopped in 42 cases; 27 patients stopped because of AEs. LIMITATIONS: No control group, missing data. CONCLUSION: This real-life study demonstrated a similar dupilumab effectiveness as that seen in clinical trials, but it also revealed a higher frequency of conjunctivitis and eosinophilia.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Conjuntivite/induzido quimicamente , Dermatite Atópica/tratamento farmacológico , Eosinofilia/induzido quimicamente , Segurança do Paciente/estatística & dados numéricos , Adulto , Anticorpos Monoclonais/efeitos adversos , Estudos de Coortes , Conjuntivite/epidemiologia , Dermatite Atópica/diagnóstico , Relação Dose-Resposta a Droga , Esquema de Medicação , Eosinofilia/epidemiologia , Feminino , França , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença
8.
J Invest Dermatol ; 139(6): 1306-1317, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30571969

RESUMO

Inflammatory caspases, activated within the inflammasome, are responsible for the maturation and secretion of IL-1ß/IL-18. Although their expression in psoriasis was shown several years ago, little is known about the role of inflammatory caspases in the context of psoriasis. Here, we confirmed that caspases 1, 4, and 5 are activated in lesional skin from psoriasis patients. We showed in three psoriasis-like models that inflammatory caspases are activated, and accordingly, caspase 1/11 invalidation or pharmacological inhibition by Ac-YVAD-CMK (i.e., Ac-Tyr-Val-Ala-Asp-chloromethylketone) injection induced a decrease in ear thickness, erythema, scaling, inflammatory cytokine expression, and immune cell infiltration in mice. We observed that keratinocytes were primed to secrete IL-1ß when cultured in conditions mimicking psoriasis. Generation of chimeric mice by bone marrow transplantation was carried out to decipher the respective contribution of keratinocytes and/or immune cells in the activation of inflammatory caspases during psoriasis-like inflammatory response. Our data showed that the presence of caspase 1/11 in the immune system is sufficient for a fully inflammatory response, whereas the absence of caspase 1/11 in keratinocytes/fibroblasts had no impact. In summary, our study indicates that inflammatory caspases activated in immune cells are implicated in psoriasis pathogenesis.

9.
JAMA Dermatol ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30304341

RESUMO

Importance: Hailey-Hailey disease (HHD) is a rare, autosomal-dominant acantholytic dermatosis characterized clinically by development of recurrent blisters and erosions in friction areas. Despite progression in our understanding of the molecular genetics of HHD, therapy remains suboptimal and there is no known cure. Objective: To determine whether the novel phosphodiesterase-4 inhibitor apremilast is effective in the treatment of HHD. Design, Setting, and Participants: Clinical case series of 4 patients with severe, treatment-resistant HHD at an outpatient clinic in the Department of Dermatology of Nice University Hospital, Nice, France. The patients were treated with apremilast; after the initial titration, the dose was 30 mg, twice daily. Main Outcomes and Measures: Objective clinical response was assessed by the treating dermatologist using the physician global assessment score; recorded adverse effects were monitored throughout the treatment at intervals of 2 to 3 months. Results: Three women and 1 man, with a mean age of 56 years, were treated and followed up for 6 to 10 months. Family history of the disease was noted in 3 (75%) of the cases. The lesions affected the axillary regions (75%), submammary regions (75%), inguinal regions (100%), and back and neck areas (50%). An improvement in the symptoms was reported by all of the patients after a treatment period of 1 month. After 6 months, the improvement of HHD lesions was reported as moderate to almost cleared among the patients. However, 2 patients developed some flares after 6 to 10 months of treatment and stopped apremilast therapy. One of the patients developed uncontrolled diffuse lesions and apremilast was reintroduced, resulting in partial control of her disease. Conclusions and Relevance: Apremilast appears to offer a low-risk therapeutic alternative or adjunct in resistant and severe forms of HHD. A prospective controlled trial with long-term follow-up is required to confirm these preliminary observations.

14.
Pharmacol Res Perspect ; 6(3): e00399, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29736244

RESUMO

Propranolol has become the first choice therapy for complicated Infantile Hemangiomas (IH). The pharmacokinetics of propranolol were evaluated after repeated oral administration of a new pediatric solution of propranolol at 3 mg kg-1 day-1 given twice daily (BID) in infants (77-243 days) with IH. A population model was built to describe the pharmacokinetics of propranolol in infants and to simulate different dosing regimens. One hundred and sixty-seven plasma concentrations from 22 infants were used in the population analysis. Weight effect was tested on apparent clearance and volume of distribution. Monte-Carlo simulations were performed for 4 dosing regimens: BID dosing with irregular or strict 12-hour intervals and 2 different 3 time daily dosing (TID) regimens. The best model was a one-compartment model with first-order absorption and elimination rates. The weight affected the clearance but not the volume. Typical oral clearance was estimated at 3.06 L hour-1 kg-1 (95% CI: 1.14-8.61 L hour-1 kg-1), close to adult clearance data. When regular BID dosing was compared to TID or irregular BID regimens, simulated median Cmin and Cmax were <20% different. To conclude, a model using a weight allometric function on clearance was established and confirmed that the dose in mg/kg should be used without adaptation by range of age in treatment of complicated IH. The simulations support the use of a BID dosing preferably to a TID dosing thanks to close Cmin and Cmax at steady state between both regimen and showed the possibility of irregular BID dosing, allowing early administration in the evening when needed.

15.
Am J Clin Dermatol ; 19(4): 609-615, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29594973

RESUMO

BACKGROUND: Psoriasis affects 2-4% of the population, with the most common clinical type being plaque psoriasis. The linear form of psoriasis is very rare. The literature on linear psoriasis (LP) consists of only case reports, and data are few. OBJECTIVE: This study aimed to better understand LP in a large-scale study. PATIENTS AND METHODS: We retrospectively retrieved the medical records from 14 French medical centers of patients newly diagnosed clinically with LP, with or without the support of histology, between 1 February and 31 July 2015. For each case, we assessed the clinical features, treatments and treatment efficacy. RESULTS: In total, 30 cases of LP (mean age 26.8 years, 13 males) were reported. Mean age at onset of LP was 20.0 years, with 18 developing LP in childhood. Ten patients had a family history of psoriasis, and two had psoriatic arthritis. A total of 19 cases were linear at onset, with concomitant classical psoriasis; these were termed "superimposed" LP. The remaining 11 cases were not associated with classical psoriasis and were termed "isolated" LP. In four of the superimposed cases, LP developed when the patient was receiving systemic treatment: methotrexate (n = 2), etanercept (n = 1) or infliximab (n = 1). Topical steroids were effective in 76% of cases in which they were used, and systemic treatment was effective in < 66%. Treatments were less effective in LP than in classical psoriasis. DISCUSSION: We identified a wide range of LP, with two profiles: isolated LP and superimposed LP. Topical treatment usually evoked clinical response, with relative resistance to systemic therapy. Methotrexate and anti-tumor necrosis factor (TNF)-α therapies can possibly unmask LP.


Assuntos
Psoríase/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/tratamento farmacológico , Psoríase/patologia , Estudos Retrospectivos , Pele/patologia , Resultado do Tratamento , Adulto Jovem
16.
Pediatr Dermatol ; 35(3): e193-e195, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29574966

RESUMO

Epidermolysis bullosa simplex is a group of inherited disorders with allelic and locus heterogeneity in which skin fragility and blistering within the skin occur. Mutations in KRT5 and KRT14 underlie the majority of reported cases. Mutations in KLHL24, a gene that encodes KLHL24 protein, have been reported recently to cause a generalized subtype of epidermolysis bullosa simplex, presumably by increasing the degradation of keratin 14. We describe a case of KLHL24-related epidermolysis bullosa simplex and highlight the burn-like pattern of scars.


Assuntos
Epidermólise Bolhosa Simples/genética , Proteínas Repressoras/genética , Pré-Escolar , Cicatriz/etiologia , Análise Mutacional de DNA , Epidermólise Bolhosa Simples/complicações , Epidermólise Bolhosa Simples/diagnóstico , Imunofluorescência , Humanos , Mutação , Pele/patologia
18.
Eur J Dermatol ; 28(6): 795-802, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30698148

RESUMO

Data on the clinical burden of chronic spontaneous urticaria (CSU) and economic consequences are lacking in France. To characterize the clinical and economic burden of CSU in symptomatic patients despite treatment by analysing data of French patients from the ASSURE-CSU study. ASSURE-CSU was an international observational study that included CSU patients with symptoms that lasted for 12 months or more despite treatment. Disease characteristics and healthcare resource use were obtained from medical records. Data on disease history, health-related quality of life (HR-QoL), and work productivity were collected from a patient survey. A total of 101 patients were analysed (76.2% female; mean age: 48.9 years) with moderate to severe disease (UAS7 score ≥16) in 43.4% and angioedema in 72.3%. The mean (S.D.) total scores of Chronic Urticaria Quality of Life (CU-Q2oL) and Dermatology Life Quality Index (DLQI) were 37.7 (22.3) and 9.7 (6.9), respectively, thus indicating a significant impact of the disease on HR-QoL. Mean absenteeism and presenteeism were 6.4% and 20.8%, respectively, with a mean loss of work productivity estimated at 20.7%. The mean (S.D.) total direct cost of CSU was €2,397 per patient per year and was mainly driven by therapies (€1,435) and inpatient costs (€859). The indirect costs for four weeks were mainly presenteeism (€421) and loss of work productivity (€420). CSU significantly impairs HR-QoL, which increases with the severity of the disease. The direct and indirect costs for the management of symptomatic CSU are an important economic burden.


Assuntos
Custos de Cuidados de Saúde/estatística & dados numéricos , Recursos em Saúde/estatística & dados numéricos , Qualidade de Vida , Urticária/economia , Absenteísmo , Adulto , Angioedema/etiologia , Doença Crônica , Efeitos Psicossociais da Doença , Estudos Transversais , Eficiência , Feminino , França , Recursos em Saúde/economia , Hospitalização/economia , Humanos , Masculino , Pessoa de Meia-Idade , Presenteísmo , Estudos Retrospectivos , Índice de Gravidade de Doença , Urticária/complicações , Urticária/tratamento farmacológico
20.
Circulation ; 136(11): 1037-1048, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-28687708

RESUMO

BACKGROUND: Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. METHODS: We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. RESULTS: We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. CONCLUSIONS: We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.


Assuntos
Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Capilares/anormalidades , Mutação em Linhagem Germinativa/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mancha Vinho do Porto/diagnóstico , Mancha Vinho do Porto/genética , Receptor EphB4/genética , Proteína p120 Ativadora de GTPase/genética , Bases de Dados Genéticas , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Linhagem
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