Objective
Immune checkpoint inhibitors (ICIs) for cancer therapy frequently induce immune‐related adverse effects (IRAEs). Therefore, most patients with preexisting autoimmune diseases have been ...excluded from clinical trials of ICIs. This study was undertaken to evaluate the safety and efficacy of ICIs in patients with preexisting autoimmune disease and cancer.
Methods
A retrospective cohort study was conducted from January 2017 to January 2018 via 3 French national networks of experts in oncology and autoimmunity. Adults with preexisting autoimmune disease who were receiving ICIs were assessed for the occurrence of flare of preexisting autoimmune disease, other IRAEs, and cancer response.
Results
The study included 112 patients who were followed up for a median of 8 months. The most frequent preexisting autoimmune diseases were psoriasis (n = 31), rheumatoid arthritis (n = 20), and inflammatory bowel disease (n = 14). Twenty‐four patients (22%) were receiving immunosuppressive therapy at ICI initiation. Autoimmune disease flare and/or other IRAE(s) occurred in 79 patients (71%), including flare of preexisting autoimmune disease in 53 patients (47%) and/or other IRAE(s) in 47 patients (42%), with a need for immunosuppressive therapy in 48 patients (43%) and permanent discontinuation of ICI in 24 patients (21%). The median progression‐free survival was shorter in patients receiving immunosuppressive therapy at ICI initiation (3.8 months versus 12 months; P = 0.006), confirmed by multivariable analysis. The median progression‐free survival was shorter in patients who experienced a flare of preexisting autoimmune disease or other IRAE, with a trend toward better survival in the subgroup without immunosuppressant use or ICI discontinuation.
Conclusion
Our findings indicate that flares or IRAEs occur frequently but are mostly manageable without ICI discontinuation in patients with a preexisting autoimmune disease. Immunosuppressive therapy at baseline is associated with poorer outcomes.
Vemurafenib/PLX4032, a selective inhibitor of mutant BRAFV600E, constitutes a paradigm shift in melanoma therapy. Unfortunately, acquired resistance, which unavoidably occurs, represents one major ...limitation to clinical responses. Recent studies have highlighted that vemurafenib activated oxidative metabolism in BRAFV600E melanomas expressing PGC1α. However, the oxidative state of melanoma resistant to BRAF inhibitors is unknown. We established representative in vitro and in vivo models of human melanoma resistant to vemurafenib including primary specimens derived from melanoma patients. Firstly, our study reveals that vemurafenib increased mitochondrial respiration and ROS production in BRAFV600E melanoma cell lines regardless the expression of PGC1α. Secondly, melanoma cells that have acquired resistance to vemurafenib displayed intrinsically high rates of mitochondrial respiration associated with elevated mitochondrial oxidative stress irrespective of the presence of vemurafenib. Thirdly, the elevated ROS level rendered vemurafenib-resistant melanoma cells prone to cell death induced by pro-oxidants including the clinical trial drug, elesclomol. Based on these observations, we propose that the mitochondrial oxidative signature of resistant melanoma constitutes a novel opportunity to overcome resistance to BRAF inhibition.
Le pica est généralement défini comme la consommation compulsive de produits non alimentaires sur une période prolongée, en dehors de tout contexte culturel. La consommation de glaçon ou pagophagie ...serait le type de pica le plus étroitement lié à la carence martiale. Nous avons étudié la prévalence des picas et leurs caractéristiques chez des sujets carencés en fer.
Cette étude prospective unicentrique a été menée à la Réunion sur des individus venant en hôpital de jour pour une perfusion de fer, en raison d’une carence martiale chronique ou d’un saignement récent. Les patients étaient interrogés sur la présence de pica. Le lien entre la présence de pica et les données démographiques/clinico-biologiques était évalué en analyses univariée et multivariable.
Notre échantillon comportait 426 femmes et 69 hommes, avec 112 picas (22,6 %), dont seulement deux chez les hommes. La pagophagie était le pica le plus fréquent (13,7 %). Il n’y avait qu’un seul cas de pica chez les patients avec hémorragie récente sans carence martiale chronique (1 %). L’analyse multivariable sur la présence de pica chez les femmes carencées en fer retrouvait comme seul facteur associé le jeune âge. Les facteurs associés à la pagophagie comparativement à un autre type de pica était le jeune âge et l’hémoglobine basse.
Le pica, notamment la pagophagie, est un phénomène fréquent à rechercher à la Réunion chez les jeunes patientes carencées en fer ou susceptibles de l’être.
Pica is a behavioral disorder generally defined as the compulsive consumption of non-edible substances for more than 1 month. The consumption of ice cubes or pagophagia is the type of pica the most closely linked to iron deficiency. We studied the prevalence of picas and their characteristics in iron deficient subjects.
This is a single-center prospective study conducted in Reunion island on individuals coming to day hospitals for an iron intravenous infusion due to an iron deficiency or a recent bleeding. Patients were asked about the presence of pica and its characteristics. The links between pica and demographic/clinico-biological data were assessed in univariate and multivariable analyzes.
Our sample included 426 women and 69 men, with a total of 112 picas (22.6 %) gathering only two men. Pagophagia was the most common pica (13.7 %). There was only one case of pica in patients with recent bleeding without pre-existing iron deficiency (1 %) . In the multivariable logistic regression analysis regarding the presence of pica, the only factor associated with pica was a young age. In the second analysis, factors associated with pagophagia compared with another type of pica were a young age and a lower hemoglobin level.
Pica, especially pagophagia, is a frequent phenomenon in young iron-deficient female patients in Reunion island.
Targeted therapy combination (TTC: antiRAF+antiMEK) is known to improve metastatic melanoma survival. Few severe skin toxicities (grade ≥3) are described with first-line TTC (17% for ...vemurafenib+cobimetinib and none for dabrafenib+trametinib) in a phase III trial. Among our 42 patients treated by TTC between January 2014 and March 2017, 4.8% (2/42) of those treated in the first line presented severe skin rash versus 19% (8/42) of patients treated in the second line after previous immunotherapy. In particular, we observed one case of Stevens-Johnson syndrome and four cases of severe drug reaction with eosinophilia and systemic symptoms syndrome under TTC in patients who had received immunotherapy previously. Thus, previous immunotherapy appears to play an important role in the skin rash onset and severity induced by TTC.
Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, ...limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ((18)FFDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on (18)FFDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides 'real-time' results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this 'coclinical' trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.
Abstract
Although molecular methods and bioacoustical analysis have been used to uncover cryptic species, the combination of both methodologies is still rare. The humbug damselfish complex, Dascyllus ...aruanus, is composed of at least two species with Dascyllus aruanus in the Pacific Ocean and Dascyllus abudafur in the Indian Ocean. However, genetic data suggest that additional species could be found. Therefore, we aimed to determine whether the sounds produced by different populations of fish could help to distinguish cryptic species. Recordings of chase and courtship sounds were made on humbug damselfish populations from Madagascar, Taiwan and French Polynesia. Chase sound features are more variable than courtship sounds, suggesting more constraints on courtship sounds, since they would contribute to premating isolation. Comparison between courtship sounds show the variation in acoustic features between Taiwan and Madagascar align with genetic differences, supporting that sounds could discriminate cryptic species in Teleosts. Moreover, differences in both acoustic features and genetic data are also found between Taiwan and French Polynesia, suggesting two clearly distinct populations. Consequently, the name D. emamo can be resurrected for the Polynesian humbug damselfish. External phenotype traits do not allow the distinction between populations, illustrating that only behaviour has been modified.
Urotensin-II (U-II) receptors are widely distributed in the central nervous system. Intracerebroventricular (i.c.v.) injection of U-II causes hypertension and bradycardia and stimulates prolactin and ...thyrotropin secretion. However, the behavioral effects of centrally administered U-II have received little attention. In the present study, we tested the effects of i.c.v. injections of U-II on behavioral, metabolic, and endocrine responses in mice. Administration of graded doses of U-II (1-10,000 ng/mouse) provoked: (1) a dose-dependent reduction in the number of head dips in the hole-board test; (2) a dose-dependent reduction in the number of entries in the white chamber in the black-and-white compartment test, and in the number of entries in the central platform and open arms in the plus-maze test; and (3) a dose-dependent increase in the duration of immobility in the forced-swimming test and tail suspension test. Intracerebroventricular injection of U-II also caused an increase in: food intake at doses of 100 and 1,000 ng/mouse, water intake at doses of 100-10,000 ng/mouse, and horizontal locomotion activity at a dose of 10,000 ng/mouse. Whatever was the dose, the central administration of U-II had no effect on body temperature, nociception, apomorphine-induced penile erection and climbing behavior, and stress-induced plasma corticosterone level. Taken together, the present study demonstrates that the central injection of U-II at doses of 1-10,000 ng/mouse induces anxiogenic- and depressant-like effects in mouse. These data suggest that U-II may be involved in some aspects of psychiatric disorders.
PDF
